摘要:

1 Introduction By JOHN A. JOULEa AND JOHN P. RICHARDb aDepartment of Chemistry The University of Manchester Manchester M13 9PL UK bDepartment of Chemistry University at Buffalo SUNY Buffalo NY 14260–3000 USA In Volume 93 of Annual Reports Section B the Reader will find discussions of work published in 1996 concerning Theoretical Organic Chemistry Polar and Free Radical Reactions Aliphatic and Alicyclic Chemistry Aromatic Compounds Heterocyclic Compounds Organometallic Chemistry (Transition Elements) Synthetic Methods and Enzyme Chemistry. The reader is referred to the Society’s bimonthly journal Natural Product Reports for authoritative reviews of the chemistry and biosynthesis of particular groups of natural products. We pick out below some of the advances which have particularly taken our interest in the reviews in Volume 93 – the selection is personal and does not claim to be representative.Radical allylations can be e§ected neatly using an aryl allyl sulfone the first example of a catalyst to promote enantioselective radical additions to electron-deficient dienes and the preparation of a C 2 -symmetric non-racemic tin hydride are amongst important advances in synthetic radical chemistry; the interested Reader should certainly consult the 1996 Organic Reactions chapter on radical chemistry. Reviews on the increasingly studied Combinatorial Chemistry together with signficant advances have featured this year. Many delightful examples of tandem/cascade processes allow the rapid construction of polycyclic systems of all types. In this context the organic synthetic chemist becomes ever more comfortable with metathesis processes – this year for example the tolerance of b-lactams to the reaction conditions and the use of metathesis processes to make crown ethers has been described.Aziridines can be produced from imines and diazo compounds or by aza-Darzens processes. Dimethyldioxirane is increasingly exploited in various oxidative procedures – much higher concentrations can be obtained using a procedure which generates solutions in chlorinated solvents. The problem presented by ring opening of 2-lithiooxazoles has been circumvented by using their borane complexes. Biocatalytic hydrolysis of Schi§ bases from racemic amino acid esters in the presence of a base to epimerise the nonhydrolysed enantiomer allowed nearly 90% conversion to one enantiomer of the amino acid; biocatalytic resolution of arylethanamines can be achieved by lipasemediated hydrolysis of their octyl oxalamic esters.Microwave irradiation increases the rate of enzyme-catalysed reactions. The enzyme-catalysed hydrolysis of phthalimides holds considerable promise as a very mild way to release amines from such protected forms. Royal Society of Chemistry–Annual Reports–Book B 1 It is becoming increasingly apparent that it is now possible to reliably model complex organic processes in solution by computational methods. Chapter 3 describes continued progress in the development of continuum models and of more explicit methods for the representation of solvent in computer simulations of organic reactions. The use of advanced computational methods to model the stability of host-guest complexes and the position of the equilibrium for a variety of complex organic reactions is also described. The use of laser flash photolysis in the generation of reactive intermediates of organic reactions have deprived these species of much of their mystery to the continuing benefit of mechanistic organic chemists. Chapter 4ii reviews methods for the generation of enols ynamines nitrenes and carbocations; and the results of structurereactivity studies on these species. 2 John A. Joule and John P. Richard

ISSN:0069-3030    

DOI:10.1039/oc093001

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

2 Theoretical organic chemistry By JIALI GAO Department of Chemistry State University of New York at Buffalo Buffalo New York 14260 USA 1 Introduction Theoretical organic chemistry encompasses a wide range of topics spanning from high level electronic structural calculations of simple organic molecules using well-established ab initio molecular orbital or density functional theory techniques to computer simulations of chemical reactions and interactions in solution. This article is divided into two sections theoretical developments and applications. In the former theoretical advances in linear scaling electronic structure methods for large systems are briefly addressed. The focus however is on the development of solvation models and simulation techniques particularly those using hybrid quantum and classical methods.In the latter section topics covered in this review include transition structure modeling aromaticity conformational and tautomeric equilibria host–guest modeling pericyclic reactions and photochemical processes. 2 Theoretical developments Theoretical treatments of organic molecules may be roughly classified in terms of electronic structure theories and empirical force fields. The former describe an organic system by quantum chemical methods which include Hartree–Fock (HF) theory post-Hartree–Fock methods density functional theory (DFT) and multiconfiguration self-consistent field (MCSCF) techniques. On the other hand empirical force fields represent a molecular system by van der Waals spheres and partial atomic charges and the potential energy surface is simply expressed by empirical potential functions.Of particular interest is the syntheses of these approaches for treatments of large molecules and solvation e§ects. In this section the significant developments in theoretical treatments for large molecular systems solvation modeling and free-energy simulation techniques will be presented. Theoretical treatment for large molecular systems The bottleneck for HF and DFT calculations is often considered to be the computation of two-electron repulsion integrals. In large systems a large number of the electron repulsion integrals are insignificant and their computation can be avoided with sophisticated screening methods. Using fast multipole methods and tree codes near- Royal Society of Chemistry–Annual Reports–Book B 3 linear scaling for the construction of the Coulomb matrix has been achieved.1–3 White and Head-Gordon have introduced a new method for DFT and HF calculations with Cartesian Gaussian basis functions by summing the density matrix into the underlying Gaussian integral formulas without explicit formation of the full set of two electron integral intermediates.Testing indicates a speedup of greater than four times for the (ppDpp) class of integrals and over 10 times for (ffDff) integrals.4 Because exchange interactions in insulators are local computation of the exchange matrix can be made to scale linearly with the system size. Indeed linear-scaling has been achieved in local density functional calculations by using real-space cuto§s. Schwegler and Challacombe have introduced a threshold criterion obtained from an asymptotic form of the density matrix which explicitly assumes an exponential decay at large distances.5 Restricted HF/3-21G calculations on a series of water clusters and polyglycine a-helices demonstrated the O(N) scaling of the algorithm.Using the fast multipole method for the Coulomb matrix with only slight modification of this procedure Burant et al. obtained the near-field exchange matrix. Since the exchange interaction for insulators is localized only small errors are introduced by its neglect in theFMMfar field. The near-field exchange method was demonstrated for HF calculations in time-scaling near-linearly with system size. Benchmark calculations on polyglycine chains water clusters and diamond pieces show microhartree accuracy and speed up to 10 times over traditional calculations for systems of greater than 300 atoms.6 In other areas Hernandez et al.proposed a linear-scaling scheme for densityfunctional pseudopotential calculations based on a formulation of density-functional theory in which the ground state energy is determined by minimization with respect to the density matrix subject to the constraints of idempotency (p2\p) and the correct number of electrons in the system. Linear scaling is achieved by assuming that the density matrix should vanish at a distance greater than a chosen cuto§.7 The algorithm is based on a method developed by Li Nunes and Vanderbilt and energy minimization is performed using the conjugated-gradient method.8 The method avoids matrix diagonalization which scales as O(N3) and has a memory requirement of O(N2).The method has also been used in extended Hu� ckel calculations.9 The idea of working with the density matrix has also been applied in other forms to DFT and semiempirical molecular orbital calculations.10–14 The treatment of large molecular systems has also been described by implementation of scalable HF calculations using a massively parallel computer.15 On a di§erent note Peng et al. described a redundant internal coordinate system constructed from all bonds valence angles and dihedral angles for optimizing molecular geometries. Redundant internal coordinates provide substantial improvements in optimization e¶ciency over Cartesian and non-redundant internal coordinates especially for flexible and polycyclic molecules. Transition structure searches are also improved.16 Baker and Chan compared various approaches towards optimization of geometry using Cartesian Z-matrix and natural internal coordinates.It is claimed that the Z-matrix representation is superior for optimization of transition structure.17 Solvation The importance of solvent e§ects in organic chemistry is emphasized by the facts that the vast majority of organic reactions are carried out in solution and that processes related to life itself occur in an aqueous environment. To characterize the reactivity of 4 Jiali Gao organic molecules and to predict the rates for organic reactions it is essential to include solvent e§ects in the theoretical treatments. However the inclusion of explicit solvent molecules means a significant increase in the size of the system and requires a statistical mechanical description of the physical properties.Methods for the treatment of solvent e§ects may be divided into two categories a continuum depiction of the solvent system characterized by its relative permittivity and a classical yet explicit representation of the solvent molecules through the use of empirical potential functions. Continuum models have been used both in quantum mechanical calculations and in classical simulations of biological macromolecules and continue to enjoy popularity thanks to their computational e¶ciency. However as the computational power increases the advantages o§ered by continuum models will continue to diminish. Explicit solvent simulations may now be routinely carried out for large scale systems including solutions and biological molecules.Even with pentium-processor based personal computers fluid simulations are now possible.18 Furthermore the accuracy and quality of empirical potential functions used in molecular dynamics and Monte Carlo calculations have tremendously increased in the past decade and these treatments may be further enhanced by the combined use of quantum mechanical methods and empirical force field as well as full ab initio potentials.19,20 Continuum models There have been several recent reviews on the theory and prospective applications of continuum models.21 Because of their computational simplicity and the possibility of parametrizing specific models there has been significant refinement and improvement of continuum models in 1996. In the past developments of continuum solvation models have been focused on aqueous solution due to its central importance in chemistry.This trend has persisted in the past year. The extremely successful semiempirical solvation model deloped by Chambers et al. which is based on the generalized Born model has been extended with the use of Class IV atomic charges.22 Chambers et al. described a new parametrization in this series of solvation models featuring a new set of geometry-based functional form for e§ective Coulomb radii and atomic surface tension terms. In addition atomic charges are obtained by both the AM1-CM1A and PM3-CM1P Class IV charge model which is a multilinear parametric method derived from Mulliken population analysis and bond orders. Of the 215 neutral solutes containing H C N O F S Cl Br and I and a wide variety of organic functionalities the mean unsigned error in the free energy of hydration is only 0.50 kcal mol~1 using CM1A charges and 0.55 kcal mol~1 using CM1P charges.The predicted solvation energies for 12 cations and 22 anions have deviations of 4.4 and 4.3 kcal mol~1 for models based on AM1 and PM3. The implementation of the polarizable continuum model (PCM) in Gaussian 94 has been further improved by including higher-order electrostatic interactions and a more realistic shape of the solute cavity defined by an isosurface of the total electron density.23 Although physically appealing it is not clear if such a cavity definition can yield such accurate results as parametrized atomic radii. The importance of these factors is assessed by comparing theoretical results to the experimentally known conformational equilibrium between syn and anti forms for furfuraldehyde and the C–C rotational barrier of 2-nitrovinylamine.Foresman et al. found that the correlation to experiment is improved when an infinite-order PCM method is used.23 An alternative implementation builds upon an early SCRF model which combines the 5 Theoretical organic chemistry PS-GVB (pseudo-spectra generalized valence bond) electronic structure calculations and electrostatic potential (ESP) fitted charges with the DelPhi Poisson-Boltzmann equation solver.24 The performance and failures of this continuum model in several well-known cases including the solvation of the methylated amines have been examined. 24 A new approach is proposed in which short-range empirical corrections based upon solvent accessibility are made for specific functional groups.This leads to a reduction in the mean error of the calculated solvation free energies for 29 test compounds by a factor of 2 to 0.37 kcal mol~1. The implementation and parametrization of calculations based on the boundary element method have been described by Horvath,25 Tawa26 and their co-workers. In the later calculations the average error in the computed free energies of solvation for 14 simple molecules is about 2.5 kcal mol~1 at the HF and DFT levels using the 6-31G* basis set. The e§ect of aqueous solvation on equilibrium geometry was also studied using a parametrized continuum model.27 Several studies have been reported on the derivation of analytical derivative methods within continuum models in electronic structure calculations.These developments have led to the calculation of static polarizability and hyperpolarizabilities for formaldehyde N-methylacetamide and methyl formate in aqueous solution,28 and provided convenient tools for the analysis of solvent e§ects on reaction paths.29 Using analytical second derivatives of the generalized conductor-like screening model (GCOSMO) Stefanovich and Truong calculated vibrational frequency shifts for several molecules including acetone methylamine formic acid acetic acid and N-methylacetamide in water.30 For acetone and methylamine the continuum model performs very well in reproducing the experimental spectral shifts. However for strong hydrogen bonding molecules like formic acid and acetic acid it is found that at least one explicit water molecule should be included in the GCOSMO calculations.For organic solvents it might be expected that continuum solvation models developed for water may be directly applied by simply changing the relative permittivity from 78 for water to that for the corresponding organic solvent. However there is no guarantee that the solute cavity size will be identical in di§erent solvents. This is further complicated by the dispersion and cavitation energies. Thus it is necessary to reoptimize the empirical parameters involved in continuum model calculations. The issue of non-aqueous solvation modeling has been addressed by several groups. Luque et al. extended the PCM method to CCl 4 solution in both ab initio HF/6-31G* and semiempirical self-consistent reaction field (SCRF) calculations.31 Parametrization of the solute–solvent interface and of the hardness atomic parameters was performed against experimental data and Monte Carlo simulation results.Errors in calculated free energies of solvation for a series of neutral organic solutes using the optimized atomic radius were less than 1 kcal mol~1. Schaefer and Karplus have introduced an analytical continuum electrostatic (ACE) model for the treatment of electrostatic solvation energies of small molecules as well as proteins.32 The method features a Gaussian charge distribution for electrostatic interactions and a novel treatment of the self-energy of the molecule in solution. Combined with the generalized Born equation for charge–charge interactions it was possible to determine analytically electrostatic contributions to the solvation energy thereby allowing the method to be applicable in molecular dynamics and molecular mechanics calculations.The error in the computed solvation free energy using the 6 Jiali Gao ACE method is 15% for small molecules (10–20 atoms) and 5.4% for the protein BPTI using the results from finite-di§erence calculations as the reference. Luo and Tucker have described a compressible solvation model based on a numerical grid algorithm for solving Poisson’s equation. The method is applicable to arbitrary charge distribution in cavities of arbitrary shape.33 Thus the local permittivity is treated as a function of the field-dependent local density [eqn. (1)] e4(R,T)\e4(o[E(R)],T) (1) where T is temperature o is density of the solvent and E(R) is the electric field at position R. e4(o[E(R)],T) and p[E(R)] are properties of the pure solvent.The electric field is determined through self-consistent solution of Poisson’s equation. Application of this method to the hydrolysis of anisole in supercritical water shows that the e§ect of solvent compression lowers the free energy barrier of reaction by as much as 14 kcal mol~1. It was found that inclusion of compression e§ects improves the agreement between the calculated and experimental dependence of the activation barrier on pressure. In closing this section Lim and Jorgensen used five sets of geometries and atomic charges derived from ab initio SCRF calculations with relative permittivities of 1.0 2.23 and 35.94 at HF/6-31G* MP2 and B3LYP levels for Monte Carlo simulations of the [2]2] cycloaddition of 1,1-dicyanoethylene (DCNE) and methyl vinyl ether (MVE).34 Thus partial atomic charges used in empirical potential functions may reflect the average charge polarization in various solvents.The best results are obtained using the charges and geometries from B3LYP/6-31G* gas-phase calculations. Explicit description of the solvent Significant progress has been made in the development of methods for explicit solvent representations in computer simulations in the past year. A large amount of e§ort has been devoted to the development of hybrid quantum mechanical and molecular mechanical (QM/MM) potentials which will be the emphasis in this section. For earlier applications the reader is referred to a recent article on the study of solvent e§ects in organic chemistry using hybrid QM/MM potentials.35 Bakowies and Thiel have presented a hierarchy of three models for hybridQM/MM calculations.36 In the simplest model A a large molecular system is reduced into a smaller QM fragment which is saturated by hydrogen link atoms in a way similar to that described by Field et al.37 The QM fragment is mechanically embedded in the remainder of the empirically treated fragment and the interactions between QM and MM fragments are purely determined by molecular mechanical force field calculations.In general the MM fragment may be regarded as solvent molecules. The more refined models B and C include a quantum mechanical treatment of electrostatic interactions between the two fragments and a semiempirical description of MM polarization. A key feature in Bakowies and Thiels treatment of electrostatic interactions is that semiempirical electrostatic potentials and MM charges derived on the basis of electronegativity equalization are used.38 Incorporation of the MNDO method and the MM3 force field allowed a number of test applications including computations of heats of formation of hydrocarbons proton a¶nities and deprotonation energies of alcohols.Transition structure determinations for a hydride transfer reaction and ring cleavage of oxiranes by nucleophiles were also described. 7 Theoretical organic chemistry In the spirit of Thiel’s model A Matsubara et al. applied an integrated molecular orbital plus molecular mechanics (IMOMM) method to investigate the organometallic reaction of Pt(PR 3 ) 2 with H 2 (R\H Me But and Ph).39 Using the Gaussian 92/DFT and MM3 programs this computation proceeds by performing of full MM geometry optimization with fixed MO atom positions.Then an ab initio gradient calculation is carried out for the QM molecule plus link atoms. A comparison of the full MO(RHF) optimized and the IMOMM(RHF/MM3) optimized structures of the reactant transition state and products for a simple hydrogenation reaction H 2 ]Pt(PR 3 ) 2 ](H) 2 Pt(PR 3 ) 2 for R\H Me But and Ph shows that the IMOMM optimization can reproduce the MO optimized structures. However the IMOMM calculations fail to reproduce some (up to 5 kcal mol~1) of the electronic e§ect of a methyl for hydrogen substitution for this model system. The energetics obtained at the IMOMM(MP2/MM3) level for the present reaction is consistent with the experimental findings. Morokuma and co-workers have also described an integrated molecular orbital plus molecular orbital (IMOMO) method for integration of two di§erent levels ofMO approximation instead of combiningMOandMMtreatments.40,41 In this approach only the active or more complex part of a molecule is treated at a higher level of theory and the rest of the molecule is modeled at a lower level of approximation.The high-level portion of the molecule is embedded in the lower-level fragment. The integrated total energy and derivatives are defined from three di§erent calculations the two independent fragments at high and low levels and the whole molecule at low levels. Thus the interaction between the two fragments is obtained from the calculation employing a low level of approximation. The structure of the transition state as well as the equilibrium structure can be optimized using the integrated energy.Model calculations for the conformation energy of ethane and n-butane the barrier for S N 2 reactions of alkyl chlorides and Cl~ and for the expoxidation of benzene indicated that these methods have a tremendous potential. The methods described above use a link atom approach to satisfy the free valencies resulting from the division of a large molecular system intoQMandMM(or separate QM) fragments. The question of continuity between the two subsystems is addressed by Rivail and co-workers through the use of a strictly localized bond orbital which is assumed to have transferable properties since the parameters for the localized bond orbitals are determined on model compounds (Scheme 1).42,43 The hybrid bond orbital pointing toward the classical atom is excluded in the QM/SCF calculation with fixed charge density (bond order).The method is physically appealing and has been used in full energy minimization for the proton exchange process between the histidine and aspartic acid system of the catalytic triad of human neutrophil elastase. In contrast to classical force fields the results obtained from this approach are found to be in good agreement with the crystallographic data. Tunon et al. have presented a coupled density functional–molecular mechanics Monte Carlo simulation method which was demonstrated for the solvation of a water molecule in liquid water.44 Using a double-zeta basis set plus polarization orbitals and non-local exchange-correlation corrections the computed atom–atom radial distribution functions are found to be in accord with the experimental data and the instantaneous and average polarization of the QM molecule has been analyzed.Frozen density functional theory (FDFT) has been used by Wesolowski et al. in a 8 Jiali Gao frozen orbital QM MM Scheme 1 Schematic representation of the localized bond orbital method study of the proton transfer reaction in water F~]HF]FH]F~.45 The method treats the solute–solvent system as a supermolecule but constrains the electron density of the solvent molecules. Thus the solvent molecules are treated quantum mechanically; however the electron densities of these molecules are kept fixed. The performance of this model is verified by comparing full and frozen DFT calculations of solute–solvent clusters.In fluid simulations an empirical valence bond (EVB) mapping potential is used to carry out molecular dynamics simulations. Next the free energy di§erence between the FDFT and the EVB potential surfaces is determined via an umbrella sampling technique. It was suggested that the FDFT method provides a convenient approach for ‘solving’ the hybrid QM/MM link atom problem although the details are not given. In order to address the interaction between QM and MM atoms in a hybrid QM/MM approach Freindorf and Gao optimized the empirical Lennard-Jones parameters for use in hybrid ab initio HF/3-21G and MM simulations.46 These parameters are associated with hybrid QM/MM potentials which should be optimized for a new combination of QM and MM methods. With a single set of parameters typically two per atom the computed hydrogen bonding geometries and energies from the hybrid HF/3-21G and OPLS potential are in excellent accord with ab initio HF/6-31G data with an rms deviation of less than 0.5 kcal mol~1 in energy and 0.1Å in hydrogen bond distance for over 80 bimolecular complexes.The e§ect of electrostatic interactions in integrated electronic structure calculations may be treated via an e§ective fragment method as demonstrated by Day et al.47 This method makes use of the perturbing Hamiltonians referred to as e§ective fragment potentials. The solvent which may consist of discrete water molecules protein or other materials is treated explicitly using a model potential that incorporates electrostatics polarization and exchange repulsion e§ects. In addition to energy calculations analytical gradients and numerical second derivatives can be determined.The method was shown to yield good accord with full ab initio calculations for the water dimer and water–formamide complex. Moriarty and Karlstrom have proposed a method to describe the exchange repulsion arising from the overlap between the wave functions ofQMandMMmolecules.48 To account for this e§ect an extra term is added to the Hamiltonian [eqn. (2)] Hij \Hij(1]sij) (2) where sij is a correction term which depends on the overlap between the wave functions of the QM system and the MM molecules. The method was tested by a computer simulation of a QM water in a classical liquid water. Wang Boyd and Laaksonen proposed another scheme to measure the interaction betweenQMandMMregions by using vibrational frequency shifts from the gas phase into solution.49 The 12 vibra- 9 Theoretical organic chemistry tional modes for methanol in its pure liquid form are derived from correlation data in molecular dynamics simulations at the ab initio HF/3-21G** level.It was found that weak coupling between the QM and MM regions yields the best agreement with experimental spectral shifts. The e§ects of solvent on the geometrical parameters of methanol were also investigated in this study. A treatment of the mutual charge polarization between theQMandMMparts of a system has been developed by Thompson by incorporating point dipole polarizabilitities into hybrid QM/MM calculations.50 A consistent treatment of the interaction between theMMpolarizable dipoles and the fullQMwave function was presented in a fashion that allows for energy conservation in molecular dynamics simulations.The implementation details are given for the NDDO semiempirical QM Hamiltonians. The method was applied to the estimation of the spectroscopic blue shift for the n–p* electronic excited states of a series of carbonyl solutes. Computed spectral shifts are in good accord with experiment and previous theoretical studies. In a somewhat di§erent approach solvent e§ects on molecular spectra have been investigated for the n–p* excited states of pyridazine in water by Zeng et al.51 This approach involves two independent calculations. First fluid simulations were performed using empirical potentials with ESP-fitted charges for the ground and excited states to generate an ensemble of configurations representing the equilibrium structure of the solvent around the chromophore.Then the liquid structure is taken and the change in the vertical excitation energy is calculated by considering solute–solvent electronic interactions. In the solvent-shift calculations the solute is treated as being polarizable with the ground and excited state molecular polarizabilities derived from finite field CNDO/S-CI calculations. Zeng et al. have examined a number of di§erent ways of deriving the ESP-fitted charges for use in spectral calculations. The best estimate of the spectral shift of the first singlet excited state is 4100cm~1 in good agreement with the observed value of 3800 cm~1. This work follows earlier calculations of Zeng et al. of the solvent spectral shifts of other diazine compounds including pyridazine pyrimidine and pyrazine.52 A hybrid QM/MM approach has been used to calculate the di§erence in the pK! values of the ground and excited state of phenol in water.This method couples gas-phase excitation energies determined using the CASPT2 method and free energy perturbation calculations to obtain the di§erence in the free energy of solvation of the ground and excited state. The calculation of the solvation energy of the excited state used a semiempirical configuration interaction method to represent phenol in Monte Carlo simulations.53 The computed acidity for phenol in its first singlet excited state (pK! \1.4) is significantly stronger than for the ground state (pK! \10). The computational results were analyzed in terms of equilibrium solvation and vertical excitation energy and comparisons with experimental data were made.A method that lies between continuum models and explicit solvent representation is the integral equation method and in particular the reference interaction site model (RISM) for the treatment of liquid states. Continuing their development of the combined RISM and HF-SCF method Hirata and co-workers applied the technique to a classical problem in physical organic chemistry the reversal of the acidity of haloacetic acid upon transfer from the gas phase into aqueous solution.54 The computed results are in good accord with experiment. This study demonstrates that the combined RISM-SCF methods are a viable approach to the study of solvation e§ects which 10 Jiali Gao complements the traditional continuum solvation model and explicit simulation methods.In addition Sato et al. formulated an analytical energy gradient method for hybrid RISM-MCSCF calculations and this method has been applied to the study of the cis and trans conformational equilibrium for 1,2-difluoroethylene in aqueous solution.55 On the ‘classical side’ several groups have used polarizable intermolecular potential functions (PIPF) for free energy calculations and liquid simulations. Gao et al. reported a PIPF potential for simulations of pure liquid amides.56 The parameters for the empirical potential functions are consistently optimized by iterative Monte Carlo simulations to reproduce experimental thermodynamic and structural data. The final parameter set yields heats of vaporization and liquid density within 3% of experimental data.A second feature of this study is that polarization energies obtained from hybrid QM/MM simulations have been used to guide parameter development. Meng et al. applied a polarizable potential to represent both the solute and solvent in free energy perturbation calculations in an e§ort to model a peculiar trend of amine hydration.57 Contrary to the intuitive expectation of an increase in hydrophobicity successive methylation of ammonia (NH 3 ) does not yield a monotonic change in the observed solvation free energies. In fact methylamine is found to be more soluble than NH 3 in aqueous solution. Previous free energy calculations using pairwise potentials have not been able to reproduce experimental trends. Although the computed increase in solvation free energy from ammonia to methylamine (**Gs \0.38 kcal mol~1; exp [0.3 kcal mol~1) is smaller than the value predicted with a pairwise-additive model,58 methylamine is still more hydrophobic than ammonia.The computed solvation free energies are found to be in agreement with another study by Ding et al. using a di§erent implementation of polarizable potential functions.59 The e§ects of polarizability on the hydration of the chloride ion in Cl(H 2 O)~n clusters for np255 have been studied by Stuart and Berne using a fluctuating charge polarization model.60,61 The issue of particular interest is the surface vs. interior solvation of the chloride ion. It was found in this calculation that even for the largest clusters simulations with polarizable water models show a preference for solvation of the chloride ion near the surface of the cluster.This behavior is however not observed with a non-polarizable model with which interior solvation occurs for clusters of nq18. The reason for this di§erence was attributed to the polarizability of water for facilitating a larger average dipole moment on the water model rather than the many-body e§ects. New developments in empirical force fields will be briefly described in closing this section. In a series of articles Halgren describes the Merck molecular force field (MMFF94) including the method used in the parametrization.62MMFF94 is aimed at achieving an accuracy similar to that of theMM3 force field for organic molecules and proteins. It is also consistently derived for simulation of condensed phase processes. The database that is used to parametrize the MMFF94 force field was primarily derived from high-quality computational results along with some extension to include experimental results including crystal structures extracted from the Cambridge Structural Database.Overall MMFF94 reproduces experimental data with root mean square deviations of 0.014Å for bond lengths 1.2° for bond angles 61 cm~1 for vibrational frequencies 0.38 kcal mol~1 for conformational energies and 0.39 kcal mol~1 for rotational barriers. The results for hydrogen bonded systems 11 Theoretical organic chemistry closely resemble those predicted by the OPLS (optimized potential for liquid simulations) potential. Allinger and co-workers have introduced an improved force field MM4 for hydrocarbons including conjugated systems and hyperconjugative e§ects.63 The new force field is designed to improve the calculation of vibrational frequencies rotational barriers and to correct small errors in the previousMM3force field.Geometries are fit to within 0.004Å for bond lengths 1° for bond angles 4° for torsional angles and 0.5% for moments of inertia. Although the MM4 force field retains most of the formalism present in MM3 several cross-terms have been added in MM4 mainly to improve vibrational frequencies which have an rms di§erence of 25–31cm~1 from the experimental values in MM4. Empirical force fields for delocalized carbocations have been improved by Reindl et al. by introduction of additional terms into AllingersMMP2program and a quantum chemical term is implemented into force field calculations for the first time.64 The calculated heats of formation are in excellent agreement with a wide range of experimental data with the largest deviation of 3.5 kcal mol~1.Calculated structures and conformations are found to be in good accord with those obtained from ab initio MP2(full)/6-31G* calculations. Free energy simulations Because of its importance there has been a continued e§ort to refine existing methods and to formulate new procedures for accurate and e¶cient evaluation of free energies in computer simulations. Chipot et al. investigated the convergence behavior of the potential of mean force (pmf) calculations using three di§erent free energy computation techniques namely the free energy perturbation method (FEP) thermodynamic integration (TI) and the slow growth (SG) technique.65 For the three model systems tested with as much as 1 ns of molecular dynamics sampling it was found that FEP and TI yield results with comparable accuracy while SG is less robust.Kumar et al. have presented an iterative approach for estimating multidimensional free energy maps.66 The method is based on a weighted histogram analysis and is demonstrated by generating the Ramachandran free energy plots for several polypeptides. A method for conformational free energy calculations in one and multidimensions was also proposed by Krzysztof.67 Kong and Brooks presented a novel and e¶cient method for performing free energy calculations.68 In this approach the conventional ‘j’ variable associated with the ‘progress’ in chemical coordinates in FEP simulations is treated dynamically and the free energy calculations are transformed into potential of mean force calculations in the j-space.This extended Hamiltonian formalism utilizes the umbrella sampling technique and the weighted histogram analysis method. The method was illustrated by computing free energies of hydration and by using a model for competitive binding. One of the most important problems in computer simulations is the use of spherical cuto§ schemes to evaluate atomic pair interaction energies. The e§ect of truncating long-range electrostatic interactions in free energy calculations is particularly signifi- cant and has been analyzed by several groups. The Born equation of solvation has often been used to correct such errors introduced by eliminating long range electrostatic interactions for ionic solutes. However it cannot be used for molecular structures other than a spherical ion and often is complicated by boundary e§ects.Kalko et 12 Jiali Gao al. performed molecular dynamics simulations using both the spherical truncation scheme and the Ewald lattice-sum method to estimate the free energy changes for the charging process of Na` Ca`` and Cl~ in water.69 Smith and Pettitt examined the problem of the anisotropic nature of the Ewald method.70 A transition between hindered and free rotation for two simple charge distributions was observed in aqueous solution; however the energy change is well below k B T (0.3 kcal mol~1). Consequently it is argued that Ewald artifacts of enforced periodicity are small and may be safely ignored. The use of the Ewald method does give better agreement with experimental results.In an alternative approach Resat and McCammon showed that numerical methods for solving the Poisson equation provide a general approach to correct the long-range electrostatic e§ects in molecular dynamics simulations.71 Aqvist has utilized a recently developed free energy simulation procedure to estimate binding free energies of two charged benzamidine inhibitors with trypsin.72 The paper showed a way of dealing with di¶culties in calculation of the absolute binding free energies due to spherical truncation of electrostatic interactions. The e§ect of neglecting truncation of dipole–dipole interactions between the solvent molecules surrounding the charged ligand on the calculated energy has been examined in particular detail and found to be significant.This study illustrates the typical problems associated with annihilation/creation of ions inside a protein. 3 Applications Catalysts and transition structures Theoretical characterization of the geometry and energetics of transition structures for organic reactions plays a central role in computational organic chemistry. The availability of accurate functional in DFT calculations has further widened the scope of these applications particularly to reactions involving transition metals. This is illustrated by the DFT study of Morokuma and co-workers of the remarkable osmiumcatalyzed dihydroxylation of olefins.73 Although extensive experimental studies as well as theoretical investigations have been carried out the central question of the problem remains the distinction between two alternative reaction mechanisms (i) a concerted [3]2] cycloaddition path and (ii) an initial [2]2] mechanism followed by isomerization to the [3]2] intermediate.Morokuma and co-workers obtained the transition structures and intermediates for the [2]2] and [3]2] cycloaddition pathways in the osmium-catalyzed dihydroxylation of olefins at the B3LYP/LANL2DZ level. The activation energy for the [2]2] process is 43.3 and 50.4 kcal mol~1 respectively for reactions in the presence and absence of ammonia as the ligand base. The [3]2] process proceeds through an early transition structure with an energy only 1.9 and 1.4 kcal mol~1 higher than the respective free and ammonia-liganded reactants. Addition of a second molecule of ammonia eliminates the barrier to the [3]2] addition. Remarkably the free and ammonia-liganded osmaoxetane intermediates of the [2]2] process are of significantly higher energy than the transition structure of the [3]2] process.It was therefore concluded that the osmium-catalyzed dihydroxylation of olefins cannot proceed through a [2]2] intermediate. Yamabe et al.74 examined the epoxidation of olefins by peracids [eqn. (3)] 13 Theoretical organic chemistry H2C ZnI I + CH2 ZnI I ZnI2 + Scheme 2 HCO 3 H]CH 2 ––CH 2 ]HCO 2 H]ethylene oxide (3) at the MP4/6-311G**//MP2/6-311G** level. The reaction is found to proceed via a two step mechanism with the initial formation of one C–O bond and the O–H bond retained. This transition structure leads to an unprecedented transient intermediate featuring aHCOO· · ·H 2 C–(OH)–CH 2 complex which is converted to another hydrogen bonded intermediate between ethylene oxide and formic acid with a hydrogen bond distance of only 1.62Å.The activation energy from the peracid–ethene complex is about 17 kcal mol~1. Electron-donating substituents were found to cause a large reduction in the activation energy for the reaction. In a separate study the reaction of (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene 1 with vinyl ketone in the presence of a chiral TiCl 2 (binaphtholate) catalyst to form enantiomerically enriched cis-cyclopropanes as products was investigated through geometry optimization in RHF/LAN1MB calculations.75 The approach of 1 from the si face of the C1 position of a vinyl ketone results in strong steric repulsion between the naphthalene ring and the trimethylsilyl group. In contrast approach from the re face is free of steric congestion and leads to the formation of the experimentally observed (1S,2R) isomer.Wu et al. have modeled the unimolecular and bimolecular elimination of methane from TiMe 4 using ab initio MO methods and the 3-21G and HW3 basis sets and predicted a high activation energy for unimolecular elimination of methane and a lower activation energy for the bimolecular elimination reaction.76 For Ti(CH 2 –CMe 3 ) 4 a preference for a-hydrogen abstraction over c-hydrogen abstraction was predicted. Frankcombe et al. have examined four possible reaction channels for the carbonylation reaction of palladium(II) complexes of mixed bidentate anionic ligands using DFT and MP2/6-31G*/Hay&Wadt methods.77 A novel pathway for isomerization via a five-coordinate transition structure from the square-pyramidal intermediate with a modest barrier of 4.2 kcal mol~1 has been identified.The Simmons–Smith cyclopropanation reaction has been studied using DFT calculations including relativistic e§ects either through e§ective core potentials or an explicit quasi-relativistic approach.78 Assuming that the reactive alkyl zinc–iodine species is monomeric a concerted mechanism was found to be the most favorable pathway for the reaction of ethene with CH 2 ZnI 2 (Scheme 2). The reaction involves an initial electrophilic attack with an activation energy of 11.5 to 14.6 kcal mol~1 while the overall reaction is exothermic by 33.5–37.8 kcal mol~1 using the BP and BLYP functions respectively. The transition structure has geometrical features similar to the intermediate structure for the barrierless addition of singlet carbene to ethene.The reaction of singlet methylene with water was studied by Gonzalez et al.79 Methylene reacts in a barrierless fashion to produce the ylide-like intermediate methyleneoxonium H 2 C~–`OH 2 which in turn undergoes a 1,2-hydrogen shift to produce CH 3 OH. Results at the QCISD(T)/6-311]]G** level indicate that the gas phase ylide and the transition state are located 6.4 and 4.9 kcal mol~1 below the reactants with an intrinsic barrier for the 1,2-hydrogen shift of 1.4 kcal mol~1. In the presence of 14 Jiali Gao the solvent the ylide is 5.5 kcal mol~1 more stable than reactants while the barrier for the hydrogen shift is increased to 7.5 kcal mol~1. Moss et al. have examined the stability and reactivity of oxa-substituted carbenes.80 The profound influence of these substituents is illustrated by the observation that the ground state of methylene is a triplet whereas that of dimethoxycarbene is a singlet calculated to lie 76 kcal mol~1 below the triplet.81 Moreover dimethoxycarbene is strongly nucleophilic while the electrophilic reactivity of methylene and the halocarbenes is suppressed.82 Kawashima et al.have found evidence both from experiment and HF/4-31G* computations indicating that 1,2-oxathietanes can be intermediates of the reaction of sulfur ylides with carbonyl compounds and decompose to form the oxirane with retention of configuration.83 It was suggested that this process may be treated as a salt-free Corey–Chaykovsky reaction. Ab initio calculations revealed that the formation of the oxirane proceeds by a concerted mechanism through a polarized transition state and an activation energy of 53.8 kcal mol~1.Yliniemela et al. performed ab initio MP2/6-31G*//HF/3-21G* calculations to locate the transition structure for the Darzens reaction of benzaldehyde and an a-haloester.84 The reaction proceeds via a two-step mechanism with initial aldol-type addition followed by cyclization to form the a,b-epoxy ester. The rate limiting step of this reaction appears to be keto–enol tautomerization since the enol intermediate reacts with benzaldehyde with a barrier of only 10–15 kcal mol~1. It has been proposed that the stereochemistry is determined by the steric requirements for the aldol addition step. In an interesting study Yamamoto et al. found that 5-endo cyclization is remarkably e§ective for the cyclisation of the 5-oxapenta-2,4-dienoyl radical even though this pathway is disfavored by Baldwin’s rules.85 Ab initio UHF/6-31G* calculations suggest that this acyl radical has a flat U-shaped geometry and can be represented as a ketene-substituted a-carbonyl radical.Aromaticity The concept of aromaticity and antiaromaticity occupies a unique position in organic chemistry. There has been considerable recent interest both in the definition of these basic concepts and in the application to the study of chemical problems. This renaissance was led by the work of Schleyer et al. who have identified the unique association of the magnetic susceptibility with cyclic delocalization of electrons. This work introduces the use of absolute magnetic shieldings computed at ring centers (non-weighted mean of the heavy atom coordinates) using quantum mechanical methods as a new aromaticity/antiaromaticity criterion.86 Negative ‘nucleus-independent chemical shifts’ (NICS) denote aromaticity while positive NICSs represent antiaromaticity.The relationship of NICS and aromatic stabilization energies has been calibrated for a set of five-membered ring heterocycles. This new definition was applied to the [10]annulene system for which ring strain precludes D 10) symmetry for the parent compound. The considerable 10p electron aromaticity is overwhelmed by the energy required to deform the CCC angles to 144°. Schleyer et al. proposed a number of theoretical structures which have been characterized as promising candidates for planar 10-membered ring systems.87 The theoretical structure energies and magnetic properties demonstrate considerable aromaticity for these higher analogs of benzene.Sulzbach et al. have explored the boundary between aromatic and olefinic character 15 Theoretical organic chemistry C C C C C2v C C C C C2v D5h D5h again using the [10]annulene system.88 Although it has been shown that the all-cis- [10]annulene adopts the boat-shaped olefinic structure with alternate single and double bonds instead of the aromatic D 10) conformation the structures and energies of compounds which contain one trans double bond have not been determined. Sulzbach et al. using MP2 and Becke3LYP methods found that a nearly planar aromatic structure which has one hydrogen pointing towards the center of the ring and a plane of symmetry which bisects the molecule (heart-shaped structure) lies at a potential energy minimum and has a lower energy than the C 2 twist conformation.These new results indicate that only high-order correlated methods will be able to correctly predict the [10]annulene potential surface and Sulzbach et al. have suggested that results obtained for similar systems using MP2 or DFT/B3LYP methods should be treated with extreme caution until verified at higher levels of theory. Using the MP4/6-31]G*//MP2/6-31]G* method Goller et al. have studied the influence of the electronegativity of ligands Y (F Cl Br I OH NH 2 CH 3 and H) on the strength of the r*-aromatic e§ect in gem-disubstituted 1H-phosphirenium cations and substituted 3-silacyclopropenes. It was found that r*-aromaticity influences the geometry of the systems.89 While there is no unique definition of absolute stabilization comparison with the ring strain energies of the corresponding carbocycles suggests that the 1H-phosphirenium cations enjoy 14–20 kcal mol~1 r*-aromatic stabilization and that silacyclopropenes are stabilized by 19–27 kcal mol~1.Glukhovstsev et al. assessed the aromatic stabilization energy of the cyclopropenyl cation to be 59.2 kcal mol~1 by computing the homodesmotic stabilization energy using G2 theory. 90 For the cyclopropenyl radical a small stabilization energy of 8.9 kcal mol~1 was obtained suggesting that this radical should not be classified as aromatic. The corresponding anion has a non-planar C4 singlet structure with a negative energy ([4.1 kcal mol~1) for the homodesmotic reaction (4).(CH) 3 ~](CH 2 ) 3 ]cyclopropene]cyclopropyl anion (4) Salts of a-sulfonyl carbanions are important intermediates in organic synthesis and have been the subject of extensive experimental and theoretical studies. Remarkably fluorination of the S-alkyl substituent has a significant e§ect on the structure and stability of a-sulfonyl carbanions. For example the pK! value of dimethyl sulfone is 31.1 whereas that of trifluoromethyl methyl sulfone is 18.8. Raabe et al. performed ab initio MP2/6-31]G*//HF/6-31]G* calculations to examine the structure of a-sulfonyl carbanions and the barrier to rotation about the Ca–S bond.91 It was found that structural changes and the conformation dependence of the rotational barrier can be explained by an interaction between the anionic lone pair orbital and the r and r* orbitals of the C–S bond through a negative hyperconjugation.Electron-withdrawing groups increase the coe¶cients at sulfur in the r* orbital and reduce its energy. There 16 Jiali Gao is also a significantly higher calculated rotational barrier for the fluorinated compound compared to dimethyl sulfone. Rauk has reported the surprising discovery that the 1-methyl-1-cyclohexyl cation has two distinct isomers and this has now been observed by B3LYP/6-31G* geometry optimizations.92 Each of the two isomers has a chair structure but with di§ering modes of hyperconjugative stabilization of the carbocation. The lowest energy structure shows C–C hyperconjugation between the empty p orbital and two C2–C3 bonds while hyperconjugation from a C–H bond is the higher energy (0.87 kcal mol~1) conformer.A transition structure which resembles the classical 1-methyl-1-cyclohexyl cation has been located at 0.25 kcal mol~1 higher in energy than the structure stabilized by C–H hyperconjugation. The elusive acepentalene radical anion was generated from a triquinacene derivative precursor in the gas phase by Haag et al.93 Computational studies at the B3LYP/6- 311]G* level with zero-point energy corrections revealed that the C4 singlet acepentalene is 3.9 kcal mol~1 lower in energy than the triplet state which has C 37 symmetry. The singlet state is stabilized by Jahn–Teller distortion and has an inversion barrier of 7.5 kcal mol~1 through a C 27 transition state. The calculated electron a¶nity of the S 0 state is 1.8 eV in accord with the experimental estimate of 1.5 eV.In a study at the BLYP/DZd level Sulzbach et al. confirmed that this is a stable molecule with a singlet ground state.94 However the C–– C double bond is twisted by 45° and the strain energy is ca. 93 kcal mol~1 in agreement with molecular mechanics results. The triplet state has a nearly perfect perpendicular arrangement at the central C––C bond (87°). It is strained by 42 kcal mol~1 and is 12 kcal mol~1 higher in energy than the singlet state. The synthesis of tetra-tert-butylethylene from di-tert-butylcarbene will be di¶cult because the barrier for dimerization (25 kcal mol~1) is much higher than for an intramolecular insertion reaction of the carbene (5 kcal mol~1). The heat of formation for 2,4,6-trinitro-1,3,5-triazine (TNTA) was predicted to be 46 kcal mol~1 using MBPT(2)//6-31G*//MBPT(2)/6-31G*]ZPE calculations.95 In a search for powerful high-energy density materials the following favorable performance properties of TNTA were reported an energy release of 304 kcal mol~1 on decomposition into N 2 and CO 2 a specific decomposition energy of 1410 cal g~1 and specific impulses of 269 s in the atmosphere and 294 s in vacuo.Conformational and tautomeric equilibria Cieplak et al. investigated the chair–twist boat equilibrium of substituted 1,3-dioxanes (Scheme 3) by use of 13CNMRspectroscopy ab initio molecular orbital and molecular mechanics methods.96 Both MP2/6-31G* and the AMBER force field yield results which are consistent with theNMRdata whereasMM3calculations fail. The calculations confirm the prediction of the critical role of electrostatic interactions in determining the barrier to chair–twist boat conversion.Gung et al. obtained relative energies for various conformers in 1,5-diene-3,4-diols at the MP2/6-31G* level which have been found to give nearly perfect diastereofacial selectivity in a number of reactions.97 The most stable conformer is found to have a gauche arrangement for the two vinyl groups and an anti orientation for the dioxyl group. The keto–enol equilibria of carboxylic acids as well as acidities of the carbon and oxygen acids have been investigated by several groups. Gordon et al. have examined the abstraction of hydrogen from both carbon and oxygen by hydride fluoride and 17 Theoretical organic chemistry O O R O O R O O R MP2 SCRF AMBER MM3 1.38 1.53 1.44 2.62 (0.0) MP2 SCRF AMBER MM3 2.98 3.18 2.04 0.26 Scheme 3 Computed energy changes (kcal mol~1) for the two equilibria at various levels of theory OH+ O H CH3 O O H CH3 CH3 O– O CH3 O O H CH2 O H O H O C+ H O H CH3 p Ka K = 26.6 p KE 2 = 21.8 p Ka E = 7.3 p KE 1 = 19.3 p Ka + = 13.1 + H+ + H+ p Ka = 4.76 (exp) p Ka = – 6.2 (exp) Scheme 4 hydroxide anions in acetic acid using ab initio MP4/6-31G]]G(dp)//6- 311]]G(dp) methods.98 The activation energy for the isomerization of acetate to enolate ion is 50.4 kcal mol~1 while the G2 values for the gas phase acidities of acetic acid at the OH and CH ends are 339.3 and 365.8 kcal mol~1 respectively.The acidity of the carbon acid in water was also investigated in hybrid Monte Carlo QM/MM simulations along with high level ab initio calculations.99 The predicted pK! and equilibrium constants which are found to be in good accord with experimental and previous theoretical estimates are summarized in Scheme 4.Wu and Lien investigated the intramolecular tautomerization of acetyl derivatives CH 3 COX (X\H BH 2 CH 3 NH 3 OH F Cl CN and NC) using ab initio molecular orbital methods at the HF and MP2/6-31G* levels and single point MP4(SDTQ)/6-311]]G** calculations. 100 The keto–enol free energy di§erences are computed to be in the range of 8.9 (X\NH 2 ) to 30.1 (X\OH)kcal mol~1 and acetaldehyde has a value of 13.6 kcal mol~1. The keto-to-enol transition has an activation barrier of 62–77 kcal mol~1 and has been correlated with the Hammett substituent resonance parameter (pR `). At the MP2 level *G‡\55.79]30.95pR `.Several studies of tautomeric equilibria in heterocyclic aromatic compounds have been reported. Hernandez et al. investigated the tautomerization of neutral hypoxan- 18 Jiali Gao thine and allopurinol in the gas phase and aqueous solution by using molecular orbital and SCRF methods.101 Hypoxanthine in the gas phase has two stable conformers of similar energy (\1 kcal mol~1) while A19 is the most stable tautomer of allopurinol and has an energy at least 4 kcal mol~1 lower than all other forms. Transfer of hypoxanthine to water reduces the di§erence in the energies of the H17 and H19 tautomers and even more favorable tautomers were identified consistent with experimental findings. The content of A19 in water is calculated to lie in the range of 38–88% of allopurinol and the di§erence between the energies of the A18 and A19 tautomers is reduced compared to the gas phase due to a stronger solvation of the former tautomer.Catalan et al. have observed that 1H-indazole is more stable than the 2H isomer by 3.6 kcal mol~1 from MP2/6-31G** calculations.102 Katritzky et al. carried out geometry optimization using a multicavity SCRF-AM1 and HF/6-31G methods for a N N O H N N H N N O H N N N N O H N N N N O H N N H17 H19 A18 A19 H H H series of molecules.103 It was demonstrated that bond lengths vary as the solvent polarity changes. Use of the Pozharski–Bird aromaticity index which is the average of bond fluctuation suggests that aromaticity is dependent on the environment of the molecule. Host–guest modeling Ion extraction by synthetic receptors has been extensively studied.Varnek and Wip§ examined the ion extraction selectivity by the ionophore calix[4]-bis-crown-6 L through molecular dynamics and free energy perturbation (FEP) calculations.104 The host molecule displays remarkable selectivity for extraction of Cs` over Na` from water to chloroform. The computational results correctly predict the larger binding free energy for Cs` with the use of standard 12-6-1 pairwise potentials without special treatment for the interaction with the ionophore. The high Cs` ionophoricity is attributed to di§erential solvation e§ects. Varnek and Wip§ also modeled the free ionophore and L·Cs` complex and L·Cs`-picrate counter ion system at the water/chloroform interface. The results of this simulation indicate that these ionophores are adsorbed at the interface and do not di§use spontaneously into the organic phase.In a combined X-ray di§raction study and molecular dynamics simulation calculation Muzet et al. have reported the structure of L·Sr(picrate) 2 ; L\tert-butyl-calix[4] arene-tetrakis(diethylamide).105 The ligand selectivity by the ionophore for Mg2` Ca2` Sr2`and Ba2` in vacuo in water and in acetonitrile was investigated. Molecular dynamics simulations show that the L·M`2 complexes are the converging type in water and in acetonitrile. This contrasts with L·M` alkali cation systems which display conformational flexibility in solution. Based on FEP calculations Muzet et al. determined a binding sequence of alkaline earth cations of Ca2`[Sr2`[Ba2`[Mg2` in accord with experiment. The relative free energies of 19 Theoretical organic chemistry association of these metal ions are Mg2`–Ca2` 29.9 kcal mol~1; Ca2`–Sr2` [6.7 kcal mol~1; and Sr2`–Ba2`,[13.8 kcal mol~1.Kollman and co-workers have performed molecular dynamics and free energy calculations to study the encapsulation of CH 4 CHCl 3 and CF 4 in a dimeric organic host in CHCl 3 as solvent.106 The host has been demonstrated to include CH 4 CH 2 Cl 2 CHCl 3 and C 2 H 2 with binding energies of[2 to[3 kcal mol~1 for methane and ethane and[1.0 to]1.8 kcal mol~1 for the chloromethanes. Using the AMBER force field Kollman and co-workers were able to reproduce the experimental trends for binding of CHCl 3 and CH 4 .107 However the binding of CF 4 was predicted to be only slightly weaker than the binding of CH 4 which conflicts with the experimental results.107 The possibility of similar 19F chemical shifts for bound and unbound CF 4 or a complex with CF 4 bound to the outside of the host has been o§ered as an explanation for the discrepancy.Kollman and co-workers also examined the interaction of the benzene dimer in solution as a model system for p–p interactions in proteins.108 Denti et al. calculated the Gibbs free energy of binding for a cyclophane –pyrene complex in water and in chloroform using the double annihilation technique.109 The computed di§erence in the free energy of binding in water and chloroform **G\10.2 kcal mol~1 favoring binding in water is slightly larger than the experimental di§erence of **G\7.1 kcal mol~1 at 303 K. The strong solvent dependence of cyclophane–pyrene complexation is due to di§erential free energies of cavitation in water and chloroform which are the result of the stronger intermolecular cohesive interactions of water compared to chloroform.McDonald and Still have applied free energy perturbation calculations to the enantioselectivity in binding of three peptide guest molecules to synthetic receptors with C 3 symmetry.110 The calculations reproduce the observed trends in enantioselectivity with errors of less than 0.7 kcal mol~1. The weakly bound guests have more conformational space in the receptor complex than do the more strongly binding guests and consequently the agreement with experiment is the best with those guests which form stronger complexes. These results indicate that obtaining the necessary converged ensemble averages is more challenging for the more weakly interacting guests because their complexes are structurally less well defined.The simulations indicate that the high enantioselectivity observed with these receptors arises in large part from the ability of the preferred guest peptides to form a greater number of hydrogen bonds with the receptor. Ivanrov et al. studied the inclusion complexes between the most commonly used cyclodextrins (a- b- and c-CD) and 1-bromoadamantane by NMR experiments and molecular dynamics (AMBER) simulations. 111 The computational results are found to be in agreement with experiment and predicted host–guest ratios of 2 1 1 1 and 1 1 for complexes to a- b- and c-CD respectively. The MM optimized structures indicate that the lowest energy complex has the guest molecule located between two a-cyclodextrins and oriented almost perpendicular to the average planes of the macrocycles.Castro et al. have determined the di§erential binding a¶nity and structural recognition between the inclusion complexes of cyclobis(paraquat-p-phenylene) P4` and 1,4-substituted phenyl or 4,4@-substituted biphenyl derivatives by spectrometric techniques and ab initio and semiempiricalMO methods.112 The computed complexation enthalpies from the PM3 method are on average within 1 kcal mol~1 of the experimental free energy and the geometry of penetration and position of the two complexes are 20 Jiali Gao Br H5 H3 H5 H3 consistent with NOE data from NMR spectroscopy. It was found that the primary basis for molecular recognition between 1,4-substituted phenyl guests and P4` is short range stabilizing electrostatic forces complemented by small amounts of polarizability and charge transfer.In contrast the recognition force for the diphenyl derivatives is dominated by polarizability with a small contribution from electrostatics. Thus the balance between molecular polarizability and electrostatics controls the di§erential binding a¶nity and structural recognition with the host P4`. Pericyclic reactions Pericyclic reactions continue to attract numerous theoretical investigations.113,114 Houk and co-workers pioneered transition structure characterization and have carried out calculations of kinetic isotope e§ects using ab initio molecular orbital and DFT methods. Recent examples include the calculation of the transition structure and the kinetic isotope e§ects on the Diels–Alder reactions of isoprene with maleic anhydride and of butadiene with ethylene.115,116 The computed kinetic isotope e§ects are typically in triple digit agreement with the experimental values.A variety of other Diels–Alder reactions have been studied by computational methods. Sustmann and Sicking investigated the reaction of amino- and hydroxysubstituted butadienes and cyano substituted ethylene at the B3LYP/6-31G* level.117 Special attention was paid to the stabilization of zwitterion intermediates by the inclusion of solvent e§ects in SCRF calculations. Solvent e§ects on two Diels–Alder reactions were also investigated by Gao and Furlani using a hybrid semiempirical AM1 and molecular mechanics potential.118 The reactions of butadiene with a number of thiocarbonyl compounds were examined using HF MP2 and B3LYP/6-31G* methods.119 The endo/exo and diastereofacial selectivity between cyclopentadiene and crotonolactone were examined by Sbai et al.through transition structure optimizations. 120 The competition between [2]2] and [4]2] cycloaddition reactions of activated ketenes and a,b-unsaturated imines was examined by ab initio MP2/6-31G* calculations and with cyclopentadiene at the MP4 and CCSD(T) levels.121,122 It was found that monosubstituted ketenes yield exclusively [2]2] adducts whereas disubstituted activated ketenes react by both pathways. Yamabe et al. proposed a new mechanism for the reaction of ketenes with cyclopentadiene to form the ‘[2]2]’ adduct.123 MP3/6-31G*//MP2/6-31G* calculations demonstrate that direct [4]2] cycloaddition between the parent ketene across its C––O bond and cyclopentadiene has the smallest activation energy among all the computationally obtained cycloadditions.The [4]2] adduct can then isomerize to the formal [2]2] adduct via a [3,3] sigmatropic shift (Claisen rearrangement). The first step has a barrier of 23.6 kcal mol~1 and the [4]2] adduct lies 14.8 kcal mol~1 below the reactant. The 21 Theoretical organic chemistry Ph Ph •+ Ph Ph • + Scheme 5 Claisen rearrangement has a barrier of 38.1 kcal mol~1 from the [4]2] adduct and the final product is 29.2 kcal mol~1 below the starting material. The transition structure for the electrocyclic ring opening of a variety of substituted cyclobutenones were located by Houk and co-workers using HF/3-21G and HF/6- 31G* methods.124 Substituent e§ects on the stereochemistry and reactivity were predicted to be small.Johnson and Daoust studied the two modes of electrocyclic ring opening of Dewar benzene as well as related structures.125 CASSCF calculations predict the existence of Mobius benzene (cis,cis,trans-cyclohexa-1,3,5-triene) in a shallow minimum ca. 100 kcal mol~1 above benzene. The computational results show that trans-Dewar benzene a substance whose existence was originally suggested by Woodward and Ho§mann in 1971 has an energy of 150 kcal mol~1 higher than benzene and that isomerization to benzene occurs with an activation barrier of 13 kcal mol~1. The thermal electrocyclic ring closure of (2E,7E)-3,4,7-trialkylnona-2,4,5,7-tetraenes is regioselective occurring at the most sterically congested vinylallene subunit to a§ord the trisubstituted alkylidenecyclobutene.The ring-opening of a model aziridinimine has been investigated by Nguyen et al. with emphasis on the stereochemistry of the [2]1] retro-cycloaddition process.126 Ring closure of both divinylallenes and vinylallenes displays high torquoselectivity [exclusive formation of the (E)-alkylidenecyclobutenes]when the substituent at C4 is a sterically demanding alkyl group and the substituent at C2 is a formyl group. These properties have been thoroughly examined by Lopez et al.127 Ab initio MP2/6- 31G*//6-31G* calculations demonstrate that the Z-transition structure is 1.18 kcal mol~1 higher in energy than the E-transition structure when the substituent at the C4 position is a tert-butyl group. This is in good agreement with the E/Zproduct ratio of 83 17 determined by experiment.On the other hand when the tert-butyl group is replaced by a methyl group the torquoselectivity vanishes. The computed energy di§erence between the E and Z transition structures is only 0.08 kcal mol~1 which may be compared with the experimental product ratio for the E/Z isomers of 50 50. Finally a formyl group at C2 has an additional torquoselective influence and the e§ect is ascribed to the reluctance of the starting vinylallenal to relinquish extended p conjugation. In contrast to the 1,6-Bergman cyclization of neutral enediyne compounds under thermal conditions the radical cations of aryl derivatives generated through chemical photochemical and electrochemical oxidation do not follow the Bergman cyclization mode but react by a 1,5-cyclization process (Scheme 5).On the basis of the results of UHF/AM1 and PMP2/6-31G*//HF/3-21G calculations it was suggested that the electronic ground state is derived from a 5p configuration.128 The SHOMO (second highest occupied molecular orbital) is the antisymmetric combination of the hybrid 22 Jiali Gao orbitals at the C1 and C4 carbon centers. Hence cycloaromatization of the enediyne radical cation to 1,4-dehydrobenzene radical cation is an electronically forbidden process. Formation of the 1,5-cyclization product is predicted to be allowed. Davidson et al. have reported a hybrid QM/MM study of the Claisen rearrangement of chorismate to prephenate in the active site of the enzyme chorismate mutase.129 The interactions between the substrate and enzyme were found to be strongest at a position close to the transition structure leading to 24.5 kcal mol~1 reduction in the barrier for reaction of the enzyme-bound substrate.Walters has published an ab initio MP4/6-31G* study of the [3,3] sigmatropic rearrangement of 3-aza-Cope reactions.130 The activation energies are predicted to be 34.6 kcal mol~1 for 3-azahexa-1,5-diene; 21.4 kcal mol~1 for 3-azoniahexa-1,5-diene; and 17.7 kcal mol~1 for 3-azahexa-1,2,5-triene. Photochemistry Photochemical processes have been extensively studied by Bearpark et al. using both high level CASSCF CASMP2 and hybrid MMVB methods. The latter approach treats the active orbitals involved in the chemical process using a parametrized valence bond Hamiltonian and uses the MM2 force field to represent the inert r-framework. The method is designed to simulate CASSCF calculations for ground and covalent excited states.Using MMVB Bearpark et al. studied the S 0 and S 1 potential energy surfaces of pentalene and the dynamics and radiationless decay were investigated by characterizing a conical intersection between the S 0 and S 1 states of fulvene.131,132 The S 1 to S 0 decay was predicted to occur in femtoseconds before a single oscillation through the crossing line is completed. Celani et al. determined the potential energy paths that control the excited-state evolution of cyclohexadiene and cZc-hexatriene (cZc-HT) from the Franck–Condon region by CASSCF/6-31G* calculations.133 It was found that both cyclohexadiene and cZc-HT undergo a barrierless motion in the 1B 2 spectroscopic state until decay to the lower lying 2A 1 state occurs via two distinct 1B 2 /2A 1 conical intersections.Remarkably both conical interactions correspond to open (acyclic) molecular structures. It is concluded that although the photochemical ring-opening of cyclohexadiene occurs in femtoseconds in the spectroscopic state the associated photochemical ring-closure reaction of cZc-HT which is initiated upon decay of 2A 1 to the ground state occurs within picoseconds of the initial excitation. Z s- cis cZc-HT s- cis Dreyer and Klessinger have shown that fulvene is the primary product of the photolysis of benzene using semiempirical MNDOC-CI and CASSCF/3-21G calculations. 134 The most probable mechanism for the photochemical isomerization of benzene to fulvene involves the intermediate structure prefulvene and 1,3-cyclopentadienylcarbene which competes with the almost barrierless formation of benzvalene 23 Theoretical organic chemistry and rearomatization to benzene.Bach et al. investigated the photochromic valence isomerization of the norbornadiene (N) and quadricyclane (Q) cation radical system using PMP4 and CCSD(T) methods.135 The calculated adiabatic ionization potential was calculated to be 7.90 eV for N and 7.12 eV for Q in accord with the experimental values of 8.34–8.43 and 7.40–7.86 eV respectively. The barrier for the N·` to Q·` transition is about 16.5 kcal mol~1. Martin et al. studied the cleavage of photoexcited C–X (X\C Cl) bonds to the carbonyl group in acetyl chloride using an ab initio spin restricted CI singles method.136 The minimum energy conformations and transition structure for the C–X bond cleavage both in the S 1 and T 1 states have been determined.It is predicted that C–Cl bond cleavage in the S 1 state can take place upon photoexcitation since the vertical transition energy is greater than the energy of the transition state for C–Cl bond cleavage. References 1 C.A. White B. G. Johnson P.M. W. Gill and M. Head-Gordon Chem. Phys. Lett. 1996 253 268. 2 C.A. White B. G. Johnson P.M. W. Gill and M. Head-Gordon Chem. Phys. Lett. 1996 248 482. 3 M. Challacombe E. Schwegler and J. Almlo� f J. Chem. Phys. 1996 104 4685. 4 C.A. White and M. Head-Gordon J. Chem. Phys. 1996 104 2620. 5 E. Schwegler and M. Challacombe J. Chem. Phys. 1996 105 2726. 6 J.C. Burant G. E. Scuseria and M. J. Frisch J. Chem. Phys. 1996 105 8969. 7 E. Hernandez M. 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ISSN:0069-3030    

