ISSN:0069-3030    

DOI:10.1039/OC99491FX001

出版商:RSC    

年代:1994

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC99491BX003

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

3 Theoretical Organic Chemistry By JONATHAN W. ESSEX Department of Chemistry University of Southampton High field Southampton SO17 lBJ UK 1 Introduction Theoretical organic chemistry spans a wide range of interests from the well-established calculations of the electronic properties for very small systems using ab initio techniques to the computer simulation of large hydrated systems many of bioorganic interest using molecular dynamics and Monte-Carlo methods. This review is broadly divided into two sections theoretical advances and applications. In the former the importance of including solvation in calculations is emphasized both through continuum treatments and explicit solvent models applied within computer simulations. Computer-simulation methodology is also addressed as are the calculation of transition states and reaction pathways; the latter are of particular importance since they control chemical reactivity.In the applications sections a special emphasis is placed on reviewing host-guest chemistry as through this discipline organic chemists are investigating the fundamental interactions that control biochemistry. Pericyclic reactions and the S,2 reaction are also reviewed since despite the considerable theoretical effort devoted to these areas in the past they are still providing challenges that stretch current theory to its limits. The calculation of equilibrium properties is also addressed as is photochemistry. It is arguably impossible for any one individual in a short article to review exhaustively the entire literature and the author has therefore been selective in presenting what he considers to be the most interesting advances in the past year.Undoubtedly this is a subjective procedure and this review is likely to be flavoured by the author’s personal research interests. 2 Theoretical Advances The theoretical techniques applied to organic chemistry can be roughly classified in terms of electronic-structure calculations and computer simulations. The former include Hartree-Fock and post-Hartree-Fock methods density functional calcula- tions and semi-empirical methods and typically provide energetic and structural information for both electronic ground states and transition states. Computer simulations usually involve empirical potential-energy functions coupled with molecu- lar dynamics or Monte-Carlo simulations and provide thermodynamic and structural data often in the condensed phase.This distinction between electronic-structure 25 Jonathan W. Essex calculations and computer simulations is becoming somewhat blurred by the development of simulation techniques using quantum mechanical potentials such as Car-Parrinello and mixed molecular-mechanics/quantum-mechanics, and by the use of classical force-fields to determine transition states. In this section the significant advances in solvation modelling computer simulations and free-energy calculations and transition state and reaction pathway searching will be presented. Solvation.-The role of solvent in influencing chemical equilibria and rates of reaction cannot be understated.However the inclusion of solvation effects in theoretical calculations is plagued by difficulties of accuracy and computational cost. The currently available techniques can be divided into two main areas those relying on a continuum description of the solvent and those in which the structure of the solvent molecules is considered explicitly. Continuum models are frequently used to model the effect of bulk solvent on quantum mechanical calculations. The alternative method of introducing a large number of water molecules into the calculation is very expensive. However in cases where the solvent participates in a reaction through a specific interaction then a continuum treatment is inadequate and that solvent molecule will need to be included explicitly in the calculation for example in the aldol condensation.' Continuum models are also finding increasing use in classical simulations especially of proteins and peptides where the expense of including a large number of solvent molecules can prove prohibitive.Increasing computer power does however make the use of explicit solvent treatments more feasible and indeed in most classical simulations explicit solvent models are the method of choice especially given the increasing use of polarizable intermolecular potential-energy functions. The progress made in each of these two areas during 1994 will be considered separately in this review and the reader is referred to two general reviews of solvation treatments for additional inf~rmation.~.~ Continuum Descriptions of Solvation.-In continuum modelling the solvent is treated as a polarizable structureless continuum; the electrostatic contribution of the free energy of solvation is usually evaluated separately from the dispersive and cavitation terms.The principal advantages of this approach are the treatment of solute-solvent polarization effects and the speed of the calculation as compared with explicit solvent models. However information on the solvent structure is unavailable and moreover the underlying assumption that the solvent can be treated as a continuum may not be valid. Uncertainties regarding the appropriate size and shape of the solute cavity also exist. While the loss of solvent structural information is unavoidable significant progress concerning the other difficulties has been made.Several reviews describing the current state of continuum modelling of solvent were published during 1994.4,5 Of particular interest is the paper by Tomasi and Persico4 in which the current state of the field was comprehensively presented both from the methodological view point and from the perspective of the chemical problems to which the approach has been E. L. Coitino J. Tomasi and 0.N. Ventura J. Chem. SOC.,Faraday Trans. 1994 90,1745. P. E. Smith and B. M. Pettitt J. Phys. Chem. 1994 98 9700. W. F. van Gunsteren F.J. Luque D. Timms and A. E. Torda Annu. Rev. Biophys. Biomol. Struct. 1994,23 847. J. Tomasi and M. Persico Chem. Rev. 1994 94 2027. A.A.Rashin and M.A. Bukatin Biophys. Chem. 1994 51 167. Theoretical Organic Chemistry successfully applied. The issue of the appropriate choice of cavity size in continuum calculations was addressed extensively by Orozco Luque and Bachs in both ab initio6" and semi-empirical treatments.' Errors in calculated free energies of hydration for a range of molecules derived using the recommended cavities were of the order of 1kcal mol- '. Continuum models applied in conjunction with empirical treatments of the solute were also found to give results sensitive to cavity size.g Agreement between the free energy of hydration of a water molecule obtained using the Poisson-Boltzmann continuum treatment with that obtained using an explicit solvent model could only be achieved by making the cavity radius charge dependent.This suggests that electrostriction is a significant problem in continuum models. In a related study using an empirical solute description cavity radii and atomic charges were optimized to reproduce experimental free energies of hydration using the Poisson-Boltzmann approach.' The possibility of combining an explicit solvent description of the solute's first hydration shell with a continuum description of subsequent hydration spheres was raised.' ',''This approach is justified since simulations using an explicit water model suggest that water beyond the first solvation shell essentially behaves as part of the bulk phase.I2 Furthermore electrostriction and dielectric saturation are explicitly treated and the sensitivity of the results to subtle changes in cavity size are reduced since the dielectric interface is further removed from the region of interest the solute.' I Perhaps this hybrid procedure offers the 'best of both worlds'; namely a continuum treatment but with explicit solvent in the critical region near the solute.A number of other methodological developments in the area of continuum solvation have been made in the past year. These include the introduction of a distance- dependent dielectric constant to the polarizable continuum model thereby eliminating the sharp discontinuity of the dielectric constant at the cavity b~undary.'~ A fast technique for solving the non-linear form of the Poisson-Boltzmann equation has been developed and applied to a number of protein systems; use of the non-linear form of the equation is particularly important in cases where the solute molecule is highly charged.'4.' The non-linear form of the Poisson-Boltzmann equation has also been solved independently using a boundary element method.' Boundary element procedures have been used to investigate the sensitivity of free energies of solvation to such parameters as cavity size and the level of sophistication of the quantum- mechanical component. " A new method for modelling solvation effects through induced atom-centred multipoles has been presented and was shown to be as accurate as finite-difference approaches but with greater efficiency.' * There has been considerable effort in the past year in combining treatments of M.Bachs F.J. Luque and M. Orozco J. Comput. Chem. 1994 15 446. ' M. Orozco and F.J. Luque Chem. Phys. 1994 182 237. F. J. Luque M. Bachs and M. Orozco J. Comput. Chem. 1994 15 847. S.W. Rick and B. J. Berne J. Am. Chem. Soc. 1994 116 3949. lo D. Sitkoff K. A. Sharp and B. Honig J. Phys. Chem. 1994 98 1978. S.L. Chan and C. Lim J. Phys. Chem. 1994 98 692. 1.1. Vaisman F. K. Brown and A. Tropsha J. Phys. Chem. 1994,98 5559. l3 M. Cossi B. Mennucci and J. Tomasi Chem. Phys. Lett. 1994 228 165. '4 M. Holst R. E. Kozack and F. Saied S. Subramanian Proteins Struct. Func. Gen. 1994 18 231. l5 M. Holst R. E. Kozack F. Saied and S. Subramaniam J. Biornol Struct. Dyn. 1994 11 1437. l6 H.-X. Zhou J. Chem. Phys. 1994 100 3152. T. Furuki A.Umeda M. Sakurai Y. Inoue R. Chujo and K. Harata J. Comput. Chem. 1994 15 90. M. E. Davis J. Chem. Phys. 1994 100 5149. 28 Jonathan W. Essex solvation with calculations using density functional theory (DFT).' 9-23 This powerful method of performing electronic structure calculations was extensively reviewed in last year's report.24 The extension of this procedure to include solvation through the Poisson-Boltzmann self consistent reaction field (SCRF),21 and polarizable 19720 continuum models (PCM)22 will undoubtedly yield many exciting results in the future. Solvation effects have also been incorporated into generalized valence-bond calcula- tions by Tannor et through the Poisson-Boltzmann equation giving an average error for solvation free energies with respect to experiment of 0.6 kcal mol- '.The combined semi-empirical/continuum-solventmodels of Cramer and Truhlar referred to as the SMx series of models have proved very popular for calculating free energies of solvation,26 particularly because the calculations are fast and easy to perform. Dixon et al.27 have developed a similar model based on the AM1 Hamiltonian which was reported to be more efficient still and gave more accurate free energies of hydration. Explicit Solvent Models.-This category of solvation modelling can be subdivided into the integral-equation methods and the models in which solvent molecules are explicitly included in the calculation. The latter are particularly popular in classical computer simulations since specific interactions such as hydrogen bonding are treated.Arguably the most significant deficiency of the majority of these studies is the failure to include polarization explicitly although this is now being addressed by a number of groups. Integral-equation methods introduce the effect of solvent through the calculation of distribution functions given an empirical pair potential-energy function.28 The method has been extended to ab initio calculation^,^^ representing an interesting development in the treatment of solvation within a quantum-mechanical framework since the structure of the solvent is included in the calculation. In terms of classical treatments of solute and solvent conventional empirical potential-energy parameters continue to be developed and refined.In particular the OPLS force-field derived by Jorgensen has been extended to cover all-atom treatments of simple hydrocarbon^,^' and class I1 force-fields that incorporate anharmonic effects and intramolecular coupling interactions have been developed for alkanes3 1,32 and poly~arbonates.~~ However these approaches all include polarization in an average sense and in situations involving charged systems a force-field that explicitly includes polarization may be preferable. Emphasis is being placed on the development and l9 K. Baldridge R. Fine and A. Hagler J. Comput. Chem. 1994 15 1217. 2o J. L. Chen L. Noodleman D. A. Case and D. Bashford J. Phys. Chem. 1994 98 11 059. 21 M. F. Ruiz-Lopez F. Bohr M.T. C. Martins-Costa and D. Rinaldi Chem.Phys. Lett. 1994 221 109. 22 A. Fortunelli and J. Tomasi Chem. Phys. Lett. 1994 231 34. 23 A.A. Rashin M.A. Bukatin J. Andzelm and A.T. Hagler Biophys. Chem. 1994 51 375. 24 C.A. Reynolds Ann. Rep. Prog. Chem. Sect. 8 1993 90 51. 25 D.J. Tannor B. Marten R. Murphy R. A. Friesner D. Sitkoff A. Nicholls M. Ringnalda W. A. Goddard 111 and B. Honig J. Am. Chem. SOC. 1994 116 11 875. 26 C.J. Cramer and D.G. Truhlar J. Comput. Aid. Mol. Des. 1992 6 629. R. W. Dixon J. M. Leonard and W. J. Hehre Isr. J. Chem. 1994 33,427. 28 J. Perkyns and B. M. Pettitt Biophys. Chem. 1994 51 129. 29 S. Ten-no F. Hirata and S. Kato J. Chem. Phys. 1994 100 7443. 30 G. Karninski E. M. Duffy T. Matsui and W. L. Jorgensen J. Phys. Chem. 1994 98 13077. 31 M.J. Hwang T.P. Stockfisch and A.T.Hagler J. Am. Chem. SOC. 1994 116 2515. 32 J.R. Maple M.-J. Hwang T. P. Stockfisch and A.T. Hagler Isr. J. Chem. 1994 34 195. 33 H. Sun S. J. Mumby J. R. Maple and A.T. Hagler J. Am. Chem. SOC.,1994 116 2978. 2' Theoretical Organic Chemistry 29 validation of polarizable water model^,^^.^' since this solvent is of course very important in living systems. Furthermore a new approach for introducing polariz- ation has been developed by Rick et based on the concept of electronegativity equalization and applied to the simulation of water. The method gave accurate predictions of gas and liquid-phase properties for a small increase in computational expense over pairwise-additive potentials and thus its extension to bioorganic simulations is very attractive.A notable area of interest in contemporary theoretical organic chemistry is the calculation of relative free energies of s~lvation,~~ allowing such diverse properties as binding constants and tautomeric equilibria to be evaluated. Absolute free energies of hydration of the acetate and methylammonium ions have been calculated in the past year using a polarizable water The calculated free energies of hydration were shown to be in good agreement with experiment without the need to invoke any reparameterization; this was not the case when a conventional pairwise-additive water model was used. It is possible to progress beyond the traditional approximation of pairwise-additive interaction potentials in computer simulations by using either the hybrid molecular- mechanics/quantum-mechanics (MM/QM) scheme or by the Car-Parrinello (CP) procedure.In recent years Gao has been instrumental in developing and applying a MM/QM procedure in which Monte-Carlo simulations are performed on a solute modelled using the semi-empirical AM 1 Hamiltonian and a solvent represented through the empirical TIP3P Further studies have been reported in 1994 investigating a range of processes including tautomeric eq~ilibria,~' the influence of solvent on the Claisen rearrangement,41 and the effect of solvent on the n+n* electronic transition of acetone.42 This approach of Gao does however suffer from the disadvantages arising from the choice of solute Hamiltonian and the absence of polarization of the solvent.The issue of the solute Hamiltonian has been addressed through the use of other models. Stanton et have used a MM/QM technique based on the PM3 Hamiltonian combined with molecular-dynamics simulations with the TIP3P water model. Relative free energies of hydration between different solute molecules were calculated. Wei and Salahub used DFT to model a solute water molecule in a combined MM/QM procedure although the response of the classical solvent to polarization of the quantum-mechanical solute was not ~onsidered;~~ it would be expected that an MM/QM approach using DFT would be ultimately more reliable than that using a semi-empirical Hamiltonian. The CP scheme is able to address both the deficiencies of the common MM/QM procedures; a DFT approach is used which is arguably preferable to a semi-empirical model and both solute and solvent are treated identically thereby allowing 34 D.N. Bernado Y. Ding K. Krogh-Jespersen and R. M. Levy J. Phys. Chem. 1994,98 4180. 35 S.-B. Zhu and C. F. Wong J. Phys. Chem. 1994 98,4695. 36 S. W. Rick S.J. Stuart and B. J. Berne J. Chem. Phys. 1994 101 6141. 37 P.A. Kollman Chem. Rev. 1993 93 2395. 38 E.C. Meng P. Cieplak J. W. Caldwell and P.A. Kollman J. Am. Chem. SOC.,1994 116 12061. 39 J. Gao and X. Xia Science 1992 258 631. 40 J. Gao and L. Shao J. Phys. Chem. 1994,98 13772. 41 J. Gao J. Am. Chem. Soc. 1994 116 1563. 42 J. Gao J. Am. Chem. SOC.,1994 116 9324. 43 R.V. Stanton L. R. Little and K. M. Merz Jr. J. Phys. Chem. 1995 99 483. 44 D. Wei and D.R. Salahub Chem. Phys. Lett. 1994 224 291. 30 Jonathan W.Essex polarization of the solvent. Owing to the computational expense of performing these calculations simulations of several picoseconds are the norm considerably less than is accessible through simulations using classical potentials. However during the course of the year a multiple time-scale method has been derived which provides the possibility of increasing simulation speed by up to a factor of 10 without compromis- ing ac~uracy.~’ Laasonen and Klein have used the CP scheme to study the dissociation of hydrochloric acid in water.46 They were able both to observe the breaking of the H-C1 bond and to characterize the solvent structure around the two ions after dissociation. CP simulations have also been used to study a metallocene-catalysed ethylene polymerization reaction.47 The simulations were able to follow the reaction from the initial complex through to propyl formation over 150 fs and suggest that the insertion step of the reaction does not have an energy barrier.Curioni et ~21.~~ investigated the protonation of 1,3,S-trioxane and 1,3-dioxolane monomers in isolation using CP simulations. The protonation of trioxane was not immediate but rapid release of formaldehyde was then observed. Dioxolane underwent rapid protonation followed by ring opening but no loss of formaldehyde followed. The implication of these results for the polymerization reactions of these molecules was discussed. Computer Simulation and Free-energy Methodologies.-In this section the advances in computer simulation and free-energy methodologies that are of particular relevance to organic systems will be addressed.It should be self-evident that since free energies determine the position of equilibria their accurate calculation must be a major goal in theoretical organic chemistry. Undoubtedly one of the most difficult problems in calculating precise free energies via condensed-phase molecular dynamics or Monte-Carlo simulations is that of adequately sampling the available conformational space of the system. Relative free energies can be evaluated using either the thermodynamic integration (equation 1)or perturbation equations (equation 2).37 I= 1 AG=S 1=0 (g),dA The free-energy difference between two states A (A = 0) and B (A = l),AG is evaluated as the integral of the ensemble average of dH/dA where H is the Hamiltonian.AG = -RTln (exp( -AH/RT)) (2) R and T are the ideal gas constant and temperature respectively and AH is the difference in Hamiltonian between states A and B. In both cases an ensemble average is evaluated (the term inside the angular brackets) and if the conformational sampling is incomplete then this average may be inadequately converged or have converged to the wrong result. A combined Monte-Carlo/molecular-dynamics scheme has been proposed which in conjunction with a continuum treatment of solvation goes some way to addressing this issue.49 Large-step Monte-Carlo moves are able to cross high 45 M. E. Tuckerman and M.Parrinello J. Chem. Phys. 1994 101 1316. 46 K. Laasonen and M. L. Klein J. Am. Chem. SOC. 1994 116 11 620. 47 R. J. Meier G.H. J. van Dorernaele S. Iarlori and F. Buda J. Am. Chem. SOC. 1994 116 7274. 48 A. Curioni W. Andreoni J. Hutter H. Schiffer and M. Parrinello J. Am. Chem. SOC. 1994 116 11 251. 49 F. Guarnieri and W.C. Still J. Comput. Chem. 1994 15 1302. Theoretical Organic Chemistry 31 energy barriers whereas molecular dynamics or in this particular implementation stochastic dynamics is able to sample well the environment of the current local minimum. Using a combination of alternate Monte-Carlo and stochastic-dynamics steps it is possible to search the conformational space of flexible molecules more efficiently than with either method in isolation.The combined Monte-Carlo/molecu- lar-dynamics scheme has been applied to the study of the conformational ther- modynamics of a series of diamides.” The simulations were able to reproduce the experimental enthalpic and entropic data for intramolecular hydrogen-bond forma- tion while at the same time demonstrating complete convergence. A similar procedure has been developed by Clamp et al.” It is perhaps worth commenting that this approach relies for its success on either having no solvent present or using a continuum treatment. If an explicit solvent model were used then the large-step Monte-Carlo component would be less efficient and perhaps yield almost zero acceptance of moves. Ewing and LybrandS2 demonstrated that poor sampling can cause significant errors in the calculation of relative solvation free energies.They estimated the free energies of hydration of a range of organophosphorus compounds and found that a conventional molecular-dynamics simulation with explicit solvent was unable to explore adequately the conformational space of the molecule. The use of a continuum treatment of solvation applied to the minimum energy conformations of the molecule was their solution to this difficult problem and gave free energies consistent with related experimental data. Straatsma and M~Cammon~~ have addressed the sampling problem by an alternative route; they calculated potentials of mean force for rotation about the peptide dihedral angles of alanine dipeptide in water and used these results as umbrella biasing potentials in simulations of larger peptides.A significant increase in sampling efficiency resulted. Beutler and van Gunsteren have developed a procedure for overcoming energy barriers by extending the simulation into a fourth dimen~ion;’~ the approach was shown to work when calculating the change in density of an atomic fluid although less efficiently than conventional procedures. The technique may however prove useful when applied to organic and biological systems. Pearlman has developed a technique for assessing the convergence of free-energy calculations by evaluating ‘free-energy derivatives’ with respect to the individual parameters in the force field.’ ’ The need to perform very long simulations to achieve reliable convergence and precise free-energy results was apparent.One way of obtaining relative free energies rapidly is to estimate the total free energy change for a process from only a single simulation. Aqvist et al.56 report a method based on linear-response theory whereas Smith and van Gunsteren use a Taylor expansion of the free energy.57 A particular difficulty in free-energy calculations arises when an atom or group of atoms is created or annihilated as in for example the mutation of ethanol to methanol in water to calculate the difference between their free energies of hydration. At the point 50 D.Q. McDonald and W.C. Still J. Am. Chem. SOC.,1994 116,11550. ” M.E. Clamp P.G. Baker C. J. Stirling and A. Brass J. Comput. Chem. 1994 15 838. ” T. J. A. Ewing and T.P. Lybrand J. Phys. Chem. 1994 98 1748. 53 T.P. Straatsma and J.A. McCammon J. Chem. Phys. 1994 101 5032. 54 T.C. Beutler and W. F. van Gunsteren J. Chem. Phys. 1994 101 1417. 5s D.A. Pearlman J. Cornput. Chem. 1994 15 105. ” J. Aqvist C. Medina and J.-E. Samuelsson Protein Engineering 1994 7 385. 57 P.E. Smith and W. F. van Gunsteren J. Chem. Phys. 1994 100 577. 32 Jonathan W. Essex in the simulation where the atoms appear or disappear the calculation can become very unstable and ill-behaved. Zacharias et aLS8overcame this difficulty by scaling the Lennard-Jones interaction potential that is usually used to describe van der Waals interactions smoothly to zero in the course of the simulation. Using conventional methodology the steeply repulsive component of the potential was present up until the .~~ atom was annihilated.Beutler et ~1proposed a similar solution although they used a soft-core potential at the point of annihilation/creation. The decomposition of calculated free-energies into contributions arising either from individual components of the force field or from groups of atoms within the molecule has proved popular in recent years since it would allow the calculated free-energy change to be interpreted in chemically meaningful terms. However it has been argued that such a decomposition is meaningless owing to the path dependence of the free-energy components. Smith and van Gunsteren presented a convincing demonstra- tion of this phenomenon for the mutation of p-cyanophenol to p-methoxyphenol in solution.60 Boresch et aL6’ agreed that free-energy decompositions are path depend- ent but they considered this approach useful and able to provide insight provided the pathway adopted in the free-energy calculation was defined.Transition States and Reaction Pathways.-The calculation of transition states and reaction routes is of considerable interest to organic chemists; this section will review recent methodological developments in this area. Although the first stage in exploring a potential energy surface is to determine stationary points-reactants transition state and products-it may prove necessary to confirm that the reaction mechanism does indeed link these stationary points. In practice this can be achieved using ‘reaction-path following’ in which the path of steepest descent from the transition state is calculated in mass-weighted Cartesian coordinates.Schlege16’ addressed some of the deficiencies of this procedure and in particular examined ways of dealing with bifurcation of reaction paths and developed more efficient algorithms that make maximal use of gradient and Hessian information. A disadvantage of conventional methods of transition-state searching is the expense associated with the large number of steps required to map the path completely together with the necessary expensive second-derivative calculation at the transition state. To .~~ address these issues Chiu et ~1 adopted a procedure described by Elber and Karpld4 in which an energy function of the entire path was minimized.The method was demonstrated to perform well in comparison with the traditional approaches of reaction path calculation and offers the possibility of efficiently calculating reaction pathways for large systems. Barnes et have investigated reaction mechanisms from the perspective of More O’Ferrall-Jencks diagrams a commonly used method for rationalizing reactivity trends and found that these diagrams successfully predicted transition-state structural variations on changing the reactants. 58 M. Zacharias T. P. Straatsma and J. A. McCammon J. Chem. Phys. 1994 100 9025. 59 T. C. Beutler A. E. Mark R. C. van Schaik P. R. Gerber and W. F. van Gunsteren Chem. Phys. Lett. 1994 222 529. P. E. Smith and W. F. van Gunsteren J. Phys. Chem. 1994 98 13 735.61 S. Boresch G. Archontis and M. Karplus Proteins Struct. Func. Gen. 1994 20 25. 62 H.B. Schlegel J. Chem. SOC. Faraday Trans. 1994 90,1569. 63 S.S.-L. Chiu J.J. W. McDouall I.H. Hillier J. Chem. SOC.,Faraday Trans. 1994 90,1575. 64 R. Elber and M. Karplus Chem. Phys. Lett. 1987 139 375. 65 J.A. Barnes J. Wilkie and I.H. Williams J. Chem. Soc. Faraday Trans. 1994 90,1709. Theoretical Organic Chemistry 33 The calculation of transition-state structures and energies can prove expensive because of the need to evaluate second-derivative information and difficult since the transition-state search may not actually find a transition state if the starting geometry is poorly chosen. Two groups have addressed this issue using methods that predict the transition state given energies geometries and force constants of the reactants and produ~ts.~~,~~ Given the level of approximation these calculations performed well generating qualitatively correct transitions states which at the very least were useful starting points for more rigorous procedures.Shaik et have proposed a method ~1.~~7~~ of finding transition states based on valence-bond theory; the transition-state wave function was approximated to that at the avoided crossing state (ACS) between reactants and products. The reliability of this approach was determined by studying various S,2 reactions and it was found that the ACS was a useful approximation to the transition state. Houk et ~1.~’ have pioneered a molecular-mechanics based approach for determin- ing the structure of transition states.Molecular-mechanics parameters for transition states are derived from ab initio results. The structure obtained by energy minimization using these parameters is presumed to represent the transition state and the difference in energy between this structure and the reactants then corresponds to the activation energy of the reaction. This approach has been criticized on a number of grounds including the fact that transition states are saddle points not minima and that electronic stabilization of the transition state can be difficult to incorporate into the model. Specifically Menger and Sherrod71 have raised the issue of the arbitrary nature of the parameters adopted and have suggested that a random method of parameter optimization rather than a rational approach may be more efficient.Eurenius and Houk7’ have investigated intramolecular hydride transfers and demonstrated that a rational approach to transition-state parameter development was effective provided that care was taken in the parameterization. Molecular-mechanical modelling of transition states has also been applied to the addition of boronates to aldehydes with considerable SUCC~SS.’~ The issue of calculating rates of reaction given knowledge of a reaction’s potential energy surface with the inclusion of tunnelling effects has been extensively addressed .~~ by Truhlar et ~ 1 A notable feature or this work was the use of high-level ab initio calculations to calculate energies at three of four points along the reaction pathway typically including reactants and transition states to correct the entire reaction swath evaluated using cheaper semi-empirical calculations.This method has been applied to the reaction of the hydroxide radical with ethane an important process in both atmospheric chemistry and combu~tion.~~ The method was able to reproduce to within a factor of two the experimental rate constants and also demonstrated the importance of including tunnelling effects; in the temperature range 25WOO K more than half the reactive events were predicted to occur by tunnelling. Furthermore this technique of 66 F. Jensen J. Comput. Chem. 1994 15 1199. 67 K. Ruedenberg and J.-Q. Sun J. Chem. Phys. 1994 101 2168. 68 S. Shaik and A.C. Reddy J. Chem. SOC.,Faraday Trans. 1994 90 1631. 69 S. Shaik A. Ioffe A.C. Reddy and A. Pross J. Am. Chem. SOC. 1994 116 262. 70 K.P. Eurenius and K.N. Houk J. Am. Chem. SOC. 1994 116 9943. 71 F. M. Menger and M. J. Sherrod J. Am. Chem. SOC. 1990 112 8071. 72 C. Gennari E. Fioravanzo A. Bernardi and A. Vulpetti Tetrahedron 1994 50 8815. 73 W.-P. Hu Y.-P. Liu and D.G. Truhlar J. Chem. SOC. Faraday Trans. 1994 90 1715. 74 V. S. Melissas and D.G. Truhlar J. Phys. Chem. 1994 98 875. 34 Jonathan W. Essex calculating reaction rates with the inclusion of tunnelling has recently been extended to the solution phase." The relative merits of transition states evaluated using ab initio semi-empirical and density-functional theories have been compared in a series of papers.Abashkin and R~sso~~ reported a method for finding transition states implemented within a density functional formulation and Stanton and Mer~~~ compared the transition states of organic and organometallic reactions found using density functional theory with those derived from ab initio and semi-empirical calculations. Non-local density functional calculations were observed to yield energetic results of similar quality to post Hartree-Fock calculations although the DFT geometries were generally less reliable. Deng and Ziegler reported the implementation of reaction-path following within DFT and tested its performance on a range of reactions including an SN2 displacement and an elimination reaction.78 It was found that the reaction paths were in qualitative agreement with ab initio results and that where discrepancies occurred between local and non-local DFT reactant and product geometries the non-local geometries were generally in better agreement with experiment.Energies of stationary points were found to be of comparable quality to MP4SDTQ results. Andres et studied the reaction of CO with CH,NHCONH using ab initio and semi-empirical calculations and found that the four-membered-ring transition state was observed at all levels of theory although there were clearly differences in geometry and energetics. Mulholland and Richards" investigated the transition states for unimolecular hydrogen fluoride elimination from a series of methylene and vinyl halides using both semi-empirical and ab initio calculations.The geometries of the transition states at the AM1 and PM3 levels were very different from the MP2/6-31 lG(d,p) results although the calculated activation energies were generally in better agreement. 3 Selected Applications Owing to the amount of literature published in the past year describing applications of theory to problems of organic chemistry only selected topics will be reviewed here. Host-guest chemistry is an area of increasing interest since the factors influencing molecular recognition can be studied in systems of tractable size. This is particularly important when trying to understand the processes that determine binding in biochemistry. The calculation of physical properties of molecules such as conforma- tional tautomeric and redox equilibria are also presented.These properties influence molecular reactivity and their calculation often requires the combination of accurate gas-phase energies with condensed-phase simulations. Finally pericyclic and SN2 reactions are reviewed. Not only are these reactions of considerable synthetic utility but they also represent a significant challenge to theory. The author believes that these areas represent a broad cross-section of the currently interesting topics. Host-Guest Chemistry.-The investigation of molecular recognition processes through the development of synthetic host molecules is an area of increasing interest in 75 D.G. Truhlar Y.-P. Liu G. K. Schenter and B.C. Garrett J. Phys. Chem. 1994 98,8396. l6 Y. Abashkin and N.Russo J. Chem. Phys. 1994 100 4417. 77 R.V. Stanton and K. M. Merz J. Chem. Phys. 1994 100,434. 78 L. Deng and T. Ziegler Int. J. Quant. Chem. 1994 52 731. 79 J. Andres V. Moliner J. Krechl and E. Silla J. Phys. Chem. 1994 98 3664. A. J. Mulholland and W. G. Richards Int. J. Quant. Chem. 1994 51 161. Theoretical Organic Chemistry organic chemistry. These systems provide the opportunity to study noncovalent interactions in relatively small molecules thereby providing information applicable to larger biological systems. The ultimate goals of these studies are the rational design of synthetic catalysts with selectivities comparable to enzymes and the design of large-scale molecular aggregates with specific physical properties. Theoretical chemis- try is increasingly being applied to these systems to assist first in the interpretation of experimental data and second in the rational design process.The binding of alkali cations to synthetic receptors was studied in some detail by a number of authors during 1994.These systems are of considerable practical interest in nuclear-waste reprocessing because of their potential for the separation of radioactive ions. In two studies Kollman et a1.81,82 investigated the binding to a synthetic cavitand consisting of eight anisole subunits in water and methanol. The cavity is complement- ary in size to Cs+ which is observed to bind the most tightly of all to the alkali ions in water-saturated chloroform. However the cavitand also shows an unusual secondary binding preference in that Na' binds more strongly than Li' and K+.83Bayly and Kollman" investigated the binding behaviour of the cavitand with the alkali metal cations through a combination of molecular-dynamics simulations and free-energy calculations under aqueous conditions.Water was adopted as solvent for this study rather than the experimental solvent of water-saturated chloroform since the composition of the water/chloroform mixture was not known and the ions would undoubtedly act as water scavengers leading to a locally water-rich environment. The relative binding-constants of the various ions with the cavitand were calculated using the thermodynamic cycle given in Figure 1. Ion binding is characterized by the free energies AGl and AG2.However these processes are difficult to simulate in practice whereas the other legs of the cycle corresponding to the free-energy change on mutating between two ions whilst bound and in solution are much easier to evaluate. H + G1 AGl * H:G1 I I AG" AGb .) t H + G2 AG2 H:G2 Figure 1 Free-energy cycle for the binding of guests G1 and G2 to the host H. AGu and AG correspond to the free-energy changes on perturbing between guests GI and G2 whilst unbound and bound to the host respectively Given AGu and AG, the difference in binding free energy between the two ions AG2 -AGl can be calculated. The practical calculation of equilibrium constants in the course of condensed-phase simulations almost invariably relies on the use of such thermodynamic cycles.The simulations reproduced the experimentally observed binding order and the calculated binding affinities were in semiquantitative agreement with experiment. Inspection of the host/guest geometries in the course of the simulations revealed that for Li+-Rb+ two water molecules accompanied the ion into *' C.I. Bayly and P. A. Kollman J. Am. Chem. SOC.,1994 116 697. B.E. Thomas IV and P. A. Kollman J. Am. Chem. SOC.,1994 116 3449. 83 D. J.Crarn R. A. Carmack M. P.deGrandpre,G. M. Lein I. Goldberg,C. B. Knobler E. F. Maverick and K.N. Trueblood J. Am. Chem. SOC. 1987 109 7068. 36 Jonathan W. Essex the cavity. However only in the case of Na’ were the ion and water molecules able to form an optimal arrangement in the cavity thereby rationalizing the increased binding constant of Na’ compared with Li’ and K ’.In the second investigations2 Thomas and Kollman repeated the calculations but using methanol as solvent. In this case the binding preference for Na’ was not observed despite the presence of two methanol molecules in the cavity with Li + and Na’ .This was attributed to the fact that methanol forms fewer hydrogen-bond interactions than water and is sterically more bulky. The 18-crown-6 cation host has been investigated by a number of research groups using a range of techniques. Troxler and WipP4 performed molecular-dynamics simulations of this species in acetonitrile and observed that the range of conformations sampled depended upon whether water or acetonitrile was used as solvent. The solvent structure in the vicinity of the isolated crown ions and in the complex was also investigated.Cieplak et studied this system under aqueous conditions using molecular dynamics and free-energy calculations. They applied the new technique of free-energy derivatives” to ascertain the size of the ion giving optimum binding to this molecule; an ion intermediate in size between Na’ and K+ was predicted to form the strongest complex. Glendening et aLS6approached this molecule from a quantum- mechanical perspective. Ab initio calculations were performed on the isolated crown and on the complexed species. The affinity of alkali metal ions for this molecule arose largely from electrostatic interactions between the cation and the nucleophilic ether backbone.Moreover these gas-phase calculations suggested that the smallest ions should bind most strongly in conflict with experiment. However when four water molecules were included in the calculations the experimental preference for K ’ binding was reproduced. This system was also studied using the combined MM/QM pr~cedure.~’ The crown was modelled by the AM1 Hamiltonian and K’ and water by molecular-mechanics potentials. Molecular-dynamics simulations were performed and the results showed the utility of this method as applied to this system. In particular the magnitude of the crown polarization was significant suggesting that ideally this contribution should be explicitly treated. It should however be noted that simulations using pairwise-additive potentials include polarization in an average sense and have .~~ proven successful in studying this type of system.Marrone et ~1also observed crown polarization in their calculation of the potential of mean force for K+ binding to 18-crown-6. The potential of mean force for the association of Cs+ to this host was evaluated using molecular dynamics by Dang;89 this study is notable in that a chloride counter-ion was included in the simulation. The calculated binding free-energies of -0.5 and -1.3 kcal mol- depending on the position of the counter ion are in good agreement with experimental results of between -1.1 and -1.4 kcal mol- ’.Metal ion complexation to aliphatic ethers a component in stabilizing cationxrown complexes was investigated through ab initio calculations on model system^,'^ with the goal of parameterizing the MM3 force-field for these molecules.The calculations showed that for stable complexes the extent to which ligand coordination reproduces a trigonal 84 L. Troxler and G. Wipff J. Am. Chem. Soc. 1994 116 1468. 85 P. Cieplak D.A. Pearlman and P.A. Kollman J. Chem. Phys. 1994 101 627. 86 E.D. Glendening D. Feller and M. A. Thompson J. Am. Chem. Soc. 1994 116 10657 ” M.A. Thompson E.D. Glendening and D. Feller J. Phys. Chem. 1994 98 10465. 8R T. J. Marrone D. S. Hartsough and K. M. Merz Jr. J. Phys. Chem. 1994 98 1341. 89 L. X. Dang Chem. Phys. Lett. 1994 27 21 1. 90 B.P. Hay and J.R. Rusad J. Am. Chem. Soc. 1994 116 6316. Theoretical Organic Chemistry 31 planar geometry is perhaps more important than the extent to which the preferred M-0 bond length is adopted.Troxler and WipP4 also performed molecular dynamics and free-energy calcula- tions on cryptand [2223 and its alkali metal complexes in acetonitrile. Whilst quantitative agreement of the calculated relative binding constants with experiment was not reproduced K+ was predicted to bind most strongly in accord with experiment. Ross and Hardin” investigated the stabilizing influence of alkali metal ions on a Guanine-rich-DNA quadruplex. The cation is considered trapped inside the quadruplex in a cavity lined by eight hydrogen-bonded carbonyl oxygen atoms. The change in binding free energy as a function of the cation was calculated in the course of molecular-dynamics simulations.Although experiment gave the most stable quadru- plex with K + and simulation gave Na’ a free-energy minimum as a function of cation size was predicted reflecting the competition between ion solvation and binding within the DNA cavity. A number of other studies were reported during the year which involved the calculation of relative free energies of binding. Duffy and J~rgensen~~ readdressed the issue of pyrazine and pyridine binding to Rebek’s acridine diacid in light of a recent crystal structure. Previous sir nu la ti on^^^ suggested that the relatively small experimen- tal preference for pyrazine over pyridine arose from the host cleft being too small to accommodate simultaneous two-point binding of pyrazine. However a crystal structure of this host with q~inoxaline~~ demonstrated that two-point binding was possible.Duffy and Jorgensen performed a new set of Monte-Carlo simulations using an all-atom parameter set and with increased host flexibility. If was found that the host was able to accommodate two-point binding by undergoing deformation and that the unexpected pyrazine/pyridine preference arose from favourable interactions between pyridine and the distant non hydrogen-bonding acid group. The simulations were able to reproduce the experimental relative free energies of binding very well. The earlier failed to predict two-point binding since full host flexibility was not included in the calculation. In Figure 2 the gas-phase minimum-energy structures for pyrazine pyridine and quinoxaline bound to the acridine host are presented; two-point binding is clearly observed for pyrazine and quinoxaline.Mark et ~1.~’ investigated the binding of para-substituted phenols to a-cyclodextrin. This study demonstrated the importance of careful analysis in the calculation of free energies. In particular the need to demonstrate closed thermodynamic cycles was emphasized as was the fact that without a reliable assessment of simulation error agreement with experimental binding-constants may be fortuitous. Free-energy calculations in host-guest chemistry have even taken on a predictive role. In a notable study Burger et ~1.~~ predicted that a specific modification of a podand ionophore host should yield high enantioselectivity between a particular D and L-amino-acid derivative.The calculations used the continuum GB/SA solvent model of chloroform 91 W.S. Ross and C.C. Hardin J. Am. Chem. SOC. 1994 116 6070. 92 E. M. Duffy and W. L. Jorgensen J. Am. Chem. SOC. 1994 116 6337. 93 W. L. Jorgensen S. Boudon and T. B. Nguyen J. Am. Chem. SOC. 1989 111 755. 94 R.A. Pascal Jr. and D. M. Ho J. Am. Chem. Soc. 1993 115 8507. 95 A. E. Mark S. P. van Helden P. E. Smith L. H. M. Janssen and W. F. van Gunsteren J. Am. Chem. SOC. 1994 116 6293. 96 M.T. Burger A. Armstrong F. Guarnieri D. Q. McDonald and W. C. Still J. Am. Chem. SOC.,1994,116 3593. Jonathan W. Essex (4 Figure 2 Gas-phase energy minima for the acridine diacid host with (a)pyrazine (b)pyridine and (c) quinoxaline (Reproduced with permission from J.Am. Chem. SOC. 1994 116 6337. 0 1994 American Chemical Society.) together with the mixed Monte-Carlo/stochastic-dynamicsmethod.49 The predicted enantioselectivity was found to agree with experiment to within 0.3 kcal mol- ’ a remarkable achievement. Theoretical methods have also been used to investigate the various specific interactions that stabilize complex formation including hydrogen bonding cation-.n interactions and hydrophobic interactions. Ab initio calculations have been used to investigate the hydrogen bonding between formic acid and f~rmamide,~~ since this complex is a model for a frequently adopted molecular recognition motif. It was found that the weakest hydrogen-bond between the carbonyl oxygen of formic acid and the formyl hydrogen contributed approximately 2.5-3.5 kcal Mol -to the complex interaction energy.Thus the formyl proton may indeed participate in hydrogen bonding and this should be remembered when designing synthetic hosts. It has been suggested that cation-.n interactions are responsible for the binding of acetylcholine to acetylcholinesterase. Ab initio calculations have been performed on the tetramethylam- monium and ammonium cations complexed with benzene and water to investigate the ’’ T. Neuheuser B.A. Hess C. Reutel and E. Weber J. Phys. Chem. 1994 98 6459. Theoretical Organic Chemistry 39 strength ofthis type ~finteraction.~~ It was found that cation-n interactions were indeed strong and in the case of the tetramethylammonium cation stronger binding to benzene than water was observed.Free-energy calculations of the binding of acetylcholine to a synthetic host99 supported the assertion that cation-n interactions are significant. The potential-energy surface of the benzene dimer has been investigated using ab initio calculations.'00 This can be regarded as the prototype system for aromatic-aromatic interactions in biochemistry. The calculations suggested that the parallel-displaced structure has the lowest energy lower than the T-shaped although entropic effects are likely to favour the T-shaped geometry with increasing temperature. On a more qualitative level molecular-dynamics simulations have been used to justify trends in binding constant without the explicit calculation of free energies.Huang et a[."' rationalized the trends in binding constant of different cyclohexanet- riols with a synthetic polyaza cleft in terms of the relative strengths of intramolecular hydrogen bonds within the triol. Chin et were able to reproduce the experimental trend in aggregate stability by determining the amount of distortion from planarity in the aggregates in the course of a molecular dynamics simulation. Finally molecular dynamics Monte-Carlo simulations and energy minimizations have been used to predict the geometry of host-guest binding in peptide'03 and glycoside' O4 binding systems and in the rational design of synthetic hosts for peptides'05 and bis- imidazoles.' O6 Conformational Equilibria.-The issue of molecular conformation is of critical importance to organic chemists since a molecule's reactivity is intimately related to the shape it adopts.Such a large amount of work has been published in the past year on conformation that it is impossible to review the entire subject exhaustively. Three areas will therefore be presented in more detail the effect of solvent on conformation the role of intramolecular hydrogen-bonding and the anomeric effect. These areas are of particular importance in determining the conformational stability of carbohydrate molecules a topic of considerable current interest. Ethane-1,2-diol is usually the molecule of choice for the investigation of intra- molecular hydrogen-bonding. Both ab initio and density-functional methods have been used to investigate the gas-phase conformations of this molecule and the effect of solvent has been introduced through the SMx series of models.'07-' Ab initio calculations at the MP4/6-31 lG**//MP2/6-31G** level showed that the two lowest energy gas-phase conformations have an intramolecular hydrogen-bond demonstrat- ing the importance of hydrogen-bonding in stabilizing conformation although a total 98 K. S. Kim J. Y. Lee S.J. Lee T.-K. Ha and D. H. Kim J. Am. Chem. Soc. 1994 116 7399. 99 P. H. Axelsen Isr. J. Chem. 1994 34 159. ''' P. Hobza H. L. Selzle and E. W. Schlag J. Am. Chem. SOC. 1994 116 3500. lo' C. Y. Huang L. A. Cabeil and E.V. Anslyn J. Am. Chem. Soc. 1994 116 2778. D. N. Chin D. M. Gordon and G. M. Whitesides J. Am. Chem. SOC. 1994 116 12033. A. Borchardt and W.C.Still J. Am. Chem. SOC. 1994 116 7467. G. Das and A. D. Hamilton J. Am. Chem. Soc. 1994 116 11 139. *05 M.F. Cristofaro and A.R. Chamberlin J. Am. Chem. Soc. 1994 116 5089. S. Mallik R.D. Johnson and F.H. Arnold J. Am. Chem. Soc. 1994 116 8902. lo' T. Oie I. A. Topol and S. K. Burt J. Phys. Chem. 1994,98 1121. C.J. Cramer and D.G. Truhlar J. Am. Chem. SOC.,1994 116 3892. 109 B. J. Teppen M. Cao R. F. Frey C. van Alsenoy D. M. Miller and L. Schafer J. Mol. Struct. (Theochem) 1994 314 169. 'lo T.S. Yeh Y. P. Chang T. M. Su and I. Chao J. Phys. Chem. 1994 98 8921. Jonathan W. Essex of ten stable conformations were identified all within approximately 4.5 kcal mol- 'of each other. Non-local density functional methods gave reasonable agreement with ab initio MP4 cal~ulations,'~~ but at less computational cost.There appears to be a concensus that this system is particularly challenging for ab initio methods; the energies of each conformation are very sensitive to basis set and level-of-correlation treat- merit.108,109Furthermore semi-empirical methods were not suitable for the confor- mational analysis of this molecule. The MM3 empirical potential-energy function was able to reproduce the ab initio potential-energy for conformations involving intra- molecular hydrogen-bonds but performed less adequately for the other conforma- tions.' lo The inclusion of solvation effects through the SMx series of models gave a free-energy of solvation in excellent agreement with experiment and the predicted aqueous conformational populations agreed with available experimental data sup- porting the use of these continuum solvation treatments in conformational analysis.lo8 Competition for hydrogen-bonding by the solvent would be expected to reduce the amount of intramolecular hydrogen-bonding in solution and this was supported by theory.Polyamines have also been used to study intramolecular hydrogen-bond- ing,' ' ' although diols are perhaps of more relevance because this motif is present in sugars. The anomeric effect is the preference of six-membered heterocycles substituted at C-2 with an electronegative group X to adopt the axial conformation (Scheme 1).Perhaps the simplest molecules that show this effect are the 2-substituted tetrahydropyrans.This series of molecules has been investigated both from the perspective of the gas-phase preference for the axial over equatorial conformation and to determine the role of solvation in affecting the conformational equilibrium. A series of ab initio calculations on tetrahydropyran derivatives have been carried out by Tvaroska and Carver.' '371 l4 Calculations of 2-fluoro and -chloro derivatives' ' provided an estimate for the gas-phase energy difference between axial and equatorial conforma- X Scheme 1 tions of approximately 2.5 kcal mol- '. The inclusion of solvent by a continuum method reduced the preference for the axial conformation by between 1 and 2 kcal mol-2-Methoxytetrahydropyran can be regarded as a model for the glycosidic linkage of carbohydrates.Not only can this system be expected to show the anomeric effect but also the exo-anomeric effect. The latter is the observed preference for the methyl group to adopt a gauche orientation with respect to the ring oxygen atom. Ab initio calculations carried out on this molecule' l4 gave a gas-phase free-energy difference between axial and equatorial conformations of 0.84 kcal mol- ' at room temperature in good agreement with the experimental result of between 0.7 and 0.9 kcal mol- ' in nonpolar solvents. Furthermore the calculations reproduced the ''I S.J. Lee B.J. Mhin S.J.Cho J.Y. Lee and K.S. Kim J. Phys. Chem. 1994 98 1129. 'I2 M. R. Kazerouni L. Hedberg and K. Hedberg J. Am. Chem. Soc. 1994 116 5279. 'l3 I. Tvaroska and J. P. Carver J. Phys.Chem. 1994 98 6452. 'I4 I. Tvaroska and J. P. Carver J. Phys. Chem. 1994 98 9477. Theoretical Organic Chemistry 41 experimentally observed exo-anomeric effect. The inclusion of solvent into the calculation reduced the magnitude of the axial preference to 0.23 kcal mol- for water in reasonable agreement with experiment. The performance of a range of molecular- mechanics force-fields was also investigated and it was found that MM3 with a dielectric constant of 1.5 was best able to reproduce the ab initio axiakquatorial conformational energy difference but was unable to calculate barriers of rotation correctly. This and related molecules have also been investigated both experimentally and theoretically by Wiberg and Marquez,"' and Jorgensen et ~1."~ Wiberg and Marquez' '' were able to reproduce the experimental anomeric effect using ab initio Hartree-Fock calculations at the 6-3 lG* level.It was found experimentally that increasing the polarity of the solvent reduced the axial preference and that this could be largely rationalized by considering the dipole moments of the axial and equatorial forms. It was also demonstrated that hydrogen bonding plays a role in the effect of solvation and this will have implications for modelling solvation using continuum treatments which exclude such specific interactions. Jorgensen et al.' l6 investigated the effect of solvent on the anomeric equilibrium of 2-methoxytetrahydropyran using Monte-Carlo free-energy calculations with explicit solvent molecules.The calculated preference for the equatorial conformation in water of 0.4 k0.2kcal mol- agreed well with experiment and was interpreted in terms of the changing dipole moment of the solute molecule. Simple continuum treatments of solvation such as SM2 and a dipolar SCRF calculation were unable to reproduce this result. Salzner and Schleyer' investigated a range of molecules using ab initio calculations in an attempt to determine which of the explanations for the anomeric effect was the most plausible namely dipolar repulsion or hyperconjugation. On balance their calculations supported the hyperconjugation explanation as being the most consistent with their results. The effect of solvent on conformation has been partly addressed in the discussion of the anomeric effect and intramolecular hydrogen-bonding.However there is a large amount of literature on this particular subject applied to other systems and in particular to peptide conformation. There is obviously great interest in the ultimate goal of predicting protein structure in solution and preliminary studies on small peptides are seen as a way of addressing the effect of solvent on conformation using a system of tractable size. Studies of dipeptides have been reported by Gould et al. ''* and Shang and Head-Gordon.' '' In both cases continuum models were used although explicit solvent has been used to calculate potentials of mean force for alanine dipeptide by Straatsma and M~Cammon.'~ demonstrated the The work of Gould et ~1."~ profound effect solvent can have on molecular conformation.Furthermore by comparison with the paper of Shang and Head-Gordon"' they demonstrated the importance of using continuum treatments that extend beyond a consideration of the molecular dipole moment. For an SCRF treatment the inclusion of terms up to 1 = 7 is advised as well as the use of a more realistic non-spherical cavity. Chan and Lim12' investigated the conformational space of a tetrapeptide using a random search coupled with energy minimization. An empirical description of the molecular energetics was I" K.B. Wiberg and M. Marquez J. Am. Chem. SOC. 1994 116 2197. W. L. Jorgensen P. I. Morales de Tirado and D. L. Severance J. Am. Chem. SOC. 1994 116 2199. U. Salzner and P. v. R. Schleyer J. Org. Chem. 1994 59 2138.I. R. Gould W. D. Cornell and I.H. Hillier J. Am. Chem. SOC. 1994 116 9250. H.S. Shang and T. Head-Gordon J. Am. Chem. SOC.,1994 116 1528. 120 S. L. Chan and C. Lim J. Phys. Chem. 1994 98 12 805. 42 Jonathan W. Essex adopted together with a finite-difference Poisson-Boltzmann treatment of solvation. It was found that the inclusion of solvation reduced the tendency for opposite charges to associate thereby increasing the number of favourable conformations considerably. The effect of solvent on the conformational equilibria of a number of organic molecules has been investigated including cocaine and derivatives,' ' amiloride,' 22 diarylguanidines,' 23 and phosphoryl choline and ethanolamine.' 24 These studies used both continuum and explicit representations of solvent together with ab initio semi-empirical and molecular mechanical descriptions of molecular energetics.Of particular note the solvation free energies obtained using a continuum model in conjunction with ab initio calculations were in fair agreement with the results obtained using the GB/SA solvent treatment with the AMBER force-field for diaryl- guanidines.' 23 GB/SA is a particularly fast method for calculating solvation free energies and these results suggest that it can be expected to work reasonably well in calculating relative conformational energies. However reservations concerning the reliability of the GB/SA model in treating n-stacking interactions were expressed. Nagy et al.' 25 performed a number of calculations on conformational equilibria comparing the performance of the GB/SA model applied in conjunction with the AMBER force-field to the results obtained using ab initio calculations to give gas-phase torsional-energy profiles followed by Monte-Carlo free-energy calculations with explicit solvent molecules to determine the solvation contribution.Their results for histamine and ethane- 1,2-diol suggested that the GB/SA solvation treatment applied with the AMBER force-field was not reliable for predicting conformational equilibria when intramolecular hydrogen bonds could form. The authors suggested that the molecular-mechanics parameters used in this procedure may need revising for this type of system. Redox Potentials and Tautomeric Equilibria.-The calculation of these physicochemi- cal properties represents a significant challenge to theory particularly when aqueous- phase equilibria are required.Two papers reporting the calculation of one-electron reduction potentials appeared in 1994. Neural networks were used by Wolfe et to predict the one-electron electrode potentials for a range of nitrobenzenes nitrofurans and nitroimidazoles. The input data to the neural network were the compound heats of formation evaluated semi-empirically and the free energies of hydration calculated using the AMl-SM2 model. An average accuracy of 70mV was reported from the calculations. A combination of quantum-mechanical calculations of gas-phase free energies together with classical computer simulations giving solution-phase free energies was adopted by Wheeler to calculate the one-electron reduction potential of p-benzoq~inone.'~~ This combination was used by Reynolds et to calculate successfully two-electron reduction potentials.One-electron potentials on the other hand are more problematic because of difficulties arising from the radical anion; the 12' B. Yang J. Wright M. E. Eldefrawi S. Pou and A.D. MacKerell J. Am. Chem. SOC. 1994 116 8722. 12* R.A. Buono T.J. Venanzi R. J. Zauhar V. B. Luzhkov and C.A. Venanzi J. Am. Chem. SOC. 1994,116 1520. 123 G. Alagona C. Ghio P.I. Nagy and G.J. Durant J. Phys. Chem. 1994 98 5422. 124 T.B. WooLf and B. Roux J. Am. Chem. SOC. 1994. 116 5916. 125 P.I. Nagy J.E. Bitar and D.A. Smith J. Comput. Chem. 1994 15 1228. 12' J. J. Wolfe J.D. Wright C.A. Reynolds and A. C. G. Saunders Anti-Cancer Drug Design 1994 9 85. 12' R. A. Wheeler J. Am. Chem. SOC.,1994,116 1 1 048. 12* C.A. Reynolds P. M. King and W. G. Richards Nature (London) 1988 334 80. Theoretical Organic Chemistry 43 gas-phase electron affinities require sophisticated treatments of electron correlation and the aqueous-phase relative free energy of hydration must consider the long-range electrostatic contribution arising from the creation/annihilation of charge. The calculated and experimental reduction potentials agreed to within 100mV.' 27 Tautomeric equilibria are fundamentally important in organic chemistry and especially in condensation reactions. Lammertsma and Pra~ad'~~ investigated the imine/enamine tautomeric equilibrium using a combination of ab initio calculations together with the SCRF continuum treatment of solvation.The calculations demon- strated the importance of using high-level basis sets together with a good description of electron correlation in these systems. Cao et al.13* investigated the tautomeric equilibria of 3-hydroxypyrazole; this represents a particularly challenging system since eight tautomers are possible. High-level ab initio calculations were performed up to MP4 and CCSD to calculate the gas-phase energies of the tautomers. The effect of solvent was introduced by first SCRF continuum calculations truncated as the dipolar term and second by Monte-Carlo free-energy perturbation calculations using explicit solvent molecules. The convergence of the ab initio results with increasing basis-set size and sophistication of correlation treatment suggests that great care needs to be taken when studying these systems to ensure reliable results.In the solution-phase Monte-Carlo simulations the authors used partial charges derived from the SCRF calculations. In this fashion they hoped to include both solute polarization and first-hydration-shell effects in the calculated free energies. The authors did however point out that the Hartree-Fock (HF) wavefunctions used to derive the charges usually overestimate gas-phase dipole moments and that by using HF/SCRF charges the solute may become too polarized. The combined ab initiolfree-energy perturbation results predicted the dominant solution-phase tautomer that was in agreement with experiment.Use of the SCRF free energies of hydration incorrectly predicted the dominant tautomer and furthermore the energies were demonstrated to be sensitive to cavity size. This discrepancy was attributed to the failure of continuum models to include an explicit description of the first hydration-shell together with the truncation of the solute multipole-expansion at the dipolar level. Histamine is an important molecule in biological systems; it not only stimulates smooth muscle contraction but also regulates the secretion of acid in the stomach. It has a very large range of accessible conformational tautomeric and protonation states and is therefore a very interesting theoretical target. These equilibria have been addressed by two separate research groups in the past year again using a combination of ab initio calculation and free-energy perturbation simulations.Worth and Richards' 3' studied the histamine monocation from the perspective of investigating the sensitivity of the simulation results to protocol. Difficulties associated with sampling and parameter generation were investigated and discussed. Nagy et al.132 performed a very comprehensive investigation of histamine conformational and tautomeric equilibria and also related their results to the proposed binding mechanism of histamine to the H receptor; they found that their equilibrium results were consistent with the thermodynamic requirements for this mechanism. 129 K. Lammertsma and B. V. Prasad J.Am. Chem. Soc. 1994 116 642. 130 M. Cao B. J. Teppen D. M. Miller J. Pranata and L. Schafer J. Phys. Chem. 1994 98 11 353. 13' G.A. Worth and W.G. Richards J. Am. Chem. Soc. 1994 116 239. 132 P.I. Nagy G.J. Durant W.P. Hoss D.A. Smith J. Am. Chem. Soc. 1994 116 4898. Jonathan W. Essex Pericyclic Reactions.-Pericyclic reactions are of fundamental importance to the synthetic organic chemist not only because a large number of atoms can be added to or modified within a molecule but also because the reactions can proceed with regio- and stereoselectivity. Theoretical calculations on this reaction type are generally devoted to rationalizing experimental behaviour and understanding the reaction mechanisms. In particular the issue of whether the reactions are concerted or proceed in a stepwise fashion has proven controversial.Owing to the interest in this general category of reactions a selective view of the work performed on the more popular pericyclic reactions will be presented. Diels-Alder Reactions.-This reaction is perhaps the most famous of all pericyclic reactions and arguably the one to which most theoretical effort has been devoted. In recent years there has been considerable controversy regarding the nature of the reaction pathway but there now appears to be general agreement that the reaction proceeds by a synchronous concerted pathway and not in a stepwise fashion (Scheme 2).133Sophisticated CASSCF calculations were used to investigate the reaction between butadiene and ethene and confirmed that the concerted pathway is the most likely reaction route; this result was backed-up by a comparison between calculated and experimental kinetic isotope effects.' 34*135 Scheme 2 The role of solvation in affecting the rate of pericyclic reactions has been extensively investigated by Jorgesen et al.' 36 Their approach involved determining the course of the reaction in the gas phase using ab initio methods calculating empirical potential- energy parameters for each frame along the reaction coordinate and then performing a classical Monte-Carlo simulation with explicit solvent molecules in which the free-energy difference between each frame was calculated using free-energy perturba- tion theory.In this fashion the experimentally observed acceleration of the Diels-Alder reaction between cyclopentadiene and methyl vinyl ketone in water was attributed to the strengthening of hydrogen bonds to the carbonyl oxygen in the transition state augmented by hydrophobic association.Justification for this result from ab initio calculations on water complexed with the above reagents has also been reported.'37 133 K.N. Houk J. Gonzalez and Y. Li Acc. Chern. Res. 1995 28 81. K. N. Houk Y. Li J. Storer L. Raimondi and B. Beno J. Chem. SOC.,Faraday Trans. 1994,90 1599. 135 J.W. Storer L. Raimondi and K.N. Houk J. Am. Chem. SOC. 1994 116,9675. 136 W. L. Jorgensen J. F. Blake D. Lim and D. L. Severance J. Chem. SOC.,Faraday Trans. 1994,90 1727. Theoretical Organic Chemistry 45 The water to carbonyl-oxygen hydrogen bond was calculated to be approximately 2 kcal mol- stronger in the transition state than the reactants.This method for calculating the effect of solvent on reaction rates relies on the gas-phase reaction profile also being the reaction coordinate followed in solution. However as Jorgensen has pointed out the use of continuum solvation treatments in determining reaction pathways in solution is not without diffi~u1ties.I~~ In an interesting study Craig and Stone have investigated Diels-Alder reactions using intermolecular perturbation theory (IMPT).13' In this approach Basis Set Superposition Error (BSSE) is eliminated and the technique has been shown to yield identical results to large basis set ab initio supermolecule calculations. Furthermore IMPT allows for the total interaction energy between fragments to be decomposed into well-characterized components allowing a reaction to be interpreted in meaningful terms.The disadvantage of the approach is that it cannot be used for molecules at close distances because the perturbation expansion is slowly convergent. Reactions must therefore be studied at large separations and the behaviour at the transition state inferred from results obtained earlier along the reaction coordinate; this assumption is probably valid when comparing closely related reactions. Furthermore the reactants are all examined at a fixed geometry. In the analysis of a range of Diels-Alder reactions reported by Craig and Stone IMPT was able to reproduce the trends in selectivity for a series of dienophile substituents in the butadiene/ethene reaction.Predictions of reactions involving unsymmetrical dienes and dienophiles were less successful and this was attributed to the fixed geometry adopted in the calculations whereas experiment is performed in solution and at finite temperature. It should however be noted that the IMPT calculations agreed quite well with ab initio calculations on the transition states. The Diels-Alder reaction has also been studied by both density functional and semi-empirical methods. Carpenter and Sosa14' applied local and non-local DFT to the reaction between ethene and butadiene. The local DFT results were found to be very poor whereas the non-local results were generally comparable with more expensive MP2 calculations although differences still existed.Jursic and Zdrav- kovski 14' studied the Diels-Alder reaction using semi-empirical methods and assumed a concerted synchronous reaction mechanism. The AM1 and PM3 methods were found to yield poor agreement with experiment suggesting that semi-empirical calculations cannot be used to study the concerted Diels-Alder reaction. Claisen and Cope Rearrangement.-The Claisen and Cope rearrangements are classified as [3,3] sigmatropic shifts. This type of reaction is illustrated in Scheme 3. When X = CH the reaction is referred to as the Cope rearrangement and when X = 0the reaction is the Claisen rearrangement. The possible transition states are also illustrated. The Claisen rearrangement is not only of intrinsic synthetic interest but is also of biochemical importance.Chorismic acid is a key intermediate in the shikimate biosynthetic pathway of phenylalanine and tyrosine; it undergoes a Claisen rearrange- 13' J. F. Blake D. Lim and W. L. Jorgensen J. Org. Chem. 1994 59 803. 13* W. T. Borden F. Williams T. Bally J. Michl M. T. Nguyen S. Shaik P. von R. Schleyer W. L. Jorgensen W. Saunders,V. Moliner Y. P. Liu D. G.Truhlar P. Paneth M. A. Rodriguez M. S. Child M. M. Francl and X. Assfeld J. Chem. SOC. Faraday Trans. 1994 90,1733. 139 S. L. Craig and A. J. Stone J. Chem. Soc. Faraday Trans. 1994 90 1663. 140 J. E. Carpenter and C. P. Sosa J. Mol. Struct. (Theochem) 1994 311 325. 141 B. S. Jursic and Z. Zdravkovski J. Mol. Struct. (Theochem) 1994 309,249. Jonathan W.Essex bis-allyl 1 bdiyl Scheme 3 C02H I OH Scheme 4 ment to prephenic acid catalysed by the enzyme chorismate mutase (Scheme 4). The effect of solvent on the Claisen rearrangement has been examined using both explicit solvent models and continuum treatments. Jorgensen et used the combination of the gas-phase reaction pathway with classical Monte-Carlo simula-tions to determine the effect of solvation on the Claisen rearrangement of ally1 vinyl ether. The experimentally observed rate enhancement of ca. lo3was reproduced by the simulations and was attributed to an increase in the number of hydrogen-bonds formed with solvent by the transition state. Gao investigated the same reaction using the MM/QM pr~cedure;~' this calculation yielded almost identical results to Jorgensen et al.' 36 although the solvent-induced rate acceleration was attributed to polarization of the transition state giving an enhanced dipole moment together with increased hydrogen bonding to the oxygen of the transition state.Davidson et ~1.l~~ investigated this system using a number ofcontinuum models in conjunction with both density functional and Hartree-Fock calculations. It was found that the PCM model with HF calculations performed well in modelling the solvent di-n-butyl ether but less satisfactorily in modelling the effect of water presumably because the continuum treatment does not explicitly consider hydrogen bonding unlike the previously described explicit-solvent methods. Interestingly the calculation of the gas-phase pathway using DFT which includes correlation gave good agreement with gas-phase experimental data.However the polarity of the transition state was considerably reduced with respect to that of the ground state resulting in a reduction in the calculated differential solvation energy. Thus the success of the gas-phase HF reaction 14' M. M. Davidson I. H. Hillier R. J. Hall and N. A. Burton J. Am. Chem. SOC. 1994 116 9294. Theoretical Organic Chemistry 47 profile applied within a classical Monte-Carlo simulation of solvent'36 may be attributed to the opposing influence of electron correlation and solvent polarization. The effect of including both correlation and solvent polarization is to yield a molecular dipole moment that is very close to that predicted at the HF level in the gas phase.Thus intermolecular potentials obtained from gas-phase HF calculation may be applied to condensed-phase simulations. Houk et a1.143,144 have been engaged in calculating kinetic isotope effects for the Claisen rearrangement as a way of interpreting experimental data in terms of a reaction pathway. As mentioned for the Diels-Alder reaction the precise nature of the reaction mechanism is controversial with aromatic and diradical transition states being postulated. Wiest Black and H~uk'~~ applied density functional theory to the calculation of the transition state for the Claisen rearrangement. The local spin density approximation was unable to describe the transition state properly whereas nonlocal methods suggested an aromatic-type transition state.The Becke3-LYP functional was able to give transition-state energies comparable with correlated molecular orbital theory and by comparison with experimental kinetic isotope effects good estimates of the transition state geometries were also obtained. Yo0 and Hou~'~~ report calculations on the same molecule but at the MCSCF/6-31G* level. The biochemically relevant Claisen rearrangement of chorismic acid and some of its derivatives have been investigated using ab initio calculations by Davidson and Hillier.'45 The relative barrier heights were in good agreement with experiment although the absolute values did not agree presumably because of the neglect of correlation and solvation in the calculations.The observed acceleration of the rearrangement reaction of chorismic acid and its derivatives with respect to ally1 vinyl ether (AVE) was attributed to both stabilization of the transition state and destabilization of the reactants. In a related the transition states for the Claisen rearrangements of AVE and chorismic acid were calculated at the HF/6-3 1 G* level extended to the MP2/6-31G* level for AVE. The calculated transition state for AVE was 'early' with little bond formation but considerable bond-cleavage and this was consistent with measured and calculated kinetic isotope effects. The transition state for chorismic acid was predicted to be more dissociative again in accord with measured kinetic isotope effects. The Cope rearrangement has been investigated by Hrovat et a1.1473148 at the CASPT2N level of theory thereby including electron correlation between the six active electrons and the other 28 valence electrons.This level of calculation represents an improvement on the CASSCF approach in which correlation between the active and inactive electrons is not evaluated. At the CASPT2N level of theory a stationary point corresponding to the transition state for the concerted reaction in which bond making and breaking are synchronous was found. No evidence for a 1,4-diyl intermediate was obtained unlike the CASSCF/6-3 lG* result. Furthermore the CASPT2N energetic results are in good agreement with experiment. These results therefore support the concerted mechanism for the Cope rearrangement.The density functional study of 143 0.Wiest K. A. Black and K.N. Houk J. Am. Chem. Soc. 1994 116 10336. 144 H.Y. Yo0 and K.N. Houk J. Am. Chem. SOC. 1994 116 12047. 14' M. M. Davidson and I. H. Hillier J. Chem. SOC. Perkin Trans. 2 1994 1415. 146 M. M. Davidson and I. H. Hillier Chem. Phys. Lett. 1994 225 293. 14' D.A. Hrovat K. Morokuma and W.T. Borden J. Am. Chem. Soc. 1994 116 1072. 148 D.A. Hrovat K. Morokuma and W. T. Borden J. Am. Chem. SOC. 1994 116 4529. Jonathan W. Essex Wiest et ~1.l~~ also yielded an 'aromatic' transition state and good estimates of the activation energies. However comparison between experimental and theoretical kinetic isotope effects supported the nonlocal DFT geometry but not that of the CASPT2N calculations of Hrovat et al.It is clear that further work is needed to determine the precise nature of this intriguing reaction. [2 + 21 Cyc1oadditions.-[2 + 21 Cycloadditions represent an important class of synthetic reaction since they represent an effective route to the formation of four-membered rings. These reactions have enjoyed extensive theoretical investigation from Woodward-Hoffmann theory through to the application of high-level ab initio calculations. Two general reaction mechanisms can be envisaged via a transoid biradical intermediate or in a pericyclic manner (Scheme 5). Bernardi et al.149 reported calculations on a range of [2 + 21 cycloadditions at the MCSCF level including calculations of the photochemical pathway. Their results indicated that for non-polar systems a concerted reaction path did not exist whereas in cases where the n system was polarized a transition state for the concerted route was found.However this transition state was higher in energy than that of the biradical pathway so that a concerted mechanism only became likely when solvent effects were considered. Interestingly the authors analysed their results in terms of a valence-bond model. Karadakov et al.' so have applied spin-coupled (SC) theory to the cycloaddition of two ethene molecules and found that the reaction proceeded via the diradical in agreement with CASSCF results. The SC wavefunctions can however be interpreted in a chemically useful fashion in terms of bonds and spin-states and in this respect they offer an advantage over molecular orbital methods.Scheme 5 The [2 + 21 cycloadditions of ketenes have proved a fertile area of theoretical investigation in the past year. The reaction of ketene with formaldimine was investigated using ab initio calculations coupled with a continuum treatment of s~lvation.'~' The reaction was predicted to proceed by a one-step process in the gas-phase whereas a zwitterionic intermediate was proposed for the solution phase in accord with experiment. Xu et ~1."~ have also investigated the reaction of fluoroketene with imines. Ketene and phosphaketene dimerization has been investigated by Salzner and Bachrach' s3 using high-level ab initio calculations. Ketene was predicted to 149 F. Bernardi A. Bottoni M.Olivucci A. Venturini and M. A. Robb J. Chem. SOC., Faraday Trans. 1994 90 1617. 150 P. B. Karadakov J. Gerratt D. L. Cooper and M. Raimondi J. Chem. SOC.,Faraday Trans. 1994,90 1643. 151 X. Assfeld M. F. Ruiz-Lopez,J. Gonzalez R. Lopez J. A. Sordo and T. L. Sordo J. Comput.Chem.,1994 15 479. 152 Z.-F. Xu D.-C.Fang and X.-Y.Fu J. Mol. Struct. (Theochem) 1994,305 191. Theoretical Organic Chemistry 49 dimerize via a polar diradicaloid intermediate in agreement with both experimental and theoretical studies. Phosphaketene on the other hand was predicted to dimerize in the classical Woodward-Hoffmann allowed [27c + 2x.J fashion because of the ability of the phosphorus derivative to accommodate strain in the cyclic transition state.S,2 Reactions.-The SN2 reaction continues to be the target of considerable theoretical and experimental interest since it represents probably the most elementary displace- ment reaction. Hase' 54 has reviewed the gas-phase SN2 reaction from the perspective of the various statistical theories computer simulations and experimental data whereas Ramsden' 55 has summarized the nature of bonding within the transition state itself. In this section the effect of solvent on the SN2 reaction will be reviewed followed by the recent results obtained from the gas phase. The effect of solvent on this reaction has been studied in a number of fashions. Billing and Mikkel~en'~~ investigated the reaction of a chloride ion with chloromethane in water. The calculated activation energy in water was found to be in good agreement with other theoretical estimates and experiment.The same reaction was studied by Mathis et ~11.l~~ using valence-bond theory together with a continuum solvation model in which the separate orientational and electronic contributions to the solvent dielectric were considered explicitly. The calculated activation free energies were in reasonable accord with experiment. Perhaps more importantly however the effect of separating the contributions to the solvent dielectric was marked. Mathis and Hyne~'~*,' 59 have investigated the S,1 decomposition of alkyl iodides using the same theoretical approach. Hu and Trular16' have investigated the reaction of fluoride with chloromethane in the presence of a single molecule of water and compared their results with experimental data from gas-phase clusters.The good agreement of rate constants and kinetic isotope effects with experiment supported their use of conventional transition state theory and the exclusion of tunnelling effects from the calculations. A large number of quantum-mechanical calculations on the S,2 reaction have been reported in the past year. In a series of papers Anh et af.161-163 investigated a range of nucleophiles and substrates using AM 1 and low level Hartree-Fock calculations (3-21Gand some 6-3 1G*). Most interestingly however they investigated the amount of distortion allowed in the transition state for an energy penalty of 1 kcal mol- ',to determine when an intramolecular displacement reaction would be feasible.Axial displacements of approximately 0.3 A were acceptable as were angular deviations of 8" off the preferred direction of attack. Identity exchange reactions where the nucleophile displaces the same leaving group from the substrate have been studied by several workers. Wladkowski et al. 164 investigated the displacement of fluoride using a range 153 U. Salzner and S. M. Bachrach J. Am. Chem. SOC. 1994 116 6850. 154 W. L. Hase Science 1994 266 998. 155 C.A. Rarnsden Chem. SOC.Rev. 1994 23 11 1. 156 G. D. Billing and K.V. Mikkelsen Chem. Phys. 1994 182 249. 15' J.R. Mathis R. Bianco and J.T. Hynes J. Mol. Liq. 1994 61 81. 15' J. R. Mathis and J.T. Hynes J. Phys. Chem. 1994 98 5445. 159 J.R. Mathis and J.T. Hynes J.Phys. Chem. 1994 98 5460. I6O W.-P. Hu and D.G. Truhlar J. Am. Chem. SOC. 1994 116 7797. 16' N.T. Anh F. Maurel B.T. Thanh H. H. Thao and Y.T. "Guessan New. J. Chem. 1994 18 473. 16' N.T. Anh F. Maurel H.H. Thao and Y.T. "Guessan New. J. Chem. 1994 18 483. 163 N.T. Anh B.T. Thanh H. H. Thao and Y. T. "Guessan New. J. Chem. 1994 18 489. 164 B. D. Wladkowski W. D. Allen and J.I. Braurnan J. Phys. Chem. 1994 98 13 532. 50 Jonathan W. Essex of basis sets and with the inclusion of correlation up to the CCSD(T) and MP4 levels; the net S,2 effective activation energy was observed to be 0.8 kcal mol- ' below the separated reactants. Deng et a1.16' studied the self-exchange reactions of the halomethanes (fluoro chloro bromo iodo) using both MP4 level ab initio and non-local density-functional calculations.The calculated activation energies were again observed to be sensitive to basis set and correlation with experiment lying between the MP4 and the non-local density functional results. Despite the simplicity of this reaction it clearly represents a very significant challenge to theory. Other systems studied include the reaction of chloride with bromomethane using Hartree-Fock calculations coupled with transition state and RRKM theorie~,'~~.'~~ and the calculation of kinetic isotope effects for a range of S,2 transition states.'68 The former' 66,'67 are particularly interesting in that an analytical potential energy function derived from the ab initio calculations was used in classical trajectory calculations and the results compared with the predictions of RRKM and transition state theories.The trajectory calculations were able to provide considerable detail concerning the course of the reaction and the partitioning of energy within the system's degrees of freedom. Photochemistry.-The nature and fate of photochemically excited species has been extensively studied by Olivucci Bernardi and Robb. The cyclohexadiene/hexatriene photochemical interconversion was studied at the CASSCF and CASSCF/MP2 levels. 69 These species are particularly interesting since the noncrossing rule which is applicable to diatomic molecules loses its validity in polyatomic systems so that two electronic states with the same symmetry may cross at a conical intersection. Indeed the 2A -+ lAl decay channel was predicted to occur via a conical intersection and with corresponding high efficiency and this result was consistent with the available experimental data.The photochemistry of buta-1,3-dienes1 70and acrolein,' carbene formation from the excited states of diazirine and dia~omethane,'~~ and the Paterno-Buchi rea~tion"~ have been studied and the fate of the excited states elucidated; all involved decay via conical intersections to some extent. 4 Conclusion Theoretical organic chemistry remains a flourishing discipline. Novel theoretical methods continue to be derived and applied to areas of contemporary interest. The more established techniques such as molecular mechanics are now easier to use on a routine basis. As computers become increasingly powerful and the methodology more refined it is clear that the application of theory to problems of organic interest can only become more important; the future is bright.Acknowledgement. JWE is a Royal Society University Research Fellow. 165 L. Deng V. Branchadell and T. Ziegler J. Am. Chem. SOC. 1994 116 10645. H. Wang L. Zhu and W.L. Hase J. Phys. Chem. 1994 98 1608. 167 H. Wang G.H. Peslherbe W. L. Hase J. Am. Chem. SOC. 1994 116 9644. R.A. Poirier Y. Wang and K.C. Westaway J. Am. Chem. SOC. 1994 116 2526. 169 P. Celani S. Ottani M. Olivucci F. Bernardi and M.A. Robb J. Am. Chem. SOC. 1994 116 10 141. 170 M. Olivucci F. Bernardi S. Ottani and M.A. Robb J. Am. Chem. SOC. 1994 116 2034. M. Reguero M. Olivucci F. Bernardi and M.A.Robb J. Am. Chem. SOC. 1994 116 2103. N. Yamamoto F. Bernardi,A. Bottoni M. Olivucci M. A. Robb and S. Wilsey,J. Am. Chem.SOC. 1994 116,2064. 173 1. J. Palmer I.N. Ragazos F. Bernardi M. Olivucci and M. A. Robb J. Am. Chem.SOC.,1994,116,2121.