DOI:10.1039/oc093003

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

3 Reaction mechanisms Part (i) Pericyclic reactions By IAN D. CUNNINGHAM Department of Chemistry University of Surrey Guildford UK GU2 5XH 1 Introduction Pericyclic reactions can be categorised as cycloadditions electrocyclisations or sigmatropic rearrangements and this format is adopted here. Several reviews have appeared in 1996 covering density functional theory (DFT) calculations of transition states (TS),1 transition metal-mediated cycloadditions,2 Diels–Alder reactions in nature,3 and metal-catalysed asymmetric 1,3-dipolar cycloadditions. 4 2 Cycloadditions Theoretical Density functional theory (Becke3LYP/6-31G*) has been used to predict energies and isotope e§ects for concerted and stepwise mechanisms of the Diels–Alder reaction; predicted barrier heights and heats of reaction are in good agreement with experimental values with the stepwise barrier predicted to be the higher by 9.6–32.2 kJ mol~1 (2.3–7.7 kcal mol~1).5 A comparison of DFT (Becke3LYP) or RHF calculated kinetic isotope e§ects with experimental values indicates a moderately asynchronous transition state for the Diels–Alder reaction of isoprene and maleic anhydride.6 Neither ab initio (HF/6-31G//AM1) nor frontier molecular orbital (FMO) analysis of the s-trans to s-cis interconversion accounts for the low reactivity of (Z)-1 towards cycloaddition of alkenes compared to (E)-1; this suggests that transition state steric restraint is the predominant factor.7 A comparison of ab initio computational methods (HF MP2 and Becke3LYP) has been made for the Diels–Alder reaction between butadiene and various thiocarbonyl compounds.8 Novel dienes and dienophiles The electron-rich 5-aminopyrazoles 2 have been shown to act as dienophiles in an inverse electron demand Diels–Alder reaction with the 1,3,5-triazine 3 (R\H alkyl; R@\H alkyl thienyl phenyl) (Scheme 1); subsequent retro-Diels–Alder and aromatisation reactions yield pyrazolo[3,4-d]pyrimidine products.9 Royal Society of Chemistry–Annual Reports–Book B 27 Scheme 1 N Et Me N F3C CF3 N N Et Me N N F3C CF3 5 4 Scheme 2 O B O O B O ( E)-1 ( Z)-1 1-(Arylthio)butadienes bearing 4-alkyl 4-alkoxy or 4-amino substituents give endo cycloadducts preferentially with maleic anhydride or maleimide dienophiles; with ethyl acrylate the regioselectivity is controlled by the O or N (where present) rather than by the S.10 Azirines (e.g.4) undergo [4]2] cycloaddition to the 4a,8a-methanophthalazine 5 with high selectivity for the electron-deficient diazadiene portion and for anti approach from the side opposite to the methano bridge (Scheme 2).11 The e§ect of the additional nitrogen on going from a 1,2,4-triazine to a 1,2,4,5- tetrazine is su¶cient to allow a successful inverse electron demand Diels–Alder reaction with electron-rich dienophiles.12 2-Ethynylbuta-1,3-diene was found to undergo cycloaddition to a range of dienophiles with regioselectivity as expected based on FMO considerations; this diene was estimated to be ca.5 times less reactive than isoprene and to undergo competing dimerisation via a diradical mechanism.13 Four mono-adducts of benzyne to [70]fullerene have been isolated; they include a [4]2] adduct across the 7,23-bond in line with earlier theoretical predictions.The lower electrophilicity of [70]fullerene compared to [60]fullerene is proposed to account for its [4]2] cycloaddition.14 Kinetics and mechanism [4]2] cycloadditions Intramolecular [4]2] cycloaddition of a cyclobutadiene to a range of unactivated (e.g. mono- di- and tri-alkyl substituted) alkenes has been reported. Although the 28 Ian D. Cunningham X CO2 Me O O X CO2Me 6 Scheme 3 cyclobutadiene portion was generated in situ by oxidation (e.g. cerium ammonium nitrate) of an iron tricarbonyl-complexed precursor the possibility of a radical cation mechanism for this cycloaddition was not discussed.15 N-Aryl-2-cyano-1-azadienes undergo ready cycloaddition to a range of electron-rich (e.g. methyl vinyl ether) and electron-deficient (e.g.methyl vinyl ketone) dienophiles with reactivities di§ering typically by a factor of only ca. 1.4. The observed regioselectivities and (to some extent the reactivities) have been rationalised usingFMOtheory withLUMO$*%/% control for reaction with methyl vinyl ether and HOMO$*%/% control for methyl vinyl ketone.16 A study of retro-Diels–Alder femtosecond reaction dynamics has been published.17 The cyclopropylideneacetates 6 (X\Br or Cl) were found to be more reactive than methyl acrylate towards furan (k3%- \16) and 6,6-dimethylfulvene (k3%- \210–230) while the acyclic analogue methyl 1-chloro-3,3-dimethylacrylate does not react (Scheme 3). The low reactivity of the non-halogenated analogue 6 (X\H) and the fluoro compound 6 (X\F) despite the latter’s low energy LUMO was interpreted as mitigating in favour of a diradical or zwittterion mechanism.18 A study of pressure e§ects on the kinetics and diastereoselectivity of the hetero- Diels–Alder reaction of b-aminoenones with highly substituted vinyl ethers has yielded separate values of activation volume *V8 for endo and exo products.For reaction of 4-phthalimido-1,1,1-trifluorobut-3-en-2-one with 2-methoxypropene the values of [37.6cm3 mol~1 for the endo mode and [41.7 cm3 mol~1 for the exo were interpreted as reflecting the relative steric demand of the methoxy vs. the methyl towards the diene trifluoromethyl group in the TS.19 Reaction of the norborna-2,5-diene 7 with furans 8 (R R@\H alkyl) yielded the endo–exo product 9 (Scheme 4) and its endo–endo isomer. The yield of the thermodynamic product the endo–exo increased as alkyl substituents were removed from C2 and C5 of the furan; this was attributed to equilibration between adducts via cycloreversion with a greater di§erence between thermodynamic and kinetic stability for the less substituted adducts.20 A diradical mechanism is proposed for the dimerisation of 2-chlorobuta-1,3-diene (chloroprene) to yield [4]2] and [2]2] dimers.This is based on the observed lack of stereospecificity in the products and the similarity of E!#5 values for [4]2] and [2]2] (the latter assumed to be via diradicals) modes. The reduced stereospecificity compared to butadiene is attributed to the ‘heavy atom e§ect’ converting the initiallyformed singlet diradicals which cyclise rapidly before rotation to triplet diradicals which do not.Low values (small negative) of the ‘volume of concert’ ([22 to [31 cm3 mol~1) are explained by the participation of ‘extended’ diradicals in product formation.21 Mechanisms involving electron transfer The balance between concerted and stepwise mechanisms continues to be of interest. A 29 Reaction mechanisms Part (i) Pericyclic reactions Cl Cl Cl Cl Cl Cl O R' R O R R' Cl Cl Cl Cl Cl Cl 7 8 9 Scheme 4 kinetic study of the reactivity of styrene-derived radical cations (generated by laser irradiation) towards a range of alkene (p2) and diene (p4) substrates has appeared. The reactions lead to cycloaddition products although whether via concerted or stepwise mechanisms is not conclusively stated.22 However the aminium salt or photoinduced electron transfer (PET) initiated cycloaddition of a series of electron-rich allenes to 1,2,3,4,5-pentamethylcyclopentadienewas proposed to proceed via a stepwise mechanism involving a diene radical cation and neutral allene to yield a distonic radical cation product which subsequently cyclises.23 Extending earlier work Hammett–Brown plots for the radical cation cycloaddition of 2,3-dimethylbutadiene to a range of di-substituted stilbenes showed curvature reflecting a change from equilibrium to rate-limiting ionisation of the stilbene with electron-donating aryl substituents (e.g.Me). These results were interpreted in terms of a concerted mechanism with only a small transfer of positive charge to the diene in the TS.24 Solvent and Lewis acid e§ects Acceleration of the Diels–Alder reaction of the cationic acridizinium bromide 10a (as diene) with cyclopentadiene (as dienophile) in aqueous compared to non-aqueous solvent has been shown to be ca.five-fold due to a hydrophobic e§ect; inclusion of a weak hydrogen-bond acceptor (10b) results in a further ca. two-fold acceleration.25 N Ar O M2+ N R Br – 10a R = H 10b R = CO2Et 11 + An LFER analysis of the inverse electron demand hetero-Diels–Alder reaction between 3,6-di(2-pyridyl)-1,2,4,5-tetrazine and substituted styrenes suggests a more dipolar TS in protic solvent (q\[1.32 in H 2 O–tert-butyl alcohol) than in aprotic solvent (o\[0.51 in toluene).26 Cycloaddition of the Lewis acid-complexed bidentate dienophile 11 (M2`\Co2` Ni2` Cu2` and Zn2`) to cyclopentadiene is accelerated up to 8]104 fold compared to the uncatalysed reaction with only a small further rate increase due to water solvent; endo selectivity is also dominated by the enhancing e§ect of the Lewis acid.27 A series of boronated alumina (BXn–Al 2 O 3 n\1–3) catalysts were found to enhance stereo- and regio-selectivity in the Diels–Alder reactions between methyl acrylate and the dienes cyclopentadiene and isoprene possibly due to steric interactions involving the catalyst surface.28 30 Ian D.Cunningham O C C Ph Ph O Ph Ph O Ph Ph 12 [3,3] [4+2] Scheme 5 Scheme 6 Cumulenes Ab initio calculations (MP3/6-31G*//MP2/6-31G*) on the apparent [2]2] cycloaddition of cyclopentadiene to ketene suggest a pathway via an initial concerted [4]2] addition across the ketene C––O with subsequent [3,3] sigmatropic (Claisen) rearrangement to yield the cyclobutanone product. For the reaction of cyclopentadiene with diphenylketene the intermediate [4]2] adduct 12 is detectable by NMR spectroscopy at low temperature (Scheme 5).29 Several theoretical studies of borderline concerted/zwitterionic imine to ketene,30 imine to isocyanate,31 and aldehyde to ketenimine32 cycloadditions have appeared.1,3-Dipolar cycloadditions The isolation of stable zwitterionic intermediates 13 in the 1,3-dipolar cycloaddition of methanesulfonyl azide 14 to the strongly-polarised alkene 15 is evidence for a nonconcerted mechanism (Scheme 6); the zwitterions yielded the formal cycloaddition products on heating. The possibility of cycloadducts formed via a concerted mechanism following reversion of the zwitterions is excluded by experiments with deuteriated samples.33 The endo product 18 is found exclusively for cycloaddition of the butenoate 17a (R\CH 3 ) to the nitrone 16 while some exo product is found for the addition of trifluorobutenoate 17b (R\CF 3 ) (Scheme 7).From the results of a PM3 analysis this has been attributed to a secondary interaction between the CF 3 group and the nitrone HOMO in a ‘concerted’ TS.34 Asymmetric cycloadditions The p-facial selectivity in the asymmetric Diels–Alder reaction of the chiral diene (S)-19 with maleic anhydride has been rationalised in terms of attack on the conformer which minimises 1,3-allylic and 1,2-eclipsing strains about the diene C2–C3 bond.35 Styrene-based polymers with chiral oxazaborolidinone units were found to catalyse the asymmetric Diels–Alder reaction between methacrolein and cyclopentadiene giving up to 99 1 exo selectivity and up to 95% ee although an explanation for the enhanced stereoselectivity is not given.36 Conversely binding of a Cl 2 Ti- 31 Reaction mechanisms Part (i) Pericyclic reactions N O MeO2C H R R MeO2C N + O – 17a R = CH3 17b R = CF3 16 + 18 Scheme 7 O O O H R¢HN OR H 3 2 19 TADDOLate† (via para positions of aryl groups) to cross-linked polystyrenes Merri- field resins or dendritic molecules led to a decrease in enantioselectivity for the Diels–Alder reaction between cyclopentadiene and the dienophile 20.The findings have been interpreted as indicating a cationic trigonal-bipyramidal complex (e.g. 21) as the catalytically active species.37 Miscellaneous The zirconium metallacycle 22 (Ar\various para-substituted phenyl; Ar@\2,6- dimethylphenyl) undergoes a [4]2] retro-cycloaddition to yield the a,b-unsaturated imine 23 and products probably derived from Cp 2 Zr––O (Scheme 8).The retrocycloaddition mechanism was proposed on the basis of the similarity of the activation parameters [*H8\110.8 kJ mol~1 (26.5 kcal mol~1) *S8\14.55 J mol~1K~1 (3.48 cal mol~1K~1)] to those commonly found for the retro-Diels–Alder reaction.38 The coupling of graphite with microwave heating as a support for Diels–Alder reactants gave rapid cycloaddition in good yield. For example cycloaddition of 1-(dimethylamino)-3-methyl-1-azabuta-1,3-diene to dimethyl acetylenedicarboxylate unreactive by conventional heating was accomplished (on graphite) in 60% yield with 10 sequential one-minute irradiations.39 †TADDOL\a,a,a@,a@-tetraaryl-1,3-dioxolane-4,5-dimethanol.32 Ian D. Cunningham N Ar Ar ¢ Ph N Zr O Ar ¢ Ph Ar [Cp2Zr=O] 22 23 + Scheme 8 O C N N – O N – O N O N O [4 + 2] [2 + 2] p4 p6 + + + Scheme 9 3 Electrocyclic reactions The reaction of ketene with a,b-unsaturated imine involves initial nucleophilic attack of imine nitrogen on the ketene sp-hybridised carbon followed by p4 or p6 electrocyclic ring closure to give [2]2] or [4]2] cycloaddition products respectively (Scheme 9). The preference of mono-substituted ketene for p4 ring closure ([2]2] product) and the enhancement of p6 ring closure ([4]2] product) for the di-substituted ketene have been rationalised by ab initio (MP2/6-31G*) and semi-empirical (AM1) calculations in terms of torquoelectronic e§ects on the conrotatory (p4) and disrotatory (p6) routes.40 A summary of torquoselectivity (i.e.whether rotation is ‘inward’ or ‘outward’) in the conrotatory electrocyclic ring-opening of 3-substituted cyclobutenes rationalised in terms of interaction of the r bond-localised FM orbitals with donor or acceptor orbitals of the 3-substituent has appeared.41 The theme has been extended to cover a range of 1- and 3-substituted cyclobutenes; calculations are typically at the RHF/6- 31G* level and the relationship between torquoselectivity and the Taft rR 0 parameter has been demonstrated.42 From a similar analysis of torquoselectivity in cyclobutenone ring-opening the smaller e§ect is attributed to di§erences in energies for the r bond-localised FM orbitals.43 An ab initio (RHF/3-21G) prediction of BF 3 –OEt 2 -enhanced ‘inward’ torquoselectivity for ring opening of 3-acetylcyclobutene has been verified by experiment.44 The electrocyclisation of vinylallenes (e.g.24) has been found to proceed with high 33 Reaction mechanisms Part (i) Pericyclic reactions • R R¢ R¢ R E 25 24 Scheme 10 regioselectivity (e.g. for cyclisation of the terminal vinyl allene in 24) (Scheme 10). First-order rate constants are lower for R\CH––O (k\300 h~1 R@\But) than for R\CH 2 OTBDMS‡ (k\900 h~1 R@\But) probably due to loss of conjugation in the TS of the former. Torquoselectivity favours ‘inward’ rotation of the allene to give the E product when R@\But; e.g. E:Z is 83 17 for 25 (R\CH 2 OTBDMS R@\But) but 50 50 for 25 (R\CH 2 OTBDMS R@\Me) so steric factors predominate. The findings were supported by ab initio (MP2/6-31G*//RHF/6-31G*) calculations.45 An ab initio theoretical study (CASSCF and MP2) proposes that Dewar benzene 26 is converted into benzene via an (allowed) conrotatory process despite the strained cis,cis,trans-cyclohexa-1,3,5-triene (Mo� bius benzene) intermediate 27 (Scheme 11).This intermediate is predicted to lie in a shallow basin with a barrier for trans-p-bond rotation to benzene of \12.5 kJ mol~1 (3 kcal mol~1); calculations also support the existence of trans-Dewar benzene 28 in a high energy basin 660 kJ mol~1 (158 kcal mol~1) above benzene.46 Reaction profiles for the conrotatory (allowed) and disrotatory (forbidden) ringopenings of some cyclobutenes (e.g. compounds 29 and 30) have been constructed using values of activation parameters obtained froexperiments involving competition trapping by O 2 and NO.Values of *H8 [e.g. 178.1 kJ mol~1 (42.6 kcal mol~1) for 29] for the disrotatory process yielded *H& 8 values [e.g. 314.8 kJ mol~1 (75.3 kcal mol~1) for 29] similar to those calculated for the orthogonal diradicals derived from the ‘diene’ products suggesting a non-concerted mechanism for this process. The value of *Hf 8 (disrotatory) for compound 30 TS was a little lower than the diradical value suggesting here a true forbidden disrotatory ring opening.47 The ring-opening of aminoazirinium ions such as 31 has been studied. The lack of products derived from the achiral ring-opened intermediate 32 and the lack of racemisation in the products which are found excludes such an electrocyclic opening as a significant process in the overall reaction (Scheme 12).48 4 Sigmatropic rearrangements Ab initio calculations indicate a low barrier of 53 kJ mol~1 (12.7 kcal mol~1) for the [1,3] chlorine migration 33]33@ via an ‘in-plane’ pathway involving interaction of the chlorine lone pair with the keteneLUMOlobe on the central carbon (Scheme 13).This ‡TBDMS\tert-butyldimethylsilyl. 34 Ian D. Cunningham H H H H 27 26 28 conrotatory disrotatory conrotatory disrotatory p-bond rotation Scheme 11 30 29 N Me N Me Me But N NMe But Me Me 32 ( R)-31 + + Scheme 12 C Cl C C O O H C C C* Cl O O H C* C C Cl O O H 33 33¢ LUMO l.p. Scheme 13 route termed ‘lone pair–LUMO mediated pericyclic reaction’ by the authors is calculated to be substantially lower in energy than the true pericyclic antarafacial [1,3] chlorine shift in the related 3-chloroprop-1-ene; the ‘lone pair–LUMO’ mechanism is also calculated to be favoured for the vinylogous [1,5] chlorine migration.49 The rate constants for the conversion of deuteriated trans-1-ethenyl-2-phenylcyclopropane 34 into 3-phenylcyclopentene 35 were determined (Scheme 14) i.e.k4* for suprafacial migration across the p-system with inversion at the migrating carbon k!3 for antarafacial migration across the p-system with retention at the migrating carbon etc. The reaction flux via the formally forbidden ([p24 ]r24] and [p2! ]r2!]) modes as indicated by k43 ]k!* was found to be almost the same as via the allowed modes suggesting that this reaction is not controlled by orbital symmetry factors.50 A theoretical treatment of the ‘allylic 1,3-strain e§ect’ with relevance to the ene reaction (an intermolecular [1,5] hydrogen migration) has appeared.51 A theoretical 35 Reaction mechanisms Part (i) Pericyclic reactions D D D D D5C6 D D D5C6 D D etc.34 35 via ksi Scheme 14 C C C Me3Si C N N SiMe3 R R H R N R CH2 H SiMe3 SbCl6 – SbCl6 – H 36 'inverse' TS + + Scheme 15 R B R B R 37 38 Scheme 16 study using semi-empirical (e.g. AM1) ab initio (e.g. HF MP2) and density functional (e.g. Becke3LYP) methods of the retro-ene reaction of methyl prop-2-ynyl ether indicates a TS with the hydrogen lying equidistant between the two carbon atoms and an aromatic TS.52 An inverse electron demand ene reaction in which the iminium salt 36 (R\alkyl) normally an enophile behaves as the ene component (H-donor) while allyltrimethylsilane (normally an ene) behaves as the enophile (Scheme 15) has been reported.This ‘reversal’ is attributed to the ability of Me 3 Si in the ‘inverse’ TS to stabilise the developing]charge on C2 of the enophile; in addition the ‘normal’ TS would involve some unfavourable steric interactions.53 Activation barriers for the [3,3] sigmatropic rearrangement (Cope) of the 9- borabarbaralanes 37 (Scheme 16) have been determined to be 45.7 kJ mol~1 (10.9 kcal mol~1) (R\But) and 40.5 kJ mol~1 (9.7 kcal mol~1) (R\Ph) by NMR spectroscopy; barriers for other substituents (R\H Me NH 2 ) were calculated (Becke3LYP/6-311G**) and found to be 41.1–35.0 kJ mol~1 (9.8–8.4 kcal mol~1).54 A dynamic NMR investigation of the related rearrangements in substituted bullvalenes 38 (R\F CN CO 2 H) gives values of E!#5 for interconversion of the major isomers similar to those found for the parent bullvalene ca.54.8 kJ mol~1 (13.1 kcal mol~1).55 The oxyanion 39 undergoes a [3,3] (Cope) rearrangement via the conformation 36 Ian D. Cunningham O – CH3 O – H RO H 7 5 4 2 40 41 39 Scheme 17 O O O O O O O O •• •• •• •• • • Scheme 18 shown. However the analogue 40 does not probably due to the destabilising e§ect of the steric interaction shown on the chair TS; instead a [1,3] carbon shift is observed (Scheme 17). There is increasing debate about how common true pericyclic [1,3] carbon shifts really are (vide supra) and the mechanism here is not explored in detail although the inversion of the migrating carbon (compare the cis stereochemistry of the Oatom at C2 relative to the methyl at C4 in 40 with the transOatom at C5 relative to methyl at C7 in 41) is consistent with a [p24 ]r2!] mechanism.56 Ab initio calculations (using e.g.MP2/6-311G**//RHF/6-31G*) were carried out to explore the [3,3] sigmatropic rearrangements of 3-oxa- -aza- -thia- and -phospha-1,5- dienes and of allyl phenyl ether and its hetero-analogues.57 The importance of using di§use functions and the value of the DFT method for theoretical treatments of [3,3] shifts has been noted.58 A DFT study of the 1,3-acyloxy shift in allyl formate and the 1,2-acyloxy shift in the ethyl formate radical favours a nucleophilic attack on the alkene or radical by the oxygen lone pair rather than a normal [3,3] mechanism involving the carbonyl p orbital particularly for the open shell (radical) case (Scheme 18).59 The aza-[2,3]-Wittig reaction continues to attract attention mainly for its synthetic potential.Incorporation of a trimethylsilyl group in 42 accelerated the rearrangement (Scheme 19). As with many rearrangements there is debate over concerted vs. stepwise mechanisms. Here the trimethylsilyl e§ect is consistent with the TS 43 based on the model of Houk60 in which a d~ charge develops on C2 while the variation in diastereoselectivity is attributed to increased preference for the less crowded 43@ rather than 43 TS.61 On the other hand the trans-2-alkyl-3-alkenylaziridines bearing a tert-butoxycarbonylmethyl N-substituent [e.g. 44 (R\alkyl; R@\H Me)] were found to yield mainly cis-2,6-disubstituted tetrahydropyridines by an aza-[2,3]-Wittig reaction (Scheme 20). While this can be explained by consideration of a TS based on the Houk model (e.g. 45) the fact that the cis isomers (i.e.R is cis relative to the alkene) of the aziridines gave a mixture of cis and trans tetrahydropyridines is taken to indicate a more complex mechanism with the possibility of an anionic ring-opened intermediate. 62 A theoretical study of the relative importance of the [1,2] (Stevens) and the [2,3] (Sommelet–Hauser) rearrangements of the ammonium ylideN-methyl-3-propenylam- 37 Reaction mechanisms Part (i) Pericyclic reactions N Me3Si R H Boc Ph N Me3Si R H Boc Ph N SiMe3 Ph Boc R SiMe3 R N Ph Boc SiMe3 R N Ph Boc 2 42 d– d– d– 43¢ d– d– d– 43 •• – •• •• – – Scheme 19 N CO2But H R H R¢ N H R R¢ CO2But N H CO2But H R¢ LDA 44 45 •• – H R Scheme 20 monium methylide found the two processes to be very close in energy; N-substitution was calculated to favour a dissociative ([1,2]) mechanism while substitution and therefore delocalisation of the double bond prefers a pericyclic [2,3] mechanism.63 An analysis of allyl methyl thioether anion rearrangements using mass spectrometry has given a value of E!#5 for the [1,4] process for 46 of 112.9 kJ mol~1 (27 kcal mol~1); this is consistent with a homolytic S–Me cleavage stepwise mechanism.A [2,3] process was observed for 47 and this appears to follow a concerted mechanism.64 S S 46 47 •• •• – – 5 Miscellaneous The cyclisation of 1-(prop-2-ynyloxy)naphthalene and related compounds which involves a Claisen rearrangement [1,5] hydrogen shift and p6 electrocyclisation was 38 Ian D.Cunningham C C N N H H H H CH2 NH C NH + 48 •• Scheme 21 Cl Cl Cl Cl Cl Cl N N Ar Ar H H Cl Cl Cl Cl Cl Cl N N Ar Ar H H Scheme 22 O N COR N O R O N R N COR 51 p4 electrocyclisation 50 49 retro-Diels–Alder p6 electrocyclisation Scheme 23 found to be greatly accelerated by microwave irradiation.65 The [2]1] cycloreversion of a model aziridinimine 48 (Scheme 21) has been studied by ab initio methods [CISDQ and QCISD(T)/6-311G(d,p)//MP2/6-31G(d,p)].The reversion mirrors the cheletropic [2]1] cycloaddition of isocyanide to imine in that the C–C bond is a§ected less than the C–N bond in the TS although the positive calculated *S8 is at variance with the negative values found experimentally.66 Rate constants for intramolecular dyotropy (e.g. Scheme 22) have been measured and compared to values for similar compounds. The trends in rate constant and the linearity of lnk vs. 1/T plots indicate a concerted ([r4]p2]) mechanism with no tunnelling.67 Evidence is presented for the formation of the 1,3-benzoxazines 49 rather than the N-acyl-1,2-dihydrobenzazetes 50 from the thermal decomposition of the benzoxazines 51 (R\alkyl phenyl) (Scheme 23); overall E!#5 values are 146–175 kJ mol~1 (34.9–41.8 kcal mol~1).The mechanism is proposed as a retro-Diels–Alder extrusion of formaldehyde followed by a p6 (rather than a p4) electrocyclisation; AM1 calculations are consistent with this although calculated E!#5 values are higher than experimental values.68 39 Reaction mechanisms Part (i) Pericyclic reactions References 1 O. Wiest and K. N. Houk Top. Curr. Chem. 1996 183 1. 2 M. Lautens W. Klute and W. Tam Chem. Rev. 1996 96 49. 3 S. Laschat Angew. Chem. Int. Ed. Engl. 1996 35 289.4 K.V. Gothelf and K. A. Jorgensen Acta Chem. Scand. 1996 50 652. 5 E. Goldstein B. Beno and K. N. Houk J. Am. Chem. Soc. 1996 118 6036. 6 B.R. Beno K. N. Houk and D. A. Singleton J. Am. Chem. Soc. 1996 118 9984. 7 G. Ohanessian Y. Six and J.-Y. Lallemand Bull. Soc. Chim. Fr. 1996 133 1143. 8 V. Barone R. Arnaud P. Y. Chavant and Y. Valle� e J. Org. Chem. 1996 61 5121. 9 Q. Dang B. S. Brown and M. D. Erion J. Am. Chem. Soc. 1996 118 5204. 10 J. Maddaluno O. Gaonac’h A. Marcual L. Toupet and C. Giessner-Prettre J. Org. Chem. 1996 61 5290. 11 J. Laue and G. Seitz Liebigs Ann. Chem. 1996 645; ibid. 1996 773. 12 G. A. McLean B. J. L. Royles D. M. Smith and M. J. Bruce J. Chem. Res. (S) 1996 448; (M) 2623. 13 H. Hopf H. Ja� ger and L. Ernst Liebigs Ann. Chem. 1996 815. 14 A. D. Darwish A.G. Avent R. Taylor and D. R. M. Walton J. Chem. Soc. Perkin Trans. 2 1996 2079. 15 J. A. Tallarico M. L. Randall and M.L. Snapper J. Am. Chem. Soc. 1996 118 9196. 16 N. J. Sisti I. A. Motorina M.-E. Tran Huu Dau C. Riche F. W. Fowler and D. S. Grierson J. Org. Chem. 1996 61 3715. 17 B. A. Horn J. L. Herek and A. H. Zewail J. Am. Chem. Soc. 1996 118 8755. 18 A. de Meijere S. Teichmann F. Seyed-Mahdavi and S. Kohlstruk Liebigs Ann. Chem. 1996 1989. 19 M. Buback G. Kuchta A. Niklaus M. Henrich I. Rothert and L. F. Tietze Liebigs Ann. Chem. 1996 1151. 20 K. Mackenzie E. C. Gravett J. A. K. Howard K. B. Astin and A. M. Tomlins J. Chem. Soc. Perkin Trans. 2 1996 1233. 21 R. A. Firestone Tetrahedron 1996 52 14 459. 22 N. P. Schepp and L. J. Johnston J. Am. Chem. Soc. 1996 118 2872. 23 W.Schmittel C. Wo� hrle and I. Bohn Chem. Eur. J. 1996 2 1031. 24 W. Yeuh and N. L. Bauld J. Chem. Soc. Perkin Trans. 2 1996 1761. 25 G. K. van der Wel J. W. Wijnen and J. B. F. N. Engberts J. Org. Chem. 1996 61 9001. 26 J. W. Wijnen S. Zavarise and J. B. F. N. Engberts J. Org. Chem. 1996 61 2001. 27 S. Otto F. Bertoncin and J. B. F. N. Engberts J. Am. Chem. Soc. 1996 118 7702. 28 M.B. Mcginnis K. Vagle J. F. Green L. Choo Tan R. Palmer J. Siler R.M. Pagni and G. W. Kabalka J. Org. Chem. 1996 61 3496. 29 S. Yamabe T. Dai T. Minato T. Machiguchi and T. Hasegawa J. Am. Chem. Soc. 1996 118 6518. 30 (a) D.-C. Fang and X.-Y. Fu Int. J. Quantum Chem. 1996 57 1107; (b) R. Lopez M. F. Ruizlopez D. Rinaldi J. A. Sordo and T. L. Sordo J. Phys. Chem. 1996 100 10 600; (c) D.-C. Fang and X.-Y. Fu Chin.J. Chem. 1996 14 97. 31 D.-C. Fang and X.-Y. Fu J. Mol. Struct. 1996 365 219. 32 D.-C. Fang and X.-Y. Fu Chem. Phys. Lett. 1996 265. 33 H. Quast M. Ach A. Ivanova E.-M. Peters K. Peters and H. G. von Schnering Liebigs Ann. Chem. 1996 1551. 34 K. Tanaka T. Imase and S. Iwata Bull. Chem. Soc. Jpn. 1996 69 2243. 35 G. T. Crisp and M. G. Gebauer J. Org. Chem. 1996 61 8425. 36 K. Kamahori K. Ito and S. Itsuno J. Org. Chem. 1996 61 8321. 37 D. Seebach R. E. Marti and T. Hintermann Helv. Chim. Acta 1996 79 1710. 38 T. A. Hanna A. M. Baranger and R. G. Bergman J. Org. Chem. 1996 61 4532. 39 B. Garrigues C. Laporte R. Laurent A. Laporterie and J. Dubac Liebigs Ann. Chem. 1996 739. 40 B. Lecea I. Arrastia A. Arrieta G. Roa X. Lopez M. I. Arriortua J. M. Ugalde and F. P. Cossý� o J. Org.Chem. 1996 61 3070. 41 W.R. Dolbier Jr. H. Koroniak K. N. Houk and C. Sheu Acc. Chem. Res. 1996 29 471. 42 S. Niwayama E. A. Kallel D. C. Spellmeyer C. Sheu and K. N. Houk J. Org. Chem. 1996 61 2813. 43 S. Niwayama E. A. Kallel C. Sheu and K. N. Houk J. Org. Chem. 1996 61 2517. 44 S. Niwayama J. Org. Chem. 1996 61 640. 45 S. Lopez J. Rodrigu� ez J. G. Rey and A. R. de Lera J. Am. Chem. Soc. 1996 118 1881. 46 R. P. Johnson and K. J. Daoust J. Am. Chem. Soc. 1996 118 7381. 47 W.R. Roth V. Rekowski S. Bo� rner and M. Quast Liebigs Ann. Chem. 1996 409. 48 H. Quast S. Aldenkortt B. Freudenreich P. Scha� fer E.-M. Peters K. Peters H. G. von Schnering and E.-U. Wu� rthwein Liebigs Ann. Chem. 1996 87. 49 R. Koch M.W. Wong and C. Wentrup J. Org. Chem. 1996 61 6809. 50 J. E. Baldwin and S.J. Bonacorsi Jr. J. Am. Chem. Soc. 1996 118 8258. 51 L. F. Tietze and G. Schulz Liebigs Ann. Chem. 1996 1575. 52 P. Va� rnai and G. Keseru� J. Org. Chem. 1996 61 5831. 53 A. R. Ofial and H. Mayr J. Org. Chem. 1996 61 5823. 40 Ian D. Cunningham 54 G. L. Herberich H.-W. Marx S. Moss P. vR. Schleyer and T. Wagner Chem. Eur. J. 1996 2 458. 55 R. Poupko H. Zimmermann K. Mu� ller and Z. Luz J. Am. Chem. Soc. 1996 118 7995. 56 L. A. Paquette S. Liang and H.-L. Wang J. Org. Chem. 1996 61 3268. 57 S. Yamabe S. Okumoto and T. Hayashi J. Org. Chem. 1996 61 6218. 58 P.M. Warner J. Org. Chem. 1996 61 7192. 59 H. Zipse J. Chem. Soc. Perkin Trans. 2 1996 1797. 60 K. Mikami T. Uchida T. Hirano Y.-D. Wu and K. N. Houk Tetrahedron 1994 50 5917; Y.-D. Wu K. N. Houk and J. A. Marshall J. Org.Chem. 1990 55 1421. 61 J. C. Anderson D. C. Siddons S. C. Smith and M. E. Swarbrick J. Org. Chem. 1996 61 4820. 62 J. A ! hman T. Jareva" ng and P. Somfai J. Org. Chem. 1996 61 8148. 63 G. L. Heard and B. F. Yates J. Org. Chem. 1996 61 7276. 64 M.R. Ahmad G. D. Dalke and S. R. Kass J. Am. Chem. Soc. 1996 118 1398. 65 F. Matloubi Moghaddam A. Sharifi and M.R. Saidi J. Chem. Res. (S) 1996 338. 66 M.T. Nguyen A. Van Keer and L. G. Vanquickenborne J. Chem. Soc. Perkin Trans. 2 1996 299. 67 K. Mackenzie J. A. K. Howard R. Siedlecka K. B. Astin E. C. Gravett C. Wilson J. Cole R. G. Gregory and A. S. Tomlins J. Chem. Soc. Perkin Trans. 2 1996 1749. 68 S. A. Glover K. M. Jones I. R. McNee and C. Rowbottom J. Chem. Soc. Perkin Trans. 2 1996 1367. 41 Reaction mechanisms Part (i

ISSN:0069-3030    

DOI:10.1039/oc093027

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

3 Reaction mechanisms Part (ii) Polar reactions By IAN W. ASHWORTH Zeneca Ltd. Process Studies Group Huddersfield Works Leeds Road Huddersfield UK HD2 1FF 1 Introduction The experimental study of reactive intermediates has continued to be of considerable interest due to the relatively facile generation of previously inaccessible species by laser flash photolytic (LFP) techniques. The application of this methodology to the generation and study of carbenium and nitrenium ions,1 ynols and ynamines2 and carboxylic acid enols3 has been reviewed. 2 Solvolysis and carbocations Studies of the reactions of a range of solvolytically generated a-substituted 1-(4- methoxyphenyl)ethyl carbocations 1 in 50 50 (v/v) MeOH–H 2 O have shown that a thioamide substituent strongly favours deprotonation to form an alkene over nucleophilic addition.4 Experimental and computational results are consistent with the conclusion that the partitioning of the carbocationic intermediate between substitution and elimination products is strongly controlled by their relative stabilities.The a-(N,N-dimethylaminothioformyl)-4-methoxybenzyl carbocation 2 has been found5 to undergo cyclisation to give the benzothiophene 3 which traps 2 with an e¶ciency comparable to an azide to yield the adduct 4. + + 1 2 3 4 R OMe Me2N S OMe S NMe2 OMe S NMe2 Ar Me2N S OMe The solvolyses of the E and Z isomers of a number of substituted hydroximoyl chlorides 5 have been studied.6 A positive *S8 and Hammett o of[1.4 were taken as Royal Society of Chemistry–Annual Reports–Book B 43 evidence of a dissociative mechanism proceeding via a nitrilium ion intermediate 6.The large di§erence in the rates of the reaction of the E and Z isomers was ascribed to a stereoelectronic e§ect. Studies of the e§ect of solvent upon the rates of solvolysis of the benzhydryldimethylsulfonium ion 7 have shown that the dependence of rate upon solvent composition may be described by an extended form of the Grunwald–Winstein equation utilising Y` and aromatic ring parameter (I) values.7 An S N 1 mechanism was proposed based on this correlation the observation of common molecule return and product selectivities in ethanol–water mixtures. A modified Grunwald–Winstein treatment has also been applied to the solvolyses of a range of (1-arylcycloalkyl)methyl toluene-p-sulfonates 8 and 9,8 where anchimeric assistance by the aryl group in the solvolysis was shown to be pronounced in the [1-(p-methoxyphenyl)cyclobutyl]- methyl toluene-p-sulfonate.n 5 6 7 8 n = 1 9 n = 2 Cl Ar N OMe Ar C N+ OMe Ph Ph S+ Ar OTs Arylcyclopropylcarbenium ions 10 were generated as transient species by LFP in 2,2,2-trifluoroethanol (TFE) and the kinetics of their reaction with methanol was studied.9 Comparison of the rates of reaction with those of the corresponding arylphenylcarbenium ions generated under similar conditions show the phenyl and cylcopropyl groups to have similar cation stabilising abilities. Lew et al.10 generated and characterised the zwitterionic 9-carboxylatoflouren-9-yl cation 11 flash photolytically in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP). Under acidic conditions the conjugate acid could be observed leading to an estimated pK! of 2 for the carboxylic acid group in HFIP.Generation of the 9-(N,N-dimethylaminothioformyl)fluoren-9-yl cation 12 under stable ion conditions facilitated its spectroscopic investigation.11 The same cation was also generated by LFP of the appropriate chloride precursor in TFE and its quenching with a range of nucleophiles was studied,11 resulting in the same conclusion reached by Richard et al.4 that the N,N-dimethylaminoformyl group stabilises the adjacent cationic centre relative to the methoxycarbonyl and unsubstituted cations. + + + 10 11 12 H Ar CO2 – Me2N S 3 Nucleophilic substitution The competition between electron transfer and bimolecular substitution pathways in nucleophilic substitution reactions has been reviewed by Speiser.12 Studies of the 44 IanW.Ashworth Scheme 1 Scheme 2 Nuc H+ Products HN R N+ O O– R N N+ OH O– R N N+ OH2 + O– Scheme 3 antihydrophobic cosolvent e§ect on the reactions of phenoxides and N-methylaniline with sodium (4-chloromethyl)benzoate 1313 suggested two di§erent geometries for the S N 2 displacement. N-Methylaniline was postulated to react with 13 via a p in-plane approach (Scheme 1) whilst the phenoxide ion reacts with13 in a direct displacement reaction (Scheme 2). Switching to the 2,6-dimethylphenoxide ion as the nucleophile led to an antihydrophobic cosolvent e§ect consistent with a change to an in-plane approach. Interestingly thiophenoxide and 2,6-dimethylthiophenoxide ions showed anomalous reactivity in the presence of added cosolvent which was interpreted in terms of a single electron transfer (SET) mechanism.Investigations of the acid catalysed decomposition of N-nitroamines in concentrated sulfuric acid using the Cox–Yates excess acidity scale showed that the free carbocations were not formed.14 A mechanism was proposed (Scheme 3) in which the aci-nitro tautomer undergoes protonation followed by S N 2 displacement by water at less than 82% sulfuric acid in water and by bisulfate at higher concentrations of acid. Incoming group 11C/14C kinetic isotope e§ects have been successfully measured for the S N 2 reaction between benzyl chloride and the labelled cyanide ion.15 The e§ects of changing para substituents upon these isotope e§ects suggest that electron withdrawing groups have little e§ect upon nucleophile–carbon distance in the transition state. An interesting intermolecular B A-2 aminolysis reaction was observed in the solid state for the binaphthyl derivative 14.16 It was found by X-ray crystallographic analysis of the racemic compound that the amino and ester groups had the wrong orientation for 45 Reaction mechanisms Part (ii) Polar reactions 18 X=H 3-Cl MeO– rds N H Ph CN X –N Ph CN X N Ph X Scheme 4 an intramolecular reaction to occur; however a second molecule within the crystal was found to be su¶ciently close that reaction could take place between the amino and ester functions of neighbouring molecules.4 Elimination reactions An elimination pathway has been found for the aminolysis of N-arylmethyl- 15 and N-aryl-sulfamate 16 esters in chloroform and acetonitrile.17 An E2 process has been postulated on the basis of b-' o!#:- and *S8 values which imply a bimolecular reaction with a strong dependence upon the electron withdrawing ability at nitrogen and the leaving group ability of the ester.Further evidence was provided by studies of the 4-nitrophenylN,N-dimethylsulfamate ester which failed to react under the experimental conditions. The aqueous hydrolysis of 2,4-dinitrophenyl esters of 4-hydroxy-Xbenzenesulfonic acid was found to be independent of pH reaction above the pK! of the hydroxy function.18 The rate of this reaction was found to correlate with the pK! of the substituted phenol and the redox equilibrium constants for the substituted quinone analogues of the postulated intermediate 17 which was taken as evidence of an E1 pathway. 17 16 15 14 NH2 OH CO2Me N H SO2OAr X N H SO2 OAr X O R2 R1 SO2 Elimination of HCl from N-chloramines to form imines has been studied19 and evidence was found which suggests a concerted bimolecular elimination mechanism.The susceptibility of the reaction rate to substituents on the a-carbon was taken as being indicative of an asynchronous mechanism in which deprotonation lags behind leaving group departure. In contrast the formation of an imine in the methoxide promoted elimination of cyanide ion from 18 has been concluded to proceed via an (E1cB) R mechanism (Scheme 4),20 as evidenced by H/D exchange at N and a negative value for *S8. 46 IanW. Ashworth An interesting alkyne forming elimination was observed in place of vinylic substitution in the reaction of the b-halocinnamate 19 with a range of nucleophiles.21 The overall reaction is a dechloromethoxylcarbonylation which is thought to occur by attack of the nucleophile upon the ester carbonyl followed by either concerted elimination of the CO 2 Me group and chloride or the formation of a vinyl anion.Failure of the substitution pathway was attributed to steric hindrance by the bulky aryl group at Cb. 19 Br Cl CO2Me 5 Addition reactions Electrophilic addition to the hindered double bond of anti-sesquinorbornene 20 has been shown to give rise to the products of cis addition to the double bond.22,23 The acid catalysed hydration22 occurs by a mechanism involving rate limiting protonation which may or may not be synchronous with the trapping of the developing carbocation. Bromination in methanol gives the expected products in a ratio which is independent of the [Br~],23 implying that the products arise from ion pair collapse and not from a solvent equilibrated ion pair.The e§ect of a b-silyl substituent on the rate of protonation of a number of alkynes and alkenes in concentrated perchloric acid solutions was investigated by Gabelica and Kresge.24 This study showed a marked rate enhancement by the b-silyl group of the rates of C-protonation and a dependence of the magnitude of this e§ect upon geometry. The nucleophilic addition of hydride from cyanoborohydride to the heteroaromatic rings of the pyrylium and thiopyrylium cations 21 and 22 with loss of aromaticity has been investigated.25 The ratios of 1,2- and 1,4-addition products are comparable to those for the reactions of the same cations (Y\H) with amine and alkoxide nucleophiles.Consideration of the activation parameters and substituent e§ects upon the cyanoborohydride reductions led to the conclusion that they were not initiated by an electron transfer process. Investigations of the activation parameters for the reactions of the C––Si bond of 1,1-diphenylsilene (Ph 2 Si––CH 2 ) with nucleophiles have provided further evidence of a mechanism involving reversible nucleophilic attack at Si followed by rate limiting 47 Reaction mechanisms Part (ii) Polar reactions protonation of the anion formed.26 The rates of reaction of tetramesityldisilene with a range of substituted phenols were studied27 and a concave Hammett plot was obtained the minimum occurring at X\H. This was taken as evidence of a change in mechanism from a rate limiting nucleophilic step in the case of electron donating substituents to a rate limiting electrophilic step in the case of electron withdrawing substituents.6 Carbonyl derivatives Intramolecular participation by a carbonyl hydrate was found in the hydrolysis of the esters 23 and 24.28 The activation parameters substituent e§ects and relative rates of hydrolysis were taken as evidence of a mechanism involving rate limiting addition of hydroxide to the keto-carbonyl which then participated in the hydrolysis of the ester. The rate and equilibrium constants for the aldol addition and elimination steps in a range of intramolecular condensation reactions were determined by Guthrie and Guo.29 Analysis of the experimental results in terms of Marcus theory led to the conclusion that the intrinsic barriers for the intramolecular reactions were similar to those for the corresponding intermolecular processes.24 R=H Me 23 R=H Me Ar O CO2Me R R R R Ar O CO2Me Intramolecular general acid catalysis of acetal hydrolysis has been demonstrated in two model systems containing alkyl acetals. The racemic trans-cyclohexane-1,2-diyl acetal 25 has a complex pH rate profile which suggests that the oxo-carbenium ion intermediate is trapped by the carboxylate anion to form 26.30 The ortho-carboxylic group enhances the rate of reaction by a factor of 220 relative to the corresponding para substituted compounds and a solvent deuterium isotope supporting a mechanism involving general acid catalysis was obtained. Brown and Kirby31 found the benzaldehyde acetal 27 to be highly reactive towards intramolecular general acid catalysed hydrolysis.An e§ective molarity of 2800 was estimated as the appropriate reference reaction was too slow to be observed. This highly e¶cient general acid catalysis was ascribed to the development of a strong intramolecular hydrogen bond. 27 26 25 O O OH O O O O OH O O H O OMe Ph 48 IanW. Ashworth The study of the enolisation of carboxylic acids esters and amides has been pursued by a number of groups. Amyes and Richard32 used NMR spectroscopy to study the exchange of deuterium into ethyl acetate catalysed by a range of 3-substituted quinuclidine bases and obtained a pK! K of 25.6 for ethyl acetate acting as a carbon acid. The enolisation of malonic acid and its mono methyl ester were studied by Eberlin and Williams,33 who obtained values of 8.13 and 8.84 respectively for pK! K.The complex dependence of the kinetics of bromination of malonic acid between pH 1 and 4.3 upon the concentration of the carbon acid was explained in terms of three di§erent mechanisms. LFP techniques have been used to generate ditipylketene (tipyl\2,4,6-triisopropylphenyl) which upon reaction with dimethylamine gave a stable amide enol 28 which could be studied spectroscopically.34 A similar approach yielded the corresponding carboxylic acid enol 29 upon hydration of the ketene intermediate.35 Kresge and co-workers36 generated the enol of acetoacetic acid by the hydration of acetylketene and studied the e§ect of pH upon the rates of ketonisation. Their findings were discussed in terms of the ionisation state of the enol alcohol and carboxylic acid. 29 28 Tip Tip OH NMe2 Tip Tip OH OH 7 Reactive intermediates The basicity of aryl nitrenes was studied by following their flash photolytic generation from the appropriate azide and subsequent protonation to form an aryl nitrenium ion.37 In the case of phenylnitrene 1M acid was required to obtain appreciable amounts of the nitrenium ion by protonation which occurred in competition with ring expansion.Biphenyl-4-yl- and fluoren-2-yl-nitrene were found to undergo side reactions less rapidly leading to substantial yields of the nitrenium ion in the absence of added acids. A pK! of 16 was estimated for the deprotonation of the biphenyl-4- ylnitrenium ion 30 to yield the singlet nitrene. The reactions of these relatively long-lived biphenyl-4-yl- and fluoren-2-yl-nitrenes with heterocyclic and carbon nucleophiles have been reviewed.38 Studies of the anilinylium ion 3139 have shown the reaction products to be spin state dependent.Reaction via the singlet nitrenium ion gives rise to the products of nucleophilic attack at the 4-position 32 or alkyl migration to yield the iminium ion 33 while reaction by way of the triplet leads to the amine through hydrogen abstraction. A range of primary secondary and tertiary phenylynamines have been generated flash photolytically and their reactions studied in aqueous solution.40 Under acidic conditions they undergo rate limiting protonation on Cb to yield keteniminium ions 49 Reaction mechanisms Part (ii) Polar reactions Scheme 5 (Scheme 5) followed by deprotonation on nitrogen in the case of primary and secondary ynamines to give ketenimines.The ketenimines derived from secondary ynamines undergo hydration to phenylacetamides while the ketenimine of the primary ynamine tautomerises to yield phenylacetonitrile. The keteniminum ions derived from tertiary ynamines have no nitrogen bound protons and therefore react with water to yield amide enols which then ketonise to yield the amide. The preparation and reactions of ketenes and bisketenes stabilised by silyl substituents has been reviewed.41 The techniques used in these preparations have also been applied to the generation and characterisation of the first stable and persistent 1,3- bisketene 34 and the first trisketene 35.42 Reigtz has reviewed the synthesis and reactions of nucleophilic carbenes,43 following the recent resurgence of interest in this area.An acyclic diaminocarbene 36 has been generated and studied by X-ray crystallography,44 which showed there to be considerable double bond character in the C–N bonds. 36 35 34 . . Me2Si C O C O N N Me2Si C O C O C C O The reactions of cyclopentadienylidene 37 fluorenylidene 38 and tetrachlorocyclopentadienylidene 39 generated by LFP with a range of alcohols and nucleophiles have been studied.45 Cyclopentadienylidene and fluorenylidene were found to react with alcohols to yield adducts by either rapid protonation or concerted insertion into the O–H bond whereas tetrachlorocyclopentadienylidene was shown to prefer a reaction pathway involving ylide formation. 38 37 X=H 39 X=Cl . . . . X X X X 50 IanW. Ashworth 8 Aromatic substitution Flash photolytic techniques have been applied to the study of electrophilic aromatic substitution reactions by McClelland and co-workers.46,47 The fluoren-9-yl cation was generated in the presence of a wide range of aromatic nucleophiles in HFIP.47 In the case of anisole the ortho and para substitution products were obtained and an intermediate observed which was assigned as the cyclohexadienyl cation 40.46 The formation of this cation was shown to be reversible by the kinetically determined rate constants for the loss of H` and fluorenyl cation.In the case of more electron-rich aromatics such as m-xylene and pentamethylbenzene the observed rate constants suggest a switch to an encounter-controlled process. The photoprotonation of 2- (diphenylmethyl)-1,3-dimethoxybenzene 41 in HFIP generates the cyclohexadienyl cation 42,47 which has been shown to undergo a retro-Friedel–Crafts alkylation reaction to form 1,3-dimethoxybenzene and the diphenylmethyl cation.This cation is then trapped by solvent or reacts with 1,3-dimethoxybenzene to either regenerate the starting material or form isomeric 43. Higher than expected levels of 43 at the beginning of the experiment were attributed to the intramolecular migration of the diphenylmethyl carbonation without separation of the carbocation–1,3- dimethoxybenzene complex. 44 42 41 X=CHPh2 Y=H 43 X=H Y=CHPh2 40 + + OMe Fl H X MeO OMe Y OMe OMe CHPh2 H OTf O X Solvolytic generation of acylium ions from aroyl trifluoromethanesulfonates (aroyl triflates) 44 in 1,2-dichloroethane enabled E§enberger et al.48 to study their behaviour as electrophiles in the Friedel–Crafts acylation.The reactions of a range of 4-substituted aroyl triflates 44 with anisole were studied and a break was found in the Hammett plot of the rate constants for acylation against r`. This was taken as evidence of a change in mechanism from rate limiting ionisation of the aroyl triflate with electron withdrawing substituents to rate limiting electrophilic addition with electron donating substituents. Vicarious nucleophilic aromatic substitution and other means of achieving replacement of hydrogen by a nucleophile have been reviewed by Ma�kosza.49 Such a methodology has been used to achieve selective functionalisation at the 4-position of the 2-quinolone 45 with 1,3-dicarbonyl compounds.50 The intermediate adduct 46 has been isolated and characterised and proceeds to the substitution product by the elimination of HNO 2 .An O-bonded a-adduct 47 between the enolate of acetophenone and 1,3,5-trinitrobenzene has been characterised byNMRspectroscopy at[40 °C.51 Upon warming this adduct isomerises to give the more thermodynamically stable C-adduct 48. Leaving group 18F/19F kinetic isotope e§ects have been investigated by Matsson and co-workers for the reaction of 2,4-dinitrofluorobenzene with piperidine.52 In THF 51 Reaction mechanisms Part (ii) Polar reactions 46 45 NH NO2 O O2N NO2 NH O OEt O EtO O2N NO2 O NO2 a significant isotope e§ect was observed suggesting leaving group departure to be rate limiting. A change to rate limiting addition of the nucleophile was observed when the same reaction was carried out in acetonitrile demonstrating that the nature of the rate limiting step may be a§ected by solvent in nucleophilic aromatic substitution reactions.An analysis of substituent e§ects on the rate constants for the aminolyses of 4-aryloxy-2,6-dimethoxy-1,3,5-triazines 49 demonstrated a clear dependence of reactivity upon o1'.53 Determination of b/6# for the reaction of 49 X\4-NO 2 or 3,4-NO 2 with a range of substituted pyridines also demonstrates the rate of reaction to be dependent upon the incoming nucleophile in support of the concerted substitution mechanism proposed previously. Further analysis of the experimental data for the pyridinolysis reactions in terms of Leßer exponents led to the conclusion that there is an imbalance between bond formation and bond breaking in the transition state resulting in the build up of negative charge on the triazine.References 1 R.A. McClelland Tetrahedron 1996 52 6823. 2 Y. Chiang A. J. Kresge S. W. Paine and V. V. Popik J. Phys. Org. Chem. 1996 9 361. 3 A. J. Kresge Chem. Soc. Rev. 1996 25 275. 4 J.P. Richard S.-S. Lin J. M. Buccigross and T. L. Amyes J. Am. Chem. Soc. 1996 118 12 603. 5 J.P. Richard S.-S. Lin and K. B. Williams J. Org. Chem. 1996 61 9033. 6 J.E. Johnson E. C. Riesgo and I. Jano J. Org. Chem. 1996 61 45. 7 D.N. Kevill S. W. Anderson and N. H. J. Ismail J. Org. Chem. 1996 61 7256. 8 M. Fujio Y. Saeki K. Nakamoto S. H. Kim Z. Rappoport and Y. Tsuno Bull. Chem. Soc. Jpn. 1996 69 751. 9 W. Kirmse B. Krzossa and S. Steenken J. Am. Chem. Soc. 1996 118 7473. 10 C. S. Q. Lew B. D. Wagner M.P. Angelini E. Lee-Ru§ J. Lusztyk and L. J. Johnston J. Am.Chem. Soc. 1996 118 12 066. 11 C. S. Q. Lew D. F. Wong L. J. Johnston M. Bertone A. C. Hopkinson and E. Lee-Ru§ J. Org. Chem. 1996 118 6805. 52 IanW. Ashworth 12 B. Speiser Angew. Chem. Int. Ed. Engl. 1996 35 2471. 13 R. Breslow and R. Connors J. Am. Chem. Soc. 1996 118 6323. 14 R. A. Cox Can. J. Chem. 1996 74 1774. 15 O. Matsson J. Persson B. S. Axelsson B. La" ngstro� m Y. Fang and K. C. Westaway J. Am. Chem. Soc. 1996 118 6350. 16 M. Smrcina S¡ . Vyskocil V. Hanus¡,M. Pola� s¡ek V. Langer B. G. M. Chew D. B. Zax H. Verrier K. Harper T. A. Claxton P. Kocovsky� J. Am. Chem. Soc. 1996 118 487. 17 W.J. Spillane G. Hogan P. McGrath J. King and C. Brack J. Chem. Soc. Perkin Trans. 2 1996 2099. 18 G. Cevasco and S. Thea J. Org. Chem. 1996 61 6814. 19 J. M. Antelo F. Arce and M.Parajo� J. Phys. Org. Chem. 1996 9 447. 20 B. R. Cho Y. C. Oh S. H. Lee and Y. J. Park J. Org. Chem. 1996 61 5656. 21 M.B. Yannai and Z. Rappoport J. Org. Chem. 1996 61 3553. 22 H. Slebocka-Tilk and R. S. Brown J. Org. Chem. 1996 61 8079. 23 H. Slebocka-Tilk D. Gallagher and R. S. Brown J. Org. Chem. 1996 61 3458. 24 V. Gabelica and A. J. Kresge J. Am. Chem. Soc. 1996 118 3838. 25 R. Beddoes D. Heyes R. S. Menon and C. I. F. Watt J. Chem. Soc. Perkin Trans. 2 1996 307. 26 C. J. Bradaric and W. J. Leigh J. Am. Chem. Soc. 1996 118 8971. 27 Y. Apeloig and M. Nakash J. Am. Chem. Soc. 1996 118 9798. 28 K. Bowden and J. M. Byrne J. Chem. Soc. Perkin Trans. 2 1996 2203. 29 J. P. Guthrie and J. Guo J. Am. Chem. Soc. 1996 118 11 472. 30 T. H. Fife R. Bembi and R. Natarajan J. Am. Chem. Soc.1996 118 12 956. 31 C. J. Brown and A. J. Kirby Chem. Commun. 1996 2355. 32 T. L. Amyes and J. P. Richard J. Am. Chem. Soc. 1996 118 3129. 33 A. R. Eberlin and D. L. H. Williams J. Chem. Soc. Perkin Trans. 2 1996 883. 34 J. Frey and Z. Rappoport J. Am. Chem. Soc. 1996 118 3994. 35 J. Frey and Z. Rappoport J. Am. Chem. Soc. 1996 118 5169. 36 Y. Chiang H.-X. Guo and A. J. Kresge O. S. Tee J. Am. Chem. Soc. 1996 118 3386. 37 R. A. McClelland M.J. Kahley P. A. Davidse and G. Hadzialic J. Am. Chem. Soc. 1996 118 4794. 38 R. A. McClelland M.J. Kahley and P. A. Davidse J. Phys. Org. Chem. 1996 9 355. 39 D. Chiapperino G. B. Anderson R. J. Robbins and D. E. Falvey J. Org. Chem. 1996 61 3195. 40 Y. Chiang A. S. Grant A. J. Kresge and S. W. Paine J. Am. Chem. Soc. 1996 118 4366. 41 A. D. Allen J.D. Colomvakos I. Egle R. Liu J. Ma R. M. Marra M.A. McAllister and T. T. Tidwell Can. J. Chem. 1996 74 457. 42 K. Sung and T. T. Tidwell J. Am. Chem. Soc. 1996 118 2768. 43 M. Reigtz Angew. Chem. Int. Ed. Engl. 1996 35 725. 44 R.W. Alder P. R. Allen M. Murray and A. G. Orpen Angew. Chem. Int. Ed. Engl. 1996 35 1121. 45 D. R. Olson and M. S. Platz J. Phys. Org. Chem. 1996 9 759. 46 R. A. McClelland F. L. Cozens and J. Li S. Steenken J. Chem. Soc. Perkin Trans. 2 1996 1531. 47 E. MacKnight and R. A. McClelland Can. J. Chem2518. 48 F. E§enberger J. K. Eberhard and A. H. Maier J. Am. Chem. Soc. 1996 118 12 572. 49 M. Ma�kosza Russ. Chem. Bull. 1996 45 491. 50 N. Nishiwaki A. Tanaka M. Uchida Y. Tohda and M. Ariga Bull. Chem. Soc. Jpn. 1996 69 1377. 51 E. Buncel J. M. Dust and R. A. Manderville J. Am. Chem. Soc. 1996 118 6072. 52 J. Persson S. Axelsson and O. Matsson J. Am. Chem. Soc. 1996 118 20. 53 J. Shakes C. Raymond D. Rettura and A. Williams J. Chem. Soc. Perkin Trans. 2 1996 1553. 53 Reaction mechanisms Part (ii) Polar reactio