ISSN:0069-3030    

DOI:10.1039/OC9949100025

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (i) Pericyclic Reactions By C.I.F. WATT Department of Chemistry University of Manchester Manchester M 13 9PL UK 1 Diels-Alder Reactions Mechanistic Studies.-Rate Product and Stereochemical Studies. Secondary deuterium kinetic isotope effects have been calculated for concerted and stepwise pathways of [4+ 21 cycloadditions and cycloreversions using ab initio methods up to MCSCF/6-31G* levels. The expected effects for the two pathways are almost always sufficiently different to expect that experiment would distinguish between them. Available experimental data on a number of symmetrical or near symmetrical reactions have been collected and the concerted pathways give an excellent fit to the data. 14C kinetic effects for butadiene reacting with ethylene or acrolein were also calculated.' Complementary studies of the stereoselectivity and pressure dependence2 in the thermal dimerization of buta-l,3-diene (1) have demonstrated the value of activation volumes in distinguishing concerted and stepwise cycloadditions (Scheme 1 ).For formation of vinyl cyclohexene (2) the [4 + 21 product AV* is 13.3 cm3 mol- less than that for the competing [2 + 21 cyclization leading to trans-1,2-divinylcyclobutane (3). Studies with (2,2)-1,4-dideuteriobuta-l,3-dieneshow that the formation of the vinylcyclohexenes occurs with only 3% loss of stereochemistry at 1 bar and less than 1% at 7 kbar providing good evidence that formation of the [4+ 2) adduct does indeed proceed by a concerted mechanism with a small amount of competing stepwise reaction which is suppressed at high pressure.A similar study carried out with chloroprene and (E)-1-deuteriochloropreneyielded AV* = -22 cm3 mol- for for- mation of the isomeric divinylcyclobutanes (4)and one of the [4+ 2) adducts (5) which is formed non-stereospecifically. The conclusion is reasonable that these three products devolve from the same biradical intermediate. For the remaining two [4+ 21 adducts products (6) and (7) A V* = -29 and -3 1 cm3 mol- and these are formed by concerted cycloaddition. Activation volumes have also been determined for reaction of N-phenylmaleimide and isoprene in the presence of aluminium chloride or lithium per~hlorate.~ These are A V* = -42 and -45 cm3 mol- 'respectively and markedly more negative than the J.W. Storer L. Raimondi and K.N. Houk J. Am. Chern. Soc. 1994 116 9675. F.-G. Klarner B. Krwaczyk B. Ruster and U. K. Deiters J. Am. Chem. SOC. 1994 116 7645 N. S. Isaacs L. Maksimovic and A. Laila J. Chem. SOC. Perkin Trans. 2 1994 495. 51 C.I. F. Watt P \ Scheme 1 corresponding uncatalysed reaction which has A V = -36 cm3 mol- ’.The results are in accord with predictions assuming prior coordination of Lewis acid and the dienophile. The activation volume for reaction of N-ethylmaleimide and anthracene- 9-methanol is more negative in water than in non-aqueous medium. Medium and Substituent Eflects. Exo-endo equilibrium ratios but not kinetic selectivities of reactions in benzene of N-phenylmaleimide with a set of p-substituted 6-phenyl-6-methylf~lvenes~ show a linear free energy relationship with 0’ substituent parameters (p = -0.701).Reactivities gave a reasonable correlation with 6-with p = -0.684 but only when N(Me) and OMe are excluded from the substituent set. Solvent effects on reactivity and selectivity were small and not notably dependent on substituent. Solvent effects have also been examined in the reactions of 5-substituted naphthoquinones with cyclopentadienes.’ Substituent effects are attenuated in the more reactive solvents and give no indication that transition state charge separation in water differs from that in other solvents. However plots of activation energy against solvent E,(30) for reactions of 5-methoxynaphthoquinone gave indications that the slope of the LFER for a set of hydroxylic solvents including water was larger than for non-hydrogen-bonding solvents.Reactions of methyl vinyl ketone and methyl vinyl sulfone in the same set of solvents were also compared and medium effects separated into those on initial state and activated complex. Stabilization of the complex by 2,2,2-trifluoroethanol and destabilization of the ground state by water were notably larger for the ketone. The effects of pressure on Diels-Alder reactions of furans are higher in dichloromethane solution than in aqueous medium.6 Exo-endo ratios and regioselectivities in Diels-Alder additions of cyclopentadiene and isoprene to methyl vinyl ketone and methyl acrylate have been determined7 in eighteen pure solvents and in aqueous mixtures including some highly fluorinated alcohols.Correlations with a number of solvent parameters show that the endo+xo M. M. Gugelchuk P.-C.-M. Chan and T.J. Sprules J. Ory. Chem. 1994 59 7723. S. Otto W. Blokzijl and J.F.B. Engberts J. Org. Chem. 1994 59 5373. J. Jenner Tetrahedron Lett. 1994 35 1189. ’ C. Caticiela J. I. Garcia J.A. Mayoral and L. Salvatella J. Chem. Soc. Perkin Trans. 2 1994 847. Reaction Mechanisms -Part (i) Pericyclic Reactions selectivity is related mainly to solvophobic parameter (Abraham's S,) and donor bonding properties (a) while regioselectivity is linked strongly to hydrogen-bond donor ability. The importance of hydrogen bonding is also indicated by ab initio MO calculations' of the transition states for cyclopentadiene reacting with methyl vinyl ketone or acetonitrile in the presence of water molecules.Hydrogen bonding to oxygen or nitrogen of the dienophile is enhanced by about 1.5-2.0kcalmol-' over the ground-state interaction. Contributions from hydrophobic interactions are more modest. The effects of added salts on rates of Diels-Alder reactions in water correlate with their effects on the internal pressure of the medium Pi,and it has been pointed out that in reactions with negative activation volumes increases in the cohesive energy of the medium as measured by Pi are indeed expected to increase rate.' Chiral Processes.-Control of stereochemistry at new chiral centres in cycloadducts is a focus of synthetic interest and can be achieved either by use of chiral dienes and dienophiles or more elegantly by use of achiral components with a chiral catalyst.Developments in both areas are reported. Chiral Components and Auxiliaries. Chiral dienophiles include esters of 2-cyanocin-namic acid with ethyl (S)-lactate or (R)-pantolactone which react with butadiene in presence of titanium tetrachloride with high and complementary diastereoselectivi- ties.' A number of chiral2-nitro-1-sulfinylalkenes undergo stereoselective Lewis acid catalysed Diels-Alder reactions with cyclopentadiene,' ' with 2-sulfinyl dienophiles generally showing higher diastereo and endo selectivity. Tetra-substituted dienophiles required high pressure for action. Diacrylate esters of a C symmetrical chiral auxiliary give Diels-Alder adducts with a range of cyclic and acyclic dienes with high stereoselectivity in ethylaluminium dichloride catalysed reactions.I2 Amongst chiral dienes used were homochiral esters of 2-pyrone-3-carboxylic acids which react with enol ethers in presence of catalytic amounts of some lanthanide shift reagents to give adducts with high >95% d.e.13 Additions of (R)-l-(p-tolysulfinyl)-1,3-8 J.F. Blake D. Lim and W. L. Jorgenson J. Org. Chem. 1994 59 803. 9 A. Kumar J. Org. Chem. 1994 59 230. 10 C. Cativiela A. Avenoza M. Paris J. Org. Chern. 1994 59 7774. 11 K. Fiji K. Tanaka H. Abe K. Matsumoto T. Harayama A. Ikeda T. Taga Y. Miwa,and M. Node J. Org. Chem. 1994 59 2211. 12 B. C. Bezuidenhoudt G. H. Castle J. V. Geden and S.V. Ley Tetrahedron Lett. 1994 35 7451. 13 I. Marko G. R. Evans J.-P. Declerq Tetrahedron 1994,50,4557;I. Marko and G. R. Evans Tetrahedron Lett. 1994 35 2767. C.I. F. Watt butadienes (8) with N-methyl maleimide14 are stereospecific (Scheme 2). Only one endo adduct (9) is formed under thermal or catalytic conditions. With excess NMA the adducts suffer [2,3]-sigmatropic rearrangement yielding enantiometerically pure all-cis cyclohexenols (10). Chiral Catalysts. For Diels-Alder reactions with conventional electron imbalance it is complex formation between dienophile and chiral catalyst that differentiates dienophile faces. Where structural studies of complexes have been undertaken it is clear that no single structural feature of the catalyst or indeed of the reactants can deliver the desired reactivity patterns.Nevertheless transition state models for some catalysed reactions are being developed and it is to be hoped that these will have some predictive power. Enantiomeric excesses of 95% have been achieved in the additions of 2-methoxybutadiene to the C,,-symmetric maleimide (1 l) catalysed by the di-azaluminolidine (12) (Scheme 3). An o-substituent in the dienophile" is essential for high e.e. (95% when R = CH and 62% when R = H). With maleic anhydride completely racemic material is produced. In the catalyst the aryl groups are 3,5-dimethylphenyls and the rn-substituents seem essential for high e.e. The structure of a complex formed between the dienophile (with R = But) and the diazaluminolidine has been deduced from 'H NMR experiments and NOE measurements and a transition state assembly which leads to the observed stereochemistry has been proposed.Scheme 3 Chiral catalysts prepared from scandium or ytterbium trifluoromethanesulfonate (R)-(+)-l,l'-bi-2-naphthol and tertiary amines produce high yields and good diastereo- and enantioselectivities in reactions between cyclopentadiene and acyl- 1,3- oxazolidin-2-ones.'6 The structure of this catalyst has been examined also" and it is believed that the axial chiralty of the binol is transferred via hydrogen bonds to the amines which in turn shield one face of the coordinated dienophile. Stable chiral (acy1oxy)boranes can be prepared by mixing a hindered monoester of tartaric acid with arylboronic acids.' These catalyse hetero-Diels-Alder reactions of l4 E.Arce C. Carreno M. B. Cid and J. L. G. Ruano J. Org. Chem. 1994 59 3421. E.J. Corey S. Sarsher and D.-H. Lee J. Am. Chem. SOC. 1994 116 12089. l6 S. Kobayahsi M. Araki and I. Hachiya J. Org. Chem. 1994 59 3758. l7 S. Kobayashi H. Ishitani M. Araki and I. Hachiya Tetrahedron Lett. 1994 35 6325. Is Q. Gao K. Ishihara T. Maruyama M. Mouri and H. Yamato Tetrahedron 1994 50 979. Reaction Mechanisms -Part (i) Pericyclic Reactions 55 Danishefsky dienes with carbonyl compounds to provide dihydropyrones in high optical purities. A chiral amino-alcohol-derived boron complex similarly catalyses additions of glyoxalate in high enantioselectivity and cis (endo) diastereoselectivity. Chiral bidentate Lewis acids based on 1,8-naphthalenediylbis(dichloroborane)and chiral amino acids or diols show some promise as catalysts of enantioselective Diels-Alder reactions.,' Chiral catalysts for cycloadditions with inverse electron demand have also been described.Silica gel effectively catalyses addition of the electron deficient 3-methoxycarbonyl-2-pyrone to butyl or benzyl vinyl ether to yield bicyclic adducts and titanium(rv) based Lewis acid catalysts incorporating either a tartrate based ligand,2 or more effectively a binol ligand, yield single product diastereoisomers in modest to excellent e.e. The combination of Yb(OTf) and binol described by Kobayashi et a!. also gives good e.e.s for addition of 3-methyloxycarbonyl-2-pyronewith both vinyl ethers and vinyl sulfides.23 The use of these chiral catalysts is not restricted to [4 + 21 cycloadditions.A C,-symmetric bis-sulfonamide-trialkyl aluminium complex for example catalyses asymmetric [2 + 21 addition of ketene with aldehydes affording optically active 4-substituted oxetan-2-ones with up to 74% e.e.,24 and the carbonyl ene reaction of methyl glyoxalate with trisubstituted alkenes can be catalysed by chiral titanium complexes derived from 6,6'-dibromobinol and diisopropoxytitanium dihalide~.~~ Syn-Diastereoisomers are produced with an e.e. of between 60 and 90%. Asymmetric cycloadditions of nitrones to ketene acetals is catalysed by chiral oxazaborolidines derived from N-tosyl-L-a-aminoacids. Best selectivities (e.e. <74%) were achieved with tyrosine-(OBzl) derived catalysts and a working model of the catalyst has been developed.26 Various Dienes and Dienophi1es.-Dienes.In contrast to the behaviour of isodicyc- lopentadiene (13) the dienes (14) (1 5) and (16) all show a preference for reaction from the top face additions to reactive dienophiles. The pattern of selectivities cannot be rationalized in terms of steric effects alone and is taken as a demonstration that the behaviour of isodicyclopentadiene arises from orbital tilting at the diene termini which can overcome steric effects such as torsional strain along the developing bonds.27 Dienes (17) and (18) incorporating the 7-oxabicycloC2.2. llheptenones and their ethylene ketals react with electron-deficient alkynes and sulfur dioxide with high selectivity for the less hindered exo face of the bicycle.28 With N-phenylmaleimide two adducts were formed differing in stereochemistry at the dienophile but both of which were the result of exo attack on the diene.With unsymmetrical alkenes regioselectivi- ties were low. Cyclodimerizations of the dienes were also highly stereo~elective.~~ l9 Y. Motoyama and K. Mikami J. Chem. Soc. Chem. Commun. 1994 1563. 2o M. Reilly and T. Oh Tetrahedron Lett. 1994 35,7209. 21 G.H. Posner J.-C. Carry J. K. Lee D. S. Bull and H. Dai Tetrahedron Lett. 1994 35 1321. 22 G.H. Posner F. Eydoux J. K. Lee and D. S. Bull Tetrahedron Lett. 1994 35,7541. 23 I. Marko and G.R. Evans Tetrahedron Lett. 1994 35 2771. 24 Y. Tamai H. Yoshiwara M. Someya J. Fukumoto and S.Miyano J. Chem. Soc. Chem. Commun. 1994 228 1. 25 M. Terada Y. Motayama and K. Mikami Tetrahedron Lett. 1994 35 6693. 26 J.-P.G. Sneerden A. W. A. Scholte op Reimer and H. W. Scheeren Tetrahedron Lett. 1994 35 4419. 27 E. R. Hickey and L. A. Paquette Tetrahedron Lett. 1994 35 2309 and 2313. 28 L. Meerpool M.-M. Vrahmi B. Deguin and P. Vogel Heh. Chim. Acta 1994 77 869. 29 L. MeerpooI M.-M. Vrahmi J. Ancerewicz and P. Vogel Tetrahedron Lett. 1994 35,11 1. C.I. F. Watt (13) Despite its electron-deficient nature l-(buta-1,3-dien-2-yl)pyridiniumbromide enters into Diels-Alder reaction3' with a range of electron-deficient alkenes and norborene. It is more reactive than isoprene and with unsymmetrical alkenes reactions show the usual para regioselectivity.The ortho-quinomethide (19) generated in situ in refluxing toluene [Scheme 4(a)] reacts in Diels-Alder fashion with both C70 and C,,.31 Three of four possible C, monoadducts and one C, monoadduct were isolated. The adducts were characterized by a combination of NMR spectroscopic methods and shown to have been formed by selective reaction at the poles of the fullerene where there is high local curvature. Additions at the equator were not observed. Benzocyclobutenol or its methyl ether react with C,,in refluxing toluene presumably via their quinine methide forms to give 1 ,g-dihydrofullerene add~cts.~~Furan-based o-quinodimethanes (20)dimerize readily affording high yields of [4 + 41 cycloadduct [Scheme 4(b)].33 Rates are only slightly retarded by alkyl substitution at the 5-position (kH/kButx 4),and it is suggested that this is consistent with a two-step cyclization via an initially formed biradical.Synthesis of an enediyne unit which occurs in many DNA-cleaving antibiotics has been achieved34 by Diels-Alder reaction of 3,4-bis(methylene)- 1,Shexadiyne (21) and reactive dienophiles including maleic anhydride (Scheme 5). With benzoquinone a bis-adduct was formed. Styrene and styrenes carrying alkoxy or thioalkyl a substitu-ents will react with benzoquinone to give modest yields of 1,4-~henanthrenediones.~' 3,5-di-t-butyl-o-quinone behaves as a heterodiene in additions with a range of acyclic dienes yielding vinyl- 1,4-benzodioxines. 36 According to calculations at the MP4SDQ/6-3 lG*//MP2/6-3 lG* level cycloaddi- tion of ethyne and 1H- 2H- and 3H-phosphole all proceed through the concerted [4 + 2) mechanism with quite synchronous bond changes.37 Calculated activation 30 S.-J.Lee C.-J. Chien C.-J. Peng and T.S. Chou J. Org. Chem. 1994 59 4367. 31 A. Herrmann F. Diederich C. Thilgen H.-U. ter Meer and W. H. Muller,Helu. Chim.Acta 1994,77,1689. 32 X. Zhang and C. S. Foote J. Org. Chem. 1994 59 5235. 33 W.S. Trahnovsky C.-H. Chou and T. Cassidy J. Org. Chem. 1994 59 2613. 34 H. Hopf and M. Theurig Angew. Chem. Int. Ed. Engl. 1994 33 1099. 35 N. D. Willmore D.A. Hoic and T.J. Katz J. Org. Chem. 1994 59 1889. 36 V. Nair and S. Kumar J. Chem. SOC.,Chem. Commun. 1994 1341. 37 S.M. Bachrach J. Org. Chem. 1994 59 5027. Reaction Mechanisms -Part (i) Pericyclic Reactions (20) R = H Me But Scheme 4 (21) Bu or SiMe3 Scheme 5 energies of 30.62 17.93 and 28.14 kcal mol- respectively support an earlier sugges- tion that other phospholes undergo rearrangement to the 2H isomer before participa- ting in cycloaddition.Dieneophiles. Cyclopropenone reacts with 1,3-diphenylisobenzofuran (Scheme 6) X-ray crystallography has confirmed that the sole observable Diels-Alder adduct (22) has the exo config~ration.~~ This was expected to equilibrate with its endo isomer (23) whose absence has been rationalized in terms of relative stabilization of the exo adduct by an attractive etherxarbonyl interaction. In the crystal structure r(O. . * C) = 2.54 A and the carbonyl is distinctly pyramidal with the carbonyl carbon displaced by 0.035 A from the plane of its ligands towards the ethereal oxygen.Signals assigned to a transiently formed exo adduct have been observed in NMR monitoring of a reacting mixture of cyclopropenone and 1,3-diphenylisobenzofuran at -30 "C. These rapidly disappear (tl,2 z 1 hour) at -20 "C so that cyclopropenone shows a preference for exo orientation with this particular diene that appears to be kinetic as well as thermodynamic. Diels-Alder reactions of cyclopropenone a~etals~~ have been used in a new tropolone annulation. 2-Azaallenium salts (24) enter into [4 + 21 cycloadditions at low temperature with dienes such as anthracene 1,3-~yclohexadiene or 2-trimethylsilyoxyhexadiene,to yield the cyclic salts (25) with stereoisomeric exocyclic iminium residues [Scheme 38 J.H.Cordes S. De Gala J. Berson J. Am. Chem. SOC.,1994 116 11 161. 39 D.L. Boger and Y. Zhu J. Org. Chem. 1994 59 3453. C.I. F. Watt Ph Ph Scheme 6 7(a)],40 Ene additions compete with cyclization in reactions with dienes in which s-cis conformations are less readily available. With alkenes such as cyclohexene ene addition occurs. Allenes carrying trichlorosulfonyl (26) or sulfinyl substituents are reactive dienophiles and yield Diels-Alder adducts41 with a range of dienes including furan at 70 "C [Scheme 7(b)]. Endo adducts predominate and with y-methylallenyl trichloromethyl sulfone E/Z mixtures are formed. E-vinylboronic esters carrying electron-withdrawing groups at the j-position react with buta- 1,3-diene and 2,3- dimethylbuta- 1,3-diene to give Diels-Alder ad duct^.^^ Ar Ar OTMS X 0 + 'I SO& cI Thiobenzophenone and thiofluorenone are reactive dien~philes~~ with the fluorenone being ca.lo4 times more reactive. Both reactions appear to be concerted 40 A. Geisler and E.-U. Wurthwein Tetrahedron Lett. 1994 35 77. 41 S. Braverman and Z. Lior Tetrahedron Lett. 1994 35 6727. 42 C. Rasset and M. Vaultier Tetrahedron 1994 SO,3397. 43 J. Schatz and J. Sauer Tetrahedron Lett. 1994 35 4767. Reaction Mechanisms -Part (i) Pericyclic Reactions showing only a small solvent dependency and having large and negative entropies of activation. For series of para-substituted benzophenones cycloadditions with 2,3- dimethylbuta-l,3-diene gave a reasonable Hammett correlation with p = 2.4.The reactions of sulfur dioxide behaving as a heterodienophile with buta-l,3-diene and isoprene have been studied at an ab initio leve144*45 Solvent effects are predicted to be important in controlling the exolendo and regiosele~tivities.~~ Intramolecular Diels-Alder Reactions. Intramolecular Diels-Alder reaction of the phenylsulfonyl bearing dienes (27) requires high temperatures (>180"C) and pro- longed reaction times,47 but acceptable yields of hydroindenes and hydronaphthalense (28) are produced. [Scheme 8(a)]. For both chain lengths the bicycles are predomi- nantly trans. The major product of reaction of (29) and (30) by Diels-Alder addition extrusion of sulfur dioxide and intermolecular Diels-Alder addition48 is the all-cis tricyclic ketone (31) [Scheme 8(b)].PhS02q U (27) n =30r4 X =H,SiMe3,PhS (29) (30) Scheme 8 2-Benzopyranones (32) undergo intramolecular cycloadditions with preferred endo addition.49 Rates and cis-stereoselectivities of intramolecular Diels-Alder reactions of trienonenes (33) are enhanced by lithium perchlorate :diethyl ether and camphorsul- fonic acid.50 2 [2 +21 Cycloadditions and Reversions Exposure of crystals of the syn-tricyclo[4.2.0.02~5]octane derivative (34) to X-rays converts it in the solid state into the cis,cis-cycloocta- 1,5-diene derivative (35) without disruption of the crystal structure [Scheme 9(a)].51 44 D. Suarez J. Gonzalez T. L. Sordo and J.A.Sordo J. Org. Chem. 1994 59 8058. 45 D. Suarez T. L. Sordo and J.A. Soedo J. Am. Chem. SOC. 1994 116 763. 46 D. Suarez X. Assfeld J. Gonzalez M. F. Ruiz-Lopez. T. L. Sordo and J. A. Sordo J. Chem. SOC.,Chem. Commun. 1994 1683. 41 S.S.P. Chou C.S. Lee M.-C. Cheng and H.-P. Tai J. Org. Chem. 1994 59 2010. 48 J. D. Winkler S. Kim K. R. Condroski A. Asensio and K.N. Houk J. Org. Chem. 1994 59 6879. 49 E. J. Bush D. W. Jones and F. M. Nongrum J. Chem. SOC. Chem. Commun. 1994 2145. 50 P.A. Grieco S.T. Handy and J. P. Beck Tetrahedron Lett. 1994 35 2663; P.A. Grieco J. P. Beck S. Handy N. Saito and J. F. Daeuble Tetrahedron Lett. 1994 35 6783. 51 A. Mori N. Kato H. Takeshita Y. Kurahashi and M. Ito J. Chem. SOC.,Chem. Comrnun. 1994 869.C.I. F. Watt 0 \ \o (33)n = 1 or2 R=HorMe K R2 0 K 150 "C ox R2FE I R' R' (36)R = H Me But (37) (38) Scheme 9 Ab initio calculations (/6-3 lG*//HF/6-3 1G*)show that the cycloaddition of ketenes and carbonyl compounds52 is both concerted and synchronous. With mono-substituted ketenes exo transition states are preferred. With a Lewis acid catalyst bonding changes are no longer synchronous and the catalyst is also exo with respect to the ring. A level of theory with configuration interaction is required to reproduce the observed regio- and stereoselectivities in calculation of the cycloaddition between methoxyketene and a conjugated imine.53 On heating the readily available methylenecyclopropanes (36) rearrange to the ketene acetals (37) which yield [2 + 21 cycloadducts with range of electron deficient alkenes [Scheme 9(b)].54 The adducts are hydrolytically unstable with cleavage of the four-membered ring occurring readily at the masked b-ketoester bond.With maleate both cis-and trans-cyclobutane dicarboxylates (38) are formed indicating a stepwise process for their formation. The ketene acetals also react with C,* providing another useful route to substituted fullerenes. *' B. Lecea A. Arrieta G. Roa J. M. Ugalde and F. P. Cossio J. Am. Chem. SOC. 1994 116 9613. 53 I. Arrastia A. Arrieta J. M. Ugalde F. P. Cossio and B. Lecea Tetrahedron Lett. 1994 35 7825. 54 S. Yamago A. Takeuchi and E. Nakamura J. Am. Chem. Soc. 1994 116 1123. Reaction Mechanisms -Part (i) Pericyclic Reactions 1,l-Dicyano-2,2-bistrifluoromethylethylene55 is an alkene comparable to TCNE in its electron deficiency and like TCNE reacts with conjugated dienes to yield both [4 + 21 and [2 + 21 adducts.Dichloroneopentylsilene reacts with 1,4-~ycloheptadiene to yield a mixture of [2 + 21 and [4 + 21 addition products.56 With cyclohepta-1,3,5- triene mixtures are again formed but of [2 + 21 and [6 + 21 adducts neither of which can arise by thermally allowed pathways. The [2 + 21 adducts are not stable but rearrange on heating to exo- and endo-silabicyclo[4.2. llnonadienes (39) presumably uia the indicated dipolar intermediate which links all the products (Scheme 10). Photolysis of hexa-t-butyltrisilene produces both di-t-butylsilene and tetra-t-butyl- disilene.The former reacts with alkenes and dienes by insertion yielding siliranes. The latter yields [4 + 21 adducts with dienes but a [2 + 21 adduct has been found in reaction with o-methyl~tyrene.~~ Cl + Scheme 10 3 Cheleotropic Reactions The term 'coarctate' has been coined to describe reactions in which two or more bonds at a single centre are made or broken at the same time.58 Examples include insertions or extrusions of carbenes. These are notoriously difficult to analyse in terms of the familiar topological probes for transition state aromaticity but these have now been extensively reviewed and an appropriate model described. Phenylacetoxycarbene generated by diazirine phot~lysis,~~ shows reactivity similar to phenylmethoxycarbene and phenylchlorocarbene in additions to electrophilic alkenes.However (phenoxymethy1)acetoxycarbene yields the hydride shift product cis-l-acetoxy-2-phenoxyethene, while (phenoxymethy1)methoxycarbene yields none of the corresponding product. Singlet t-butylchlorocarbene generated at low tempera- ture by photolysis of t-butylchlorodiazirine in an N,matrix decays by carbene insertion into a C-H bond at 11K.60 Temperature dependence of rates of this 55 R. Bruckner and R. Huisgen Tetrahedron Lett. 1994 35 3285. 56 W. Ziche C. Seidenschwarz N. Auner E. Herdtwick,and N. Sewald Angew. Chem. Int. Ed. Engl. 1994,33 71. 57 M. Weidenbruch E. Kroke H. Marsmann S. Pohl and W. Saak J. Chem. SOC.,Chem. Commun. 1994 1233. 58 R. Herger Angew.Chem. Int. Ed. Engl. 1994 33 245. 59 R.A. Moss S. Xue and W. Liu J. Am. Chem. SOC. 1994 116 1582. 60 P.S. Zuev and R.S. Sheridan J. Am. Chem. SOC.,1994 116,4123. C.I.F. Watt (43) (41) X = CH2,0,CH=CH or CH2CH2 Me0 (46) (47) Scheme 11 insertion yield curved Arrhenius plots and deuterium isotope effects are large with apparent complete inhibition of reaction at the lowest temperatures. Quantum mechanical tunnelling is suggested to account for the observations. Sulfur dioxide adds slowly (8 days at 25 "C) in homocheleotropic fashion61 to 3,3-dimethylpenta-l,4-diene to yield the bicyclic sulfone (40)[Scheme 11(a)]. Rates are only weakly sensitive to the presence of acid catalysts and unaffected by added radical scavengers.With the bicyclic dienes (41) homocheleotropic addition yielding sulfones (42) competes with cheleotropic addition yielding the sulfolenes (43) which can add a second equivalent of sulfur dioxide [Scheme ll(b)]. In all cases the sulfolenes are the thermodynamic products but the nature of the bridge X has a marked effect on rates and equilibria. Thus when X = CH, homocheleotropic addition is favoured and the sulfolane is formed at -20 "C.At higher temperatures the sulfolene is formed. With X = (CH=CH) the modes compete kinetically. When X = 0 or CH,CH, only sulfolene formation is observed. J.-M. Roulet B. Deguin and P. Vogel J. Am. Chem. SOC.,1994 116 3639. Reaction Mechanisms -Part (i) Pericyclic Reactions Thermolysis of dimethyl- 1,3,4-0xadiazolines affords an entry to carbenes and thermolysis of the butynyloxymethoxyoxadiazoline (44) affords a tricycle array (45) whose formation can be rationalized by a cascade of carbene and other reactions [(Scheme 11 (c)] .62 Thermolysis of spiro-fused p-lactam oxadiazolines (46) appears to yield P-lactam-4-ylidines (47) which can cyclopropanate alkenes [Scheme 11 (d)] .63 Experiments with maleate or fumarate show that the additions are stereospecifically cis with respect to the alkene component.4 1,3-Dipolar Cycloadditions 0xyallyl.-Debromination of cis-1,Sdibromo-1,5-dimethylcyclopentanone can be carried out at low temperature in aprotic solvents using [Cr(CO),NO]- as its (PPh3)N+ salt (Scheme 12).64 Even at -120 "C the expected 2,5-dimethylcyclo- pentyloxyallyl was not observable by NMR spectroscopy.Dimers are formed with the major product being the cis-dioxane compound (48) which has only one of four connectivity patterns possible from union of two oxyallyl units. This compound is thermally labile yielding the isomers (49) and (50). 0 \I Diazoa1kanes.-The reaction of diazomethane with allene has been reexamined and found to be regioselective rather than regiospecific as earlier work had indicated. The regioisomers 4-methylene- 1 -pyrazoline and 3-methylene- 1 -pyrazoline are formed in 93 :7 ratio at 25 0C.65 The new experimental data can be reproduced qualitatively at least by high level ab initio theory but not by semiempirical methods nor indeed by small basis set ab initio methods.Cycloreversion and nitrogen extrusion are competing thermal reactions in the decomposition of the 1-pyrazoline (51) (Scheme 13). Rates and product ratios are only weakly solvent dependent but the cycloreversion is more sensitive than the nitrogen 62 K. Kassam and J. Warkentin J. Org. Chem. 1994 59 5071. 63 M. Zoghbi S.E. Horne J. Warkentin J. Org. Chem. 1994 59 4090. 64 A. P. Master M. Parvez T.S. Sorensen and F. Sun J. Am. Chem. SOC. 1994 116 2804. 65 A. Rastello M. Bagatti and R. Gandolfi Tetrahedron 1994 50 5561. C.Z.F. Watt 0 Scheme 13 extrusion. Non-polar solvents give higher reactivity and larger amounts of cyclorever- sion. Nitrones and Nitrile Oxides.-The homoadamantane incorporated nitrone (52) shows unusual reactivity in adding to nitrileP to give A4-1,2,4-0xadiazoline derivatives albeit under high temperature and with long reaction times [Scheme 14(a)].With acrylonitrile a 55:45 mixture of C=C and C-N cycloadducts is formed. This reactivity pattern is probably evident with this particular compound only because competing modes of nitrone decomposition are blocked by the adamantyl framework. N-alkylhydroxylamines can be formed from ‘normal’ nitrones under cycloaddition conditions and some unexpected losses in stereoselectivity in cycloadditions have now been shown to arise from interconversion of dipolarophiles such as dimethyl maleate and dimethyl fumarate induced by small amounts of such corn pound^.^^ In toluene solvent the additions of C-methyl-N-phenylnitrone (53)with substituted styrenes yields adducts (54) in which cis/trans ratios are all ca.65 :35 except when there is an o-hydroxyl group in the dipolarophile [Scheme 14(b)].68 Then only the cis isomer is produced showing the importance of the hydrogen bonding in the TS. (53) (54) Scheme 14 66 Y. Yu M. Ohno and S. Eguchi J. Chem. SOC.,Chem. Commun. 1994 331. 67 H.G. Aurich G. Frenzen and M.G. Rohr Tetrahedron 1994 50 7417. U. Chiacchio F. Casuscelli A. Corsaro A. Rescfina G. Romeo and N. Uccella Tetrahedron 1994 50 667 1. Reaction Mechanisms -Part (i) Pericyclic Reactions 1,3-Dipolar cycloadditions of pyrazol-4-one-N,N-dioxides (55) show a kinetic preference for formation of exo adducts with wide range of alkenes (Scheme 15).69 With polar asymmetrically substituted alkenes the observed orientations of addition are in agreement with the predictions of perturbation theory with bonding of the oxygen of the nitrone and C of the alkene occurring where the coefficient of the interacting frontier is largest.Acrylonitrile oxide has been generated in situ by dehydration of 1-nitropropene and adds as a 1,3-dipole to norbornene to yield both exo and endo 2-isoxazoline adducts in 3 :1 ratio7' in only moderate overall yield. (55) (a) R' = R2= C02Me (b) R' = Me; R2= C02Me Scheme 15 Others.-The pyrroles (56) and (57) are formed in a 54 :47 ratio from 1,3-dipolar addition of the isotopically labelled munchones (58)with methyl pr~piolate,~' showing that there is little inherent electronic imbalance between their carbon termini (Scheme 16).Regioselectivities in a reaction with a series of arylthio alkyl and phenyl substituted munchones are also reported and selectivities are only greater than 80% when one or other of the reacting carbons carries hydrogen. The contributions of frontier interactions to the selectivities seems to be minimal. (58)(a) R' = CH3 R2= CH3 (b) R' = 13CH3 R2 = CH3 (57) Scheme 16 5 [3,3] Sigmatropic Shifts These remain by far the commonest of molecular rearrangements. Both Cope and Claisen processes are used in many guises in important synthetic reactions. Detailed descriptions of transition state geometries and bonding arrangements therein continue to challenge experimentalists and theoreticians. 69 M.Eto Y. Yoshitake K. Harano and T. Hisano J. Chem. SOC.,Perkin Trans. 2 1994 1337. 'O P.W. Ambler R. M. Paton and J. M. Tout J. Chem. SOC.,Chem. Commun. 1994 2661. " B. P. Coppola M.C. Noe D.J. Schwarz R. L. Abdon and B. M. Trost Tetrahedron 1994 50 93. C.I. F. Watt Cope Rearrangements.-CASSCF-MP2 calculations on the Cope rearrangement using large basis sets predict a single aromatic transition A semiempirical of the Cope rearrangement of singly annelated semibulvalenes (59) with n = 2-5 (Scheme 17) yields qualitatively similar results with MNDO AM1 and PM3 methods. Trends if not absolute values in available experimental rate and equilibrium measurements were reproduced. When n = 2 the ground state of the molecule is predicted to be a symmetrical homoaromatic species (60).Scheme 17 Von Doering et a/. have determined activation parameters (AH* = 29.9 kcal mol- ' and AS = -15.0e.u.) for Cope rearrangement of [6-'3C]-(E)-1,4-diphenylhexadiene (Scheme 18).74 In this compound (61) phenyls are at active positions in any allyl radical formed by C-3-C-4 homolysis (62) yet the parameters and a negative activation volume (AV* = -13.4cm3 mol-') point to ring formation in the transi- tion state. These should be compared with AH* = 21.2 kcal mol- ' and AS* = -20.8 e.u. for rearrangement of 2,5-diphenylhexa-1,5-diene(63) where the phenyl groups would be at the nodal position of an allyl radical. The relative reactivities are more consistent with reaction with initial C-1-C-6 formation via a cyclohexa-l,4-diyl radical (64).New measurements of rates and equilibria for the cis-trans isomerism of 1,l'-bi-3-phenylcyclohex-2-enylidenes provide an estimate of the stabilization in the cinnamyl radical and thermochemical analysis of these reactions and other phenyl substituted hexadienes is presented. Relative to the appropriate non-interacting diphenylcyclohexa- 1,4-diyl radicals (65) estimated ener- gies of concert are 15.9 and Okcalmol-' respectively for the isomeric diphenyl- hexadienes. Other molecules with structural features which might promote a stepwise Cope in rearrangement by a cyclohexane- 1,4-diyl intermediate include octa- 1,2,6-triene~,~ which one of the radical centres would be allylic and an estimate using Benson's group increments suggest that the biradical could lie as much as 17.6 kcal mol- ' below a concerted transition state.Pyrolysis of (E)-5-methylocta-l,2,6-triene(66) yields (E)-4-methyl-3-methylene-1,5-heptadiene (67)(Scheme 19) with activation parameters AH+ = 30.9kcalmol-' and AS* = -12.7eu. With optically active material the rearrangement occurs with 68 % retention of enantiomeric purity corresponding to a 72 D.A. Hrovat K. Morokuma and W.T. Borden J. Am. Chem. SOC. 1994 116 1072. 73 T.V. Williams and H.A. Kurz J. Chem. SOC.,Perkin Trans. 2 1994 147. 74 W. von E. Doering L. Birladeanu K. Sarma J. H. Teles F.-G.Klarner and J.-S. Gehrke J. Am. Chem. SOC. 1994 115 4289. 75 T. A. Wessel and J. A. Berson J. Am. Chem. SOC. 1994 116 493. Reaction Mechanisms -Part (i) Pericyclic Reactions R or (a) R = H and R’ = Ph (b) R = Ph and R’= H R R (64) (62) Scheme 18 15.5% contribution that is antarafacial with respect to the ally1 subunit.The simplest explanation of this result is that the anticipated diversion from a concerted to a two-step pathway has occurred with a conformationally mobile biradical intermedi- ate. Scheme 19 Anionic oxy-Cope rearrangement of (R)-(E)-1-phenylhexa- 1,5-dien-3-01 (68) yields the rearrangement product (69) with 30% e.e.76 [Scheme 20(a)]. This result and similar ones with other simple substrates suggest a preference for the anionic oxygen to adopt the pseudo-axial orientation on the chair-like transition state. The preference however is clearly not strong and it is easily overcome by additional steric constraints in more highly substituted arrays.l6 E. Lee Y. R. Lee B. Moon 0.Kwon M.S. Shim and J.S. Yun J. Org. Chern. 1994 59 1444. C.I.F. Watt Cope rearrangements which usually require T > 200 "C in acyclic 1,5-diynes occur readily in cycloocta-l,5-diynes.77 Thus the bicyclic alcohol (70) yields the bis-allene (71)with tl,* z 6.4hrs at 50 "C [Scheme 20(b)]. Absence of the exocyclic double bond renders the rearrangement faster yet. 0- OH Ph Scheme 20 Claisen Rearrangements.-Transition states have been located and kinetic isotope effects calculated for the prototype Claisen rearrangement7' of ally1 vinyl ether. There are significant discrepancies between experimental and RHF/6-3 lG* and MP2/6-3 lG* calculated values.Complete active space CASSCF calculation using the 6-31* basis set gives a single transition structure with more bond breaking and the calculated heavy atom effects are in better agreement with experiment. Bond orders of 0.31 (C-0) and 0.18 (C-C) are found using the modified Pauling bond order relationship compared with estimates from experiment of 0.33 and 0.17 respectively. Transition states energetics and kinetic isotope effects in both Cope and Claisen rearrangements have also been calculated using density functional theoretical methods.79 Non-local spin density approximations are necessary for good agreement between experimental and calculated activation energies. These DFT methods then provide descriptions of transition state geometries and associated kinetic isotope effects for comparison with experiment which are on a par with correlated MO theory.Two independent high level MO studies of the conversion of chorismic acid into prephenic acid have been reported."." These predict a loose transition state with appreciably elongated breaking C-0 bonds and a long developing C-C bond in contrast to the results of 77 K. Iiada and M. Hirama J. Am. Chem. SOC. 1994 116 10310. '' H.Y. Yo0 and K.N. Houk J. Am. Chem. SOC. 1994 116 12047. 79 0.Weist K. A. Black and K.N. Houk J. Am. Chem. SOC. 1994 116 10336. 0. Weist and K.N. Houk J. Org. Chem. 1994 59 7582. M. M. Davidson and I. Hillier J. Chem. SOC. Perkin Trans. 2 1994 1415. Reaction Mechanisms -Part (i) Pericyclic Reactions semiempirical methods.Comparisons with allyl ether suggest that rate enhancements in the chorismate rearrangement follow from both ground state destabilization and transition state stabilization involving electron delocalization into the ring. (72) X = OTMS or COOMe (74) Scheme 21 I4C kinetic isotope effects have been measuredg2 for the C-1 C-2 C-4 and C-6 positions in the rearrangements of 2-(trimethylsily1oxy)- and 2-(methoxycarbonyl)-3- oxahexa-1,5-dienes (72) [Scheme 21(a)]. The data together with earlier C-4 and C-6 dueterium isotope effects were fitted to transition structure models using the Bebovib method. The only models yielding reasonable fits agree that bond breaking at C-4 is greater than 70% while bond making is less than 20%.If a recent suggestion that conversion of an alkene radical into an allyl radical loosens C-N bending motions is incorporated then the imbalance between bond breaking is reduced but not eliminated. In the Claisen rearrangements of the 5-substituted adamantylidene compounds (73) and (74) the new bonds are formed mainly at the alkene face syn to the 5-substituent (1.33 < syn/anti < 1.56) [Scheme 21(b)].g3 Replacement of hydrogen by phenyl or oxyanion at the alkylidene terminus in the latter does not alter the preference. These and related oxy-cope and allyl vinyl sulfoxide rearrangements show a remarkably 82 L. Kupczyk-Subotkowska W. H. Saunders H. J. Shine and W. Subotkowska J.Am. Chem. SOC.,1994,116 7089. 83 A. Mukherjee Q.Wu and W. J. le Noble J. Org. Chem. 1994 59 3270. C.I.F. Watt constant face selectivity. It is suggested that newly forming bonds are always electron deficient and stabilized through hyperconjugation with antiperiplanar vicinal bonds. The isomeric aryl4,6-di-O-acetyl-dideoxy-~-erythro-hex-2-ene pyranosides (75) and (76)rearrange at 170 "C to the expected Claisen products (Scheme 22).84 Surprisingly the a-anomer in which the migrating group is expected to be quasi-axial is ca. 100 times less reactive than its anomer. AM calculations and 'H NMR coupling constants however showed that both anomers adopted conformations with axial aryloxy groups. The optimized transition state for the rearrangement of the a-anomer has a chair form for the reacting atoms and for the unsaturated sugar moiety.For the p-anomer the sigmatropic unit again adopts a chair but the sugar moiety adopts the ring B form. Both can benefit from anomeric stabilization. & rrn = 35hours * ' O R (75) &-o-.-AcO D rlR = 0.5 hours R \ AcO8-0 OH AcO (76) AcO Scheme 22 The Claisen rearrangement of aryl allenylmethyl ethers (77) to 2-(o-hy-droxyary1)buta- 1,3-dienes cannot be induced thermally nor are they catalysed by protic acids [Scheme 23(a)]. However with tris(4-bromopheny1)aminiumin acetonit- rile [3,3] shifts occur at room temperature in the first example of a cation radical induced Claisen reaction.85 The thio-Claisen reaction is poorly characterized compared to its oxygen analogue but has been put to good synthetic use as the basis of a stereocontrolled construction of vicinal tertiary centres.86 Semiempirical calculations (MNDO) on the 3-aza-Claisen rearrangement favour reaction via a spin paired chair transition state and predict enhanced rates for a variant with the nitrogen carrying an anionic s~bstituent.~~ The y,h-unsaturated nitrile (78) equilibrates at room temperature with the N-allylketene (79) [Scheme 23(b)].88 Neither rates nor equilibrium compositions (ca.50 50) are strongly dependent of solvent and experiments with isotopically labelled material 84 K. K. Balasubramanian N. G. Ramesh A. Pramink and J. Chandrasekar J. Chem. SOC.,Perkin Trans. 2 1994 1399. 85 S. Dhanalekshimi C.S. Venkatachalam and K. K. Balasubramanian,J. Chem.SOC.,Chem.Commun. 1994 511. 86 P.N. Devine and A. I. Meyers J. Am. Chem. SOC.,1994 116 2633. J.C. Gilbert and K.R. Cousins Tetrahedron 1994 50 10671. R. Bruckner and R. Huisgen Tetrahedron Lett. 1994 35 3281. Reaction Mechanisms -Part (i) Pericyclic Reactions +* R’ --2R* 3R (77) NC !$:F3 (78) (79) Scheme 23 excludes dissociative pathways. The reaction is best described as a 3-aza Claisen rearrangement. 6 [1,3] Shifts The stereochemical requirements for concerted and allowed [1,3] shifts are usually sufficiently demanding that non-concerted pathways compete and often are followed exclusively. Nevertheless because pathways are competitive rearrangements of this type remain a valuable testing ground for the limits of pericyclic processes.Vinylcyclopropane Rearrangements.-The thermal isomerization of vinylcyclo-pro- pane to cy~lopentene~~ has been investigated using specifically deuteriated precursors syn-(E)- and syn-(Z)-2,3,2’-d3-vinylcyclopentene(80). At 300 “C k = 3.4 x s-’ the resultant three stereoisomeric 3,4,5-d3-cyclopentenes [Scheme 24(a)] have been identified and quantified by NMR to allow extraction of relative rates for the four stereochemically distinct combinations of supracacial and antarafacial at the ally1 array and of retention and inversion at the migrating carbon in the 1,3-migration. These are kSi = 4070 k, = 23% kai = 13% and k, = 2470 so that there is no significant kinetic preference for the formally allowed si and ar pathways and diradical intermediates seem obligatory.(1 R,2S)-trans-l-[(E)-l -propenyl]-2-phenylcyclop-ropane is reversibly equilibrated with its enantiomer and with enantiomers of cis-1-[ (E)-1-propenyl]-2-phenylcyclopropane.Isomers of 3-methyl-4-phenylcyclopen-tene form more slowly and kinetic and stereochemical measurements again show that all four distinct reaction pathways occur.9o Relative contributions are remarkably close to those found in the absence of the phenyl substituent and it seems that stereochemistry in these rearrangements has little to do with orbital symmetry or mass or the radical stabilizing abilities of substituents. The diphenylethenylidenecyclopropanes (81) rearrange thermally to 89 J. E. Baldwin K.A. Villarica D. I. Freedberg and F.A. L. Anet J. Am. Chem. SOC. 1994 116 10845 J. E. Baldwin and S. Bonacorsi J. Org. Chern. 1994 59 7401. c.I. F. Watt diphenylethenylidenylcyclopentenes(82) between lo2 and lo3 faster than vinylcyclo- propanes [Scheme 24(b)].9' With a stereochemically defined substrate for R3 = R4= Me and R' = R2 = H a mixture of cis and trans-3,5-dimethylcyclopen-tenes was formed. Reaction via a biradical intermediate rather than by 1,3-sigmatropic shift seems likely. Flash vacuum thermolysis of N-acyl cyclopropyl imines carrying phenyl or phenacyl substituents at C-1 or C-2 of the cyclopropane has yielded 2-p~rrolines.~~ Without these substituents only polymeric products were obtained. Vinylcyclobutane Rearrangements.-Rearrangements of 2-vinylcyclobutanol (83) to 3-cyclohexanolg3 are base catalysed (Scheme 25) proceeding via an anionically accelerated 1,3-shift and first order rate constants for the potassium salt in THF vary inversely with salt concentration suggesting that ion pair dissociation precedes rearrangement.The Z isomer epimerizes to the E isomer 36 times faster than the E isomer yields the ring-opened product. Secondary deuterium isotope effects are kHz/kD2= 1.34 at the vinyl terminal and k,/kD = 1.12 at the carbinol position and are consistent with an allyl anion/aldehyde intermediate (84). RHF ab initio computa-tional studies on sodium 2-vinylcyclobutoxide using a 3-21G basis set found four distinct energy minima corresponding to allyl anion/aldehyde species with oxygen coordinated metal ion two with trans,and two with cis geometries at the allyl residue.Bicyclic Arrays.-Thermolysis of 7,7-dimethylbicyc10[3.2.O]hept-2-ene~~at 275 "C yields none of the 1,3-carbon shifted product. Instead over 84% of reaction is fragmentation to cyclopentadiene and isobutylene. Of the remaining l6% the bulk could arise by a 1,5-hydrogen shift from the endo methyl to C-3.Reaction is one order of magnitude slower than in 2,2-dimethylvinylcyclobutane. 91 K. Mixuno H. Sugita T. Kamada and Y. Otsuji Chem. Letters 1994 449. " P.L. Wu and W. S. Wang J. Org. Chem. 1994,59 622. 93 N.J. Harris and J. J. Gajewski J. Am. Chem. SOC. 1994 116 6121. 94 T. E. Glass P. A. Leber and P. L. Sandall Tetrahedron Lett. 1994 35 2675. Reaction Mechanisms -Part (i) PericycIic Reactions (83)R = R2= H R = D; R2 = H R=H;R2=D Scheme 25 7 Electrocyclic Reactions A new route to 1,2-dihydrocyclobutylarenes95uses the double cyclization of ene-diallenes (85) [Scheme 26(a)].When the allenes substituents are phenyl the initially formed bismethylenecyclohexadiene rearranges thermally to the cyclo- butylarene. When the allenes carry terminal t-butyl groups the reaction does not occur. Benzylidenebenzocyclobutenones (86) suffer photoinduced E-2 isomerism [Scheme 26(b)]. A flash photolysis study has established the intermediacy of the ketene-allene (87) which has a lifetime of 26 ns in acetonitrile and can be trapped by water or methanol.96 Initial products of photoisomerization of highly alkylated butadienes (88) which cannot adopt a planar conformation are bicyclo[ 1.1 .O]butanes [Scheme 26(~)].~’ The photoproducts are not stable but rearrange to the cyclobutenes presumably by homolysis of the central bond and hydrogen atom migration.The completely substituted diene with R’ = R2 = methyl also yields the bicyclo[l.l.O]butane as the major product but surprisingly also 25% of the cyclobutene electrocyclic ring closure product. Solvent effect in disrotatory ring openings of cyclopropanone and 2,2-dimethylcy- clopropanone to the isomeric oxyallyls have been calculated by Monte-Carlo simulation^.^^ TS and ground state geometries were obtained by (4/4) CASSCF calculation with a 6-3 1G*basis set and charges determined for use in fluid simulations. The results are in good agreement with available experimental data and support the intermediacy of the oxyallyls in cyclopropanone stereoisomerizations.Transition states are close to the oxyallyls and have diradical rather than dipolar character. Reaction of chlorocarbene and arylchlorocarbenes with 2-vinylpyridine yields 3-substituted indolizine~,’~ by a mechanism believed to involve cyclization of an 9s F. Toda K. Tanaka I. Sano and T. Isozaki Angew. Chem. Int. Ed. Engl. 1994 33 1751. 96 R. Boch J. C. Tradley T. Durst and J.C. Scaiano Tetrahedron Lett. 1994 35 19. 97 H. Hopf H. Lipka and M. Tratteberg Angew. Chem. Int. Ed. Engl. 1994 33 204. 98 D. Lim D. A. Hrovat W. T. Borden and W. L. Jorgensen J. Am. Chem. SOC. 1994 116 3494. R. Bonneau Y. N. Romashin M. T. H.Liu and S. E. MacPherson J. Chem. SOC.,Chem. Commun. 1994 509. C.I.F. Watt 4Ar 'L (88)(a) R' = R~= H (b)R1= H R2= Me (c) R2 = R' = Bu' Scheme 26 initially formed pyridinium ylid and elimination of HC1 from the resulting dihydroin- dolizine. In presence of acid the equilibrating mixture of (89) and (90) cleanly forms a dimer (91) whose structure is confirmed by X-ray crystallography (Scheme 27).'0° 8 Miscellaneous Processes 1,9acyl Migrations.-In methanol solution 5-benzyl-l,2,3,4,5-pentakis(methoxycar-bony1)cyclopentadiene rearranges thermally by 1,5-migration of methoxycarbonyl groups."' Under the same conditions 5-p-methoxybenzyl-l,2,3,4,5-pentakis(methoxycarbony1)cyclopentadiene fragments presumably via an ion pair mechanism yielding 1,2,3,4,5-pentakis(methoxycarbonyl)cyclopentadiene7and p-methoxybenzyl methyl ether.Rearrangements of Vinyl Aziridines.-Optically active vinyl aziridines (92) are quantitatively transformed into allylic imines (93) by heating in refluxing benzene (Scheme 28).' O2 Reactions are stereospecific and product stereochemistries are loo J. B. Press K. L.Sorgi J. J. McNally and G. C. Leo J. Org. Chem. 1994 59 5088. E.A. Jefferson and J. Warkentin J. Org. Chem. 1994 59 463. lo* J. Ahman P. Somfal and D. Tanner J. Chem. SOC. Chem. Commun. 1994 2785. Reaction Mechanisms -Part (i) Pericyclic Reactions Scheme 27 / C02Bu' I Scheme 28 consistent with the indicated transition structure. With LDA an aza-[2,3] Wittig rearrangement occurs yielding only the cis-2,6-substituted tetrahydropyridine (94) and again the stereochemistry is consistent with the depicted transition structure.' O3 Stereoisomeric aziridines in which the vinyl group and alkyl substituent were cis on the cyclopropane gave no allylic imine under thermolysis and the aza-Wittig rearrange- ment yielded almost equal amounts of cis and trans-2,6-disubstituted tetrahydro- pyridine.In this case presumably there is steric interference to the nitrogen inversion which is required to place the participating homodienyl components in the cis arrangement necessary for concerted processes. Ene and Retro-ene Reactions.-Solvent effects in the ene additions of diethyl azodicarboxylate (DEAD) and N-phenyltriazolinedione (NPTAD) to 2-methyl-2-butene have been examined.lo4 In neither case is the dependence large but with DEAD rates seem to be most sensitive to solvent acidity while the reactions of NPTAD are related to solvent nucleophilicity.Excellent correlations are obtained in lo3 J. Ahman and P. Somfai J. Am. Chem. SOC. 1994 116 9781. '04 G. Desimoni G. Faiti P. P. Righetti A. Sfulcini and D. Tsygdnov Tetrahedron 1994 50 1821. C.I.F. Watt X (95) X = H,H 0,CH2 Y = CH2 C=C(CH3)2,C(CH2)2 (96) Y = CH2 or C(CH2)2 Scheme 29 both cases between reactivities of these are enophiles and dienophiles. The thermal decomposition of allylsulfinic acid is formally a retro-ene reaction yielding propene and sulfur dioxide. The activation volume has been found to be negative AV* = -5.5 cm3 mol- ' despite a large positive reaction volume AV* E 20cm3mol-' and is consistent with a fully concerted process as is a substantial deuterium kinetic isotope effect (kH/kD = 2.5 at 97 "C).lo5 Solvent effects are small.Hydrogen Transfer in syn-Sesquinorbornenes-A series of syn-sesquinorbornene disulfones (95) have been prepared and structures determined by X-ray crystallogra- phy.lo6 These rearrange thermally by transfer of the endo-a-sulfonyl hydrogens to the nearby norbornenyl double bond and relative rates at 160 "C have been determined and span a more than lo4 range. Compounds with the central cyclopropane (X = CH,) are most reactive and those in dihydro series (X = H,H) the least. Rates correlate poorly with geometric parameters such as intra-gap distances but it is clear that steric compression is important with non-bonded interactions particularly when X = CH, being transmitted via the 'wings' of the molecules to the hydrogen transfer site.For two of the series (96) with X = CH, singly and doubly deuteriated iso- topolymers have been prepared and primary kinetic isotope effects determined. When Y = C(CH,), kH,/kHD = 2.9 and kHH/k,D = 8.5 at 100"C. The ratios obey the rule of geometric mean and seem consistent with a concerted cZs+ c2s+ 7cZs shift of hydrogens from one site to the other. A computational study of this reaction was able to reproduce the experimental ratios without including tunnelling corrections. When Y = CH, the reaction is ca. lo3times slower and kHH/kHD = 2.1 and kHH/kDD= 11.2.lo5 S. D. Hiscock N.S. Isaacs M. D. King and D. J. Young J. Chem. SOC.,Chem. Commun. 1994 1381. lo' G.A. O'Dougherty R.D. Rogers and L.A. Paquette J. Am. Chem. SOC. 1994 116 10883. Reaction Mechanisms -Part (i) Pericyclic Reactions The rule of geometric mean is clearly not obeyed and furthermore Arrhenius plots give AHHIAH = 0.4 and A,,/A, = 0.004 suggesting the occurrence of quantum mechan- ical tunnelling possibly related to the higher reaction barrier in these compounds. Non-concerted pathways however cannot be excluded. Enediyne Cyc1izations.-Rates have been determined for Bergman cyclization of some simple aromatic enediyneslo7 and are not appreciably different from those of the corresponding acyclic non-aromatic arrays.Rates are however very sensitive to acetylenic terminal substitution; a single alkyl substituent raised the activation energy by 3 kcal mol- and a second by another 6 kcal mol- High level ab initio calculations on the prototype cyclization of hex-3-ene-1 ,5-diynelo8 to the singlet p-benzyne biradical predict a barrier of 25.0 kcal mol- for the cyclization and an enthalpy of reaction of 4.9 kcal mol- ' to be compared with experimental values of 32 and 14 kcal mol -respectively. The discrepancy between calculated and experimental reaction enthalpies is substantial but the experimental measurements assume the additivity of group energy increments and it is suggested that this assumption is not well founded. The calculations do not support Nicolaou's suggestion that the cyclization is initiated in enediyne-based anticancer agents by a compression of the C-3-C-3' distance from 3.6 to 3.2& lo' J.W.Grissom T.L. Calkins H.A. McMillen and Y. Jiang J. Org. Chem. 1994 59 5833. lo* R. Lindh and B.J. Persson J. Am. Chem. SOC. 1994 116 4963.

ISSN:0069-3030    

DOI:10.1039/OC9949100051

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (ii) Polar Reactions By J.M. PERCY School of Chemistry University of Birmingham Edgbaston Birmingham 815 2T UK 1 Introduction The mechanisms or reactions mediated by catalytic antibodies' and mechanistic aspects of p-lactam and penicillin hydrolysis2 were reviewed while Menger provided an organic perspective on enzyme rea~tivity.~ Deslongchamps summarized his seminal studies of stereoelectronic effects on the reactions of acetals and ketal~,~ while kinetic techniques for the diagnosis of concerted reaction mechanisms were reviewed. Laser flash photoloysis and pulse radiolysis have made an invaluable contribution to the subject allowing the generation of reactive intermediates such as carbocations and carbanions; the scope of these methods has been summarized.6 Theory and experiment combined in a valuable interplay in the determination of transition state structure,' while the key principles of the curve crossing model were elucidated in a primer article.' The unique chemical properties of perfluorinated resinsulfonic acids were sum- marized,' and A,E mechanism for electrophilic addition was appraised.'' The SET description of the mechanism of aromatic nitration has gained considerable popularity but detailed studies support the polar mechanism proposed originally by Ingold.' ' Mandolini reviewed the mechanisms of metal-catalysed reactions of crown ether substrates," and aspects of the chemistry of bases were reviewed including the solution structures of lithium dialkylamides' and the properties of proton sponges.14 2 Solvolysis and Carbocations It seems appropriate to start this section by reporting recent results from the Olah group.Under superacid conditions (DF/SbF,/SO,CIF/ -78"C) the 2-propyl cation ' J. D. Stewart I. J. Liotta and S. J. Benkovic Acc. Chem. Res. 1993 26 370. F.M. Menger Acc. Chem. Res. 1993 26 206. S. Wolfe Can. J. Chem. 1994 72 1014. P. Deslongchamps Y. L. Dory and S. Li Can. J. Chem. 1994 72 2021. A. Williams Chem. SOC. Rev. 1994 23 93. P.K. Das Chem. Rev. 1993 93 119. ' I. H. Williams Chem. Soc. Rev. 1993 22 277. S. Shaik J. Mol. Liq. 1994 61 49. G. A. Olah in 'Acidity and Basicity of Solids' NATO AS1 Ser. Ser. C No. 444 1994 p. 305. lo W.A. Smit R. Caple and I.P. Smoliakova Chem. Rev. 1994 94 2359. l1 L. Eberson M. P. Hartshorn and F. Radner Acta Chem. Scand. 1994 48 937. l2 R. Cacciapaglia and L. Mandolini Chem. Soc. Rev. 1993 22 221. l3 D.B. Collum Acc. Chem. Res. 1993 26 206. l4 A. L. Llamas-Saiz C. Foces-Foces and J. Elguero J. Mol. Struct. 1994 328 297. 79 J. M. Percy underwent isotopic (H/D) exchange via a gitonic intermediate in which adjacent carbon atoms bore substantial positive charge. Possible structures for the intermediate were investigated by ab initio methods.' Gitonic intermediates may also be important in the superacid chemistry of organic nitriles and possible structures for diazonium dications were investigated.16 In superacid media orthoester (1) ionized to a dioxolanium cation (2) (Scheme 1).l7 On warming to -70 "C,attack of the sidechain methoxy group occurred at C-2 establishing the equilibrium which favoured (3) by a factor of 4 1. An acidity function study of the cyclization of substituted aryl propiophenones (4)to indenes (Scheme 2) supported a mechanism involving a dication intermediate.I8 Monoprotonation of the ketone carbonyl group afforded a monocation (5) which displayed negligible reactivity towards benzene and would therefore be incompetent in the cyclization. The formation of dication (6) triggered rate-limiting attack by the aromatic nucleophile. The result may have general implications for Friedel-Crafts and related reactions. A number of groups reported the results of solvolysis studies. Della and co-workers argued that the solvolysis of (7a) in 80% aqueous ethanol occurred via C1.1.11 bicyclopentyl cation (8).19 A large (1.30-1.37 X = D) y-deuterium isotope effect was measured consistent with a large transannular interaction between the C-D bond and the cationic centre.A Hammett correlation with a revealed the largest reaction constant (p = -2.30) measured to date using these substituent constants. The result contrasts with the fate of iodide (7b) in the presence of azide anion. Bicyclo[1.1.0]- butane derivative (9) was formed via a transition state believed to resemble (8).20 Bentley and co-workers have compiled a comprehensive listing of relative nucleo- fugacities in solvolytic S,1 reactions.21 The scale spans 17 orders of magnitude from acetate to triflate.Huang and Bennet reported homoallylic participation in the solvolysis of bisadamantylidene derivative ( The substrate underwent solvolysis 4 x lo5times more slowly than 2-adamantyl tosylate under the same conditions with l5 G.A. Olah N. Hartz G. Rasul G.K.S. Prakash M. Burkhart and K. L:ammertsma J. Am. Chem. SOC. 1994 116 3187. l6 G. Rasul G. K. S. Prakash and G. A. Olah J. Am. Chem. SOC. 1994 116 8985. l7 R.F. Childs G.J. Kang T.A. Wark and C.S. Frampton Can. J. Chem. 1994 72 2084. l8 S. Saito Y. Sato T. Ohwada and K. Shudo J. Am. Chem. SOC. 1994 116 2312. l9 E. W. Della C.A. Grob and D.K. Taylor J. Am. Chem. SOC.,1994 116 6159. 2o K.B. Wiberg and S. McMurdie J. Org. Chem. 1993 58 5603. 21 T. W. Bentley M. Christl R. Kemmer G. Llewellyn and J.E. Oakley J. Chem.SOC.,Perkin Trans. 2 1994 253 1. 22 X. Huang and A. J. Bennet J. Chem. SOC.,Perkin Trans 2 1994 1279. Reaction Mechanisms -Part (ii) Polar Reactions D Scheme 2 xA Y (7a) Y = Br (8) (9) (7b) Y = I a low Grunwald-Winstein m value (0.66).Steric crowding in (10) further ruled out the possibility of nucleophilic participation by the solvent. Titrimetric methods are used typically to follow the course of solvolysis reactions. Creary and Jiang reported a convenient NMR titration method suitable for following the departure of leaving groups more acidic than 4-nitrobenzoic acid.23 The method used 2,6-lutidine as a basic probe and avoided the use of deuteriated solvents. The powerful LFP technique was used to generate cations (1 la)-( 1 l~).~~ The most stable cation (1 la) was less reactive towards nucleophilic attack by methanol than the 4-methoxybenzyl cation consistent with the view that increased electron demand triggers enhanced 51-participation from the 4-methoxy group.When the para-substituent was a less effective donor such as a methyl group the more usual reactivity order was observed and (1 1 b) reacted more rapidly than the 4-methylbenzyl cation. Richard and co-workers discussed the nature of nucleophilic solvation of substituted ” X. Creary and Z. Jiang J. Org. Chem. 1994 59 5106. 24 N. P. Schepp and J. Wirz J. Am. Chem. SOC. 1994 116 11 749. J. M. Percy @='@ 4 X/0""H3 (10) X = OTS (lla)X= OCHa (11b) X = CH3 (llc) X = H cumyl cations (12) by alcohol solvents.25 As the cation became more stable the specific interaction depicted in (13) was detected by a good linear correlation between gas-phase and solution-phase Gibbs Free Energies of cation formation with non-unit slope.Solvent effects upon selectivity of nucleophilic attack upon carbocations were measured by the Bentley group.26 An earlier chapter in this series reported preliminary findings concerning the hydrolysis of tetraaryl orthocarbonates. Full publications concerning these highly oxygenated species that the low reactivity of orthocarbonates (14) is due to a significant imbalance between the degree of charge build up on the inductively destabilized cationic centre and charge delocalization via the oxygen atom lone pairs.The high degree of imbalance arises because of high steric constraint in (14) and the extensive reorganization required to progress to a planar cation. Attempts to analyse changes in transition state positions using conventional (two dimensional) Jencks-More O'Ferrall diagrams were unsuccessful. However three dimensional reaction cubes were used to some effect. A surprising result was reported by Lambert and co-workers.28 The diethoxyphos- phoryl group appeared to participate in the solvolysis of (15) and a hyperconjugative mechanism was proposed to provide stabilization of the incipient fi-cation. Stabiliz- ation of carbenium ions by the carbon-silicon bond (p-effect) is of course well known and an attempt to observe a p-silyl cation directly in trifluoroethanol was reported.29 The UV spectrum of a transient generated in the LFP experiment was consistent with the formation of a cation (16) displaying considerable methylenefluorenylidene character.High level ab initio calculations suggested that the presence of a silicon atom would perturb dramatically the balance between benzyl and tropylium cation ta~tomers.~' In the parent hydrocarbon system tropylium cation (17a) is 29 kJ mol- 25 J. P. Richard V. Jagannadhan T.L. Amyes M. Mishima and Y. Tsuno J. Am. Chem. SOC.,1994,116,6706. 26 T.W. Bentley and Z. H. Ryu J. Chem. SOC.,Perkin Trans. 2 1994 1279. '' P. Kandanarachchi and M. L. Sinnott J. Am. Chem. SOC. 1994 116 5601. '' J. B. Lambert R. W. Emblidge and Y. Zhao J. Org. Chem. 1994 59 5397.29 C. S. Lew R. A. McClelland L. J. Johnston and N. P. Schepp J. Chem. SOC.,Perkin Trans. 2 1994 395. 'O A. Nicolaides and L. Radom J. Am. Chem. SOC.,1994 116 9769. Reaction Mechanisms -Part (ii) Polar Reactions 83 A (17a) X = C (I&) x= c (17b)X=Si (18b) X= Si more stable than (18a) whereas the silabenzyl cation (18b) was predicted to be 29 kJ mol- more stable than (17b). 3 Other Nucleophilic Substitutions Kirby and co-workers described the hydrolysis of a glucose tetraphosphate derivative (19) a reaction that features nucleophilic ~atalysis.~' At high pH (19) occupies inverted chair conformation (20) and displacement of the 4-nitrophenolate leaving group occurs with nucleophilic participation by the C-2 phosphate dianion.Participa- tion was not detected in the hydrolysis of the a-anomer. King characterized an interesting ring-opening reaction of lactones to o-alkoxyes- Scheme 3 shows an example which occurred with almost complete inversion of configuration oia attack by methanol at the asymmetric carbon of intermediate (21 ). 0 OxMe HC(OMe)3 e0 + OMe H2S04 MeOH -Meo2CToMe L b. R 98% 8.8. S > 95% 8.8. Scheme 3 An interesting theoretical paper discussed the possibility of the direct inline displacement mechanism with inversion [via transition state (22)] for substitution at 31 P. Cammileri R.F.D. Jones A. J. Kirby and R.Stromberg J. Chem. SOC.,Perkin Trans. 2 1994 2085. 32 S.A. King. J. Org. Chem. 1994 59 2253. J. M. Percy vinylic carbon.33 The authors concluded that the barrier for the concerted mechanism may not be prohibitively high in the gas phase or in solution and cited experimental studies from the synthetic literature to support their hypothesis.Vinyl triflates and vinyl iodonium salts (both species containing excellent leaving groups) undergo substitution reactions with almost or complete inversion of alkene configuration consistent with the concerted displacement mechanism. CI Ph Ph NaN, - / DMF -10 "C (23) Scheme 4 A range of formal S,2' displacement reactions were reported from cyclobutenone (23).34Scheme 4 shows an example. When the acetoxy adduct (24) was dissolved in methanolic sodium methoxide butenolide (25) was obtained following an interesting series of reactions.Ring opening reactions of optically pure @)-styrene oxide were examined in a careful stereochemical In water at pH 11 ring opening occurred with 93% inversion of configuration uia water attack at the benzylic (a) carbon. At higher pH hydroxide ion attacked both CI and fi-carbon atoms at comparable rates leading to complete racemization. The 7% of retained product in the reaction performed at pH 11 arose via the latter route. In acid an enatiomerically enriched mixture of diols was obtained (67% inversion 33% retention) and a range of mechanistic explanations for its formation were discussed. The trifluoroethanolysis of silyl ether (26) was subject to general acid general base and bifunctional catalysis; (27)depicts a possible transition state.36 Brarnsted constants for general acid (aA= 0.65) and general base (fiB = 0.72) fell within experimental error 33 M.N.Glukhovtsev A. Pross and L. Radom J. Am. Chem. Soc. 1994 116 5961. 34 J. L. Dillon and Q. Gao J. Org. Chem. 1994 59 6868. 35 B. Lin and D.L. Whalen J. Org. Chem. 1994 59 1638. 36 P.E. Dietze C. Foerster and Y. Xu J. Org. Chem. 1994 59 2523. Reaction Mechanisms -Part (ii) Polar Reactions of each other consistent with a constant for bifunctional catalysis of zero (PAB). Exploded transition-state representations of phosphate monoester dianion hydroly- sis were confirmed by a detailed kinetic isotope effect The hydrolysis of 4-nitrophenyl phosphate in water catalysed by phosphatases and the solvolysis in t-butanol were examined.Catalysis of phosphate diester hydrolysis by La3+ was reported by two groups. Breslow and Zhang described the hydrolysis of bis(4-nitropheny1)phosphate in the presence of hydrogen peroxide and a cyclodextrin host,38 while the catalytic hydrolysis of (28) involved two La3 + cations.39 The metal cations acted cooperatively the first as a source of coordinated hydroxide ion and the second as a Lewis acid resulting in a reported rate acceleration of 1013. Methyl transfer reactions between (29) and a large family of amine nucleophiles were studied.40 Unusually a close linear relationship (equation 1) was discovered between the Swain-Scott n constant and the Ritchie N parameter. N+ = 2.ln -4.3 (1) Also light-atom electrophiles (amines water hydroxide azide and cyanide anion) were considerably more reactive than thiosulfate thiocyanate iodide and bromide ions all usually reactive nucleophiles towards methyl derivatives.A broken pH-rate profile encountered in a study of the hydrolysis of sulfinamide (30) suggested the existence of a sulfurane intermediate. An l8Olabelling study confirmed the presence of the hypervalent intermediate and indicated that it underwent pseud~rotation.~' 4 Elimination Reactions Mechanisms of solvolytic elimination reactions were reviewed by Thibblin.42 An ab initio study of the E2 elimination at the MP2/6-31+ G* level calculated transition state structures for the reactions of chloroethane with 11 bases.43 The calculations 37 A.C. Hengge W.A. Edeus and H. Elsing J.Am. Chem. SOC. 1994 116 5045. R. Breslow and B. Zhang J. Am. Chem. SOC. 1994 116 7893. j9 A. Tsubouchi and T.C. Bruice J. Am. Chem. Soc. 1994 116 11 614. 40 J. W. Bunting J. M. Mason and C.K. M. Heo J. Chem. SOC.,Perkin Trans. 2 1994 2085. 41 T. Okuyama J. P. Lee and K. Ohnishi J. Am. Chem. SOC. 1994 116 11 614. 42 A. Thibblin Chem. SOC. Rev. 1993 22 427. 43 S. Glad and F. Jensen J. Am. Chem. SOC.,1994 116 9302. J. M. Percy reproduced movements on the three dimensional energy surface predicted by Jencks-More O’Ferrall diagrams from a central E2 transition state devoid of E1,B character. However the study revealed that there was no simple correlation between transition state geometry symmetry and the size of the primary kinetic isotope effect.Treatment of (31) with sodium ethoxide in ethanol/DMSO solvent led to the exclusive formation of phenyl vinyl sulfide.44 Though substitution products could be formed by direct attack or episulfonium ion pathways none was observed. Failure to observe isotopic exchange of the methylene protons attached to the sulfur bearing carbon was taken as evidence against an E1,B pathway and to be in favour of a E2 process. Eliminations from cis-and trans-1,2-dichlorocycloalkanesto form the same 1 -chlorocycloalkene were performed competitively using a sodium amide/sodium t-butoxide base mixture in THF.45 In the trans isomer dehydrochlorination occurred to an unusual extent via a syn elimination. Changing to a less complex base (such as a t-butoxide salt alone) lowered the rate of the syn elimination.Two studies of antibody-catalysed elimination were reported. Catalytic antibody 43D4-3D12 accelerated the dehydrofluorination of (32) by a factor of lo5. An anti elimination occurred via an E2 or E1,B mechanism and apparently without acid catalysis of fluoride ion depart~re.~~ The Scripps group raised a catalytic antibody using (33) a mimic for an eclipsed E2 transition state in the ha~ten.~~ The antibody catalysed a syn elimination (Scheme 5). 0 P h v Ph Scheme 5 A Grob-type fragmentation (D,D mechanism) was reported for the conversion of N-haloamino acids to aldehydes.48 Hammett correlations were obtained varying the alkyl substituent at the a-carbon (p* = -3.9) and on the nitrogen atom (p* = -2.1) 44 H.-Q.Xie N. Truomg E. Buncel and J.G. Purdon Can. J. Chem. 1994,72 448. 45 A. P. Croft and R. A. Bartsch J. Org. Chem. 1994 59 1930. 46 K. Shohat T. Uno and P.G. Schultz J. Am. Chem. SOC. 1994 116 2261. 47 B. F. Cravatt J. A. Ashley K. D. Janda D. L. Boger and R. A. Lerner J. Am. Chem. SOC.,1994,116,6013. 48 X. L. Armesto M. Canle M. Losada and J.A. Santaballa J. Org. Chern. 1994 59 4659. Reaction Mechanisms -Part (ii) Polar Reactions indicating that C-C bond separation is extensive and leads nitrogen-halogen bond cleavage (Scheme 6). Scheme 6 Nucleophilic displacements from N-bromoacetophenone oxime occurred by para- llel direct and elimination-addition pathways.49 The inversion of oxime configuration from the syn to the less thermodynamically stable anti diastereoisomer led to the detection of a nitrosostyrene intermediate in which rotamer (34) is more reactive.Scheme 7 outlines the overall conversion. MeoH anti 0 Scheme 7 In non-polar solvents the reaction with weakly basic nucleophiles afforded syn products uia an S,2 displacement of bromide. In the Schmidt reaction of gem-diazide (35) in acidic acetonitrile and elimination across the carbon-nitrogen double bond of the kinetically competent iminodiazonium cation (36) leads to the formation of aryl nitrile product^.^' In water gem-diazide hydrolysis led to the isolation of 4-methoxybenzaldehyde as the major reaction product. 49 K. Wirnalasema and D. C. Haines J. Org. Chem. 1994 59 6472. 50 J. P. Richard T.L. Amyes Y.-G.Lee and V. Jagannadhan J. Am. Chem. SOC. 1994 116 10833. J. M. Percy 5 Addition Reactions Various aspects of the Michael addition reaction have attracted the attention of investigators. Hoz has used the reaction as a case study of the relationship between transition state structure location and the nature of reactant and product states.” Addition reactions to N-methyl vinylpyridinium cations (37) were studied using a wide range of amine nu~leophiles.~~ The addition rates correlated well with the Ritchie N parameter establishing the utility of the scale for probing reactions at tetravalent sp2 hybridized electrophiles. A study of the reactions of synthetically important Gilman and heterocuprate reagents to cyclic enones concluded that the addition reactions occurred via a polar mechanism leading directly to the formation of metal en~lates.’~ Mechanisms involving SET processes have achieved some popularity for the description of these important reactions but in the recent study the formation of kinetically important 7t complexes could not be excluded.The cytotoxic compound CC-1065 contains a rich array of functional groups. A key feature is the y-cyclopropyl enone a Michael acceptor identified as a site for attack by biological nucleophiles. Scheme 8 shows parallel mechanisms for the specific-acid- catalysed reaction of analogue (38) with hydroxide ethoxide and chloride anions.54 I 1 Nu-Nu-Nu )-jjR H OH H OH Scheme 8 Direct attack yielding (39) competed with opening of the distal bond of the cyclopropane ring to afford a carbenium ion (stabilized presumably by homoallylic or phenonium participation).Nucleophilic trapping led to the formation of [indolo] piperidine products. 51 S. Hoz Acc. Chem. Res. 1993 26 69. 52 C. K. M. Heo and J. W. Bunting J. Chem. SOC. Perkin Trans. 2 1994 2279. 53 A. S. Vellekoop and R.A. J. Smith J. Am. Chem. SOC. 1994 116 2902. 54 M.A. Warpekoski and D. E. Harper J. Am. Chem. SOC.,1994 116 7573. Reaction Mechanisms -Part (ii) Polar Reactions Electrophilic additions to enol ethers formed the subject of a number of important papers. Fecapentaene is one example of a remarkable class of polyenic natural products. The key functionality is a highly conjugate enol ether which hydrolyses by an extremely unusual mechanism.Kresge and co-workers examined the hydrolysis of both diastereoisomers of 1-methoxybutadiene to explore the effect of conjugation upon the normal vinyl ether hydrolysis mechanism. Both isomers hydrolysed more slowly than methyl vinyl ether despite the higher degree of stabilization of the intermediate oxacarbenium ions and there was a marked dependence of reactivity upon configuration. The 2 diastereoisomer was 160 times less reactive than methyl vinyl ether while the E diastereoisomer was only eight times less reactive; both reacted exclusively through protonation at the 6-positi0n.’~ A study of intramolecular catalysis of enol ether hydrolysis yielded the highest EM (6 x 104M) for a reaction involving a proton-transfer step to date.The development of a strong intramolecular hydrogen bond between the /?-carbon atom of enol ether (41) and the ammonium proton presumably relieves some peri strain as the system progresses towards the transition state.’ OMe Alkenyl glycosides are important intermediates in oligosaccharide synthesis and a recent study reveals that protonation occurs via protonation at carbon.57 The glycosidicC-0 bond of (42)therefore remains intact during the hydrolysis reaction. At pH 3 (42) was 4.5 times more reactive than the /?-anomer. One of the techniques developed for the generation of high concentrations of enol intermediates found a synthetic application. Vinyl ketene acetal (43) was used to generate a concentrated (0.2 M) solution of acetaldehyde enol which formed a 1 1 copolymer with maleic anhydride upon treatment with tributyltin hydride and a radical initiat~r.~~ Furan when converted into pentaamine osmium(1r) complex (44) behaved like a typical enol ether.For example iminium salt (45)was formed when (44) was dissolved in a solution of acetonitrile containing methyl triflate.’9 High asymmetric induction in enol ether protonation was achieved by a catalytic antibody.60 Enol ether (46)formed S ketone (47) exclusively; however (47)and the R enantiomer bound to the antibody with similar affinities consistent with the antibody exercizing maximal chiral discrimination between the transition states. 55 Y. Chiang R. Eliason G.H.-X. Guo and A.J. Kresge Can. J. Chem. 1994 72 1632. 56 A. J.Kirby and F. O’Carroll J. Chem. SOC.,Perkin Trans. 2 1994 649. 57 H. K. Chenault and L. F. Chafin J. Org. Chem. 1994 59 6167. A.K. Cederstav and B. M. Novak J. Am. Chem. Soc. 1994 116,4073. 59 H. Chen L. M. Hodges R. Liu W. C. Stevens M. Sabat and W. D. Harman J. Am. Chem.SOC. 1994,116 5499. 6o G.K. Jahangiri and J. L. Reymond J. Am. Chem. SOC. 1994 116 11 264. J. M. Percy OMe A0-F5-doR (Ma) R = But (48b) R = H Protiolysis of enol ether (48a) led to the formation of enol (48b) and none of the corresponding ketone.61 In THF or ether solution ketone (49)existed exclusively as enol (50). The combined fluorine atom substituent effects acted to destabilize ketone forms rather than by stabilizing enol tautomers. The mechanism of alkene bromination remains a problem of current interest.In an elegant study Rodebaugh and Fraser-Reid examined the reactions of o-alkenyl glycosides key species in the armed-disarmed glycosylation strategy with N-bromosuccinimide (NBS).62 MeCN -40°C 90% Scheme 9 Exploiting the different hydrolytic reactivities of the o-alkenyl glycosides elec- trophilic bromination was shown to be reversible with bromonium ion transfer 61 R. A. Correa P. E. Lindner and D. M. Lemal J. Am. Chem. SOC.,1994 116 10795. 62 R. Rodebaugh and B. Fraser-Reid J. Am. Chem. SOC. 1994 116 3155. Reaction Mechanisms -Part (ii) Polar Reactions occurring between competing alkene nucleophiles. Rozen and colleagues in Tel-Aviv described the preparation and reactions of methyl hypofluorite MeOF a powerful oxygen electrophile unlike all the other 0-F reagents.63 Regioselective anti-1,2-addition occurred with most alkenes including indene (Scheme 9).Additions to alkynes included an interesting (and remarkably efficient) tetra- fluorination of 1,2-diphenylethyne described by the Olah group (Scheme NOBF, PPHF Ph-Ph CHzClp 0°C Ph? FF Ph 75% Schemm 10 Nitrosation of the alkyne initiated the sequence followed by fluoride ion attack on the vinyl cation intermediate. Alkyne protonation under mild conditions (neat trifluoroacetic acid) initiated the quantitative biscyclization depicted in Scheme 1 1 .65 OR OR CF&OZH -4 RO RO Scheme 11 6 Aromatic Addition and Substitution This section deals mainly with addition reactions.The one exception concerns the transfer of the triazinyl group between substituted pyridines.66 The Brsnsted plot for the reaction of salt (51) with substituted pyridines contained a break where the pK,s of incoming and outgoing species were equal. The result was entirely consistent with the 63 S. Rozen E. Mishami M. Kol and I. Ben-David J. Am. Chem. SOC. 1994 116 4281. 64 C. York G.K.S. Prakash and G.A. Olah J. Am. Chem. SOC.,1994 116 6493. 65 M.B. Goldfinger and T. M. Swager J. Am. Chem. Soc. 1994 116 7895. 66 A. H. M. Redrew J. A. Taylor J. M. J. Whitmore and A. Williams J. Chem. SOC.,Perkin Trans. 2 1994 2383. J. M. Percy formation of a highly stabilized Meisenheimer complex. The Brlernsted constant for the reaction (Peg= 1.O) was significantly smaller than the value obtained for concerted acyl transfer reactions (Peg= 1.6).The regioselectivities of aromatic sulfonation of halobenzenes halonaphthalenes and anthracenes has been described using sulfur trioxide as the ele~trophile.~~ Partial rate factors were calculated for the various aromatic nucleii. Rate constants for aromatic iodination were measured,68 forming a good correlation with the a-basicity of the aromatic substrate. The correlation constitutes a potential test for distinguishing between polar and SET reaction mechanisms. For example mesitylene displays higher a-basicity than durene whereas consideration of their redox potentials predicts that durene should participate more readily in SET reactions.The higher reaction rate of mesitylene with an iodine electrophile is therefore consistent with a polar reaction mechanism. A similar conclusion was reached for bromination acylation mercuri- ation and thalliation reactions while the order of reactivity observed for aromatic nitration suggested an SET pathway. Brosh and Kochi examined the mechanism of aromatic nitrosation6’ in acetonitrile and measured a significant primary isotope effect associated with a rate-determining deprotonation of the Wheland intermediate. The unusual mechanistic feature was attributed to the high Lewis basicity of nitrosoarenes. A mild nitration mixture containing dinitrogen pentaoxide was generated in dich- loromethane solution from ozone and nitrogen dioxide.70 Under these conditions the nitrations of propiophenone and related ketones (Scheme 12) yielded remarkably high proportions of ortho product (ortho:meta 1.1-3.8 :1) via a delivery mechanism involving (52).n 0 Scheme 12 67 H. Cerfontain Y. Zou B. H. Bakker and F. van de Griendt Can. J. Chem. 1994,72 1966. 68 C. Galli and S.D. Giammarino J. Chem. SOC. Perkin Trans. 2 1994 1261. 69 E. Bosch and J.K. Kochi .I.Org. Chem. 1994,59 5573. ’O H. Suzuki and T. Murashima J. Chem. SOC.,Perkin Trans. 2 1994 903. Reaction Mechanisms -Part (ii) Polar Reactions None of the sidechain positions were attacked. A study of sulfinamide hydrolysis revealed an arylthiolation reaction believed to involve an arylsulfenium ion intermedi- ate (Scheme 13).7’ Scheme 13 A sequence of intersecting cyclization and rearrangement reactions was proposed to explain the conversion of 2-nitrobenzyl alcohol into (53)in moderate (66%) yield in trifluoromethanesulfonic acid.’* Under the same conditions a converging mechanism led to the efficient (78%) formation of (54).OSO2CF3 (53)X = COZH (54)X= H ’’ H. Takeuchi H. Oya T. Yanase K. Itou T. Adachi H. Sugiura and N. Hayashi J. Chem. Soc. Perkin Trans. 2 1994 827. ’* R.P. Austin and J.H. Ridd J. Chem. SOC. Perkin Truns.2 1994 1411. J.M. Percy 7 Carbanions and Proton Transfer Taft Koppel and co-workers reported a major compilation of gas phase acidities measured using pulsed ion cyclotron resonance.73 Strong neutral Brernsted acids included aryl malononitriles fluorosulfonylmethanes sulfonimides and other oxygen acids.The compilation which identified (55) as the strongest gas-phase acid to date should form a useful reference scale. Sulfur-stabilized carbanions exhibit a wide range of uses as reagents and carbon nucleophiles in synthetic organic chemistry. A theoretical study explored the acidity trend in the series dimethylsulfide dimethylsul- foxide and dimethyl~ulfone.’~ The main effect of the added oxygen atoms was exerted through an inductive channel rather than providing a route for delocalizing the negative charge. The increasing acidity was attributed to destabilization of the carbon acid rather than stabilization of the conjugate base. In DMSO solution (56) ionized spontaneously and completely; pK,s for a number of other highly delocalized carbanions were reported in the same study.75 Fluorohydrocarbons often display relatively low pK,s; for example tris(trifluoromethy1)methane (57) was relatively acidic in DMSO (pK = 12.6) while bicyclic fluorohydrocarbons (58k(59) were all considerably less acidic.(58a)X=H (59) (58b) X= F The difference in acidities was attributed to the non-availability of hyperconjugative interactions between the carbanion and C-F r~* orbitals in the bicyclic carbon acids due to ~rthogonality.~~ Supercritical water (4OO0C 300 bar) has been used as a medium for studying isotopic exchange into di-n-b~tylamine.~~ Deuterioxide-catalysed isotopic exchange occurred most rapidly at C-1 and C-3. The C-4 methyl protons exchanged less rapidly while the C-2 methylene protons were least reactive.The relative acidities of the various chain positions appeared to alternate with the odd positions being more acidic and the even positions less so. Oxygen acids (60)-(62) have very similar pK,s in DMSO (11.2 f0.2) but very different 0-H bond dissociation energies suggesting that resonance stabilization in the -ate form is a more powerful determinant of acidity than the strength of the scissile 0-H bond.78 Fluorenyl esters (63a)-(63c) proved to be relatively strong carbon acids with pK,s of 7.40 10.51 and 11.52 in water re~pectively.~~ Though much of the acid strength lies in the carbanion stabilizing effect of the fluorenyl group and the high 73 I. A. Koppel R.W. Taft F.Anvid S.Z. Zhu L. Q. Hu K. S. Sung D. D. Desrnarteau L. M. Yagupolskii Y. L. Yagupolskii,N. V. Ignatev N. V. Kondratenko,A. Y. Volkonskii V. M. Vlasov R. Notario and P. C. Maria J. Am. Chem. SOC.,1994 116 3047. 74 P. Speers K. E. Laidig and A. Streitweiser J. Am. Chem. SOC. 1994 116 9257. 75 T. Kinoshita H. Kirnura I. Nakajirna S. Tsuji and K. Takeuchi J. Chem.SOC. Perkin Trans.2 1994 165. 76 I. A. Koppel V. Pihl J. Koppel F. Anvia and R. W. Taft J. Am. Chem. SOC. 1994 116 8654. 77 J. Yao and R.F. Evilia J. Am. Chem. SOC. 1994 116 11 229. 78 F.G. Bordwell and A.V. Satish J. Am. Chem. SOC. 1994 116 8885. 79 Y. Chiang J. Jones and A. J. Kresge J. Am. Chem. SOC. 1994 116 8358. Reaction Mechanisms -Part (ii) Polar Reactions (ma)X = S;Y = 0 (63b) X= 0;Y = S (63b) X = 0;Y = 0 fulvenoid character of the enolates the thiono C=S group in (63a) exerts a significant further effect worth three pK units.Rate constants for acid-catalysed protonation of the enolates were also reported. Two groups generated related fulvene diol (64) by LFP.80,81 All the rate and equilibrium constants for (64)were isolated and the authors concluded that the benzocyclopentadienyl (indenyl) and carbonyl groups exerted similar carbanion stabilizing effects. Dienol (65) is a strong acid (pKf = 0.99) and conjugate base (66) is a much stronger carbon acid (pKHK = 15.19) than phenylacetate anion (pKHK = 30.2) demonstrating the powerful carbanion stabilizing effect of a cyano group.82 The phenylalkynyl group also exerts a powerful pK lowering effect (zten pK units) and amine (67) is a strong nitrogen acid (pK = 10.28 & 0.01).83 The enolization of pyrazinyl ketone (68) is initiated by protonation at nitrogen; the enol(69) is stabilized by the formation of an intramolecular hydrogen bond consistent with the low pK and high equilibrium constant recorded for (68).84 The fury1 nucleus in (70) stabilizes the keto form relative to the en01.~~ Though the acidities of ketones ‘O J.-I.K.Almstead B. Urwyler and J. Win J. Am. Chem. SOC. 1994 116 954. J. Andraos A. J. Kresge and V. V. Popik J. Am. Chem. SOC. 1994 116 961. ’’ J. Andraos Y. Chiang A. J. Kresge I. G. Pojarlieff N. P. Schepp and J. Wirz J. Am. Chem.SOC.,1994,116 13. 83 J. Andraos Y. Chiang A. S. Grant H.-X. Guo and A.J. Kresge J. Am. Chem. SOC. 1994 116 741 1. 84 A. R. E. Carey R.A. More O’Ferrall M.G. Murphy and B.A. Murray J. Chem. SOC.,Perkin Trans. 2 1994 247 1. A. Fontana and R.A. More O’Ferrall J. Chem. SOC.,Perkin Trans. 2 1994 2453. J. M. Percy (71a) and analogous (and less acidic) sulfones (71b) differ by x ten pK units the rates of deprotonation are remarkably similar.86 Deprotonation of the sulfones is only two to three orders of magnitude slower than the deprotonation of the ketones. As the carbanion stabilizing effect of the sulfonyl group is primarily inductive minimal solvent reorganization is required upon deprotonation in contrast to the extensive changes required on passage from ketone to enolate. In terms of Marcus theory sulfones are around two orders of magnitude more intrinsically acidic than ketones.(71a) Y = C=O (71b) Y = SOP Exchange of the imidazole C-2 proton occurred rapidly in complex (72); slower exchange at C-4 and C-5 was also detected along with rapid exchange of the C-8 proton in purines. The chromium catalyst was the most effective species reported to date; exchange rates exceeded those obtained for proton-catalysed C-2 H exchange.' The quenching of amide enolates using anilide (73) as the chiral acid occurred in high e.e.88The pK of the acid falls two to three units below those of the amides used in the study; a difference in pK of this magnitude allows the protonation reaction (k,) to occur at a reasonable rate while maintaining a useful energy difference between the diastereoisomeric transition states while ensuring that the back or return reaction is (k1)negligible (k,>>k-,).Kinetic isotope effects were used to identify a non-concerted carbanionic mechanism for the reaction shown in Scheme 14. Treatment of vinylcyclobutanol (74) with potassium hydride forming the alkoxide under ion-pair dissociating conditions resulted in the formation of (76). Instead of the 1,3-shift from (75) the rearrangement probably involves carbanionic intermediate (77).89 86 S. Wodzinski and J. W. Bunting J. Am Chem. SOC.,1994 116 6910. 87 E. Buncel 0.Clement and I. Onyido J. Am. Chem. SOC. 1994 116 2679. E. Vedejs N. Lee and S.T. Sahata J. Am. Chem. SOC. 1994 116 2175. 89 N. J. Harris and J.J. Gajewski J. Am. Chem. SOC.,1994 116 6121.Reaction Mechanisms -Part (ii) Polar Reactions 0- (74) (75) Scheme 14 8 Carbonyl and Related Reactions Equilibrium constants were reported for the formation of dimethyl acetals from benzophenone pinacolone and methyl formate.” The latter case (an orthoester is formed of course) represents the first example of the determination of an equilibrium constant for this reaction of an acyclic ester. Hammett correlations were constructedg1 for the acid-catalysed breakdown reactions of acetophenone dimethyl acetal (p = -2.28) (the reference compound for Guthrie’s study”) and the hemiacetal (p = -2.29) using a stopped-flow pH-jump technique. Hemiacetal breakdown involved a general-acid-catalysed expulsion of methoxide from the conjugate base.MeC02- +MeC02Ph -(MeC0)20 + PhO-Scheme 15 The equilibrium shown in Scheme 15 was studied from both directions by the Canterbury group.92 Brernsted constants were reported for both reactions in water and chlorobenzene and the transfer reactions were faster in the organic solvent. Non-polar organic solvents such as chlorobenzene or dichloromethane may be the media of choice for the acetylation of more basic phenolates instead of the more polar DMF. Sanders and co-workers described catalytic acyl transfer (Scheme 16) with turnover inside the cavity of a porphyrin 90 J. P. Guthrie and J. Guo Can. J. Chem. 1994 72 2071. 91 R. A. McClelland K. M. Engel1,T. S. Larsen and P. E. Sorensen J.Chem.SOC.,Perkin Trans. 2,1994,2199. 92 S.A. Ba-Saif A.B. Maude and A. Williams J. Chem. SOC. Perkin Trans. 2 1994 2395. 93 L.G. Mackay R. S. Wylie and J.K. M. Sanders J. Am. Chem. SOC. 1994 116 3141. J. M. Percy Scheme 16 Though only a small effective molarity (2M) was calculated for the reaction the non-covalent pre-organization of electrophile and nucleophile is a notable feature. The question of the origin of the Thorpe-Ingold effect and high effective molarities in enzyme-catalysed reactions remain subjects for discussion. Bruice and Lighthouse94 calculated the conformer populations of gem dialkylated a,o-dicarboxylic acid derivatives which cyclized to anhydrides. The paper concluded that the presence of gem dialkyl substituents favoured productive conformations or resulted in a propinquity effect of the type proposed by Menger.Thiol proteases catalyse the hydrolysis of amide bonds and (thiomethy1)imidazole (78) contains a sulfur nucleophile and an acid/base system to assist with tetrahedral intermediate formation and breakd~wn.~’ Catalysis of the hydrolysis of unactivated formyl amides was observed between pH 6.5 and 9. The cyclization of amide (79) to perimidine (80) occurred spontaneously in aqueous DMSO presumably with some relief of peri strain (Scheme 17).96 An interesting proton switch mechanism involving two molecules of water was identified as the rate determining step. 0 (79) Scheme 17 94 F. C. Lighthouse and T.C. Bruice J. Am. Chem. SOC.,1994 116 10 789. 95 J. W. Keillor A.A. Neverov and R. S. Brown J. Am. Chem. SOC.1994 116 4669. 96 A.S. Baynham and F. Hibbert J. Chem. SOC.,Perkin Trans. 2 1994 1435. Reaction Mechanisms -Part (ii) Polar Reactions Less well-known carbonyl derivatives include selenocarboxylic acids.97 In the solid state or in non-polar solution the C=O group was identified while the THF solution at low temperature contained (81) stabilized by hydrogen bonding to the O-H group. Raman spectroscopy was used to study the hydrolysis of cyanate anion. Two parallel reactions led to the formation of urea and carbamate anion which failed to interconvert under the reaction condition^.'^ 9 Other Reactions A number of papers have discussed mechanistic aspects of the chemistry of important oxidants oxidized species or oxidation reactions. The Baeyer-Villiger oxidation of cyclic ketones occurred efficiently when oxygen was bubbled through a solution of the ketone containing benzaldehyde (Scheme 18).0 9 90% Scheme 18 The reaction proceeded in the absence of metal catalysts and involved the formation of perbenzoic acid (detected by I3C NMR) in sitwg9 The Criegee rearrangement has been used to synthesize oxepines from cyclohexenyl hydroperoxide (82) (Scheme 19).loo Trifluoroacetylation in the presence of amine bases led to the formation of F3CC00 OOH tP I Scheme 19 97 H. Kageyama T. Murai T. Kanda and S. Kato J. Am. Chem. SOC. 1994 116 2195. 98 N. Wen and M. H. Brooker Can. J. Chem. 1994 72 1099. 99 K. Kaneda S.Ueno,T. Imanaka E. Shimotsuma Y. Nishiyama,and Y. Ishii J. Org.Chem.1994,59,2915. loo R. M. Goodman and Y. Kishi J. Org. Chem. 1994 59 5125. 100 J. M. Percy cyclohexenone via an elimination. However running the acylation reaction without an amine base but in the presence of a catalytic amount of DMAP led to the formation of the oxepine (83) by a ring expansion reaction. The reviewer has written a two-step mechanism for this conversion. Dimethyldioxirane is an extremely effective oxidant under a range of mild conditions. The oxidation by insertion of (84) was accelerated by solvents capable of hydrogen bonding to the oxidant (Scheme 20)."' Scheme 20 A solvent isotope effect (k,/k = 1.1) was measured in chloroform which appeared to be the solvent of choice. Some remarkably stable ozonides were reported including (85).'02 Less-substituted species decomposed to 1,5-dicarbonyl products when treated with triphenylphosphine but (85) survived several days at reflux in diethyl ether.Ozone proved to be the reagent of choicelo3 for the stereoselective oxidation of 1,3-dithian- (S)-oxide to trans-dioxide (86). The C-2 methylene protons of (86) underwent exchange in neutral D,O (t1,* = 4 hours) and a pK of 24.9 were reported in DMSO. The Dess-Martin periodinane reagent has been used extensively for a range of demanding oxidations. However reproducibility has proved a problem because of the presence of decomposition products in many samples. Schreiber and Meyer'04 have addressed the problem identifying (87) as the reactive species in most oxidations. Oxidation reactions of organic compounds in aqueous solutions of bromine have been reviewed.'05 The Hoffmann rearrangement of aromatic amides to arylamines 'O' R. W. Murray and D. Gu J. Chem. SOC. Perkin Trans. 2 1994 451. Io2 H. Mayr J. Baran E. Will H. Yamakoshi K. Teshima and M. Nojima J. Org. Chem. 1994,59,5055. V. K. Aggarwal I. W. Davies R. Franklin J. Maddock M. F. Mahon and K. C. Molloy J. Chem. Soc. Perkin Trans. 2 1994 2363. '04 S. D. Meyer and S. L. Schreiber .I.Org. Chem. 1994 59,7549. J. Palou Chem. SOC.Rev. 1994 23 357. Reaction Mechanisms -Part (ii) Polar Reactions relies on an N-bromination reaction usually performed under alkaline conditions. The reactive brominating species formed in alkaline aqueous solutions of N-bromosuc- cinimide has been identified as (88).'06 The formation of (88)is unexpectedly slow and its stability is low above -5°C.Modifying the Hoffmann protocol to exploit this information allowed the reaction yields to be improved dramatically. (87) 10 Probes of Polar Reactions Most of the activity reported in this area dealt with solvation or with kinetic isotope effects. The well-known decarboxylative ring opening of benzisoxazole-2-carboxylate has been used as a probe of solvation effects. A unified scale of solvent parameters for specific and non-specific interactions was used to interpret the results.' O7 The dependence of the E,(30) scale on solvent composition has been investigated using a range of empirical solvent parameters.lo8 Marcus has shown that specific solvation effects are particularly important in non-polar solvents.The finding implies that polarity scales derived using specific solutes may not be transferrable for use with other s~lutes.''~ The SWAG model which quantifies solvation by summing increments from polar and non-polar groups with solvent components has been applied to the enolization of acetylacetone."' The keto and enol forms are of similar polarity while the cis enol is most hydrophobic and the keto form has the highest dipolar character. The 4-methoxybenzyl dimethylsulfonium cation (89) has been proposed as a chemical probe for the determination of the role of solvent nucleophilicity." Buncel lo6 C. H. Senariayake L. E. Fredenburgh R. A. Reamer R. D. Larsen T. R. Verhoeven and P.J. Reider J. Am. Chem. SOC. 1994 116 7947. lo' D.C. Ferris and R. S. Drago J. Am. Chem. Soc. 1994 116 7509. R. D. Swierczynski and K. A. Connors J. Chem. SOC. Perkin Trans. 2 1994 467. lo9 Y. Marcus J. Chem. SOC. Perkin Trans. 2 1994 1015. 'lo W. Blokzijl J. B. F. N. Engberts and M. J. Blandamer J. Chem. SOC. Perkin Trans. 2 1994 455. D.N. Kevill N. H. J. Ismail and M. J. D'Souza J. Org. Chem. 1994 59 6303. 102 J.M. Percy and co-workers' l2 have tuned the nucleophilicity of substituted phenolates in the sulfonyl transfer reaction with (90). Conventional Brarnsted correlations (constant solvent vary phenoxide pK,) yielded different values for pN in a each of the solvents studied suggesting a shift in transition-state structure. However when the pK of the nucleophile was varied by changing the solvent composition each phenolate yielded the same value of BN (0.6).The result implies a single transition state structure with systematic variations in the intrinsic barrier for sulfonyl transfer.Reliable isotopic fractionation factors are required if proton inventory methods are to be used successfully. NMR methods were used to obtain fractionation factors for benzylamine and benzylammonium cation.' ' Unlike in the corresponding oxygen case the development of positive charge at nitrogen does not increase the fractionation factor. Values of = 0.958 _+ 0.07 and $ammonium = 0.80 & 0.13 were obtained. Kinetic isotope (p)effects upon the identity reaction of (91) and (92) with bromide ion were measured.' l4 Br Br PhYCL3 (91) (92) (9%) X = H (93b) X = OSiMe3 (93c)X = C02Me Kinetic isotope effects were also used to probe the [3,3] Claisen rearrangement' of ally1 vinyl ether (93a) and the hetero-Cope rearrangements'16 of (93b) and (93c).The investigation of (93a) concludes strongly that the aqueous acceleration of the Claisen rearrangement is not due to the development of polar or ion-pair character in the transition state. Deuterium (D,)effects at C-4 and C-6 failed to show the anticipated increase in heterolytic bond breaking as the solvent became more polar. The rate of ion pair formation from (93a) was calculated under rearrangement conditions and the value obtained was too small to explain the observed reaction rates. A rigorous isotope effect study of the hydrolysis of both anomers of glucopyranosyl fluoride reached some interesting conclusions.' ' The a-anomer hydrolysed through the familiar exploded S,2 transition state while the p-anomer reacted by an.SN1 mechanism.Both anomers reacted in the 4C1conformation in contradiction of the antiperiplanar lone pair hypothesis. '12 R. M. Tarkka W. K. C. Park P. Liu E. Buncel and S. Hoz J. Chem. SOC.,Perkin Trans. 2 1994,2439. 'I3 C.H. Arrowsmith H.-X. Guo and A.J. Kresge J. Am. Chem. SOC. 1994,116 8890. '14 A. R.Stein Can. J. Chem. 1994 72 1789. J.J. Gajewski and N.L. Brickford J. Am. Chem. SOC. 1994 116 3165. L. Kupczyk-Subotkowska W. H. Saunders H. J. Shine and W.Subotkowski J. Am. Chem. SOC. 1994 ''' Y. 116 7088. Zhang J.Bommuswamy and M.L. Sinnott J. Am. Chem. SOC. 1994 116 7557.