ISSN:0069-3030    

DOI:10.1039/oc093043

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

OBun O O I ButO N O Ph OBun + O Ph OBut (55%) (28%) TEMPO K2CO3 Scheme 1 3 Reaction mechanisms Part (iii) Free-radical reactions By STEPHEN CADDICK VERN M. DELISSER and CRAIG L. SHERING The Chemistry Laboratory University of Sussex Falmer Brighton UK BN1 9QJ 1 Introduction Progress continues unabated in the area of free radical chemistry and numerous exciting developments have been reported in the last year with an increasing number of review articles highlighting the speed with which the state of the art changes.1 Most of the important synthetic developments have been a consequence of the increased availability of quantitative data and more important additions have been made to this data.2 Once again there has been considerable debate on the intermediacy of free-radicals in iron(III)-mediated alkane oxidation reactions and there appears in the literature to be a general consensus that radicals are involved in some of these reactions.3 2 Initiators promoters reagents and precursors The search for alternative methods for generating and utilising radicals in synthesis is a high priority.Recently Jang has shown that hypophosphorous acid can mediate iodide and certain bromide reductions in aqueous solution.4 Recent work has demonstrated that hypervalent iodine reagents can be used to generate iodine radicals which can then undergo oxidation reactions. The intermediacy of free radicals has been demonstrated by trapping with TEMPO (tetramethylpiperidineN-oxyl) as shown in Scheme 1.5 Magnus et al. have developed oxidation procedures using iodosylbenzene and Royal Society of Chemistry–Annual Reports–Book B 55 Si O 1 Si O Si O N3 N3 SiO N3 N3 2 91% PhIO TMSN3 TEMPO –45 °C PhIO TMSN3 TEMPO –45 °C 90% Scheme 2 trimethylsilyl azide to mediate some interesting transformations.It has been found that treatment of 1 with TMSN 3 and PhIO in the presence of TEMPO leads to the diazide 2 and further experiments support the intermediacy of azido radical formation (Scheme 2).6 TEMPO has also been used as a trap for a range of organometallic reagents as illustrated by Nagashima and Curran (Scheme 3).7 The work provides a simple procedure for the transformation of a halide to an alcohol although the success of the transformation is dependent on the organometallic reagent used. The advent of combinatorial synthesis has demanded new reactions and technologies and although radical chemistry has much to o§er this area little work has been reported so far.However recently Curran and Hadida have reported a new reagent tris[(2-perfluorohexyl)ethyl]tin hydride which is readily prepared and will promote standard radical reductions under stoichiometric and catalytic conditions (using NaCNBH 3 ). The reactions are carried out under biphasic conditions using tert-butyl alcohol and (trifluoromethyl)benzene and the products are readily separated without using chromatography. 19F NMRcan be used to detect the presence of any impurities (which were not observed) and the reagent’s use was extended to some simple addition processes.8 3 Intramolecular reactions Radical cyclizations continue to find considerable utility in organic synthesis and in a very nice piece of methodology Crich et al.have examined the use of polarity reversal catalysis to improve the ratios of five- versus six-membered ring formation in vinyl radical cyclizations.9 It is well known that the ratio of endo to exo products is directly 56 S. Caddick et al. n–C6H13M TEMPO THF –78 °C – room temp. N n–C6H13O M Yield (%) CuCN•ZnI CuCN•Li MgBr Li 26 68 70 78 Scheme 3 I OH OH H H OH TBTH 3 1 PhSeSePh/TBTH 5 1 3 Scheme 4 related to concentration; the use of a high stannane concentration is required to obtain the 5-exo products. The problem is that these conditions may lead alternatively to direct reduction and therefore it is important to be able to modify the concentration but still minimize rearrangement; this requires the use of a more e¶cient hydrogen atom donor.Benzeneselenol is an excellent hydrogen atom donor for alkyl radicals [k 25 \2.1]109 s~1 cf. tributyltin hydride (TBTH) k 25 \2.4]106 s~1] and can be generated by reaction of PhSeSePh with TBTH. Treatment of 3 with stoichiometric TBTH and catalytic PhSeSePh led to improved ratios of 5-exo products as shown in Scheme 4. Presumably benzeneselenol is a poor hydrogen atom donor for vinyl radicals; this is consistent with earlier work from the Crich group which had shown that benzeneselenol is a poor hydrogen atom donor for aryl radicals. Some other notable recent examples of intramolecular cyclization reactions include addition of alkyl radicals generated from 4 to enynes using TBTH or SmI 2 to give dienes 5.10 Fu and Hays report addition of a-alkoxyl radicals to alkenes; the generation of the a-alkoxyl radical uses the addition of TBTH to aldehydes and is perhaps unsurprising.However the reactions are carried out using only 5–15% (Bu 3 Sn) 2 Oand 0.5 equiv. of PhSiH 3 ; the reaction proceeds by generation of TBTH using the known transformation of tin alkoxides with silicon hydrides. The procedure is simple to carry out and proceeds to give good yields of cyclization products (Scheme 5).11 Russell and Li have described cyclization of N-phenylacrylamide with ButHgI–KI followed by photolysis with Ph 2 S 2 as shown in Scheme 6.12 The reactions succeed because the initially formed a-carbonyl radicals are relatively unreactive toward PhSSPh but the product nucleophilic radicals trap out rapidly. Booker-Milburn et al. have extended some of their results on iron(III)-mediated radical cyclization reactions.13 They have found that cyclopropanone acetal undergoes oxidative cyclization with Fe(NO 3 ) 3 and can be trapped with external radical 57 Reaction mechanisms Part (iii) Free-radical reactions X O Br X O 5 4 SmI2 Bu tOH DMPU 79–84% TBTH AIBN 80 °C 32–74% O Ph OH Ph Ph OH + (Bu3Sn)2O PhSiH3 EtOH AIBN 80 °C 85% 1.2 1 or Scheme 5 Scheme 6 Me3SiO EtO SPh EtO O 66% Fe(NO3)3 (PhS)2 DMF Scheme 7 traps to give the desired product in good yields.The use of ferric nitrate appears to be advantageous even when preparing the chlorine atom transfer products and has promise as a non-tin method for the production of carbon-centred radicals (Scheme 7). The use of Lewis acids has become extremely popular in radical chemistry usually as a method for attempting to control the stereoselectivity of a particular process.However Bowman et al. have elegantly shown the di§erential reactivity of a complexed and thus electrophilic aminyl radical to great e§ect in some tandem cyclization reactions as exemplified in Scheme 8.14 The addition of aryl radicals to cyclic vinylsilanes has been reported by Mignani and co-workers who have used this to prepare novel bicyclic adducts (Scheme 9).15 The radical variant of the Brook rearrangement described by Tsai and co-workers has been used to develop some nice cyclization sequences and an extremely clever extension has been recently reported.16 The incorporation of the radical acceptor onto the silane to allow migration and thus allow ultimate trapping by addition is an interesting concept which may find some use in target synthesis (Scheme 10).58 S. Caddick et al. PhSe N Bn TBTH MgBr2•OEt2 27% N Bn Scheme 8 Si Ph Ph N H Br Pr nSnH AIBN 40% Si NH Ph Ph 3 Scheme 9 Si Br O TBTH AIBN HO OH + HO OH 21% 40% Scheme 10 Sibi and Ji have described an investigation into the radical cyclization of Nenoyloxazolidinones. The use of oxazolidinones in mediating diastereoselective radical reactions has been fairly extensively explored; one of the problems which may arise is the predominant conformation at low temperatures. For example treatment of 6 with TBTH under photochemical conditions gave no desired cyclization but by carrying out the reaction at elevated temperature the desired cyclization product 7 was isolated (Curtin–Hammett principle). Most interesting was the behaviour of the substrate toward tris(trimethylsilyl)silane (TTMSS) which under analogous conditions gave only a 13% yield of the desired product.The authors propose that the presence of tri-n-butyltin halide a§ects conformation and consistent with this hypothesis the addition of tri-n-butyltin chloride to the TTMSS-mediated reaction led to good yields of cyclized product. Indeed even the TBTH-mediated reaction showed an improvement when carried out in the presence of the added tin chloride reagent (Scheme 11). Although tri-n-butyltin chloride is likely to be a§ecting the conformation it is worth noting the poor yields of cyclized products that are isolated when reactions are carried out in the presence of an additive at room temperature.17 Togo et al. have proposed that nitrogen-centred radicals can be generated by irradiation of the parent amine and diacyloxyiodoarenes using a tungsten lamp to give bicyclic products 8 in moderate to good yields.18 The presence of the sulfonyl group was essential for cyclization; when other electron-withdrawing groups were used (trifluoroacetyl benzoyl etc.) and if a suitably positioned hydrogen was available an alternative Ho§man–Loßer–Freytag pathway could be observed.The same workers have described related work on alkoxylation (Scheme 12).19 Some intramolecular substitution reactions of sulfonyl-substituted indoles and related systems have been reported. Thus fused indoline systems 9 were synthesised in 59 Reaction mechanisms Part (iii) Free-radical reactions Scheme 11 NH SO2CF3 I2 hn 40–80% N SO2CF3 8 OH O I2 hn ArI(O2CMe)2 60% Scheme 12 good yield by ipso-substitution of the sulfonyl residue and vinyl and aryl radical additions were demonstrated (Scheme 13).20 Radical based carbonylations developed by Ryu and others have gained increasing utility in synthesis and Fallis and Brinza have described a tandem reaction involving the cyclization of acyl radicals onto hydrazones as shown by the transformation of 10 into 11 (Scheme 14).21 In the natural product area Murphy and co-workers have extended their versatile tetrathiafulvalene(TTF)-mediated radical polar crossover technology to model studies of Aspidosperma alkaloids as shown in the transformations in Scheme 15.The incorporation of the amide functionality by trapping the intermediate sulfonium species is a very elegant method for the introduction of such a useful functional group.22 60 S.Caddick et al. TBTH AIBN N O 9 57% N Br SO2Tol TBTH AIBN N 31% N TolSO2 Br O Scheme 13 H Br N Ph2N 10 AIBN C6H6 TBTH 80 °C 1100 psi 5 h CO NHNPh2 O 11 69% Scheme 14 N N2 + SO2CH3 TTF CH3CN 48 h 41% N HN CH3 O SO2CH3 Scheme 15 4 Intermolecular reactions From a synthetic viewpoint intermolecular radical reactions have been less extensively used than intramolecular variants; however in the last few years there has been an increase in activity in this area. Of course intermolecular radical reactions are wellestablished in the polymer area. In attempts to develop methods for the synthesis of polymers containing multiple stereogenic centres Porter et al. have examined the e§ect of a range of chiral auxiliaries on simple radical telomerizations of acrylamides and 61 Reaction mechanisms Part (iii) Free-radical reactions I B O O B O O 71% OBu OBu TBTH ln•(initiator) Scheme 16 Br Br TBTH AIBN CN H H CN Br 59% H H CN Br H H CO2Me CN 30% TBTH AIBN CO2Me Scheme 17 conclude that the penultimate chiral centre controls the stereochemistry of the ultimate chiral centre.The nature of the e§ect is dependent on the auxiliary used; thus with oxazolidines the erythro product is formed but with sultams the threo isomers are formed.23 The versatility of the carbon–boron bond in organic synthesis makes methods for its introduction into organic molecules of particular interest. Batey et al. have described the generation of a-boryl radicals which undergo addition and substitution reactions as shown in Scheme 16. The report showed using competition experiments that such radicals are ambiphilic and yields of adducts are optimal when telomerization is avoided.24 The related use of a-bromo radicals has also been explored by Tanabe et al.who have shown that gem-dibromocyclopropanes undergo highly stereocontrolled sequential radical addition reactions. The first addition leads to a monobromocyclopropanone which of course could have considerable synthetic potential in non-radical reactions; however the authors show its ability to undergo further inter- or intramolecular reactions which proceed with inversion due to steric hindrance (Scheme 17).25 Perhaps one of the most innovative developments in this area comes from Dang and Roberts who have described a superb new homolytic aldol reaction.26 It has been shown that acyl radicals will undergo radical addition to alkenes although it is often ine¶cient due to poor hydrogen atom abstraction of the adduct radical from the donor.These workers showed that thiols can be used as catalysts to abstract the acyl 62 S. Caddick et al. R H O + OAc R O OAc RSH In 60 °C 55–80% CATALYTIC CYCLE R O • OAc R H O R O OAc RS• RSH R O OAc RSH • Scheme 18 hydrogen e¶ciently and thence to act as a hydrogen atom donor to the adduct radical as shown in the catalytic cycle illustrated in Scheme 18. The reactions proceed in moderate to good yields and there is now a clear and exciting opportunity for asymmetric catalysis using a chiral non-racemic hydrogen atom donor. Substitutions Peukert and Giese have reported an important radical-induced S N 1 substitution reaction.27 They showed that radicals 12 and 13 produce 15–18 via a common intermediate proposed to be 14 (Scheme 19).The understanding of such mechanistic pathways is essential for the design of therapies which involve DNA modification. Barton and Fontana have extended their work on radical based transformations of carboxylic acids to the synthesis of dialkyl selenides. As with the related transformations which lead to phosphonic acids and thiols the photolysis of pyridinethione oxycarbonyl (PTOC) esters with elemental selenium gave dialkyl selenides.28 The addition of aminyl radicals to allylstannanes provides a basis for a reductive allylation of sulfonyl azides by allylstannane as shown in Scheme 20.29 The generation of the aminyl radicals takes place by addition of the stannyl radical to the azido 63 Reaction mechanisms Part (iii) Free-radical reactions O Ph OR OPO(OEt)2 12 O Ph OR • • OPO(OEt)2 13 O Ph OR • + 14 O Ph OR OMe O Ph OR O Ph OR O Ph OR OMe OMe OMe 15 16 17 18 MeOH TBTH Scheme 19 SO2N3 + SnPh3 AlBN Benzene SO2NH 91% Scheme 20 R N2 O + SnBu3 i AlBN Benzene R O 60–80% ii KF–H2O Scheme 21 functional group.The reactions appear to work well using a range of substrates and this is an important addition to the growing use of azides in radical transformations. The addition of stannyl radicals to carbenoids has been described by the same group giving a-stannyl ketone radicals which can be quenched using a hydrogen atom donor or by addition (Scheme 21).30 Allyl sulfones have been shown by Chatgilialoglu et al. to be useful partners in simple radical allylation reactions.31 Quiclet-Sire and Zard have described a very simple and elegant radical allylation sequence which has been used to give a range of interesting products.The reactions proceed because the allyl aryl sulfone is used in excess (3–6 equiv.) and inevitably is the species which performs the allylation; the ArSO 2 radical does not undergo a-elimination and therefore undergoes addition to 64 S. Caddick et al. Scheme 22 CF3 Ph 20 49–61% Ph SO2CF3 (19) AlBN Scheme 23 N Boc SO2Tol N Boc SnBu3 60% TBTH AlBN Scheme 24 the alkly allyl sulfone which after a-elimination then propagates the chain. Clearly it is generally possible to intercept the intermediate radical with another addition process providing it is faster than the allylation (Scheme 22).32 Sulfones have also gained utility in a novel alkynylation procedure described by Gong and Fuchs.They reported alkynylation of activated and unactivated hydrocarbons using alkynyl trifluoromethyl sulfone 19 with appropriate initiation. The mechanistic details are still unclear and may involve either direct ipso substitution or carbene formation followed by rearrangement. Either case leads to the formation of the trifluoromethylsulfonyl radical which can undergo a-elimination and in a very elegant experiment these workers treated the sulfone 19 with an alkene and isolated addition product 20 in good yields (Scheme 23).33 Another example of ipso substitution but using an aryl sulfone is shown in Scheme 24. Thus treatment of the indoline-7-sulfone with TBTH gives the desired stannane presumably via radical ipso substitution.34 Minisci and co-workers have also recently described an ipso substitution reaction of vinyl and aryl chlorides.35 65 Reaction mechanisms Part (iii) Free-radical reactions O N Ph O O Lewis acid R–I TBTH Et3B O2 CH2Cl2 78 °C O N Ph O O R 0.5 MgI2 0.5 Ligand 86% Yield 79% ee O N N O Ligand = Scheme 25 Sn CH3 H 21 Stereoselectivity More reports on studies relating to asymmetric radical reactions have appeared and such is the interest that there is a new book on the subject.36 The use of substrate37 or induced-substrate (auxiliary) control38 as a mechanism for achieving stereocontrol has been described.An alternative to these strategies is the use of a reagent based approach which may employ Lewis acids and can pave the way for catalysis.39 The major benefit of using a reagent based strategy is really only founded if a catalytic variant can be developed.In order for catalysis to be viable there are several classical problems which need to be addressed; of particular importance is the dissociation of the catalyst –substrate to enable turnover. Sibi et al. have described the first example of a catalyst which promotes enantioselective radical additions to electron deficient alkenes as shown in Scheme 25. The choice of such a transformation is not only synthetically important but also provides a basis for turnover as the substrate and products di§er in their Lewis basicity. The yields were good and the enantioselectivities are very promising. It will be interesting to see how widely these principles can be used; perhaps such asymmetric radical reactions will become powerful tools in synthesis.40 A conceptually di§erent approach has been described by Curran41 and Roberts.42 In the Curran approach a C 2 -symmetric chiral non-racemic tin hydride 21 has been prepared and used in the reduction of 22 which proceeds to give modest but meaningful levels of enantioselectivity (Scheme 26).The Roberts procedure uses an optically active thiol thus avoiding the use of tin reagents. The group had previously demonstrated that hydrosilylation of prochiral alkenes can be improved by using a thiol catalyst to accelerate the hydrogen atom transfer step. In a beautifully conceived approach the feasibility of enantioselective 66 S. Caddick et al. Ph Ph O Br 12–70% Yield 11–40% ee In Ph Ph O H 22 21 Scheme 26 O O O O Ph3Si * Ph3SiH In R*SH 23 72% (50% ee) Scheme 27 hydrogen atom transfer in the enantioselective hydrosilylation of methylenelactone 23 was demonstrated.Although the levels of enantioselectivity are presently modest it should be possible to improve the method (Scheme 27). References 1 P. J. Parsons C. S. Penkett and A. J Shell Chem. Rev. 1996 96 195; C. H. Schiesser and L. M. Wild Tetrahedron 1996 52 13 265. 2 S. J. Garden D. V. Avila A. L. J. Beckwith V. W. Bowry K. U. Ingold and J. Lustyk J. Org. Chem. 1996 61 805; W.R. Dolbier Jr. X. X. Rong B. E. Smart and Z.-Y. Yang J. Org. Chem. 1996 61 4824; C. Tronche F. N. Martinez J. H. Horner M. Newcomb M. Senn and B. Giese Tetrahedron Lett. 1996 37 5845. 3 D.H.R. Barton Chem. Soc. Rev. 1996 237; F. Minsici F. Fontana S. Araneo F.Recupero and L. Zhao Synlett 1996 119; D. W. Snelgrove P. A. Macfaul K. U. Ingold and D. D. M. Wayner Tetrahedron Lett. 1996 37 823; M. Newcomb P. A. Simakov and S.-U. Park Tetrahedron Lett. 1996 37 827. 4 D.O. Jang Tetrahedron Lett. 1996 37 5367. 5 M. Ochiai T. Ito H. Takahashi A. Nakanishi M. Toyonari T. Sueda S. Goto and M. Shiro J. Am. Chem. Soc. 1996 118 7716. 6 P. Magnus J. Lacour P. A. Evans M. B. Roe and C. Hulme J. Am. Chem. Soc. 1996 118 3406. 7 T. Nagashima and D. P. Curran Synlett. 1996 330. 8 D.P. Curran and S. Hadida J. Am. Chem. Soc. 1996 118 2531. 9 D. Crich J.-T. Hwang and H. Liu Tetrahedron Lett. 1996 37 3105. 10 J.-P. Dulcere E. Dumez and R. Faure Synlett 1996 391. 11 D. S. Hays and G. C. Fu J. Org. Chem. 1996 61 4. 12 G. A. Russell and C. Li Synlett 1996 699.13 K. I. Booker-Milburn B. Cox and T. E. Mansley Chem. Commun. 1996 2577. 14 W.R. Bowman P. T. Stephenson and A. R. Young Tetrahedron 1996 35 11 445. 15 D. Damour M. Barreau F. Dhaleine G. Doerflinger M. Vuilhorgne and S. Mignani Synlett 1996 890. 16 Y.M. Tsai K. H. Tangard W. T. Jiaang Tetrahedron Lett. 1996 52 7767. 17 M.P. Sibi and J. Ji J. Am. Chem. Soc. 1996 118 3063. 18 H. Togo Y. Hoshina and M. Tokoyama Tetrahedron Lett. 1996 37 6129. 19 T. Muraki H. Togo and M. Tokoyama Tetrahedron Lett. 1996 37 2441. 20 S. Caddick K. Aboutayab K. Jenkins and R. I. West J. Chem. Soc. Perkin Trans. 1. 1996 675. 21 I. M. Brinza and A. G. Fallis J. Org. Chem. 1996 61 3580. 22 M. Kizil C. Lampard and J. A. Murphy Tetrahedron Lett. 1996 37 2511. 23 N. A. Porter R. L. Carter C. L. Mero M. G. Roepel and D.P. Curran Tetrahedron 1996 52 4181. 24 R. A. Batey B. Pedram K. Yong and G. Baquer Tetrahedron Lett. 1996 37 6847. 25 Y. Tanabe K. Wakimura and Y. Nishii Tetrahedron Lett. 1996 37 1837. 26 H.-S. Dang and B. P. Roberts Chem. Commun. 1996 2201. 27 S. Peukert and B. Giese Tetrahedron Lett. 1996 37 4635. 28 D. H. R. Barton and G. Fontana Tetrahedron 1996 52 11 163. 67 Reaction mechanisms Part (iii) Free-radical reactions 29 H.-S. Dang J. Chem. Soc. Perkin Trans. 1 1996 1493. 30 H.-S. Dang J. Chem. Soc. Perkin Trans. 1 1996 769. 31 C. Chatgilialoglu A. Alberti M. Ballestri D. Macciantelli and D. P. Curran Tetrahedron Lett. 1996 37 6391. 32 B. Quiclet-Sire and S. Z. Zard J. Am. Chem. Soc. 1996 118 1209. 33 J. Gong and P. L. Fuchs J. Am. Chem. Soc. 1996 118 4486. 34 K. Aboutayab S. Caddick K. Jenkins S. Joshi and S. Khan Tetrahedron 1996 52 11 329. 35 S. Araneo R. Arrigoni H.-R. Bjorsvik F. Fnatana L. Liguori F. Minisci and F. Recupero Tetrahedron Lett. 1996 37 6897. 36 Stereochemistry of Radical Reactions. D. P. Curran N. A. Porter and B. Giese VCH Weinheim 1996. 37 M. Roth W. Damm and B. Giese Tetrahedron Lett. 1996 37 351. 38 R. A. Ewin K. Jones and C. G. Newton J. Chem. Soc. Perkin Trans. 1. 1996 1107. 39 M.P. Sibi and J. Ji J. Org. Chem. 1996 61 6090. 40 M.P. Sibi J. Ji J. H. Wu S. Gurtlet and N. A. Porter J. Am. Chem. Soc. 1996 118 9200. 41 D. Nanni and D. P. Curran Tetrahedron Asymm. 1996 7 2417. 42 M.B. Haque and B. P. Roberts Tetrahedron Lett. 1996 37 9123. 68 S. Caddick et al.