ISSN:0069-3030    

DOI:10.1039/OC9949100079

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (iii) Free-radical Reactions By S. CADDICK" and K. ABOUTAYAB School of Chemistry and Molecular Sciences University of Sussex Falmer Brighton BNl 9QJ UK 1 Introduction Free-radical intermediates continue to attract a good deal of interest from both synthetic and mechanistic standpoints. A lively debate regarding the intermediacy of radical intermediates in certain Gif systems continues;' evidence to suggest a non-dissociative mechanism for the synthetically useful b-(acy1oxy)alkyl radical rearrangement has also recently been disclosed;2 Newcomb and Chestney have developed a mechanistic probe for distinguishing between carbocation and radical intermediates3 and Jenkins has discussed the 'b-oxygen effect' in radical reactions which can be both activating and deactivating and can be attributed to polar effect^.^ 2 Initiators Promoters and Mediators Developments in experimental procedures utilizing the ubiquitous tin-based radical reducing agents have featured extensively.Nakamura and coworkers for e~arnple,~ have described sonochemical (as opposed to AIBN) initiated hydro and hydroxystan- nylation of C-C multiple bonds with triphenyltin hydride. These tin-based reagents whilst widespread in their synthetic use are far from ideal for preparative purposes. One of the disadvantages of utilizing tributyltinhydride (TBTH) in radical-based transformations is the decomposition of the reagent unless carefully stored and used. Podesta Mascaretti and coworkers have recently utilized trineophyltin hydride as an alternative to TBTH and further recent disclosures from their laboratories detail the preparation of trineophyltin deuteride as a useful reagent for the deuteriation of sensitive organic molecules.6 The reagent is soluble in a range of organic solvents is apparently stable to air and undergoes no noticeable decomposition when kept at room temperature for months.In order to avoid contamination of products with ' F. Minisci and F. Fontana Tetrahedron Lett. 1994 35 1427; F. Minisci F. Fontana S. Araneo and F. Recupero Tetrahedron Lert. 1994 35 3759; D. H. R.Barton and D. R. Hill Tetrahedron Lert. 1994 35 1431. D. Crich and Q. Yao J. Am. Chem. SOC. 1994 116 2631. M. Newcomb and D. L. Chestney J. Am. Chem. Soc. 1994 116 9753. I.D. Jenkins J. Chem. Soc. Chem. Commun. 1994 1227. E. Nakamura Y. Imanishi and D. Machii J. Org. Chem. 1994 59 8178. J. C. Podesta N. Giagante A. E. Zuniga G. 0.Danelon and 0.A. Mascaretti J. Org. Chem. 1994,59,3747. 103 S. Caddick and K. Aboutayab organotin residues from reactions using TBTH a number of polymer-bound tin reagents have been described. However such appealing reagents have yet to gain widespread recognition and utility in synthesis. Dumartin and coworkers have recently reported an alternative preparation to their own polymer-bound reagent; the ease of preparation may encourage synthetic chemists to utilize this in preference to TBTH.7 Maitra and coworkers have reported the use of water as a solvent for tin-mediated halide reduction.* The experimental procedure involves heating (90"C) a suspension of the halide TBTH AIBN and NaHCO for 24 hours; and a phase-transfer catalyst can aid the reduction of water-insoluble substrates.Collum and coworkers have also reported developments in this area using (1) in conjunction with sodium borohydride and 4,4'-azobis(4-cyanovaleric acid) (ACVA). A range of halide reduction and reductive cyclizations are reported to proceed in good yields.' The development of silicon-based radical chain promoters has in recent years also been the subject of interest although the strength of the Si-H bond is crucially important for the successful application of these reagents to radical reactions. Oba and Nishiyama have reported the use of silanes (2) to promote reduction of organic halides and thioxocarbamates.The reagents appear to be simple to prepare and may provide a useful alternative to TBTH." Moving away from Group 14 hydrides Jones and coworkers have reported an interesting approach to aryl radicals as illustrated in Scheme 1. Thus treatment of iodide (3) with CoCl and methylmagnesium bromide led to the isolation of cyclization product (4) in 71YOyield.' Murphy and coworkers have continued exploring the synthetic application of radical cyclizations mediated by tetrathiofulvalene (TTF). This method appears very promising as illustrated in the formation of (6) from substrate (5) uia tandem cyclization (Scheme 2).12 Following early investigations Schwartz and Liu have examined reduction of aryl G.Dumartin G. Ruel J. Kharboutli B. Delmond M.-F. Connil B. Jousseaume and M. Pereyre SYNLETT 1994 952. U. Maitra and K. Das Sarma Tetrahedron Lett. 1994 35 7861. R. Rai and D. B. Collum Tetrahedron Lett. 1994 35 6221. M. Oba and K. Nishiyama J. Chem. Soc. Chem. Commun. 1994 1703. A. D. Clark D.I. Davies K. Jones and C. Millbanks J. Chem. Soc. Chem. Commun. 1994,41. C. Lampard J. A. Murphy F. Rasheed N. Lewis M. B. Hursthouse and D. E. Hibbs Tetrahedron Lett. 1994 35 8675. Reaction Mechanisms -Part (iii) Free-radical Reactions (3) (4) 71% Reagents i CoCl, MeMgI Scheme 1 halides using the [TiCl,Cp,]/NaBH system. They find that by changing the solvent from DMF to DMA they are able to promote radical cyclizations as illustrated in the transformation of (7) into (8) (Scheme 3).13 (7) (8) Reagents i Cp,TiCl (0.5eq) NaBH, DMA 75 "C Scheme 3 Zard and coworkers have examined the utility of nickel-mediated radical formation and detail a number of synthetically useful transformations as exemplified in the isolation of (10) from (9) in Scheme 4.14 Photolytic methods remain particularly appealing for the generation of alkyl radicals.Cossy and coworkers have recently detailed a useful cyclization method in which irradiation of alkyl halides in the presence of triethylamine leads to alkyl radicals which undergo cyclization in good yield as shown in Scheme 5." Mattay and Kirschberg have also described a similar cyclization strategy. Thus a range of cyclopropyl ketones undergo photoinduced cleavage with subsequent cyclization as shown in the transformation of (13) into (14) (Scheme 6).16 Enones have also been shown to serve as useful precursors to alkyl radicals.Pandey l3 Y. Liu and J. Schwartz J. Org. Chem. 1994 59 940. J. Boivin M. Yousfi and S.Z. Zard Tetrahedron Lett. 1994 35 5629. J. Cossy J.-L. Ranaivosata and V. Bellosta Tetrahedron Lett. 1994 35 8161. l6 T. Kirschberg and J. Mattay Tetrahedron Lett. 1994 35 7217. S. Caddick and K. Aboutayab (9) (10) 76% Reagents i Ni powder AcOH Pr'OH t-dodecanethiol Scheme 4 Reagents i NEt, hv (254nm) MeCN Scheme 5 Reagents i NEt, hv (300nm) MeCN Scheme 6 aCO2Et La.-CO2Et (15) (16)98% Reagents i hv (405 nm) DCA Ph,P DMF/Pr'OH H,O Scheme 7 and coworkers have found that photolysis of enones such as (15) with Ph,P and dicyanoanthracene (DCA) leads to (16) in excellent overall yields (Scheme 7).17 The addition of triphenylsilanethiol to alkenes has been illustrated.This useful reagent has been used as an H,S equivalent and as a mediator of cyclization as highlighted in Scheme 8.'* Burton and coworkers have reported a novel radical addition process which has been used in the preparation of fluorinated phosphonates as shown in Scheme 9. Thus l7 G. Pandey S. Hajra and M. K. Ghorai Tetrahedron Lett. 1994 35 7837. '* B. Hache and Y. Gareau Tetrahedron Lett. 1994,35 1837. Reaction Mechanisms -Part (iii) Free-radical Reactions (17) (18) 80% cis:tmns 4:l Reagents i Ph,SiSH AIBN hv; ii TFA Scheme 8 (ROkP + F$-(F (RO)~P(0)CF2CF21 Br Scheme 9 irradiation of trialkyl phosphite (19) with halide (20) leads to phosphonate (2l).I9 Samarium-promoted transformations continue to find use in a range of synthetic applications such as Julia alkenylation,20 deoxygenation of aldonolactones2 and ulosonic acids,22 and Reformatsky reactions.23 3 Intramolecular Reactions General.-With a potentially useful 6-endo-dig cyclization reaction Marco-Contelles and coworkers have prepared cyclitols.They explain that the strained nature of the transition state required for the 5-exo-dig mode governs the regiochemical outcome of the cyclization as illustrated in the isolation of (23) from (22) (Scheme (22) (23)66% Reagents i TBTH AIBN toluene Scheme 10 The formation of larger rings has been cleverly exploited as part of a tandem cyclization strategy by Pattenden and coworkers.Scheme 11 shows one example of the l9 H.K. Nair and D. J. Burton J. Am. Chem. SOC. 1994 116,6041. 2o M. Ihara S. Suzuki T. Taniguchi Y. Tokunaga and K. Fukumoto SYNLETT 1994 859. 21 S. Hannesian and C. Girard SYNLETT 1994 861. 22 S. Hannesian and C. Girard SYNLETT 1994 863. 23 S. Hannesian and C. Girard SYNLETT 1994 865. 24 J. Marco-Contelles M. Bernabe D. Ayala and B. Sanchez J. Org. Chem. 1994 59 1234. S. Caddick and K. Aboutayab H (24) (25) 55% Reagents i TBTH AIBN benzene Scheme 11 (26) (27)56% Reagents i TBTH AIBN Scheme 12 type of impressive transformation which can be achieved by such a method.2s Kim and coworkers have detailed an interesting new approach to N-heterocycles by addition of a carbon-centred radical to an azide as shown in Scheme 12.26 The formation of cyclopropanes by radical cyclization has been reported by several groups in the past year.Gravel and Denis have utilized an addition-elimination terminated cyclopropanation reaction as illustrated in Scheme 13. It is interesting to note that under the reaction conditions no products resulting from addition of phenylthio or tri-n-butylstannyl radical to the vinyl cyclopropane are ob~erved.~’ PhS Reagents i (Bu,Sn), hv AIBN Scheme 13 An alternative method is described by Malacria and coworkers. In this work the addition of a vinyl radical to an alkyne initiates a tandem cyclization reaction; a 3-em-trig cyclization gives the cyclopropane-containing product (3 1) (Scheme 14).28 25 G.Pattenden A.J. Smithies and D.S. Walter Tetrahedron Lett. 1994 35 2413; M.J. Begley G. Pattenden A. J. Smithies and D. S. Walter Tetrahedron Lett. 1994 35,2417. S. Kim G.H. Joe and J. Y. Do J. Am. Chem. Soc. 1994 116 5521. ” R.C. Denis and D. Gravel Tetrahedron Lett. 1994 35,4531. M.Journet and M. Malacria J. Org. Chem. 1994 59 718. Reaction Mechanisms -Part (iii) Free-radical Reactions 'I' f9J (31) 48% Reagents i TBTH AIBN benzene Scheme 14 q~i * O P E I (32) (33)46% Reagents i TBTH AIBN benzene Scheme 15 The intermediacy of a diene in the aforementioned example has been recognized and utilized in an intramolecular Diels-Alder reaction.This powerful new synthetic methodology has excellent potential for use in target synthesis (Scheme 15).29 Indoles have been prepared by radical cyclizations which illustrate the versatility of organostannane chemistry. Fukuyama and coworkers3' use TBTH to initiate cyclization of an isonitrile (Scheme 16).The resulting tin-substituted indole is then used most economically in palladium(0)-induced cross couplings to yield a range of substituted indoles. rR NC i'ii -H (34) (35) Reagents i TBTH AIBN; ii Pd(o) R'X NEt Scheme 16 Acyl radicals are readily generated from a number of precursor^^^ and have been used recently to good effect in a novel macrocyclization methodology described by 29 M. Journet and M.Malacria J. Org. Chem. 1994 59 6885. 30 T. Fukuyama X. Chen and G. Peng J. Am. Chem. SOC. 1994 116 3127. 31 J.H. Penn and F. Liu J. Org. Chem. 1994 59 2608. S. Caddick and K. Aboutayab 0 (37)78% Reagents i (TMS),SiH AIBN CO (10 atm) Scheme 17 (38) Reagents i TBTH AIBN Scheme 18 Ryu Sonoda and coworkers. In this interesting tandem process intermolecular carbonylation is used to generate an intermediate acyl radical which then undergoes macrocyclization as shown in Scheme 17.32 Acyl radicals also feature in a novel tandem-cyclization approach to steroid skeleta. Thus treatment of acyl selenide (38) with TBTH under standard conditions led to the isolation of tetracycle (39) in 53% yield as a single isomer (Scheme 18).33 A number of interesting reports highlight the synthetic utility of intramolecular addition of radicals to aromatic systems.Zard and coworkers have described a useful application to the synthesis of indoles as shown in the transformation of halides or xanthates into indolones using di-t-butyl peroxide or nickel powder (Scheme 19).34 Addition of vinyl radicals to furans has also been shown to be effective in an elegant approach to cyclopentenes as shown in the transformation of vinyl iodide (42)into (43) (Scheme 20).35 Two interesting reports have also described approaches to fused heterocyclic aromatic systems involving radical addition to pyrroles and in dole^.^^ 32 1. Ryu K. Nagahara H. Yarnazaki S. Tsunoi and N. Sonoda SYNLETT 1994 643. 33 L.Chen G. B. Gill and G. Pattenden Tetrahedron Lett. 1994 35 2593. 34 J. Axon L. Boiteau J. Boivin J. E. Forbes and S. Z. Zard Tetrahedron Lett. 1994,35 1719; J. Boivin M. Yousfi and S. Z. Zard Tetrahedron Lett. 1994 35 9553. 35 P. J. Parsons M. Penverne and I. L. Pinto SYNLETT 1994 721. 36 Y. Antonio M. E. De La Cruz E. Galeazzi A. Guzrnan B. L. Bray R. Greenhouse L. J. Kurz D. A. Lustig M. L. Maddox and J. M. Muchowski Can.J. Chem.,1994,72,15; D. R. Artis I.-S. Cho S. Jaime-Figueroa and J. M. Muchoski J. Org. Chem. 1994,59 2456. Reaction Mechanisms -Part (iii) Free-radical Reactions 0 (40a) X = SCSOMe (41a) X = SCSOMe 57% (40b)X = CI (41b) X = CI 78% Reagents i (X = SCSOMe) di-t-butyl peroxide; ii (X = Cl) Ni AcOH Scheme 19 OTHP lBS0 OTBS (42) Reagents i TBTH AIBN Scheme 20 ”* XH XH Ro&H X’ 0’ “ W 0’ R RoRO OR -RoRO OR H.Ro RO - H Scheme 21 Trans1ocations.-New radical translocations continue to be developed.37 Two of the most important synthetic contributions have been reported simultaneously by Crich3* and by C~rran.~~ These groups have established independently the viability of a radical-mediated approach to inversion of p-mannose linkages. The general concept shown in Scheme 21 relies on the propensity of radicals at C-1 of the mannose to abstract a hydrogen-atom from TBTH using their least hindered a-face. The two groups have successfully illustrated this elegant concept using different 37 D.P. Curran and H. Liu J. Chem. Soc. Perkin Trans 1 1994 1377; P.J.Parsons and S. Caddick Tetrahedron 1994 47 13523; S. Bogen M. Journet and M. Malacria SYNLETT 1994 959; A. De Smaeker A. Waldner P. Hoffman and T. Winkler SYNLETT 1994 330. 38 J. Brunckova D. Crich and Q. Yao Tetrahedron Lett. 1994 35 6619. 39 N. Yamazaki E. Eichenberger and D. P. Curran Tetrahedron Lett. 1994 35 6623. 112 S. Caddick and K. Aboutayab Me. ON OMe " 0-..-I Reagents i TBTH AIBN Scheme 22 (48) (49) Reagents i TBTH AIBN Scheme 23 tactics. The Crich group utilize bromo-acetal precursors in a 1,5 hydrogen-atom translocation approach (Scheme 22).38 The Curran group exploit a 1,6 hydrogen-atom abstraction using their recently developed PRT approach (Protection and Radical Translocation) as shown in the isolation of (49) from reduction of (48) (Scheme 23).39 At present both approaches suffer from a competing reduction which quenches the radical prior to translocation.It should be possible to optimize the approach using a less-efficient hydrogen atom donor. Until recently most of the reported translocation work had been initiated by halide reduction. However Burke and coworkers have highlighted a useful alternative based on thiol addition to an alkyne as shown in Scheme 24. Thus addition of thiophenol radical to (50)leads to cyclization product (51) (69%) presumably via an intermediate vinyl radical which undergoes translocation and concomitant cyclization .40 Diazonium salts can also serve as radical precursors in translocation processes. Weinreb and coworkers4' have exploited this reactivity in their a-methoxylation of substituted pyrrolidines uia o-aminobenzamides as shown in Scheme 25.Murphy and coworkers extend the synthetic utility of their recently described TTF methodology in a translocation/cyclization sequence as illustrated in the formation of (55) from (54) in 45% yield (Scheme 26).42 40 S.D. Burke and K. W. Jung Tetrahedron Lett. 1994 35 5837. 41 G. Han M.C. McIntosh and S. M. Weinreb Tetrahedron Lett. 1994 35 5813. 42 M. J. Begley J.A. Murphy and S. J. Roome Tetrahedron Lett. 1994 35 8679. Reaction Mechanisms -Part (iii) Free-radical Reactions i i’i -(51) 69% Reagents i PhSH AIBN benzene Scheme 24 Reagents i NaNO, HCl CuCl MeOH rt Scheme 25 (54) Reagents i TTf; ii base Scheme 26 Of course heteroatom-centred radicals have long been known to undergo syntheti- cally useful atom-abstraction reactions.Recently Ryu Sonoda and Tsunoi have described an interesting sequence based on a hydrogen atom translocation/carbonyla-tion sequence,43 (56) to (57) and Kim and coworkers have described an interesting 1,5-silicon translocation process (58) to (59) (Scheme 27).44 Stereoselectivity.-Stereocontrol in radical cyclizations is an important issue and a number of reports have illustrated the very high levels of diastereoselectivity which can be obtained from cycli~ations.~~ Nishida and coworkers have used a chiral auxiliary approach. Cyclization of (60) under TBTH/BEt conditions led to the products (61a) 43 S.Tsunoi I. Ryu and N. Sonoda J. Am. Chem. SOC.,1994 116 5437. 44 S. Kim J. Y. Do and K. M. Lim J. Chem. SOC. Perkin Trans 1 1994 2517. 45 M. Zahouily M. Journet and M. Malacria SYNLETT 1994 366. S. Caddick and K. Aboutayab 0 (57)50% OTMS (9) (59)92% Reagents i Pb(OAc), CO; ii TBTH AIBN Scheme 27 0 (60)R* = (-)-8-phenylmenthyl Additive Yield A:B None 88% 58:42 MAD 79% 96:4 Reagents i TBTH BEt Scheme 28 and (61b) in good yield but with no diastereoselectivity; with Lewis acids such as methylaluminium bis(2,6-di-t-4-methylphenoxide)(MAD) significant enhancements in rate and moderate to excellent levels of diastereocontrol were achieved (Scheme 28).46 Curran and coworkers47 have highlighted the potential of substrate-controlled group-selective radical cyclizations.Treatment of the iodide (62) with TBTH induces a stereoselective cyclization with isolation of (63a) (82%; exolendo ratio 94 :6) (Scheme 29). Group selectivity here is rationalized in terms of preferential reaction of the radical with one of the diastereotopic alkenes via a chair transition state having the methyl group equatorial (62a). Reactions in which diastereotopic radicals compete for a single 46 M. Nishida E. Ueyama H. Hayashi Y. Ohtake Y. Yamaura E. Yanaginuma 0.Yonemitsu A. Nishida and N. Kawahara J. Am. Chem. SOC. 1994 116 6455. 47 D.P. Curran H. Qi N.C. DeMello and C.-H. Lin J. Am. Chem. SOC. 1994 116 8430. React ion Mechanisms Part (iii) Free-radical Reactions Me02C.. LP -i Me H endo Reagents i TBTH AIBN Scheme 29 Pr Pr Pr\ N r (65) Scheme 30 alkene were also described but this approach has as yet yielded only modest diastereoselectivities.The general approach is very appealing and is applicable to asymmetric synthesis either using an enantiomerically enriched substrate or by using a similar auxiliary controlled process.48 Heteroatom-centred Radicals.-Cyclization of heteroatom-centred radicals has also been an area of considerable recent activity with a great deal of emphasis on nitrogewcentred radical^.^' Tsakaniktsidis and Maxwell have found that cyclization of aminyl radical (64) is enhanced by the addition of (Bu,Sn),O although the reasons for this observation are presently unclear (Scheme 30).’O Zard and coworkers have reported tandem cyclization of amidyl radicals thus treatment of 0-benzoyl hydroxamic acid (67) with TBTH/AIBN leads to tricyclic adduct (68) in good yield (Scheme 31).’l 48 D.P. Curran S.J. Geib and C.-H. Lin Tetrahedron Asymmetry 1994 5 199. 49 W. R.Bowman D. N. Clark and R. J.Marmon Tetrahedron 1994,50 1275; W. R. Bowman D. N. Clark and R. J. Marmon Tetrahedron 1994,50,1295; J. Boivin E. Fouquet and S. Z. Zard Tetrahedron 1994,50 1745; J. Boivin E. Fouquet and S.Z. Zard Tetrahedron 1994 50 1757; J. Boivin E. Fouquet A.-M. Schiano and S. Z. Zard Tetrahedron 1994 50 1769. 50 B. J. Maxwell and J. Tsakaniktsidis J. Chem. SOC. Chem. Commun. 1994 533. 5’ A.-C. Callier B. Quiclet-Sire and S.Z. Zard Tetrahedron Lett.1994 35 6109. S. Caddick and K. Aboutayab 0 - i H (68)73% Reagents i TBTH AIBN Scheme 31 (69) (71)74% Reagents i Bu,SnCl NaBH, AIBN Scheme 32 A similar strategy has been used for the generation of iminyl radical^.'^ Oxygen-centred radicals also undergo cycli~ation~~ and recently Newcomb and coworkers have developed a convenient precursor for the generation of allylic and homoallylic alkoxycarbonyloxy radicals.54 4 Intermolecular Reactions General.-Yus and coworkers have illustrated the viability of a novel process which they suggest proceeds by intermolecular addition of a vinyl radical to an alkene as illustrated in Scheme 32.’’ With a very similar transformation Hosomi and coworkers have reported addition of iodide (72) to acrylonitrile which proceeds in good yield when carried out with intermittent addition of TBTH without an initiator at room temperature! (Scheme 33)? Narasaka and coworkers have explored the synthetic utility of electrophilic arenesulfonyl radicals.They find that treatment of sodium(toly1)sulfinate with an oxidant in the presence of an electron-rich alkene leads to addition products as exemplified in Scheme 34.57 Acyl radicals readily undergo intramolecular cyclization reactions however analog- 52 J. Boivin A.-M. Schiano and S.Z. Zard Tetrahedron Lett. 1994 35 249. 53 D.J. Pasto and F. Cottard Tetrahedron Lett. 1994 35 4303. 54 M. Newcomb and B. Dhanabalasingam Tetrahedron Lett. 1994 35 5193. 55 F. Foubelo F. Iloret and M.Yus Tetrahedron 1994 6715. 56 K. Miura D. Itoh T. Hondo and A. Hosomi Tetrahedron Lett. 1994 35 9605. ” K. Narasaka T. Mochizuki and S. Hayakawa Chern. Lett. 1994 1705. Reaction Mechanisms -Part (iii) Free-radical Reactions (72) (73) (74) 60% Reagents i TBTH benzene rt Scheme 33 SEt ArS0,Na + -SEt (75) (76) (77)87% Reagents i Mn(nI) MeOH 0 “C Scheme 34 ous intermolecular processes are far less common and in a recent report Narasaka and Sakurai show that intermolecular addition of acyl radicals to electron-deficient alkenes can be promoted by oxidation of chromium complexes (78) as shown in Scheme 35. The use of acetonitrile as a solvent is essential for high yields.’* (78) (79)68% Reagents i Cu(acac), methyl acrylate rt Scheme 35 Following an earlier report on the preparation of phosphonic acids by addition of carbon-centred radicals to white phosphorous Castagnino Barton and Jaszberenyi have shown that a similar approach can be used for the preparation of thiols by addition to elemental sulf~r.’~ Robertson and Burrows have utilized a radical rearrangement to prepare or-trimethylsilyl aldehydes as shown in the transformation of (80) into (81) (Scheme 36).60 Stereoselectivity in Intermolecular Reactions.-Stereoselective intermolecular radical reactions continue to be an area of activity,61 and Belekon and coworkers have H.Sakurai and K. Narasaka Chem. Lett. 1994 2017. 59 D. H. R. Barton E. Castagnino and J. C. Jaszberenyi Tetrahedron Lett. 1994 33,6057. 6o J.Robertson and J.N. Burrows Tetrahedron Lett. 1994 35,3777. D. P. Curran E. Eichenberger M. Collis M.G. Roepel and G. Thoma J. Am. Chem. Soc. 1994,11,4279; Y. Guindon C. Yoakim V. Gorys W. W. Ogilvie D. Delorme J. Renaud G. Robinson J.-F. Lavallee A. Slassi G. Jung J. Rancourt K. Durkin and D. Liotta J. Org. Chem. 1994 59 1166; W. Smadja SYNLETT. 1994 1; K. Paulini and H.-U. Reibig Chem. Ber. 1994 127 685; J.O. Metzger K. Schwarzkopf W. Saak and S. Pohl Chem. Ber. 1994 127 1069. S. Caddick and K. Aboutayab Reagents i PhSH AIBN Scheme 36 I. I Reagents i TBTH AIBN RX; ii HCl Scheme 37 Reagents i FeSO, H,O, DMSO Scheme 38 described a potentially useful approach to a-amino acids.62 Addition of thermally generated carbon-centred radicals to the dehydroalanine residue of enantiomerically enriched nickel(I1) Schiff base complex (82) affords amino acid (83) after hydrolysis (Scheme 37).Baciocchi and coworkers continue their excellent investigations on homolytic aromatic substitution reactions. In some of their most recent work they have demonstrated that enantiomerically enriched a-haloesters undergo diastereoselective addition to heteroaromatic systems as highlighted in Scheme 38.63 Curran and coworkers have described some asymmetric group transfer addition reactions. Addition of selenomalonitrile (87) to enol ether (88) leads to product (89) in 62 R.G. Gasanov L. V. Il'inska M. A. Misharin V. I. Maleev N. I. Raevski N. S. Ikonnikov S. A. Orlova N. A. Kuzmina and Y.N. Belokon J.Chem. SOC.,Perkin Trans. 1 1994 3343. 63 E. Baciocchi E. Muraglia and C. Villani SYNLETT 1994 821. Reaction Mechanisms -Part (iii) Free-radical Reactions CN (89)91% Reagents i hv AIBN Scheme 39 $p Bu' (90) Reagents i Bu'HgC1 NaBH, 25 "C Scheme 40 good yield with a high degree of stereocontrol (Scheme 39).64 The highly asymmetric selenium-transfer step is attributed to the considerable pyramidalization i.e. a product-like transition state (88a). In further studies Curran and his collaborators have examined the addition of carbon-centred radicals to axially chiral racemic imides (90). They note that addition of t-butyl radical to (90) leads to the product (91) with high levels of stereoselectivity (Scheme 40). Equilibration studies show that the reactions are kinetically controlled and enantiopure auxiliaries of this type will undoubtedly prove useful in asymmetric synthesis.Careful choice of promoter can have an important influence on the stereochemical outcome of radical reactions. Apeloig and Nakash demonstrate that simple reduction of gem-dichlorocyclopropanes can lead to different or even the reversal of product ratios as shown in Scheme 41 .66 It is suggested that the observed stereoselectivity is due to the interaction of the reagent and the y-substituent. 64 D. P. Curran S. J. Geib and L. H. Kuo,Tetrahedron Lett. 1994 35 6235. 65 D. P. Curran H. Qi S. J. Geib and N.C. DeMello J. Am. Chem. SOC. 1994 116 3131. 66 Y. Apeloig and M. Nakash J. Am. Chem. SOC.,1994 116 10781.S. Caddick and K. Aboutayab (-) (93b) i (93a)/(93b) 1.3 :1 ii (93a)/(93b) 1 4.6 Reagents i TBTB AlBN; ii (TMS),SiH AlBN Scheme 41 TMST Br (94) (954 (95b) % Lewis acid Ratio Yiild 0 1.3~1 63% 0.1 3:l 45% 1.1 8.6:l 62% Reagents i allyl(tributyl)tin AIBN Lewis acid CH,Cl, hv Scheme 42 Highly stereoselective intermolecular radical addition reactions can be promoted using a chelation-control strategy with Lewis acids and this approach is becoming increasingly popular. Europium-derived Lewis Acids appear promising in this regard as demonstrated by Nagano and K~no.~~ They report that allylation of substrate (94) proceeds in reasonable yield but with enhanced stereoselectivity when either catalytic or stoichiometric quantities of [Eu(fod),] are used (Scheme 42).A range of investigations have been carried out on stereoselective radical addition reactions of cyclic a-sulfinyl radicals by the groups of Renaud and Curran.68 In allylation studies certain Lewis acids were found to enhance stereoselectivity. The use of stoichiometric methylaluminium diphenoxides was found to provide products (97a) and (97b) with the highest levels of stereocontrol; however efficient catalysis is possible as shown in Scheme 43. It is interesting to note that the stereocontrolled transformation of (96) into (97) can also be enhanced (cisltrans 1:7) using diarylurea (98) presumably by hydrogen bonding of the intermediate radical species.69 67 H. Nagano and Y. Kuno J. Chem.SOC. Chem. Commun. 1994,987. 6a P. Renaud N. Moufid L.H. Kuo and D.P. Curran J. Org. Chem. 1994 59 3547; P. Renaud P.-A. Carrupt M. Gerster and K. Schenk Tetrahedron Lett. 1994 35 1703; P. Renaud and T. Bourquard Tetrahedron Lett. 1994 35 1707. 69 D. P. Curran and L. H. Kuo J. Org. Chem. 1994 59 3259. Reaction Mechanisms -Part (iii) Free-radical Reactions 0-0- I &ePh i + o.-v (96) (974 (97U % Lewis acid Ratio Yield 0.1 %:15 63% 1 .1 90:2 72% Reagents i ally1 (tributyl)tin MAD Scheme 43 H1&8°2C H H C02CBH17 (98) (99) X = O,CH Reagents i RCH=X AIBN THF Scheme 44 Polymers.-Porter and coworkers have examined the stereochemistry and control of dispersity in free-radical telomerizati~ns;~~ they propose a model for the low selectivity associated with telomerization of poly(ally1 acetate) from poly (camphor sultam a~rylamide).~ Waymouth and Hsiao have reported free-radical hydrosilylation of poly(phenylsi1ane) as shown in Scheme 44.72The mild and general nature of the procedure should lend itself to the preparation of a range of polymers with a view to optimizing their physicochemical properties.The synthesis of poly(sily1 enol ethers) is the subject of a recent disclosure by Endo and coworkers. The wide range of transformations which silyl enol ethers undergo obviously makes them useful intermediates for the preparation of a wide range of polymer congeners. However these useful species are not generally stable under polar 70 N. A. Porter G. S. Miracle S.M. Canniuaro R. L. Carter A.T. McPhail and L. Liu J. Am. Chem. SOC. 1994 116 10255. 7L W.-X. Wu A.T. McPhail and N.A. Porter J. Org. Chem. 1994 59 1302. 72 Y. L. Hsiao and R. M. Waymouth J. Am. Chem. SOC.,1994 116 9779. S. Caddick and K. Aboutayab Scheme 45 polymerization conditions and the use of a radical approach has allowed their preparati~n.~~ The process is outlined in Scheme 45and involves the ring opening of an appropriate cyclopropane to produce the polymers which are very soluble in organic solvents. Successful ‘living’ free-radical polymerizations depend on promoters which revers- ibly terminate a growing polymer chain; the search for such compounds continues. Following early work by Georges et describing the use of TEMPO Ha~kes~~ has identified (103) as a useful alternative giving low dispersity polymers and block copolymers with defined block lengths and end groups.Alternative promoters of such living radical polymerizations are clearly desirable and Wayland Fryd and coworkers have developed an alternative to the TEMPO based systems using (tetramesity1porphyrinato)cobalt neopentyl which promotes the formation of acrylate block copolymer^.^^ 5 Applications of Radical Processes to Synthetic and Biological Chemistry Synthetic Chemistry.-Radical reactions are often utilized as key steps in natural product synthesis77 but more routine transformations can be incorporated into elegant synthetic plans. In a beautiful example Roy and coworkers have developed a simple two-step synthesis of racemic dihydrosesamin (106) from the readily available 3,4-methylenedioxycinnamylalcohol (104) as shown in Scheme 46.78 Radical rearrangements also find use in target syntheses.Roberts and coworkers 73 S. Mizukami N. Kihara and T. Endo J. Am. Chem. Soc. 1994 116 6453. 74 M. K. Georges R. P. N. Veregin P. M. Kazmaier and G. K. Hamer Macromolecules 1993 26 2987. 7s C.J. Hawkes J. Am. Chem. Soc. 1994 116 11 185. 76 B.B. Wayland G. Poszmik S.L. Mukurjee and M. Fryd J. Am. Chem. SOC. 1994 116 7943. 77 K. A. Parker and D. Fokas J. Org. Chem. 1994,59,3927;A. M. Gomez J. C. Lopez and B. Fraser-Reid J. Org. Chem. 1994 59 4048. 78 G. Maiti S. Adhikari and S. C. Roy Tetrahedron Lett. 1994 35 3985. Reaction Mechanisms -Part (iii) Free-radical Reactions Ar -OH __ci f;fAr ii * yJAr Ar Ar” (104) Ar =3,4-Methylenedioxyphenyl (105) (106) 80% cis :frans7:1 Reagents i NBS CH,CI,; ii TBTH AIBN Scheme 46 (107a) Scheme 47 i -0@ 0e (110) (111) 78% Reagents i LiDBB THF -78 “C Scheme 48 utilize the rearrangement of (107a) to (109) in their synthesis of tribactams (Scheme 47).79 Rawal and Dufour” have developed a fragmentation-cyclization route to di- and triquinanes exemplified in Scheme 48.The sequence is initiated by reductive cleavage of the C-C bond B to the carbonyl of the strained tricyclic ketone (110)with lithium di-t-butylbiphenylide (LDBB). This yields the radical-enolate (1 10a) and the radical centre then adds to the pendant alkene to form a new ring in (111).Biological Chemistry.-Radicals are ubiquitous in biological systems and recently Falvey and Fenick have described their investigations using uracil derivatives. They find that radicals such as (1 12) and (1 13) experience more resonance stabilization than would normally have been expected.” 79 A. Padova S. M. Roberts D. Donati A. Perboni and T. Rossi J. Chem. SOC.,Chem. Commun. 1994,441. V.H. Rawal and C. Dufour J. Am. Chem. SOC. 1994 116 2613. D. J. Fenick and D. E. Falvey J. Org. Chem. 1994 59 4791. S. Caddick and K. Aboutayab [ 'y] vc L OpCGG OpCGG OpCGG Sugiyama Ohmori and Saito have described a novel oligodeoxynucleotide (114) which they have used to trap the proposed C-4' radical in bleomycin-mediated DNA damage.The isolation of exo-methylene (116) after treatment with a bleomycin derivative (Scheme 49) provides good evidence for the intermediacy of radical (115p2 Silverman and coworkers have used the ring opening of cinnamylamine oxide as a probe for the mechanism of monoamine oxidase-catalysed oxidation reactions. The authors conclude that there is no evidence to suggest a nucleophilic mechanism and an electron-transfer mechanism appears more likely.83 82 H. Suiyama K. Ohmori and I. Saito J. Am. Chem. SOC. 1994 116 10326. 83 R. B. Silverman X. Lu J. J. P. Zhou and A. Swihart J. Am. Chem. SOC. 1994 116 11 590.

ISSN:0069-3030    

DOI:10.1039/OC9949100103

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

5 Aliphatic and Alicyclic Chemistry By PETER QUAYLE Department of Chemistry University of Manchester Manchester M 13 9PL UK 1 Introduction The application of modern synthetic methodology to the synthesis of complex natural products as exemplified by the total synthesis of bleomycin A (l),' swinholide A (2), zaragozic acid (3)3 and calyculin A (4),4has been truly outstanding this year. No doubt the limits of synthetic methodology will be further stretched in the near future by even more complex targets such as maitotoxin (5),5the largest natural non-polymer product yet isolated. The validation of synthetic methodology in this context is however coming under attack as demonstrated by a perceptible but real change in long term research goals of many groups.The rapid screening of potential medicinal agents by pharmaceutical companies has brought about the requirement for the development of automated synthetic sequences which enable the synthesis of chemical libraries. The development of such processes has begun to challenge the ingenuity of synthetic chemists as evidenced by the rapid growth of publications in this field.6 Recent advances in solid-phase oligosaccharide and glycopeptide synthesis7 will doubtless further blurr the boundaries between molecular biology and organic chemistry as multidisciplinary teams probe fundamental biological processes such as cellkell recognition phenomena.' The interplay between molecular biology and synthetic organic chemistry is also much in evidence as demonstrated by the use of catalytic antibodies as standard synthetic reagentsg and in approaches to the chemical synthesis of artificial enzymes." All of these developments are quite apt given that this year marks the centennial anniversary of Fischer's 'lock and key' paradigm for enzyme specificity.' One can envision that a similar interplay between synthetic chemistry and 1 D.L. Boger S. L. Colletti T. Honda and R. F. Menezes J. Am. Chem. SOC. 1994 116 5607. 2 I. Paterson K. Yeung R. A. Ward J.G. Cumming and J. D. Smith J. Am. Chem. SOC. 1994 116,9391. 3 E.M.Carreira and J. Du Bois J. Am. Chem. SOC. 1994 116 10825. 4 N. Tanimoto S. W. Gerritz A. Sawabe,T. Noda S.A. Filla and S. Masamune Angew. Chem. Int. Ed. Engl. 1994 33 673. S M. Murata H. Naoki S.Matsunaga M.Satake and T. Yasmuto J. Am Chem. SOC. 1994 116 7098. 6 M. Famulok and D. Faulhammer Angew. Chem. Int. Ed. Engl. 1994,33,1332; K. Burgess A. I. Liaw and N. Wang J. Med. Chem. 1994 37 2985. 7 M. Schuster P. Wang J.C. Paulson and C. Wong J. Am. Chem. SOC. 1994 116 1135. 8 A. Giannis Angew. Chem. Int. Ed. Engl. 1994 33 178. 9 K. Shokat T. Uno and P.G. Schultz J. Am. Chem. SOC. 1994 116 2261. 10 R. Breslow Red. Trav. Chim. PQJJS-EQS,1994 113 493; A.M. Reichwein W. Verboom and D.N. Reinhoudt ibid. 1994,113,343; L. G. Mackay R.S. Wylie and J. K. Sanders J.Am. Chem. SOC.,1994,116 3141. 11 F. W. Lichtenthaler Angew. Chem. Int. Ed. Engl. 1994 33 2364. 125 126 Peter Quayle materials science could lead to the development of new materials possessing useful bulk properties.Nevertheless the development of ‘new’ synthetic methodology continues to rise exponentially as witnessed by the number of review articles published annually. A broad range of topics has been discussed in a newly launched review journal which J.S. Miller and A. J. Epstein Angew. Chem. Int. Ed. Engl. 1994 33 385. Aliphatic and Alicyclic Chemistry 127 should have wide appeal to the community at large.I3 The development of new synthetic routes to a variety of natural and unnatural products of biological interest (including vitamin D3,14C-aryl glycosides,’ anticancer drugs,16 antitumour prod- rugs,17 anti-HIV agents,’ s oligonucleosides l9 glycoconjugates,20 peptidomimics,21 protein chemistry,22 molecular recognition phenomena,23 antimalarial^,^^ angioten-sin antagonist^,^ carbocyclic nucleosides,26 a-and p-amino acid^,^'.^' and enediyne antibiotic^^^) has attracted in-depth coverage this year.The study of enzyme-mediated biochemical pathways3’ and applications of enzymes in organic synthesis31 continue to be fertile areas of investigation as does the study of molecular recognition processes32 and supramolecular chemistry3 in general. The use oforgan~metallics,~~ free radicals,35 and carb be no id^'^^ in organic synthesis is now de rigueur. The impressive advances in asymmetric synthesis37 and the specific challenges which such processes present upon conversion to large-scale reactions38 have been Contemporary Organic Synthesis Royal Society of Chemistry Cambridge UK.l4 H. Dai and G. H. Posner Synthesis 1994 1383. lS C. Jaramillo and S. Knapp Synthesis 1994 1. l6 S.P. Gupta Chem. Rev. 1994 94 1507. l7 L.S. Jungheim and T.A. Shepherd Chem. Rev. 1994 94 1553. H. Laatsch Angew. Chem. Int. Ed. Engl. 1994 33,422. l9 W. J. Stec and A. Wilk Angew. Chem. Int. Ed. Engl. 1994 33 709. 2o T. Ogawa Chem. SOC.Rev. 1994 23 397. 21 R. M. J. Liskamp Angew. Chem. Int. Ed. Engl. 1994,33,305; R. M. J. Liskamp Red. Trav. Chim. Pays-Bas 1994 113 1. ” ‘3rd International Symposium on Protein Structure-Function Relationships’ Pure and Applied Chemistry 1994 66 1. 23 e.g. Y. Kuroda and H. Ogoshi Synlett 1994 319. 24 W. Zhou and X. Xu,Acc. Chem. Res. 1994 27 211. 2s D. Middlemiss and S. P. Watson Tetrahedron 1994 50 13 049.L. Agrofoglio E. Suhas A. Farese R. Condom S. R. Challand R. A. Earl and R. Guedj Tetrahedron 1994 50 10611. 27 R. 0.Duthaler Tetrahedron 1994 50 1539. 28 D.C. Cole Tetrahedron 1994 50 9517. 29 Tetrahedron 1994 50 1296. 30 V. Ullrich and R. Brugger Angew. Chem. Int. Ed. Engl. 1994,33 191 1; U. Pindur and G. H. Schneider Chem. SOC.Rev. 1994,23,409;T. A. Spencer Acc. Chem. Res. 1994,27,83;A. I. Scott Tetrahedron 1994 50 13315. 31 L. Kvittingen Tetrahedron 1994,50,8253;P. Besseand H. Veschambre ibid. 1994,50,8885;H. Waldmann and D. Sebastian Chem. Rev. 1994,94 911. 32 C. A. Hunter Chem. SOC. Rev. 1994,23 101 ;I. D. Kuntz E. C. Meng and B. K. Shoichet Acc. Chem. Res. 1994 27 117. ’’ V.V. Kane W.H. De Wolf and F. Bickelhaupt Tetrahedron 1994 50 4575; ‘Cyclophanes’ Top.Curr. Chem. 1994 172 1; T. Jorgensen T. K. Hansen and J. Becher Chem. SOC.Rev. 1994 23 41. 34 H. Butenschon Angew. Chem. Int. Ed. Engl. 1994,33,636;A. de Meijere and F. E. Meyer ibid. 1994,33 2379; C. Lambert and P. von R. Schleyer ibid. 1994,33,1129;A. Togni and L. M. Venanzi Angew. Chem. Int. Edn. Engl. 1994,33,497;‘OMCOS-7’ Pure and Applied Chemistry 1994,66,1415 et seq.; T. J. Collins Acc. Chem. Res. 1994,27,279; E. Negishi and T. Takahashi Acc. Chem. Res. 1994,27 124; Tetrahedron 1994 50 285; D. J. Burton Z. Yang and P.A. Morken ibid. 1994 50 2993; ibid. 1994 50 5845. 35 J. Iqbal B. Bhatia and N. K. Nayyar Chem. Rev. 1994 94 519; A. Albini M. Mella and M. Freccero Tetrahedron 1994 50 575. 36 A. Padwa and D. J. Austin Angew.Chem. Int. Ed. Engl. 1994,33 1797; H. Schmalz ibid. 1994,33,303;T. Ye and M.A. McKervey Chem. Rev. 1994 94 1091. 37 V.K. Aggarwal Angew. Chem. Int. Ed. Engl. 1994,33 175; T. Bach ibid. 1994,33,417; F. Effenberger ibid. 19994 33 1555; G. Kaupp ibid. 1994 33 728; H.C. Kolb M.S. VanNieuwenhze and K.B. Sharpless Chem. Rev. 1994,94,2483; C. S. Poss and S. L. Schreiber Acc. Chem. Res. 1994,27,9;W. Adam and M. U. Richter Acc. Chem. Res. 1994,27,57;T. G. Grant and A. I. Meyers Tetrahedron 1994,50,2297; Tetrahedron 1994 50 4235. 38 B. Cornils W.A. Herrmann and M. Rasch Angew. Chem. Int. Ed. Engl. 1994 33 2144; S. Kotha Tetrahedron 1994 50 3639. 128 Peter Quayle discussed in some detail. Despite these advances the use of non-racemic intermediates from the ‘chiral pool’ still remains an attractive proposition for many synthetic sequence^.^' As stated above the art of organic synthesis has in certain quarters become an undervalued currency those non-believers should consult the recent reviews on paclitaxel (Tax01)~’ and alkaloid4’ synthesis for rejuvenation.In a similar vein the chemistry of C6,and related systems has caught the imagination of theoretical and synthetic chemists alike as indicated by the frequency of reviews in this area.42 The current awareness of the synthetic community to environmental problems has evoked numerous responses including the investigation of aqueous reaction media,43 ~onochemical~~ and electrochemical technique^,^' and the solid state46 for conducting organic reactions.Toxicological properties of organochlorine compounds have been reviewed;47 curiously a recent study suggests that in seals at least that there is a preferential accumulation of ( + )-a-HCH in the brain:* 2 Aliphatic Chemistry General.-The theory of coarctate transition states has been re~iewed.~’ Overviews of hetero Diels-Alder reactions” including asymmetric variants,’ halohydrin~,’~ furan -+1,4-dicarbonyl inter conversion^,^ benzotria~oles,~~ MVP-type redox reaction^,^ a-oxoketene~,’~ and a refreshingly critical discussion of the now-fashionable Grif- fith-Ley TPAPS7 oxidant have appeared. Reductions.-Asymmetric hydrogenations are now becoming widespread in synthetic appeal. For example the DuPHOS-Rh system has been used to good effect in the synthesis of uncommon amino acids with uniformly high levels of asymmetric induction (>98.5% e.e.).” The Dupont have recently disclosed that either D-or L-ar-amino acids may be prepared by catalytic asymmetric reduction of the corresponding dehydroamino acids; again the degree of induction is high (96-97% e.e.) but more importantly the sense of induction is controlled by an easy modification of the chiral modifier which in this case was D-glucose.Related 39 e.g.,D. Tanner Angew. Chem. Int. Ed. Engl. 1994,33,599;H. Redlich Angew. Chem. Int. Ed. Engl. 1994 33 1345. 40 K.C. Nicolaou and D.J. Austin Angew. Chem. Int. Ed. Engl. 1994 33 15. “ U. Beifuss Angew. Chem. Int. Ed. Engl. 1994 33 1144. 42 e.g. E.C. Constable Angew. Chem. Int. Ed.Engl. 1994 33 2269. I3 A. Lubineau J. Auge and Y. Queneau Synthesis 1994 741. I4J. M. Pestman J. B. F.N. Engberts and F. deJung Red. Trau. Chim. Pays-Bas. 1994 113 533. 45 J. Yoshida Top. Curr. Chem. 1994 170 39. N. B. Singh R.J. Singh and N. P. Singh Tetrahedron 1994 50 6441. D. Henschler Angew. Chem. Int. Ed. Engl. 1994 33 1920. 48 K. Moller C. Bretzke H. Huhnerfuss R. Kallenborn J. N. Kinkel J. Kopf and G. Rimkus Angew. Chem. Int. Ed. Engl. 1994 33 882. 49 R. Herges Angew. Chem. Int. Ed. Engl. 1994 33 255. J. Streith and A. Defoin Synthesis 1994 1107. 51 H. Waldmann Synthesis 1994 535. 52 C. Bonini and G. Righi Synthesis 1994 225. 53 G. Piancatelli J. Auge and Y. Queneau Synthesis 1994 867. 54 A. R. Katritzky X. Lan and W. Fan Synthesis 1994 445.55 C. F. de Graauw J.A. Peters H. v. Bekkum and J. Huskens Synthesis 1994 1007. 56 C. Wentrup W. Heilmayer and G. Kollenz Synthesis 1994 1219. ” S.V. Ley J. Norman W. P. Griffith and S. P. Marsden Synthesis 1994 639. 58 M.J. Burk J. R. Lee and J. P. Martinez J. Am. Chem. SOC. 1994 116 10847. 59 T.V. RajanBabu T. A. Ayers and A. L. Casalnuovo J. Am. Chem. SOC. 1994 116,4101. Aliphatic and Alicyclic Chemistry 129 reductions of olefins,60 enamines,6' and ketones6 merely underscore the universal appeal of this approach to EPC synthesis (Scheme 1). Buchwald has developed a general approach to optically enriched amines and alcohols via the hydrosilylation of enamine~,~~ and ketones6' in conjunction with chiral titanocene catalysts irnine~,~~ (Scheme 2).Asymmetric borane reductions can provide functionalized alcohols with good/excellent levels optical purity66 (in certain cases >99% e.e.); one must always be aware however of the potential substrate dependence of these reductions upon the sense of induction67 (Scheme 3). Oxazaborilidine-mediated ketone reductions again have been used extensively for the enantioselective synthesis of alcohols.68",68b A highlight in this area is the observation by Heimstra and Speckamp that desymmetrization of meso-imides is possible using these reagents affording the corresponding imides with reasonable levels of optical purity (between 76% and 87% e.e.)69 (Scheme 4). Bullock has developed a highly efficient method for the ionic reduction of hindered 01efins.~' Oxidations.-The use of dimethyldioxirane (DMD) and its analogues as versatile oxidizing agents continues to gain acceptance.The major advantages of DMD over more conventional reagents such as peracids is that the by-product of the oxidation sequence acetone is relatively innocuous and that in many cases the oxidation reaction takes place under neutral mild reaction conditions. There are numerous examples of the use of this reagent in synthetic sequences this as depicted below (Scheme 5). Of note is the observation that oxidation of cyclohex-2-en-1-01 and its derivatives is uniformly trans-selective with this reagent78 (Scheme 6). Phot~lysis~~ of the diazo compound (6) in oxygen-saturated CFC1 at 183 K afforded the isolable dioxirane (7) in 55% yield as a crystalline solid (m.p.62-64 "C).Dioxirane (7) slowly decomposes to the ester (8) at the rate of 10% conversion per day (Scheme 7). Bolm"" has developed a Baeyer-Villiger-type lactone synthesis which utilizes molecular oxygen (at 1 atm. pressure) in conjunction with a variety of copper(I1) complexes. Incorporation of C,-symmetric ligands around the metal centre induces optical yields 6o J.N. Freskos S. A. Laneman M. L. Reilly and D. H. Ripin Tetrahedron Lett. 1994 35 835. 61 J. D. Armstrong 111 K. E. Eng J. L. Keller R. M. Purick F. W. Hartner W.-B. Choi D. Askin and R. P. Volante Tetrahedron Lett. 1994 35 3239. 62 D. M. Garcia H. Yamada S. Hatakeyama and M. Nishizawa Tetrahedron Lett. 1994 35 3325. 63 N. E. Lee and S.L. Buchwald J. Am. Chem.Soc. 1994 116 5985. 64 C. A. Willoughby and S. L. Buchwald J. Am. Chem. Soc. 1994 116 11 703. 65 M.B. Carter B. Schiott A. Gutierrez and S.L. Buchwald J. Am. Chem. Soc. 1994 116 1167. 66 D. A. Beardsley G. B. Fisher C. T. Goralski L. W. Nicholson and B. Singram Tetrahedron Lett. 1994,35 1511. 67 P. V. Ramachandran B. Gong and H. C. Brown Tetrahedron Lett. 1994 35 2141. (a)R. Hett R. Stare and P.Helquist Tetrahedron Lett. 1994,35,9375;(b)G. J. Qualich J. F. Blake and T.M. Woodall J. Am. Chem. Soc. 1994 116 8516. 69 R. Romagnoli E. C. Roos H. Hiemstra M. J. Moolnaar N. Speckamp B. Kaptein and H. E. Schoemaker Tetrahedron Lett. 1994 35 1087. 70 R.M. Bullock and J.-S. Song J. Am. Chem. Soc. 1994 116 8602. 71 J.T. Link S.J. Danishefsky and G. Schulte Tetrahedron Lett.1994 35 9131. 72 J.T. Link and S.J. Danishefsky Tetrahedron Lett. 1994 116 9135. 73 P. Bovicelli P. Lupattelli D. Fracassi and E. Mincione Tetrahedron Lett. 1994 35 935. 74 T. K. Park J. M. Peterson and S.J. Danishefsky Tetrahedron Lett. 1994 35 2671. 75 J. K. Crandall and T. Reix Tetrahedron Lett. 1994 35 2513. 76 X. Wang B. Ramos and A. Rodriguez Tetrahedron Lett. 1994 35 6977. 77 D. Kuck A. Schuster C. Fusco M. Fiorentino and R. Curci J. Am. Chem. Soc. 1994 35 2375. 78 M. Kurihara S. Ito N. Tsutsumi and N. Miyata Tetrahedron Lett. 1994 35 1577. 79 A. Kirschfeld S. Muthusamy and W. Sander Angew. Chem. Int. Ed. Engl. 1994 33 2212. (a)C.Bolm G. Schlingloff and K. Weickardt Angew. Chem. Int. Ed. Engl. 1994,33,1848; (b)G.-Z. Wang U. Andreasson and J.E. Backvall Tetrahedron Lett. 1994 35 1037. 130 Peter Quayle mH:rIMe (R R) -Pr -DuPHOS -Rh* CH;:? (ref 58) H2 Br Br >98.5% e.8. 0.05-0.1d% ‘qNHCoMe [LRH (COD)]Sb~ (ref 59) 30-40pSi C02Me H2 / THF 97.2% 8.e. Me 0 Me [Ru(R -BINAP) CIA * R0V!O2H (ref 60) MeOHI NEt3 155 “c H2 (S)-BINAP * (ref 61) RuCl2 70% (82%e.e.) Y a:Bw Y H H cgHlg% (ref 62) ((R)-BINAP] RuCl2 H2(1OOatm);(0.01 q) cgHlg5 OMe OMe MeOH; tt;40hr 100% yield (99%e.e.) Scheme 1 Aliphatic and AlicycEic Chemistry i -iii I (ref 63) R*Me 89 -96% e.e. vi -vii \ i,k-v L(.. R2 RR,, R~AN-R3 H 65-90% yield 67-88% yield (53-99% e.e.) (1 2 -97% e.e.) (ref64) (ref 65) Reagents i 2 eq.BuLi; ii 2.5 eq. PhSiH,; iii H,; iv Me,SiO[Me(SiO)H],SiMe; v TBAF; vi IOmol% Bu"Li; vii 15mol% PhSiH,; viii H, R'R2C=NR3 Scheme 2 in the region of 50-70% (Scheme 8). Clearly this methodology has many potential applications provided that the optical yields can be improved. A related methodsob for the oxidation of secondary alcohols to ketones has also appeared (Scheme 9). Sulfoxides are useful synthetic intermediates a number of reports have appeared this year detailing new or improved methods for their The use of a catalytic quantity of an optically pure sulfonylimine in conjunction with stoichiometric hydrogen peroxide as a reoxidant is particularly appealing.84 The development of catalytic oxidizing procedures using hydrogen peroxide as a reoxidant is a popular theme,85 as is the use of chemoenzymatic oxidation^^^-'^ (Scheme 10).W. B. Jennings M. J. Kochanewcz C. J. Lovely and D. R. Boyd J.Chem.SOC.,Chem. Commun. 1994,2569. 82 J. F. Bower and J. M. J. Williams Tetrahedron Lett. 1994 35,71 11. 83 K. M. Poss S. T. Chao E. .M. Gordon P. J. McCann D. P. Santafianos,S.C. Traeger R. K. Varma and W. N. Washburn Tetrahedron Lett. 1994 35,3461. 84 P. C. Bulman Page J. P. Heer D. Bethell E. W. Collington and D. M. Andrews Tetrahedron Lett. 1994 35,9629. '' W. P. Griffith A. M. Z.Slawin K. M. Thompson and D. J. Williams J. Chem.SOC.,Chem. Commun. 1994 569. 86 C.R.Johnson L. S. Harikrishnan and A. Golebiowski Tetrahedron Lett. 1994 35,7735. " C. R. Johnson A. Golebiowski M. P. Braun and H.Sundram Tetrahedron Lett. 1994 35 1833. " T. Hudlicky J. Rouden H. Luna and S. Allen J. Am. Chem. SOC. 1994 116 5099. 89 D. R.Bayd,N. D. Sharma S.A. Barr H. Dalton J. Chima G. Whited and R. Seemayer,J. Am. Chem.SOC. 1994 116 1147. 132 Peter QuayEe 2 &NR2 -L c'B(-&)2 81 -88% yieM (75-99% e.e.) (ref 66) 90% 8.8. OMe OH I 90% 8.8. (R) 92%e.e. (S) (ref 67) Reagents i rt 36 h; ii NaOH H,O,; iii H,O+ Scheme 3 Aliphatic and Alicyclic Chemistry 0.1 eq ?*F:ph 0.6 BH3- THF 8-0 i CHI Ph-0 c02Me 95% Ph 85%/NaHITMF cph/ 1 ""Wo+Ph Ph-O@' C02Me THF; A H HO Serevent' (ref 68a) Ph AcO Ph H'B-o (ref 69) 0soc-k8.DMw*Amy;Ac EH3.THF 0 ' ' Ph Ph 51%; 87%8.8.Scheme 4 134 Peter Quayle Ph’ 0% P H i NaH; CHGN iii. CHGN; R to refiux 42% (ref 72) 0 Reagents ii TBAF THF; iii NaH BnBu DMF Scheme 5 Aliphatic and Alicyclic Chemistry (ref 73) Bno F (ref 74) hi NaH BnBr DMF (72%) 0-Bn 0 (ref 75) T~NH' 56% TS'. - (ref 76) (ref 77) -20 oc 98% Scheme 5 (cont.) 6I_ 6,. 6 Peter Quayle + 0 trans :cis 77 23 OTBDMS OTBDMS 93 7 Reagents i oxone@ 2,6-dimethylcyclohexanone Scheme 6 Scheme 7 Synthetic applications of the Sharpless asymmetric dihydroxylation protocol attest to its fundamental importance in asymmetric ~ynthesis’~-~~ (Scheme 11).A particular-ly topical application of this methodology is that reported by Hawkinsg3 concerning the kinetic resolution of C70 C76 and CS4.Hale94 has observed anomalous stereochemical behaviour in the oxidation of 1,l-disubstituted alkenes with this system; such reports will add further interest to the mechanistic debate concerning these reaction^.'^ Jacobseng6 asymmetric epoxidation has also spawned a variety of 90 T.Nakarnura N. Waizumi Y. Horiguchi and I. Kuwajima Tetrahedron Lett. 1994 35 7813. 91 K.P. M. Vanhessche Z.-M. Wang and K. B. Sharpless Tetrahedron Lett. 1994 35 3469. 92 H.Wagner and U. Koert Angew. Chem. Int. Ed. Engl. 1994,33,1873. 93 J. M. Hawkins M. Nambu and A. Meyer J. Am. Chem. SOC. 1994,116,7642. 94 K.J. Hale S. Manaviazar and S. A. Peak Tetrahedron Lett. 1994 35 425. 95 A. Veldkamp and G.Frenking J. Am. Chem. SOC. 1994,116,4937;H.Becker P.T. Ho H.C. Kolb S. Loren P.-0. Norrby and K. B. Sharpless Tetrahedron Lett. 1994 35 7315. 96 W.Zang N. H. Lee and E.N. Jacobsen J. Am. Chem. SOC. 1994,116,425. Aliphatic and Alicyclic Chemistry cat+ = cu 1 Scheme 8 1 021 N2 __._3 i\ 0.5% A BU' BU' 00% 0 Scbeme 9 synthetic application^^'-^^ (Scheme 12). Kende' O0 has reported that diphenylphos- phinic anhydride mediates a high-yielding conversion of alkenes to epoxides whilst Aggarwal has developed a novel catalytic cycle for the synthesis of epoxides from aldehydes and sulfur ylides' O1 (Scheme 13). Olefins and Acetylenes.-The titanium-induced reductive coupling of aldehydes and ketones (McMurray reaction) provides a general method for the synthesis of olefins.97 J. F. Low and E.N. Jacobsen J. Am. Chem. SOC. 1994 116 12 129. 98 S. D. Rychnovsky and K. Hwang Tetrahedron Lett. 1994,35 8927. 99 S. Chang R. M. Heid and E. N. Jacobsen Tetrahedron Lett. 1994,35 669. loo A.S. Kende P. Delair and B. E. Blass Tetrahedron Lett. 1994 35 8123. V. K. Aggarwal H. Abdel-Rahman R. V. H. Jones H. Y. Lee,and B. D. Reid J. Am. Chem.SOC.,1994,116 5973. 138 Peter Quayle 8 S ArO 'Me ArO"Me (R) (ref 81) 34% 8.8. H (d.8. = 99 :1) 32% (ref 86) 90% (ref 87) Q -b TBSd Mannojirimyun (ref 89) Br)$-,& Bra:: OH >98% 8.8. Reagents i ButO2H Ti(OPr'), L-DET CH,Cl, -20 "C;24 h; ii isoprenyl acetate Pseudomonas cepacia lipase; iii Pseudomans putida 39D; iv H, Pd-C MeDH Scheme 10 Aliphatic and Alicyclic Chemistry OPiv OPW (ref 90) 00% 94%e.e.(R) (ref 91) 98% (ref 92) Reagents i OsO (1 rnol%) DHDQ-PHN K,Fe(CN), K,CO, Bu'OH H,O; ii MeN(H)CH,CH,N(H)Me Scheme 11 However a reinvestigation of the homocoupling of acetophenone conclusively demon- strates that the major product of this reaction is the 2 isomer and not the E isomer as originally claimedlo2 (Scheme 14). This reappraisal may be general for those couplings leading to tetrasubstituted double bonds. A general approach to the synthesis of 2 iodo-olefins using a-iodoalkyl ylides has many potential synthetic applications' O3 (Scheme 15). The syn elimination of hypoiodous acid from iodoso compounds leading to olefins was reported by Reich in 1978.Unfortunately this methodology has been somewhat upstaged by the use of related selenoxide/sulfoxide eliminations although application of this reaction in a real synthetic context by Fuchs clearly demonstrates the synthetic potential of this procedurelo4 (Scheme 16). In a related context the Ramberg-Backlund reaction has enjoyed a resurgence in interest of late as illustrated by its application in Trost's synthesislo5 of (+)-solamin (Scheme 17). lo2 P.G. Anderson Tetrahedron Lett. 1994 35 2609. '03 H. Chen T. Wang and K. Zhao Tetrahedron Lett. 1994 35 2827. lo4 S. Kim and P. L. Fuchs Tetrahedron Lett. 1994 35 7163. lo' B.M. Trost and Z. Shi J. Am. Chem. SOC.,1994 116 7459. 140 Peter Quayle OAC (ref 98) 0 0 35% 8.8.PI' (ref 99) 0-Qo 70% 8.8. Scheme 12 Organometallic-based approaches to olefin synthesis are legion; among the most impressive of these are the Matin'06 and Pandit'O' approaches to manzamine A which utilize a Grubbs metathesis reaction for the construction of the E and D rings respectively (Scheme 18). Heck,'08-''o Stille 111,112 Suzuki,"3*114 and Trost"' lo6 S. F. Martin Y. Liao Y.Wong and T. Rein Tetrahedron Lett. 1994 35 691. lo' B. C. Borer S. Deerenberg H. Bieraugel and U. K. Pandit Tetrahedron Lett. 1994 35 3191. lo' T. Jeffery Tetrahedron Lett. 1994 35 3051. lo9 D. C. Horwell P. D. Nichols and E. Roberts Tetrahedron Lett. 1994 35 939. Y. Koga M. Sodeoka and M. Shibasaka Tetrahedron Lett.1994 35 1227. A. Degl'Innocenti A. Capperucci L. Bartoletti A. Mordini and G. Reginato Tetrahedron Lett. 1994,35 208 1. 'I2 H. K. Patel J. D. Kilburn G. J. Langley P. D. Edwards T. Mitchell and R. Southgate Tetrahedron Lett. 1994 35 481. G. Mazal and M. Vaultier Tetrahedron Lett. 1994 35 3089. 'I4 K.K. Wang and Z. Wang Tetrahedron Lett. 1994 35 1829. K. Togashi M. Terakado M. Miyazawa K. Yamamoto and T. Takahashi Tetrahedron Lett. 1994,35 3333. Aliphatic and Alicyclic Chemistry PhCHO + Me2S + Rh2(0Ac) N&HPh H.A; (ref 101) 3hr Ph 70% Scheme 13 (ref 102) Scheme 14 reactions continue to be used extensively for the coupling of unsaturated fragments; illustrative examples are given in Scheme 19. Note should be made of the Jeffery'" and Buchecker' results concerning the development of aqueous and heterogeneous modes of the Heck and Suzuki reactions respectively.Elucidation of the factors controlling palladium-mediated asymmeric allylation reactions continues to be an active area of research.' '' The synthesis of functionalized unsaturated systems continues to be a growth area which relies almost exclusively upon transition-metal- based strategies for implementation' 18-' 24 (Scheme 20); notable exception^'^^"*^ to '16 G. Marck A Villiger and R. Buchecker Tetrahedron Lett. 1994 35 3277. '" C. Breutel P. S. Pregosin R.Salzmann and A. Togni J.Am. Chem. SOC.,1994,116,4067; B. M. Trost and R.C. Bunt J.Am. Chem.SOC.,1994,116,4089; A. Gogoll,J. Ornebro H. Grennberg and J.-E.Backvall J. Am. Chem. SOC. 1994,116,3631; P. Sennhenn B. Gabler and G. Helmchen Tetrahedron Lett. 1994,35 8595. F. Babudri V. Fiandanese L. Mazzone and F. Naso Tetrahedron Lett. 1994 35 8847. '19 S. Ikeda and Y. Sato J. Am. Chem. SOC.,1994 116 5975. 142 Peter Quayle (ref 103) (2 -major) Reagents i Bu"Li; ii I,; iii NaN(TMS),; iv R'CHO Scheme 15 Scheme 16 R20-P1 i -(ref 105) so2qo >95% R201r3 Reagents i Bu'OK Bu'OH CCl Scheme 17 this generalization are depicted in Scheme 21. The development of new routes to vinylstannanes,' 26 ~inylsilanes,'~~ and optically enriched ally1 silanes' 28 continues to be the focus of much attention (Scheme 22). The Cinderella area of polyacetylene 120 N. Chatani T.Morimoto T. Muto and S. Murai J. Am. Chem. SOC. 1994 116 6049. 121 L. Deloux E. Skrzypczak-Jankun B. V. Cheesman M. Srebnik and M. Sabat J. Am. Chem. SOC.,1994 116 10302. 122 B. M. Trost and T.J. J. Miiller J. Am. Chem. SOC. 1994 116 4985. 123 D. C. Harrowven and H. S. Poon Tetrahedron Lett. 1994,35 9101. 124 M. Alami B. Crousse and G. Linstrumelle Tetrahedron Lett. 1994 35 3543. 125 (a)B. M. Trost and C. Li J.Am. Chem. SOC.,1994,116,3167; (b)E. Doris L. Dechoux and C. Mioskowski Tetrahedron Lett. 1994 35 7943. 126 D. M. Hodgson L. T. Boulton and G. N. Maw Tetrahedron Lett. 1994,35 2231. 127 F.J. Blanco P. Cuardrado A. Gonzalez F. J. Pulido and I. Fleming Tetrahedron Lett. 1994,35 8881; D. M. Hodgson and P. J. Comina ibid. 1994,35,9469; J. A. Soderquist and J.C .Colberg ibid. 1994,35 27. 128 Y. Landais D. Planchenault and V. Weber Tetrahedron Lett. 1994,35,9549; Y.Hatanaka K. Goda F. Yamashita and T. Hiyama ibid. 1994 35 7981. Aliphatic and Alicyclic Chemistry (ref 107) [cat] = [ Scheme 18 chemistry' 29 has stimulated much interest in developing new routes to functionalized mono- and bis-acetylene starter units' 30-' 33 (Scheme 23). Alkylation Reactions.-Carbonyl Alkylation Afdof and Related Reactions. Enan-tioselective deprotonation of mem cyclic ketones is now a well established asymmeter- ization reaction and has been used to good effect this year in the synthesis of tropane alkaloids' 34 (Scheme 24). The initial deprotonation reaction proceeded with ca. 90% e.e. when conducted in the presence of 0.5 equivalents of LiC1.The synthesis of lZ9 J. Anthony C. Boudon F. Diederich J. Gisselbrecht V. Grarnlich M. Gross M. Hobi and P. Seiler Angew. Chem. Int. Ed. Engl. 1994 33 763. 130 D. Grandjean P. Pale and J. Chuche Tetrahedron Lett. 1994 35 3529. 13' C. H. Cummins Tetrahedron Lett. 1994,35 857. 13' J. S. Yadav and V. P. Prahlad Tetrahedron Lett. 1994 35 641. 133 Y. Fukue S. Oi and Y. Inoue J. Chem. SOC. Chem. Commun. 1994 2091. 134 M. Majewski and R. Lazny Tetrahedron Lett. 1994 35 3653. 144 Peter Quayle I PhI + 7c0,w c Ph~co,Me (ref 108) 96% (ref 111) OBn OBn b-FF 85% (ref 116) Reagents:i 5% [Pd(OAc),(PPh,),] K,CO or Na,CO, PTC H,O MeCN; ii SnBu,R PdCl,(MeCN),; iii Pd(o) HOAc; iv Pd/C Ph,P Na,CO, 17 h 80°C Scheme 19 novel C,-symmetric vicinal diamines for use in such asymmetric deprotonation reactions has also been described'35 (Scheme 24).Cahiez has demonstrated that manganese enolates undergo highly regioselective alkylation reactions; importantly over alkylation does not appear to be a problem in these systems'36 (Scheme 25).Silver triflu~roacetate'~~ has been used to promote the alkylation of silyl enol ethers under K. Bambridge M. J. Begley and N. S. Simpkins Tetrahedron Lett. 1994 35 3391. 13' G. Cahiez B. Figadere and P. Clery Tetrahedron Lett. 1994,35,3065; G.Cahiez K. Chau and P. Clery ibid. 1994 35 3069. 13' P. Angers and P. Canonne Tetrahedron Lett. 1994 35 367. Aliphatic and Alicyclic Chemistry 145 (ref 118) JMe + Bu"-H + Ph-SnEt3 80% (ref 1 1 9) pi(') Ec(ref 120) E R-H + (ref 121) Me02C+Y \ 0 Meo2cwR' \v 2.9 1 Reagents i Bu"Li -78°C; ii Cp,Zr(H)CI; iii E'; iv EZ Scheme 20 146 Peter Quayle Me02C *Me C02Me >-CH30bC02Me (ref 125a) <C02Me c02Me (ref 125b) Reagents i 0.3eq.Ph,P cat. HOAc cat. NaOAc toluene 80 "C Scheme 21 I (ref 126) =*= ll,IW (ref 127) 55% yield 35% yield Reagents i Bu,SnCHBr, LiI CrCl, DMF-THF 25 "C; ii (PhMe,Si),CuCNH,; iii Ef; iv (TMS),SiH CH,Cl, Rh,( OAc) Scheme 22 Aliphatic and Alicyclic Chemistry (ref 130) (ref 131) (ref 132) R1-H + COP + R2Br -vl R'-Co# (ref133) Reagents i Ph,P CBr,; ii NEt,; iii NaHDMS THF -100 "C; iv Ph,P CCl,; v Li THF; vi K,CO, Cu' Ag' Scheme 23 mild conditions.The stereoselective alkylation of enolates and related intermediates possessing chiral auxiliaries has been used extensively in natural product syn-thesis' 38-144 (Scheme 26). The use of Evans auxiliaries in asymmetric alkylation/aldol reactions 14'9 146 (Scheme 27) has been further bolstered by Da~ies's'~~ development of the related 'Quat' chiral auxiliaries (9),which offer the advantage of milder methods for auxiliary removal. Kobayashi14* has developed an anti-selective catalytic aldol sequence utilizing a chiral tin@) catalyst whilst Mikami14' has demonstrated that the related A.G. Myers B. H. Yang H. Chen and J. M. Gleason J. Am. Chem. SOC. 1994 116 9361. 139 D. Askin K.E. Eng K. Rossen R. M. Purick K. M. Wells R. P. Volante and P.J. Reider Tetrahedron Lett. 1994,35 673. 140 M. Mehlfuhrer H. Berner and K. Thirring J. Chem. SOC.,Chem. Comrnun. 1994 1291. R. M. Williams P. Colson and W. Zhai Tetrahedron Lett. 1994 35 9371. A. B. Smith A. Pasternak. A. Yokoyama and R. Hirschmann Tetrahedron Lett. 1994 35 8977. R. Cotton A. N. C. Johnstone and M. North Tetrahedron Lett. 1994 35 8859. M.T. Reetz F. Kayser and K. Harms Tetrahedron Lett. 1994 35 8769. H. Kigoshi M. Ojika T. Ishigaki K. Suenaga T. Mutou A. Sakarura T. Ogawa and K. Yamada J. Am. Chem. SOC. 1994 116 7443. K. G. Carson and B. Ganem Tetrahedron Lett. 1994 35 2659. S. G. Davies G. J. Doisneau J. C. Prodger and H. J. Sanganee Tetrahedron Lett. 1994 35 2369.S. Kobayashi and T. Kawasuji Tetrahedron Lett. 1994 35 3329. 149 K. Mikami and S. Matsulawa J. Am. Chem. SOC.,1994 116 4077. ''13 148 Peter Quayle (ref 134) Me (ref 135) -70 "C Scheme 24 OSiMe3(y i-iii * &Ph 09% (ref 136) iv ii iii ~ Ph+ 85% 61% 3.8:l Reagents i MeLi; ii MnC1,; iii PhCH,Br; iv LDA Scheme 25 Aliphatic and Alicyclic Chemistry (ref 138) (ref 139) But PhCON iv iii (ref 140) lYNMe 0 Ph v, L (ref 141) CBzNJo H *C02Me (co2Me vii. iii (ref 143) A A ZNH CO~BU' ZNH C02But (3:1) Reagents i 2eq. LDA LEI; E'; iii ally1 bromide; iv L,DA; v NaN(SiMe,),; vi RX; vii 2eq. LHMDS Scheme 26 150 Peter Quayle (ref 145) 60% (9) Scheme 27 titanium-promoted reaction proceeds via a closed transition state (Scheme 28).Functionalized allylboranes' and stannanes' 'l,' 52 continue to provide new path- ways for the asymmetric synthesis of a variety of functionalized intermediates (Scheme 29). The use of carbon-centred radicals in asymmetric synthesis is now a well- recognized phenomenon' 53*154 (Scheme 30).In certain cases154 the stereochemical outcome of these alkylation reactions is complementary to that observed using polar reagents. The use of transition metals as either temporary stereocontrol elements or as chiral modifiers in alkylation reactions has been used extensively of late,155*' 56 as illustrated below (Scheme 31). In certain cases' 56 the stereochemical outcome of the reaction may be radically affected by seemingly small changes in the ligand environment around the metal centre.Conjugate Additions. The role of copper additives in a number of carbon-centred conjugate addition reactions has come under scrutiny again this year.' Irrespective 150 A.G. M. Barrett M. A. Seefeld and D.J. Williams J. Chem. SOC.,Chem. Commun. 1994 1053. 15' S. J. Stanway and E. J. Thomas J. Chem. SOC. Chem. Commun. 1994 285. lS2 J. S. Carey and E. J. Thomas J. Chem. SOC.,Chem. Commun. 1994 283. 153 H. Nagno and Y. Kuno J. Chem. SOC.,Chem. Commun. 1994,987. 154 K. Haraguchi H. Tanaka S. Saito K. Yamaguchi and T. Miyasaka Tetrahedron Lett. 1994,35,9721. C.K. Wada and W.R. Roush Tetrahedron Lett. 1994 35,7351. 15' L. Schwink and P.Knochel Tetrahedron Lett. 1994 35,9007. 15' J. Kabbara S. Flemming K. Nickisch H. Neh and J. Westermann,Tetrahedron Lett. 1994,35,8591; A. S. Vellekoop and R. A. J. Smith J. Am. Chem. SOC.,1994,116,2902; N. Krause R. Wagner and A. Gerold ibid. 1994 116 381. Aliphatic and Alicyclic Chemistry 151 sn(OTf)n),/ *SIP OH 0 OH 0 cat. PhCHO + TBSOi(OSiMe3OPh PhvOPh + PhvOPh OTBS h S syn anti 6 9 4 (ref 148) (up to 95% e.e.) (ref 149) L Scheme 28 of finer mechanistic detail Michael reactions especially as their asymmetric variants have proved to be highly useful in a variety of synthetic (Scheme 32). Particularly impressive is Yamamoto's discovery'64 that a$-unsaturated aldehydes undergo site-selective conjugate addition reactions with organolithium and -mag- nesium reagents when conducted in the presence of the bulky Lewis acid ATPH.3 Alicyclic Chemistry Cyclopropanes-The isolation of FR-900848 (10) has served as a catalyst for heightened interest in the development of new synthetic methodology in this area especially for the synthesis of linear arrays of polycyclopropanes. Zer~her'~' has shown that the allylic alcohol (1 1) undergoes stereoselective cyclopropanation to Is* B. H. Lipshutz and M. R. Wood J. Am. Chem. Soc. 1994 116 11 689. lS9 Z. Jin and P. L. Fuchs J. Am. Chem. Soc. 1994 116 5995. 160 G. Li D. Patel and V.J. Hruby Tetrahedron Lett. 1994 35 2301. 16' M. Nomura and S. Kanemasa Tetrahedron Lett. 1994 35 143. G. Pain D. Desrnaele and J. d'Angelo Tetrahedron Lett.1994 35 3085. Z. Wang and L.S. Jirnenez J. Am. Chem. SOC.,1994 116 4977. 164 K. Muruoka H. Imoto S. Saito and H. Yamamoto J. Am. Chem. SOC. 1994,116,4131. C.R. Theberge and C.K. Zercher Tetrahedron Lett. 1994 35 9181. 152 Peter Quayle (reg 150) Bu3Snv iv. i R-(reg 151) NBn2 I NBn2 OH Reagents i RCHO; ii H,O, NaOH; iii H30+;iv SnBr, -78°C Scheme 29 afford the syn-bicyclopropanes (12) and (13) in good yields (65% and 72% respectively). The sense of induction in these cyclopropanation reactions is reagent controlled use of the (+)-tartrate dioxaborane (14) affords the syn isomer (12) whilst the (-)-tartrate-derived dioxaborane (15) leads to the anti isomer (13) (Scheme 33). Nobayashi has utilized a related catalyst system for the asymmetric synthesis of the tin-and silicon-substituted cyclopropanes (16).Enantioselectivities in the region of 70-80% were routinely observed in these investigations (Scheme 34).166 The use of copper and rhodium-catalysed cyclo-propanation reactions have again been much in evidence. Kanema~a'~~ has demon-strated that styrene derivatives undergo cyclopropanation with diazoesters in the presence of C,-symmetric 1,2-diamine-m0difiedcopper salts in moderate to excellent optical yields. This process has been applied to the synthesis of chrysanthemic acid (Scheme 35). Martin168has utilized intramolecular cyclopropanation reactions in the presence of chiral rhodium catalysts to prepare functionalized lactones with high levels of optical purity (Scheme 35).Alternatively Charette'69 has shown that glucose-derived allylic ethers undergo cyclopropanation reactions in good chemical yields (>90%0) and with useful levels of diastereoisomeric purity (11 :1 to 17 1). A simple synthesis' 70 of the cis-functionalized cyclopropane (17) the isolation' 71 of the highly 166 N. Imai K. Sakamoto H. Takahashi and S. Kobayashi Tetrahedron Lett. 1994,35 7045. 16' S. Kanemasa S. Hamura E. Harada and H. Yamamoto Tetrahedron Lett. 1994 35 7985. S. F. Martin M. R. Spaller S. Liras and B. Hartmann J. Am. Chem. SOC. 1994 116 4493. 169 A. B. Charette N. Turcotte and J. Marcoux Tetrahedron Lett. 1994 35 513. L. Dechoux and E. Dons Tetrahedron Lett. 1994,354 2017. 17' W. E. Billups W. Luo and M. Gutierrez J.Am. Chem. Soc. 1994 116 6463. Aliphatic and Alicyclic Chemistry (ref 153) major 0 t-* TBDM$ OTBDMS TBDM$ OTBDMS 10 :1 + 0 .. IS TBDMSO ~TBDMS Scheme 30 unsaturated system (18),and the intermediacy'72 of the related cyclopropene (19)have also been documented (Scheme 36).Merlic' 73 has reported the cyclopropanation of c6 using a Fischer carbene complex. Cyc1obutanes.-Rosini '74 has developed a facile procedure for the preparation of bicyclo[3.2.0]hept-3-en-6-onesbased upon an intramolelcular [2 +23 cycloaddition reaction. Photochemical'75 techniques have also been employed for the synthesis of related bicyclic structures in which a 'silicon tether' was used to control the regiochemistry of the cycloaddition reaction.Related intramolecular cycloaddition reactions of optically active allenes afford cycloadducts with high levels of isomeric purity.' 76 Fukumoto' 77 has utilized a tandem Michael addition-alkylation sequence for the preparation of donor-acceptor cyclobutanes which are of synthetic utility (Scheme 37). Cyclobutane derivatives of c~nduritol'~~ have been prepared from 172 P. A. Wade and P.A. Kondracki J. Chem. SOC.,Chem. Commun. 1994 1263. 113 C. A. Merlic and H. D. Bendorf Tetrahedron Lett. 1994 35 9529. 174 E. Marotta P. Righi and G. Rossini Tetrahedron Lett. 1994 35 2949. 175 M. T. Crimmins and L. E. Guise Tetrahedron Lett. 1994 35 1657. 176 E. M. Carreira C. A. Hastings M. S. Shepard L. A. Yerkey and D. B. Millward J. Am. Chem. SOC.,1994 116 6622.177 M. Ihara T. Taniguchi and K. Fukumoto Tetrahedron Lett. 1994 35 1901. 178 Y. Kara M. Balci S. A. Bourne and W.H. Watson Tetrahedron Lett. 1994 35 3349. 154 Peter Quayle 0J: MeMg I THF -40% C h$: (ref 155) OX0 93% OX0 OH C~QH&HO I * CIQHS~WM~ N(H)Tf 699'0 92% 8.8. I I" OH (ref 156) ginnol; 92% 8.8. Reagents i [Br(CH,),], Zn; ii Bu,Cu(CN)Li Scheme 31 cyclooctatetraene. The synthetic utility'" of cyclobutanes is exemplified in an approach to the perhydrohistrionicotoxin ring system which utilizes a fragmentation reaction of a cyclobutane derivative in a key step (Scheme 38). Cyclopentanes-The synthesis of cyclopentane derivatives remains a growth area. Significant advances this year include the use of the Pauson-Khand (PK) reaction in an asymmetric fashion,'80.'81 including its application to carbohydrate chemistry18* and the development of a catalytic process for intramolecular PK reactions'83 (Scheme 39).A mechanistic' 84 investigation into the stereochemistry of the thermal vinylcyc- lopropanesyclopentene rearrangement has appeared; the transition-metal-catalysed 17' D. L. Comins and X. Zheng J. Chem. SOC.,Chem. Commun. 1994,2681. lE0 V. Bernardes X. Verdaguer N. Kardos A. Riera A. Moyano M.A. Pericas and A.E. Greene Tetrahedron Lett. 1994 35 575. X. Verdaguer A. Moyano M. A. Pericas A. Riera V. Bernardes A. Greene A. Alvarez-Larena and J. F. Piniella J. Am. Chem. SOC. 1994 116 2153. N. Naz T.H. Al-Tel Y. Al-Abed and W.Voelter Tetrahedron Lett. 1994 35 8581. N. Jeong S.H. Hwang Y. Lee and Y.K. Chung J. Am. Chem. SOC. 1994 116 3159. 184 J.E. Baldwin K.A. Villarica D.I. Freedberg and F.A. Anet J. Am. Chem. SOC.,1994 116 10845. Aliphatic and AIicyclic Chemistry * i-ui (ref 158) I C6H13 A 82% Ph Ph )7 Br )7 ArYYN7fo(ref 160) hr'v -NKo 0 0 CH3 0 0 vl vH (ref 162) -MeO 60% 58Yo 8.0. viii. k (ref 163) QT+ -Qo H Nuc 0 0 50-90% (ref 164) Reagents i MeLi Me,ZnLi cat. Me,Cu(CN)Li,; ii 4-isopropylcyclohex-2-enone; iii hexanal; iv ArMgBr CuBr DMS; v NBS -78°C; vi methyl acrylate; vii H,O+; viii NaH; ix H,C=CHS+Ph,; x ATPH; xi Nuc-Scheme 32 156 Peter Quayle HO OH ".pH-oH ZnEt,. CHzI2 -/ Ph 67% (12) (ref 16!5) Ph ZnEt Ph 72% H-&;oH H Scheme 33 variant has been utilized in the preparation of functionalized cyc10pentene.s'~~ (Scheme 39).Zirconium-based methods for the preparation of cyclopentanes have received much attention of late as illustrated below.186 The mild conditions and non-polar nature of the intermediates involved in these transformations suggests that synthetic exploita- tion will ensue relatively rapidly. PiersI8' has described a novel cyclopentenone annulation procedure which should be of some synthetic utility (Scheme 40). The palladium-catalysed cycloaddition of TMM with C, has been reported. 88 Cyclohexanes-Diels-Alder approaches again figure extensively in the preparation of functionalized cycl~hexanes'~~-~~~ (Figure 1).The development of em-selective K. Hiroi and Y. Arinaga Tetrahedron Lett. 1994 35 153. 186 T. Luker and R. J. Whitby Tetrahedron Lett. 1994 35 785. E. Piers K. L. Cook,and C. Rogers Tetrahedron Lett. 1994 35 8573. "'L. Shiu T. Lin S. Peng G. Her D. D. Ju S. Lin J. Hwang C. Y. Mou and T. Luh J. Chem. Soc. Chem. Commun. 1994 647. K. Maruoka H. Imoto and H. Yamamoto J. Am. Chem. SOC. 1994 116 12115. Aliphatic and Alicyclic Chemistry Me2PhSi*O"H 81% 8.8. (16) Scheme 34 (R' = I -menthyl) t~s:&=8:12 (frans= 74% e.e.) Rhd(5S)-MEPyL (ref 168) 75% yield (>949/0e.8.) Scheme 35 158 Peter Quayle -i B&&o&R (reflss) BnO OH R3 major Reagents i ZnEt, CH,I, toluene -30 "C Scheme 36 cycloadditi~ns,'~~ new asymmetric catalyst and a variety of promoters have been documented.'99~200 The first direct evidence for a 'biological Diels-Alder' reaction has also been reported this year.Ig0 Medium Rings.-This area has been dominated by the development of synthetic strategies towards the total synthesis of paclitaxel (Tax01)~' and enediyne antitumour agents * O E..J. Corey S. Sarshar and D. Lee J. Am. Chem. SOC. 1994 116 12089. 19' M. W. Wright T. L. Smalley Jr. M. E. Welker and A. L. Rheingold J. Am. Chem. SOC.,1994,116,6777. 19' K. Mikami Y. Motoyama and M. Terada J. Am. Chem. SOC. 1994 116 2812. 193 K. Maruoka M. Akakura S. Saito T. Ooi and H. Yamamoto J. Am. Chem. SOC. 1994 116 6153. 194 W. Oppolzer B.M.Seletsky and G. Bernardinelli Tetrahedron Lett. 1994 35,3509. 19' P.A. Grieco S.T. Handy and J. P. Beck Tetrahedron Lett. 1994 35,2663. 196 I. E. Marko and G. R. Evans Tetrahedron Lett. 1994 35,2767. 19' 1. E. Marko and G. R. Evans Tetrahedron Lett. 1994 35,2771. 198 L.Meerpoel M. Vrahami J. Ancerewin and P. Vogel Tetrahedron Lett. 1994 35 111. 199 Z. Zhang F. Flachsmann F. M. Moghaddam and P. Riiedi Tetrahedron Lett. 1994 35,2153. 'O0 G.Jenner Tetrahedron Lett. 1994 35,1189. '01 D.A. Singleton and A.M. Redman Tetrahedron Lett. 1994 35,509. '02 Y. Motoyama and K. Mikami J. Chem. SOC. Chem. Commun. 1994 1563. H. Oikawa Y. Suzuki A. Naya K. Katayama and A. Ichihara J. Am. Chem. SOC. 1994 116 3605. ,04 M.D. Shair T. Yoon T. Chou and S.J. Danishefsky Angew.Chem. Int. Ed. Engl. 1994 33 2417. Aliphatic and Alicyclic Chemistry 0 k;M hv > 350nrn (ref 1 75) 70-80% %Me OH o'si-Me' 'Me 0-SiMe (ref 176) 1.2 1 92% 9.8. (91% 9.9.) (92% e.e.) (ref 177) H c02Me 67% Scheme 37 Large Rings.-The synthesis of large rings has enjoyed a resurgence of interest of late. This is primarily due to the interest in developing 'artificial enzymes' which require binding pockets afforded by molecules such as (20).205 In addition a number of groups are attempting to develop a rational de nouo synthesis of C, (Scheme 41) and its derivativeszo6 whilst others are interested in preparing cyclic polyunsaturated systems such as (21k(24)which may possess interesting physical properties.207 '05 H.L. Anderson A. Bashall K. Henrick M. McPartlin and J. K. M. Sanders Angew. Chem. Int. Ed. Engl. 1994 33 429. '06 P. W. Rabideau A. H. Addourazak H. E. Folsom Z. Marcinow A. Sygula and R. Sygula J. Am. Chem. Soc. 1994 116 7891. A. de Meijere S. Kozhushkov C. Puls T. Haumann R. Boese M.J. Cooney and L.T. Scott Angew. Chem. Int. Ed. Engl. 1994 33 869. 160 Peter Quayle 0 -hv 80% 1 Lii (ref 179) major Reagents i SmI, THF,DMPU; ii TFA Scheme 38 Aliphatic and AIicyclic Chemistry -Me02CQ0-ph - Me02C (ref 182) Me02C - MeO& ?7% 75% (ref 183) ". Me E m e8 \ (ref 185) hr Eas-0 Ph (89%ds) Reagents i Co,(CO), benzene; ii DMSO 50 "C; iii DME 120"C 24 h CO (3 atm) 3 mol% Co,(CO), 10mol% P(OPh),; iv Pd(o) MeCN 80°C Scheme 39 162 Peter Quayle 1 ii (ref 186) H 73% C02Me%b C02Me iii -p3OH 4- iii - &o H a OH Reagents i Cp,ZrBu,; ii LiC=CCH,Cl; iii Bu"Li THF -78 "C Scheme 40 Aliphatic and Alicyclic Chemistry ex0 > R= Ph 8x0 endo =96:4 (81% yield) R=Me,exo:endo =87:3 (72% yield) (ref 191) (ref 194) P I [Co]= Pyr(DMG)2 71% (ref 196 197) (ref 1 98) (ref 201) Me2PhSi (ref 201) Figure 1 164 Peter Quayle i,ii iii _3.Reagents i 2,4,6-Heptatrienone glycine (cat) norbornadiene-toluene reflux 72 h; ii PCI, toluene reflux 3 h; iii FVP 1OOO"C Scheme 41