ISSN:0069-3030    

DOI:10.1039/oc093055

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

4 Aliphatic and alicyclic chemistry By PETER QUAYLE Department of Chemistry University of Manchester Manchester M13 9PL UK 1 Introduction This year saw the passing of an icon of contemporary organic chemistry. It is fitting therefore that a short personal account of the development of the Birch reduction should have appeared.1 As pointed out by the author application of the Birch reduction to heterocyclic systems has received scant attention but has been the subject of a timely review.2 World-wide interest in the chemistry of fullerenes,3 buckybowls4 and enediynes5 continues unabated. Applications of combinatorial6 and solid-phase techniques7 are now well established and find uses in many diverse areas of synthesis ranging from medicinal chemistry to catalyst design.8 A resurgence in interest in carbohydrate chemistry is manifested in the appearance of seminal articles by Danishefsky9a and Fraser-Reid9b on the chemistry of unsaturated sugars.An extensive review by Boons10a on oligosaccharide assembly and articles concerned with the synthesis of inhibitors of carbohydrate-processing enzymes10b and glycosphingolipid biosynthesis11a all attest to a growing awareness in the synthetic community of this much neglected area of natural product chemistry.11b Multifarious aspects of bioorganic chemistry continue to be the focus of much attention.12 From the parochial viewpoint of the synthetic chemist the practical use of catalytic antibodies for the catalysis of a variety of synthetic transformations is now a real possibility.12a Enzymemediated transformations,13 amino acid chemistry,14 reactions in aqueous media15 and higher order cycloaddition reactions16 have again come under scrutiny.The synthesis and chemistry of organofluorine compounds have enjoyed something of a renaissance of late,17a certain aspects of which may have dramatic consequences on the ecosystem as a whole.17b The literature concerned with organometallic-based18 transformations including controlled methods for the polymerisation of olefins,18 continues to expand exponentially pride of place in this area continues to be the burgeoning use of palladium-mediated19 transformations whilst organo-titanium,20 - zirconium,21 -samarium,22 -ruthenium23 and -zinc24 reagents continue to gain importance. The realisation that these can be used in ‘tandem’ or cascade25 reactions can greatly simplify approaches to a variety of structurally complex molecules and presumably these reagents will be the focus of further attention in the future.The development of tandem reactions in general is currently much in vogue a definitive appraisal of much of this chemistry can be found in a compilation of articles edited by Wender.26 The use of free radicals in organic synthesis27 has been extensively re- Royal Society of Chemistry–Annual Reports–Book B 69 appraised this year including a compilation par excellence by Giese et al.28 which is a gold-mine of information. The underlying chemical principles associated with ‘molecular recognition’,29 self replication30 and self assembly31 phenomena continue to attract academic interest and practical applications of functionalised supramolecular assemblies32 are now on the horizon.It should not be forgotten that many of the advances in these areas are themselves associated with the continued development of advanced analytical tools e.g. electrospray mass spectrometry33 and X-ray crystallography.34 O O O N S O R OH HO 1a epothilone A (R = H) 1b epothilone B (R = CH3) OMe H N S H H 2 OBz H OAc O O AcO OH HO O BzNH Ph O OH 3 The subtlety of molecular recognition in vivo is highlighted this year by the isolation35 a of epothilones A 1a and B 1b which exhibit cytotoxic activity towards mouse fibroblasts and in vitro activity against breast and colon cell lines. It is indeed ironic that relatively uncomplex natural products such as 1 and curacin35b 2 have the same biological activity and mode of action as more complex structures such as Taxol 3 whilst there is no apparent structural homology between the two compounds.Furthermore it is rather poignant that Danishefsky36 reported the total synthesis of 1 within six months of the report of its structure! Some would question the merits of funding research programmes directed towards the synthesis of newly isolated natural products such as prymnesin-237 4 or maitotoxin38 5. However it is only by attempting such synthetic endeavours that we realise the inadequacies of the synthetic methodology to 70 Peter Quayle O O O O O O O O O Cl Me HO NHR HO OH O O OH Cl O O O HO OH HO OH OH OH OH OH OH OH OH O O OH OH OH Cl OH OH Me O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O Me Me OH HO H H H H H H Me Me Me H H Me H Me H Me H H OH H H OH HO H OH H H H H HO NaO3SO H H OH H H H H HO Me OH Me OSO3Na HO Me OH H OH OH H Me H Me H HO HO OH H H H H HO H H H HO H OH HO H H OH H Me OH H Me H H H HO Me Me H H H H H Me Me Me OH OH OH A B C D E F G H I J K L M N 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 91 5¢ 1¢ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z A¢ B¢ C¢ D¢ E¢ F¢ 142 140 164 135 130 125 120 115 110 105 100 155 95 90 85 80 150 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 1 143 144 5 4 145 71 Aliphatic and alicyclic chemistry O O O O O HO OH HO OH HO OH HO NHAc O HO O O O O O OH OH HO HO HO (CH2)12CH3 N H (CH2)14CH3 O OH H3C HO OH OH 6 O O HO HO OH 7 HN CO2H N NH O Me O Me O HN HN HN NH Me O HO2C O O Me Me OMe Me O 8 O Me Me O OH OH O Me OH O O OH OH Me O Me OH O OR Me Me O Me OMe HO Me Me OH MeO R OR1 9 swinholide A R = R1 = Me O O Me Me HN N O Me Me Me N O (+)-paraherquamide B 10 H Me 72 Peter Quayle O N O O O R O N O O O R Ph i–iii I N RAM H O iv v H2N O [ref.45( a)] [ref. 47( a)] [ref. 47( b)] O O Br + ZnBr vi vii O O R cat. R + [ref. 48] PCy3 Ru PCy3 Cl Cl cat. = Ph S OSiMe3 R1 R + R3CHO + R2NH2 viii ix HO R3 NHR2 R1 [ref. 50] Scheme 1 Reagents and conditions i LDA (2 equiv.) THF 0 °C; ii PhCH 2 Br (2 equiv.); iii NH 4 Cl (aq.); iv Bu 3 SnPh ultrasound 40 W Pd0; v trifluoroacetic acid (TFA); vi PdII THF room temp. 18 h; vii MeONa MeOH 70 °C; viii Sc(OTf) 3 (10 mol%); ix LiBH 4 . 73 Aliphatic and alicyclic chemistry O OTBS S S O O HO H CH3 H OH H H H HO H [ref. 51] steps N OH HO H HO (–)-rosmarinecine O RO O O2N O OG* + [ref. 52] Et H OH H 55% (1:1 mixture of isomers) [ref.54] [ref. 56] i ii I N X Y Ac Pd0 X N Ac Y Et (continued) 74 Peter Quayle O RO A O Br O OR O H A 70–80% A = NTs C(CO2Me)2 O O O SePh O Pd0 iii 65% O O O H H H H H [ref. 57] [ref. 58] [ref. 62] X Cr(CO)3 X R R1 32–87% iv v Scheme 2 Reagents and conditions i 0.6 equiv. Et 2 AlCl 3% Ti(OPr*) 4 ; ii O 2 ; iii Bu 3 SnH AIBN heat; iv RC–– – CH; v R@C–– – CH. 75 Aliphatic and alicyclic chemistry S C7H15 OBn OMe OMe + SiMe3 C7H15 OBn OMe –e– (ref. 64) 53% (ref. 65) OMe OMe OH OBn OAc H OAc O MeO OBn O –e– 68% Scheme 3 hand and this realisation provides the impetus for the development of more selective and economic synthetic transformations.23b In terms of total synthesis a number of elegant reports have appeared this year including the synthesis of the Mbr-1 antigen 6,39 macrolactin A 7,40 microcystin-LA 8,41 swinholide A 9,42 Taxol 143 and paraherquamide B 10.44 2 Aliphatic chemistry General A major growth area in recent years has been the interest in solid-phase organic synthesis.There are a myriad examples this year dealing with applications of this technique a timely review7 provides a comprehensive guide to those reactions which have succumbed to this methodological onslaught and perhaps more importantly an indication of those reactions which have not been attempted on solid support. Examples of the more recent and potentially general applications include aldol,45 iterative aldol,46 Suzuki47a and palladium-mediated coupling reactions of organozincs 47b ring-closure metathesis reactions,48 combinatorial approaches to chiral phosphine ligand synthesis49 and Mannich-type reactions,50 Scheme 1.The current interest in developing ‘cleaner’ more e¶cient processes has resulted in the report of a number of tandem or cascade reaction sequences. The basic notion behind such reactions of course is not new and dates back to Robinson’s tropinone synthesis of 1917. However what is astonishing is the degree of sophistication which can now be brought to bear in terms of the timing of individual bond-forming reactions and the complexity of the intermediates which can now be incorporated into such sequences. A number of representative examples including a classical polyene cyclisation51 [using optically pure starting materials via Sharpless asymmetric di- 76 Peter Quayle Scheme 4 Reagents and conditions i Tf 2 O pyridine; ii AgOTf; iii HNBn 2 LiBF 4 CH 3 CN 62%; iv Et 2 NSF 3 THF room temp.94%; v LIP–MCPBA. hydroxylation (AD) chemistry] tandem [4]3]–[3]2] cycloadditions of nitroalkenes 52 alkylation–homoaldol reactions,53 titanium-catalysed cascades of unsaturated alanes,54 enzyme-initiated oxidation–Diels–Alder reactions,55 palladiumcatalysed cascade reactions,56,57 radical cascades58–60 and Michael–Dieckmann sequences 61 and multiple metal-mediated cycloaddition reactions,62 Scheme 2. In a similar vein preparative electrochemical reactions have been regarded by most syn- 77 Aliphatic and alicyclic chemistry O OTBS OTf H H + O Li PhSO2 OBn O OTBS SO2Ph O OBn H H 98% RO H SiPh3 O i (ref. 71) [ref. 71( a )] RO SiPh3 O Li CHO RO O SiPh3 OH steps O N O O S 52% W-lamp (500 W) H O H H SPyr (ref.72) O OH O 75% overall yield Scheme 5 Reagents and conditions i BunLi THF. thetic chemists with a fair degree of scepticism. The recent report of a very simple electrochemical reactor63 should engender further investigations into this technique as such processes can be high yielding easy to perform and again can a§ord rapid access to quite complex structures,64,65 Scheme 3. Oxidation Epoxides are well recognised as being valuable synthetic intermediates,66–68 Scheme 4 a situation which has been enhanced considerably since the development of the Sharpless–Katsuki reaction. In related areas Katsuki69a has reported that Mn–salen complexes e§ect highly enantioselective epoxidation of enol derivatives whilst Bhakuni69b has demonstrated that liposomised m-chloroperbenzoic acid (MCPBA) e§ects highly enantioselective epoxidation of functionalised olefins Scheme 4.The synthetic utility of oxiranyl anions is becoming more widespread70,71 as is the chemistry of oxiranyl radicals,72 Scheme 5. The synthetic chemistry of endo-peroxides derived from cyclic dienes is not well developed in areas other than the reduction of the O–O 78 Peter Quayle O O i 74% OBu OH + OH OBu (ref. 73) ascaridole 9 1 11 Scheme 6 Reagents and conditions i BunLi THF,[78 °C. bond. In an interesting development Little73 has demonstrated that peroxides such as 11 undergo facile reactions with reactive organometallics to a§ord synthetically versatile mono-alkylated allylic diols Scheme 6. Dimethyl dioxirane (DMDO) and its derivatives continue to find application as selective oxidising agents,74,75 as does methylrhenium trioxide (MTO),76 Scheme 7.Of note is Yang’s77 report of the first enantioselective epoxidation of trans-olefins which utilises the C 2 -symmetric reagent 12 Scheme 7. The use of a silicon residue as a masked hydroxy group continues to find applications78 and has been reviewed,79 whilst recent methodological improvements by Fleming80 will further expand the scope of this procedure Scheme 8. The finer mechanistic subtleties81 of the Sharpless asymmetric dihydroxylation reaction continue to be unravelled. Irrespective of these controversies synthetic applications82 continue to be reported as illustrated in Scheme 9. In contrast to the accepted paradigm for dihydroxylation reactions it was reported that the hindered olefin 13 underwent dihydroxylation (in the presence of toluene-p-sulfonamide) to a§ord the diol 14 with p-facial selectivity opposite to that expected for such reactions,83 Scheme 9.Further reports from the Sharpless group have demonstrated the viability of catalytic aminohydroxylation84a and diamination84b reactions Scheme 9. Other useful oxidation reactions reported this year include the conversion of allenes into a-hydroxy ketones,85 the formation of quinols from phenols,86 and the aerobic oxidation of alkanes in the presence of copper salts.87 Functional group preparations The preparation of bis- and tris-ketenes,88 the use of Weinreb’s amide on solid support for the synthesis of ketones,89 and radical carbonylation reactions have been described this year.90 The direct acylation of olefins with carbon monoxide at ambient temperature in the presence of ‘waterless’ zeolites such as H-ZSM-5 has been observed spectroscopically and has many industrial applications if its e¶ciency can be optimised 91 Scheme 10.Novel ketone amination,92 lanthanide-catalysed Mannich reactions 93 radical-promoted oximations94 and alkene aziridination95 sequences have also appeared. The use of the Mitsunobu96 reaction for the synthesis of amines from alcohols under mild conditions will doubtless find many synthetic applications as will direct allylic amination97 and azidonation,98 Scheme 11. The Wittig reaction has been reviewed:99 new synthetic applications include the olefination of lactones100 and control of double bond stereochemistry by remote polar functional groups.101 Functionalised alkenes are available from the reaction of electron deficient alkenes with nucleophilic carbenes102a,b or by novel radical-mediated 79 Aliphatic and alicyclic chemistry O O O OH i 99% AcO H ii 62% H O O O AcO O N Cr(CO)5 SPh O N Cr(CO)5 S+ iii 64% O– Ph Ph Ph Ph Ph O 92% (75% ee) iv O O O O O Br Br 12 catalyst = [ref.74( a)] [ref. 74( b)] [ref. 76] H Scheme 7 Reagents and conditions i dimethyldioxirane (DMDO) CH 2 Cl 2 0 °C; ii DMDO acetone,CH 2 Cl 2 0 °C; iii MTO,CH 2 Cl 2 MeOH,H 2 O 2 ; iv Oxone catalyst NaHCO 3 CH 3 CN H 2 O. 80 Peter Quayle Et SiPh2 OH OH OH Et 87% (ref. 78) i–iii O Ph2Si iv v HO (ref. 80) (I)-lavendulol 2 steps Scheme 8 Reagents and conditions i I`(collidine) PF 6 ~ CH 2 Cl 2 ; ii Bu 3 SnH–Et 3 B hexane; iii H 2 O 2 KF KHCO 3 ; iv HCl KF MeOH; v H 2 O 2 KHCO 3 KF.13 Scheme 9 Reagents and conditions i AD-mix-b MeSO 2 NH 2 H 2 O 2 ButOH; ii (DHQD) 2 PYR K 2 OsO 2 (OH) 4 Fe3` p-TolSO 2 NH 2 K 2 CO 3 ; iii (DHQD) 2 ·PHAL TsNClNa; iv ArN––Se––NAr. 81 Aliphatic and alicyclic chemistry Scheme 10 Reagents and conditions i MeSiCl 3 ; ii 180 °C; iii dicyclohexylcarbodiimide hydroxybenzotriazole; iv base E`; v R@M; vi Bu 3 SnH CO (95–100 atm) AIBN 80 °C; vii CO zeolite H-ZSM-5. reactions which do not rely upon organotin hydrides for initiation,103 Scheme 12. Yamamoto has developed a ‘catalytic’ Shapiro reaction which requires substoichiometric quantities (0.3 equiv.) of bases such as LDA or LiTMP. A formal synthesis of (])-a-cuparenone nicely demonstrates the utility of this improved procedure 104 Scheme 13. In a new development Fuchs has reported that ethynyl and vinyl trifluoromethyl sulfones undergo direct (regioselective) C–H insertion reactions under thermal or photolytic conditions generating the corresponding alkenes or acetylenes in good overall yields.105a,b Mechanistic investigations showed that these reactions proceeded via free radical pathways,105c Scheme 14.Bromoalkenes are versatile intermediates whose preparation is sometimes problematical. Reports this year provide simple solutions to the synthesis of a-haloenones106 and the (Z)-1- bromoalk-1-enes,107 Scheme 15. The synthesis of ethers and oxygen heterocycles has been addressed by a number of workers. Again the mild conditions associated with the Mitsunobu reaction have been used to good e§ect in the synthesis of a number of oxygen heterocycles.108 Cationic palladium complexes have been found to be e§ective for the promotion of hetero-Diels–Alder reactions between relatively unactivated dienes with aldehydes.109 The stereoselective introduction of glycosidic linkages continues to challenge the synthetic chemist.10a Two novel approaches to this problem110,111 are outlined in Scheme 16.Organometallic-based transformations are again much in evidence this year. As suggested last year,112 olefin metathesis reactions could have almost universal application now that well characterised readily accessible and functionally tolerant catalysts have been described.113 A few representative examples which hopefully indicate the potential scope of this reaction are shown in Scheme 17.114–123 Future developments in this area may well include a kinetic resolution strategy for asymmetric ring closure metathesis a theme which at present is at an embryonic stage of development.124 82 Peter Quayle O OBn BnO OBn Br OBn OSiMe3 i O NH CF3 O 55% (ref.92) O OBn BnO OBn OBn ii N H3C OBn (ref. 94) OH NC PBu3 + NTs 2 iii iv NH 2 76% (ref. 96) ArNO2 + CO + cat. NHAr + CO2 (ref. 97) N N R R cat. = Ru3(CO)12 + (R = H Me OMe Cl) Scheme 11 Reagents and conditions i (salen)Mn(N) (CF 3 CO) 2 O pyridine CH 2 Cl 2 [78 °C; ii PhSO 2 (CH 3 )C––NOBu Me 3 SnSnMe 3 hv; iii TsNH 2 PhH room temp. 24 h; iv Na` Naphth~ THF,[30 °C; v (PhIO)n TMSN 3 CH 2 Cl 2 ,[30 °C. O O O O O O H O O O O O H CO2Me 90% i (ref. 100) O OTBDPS HN SO2 Cl OTHP ii iii OTBDPS HN SO2 Cl OTHP CO2Me (ref. 101) 'single isomer' O O CO2Me OTHP O O 65% iv–vi O O N MeO OMe OMe OMe THPO O O O [ref.102( b)] Scheme 12 Reagents and conditions i Ph 3 P–– CHCO 2 Me PhMe 140 °C; ii LiN(SiMe 3 ) 2 HO 2 C(CH 2 ) 4 P`Ph 3 Br~; iii CH 2 N 2 Et 2 O; iv LiOH H 2 O; v DPPA Et 3 N; vi 2,2-dimethoxy-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazole heat; vii AIBN. PhMe heat. 84 Peter Quayle p-Tol CH3 O N Ph H H2N + p-Tol CH3 N N Ph + CH3 p-Tol N N Ph i 86% i 84% p-Tol CH3 CH3 p-Tol O CH3 CH3 CH3 p-Tol (ref. 104) (+)-a-cuparenone Scheme 13 Reagents and conditions i LDA (0.1 equiv.) Et 2 O. R SO2 CF3 + O CH3 O CH3 R i (major) ~ 90% [ref. 105( a)] SO2CF3 Ph + O Ph O 65% ii [ref. 105( b)] Scheme 14 Reagents and conditions i heat; ii AIBN heat. Palladium-catalysed coupling reactions continue to be used extensively,125–138 Scheme 18. Significant advances this year include the synthesis of oxygen heterocycles via sp2–X insertion reactions,139,140 and definitive mechanistic studies into Heck,141,142 amination143 and cine substitution144 reactions Scheme 19.The use of trifluoromethanesulfonates (triflates) in transition metal-catalysed coupling reactions is now well established,145 but problems may arise in the preparation of the triflates themselves. Netscher has presented a detailed study of such reactions and has shown 85 Aliphatic and alicyclic chemistry Scheme 15 Reagents and conditions i Oxone NaBr H 2 O CCl 4 ; ii Bu 3 SnH Pd(PPh 3 ) 4 . OH OH OBn OBn BnO BnO O OBn OBn BnO BnO i (ref. 108) 91% O OR RO RO O S O O CH3 H + O S O O O BnO OBn (ref. 110) O O O O BnO OBn ii BnO BnO O OBn O Si Osugar BnO BnO S Ph O O OBn OH BnO BnO Osugar iii (ref.111) 42–82% overall Scheme 16 Reagents and conditions i NCCH––PBu 3 (1.5 equiv.) PhH 100 °C; ii Raney Ni PhH heat; iii 2,6-di-tert-butylpyridine Tf 2 O Et 2 O–CH 2 Cl 2 . 86 Peter Quayle N BnO BnO O OMe O OBn N BnO BnO O OBn i 70% Ru Ph Ph PCy3 Cl Cl PCy3 catalyst A OMe MeO O O i OMe O O 94% MeO (ref. 114) (ref. 115) O H OTBS CH3 O O O H H O O O H H CH3 OTBS H 36% i (ref. 119) Scheme 17 Reagents and conditions i catalyst A (5% w/w) PhMe 110 °C; ii catalyst A (6 mol%) CH 2 Cl 2 room temp.; iii Cp 2 Ti––CH 2 THF 25 °C. that when the alcohol or phenol is hindered high yields of alternative products such as sulfinate esters can be obtained hindered bases such as 2,6-lutidine and DIPPA are preferred in these problem cases,146 Scheme 20. The beneficial e§ect of adding catalytic quantities of copper salts to Stille coupling reactions has been utilised by Nicolaou147 in the synthesis of bisglycals.The use of stoichiometric148 amounts of copper salts as a replacement for palladium in Stille couplings and copper-mediated intramolecular coupling of bis-stannanes are useful variations on this chemistry and fuel the mechanistic debate concerning these reactions,149 Scheme 21. Cuprates150 and highly coordinated zincates151 have been found to act as very selective metallating agents. Copper-catalysed enantioselective conjugate addition reactions of dialkyl zincs152 have also been reported albeit with moderates ees. These reports are of particular interest as the organozinc reagents themselves can be prepared in the presence of electrophilic functional groups which is not necessarily the case with other nucleophilic metal systems.The development of new ligands for asymmetric conjugate reactions of cuprates has again been the focus of much inter- 87 Aliphatic and alicyclic chemistry OMe OMe OTf O TBS O OMe OMe O TBS i 82% Bu3Sn n-C6H13 SO2CF3 H Ph n-C6H13 SO2CF3 H ii Ph I + 91% (ref. 125) (ref. 127) O HO NH SnBu3 O O O HO HN O O HN O OH O (±)-alisamycin OH O NH Br + O iii 64% (ref. 128) O Scheme 18 Reagents and conditions i Pd0; ii Pd0 80 °C PhH; iii Pd0 DMF–THF. est.153 The mechanism of cuprate additions to ynoates154 and the role of TMS iodide155 in the conjugate addition of alkylcopper reagents to enones have again been the subject of some scrutiny the intermediacy of Cu–p-complexes was proposed in both cases. In a definitive study Bertz156 has developed a new class of organocuprates which incorporate b-silicon substituents in the non-transferable ligand.These reagents have greater thermal stability than conventional cuprates yet exhibit enhanced reactivity towards enones in conjugate addition reactions Scheme 22. The Nozaki–Hiyama–Kishi reaction has found extensive application in organic synthesis a position which will doubtless be further maintained by the development of a cycle which is catalytic in chromium,157 Scheme 23. A variety of cobalt- and iron-catalysed coupling reactions have appeared this year which are also of interest due to their chemoselectivity158 or ability to couple with unreactive functionalities such as vinyl chlorides,159 Scheme 24. 88 Peter Quayle Br CH3 HO O H Me 73% i (ref.139) Me3Sn Ph + ArPd X Ph Ar (ref. 144) [Pd] Ph Ar ? Scheme 19 Reagents and conditions i Pd(OAc) 2 Tol-BINAP K 2 CO 3 PhMe 100 °C. N + (F3CSO2)2O + ROH ROSO2CF3 ROSOCF3 (ref. 146) competing process for hindered alcohols Scheme 20 Asymmetric transformations A striking example of an ‘absolute’ asymmetric reaction was reported by Sakamoto et al.160 in which photolysis of the crystalline thioamide 15 which exists in a chiral space group a§orded the b-thiolactam 16 with 94% ee at 58% completion. Feringa’s and Kellogg’s groups have reported that the versatile synthetic intermediate 17 can be obtained in essentially optically pure form ([99% ee) using second-order asymmetric transformations,161 Scheme 25. New catalyst systems for asymmetric cyclopropanations 162 Michael reactions,163 aldol,164 Mukaiyama-type reactions165,166 and Diels–Alder reactions167 represent useful additions to present methodology as does the first example of an enantioselective catalytic protonation of a silyl enol ether,168 Scheme 26.Desymmetrisation of polyols169 and epoxides170 is a potentially powerful strategy for asymmetric synthesis and has been further refined this year Scheme 27. The application of asymmetric reductions171–177 and aldol-type178–182 reactions continues to be explored for the synthesis of stereochemically complex intermediates as illustrated in Scheme 28. Asymmetric 1,3-dipolar cycloadditions have enormous synthetic potential a prospect which has been realised by a number of workers,183,184 Scheme 29. 89 Aliphatic and alicyclic chemistry Scheme 21 Reagents and conditions i Pd(PPh 3 ) 4 CuCl,K 2 CO 3 THF 25 °C 0.5 h; ii copper thiophene-2-carboxylate (1.5 equiv.) NMP 0 °C 15 min; iii CuCl (5 equiv.) DMF 60 °C.O O Bu 98% O O Bu 64% (ref. 156) Scheme 22 Reagents and conditions i,Bun (TMSCH 2 ) CuLi Et 2 O,[78 °C ca. 5 s; ii BuCu(thexyl) Li·LiCN Et 2 O,[78 °C ca. 5 s. 90 Peter Quayle Scheme 23 Reagents and conditions i CrCl 2 (15 mol%) Mn TMSCl THF room temp.; ii CrCl 2 (7 mol%) Mn TMSCl THF room temp.; iii p-TsOH cat. H 2 O. Ph Br + AcO Zn 2 Ph AcO i (ref. 158) 88% O Cl + BuMnCl O Bu i 74% (ref. 159) Scheme 24 Reagents and conditions i 3%Fe(acac) 3 THF NMP room temp. Scheme 25 Reagents and conditions i hv solid state; ii Candida antarctica n-hexane BunOH. 91 Aliphatic and alicyclic chemistry OSiMe3 Ph O Ph 89% (90%ee) (ref.168) Scheme 26 Reagents and conditions i (R)-BINOL-Me SnCl 4 2,6-dimethylphenol [80 °C. Scheme 27 Reagents and conditions i 2mol% catalyst B Et 2 O. 3 Alicyclic chemistry Cyclopropanes The Simmons–Smith cyclopropanation is undoubtedly one of the most synthetically useful methods for the preparation of cyclopropanes. Charette has published the results of in-depth spectroscopic185 and structural186 studies of the reactive intermediates generated during the course of these reactions. Synthetic applications by this187,188 and other groups189 have centred upon the use of asymmetric variations of this reaction in synthesis of U-106305 and FR-900848. Falck’s synthesis of FR-900848 utilised a diastereoselective coupling of lithiocyclopropanes,190a whereas the approach adopted by Zercher relied upon ylide chemistry for the installation of contiguous cyclopropanes,190b Scheme 30.The transition metal-catalysed decomposition of a- diazocarbonyl compounds has been exploited in both an intermolecular191 and intramolecular192–194 sense to provide a variety of functionalised cyclopropanes Scheme 31. The synthetic potential of the Kulinkovich195 reaction has been investigated by a number of workers who report that mono- and poly-cyclic cyclopropanes are readily accessible by this methodology Scheme 32. Hanessian196 and Warren197 have utilised intramolecular displacement reactions for the synthesis of optically active cyclopropanes. Wege198 has developed a highly convergent strategy to (^)-favelanone based upon a Diels–Alder reaction of the highly reactive cyclopropene 18 Scheme 33.92 Peter Quayle Scheme 28 Reagents and conditions i TiCl 4 [78 °C; ii (allyl)SnBu 3 ; iii (ipc) 2 BCH 2 CH––CHMe,[78 °C; iv H 2 O 2 NaOH. Cyclobutanes Cyclobutyl ketones are useful synthetic intermediates199 which are now readily available200 from substituted 1,4-dihalobutanes by treatment with lithium naphthalenide. Cycloaddition201 of ketones with cyclopentadiene at low temperatures (\ [30 °C) a§ords unstable [4]2] cycloadducts 19 which undergo [3,3] sigmatropic rearrangements to cyclobutanones 20 the formal products of [2]2] cycloaddition in good 93 Aliphatic and alicyclic chemistry CH3 N O O O + Ph N O– Ph + O PhN Ph CH3 N O O endo > 95 5 (93% ee) (ref 184) i O O Ph Ph Ph Ph O O Ti OTs OTs Me Me Catalyst C O Scheme 29 Reagents and conditions i catalyst C room temp.24 h. overall yields. Photocycloaddition reactions provide access to diversely functionalised cyclobutanes,202 as does the copper triflate203 variant of this procedure. Sequential cycloadditions of functionalised cyclobutadienes prepared in situ from cyclobutadiene –Fe(CO) 3 complexes provide a novel approach to the synthesis of oligomeric cyclobutanes–‘ladderanes’.204 The pKa of protons in the cubane 21 has been estimated as lying between 20.5 and 22.5 deprotonation of 21 can be e§ected using NaN(SiMe 3 ) 2 to form a stable anion which can be trapped with a variety of electrophiles,205 Scheme 34. Cyclopentanes Application of the Trost metal-catalysed Alder–ene reaction to natural product synthesis has gained momentum as exemplified in approaches to the picrotoxanes206 and pumiliotoxins,207 Scheme 35.Cobalt208 and samarium209 analogues of the Trost palladium reaction have also appeared. Tandem ketyl–olefin coupling reactions,210 nickel catalysed alkynyl enone cyclisations,211 and cyclisation of organozinc212,213 reagents provide valuable new strategies for the synthesis of fused cyclopentanes Scheme 36. Bicyclo[3.3.0]octanes and bicyclo[4.3.0]nonanes are readily accessible using Piers’s bifunctional organocopper chemistry,214 whilst spiro[cyclopentane-1,1@- indane]diones a structural feature of fredericamycin A may be obtained215 in optically pure form from readily available epoxy alcohol derivatives Scheme 37. The synthesis of cyclopentane derivatives via C–H insertion reactions is now well established Taber216 has developed semi-empirical rules which allow prediction of the stereochemical outcome of these reactions Scheme 38.The Pauson–Khand reaction has seen many developments advances this year including its application to solidsupported synthesis,217 photochemical activation218 and its application to the synthesis of cyclopentanes fused to carbohydrate219 and b-lactam220 templates Scheme 39. Analogous titanium221 and iron222 [2]2]1] cycloadditions further expand the potential scope of this general strategy whose synthetic utility will doubtless be the subject of future studies. Cyclohexanes The synthesis of functionalised cyclohexanes from aromatic compounds has seen 94 Peter Quayle Scheme 30 Reagents and conditions i N,N-dimethyl-2-butyl-1,3,2-dioxaboralane-2- carboxamide Zn(CH 2 I) 1,2-dimethoxyethane CH 2 Cl 2 0 °C; ii BusLi; iii [ICu(PBu 3 )]; iv O 2 ; v (CH 3 ) 3 S(O)CH 2 DMSO.something of a revival as highlighted in an overview of the area,223 Scheme 40. The Diels–Alder reaction has again been the subject of much scrutiny both from a theoretical224 and synthetic standpoint. The use of copper,225 niobium and tantalum226 complexes and boron-containing Brønsted–Lewis acids227,228 enable Diels–Alder reactions to be performed at low temperatures and with good to excellent levels of asymmetric induction. Some examples of interesting Diels–Alder reactions are given in Fig. 1 (see refs. 229–237). The total synthesis of (])-digitoxigenin238 and 95 Aliphatic and alicyclic chemistry O RO R1O OR2 O R1O OR2 CO2Et OR (ref 191) i OMOM C O N2 OMOM CO2Me H OMOM O H CO2Me 58% ii (ref 192) O O CHN2 O O CH3 O O O CH3 O 61%(90% ee) iii O O But But catalyst D Scheme 31 Reagents and conditions i EtO 2 CCHN 2 Rh(OAc) 4 CH 2 Cl 2 room temp.; ii Cu(acac) 2 ClCH 2 CH 2 Cl heat; iii [Cu(MeCN) 4 ]PF 6 catalyst D.(])-andrenosterone239 both utilise intramolecular Diels–Alder (IMDA) reactions as key steps albeit of di§ering types Scheme 41. Organometallic240–245 and free-radical cyclisations246,247 and conjugate addition reactions248–251 all provide ready access to functionalised cyclohexanes Scheme 42. Finally a general route to the synthesis of (more potent) analogues of the acetylcholinesterase inhibitor huperzine A 22 and their interaction with AChE has been reported.252 It is hoped that such studies will result in the development of new agents for the management of Alzheimer’s disease.96 Peter Quayle CO2Me Ph ( ) n OH Ph ( ) n n = 1 77% n = 2 89% [ref. 195( b)] R1 NR2 O LnTi R3 + R1 NR2 R3 50–75% [ref. 195( c)] i Scheme 32 Reagents and conditions i Ti(OPr*) 4 Pr*MgCl. Scheme 33 Reagents and conditions i LiEt 3 BH THF [78 °C; ii TFA CH 2 Cl 2 0 °C; iii ButOK ButOH. 97 Aliphatic and alicyclic chemistry OMe O O R I I R O i ii 45% overall for R = CH3 (ref 200) + O • R1 R2 O R2 R1 19 (ref 201) O R1 R2 H H 20 Claisen T > –30 °C Ha OMe Hb Hc + MeO MeO iii [ref. 202( a)] [4 + 2] (continued) 98 Peter Quayle Scheme 34 Reagents and conditions i Li cat. naphthalene THF 0 °C; ii H 3 O`; iii hv Pyrex filter PhH; iv naphthalene-2-methanol THF pyridine; v ceric ammonium nitrate dry acetone,[46 to 0 °C; vi NaN(SiMe 3 ) 2 .99 Aliphatic and alicyclic chemistry O Br TBDMSO TBDMSO CH3 O Br RO CH3 RO 70% i P P ( )3 (ref. 206) OBn OH H NH H H ii 61% (+)-pumiliotoxin C Scheme 35 Reagents and conditions i Pd(OAc) 2 (cat.) 2-diphenylphosphinobenzoic acid (cat.); ii (dba) 3 Pd 2 ·CHCl 3 (2.5 mol%) N,N@-bis(benzylidene)ethylene diamine (BEEDA) (5 mol%) polymethylhydrosiloxane (PMHS) (10 equiv.) AcOH (1 equiv.) dichloroethane. Medium large and polycyclic ring systems The use of [4]3] cycloadditions has been e§ectively utilised for the stereoselective synthesis of functionalised 8-oxabicyclo[3.2.1]octenes,253–255 which are themselves versatile synthetic intermediates. A related strategy has also been applied to the synthesis (])-5-epitreulenolide,255a Scheme 43. An intramolecular palladium-TMM cycloaddition reaction has been applied to the synthesis of ([)-isoclavukerin A256 whilst metal-promoted higher-order cycloaddition reactions have also been utilised to good e§ect for the synthesis of a variety of cycloheptane derivatives,257 Scheme 44.The synthesis of cyclooctanes is still dominated by the global preoccupation with the taxane diterpenoids. Representative approaches to the central core of this ring system include pinacol-type couplings,258 IMDA259 and intramolecular alkylation reactions as depicted in Scheme 45.260 Radical261 and metal-promoted262 ring enlargement reactions have general applicability to the synthesis of medium-sized rings. The synthesis of enediyne-containing macrocycles has again been the subject of much interest resulting in the synthesis of the basic core of C-1027263 and a functionalised model system of the neocarzinostatin chromophore.264 Most syntheses of this compound rely upon now well-established palladium-catalysed coupling reactions for the installation of the enediyne moiety.However in a novel departure Nicolaou has reported that macrocyclic enediynes can be prepared via a retro-Diels–Alder sequence 265 Scheme 46. The syntheses of a number of carbocycles of theoretical interest e.g. 23 24 and 25 Fig. 2 have appeared this year (see refs. 266–268). 100 Peter Quayle Scheme 36 Reagents and conditions i SmI 2 (1 equiv.) THF HMPA 0 °C; ii Bu 2 Zn BuZnCl Ni(COD) 2 (5 mol%) PPh 3 (25 mol%); iii R 2 Zn or RZnCl Ni(COD) 2 (5 mol%); iv Et 2 Zn (2 equiv.) MnBr 2 (5 mol%) CuCl (3 mol%) DMPU 60 °C 0.5–3h. 101 Aliphatic and alicyclic chemistry Scheme 37 Reagents and conditions i TMSBr,[78 °C; ii BF 3 ·OEt 2 0 °C.N2 O O MeO2C MeO2C O O 89% i (ref. 216) O O CO2Me O O 85% i N2 CO2Me Scheme 38 Reagents and conditions i Rh 2 (C 7 H 15 CO 2 ) 4 CH 2 Cl 2 . 102 Peter Quayle OMBn NTs O O NTs O H CO2H 'good yield' i,ii EtO2C EtO2C O EtO2C EtO2C iii 95% O MBnO OMe O O OMe H 30% iv (ref. 219) (ref. 218) (ref. 217) N BnO O N BnO O H 95% v,vi (ref. 220) O Scheme 39 Reagents and conditions i Co 2 (CO) 8 NMO CH 2 Cl 2 ; ii TFA CH 2 Cl 2 ; iii Co 2 (CO) 8 (1 atm) hv DME; iv Co 2 (CO) 8 CO(1 atm) 110 °C; v Co 2 (CO) 8 PhMe room temp.; vi heat. 103 Aliphatic and alicyclic chemistry OH MeO OH OH MeO O i 61% (ref. 223) HO (NH3)5Os2+ O (NH3)5O5 O 86% ii (ref. 223) O N But Cr(CO)3 O N But iii,iv (ref. 223) Scheme 40 Reagents and conditions i NaIO 4 ; ii but-3-en-2-one Pr 2 *NEt; iii MeLi; iv allyl bromide.R OSO2 O SO2 R (ref. 229) B F O O – N H H B O O O O Ph – F (ref. 230) OR (continued) 104 Peter Quayle OBn OR BnO OBn OBn BnO OR O O H CO2Me H OBn (ref. 232) N O OSiR3 MeO N MeO O CO2Me OH (ref. 233) O O O (ref. 234) O P(OEt)2 O OAc O PPh2 O (ref. 235) N O SOTol Boc N O Boc (ref. 236) Fig. 1 105 Aliphatic and alicyclic chemistry (continued) Scheme 41 Reagents and conditions i PhMe 200 °C 3 h; ii PhMe 200 °C 18 h; iii Nu~; iv CeIV; v Bun 3 SnH AIBN heat. 106 Peter Quayle OMOM MeO Li Fe(CO)3 OMe MeO + + BF4 – OMOM MeO OMe Fe(CO)3 OMe MeO O O H CN MeO O H steps NMe (ref. 244) O I CO2Me TBSO O CO2Me H TBSO (ref. 247) 85% v OH lycoramine Scheme 41 107 Aliphatic and alicyclic chemistry Scheme 42 Reagents and conditions i (dba) 3 Pd 2 ·CHCl 3 HCO 2 H dichloroethane room temp.; ii (CH 3 ) 2 C~CN (2 equiv.) [78 °C; iii H 3 O`; iv Pd0 CuI; v Bu 3 SnH NiII; vi heat; vii base; viii BusLi THF,[78 °C 5 min; ix MeOTf Et 2 O 0 °C 3 h.108 Peter Quayle Scheme 43 Reagents and conditions i EtMgCl (1 equiv.); ii Zn–Ag; iii 2,4-dibromopentan- 3-one; iv Rh 2 L 4 ; v catalyst,[78 °C CH 2 Cl 2 ; vi 140 °C. 109 Aliphatic and alicyclic chemistry Scheme 44 Reagents and conditions i Pd(OAc) 2 ) (Pr*O) 3 P Me 3 SnOAc; ii DBU. 110 Peter Quayle O CHO O O O O OH OH i 74% (ref. 258) O OTIPS OMe TBSO TBSO H O H H OMe OTIPS (ref. 259) ii 95% CHO O O SO2Ph O O O O O O SO2Ph O iii iv 95% (ref. 260) O CO2Et O N S N CH3 O CO2Et CH3 v 76% (ref.261) O Br ButO H MeO2C ButO CO2Me H O ButO CO2Me H O vi vii 63% (2.5 1) + Scheme 45 Reagents and conditions i SmI 2 25 °C; i PhMe 140 °C 110 h; iii LiN(SiMe 3 ) 2 . THF 0 °C; iv Dess–Martin; v Bun 3 SnH PhH 80 °C AIBN; vi In,H 2 O; vii DBU. 111 Aliphatic and alicyclic chemistry OTBS MPMO OTES CHO TBSO TBSO OTBS MPMO OTES TBSO TBSO 84% (ref. 263) H O O O O OH OH 84% ii,iii (ref. 264) OH 90% iv (ref. 265) OH Scheme 46 Reagents and conditions i LiN(SiMe 3 ) 2 CeCl 3 THF [30 °C]room temp.; ii TiCl 3 DME Zn–Cu; iii H 3 O`; iv KH THF 25 °C 30 min. Fig. 2 112 Peter Quayle References 1 A. J. Birch Pure Appl. Chem. 1996 68 553. 2 T. J. Donohoe R. Garg and C. A. Stevenson Tetrahedron Asymmetry 1996 7 317. 3 P. Timmerman H. L. Anderson R. Faust J.-F. Nierengarten T. Habicher P.Seiler and F. Diederich Tetrahedron 1996 52 4925; N. S. Goro§ Acc. Chem. Res. 1996 29 77. 4 P.W. Rabideau and A. Sygula Acc. Chem. Res. 1996 29 235. 5 J.W. Grissom G. U. Gunawardena D. Klingberg and D. Huang Tetrahedron 1996 52 6453; B. Ko� nig Angew. Chem. Int. Ed. Engl. 1996 35 165. 6 A.W. Czarnik and J. A. Ellman (eds.) Acc. Chem. Res. 1996 29 111. 7 H.C. J. Ottenheijm and D. C. 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Chen J. 118 12 541. 200 K. Ramig Y. Dong and S. D. van Arnum Tetrahedron Lett. 1996 37 443. 201 S. Yamabe T. Dai T. Minato T. Machiguchi and T. Hasegawa J. Am. Chem. Soc. 1996 118 6518. 202 (a) Y. Nakamura T. Mita and J. Nishimura Tetrahedron Lett. 1996 37 3877; (b) T.D. Golobish and W. P. Dailey ibid. 3239; (c) D. I. Schuster J. Cao N. Kaprinidis Y. Wu A. W. Jensen Q. Lu H. Wang and S. R. Wilson J. Am. Chem. Soc. 1996 118 5639. 203 S. Ghosh d. Parta and S. Samajdar Tetrahedron Lett. 1996 37 2073. 204 W. Li and M. A.Fox J. Am. Chem. Soc. 1996 118 1752. 205 K. Lukin J. Li R. Gilardi and P. C. Eaton Angew. Chem. Int. Ed. Engl. 1996 35 864. 206 B. M. Trost and M.J. Krische J. Am. Chem. Soc. 1996 118 233. 207 M. Toyata T. Asoh and K. Fukumoto Tetrahedron Lett. 1996 118 4401. 208 D. Llerena C. Aubert and M. Malacria Tetrahedron Lett. 1996 37 7353. 209 T. K. Sarkar and S. K. Nandy Tetrahedron Lett. 1996 37 5195. 210 (a) G.A. Molander and C. R. Harris J. Am. Chem. Soc. 1996 118 4059; (b) J. J.C. Grove� C. W. Holzapfel and D. B. G. Williams Tetrahedron Lett. 1996 37 1305. 211 J. Montgomery and A. V. Savchenko Tetrahedron Lett. 1996 118 2099. 212 E. Riguet I. Klement C. K. Reddy G. Cahiez and P. Knochel Tetrahedron Lett. 1996 37 5865. 213 C. Meyer I. Marek and J.-F. Normant Tetrahedron Lett. 1996 37 857.214 E. Piers and A. M. Kaller Tetrahedron Lett. 1996 37 5857. 215 Y. Kita S. Kitagaka R. Imai S. Okamoto S. Mihara Y. Yoshida S. Akai and H. Fujioka Tetrahedron Lett. 1996 37 1817. 216 D. F. Taber K. K. You and A. L. Rheingold J. Am. Chem. Soc. 1996 118 547. 217 G. L. Bolton Tetrahedron Lett. 1996 37 3433. 218 B. L. Pagenkopf and T. Livinghouse J. Am. Chem. Soc. 1996 118 2285. 219 V. S. Borodkin N. A. Shpiro V. A. Azov and N. K. Kocheykov Tetrahedron Lett. 1996 37 1489. 220 B. Alcaide C. Polanco and M. A. Sierra Tetrahedron Lett. 1996 37 6901. 221 (a) F.A. Hicks and S. L. Buchwald J. Am. Chem. Soc. 1996 118 11 688; (b) K. Suzuki H. Urabe and F. Sato ibid. 8729. 222 M. A. Sigman and B. E. Eaton J. Am. Chem. Soc. 1996 118 11 783. 223 T. Bach Angew. Chem. Int. Ed. Engl. 1996 35 729.224 R. Sustmann S. Tappanchai and H. Bandmann J. Am. Chem. Soc. 1996 118 12 555. 225 A. K. Ghosh P. Mathivanan and J. Cappiello Tetrahedron Lett. 1996 37 3815. 226 J. Howarth and K. Gillespie Tetrahedron Lett. 1996 37 6011. 227 K. Ishihara H. Kurihara and H. Yamamoto J. Am. Chem. Soc. 1996 118 3049. 228 P. A. Grieco M. D. Kaufman J. F. Daeuble and N. Saito J. Am. Chem. Soc. 1996 118 2095. 229 P. Metz D. Sdng and B. Plieker Tetrahedron Lett. 1996 37 3841. 230 L. Garnier B. Plunian J. Mortier and M. Vaultier Tetrahedron Lett. 1996 37 6699. 231 J. M.D. Fortunak J. Kitteringham A. R. Mastrocola M. Mellinger N. J. Sisti J. L. Wood and Z.-P. Zhuang Tetrahedron Lett. 1996 37 5683. 232 S. Paul R. Roy S. N. Suryawanshi and D. S. Bhakuni Tetrahedron Lett. 1996 37 4055. 233 H. Schlessinger and C.P. Bergstrom Tetrahedron Lett. 1996 37 2133. 234 C. D. Gabbutt B. M. Heron J. D. Hepworth and M.M. Rahman Tetrahedron Lett. 1996 37 1313. 235 C. K. McClure K. J. Herzog and M.D. Bruch Tetrahedron Lett. 1996 37 2153. 236 J. M. Bartolome� M. Carmen Carreno and A. Urbano Tetrahedron Lett. 1996 37 3187. 237 M.-J. Arce A. L. Viado Y.-Z. An S. I. Khan and Y. Rubin J. Am. Chem. Soc. 1996 118 3775. 238 G. Stork F. West H. Y. Lee R. C. A. Issacs and S. Manabe J. Am. Chem. Soc. 1996 118 10 660. 239 C. D. Dzierba K. S. Zandi T. Mo� llers and K. J. Shea J. Am. Chem. Soc. 1996 118 4711. 240 B. M. Trost and Y. Li J. Am. Chem. Soc. 1996 118 6625. 241 M. F. Semmelhach and H.-G. Schmalz Tetrahedron Lett. 1996 37 3089. 242 M. Bamba T. Nishikawa and M. Isobe Tetrahedron Lett. 1996 37 8199. 243 S.-S.P. Chou and C.-H. Hsu Tetrahedron Lett. 1996 37 5373. 244 E. J. Sandoe G. R. Stephenson and S. Swanson Tetrahedron Lett. 1996 37 6283. 245 D. Llerena C. Aubert and M. Malacria Tetrahedron Lett. 1996 37 7027. 246 J. Cossy and S. BouzBouz Tetrahedron Lett. 1996 37 5091. 247 H. Nemoto M. Shiraki N. Yamada N. Raku and K. Fukumoto Tetrahedron Lett. 1996 37 6355. 248 M. E. Jung Y. M. Cho and Y. H. Jung Tetrahedron Lett. 1996 37 3. 249 H. Haigawara and M. Kato Tetrahedron Lett. 1996 37 5139. 250 S. Nara H. Toshima and A. Ichihra Tetrahedron Lett. 1996 37 6745. 251 J. Barluenga A. A. Trabanco J. Flo� rez S. Garcý� a-Granda and E. Martý� n J. Am. Chem. Soc. 1996 118 13 099. 252 A. P. Kozikowski G. Campiani L.-Q. Sun S. Wang A. Saxena and B. P. Doctor J. Am. Chem. Soc. 1996 117 Aliphatic and alicyclic chemistry 118 11 357.253 M. Lautens R. Aspiotis and J. Colucci J. Am. Chem. Soc. 1996 118 10 930. 254 M. Harmata S. Elomari and C. L. Barnes J. Am. Chem. Soc. 1996 118 2860. 255 (a)H.M.L. Daves G. Ahmed and M. R. Churchill J. Am. Chem. Soc. 1996 118 10 774; (b)H.M.L. Davies and B. D. Doan Tetrahedron Lett. 1996 37 3967. 256 B. M. Trost and R. I. Higuchi J. Am. Chem. Soc. 1996 118 10 094. 257 J. H. Rigby V. De Sainte Claire and M.J. Heeg Tetrahedron Lett. 1996 37 2553; J. H. Rigby and P. Sugathapala ibid. 5293; J. H. Rigsby M. M. Niyaz and P. Sugathapala J. Am. Chem. Soc. 1996 118 8178. 258 S. S. Swindell and W. Fan Tetrahedron Lett. 1996 37 2321. 259 J. D. Winkler S. K. Bhattacharya and R. A. Batey Tetrahedron Lett. 1996 37 8069. 260 I. Hanna T. Prange� and R.Zeghdoudi Tetrahedron Lett. 1996 37 7013. 261 M. T. Crimmins S. Huang and L. Guise-Zawacki Tetrahedron Lett. 1996 37 6519. 262 C.-J. Li D.-L. Chen Y.-Q. Lu J. X. Habberman and J. T. Mague J. Am. Chem. Soc. 1996 118 4216. 263 I. Sato Y. Akahori K.-I. Iida and M. Hirama Tetrahedron Lett. 1996 37 5135. 264 M. Eckhardt and R. Bru� ckner Angew. Chem. Int. Ed. Engl. 1996 35,1093. 265 M. E. Bunnage and K. C. Nicolaou Angew. Chem. Int. Ed. Engl. 1996 35 1110. 266 C. Z. Liu and P. W. Rabideau Tetrahedron Lett. 1996 37 3437. 267 T. Kawase N. Ueda H. R. Darabi and M. Oda Angew. Chem. Int. Ed. Engl. 1996 35 1556. 268 H. Higuchi N. Hiraiwa S. Kondo J. Ojima and G. Yamamoto Tetrahedron Lett. 1996 37 2601. 118 Peter Quayle 119 Aliphatic and ali