ISSN:0069-3030    

DOI:10.1039/OC9949100125

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

6 Aromatic Compounds By A. P. CHORLTON ZENECA Specialties Hexagon House Blackley Manchester M9 8ZS,UK 1 General and Theoretical Studies The Mills-Nixon effect states that small ring annelation onto benzene would induce significant bond length alternation within the benzene nucleus. The existence of this phenomenon has been the subject of conflicting papers. The effect of fusion of angular strained rings on benzenes (Scheme 1) has been studied by crystallographic and computational techniques.’ The results of these studies show characteristic features of small strained rings such as electron density deformations consistent with ‘bent bonds’. In no case was any appreciable bond alternation observed thus denying the existence of the Mills-Nixon effect. Shepherd has demonstrated that this is also the case with biphenylenoC2,l -a]bi~henylene.~ Scheme 1 The strained benzocyclopropanes required for the above studies are the result of pioneering synthetic work by bill up^.^.^ Siegel has elegantly highlighted the anachron- istic nature of bond alternation in a paper entitled ‘Mills-Nixon Effect Wherefore Art Thou?’.’ From the contrary viewpoint theoretical studies of the Wheland intermediates from benzocycloalkenes have vindicated the Mills-Nixon hypothesis.6 Similar bond alternation has been observed by X-ray crystallography of the arenium cation (l).’ R.Boese D. Blaser W. E. Billups M. M. Haley A. H. Maulitz D. L. Mohler and K. P.C. Vollhardt Angew. Chem. Int. Ed. Engl. 1994 33 313. M. K. Shepherd J.Chem. SOC. Perkin Trans. 1 1994 1055. ’ W. E. Billups and D. J. McCord Angew. Chem. Int. Ed. Engl. 1994 33 1333. W. E. Billups D.J. McCord and B. R. Maughon J. Am. Chem. SOC.,1994 116 8831. ’ J. S. Siegel Angew. Chem. Int. Ed. Engl. 1994 33 1721. M. Eckert-Maksic Z.B. Maksic and M. Klessinger J. Chem. SOC. Perkin Trans. 2 1994 285. ’ R. Rathore S.H. Loyd and J. K. Kochi J. Am. Chem. SOC. 1994 116 8414. 165 A. P. Chorlton Besides having the conventional 6.n electron aromaticity the 3,5-dehydrophenyl cation (2) is stabilized by three-centre two-electron (3c-2e) bonding (3) in the ring plane (in-plane aromaticity). Calculations have shown that the 3,5-dehydrophenyl cation (2) with its double aromaticity is more stable than the phenyl cation.8 Semiempirical calculations (SINDO1 ) of delocalization energies were performed for a large number of mono- and polycyclic hydrocarbons.This information has been used to produce an aromaticity index for polycyclic hydrocarbon^.^ Taylor has shown that three isomers of C,,H, can in principle exist and that they will probably be aromatic." The topological resonance energy (TRE) method has revealed that typical derivatives of c60 are moderately aromatic like the parent C, molecule. For most c60 derivatives polyvalent molecular anions are at least as aromatic as the neutral species whereas polyvalent molecular cations are much less aromatic in nature.' ' The TRE method has also been applied to linear (4) and zigzag (5) isomers of cyclopolyacenes. In general zigzag cyclopolyacenes have been found to be more aromatic than the linear cyclopolyacenes.'2 Interactions between .n systems are fundamental to understanding the nature of such diverse phenomena as base-base interaction in DNA intercalation of drugs in DNA and packing of homogeneous and heterogeneous aromatic molecules in crystals.The benzene-benzene interaction is the prototype of these interactions. To gain more information about these interactions the potential energy surfaces of the benzene dimer have been studied by ab initio methods. These have revealed that the most stable structures were found to be the parallel-displaced structure followed by two T-shaped structures.' P. von R. Schleyer H. Jiao M. N. Glukhovtsev J. Chandrasekhar and E. Kraka J.Am Chem. SOC.,1994 116 10129. S. Behrens A.M. Koster and K. Jug J. Org. Chem. 1994 59 2546. lo R. Taylor J. Chem. SOC.,Perkin Trans. 2 1994 2497. l1 J. Aihara and S. Takata J. Chem. SOC.,Perkin Trans. 2 1994 65. J. Aihara J. Chem. SOC. Perkin Trans. 2 1994 971. l3 P. Hobza H.L. Selzle and E. W. Schlag J. Am. Chem. SOC.,1994 116 3500. Aromatic Compounds 167 The bicyclopropenyls (6k(8) have been synthesized by the vacuum gas phase elimination of p-halocyclopropylsilane precursors over solid fluoride. Of these bicycloprop-2-enyl (6) occupies the most important position in this family since it is one of only four isomers of benzene in which each carbon is bound to only one hydrogen atorn.l4 The a,3-dehydrotoluene biradical and related structures have been recently the subject of considerable interest in relation to the proposed mechanism of DNA cleaving agents (see preparation of benzenes from non-aromatic precursors).This has fuelled interest in the longstanding problem of the heats of formation of biradicals; to this end a number of techniques have been applied. The photoelectronic spectrum of a,3-dehydrotoluene biradical(9) has been measured; the ionization potential obtained from this data has been compared to those of benzyl radical and m-tolyl radical. This suggests that the singlet-triplet splitting of (9) is less than 5 kcal mol-' and that AH,,,, (9) lies just a little below (I kcalmol-') the additivity estimate of 109 kcal mol- '.' The absolute heats of formation for (x,2-( lo) a,3-(9) and a,4- dehydrotoluene (1 1) biradicals have been determined from the measured threshold energies for dissociation of chloride bromide and iodide ion from the corresponding o- m-,and p-halobenzyl anions in the gas phase.The 298 K heats of formation obtained for the iodobenzyl anions resulting from (9) (lo) and (11) are all found to be 103 f3 kcal mol- '. This value compares well with values obtained from MCSCF calculations (105-106 kcal mol- ').16 Picosecond optical grating calorimetry has been used to determine the energy separation between the singlet and triplet states of the diradical of m-naph- thoquinomethane (12); a value of 18.5 kcalmol-' for AE, for (12) was ~btained.'~ Distonic radical ions are reactive intermediates with spatially separated radical and charge sites.FT-ICR mass spectrometry of protonated 4-iodoaniline yields the distonic isomer of ionized aniline (Scheme 2).18 The structure of the benzene cation C6H is discussed in an article entitled 'Molecular Distortions in Reactive Intermediates'. The rotational isomerism of l4 W. E. Billups M. M. Haley R. Boese and D. Blaser Tetrahedron 1994 50 10 693. C.F. Logan J.C. Ma and P. Chen J. Am. Chem. SOC. 1994 116 2137. I6 P.G. Wenthold S.G. Wierschke J. J. Nash and R. R. Squires J. Am. Chem. SOC. 1994 116 7378. " M.I. Khan and J. L. Goodman J. Am. Chem. SOC. 1994 116 10342. L.J. Chyall and H.I. Kenttamaa J. Am. Chem. SOC. 1994 116 3135. l9 T.A. Miller Angew. Chem. Int. Ed. Engl. 1994 33 962. A. P. Chorlton Scheme 2 R3 R3 syn anti Scheme 3 disubstituted benzenes has been studied.If there were restricted rotation then two isomers syn and anti,could exist (Scheme 3). Ortho and meta substituted tolyldi(1-adamanty1)methanolswere synthesized as models to examine this form of isomerism. It was found that the ortho-substituted derivative gives essentially the anti isomer (antilsyn 11.6) the meta-derivative mainly syn (antilsyn 0.77). Thermal equilibration converts the anti ortho isomer also exclusively into syn ortho while the antilsyn ratio is virtually unchanged for the meta derivative.” The relative stability of the conformation equilibria between meta syn and anti isomers has also been examined.’l Conformational studies have revealed that 1,8-diacylnaphthalenes exist solely in the anti (racemic) conformation.22 Hexakis(fluorodimethylsily1) benzene (13) has been studied by NMR and crystallography.At low temperature it was found that the rotation of the silyl groups was frozen but the fluorine atom transfer between vicinal silyl groups is rapid. This ‘merry-go-round process’ corresponds to a cyclic network of consecutive intramolecular S,2 (Si)-type Walden inversions which are very rapid because each silicon atom already forms a quasi-pentacoordinate str~cture.’~ FMqSi SiMqF SiM%F (13) 20 J. S. Lomas and V. Bru-Capdeville J. Chem. SOC.,Perkin Trans. 2 1994 459. 21 J. E. Anderson V. Bru-Capdeville P. A. .Kirsch and J. S. Lomas J. Chem. SOC.,Chem. Commun. 1994 1077. 22 D. Casarini L. Lunazzi E.Foresti and D. Macciantelli J. Org. Chem. 1994 59 4637. 23 K. Ebata T. Inada C. Kabuto and H. Sakurai J. Am. Chem. SOC. 1994 116 3595. Aromatic Compounds 2 Preparation of Benzenes from Non-aromatic Precursors The burgeoning interest in the thermal cyclization of enediynes to aromatics via Bergman cyclization and related processes continues. This is highlighted by a recent issue of Tetrahedron that was devoted to this The activation parameters for the Bergman cyclization of acyclic enediynes (14) and acyclic aromatic enediynes (15) have been determined. It can be concluded from this data that there exists little difference in the activation parameters for acyclic aromatic (1 5) and nonaromatic enediynes and that the acetylene substituent is the primary determining factor in the rate of enediyne cy~lization.~' Magnus has found that azabicyclo[7.3.llenediynes (1 6) undergo cycloaromatiz- ation at dramatically different rates despite the fact that the distance between the bonding acetylenes is practically identical; when the carbamate protecting group is removed to give the secondary amine (17) this cycloaromatizes more rapidly and the entropy of activation changes from a negative to a positive. The origin of this difference has been ascribed to intramolecular hydrogen bonding between the NH and the c=o.26 The rate of singlet-to-triplet intersystem crosslinking in 1,6didehydrobenzene has now been studied. The inability of an applied external magnetic field to affect the rate and product formation and distribution indicates the absence of intersystem crossing in 1,4-didehydro benzene.The Bergman thermal cycloaromatization can also be effected under photochemical conditions.28 Several novel procedures for the synthesis of the enediyne precursors and their subsequent cycloaromatization have been demosntrated. These include [2,3] sigmatropic shifts,29 pinacol rearrangement,30 ceric ammonium nitrate oxidative cy~lization,~' and the use of q2-Co2(Co),complexed acetylene^.^^ A significant effort has been channelled into the synthesis of a model analogous to the anticancer agent neocazinostatin (18);33,34 a typical example of this is shown in Scheme 4.33 24 Tetrahedron 1994,50 131 1. 25 J. W. Grissom T. L. Calkins H. A. McMillen and Y.Jiang J. Org. Chem. 1994 59 5833. 26 P. Magnus and R. A. Fairhurst J. Chem. SOC. Chem. Commun. 1994 1541. 27 W.B. Lott T. J. Evans and C. B. Grissom J. Chem. SOC.,Perkin Trans. 2 1994 2583. 28 N. J. Turro A. Evenzahav and K. C. Nicolaou Tetrahedron Lett. 1994 35 8089. 29 H. Audrain T. Skrydstrup G. Ulibarri C. Riche A. Chiaroni and D. S. Grierson Tetrahedron 1994,50 1469. 30 T. Nishikawa A. Ino and M. Isobe Tetrahedron 1994 50 1449. 31 T. Brandstetter and M. E. Maier Tetrahedron 1994 50 1435. 32 P. Magnus Tetrahedron 1994,50 1397. 33 J. Suffert and R. Bruckner SYNLETT 1994 51. 34 K. Toshima K. Ohta T. Kano T. Nakamura M. Nakata and S. Matsumura J. Chem. SOC. Chem. Commun. 1994 2295. A. P. Chorlton 0 I OMe OMe -(16) R = Ad02C (17) R=H OMe 0 A Meyoyo HOv-NHMe OH Work in this are2 has resulted in the observation of a number of unexpected produ~ts.~’-~~ The majority of these products arise from intramolecular quenching of the a-3-dehydrotoluene biradical by the initiating thiol (Scheme 5).36 Grissom has elaborated on the Bergman cycloaromatization by tethering various 35 H.Sugiyama K. Yamashita T. Fujiwara and I. Saito Tetrahedron 1994 50 1311. 36 H. Sugiyama T. Fujiwara and I. Saito Tetraheduon Lett. 1994 35 8825. 37 P. A. Wender and M. J. Tebbe Tetrahedron 1994 50 1419. 38 K. Toshima K. Yanagawa K. Ohta T. Kano and M. Nakata Tetrahedron Lett. 1994 35 1573. 39 S. Kawata T. Oishi and M. Hirama Tetrahedron Lett. 1994 35 4595.Aromatic Compounds Scheme 4 OH I Scheme 5 Scheme 6 radical acceptors (olefin carbonyl oxime itri rile)^'^^ which participate in tandem enediyne-radical cyclizations to give functionalized tricycles (Scheme 6).41 The diradicals produced by the cyclization of enediynes are thought to be responsible for the cleavage of DNA. Similar diradical species can be produced by thermal ring-opening of cyclobutenones (19)43 and by photoirradiation of dia- zoketones (20).44Both these processes lead to a cleavage of DNA presumably by involvement of the diradical (21). Enediynes have also been employed in a new synthetic route to benzocyclobutenes (Scheme 7).45 The benzannulation of an unsaturated Fischer carbene complex and an alkyne 40 J.W. Grissom T. L. Calkins D. Huang and H. McMillan Tetrahedron 1994 50 4635. 41 J. W. Grissom D. Klingberg S. Meyenburg and B. L. Stallman J. Org. Chem. 1994 59 7877. 42 J. W. Grissom and B. J. Slattery Tetrahedron Lett. 1994 35 5137. 43 R. W. Sullivan V. M. Coghlan S. A. Munk M. W. Reed and H. W. Moore J. Org. Chem. 1994,59,2216. 44 K. Nakatani S. Isoe S. Maekawa and I. Saito Tetrahedron Lett. 1994 35 605. 45 F. Toda K. Tanaka I. Sano and T. Isozaki Angew. Chem. Int. Ed. Engl. 1994 33 1757. 172 A. P. Chorlton / Scheme 7 continues to be of increasing interest. This reaction gives a variety of products depending on the structure and substitution of the carbene the metal and the alkyne employed but typically cyclopentadiene and phenol derivatives are the main products.The commonly accepted mechanism is depicted in Scheme 8. In this proposed mechanism only the cyclohexadienone intermediate (23) has been isolated and characterized. Barluenga et a!. have succeeded in isolating and characterizing complexes that correspond to the intermediates (24) and (25).46 A high degree of regioselectivity is one of the key features of this reaction. The major contributor to the regioselectivity is the steric differential between the two substituents on the alkyne which leads to preferential formation of the phenol (26) where the larger substituent (R,) is incorporated adjacent to the hydroxyl group. Wulff has found that this normal regioselectivity can be reversed by the use of stannyl alkynes (Scheme 9).47 The a-silylated vinyl carbene (27) can also act as a more stable synthon for the unstable parent vinyl carbene; the benzannulated product being desilylated with TFA.48 Reversed regioselectivity has also been observed in the metal-catalysed rearrapge- ment of cyclopropenes; a Fischer benzannulation variant.This process is thought to proceed via the ccmmon intermediate (28).49 The synthetic utility of the Fischer carbene benzannulation methodology is elegantly illustrated by its use in the construction of the tetracyclic ring system of steroids (Scheme 46 J. Barluenga F. Aznar A. Martin S. Garcia-Granda and E. Perez-Carreno J. Am. Chem. Soc.,1994,116 11 191. 41 S. Chamberlin M.L. Waters and W.D. Wulff J. Am. Chem. SOC. 1994 116 3113. 48 S.Chamberlin and W. D. Wulff J. Org. Chem. 1994 59 3047. 49 M. F. Semmelhack S.Ho D. Cohen M. Steigerwald M. C. Lee A. M. Gilbert W. D. Wulff and R.G. Ball J. Am. Chem. SOC. 1994 116 7108. 50 J. Bao W. D. Wulff V. Dragisich S. Wenglowsky and R.G. Ball J. Am. Chem. SOC. 1994 116 7616. Aromatic Compounds X X X [MI = M(CO),; X = NR2 OR RNCOR'. Scheme 8 The Diels-Alder reaction continues to demonstrate its synthetic utility by its iterative use in the construction of linear chains of fused aromatic ring^.^'-'^ A typical example is given in Scheme 1 1 ." The efficient synthesis of anthraquinones has also been of current interest.5L56 Two new dieneophiles have been developed which have allowed the synthesis of benzocyc- lobutenediones (Scheme 12)57 and aromatic amines (Scheme 13).58 A number of anionic [4 + 21 cycloaddition processes equivalents of the Diels-Alder reaction have been established (Schemes 1459 and 1560).In a related process 2,4,6-trianylthiopyridinium salt (29) reacts with arylacetal- 51 M. Loffler and A. D. Schluter SYNLETT 1994 75. 52 R. W. Alder P. R. Allen L. S. Edwards G. I. Fray K. E. Fuller P. M. Gore N. M. Hext M. H. Perry A. R. Thomas and K. S. Turner J. Chem. SOC. Perkin Trans. 1 1994 3071. 53 D. Giuffrida F. H. Kohnke M. Parisi F. M. Raymo and J. F. Stoddart Tetrahedron Lett. 1994,35,4839. 54 G. Majumadar K.V. S.N. Murty and D. Mal Tetrahedron Lett. 1994 35 6139. 55 M. Couturier and P. Brassard Synthesis 1944 703. 56 A.T. Khan B. Blessing R. R. Schmidt Synthesis 1994 255.57 A. H. Schmidt C. Kunz M. Malmbak and J. Zylla Synthesis 1994 422. 58 A. Loffler and G. Himbert Synthesis 1994 383. 59 A. Tyrala and M. Makosza Synthesis 1994 265. 6o G. Majumdar R.Pal K. V.S. N. Murty and D. Mal J. Chem. SOC. Perkin Trans. 1 1994 309. A. P.Chorlton Reagents i HCrCSnBu, THF 50°C; ii TBSOTf NEt Scheme 9 Reagents i Danishefsky's diene CH,CN 25 "C 16h 1 atm CO; ii 1lOT 23 h Scbeme 10 Scheme 11 Scheme 12 Aromatic Compounds 175 R I II m2Me NMe2 C02Me Scheme 13 NH2 Scheme 14 m 00 @-qp OH 0 00 Scheme 15 dehydes (30) in the presence of base uia a 2,5-[C +C,] ring transformation to give 2,4,5-triarylthiobenzophenone(31).61 A novel electrophile-induced benzannulation reaction has been developed indepen- dently (Scheme 16).62963 T.Zimmermann Synthesis 1994 252. M.B. Goldfinger and T.M. Swager J. Am. Chem. SOC. 1994 116 7895. 63 M. A. Ciufolini and T. J. Weiss Tetrahedron Lett. 1994 35 1127. A. P. Chorlton ?/,, -H+ &-J-Scheme 16 Scheme 17 The dehydrative aromatization of cyclohexenone oximes has traditionally been realized by a low yielding Semmler-Wolff reaction. Matsumoto has demonstrated that cyclohexenone oximes can be smoothly dehydrated to the corresponding anilines by the catalysis of palladium on carbon (Scheme 17).64 3 Non-aromatic Compounds from Benzene Precursors Oxidation of phenols to 1,6benzoquinone monoketals continues to be of interest. This transformation is generally achieved by anodic oxidation6' or uia the use of hypervalent iodine reagents such as phenyliodine diacetate or bis(trifluor0-acetoxy)iodo] benzene.66 This methodology has been employed as the key step in the synthesis of the antibiotics bromoxone (32)67 and LL-C10037a (33) (Scheme 18).68 The synthetic utility of this technique has been extended to the preparation of 4-fluorocyclohexane-2,5-dienonesby using pyridinium polyhydrogen fluoride in conjunction with hypervalent iodine (Scheme 19).69 The oxidative cleavage of catechols has been the subject of a number of investigations.This process is a key step in the biodegradation by soil bacteria of naturally occurring aromatic molecules and many aromatic environmental pollutants. Two types of oxidative cleavage are found ortho- or intradiol where cleavage is between the two hydroxy groups; and meta- or extradiol where cleavage is adjacent to the two hydroxy groups.Enzymatic extradiol cleavage of 2,3-dihydroxyphenyl-propionic acid (34) has been demonstrated (Scheme 20).70Intradiol cleavage of catechols has been achieved by a number of workers in a biomimetic fashion with 64 M. Matsumoto J. Tomizuka and M. Suzuki Synth. Commun. 1994 24 1441. 65 E.C.L. Gautier N. J. Lewis A. McKillop and R. J.K. Taylor Synth. Commun. 1994 24 2989. 66 A. McKillop L. McLaren and R.J.K. Taylor J. Chem. SOC. Perkin Trans. 1 1994 2047. E. C. L. Gautier N. J. Lewis A. McKillop and R.J. K. Taylor Tetrahedron Lett. 1994 35 8759. P. Wipf and Y. Kim J. Org. Chem. 1994 59 3518.69 0.Karam J.-C. Jacquesy and M.-P. Jouannetaud Tetrahedron Lett. 1994,35 2541. 'O W. W. Y. Lam and T. D. H. Bugg J. Chem. SOC. Chem. Commun. 1994 1163. Aromatic Compounds Scheme 18 Scheme 19 OH MhpB &IH ___c 0,.Fez+ (34) -0pC OH Scheme 20 iron(1rr)-catalysed ~xidation.~'-~~ This general sequence is illustrated in Scheme 21. Nucleophilic addition of organometallics to arenes provides a useful procedure for the generation of non-aromatic compounds from aromatic systems. The methodology of Meyer~,~~ diastereoselective addition of organometallics to chiral naphthalene oxazoles has been used to prepare dihydronaphthalenes of high enantiomeric purity (Scheme 22). 'v7 Kundig has demonstrated that a non-asymmetric variant of this process can be applied to the benzene ring (Scheme 23).77 71 S.R.Kaschabek and W. Reineke J. Org. Chem. 1994 59,4001. 72 J. E. Baldwin M. R. Spyvee and R. C. Whitehead Tetrahedron Lett. 1994,35 6575. 73 T. Funabiki M. Ishikawa Y. Nagai J. Yorita and S. Yoshida J.Chem.SOC.,Chem. Commun. 1994,1951. 74 A. N. Hulme and A.I. Meyers J. Org. Chem. 1994 59 952. '' M. K. Mokhallalati K. R. Muralidharan and L. N. Pridgen Tetrahedron Lett. 1994 35 4267. 76 X.Bai S.W. Mascarella W.D. Bowen and F.I. Carroll J. Chem. SOC. Chem. Commun. 1994 2401. 77 E.P. Kundig A. Ripa R. Liu and G. Bernardinelli J. Org. Chem. 1994 59 4773. A. P. Chorlton 0 Scheme 21 .. R’ Oy -Wii Reagents i R3Li; ii E+; iii H+ Scheme 22 Reagents i MeLi; ii RX;iii CO Scheme 23 OMe + Meo..& Reagents i BF,; ii DDQ Scheme 24 Complexation of anisole with pantaammineosmium(11) facilitates a non-concerted Diels-Alder reaction with N-methylmaleimide (Scheme 24).78 M.E.Kopach and W. D. Harman J. Org. Chem. 1994 59 6506. Aromatic Compounds Scheme 25 Scheme 26 hv -OY" hv - -A Scheme 27 Chiral naphthalene derivatives undergo [4 +23 cycloaddition with singlet oxygen. The diastereoselectivity of this reaction is dependent on the n-facial selectivity of the substituent (Scheme 25).79 Photocycloaddition of olefins to benzenoids releases the aromaticity of the ring and gives access to complex non-aromatic polycycles. Gilbert has shown that 3-benzylazaprop- 1 -enes undergo intramolecular meta photocycloaddition to give linear azatriquinanes with high selectivity (Scheme 26).80 Wagner has applied the use of chiral auxiliaries to ortho photocycloaddition.This has resulted in diastereoselective cycloaddition and kinetic resolution of the products (Scheme 27).81 l9 W. Adam and M. Prein Tetrahedron Lett. 1994 35 4331. D. C. Blakemore and A. Gilbert Tetrahedron Lett. 1994 35 5267. P. J. Wagner and K. McMahon J. Am. Chem. SOC. 1994 116 10827. 180 A. P. Chorlton The influence of arene substituents on the mode and regiochemistry of the photocycloaddition of furan to the benzene ring has been examined. An interesting observation in this work was isolation of 2-(2'-fury1)benzonitrile (35) from the photoreaction of furan with o-fluorobenzonitrile.This is thought to arise from the ortho cycloadduct (36) via ring opening of the resulting cyclobutene (37).82 (37) 4 Substitution in the Benzene Ring Electrophilic Substitution.-Electrophilic aromatic substitution is generally considered to proceed via the rate-limiting collapse of the electrophile (E) and the aromatic substrate (ArH) to form the o-complex (EArH) or Wheland intermediate. Since many electrophiles are also oxidizing agents an alternative mechanism involving an initial electron transfer to generate the aromatic cation radical (ArH") as the reactive intermediate has been presented. Prior to the formation of the latter are the transient charge-transfer complexes (ArH-E). This process has been studied by examination of the intermediates in aromatic halogenation with iodine monochloride.Kochi has established by spectral studies the formation of the charge transfer complex (ArH-ICI) which suffers electron transfer to afford the reactive triad (ArH' +I*Cl-). This aromatic cation radical is then quenched with chloride or iodine respectively. Iodination versus chlorination thus represents the competition between radical-pair and ion-pair collapse from the reactive triad. The product selectivity can be modulated by solvent polarity non polar solvents giving higher yields of chloro products and polar solvents giving an enhancement of iodo products.83 O'Malley in a similar study demonstrated that iodination predominates in benzonoid arenes whereas chlorination is the sole reaction with polycyclic aromatics.84 Lewis acid catalysed iodination of mesitylene and durene however appears to proceed via a o-complex (IArH).85 Aromatic compounds can be mildly and efficiently iodinated with pyridine-iodine monochloride complex.86 Introduction of iodine into the aromatic nucleus has also been achieved with iodine and a mercury@) salt87 and with iodine monofluoride generated in situ.88 Diaryliodonium salts (Ar,I)+X are an important class of polyvalent iodine compounds.They are generally synthesized indirectly via aryl iodides. However a reagent prepared from a 1:2 molar ratio of (di-acet0xy)iodobenzene and trifluoromethanesulfonic acid facilitates their preparation from aromatic compounds under mild condition^.^' 82 H.Garcia A. Gilbert and 0.Griffiths J. Chem. SOC.,Perkin Trans. 2 1994 247. S.M. Hubig W. Jung and J. K. Kochi J. Org. Chem. 1994 59 6233. 84 D.E. Turner R.F. O'Malley D.J. Sardella L.S. Barinelli and P. Kaul J. Org. Chem. 1994 59 7335. 85 C. Galli and S. Di Gaimmarino J. Chem. SOC.,Perkin Trans. 2. 1994 1261. 86 H.A. Muathen J. Chem. Rex (S) 1994 405. A. Bachki F. Foubelo and M. Yus Tetrahedron 1994 50 5139. 88 0.Thinius K. Dutschka and H. H. Coenen Tetrahedron Lett. 1994,35 9701. 89 T. Kitamura J.-I. Matsuyuki and H. Taniguchi Synthesis 1994 147. Aromatic Compounds Scheme 28 Regioselective bromination has been the subject of a number of papers. The nuclear versus side-chain bromination of methyl substituted anisoles by N-bromosuccinimide has been studied.This investigation led to the conclusion that methyl-substituted anisoles are para brominated rather than side-chain brominated if at least two methyl groups are present at positions 3 and 5 (Scheme 28).90 N,N-disubstituted anilines are preferentially brominated in the ortho position in the presence of surfactant.” Bromination of 2-acetoxymethyl-4-isopropoxy-5,7-dimethoxynaphthalene (38) in buffered solution affords the 8-monobromo compound (39) whereas monobromina- tion in the absence of the buffer yields the isomeric 1-bromonaphthalene (40).This difference in regioselectivity is thought to arise because the 8-bromo compound (39) is the kinetic product whereas the 1-bromo compound (40) is the thermodynamic product.The presence of the buffer traps the HBr thus preventing isomerization to the 8-bromo compound (39).92 OMe opi OMe OPi Me0 OAc Me0 OAc Me0 OAc br (39) a-Cyclodextrin has been shown to catalyse the aqueous bromination of various aromatic ~ubstrates.~~ A new mild chlorination method of aromatics has been developed. In this procedure hydroxy(tosy1oxy)iodobenzene (Koser’s reagent) and lithium or sodium chloride chlorinate polyalkylbenzenes on the ring. This methodol- ogy has been extended to bromination and i~donation.~~ The mechanism of aromatic nitration continues to be the focus of active interest. Gas phase studies without the complicating effects of a solvating environment are directly comparable to those of theoretical methods. Cacace has studied the gas phase aromatic substitution by (CH,ONO,)H+ ions by a combination of FT-ICR mass spectrometry and atmospheric pressure radiolytic techniques.The evidence from these experiments supports a mechanism involving preliminary formation of a Wheland intermediate from the attack of CH,OH-NO; complex on the arene followed by its isomerization 90 G.-J. M. Gruter 0.S. Akkerman and F. M. Bickelhaupt J. Org. Chem. 1994,59 4473. 91 G. Cerichelli and G. Mancini Tetrahedron 1994 50 3797. 92 R.G.F. Giles I. R. Green L.S. Knight V.R. L. Son P. R. K. Mitchell and S.C. Yorke J. Chem. SOC. Perkin Trans. 1 1994 853. 93 O.S. Tee and B.C. Javed J. Chem. SOC.,Perkin Trans. 2 1994 23. 94 P. Bovonsombat E. Djuardi and E. McNelis Tetrahedron Lett. 1994 35 2841. A.P. Chorlton Scheme 29 into the more stable o-protonated nitrobenzene structure uia a proton shift whose rate x is estimated to be ~3.6 107s-' at 315K.95 The thermal and photochemical nitration of aromatic systems has been studied. In this process aromatic hydrocarbons are readily nitrated by nitrogen dioxide in dichloromethane. The initial red colour observed is due to the metastable charge transfer complex (ArH NO+)NO,. Irradiation of this complex gives aromatic nitration even at -78 "C,where the thermal nitration is too slow to compete. In the absence of irradiation the same products are formed at room temperature. The photochemical and thermal processes are thought to proceed through the intermediacy of the radical-cation-containing (ArH + NO ) NO .96 When various alkyl-substituted p-dialkoxybenzenes are subjected to reaction with nitrogen dioxide either nitration or oxidative dealkylation products are formed (Scheme 29).The reason for this is that the aromatic radical intermediate (ArH") undergoes homolytic coupling with NO (which leads to aromatic nitration) and nucleophilic attack by NO; (which results in oxidative dealkylation). This competi- tion between nitration and oxidative dealkylation can be effectively modulated by solvent polarity and added nitrate.97 In a similar study the nitration and oxidation of 4-methoxyphenol by nitrous acid in aqueous acid has been examined.98 Nitrogen dioxide in the presence of ozone acts as a powerful nitrating agent converting non-activated arenes e.g.polychlorobenzenes into their corresponding nitro derivatives in good yields.99 This reaction known as the Kyodai nitration appears to be an electrophilic aromatic process and is characterized by unique features such as high ortho-directing trends of the acyl,"' ester,"' and halogen substitu- ents.'" The neutral conditions of this procedure also allow the nitration of acid-labile aromatic acetals and a~yls.''~ The initial products in the Kyodai nitration have been found to be composed of mainly rneta-nitro derivatives but this isomer distribution is rapidly replaced by the ortho and para isomers as the reaction proceeds. This suggests the operation of an electron-transfer mechanism involving nitrogen dioxide as the initial elec trophile.O4 Olah has reported a convenient and simple method for the nitration of aromatics. In this procedure a mixture of sodium nitrate and chlorotrimethylsilane generates nitryl 95 M. Aschi M. Attina F. Cacace and A. Ricci J. Am. Chem. SOC. 1994 116 9535. 96 E. Bosch and J.K. Kochi J. Org. Chem. 1994 59 3314. 97 R. Rathore E. Bosch and J. K. Kochi Tetrahedron 1994 50 6727. 98 B.D. Beake J. Constantine and R.B. Moodie J. Chem. SOC.,Perkin Trans. 2 1994 335. 99 H. Suzuki T. Mori and K. Maeda Synthesis 1994 841. loo H. Suzuki and T. Murashima J. Chem. SOC.,Perkin Trans. 1 1994 903. lo' H. Suzuki J.-I. Tomaru and T. Murashima J. Chem. SOC.,Perkin Trans. 1 1994 2413. lo' H. Suzuki and T. Mori J. Chem. SOC. Perkin Trans. 2 1994 479. lo3 H. Suzuki S.Yonezawa T. Mori and K. Maeda J. Chem. SOC. Perkin Trans. 1 1994 1367. '04 H. Suzuki T. Murashima and T. Mori J. Chem. SOC. Chem. Commun. 1994 1443. Aromatic Compounds chloride in situ which in the presence of aluminium chloride catalyst nitrates aromatic substrate^."^ The nitration of toluene with n-propyl nitrate has been carried out in the presence of the zeolite H-ZSM-5 as a catalyst. Under optimized conditions the product distribution o :m :p 5 :0 :95 was achieved.'06 Aromatic nitrosation unlike electrophilic aromatic nitration is by and large restricted to only the most electron-rich substrates such as phenols and anilines. Kochi has demonstrated that the less-reactive anisoles and polymethylbenzenes can be nitrosated with the electrophilic nitrosonium salt NO+BF in good yield under mild conditions in which the conventional procedure (based on nitrite neutralization with strong acid) is ineffective.'07 Ryu has shown that 1,3-dicyclohexylcarbodiimide(DCC) in the presence of sulfuric acid or aluminium chloride and an arene substrate give corresponding cyclohexylated arenes in good yield.'08 In this reaction DCC served as a cyclohexyl carbocation source.In an extension of this work a number of cyclohexylamide derivatives have also been used successfully as a source of the cyclohexyl carbocati~n.'~~ The synthesis of C-aryl glycosides has been reviewed this covers Fredel-Crafts (F-C) approaches to their preparation.' 1-Arylalkanes are not usually available via direct F-C alkylation of aromatic substrates on account of the tendency of the primary carbocation intermediates to rearrange.Smith has demonstrated that moderately activated benzenoid compounds undergo alkylation with allylic alcohols in the presence of acidic K10 clay to give almost exclusively 1-arylalk-2-enes by attack at the terminal positions of the intermediate ally1 cation. Catalytic hydrogenation of these derivatives yields the corresponding 1-arylalkanes.' ' ' In a similar manner cation-exchanged Montmoril- lonite-catalysed F-C alkylations have been carried out using methyl vinyl ketone and 4-hydroxybutan-2-one without the many side reactions such as isomerization transalkylation polymerization and polyalkylation that are known to take place when these substrates are used with traditional F-C catalysts."2,' l3 The activation of K1O-montmorillonite-supported zinc chloride (Clayzic) has been investigated as a catalyst in the F-C benzylation of benzene and halobenzenes.It has been found that thermal activation in air can give a rate enhancement greater than 30 compared to unactivated Clayzic in the benzylation of benzene.' ' Montmorillonite can support iron(m) chloride (Clayfec) when this catalyst is used in F-C acylations; chlorostyrene products as well as the expected acylated products are produced (Scheme 30).' ' Thg zeolite H-ZSM-5 has been used to catalyse F-C benzoylations. This catalyst is noted for its remarkable para selectively."6 When H-ZSM-5 is used in the Fries G.A. Olah P. Ramaiah G. Sandford A. Orlinkov and G.K. S. Prakash Synthesis 1994,468. lo6 T. J. Kwok K. Jayasuriya R. Damavarapu and B. W. Brodman J. Org. Chem. 1994 59 4939. lo' E. Bosch and J.K. Kochi J. Org. Chem. 1994 59 5573. J.N. Kim K. H. Chung and E. K. Ryu Tetrahedron Lett. 1994 35,903. I09 K.H.Chung J.N. Kim and E. K. Ryu Tetrahedron Lett. 1994 35,2913. 'Io C. Jaramillo and S. Knapp SYNLETT 1994 1. 'I1 K. Smith and G. M. Pollaud J. Chem. Soc. Perkin Trans. 1 1994 3519. J.-I. Tateiwa H. Horiuchi K. Hashimoto T. Yamauchi and S. Uemura J. Org. Chern. 1994 59 5901. 'I3 J.-I. Tateiwa T. Nishimura H. Horiuchi and S. Uemura J. Chem. Soc. Perkin Trans. 1 1994 3367. S. J. Barlow T.W. Bastock J. H. Clark and S. R. Cullen J. Chem. SOC.,Perkin Trans. 2 1994 41 1. T.W. Bastock J.H. Clark P. Landon and K.Martin J. Chem. Res. (S) 1994 104. 'I6 V. Paul A. Sudalai T. Daniel and K. V. Srinivasan Tetrahedron Lett. 1994 35,2601. A. P. Chorlton Me 0 Me CI MeCOCl &Me + Me Me Me Me Me Me Scheme 30 rearrangement of phenylacetate there is an unexpected tendency for the production of o-hydroxyacetophenone.' ' The regioselectivity in the benzoylation of 2-methoxynaphthalene is strongly influenced by the Lewis acid catalyst used. InCl, FeCl, SnCl, or ZnC1 give predominately the 2-benzoyl-6-methoxynaphthalene (41) whereas AlCI, SbCl, or TiCl give 1-benzoyl-2-methoxynaphthalene(42) as the major product." RCOl moMe moMe 0 (411 Phenols have been found to undergo facile C-benzoylation with a,a,a-tri-chloro- toluene in the presence of phase transfer catalyst to afford hydroxbenzophenone.' l9 Scandium trifluoromethane sulfonate Sc(OTf), was found to be a novel catalyst for F-C acylation.The reaction proceeds smoothly even in the presence of a catalytic amount of Sc(OTf), which can be recovered and reused.'*' The ortho acylation of anilines by nitriles (Sugasawa reaction) in the presence of BCl and a second Lewis acid appears to proceed through an intermediate 'Supercomplex' (43) including all four components (Scheme 31).12' It was found that the chloride affinity of the second Lewis acid governs supercomplex formation. Therefore judicious choice of the Lewis acid leads to yield improvements. This method has been used as the key intermediate in the preparation of a new generation of transcriptase inhibitors.22 A number of interesting Lewis acid mediated electrophilic substitution reactions related to the F-C reactions have been reported (Scheme 32).123*124 Independent groups of workers have developed similar methodologies for the ortho-specific formylation of phenols without the use of HMPA. This is achieved by 117 I. Neves F. Jayat P. Magnoux G. Perot F. R. Ribero M. Gubelrnann and M. Guisnet J. Chem. SOC. Chem. Commun. 1994 717. 118 S. Pivsa-Art K. Okuro,M. Miura S. Murata,and M. Nomura J.Chem.SOC.,Perkin Trans. 1,1994,1703. 119 C. Sarangi and Y.R. Rao J. Chem. Res. (S) 1994 392. 120 A. Kawada S. Mitamura and S. Kobayashi SYNLETT 1994 545. 121 A. W. Douglas N.L. Abrarnson I.N. Houpis S. Karady A. Molina L.C.Xavier and N. Yasuda Tetrahedron Lett. 1994 35 6807. 122 I. N. Houpis A. Molina A. W. Douglas L. Xavier J. Lynch R. P. Volante and P. J. Reider Tetrahedron Lett. 1994 35 6811. 123 G. A. Olah Q. Wang and G. Neyer Synthesis 1994 276. 124 G. Sartori F. Bigi R. Maggi and F. Tornasini Tetrahedron Lett. 1994 35 2393. Aromatic Compounds 2 II Scheme 31 Scheme 32 treating the aryloxymagnesium salts with paraformaldehyde followed by acidic ~ork-up.'~~*'~~ Conventional Vilsmeier formylation [POCl, (Me),NCHO] of naphthalene (44)affords the expected product (45). However if the bulky formamide N-neopentylformamide is used significant quantities of (46) and (47)are formed along with (45)"' In an extension of the Vilsmeier reaction a vinylogous formylation has been achieved with 3-trifloxypropeneiminium triflate (Scheme 33).' 28 A new regioselective tandem amidation reaction of electron-rich arenes has been established (Scheme 34).lz9 Leblanc has extended the utility of his amination reaction of arenes with electron-deficient azodicarboxylates.The procedure can now be used to produce amines from poorly reactive arenes like xylenes and the use of unsymmetrical azodicarboxylates now allows the synthesis of arylhydrazines (Scheme 35).l3O The Bamberger rearrangement is the most convenient and economical method for R. Aldred R. Johnston D. Levin and J. Neilan J. Chem. SOC.,Perkin Trans. 1 1994 1823. '26 R.X. Wang X.Z. You Q.J. Meng E. A. Mintz and X. R. Bu Synth. Commun. 1994 24 1757. "'S.V. Pansare and R. G. Ravi SYNLETT 1994 823. G. Maas R. Rahm M. Scheltz and E.-U. Wurthwein J. Org. Chem. 1994 59 6862. T. Cablewski P.A. Gurr K.D. Raner and C.R. Strauss J. Org. Chem. 1994 59 5814. H. Mitchell and Y. Leblanc J. Org. Chem. 1994 59 682. 186 A. P. Chorlton CHO Formylation <.~ 0 (44) (45) CHO (46) (47) I ii -M \mGe Me\N-CH=CH-CHO OMe H CHO Reagents i (CF,SO,),O; ii H20 Scheme 33 R R R -0 0 OH 2-2, Y OYNH R’ Scheme 34 the synthesis of para-aminophenols directly from nitrobenzenes. Phosphinic acid has been utilized as a hydrogen donor in this rearrangement (Scheme 36).13’ Cerfontain has carried out an in-depth study on the positional reaction order in the sulfonation of phenyl- and naphthyl-substituted naphthalenes with Nucleophilic Substitution.-Aromatic radical nucleophilic substitution or S, 1 has been shown to be an excellent means of effecting the nucleophilic substitution of unactivated aromatic compounds possessing suitable leaving groups.The mechanism of the reaction is a chain process the propagation steps are shown in Scheme 37. Scheme 37 depicts a nucleophile substitution in which radicals and radical anions are intermediates. However this chain process requires an initiation step such as equation 1. In a few systems spontaneous electron transfer (ET) from the nucleophile to the substrate has been observed. When ET does not occur spontaneously it can be induced A. Zoran 0.Khodzhaev and Y.Sasson J. Chem. SOC.,Chem.Commun. 1994 2239. 132 H. Cerfontain Y. Zou and B. H. Bakker Red. Trau. Chim. Pays-Bas 1994 113 517. Aromatic Compounds 0 0 C13Cr'OKN=NKOACCI, +P Reagents i ZnC1,; ii Zn HOAc; iii Bu,NF; iv Ac,O Scheme 35 OH Scheme 36 Initiation Step FU +e'-(Rx)' -1 Propagation Steps (RX)'-R + >t 2 R' + Nu-3 -(RNU)*-+ RX -RNu+(RX)" (RNu)" 4 RX + Nu-5 -RNu+>C Scheme 37 by a number of procedures. Recently Alonso and Lund have respectively used ultra~ound'~~ and electrochemical methods' 34 for this process. The mechanism and reactivity in ET-induced aromatic nucleophilic substitution has been comprehensively reviewed. 35 Aromatic nucleophilic substitution with carbon nucleophiles is an important 133 P. G. Manzo S.M. Palacios and R. A. Alonso Tetrahedron Lett. 1994 35 677. 134 H. Balshev and H. Lund Tetrahedron 1994 50 7889. J.-M. Saveant Tetrahedron 1994 50 10 117. A. P. Chorlton &N=NsBu' CH30COCHfiOCH3 KBU~~DMSO~IIV 0°C,2h + Ph PhN2BF4 -Ph -ArCl + NH3 + &Me POM ;/ e -[ NO2 MeO2C C02Me MeO& C02Me Scheme 38 method for the formation of carbonsarbon bonds. A number of examples are given in Scheme 38.'36-139 Carbon-carbon bonds can also be formed via vicarious nucleophilic substitution (VNS) of hydrogen. The reaction of a-halogenoesters with nitro aromatics has been exploited by a number of workers (Scheme 39).140*141 Makosza has shown that oxidative products can also be formed in preference to the VNS product in the reaction of the carbanion of dithianes with nitroarenes (Scheme 40).14* An elegant example of VNS has been demonstrated by Jung.The key step in this M. Tona F. Sanchez-Baesa and A. Messeguer Tetrahedron 1994,50 8117. T. Sakakura M. Hara and M. Tanka J. Chem. SOC.,Perkin Trans. 1 1994 283. C. Combellas C. Suba and A. Thiebault Tetrahedron Lett. 1994 35 5217. 139 W.-S. Li and J. Thottathil Tetrahedron Lett. 1994 35 6595. I4O G.A. DeBoos and D.J. Milner Synth. Commun. 1994 24 965. 14' 0.Haglund and M. Nilsson Synthesis 1994 242. 142 M. Makosza and M. Sypniewski Tetrahedron 1994 50 4913. Aromatic Compounds Scheme 39 Scheme 40 reaction is the trapping of an a-ketosulfonium salt generated by a Pummerer rearrangement of a 2-(phenylsulfinyl) phenol (Scheme 41).143 A novel nucleophilic aromatic substitution reaction has been described in which the methoxy group of l-methoxy-2-(diphenylphosphinyl)-naphthalene is readily replaced with Grignard reagents alkoxides and amides (Scheme 42). 144 Aromatic nucleophilic substitution by arylselenides has been demonstrated. The arylselenolate ions were produced through reductive cleavage of the Se-Se bond in diaryIselenides.l4' Nucleophilic displacement of 2,4,5-trichloronitrobenzene with potassium fluoride to give 2,4-difluoro-5-chloronitrobenzene is the key step in the cost- effective preparation of 2,4-difluoroaniline and 1,3-difluoroben~ene.'~~ A new example of nucleophilic aromatic substitution of hydrogen has been described.In this process aniline is reacted with azobenzene in the presence of base under aerobic conditions to generate 4-(phenylazo)diphenylamine in high yield (Scheme 43).14' Substitution via Organometallic Intermediates.-Directed ortho-metailation (DoM) continues to be exploited in the synthesis of aromatic compounds. A number of investigations have been carried out into the reactivity and regioselectivity of DoM. In general the DoM group possesses a hetero atom containing an unshared pair of electrons which serve to coordinate the organolithium oligomer as a prelude to the 143 M. E. Jung C. Kim and L. Von dem Bussche J. Org. Chem. 1994 59 3248. 144 T. Hattori J.-I. Sakamoto N. Hayashizaka and S. Miyano Synthesis 1994 199. 14' W. Boa Y.Zhang and S. Chen Synth.Commun. 1994 24 1339. 146 J. Mason and D. J. Milner Synth. Commun. 1994 24 529. 147 M.K. Stern B.K. Cheng F.D. Hileman and J.M. Allman J. Org. Chern. 1994 59 5627. A. P. Chorlton OH OH0 Ph Me OR Scheme 41 Reagents i R,CMgBr; ii RONa; iii R,NLi Scheme 42 ultimate hydrogen metal exchange. For such directing groups the availability of this unshared electron pair is the key to predicting the rate and extent of metallation provided by a particular DoM group in a particular environment. So in the case of anisole resonance of the lone pair on oxygen into the aromatic ring effectively depletes Aromatic Compounds Scheme 43 the coordinating power of the methoxy A decrease in availability of the oxygen lone pair for resonance and an increase in the acidity of the ring protons in anisole should effectively enhance the efficiency of the DoM process.This has been demonstrated a significant rate acceleration being obtained for the DoM of p-fluoroanisole. 149 The rate and regioselectivity of DoM can be dramatically affected by the use of TMEDA. This is thought to be due to the TMEDA reducing the oligomeric structure of alkyl lithiums down to a less sterically demanding dimeric structure . 48 9' O Significant differences in regioselectivity of DoM have been observed with 5-methoxy-2,3-dihydrobenzofuran (49) and -pyran (50).The furan (49) gives preferential lithiation at the CI position whereas with the pyran (50) p lithiation predominate. This is thought to be due to inductive contributions by the ether oxygen being significantly affected by ring size."' The regiochemical metallation of alkyl(alky1thio)benzenes with butyllithium or with the superbasic mixture of butyllithium with potassium t-butoxide has been studied.The reaction pattern depends on the substrate and base used.'52 A reverse of the expected regioselectivity has been observed when ethoxyvinyllithium-HMPA is used as a base (Scheme 44).'53 A number of recent synthetic advances in the use of DoM chemistry have been made. Sequential reaction of prochiral Cr(CO),($-arene) complexes with chiral amine bases and electrophiles yields chiral complexes (Scheme 45).154,'55 The use oflactones as the electrophile in DoM processes provides a mild alternative to Friedel-Crafts acylation (Scheme 46).lS6 The carboxylic group is a recent addition to the synthetic armoury of groups which facilitate D0M.ls7 14' D.W. Slocum R. Moon J. Thompson D. S. Coffey J. D. Li and M. G. Slocurn Tetrahedron Lett. 1994 35 385. 149 D. W. Slocurn D. S. Coffey A. Siegel and P. Grimes Tetrahedron Lett. 1994 35 389. 150 M. Khaldi F. Chretien and Y. Chapleur Tetrahedron Lett. 1994 35 401. ''I L.A. Paquette M.M. Schulze and D.G. Bolin J. Org. Chem. 1994 59 2043. S. Cabiddu C. Fattuoni C. Floris S. Melis and A. Serci Tetrahedron 1994 50 6037. M. Shirnano and A.I. Meyers J. Am. Chem. SOC. 1994 116 10815. 154 D.A. Price N.S. Simpson A.M. Mcleod and A.P. Watt Tetrahedron Lett. 1994 35 6159. 155 E. P. Kundig and A. Quattropani Tetrahedron Lett.1994 35 3497. 156 T. J. Brenstrum M. A. Brimble and R. J. Stevenson Tetrahedron 1994 50 4897. 15' J. Mortier J. Moyroud B. Bennetau and P.A. Cain J. Org. Chem. 1994 59 4042. 192 A. P.Chorlton Scheme 44 OM0 1 OM0 SiM% THF MeiCI. -78 "c Scheme 45 R' 0 R' 0 R2#NPi2 BU'LI -:eNF'+2 + a TMEDA R3 -78 "C oo R' R2,R3 = H OM0 n= 1.2 Scheme 46 N-fluorobenzenesulfonamide and N-fluoro-0-benzenedisulfonimide have been used as fluorine electrophiles in DoM to give access to a variety of monofluorinated aromatics.' 58 Aryllithium reagents prepared by halogen-lithium exchange have also provided a number of synthetic advances. o-Trimethylsilylphenyllithiumcan act as a synthetic equivalent of o-halophenyllithium (Scheme 47).59 Stable 2-lithio-6-nitrophenol derivative have been formed.The stability of these derivatives has been attributed to a chelation effect between the lithium and the nitro group aided by an inductive effect. These species have been trapped by a variety of 15' V. Snieckus F. Beaulieu K. Mohri W. Han C. K. Murphy and F. A. Davis Tetrahedron Lett. 1994,3S 3465. 159 M. Takahashi K. Hatano M. Kimura T. Watanabe T. Oriyama and G. Koga Tetrahedron Lett. 1994 35 579. Aromatic Compounds 193 Scheme 41 ““QBr OE j OH 02N9E P \ Me Me Reagents i PhLi; ii E+ Scheme 48 electrophiles’ 6o and also undergo metallo-Fries rearrangement (Scheme 48).16 Using the method of iodine-lithium exchange 1,3- and 1,4-dilithobenzenes have been generated in solution and isolated in the dry state for the first time.’62 Transition metal-catalysed cross-coupling reactions continue to be widely used for the functionalization of aromatic compounds.Most of these processes involve aryl or vinyl halides (or equivalents) with alkenes or hetero-substituted vinyl compounds or arenes. The Heck and Stille/Suzuki coupling reactions are among the most commonly used. The Heck type process is a palladium-catalysed vinylation of aryl halides. The utility of the reactions has been extended by the development of aqueous processes,163 polymer-bound palladium catalysts,164 and the use of aryl diazonium compounds in place of aryl halogenides. Functionalized olefins such as a-methoxyketenesilyl acetals’66 and [2-(dimethy1amino)ethoxylethenealso increase the synthetic scope of the Heck reaction.’67 The palladium-catalysed coupling between organostannanes 160 I. R. Hardcastle P. Quayle and E. L. Ward Tetrahedron Lett. 1994 35 1747. I. R. Hardcastle and P. Quayle Tetrahedron Lett. 1994 35 1749. 16’ M. Fossatelli R. den Besten H. P. Verkruijsse and L. Bradsma Red. Trau. Chim. Pays-Bas 1994 113 527. T.Jeffery Tetrahedron Lett. 1994 35 3051. P.-W. Wang and M.A. Fox J. Org. Chem. 1994 59 5358. M.Beller H. Fischer and K. Kuhlein Tetrahedron Lett. 1994 35 8773. 16’ T. Sakamoto Y. Kondo K. Masumoto and H. Yamanaka J. Chem. SOC.,Perkin Trans. 1 1994 235. 16’ M.Larhed C. M. Anderson and A. Hallberg Tetrahedron 1994 50 285. A. P. Chorlton Reagents i Pd(PPh,), Na,CO, MeOH/H,O Scheme 49 and unsaturated halides of sulfonates -the Stille coupling -has been the subject of a number of advances which include rate increases with copper(1) salts as cocatalysts,'68 polymer-bound aryl iodides (for combinatorial synthesis),' 69 and n-tributylallenyl stannanes as arylallene precursors.' 70 When the organostannane is replaced by aryl boronic acid the reaction is known as the Suzuki coupling.In this variant particular attention has been paid to the catalyst. Phosphine-free palladium catalysts give a significant rate acceleration and fewer side simple heterogeneous hydrogenation catalysts have also been The Suzuki coupling is carried out in the presence of a base but this is not always compatible with labile functionality present in the reactants.The function of the base in the coupling is thought to be to form a boronate anion that is capable of effecting boron-to-palladium !ransmetallation. Wright has demonstrated that the fluoride anion which has a high affinity for boron can be used to effect the Suzuki coupling under non-basic conditions.' 74 Axially chiral biphenyls have been syn- thesized by the Suzuki cross-coupling of tricarbonyl(arene)chromium complexes with aryl boronic acids (Scheme 49).'753'76 The synthetic utility of cross-coupling has been further exploited with the introduction of a number of new procedures. These include nickel-catalysed reactions of aryl halides in ~yridine,'~~ cross-coupling of arylzinc reagents which have been generated in situ from aryl iodides with a Zn(Agtgraphite couple '78and the use of ar~l'~~ and alkyl halide silanes'" in place of boronic acids and organo stannanes.Similar transition metal methodologies have been used for the introduction of a diverse range of functionalities into the aromatic nucleus. These are illustrated in Scheme 50.' '-I 84 Meyers has reported the chiral oxazoline-mediated Ullmann V. Farina S. Kapadia B. Krishnan C. Wang and L. S. Liebeskind J. Org. Chem. 1994 59 5905. 169 M.S. Deshpande Tetrahedron Lett. 1994 35 5613. 170 D. Badone R. Cardamone and U. Guzzi Tetrahedron Lett. 1994 35 5477. 17' T.I. Wallow and B. M. Novak J. Org. Chem. 1994 59 5034. 17' E. M. Campi W. R. Jackson S. M. Marcuccio and C.G.M. Naeslund J. Chern.SOC. Chem. Comrnun. 1994 2395.173 G. Marck A. Villiger and R. Buchecker Tetrahedron Lett. 1994 35 3277. S. W. Wright D. L. Hageman and L. D. McClure J. Org. Chem. 1994 59 6095. 175 M. Uemura and K. Kamikawa J. Chem. SOC. Chern. Cornmun. 1994 2697. 176 M. Uemura H. Nishimura K. Kamikawa K. Nakayama and Y. Hayashi Tetrahedron Lett. 1994,35 1909. 177 H. Kageyama T. Miyazaki and Y. Kimura SYNLETT 1994 371. 178 A. Furstner R. Singer and P. Knochel Tetrahedron Lett. 1994 35 1047. Y. Hatanaka K.-I. Goda and Y. Okahara Tetrahedron 1994 50 8301. I8O H. Matsuhashi M. Kuroboshi Y. Hatanaka and T. Hiyama Tetrahedron 1994 50 6507. Y. Kubota T.-A. Hanoka K. Takeuchi and Y. Sugi SYNLETT 1994 515. Y. Kubota T.-A. Hanoka K. Takeuchi and Y. Sugi J. Chem. Soc. Chem. Commun. 1994 1553.Aromatic Compounds 195 coupling which affords C,-symmetric biaryls.' 85*186 This methodology was used as the key step in the synthesis of ellagitannin (Scheme 50).ls7 Lipshutz has used intramolecular oxidative coupling of cyanocuprate intermediates to synthesize chiral biaryls.'88 Substitution via Aryl Radicals.-The tandem radical addition-cyclization of sub- stituted diethyl benzyl malonates (51) and alkynes (52) induced by manganese(II1) acetate has been reported. Tetrahydronaphthalenes (53)and spiro[4,5]decatrienes (54) are formed due to competing 6-endo- and 5-em-dig cyclizations.' 89 6-Endo-aryl radical cyclization is also observed in a convergent stereocontrolled synthetic route to linearly hexaannulated condensed hydroaromatic systems (Scheme 51).' 90 Tributyltin hydride-mediated radical cyclizations are useful synthetic transform- ations.A number of alternative procedures for the generation of aryl radicals have been developed and these have been applied to the synthesis of arylated heterocycles (Scheme 52).' 91-194 The reaction of 2,6-dichlorobenzoquinone N-chlorimine with phenol generates the blue anion of indophenol (the Gibbs reaction Scheme 53). This reaction is used as a colorimetric assay for phenols. In an investigation of this reaction the indophenol was found to form via a radical electrophilic aromatic substitution (S,,Ar) on phen01.l~~ The oxidative coupling of phenols is an important synthetic method for the construction of hydroxylated bi- and polyaryls. This reaction usually produces mixtures of compounds from which hydrsxylated biaryls and triaryls have to be separated.Sarturi has found that AlCI in CH,NO promotes a highly selective coupling of phenolic substrates.' 96 Phenolic oxidative coupling can also be achieved rapidly and efficiently under microwave irradiation with FeC13.6H,0 in the solid state.197 5 Condensed Polycyclic Aromatic Compounds Benzenoid Aromatics.-The discovery of the spherical C60 molecule known as a buckminsterfullerene (55) has generated a renewed interest in aromatic hydrocarbons with curved surfaces. Corannulene (56) which represents the polar cap of buckminster- fullerene has been prepared by a new synthetic route.'97 Ab initio calculations predict planar transition states for bowl-to-bowl inversion in corannulene (56) ethenocoran-nulene (57) and semibuckminsterfullerene (58) with energy barriers of 14.4 34.4 and M.Durandetti S. Sibille J.-Y. Nedelec and J. Perichon Synth. Commun. 1994 24 145. A.P. Melissaris and M.H. Litt J. Org. Chem. 1994 59 5818. T.D. Nelson and A.I. Meyers J. Org. Chem. 1994 59 2655. T. D. Nelson and A. I. Meyers Tetrahedron Lett. 1994 35 3259. T. D. Nelson and A.I. Meyers J. Org. Chem. 1994 59 2577. B. H. Lipshutz F. Kayser and Z.-P. Liu Angew. Chem. Int. Ed. Engl. 1994 33 1842. A. Citterio R. Sebastiano A. Maronatti R. Santi and F. Bergamini J.Chem.SOC.,Chem. Commun. 1994 1517. 190 S. P. Jayanta K. Mukhopadhyaya and U.R. Ghatak J. Org. Chem. 1994 59 2687. 19' A. J. Clark D.I. Davies K. Jones and C. Millbanks J. Chem. Soc. Chem. Commun. 1994 41. Y. Liu and J. Schwartz J. Org. Chern. 1994 59 940. 193 M.J. Begley J.A. Murphy and S.J. Roome Tetrahedron Lett. 1994 35 8679. 194 C. Lampard J. A. Murphy F. Rasheed N. Lewis M. B. Hursthouse and D. E. Hibbs Tetrahedron Lett. 1994 35 8675. 195 I. Pallagi A. Toro and 0.Farkas J. Org. Chem. 1994 59 6543. 196 G. Satori R.Maggi F. Bigi and M. Grandi J. Org. Chem. 1994 59 3701. 19' D. Villemin and F. Sauvaget SYNLETT 1994,435. A. P.Chorlton 032 Br + HOG + CO li R' But' 96% 98% Aromatic Compounds several steps I ?Me MeoQ Me0 Me0 Med bMe Reagents i PdCl, dppp base; ii e- Ni DMF; iii HO(Me),CC-CH PdCI,(PPh,), NEt, 40 min; iv KOH (2.5eq) Pr'OH reflux 2.5h; v Cu.py DMF reflux Scheme 50 74 kcal mol- respectively.'98 A large range of bowl-to-bowl inversion barriers have been calculated for heterocorannulenes :pentaazacorannulene has a barrier eight times that of corannulene whilst in pentaborazacorannulene it is less than 1kcal mol-'.'99 Cyclopentacorannulene (59) has been found to be locked into a bowl shape at least on an NMR timescale.200 Considerable synthetic effort has been directed at synthesizing these bowl shaped molecules.This has resulted in the synthesis of a C, hydrocarbon (60) whose carbon framework represents half of the buckminsterfullerene C, (55) surface. These compounds have been referred to as semibuckminsterfullerenes.201Similar C, fragments have also been synthesized uiz.(61)-(63).202-204 lg8 A. Sygula and P. W. Rabideau J. Chem. SOC. Chem. Commun. 1994 1497. 199 R.L. Disch and J.M. Schulman J. Am. Chem. SOC.,1994 116 1533. S. Sygula H. E. Folsom R. Sygula A. H. Abdourazak Z. Marcinow F. R. Fronczek and P. W. Rabideau J. Chem. SOC.,Chem. Commun. 1994 2571. P. W. Rabideau A. H. Abdourazak H. E. Folsom Z. Marcinow A. Sygula and R. Sygula J. Am. Chem. Soc. 1994 116 7891. '02 S. Hagen U. Nuechter M. Nuechter and G. Zimmermann Tetrahedron Lett. 1994.35 7013. '03 F. Sbrogio F. Fabris and 0.De Lucchi SYNLETT 1994 761. '04 M. J. Plater Tetrahedron Lett. 1994 35 6147. A. P. Chorlton t R‘-CZC-H COaEt CO2Et w-p Me b02Me Me i=o&fe Scheme 51 The semibuckminsterfullerene (58)C,,H, has been viewed as a rational precursor to the C, skeleton.AM1 and PM3 SCF-MO calculations suggest that dimerization of (58)to (64)by a mechanism involving six concurrent n2s +n4s additions (Scheme 54) corresponds to a stationary point with six negative force constants; the first stepwise n2s +n4s transition state is found to be highly unsymmetrical with a large barrier to rea~tion.~” Ester and ether derivatives of triphenylene have been widely studied as discotic liquid crystals. This interest has resulted in a number of more practical and economic syntheses of these triphenylene derivatives. 2,3,6,7,10,1l-Hexamethoxytriphenylene has been prepared by oxidative trimerization of 1,2-dimethoxybenzene with iron(rI1) chloride and sulfuric acid in nearly quantitative yield.206 Unsymmetrical derivatives have been prepared independently by similar methods (Scheme 55).207.208 (W (W (n) ’05 M.J. Plater H. S. Rzepa and S. Stossel J. Chem. SOC. Chem. Commun. 1994 1567. ’06 H. Naarmann M. Hanack and R. Mattmer Synthesis 1994 477 ’07 N. Boden R. J. Bushby and A.N. Cammidge J. Chem. SOC.,Chem. Cornrnun. 1994 465. ’08 J. W. Goodby M. Hird K. J. Toyne and T. Watson J. Chem. SOC.,Chem. Commun. 1994 1701. Aromatic Compounds 2RMgBr + CoCI -R2 + Co + 2 MgBrCl 2RMgBr + Co -RzCo+ MgBr + Mg R2Co+ 2 ArBr -R + CoBr + 2k' Fe I R2 Reagents i CoCI, RMgBr; ii Cp,TiCl, NaBH,; iii TTF H,O Me,CO Scheme 52 + "Ct Scheme 53 A. P. Chorlton Scheme 54 OR’ PO OR’ Reagents i FeCl,; ii MeOH Scheme 55 Phenanthrenes have been synthesized by the cyclization of stilbenes by flash vacuum pyrolysis209 and by a palladium-catalysed domino process (Scheme 56).2lo The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene is metabolically converted into the highly carcinogenic diol epoxide (65).Meehan has developed an improved economical formal route to this compound.’l’ The next stage in tumorigen- esis is the binding of DNA to this mutagenic metabolite diol epoxide (Scheme 57). To permit further study of this process the derivatives of the amino trans ring opening of these diol epoxides have been synthesi~ed.~~’,~~~ In an advance of these studies the 209 M. J. Plater Tetrahedron Letr. 1994 35 801. 210 G. Dyker and A. Kellner Tetrahedron Lett.1994 35 7633. 211 G. R. .Negrete and T. Meehan Tetrahedron Lett. 1994 35 4727. 212 M. K. Laksham S. Chaturvedi and R. E. Lehr Synth. Commun. 1994 24 2983. 213 V. Y. Shafirovich P. P. Levin V. S. Kuzmin T. E. Thorgeirsson D. S. Kliger and N. E. Geacintov J. Am. Chem. SOC. 1994 116 63. Aromatic Compounds I 1 0 + 0 \ Scheme 56 HO Ho Scheme 57 N6-deoxyadenosine adducts resulting from the cis and trans ring opening of phenanthrene-9,lO-oxide have been prepared.2 l4 Non-benzenoidAromatics.-Ab initio quantum mechanical methods molecular mech- anics and semiempirical theoretical methods have been used to predict the molecular structures and energies of the plausible isomers of [10)annulene. These calculations have revealed a wealth of energetically low-lying structural isomers of the same (CH), connectivity.2l5 2,7-Methanocyclodeca[u]azulene (66) has been synthesized and its properties examined by 'H NMR.These studies have revealed that (66) is composed of a delocalized methano[lO]annulene and localized azulene moieties; there is no '14 M. K. Lakshman X.Xiao J. M. Sayer A.M. Cheh and D. M. Jerina J. Org. Chem. 1994 59 1755. Y. Xie H. F. Schaefer 111 G. Liang and J. P. Bowen J. Am. Chem. SOC.,1994 116 1442. 202 A. P. Chorlton contribution from the peripheral l8.n-electron system.2 l6 In a similar study annulenes fused with azulene were examined. It was found in the 10,12-bisdehydr-3-isopropyl-9,14-dimethyl[ 14]annulene[a]azulene (67) that the fusion of the azulene ring sup- presses the diatropicity of [4n + 21 14.n-electron system to a smaller extent than the benzene ring.21 7,21 A series of tetramethyloctadehydrodihydro[26]- -[28]- -[30]- -[32]- and -[34]- annulenediones (68)-(72) have been synthesized and their properties examined.2 The dications of (68) and (69) were found to be significantly paratropic and diatropic respectively.This is the first confirmation of the alternation of the tropic nature between [4n + 23.n and 4n.n electron systems in monocyclic annulenediones.220 (a) m= n= 1 [a)- (69)[28&m=l,n=2 (70)130). m-n= 2 (71) [32).m= 2 n= 3 (72) [a). m = /I = 3 In an analogous study methano-bridged dichlorodidehydroC 161- -[20]- and -[24]annulendiones were prepared (Scheme 58).22 These annulendiones exhibited 216 K.Ito H. Kawaji and M. Nitta Tetrahedron Lett. 1994 35 2561. 217 H. Higuchi J. Ojirna M. Yasunarni K. Fujirnori and M. Yoshifuji Tetrahedron Lett. 1994 35 1259. 218 H. Higuchi J. Ojirna M. Yasunarni K. Fujirnori M. Ueno M. Yoshifuji and G. Yarnarnoto J. Chem. SOC. Perkin Trans. 1 1994 1167. 219 H. Higuchi S. Kondo Y. Watanabe J. Ojirna and G. Yarnamoto J. Chem. SOC.,Perkin Trans. 1 1994 1957. 220 H. Higuchi S. Kondo Y. Watanabe J. Ojirna and G. Yarnarnoto J. Chem. SOC.,Chem. Commun. 1994 877. 221 H. Higuchi K. Asano J. Ojirna K. Yarnarnoto T. Yoshida J. Adachi and G. Yarnarnoto J. Chem. SOC. Perkin Trans. 1 1994 1453. Aromatic Compounds 0 (75) (24)-m= n=3 (74) m = 1 n = 0 Scheme 58 Reagents i LiOH; ii Br,; iii Bu'OK Scheme 59 strong diatropicity in D,SO due to the dicationic 1471 1871 and 2271-electron species and their diatropicities were shown to increase with increasing ring size.In this investigation the intramolecular Glaser coupling of (73) to give (74) also gave the biproduct (75). The dication of (75) exhibited diatropicity ascribable to the formation of a cationic 1071-electron species.222 Gellman has developed a new synthetic route to the 16-methano[lO]annulene skeleton. The key step in this route is the semibenzylic Favorskii rearrangement of the C4.4.2)propellane (76) to the C4.4.13 propellane. This methodology now provides access to 1,6-methano[ lolannulene derivatives bearing substituents on the bridge carbon (Scheme 59).223 6 Cyclophanes The intramolecular [2 + 21 photocyloaddition of vinyl arenes has been successfully applied to the synthesis of cy~lophanes.~~~ A recent example of this process is the synthesis of metacyclophanes (Scheme 60).225 Conformational studies have been carried out on selectively methylated [2.2] (1,3)( 1,4)cyclophanes.Dynamic 'H NMR spectroscopy was employed to estimate the 222 H. Higuchi C. Sakon K. Asano J. Ojima M. Iyoda K. Inoue and G. Yamarnoto J. Chem. Soc. Perkin Trans. 1 1994 2915. 223 D. G. Barrett G.-B. Liang D.T. McQuade J. M. Despers K. D. Schladetzky and S. H. Gellman J. Am. Chem. SOC.,1994 116 10525. 224 J. Nichimura Y. Okada S. Inokuma Y. Nakamura and S. R. Gao SYNLETT 1994 884. "' Y.Okada F. Ishii Y. Kasai and J. Nishimura Tetrahedron 1994 50 12 159. A. P. Chorlton OMe OMe Me0 OMe Scheme 60 relative conformational barrier in each C2.21 cyclophane. These results show that there is an increase of about 13 kJ mol-going from the parent [2.2](1,3)(1,4)cyclophane (77) to its 12,15-(78) and 12,16-dimethyl (79) derivatives.226 (78) (79) (80) (1,4)Naphthaleno[2.2]-meta-cyclophanes (80) have been synthesized via the sulfox- ide pyrolysis method. These derivatives were found to be conformationally rigid up to 1500C.2278-Methoxy-[2.2]-rneta-cyclophanes form charge transfer complexes with tetracyanoethylene. The effect of substituent has a dramatic effect on the absorption of the charge transfer band. Electron-donating substituents give substantial bathoch- romic shifts whereas no complexes are formed when electron-withdrawing groups are introduced (Scheme 61).228 Cyclophanes have also been employed as effective chiral auxiliaries for asymmetric synthesis (Scheme 62).229 Paracyclophane (83) undergoes ring-opening metathesis polymerization to give poly(pphenyleneviny1ene) (PPV).This polymerization proceeds in a living fashion that provides PPV with a narrow polydispersability and a molecular weight which increases linearly with the amount of monomer reacted (Scheme 63).230 226 Y.-H. Lai A.H.-T. Yap and I. Novak J. Org. Chem. 1994 59 3381. 227 T. Yamato K. Noda K. Tokuhisa and M. Tashiro J. Chem. Res. (S) 1994 210. 228 T. Yamato J.-I. Matsumoto N. Shinoda S. Ide M.Shigekuni and M. Tashiro J. Chem. Res. (S) 1994 178. 229 V. Rozenberg V. Kharitorov 0.Antonov E. Sergeeva A. Aleshkin N. Ikonnikov S. Orlova and Y. Belokun Angew. Chem. Int. Ed. Engl. 1994 33 91. 230 Y.-J. Mia0 and G.C. Bazan J. Am. Chem. SOC. 1994 116 9379. Aromatic Compounds (81) R'=Bu',R~=R~=H,&~~~~ (82) R' = But = OMe R3= H,A,,,,x 640 Scheme 61 OH syn-L Syn-0 Scheme 62 A. P. Chorlton Mez(But)SiO ei Reagents i Mo~(2,6-Pr:Ph)](CHCMe2Ph)[OCMe(CF,),] Scheme 63