ISSN:0069-3030    

DOI:10.1039/oc093069

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

5 Aromatic compounds By ALAN P. CHORLTON Zeneca Specialties Hexagon House Blackley Manchester UK M9 8ZS 1 General and theoretical studies Aromaticity is one of the fundamental concepts of organic chemistry. Methods of assessment of aromaticity have been the subject of a great deal of interest. This debate centres round conflicting hypotheses that aromaticity is at least a two dimensional phenomenon the classical view opposed by the concept that aromaticity can be fully described by magnetic criteria. Krygowski and Cyranski have put forward a model that supports the classical view.1 In this model the energetic and geometric components that contribute to aromaticity can be separated. Schleyer et al. however support the magnetic concept of aromaticity and in a recent study have demonstrated how NMRshifts in larger aromatic systems can be correlated with the magnetic susceptibility exaltations to provide an e¶cient aromaticity probe.2 Bird has made a study of diamagnetic susceptibility enhancements for a large number of aromatic systems and has concluded that there is no apparent justification for the separation of classical and magnetic concepts of aromaticity.3 Katritzky et al.have shown that the aromaticity of a system can vary depending on its molecular environment. Aromaticity of a number of systems has been studied experimentally and theoretically and is found to increase with the polarity of the medium.4 Bond fixation and aromaticity have been studied in a number of strained annulated benzenes. The biphenylene fused dihydropyrene 1 has been examined by NMR spectroscopy.Analysis of this data indicates that biphenylene has about 55% of the relative bond fixing ability of benzene and has a Dewar resonance of 1.59 times that of benzene which compares favourably with a calculated Dewar resonance energy 1.55 times that of benzene.5 A comprehensive study of the bond resonance energies of polycyclic benzenoid and non-benzenoid hydrocarbons has been carried out.6 Incorporation of the biphenylene moiety into a cyclic system gives the cyclic [n]phenylenes; theoretical studies of [6]phenylene (antikekulene) 2 have shown it to be planar and to be appreciably destabilized relative to the linear [6]phenylene 3.7 Theoretical studies have been carried out on kekulene 4 to establish whether it exists in a benzenoid resonance form 5 or the annulenoid form 6 consisting of an outer [30]annulene and an inner [18]annulene which would give rise to superaromaticity.This work concludes that the benzenoid representation of kekulene is the most realistic.8 A recent high level ab initio study has concluded that [5]pericyclyne 7 is not homoaromatic based on geometric energetic and magnetic criteria.9 Royal Society of Chemistry–Annual Reports–Book B 119 1 2 3 4 5 6 R R R R R R R R R R 7 R = CH3 Theoretical studies on the valence isomers of benzene have attracted attention. Results of semiempirical MNDOC-CI and ab initio CASSCF calculations have revealed that fulvene 8 is a primary product of the photolysis of benzene. The most probable mechanism for the photochemical isomerization of benzene to fulvene in- 120 Alan P. Chorlton 1 * S0('A19) 245 nm • • • • S1('B24) 9 10 8 Scheme 1 H H H H 11 12 Scheme 2 D D 13 D D H H • 15 D D • • 14 • • Scheme 3 volves the intermediate structures prefulvene 9 and 1,3-cyclopentadienylcarbene 10 (Scheme 1).10 Similar calculations on the electrocyclic ring opening of Dewar benzene predict conrotatory electrocyclic ring opening to give the unknown Mo� bius benzene 11.This is contrary to the assumed disrotatory ring opening of Dewar benzene to give benzene. These calculations also support the existence of another new benzene isomer trans- Dewar benzene 12 (Scheme 2).11 The thermal isomerization of [1,4-D 2 ]-benzene 13 and [1,2-13C 2 ]-benzene 14 have been studied in excess hydrogen at 750–850 °C in a quartz flow system. In both cases the main isomerization products are the corresponding meta isomers.The data suggest a radical intermolecular interchange of benzene carbons by 1,2-carbon shifts. In the deuterium case the rearrangement is thought to proceed via the bicyclo[3.1.0]hexanyl intermediate 15 (Scheme 3).12 Theoretical interest in benzyne has been renewed because of the discovery that p-benzyne derivatives formed by Bergman cyclization are involved in DNA-cleaving activity of antitumour antibiotics. Ab initio calculations of hydrogen abstraction reaction of phenyl radical and p-benzyne suggest that the rate of hydrogen abstraction for p-benzyne diradical at room temperature should be 14 times lower than the phenyl radical.13 In an experimental study the hydrogen abstraction rate of 9,10-dehydroan- 121 Aromatic compounds thracene was found to be 100–200 times lower than the phenyl or 9-anthryl radical.14 The 13C dipolar NMR spectrum of matrix isolated [1,2-13C 2 ]o-benzyne has been reported.The resulting 13C spectrum was analysed to obtain the 13C chemical shift tensor of the two labelled carbons and to determine the length of the triple bond which compares favourably to the triple bond in cycloctyne.15 The isomeric o- m- and p-benzyne negative ions have been formed in gas-phase experiments and their thermochemical properties were investigated. The meta and para isomers were previously unknown.16,17 Theoretical studies gave good agreement between experimental estimates for electron proton and hydrogen atom binding energies. The 1,3,5-trimethylbenzene negative ion 16 has also been characterized.18 CH2 – H2C CH2 •• • • 16 Interactions between aromatic units play a significant role in supramolecular chemistry.These interactions are important in diverse phenomena such as base–base interactions in DNA intercalation of small molecules between nucleotides packing of aromatic molecules in crystals the tertiary structures of proteins and host–guest binding. To gain more information about these interactions a theoretical study has examined benzene and toluene dimers in the gas phase and in aqueous solution. These calculations have revealed that the T-shaped benzene dimer is more stable than its stacked homologue and with toluene the T-shaped structure is also favoured.A conclusion that could be made from these results is that the toluene dimers are a better model for the study of p–p interactions in proteins.19 In a similar study the interactions between toluene and the ammonium cation have been examined.This interaction was calculated to be 3 kcal mol~1 and this type of association is shown to be clearly favoured in non-polar environments. These observations concur with the analysis of Phe–Lys interactions in several protein structures.20 Dougherty and co-workers have performed a series of ab initio computational studies on the binding of the sodium cation to the p face of a range of aromatic structures. An excellent correlation between the binding energy and electrostatic potential of these complexes was obtained.21 The thermochemistry of molecular complexes of halogens with benzene and benzene derivatives has been studied.22 The measurement of proton a¶nities in aromatics is especially important in the context of electrophilic substitution reactions yielding insight into the reaction mechanism and reactivity of substituted benzene derivatives.Experimentally proton a¶nities are very di¶cult to determine. A theoretical study of the additivity of proton a¶nities in aromatics and polysubstituted benzene molecules has proved to give very good agreement with the latest experimental data.23,24 2 Preparation of benzene molecules from non-aromatic precursors The resurgence of interest in the cyclization of enediynes to aromatics via Bergman cyclization and related processes continues. This is in large part due to the inter- 122 Alan P. Chorlton • R • R Rh cat. Rh R Rh• • Scheme 4 1 equiv. RhCl(Pri 3P)2 Et3N C6D6 70 °C 12 h [Rh]• [Rh]• [Rh] • • Scheme 5 mediacy of arene diradicals which are implicated in the DNA-cleaving activity of the eneyne family of antitumour antibiotics.With respect to the preparation of benzenes from non-aromatic precursors a number of recent contributions in this area have synthetic and methodological significance.25,26 A rhodium(I)-catalysed variant of the Myers cycloaromatization has been developed and is summarised in Scheme 4. An example of the utility of this process is shown in Scheme 5.27 An acyclic enediyne possessing an aminomethyl group 17 has been designed and synthesized as a potential substrate for pyridoxal-dependant enzymes. Cycloaromatization of 17 was achieved with pyridoxal or isonicotinaldehyde (Scheme 6).28 Shibuya et al. have developed a methodology in which cis-enediynes are generated via hydrolysis and decarboxylation of malonate ester derivatives (Scheme 7).29 Meyers cycloaromatization has been used in conjunction with an intramolecular Diels–Alder reaction in a cascade sequence (Scheme 8).30 The reaction of Fischer carbene complexes with alkynes continues to be of synthetic importance for the preparation of oxygenated benzene molecules.This methodology has been extended to incorporate the use of conjugated 1,3-diynes. This new procedure provides a new stratagem for the synthesis of biaryls (Scheme 9).31 The intermediates and transition structures of the benzannulation of heteroatomstabilized chromium carbene complexes with ethyne have been subjected to a density functional study. This work reveals a number of interesting observations regarding the mechanism and explains the experimental observation that aminocarbenes require a greater reaction temperature compared with hydroxycarbenes.32 In the above process the aromatic ring-forming reaction can be viewed as 6p-electrocyclisation of dienylketene 18 (Scheme 10).By analogy dienylvinylidenes can be invoked as precursors to a novel 6p-electrocyclization process (Scheme 11). This hypothesis has been tested out 123 Aromatic compounds Scheme 6 Reagents i PL-HCl (1 equiv.) NEt 3 (2 equiv.) dioxane 37 °C 40 min.; ii Ac 2 O Pyr. rt 12 h; iii HCl H 2 O acetone rt 1.5 h R1 R2 R3 CO2R4 MeO CO2R4 R1 R2 R3 CO2H MeO CO2R4 R1 R2 R3 • OMe CO2R4 R1 R3 R2 CO2R4 OMe • • Scheme 7 successfully to provide a novel aromatic ring forming cyclization (Scheme 12).33 Two novel benzannulation methods have been developed which provide ready access to highly substituted arenes (Scheme 13),34 and an easy synthesis of paracyclophanes (Scheme 14).35 The ring expansion of 4-alkenyl (or aryl) cyclobutenones to aromatic systems has led to a number of useful synthetic applications.These include the synthesis of the monoterpene espintanol (Scheme 15)36 and highly substituted annulated furans (Scheme 16).37 If 4-allenylcyclobutenones are thermally ring expanded reactive o-quinomethanes are formed and can be trapped. The reaction has synthetic 124 Alan P. Chorlton • refluxing benzene • • • • • • H H 50% Scheme 8 OR (CO)5Cr OH Ph Ph OR Ph Ph Scheme 9 • O OH 18 Scheme 10 •M M H M = Transition metal Scheme 11 Scheme 12 125 Aromatic compounds Scheme 13 (CH2)10 (CH2)10 Pd(PPh3)4 toluene 65 °C 1 h high dilution 48% Scheme 14 Scheme 15 Bun Bun OMe O Bun Ar i D ii TFA O Bun MeO MeO Bun Bun 74% Scheme 16 potential as a route to highly substituted phenols benzofurans and aryl analogues of hexahydrocannabinol (Scheme 17).38 The Diels–Alder reaction is often used in preference to conventional aromatic substitution to construct highly substituted benzenoid systems to limit regiochemical problems.The synthesis of multisubstituted naphthalenes,39 anilines40 and p-terphenyl41 are recent examples (Scheme 18). 126 Alan P. Chorlton MeO MeO O OH • CH3 CH3 CH3 CH3 H3C CH3 O MeO MeO OH O OH OMe OMe H H C6H6 40–50 °C Scheme 17 Scheme 18 A novel benzannulation sequence based on chromium(0)-promoted [6p]4p] cycloaddition followed by a Ramberg–Ba� cklund rearrangement has been disclosed.A noteworthy feature of this two-operation methodology is the simultaneous production of two rings during the cyclization process (Scheme 19).42 A number of new methods for the regioselective synthesis of naphthalene derivatives have been developed (Scheme 20).43–45 In a new simple route to phenanthrenes aryl pinacols have been 127 Aromatic compounds Scheme 19 Scheme 20 found to react in triflic acid to give substituted phenanthrenes in excellent yield. The regiochemistry of this reaction can be controlled by deactivating substituents (Scheme 21).46 3 Non-aromatic compounds from benzene precursors The biotransformation of benzene and its derivatives to their corresponding cisdihydrodiols has been exploited as a key step in the synthesis of highly oxygenated natural products.The current status and future perspectives of this transformation in organic synthesis have been reviewed.47,48 Recent advances in the this area include the dioxygenase-catalysed oxidation of dihydronaphthalenes49 and the synthesis of deuterated carbohydrates (Scheme 22).50 The muconic acid pathways provide key routes for the microbiological degradation of benzene derivatives (Scheme 23). Kirby and co-workers have shown that (Z,Z)-3- methylmuconic acid 19 undergoes enzymic cyclization by syn addition of carboxy groups to the distal double bond to form the S-4-methylmuconolactone 20 in bacteria 128 Alan P. Chorlton OH HO Cl Cl TfOH 98% Cl Cl Scheme 21 Scheme 22 Reagents i Pseudomonas putida Me OH OH 4 HO2C Me CO2H 19 O Me HO2C O H 3 3 S 21 O O CO2H S Me 20 ii i 4 Scheme 23 Reagents i bacteria; ii fungi 129 Aromatic compounds + O O O O O O 22 Scheme 24 Scheme 25 whereas in fungi syn cyclization of 19 gives the S-muconolactone 21.51 This group have also reported the synthesis and absolute configurations of 3- and 4-methylmuconolactones 21 and 20.52 Chlorinated aromatics are well known recalcitrant pollutants because of their slow biodegradation by micro-organisms.It has been demonstrated that 2,4,6-trichlorophenol can be degraded chemically by the action of hydrogen peroxide catalysed by iron tetrasulfophthalocyanines.53 The oxidation of an aromatic ring with dimethyldioxirane has been the subject of a number of studies;54,55 hexamethylbenzene gave the triepoxide 22 in 51% yield (Scheme 24).55 Addition to functionalized arenes provides a useful procedure for the generation of non-aromatic compounds from aromatic systems this area has been reviewed.56 The conjugate addition of organolithium reagents to arenes is one of the most useful examples of this type of process.Two examples highlighting the power of this methodology are given in Scheme 25.57,58 The irradiation of aromatics in the presence of alkenes provides [2]2] [3]2] and [4]2] cycloadducts. Tethering the alkene to the arene gives a degree of control in this process and allows the synthesis of complex multi-ring compounds from simple precursors. An excellent example of this concept is the total synthesis of (^)-ceratropicanol in seven steps the key step being an intramolecular [3]2] photocycloaddi- 130 Alan P. Chorlton Scheme 26 H H H NC hn 254 nm (PhCO2)2 CH3CN 90–95 °C Scheme 27 N O H H Ar Ar C N O + – Scheme 28 tion (Scheme 26).59 The previous synthesis of ([)-ceratropicanol had involved 19 steps.In a similar process Wender et al. have accessed the complex fenestrane skeleton in three steps (Scheme 27).60 Polycyclic aromatics have been shown to undergo 1,3- dipolar cycloadditions with 3,5-dichloro-2,4,6-trimethyl- and 2,4,6-trimethyl-benzonitrile oxide (Scheme 28).61 4 Substitution in the benzene ring Electrophilic substitution The desire to introduce fluorine into aromatic compounds to influence physical chemical and biological properties has led to a number of new fluorination methodologies. Banks et al. have provided a full account of the conception and laboratory synthesis of the site-selective and easily handled 1-alkyl-4-fluoro-1,4-diazoniabicyclo[ 2.2.2]octane salts.62 It may be argued that the problem of electrophilic fluorination has been solved by the use of such stable electrophilic fluorinating agents.However these agents have initially to be prepared by the direct use of fluorineThe controlled use of elemental fluorine as an electrophile would clearly be beneficial on a large scale. In this respect a direct fluorination method for the synthesis of 4- fluorobenzoic acid in formic acid and sulfuric acid has been developed.63 A mild chlorination of aromatic compounds has been reported with tin(IV) chloride and lead tetraacetate. This methodology is particularly e§ective for selective chlorination of polyalkylbenzenes and also obviates the need for chlorine gas.64 Regioselective introduction of bromine into aromatic substrates has been the focus of a number of investigations.Highly e¶cient para-selective bromination of simple aromatics has 131 Aromatic compounds OMe OMe OMe OMe OAc X PhI(OAc)2 TMSX X = Cl or Br Scheme 29 been achieved by means of bromine and a reusable zeolite.65 The ortho para ratio of bromination of anilines can be controlled to varying degrees depending on the surfactants employed.66 Iodoarenes are key substrates for transition metal coupling reactions; this has fuelled a need for more versatile iodination procedures. N-Iodosuccinimide in acetonitrile has proved to be a mild and regiospecific method for the introduction of iodine into a wide range of methoxy-substituted benzenes and naphthalenes. 67 Deactivated aromatic systems can be iodinated in a system consisting of iodine sulfuric acid and perfluorocarbon solvent through which elemental fluorine is passed.68 A novel method for the haloacetoxylation of 1,4-dimethoxynaphthalenes using hypervalent iodine chemistry has been developed.This transformation represents a formal addition of AcOX to benzyne and thus 1,4-dimethoxynaphthalenes represent benzyne equivalents (Scheme 29).69 Nitrogen dioxide in the presence of ozone acts as a powerful nitrating agent for aromatic substrates (the Kyodai nitration). This process o§ers regiospecific advantages over conventional nitration methodologies. The Kyodai nitration of methyl phenylacetate gave an overall yield of 85% of which 88% was the o-nitro isomer. This is the highest ortho-isomer proportion so far observed in electrophilic aromatic nitration.70 A similar reversal of selectivity has been observed in the Kyodai nitration of naphthalene where the 1-nitro 2-nitro isomer ratios were found to be remarkably high.This enhancement in regioselectivity compared with conventional nitrations has been interpreted in terms of an electron transfer mechanism involving the nitrogen trioxide as the initial electrophile.71 In an attempt to render the Kyodai nitration more user friendly ozone has been replaced by oxygen in the presence of tris(pentane-2,4- dionato)iron(III) use of this procedure has allowed moderately activated arenes to be nitrated in fair to good yields.72 High para-selective nitration of simple aromatic compounds has been achieved by a solvent free process using a stoichiometric quantity of nitric acid and acetic anhydride at 0–20 °C in the presence of b-zeolite as the catalyst.This process represents a clean synthesis of simple nitroaromatics the zeolite being easily recovered and the only byproduct formed is acetic acid.73 Sulfuric acid supported on silica gel has also been used e§ectively as a catalyst for aromatic nitration.74 Heterogeneous catalysis of the Friedel–Crafts (F–C) alkylation has been achieved with copper or zinc chloride doped natural phosphate and tricalcium phosphate. The process gives high levels of monoalkylated products.75 The bond-forming step in F–C alkylation reactions has been investigated through use of a method for introducing essentially free carbocations into an aromatic solvent in the absence of catalyst. This study supports the view that the methanism proceeds through a single transition state.76 Chlorobenzotrifluorides under typical F–C reaction conditions react e¶ciently with aromatic compounds to a§ord dichlorodiphenylmethanes in an excellent yield.The expected difluorodiphenylmethanes are not isolated as a result of halogen exchange (Scheme 30).77 132 Alan P. Chorlton R + X CF3 Cl Cl R R R = H Me X OMe X = 2-Cl X = 4-Cl Yield > 90% AlCl3 (3 moles) EDC 0 °C Scheme 30 Scheme 31 The F–C acylation is generally performed using aluminium chloride as a Lewis acid catalyst. This process can be particularly problematical in an industrial situation where the reaction requires more than a stoichiometric amount of aluminium chloride which cannot be reused because of its instability in aqueous workup.In order to solve these problems several approaches to catalytic F–C acylation have been reported. These include hafnium trifluoromethanesulfonate (triflate),78,79 zirconium tetrachloride 80 metal bis(trifluoromethylsulfonyl)amides,81 lanthanide triflate–lithium perchlorate82 and polymer-supported scandium catalysts.83 Anisole undergoes regiospecific trifluoracetylation in neat trifluoroacetic anhydride in the presence of CoCl 2 as catalyst. However with a 1 1 anisole trifluoroacetic anhydride ratio only the para-dimerized product is obtained (Scheme 31).84 A number of novel Lewis acid mediated electrophilic substitution reactions related to the F–C reaction have been reported (Scheme 32).85–87 The regioselectivity of the Gattermann–Koch formylation of 1-methylnaphthalene using various compositions of HF–SbF 5 has been examined.It was found that 4-methyl-1-naphthaldehyde was formed preferentially when the ratio of SbF 5 1- methylnaphthalene was 1 1. However if the ratio of SbF 5 to 1-methylnaphthaldehyde was increased a mixture of the 4-methyl-1-naphthaldehyde and 1-methyl-2-naphthaldehyde were formed. This regioselective di§erence was rationalised as being derived from the protonation of 1-methylnaphthalene under a solvent-cage-like atmosphere (Scheme 33).88 Deformylation of aromatic aldehydes has been achieved e¶ciently with scandium trifluoromethanesulfonate as a catalyst.89 The first example of a thia-Fries rearrangement has been reported. In this process aryl phenylsulfinates are treated with aluminium chloride at 25 °C to give good yields of (phenylsulfinyl)phenols (Scheme 33).90 The aza-Claisen rearrangement has been promoted by the use of zeolites (Scheme 34).91 Symmetrical binaphthyl derivatives have been formed in a high yielding catalytic process from naphthalene derivatives using NaNO 2 and CF 3 SO 3 H.This reaction is presumed to proceed via a radical cation intermediate (Scheme 34).92 133 Aromatic compounds Scheme 32 Scheme 33 Nucleophilic substitution The generally accepted mechanism for nucleophilic aromatic substitution is an addition –elimination process and involves the formation of a Meisenheimer type of intermediate. Whether the rate limiting step of this mechanism is the formation of the intermediate or expulsion of the leaving group has been found to depend on the 134 Alan P. Chorlton R N R¢ R¢¢ R NH R¢ Zeolite 80 °C Hexane 2 h R¢¢ + R N R¢ R¢¢ CH3 Scheme 34 Scheme 35 character of the nucleophile and the leaving group as well as on the solvent.Matsson and co-workers have studied the solvent dependent leaving group fluorine kinetic isotype (FKIE) e§ect in a nucleophilic aromatic substitution reaction of 2,4-dinitro- fluorobenzene with piperidine. A significant FKIE was observed in THF suggesting that in this solvent departure of the leaving group is the rate-limiting step. However with acetonitrile as the solvent no such FKIE was observed which is consistent with addition of the nucleophile to the aromatic substrate being the rate-limiting step.93 The kinetics and mechanism of the reaction of 2,4-dinitrofluorobenzene with hydroxide ion in ‘water in oil’ microemulsions has been investigated.The results show that the rate of the reaction depends mainly on the nature of the surfactant molecules and the amount of water present in the microemulsion. The reaction rate is enhanced by about 40-fold in cationic microemulsions relative to aqueous solutions and by three orders of magnitude in relation to anionic microemulsions.94 1,3,5-Trinitrobenzene is known to react with aldehydes and ketones containing an a-hydrogen to yield only the carbon-bonded Meisenheimer complexes; the oxygencentred adducts have surprisingly never been detected. Buncel et al. have presented unequivocal evidence for the low temperature existence of an oxygen-bonded enolate Meisenheimer complex. As the temperature is allowed to rise the carbon-bonded Meisenheimer complex becomes the major product.95 The reaction of 3,5-difluoro-4-chloronitrobenzene with thiophenoxide anion leads predominantly to substitution of the chlorine atom through an S N Ar orbital-controlled process.However when the harder methoxide anion is used the substitution of the meta-fluorine atom becomes the dominant pathway. Kinetic measurements and theoretical calculations indicated that the observed meta substitution of fluorine is an S N Ar charge-controlled reaction with a loosely bonded transition state (Scheme 36).96 The regioselective nucleophilic substitution of tri- and di-substituted fluorobenzoates and fluorobenzonitriles has been accomplished by sequential addition of various oxygen and nitrogen nucleophiles. An example is given in Scheme 37.97 135 Aromatic compounds SPh F F NO2 85% Cl F F NO2 Cl F OCH3 NO2 67% PhS– MeO– Scheme 36 NC F F N Boc OK NC F O NBoc + HO2C OMe O NBoc i KOMe ii NaOH Scheme 37 Scheme 38 A convenient synthesis of triarylamines via ester-mediated nucleophilic aromatic substitution has been disclosed.This method complements the traditional Ullmantype condensation of diarylamines with haloarenes (Scheme 38).98 The use of pyridine as a cocatalyst for the synthesis of N-phenylanthranilic acid by the Ullman reaction has been reported.99 A new one-pot procedure for the synthesis of polyfluoroanisoles from poly- fluoroanilines has been developed.100 Aromatic fluorides can be formed e¶ciently via diazotization of aminoarenes followed by in situ fluorodediazoniation of the diazonium ions; this has successfully been accomplished using hydrogen fluoride in combination with base solutions.101 The formation of carbon–carbon bonds via vicarious nucleophilic substitution (VNS) of hydrogen continues to be exploited.Alkylnitrobenzenes,102 p-nitroarylaldehydes103 and a-disubstituted-p-anitrophenylacetic esters104 have been made in this way (Scheme 39). Makosza et al. have developed a VNS methodology which proceeds via heterocyclic ring opening (Scheme 40).105 VNS of hydrogen with amine nucleophiles has been demonstrated. In this process 1,1,1-trimethylhydrazinium iodide was utilized as a VNS reagent for the introduction of amino groups into nitroaromatic substrates (Scheme 41).106 VNS methodology has significant synthetic utility; however the requirement for an auxiliary leaving group has a number of disadvantages including complexity of the nucleophile.Nucleophilic aromatic substitution of hydrogen with oxidation at the intermediate r-complex does not have this limitation but su§ers from others namely the sensitivity of nucleophiles towards oxidation. This problem can be overcome if an 136 Alan P. Chorlton Scheme 39 Scheme 40 NO2 NO2 NO2 NO2 NH2 NH2 2 equiv.(CH3)3N+–NH2 NaOMe DMSO I– Scheme 41 oxidant can be found that oxidizes the r-complex faster than the starting nucleophile. The use of KMnO 4 in liquid ammonia and photochemical oxidation have both been shown to lead to successful examples of oxidative nucleophilic substitution of hydrogen (Scheme 42).107,108 The reaction of 1,3,5-trinitrobenzene with methoxide and hypochlorite gives 3,5- dichloro-2,4,6-trimethoxynitrobenzene as the major product and 1,3,5-trichloro-2,4,6- 137 Aromatic compounds Scheme 42 NO2 O2N NO2 NO2 Cl Cl MeO OMe OMe Cl Cl Cl MeO OMe OMe + MeO– MeOH ClO– H2O Scheme 43 trimethoxybenzene as the minor product.This could formally be regarded as oxidative nucleophilic substitution of hydrogen but it is thought to take place via a three step mechanism involving nucleophilic addition of methoxide ion electrophilic chlorination by attack of hypochlorite ion trans to the methoxy group and base-induced E2 elimination (Scheme 43).109 Substitution via organometallic intermediates The burgeoning interest in transition metal-catalysed cross-coupling reactions continues. This area dominates the literature for new methodologies for the functionalisation of aromatic compounds. The advances in this area include improvements in catalysts extension of methodologies to new substrates solid-phase processes new synthetic applications and processes for the arylation of amines and thiols.The palladium-catalyst reaction of organic halides with alkenes (Heck reaction) has become a well established synthetically important method for forming carbon–carbon bonds. Recent advances include the use of tetraalkylammonium salts which can lead to enhanced reactivity selectivity and which obviate the need for phosphine ligands used molten as solvents and in certain cases allow aqueous processes to be carried out.110,111 Tetraalkylammonium salts have also been used in an e¶cient palladiumcatalysed coupling of terminal alkynes with aryl halides.112 Nanostructured palladium clusters can be stabilized in propylene carbonate; these colloidal solutions can also catalyse the Heck reaction in the absence of phosphine ligands.113,114 One disadvantage of cross-coupling reactions is that they are in general limited to expensive aryl iodide or bromide substrates.Recent developments have addressed this 138 Alan P. Chorlton Scheme 44 Scheme 45 issue. The more economic and synthetically accessible chloroarenes,115,116 arylmesylates117,118 and arenediazonium salts119 have all been successfully used in crosscoupling reactions. The palladium-catalysed cross-coupling of aryl halides and organozinc reagents (Negishi–Kumada reaction) o§ers advantages over the aryltin derivatives (Stille reaction) and boronic esters (Suzuki reaction). This process can tolerate many functionalities and can be e§ected under milder reaction conditions especially using a copper(I) cocatalyst.120 The robustness and high generality of transition metal cross-coupling reactions has led to solid-phase variants being developed for combinatorial synthesis.A solid-phase variant of the Suzuki reaction has been developed.121 Microwaveassisted solid-phase Suzuki coupling gives very fast reaction times.122 A solid-phase version of the Negishi–Kumada reaction has also been developed.123 Libraries of aromatic amines have also been produced by solid-phase transition metal-catalysed coupling reactions between aryl bromides and amines.124,125 In the above solid-phase processes the aryl moiety is generally linked to the polymer backbone via an ester or amide which is subsequently cleaved at the end of the reaction sequence to yield the final product.These processes are limited because the functionalized aromatic always contains an acid amide or ester grouping. Han et al. have developed a solid-phase Suzuki-coupling in which the aryl halide is linked to the polymer via an aryl silane linkage. This arylsilane linker can be cleaved with a variety of electrophiles such as H` I` Br` Cl` Ac`andNO 2 ` to give more diversity in the combinatorial libraries.126 The synthetic utility of the Heck reaction has been extended to give high levels of enantioselectivity (Scheme 44).127 Allylic alcohols have been synthesized via palladium-mediated reactions of stannoxanes with aryl halides (Scheme 45).128 Oligophenylenes are of interest for use in electro- and photo-chemical devices. The Suzuki aryl–aryl coupling when used in an iterative processes has proved successful in 139 Aromatic compounds R Br R Br + B(OH)2 Br R R > 95% (HO)2B R R 40–60% Br R R Br Br 85% toluene Na2CO3(aq) [Pd] 3 d reflux BunLi B(OCH3)3 HCl(aq) 11 toluene Na2CO3(aq) [Pd] 3 d reflux i ii iii Scheme 46 R1 X HN NH R2 N NH R2 R1 + PdCl2[P( o-tol)3]2 NaOBut X = Br I Scheme 47 the synthesis of various oligophenylenes;129–132 an example of this is given in Scheme 46.129 Transition metal-catalysed cross-couplings have primarily focused on aryl–aryl or aryl–alkene/alkane bond formation.Recently a number of groups have turned their attention to the arylation of amines. The groups of Buchwald and Hartwig have independently developed second generation palladium catalysts for the conversion of aryl bromides and iodides to mixed secondary and tertiary aryl amines.133–136 The synthetic utility of this reaction has found application in the synthesis of the arylpiperazines which have provoked recent interest because of their medicinal and electronic properties (Scheme 47).137–139 Solid-phase synthesis of arylamines via palladium-catalysed amination of polymer bound aromatic bromides has also been reported.124,125 The introduction of sulfur into the aromatic ring has also been successfully achieved via palladium-catalysed coupling reactions (Scheme 48).140–142 Palladium-catalysed carbonylation and hydroformylation methodologies continue to be developed two useful contributions are outlined in Scheme 49.143,144 140 Alan P.Chorlton S Ar R R X S R R ArSCN 2SmI2 PdCl2 cat Pd S O NHMe R X = I OTf i NaSTlPS Pd(PPh3)4 ii (Bu)4NF SH Scheme 48 N O O X + NH2 NHCO N O O PdCl2L2 PPh3 DBU–CO–DMAc OTf CHO CO R3SiH Pd(OAc)2 ligand Et3N DMF 70 °C Scheme 49 As the examples above testify palladium and nickel are the dominant catalysts in this area.Allred and Liebeskind have developed a copper-mediated cross-coupling of organostannanes with organic iodides. This protocol is simple and also o§ers the advantage of a rapid reaction rate at low temperatures and although it is stoichiometric in copper it may prove to be a competitor to many palladium-catalysed processes. 145 Copper catalysts have also found use in the direct amination of nitrobenzenes with o-alkylhydroxylamines and in the oxidative electrophilic amination of cyanocuprates with lithium amides (Scheme 50).146,147 Directed ortho-metallation (DOM) continues to be exploited as an e§ective synthetic tool for the construction of regiospecifically substituted aromatic rings.Spangler 141 Aromatic compounds Scheme 50 SO2OPri CONPr2 i SO2OPri CONPr2 i CONPr2 i + + i Bu nLi ii MeI 90% 6% 90% recovered Scheme 51 CF3 Cl CF3 Cl CF3 Cl Li Li CF3 Cl CF3 Cl COOH COOH CO2 CO2 LiCH(CH3)C2H5 LiC4H9 Scheme 52 has demonstrated that alkyl benzenesulfonates are very powerful ortho directors relative to known DOM groups (Scheme 51).148 The DOM capacity of the carboxylic group has been classified as intermediate in reactivity compared with a selection of DOM groups.149 The metallation of fluoroarenes carrying chlorine or bromine as additional substituents always occurs ortho to the fluorine when potassium tert-butoxide activated butyllithium or lithium 2,2,6,6-tetramethylpiperidine is used as the base.150 The control of DOM selectivity can be modulated by the choice of base (Scheme 52).151 142 Alan P.Chorlton FVP 1–2 torr 1200–1300 °C Scheme 53 O O Me3 SiO OSiMe3 LDA ClSiMe3 FVP 1000 °C Scheme 54 5 Condensed polycyclic aromatic compounds Benzenoid aromatics Curved polycyclic aromatic hydrocarbons (PAH) of five- and six-membered rings organised in the same arrangement as those found on the surface of fullerenes have attracted considerable attention since the first isolation of C 60 . Scott et al. have achieved the synthesis of a fullerene fragment which comprises 60% of C 60 . The benefits of this synthesis are that the C 36 H 12 fragment is obtained in just one step by vacuum pyrolysis (FVP) of the commercially available precursor decacylene (Scheme 53).152 In a similar approach towards C 60 fragments the chromium complexes of butyldecacylene and tri-tert-butyl-decacylene have been considered as possible precursors to bowl-shaped PAHs.153 Corannulene is the simplest of the curved PAHs.Lin and Rabideau have reported a new corannulene synthesis via the FVP of silyl vinyl ethers (Scheme 54).154 This procedure may have advantages where the usual precursor the bis(chlorovinyl) derivative is not accessible from the diketone. The addition of an extra five-membered ring to the corannulene carbon framework increases significantly both the curvature and rigidity of the system. The barriers to inversion of corannulenes are in the range *G‡\10–11 kcal mol~1 whereas the cyclopentacorannulene 23 has been determined at *G‡\27.61–27.67 kcal mol~1 over the temperature range 52.1–99.3 °C.Deuteration of cyclopentacorannulene 23 takes place with p-facial stereochemistry to give exclusively the exo-dideuteriocyclopentacorannulene 24.155 Gas phase argon ion fragmentation of hexafluorotribenzotriphenylene generates a key fullerene fragment trifluorohemifullerene (Scheme 54).156 Mass spectral evidence for the formation of trace quantities of C 60 from mellitic trianhydride has been reported (Scheme 56).157 143 Aromatic compounds F F F F F F F F F + other Fragments Scheme 55 O O O O O O O O O Ph2O reflux 24 h C60 trace by MS Scheme 56 FVT 1000 °C Scheme 57 23 H D H 24 D PAHs containing fully unsaturated five-membered rings as integral components of their trigonal carbon networks have also attracted interest due to their photophysical and biological properties.These non-alternant cyclopenta-fused PAHs are thought to arise from alternant PAHs. These transformations have been studied by FVP by a number of groups.158–160 An example of this is the conversion of triphenylene to cyclopent[h,i]acephenanthrylene (Scheme 57).160 The PAH dibenzotetraphenylperiflanthene 25 synthesized via an e¶cient high yielding oxidative coupling was found to emit blue light under conditions of electrogenerated chemiluminescence (Scheme 58).161 A number of previously unknown dicyclopentapyrenes have been synthesized via FVP of bis(chlorovinyl) precursors (Scheme 59).162 The interest in C 60 and 144 Alan P. Chorlton O Fissure-coupling Fjord-coupling Cove-coupling i heat ii H+ CoF3–TFA reflux 25 Scheme 58 Cl Cl Cl Cl Cl Cl Scheme 59 145 Aromatic compounds AlCl3–CuCl2 Scheme 60 fullerene precursors has led to a renaissance of interest in PAHs from a synthetic and materials viewpoint.Molecular electronics research has recently focused on thin film devices. There is therefore a requirement for organic materials that can be vapour deposited to give controlled films without thermal degradation. A number of C 54 PAHs have been synthesized which fulfil these application requirements (Scheme 60).163 27 26 The biphenylene dimer 26 has been synthesized and has been considered as a molecular fragment of a two dimensional carbon-net 27 (Scheme 61).164 A family of graphite ribbons have been synthesized by stilbene-like photocyclizations (Scheme 62).165 The cyclic PAHs coronene 28 and [7]circulene 29 have both been synthesized by new methods (Scheme 63).166,167 The highly hindered PAH decaphenylanthracene 30 has been synthesized.Despite the highly sterically crowded nature of the anthracene moiety it still retains the characteristics of a normal anthracene.168 Non-benzenoid aromatics Benz[a]azulenes 31 are a well-known class of polycyclic non-benzenoid aromatics. The dearth of synthetic methodologies for their preparation has hindered progress in this area. Anovel one-pot tropylium ion-mediated furan ring opening process has been 146 Alan P. Chorlton R R R R hn I2 Scheme 61 Scheme 62 147 Aromatic compounds Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 30 O R R O Ph3C+BF4 – Scheme 63 31 32 developed that allows the successful synthesis of benz[a]azulene derivatives (Scheme 64).169 Protonation of azuleno[1,2-a]acenaphthylene 32 has been studied in superacids.The resulting monocation is best viewed as an azulenium ion having strong tropylium ion character with limited charge delocalisation into the naphthalene moiety.170 A series of push-pull azulenes have been synthesized and the e§ect of the substituents has been examined by NMR and UV–VIS spectroscopy.171 Ring strain precludes D 10h symmetry for the parent [10]annulene 33. A number of planar all-cis[10]annulene derivatives (34 and 35) have been proposed which takes advantage of strain to overcome the planarity problem in simple all-cis derivatives of 33. Theoretical studies on the aromatization of these derivatives indicates that they are attractive candidates worthy of experimental investigation.172 10p 10p 10p 33 34 35 148 Alan P.Chorlton Scheme 64 The novel thia[13]annulene 36 had been prepared and is notably diatropic and shows about 40% of the ring current of the parent bridged [14]annulene 37.173 Mechanistic studies on the formation of fullerenes suggests that monocyclic species play a key role in formation of carbon cages. Tobe et al. have designed dodecadehydro[18]annulene 38 and hexadecadehydro[24]annulene 39 annulated by [4.3.2]propellatriene units as new viable precursors of cyclo[18]carbon 40 and cyclo[24]carbon 41. The C 18 ~ and C 24 ~ ions were observable when the precursors 38 and 39 were subjected to negative ion LD-TOF mass spectrometry. A photochemical study of 38 was carried out in furan which gave a number of products including the 149 Aromatic compounds Scheme 65 furan adduct 42 which may have resulted from cyclo[18]carbon 40 (Scheme 64).174 6 Cyclophanes Recent advances in cyclophane chemistry have been reviewed by Bodwell.175 The first example of a corannulene cyclophane 43 has been reported.The e§ect of the cyclophane is to lock e§ectively the corannulene into only one bowl form.176 The remarkably distorted 1,8-dioxa[8](2,7)pyrenophane 44 was prepared by the valence isomerization and dehydrogenation of the tethered [2,2]metacyclophanediene 45. In the crystal the overall bend is nearly 90°. 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Sakaguchi and M. Maruta Synlett 1996 171. 82 A. Kawada S. Mitamura and S. Kobayashi Chem. Commun. 1996 183. 83 S. Kobayashi and S. Nagayoma J. Org. Chem. 1996 61 2256. 84 J. Ruiz D. Astrue and L. Gilbert Tetrahedron Lett. 1996 37 4511. 85 A. Orlinkov I. Akhrem S. Vitt and M. Vol’pni Tetrahedron Lett. 1996 37 3763. 86 V.G. Nenajdenko I. L. Baraznenok and E. S. Balenkova Tetrahedron 1996 52 12 993. 87 N. Yonezawa Y. Tokita T. Hino H. Nakamura and R. Katakai J. Org. Chem. 1996 61 3551. 88 M. Tanaka M. Fuijiwara H. Ando and Y. Souma Chem. Commun. 1996 159. 89 C. B. Castellani O. Carugo M. Giusti C. Leopizzi A. Perotti A. G. Invernizzi and G. Vidari Tetrahedron 1996 52 11 045. 90 M. E. Jung and T. I. Lazarova Tetrahedron Lett. 1996 37 7. 91 R. Sreekumar and R. Padmakumar Tetrahedron Lett. 1996 37 5281. 92 M. Tanaka H. Nakashima M. Fujiwara H. Ando and Y. Souma J. Org. Chem. 1996 61 788. 93 J. Perrson S. Axelsson and O. Matsson J. Am. Chem. Soc. 1996 118 20. 94 E. N. Durantini and C. D. Borsarelli J. Chem. Soc. Perkin Trans. 2 1996 719. 95 E. Buncel J. M. Dust and R. A. Manderville J. Am. Chem. Soc. 1996 118 6072.96 M. Cervera J. Marquet and X. Martin Tetrahedron 1996 52 2557. 97 K.M. Wells Y.-J. Shi J. E. Lynch G. R. Humphery R. P. Volante and P. J. Reider Tetrahedron Lett. 1996 37 6439. 98 T. Hattori T. Satoh and S. Miyano Synthesis 1996 515. 99 R. F. Pellon T. Mamposo R. Carrasco and L. Rodes Synth. Commun. 1996 26 3877. 100 N. Takechui Y. Fukai K. Oka and R. Huisgen Chem. Lett. 1996 23. 101 N. Yoneda and T. Fukuhara Tetrahedron 1996 52 23. 102 D. J. Bull M.J. Fray M. C. Mackenny and K. A. Malloy Synlett 1996 647. 103 A. R. Katritzky and L. Xie Tetrahedron Lett. 1996 37 347. 104 N. J. Lawrence J. Liddle and D. A. Jackson Synlett 1996 55. 105 M. Makosza M. Sypniewski and T. Glinka Tetrahedron 1996 37 3189. 106 P. F. Pagoria A. R. Mitchell and R. D. Schmidt J. Org. Chem. 1996 61 2934.107 M. Cervera and J. Marquet Tetrahedron Lett. 1996 37 7591. 108 M. Makosza K. Stalinski and c. Klepka Chem. Commun. 1996 837. 109 F. B. Mallory D. S. Amenta C.W. Mallory and J.-J. J. C. Cheung J. Org. Chem. 1996 61 1551. 110 T. Je§ery Tetrahedron 1996 52 10 113. 111 D. E. Kaufmann M. Nouroozian and H. Henze Synlett 1996 1091. 112 J.-F. Nguefack V. Bolitt and D. Sinou Tetrahedron Lett. 1996 37 5527. 113 M. T. Reetz R. Breinbauer and K. Wanniger Tetrahedron Lett. 1986 37 4499. 114 M. T. Reetz and G. Lohmer Chem. Commun. 1996 1921. 115 S. Saito M. Sakai and N. Miyaura Tetrahedron Lett. 1996 37 2993. 116 K.-I. Gouda E. Hagiwara Y. Hatanaka and T. Hiyama J. Org. Chem. 1996 61 7232. 117 Y. Kobayashi and R. Mizojiri Tetrahedron Lett. 1996 37 8531. 118 M. Rottlander N. Palmer and P.Knochel Synlett 1996 573. 152 Alan P. Chorlton 119 S. Darses T. Je§ery J.-P. Genet J.-L. Brayer and J.-P. Demoute Tetrahedron Lett. 1996 37 3857. 120 A. Weichert M. Bauer and P. Wirsig Synlett 1996 473. 121 J. W. Guiles S. G. Johnson and W.V. Nurray J. Org. Chem. 1996 61 5169. 122 M. Larhed G. Lindeberg and A. Hallberg Tetrahedron Lett. 1996 37 8219. 123 S. Marquais and M. Arlt Tetrahedron Lett. 1996 37 5491. 124 Y. D. Ward and V. Farina Tetrahedron Lett. 1996 37 6993. 125 C. A. Willoughy and K. T. Chapman Tetrahedron Lett. 1996 37 7181. 126 Y. Han S. D. Walker and R. N. Young Tetrahedron Lett. 1996 37 2703. 127 O. Loiseleur P. Meier and A. Pfaltz Angew. Chem. Int. Ed. Engl. 1996 35 201. 128 G. A. Kraus and B. M. Watson Tetrahedron Lett. 1996 37 5287. 129 P. Galda and M.Rehahn Synthesis 1996 614. 130 M. A. Keegstra S. De Feyter F. C.De Schryver and K. Mullen Angew. Chem. Int. Ed. Engl. 1996 35 774. 131 S. Chodorowski-Kimmes M. Beley J.-P. Collin and J.-P. Sauvage Tetrahedron Lett. 1996 37 2963. 132 P. Liess V. Hensel and A.-D. Schluter Liebigs Ann. 1996 1037. 133 J. P. Wolfe and S. L. Buchwald J. Org. Chem. 1996 61 1133. 134 J. P. Wolfe S. Wagaw and S. L. Buchwald J. Am. Chem. Soc. 1996 118 7215. 135 M. S. Driver and J. Hartwig J. Am. Chem. Soc. 1996 118 7217. 136 J. F. Hartwig S. Richards D. Baranano and F. Paul J. Am. Chem. Soc. 1996 118 118 3626. 137 S.-H. Zhao A. K. Miller J. Berger and L. A. Flippin Tetrahedron Lett. 1996 37 4469. 138 A. J. Pearson A. M. Gelormini M. A. Fox and D. Watkins J. Org. Chem. 1996 61 1297. 139 S.-K. Kang H.-W. Lee W.-K.Choi R.-K. Hung and J.-S. Kim Synth. Commun. 26 4219. 140 I. W.J. Still and F. D. Toste J. Org. Chem. 1996 61 7677. 141 H. Harayama T. Kozera M. Kimura S. Tanaka and X. Tamaru Chem. Lett. 1996 543. 142 J.-C. Arnould M. Didelot C. Cadilhac and M.J. Pasquet Tetrahedron Lett. 1996 37 4523. 143 R. J. Perry and B. D. Wilson J. Org. Chem. 1996 61 7482. 144 H. Kotsuki P. K. Datta and H. Suenga Synthesis 1996 470. 145 G. D. Allred and L. S. Liebeskind J. Am. Chem. Soc. 1996 118 2748. 146 S. Seko and N. Kawamura J. Org. Chem. 1996 61 442. 147 A. Alberti F. Cane P. Dembech D. Lazzari A. Ricci and G. Seconi J. Org. Chem. 1996 61 1677. 148 L. A. Spangler Tetrahedron Lett. 1996 37 3639. 149 G. Ameline M. Vaultier and J. Mortier Tetrahedron Lett. 1996 33 8175. 150 F. Mongin and M. Schlosser Tetrahedron Lett.1996 37 6551. 151 F. Mongin O. Desponds and M. Schlosser Tetrahedron Lett. 1996 37 2767. 152 L. T. Scott M. S. Bratcher and S. Hagen J. Am. Chem. Soc. 1996 118 8743. 153 K. Zimmermann R. Goddard C. Kruger and M.W. Haenel Tetrahedron Lett. 1996 37 8371. 154 C. Z. Liu and P. W. Rabideau Tetrahedron Lett. 1996 37 3437. 155 A. Sygula A. H. Abdourazak and P. W. Rabideau J. Am. Chem. Soc. 1996 118 339. 156 M. J. Plater M. Praveen B. K. Stein and J. A. Ballantine Tetrahedron Lett. 1996 37 7855. 157 G. Adamson and C. W. Rees J. Chem. Soc. Perkin Trans. 1 1996 1535. 158 R. F. C. Brown K. J. Coulston and F. W. Eastwood Tetrahedron Lett. 1996 37 6819. 159 M. Sarobe L. W. Jenneskens and U. E. Wiersum Tetrahedron Lett. 1996 37 1121. 160 R. H. G. Neilen and U. E. Wiersum Chem. Commun.1996 149. 161 J. D. Debad J. C. Morris V. Lynch P. Magnus and A. J. Bard J. Am. Chem. Soc. 1996 118 2374. 162 L. T. Scott and A. Necula J. Org. Chem. 1996 61 386. 163 M. Muller J. Peterson R. Strohmaier C. Gunther N. Karl and K. Mullen Angew. Chem. Int. Ed. Engl. 1996 35 886. 164 A. Rajca A. Safronov S. Rajca C. R. Ross and J. J. Stezowski J. Am. Chem. Soc. 1996 118 7272. 165 F. B. Mallory K. E. Butler A. C. Evans and C. W. Mallory Tetrahedron Lett. 1996 37 7173. 166 J. T. M. Van Dikj A. Hartwijk A. C. Blecken J. Lugtenburg and J. Cornelisse J. Org. Chem. 1996 61 1136. 167 K. Yamamoto H. Sonobe H. Matsubara M. Sato S. Okamoto and K. Kitaura Angew. Chem. Int. Ed. Engl. 1996 35 69. 168 X. Qiao M. A. Padulas D.M. Ho N. J. Vogelaar C. E. Schutt and R. A. Pascal Jr. J. Am. Chem. Soc.1996 118 741. 169 K. Yamamura T. Yamane M. Hashimoto H. Miyake and S.-I. Nataksuji Tetrahedron Lett. 1996 37 4965. 170 K. K. Laali S. Bolvig S. Kuroda M. Oda M. Mouri I. Shimao T. Kajioka and M. Yasunami J. Chem. Soc. Perkin Trans. 2 1996 1091. 171 J. Zindel S. Maitra and D. A. Lightner Synthesis 1996 1217. 172 P. v. R. Schleyer H. Jiao H. M. Sulzbach and H. F. Schaefer J. Am. Chem. Soc. 1996 118 2093. 173 R. H. Mitchell and V. S. Iyer J. Am. Chem. Soc. 1996 118 722. 174 Y. Tobe T. Fujii H. Matsumoto K. Narmura Y. Achiba and T. Wakabayashi J. Am. Chem. Soc. 1996 118 2758. 175 G. J. Bodwell Angew. Chem. Int. Ed. Engl. 1996 35 2085. 153 Aromatic compounds 176 T. J. Seiders K. K. Baldridge and J. Siegel J. Am. Chem. Soc. 1996 118 2754. 177 G. J. Bodwell J. N. Bridson T. J. Houghton J. W.J. Kennedy and M. R. Mannion Angew. Chem. Int. Ed. Engl. 1996 35 1230. 178 A. Pelter R. A. N. C. Crump and H. Kidwell Tetrahedron Lett. 1996 37 1273. 179 Y. Sakamoto N. Miyoshi and T. Shinmyoza Angew. Chem. Int. Ed. Engl. 1996 35 549. 154 Alan P. Chorlton