ISSN:0069-3030    

DOI:10.1039/OC9949100165

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

7 Heterocyclic Compounds By P.W. SHELDRAKE Smith Kline Beecham Pharmaceuticals Old Powder Mills Nr Leigh Tonbridge Kent TN11 9AN UK 1 Introduction In last year's Chapter a number of examples illustrating the versatility of metallated derivatives of a variety of heterocyclic compounds were included. These convenient synthetic tools continue to be exploited and reviews have appeared that cover imida~oles,~ The metallation isoxazoles,' oxazoles,2 pyrazole~,~ and dia~ines.~ strategy can be commended for its scope and efficiency; the best examples still find their way into the body of the review. 2 Three-membered Rings Asymmetric epoxidation of styrene has been accomplished in up to 86% enantiomeric excess and 88% yield,6 using the manganese catalyst (1)with rn-chloroperbenzoic acid and N-methylmorpholine N-oxide in dichloromethane at -78 "C.With the catalyst (2) and sodium hypochlorite and a pyridine N-oxide as co-oxidants a cis-cinnamic ester was epoxidized with 96% enantiomeric ex~ess.~ A closely related catalyst has been used' in conjunction with iodosylbenzene to epoxidize trans-stilbene (65% yield 62% e.e.) and a chromene (78% yield 96% e.e.). 'But BU' ' (1) R1= Ph; R2 = OSiPrgi (2) R' = (CH& R2= Bu' ' B. Iddon Heterocycles 1994 37 1263. 'B. Iddon Heterocycles 1994,37 1321. ' M. R. Grimmett and B. Iddon Heterocycles 1994 37 2087. B. Iddon and R.I. Ngochindo Heterocycles 1994 38 2487. A. Turck N. PIC and G. Queguiner Heterocycles 1994 37 2149. ti M. Palucki P.J.Pospisil W. Zhang and E.N. Jacobson J. Am. Chern. SOC. 1994 116 7880. ' E.N. Jacobson L. Deng Y.Furukawa and L. E. Martinez Tetrahedron 1994 50 4323. N. Hosoya A. Hatayama R. hie H. Sasaki and T. Katsuki Tetrahedron 1994 50 4311. 207 P. W. Sheldrake (3) Reagents i LDA THF -78 "C;ii R'R'C=O Scheme 1 0 0&OR1 Reagents i R'Li or R'MgCI -85 "C Scheme 2 A R' (7) Reagents i R:NH [Yb(OTf),] CH,Cl Scheme 3 Manganese(rr1) tetraphenylporphyrin is the catalyst for epoxidizing cis-olefins with tetra-n-butylammonium periodate.' 2-Chloromethylpyridine (3) can be used lo to prepare oxiranes (4) a method analogous to the Darzens reaction (Scheme 1). Homochiral oxirane esters (5) are converted into ketones (6)using organolithium or Grignard reagents' with little loss of stereochemical integrity; enantiomeric excesses of 92-99Y0 were achieved (Scheme 2).The opening of oxiranes (7) by an amine in the presence of a lanthanide(I1r) trifluoromethanesulfonate occurs in high yield and with over 99% regioselectivity (Scheme 3). The ytterbium salt is especially effective." The same salt has been used in the aminolysis of N-tosylaziridines,' though in this case the regioselectivity is more variable (75-98 YO). A theoretical study of substituted oxirenes suggests that dimethyloxirene is a true minimum on the potential energy surface. l4 There is a review of the synthesis of chiral aziridines and their use in stereoselective transformations.' The readily available 2-bromoacrylamide (9) reacts with primary amines to give the anticipated aziridine D.Mohajer and S. Tangestaninejad Tetrahedron Lett. 1994 35,945. lo S. Florio and L. Trosi Tetrahedron Lett. 1994 35,3175. L. Pegorier Y. Petit A. Mambu and M. Larcheveque Synthesis 1994 1403. M. Chini P. Crotti L. Favero F. Macchia and M. Pineschi Tetrahedron Lett. 1994 35,433. M. Meguro N. Asao and Y. Yamarnoto Tetrahedron Lett. 1994 35,7395. l4 J. E. Fowler J. M. Galbraith G. Vacek and H. F. Schaefer 111 J. Am. Chem. SOC.,1994 116 9311. I5 D. Tanner Angew. Chem. Int. Ed. Engl. 1994 33,599. Heterocyclic Compounds Reagents i RNH Scheme 4 i Ria&@ 92-98% R2 (11) RY2But Reagents i LDA R' = alkyl; R2 = H Me * (12) Scheme 5 Ar R' + ArN=S=NAr 53% R2 I Reagents i [PdCl,(PhCN),] toluene 130"C Scheme 6 derivatives (10) as single diastereoisomers (Scheme 4).In only one case was a minor diastereoisomer detected. ' Aziridines (11) undergo an aza-[2,3]Wittig rearrangement on treatment with strong base to give 1,2,3,6-tetrahydropyridines(12) (Schemes 5).' The palladium-catalysed reaction of aziridines (13) with sulfur diimides (14) produces imidazolidine-2-thiones (1 5) that have mysteriously gained a carbon atom (Scheme 6). Carbon-13 labelling showed that both the methylene carbon and the thiocarbonyl carbon atom of the product derive from the methylene carbon of the starting aziridine i.e. two mols of (13) produce one of (15).'* Treatment of olefins with N-(p-tolysulfony1)iminophenyliodinanein the presence of l6 P.Garner 0. Dogan and S. Pillai Tetrahedron Lett. 1994 35 1653 " J. Ahrnan and P. Sornfai J. Am. Chem. SOC. 1994 116 9781. J.-0. Baeg and H. Alper J. Am. Chem. Soc. 1994 116 1220. P.W. Sheldrake s n3 II n Reagents i (EtO),PSSBr; ii TBAF Scheme 7 Ph Reagents i Oxone@ (C,H,,),NMeCI CHzCIz HzO Scheme 8 (211 Reagents i hv (2305 nm) Scheme 9 copper(1) or copper(I1) triflate or perchlorate gives N-to~ylaziridines'~ in 55-95 % yield. An olefin (16) can be converted into a thiirane (18)using the thioxaphosphorane sulfenyl bromide indicated via the adduct (17) which is reacted with tetra-n-butylammonium fluoride (Scheme 7).20 Oxidation of the bis-thioketal(19) with buffered Oxone@ gives the dithiirane (20)in modest yield;*' compound (20) is the first isolable dithiirane (Scheme 8).More difficult to capture is l,1-dimethyl-1H-silirene (22)prepared by irradiation of 2-sila-l,3-bis(diazo)propane(21) in an argon matrix at 10K (Scheme 9). It is the first silirene to be observed without substituents on the double bond.22 3 Four-membered Rings Heterocyclic chemists might regard paclitaxel (TaxoP) as an oxetane with complicated l9 D. A. Evans M. M. Faul and M.T. Bilodeau J. Am. Chem. SOC. 1994 116 2742. 2o G. Capozzi S.Menichetti S. Neri and A. Skowronska Synlett 1994 267. A. Ishii T. Akazawa T. Maruta J. Nakayama M. Hoshino and M. Shiro Angew. Chem. Int. Ed. Engl. 1994 33 777. 22 M. Trommer W. Sander and C. Marquard Angew. Chem. Int. Ed. Engl. 1994 33 766.Heterocyclic Compounds 21 1 TBDMSO TBDMSO ___c BuQC iii 77% Bu’02C NCH2Ph H Reagents i LiN(TMS)CH,Ph MeCHO; ii TBDMSCl; iii EtMgBr Scheme 10 appendages! In the noteworthy achievement of its total synthesis23 oxetane formation was possibly the most straightforward step. There are reviews on the synthesis of natural /?-lactam antibiotic^^^ and on the use of organosilicon and organotin compounds in the synthesis and transformation of lactam tam^.^^ A three-component condensation initiated by Michael addition of lithium N-benzyl(trimethylsily1)amide to unsaturated ester (23) and followed by capture of acetaldehyde gives the fi-amino acid derivative (24) stereoselectively.26 This is ring closed to the fi-lactam (25) in good yield (Scheme 10).The carbamoylcobalt (111) salophen derivative (26) undergoes homolytic cleavage on heating in toluene.27 Cyclization (4-exo-trig) and dehydrocobaltation gives the /?-lactam (27). Irradiation2* of (28) permits isolation of the intermediate (29); the subsequent thermal elimination of cobalt to form (30) was inefficient (Scheme 11). Isoxazolines (31) are converted into /?-lactams (32) on treatment with tetra-n- butylammonium fluoride,29 but the yields are only moderate (Scheme 12). The /?-lactam (33) is converted into penam (34) by ferric nitrate/cupric nitrate. Manganese acetate/cupric acetate gives the corresponding acetate (35). The relevance of the study to the Baldwin mechanistic hypothesis on the biosynthesis of penicillin is described3’ (Scheme 13).The bicyclic thiazinone (36) gives a 1-fi-methylcarbapenem (37) by Eschenmoser sulfide contraction (Scheme 14). The phosphate ester was then displaced by a thiol in good overall yield.31 Azet-2(3H)-one (39) derived from 4-acetoxyazetidin-2-one (38) reacts with 1,3- dipoles to give for example (40) (Scheme 15). Polymer-bound derivatives of (38) and of the 1,3-dipole precursor were used to confirm the presence of free (39) by the three-phase test . Treatment of the malonate (41) with cyanide in DMSO gives the expected product (43); but use of chloride gives the rearranged product (44)(Scheme 16). The behaviour is explained by different reactions of common intermediate (42) with the two anions.33 23 K. C. Nicolaou Z. Yang J. J. Liu H.Ueno P.G. Nantermet R. K. Guy,C. F. Claibourne J. Renaud E. A. Couladouros K. Paulvannan and E. J. Sorensen Nature (London) 1994 367 630. 24 R. Southgate Contemp. Org. Synth. 1994 1 417. 25 G. A. Veinberg and E. Lukevies Heterocycles 1994 38 2309. 26 N. Asao T. Shimada N. Tsukada and Y. Yamamoto Tetrahedron Lett. 1994 35 8425. ” G. Pattenden and S. J. Reynolds J. Chem. SOC.,Perkin Trans. I 1994 379. 28 G.B. Gill G. Pattenden and S.J. Reynolds J. Chem. SOC. Perkin Trans. I 1994 369. 29 C. Ahn J. W. Kennington Jr. and P. De Shong J. Org. Chem. 1994,59 6282. ’O W. Cabri I. Candiani and A. Bedeschi J. Chem. SOC. Chem. Commun. 1994 597. ” 0.Sakurai T. Ogiku M. Takahashi H. Horikawa and T. Iwasaki Tetrahedron Lett. 1994,35 2187. ’’A.M. Costero M. Pitarch and M.L. Cano J. Chem. Res. (S) 1994 316. 33 P. J. Gilligan and P. J. Krenitsky Tetrahedron Lett. 1994 35 3441. P. W. Sheldrake OBn 40% i N Bn (salophen)CoKNBn )-FOB. 0 0 Reagents i A toluene; ii hv Scheme 11 R (31) R = Ph C02Et Reagents i TBAF THF 0 “C Scheme 12 Oxetanes (45) are rearranged by boron trifluoride etherate to give derivatives (46) of larger cyclic ethers (Scheme 17). A similar rearrangement of the corresponding oxiranes is also reported.34 The preparation of 2H,SH-benzo[ 1,2-b;4,5-b’)bisthiete (48) by flash vacuum pyrolysis of (47) is rep~rted.~’ Further reactions of the bisthiete often involve thiaquinonemethides giving for example (49) with dimethyl acetylenedicar- boxylate3’ (Scheme 18). lH-NaphthoC2,l-blthiete and 2H-naphtho[2,3-b]thiete were also prepared by this meth~dology.~~ 4 Five-membered Rings There are reviews of the chemistry of 2-oxazolines (1985Spre~ent);~~ benzotriazolylal-34 A.Itoh Y. Hirose H. Kashiwagi and Y. Masaki Heterocycles 1994 38 2165. 35 H. Meier and A. Mayer Angew. Chem. lnt. Ed. Engl. 1994,33 465. A. Mayer and H. Meier Tetrahedron Lett. 1994 35 2161. 37 T. G. Grant and A. I. Meyers Tetrahedron 1994 50 2297. 213 Heterocyclic Compounds (33) (34) X = NO2 (35) X = COCH3 Reagents i Fe(NO,),/Cu(NO,),; ii Mn(OAc),/Cu(OAc), MeCN Scheme 13 Reagents i NaH PPh, DMF; ii (PhO),POCl Scheme 14 H Ph (38) (39) (40) Reagents i PhCH(CO,Me)N=CHPh Scheme 15 kylations and benzotriazole-mediated heteroalkylations;38 and recent advances in the cycloaddition chemistry of isomiinchnones and thioisomiinchnones.39 Also reviewed are synthetic approaches to b~tenolides;~' the ketoxime-based pyrrole ~ynthesis;~' recent (1990-93) developments in indole ring synthesis;42 and anellated heterophos- ph01es.~~ 4-Iodo-3-trimethylsilylfuran,a potentially useful intermediate is available in 80% yield44 from 3,4-bis(trimethylsilyl)furan on treatment with iodine/silver trifluoro- 38 A.R. Katritzky X.Lan and W.-Q. Fan Synthesis 1994 445. 39 M. H. Osterhout W. R. Nadler and A. Padwa Synthesis 1994 123. 40 D. W. Knight Contemp. Org. Synth. 1994 1 287. *' B. A. Trofinov and A. I. Mikhaleva Heterocycles 1994 37 1193. *' G.W. Gribble Contemp. Org. Synth. 1994 1 145.43 R. K. Bansal K. K. Karaghiosoff and A. Schmidpeter Tetrahedron 1994 50 7675. ** Z.Z. Song and H.N.C. Wong Liebigs Ann. Chem. 1994 29. P. W.Sheldrake Ph-N (43) (44) Reagents i NaCN DMSO; ii NaCl DMSO Scheme 16 Me (45) n= 1,2,3 Reagents i BF,.OEt, CH,Cl Scheme 17 acetate at -78 "C.The tributyltin-substituted butenolide (50) can be converted into the corresponding chloro bromo or iodo derivatives (51) on treatment with the halogen in a chlorinated solvent.45 The iodo compound had not been previously reported (Scheme 19). 2,5-Dimethoxy-2,5-dihydrofuran (52) reacts with 2-iodophenol (53)under pallad- ium catalysis to give the 2,3-dihydrobenzofuran (54).Treatment with boron tri- fluoride gives the benzofuran (55) (Scheme 20).46 Using a 2-iodoaniline-derived carbamate (56) as substrate produces (57).Cycliz-ation to the indole (58)is effected with trifluoroacetic acid (Scheme 21).47 The exocyclic methylene compound (60) is readily prepared from cyclohexane- 1,3- dione (59) and diethylpropargylsulfonium bromide. It reacts with electron-deficient alkenes in an ene reaction giving furans (61) (Scheme 22).48 3-Lithiothiophene is stable in hexane at room temperature:' a significant solvent 45 G. J. Hollingworth J. R. Knight and J.B. Sweeney Synth. Commun. 1994 24 755. 46 K. Samizu and K. Ogasawara Heterocycles 1994 38 1745. 47 K. Samizu and K. Ogasawara SYNLETT 1994 499. 48 A. Ojida A. Abe and K. Kanematsu Heterocycles 1994 38 2588. 49 X.Wu T.A. Chen L. Zhu and R.D.Rieke Tetrahedron Lett. 1994 35 3673. Heterocyclic Compounds TOH ii HS HO' (47) (49) E=C02Me Reagents i FVP; ii Me0,CC-CC0,Me Scheme 18 0 Bu&n d o -d 5940% o i X (50) (51)X = CI Br I Reagents i X, chlorinated solvent Scheme 19 I + Uo* (53) (55) (54) Reagents i Pd(OAc), PriNEt BnEt,NCI DMF 70°C; ii BF,.Et,O Scheme 20 effect. The thioanhydride (62) reacts with bis(cyclopentadieny1)dimethyltitanium to give the 2,Sdimethylenethiolane (63),which is stable to isomerization in the absence of acid.50 Tosic acid brings about quantitative conversion into the thiophene (64) (Scheme 23). M.J. Kates and J. H. Schauble J. Org. Chem. 1994 59 494. P. W. Sheldrake OMe (56) R' = H OMe; (57) (58) R2 = Et Bu' Reagents i (52) Pd(OAc), PriNEt BnNEt,Cl DMF 80°C; ii 6% TFA CH,CI Scheme 21 (59) (60) (61) Z = COCH3,C02Et,CN Reagents i HC-CCH,SEt,Br KOBu' THF; ii CH,=CHZ Scheme 22 i ii ___t 0 0-Me Me (62) R' R2 = H alkyl Ph (W Reagents i [TiMe,Cp,]; ii TsOH Scheme 23 The tributylphosphine/carbon disulfide adduct reacts with a strained olefin for example (65) and benzaldehyde to give a 2-benzylidene- 1,3-dithiolane (66) (Scheme 24)?' Treatment of the thienopyrrolotriazole (67) with tosic acid gives thieno[3,4-c] pyrrole (68) as its tosylate salts2 by 1,3-dipolar cycloreversion.The free base is obtained using sodium carbonate. Reactions of (68) uia its dipolar tautomer (69) were recorded (Scheme 25). It has been found that treatment of 1-arylpyrrole-2-carboxaldehydes with triflic acid in refluxing 1,Zdichloroethane brings about their conversion into l-arylpyrrole-3- carboxaldehydes; at equilibrium the proportion of the latter is 95% or better.53 There is a convenient synthesis of 2-arylpyrroles (71) starting from 1-propargylbenzotriazole (70) as indicated54 in Scheme 26.51 R.A. Aitken T. Massil and S.V. Rant J. Chem. SOC.,Chem. Commun. 1994 2603. 52 C.-K. Sha and C.-P. Tsou J. Chem. SOC.,Perkin Trans. I 1994 3065. s3 P. Dallemagne S. Rault F. Fabis H. Durmoulin and M. Robba Synth. Commun. 1994,24 1855. 54 A. R. Katritzky J. Li and M. F. Gordeev Synthesis 1994 93. Heterocyclic Compounds Reagents i Bu,P-CS, PhCHO Scheme 24 (67) R’ R2= H Me,Ph (68) (69) Reagents i TsOH; ii Na,CO Scheme 25 I ii.iii mAr 4540% N H Reagents i BuLi; ii ArCH=NTos; iii NaOH EtOH Scheme 26 Another application of benzotriazole meth~dology~~ converts the iminophos- phorane (72) into the synthon (73). This can be converted into 3H-benzazepine (74)or into a 2,3-diarylpyrrole (75) both in good yield (Scheme 27). Substituted 1,3 -dienes (76) undergo cycloaddi tion with N-sulfinyl-p-toluenesul-fonamide. Treatment of the adducts (77) with trimethylphosphite/triethylamine gives 1-tosylpyrroles (78) (Scheme 28).56 Reaction of 1,3-diketones (79) with the azoalkene (80)gives access to pyrroles (82) via the protected 1-(Boc-amino) derivatives (81) (Scheme 29).57 55 A. R. Katritzky J. Jiang and P. J. Steel J.Org. Chem. 1994 59 4551 56 P. J. Harrington and I. H. Sanchez Synth. Commun. 1994 24 175. 57 A. J.G. Baxter J. Fuher and S. J. Teague Synthesis 1994 207. P. W. Sheldrake <N =PPh3 Reagents i Ph,P=CH,; ii BuLi; iii o-C,H,(CHO),; iv ArCOCOAr Scheme 27 i ii 8344% 80% R' XR4 I Tos (76) R' R2 R3 R4 = H,Me Ph (77) (78) Reagents i TosN=S=O; ii P(OMe), NEt Scheme 28 Reagents i Bu'OH heat; ii HC1 MeOH; iii NaNO, HCl MeOH Scheme 29 Heterocyclic Compounds - i ii R’YNH2 C02R2 2048% (83)R’ = alkyl; R2 = Me Et Reagents i MeO,ECCO,Me; ii NaOMe MeOH Scheme 30 0 (MeO),P ,C02Me Reagents i (MeO),POCH,COMe NaH THF; ii (EtO),POCH,CN NaH THF Scheme 31 R’ R2 - iRq &O2CH2Ph -76% R’ H (88)R’ R2= alkyl (89) Reagents i CNCH,CO,CH,Ph DBU THF Scheme 32 Esters of a-aminoacids (83) are quickly converted into 3-hydroxypyrroles (84)by way of their adducts with dimethyl acetylenedicarboxylate (Scheme 30).58 1,2-Diaza- 1,3-dienes (85) are starting materials for the preparation of pyrroles with less usual sub~tituents.~’ Reaction with dimethyl (2-oxopropy1)phosphonategives the pyrrole-3-phosphonates (86)and use of a cyanomethylphosphonate results in similar 2-aminopyrrole-3-phosphonates(87) (Scheme 31).A range of 2-unsubstituted pyrroles (89) is available by the condensation of benzyl isocyanoacetate with the readily prepared nitroolefins (88) (or the corresponding 2-acetoxynitroalkanes) (Scheme 32).60 The oxidation of substituted pyrrolidines (90) into pyrroles (91) with ‘activated’ 58 P.Kolar and M. Tisler Synth. Cornmun. 1994 24 1887. 59 O.A. Atlanasi P. Filippone D. Giovagnoli and A. Mei Synthesis 1994 181. 6o T. D. Lash J. R. Bellettini J. A. Bastian and K. B. Couch Synthesis 1994 170. P.W.Sheldrake (90) R' R2 R3 R4 seetext (91) Reagents i activated MnO, THF reflux Scheme 33 But // But (92)X = 0,S (93) (94) Reagents i FVP 400°C Scheme 34 manganese dioxide has been studied.6' In general one of the substituents R, R, or R must have a carbonyl group next to the ring; the reaction fails if R,is benzoyl (Scheme 33). Flash vacuum pyrolysis of the benzofurylnitrone (92) gives a mixture of a benzofuro[2,3-c]pyrrole (93) and a benzofuro[2,3-c]pyridin-3-one (94) (Scheme 34).The mechanism involves an initial 1,7-dipolar cyclization. The corresponding benzothiophene starting material reacts similarly.62 The acid-catalysed cyclization of B,y-unsaturated amides has been studied.63 Thus (3E)-pent-3-enamide (95) gives 5-methylpyrrolidin-2-one (96) but (3E)-hex-3-enam- ide (97) gives a piperidin-2-one (98) (Scheme 35). If benzaldehyde is added to such reactions further interesting though mechanisti- cally distinct cyclizations are apparent.64 Thus the secondary pentenamide (99a) undergoes both condensation and cyclization onto the benzene ring giving (100).The primary amide (99b) gives a pyrrolidin-2-one (101),which in a different acid system is converted into a piperidin-2-one (102) (Scheme 36).Radical-induced cyclization is effective for the formation of five-membered rings. Homolytic cleavage of the N-S bond of imine (103) gives the cyclized radical (104) and a product is obtained either by hydrogen abstraction (105)or following reaction with a suitable acceptor giving for example (106) (Scheme 37).65 61 B. Bonnaud and D. C. H. Bigg Synthesis 1994 465. 62 J. Bussenius. N. Laber T. Muller and W. Eberbach Chem. Ber. 1994 127 247. 63 C. M. Marson and A. Fallah Tetrahedron Lett. 1994 35 293. 64 C.M. Marson U. Grabowska T. Walsgrove D. S. Egglestone and P. W. Baures J. Org. Chem. 1994,59 284. 65 J. Boivin E. Fouquet and S.Z. Zard Tetrahedron 1994 50 1745. Heterocyclic Compounds 221 Reagents i CF,SO,H Scheme 35 I !H i - 74% HR (99a) R = CH2Ph (100) R = CH2Ph (9%) R = H iii (101) Reagents i PhCHO PPA; ii PhCHO MeSO,H P,O,; iii PPA Scheme 36 If an amine radical is similarly generated from (107) then the ensuing cyclizations form a quite complex ‘cage’ amine (108) (Scheme 38).66 Palladium-catalysed chemistry gives access to cyclic amines (111) from simple acyclic starting materials (Scheme 39).A Heck olefination of vinyl bromide (109) by the W.R. Bowman D.N. Clark and R.J. Marmon Tetrahedron 1994 50 1295. P.W. Sheldrake (106) R =C02Et etc. Reagents i Bu,SnH; ii CH,=CHE Scheme 37 4NSPh i>F&- (107) Reagents i Bu,SnH Scheme 38 Tos (109) (110) n =1,2 Reagents i Pd(o) Na,CO Scheme 39 protected aminoalkyl olefin (110) is followed by a catalysed cy~lization.~’ Cyclizations brought about by olefin metathesis using a molybdenum-carbene complex have been used to prepare a range of bicyclic amides (113).The dienes (1 12) are readily prepared and entry is gained to pyrrolizidine indolizidine quinolizidine pyrrolidinoazocines and piperidinoazocine systems68 (Scheme 40). Treatment of N-Boc-proline methyl ester (114) with iodosylbenzene and azido- 67 R.C. Larock H. Yang S. M. Weinreb and R.J. Herr J. Org. Chem. 1994 59 4172. 68 S.F.Martin Y. Liao H.-J. Chen M. Patzel and M.N.Ranser Tetrahedron Lett. 1994 35 6005. Heterocyclic Compounds 0 i I (112) n =1,2;n =0,1,2,3;R=H,Me (113) Reagents i PhMe,CCH=Mo=N[2,6( Pr'),C,H ,][OCMe(CF,),] , C,H, 20-50 "C Scheme 40 i C02Me 70% N3 +co2Me I 1 C02Bu' C02Bu' (114) (1 15) Reagents i (PhIO), Me,SiN, CH,Cl, -40°C Scheme 41 (116) R = H Me Ph; n = 14 (1 1 7a) (117b) Reagents i Me0,CC-CCO ,Me DMSO 135 "C Scheme 42 trimethylsilane leads to functionalization at C-5,producing6' the azide (1 15) (Scheme 41)'' Enamines (116) better viewed as vinylogous carbamates react with dimethyl acetylenedicarboxylate to give the bicyclic products (1 17a) and (1 17b) (Scheme 42) with a notable scission of the double bond in the starting material.71 The authors suggest a mechanism.The first catalytic iron-mediated carbon-nitrogen bond formation involving allenyl imines (1 18) and carbon monoxide is reported,72 the products being 3-alkylidene-4- pyrrolin-2-ones (1 19) (Scheme 43).A good degree of asymmetric induction is achieved in the intramolecular Heck 69 P. Magnus and C. Hulme Tetrahedron Lett. 1994 35 8097. 'O P. Magnus C. Hulme and W. Weber J. Am. Chem. Soc. 1994 116 4501. " S. Jiang Z. Janousek and H. G. Viehe Tetrahedron Lett. 1994 35 1185. l2 M.S. Sigman and B. E. Eaton J. Org. Chem. 1994 59 7488. P. W. Sheldrake i 62-72% -R1$0 44mNR3 R2 Y R3 (118) R, F$ R3 = alkyl (119) Reagents i lOmol YOFe(CO), CO THF Scheme 43 H Reagents i Pd(o) optically active ligand Scheme 44 (122) R = Ph alkyl (1 23) (124) Reagents i Ph,C=NH; ii THF 5&55 "C Scheme 45 reaction of (120) using chiral ligands for the palladium.73 One of the less common ferrocene phosphine derivatives (R)-(S)-BPPFOH,gives the best results (Scheme 44).The addition of an imine to a (1-alkyny1carbene)chromiumcarbonylcomplex (122) gives an adduct (123) which on heating to eliminate chromium forms a substituted 2H-pyrrole (124) (Scheme 45).74 A synthesis of the antibiotic (+ )-preussin (127)is based on the protic acid promoted aza-Cope rearrangement of the oxazolidine (125) to the pyrrolidine (126) (Scheme 46).75 3H-Indole (129)has been observed spectroscopically for the first time76 (Scheme 47). It is stable in ether at -100"C. Using an alternative preparation it was found that even in aqueous solution at pH9 it had a half life of about 100 seconds. 73 Y. Sato S. Nukai M. Sodeoka and M. Shibasaki Tetrahedron 1994,50 371. 74 F.Funke M. Duetsch F. Stein M. Noltemeyer and A. de Meijere Chem. Ber. 1994 127 911. 75 W. Deng and L. E. Overman J. Am. Chem. SOC. 1994,116 11 241. 76 I.G. Gut and J. Wirz Angew. Chem. Int. Ed. Engl. 1994 33 1153. Heterocyclic Compounds Reagents i CSA CF,CH,OH; ii EtOCOCl; iii CF,CO,H; iv LiAlH Scheme 46 Reagents i hv Scheme 41 Ring closure of trichloroacetamide (1 30) is brought about by nickel/acetic acid to give N-methylindolone (13 1).77 Similarly,78 haloacetamides (132) are closed onto an alkene to give the saturated compounds (133) (Scheme 48). Isonitriles (134) are starting materials for a novel tin-mediated indole synthesis.79 Treatment with tributyltin hydride gives the hitherto unreported N-unprotected 2-stannylindoles (135) (Scheme 49).These are prone to destannylation a process readily completed with aqueous acid but they may be further transformed in situ by palladium-catalysed coupling with aryl halides. Yields are good. Diazo-compounds (136) are converted into isomunchnones (137) using rhodium acetate. Intramolecular addition to the alkene gives (138) in high yield.80 The isomiinchnone from (139) adds across the indolyl n-bond to give (140) (Scheme 50).81 Acylation of acetone oxime (141) using an N-methyl-N-methoxyamide followed by cyclization of the intermediate gives 3-methyl-5-substituted isoxazoles (142) (Scheme 51).82 Treatment of isoxazoles (143) with hexacarbonylmolybdenum effects conversion into 4-pyridones (144) (Scheme 52).83 Treatment of imidazoles (145a) with ethyl chloroformate and allyltributylstannane gives the adduct (146a) (Scheme 53).The reaction extends to oxazoles (145b) and thiazoles (145~).~~ l7 J. Boivin M. Yousfi and S.Z. Zard Tetrahedron Lett. 1994 35 9553. 'I3 J. Boivin M. Yousfi and S.Z. Zard Tetrahedron Lett. 1994 35 5629. 79 T. Fukuyama X. Chen and G. Peng J. Am. Chem. SOC. 1994 116 3127. A. Padwa D.J. Austin and A.T. Price Tetrahedron Lett. 1994 35 7159. A. Padwa D. J. Hertzog and W.R. Nadler J. Org. Chem. 1994,59 7072. 82 T. J. Nitz D. L.Volkots D.J. Aldous and R.C. Oglesby J. Org. Chem. 1994 59 5828. 83 M. Nitta and T. Higuchi Heterocycles 1994 38 853. 84 T. Itoh H. Hasegawa K. Nagata and A. Ohsawa J. Org. Chem. 1994 59 1319. P.W.Sheldrake i Q,%" Me 0 ___) Me 70% (Ph (Ph (132) R = Me,CI;X = CI,Br (133) Reagents i Ni AcOH IPA; ii Ni AcOH PhSeSePh IPA Scheme 48 The substituted imidazole (148) was prepared from the substituted pyrrolidinone (147) using the tactic of preferential anion formation adjacent to the pyridine ring (Scheme 54).85 The story of how this reaction was developed into an industrial process makes interesting reading.86 The bicyclic imidazoles (150) are obtained by the tin(1v) or titanium(1v)-mediated condensation of the simple cyclic amides (149) with aminoacetaldehyde diethyl acetal (Scheme 55).*' (134) R = alkyl Ph C02M (1%) Reagents i Bu,SnH AlBN MeCN 100% Scheme 49 Gold's salt (151) and methyl N-methylglycinate combine under the action of methoxide to give 1-methylimidazole-5-carboxylic methyl ester (1 53) (Scheme 56).88 Reaction of bromoketone (154) with a primary amine in ether at -78 "Cgives the expected aminoketone (1 55) for immediate conversion into a 1,4-disubstituted imidazole (1 56) (Scheme 57).89 The sequential metallation and derivatization of l-methyl-2,4,5-tribromoimidazole (1 57) has been demonstrated.Operations commence at C-2 to give (1 58) and then 85 J. F. Hayes M. B. Mitchell and G. Procter Tetrahedron Lett. 1994 35 273. 86 J.F. Hayes and M.B. Mitchell Chem. Br. 1993 1037. 87 D. H. Hua F. Zhang J. Chen and P. D. Robinson J. Org. Chem. 1994 59 5084. R. Kirchlechner M. Casutt V. Heywang and M. W. Schwartz Synthesis 1994 247. 89 T. N. Sorrel1 and W. E. Allen J. Org. Chem. 1994 59 1589. Heterocyclic Compounds + 1 i -(136) n = 1,2 (137) Reagents i Rh,(OAc) Scheme 50 i ii -94% "OH (141) Reagents i BuLi PhCH,CONMe(OMe); ii H,SO, H,O Scheme 51 -0 (143) R = alkyl Ph Reagents i Mo(CO), MeCN H,O Scheme 52 P.W.Sheldrake C02Et (14s) X = NH (1 46a) X = NC02Et (145b) X = 0 (146b) X = 0 (14%) X = S (146~)X = S R, R2 = H Me Reagents i Bu,SnCH,CH=CH, ClCO,Et Et,N Scheme 53 N&N? i,85% \ ii iii -32 0 M9S / Reagents i BuLi; ii KOBu'; iii MeSC,H,CN Scheme 54 (149) n = 1,2 (150) Reagents i (EtO),CHCH,NH, mesitylene SnCI or TiCI, 140 "C Scheme 55 Reagents i MeNHCH,CO,Me NaOMe Scheme 56 Heterocyclic Compounds (154) (155) R' R2=alkyl (1w Reagents i R2NH, Et,O -78 "C; ii HCONH Scheme 57 (157) (158) (159) Reagents i Bu"Li -70°C; ii CO,; iii 2eq Bu"Li; iv electrophile (E) Scheme 58 XMe II H 0 (160) X = CI Br I (161) n = 1,3 Reagents i DBN; ii DBU Scheme 59 move to C-5,giving (159).This is capable of further transformation (Scheme 58)." DBU or DBN reacts with 4-halo-3,5-dimethyl-l-nitro-1H-pyrazoles (160) to give (161) in which unusually one of the rings of the base has been opened (Scheme 59).The postulated mechanism involves a diazaf~lvene.~' The spirocyclic derivatives (162) of 2,3-diaminopyridines can be reacted with a variety of nucleophiles (amines thiols alcohols or carbon nucleophiles) oia oxidized species (163) produced by manganese dioxide resulting in the product of 6-substitution (164) (Scheme 60)." Oxidation of glyoxal bisoxime (165) with dinitrogen tetraoxide provides the first preparation of unsubstituted furoxan (166) (Scheme 61).93 Alkylation of benzo-1,2,3-thidiazoIe results in isolation of 3-alkylated salts (167).However in basic methanol it is the 2-alkylated species in equilibrium with (167) that 90 G. Shapiro and B. Gomez-Lor J. Org. Chem. 1994 59 5524. 91 H. Lammers P. Cohen-Fernandes and C. L. Habraken Tetrahedron 1994 50 865. 92 S. Schwoch W. Kramer R. Neidlein and H. Suschitzky Helv. Chim. Acta 1994 77 2175. 93 T.I. Godovikova S. P. Golova Y.A. Strelenko M. Y. Antipin Y.T. Struchlov and L. I. Khmelnitskii Mendeleev Commun. 1994 7. 230 P. W. Sheldrake L (162) X = H Br (1W Reagents i MnO,; ii nucleophile (Nuc) Scheme 60 Reagents i N,O, CH,Cl Scheme 61 1 -’CRx-(167) R = H alkyl Ph PhCO Reagents i NEt, MeOH Scheme 62 rearranges to give a lH-4,1,2-benzothiadiazine(168) which is then alkylated by excess starting material (Scheme 62).94 The reaction of tetraazoles (169) with acetic anhydride to give 2-aryl-5-methyl-173,4- oxadiazoles (170) is reported (Scheme 63).” The 0-tosyl oximes (1 7 1) are converted after acetylation of the free amino group into pyrazolo[5,1-c]-l,2,4-triazoles (172) apparently by direct displacement of tosylate (Scheme 64).96 The symmetric diketone (173) was reacted with guanidine to produce the pentacycle (174) a model for ptilomycalin A (Scheme 65).97 In the case of the natural product itself diketone (175) was closed in two steps using 0-methylisourea (forming the left ring) then ammonia to give (176) (Scheme 66).Subsequent treatment with acid then base was needed to form the spirocyclic rings.98 Two groups have reported the total synthesis of gelsemine (177). One approach 94 S. Chandrasekhar and D.K. Josh J. Chem. Res. (S) 1994 56. ” B. S. Jursic and Z. Zdrankovski Synth. Commun. 1994 24 1575. 96 K.Kirsche E. Wolff M. Rarnrn G. Lutze and B. Schulz Liebigs Ann. Chem. 1994 1037. ’’P. J. Murphy and H. L. Williams J. Chem. Soc. Chem. Commun. 1994 819. 98 B. B. Snider and Z. Shi J. Am. Chem. SOC.,1994 116 549. Heterocyclic Compounds 23 1 Reagents i Ac,O Scheme 63 (171) R' = Me But R2= alkyl aryl Reagents i Ac,O; ii 2M NaOH MeOH Scheme 64 H& i -(173) (174) Reagents i HN=C(NH,), DMF Scheme 65 involved forming a tricyclic ketone,99" the oxindole moiety then being built on the ~arbonyl.~~' In the second approach the tetrahydropyran ring was formed last.'00 5 Six-membered Rings There is a review on iminophosphoranes as useful building blocks for the preparation of nitrogen-containing heterocycles,"' and a review on the enamine rearrangement of heterocyclic systems containing a pyridine ring102 covers much work previously only available in Russian.99 (a)Z. Sheikh R. Steel A. S. Tasker and A. P. Johnson J. Chem.Soc. Chem. Commun. 1994,763; (b)J. K. Dutton R. W. Steel A. S. Tasker V. Popsavin and A. P. Johnson J. Chem. SOC.,Chem.Commun. 1994 765. loo N. J. Newcombe F. Ya R.J. Vijn H. Hiemstra and W. N. Speckamp J. Chem. SOC.,Chem. Commun. 1994 167. lo' P. Molina and M. J. Vilaplana Synthesis 1994 1197. lo2 S. P. Gromov and A. N. Kost Heterocycles 1994 38 1127. P. W. Sheldrake Me. i ii - 37% (175) R = SiPh,Bu' (176) Reagents i HN=C(OMe)NH, PriNEt DMSO; ii NH, NH,OAc Bu'OH Scheme 66 The resolution of 1,2-diols using a C,-symmetric diphenyltetrahydrobipyran (178) is reported.lo3 The reagent when heated for a sufficient time with two equivalents of racemic diol gives a single derivative (179) leaving one enantiomer of the diol (180) (Scheme 67). The derivatized enantiomer is recovered by an exchange reaction or by lithium/liquid ammonia cleavage.A variation of the principle has been applied to the preparation of 2-substituted-2-hydroxycarboxylic acids.'04 Treatment of 2-(hydroxyalky1)dihydropyrans (181)with rhenium(vI1) oxide and 2,6-lutidine gives spiroketals (182) (Scheme 68).'05 Reaction of the ortho-quinone (183) with 1,4-diacetoxybuta-l,3-diene produces the benzodioxine (184)in the first reported exampleslo6 of such a reaction where an acyclic diene reacts as the 27c component (Scheme 69). Reaction of the dibromide (185)with catechol (as its disodium salt) is shown to give (186) with involvement of an intermediate epoxide'07 (Scheme 70). Previously it was suggested that the reaction proceeded by sequential bromide displacements to give a different product (187). The readily available (188) cyclizes on treatment with hydrogen chloride at high pressure to give (189) from which 3,5,6-trichloropyridin-2-one (190) is obtained using aqueous base (Scheme 71).'08 lo3 P.J. Edward D.A. Entwistle S.V. Ley D. R. Owen and E. J. Perry Tetrahedron Asymmetry 1994 5 553. R. Downham K.S. Kim S.V. Ley and M. Woods Tetrahedron Lett. 1994 35 769; G.J. Boons R. Downham K. S. Kim S.V. Ley and M. Woods Tetrahedron 1994 50 7157. R. S. Boyce and R. M. Kennedy Tetrahedron Lett. 1994 35 5133. lo' V. Nair and S. Kumar J. Chem. Soc. Chem. Commun. 1994 1341. lo' P. A. Procopiou P. C. Cherry M. J. Deal and R. B. Lamont J.Chem. SOC.,Perkin Trans. I 1994 1773. lo* R.G. Pews and J.A. Gall J. Org. Chem. 1994 59 6783. Heterocyclic Compounds Ph Phcf)0ie$ + &H Ph (178) (179) (180) Reagents i 2eq RCHOHCH,OH CSA toluene Scheme 67 Reagents i Re,O, 2.6-lutidine Scheme 68 (183) (184) Reagents i AcOCH=CHCH=CHOAc 120 "C Scheme 69 Reaction of 2-lithioaza heteroaromatics (191) with cyclobutenediones (192) gives the expected adducts which after acetylation and heating give pyridone-based bicycles (193) (Scheme 72).'09 Slight variation of the starting materials permits a palladium- catalysed coupling/rearrangement.1H-Benz[de]isoquinoline (195) is reported,"' formed by the action of ammonia on (194). Use of a primary amine gives (196) trapped by dipolarophiles (Scheme 73). The triptycene-substituted 2,2'-bipyridyl (197) is described as a 'molecular brake'. With the brake disengaged (as depicted) the trypticene spins freely; on addition of A.G.Birchler F. Liu and L. S. Liebeskind J. Org. Chem. 1994 59 7737. 'lo C.-K. Sha and D.-C. Wang Tetrahedron 1994 50 7495. P.W.Sheldrake Scheme 70 Reagents i HCI solvent 1W200 atm.; ii NaOH H,O CICH,CH,CI Scheme 71 0 (191) 2= S NMe CH = CH (192) R' RZ= alkyl ph OPS Reagents i combine; ii Ac,O; iii heat Scheme 72 mercury(II) coordination of the metal between the nitrogens changes the conformation of the bipyridyl unit which then acts as a barrier to rotation as evidenced by profound changes in the NMR.' The amide (198) can be substituted with a high degree of diastereoselectivity owing to the attached chiral auxiliary."' Reduction of the amide (199) allows the nitrogen substituent to be removed by catalytic hydrogenation giving access to asymmetric 3-substituted piperidines (200) (Scheme 74).The reaction of imine esters (201) with 1,3-dienes has been in~estigated."~ Since phenylmenthyl esters and either (R)-or (S)-1 -phenylethylamine are used significant 'I1 T. R. Kelly M. C. Bowyer K. V. Bhaskar D. Bebbington A. Garcia F. Lang M.H. Kim and M.P. Jette J. Am. Chem. SOC. 1994 116 3657. L. Micouin T. Varea C. Riche A. Chiaroni J.-C. Quirion and H.-P. Husson Tetrahedron Lett. 1994,35 2529. P.D. Bailey D. J. Landesbrough T.C. Hancox J. D. Heffernan and A. B. Holmes J. Chem. SOC.,Chem. Commun. 1994 2543. Heterocyclic Compounds 235 FOzEt -Em2c& Y \/ Reagents i NH,; ii RNH Scheme 73 OM / HOTPh HOTph H i ii R (198) (199) Reagents i Bu'Li; ii RX; iii LiAlH,; iv H, Pd-C !3cheIne 74 diastereoselection in the formation of (202) would be expected.A match/mismatch situation exists between the two chiral moieties but the best diastereoisomeric excess is over 95% (Scheme 75). Closure of the final ring in (204)was achieved by incorporation of the nitrogen of the nitro group in (203) under the action of tris(dimethy1amino)methane (Scheme 76).' l4 The first ring closure involved in converting (205) into (206) (the amide is made in the second step after reduction) exemplifies the vinylogous Bischler-Napieralski reaction (Scheme 77).' 'I4 D. Sole A. Pares and J. Bonjoch Tetrahedron 1994 50 9769. 'I5 A. J. Marquart B.L. Podlogar E. W. Huber D.A. Demeter N. P. Peet H. J. R. Weintraub and M. R. Angelastro J. Org. Chem. 1994 59 2092. P. W. Sheldrake (201) R' = phenylmenthyl R2 = PhCHMe Reagents i CH,=C(Me)C(Me)=CH Scheme 75 OpN-0 HN/Q 0 0 i __c Me Me (203) Reagents i HC(NMe,) Scheme 76 i ii -(205) Reagents i PPSE; ii NaBH Scheme 77 1-Benzoylindoles (207) are converted into indolo[2,3-a]isoquinolones (208) by the action of dimethyl malonate and manganese(II1) acetate (Scheme 78).' The imine (209) can be cyclized in intramolecular heteroene reactions to give either (210) using ferric chloride or (21 1) using titanium tetrachloride'l7 (Scheme 79). In both cases the enantiomeric excess is 98%. The palladium-catalysed cyclization of a range of 2-alkenylaniline and benzylamine derivatives has been investigated.'18 Conversions such as (212) into (213) and (214) l6 C.-P.Chuang and S. F. Wang Tetrahedron Lezt.. 1994 35 1283. 'I7 S. Laschat and M. Grehl Angew. Chem. Int. Ed. Engl. 1994 33 458. P. A. van der Schaaf J.-P. Sutter M. Grellier G. P. M. van Mier A. L. Spek,G. van Koten and M. Pfeffer J. Am. Chem. SOC. 1994 116 5134. Heterocyclic Compounds (207)R' = COW,CN COW R2=H,W,Ph Reagents i CH,(CO,Me), Mn(OAc) Scheme 78 i c-- Reagents i FeCl, CH,CI,; ii TiCl, CH,Cl Scheme 79 into (215) are examples (Scheme 80).The ring size obtained in the product is not readily predictable. The dithionite reduction of pyridinium salts (216) to 1,4-dihydropyridines (217) is reported (Scheme Sl).' '' More commonly such a reaction involves a pyridine with an electron-withdrawing substituent.Pyridines or pyridazines (218) react with a chloroformate and bis(tributy1- tin)acetylene to give the acetylene adducts (219) (Scheme 82).l2O The pyridine (220) is cunningly set up for a base-catalysed rearrange-ment-cyclization leading to 5-amino-1,2-dihydrothien0[2,3-h][1,6]naphthyridine (221) (Scheme 83). The nitrile-stabilized anion formed in the side chain can displace sulfur affording the carbon skeleton.' 21 Acetylenic amines (222) are cyclized in xylene at 150"Cto give (via the ketene) cyclic amides (223) usually in excellent yield (Scheme 84).'22A low point is the ten-membered ring (only lo%) but larger rings give good yields.A study was carried out of the conformation of the condensation product formed by 'I9 Y.S. Wong C. Marazano D. Gnecco and B.C. Das Tetrahedron Lett. 1994 35 707. T. Itoh H. Hasegawa K. Nagata M. Okada and A. Ohsawa Tetrahedron 1994 50 13089. K. Sasaki R.A.S. Shamsur S. Kashino and T. Hirota J. Chem. SOC.,Chem. Cornmun. 1994 1767 D. I. MaGee and M. Ramaseshan Synlett 1994 743. P.W. Sheldrake G*i ii 7 k2 cr Reagents i [PdCI,(MeCN),] NaOAc MeOH; ii Ph,P Scheme 80 (216) R' = alkyl R2,R3= H Me Reagents i Na,S,O, K,CO, H,O toluene Scheme 81 (218) X= CH N R' R2 = H C02Me Reagents i Bu,SnCGCSnBu, CIC0,Et Scheme 82 5-chloro-2-methylpentanaland l-amino-3-hydroxybutane.'23 The finding that there is a single preferred conformation suggested a synthesis of xestospongin A (224) based on the retrosynthesis via (225) and (226) indicated in Scheme 85.Intramolecular palladium-catalysed coupling of (227) produced a coupled product (228) but it was found that the stereochemistry of the N-0 bond relative to the lZ3 T.R. Hoye J.T. North and L. J. Ho J. Am. Chem. SOC.,1994 116 2617. Heterocyclic Compounds Reagents i KOBu' dioxane Scheme 83 (222) n = 1-6,8,10 Reagents i 150 "C,xylene Scheme 84 CN ?*" Scheme 85 dioxolane ring had been inverted (Scheme 86). The phenomenon was confined to the 2 enol ether (227) and a rationalization was presented.' 24 Reaction of 3-methyl-5-nitropyrimidin-4(3H)-one (229) with cyclohexanone gives the pyrimidine (230) (Scheme 87).'25 Other ketones may also be used; a similar reaction of nitropyridinones is already known.4-(Hydroxyimino)hexahydropyrimidines (231) are shown to interconvert with 4-aminotetrahydropyrimidin-3-oxides(232) according to the nature of the solvent 12' K. F. McClure S. J. Danishefsky and G.K. Schulte J. Org. Chem. 1994 59 355. 12' N.Nishiwaki T. Matsunaga Y. Tohda and M. Ariga Heterocycles 1994 38 249. P. W.Sheldrake ,OMe Reagents i 10% Pd on C NEt, MeCN Scheme 86 [T; -i I Reagents i cyclohexanone NH Scheme 87 Reagents i MeOH; ii aprotic solvent Scheme 88 (233) Reagents i NaH DMF Scheme 89 Heterocyclic Compounds 24 1 (235) R' R2 R3 = H alkyl Reagents i combine; ii oxidize Scheme 90 CI No2 (238) R = Me Et (239) (240) X = S n = I 2 X=O,n =1 Reagents i A Scheme 91 (Scheme 88).Directed syntheses of each tautomer were used to approach the equilibrium from each direction.'26 Treatment of the dichloropyridazine (233) with sodium hydride was not expected to give the pyrazolylquinoxalinone (234). The structure of the product was established by X-ray crystallography (Scheme 89).' 27 Reaction of chloroiminium salts (235) with the S-methylisothiocarbonhydrazide salt (236) followed by oxidation gives unsymmetrically substituted 1,2,4,Stetraazines (237) (Scheme 90). The yields are certainly not good but this is a quick preparation of the target using readily available materials.lz8 Reactions of the ylid (238) have been reported for the first time.'" With suitably activated aromatic or heteroaromatic compounds it gives products exemplified by (239) obtained from 4-chloro- 1-nitrobenzene.Therrnolysis of a-alkylthio-N-aziridinylimines (240)gives good yields of 1,4-dithiins 1,4-oxathiins or lP-dithiepines (241) (Scheme 91).I3O D. Korbonits E. Tobias-Heja K. Simon and P. Kalonits Liebigs Ann. Chem. 1994 19. G. Heinisch B. Matuszczak and K. Mereiter Heterocycles 1994 38 2081. ''' S.C. Fields M.H. Parker and W. R. Erickson J. Org. Chem. 1994 59 8284. 129 M. Makosza and M. Sypniewski Tetrahedron 1994 50 4913. 130 S. Kim and C. M. Cho Heterocycles 1994 38 1971. P. W. Sheldrake Reagents i Li NH,(liq); ii I, KI H,O Et,O Scheme 92 (244) (245) Reagents i 200"C Smin Scheme 93 (246) (247) Reagents i [Rh,(OAc),] Scheme 94 Dienes (242) are readily available from diacetylenes and thiols.Where R2 is benzyl lithium/liquid ammonia deprotection followed by mild oxidation forms 1,2-dithiins (243) (Scheme 92).13' On brief heating at 200 "Cthe 1,2-dithiin (244) does not undergo the expected sulfur extrusion but instead forms the 1,2,3-trithienepine (245) (Scheme 93).132 6 Seven-membered Rings Recent developments in the synthesis of medium ring ethers have been reviewed.'33 The diazo-compound (246) on treatment with rhodium acetate gives ether (247) (Scheme 94). In this instance the phosphonate and ketone groups provide convenient 131 M.Koreeda and W. Yang SYNLETT 1994 201.w. schroth*E. Hintzsche*R. SPltzner H.hgartinger and V. Siemund Tetrahedron Lett. 1994,35 1973. M.C. Elliott Contemp. Org. Synth. 1994 457. Heterocyclic Compounds Reagents i CH,=CCICN K,CO, DMF Scheme 95 I R4 (251) R' R2 R3,R4 = H But,Br CI (252) Reagents i for X = NR H,NR K,CO, THF; for X = S Li,S A1,0, THF; for X = P(O)Ph Na,PPh toluene reflux H,O Scheme % means for further elaboration of the product.' 34 The combination of oxygen and benzaldehyde brings about the conversion of cyclohexanone into caprolactone in the absence of metal catalysts.' 35 The reaction occurs at 40 "C but if benzoyl chloride is included in the mix yields are increased and a temperature of 20 "C suffices. 2,2'-Dihydroxybiphenyl (248) reacts with 2-chloroacrylonitrile under basic condi- tions to give the dibenzo[dfl[1,3]dioxepine (250) (Scheme 95).It is believed that the initial Michael adduct loses HCl giving (249); otherwise an eight-membered ring might have formed.' 36 The dibromides (251) are available from catechol. On treatment with a range of nucleophiles they are converted into nitrogen sulfur or phosphorus-containing heterocycles (252) (Scheme 96).137 The diol precursors of (251) can be converted into the corresponding cyclic ethers. Catalytic reduction of the sugar-derived azide (253) gives the stable bicyclic hemiaminal (254) (Scheme 97). Further hydride reduction produces the hexahydro- 1H-azepine (255).' 38 lJ4 C.J. Moody E.-R. H. B. Sie and J. J. Kulagowski J. Chem.Soc. Perkin Trans. I 1994 501. lJ5 K. Kaneda S. Ueno T. Imanaka E. Shimotsuma Y. Nishiyama and Y. Ishii J. Org. Chem. 1994,59 2915. R. E. Johnson and E. R. Bacon Tetrahedron Lett, 1994 35 9327. J.G. Walsh P. J. Furlong and D. G. Gilheany J. Chem. Soc. Chem. Commun. 1994 67. 13' R.A. Farr A. K. Holland E. W. Huber N. P. Peet and P. M. Weintraub Tetrahedron 1994 50 1033. P. W. Sheldrake HO Reagents i H, Pd; ii NaBH,CN HOAc Scheme 97 OAc (2%) Reagents i [(Ph,P),Pd] NaPF, MeCN Scheme 98 L PhthNQ P"thNvN-$ )" 589b i ii 0 1" co#3 C0,Me (258)n = 1,2 (2%) Reagents i CF,SO,H (CF,SO,),O CH,Cl,; ii NaI Scheme 99 Palladium-catalysed cyclization of the acetate (256) gives the benzazepinium salt (257) (Scheme 98).'39 Compare the parallel study' l8 mentioned above (Scheme 80).Both 7,5- and 7,6-fused bicyclic lactams (259) can be formed by intramolecular N-acyliminum ion cyclization of enamides (258) (Scheme 99). 140 Apparently similar is the titanium tetrachloride induced cyclization of (260). However the product is not a 7,5-fused bicycle,14' although the intermediacy of such a species is indicated. Bond migration results in the 6,5-fused product (261 ) (Scheme 100). The benzothiadiazepine (262) was treated with methylamine in the expectation of producing a fused diketopiperazine. The product is however the bisamide (264) M. Grellier M. Pfeffer and G. van Koten Tetrahedron Lett. 1994 35 2877. J. A. Robl Tetrahedron Lett. 1994 35 393. 14' K. D. Moeller C. E. Hanau and A.d'Avignon Tetrahedron Lett. 1994 35 825. Heterocyclic Compounds Reagents i TiCl Scheme 100 (262) (263) Reagents i NaHCO,; ii MeNH Scheme 101 (265) R = H Ph (266)R = H Ph formed from the b-lactam (263) which could be prepared in excellent yield by the action of bicarbonate (Scheme 101).l4* The thienoborepins (265) and (266) have been prepared. As might be expected (265) is the more labile. MO calculations redox properties and spectroscopic data are R. Silvestri E. Pagnozzi G. Stefancich and M. Artico Synth. Commun.,1994 24 2685. P.W. Sheldrake TBDP!SOGCO,H he i I “-& OMPM 7Me’* Me OTBDPS (270) (2711 Reagents i 2,2’-dipyridyldisulfide Ph,P CH,Cl,; ii AgBF, toluene 110”C Scheme 102 re~0rted.I~~ of which varacin (267) is the best known 1,2,3,4,5-Benzopentathiepins have been shown to be asymmetric molecules.There is a high energy barrier to inversion of the low energy chair conformation of the polysulfide ring. With a chiral derivatizing agent diastereoisomers are formed.144 The indolopentathiepin (268) has been prepared albeit in 7% yield by the action of phosphorus pentasulfide on isatin. 45 4-Phenyl-4,5-dihydr0-3H-dinaphtho[2,1-c;l’,2’-e]phosphepine (269) has been resolved as a palladium complex.146 It is an effective ligand for asymmetric rhodium-catalysed hydroformylation of styrene. 7 Larger Rings The cyclization of the saturated 7-hydroxyacid (270) in 73% yield represents an unprecedented yield for the formation of an eight-membered lactone (Scheme lO2).I4’ High yields of lactones have also been achieved by the combined action of titanium dichloride ditriflate (1 to 5 mol%) p-trifluorobenzoic anhydride (1.1 equivalents) and chlorotrimethylsilane (three equivalents) on hydroxyacids.Slow addition was used giving yields from 56% for a 12-membered lactone to nearly 90% for 15-membered or larger lactones. 148 2-(o-Haloalkyl)dithianes or thioxoanes (272) undergo ring expansion via the sulfonium or ononium salt intermediates (273) (Scheme 103). Eight- nine- or ten-membered ring products (274) are e~ernplified.’~’ 143 Y. Sugihara R. Miyatake T. Yagi T. Murata M. Jinguji T. Nakazawa and A. Imamura Tetrahedron 1994 50 6495. 144 B. S. Davidson P. W. Ford and M. Wahlman Tetrahedron Lett.1994 35 7185. 145 J. Bergmann and C. Stalhandske Tetrahedron Lett. 1994 35 5279. 146 S. Gladiali A. Dore D. Fabbri 0.DeLucchi and M. Manassero Tetrahedron Asymmetry 1994,5,511. 14’ K. R. Buszek N. Sato and Y. Jeong J. Am. Chem. SOC. 1994 116 5511. 14’ I. Shiina and T. Mukaiyama Chem. Lett. 1994 677. J. J. De Voss and Z. Sui Tetrahedron Lett. 1994 35 49. Heterocyclic Compounds R2 (272) Z = 0 S; X= CI Br rn =2,3n =O,l (273) (274) Reagents i PriNEt DMF reflux Scheme 103 Ar i - (27%) n = 1; R = H Me (275b)n =OR=H Reagents i acid Scheme 104 Reagents i Me,AlCl toluene reflux; ii LiAlH Scheme 105 Acid-catalysed cyclization of (275a) gives l-azabicyclo[3,3,l]nona-3,6-dienes(276) (Scheme 104).150Similar reaction of (275b) gives a pyrrolizine derivative after a rearrangement.' '' The stereochemistry of the 3-aza-Cope rearrangement of N-alkyl-N-allylenamines (277) has been investigated.15* The initial product (278) was reduced to (279) (Scheme 105).l-Methyl-2-vinylpyrrolidine or the corresponding piperidine (280) undergoes a E. Csuzdi I. Ling G. Abraham I. Pallagi and S. Solyom Liebigs Ann. Chern. 1994 347. 151 E. Csuzdi I. Pallagi G. Jerkovich and S. Solyom SYNLETT 1994 429. 152 G. R. Cook and J. R. Stille Tetrahedron 1994 50,4105. P.W.Sheldrake Reagents i Me0,CC-CCO,Me H' Scheme 106 Reagents i hv H,O MeCN Scheme 107 (285) X = CH2 (CH2)2 S (286) Reagents i (HCHO), HCECC0,Me Scheme 108 Michael addition with a suitable acetylenic ester followed by an aza-Claisen rearrangement to give unsaturated cyclic amines (28 1) (Scheme 106).'53 Irradiation of the chloroenaminoketones (282) gives a mixture of products in which the rearranged keto-amide (283) predominates over diketone (284) (Scheme 107).' s4 When amino acids (285) are reacted with paraformaldehyde and methyl propiolate the first-formed product of azomethine ylid [3 + 2) cycloaddition (286) reacts further after Michael addition finally giving (287) (Scheme 108).' 55 Macrocyclic imides (289) released in situ from (288) are more electrophilic than succinimide and amide-esters (290) are produced in high yield by transacylation (Scheme 109).' 56 153 E.Vedejs and M. Gingras J. Am. Chem. SOC. 1994 116 579. 15* J.B. Bremner B.M. Eschler B. W. Skelton and A. H. White Aust. J. Chem. 1994 47 1935. 155 H. Ardill R. Grigg J. F. Malone V. Sridharan and W. A. Thomas Tetrahedron 1994 50 5067. T. Koch and M. Hesse Helu. Chim. Acta 1994 77 819. Heterocyclic Compounds (288)n = 1,5 (289) Reagents i [Pd(Ph,P),] HCO,H NEt, dioxane 100"C (290) Scheme 109 (291) R= H Ar (292) Reagents i K,CO, DMF Scheme 110 The cyclic dipeptide (292) is formed from (291) in high yield by fluoride displacement.157 This is the first such S,Ar based macrocyclization (Scheme 110). The preparation of dithiacyclooctynes (293) (294) and (295) is reported,' 58 together with enthalpies of formation and ring-strain calculations. Treatment of dithiols (296) with a thiirane (297) produces benzotrithiepins or benzotrithiocins (298) usually in good yields (Scheme 11 1).15' lS7 R.Beugelmans J. Zhu N. Husson M. Bois-Choussy and G. P. Singh J. Chem. SOC.,Chem. Commun. 1994,439. H. Meier Y. Dai H. Schuhmacher and H. Kolshorn Chem. Ber. 1994 127 2035. 159 R. Sato M. Okanuma S. Chida and S. Ogawa Tetrahedron Lett. 1994 35 891. P. W. Sheldrake (--I (]I 5 S C31 S i SH n (296) n = 0,l (297) (298) R = H Ph (CH,) Reagents i Et,N DMSO Scheme 111 (299) (300) Reagents i KOH 0, EtOH Scheme 112 And finally potassium hydroxide/oxygen treatment of bis(se1enocyanate) (299) gives (300); its 3,4,13,14-tetraselenatricyclo[14.4.0.0601 ']icosa-l(16),6,8,10,17,19- hexaene structure was securely proven by X-ray crystallography (Scheme 112).160 160 S.Ogawa S. Ohara Y. Kawai and R. Sato Heterocycles 1994 38 491.

ISSN:0069-3030    

DOI:10.1039/OC9949100207

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

8 Organometallic Chemistry By G. R. STEPHENSON School of Chemical Sciences University of East Anglia Norwich NR4 7TJ UK 1 Organometallic Complexes in New Materials In recent years there has been a boom in organic chemistry related to materials science. At the organometallic wing of the subject there has been a similar awakening to the possibilities of interdisciplinary research in which the special effects available from the use of a transition metal can offer advantages. Work in this area has been progressing over several years and looking back over 1994 at the contributions from the many research groups now active in the field the rate of conceptual advance is striking. This year's Annual Report will begin with a survey of developments in this topic. Nonlinear Optical Electrical and Magnetic Properties.-The use of transition metals to polarize extended conjugated n-systems is a typical strategy in the design of organometallic materials combining donor and acceptor groups.The dimethylamino- stilbazole complex (1) combines an organic donor (the dimethylamino group) with an beC = 61 x loao organometallic acceptor formed through coordination of the pyridine ring to tungsten. This complex was easily obtained from W(CO),.THF which is made by photolysis of tungsten hexacarbonyl.' Substantial fl values were observed for this compound. Attachment of smaller polarizable ligands around metal centres is also effective. Thiolate adducts of nickel have been used in a comparative study of the design of molecules with large nonlinearities.2 Molybdenum-based organometallics demon- strate third-order susceptibility properties3 and platinum ethynyl complexes were examined in optical limiting st~dies.~ Because of its exceptional stability ferrocene has long been popular in materials D.R. Kanis P.G. Lacroix M. A. Ratner and T.J. Marks J. Am. Chem. Soc. 1994 116 10089. J. Waite M. G. Papadopoulos S.N. Oliver and C. S. Winter Mol. Cryst. Liq. Cryst. Sci. Technol. Sect. B 1994 6 297. T. Zhai C. M. Lawson G. E. Burgess M. L. Lewis D. C. Gale and G. M. Gray Opt. Lett. 1994,19,871. J. Staromlynska P. B. Chapple J. R. Davy T.J. McKay Proc. SPIE-lnt. SOC. Opt. Eng. 1994 2229 59. 25 1 G.R. Stephenson Figure 1 applications. The bis( 1,3-dithiolylidene)dihydroanthracenecore has been functional- ized with two ferrocene units to form the structure (2) shown in Figure 1.The multi-stage redox properties of the product have been examined.' Similar building blocks are combined in the disubstituted ferrocene (4) which was easily obtained from the diformyl ferrocene (3) as shown in Scheme 1. The conductivity and magnetic properties of TCNQ complexes of (4) have been examined.6 F* BuU MF,-78" 0 Scheme 1 Organometallic Liquid Crystals and Effects Chemicals.-The ferrocene-based liquid crystal (5) has been found to form a chiral smectic C phase.7 Smectic A behaviour has been observed with rhodium adduct (6) of the salen-type ligand (shown in Figure 2)8 and its iridium counterpart. The ferrocenophane (7)also showed smectic C properties.' The phase transition for (7) (l0OOC) occurs at a rather higher temperature than observed for (6) (83"C),while the temperature of the phase transition to smectic A for (6) was higher still at 141 "C.A benzocrown ether has been transformed into a highly effective FTIR-readable molecular sensor for alkali metal ion ratioing by the attachment of a tricarbonyl- ' G. J. Marshallsay and M. R. Bryce J. Org. Chem. 1994 59 6847. A. Togni M. Hobi G. Rihs G. Rist A. Albinati P. Zanello D. Zech and H. Keller Organometallics 1994 13 1224. ' C. Imrie and C. Loubser J. Chem. SOC. Chem. Commun. 1994 2159. * P. Berdaque J. Courtieu and P. M. Maitlis J. Chem. SOC.,Chem. Commun. 1994 1313. A. Werner and W. Friedrichsen J. Chem.SOC. Chem. Commun. 1994 365. Organometallic Chemistry Figure 2 chromium group. Differential responses for different alkali metals can be distinguished by careful analysis of the metal carbonyl vibrational band envelope by principal component analysis. lo In (8) a tritiated oligodeoxyribonucleotide-basedphosphite is complexed to pentacarbonyltungsten for use in DNA-probe-based diagnostics.' FTIR-readout features in a new probe for SH groups in biomolecules which has been shown to be stable in aerated aqueous solutions despite the presence of Fe(CO),Cp moiety.'* Organoiron complexes [Fe(CO),C,H,] have also been used to tag surface NH groups on protein^.'^ Organometallic Structures.-Incorporation of c60 into an organometallic molecule is a certain way to form an eye-catching structure.A cyclic voltametric study of ferrocenyl-substituted fulleropyrrolidines shows that the reduction potentials are more negative than those measured for unsubstituted C6,.14 Organometallic salts of fullerides obtained by reaction with Mn(Cp*) have also been examined electrochemi- ~a1ly.l~ Organometallic chemistry can be used for the elaboration of the carbon lo C.E. Anson C.S. Creaser and G.R. Stephenson J. Chem. SOC.,Chem Commun. 1994 2175. l1 J. M. Dalla Riva Toma and D. E. Bergstrom J. Org. Chem. 1994 59 2418. B. Rudolf and J. Zakrzewski Tetrahedron Lett. 1994 35 9611. l3 C.E. Anson C. S. Creaser 0.Egyed M. A. Fey and G. R. Stephenson J. Chem. Soc. Chem. Commun. 1994 39. l4 M. Maggini A. Karlsson G.Scorrano G. Sandona G. Farnia and M. Prato J. Chem. SOC. Chem. Commun. 1994 589. l5 J. P. Seleque S. Dev T. F. Guarr J. W. Brill and E. Figueroa Proc. Electrochem. Soc. 1994 24 1245. G.R. Stephenson framework of fullerene structures. A palladium catalysed [3 + 21 cycloaddition adds a trimethylenemethane unit to form a fluorescent fullerene derivative.I6 Organization of organometallic complexes such as tricarbonyl(cyclopentadieny1)-manganese and ferrocene derivatives on a gold surface affords photosensitive Figure 3 self-assembled monolayers.' The reverse concept an organic framework with attached metal atoms (Figure 3) is the long term aim of work at the Max-Planck- Institut fur Polymerforschung in Mainz. Substituted tricarbonyl(cyc1obutadiene)iron complexes obtained by palladium catalysed coupling reactions with alkynes have been prepared as staging points towards these structures.'8 The supramolecular building block (9) illustrates another approach to regularly spaced metal-containing (9) structures.' Nano-sized chromium clusters have been formed by complexation of phenyltriethoxysilane with chromium hexacarbonyl to form an $-complex equipped with sol-gel functionality.Sol-gel processing combining 1,4-bis(triethoxysilyl)benzene l6 L.-L. Shiu,T.-I. Lin S.-M. Peng G.-R. Her D. D. Ju S.-K. Lin J.-H Hwang C. Y. Mou,and T.-Y. Luh,J. Chem. SOC. Chem. Commun. 1994,647. E.W. Wollman D. Kang C.D. Frisbie 1. M. Lorkovic and M. S. Wrighton J. Am. Chem. Soc. 1994,116 4395. '* J. E.C. Wiegelmann U.H. F. Bunz and P. Schiel Organometallics 1994 13 4649. l9 E. C. Constable A. J. Edwards M.d. Marcos P. R. Raithby R. Martinez-Maiiez and M. J. L. Tendero Inorg. Chim. Acta 1994 224 11. Organometallic Chemistry and the chromium complex produced extended metal-containing arrays.20 On a smaller scale four tricarbonylchromium units have been dispersed around a cyclobu- tadiene ligand in structure ( As with C,, organometallic coupling methods can be used to form metal-free products of considerable structural importance. Quinonyl- and arylporphyrins have been obtained by benzannulation of Fischer carbene complexes and palladium catalysed coupling with arylboronic acids respectively.22 Polymetallic Rods and Dipoles.-One of the beauties of this subject is that it seems possible to justify making compounds simply because they have interesting structures.Over the last year some remarkable organometallic rods have been prepared (Figure 4).The polycationic iron-based structure (11)23 and the dirhodium or diiridium bis-alkyne complex based on 4,4'-dialkyn~lbiaryls~~ provide remarkable examples. Bent rods in which metal acetylide adducts are further complexed at the alkyne links2' or in which the alkynes are alkynylferrocene moieties26 show further possibilities. + + + ke ire ke 49 49 (11) Figure 4 As with the metal-polarized n-systems prepared in search of NLO effects discussed earlier bimetallic rod-like polyene and polyyne structures offer interesting elec- trochemistry and the prospect of electrochemically generated cationic dipoles.The dimanganese complex (13) obtained from (12) (Scheme 2) contains a butadiene centre-unit linked at each end as a carbene ligand. Electrochemical reduction forms a 2o K. M. Choi and K. J. Shea J. Am. Chem. SOC. 1994 116 9052. 21 F.-E. Hong Y.-T. Chang C.-T. Chen S.-L. Wang and F.-L.Liao J. Organomet. Chem. 1994,480 75. 22 C.-S. Chan A.K.-S. Tse and K.S. Chan J. Org. Chem. 1994,59 6084. 23 A. S. Abd-El-Aziz and C. R. de Denus J. Chem. SOC.,Chem. Commun. 1994 663. 24 R. R. Tykwinski and P.J. Stang Organometallics 1994 13 3203. 25 H. Lang M. Herres and W. Imhof J. Organomet. Chem. 1994 465 283. 26 K. Onitsuka X.-Q. Tao and K. Sonogashira Bull. Chem. SOC.Jpn. 1994 67 2611. 256 G.R. Stephenson Me Me I)BuLl c 2) cut 3) 02 11) 2BuLi Me‘ - + e- MeP.(eledrochem. reduction) (13) Me’ Scheme 2 + I-.- Scheme 3 CP’ ,Re ON bPh3 1.5Cu(OAc) ___) Py = cP\ ‘“b Re= Ph3 NO = =Re I,PPh3 ‘CP* Scheme 4 Organometallic Chemistry 257 bimetallic radical anion.27 The diiron complex (14) provides an interesting parallel (Scheme 3) since in this case each iron atom is bound to the butadiene centre portion through a o-bond. Electrochemical oxidation leads via a radical cation (15) to the dication (16) with a biscarbene structure.28 Metal-capped polyyne rods have also been prepared. One approach to the tetrayne (18)is a copper-mediated coupling of the rhenium diyne complex (17) shown in Scheme 4.29 In a mixed rhenium/manganese analogue with a bis-alk~ne,~’ unsymmetrical charge-distribution can be anticipated in the cationic structure that is formed by removal of an OMe group from a Fischer carbene complex and uneven charge distribution would lead to a rod-like dipole structure.The product is reported to have an intense absorption at 480 nm. 2 Physical Studies of Organometallics Because of the practical difficulties involved the techniques of physical organic chemistry are relatively infrequently applied to the study of organometallic structures. When studies of this type are attempted however interesting information almost always emerges. In a stopped-flow kinetic study of reversible methoxide addition to Fischer carbene complexes equilibrium constants for the formation of the tetrahedral intermediate were found to be eight orders of magnitude higher than those for the corresponding reaction of the ester in methyl ben~oate.~’ There is also much scope for bond-energy studies.The strength of the metal-alkene bond in titanium complexes thought to be involved in Ziegler-Natta catalysts has been calculated by the MCPF method.32 X-Ray crystallography has been brought to bear on the study of molecular recognition between metal carbonyl moieties. The tetrahedra of nickel tetracarbonyl have been found to stack together neatly in a dense three-dimensional array. A no less remarkable interlocking packing pattern was observed for iron penta~arbonyl.~~ Rotational barriers have been measured in trimethylenemethane tricarbonyliron and iron carbonyl phosphine complexes.34 Voltammetric studies of metallocene~~~ and an analysis of isomerization of tricarbonylchromium phosphine complexes using cyclic voltammetry simulation36 provide further examples.3 The Role of Organometallic Complexes in Asymmetric Synthesis Where the synthesis of organic target molecules is concerned the most active frontier is the search for increasingly general and efficient enantioselective methods. Where organometallic intermediates are used in bond-forming reactions the asymmetric and enantioselective modification of these processes has been increasingly a major focus of research effort. Palladium catalysed allylic substitution and cross coupling performed 27 A. Rabier N. Lugan and R. Mathieu Organometallics 1994 13 4776.B. A. Etzenhouser Q. Chen and M. B. Sponsler Organometallics 1994 13 4176. 29 M. Brady W. Weng and J. A. Gladysz J. Chem. SOC. Chem. Commun. 1994 2655. ’O W. Weng T. Bartik and J. A. Gladysz Angew Chem. Int. Ed. Engl. 1994 33 2199. C. F. Bernasconi F. X. Flores J. R. Gandler and A. E. Leyes Organometallics 1994 13 2186. 32 V. R. Jensen M. Ystenes K. Warnmark B. Akermark M. Svensson P. E. M. Siegbahn and M. R.A. Blomberg Organometallics 1994 13 282. 33 D. Braga F. Grepioni and A.G. Orpen Organometallics 1994 13 3544. ” V. Branchadell L. Deng and T. Ziegler Organometallics 1994 13 3115. 35 D. Obendorf E. Reichart C. Rieker and H. Schottenberger Electrochim. Acta 1994 39 2367. ” A.W. Bott Curr. Sep. (Eng) 1994 13 45. G.R.Stephenson in the presence of chiral ligands and strategies for the enantioselective preparation of stoichiometric metal complexes have been particularly of note and much progress has been made during 1994. Asymmetric Allylic Substitution.-An q3-1,3-diphenylallyl electrophile has proved a popular test system for the evaluation of chiral ligands in asymmetric allylic substitution. The two ends of the allyl unit are diastereotopic while a chiral ligand is present in the palladium complex and structures of this type are easily obtained by the displacement of acetate or other leaving groups from starting materials such as (19) (Scheme 5). P AcO h d Ph [ p m h ~ p h -] Me02C CO2M62Ph \ Ph (19) (20) (21) Scheme 5 Excellent results have been obtained with ligands that contain one phosphine and one amine heterocentre.Helmchen’s oxazoline-based ligand (22) provides a typical example. Allylic displacement by the enolate formed from dimethyl malonate can often be in the high 90% range. The palladium complex of (22) has been studied in solution by NMR and in the solid state by X-ray cry~tallography.~~ Sulfur and nitrogen can also be combined and in the case of (23) the William’s group at Loughborough have obtained the product (21) in 92% yield and 96% enantiomeric excess.38 The effect of substituents on the aromatic rings flanking the allyl unit on enantioselectivity and degree of conver- sion have been e~amined.~’ In the case of the chiral ligand (24) a much closer spacing is present between the nitrogen and phosphorous atoms which are linked directly by a covalent bond.40 In contrast ligands of type (25)41 can offer much wider spacings and have the chiral element the axis of chirality in the binaphthyl unit far more remote from the ligand sites.Nonetheless enantiomeric excesses as high as 96% have been achieved though both the rate and enantioselectivity of the reaction were found to be highly dependent on spacing in the chelate chain. Diamine ligands [e.g. (26)] for asym- metric modification of this reaction have also been examined but enantiomeric excess- es are typically lower in the range 62-88%.42*43 Bisaziridines have been employed as chiral ligand~.~~ In the chiral acetal(27) sulfur and oxygen are employed as the metal- binding sites.45 Examples of chiral ligands are shown in Figure 5.For (21) (Scheme 5) the palladium-ally1 moiety is prochiral. With an unsymmetri- cally substituted ligand on the other hand planar chirality is present in the metal/q3- 37 J. Sprinz M. Kiefer G.Helmchen M. Reggelin G. Huttner 0.Walter and L. Zsolnai Tetrahedron Lett. 1994,35. 1523. ’’ J.V. Allen S. J. Coote G. J. Dawson C. G. Frost C. J. Martin and J. M. J. Williams J. Chem. Soc. Perkin Trans. I 1994 15 2065. 39 J. V. Allen J. F. Bower and J. M. J. Williams Tetrahedron Asymmetry 1994 5 1895. G. Brenchley E. Merifield M. Willis and M. Fedouloff Tetrahedron Lett. 1994 35 2791. 41 H. Kubota and K. Koga Tetrahedron Lett. 1994 35 6689. 42 P. Gamez B. Dunjic F. Fache and M. Lemaire J. Chem. Soc.Chem. Commun. 1994 1417. ” J. Kang W.O. Cho and H.G. Cho Tetrahedron Asymmetry 1994 5 1347. 44 D. Tanner P. G. Anderson A. Harden and P. Somfai Tetrahedron Lett. 1994 35 4631. 45 C.G. Frost and J. M. J. Williams Synlett 1994 7 551. Organometallic Chemistry 259 allyl moiety. The ligand MOP-phen (28) has been evaluated in the presence of formic acid to transfer a hydrogen atom to the allyl ligand.46 In the case of the vinylsilane (30) this provides an alternative asymmetric synthesis of allyl~ilanes.~’ An X-ray structure dN-SiPh213d +h (24) phh Ph phBAph 00 MeN NMe hSPh HH analysis of an intermediate palladium allyl complex has been perf~rmed.~~ In an un- usual example of asymmetric induction in the formation of axial chirality the popular chiral ligand (R)-BINAP (29) was employed to form (32) from (31) (Scheme 6).49 Pd,(dba),,-CHC13 (28) HCOY Me3Si 0 93% yield 91% 8.8.46 T. Hayashi H. Iwamura and Y. Uozumi Y. Matsumoto F. Ozawa Synthesis 1994 526. 47 T. Hayashi H. Iwamura and Y. Uozumi Tetrahedron Lett. 1994 35,4813. 48 T. Hayashi H. Iwamura M. Naito Y. Matsumoto and Y. Uozumi J. Am. Chem. SOC. 1994 116 775. 49 J. -Y. Legros and J.-C. Fiaud Tetrahedron 1994 50 465. G. R. Stephenson An alternative approach to asymmetric induction is to include a chiral centre in the nucleophile. A chiral enamine has been used in this way.” Metal-catalysed allylic acetoxylation can induce asymmetry in the preparation of starting materials for allylic substitution.Asymmetric modification of palladium copper and nickel acetoxylation catalysts has been examined but gives products with low enantiomeric excess.” Asymmetric Coupling Reactions.-Differentiation of enantiotopic ends of symmetri- cally substituted alkenes and enantiotopic alkene groups in prochiral dienes offer two distinct approaches for asymmetric Heck-coupling reactions. Coupling trifloxyben- zene with the alkene (33) under the influence of (S)-BINAP as the chiral ligand gives access to precursors for non-racemic cyclic lactones in up to 72% enantiorneric ex- c~ss.’~ With a vinyl halide as the coupling partner and norbornene as the alkene substituted chiral norbornanes such as (34) have been obtained in up to 93% enan-tiomeric excess (Scheme 7).53 In this case too BINAP was used as the chiral Ph B,/\\/Ph Pdcat.* (R)-BINAP Scheme 7 auxiliary. BINAP also figured in the enantioselective differentiation of alkenes in the diene (35) (Scheme 8). With (36) enantioface differentiation holds the key to Pdcat. & (R&,PO4 )-BINAP * H NMP 94% Scheme 8 50 K. Hiroi J. Abe K. Suya S. Sato and T. Koyama J. Org. Chem. 1994 59 203. H. Yang M.A. Khan and K.M. Nicholas J. Mol. Catal. 1994 91 319. 52 Y. Koga M. Sodeoka M. Shibasaki Tetrahedron Lett. 1994 35 1227. 53 F. Ozawa Y. Kobatake A. Kubo and T. Hayashi J. Chem. SOC.,Chem. Commun. 1994 1323 Organometallic Chemistry asymmetric induction. Full details of both these reactions have now appeared.54 Pal- ladium catalysed enyne cycloisomerizations can also be used to form chiral centres.A covalently attached chiral auxiliary in the ligand has been used in an attempt to gain diastereoselectivity in the coupling step. A 50% d.e. has now been achieved.55 Asymmetric Epoxidation.-The contemporary challenge is the asymmetric epoxida- tion of unfunctionalized alkenes. Epoxidation catalysts reported by Jacobsen were feted as reagent of the year for 1994 and throughout the year both Jacobsen and Katsuki have kept up a steady flow of papers reporting new developments in the field. Other workers (Nagata Imagawa Yamada and M~kaiyama,~~?~~) have also been active in this highly competitive area. Jacobsen's research group can achieve excellent enantioselectivity (as high as 93%) for the epoxidation of 1-phenylcy~lohexene.~~ 1,3-Dienes can also be used as substrates and in the case of (37) (Scheme 9) 91% 90% 8.8.(37) Me Me 32% yield Scheme 9 enantiomeric excess was achieved for the epoxidation of the least substituted alkene linkage.59A convenient procedure for the large-scale preparation of the chiral manga- nese catalyst (38 R = 'Bu) has been reported.60 Katsuki also reports an enantiomeric 54 Y. Sato S. Nukui M. Sodeoka and M. Shibasaki Tetrahedron 1994 50 371. 55 B. M. Trost and B. A. Czeskis Tetrahedron Lett. 1994 35 211. 56 T. Nagata K. Imagawa. T. Yamada and T. Mukaiyama Inorg. Chim. Acta 1994 220 283. 5' T. Nagata K. Imagawa T. Yamada and T. Mukaiyama Chem. Lett. 1994 1259. '. '' B. D. Brandes and E.N. Jacobsen J.Org. Chem. 1994 59 4378. 59 S. Chang R. M. Heid and E.N. Jacobsen Tetrahedron Lett. 1994 35 669. 6o J. F. Larrow E.N. Jacobsen Y. Gao Y. Hong X. Nie and C. M. Zepp J. Org. Chem. 1994 59 1939. G. R. Stephenson excess in the high 90s. A series of papers in SynEett this year report the progress of this work. Enantioselective epoxidation of chromenes using hydrogen peroxide and a cata- lyst of the general type (38),6’and the more elaborate ligand (39)containing two chiral axes as well as the chiral ligand-set around manganese,62 had culminated with a dis- cu~sion~~ of the origin of chiral discrimination in enantioface recognition with simple alkenes. Two fulI papers in Tetrahedron report the details of earlier studies of epoxida- tion of substituted styrenes64 and dihydr~naphthalene~’ substrates.Use of catalysts of this type for the oxidation of aryl sulfides to sulfoxides has also been reported.66 Asymmetric Cyclopropanation Hydrogenation and Hydrosi1ation.-Compared to asymmetric epoxidation the cyclopropanation of unfunctionalized alkenes has prog- ressed more slowly. Chiral ligands based on 2,6-disubstituted pyridines have become popular. Ruthenium complexes have been employed to give an efficient carbene trans- fer from trirnethylsilyldiaz~methane.~~ Diazoesters can also be used (Scheme 10)and with 1-heptene as the substrate the product (40)was obtained as the major isomer in 99% enantiomeric excess.68 N* (40)99%e.e. Scheme 10 In asymmetric hydrogenation improved techniques and improved understanding of the hydrogenation process have been the objectives of recent work.Kinetic studies of asymmetric rhodium-based catalysts have been performed by the Brunner A water soluble version of BINAP has been developed by sulfonation of the aromatic rings. In this example four sulfonic acid groups are attached and the best results were obtained with ruthenium as the catalytically active metal.70 Attaching homogeneous catalysts to a solid support is also a commonly employed stratagem but such solid phase reagents are often less active and less enantioselective than their solution-state counterparts. Now a solvent/thin-film interface system has been developed to over- come this diffic~lty.~~ More unusual ligands and metal systems have been reported.The asymmetric hydrogenation reaction illustrated in Scheme 11 is highly 61 R. Irie N. Hosoya and T. Katsuki Synlett 1994 255. 62 H. Sasaki R. Irie and T. Katsuki Synlett 1994 356. 63 T. Hamada R. Irie and T. Katsuki Synlett 1994 479. 64 N. Hosoya A. Hatayanma R. Irie H. Sasaki and T. Katsuki Tetrahedron 1994 50 431 1. 65 H. Sasaki R. hie T. Hamada K. Suzuki and T. Katsuki Tetrahedron 50 118277. 66 K. Noda N. Hosoya R. hie Y. Yamashita and T. Katsuki Tetrahedron 1994 50 9609. 67 S.-B. Park H. Nishiyama Y. Itoh and K. Itoh J. Chem. SOC.,Chem. Commun. 1994 1315. 68 H. Nishiyama Y. Itoh H. Matsumoto S.-B. Park and K. Itoh J. Am. Chem. SOC.,1994 116 2223. 69 H. Brunner J. Furst U. Nagel and A. Fischer Z. Naturforsch. 1994,49b 1305. ’O K.Wan and M. E. Davis Tetrahedron Asymmetry 1994 4 2461. ” K.-T. Wan and M. E. Davis Nature (London) 1994 370 449. Organometallic Chemistry gpcy* re PPh2 CO Me (41) LCO2Me H2 RWnW2BF4MeOH * r:02fvle 100% yield 97% 8.8. n .H7 37% 99% e.e. + MeGPh n (42)34% 99% 8.8. Scheme 11 effective with a chiral catalyst system based on rhodium and the ligand (41).72Asym-metric hydroboration proceeds similarly. Titanium complexes are an unusual choice for hydrogenation but a system developed by Buchwald based on a C,-symmetric catalyst has proved highly effective. Hydrogenation of imine~~~ proceeds at moderate pressures (15-80 psi) to afford the chiral benzylamines with enantiomeric excesses in the range 92-99%. Kinetic resolution based on this system74 is even more effective affording (42) in 99% enantiomeric excess.BINAP is typically used in enantioselective hydr~silation.’~ In a more unusual case (Scheme 12) the chiral auxiliary (43) was constructed from two chiral ferrocene moie- ties.76 Selenium- and tellurium-bridged structures were also used. Asymmetric Induction in q6-Chromium Arene Complexes.-The use of tricarbonyl- chromium complexes of aromatic ligands in organic synthesis is the most highly developed of the stoichiometric strategies for metal-derived stereocontrol. It is thus not surprising that the induction of asymmetry in such complexes has received consider- able attention. The key theme for 1994 has been enantioselective deprotonation. 72 A. Togni C.Breutel A. Schnyder F. Spindler H. Landert and A. Tijani J. Am. Chem. SOC. 1994,116,4062. 73 C.A. Willoughby and S.L. Buchward J. Am. Chem. SOC. 1994 116 8952. 74 A. Viso N. E. Lee and S. L. Buchward J. Am. Chem. soc. 1994 116 9373. 75 X. Wang and B. Bosnich Organometallics 1994 13 4131. 76 Y. Nishibayashi J. D. Singh K. Segawa S. Fukuzawa and S. Uemura J. Chem. SOC. Chem. Commun. 1994 1375. G.R. Stephenson Me Ph,SiH,. Rh(l)cat. * ArXR 0 2) HCI MeOH HO H Scheme 12 Lithiated chromium-bound arenes are useful reagents for bond formation so the use of chiral lithium amide bases to metallate prochiral chromium arene complexes is an attractive strategy. The LDA-like chiral base (44)has been employed to good effect by the Simpkins group at Nottingham producing (45) in up to 84% enantiomeric excess by trapping the metallated aromatic ring with trimethylsilyl chloride in the presence of lithium ~hloride.~ Metallation of prochiral starting materials derived from acetals is similarly efficient though competing reaction arising through metallation at the benzylic position complicates the process.78 Kiindig has reported the use of a chiral amide base derived from borneol and l-phenylethylamine,79 and in Uemura’s group chiral diamines have been combined with butyllithium.80 Work continues on systems in which chirality present in the aromatic starting material induces asymmetry in a prochiral metal-bound aromatic ligand.In the case shown in Scheme 13 the inducing c;(CO)3 83%(45)yield 84% e.e.Scheme 13 77 D. A. Price N. S. Simpkins A.M. MacLeod and A. P. Watt Tetrahedron Lett. 1994 35 6159. ” D.A. Price N. S. Simpkins A.M. MacLeod and A. P. Watt J. Org. Chem. 1994 59 1961. 79 E. P. Kundig and A. Quattropani Tetrahedron Lett. 1994 35 3497. 8o M. Uemura Y. Hayashi and Y. Hayashi Tetrahedron Asymmetry 1994 5 1427. Organometallic Chemistry 265 chirality is removed after the asymmetric induction step to leave a 2-substituted styrene as the final product.81 Kinetic resolution8’ of the tricarbonylchromium complex of 2-methylbenzylalchol continues a line of successful investigations by a number of groups that combine biotransformations with metal-bound organic substrates. Induction of asymmetry adjacent to the chromium-bound ring has also been an important objective.The tartrate-based titanium-mediated sulfur oxidation has been used to good with a 2-substituted phenylthioether chirality at sulfur and within the q6-arene complex can be induced at the same step. Asymmetric Induction in q4-Tricarbonyliron Complexes-The lipase-mediated bio- transformation approach discussed earlier for chromium arene complexes has also been employed with the q4-diene complexes in the tricarbonyliron series.82 Induction of asymmetry by the addition of achiral nucleophiles to tricarbonyliron complexes containing chiral substituents has also yielded enantiomerically enriched diene complexes in up to 84% enantiomeric excess.84 Inclusion of the chiral auxiliary as a ligand at the metal is possibly a more subtle approach since through its presence as an auxiliary ligand the functionality on the diene complex need not be changed in order to gain access to the enantiopure series.An extensive series of chiral phos- phines has been examined.85 With electron-donor substituted complexes resolution has been performed by the chemical separation of chiral oxazolidine-substituted ligands.* Asymmetric Pauson-Khand Reaction.-The Pauson-Khand reaction which forms substituted cyclopentenones from alkynes by a cobalt-mediated cyclocarbonylation reaction has been growing in popularity and its application in organic synthesis will be discussed in detail in the next section. In 1994 considerable progress has been made with the asymmetric modification of this reaction.Currently stratagems centre on the inclusion of a chiral auxiliary in one of the organic substrates. With a non-racemic chiral alkoxyalkyne practical access to substituted cyclopentenones can be achieved. Although asymmetric induction is not complete the diastereoisomers can be separated after the cobalt-mediated cyclization step.* More elaborate chiral ligands afford organocobalt substrates of type (46) (Figure 6) which combine with norbornene to give a 92 1 ratio of diastereoisomers.88 The chiral auxiliary can also be included in the alkene ~o-reactant.~~ A further variant of this process employs unsaturated sugar in the cycloreaction with a cobalt-bound alkyne attached via an acetal at the aldehyde carbon P. W. N. Christian R. Gil J.Muiiiz-Fernandez S. E. Thomas A. T. Wierzchleyski J. Chem. Soc. Chem. Commun. 1994 1569. ‘2 M. Uernura H. Nishirnura S. Yarnada Y. Hayashi K. Nakamura K. Ishihara and A. Ohno Tetrahedron Asymmetry 1994 5 1673. 83 S. L. Griffiths S. Perrio and S. E. Thomas Tetrahedron Asymmetry 5 1847. 84 C. W. Ong and R. H. Hsu Organometallics 1994 13 3952. J. A. S. Howell A. D. Squibb A. G. Bell P. McArdle D. Cunningham Z. Goldschmidt H. E. Gottlieb and D. Hezroni-Langerman Organometallics 1994 13 4336. 86 J. A. S. Howell A. G. Bell P. J. O’Leary P McArdle D. Cunningham G. R. Stephenson and M. Hastings Organometallics 1994 13 1806. ” V. Bernardes X. Verdaguer N. Kardos A. Riera A. Moyano M. A. Pericas and A. E. Greene Tetrahedron Lett. 1994 35 575. ” X.Verdaguer A.Moyano M. A. Pericas A. Riera V. Bernardes A. E. Greene A. Alvarez-Larena and J. F. Piniella J. Am. Chem. Soc. 1994 116 2153. 89 J. Castro A. Moyano M. A. Pericas A. Riera and A. E. Greene Tetrahedron Asymmetry 1994 5 307. G.R. Stephenson Figure 6 of the sugar chain." The alkyne can also be attached by an ether link to an alcohol adjacent to the unsaturated portion of the sugar unit." In a total synthesis of (-)-a-kainic acid (47)' Pauson-Khand cyclization of an enyne complex with a chiral spacer between the two unsaturated ligands affords a key intermediate which was elaborated as shown in Scheme 14.92 1) PdC HS Me3N0 2) H + ___t 3) TsCl 4) MOMCl 5) Fe(0). TMSCI Me& P OMOM Ts + isomer (47) Scheme 14 4 Stoichiometric Organometallic Complexes in Organic Synthesis Pauson-Khand Cyc1izations.-The mechanism of the Pauson-Khand reaction sug- gests that the process should be catalytic in the cobalt carbonyl but normally a stoichiometric hexacarbonyl dicobalt alkyne complex is employed.A catalytic version of an intramolecular Pauson-Khand reaction has now been described.93 Another variant is to form the cobalt carbonyl complex in situ from cobalt dibromide and zinc Alternatives to the use of cobalt are also under investigation. Pearson's group W. E. Lindsell P. N. Preston and A. B. Rettie Carbohydr. Res. 1994 254 311. 91 J. Marco-Contelles Tetrahedron Lett. 1994 35 5059. 92 S. Yo0 and S.H. Lee J. Org. Chem. 1994 59 6968. 93 N. Jeong S.H. Hwang Y. Lee and Y.K. Chung J.Am. Chem. SOC. 1994 116 3159. 94 M. Periasamy H. R. Reddy and A Devasagayaraj Tetrahedron 1994 50 6955. Organometallic Chemistry at Case Western Reserve have reported the use of iron pentacarbonyl in the cyclization of an alkyne and alkene to form a cy~lopentenone.’~ More normally it is dicobalt octacarbonyl that is used to form cyclopentenones in this fashion. This reaction is highly versatile and even the presence of a cyclopropane ring on the alkene does not interfere with the efficiency of the cobalt-mediated rea~tion.’~ The Pauson-Khand reaction has reached the stage of development where it can be employed in target molecule synthesis. A 6,5,5-ring system terminating in a trisubstituted cyclopen- tenone has been formed in this way in a model study for the CDE rings of xest~bergsterol.~~ Diastereoselectivity greater than 14 1 was notable in this case.The Nicholas Reaction.-The binding of two cobalt atoms to an alkyne also holds the key to the Nicholas reaction in which a metal-stabilized propargyl cation is combined with a nucleophile. Two examples of intramolecular electrophilic aromatic substitu- tion using this approach have been described. Reactions of this type can occur at temperatures as low as -78 OC9*and have been shown to be enantiospecific.” The use of sugar-derived starting materials such as (48) features in studies leading towards enantioselective synthesis of oxepane sub-units of marine polyether toxins. loo Considerable manipulation via (49) however is needed to achieve the required building block which is liberated from the complex (50)by oxidation of Co,(CO) with I (Scheme 15).A more straight-forward application is the use of a propargyl aldehyde complex with a silyl enol ether nucleophile in a stereoselective total synthesis of bengamide E. Scheme 15 Because complexation to cobalt bends the alkyne away from a linear structure the Nicholas reaction has found considerable application in the synthesis of cyclic 95 A. J. Pearson and R. A. Dubbert Organometallics 1994 13 1656. 96 A. Stolle H. Becker J. Salaiin and A. de Meijere Tetrahedron Lett. 1994 35 3517. 97 M.E. Krafft and X. Chirico Tetrahedron Lett. 1994,35 4511. 98 D. D. Grove J. R. Corte R. P. Spencer M. E. Pauly and N. P. Rath J. Chem. SOC. Chem. Commun.1994 49. 99 A. V. Mueheldorf A. Guzman-Perez and A. F. Kluge Tetrahedron Lett. 1994 35 8755. loo S. Tanaka N. Tatsuta 0.Yamashita and M. Isobe Tetrahedron 1994 50 12883. lo’ C. Mukai 0.Kataoka and M. Hanaoka Tetrahedron Lett. 1994 35 6899. G. R. Stephenson enediynes. A typical strategy is to employ a propargyl leaving group in an intramolecular reaction with an enol ether-based nucleophile. In the case of (51) however cyclization ultimately gives rise to the rearranged allenic structure (52) (Scheme 16).'02 Since both the Pauson-Khand and the Nicholas reactions employ stoichiometric transition metal complexes for activation and control these approaches to carbon- carbon bond formation are particularly attractive when combined in a single synthesis.In this way the cobalt complex can play a double role and so best reward the effort of its attachment to synthetic intermediates. Indeed when viewed as a decomplexation method the Pauson-Khand reaction is extremely attractive since key skeletal bonds are formed during the decomplexation event. The total synthesis of (+ )-epoxydic-TBSOvfl;3a C OR 1 n 0 (co)~co-co(co)~ 0 TBSO (51) (52) Scheme 16 Me Steps -OMe Scheme 17 tymene (Scheme 17) from Schreiber's group provides an excellent illustration of this approach. The synthetic route begins by the combination of two chiral building blocks (53)and (54) by a conventional acetylide displacement of a triflate. The triflate (53)is in enantiopure form and (54) was racemic hence the product (55) was formed as a 1 :1 M.E. Maier and D. Langenbacher Synlett 1994 713-716. Organometallic Chemistry mixture of diastereoisomers. The undefined chiral centre however is corrected in the Nicholas step. After complexation with dicobalt octacarbonyl the Nicholas reaction is promoted with trimethylsilyl triflate. There are two propargyl leaving groups leading to an issue of chemoselectivity. Under the conditions used the major product is the ether (56) containing the terminal alkene needed for the intramolecular Pauson- Khand step. This compound like the ethyl ether by-product was formed as a single diastereoisomer illustrating the point that the cobalt-mediated step was stereoconver- gent. Thus chirality originating in (53) which itself was prepared in five steps from the terpene natural product @)-pulegone has been successfully relayed to this point in the target structure.Removal of the metal by the Pauson-Khand cyclization completes the final two rings of the target molecule again in a stereocontrolled fashion.'03 Scheme 18 illustrates an unusual variant of hexacarbonyl dicobalt alkyne chemistry in which radical-mediated steps are performed adjacent to the cobalt-bound portion of the ligand.lo4 52% Scheme 18 The Dotz-Wulff Cyc1ization.-It was Dotz working as a Ph.D. student in the laboratory of E.O. Fisher who first discovered that vinyl and aryl-substituted Fischer carbenes can be induced to cyclize with alkynes to give 1,4-dioxygenated aromatic products.Since then a good many groups have employed this reaction though it is work in the two laboratories of Dotz and Wulff which has had the greatest impact defining the scope and selectivity of processes of this type. In contrast to the Pauson-Khand reaction in which carbon-carbon bonds are formed during metal removal the Dotz-Wulff cyclization forms carbonsarbon bonds during the attach-ment of the metal. The strategic importance of this point is discussed later in the Report. Typically at the present time the cyclization reaction is combined with an oxidative work-up to produce a metal-free product. With a relatively vigorous oxidative procedure quinone products can be obtained. lo' Progress has been made in the search to define intermediates in the mechanism of this multistep cyclization.In Oviedo the Barluenga group has characterized tetracarbonylvinylcarbene(57) and metallohexa- triene (58) intermediates as shown in Scheme 19.'06 Low temperature infrared studieslo7 have also been used to probe the reaction sequence that leads to the cyclization products. Intramolecular reactions are often used to ensure regiocontrol. Intramolecular benzannulation has been achieved by the use of a dialkoxysilane link in the tether. T. F. Jamison S. Shambayati W. E. Crowe and S.L. Schreiber J. Am. Chem. SOC. 1994 116 5505. Io4 G. G. Melikyan 0.Vostrowsky W. Bauer H. J. Bestmann M. Khan and K. M. Nicholas J. Org. Chem. 1994 59 222. S. Chamberlin and W. D. Wulff J. Org. Chem. 1994 59 3047. J. Barluenga,F. Azner A.Martin S. Garcia-Granda and E. Perez-Carreiio,J. Am. Chem. SOC.,1994,116 11 191. lo' J. R. Knorr and T. L. Brown Organometallics 1994 13 2178. 270 G.R. Stephenson r 1 I C02Me \ Scheme 19 These reactions proceed most efficiently when a further alkene is added to the reaction mixture.'" The use of stannyl substituents on the alkyne has been found to reverse the normal regioselectivity in intermolecular benzann~lation.''~ In many reactions of this type indene formation occurs in competition with benzannulation. The effect of the metal in directing the reaction towards phenolic products has been assessed. The rank order for efficiency of access to phenolic products is chromium > tungsten > molyb-denum."' With alkyne-substituted Fischer carbene complexes quite a variety of product types can be obtained.With chromium and tungsten reaction with alkynes can afford tricyclic structures,' ' while enaminones' l2 can give rise to (59). Scheme 20 also shows an ingenious enyne metathesis in which the substituents on a catalytic quantity of the Fischer carbene complex are duplicated in an enyne co-reactant (60).' ' Metal-mediated [2 + 2 + 2) Cycloadditions.-Dicarbonyl(cyclopentadienyl)cobalt has typically been used to promote the [2 + 2 + 21 co-cyclization of a,o-diynes and alkynes. Nickel'14 catalysts offer an alternative procedure. A nitrile in the place of one of the alkynes affords substituted pyridines. This has been applied in Vollhardt's group in routes to ergot alkaloids." The use of the bistrimethylsilylethyne as a co-reactant is a typical stratagem.Ethyne itself under pressure has also been used and in the reaction leading to the formation of (61) offered a product with high optical purity.'16 A procedure for the general application of these methods to form lo' M. F. Gross and M. G. Finn J. Am. Chem. SOC.,1994 116 10 921. lo9 S. Chamberlin M.L. Waters and W.D. Wulff J. Am. Chem. Soc. 1994 116 3113. 'lo W. D. Wulff B. M. Bax T. A. Brandvold K. S. Chan A. M. Gilbert and R. P. Hsung Organornetallics 1994 13 102. '11 A. Segundo J.M. Moreto J.M. Vifias and S. Ricart Organometallics 1994 13 2467. '12 R. Aurnann M. Koprneier K. Roths and R. Frohlich Synlett 1994 1041. 11' S. Watanuki N. Ochifuji and M. Mori Organometallics 1994 13 4129.'14 Y.Sato T. Nishirnata and M. Mori J. Org. Chem. 1994 59 6133. '15 C. Saa D. D. Crotts G. Hsu and K. P.C. Vollhardt SynIett 1994 487. '16 G. Chelucci M. A. Cabras and A. Saba Tetrahedron Asymmetry 1994 5 1973. Organometallic Chemistry 271 EtO W(CO)5 ? p yo-E'oso + Ph Ph (59) Scheme 20 alkyl-substituted 2-cyano-6-(2-pyridyl)pyridineshas been described.' It is interesting to compare these reactions with alternative cyclization strategies to produce aromatic rings. For example Fischer carbenes of the type discussed in the preceding section can be combined with two alkynes by heating in acetonitrile to produce an aromatic ring. An intramolecular synthesis of the steroid ring system has been achieved in this way (Scheme 21)."* Palladium catalysed coupling can also give rise to aromatics.The combination of tributylvinylstannane with the bistriflate (62) affords a chiral arene."' OTBDMS TBSO 63% eSnBu Pd(PPh& OTf TfO NMP Me Scheme 21 11' G. Chelucci M.A. Cabras and A. Saba J. Heterocyclic Chem. 1994 31 1289 J. Bao W.D. Wulff V. Dragisich S. Wenglowsky and R.G. Ball J. Am. Chem. SOC. 1994 116 7616. '19 J. Barry and T. Kodadek Tetrahedron Lett. 1994 35 2465. G.R. Stephenson Photochemistry of Carbene Complexes-Access to amino acids and 8-lactams by photolysis of carbene complexes with suitable unsaturated co-reactants has continued to develop particularly through the efforts in the Hegedus group at Colorado State. Cyclization (Scheme 22) with a substituted imidazole gives access to the 8-lactam (63).120 Thio-substituted 8-lactams can also be obtained.I2' Using an aldehyde as a co-reactant p-lactones are formed.' 22 Scheme 22 Iron Acyl Enolates.-The highly successful chiral enolate equivalents developed some years ago in the groups of Davies and Leibeskind continue to find favour in natural product synthesis.Davies has published two alternative resolution procedures to form the enantiopure reagent (Figure 7). Menthol'23 and provide the source of the chiral auxiliaries in these processes. Enolates developed from the metal acyl species have been used to open epoxides derived from protected sugars.'25 Figure 7 1,CDifunctionalization of Dienes.-Palladium catalysed oxidation of 1,4-dienes in the presence of nucleophiles typically gives rise to disubstituted alkenes.Intramolecular delivery of one of the nucleophiles has been used to form oxaspirocyclic products. 26 New developments allow carbonsarbon bond formation based on these principles. In the synthesis of (64) (Scheme 23) intramolecular nucleophile attack is followed by interception of the organopalladium intermediate by carbon monoxide to form the amide substituent. Since nucleophile addition occurs trans and carbonyl insertion proceeds on the face carrying the metal this reaction is highly stereocontrolled but regioselectivity was incomplete. The best results were obtained in dichloromethane with one atmosphere pressure of carbon monoxide. At high pressure in THF the L.S. Hegedus and W.H. Moser J. Org. Chem. 1994 59 7779. B. Alcaide L. Casarrubios G. Dominguez and M. A. Sierra J. Org. Chem. 1994 59 7934. P.-J. Colson and L. S. Hegedus J. Org. Chem. 1994 59 4972. S. J. Cook J. F. Costello S. G. Davies and H.T. Kruk J. Chem. Soc. Perkin Trans. I 1994 2369. S. C. Case-Green J. F. Costello S.G. Davies N. Heaton C.J. R. Hedgecock V. M. Humphreys M. R. Metzler and J.C. Prime J. Chem. Soc. Perkin Trans. I 1994 933. S.G. Davies H. M. Kellie and R. Polywka Tetrahedron Asymmetry 1994 5 2563. P.G. Anderson Y.I.M. Nilsson and J.-E. Backvall Tetrahedron 1994 50 559. Organometallic Chemistry 0 (64)+ regiobomer Scheme 23 alternative regioisomer was referr red.'^^ In a variant of this procedure again using a substituted cyclohexadiene starting material external nucleophile attack (by chloride) is combined with intramolecular capture of the palladium by a pendent alkyne.Finally halogen addition to the palladium centre and reductive elimination complete a vinyl halide. Stereochemistry around the six-membered ring is fully controlled in this reaction but a mixture of E and 2 exocyclic alkenes was obtained.'28 Deprotection using Transition Metal Chemistry.-Palladium catalysed allylic dis- placement can be used as a method to detach allyl protecting groups from synthetic intermediates. Typical examples appearing this year employ allyl ester' *' and carbon- ate~'~' in the presence of an appropriate nucleophile (morpholine and diethylamine respectively). Phenol leaving groups allow the development of a palladium catalysed reductive deprotection of aryl allyl ethers.In the case of 4-t-butylphenol exceptionally efficient deprotection was possible.' 31 The allyloxycarbonate version of the reaction has been used in the synthesis of phosphonopeptides from Fmoc phosphonodipept- ides.' 32 Allylic anchoring groups can also be combined with palladium catalysed de- tachment in work related to solid-phase synthesis of pep tide^.'^^ In these cases tributyltin hydride was used in conjunction with the palladium catalyst. In a further example trimethylsilylazide was chosen as the nucleophile.' 34 The application of water-soluble catalysts in palladium catalysed detachment of allyl protecting groups illustrates a further important step forward.' 35 Homogeneous or biphasic media can be used and diethylamine is employed as the allyl scavenger.Transition Metals in Amino Acid Chemistry.-The examples of peptide deprotection and detachment from solid phases presented in the preceding section draw attention to the compatibility of transition metal based methods with amino acid chemistry. In Scheme 24 through the use of LDA to generate an anionic intermediate the allyl group detached from the ester becomes incorporated stereoselectively as a substituent on the glycine component of the dipeptide.' 36 Elaboration of side-chain functionality has also 12' P.G. Anderson and A. Aranyos Tetrahedron Lett. 1994 35 4441. 12' J.-E. Backvall Y. I. M. Nilsson P. G. Anderson R. G. P. Gatti and J.Wu Tetrahedron Lett. 1994,35 5713. 129 S. Okamoto N. Ono K. Tani Y. Yoshida and F. Sato J. Chem. SOC.,Chem. Commun. 1994 279. lJo J.P. GenCt E. Blart M. Savignac S. Lemeune S. Lemaire-Audoire J.-M. Paris and J.M. Bernard Tetrahedron 1994 50 497. 13' R. Beugelmans S. Bourdet A. Bigot and J. Zhu Tetrahedron Lett. 1994 35 4349. lJ2 D.. Maffre-Lafon R. Escale P. Dumy J.-P. Vidal and J.-P. Girard Tetrahedron Lett. 1994 35 4097. lJ3 P. Loyd-Williams A. Merzouk F. Guibe F. Albericio and E. Giralt Tetrahedron Lett. 1994 35,4437. lJ4 G. Shapiro and D. Buechler Tetrahedron Lett. 1994 35 5421. 13' S. Lemaire-Audoire M. Savignac E. Blart G. Pourcelot and J. P. Genet Tetrahedron Lett. 1994 35 8783. 13' U. Kazmaier J. Org. Chem. 1994 59 6667. G.R.Stephenson Scheme 24 been examined. Phosphorus-substituted arylamino acids are popular targets. Pallad- ium catalysed coupling between an iodoarene and H,PO,Me produces an arylphos- phinate side-chain.' 37 Alternatively the use of a 4-iodoarylphosphinate ester in pallad- ium catalysed coupling with the organozinc reagent derived from iodoserine can also produce novel tyrosine-like structures with an acidic phosphonomethyl centre in place of the phenolic OH group.' 38 Carbonylation of a trifluoromethylsulfonate derivative of tyrosine produces the corresponding benzoic acid derivative.' 39 Palladium coupling with ~inylhalide'~' and ~inyltin'~' side-chain groups produces elaborated diene enyne styryl and alkyl side-chains. A synthesis of (+)-bulgecenine in Hegedus's laboratory provides a fine illustration of the advantages of making use of anions stabilized by stoichiometric metal com- plexes.Deprotonation of an aminocarbene complex and reaction of the resulting anion with an aldehyde provide a key intermediate for the synthetic route.'42 Electrophilic metal complexes can also be employed with amino acids. Nucleophile addition by the amino substituent in amino acid esters in reactions with electrophilic tricarbonyliron cyclohexadienyl complexes have been examined. 143 The same elec- trophiles can be used in the synthesis of uncommon amino acids by combination with a Schiff-base derived n~cleophile.'~~ A total synthesis of K-13145 has been based in Pearson's laboratory on an electrophilic arylruthenium complex.A related q6-elec- trophile in the tricarbonylmanganese series forms the basis for model studies for the construction of the CFG rings of ristocetin Heterocyclic Synthesis.-Organometallic chemistry is employed surprisingly frequent- ly in the synthesis of heterocycles. Typical of such procedures are the cyclization routes to substituted indoles starting from aniline derivatives. A 2-alkynyl aniline is a com- mon starting material.'47 This procedure can be modified to include carbonyl insertion to form in a methanol solvent 2-substituted 3-carbomethoxyindoles.'48 With alkyl halides present 3-ketoindoles are formed.'49 The formation of (65) in 13' H. Lei M.S. Stoakes K. P. B. Herath J. Lee and A. W. Schwabacher J. Org. Chem. 1994 59 4206. 13* R.L. Dow and B. M. Bechle Synlett 1994 293. 139 R. G. Franz J. Weinstock R. R. Calvo J. Samanen and N. Aiyar Org. Prep. Proced. Int. 1994,26 533. 140 G. T. Crisp and P. T. Glink Tetrahedron 1994 50 2623. 14' G. T. Crisp and P. T. Glink Tetrahedron 1994 50 3213. 142 G. Schmeck and L.S. Hegedus J. Am. Chem. SOC.,1994 116 9927. 143 L.A. P. Kane-Maguire R. Kanitz P. Jones and P. A. Williams J. Organomet. Chem. 1994 464,203. 144 J. P. Genet R. D. A. Hudson W.-D. Meng E. Roberts G. R. Stephenson and S. Thorimbert Synlett 1994 631. 14' A.J. Pearson and K. Lee J. Org. Chem. 1994,59 2304. 146 A.J. Pearson and H. Shin J. Org. Chem. 1994 59 2314. 14' S. Cacchi V. Carnicelli and F. Marinelli J. Organomet. Chem 475 289. 14* S. Kondo F. Shiga N. Murata T. Sakamoto and H.Yamanoka Tetrahedron 1994 50 11 803. A. Arcadi S. Cacchi V. Carnicelli and F. Marinelli Tetrahedron 1994 50 437. Organometallic Chemistry Scheme 25 Scheme 25 is a typical example. A 2-iodoaniline can combine intermolecularly with an alkyne again affording a 2,3-disubstituted product. A 5-HT receptor agonist has been obtained in this way.’5o With an enamine derived from a 2-iodoaniline an intra- molecular coupling exploiting the carbon-iodine bond provides an alternative.’” Less common routes to indoles start from 2-nitro~tyrenes”~ with a palladium cata- lyst or aryl isonitriles with a ruthenium cataly~t.’’~ These routes to indoles involve a disconnection that forms bonds in the heterocyclic ring. Grigg has used palladium catalysed cyclization/anion capture to build bonds in both carbocyclic and aromatic rings of tetrahydroindoles.The example shown in Scheme 26 combines the Pd(0)cat NaBPh4 PhOMe AC AC 69% Scheme 26 process with a final carbon-carbon bond forming step during removal of the palladium from the reaction intermediate.’ 54 Seven-membered partially saturated heterocyclic rings have also been formed using palladium catalysis. Nucleophilic addition to an q3-7c-allyl intermediate figured in the formation of (66),’” and in the absence of the acetate leaving group stoichiometric palladium chloride ally1 complexes have been used instead (Scheme 27).ls6 Alkenes bound to transition metals are also electrophilic. Palladium catalysed intra- molecular nucleophile addition combined with interception of the a-bound or-ganometallic intermediate with a vinylhalide affords a pyrrolidine.’57 For pyrrole ‘’O C. Chen D. R. Lieberman R. D. Larsen R.A. Reamer T. R. Verhoeven P. J. Reider I. F. Cottrell and P. G. Houghton Tetrahedron Lett. 1994 35 6981. ‘’I K. Koerber-Ple and G. Massiot Synlett 1994 759. 152 M. Akazome T. Kondo and Y. Watanabe J. Org. Chem. 1994 59 3375. lS3 G.C. Hsu W. P. Koser and W. D. Jones Organornetallics 1994 13 385. R. Grigg J. Heterocyclic Chem. 1994 31. 631. M. Grellier M. Pfeffer and G. van Koten Tetrahedron Lett. 1994 35, 2877. 156 P. A. van der Schaaf J.-P. Sutter M. Grellier G. P. M. van Mier A. L. Spek G. van Koten and M. Pfeffer J. Am. Chem. SOC. 1994 116 5134. ’’’ R.C. Larock H. Yang S.M. Weinreb and R.J. Herr J. Org. Chem. 1994 59 4127. G. R. Stephenson OAc I Scheme 27 -Ph Ph Ph Scheme 28 ring formation carbenes are popular starting materials. Reaction with an a,b-un- saturated imine affords (67) under thermal conditions (Scheme 28).' 58 Aminoalkenyl substituted carbenes and acid chlorides also react to form substituted pyrroles.' 59 Alkynyl carbenes and imines form five-membered heterocycles.' 6o With diazo- methane the carbene unit remains in place and cycloaddition occurs at the alkyne again forming a five-membered heterocycle.'61 Aminocarbenes react intermolecularly with alkynes to afford furans with the extra CO unit originating from a carbon monox- ide molecule.'62 Other cyclizations are possible. Allenyl imines can be cyclized by reactions via pentacarbonyliron to form highly unsaturated lactams,' 63 and palladium catalysed carbonylation of 2-bromoacetophenones in the presence of an isocyanide affords alkylidene-substituted lactams.' 64 Palladium coupling also has a role in het- erocyclic synthesis.The iodopyridine (68) combines with a 2-substituted phenyl- boronic acid to afford (69) (Scheme 29).'65 Five-membered rings are formed from 2-aminothiophenol and aryl halides by carbonyl insertion.'66 Oxygen heterocycles are accessible in a similar way. 3,4-Disubstituted coumarins are formed from unsaturated esters of 2-iodophenol phenylacetylene and carbon monoxide.'67 Coupling reactions can be used to functionalize existing heterocycles. For example vinyltin coupling to a chloro-substituted heterocycle allows efficient carbonsarbon T.N. Danks and D. Velo-Rego Tetrahedron Lett. 1994 35,9443. R. Aumann B. Jasper R. Goddard and C. Kriiger Chem. Ber. 1994 127 717. 160 F. Funke M. Duetsch F. Stein M. Noltemeyer A. de Meijere Chem. Ber. 1994 127 911. 16' C. Baldoli P. Del Buttero E. Licandro S. Majorana A. Papagni and A. Zanotti-Gerosa J.Organomet. Chem. 1994,476 C27. 162 C. Bouancheau A. Parlier M. Rudler H. Rudler J. Vaissermann and J.-C Daran Organometallics 1994 13 4108. M.S. Sigman and B.E. Eaton J. Org. Chem. 1994 59 7488. 164 S. Hamaoka M. Kawaguchi and M. Mori Heterocycles 1994 37 167. 16' F. Guillier F. Nivoliers A. Godard F. Marsais and G. Queguiner Tetrahedron Lett. 1994 35 6489. R. J. Perry and B.D. Wilson Organometallics 1994 13 3346. 16' M. Catellani G. P. Chiusoli M. C. Fagnola and G. Solari Tetrahedron Lett. 1994 35 5923. 277 Organometallic Chemistry Scheme 29 bond formation.'68 A similar reaction with an iodoheterocycle in this case protected as its N-benzyl derivative and vinylzinc as the co-reactant has been re~0rted.l~~ 3-Stannylindoles can be elaborated by coupling with vinyl triflates.' 70 Pyrimidinyl trif- lates behave similarly. ' N-Protected iodoimidazoles are dimerized by palladium catalysis to form bisimidazoles. 72 Thienothiophenes can be metallated and coupled with aryl halides173 and bromoindoles can be combined with arylboronic acids.'74 In this regard the cross-coupling procedures that attach aromatic rings are similar to those discussed for vinyl groups earlier in this section.Heck coupling is also possible as shown by the formation of (71) from (70). (Scheme 30).'75 bCN M e \ N b N Pd(OAC)~ HOAc OAN IMe A IMe (70) (711 Scheme 30 Mention of two heterocyclic n-complexes concludes this section. The tricarbonyl- chromium complex of thiophene has been metallated and combined with benzal- dehyde' 76 and the problem of chromium complexation of pyridines originally over- come by silylation on the aromatic ring has now been extended albeit in low yield to 2,6-dimethylpyridine.' 77 L.-L. Gundersen Tetrahedron Lett. 1994 35 3155. 169 L.-L. Gundersen A. K. Bakkestuen A. J. Aasen H. Bverls and F. Rise Tetrahedron 1994 50 9743. 170 P. G. Ciattini E.Morera and G. Ortar Tetrahedron Lett. 1994 15 2405. 17' J. Sandosham and K. Undheim Heterocycles 1994 37 501. 17' M. D. Cliff and S.G. Pyne Synthesis 1994 681. 173 D. Prim and G. Kirsch J. Chem. Soc. Perkin Trans. 1 1994 2603. 174 G. M. Carrera Jr and G. S. Sheppard Synlett 1994 93-94. 175 K. Hirota H. Kuki and Y. Maki Heterocycles 1994 37 563. '16 M. Struharik and S. Toma J. Organomet. Chem. 1994 464,59. 177 A. Goti and M. E. Semmelhack J. Organomet. Chem. 1994 470 C4. G. R. Stephenson Carbon-Carbon Bond Formation during the Formation of q" n-Complexes.-In principle when stoichiometric transition metal complexes are used in organic synthesis multiple use of the transition metal should be the goal. Otherwise a catalytic procedure would be more appropriate.During the preceding sections examples have been seen where carbon<arbon bond formation has occurred during the formation of a n-complex and during its decomplexation reaction. If these steps can be combined with metal-mediated reactions exploiting properties of the intermediate metal complexes then the decision to include a transition metal will no longer involve unavoidable redundant steps which fail to advance the skeletal bond formations needed to complete the target molecule. From this stand-point it can be seen that complexation steps which combine the two objectives of attachment of the metal and skeletal bond formation are of particular strategic importance. Once rare these types of bond forming reactions are now becoming more common.Examples arising in chromium carbene benzannulation reactions have already been mentioned. A stereoselective example has now been deve10ped.I~~ In this case (Scheme 31) an optically pure protected propargyl alcohol (72) serves as the co-reactant and the chiral q6-chromium complex is formed with high diastereoselectivity. The chiral centre in the propargyl unit controls the induction of planar chirality in the n-complex. r OMe (-) 68% Scheme 31 Cobalt-mediated benzannulation reactions can be modified to give access to metal n-complexes. For example the use of an allene as a reaction partner with dicarbonyl- (cyc1opentadieny)cobalt and an x,w-alkyne affords q4-CoCp polycyclic products. In the case of (73) (74) and (75) were formed as a 7 3 mixture of diastereoisomers.A variety of complexed ring systems are accessible (Scheme 32).'79 Vollhardt has also reported' 8o new cyclization reactions of furan- and thiophene-containing alkynes which allow the isolation of q4-cobalt complexes. Two alkynes can be combined by reaction with iron pentacarbonyl to form q4-complexes of cyclobutadienone.' 8' Allenes react with Fe,(CO) to produce bimetallic metal-substituted allyl structures and traces of back-to-back n-allyls bound to Fe2(C0)6.'82 Yields are very low but in the Fe,(CO) case the central carbon-carbon bond between the two allyl portions has been formed in the process providing an unusual route to unusual structures and an interesting comparison with the alkyne series (Scheme 33).Reactions which rearrange one type of n-system to another are also relevant to this 178 R. P. Hsung and W. D. Wulff .I.Am. Chem. Soc. 1994 116 6449. 17' C. Aubert D. Llerena and M. Malacria Tetrahedron Lett. 1994 35 2341. 180 R. Boese D. F. Harvey M. J. Malaska and K. P.C. Vollhardt J. Am. Chem. Soc. 1994 116 11 153. A. J. Pearson and R. J. Shively Jr Organometallics 1994 13 578. lE2 A.M. Kuonen J. Raemy and T. A. Jenny Chimia 1994 48 362. Organometallic Chemistry (73) (74) (75) 7:3 Scheme 32 R RR 1439% 1-9% Scheme 33 issue. For example the carbene complex (76),accessible via iron-mediated opening of vinyl epoxides can be combined with a trimethylsilylenol ether to form an q4-diene complex (Scheme 34).' 83 Another curious example affording an q4-diene complex is provided by the photoloysis of (77) with cycl~hexene.'~~ Molybdenum carbyne complexes carrying cyclopropyl substituents rearrange to form formyl-substituted q4-diene complexes,' 85 and allenyl tungsten complexes undergo carbonyl insertion upon reaction with amines to form l-amide-substituted q3-allyl complexes.' 86 An Mn(CO) acyl complex rearranges to form the Mn(CO) complex of an q3-allyl with lB3 W.Fortsch F. Hampel and R. Schobert Chem. Ber. 1994 127 711. 184 C.-H. Sun N.-C. Shang L.S. Liou and J.-C. Wang J. Organomet. Chem. 1994 481 179. 18' M. D. Mortirner J.D. Carter K. B. Kingsbury K.A. Abboud and L. McElwee-White J. Am. Chem. SOC. 1994 116 8629. 186 T.-W. Tseng I.-Y. Wu J.-H. Tsai Y.-C. Lin D.-J.Chen G.-H. Lee M.-C. Cheng and Y. Wang Organometallics 1994 13 3963. G.R. Stephenson OSiMe3 Med 91% Ph. Ph. \ hv F~(co) Scheme 34 intramolecular coordination of an adjacent amide carbonyl The asymmetric induction methods that open up new routes to optically pure complexes with planar chirality (discussed in section 3) and complex-forming reactions that also form skeletal bonds (discussed above) constitute crucial strategic objectives that will facilitate more efficient applications of stoichiometric metal complexes in organic synthesis. Widely applicable ‘set-piece’ reactions such as the Pauson-Khand and Nicholas reactions the Dotz-Wulff cyclization metal-mediated [2 + 2 + 21 steps and metal-stabilized anions such as the Davies chiral enolate system will have a major role to play in the development of these opportunities in future years.Also of importance are varied and versatile bond-forming methodologies based on particular metal n-complex classes. Indeed the ‘virtuoso capabilities’ of these metal/ligand assemblies may ultimately hold the key to the truly general application of these methods in organic synthesis. The 1994 Report ends with a selection of some of the best examples to appear during the year of the use of metal complexes in organic synthesis and a selection of reactions that will enhance versatility. Tricarbonyliron Chemistry.-The 24-membered polyyne macrolide macrolactin A (78) (Scheme 35) offers a suitable challenge to put the control effects of q4-diene tricarbonyliron complexes to good use.Results from the laboratories of Donaldson at Marquette University and Grte at Rennes concentrate on approaches in which two of the three diene linkages originate as tricarbonyliron complexes. In both sections control of functionality adjacent to the tricarbonyliron group is an issue and in the lower portion a remote chiral centre must also be controlled. Addressing the top (Cl-Cll) segment Donaldson had made progress with a route that commenced with a heterocycloaddition. After ring opening this affords an aldehyde intermediate which is extended by addition of carbons 1-3 by a Wittig-Horner step producing predomi- nantly the required Z isomer (Scheme 36). The lower (ClGC24) portion of the target has also been addressed in this work.Nucleophile addition to aldehyde groups adjacent to tricarbonyliron diene complexes A. AbuBaker C. D. Bryan A. W. Cordes and N. T. Allison Organometallics 1994 13 3375. Organometa11ic Chemistry 28 1 OH I 11 Q 16 Scheme 35 52% Scheme 36 typically lack stereocontrol. In the case shown in Scheme 37 product (80)was formed as a 1 :1 mixture of stereoisomers but hydrolysis of the acetal and formation of the cyclic hemiacetal in (81) proceeded with epimerization at the carbon atom a to the metal complex providing a 3 :1mixture which can be separated by chromatography. Introduction of the methyl group (C24 in the target) completed the lower carbon chain and provided a means to relay chirality to C23.Cyclization to form the ether (82) and ionic reduction next to the tricarbonyliron group complete a sequence of reactions in which the chirality of attachment of the tricarbonyliron group in (79) has been used to control asymmetry at a carbon atom four centres away from the q4 portion of the ligand.' ** In Grke's laboratory work with optically pure metal complexes has also addressed the lower portion of the macrolactin target structure culminating in the preparation of the intermediate (84) with the aldehyde present that would be needed for an aldol approach to the C13-Cl5 sequence of two stereocentres. In this convergent approach an optically pure building block introduces the C23 stereocentre in pre-built form and W.A. Donaldson P.T.Bell Z. Wang and D.W. Bennett Tetrahedron Lett. 1994 35 5829. G.R. Stephenson (79) Scheme 37 ,P h (83) 1) Swap protecting groups 12) Et. SiH. TFA 13) Fthctionalgroup interconversion Scheme 38 Organometallic Chemistry issues of remote asymmetric induction do not arise. Conversion of (83) into (84)again employs an ionic reduction. To complete the reaction sequence shown in Scheme 38 it is necessary to swop protecting groups and effect a two-step functional group interconversion to achieve the required structure.' 89 In a synthesis of an optically pure sample of Streptomyces by-product SS20846A (which proved the absolute configuration of this metabolite) the sorbaldehyde complex (79) (X = Me) (which is also available in optically pure form) was again employed.After formation of the imine hetero-Diels-Alder functionalization was optimized to afford diastereoselective access to (85),for which the relative stereochem- istry was proved by X-ray crystallography. A sequence of two reduction steps afforded the alcohol (86) as a 7 :3 mixture of diastereoisomers. The target (87) was completed by simultaneous deprotection of the nitrogen and detachment of the metal by oxidation with ceric ammonium nitrate at low temperature. The specific rotation of the (-) isomer (87) obtained in this way matched the -15" value for the [aIDvalue for the natural product (Scheme 39).I9O Scheme 39 Because of the predictability of diastereoselective reactions using tricarbonyliron complexes and the fact that optically pure examples of these compounds are now widely available these methods have become attractive for enantioselective synthesis and for the proof of absolute configurations.Recently a detailed circular dichroism study of the metal complexes has been described."' An empirical rule relates the cyclic q4-diene complexes to the CD curves (analysed earlier by other researchers) in the acyclic series. T. Benvegnu L. Schio Y. Le Floc'h and R. Gree Synlett 1994 505. 190 Y. Takernoto S. Ueda J. Takeuchi T. Nakarnoto and C. Iwata Tetrahedron Lett. 1994 35 8821. 19' G.R. Stephenson and P.W. Howard J. Chem. Soc. Perkin Trans I 1994 2873. G.R. Stephenson The lability of alcohol leaving groups adjacent to the metal complexes exploited to gain diastereoselectivity in Scheme 37 can also be employed in carbon-carbon bond formation.Examples which make use of intermediates available through highly effective functionalization of aldehydes using chiral organoboron reagents have been reported from the Roush group.'92 This approach is now being applied the asymmetric synthesis of ikar~gamycin.'~~ In another case a diene complex obtained from a ligand constructed from ( +)-L-arabinose has been elaborated diastereoselectively to form (88).' 94 Opening of ally1 epoxides with iron carbonyl reagents affords ferralactone Scheme 40 intermediates. Diastereoselective functionalization adjacent to the q3-allyl unit in these structures has been examined in the Ley group in Cambridge. The products can be converted by simple treatment with barium hydroxide into the corresponding q4-diene complexes with the asymmetry of the carbon bearing the alcohol group still intact.19' Functionalization of substituents at C2 of a tricarbonyliron-bound diene has also been examined and intermediates obtained in this way can be further cyclized by intramolecular anion addition reactions that proceed via intermediate Fe(C0); c~rnplexes.'~~ Ally1 anion complexes of Fe(CO) have been examined directly in reactions with carbon-based electrophiles.a$-Unsaturated ketones can be obtained in this way by carbonyl insertion. Replacing a metal-bound carbon monoxide by triphenylphosphine gives rise to heterodiene complexes containing a dicarbonylphos- phine-iron group.' 97 Electrophilic $-cyclohexadienyl complexes are also important intermediates in organic synthesis.Precursors for a route to aranorosin have been obtained by intramolecular nucleophile addition affording spirocyclic products. 19' An alternative cyclization procedure extends the oxidative methods for heteroatom addition adjacent to q4-cyclohexadiene tricarbonyliron complexes. The addition of benzyl amines mediated by oxidation using either very active manganese dioxide or the ferrocinium cation has been re~0rted.l~~ New types of nucleophiles are also under examination for the functionalization of q'-dienyl complexes. This is important when weak directing groups are present on the metal-bound portion of the ligand.'" W. R. Roush and C. K. Wada Tetrahedron Lett.1994,35 7347. W. R. Roush and C.K. Wada J. Am. Chem. SOC.,1994 116 2151. 194 E. Hessler H.-G. Schmalz and G. Durner Tetrahedron Lett. 1994 35,4547. 19s S. V. Ley G. Meek K.-H. Metten and C. Pique J. Chem. SOC. Chem. Commun. 1994 1931. 196 J.-L. Wang C.-H. Ueng S.-J. Cheng and M.-C. P. Yeh Organometallics 1994 13 4453. S. Chang J. Yoon and M. Brookhart J. Am. Chem. SOC. 1994 116 1869. 19* H.-J. Knolker G. Baum and M. Kosub Synlett 1994 1012. H.-J. Knolker A.-A. El-Ahl and G. Weingartner Synlett 1994 194. G.R. Stephenson and K. Milne Aust. J. Chem. 1994 47 1605. Organometallic Chemistry Tricarbonylchromium Chemistry .-Synthetic applications of arene complexes bearing the tricarbonylchromium group have been advanced by the preparation of analogues of dihydroheliporin E and dihydropseudopterosin G.201Several aspects of tricar- bonylchromium chemistry have been discussed earlier in this report where methods of asymmetric induction were described.Another important development which has gained momentum this year has been the use of metal-catalysed coupling reactions in the presence of the tricarbonylchromium group particularly in reactions that elaborate functionality attached to the metal-bound arene itself. Typical examples are shown in Scheme 41. Palladium catalysed cross-coupling between complexed aryl 91% triflates and vinyl tin reagents,202 and the use of Suzuki-type coupling combining complexes of aryl bromides with arylboronic a~ids~~~*~~~ and carbonylation of the chromium-bound aryl chloride205 have all been reported.Work on stereocontrolled elaboration of functionality adjacent to tricarbonyl- chromium complexes has also advanced and parallel developments in the tricar- bonyliron series discussed in the preceding section. An asymmetric Baylis-Hillman coupling reaction promoted with DABCO gives diastereoselective access to (89)206 (Scheme 42). Nucleophile addition to an q'-tropylium complex using copper/zinc- Scheme 42 201 H.-G. Schmalz A. Schwarz and G. Diirner Tetrahedron Lett. 1994. 35,6861. 202 A.M. Gilbert and W. D. Wulff J. Am. Chem. Soc. 1994 116 7449. 203 M. Uemura and K. Kamikawa J. Chem. Soc. Chem. Commun. 1994 2697. 204 M. Uemura H. Nishimura K. Kamikawa K. Nakayama and Y. Hayashi Tetrahedron Lett. 1994 35 1909.205 J.-F. Carpentier E. Finet Y. Castanet J. Brocard and A Mortreux Tetrahedron Lett. 1994 35,4995. 206 E. P.Kiindig L. Hii Xu,and B. Schnell Synlett 1994 413. 286 G.R. Stephenson based nucleophiles to introduce a functionalized side-chain prepares the way for a further example of intramolecular nucleophile addition this time to an q6 cyclohepta-triene ligand.207 Nucleophile addition to neutral q6-arene complexes affords q5-anions that can be trapped with electrophiles. Carbonyl insertion can also be promoted in this way. Other Metal n-Complexes as Synthetic Intermediates..-Although tricarbonyliron and tricarbonylchromium complexes are now the most widely used organometallocar- bony1 n-complexes quite a wide variety of other metal/ligand systems are popular.Electrophilic tricarbonylmanganese arene complexes have been combined with nuc- leophiles stabilized by metal ~arbenes.~'~ Phosphonate reagents have been obtained by reaction with trimethylphosphite,2 lo shadowing access to phosphonium salts in the tricarbonylchromium series through reactions of the metal-bound tropylium ca-tion.21 A more unusual study of cycloaddition reactions to neutral q5-tricarbonyl- manganese complexes has been reported.212 Also popular for the stabilization of q6-cation complexes is the FeCp unit. This has been employed to promote the displacement of aryl chlorides by hydroquinone in a route to polyaromatic ethers.21 Selective arylation of diols can be performed using FeCp-bound arylpropyl ethers to transfer the aryl group,214 and 1,6dichlorobenzene can be selectively elaborated by displacement of one halide with a phenoxide n~cleophile.~'' Substituent effects in q6-arene complexes of FeCp have been examined.2 l6 Ruthenium analogues employing the pentamethylcyclopentadienyl ligand (Cp*) have received attention.21 Access to cationic complexes of this type by direct complexation of enones combined with deoxygenation has been reported.218 The chemistry of cyclopentadienone ligands bound to RuBrCp* has been examined,219 and unusual cationic alkyl nitrosyl ruthenium complexes of Cp* can be elaborated by direct reaction with a$-unsaturated esters.220 An unusual ring-opening reaction in cationic (Cp*)Co complexes gives rise to ring-opened products of type (90)via an intermediate with an agostic hydrogen.221 The Fe(CO),Cp metal/ligand system retains popularity with work examining [3 + 21 ~y~loadditions~~'~~'~ and electrophilic ring-closure reactions224 being reported this year.The molybdenum counterparts have been utilizedz2' in enolates that are '07 M.-C. P. Yeh and C.-N. Chuang J. Chem. SOC. Chem. Commun. 1994 703. '08 E. P. Kiindig A. Ripa R. Liu and G. Bernardinelli J. Org. Chem. 1994 59,4773. '09 F. Rose-Munch C. Susanne F. Balssa and E. Rose J. Organomet. Chem. 1994 476 C25. 'lo T. Lee H.B. Yu Y.K. Chung W.A. Hallows and D.A. Sweigart Inorg. Chim. Acta 1994 224 147. 'I1 D.A. Brown J. Burns W.K. Glass D. Cunningham T. Higgins P. McArdle and M.M. Salama Organometallics 1994 13 2662. 212 C. Wang J.B. Sheridan H.-J. Chung M. C. Cote R. A. Lalancette and A. L. Rheingold 1. Am. Chem. SOC. 1994 116 8966. 'I3 A. S. Abd-El-Aziz D. C. Schriemer and C. R. de Denus Organometallics 1994 13 374. 214 A. J. Pearson and A. M. Gelormini J. Org. Chem. 1994 59 281. 215 A. J. Pearson and A.M. Gelormini J. Org. Chem. 1994 59 4561. '16 P. G. Gassman and P. A. Deck Organometallics 1994 13 2890. '17 D.T. Glatzhofer Y. Liang G.P. Funkhouser and M.A. Khan Organometallics 1994 13 315. '18 R Carreno F. Urbanos F. Dahan and B. Chaudret New J. Chem. 1994 18 449. '19 K. Kirchner K. Mereiter K. Mauthner and R. Schmid Organometallics 1994 13 3405. 220 E. Hauptman M. Brookhart P. J. Fagan and J. C. Calabrese Organometallics 1994 13 774. 221 J.C. Nicholls and J.L. Spencer Organometallics 1994 35 7889."'S. Jiang and E. Turos Tetrahedron Lett. 1994 35 7889. 223 T. Chen S. Jiang and E. Turos Tetrahedron Lett. 1994 35 8325. 224 D. P. Dawson W. Yongskulrote J. M. Bramlett J. B. Wright B. Durham and N. T. Allison Organometal-lics 1994 13 3873. 225 M.-F Liao G.-H. Lee S.-M. Peng and R.-S. Liu Organometallics 1994 13 4973. Organometallic Chemistry 287 reminiscent of the Davies enolate system in stereoselective reactions that form 4-pentene-1,3-diols. Cyclopentadienone chemistry exploits a cationic q4-complex,226 and (in an acyclic series) cationic q4-complexes of isoprene have been selectively elaborated with alkyllithium and Grignard reagents.227Stereocontrolled functionaliz-ation of enolates in q2-complexes of cyclopentenone has been examined.228 Or-ganocopper reagents have been added to enones adjacent to neutral ally1 CpMo(CO) complexes and related conjugate addition reactions to extended n-systems have been shown to give moderate diastereosele~tivity.~~~ In the tungsten carbonyl series nucleophiles have been reacted with cationic q4-2-methoxycarbonyl-1,3-pentadiene complexes.230 Me Me ($+= d (90) Me S02Ph BnO HPF e I ie+(co) 1 Nu-MeY+@So2Ph Nu Scheme 43 Fe(CO) complexes are more typical for stoichiometric attachment to alkenes.A bis Fe(CO) complex of a divinylketone has been described.231 Optically pure q2-complexes carrying an allylic leaving group can be converted into cationic q3 226 R. H. Yu J. S. McCallum and L.S. Liebeskind Organornetallics 1994 13 1476. 227 A. J. Pearson and M. K. Babu Organornetallics 1994 13 2539. 228 D. Schinzer T. Blume and R.U. R. Wahl Synlett 1994 297. 229 S.-H. Lin S.-F. Lush W.-J. Cheng G.-H. Lee S.-M. Peng Y.-L. Liao S.-L. Wang and R.-S. Liu Organornetallics 1994 13 1711. 230 M.-H. Cheng Y.-H. Ho Chen,G.-H. Lee S.-M.Peng S.-Y Chu,and R.-S. Liu Organornetallics 1994,13 4082. L31 A. C. C. Cano N. Zufiiga-Villarreal,C. T. Alvarez R. A. Toscano M. Cervantes A. Daz and H. Rudler JZ3’ A. J. Pearson and R.J. Shively Jr Organornetallics 1994 13 578. G.R. Stephenson intermediates and further elaborated by regio- and stereoselective nucleophile addi- The product (91) was obtained in >96% enantiomeric excess in this way (Scheme43).Rhenium nitrosyl complexes have been extensively studied in the Gladysz group at Utah.233*234 232 A.M. Kuonen J. Raemy and T.A. Jenny Chimia 1994,48 362. 233 W. Fortsch F. Hampel and R. Schobert Chern. Ber. 1994 127 711. 234 C.-H. Sun N.-C. Shang L.S. Liou and J.-C. Wang J. Organomet. Chem. 1994 481 179.

ISSN:0069-3030    

DOI:10.1039/OC9949100251

出版商:RSC    

年代:1994

数据来源: RSC