ISSN:0069-3030    

DOI:10.1039/oc093119

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

R1 N R2 N2 H CO2Et N R1 CO2Et 42–93% i or ii or iii 3 2 1 R1 = Ar Bu t R2 = Ar PhCH2 + R2 Scheme 1 Reagents i BF 3 ·Et 2 O; ii AlCl 3 ; iii TiCl 4 6 Heterocyclic compounds By Peter W. Sheldrake SmithKline Beecham Pharmaceuticals Old Powder Mills Nr Leigh Tonbridge Kent UK TN11 9AN 1 Three-membered rings Formation of aziridines by the addition of a diazo compound to an imine has been reported by several authors. For example imines 1 react with ethyl diazoacetate 2 in the presence of a Lewis acid catalyst to give aziridines 3 usually as a mixture of cis- and trans-isomers,1 although conditions are reported which result in formation of only the cis-isomer (Scheme 1). 1,3,5-Triarylhexahydro-1,3,5-triazines (in e§ect formaldehyde imines) react with 2 the preferred catalyst in this case being tin(IV) chloride giving 3 R1\H in 50–86% yield.2 The reaction of imine 4 with phenyldiazomethane was carried out using rhodium acetate and 20 mol%of the chiral auxiliary 5.The predominant product was (R,R)-6 in 97% enantiomeric excess; it is unfortunate that it was accompanied by the corresponding cis-isomer (Scheme 2).3 A more complex example was provided by the conversion of 7 into 8 using rhodium acetate4 (Scheme 3). The diazabicyclo[3.1.0]hexane produced is envisaged as an intermediate in mitomycin synthesis. The rhodium acetate catalysed decomposition of N-(p-nitrophenylsulfonyl) iminophenyliodinane (NsN–– IPh) in the presence of olefins 9 a§ords aziridines 10 in up to 85% yield. For the most part olefin geometry is retained though there is partial loss of stereospecifity using cis-stilbene (Scheme 4).Chiral auxiliaries were investigated demonstrating potential for asymmetric synthesis.5 The bromo-amide 11 condensed with the diphenylphosphinylimine 12 gave a single Royal Society of Chemistry–Annual Reports–Book B 155 N Ph SO2(CH2)2SiMe3 N SO2(CH2)2SiMe3 Ph Ph O S 55% i 6 5 4 Scheme 2 Reagents i PhCHN 2 Rh 2 (OAc) 4 82% i 8 7 N H N OMe COMe N2 O H H H OMe O COMe N N Scheme 3 Reagents i Rh 2 (OAc) 4 9 10 i up to 85% H R1 R3 R2 Ns N R1 R2 H R3 Scheme 4 Reagents i NsN––IPh Rh 2 (OAc) 4 i 11 12 13 71% S O2 N Br O N N S O2 O H H Ph POPh2 N Ph POPh2 Scheme 5 Reagents i LiN(SiMe 3 ) 2 diastereoisomer of aziridine 13 in an aza-Darzens reaction (Scheme 5). The sultam can be hydrolysed using lithium hydroxide.6 Bromide 14 R\Ph condenses with a sulfonylimine 16 using a fairly large catalytic quantity of dimethyl sulfide with potassium carbonate in acetonitrile.The cis/trans ratio of the product 17 R\Ph was variable7 (Scheme 6). The ylide from 15 R\Ph is the intermediate. The isolated salt 15 R\CO 2 Et reacts in the same way to give 17 R\CO 2 Et; some stereoselectivity was achieved favouring the cis-product.8 Oxiranes 18 react with iminophosphoranes and a zinc halide catalyst to give the 156 PeterW. Sheldrake R = Ph CO2Et + Br– + 14 15 16 17 i ii N R Ar SO2Ar2 R R Br S Me2 Ar N SO2Ar2 Scheme 6 Reagents i,Me 2 S; ii K 2 CO 3 up to 84% i 19 18 R1 = aryl alkyl R2,3,4 = alkyl H R5 = Ph Pri O N R1 R2 R4 R3 R2 R1 R3 R4 R5 Scheme 7 Reagents i Ph 3 P––NR5 ZnCl 2 R1 R2 = alkyl 64–92% i 21 20 R1 OR2 N O TosO R1 CO2R2 N Scheme 8 Reagents i Et 3 N corresponding aziridines 19 (Scheme 7).Oxiranes with one CH 2 and those spiro to rings were found to be the most reactive.9 Tosylated* oximes 20 are e¶ciently cyclised by triethylamine in dichloromethane to give 2H-azirinecarboxylic esters 21 (Scheme 8). When quinidine was used as the base the (R) product was obtained with 81% enantiomeric excess but in only 40% yield. Borohydride reduction of 21 was found to give only the cis-aziridine.10 Irradiation of 22 in acetone below [60 °C caused decarbonylation to give a cyclohexadiene which by photofragmentation gave a phthalimide and N-ethoxycarbonyl Dewar pyrrole 23 (Scheme 9). This was demonstrated by carrying out the irradiation in the presence of 1,3-diphenylisobenzofuran thereby trapping 23 as its Diels–Alder adduct. Above[60 °C only 1-(ethoxycarbonyl)pyrrole was observed.11 The Darzens condensation of (-)-8-phenylmenthyl chloroacetate 24 with symmetrical ketones a§orded glycidic esters 25 in 77–96% diastereoisomeric excess (de) (Scheme 10).Using unsymmetrical ketones the (Z)-glycidic ester was the predominant product again formed in high de (93% for acetophenone).12 The sulfonium salt 26 is readily prepared from Eliel’s oxathiane by alkylation with benzyl alcohol–trif- *Tosyl (Tos)\toluene-p-sulfonyl. 157 Heterocyclic compounds i 23 22 NCO2Et NMe O O NCO2Et CO Et Ph Ph Et Scheme 9 Reagents i light 254nm + R* = (–)-8-phenylmenthyl R1 R2 = alkyl Ph 24 25 39–81% R1 R2 O R1 R2 H CO2R* O i OR* O Cl Scheme 10 Reagents i ButOK + OTf – i 38–58% O S Ph O H Ar Ph H 26 27 Scheme 11 Reagents i ArCHO NaH luoromethanesulfonic anhydride–pyridine.Ylide generation using sodium hydride and reaction with an aromatic aldehyde gave epoxides 27 in 97.9–99.9% enantiomeric excess (ee) though in 38–58% yield (Scheme 11). The auxiliary was recovered in good yield.13 The combination of nonafluorobutanesulfonyl fluoride and 1,8-diazabicyclo[5.4.0]- undec-7-ene (DBU) has been reported as a reagent for converting 1,2-diols into epoxides. Good yields were obtained even in sterically demanding situations.14 The dynamic kinetic resolution of epichlorohydrin 28 has been achieved using enantioselective ring opening with azidotrimethylsilane catalysed by chromium(III) azide complex 29 (Scheme 12). 3-Azido-1-chloro-2-(trimethylsilyloxy)propane 30 was obtained in 76% yield and in 97% enantiomeric excess.15 In a study of metallating reagents for aromatic halides epoxide 31 was reacted at [78 °C with the zincate prepared from methyllithium (3 equiv.) and zinc thiocyanate to give 32 the product of a 5-exo ring closure along with a little 33 (Scheme 13).By contrast the corresponding cuprate prepared using copper(I) cyanide gave only 33 the 6-endo product. When chiral 31 was used the enantiomeric purity was unchanged in either reaction.16 A method has been reported for preparing solutions of dimethyldioxirane in chlorinated solvents at four to five times the concentration usually obtained in acetone. The more concentrated solutions were found to be no less stable.17 The ketone 34 derived 158 PeterW. Sheldrake 28 29 30 i ii Cl O Cl N3 OTMS O But But N But But N H O H Cr N3 Scheme 12 Reagents i 2mol% 29; ii 0.5 equiv.TMSN 3 by slow addition Scheme 13 Reagents i Li 3 ZnMe 3 (SCN) 2 ; ii Li 3 Cu(CN)Me 3 34 35 O O O O O O Cl Cl O O O O O O from fructose has been used with Oxone' in the asymmetric epoxidation of trans olefins and trisubstituted olefins. Enantiomeric excesses up to 95% were recorded.18 Dioxirane 35 prepared in situ from the ketone and Oxone' epoxidises trans stilbene in 95% yield and 76% enantiomeric excess.19 159 Heterocyclic compounds 36 37a X = I 37b X = OAc i HO Ar X O Ar Scheme 14 Reagents i Ag(collidine) 2 ClO 4 I 2 39 38 80–86% i X = Ph PhS FC6H4 CH2=CH C4H9 O O X O C4 H9 OH X Scheme 15 Reagents i BuLi Pr* 2 NH ButOK ii i 42 41 40 N N N But Ac Cl Cl Scheme 16 Reagents i Ac 2 O BF 3 ·OEt 2 ; ii KOH 44 43 N TBDMSO OAc H H O H N H O H H TBDMSO CO2H Me 2 Four-membered rings Iodocyclisation of dienols 36 gave oxetanes 37a predominantly (Scheme 14).The products were not conveniently separable but after displacement of iodide by acetate 37b was found to contain less than 10% of the alternative tetrahydrofuran product.20 Treatment of oxiranyl ethers 38 with a complex base forms an internal nucleophile that attacks the oxirane to give oxetanes 39 (Scheme 15). In the products the 2,3-anti configuration predominated except where X is a phenylthio group.21 1-Acetyl-3-chloroazetidine 41 was obtained by treatment of the tertiary amine 40 with acetic anhydride–boron trifluoride. Hydrolysis of the amide led to a transannular cyclisation giving azabicyclo[1.1.0]butane 42 (Scheme 16). In an NMRexperiment the 160 PeterW. Sheldrake R1 = Et i 45 46 N R1 O C6H4 OMe N C6H4OMe Ph S Ar O Br R1 SPh Ar OAc Scheme 17 Reagents i Bu 3 SnH AIBN i 30–70% R1 = Me BnO H R2 = Me H BnO R3 = Ph Me 47 48 X = Br I N R3 X H R2 R1 O O R1 R2 H N R3 Scheme 18 Reagents i Bu 3 SnH AIBN R1R2NH R1 R2 = H lower alkyl 49 50 51 N OTos Me O HO Me N OTos N H Me O R1R2N Scheme 19 Reagents i R1R2NH yield of 42 was quantitative.Reaction of 42 with ethyl chloroformate gave 1- ethoxycarbonyl-3-chloroazetidine.22 On the b-lactams the preparations of 43 and 44 pivotal intermediates for 1-b- methyl carbapenem synthesis have been reviewed.23 More examples of radical reactions in the b-lactam area are now appearing. Treatment of bromoamides 45 with tributyltin hydride and AIBN gave the b-lactam 46 (Scheme 17).24 In the case of 47 the same reagents were used to close the appended ring giving 48 (Scheme 18).25 The N-tosyloxyazetidinone 49 underwent an unusual addition of simple secondary amines with loss of tosylate.To explain this enolisation to 50 is suggested with attack of the amine by the mechanism shown in Scheme 19 leading to 51. In some cases by-products showed that nucleophilic attack can occur at all three of the ring carbon atoms.26 4-Formyl-b-lactams 52 well known from standard synthetic methodology are readily converted into formate esters 53 (Scheme 20). In a few cases oxidation to the 4-carboxylic acid was observed.27 161 Heterocyclic compounds 55 54 i ( )n ( )n N N O O O O Scheme 21 Reagents i Mo(––CHCMe 2 Ph)(––NC 6 H 3 Pr* 2 )[OCMe(CF 3 ) 2 ] 2 57 56 i ii N N CO2CHPh2 S S O O H H TBDMSO TBDMSO S S OH CO2CHPh2 H H Scheme 22 Reagents i MeSO 2 Cl Et 3 N; ii heat Na+ i 58 59 N S N O O H H H H TBDMSO TBDMSO O CO2CH2CH=CH2 O – CO2CH2CH=CH2 Scheme 23 Reagents i Ph 3 P NaH Scheme 20 Reagents i MCPBA A b-lactam will withstand the conditions under which an olefin metathesis reaction is used to close another ring as exemplified by the conversion of 54 into 55 (Scheme 21).28 Cyclisation of alcohol 56 was achieved by generation of an acyliminium ion with methanesulfonyl chloride and interaction with a ketene dithioacetal terminator to give 57 (Scheme 22).The ketene dithioacetal was removed by a singlet oxygen mediated cleavage to give the corresponding ketone.29 A new route to carbapenems relies on an Eschenmoser ring contraction applied to 1,3-thiazinones such as 58 conveniently prepared from thioesters of 44.Extrusion of sulfur on treatment with sodium hydride–triphenylphosphine gives enolate 59 162 PeterW. Sheldrake Scheme 24 Reagents i light 62 63 64 65 i ii iii iv N H H O OH MeO2C H N H N H H H N N Scheme 25 Reagents i soda lime; ii LiAlH 4 ; iii H 2 O 2 ; iv Bu5Li (Scheme 23).30 Capture of the enolate by diphenylphosphoryl chloride to permit subsequent displacement of the oxygen by a thiol was already known. Thioamide 60 is not chiral but its crystals are. When the powdered crystals are placed between Pyrex plates and irradiated azetidinethione 61 is formed e¶ciently (96% yield at 58% conversion) as a crystal and exhibits 94% enantiomeric excess (Scheme 24). The phenomenon arises from the chiral environment of the crystal lattice and minimal molecular motion of the intermediate radicals.31 3 Five-membered rings Amide 62 is easily available from a 2,5-disubstituted pyrrolidine.Closing the final ring using soda lime and reductive elimination of the alcohol in 63 gave the pleasingly symmetric amine 64 shown to be a relatively strong base though its precise pK! was not determined. The N-oxide of 64 treated with tert-butyllithium gave an azomethine which produced the remarkable dimer 65 (Scheme 25).32 Iodocyclisation of E-homoallylic tosylamides 66 leads to pyrrolidines 67 and/or 68. In the absence of base the product is 68; using potassium carbonate a strong preference ([25 1) for 67 was found (Scheme 26). The apparent violation of Baldwin’s rules (the overall process being e§ectively 5-endo-trig) can be explained by the reaction being electrophile rather than nucleophile driven.33 Asymmetric deprotonation of Boc-protected amines 69 using sec-butyllithium–([)- 163 Heterocyclic compounds i R1 R2 = H Me Et Ph 66 67 68 N N NH R1 R2 Tos Tos Tos R1 R1 R2 I R2 I Scheme 26 Reagents i I 2 base Scheme 27 Reagents i BusLi (-)-sparteine 72 71 67–85% R1 R2 = H Me MeO i ii N R1 R2 Br N E R1 R2 Scheme 28 Reagents i BuLi; ii electrophile E 74 73 i ii N SnBu3 N H E Scheme 29 Reagents i BuLi; ii electrophile E sparteine in toluene at [78 °C (the choice of solvent being important) led to cyclisation and formation of the (S)-2-arylpyrrolidines 70 in up to 75% yield and 96% enantiomeric excess (Scheme 27).34 Transmetallation of the allylated bromoanilines 71 with butyllithium brought about anionic cyclisation to indolines 72 where the intermediate cyclised carbanion could be captured with various electrophiles35 (Scheme 28).Oxidation of the products 72 to indoles was also reported.36 The stannane 73 has been used in a similar fashion (Scheme 29). Where the electrophile was a proton the product 74 is pseudoheliotridane. Note that the stereochemistry is preserved in the reaction.37 The preparation of 3-substituted pyrrolidines using the same principle was also reported.38 Radical ring closure reactions are useful for forming pyrrolidine rings. The (phenyl- 164 PeterW. Sheldrake 78 77 i I – I – i 76 75 N+ SePh Me Me N+ Me Me N+ N+ I Scheme 30 Reagents i Bu 3 SnH initiator R = Me Ph H X = Cl Br I 80 79 i N Bn R N R X O CO2Me O CO2 Me Bn Scheme 31 Reagents i Bu 3 SnH AIBN R1 = H Ph R2 = H alkyl Ph i ii 81 82 R1 CO2Me NH Bn N Bn CO2Me R1 R2 Bt N R1 R2 CO2Me Bn Scheme 32 Reagents i R2CHO benzotriazole (Bt); ii SmI 2 selenenylethyl)allylammonium salt 75 illustrates the tactic for forming the 3,4 bond39 (Scheme 30); other more complex examples were described.40 Using homoallyl iodomethylammonium salts such as 77 the pyrrolidine 2,3 bond was formed.41 Radicals formed from a-haloamides 79 undergo a 5-endo-trig closure to give pyrrolidinones 80 (Scheme 31).42 Amines 81 condense with an aldehyde and benzotriazole (Bt) giving the adducts; subsequent treatment with samarium iodide yields pyrrolidines 83 in 51–70% yield (Scheme 32).Where the possibility exists the reactions produce mixtures of diastereoisomers. 43 Cyclisation of unsaturated sulfonamides such as 83 induced by palladium acetate –oxygen gives products incorporating an allylamine moiety e.g.84 (Scheme 33). 165 Heterocyclic compounds i i 93% 86% 83 84 85 86 NH N Tos Tos Tos HN N Tos Scheme 33 Reagents i Pd(OAc) 2 O 2 DMSO 87 i ii 88 89 COCF3 N N COCF3 N OTBDMS COCF3 OTBDMS OTBDMS Scheme 34 Reagents i ruthenium carbene catalyst; ii molybdenum carbene catalyst Scheme 35 Reagents i NaOEt; ii LDA Similarly 85 gives the dihydroquinoline 86. This is in contrast to the previously reported cyclisation of 2-allylaniline with palladium chloride which gave 2-methylindole. 44 The triene 87 is set up to undergo pyrrolidine formation in an olefin metathesis reaction. A ruthenium carbene catalyst produced the 2,5-trans disubstituted product 88 whereas a molybdenum carbene catalyst gave the corresponding cis-isomer 89 (Scheme 34).Yields were high in each case.45 When aziridine 90 was exposed to a catalytic quantity of sodium ethoxide in ethanol the internal malonate anion opened the aziridine to give pyrrolidinone 91 (Scheme 35). In contrast the use of excess lithium diisopropylamine (LDA) brought about attack by 166 PeterW. Sheldrake 98 R = alkyl PhCH2 H 99 i ii 71–86% N N Boc N Boc N O O R Scheme 37 Reagents i Na NH 3 ; ii RX 95 94 93 R1 = Cl Me MeO NO2 ; R2 = alkyl iii i ii N N Cl Cl N CHO O O R2 R1 R1 R1 R2 Ar R2 R2 Scheme 36 Reagents i (COCl) 2 ; ii Pr* 2 NEt; iii Br 2 97 96 N O O N Cl N O Cl Cl the amide nitrogen on the tert-butyloxycarbonyl group generating the bicycle 92.46 On treatment with oxalyl chloride followed by Hu� nig’s base N-formylanilines gave intermediates 94 which on further treatment with bromine formed isatins 95 (Scheme 36).The reaction also succeeded with N-formylindoline giving a tricyclic product.47 Phosphorus pentachloride treatment of isatin itself has always been said to give &lsquosatin chloride’ 96. This compound has now been shown48 to be a ‘phantom’ and the true structure of the product is 97. This discovery is remarkably reminiscent of the ‘misbehaviour’ of pyrrolidin-2-one with phosphorus pentachloride.49 The Birch reduction is applicable to electron deficient pyrroles such as 98. It was shown that the intermediate anion can be protonated or trapped with an alkylating agent to give 99 (Scheme 37).50 An attempted double acetamidomalonate displacement on 1,4-dichlorobut-2-yne using excess base gave pyrrole 100.It was postulated that the reaction proceeds via intermediates 101 and 102 (Scheme 38).51 Treatment of the vinylamidinium salt 103 with sarcosine ethyl ester and base produced 3-aryl-1-methylpyrrole-2-carboxylate 104 (Scheme 39). Interestingly use of ethyl glycinate gave the 2,5-disubstituted pyrrole 10552 Titanium tetrachloride mediated condensation of silyl enol ethers 106 and hydrazones 107 followed by acid catalysed cyclisation and removal of the 167 Heterocyclic compounds + 100 101 102 i NH CH3 CO2Et Ac NH CO2Et CO2Et Cl Cl O NH C C H2C CO2Et CO2Et O N CO2Et Scheme 38 Reagents i NaOEt + X – i ii 103 104 105 Me2N Ar NMe2 NH CO2Et Ar N Me Ar CO2Et Scheme 39 Reagents i MeN(H)CH 2 CO 2 Et NaH DMF; ii H 2 NCH 2 CO 2 Et NaH + R1 R2 R3 = lower alkyl aryl 106 107 108 i ii iii 33–65% NH R1 R2 R3 R1 OSiMe3 R2 N NMe2 R3 AcO Scheme 40 Reagents i TiCl 4 ; ii TsOH; iii Na NH 3 dimethylamino group with sodium–liquid ammonia led to 2,3,4-trisubstituted pyrroles 108 (Scheme 40),53 in an overall yield of 33–65%.The position of acetylation of 3-substituted 1-phenylsulfonylpyrroles 109 depends on the catalyst. Boron trifluoride gave substitution at the 5-position but use of aluminium chloride led to 2-acylation forming 110 and 111 respectively (Scheme 41).54 N-Arylalkenesulfinamides 112 were prepared from N-sulfonylarenamines and alkenyllithiums. On heating they undergo a [3,3] rearrangement to 113 which cyclises with loss of sulfinic acid to give indoles 114 in up to 83% yield (Scheme 42).55 Tolylsulfonyl derivatives 115 of a number of heterocycles are converted into the corresponding stannanes 116 on treatment with tributyltin hydride (Scheme 43).Examples were given for pyrrole indole pyrazole furan thiophene and their benzo derivatives.56 168 PeterW. Sheldrake i ii 109 110 111 N R SO2Ph N SO2Ph R N R PhSO2 O O Scheme 41 Reagents i Ac 2 O BF 3 ·OEt 2 ; ii Ac 2 O AlCl 3 i R1 R2 = H Me (CH2)4 112 113 114 NH S R2 R1 O N H R1 NH S+ O – R2 R1 R2 Scheme 42 Reagents i heat i X = O S N 115 116 X SnBu3 SO2Tol X Scheme 43 Reagents i Bu 3 SnH AIBN i X = NH; R = H Me Cl Br X = O S; R = H 117 118 X CO2H CO2H X R R Cl CHO Scheme 44 Reagents i POCl 3 DMF Reaction of diacids 117 with DMF–phosphoryl chloride gave 118; the reaction being equally applicable to the synthesis of indoles benzofurans and benzothiophenes (Scheme 44).57 Reaction of acetylenic diols 119 with iodine induced (electrophile driven) 5-endo-dig cyclisation to iodofurans 120 (Scheme 45).58 Reaction of thiophenes such as 121 with acetic anhydride–toluene-p-sulfonic acid gave thieno[2,3-c]furans in this example 122 (Scheme 46).The products are reactive dienophiles; it is easy to contrive examples where the ensuing 4]2 reaction is intramolecular. Furo[3,4-b]indoles have been prepared by the same methodology.59 The combination of phenyliodonium acetate–iodine cyclises alcohols 123 via an alkoxyl radical forming the aryl–oxygen bond of ethers 124 (Scheme 47). The starting alcohols can be primary secondary or tertiary.60 Aryl–oxygen bond formation was 169 Heterocyclic compounds i 121 122 79% S S O SEt Ph S+ Ph O O – Et Scheme 46 Reagents i Ac 2 O TsOH 22–70% i 124 123 n = 1,2,3 R1 R2 = H alkyl ( ) n ( ) n R2 OH R1 O R1 R2 Scheme 47 Reagents i PhI(O 2 CCH 3 ) 2 I 2 up to 93% i 126 125 n = 1,2,3 ( ) n ( ) n Me Me OH O Br Me Me Scheme 48 Reagents i Pd(OAc) 2 Tol-BINAP K 2 CO 3 120 119 R1 = Ph Me CO2Me; R2 = Bu Ph i 47–88% O R1 R2 I R2 OH R1 HO Scheme 45 Reagents i I 2 NaHCO 3 brought about by palladium(0) catalysis in the conversion of 125 to 126 (Scheme 48).All reported examples except one were of tertiary alcohols; the sole case of a secondary alcohol gave a 32% yield.61 Construction of a cyclic ether by an addition–elimination reaction on the iodotolylsulfonylalkene moiety of 127 is a simple but e§ective tactic (Scheme 49). Note that in the five-membered product 128 the double bond remained exocyclic but moved into the six-membered ring of product 129.62 Treatment of 130 with caesium fluoride gave the carbonyl ylide 131 which reacted with alkenes allenes aldehydes ketones and imines.63 Bis(chloroalkyl)ethers 132 are precursors of unstabilised carbonyl ylides 133 samarium diiodide being the reagent.64 These carbonyl ylides were reacted with alkenes and alkynes (Scheme 50).Treatment of thiophene 134 with potassium fluoride e§ected an elimination of both 170 PeterW. Sheldrake 129 128 127 n = 2 i n = 1 i ( ) n I O O SO2Tol HO SO2Tol SO2Tol Scheme 49 Reagents i KN(SiMe 3 ) 2 R1 R2 = alkyl 133 132 ii _ _ i 131 130 _ Ar O Cl Me3Si Ar O+ Cl O R2 R1 Cl O+ R2 R1 R1 O+ R2 Scheme 50 Reagents i CsF; ii Sm I 2 136 135 134 ii i S S Me3Si I(OTf) Ph S Scheme 51 Reagents i KF 18-crown-6; ii C 6 H 6 substituents to give a species depicted (unsatisfactorily) as 135 (Scheme 51).It is highly reactive giving 136 in benzene and reacting with furan or anthracene in a 4]2 manner. With 2,3-dimethylbuta-1,3-diene it underwent a 2]2 addition and an ene reaction.65 Diallyl sulfide undergoes an olefin metathesis reaction with a molybdenum carbene catalyst giving 2,5-dihydrothiophene 137 in essentially quantitative yield (Scheme 52). Diallyl ether behaved in the same way.66 Sulfides 138 n\1 form dihydrobenzothiophenes 139 on treatment with phenyliodonium trifluoracetate. The reaction is capable of producing larger rings (Scheme 53).67a The same reagents were used for intramolecular aryl–aryl bond formation where the chain linking the aromatic groups may optionally contain a heteroatom.67b Pyrazoles 141 were formed from aromatic carboxylic acid chlorides 140 in a one-pot 171 Heterocyclic compounds 137 i S S Scheme 52 Reagents i Mo(––CHCMe 2 Ph)(––NC 6 H 3 Pr* 2 )[OCMe(CF 3 ) 2 ] 2 i ii 139 n = 1,2,3 x = 0,1,2 138 ( ) n ( ) n S S R R Bn MeO MeO (MeO) x (MeO) x Scheme 53 Reagents i PhI(OCOCF 3 ) 2 BF 3 ·OEt 2 ; ii MeNH 2 141 140 21–58% i ii iii Ar Cl O N N Ar CN NH2 R Scheme 54 Reagents i CH 2 (CN) 2 NaH; ii Me 2 SO 4 ; iii RNHNH 2 Et 3 N R = alkyl aryl 143 142 42–88% i N N N N Me Me Me Me R O Scheme 55 Reagents i CO CH 2 ––CHR Ru 3 (CO) 12 three-step procedure summarised in Scheme 54.Although more than one regioisomer is in principle possible only that shown was formed the regiochemistry being established by X-ray crystallography.68 The reaction of 1,2-dimethylimidazole 142 with an alkene and carbon monoxide catalysed by triruthenium dodecacarbonyl gave the acylated imidazole 143 in 68% yield (Scheme 55).There are relatively few approaches to such acylated imidazoles.69 Treatment of N-butyl-2,6-dinitroaniline 144 with sodium hydroxide gave the benzimidazole N-oxide 145 in 95% yield (Scheme 56). Both nitro groups are needed and displacement of the butylamino group by hydroxide can be a competing reaction; otherwise the authors did not comment on the reaction mechanism.70 The 4-chloro-2-oxopyridine-3-carbaldehydes 146 react with azide by chloride displacement and cyclisation giving the 5,6-dimethylisoxazolo[4,3-c]pyridin-4(5H)-ones 147 (Scheme 57). When R\Me the intermediate azido compound was isolable.71 The 172 PeterW. Sheldrake Scheme 56 Reagents i NaOH R = H Me 146 i 147 N N O N Cl Me O R O Me Me Me O R Scheme 57 Reagents i NaN 3 100% 96% 150 149 148 ii i N N N N O Ph O Ph Ph O N3 NH2 Scheme 58 Reagents i PhI (OAc) 2 ; ii heat similar 3-phenylisoxazolo[3,4-c]pyridine 149 was prepared by treatment of 3-amino- 4-benzoylpyridine 148 with phenyliodonium acetate or by thermolysis of the azide 150 (Scheme 58).72 A novel synthesis of 3-amino-1,2-benzisoxazoles 152 involved a nucleophilic aromatic substitution reaction by hydroxamate anion on the activated ortho substituent in benzonitriles 151 followed by ring closure and deacetylation (Scheme 59).This procedure73 is claimed to be superior to other methods. It has not usually been possible to use 2-lithiooxazoles synthetically as they ring open to form an isonitriloenolate.Now it has been reported that the borane complexes of a number of 5-substituted oxazoles can be deprotonated reacted with an electrophile and recovered from the complex to give the 2-substituted oxazoles in good yield.74 A usable degree of asymmetric induction in the reaction of a nitrone and allyl alcohol was reported when the reaction was carried out as indicated in Scheme 60. The chirality is derived from a tartrate ester–zinc complex. The reaction was carried out in chloroform but usable enantiomeric excess in the isoxazoline product 153 was only obtained when small quantities of another oxygen containing solvent were added.75 The selenium dioxide promoted oxidative rearrangement of 2-alkyloxazolines 154 173 Heterocyclic compounds X = F Cl NO2 R = H Halogen MeO BnS 152 151 43–80% i N O X CN NH2 R R Scheme 59 Reagents i AcN(H)OH ButOK 153 i ii iii OH R OH N O Scheme 60 Reagents i Et 2 Zn; ii (R,R)-DIPT; iii RC(Cl)––NOH 155 154 i R1 = H Me Ph R2 = Ph Pri O N R1 R2 N O O R1 R2 Scheme 61 Reagents i SeO 2 i i 158 156 157 R = Me Ph n = 1,2 Z E ( ) n ( ) n ( ) n R O N O OH N+ O O – Me O R O O NH H O Scheme 62 Reagents i heat via the 2-acyl derivative to dihydrooxazinones 155 represents a convenient preparation of these compounds including 3-unsubstituted examples which are otherwise not readily accessible (Scheme 61).76 Further studies on the reaction mechanism have been reported.77 The oximes 156 are configurationally stable at elevated temperatures.The (E)- oximes reacted via a concerted 1,3-azaprotio cyclotransfer reaction to give six- and seven-membered cyclic dipoles 157 whilst the Z-isomers gave fused isoxazolidines 158 via 1,2-prototropy and cycloaddition (Scheme 62).78 Thiobenzamide 159 and alkynyl(phenyl)iodonium methanesulfonate form thiazoles 160 according to the sequence outlined in Scheme 63.79 Thioamides 161 can be converted into benzothiazoles 162 by reaction with butyllithium which initiates a sequence of directed lithiation aryne formation cyclisation 174 PeterW.Sheldrake 57% .. 160 159 i Ph NH2 S N S C4H9 Ph S I Ph Ph HN S IPh C S HN Ph C4H9 Ph C4H9 C HN C4H9 Scheme 63 Reagents i PhI(OSO 2 Me)C–– – C–C 4 H 9 162 161 X = Cl F R = Bu t OPri i ii S N X HN R S E R Scheme 64 Reagents i BuLi; ii electrophile E 164 163 R = alkyl aryl 36–95% i Cl N N Ar N R N N R Ar Scheme 65 Reagents i NaN 3 and quenching (Scheme 64).Considerable variety was exemplified in the final quenching electrophile.80 Imidoyl chlorides 163 react with sodium azide in a two-phase system to form 1,5-disubstituted tetrazoles 164 (Scheme 65).81 From a discussion (covering the furanofurans thienothiophenes benzofurans and benzothiophenes) of whether the most stable fused heterobicycles in a series are the most aromatic it was concluded that there need not be any direct relationship in such isomers between the thermodynamic stability and their aromaticity since thermodynamic stability is influenced by strain and other e§ects.82 4 Six-membered rings It was known that pyridine and butyllithium in a 3 1 molar ratio produce an isolable complex 165 but now a new complex a bis(pyridyl)dihydropyridyllithium dimer 166 175 Heterocyclic compounds 166 165 py py N Bu H Li N N H H H H Li Li py py py py 167 69% i N N OH OH CO2Bn Scheme 66 Reagents i ClCO 2 Bn NaBH 4 NaHCO 3 MeOH,[80 °C 97% 99% 170 169 168 ii i N N Ph Ph Ph O O Me N Me Me Scheme 67 Reagents i L-Selectride; ii LiAlH 4 TiCl 3 has been isolated from the same reactants in the presence of excess pyridine.The complex has been characterised both in solution and as a crystal.83 Alkylation of 2-pyridone with benzyl chloride produces the 1-benzyl derivative no matter what form of heating is used. The use of benzyl bromide or benzyl iodide without solvent or base in a microwave oven gave mixtures of the 3-benzyl and 5-benzyl derivatives.84 Reduction of 3-hydroxypyridine with benzyl chloroformate–sodium borohydride led regiospecifically to the tetrahydropyridine 167 (Scheme 66); complexation of borohydride to the hydroxy group is believed to occur.85 The reduction of pyridone 168 can be controlled by the choice of reagent Selectride' gave exclusively the dihydropyridone product 169 while lithium aluminium hydride–titanium trichloride led to the tetrahydropyridine 170 (Scheme 67).86 Lithium aluminium hydride gave both products.Permutations of lithium aluminium hydride/deuteride reductions with methanol/methan[2H]ol quenches were used to gain mechanistic information. After N-oxidation the pyridylacetylene 171 reacted with oxygen sulfur or nitrogen nucleophiles (Scheme 68) via 172 to give 173 in an intramolecular Reissert–Henze-type reaction.87 176 PeterW. Sheldrake 173 172 171 ii i AcO– + N Ph N Nuc Ph O N O Ph Scheme 68 Reagents i H 2 O 2 AcOH; ii nucleophile (see text) i 175 174 N O CO2H CO2H O N H N H O CO2H O CO2H N Scheme 69 Reagents i NaBO 3 ·4H 2 O 176 i CF3CO2 – + N NH2 N NH H H Scheme 70 Reagents i HCHO TFA cyclopentene Palladium(0) couplings of 2-chloroquinoline have been reported; Stille Suzuki and carbonylation reactions were exemplified but a Heck reaction (which presumably relies on the same organopalladium species) unaccountably failed.88 Keto-acids of the type 174 can be oxidatively decarboxylated by perborate (Scheme 69) to give acids 175.89 2-Aminopyridine (and other similar aminoheterocycles) reacts with formaldehyde together with an alkene to give tricycles of which 176 is a typical example (Scheme 70).90 Pyridyl ketone 177 reacted with an iminium salt to form an intermediate 178 which can progress in two ways (Scheme 71).The Michael pathway (preferred when R1\H) led to a U-shaped terpyridine 179. Reaction by an aldol pathway led to an S-shaped product 180 and predominated when R1\alkyl.91 When ketone 181 was reacted with phosphorus oxychloride in the expectation of preparing 4-(trifluoromethyl)quinoline 2-(trifluoromethyl)quinoline 182 (Scheme 72) was obtained. No rearrangement of benzene ring substituents was observed. No 177 Heterocyclic compounds R1 = H alkyl aryl 180 179 178 177 i N O O N R1 N N N R1 N N N R1 Scheme 71 Reagents i R1CH––N`Me 2 X~ NH 4 OAc 182 181 i NH O CF3 N CF3 Scheme 72 Reagents i POCl 3 184 183 i R1 R3 = H Me R2 = Me Ph R4 = Me EtO R2 N Bn N Bn Me R1 R3 R1 R2 R3 O R4 Scheme 73 Reagents i R4COCH 2 COCH 3 information was provided on whether the trifluoromethyl shift is intra- or intermolecular.92 1-Azabuta-1,3-dienes 183 can react with acetylacetone or ethyl acetoacetate to give unsymmetrically substituted 1,4-dihydropyridines 184 (Scheme 73). Unfortunately not all combinations of substituents gave acceptable yields.93 Camptothecin analogues were prepared using intramolecular [4]2] cycloadditions of N-arylimidates (and 4H-3,1-benzoxazin-4-ones) acting as 2-aza-1,3-dienes. The key step is illustrated by the conversion of 185 to 186 (Scheme 74).94 Addition of the lithium enolate of 187 to the pyridinium species 188 gave 189 after 178 PeterW. Sheldrake 82% 186 i 185 NH N O O Me CN N N MeO MeO O CN Me Scheme 74 Reagents i,Me 3 O`BF 4 189 188 187 i NH N+ CO2But O O But O N NH O O But H H CO2But O H Scheme 75 Reagents i LDA 191 60% 190 i NH OBn OH H N OBn I H OH Scheme 76 Reagents i NaI (CH 2 O)n H 3 O` further cyclisation of the first-formed intermediate as a single diastereoisomer (diastereoisomeric excess 95%) (Scheme 75).95 In the synthesis of pumiliotoxins A and B the crucial step was the iodide promoted iminium ion–alkyne cyclisation which converted 190 to 191 (Scheme 76).96 Reaction of diene 192 with a trimethylsilylimine gave after aqueous work-up the highly substituted 4-piperidone 193 (Scheme 77).Enantiomeric excess was in the 80–98% range though yields were only moderate.97 The trifluoromethanesulfonamides 194 were cyclised by phenyliodonium acetate –iodine giving 195 by formation of the aryl–nitrogen bond (Scheme 78).98 This should be compared with the analogous formation of an aryl–oxygen bond in Scheme 47.Cyclisation of trifluoroacetamides 196 (Scheme 79) produces tetrahydroisoquino- 179 Heterocyclic compounds 193 192 R = Me MOM TMS TBDMS i N OMe OR NH O Ar OR Scheme 77 Reagents i ArC(H)––NTMS ZnCl 2 ; ii H 2 O 13–84% 195 194 X = CH2 O R = H lower alkyl n = 1 2 i ( ) n ( ) n X HN X N SO2CF3 R SO2CF3 R Scheme 78 Reagents i PhI(OCOCH 3 ) 2 I 2 197 196 X = Br CO2Me NO2 85–94% i N X X HN COCF3 COCF3 Scheme 79 Reagents i (HCHO)n HOAc H 2 SO 4 i 31–86% 198 199 N O O Me NH NH Scheme 80 Reagents i tryptamine 1M HCl lines 197 in a manner complementary to the Pictet–Spengler reaction in that electrondonating groups on the benzene ring are not necessary.99 Azalactones 198 have been used in a Pictet–Spengler reaction to give tetrahydro-b- carbolines 199 (Scheme 80).Phenylpyruvates were detected in solution but the reaction may still involve the enamides.100 Thioamides 200 undergo a novel Reformatsky reaction to give 201 which were cyclised by polyphosphoric acid to quinolines 202 (Scheme 81).101 The reaction of salicylaldimines 203 with alkenes gave tetrahydroisoquinolines 204 in 70–91% enantiomeric excess when a catalytic (20 mol%) quantity of a chiral ytterbium complex was used (Scheme 82). The catalyst was prepared from ytterbium 180 PeterW. Sheldrake i ii 200 201 202 N N N O CO2Et EtO2C CO2Et S R R R Scheme 81 Reagents i BrCH(CO 2 Et) 2 Zn; ii PPA i 203 204 OH N Ar NH R2 R1 Ar OH Scheme 82 Reagents i cis-R1CH–– CHR2 Yb(OTf) 3 (R)-(])-BINOL DBU X = NH O 205 206 207 + i XH X X CO2Me CO2Me CO2Me Scheme 83 Reagents i see text trifluoromethanesulfonate and (R)-binaphthol.This is the first example in which an aza-Diels–Alder reaction of this type employs less than a stoichiometric amount of the chiral catalyst.102 Amines 205 (X\NH) cyclise spontaneously (they are generated in situ by reductive amination of the corresponding ketone). (E)-Geometry in the Michael acceptor gave 206 (X\NH) exclusively while the (Z)-isomer gave 207 (X\NH) (Scheme 83). The corresponding alcohols which cyclised using sodium hydride in THF showed reversed selectivity. Thus (Z)-205 (X\O) produced 206 (X\O) in a 97 3 ratio while (E)-205 (X\O) shows only a 3 1 preference forming mainly 207 (X\O).103 Many challenging synthetic targets of current interest possess complex polycyclic polyether systems for which general synthetic methods are being sought.Ester–alkenes such as 208 can be converted to isolable enol ether–alkenes 209 by Tebbe’s reagent (Scheme 84) and further treatment with the same reagent brings about cyclisation by olefin metathesis to 210. The sequence can be accomplished in one-pot using excess reagent and is also applicable to the formation of a seven-membered cyclic ether.104 Acyl radical induced cyclisation of 211 gave 212 as the major product (Scheme 85). In this case the functionality is such that iteration is possible the methyl ester was converted into an acyl selenide the ketone reduced and the resulting alcohol reacted with methyl propiolate.105 Ring expansion of epoxides is a potentially versatile strategy; thus bromo bis(epoxide) 213 underwent rearrangment to 215 using silver ion 181 Heterocyclic compounds i 208 X = O 209 X = CH2 210 O O O O O H H H H H H H H H BnO BnO BnO BnO O X H H H Scheme 84 Reagents i Tebbe’s reagent ( ) n ( ) n i 211 212 n = 1 2 O CO2Me COSePh CO2Me O H H O Scheme 85 Reagents i (Me 3 Si) 3 SiH Et 3 B air ii i i 215 214 213 R = CH2OTBDPS Br R R R O OTf O O O O O H H H H H OH H Scheme 86 Reagents i AgOTf; ii Tf 2 O i 218 217 216 O O OTBS H O O OTBS OTf OTBDPS H H H H O H H OTBDPS SO2Ph O Scheme 87 Reagents i TsOH either directly or via 214 depending upon the conditions (Scheme 86).106 Compound 217 was formed by alkylation of an oxiranyl anion with 216; subsequent rearrangment of 217 by acid gave 218 (Scheme 87).Reduction of the ketone followed by protecting group manipulation can be used to re-establish the silyl ether–trifluoromethanesulfonate arrangement allowing iteration of the process.Three rings were constructed in this way.107 An acylated Meldrum’s acid 219 reacted with enol ethers giving 220 which underwent rearrangement and decarboxylation in acid to give 2,5-disubstituted pyran-4- ones 221 (Scheme 88).108 A fairly general coumarin synthesis is exemplified in Scheme 89.109 182 PeterW. Sheldrake R1 = Me Et Bn 221 220 219 R2 = H alkyl ii i O O O O OOH R1 O R2 BuO O O O R2 R1 OH R1 Scheme 88 Reagents i BuOCH–– CHR2; ii TsOH 82% i 223 222 MeO MeO OH MeO MeO O O Scheme 89 Reagents i H–C–– – C–CO 2 Et Pd(OAc) 2 NaOAc HCO 2 H 226 225 224 i ClO4 – O CHO CO2Me O CO2Me O MeO MeO O O N Ph N+ N Ph Scheme 90 Reagents i K 2 CO 3 228 227 X = Br I i O O X N O O N Scheme 91 Reagents i imidazole K 2 CO 3 An asymmetric intramolecular Stetter reaction can be e§ected using 224 with 225 as catalyst (Scheme 90).The catalytically active species is the nucleophilic carbene formed by deprotonation. Products 226 showed enantiomeric excess in the range 41–74%.110 3-Iodochromone 227 underwent an addition–elimination reaction with imidazole (and other azoles) giving the 2-substituted chromones (Scheme 91).111 Oxidative rearrangement of hydroxyalkylfuran 229 was used to produce 230a (Scheme 92); the corresponding acetate 230b is a precursor to a pyrylium ylide which 183 Heterocyclic compounds 230 a R = H b R = Ac i ii iii 229 231 Me O O RO O OTBS Me OTBS OH Me O OTBS O Scheme 92 Reagents i ButOOH/VO(acac) 2 ; ii Ac 2 O Et 3 N DMAP; iii DBU i 232 233 ii dienophile = cyclopentene N-phenylmaleimide S Ph HN N Ph S Ac S Ph H X X N Ac Ar Me Ar Ar Me Me Scheme 93 Reagents i AcCl pyridine; ii dienophile 234 235 236 i ii N N O O O Ar1 Ar2 Ar1 Ar2 O O N N O Ar2 Ar1 O+ Ar1 Ar2 O – Scheme 94 Reagents i norbornadiene BF 3 ·OEt 2 ; ii heat cyclised to give 231 as the main product an intermediate in an approach to taxanes.112 Thioamides 232 derived from an optically active amine can be activated by N-acetylation and then undergo [4]2] addition to give thiopyrans 233 in excellent yield and with[98% diastereoisomeric excess (Scheme 93).113 Disubstituted 1,3,4-oxadiazin-6-ones 234 undergo [4]2] addition with norbornadiene giving 235 (Scheme 94).Sequential loss of nitrogen and cyclopentadiene leaves 3,6-disubstituted pyran-2-ones 236.114 a-Formylamides 237 are simple to prepare; they react with aldehydes under acidic conditions in the first convenient route to 6-unsubstituted 2,3-dihydro-1,3-oxazin-4- ones 238 (Scheme 95).115 (1R,2S)-Ephedrine condenses with phenylglyoxal to give a diastereoisomeric mix- 184 PeterW.Sheldrake R1 = alkyl R2 = H Me 238 237 ii i Ph NH R1 O O NH R1 Ph O N Ph H R1 R2 O OH Scheme 95 Reagents i HCO 2 Et NaH; ii R2CHO HCl i 240 239 Ph Me Ph Me N Me N Me O Ph O O O Ph N Me O Ph Me Ph O Scheme 96 Reagents i room temp. R = H TBDMS 243 242 241 i N N NH2 Cl H2N O RO O HN RO O Cl NH2 N N HO N N N NH2 Cl RO OH Scheme 97 Reagents i AcOH ture of 2-benzoyloxazolidines 239. On standing this mixture was transformed into (3R,5S,6R)-4,5-dimethyl-3,6-diphenyloxazin-2-one 240 (Scheme 96). The driving force and mechanism were not elucidated.116 When the 3@-keto pyrazine nucleoside 241 was treated with acetic acid the pyrido[ 2,3-b]pyrazine 243 was formed via hemiaminal 242 (Scheme 97).The closely analogous compound with an ester group in place of the chlorine does not undergo rearrangement.117 185 Heterocyclic compounds ii iii i 245 244 N S S N MeO MeO Cl CN N N CN OR MeO MeO MeO MeO HN CN S CN Scheme 98 Reagents i Ph 3 P; ii ROH heat; iii ROH NaH R1 = H alkyl 249 248 247 246 Y = OEt NR2 iii ii i N Cl N CO2Et HN Cl CO2Et N Cl Ar Ar N N CO2Et Ar Y Cl H R1 N N Ar R1 Scheme 99 Reagents i,Pr* 2 NEt; ii R1CH––CHY; iii KOH EtOH or ButOK ButOH Reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with o-aminobenzonitriles gives adducts such as 244 (Scheme 98). Then in one or two steps the sulfur–sulfur bond cleaves and a quinazoline-2-carbonitrile 245 was formed.118 Hydrazones 246 can be dehydrochlorinated to give the diazadiene mixture 247.This reacted regioselectively with an electron-rich alkene to give a tetrahydropyridazine 248 (Scheme 99). Treatment with strong base induced two eliminations forming the pyridazine 249119 Treatment of 250 with formaldehyde gave pyrrolo[1,2-a]quinoxaline 251 (Scheme 100). It is at first slightly puzzling that benzaldehyde gives the same product but this fact should make it easier to discern the mechanism.120 A set of group additivity parameters has been devised which permits prediction of enthalpies of formation of azines.121 They also have some application to fused fivemembered heterocycles. 5 Seven-membered rings Optically active 2H-azepines 253 can be prepared from precursors 252 available through a simple sequence starting with amino acids (Scheme 101).The 2H-azepines 186 PeterW. Sheldrake 251 250 i or ii N NH2 NH2 N N Scheme 100 Reagents i HCHO; ii PhCHO 252 253 i R1 R2 = Alkyl N NH Boc O R2 R2 R1 H R1 H AcO Scheme 101 Reagents i TFA i ii 254 255 M = P As Sb Bi Br Br Li Li M Ph Scheme 102 Reagents i ButLi; ii PhMCl 2 undergo an easy isomerisation into 3H-azepines.122 Dibromide 254 can be dilithiated with tert-butyllithium and the intermediate reacted with any of a number of dichlorides to give 3-benzoheteroepines 255 (Scheme 102). The products were shown to have half-lives varying from 82 h (M\P) to under one minute (M\Bi).123 The aldehydes and imines 256 were converted thermally into dihydroazepines 257 and/or the bridged structures 258 (Scheme 103).124 Further studies showed that the mechanism involves a [1,6]hydride-shift (antarafacial) forming 259 followed by a conrotatory 1,7-cyclisation.125 The allylsilane 260 was prepared by an allylsilane–imine cyclisation; on treatment with formaldehyde it formed 261 which underwent another such cyclisation to give the azabicyclo[3.2.1]octane 262 (Scheme 104).126 Azepine 263 was converted into 264 under Mitsunobu conditions (Scheme 105).On treatment with methanesulfonyl chloride however it underwent ring contraction to the chloromethylpiperidine 265.127 The indole derivative 266 cyclised to 267 using sodium hydride the combination of the ketone and phenylsulfonyl substituents permitting by addition–elimination an overall nucleophilic substitution of the indole (Scheme 106).128 Naphtho[2,1-b][1,8]naphthyridine 268 gave on treatment with hydrogen peroxide the 1,4-oxazepine 269 together with its N-oxide (Scheme 107).No similar reaction was observed with 1,8-naphthyridine or acridine.129 187 Heterocyclic compounds 256 Y = O NR2 + 257 258 i _ 259 N N O Y N R1 H Bn H N N N O Bn N Bn O N N YH R1 R1 Y H N+ Bn R1 YH O N N Scheme 103 Reagents i heat R = H Pri Bui 262 261 260 i ii + HN R SiMe3 SiMe3 R N N R Scheme 104 Reagents i HCHO; ii TFA 56% 94% 265 264 263 R = Bn CH2CH2Ar ii i N HO OBn BnO OH R N BnO OH OBn Cl R O N BnO OBn R Scheme 105 Reagents i Ph 3 P DEAD PhCO 2 H; ii MeSO 2 Cl Et 3 N Simple amidrazones can be cyclised with formaldehyde to give 1,2,4-triazoles. The same was shown to be true if both ortho positions of the N-3 aryl substituent in 270 are blocked.However with an ortho position free 270 and formaldehyde cyclised to give a benzotriazepine 271 (Scheme 108).130 6 Larger rings The 3]1 approach to the porphyrins depicted in Scheme 109 is the subject of a short review131 and specific examples.132,133 A limitation of the synthesis is that one component must be symmetrical:otherwise the problem of isomer formation o§sets 188 PeterW. Sheldrake 267 266 n = 0,1 i ( ) n ( ) n PhSO2 N NH N O HN PhC O PhC O O Scheme 106 Reagents i NaH i 43% 268 269 N N O NH N H OAc Scheme 107 Reagents i,H 2 O 2 AcOH Scheme 108 Reagents i HCHO TsOH H H H H H N N N N N R2 R1 R2 R1 R3 R4 R3 HN CHO CHO R4 N N CO2H CO2H Scheme 109 the convergent character of the approach. An interesting o§shoot involves the use of 3-hydroxypyridine-2,6-dicarbaldehyde to form the porphyrinoid 272 in which the pyridine unit adopts a quinomethane form.134 The 1,5-diazacyclooctane 273 was prepared in good yield from toluenesulfonamide and 1-chloro-2-(chloromethyl)prop-2-ene.Much of its reactivity involves transannular 189 Heterocyclic compounds H H 272 Me Et Et Et Et Me N N O N N 68% 82% 275 274 273 ii i TosN NTos NH HN Me Me TosN NTos Br Br Scheme 110 Reagents i LiAlH 4 ; ii Br 2 (slow addition) 277 276 i O O Ph Ph O O Ph Ph O I OMe Scheme 111 Reagents i I`(collidine) 2 ClO 4 ~ MeOCH 2 CH 2 OH cyclisation e.g.lithium aluminium hydride reduction to 274 or bromination to 275 (Scheme 110).135 Treatment of but-2-enyl-1,3-dioxolane 276 with a positively charged iodine compound formed 1,4-dioxocane 277 with remote asymmetric induction (Scheme 111).The methoxyethoxy unit is displaceable using a Grignard reagent and the iodide by a nucleophile hydrogenolysis then yielded a chiral 1,4-diol.136 The tetrathiacyclooctadiene 278 was prepared from the disodium salt of ethene-1,2- dithiol by treatment with iodine. It is thermally stable in refluxing xylene but in acetonitrile–chloroform solution it was converted into the remarkable 16-membered ring 279 (Scheme 112).137 Pyrrolidine 280 was acylated by a suitable acid chloride to give the salt 281 which rearranged stereoselectively via its enol form to give the nine-membered lactam 282 (Scheme 113).138 Diazacyclodecadiyne 283 underwent an extensive rearrangement on treatment with 190 PeterW. Sheldrake 278 279 i ii S S S S S – Na+ S S S S S S S S S – Na+ Scheme 112 Reagents i I 2 KI; ii MeCN–CHCl 3 + Cl – 280 281 282 R1 = H Ph R2 = H Me Ph Cl OBn NPhth i N CO2Et R1 R1 CO2Et N O R2 O N CO2Et R2 R1 Scheme 113 Reagents i R2CH 2 COCl Scheme 114 Reagents i 5%Pd on charcoal MeOH i 286 285 O O O O O O O O O O Scheme 115 Reagents i Ru(–– CHPh)(PCy 3 ) 2 Cl 2 palladium on charcoal to give 3,3@-bipyrrole 284 (Scheme 114).The mechanism involves the formation of two new carbon–carbon bonds the cleavage of one triple bond two allylic rearrangements and two dehydrogenation steps and the yield is still 95%!139 The versatility and scope of the olefin metathesis reaction is further illustrated by the 191 Heterocyclic compounds 288 287 iii iv i ii H H H H N N N N N N N N NH2 NH2 S S Scheme 116 Reagents i EtBr; ii H 2 N(CH 2 ) 2 NH(CH 2 ) 2 NH(CH 2 ) 2 NH 2 ; iii DIBAL; iv NaF 289 Pr3+ N N N N CO2 – CO2 – CO2 – MeO high-yielding conversion of the diallyl polyether 285 into the crown ether 286 (Scheme 115).140 Tricycle 287 was readily prepared from dithiooxamide and triethylenetetramine.Reduction forms a cleverly conceived bis-aminal which by aminal opening and further reduction completed an e¶cient synthesis of ‘cyclen’ 1,4,7,10-tetraazacyclododecane 288 (Scheme 116).141 And finally there is the cyclen–praeseodymium complex 289 using which it is possible to estimate temperature from the 1H NMRspectrum. 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ISSN:0069-3030    

DOI:10.1039/oc093155

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

7 Organometallic chemistry the transition metals By G. R. STEPHENSON School of Chemical Sciences University of East Anglia Norwich UK NR4 7TJ 1 Synthetic chemistry by catalytic procedures This year the Report begins with a survey of the most important catalytic procedures that employ transition metals to build skeletal bonds. Because of the constraints on space minor (or new but relatively untried) catalysis systems have been omitted from this section as have catalytic procedures that e§ect functional group transformations such as oxidations and reductions. For organic synthesis it is widely applicable catalytic methods that form important bonds which merit the focus of attention. In Section 3 however mechanistic studies of catalytic cycles and more unusual catalytic procedures are discussed.Metal catalysed allylic displacements Palladium allyls in synthesis asymmetric modifications Studies of the induction of asymmetry in palladium catalysed substitution in the 1,3-diphenylallyl system continue to be the main focus of attention. An ever wider range of ligands is under investigation. Phosphine (e.g. 1)1 and diphosphinite (e.g. 2)2 ligands employ only phosphorus but mixed combinations such as P,N (3,3 4,4 5,5 6,6 or 7,7) or P,S (8,8) are now more popular. Some lack phosphorus altogether.9,10 In most cases the ee of the product is variable depending on nucleophile conditions or the nature of additives and although results in the high 90% range are possible there N O PPh 3 P Me Ph Me 1 O O O Ph O Ar2P O OPh PAr2 2 P N Me Ph P N Me Ph 4 Royal Society of Chemistry–Annual Reports–Book B 197 CpFe N P P Ph o-MeOC6H4 o-MeOC6H4 Ph 5 PPh2 Me N N Me Ph H 6 Fe PPh2 N Pri N Pri 7 Ph2P S O AcO AcO OAc OAc 8 Ph2P N N 9 NH O NH O PPh2 PPh2 12 N S N O Me Ph 10 Me N N P P ( ) n ( ) n Me 11 Ph Ph n = 2–6 is not yet a single system which stands clear of the rest in terms of generality of application.There have been attempts to step back to first principles in ligand design,11 while in other cases more elaborate macrocyclic structures have increased the numbers of ligand sites and are structurally more complex as in the N,N,P,P example 11.12 An N,N,P,P structure 12 with more degrees of freedom has been employed with cyclopentenyl acetate.13 The naphthyl analogue has also been examined.14 Ligands of this type have also been used with intramolecular allylic substitution as in the case that forms 13 (Scheme 1).15 Cyclisation of 14 with the ligand 15 proceeds in 87% ee.16 Cyano esters17 and amine18 nucleophiles have been used.An elaborate biferrocene- 198 G.R. Stephenson MeO NH OAc MeO N 13 97% yield; 91% ee i H Scheme 1 Reagents i 12 [(C 3 H 5 )PdCl] 2 Et 3 N O O Ph O O Ph O 16 O O Ph O N (–) N N N Cl NH HN O O PPh2 Ph2P Ph Ph N N N N Cl H 17 i Scheme 2 Reagents i (dba) 3 Pd 2 ·CHCl 3 MeO2C CO2Me OCO2Me 14 Ph2P N O Ph 15 based catalyst with an unusual Rh–Pd two-component system has been tried in the cyano ester case.17 These asymmetric allylation procedures are finding application in synthesis as in routes by Trost to (])-polyoxamic acid with 12,19 or vigabatrin,20 which uses the naphthalene analogue Williams’ route to b-amino acids,21 or a synthesis of carbocyclic nucleosides by Crimmins and King.22 Variants on the allylic substitution include a reduction mediated by formic acid,23 and the use of chiral palladium catalysts for asymmetric elimination reactions in mono-24 and bi-cyclic25 frameworks.Finally a prochiral substrate 16 with a variant on 12 gives enantioselective access to nucleosides with asymmetric induction at the stage that displaces the leaving group (Scheme 2).26 A similar approach a§ords carbovir using 18 as the nucleophile.27 Other palladium catalysed allylic displacements Turning aside from chiral ligands the main impression from the 1996 literature is that attention is focusing on particular classes of nucleophiles. The use of 17 (discussed above) and 18 is typical. The nucleophile 19 leads to azapurine analogues of the 199 Organometallic chemistry the transition metals MeO2C MeO2C SnBn3 + O MeO2C MeO2C OH Bu3Sn OH MeO2C CO2Me i ii 20 Scheme 3 Reagents i Pd(MeCN) 2 Cl 2 Pd(cod)Cl 2 Pd 2 (dba) 3 ·dba or Pd(bipy)Cl 2 ; ii Pd(PPh 3 ) 4 Pd(dba)(dppf) Pd(dba)(PPh 3 ) 2 or Pd(dba)(AsPh 3 ) 2 N N N N NCONPh2 NHAc H 18 N N N N N NH2 H 19 natural structures.28 Carbocyclic nucleoside analogues have been accessed using 17.29,30 Uracil has also been employed.31 Progress with directing groups includes the demonstration of ipso addition to a 1-OMe substituted allyl,32 and di§erentiation of leaving groups in a 2-silyl-1,4-diacetoxybut- 2-ene system.33 A 1-phenyl substituent on the allyl directs x in an unusual phenoxycarbonylation.34 The 1-phenyl substitution pattern also figures in a rearrangement of allylic sulfoximines to a§ord N-tosyl allylic secondary amines.35 A range of other substituents can also give good control.36 Direct cyclisation of pendant tosylamines37 and 4-methoxybenzylamines38 also o§er good routes to cyclic amines.More unusual procedures include switching pathways between nucleophilic centres in 20,39 and between pathways that follow on from the opening of silyl-substituted allylic epoxides (Scheme 3).40 Carbon dioxide has been used to promote substitution of allylic alcohols.41 Displacement of a formate ester from 21 is the first step in a stereocontrolled reduction. This works best with the SO 2 Tol substituent and constitutes a key step in a synthesis of ([)-solavetivone (Scheme 4).42 Chirality transfer from chiral allylic starting materials is a well established route to enantiopure products.An unusual example rearranges a SiPh 2 SiMe 2 Ph ether to form an allylsilane with an SiMe 2 Ph substituent.43 Enantiopure vinylcyclopropanes have been made by chirality relay in a cyclisation process.44 Allylic acetates can be epimerised by palladium catalysts and this has been applied to an enzyme mediated dynamic kinetic resolution process; enzymes and palladium catalysts can be used together.45 In another rearrangement linalyl acetate gave geranyl acetate.46 This is a simple but convenient process. Another simple use of allylic substitution is the removal of allylic protecting groups from nitrogen47 and oxygen.48 200 G.R. Stephenson SO2Tol O H O 21 SO2Tol ( R) H R S 9 1 i Scheme 4 Reagents i Pd(acac)Bun 3 P HCO 2 H Et 3 N TfO OTf OTf R 22 + Ph3Si MgBr 99% ee 53% yield i Scheme 5 Reagents i PdCl 2 [(S)-Alaphos] LiBr Et 2 O–PhMe Palladium catalysed coupling reactions Asymmetric modifications The flow of papers reporting asymmetric coupling has slowed though not due to diminished importance of the topic–the search is on now for highly enantioselective examples.Chemical yield of 98% combined with an ee of 99% sets the standard in an asymmetric Heck coupling using 2,3-dihydrofuran and a chiral P,N-type ligand (the But analogue of 15).49 Enantioselection in the oxidative addition of palladium catalysts to 22 allows symmetry splitting by coupling to magnesium acetylides (Scheme 5).50 Heck coupling chemistry Coupling to allylic alcohols has been controlled to retain the alcohol feature51 as an alternative to the common rearrangement to substituted ketones (e.g.in a recent glycal synthesis).52 A further option is demonstrated with methyl 4-hydroxybut-2-enoate to introduce a lactone substituent.53 Allyl amine derivatives have been used with aryl halides54 and enol triflates.55 Regiocontrol of the destination of the C––C double bond has been addressed by Hallberg’s group in five-56 and six-membered57 rings. More unusual coupling partners include hypervalent iodonium salts,52 diazonium salts,58 diaryltellurium compounds,59 MeF 2 SiCH––CHPh,60 and highly substituted heterocycles such as 23 which promises access to C-nucleoside analogues.61 Gene� t’s group has produced intra-62 and inter-molecular63 examples where regiocontrol of the site of coupling is switched by choices of reagent or conditions.The latter case uses a formic acid trap to e§ect overall reduction. This is becoming a popular procedure and in the case tt forms 24 constitutes an alternative to conjugate addition (Scheme 6).64 Heck coupling has been performed on a solid support65 (a prerequisite for its use in combinatorial library synthesis) at high pressure,66,67 and in molten salt media.68,69 The use of clusters as catalysts has been examined.70,71 NMR analyses72,73 and kinetics74 have been used to study Heck coupling. Applications in synthesis include key steps in routes to carbapenems,75 pyrimidine 201 Organometallic chemistry the transition metals N N Cl I 23 O N N Cl O i 81% N O Ph O I N O Ph O 24 ii Scheme 6 Reagents i Pd(OAc) 2 AsPh 3 Et 3 N Ag 2 CO 3 ; ii Pd(OAc) 2 (PPh 3 ) 2 HCO 2 H Et 3 N nucleosides,60 vincadi§ormine,76 ellipticine,77 cardenolides,78 and in a total synthesis of optically active chanoclavine-I.79 Heck coupling is a mature reaction where the scope is well defined which can be applied with confidence in synthesis and where the thrust of onward development strives for enhanced control.Suzuki chemistry Suzuki coupling to a§ord biaryls tolerates considerable steric constraints as shown in an example which combines pentasubstituted aryl halides and arylboronic acids.80 Another striking application produces rod-like oligo-p-phenylenes from 4-biphenylboronic acid and 1,4-dibromoarenes.81 Stepwise replacement in 1,2-dibromides has been described.82 Examples this year point to heterocyclic coupling partners with substituted pyridines being particularly in vogue.83–86 Examples with indoles,87 pyrrolopyrimidines 88 and pyrroles,89 show the scope of this coupling process.In the last example both triflate and boronic acid components were heterocycles. A variety of boronic esters can be used (from 1,2-90,91 and 1,3-diols92) and other organoboron derivatives.93 As with the Heck reaction use of clusters71 and polymer supports has been examined,94,95 and less usual coupling partners evaluated (iodonium96 and aryldiazonium97 salts) self-coupling of two arylboronates,98 and sp3 carbon centres in this case a cyclopropyl iodide).99 Uses in synthesis include routes to rigidin88 and the left hand subunit of milbemycin b3.100 Stille chemistry Hindered biaryl systems101 and heterocycles have also been targeted in developments of the use of Stille coupling.Heterocyclic tin reagents such as pyrrole,102 furan103 and thiophene104 present no problems. The tin reagent 25 a§ords dimethyl sulfomycinamate 26 (Scheme 7),105 and the thiophene system has been used to make orthogonally- 202 G.R. Stephenson N MeO2C O N O Me OTf N S Bu3Sn CO2Me N O N O Me MeO2C S N CO2Me i 25 26 Scheme 7 Reagents i Pd cat. LiCl fused oligothiophenes,106 or end-capped linear oligomers.107 Coupling of organotin components to heterocycles is also well represented. Selectivity has been observed with dihalopurines,108 and other examples include chiral oxazolines,109 pyrrolidone derivatives,110 thiazolines,111 pyridines,112 and 27113 and 29,114 which a§ord hydrogen bonded oligomers (28) and (30) (Scheme 8) a ligand designed to impose tetrahedral coordination.Copper salts (as used in the preparation of 28) have been evaluated as promoters in coupling with enol triflates.115 Selectivity for iodide replacement in the presence of SO 2 CF 3 ,116 and tin in the place of boron,117 illustrate possibilities for control and unusual variants include coupling to allyl carbonates (a hybrid Stille–allylpalladium chemistry),118 and the introduction of an allyl alcohol substituent with 31 (Scheme 9).119 Syntheses of asuka-mABA and limocrocin,120 a macrolide related to macrolactin A,121 phosphorylated tyrosine derivatives,122 oligonucleotides bearing a tricyclic carbazole,123 and ([)-papuamine and ([)-haliclondiamine124 all rely on important Stille coupling steps. The latter example e§ects homocoupling of alkenylstananes with copper promoted conditions and PdCl 2 (PPh 3 ) 2 in air to close a 13-membered ring.Coupling to anions Organometallic nucleophilic coupling partners extend the use of organotin reagents to other metals currently most commonly zinc. Polymer-supported chemistry has been achieved here too.125 Propyl,126 butyl,127 and more interesting iodoserine-derived alkyl-zinc halides128 have been used. Alkene (e.g. trifluoromethyl-129 and OCONEt 2 - substituted130 alkenylzinc bromides) and arene131–133 examples are more closely related in scope to the Stille counterparts. Again the heterocycle theme continues with indole134,135 and oxazole136 examples and a heteroorganoaluminium coupling reaction. 137 In another case where zinc is superseded hydrozirconation is combined with palladium catalysed coupling to form arylselenobutadienes.138 Zinc cyanide o§ers a change of nucleophile,139 and there has been a flood of applications of palladium catalysed coupling with nucleophiles for the amination of aryl iodides,140–143 including an intramolecular example which forms indolines and tetrahydroquinolines,144 and a similar approach to the synthesis of aminopyridines.145 Possibly the most interesting nucleophile this year is Ph 2 PH which has been used to elaborate aryl triflates in syntheses of phosphine-containing amino acid analogues.146 Coupling to alkynes The combined use of copper and palladium salts is now classic for coupling alkynes 203 Organometallic chemistry the transition metals N N Br Br 27 + NH Me3Sn SnMe3 HN ButO O OBut O N N ButO O OBut O N N H N N NH N ButO O OBut O H n H i N N Cl Cl Me3Sn CN + N N CO2H CO2H 30 29 28 ii iii iv Scheme 8 Reagents i PdCl 2 (PPh 3 ) 2 CuBr; ii Pd(PPh 3 ) 4 ; iii EtOH HCl; iv HCl aq AcOH Me I + Sn O Bu2 31 i Me OH Scheme 9 Reagents i Pd(PPh 3 ) 4 ; LiCl DMF with alkenyl and aryl halides.In the alkenyl series routes to polyenes,147 enynes148 and diynes149 are attractive. This coupling can be performed in the presence of an aryl telluride substituent and an alkenyl halide.150 With arenes aryl bromides151 and 204 G.R. Stephenson N SiMe3 PhSO2 32 N PhSO2 SiMe3 i 95% ee Scheme 10 Reagents i Pd cat. TRAP HOAc iodides152,153 are still typical but as with the other coupling processes described this year there is interest in diaryliodonium salts.153,154 An aryl iodide can be displaced in the presence of an aryl chloride.155 Triflates are convenient coupling partners.156 Examples of coupling with heterocycles remain a major theme with two procedures described for thiophenes using Pd(PPh 3 ) 4 (CuI Et 3 N;157 CuBr LiBr piperidine158) one with pyrroles,159 and one with 2-chloroquinolines.160 These alkyne couplings are sometimes mixed with aspects of the procedures described above as in coupling between alkynylzinc reagents and 3-iodopropenoic acid (without protection),161 and procedures that use alkynyltin reagents.162,163 Tributyltin hydride is an additive in a one-pot procedure to prepare enediynes,164 and a distannylalkyne is linked at both ends to iodobinaphthyls in a synthesis of a bisbinaphthol.165 Substituted uracils,166,167 nucleosides,168 terinafine,169 (])-himbacine170 and the neocarzinostatin chromophore171 show the power of the reaction in recent synthetic applications and two examples the construction of rod-like conjugated polyynes172 and dendrimers with dialkynylarene links,173 illustrate the use of alkyne coupling in materials science.Combining alkenes and alkynes Asymmetric modification of alkene-to-alkyne coupling has been reported.174 The procedure works excellently with 32 (Scheme 10). The usual products from alkene-toalkyne coupling are 1,3-dienes. Switching to form alkenyl chlorides can be e§ected with LiCl–CuCl 2 additives.175,176 Cycloaddition gives access to combinatorial libraries by a route with alkene-toalkyne coupling as the first step.177 The reaction is a key step in Trost’s synthesis of (])-cassiol,178 Kibayashi’s synthesis of (])-streptazolin,179 and Fukumoto’s formal total synthesis of (])-aphidicolin,180 and a reductive version (using polymethylhydrosiloxane and acetic acid) was used by the same research group for (])-pumiliotoxin C.181 Coupling two alkynes is a key step on the way to siccanin.182 Tandem and cascade coupling reactions Asymmetric palladium catalysis The asymmetric Heck procedure described earlier can be combined with an additional C–C bond formation by the anion capture process.This tandem reaction gives 87% ee and has been applied in a total synthesis of ([)-*9(12)-capnellene.183A more extensive asymmetric tandem process figures in a synthesis of (])-xestoquinone. The cyclisation of 33 gave the product in 67% ee (Scheme 11) leaving only hydrogenation of the alkene and conversion into a quinone to complete the synthesis.184 Palladium catalysis in tandem coupling Oxidative addition followed by a sequence of bond formations to alkenes is a typical 205 Organometallic chemistry the transition metals OMe OMe O O O Tf 33 MeO MeO O Me O i Scheme 11 Reagents i Pd 2 (dba) 3 (S)-(])-BINAP PMP O I i O NR2 34 Scheme 12 Reagents i Pd(OAc) 2 PPh 3 K 2 CO 3 H 2 C–– C––CH 2 NHR 2 tandem process.With 33 the final step is b-elimination but if the last alkene carries an organotin substituent insertion into the C–Sn bond and reductive elimination can finish the cycle.185 Anion capture can also end the sequence.186 An allylic acetate can serve either at the end187 or at the start.188 Tandem cyclisation has been performed with allyloxy substituents and the C––C link of a dehydro-sugar.189 Aryl iodides are good for the initial oxidative addition and cyclisations employing alkenes and b- elimination,190 an organotin ending,191 or an intermolecular combination employing cyclisation via a p-allyl intermediate,192 have been described.An alkyne can pick up the intermediate formed by oxidative addition. Alkenes also end the process,193 but anion capture by formate194 or intramolecular addition of a carboxylate group195,196 provide alternatives. Coupling a prop-2-ynyl ether-substituted aryl iodide with allene and an amine brings four components together in sequence to form 34 (Scheme 12).197 The alkene–alkyne coupling process can be combined with C–C bond formation with an aryl halide,198 or anion trapping with NaBPh 4 .199 Other variations combine alkenyl triflate with allene and an enolate,200 or e§ectively add CN and an acyl group across an alkyne.201 Iodophenols add across alkynes to form benzofurans.202,203 Intramolecular cyclisation of an aryl iodide with two alkynes forms a central aromatic ring,204 and an alkene with two alkynes forms a cyclohexadiene.205 Enynes cyclise to form 1,4-disubstituted arenes,206 and two molecules of ethyne combine with tin reagents to form stannoles.207 Examples of cyclopropane ring-opening reactions during tandem processes lead to a wide variety of structures.208–213 The current emphasis in research on modification of reactions to allow them to be performed on a polymer support has borne fruit in the field of tandem coupling.214 An example of a three component coupling using a dihydropyran-functionalised polystyrene has been described.215 Tandem reactions combined with carbonylation have been popular adding an alkenyl halide and CO across an alkyne216 or alkene.217,218 Closure of a phenol to an 206 G.R.Stephenson N2 O O O H H Me O 38 N O O H SO2Ar Rh Rh 4 i Scheme 13 Reagents i RhII catalyst Ar\4-(C 12 H 25 )C 6 H 4 room temperature alkene,219 or intermolecular combination of bromoaniline and alkenyl halide derivatives with carbonylation a§ords lactone219 and lactam220 products respectively. A triple carbonyl insertion has been described.221 Wacker oxidation and 1,4 difunctionalisation When modified for intramolecular nucleophile addition the Wacker oxidation can form skeletal bonds. Cyclic hemiacetals are the product.222 This cyclisation has been performed on a carbohydrate framework.223A lactone forms when a trimethylsilylalkyne is used in place of the normal alkene.224 1,4-Difunctionalisations is a related process and e§ective cyclisation reactions can be achieved.Interception of the palladium allyl intermediate with a chloride from LiCl is a common strategy,225 but with correctly placed branching on the diene b-elimination can be brought into play to leave a diene in the product.226 The mechanisms of both the 1,4-difunctionalisation,227 and Wacker228 reactions have been under investigation during 1996. Catalysis of carbene additions and insertions Asymmetric rhodium catalysis Just as palladium dominates coupling chemistry so rhodium dominates carbene addition and insertion. Asymmetric modification of this chemistry is receiving great attention.Cyclic amides such as 35229 and 36230 have proved useful ligands in cyclopropanation but optical yields are variable. Proline-derived ligands such as 37 have been popular,231–233 and since any chiral carboxylic acid can be used wide selections of chiral ligands can be surveyed.234,235 Asymmetric cyclopropanation has been combined with a Cope rearrangement to access the tremulane skeleton in 38 using a long-chain variant of 37 (Scheme 13).236 Optical purity of the product however was poor. Chiral auxiliaries attached to the diazo ligand have also been employed.237,238 N O O OMe 35 N O 36 PhthN N H O O 37 4-BuC6H4SO2 207 Organometallic chemistry the transition metals Rhodium catalysed insertion The conceptually most straightforward use of rhodium carbenes is in CH insertions.A diazo ester can be cyclised onto an otherwise unactivated CH 2 group forming a new bond where normally this would not be possible.239 Insertion next to silyl ethers,240 at allylic positions241 and at the CH 2 of allyl ether substituents242 are among the examples described this year. Sometimes the outcome is elimination and this gave a simple synthesis of (Z)-a,b- unsaturated carbonyl compounds.243 Reaction with amine N–H bonds makes amino acid derivatives. PhC–– N 2 CO 2 R244 and CF 3 C––N 2 CO 2 R245 a§ord phenyl- and tri- fluoromethyl-substituted products. MeCOC––N 2 CO 2 Me has been used with Z-protected alinamide at the start of a synthesis of (])-nostocyclamide.246 Insertion into a Si–H bonds has been described.247 With aromatic rings simple cyclisation of a substituent by C–H insertion is sometimes the major reaction pathway.248 Rhodium catalysed cyclopropanation Cyclopropanation is also a straightforward outcome and has been reported in both inter-249 and intra-molecular250 versions.Such reactions are finely balanced and other cyclisation products can dominate.251 When ‘cyclopropanation’ occurs at an aromatic ring ring expansion a§ords a substituted cycloheptatriene.252 A rhodium catalysed aziridination has been described.253 Rhodium catalysed addition Rhodium carbenes are electrophilic and this can initiate more elaborate chemistry through addition at C––C bonds in dihydrofuran (in a formal total synthesis of aflatoxin B 2 )254 and pyrroles.255 Reaction at the oxygen of cyclic ethers (resulting in ring expansion)256 or ketones257,258 e§ects cyclisation and intermediates can be trapped in further conventional cycloaddition reactions.258,259 Other metals Palladium catalysts have been used to e§ect cyclopropanation with diazo esters,260 and nickel(0) carbene intermediates have been proposed in reactions that form alkenes from gem-dihalides.261 Cu(acac) 2 is popular in the place of Rh 2 (OAc) 4 ; examples continue to appear.262 Alkene metathesis Molybdenum and ruthenium catalysts are currently most popular and asymmetric modification of the molybdenum alkylidene system with the complex 39 provides an example of kinetic resolution in ring-forming catalysis.263 This type of cyclisation in which a ring is formed by loss ofH 2 C––CH 2 from a pair of terminal alkenes is proving very popular with synthetic chemists.Simple examples that form nitrogen heterocycles illustrate the two now classic catalyst systems 40264 and 41.265 Dihydrothiophene has been made by cyclisation of diallyl sulfide which was possible with the molybdenum catalyst but not with 41.266 Cyclisation on a carbohydrate framework appears in a formal total synthesis of castanospermine.267 Applications to form larger rings are particularly attractive with products 42,268 43,269 44,270 and linked amino acids271 resulting from ruthenium268–270 and molybdenum271 catalysis.The lack of stereodefinition in 43 was not a problem since the 208 G.R. Stephenson O O O O O O H H O O H H 45 46 i ii Scheme 14 Reagents i 3mol% 41; ii 13mol% 40 H O F3 C CF3 Mo Ph N H O F3C CF3 39 O F3C CF3 Mo Ph N Me O CF3 40 CF3 PCy3 Ru PCy3 R Cl Cl 41 N O H O 42 O O MeO MeO 43 O O 44 R = Ph or CH CPh2 alkene was merely a consequence of the cyclisation strategy and was reduced out to complete (])-lasiodiplodin.The ruthenium system has been used with allylglycines in peptides either in solution or on solid supports.271 Similar applications appear in syntheses of the carbocyclic nucleoside 1592U89272 and novel b-lactams.273 There have been some nice applications in polyether synthesis; ruthenium was used for synthesis of 45,274 and molybdenum for 46 (Scheme 14).275 Dibenzocrown ethers with a –OCH 2 CH––CHCH 2 O– link,276 and dimers of cyclodextrins with –OCH 2 CH 2 CH––CHCH 2 CH 2 O– spacers277 have been made using 41 (R\CHPh). TheCH–CH––CPh 2 version of the catalyst has been used to modify ferrocene substituents278 and to form liquid crystal oligomers.279 The combination of 47 with hex-3-ene forms a tetrasubstituted cyclopentane.280 A polymer-supported metathesis process has been described.281 Enyne metathesis by ruthenium282 or molybdenum283 can a§ord varied products such as 48282 or 49.283 In the case of 50 a tandem cyclisation has been achieved (Scheme 15).284 Diynes have also been cyclised by metathesis reactions using a polymer-mounted molybdenum system.285 209 Organometallic chemistry the transition metals CO2Me CO2Me N O Me 47 48 O2N O N O 49 OSiEt3 Me OSiEt3 i 50 Scheme 15 Reagents i 41 R\CHCHCPh 2 As far as the development of organometallic catalysts is concerned the exploration of the scope of these two complementary metathesis catalysts 40 and 41 has been the great success story of 1996 reminiscent of the great push to begin the serious exploitation of palladium catalysed coupling a few years ago.2 Synthetic chemistry by stoichiometric procedures g1-Complexes Organotitanium and zirconium chemistry The stoichiometric chemistry of r-bonded complexes of titanium and zirconium provides a highly fully developed system for synthetic transformations. The chemistry resembles a catalytic cycle in slow motion with the advantage that reaction conditions can be varied along the pathway and reactants can be added at intermediate stages. Initial introduction of the zirconium often proceeds with concomitant C–C bond formation as in an elegant application towards the dolabellane skeleton. Linking two double bonds at the first step provides an intermediate bis-g1 complex. Now an organolithium nucleophile (CH 2 ––CMeCHClLi) is added and the resulting zirconate rearranges with displacement of Cl to a§ord an g1,g3-allyl intermediate which is trapped by electrophiles.286 The zirconacycle formed by linking two alkynes can combine with 1,2-diiodobenzene to form substituted naphthalenes.One C–C bond is formed in the reaction that introduces the metal and a further two are made as the metal is detached.287 Titanium and zirconium cyclise enynes to a§ord g1,g1 metallacycles which are decomplexed with acid.288 The product of hydrozirconation of an alkyne has been used as a nucleophile with an epoxide in a synthesis of (])-curacin A.289 Cyclopentadienylirondicarbonyl chemistry In the classic g1-CpFe(CO) 2 series carbonyl insertion promoted by Lewis acids has 210 G.R. Stephenson Me O (CO)3Cr Me (CO)3Cr (CO)3Cr Me OH CO2Me Mn(CO)4 O i ii 51 Scheme 16 Reagents i PhCH 2 Mn(CO) 5 ; ii CH 2 ––CH 2 CO 2 Me Cl N NMe2 + Me Mo(CO)3 N NMe2 Mo(CO)3 Cl N Mo(CO)3Cl Ph Ph NMe2 i ii 52 Scheme 17 Reagents i room temp.; ii Ph-C–– – C-Ph been explored.290 A naphthalenylmethyl complex has been prepared from bromomethylnaphthalene and compared with the corresponding Co(CO) 4g1-complex.291 Related CpW(CO) 3 complexes have been prepared from 7-bomohept-6-ynal by bromide displacement and cyclisation.292 CpFe(CO) 2 bound to the nitrogen of maleimide has been used to elaborate amino acids.293 Cyclopentadienylironcarbonyl triphenylphosphine complexes are now famous as chiral auxiliaries. Asymmetric elaborations of the acyl groups –COCH 2 Ph294 and –COCH 2 SMe,295 have been examined.Tetracarbonylmanganese chemistry ortho-Metallated aryl ketone complexes react with PhNSO to form an imine with loss of SO 2 .296 Under di§erent conditions however SO 2 inserts into the C–Mn bond.297 The cyclometallation can be performed in the presence of a tricarbonylchromium group (vide infra) on the aromatic ring and the reactivity of the C–Mnbond leads to 51 as the major product (Scheme 16).298 In a reverse approach to the related cyclometallated molybdenum complex an g6-arene donates the metal by oxidative addition to form 52 which can be elaborated by reaction with alkynes (Scheme 17).299 g2-Complexes Cyclopentadienylrheniumnitrosyl chemistry Complexation of unsaturated alcohols by CpRe(NO)PPh 3 a§ords cationic g2-complexes. Chemoselective oxidation and Wittig extension a§ord 53 which can be reduced at the ketone in the presence of the rhenium (Scheme 18).300 Hydride reduction of a four-electron rhenium alkyne complex gives 54.301 g3-Complexes Tetracarbonyliron chemistry Diastereoselective complexation of an enantiopure allylic benzoate gives the precursor for the cationic chiral g3-complex 55 which reacts with nucleophiles with complete 211 Organometallic chemistry the transition metals Cp Re ON PPh3 Me O Cp Re ON PPh3 HO Me + + Re H Ph Ph Cp Br i 53 54 Scheme 18 Reagents i NaBH 4 MeOH O O Me CpW(CO)2 59 O O HO H Me 65% i ii iii Scheme 19 Reagents i NO`; ii I~; iii (CH 3 ) 2 CHCHO stereocontrol to set a new chiral centre in the metal-free product.302 The SO 2 Ph group directs nucleophiles to the far end of the p-system.The ester in 56 has the same e§ect and this electrophile has been used with an enantiopure enamine nucleophile in a kinetic resolution that gives a product in 64% ee.303 Enantiomerically enriched 57 has been used stereoselectively with prochiral nucleophiles.304 The related neutral Fe(CO) 2 NO complex 58 and an ester analogue have been resolved and their CD curves reported.305 Me SO2Ph Fe(CO)4 BF4 – + CO2Me Fe(CO)4 BF4 – + Me CO2Me Fe(CO)4 BF4 – + Me Fe(CO)3NO 55 56 57 58 NHR* O Cyclopentadienyltungstendicarbonyl chemistry Development of the cyclopentadienyltungsten complexes continues in the Liu group.g1-Prop-2-ynyl structures rearrange to give complexes such as 59 which can be converted into cationicCpW(CO)NO complexes which react with iodide and can then be elaborated as nucleophiles (Scheme 19).306 g3-CpW(CO) 2 complexes have been formed by alkylidene migration.307 g4- and g5-Complexes Tricarbonyliron chemistry The continued development of routes to carbazole natural products nicely illustrates how e§ectively the chemistry of the g5-cyclohexadienyl complexes and the g4-cyclohexadiene counterparts can be exploited together.Nucleophilic attack by the specifically substituted aminobenzofuran 60 is followed by oxidative cyclisation with I 2 to complete the first total synthesis of furostifoline (Scheme 20).308 The use of the now 212 G.R. Stephenson Fe(CO)3 + BF4 – + Me NH2 O Fe(CO)3 Me NH2 O NH O Me 60 i ii OMe NH2 Fe(CO)3 D 61 Me Me (OC)3Fe NH OMe Me Me H H ii Scheme 20 Reagents i MeCN; ii I 2 py OMe O MeO Fe(CO)3 62 HN OMe Fe(CO)3 + O 63 HN OMe Fe(CO)3 64 i ii iii O Scheme 21 Reagents i,Me 3 SiCN; ii H 2 NNH 2 ; iii H 2 Raney Ni more familiar oxidising conditions (MnO 2 or Cp 2 FePF 6 ) failed in this case but are normally309 widely applicable and convenient for the formation of dihydrocarbazoles.With two-electron oxidising agents good regio- and stereo-selectivity has been observed for the removal of the 6-syn hydrogen (or the corresponding deuterium in 61) but regioselectivity depends on the nature of the oxidising agent.310 Addition of CN to a cyclohexadienyl unit followed by reduction puts in place a –CH 2 NH– fragment. In the case of 62 reduction and cyclisation take place in the same reaction to form 63 (Scheme 21).311 The regioisomeric amide 64 was prepared by cyclisation of an aminoalkyl side-chain to the nitrile. The trimethylsilylalkyl ester 65 introduces a precursor to a –CH 2 CH 2 NH– fragment.This approach is used to form 66 (Scheme 22) in a formal total synthesis of lycoramine in which the presence of donor substituents on the arene flattens the structure of the cyclohexadienyl complexes to allow the nucleophile in to build the quaternary centre.312 Amines have been added directly to cyclohexadienyl complexes.313 This has been employed with an optically active exocyclic dienyl complex.314 Novel organometallic ligands have been made in this way using Ph 2 PH in place of the amine.315 Addition of an amino acid derivative provides 213 Organometallic chemistry the transition metals MeO MOMO OMe Fe(CO)3 + BF4 – MOMO OMe NC O SiMe3 O MeO MeO CN ii iii iv v NC O SiMe3 O 65 66 O O Fe(CO)3 i Scheme 22 Reagents i NaH; ii TBAF; iii Me 3 NO; iv (CO 2 H) 2 then 10%H 2 SO 4 ; v aq NaOH diastereomerically pure N-protected amino acids under the control of the chirality of the metal complex.316 The chemistry of 1-methoxy- and 1-acetoxy-cyclohexadienyl complexes and their acyclic counterparts 67 and 68 has been described.317 The corresponding pair of substituents SPh318 and SO 2 Ph319 have also been examined.With an alkene extension conjugate addition of nucleophiles is possible. In the case of 69 a prochiral centre MeO Fe(CO)3 PF6 – AcO Fe(CO)3 PF6 – Fe(CO)2PPh3 Me + PF6 – 67 68 69 + + is present and reaction with Ph 2 CuLi gives an 8:1 mixture of diastereomers.320 This cyclohexadienyl complex was itself obtained by nucleophile addition to 70 and replacement of CO by PPh 3 in a later step.The Fe(CO) 2 (Ph 3 P) complex 71 has been prepared by CO–phosphine exchange.321 Structures 67–73 illustrate the increasing range of substitution patterns now available. Donor alkoxy substituents at C-1 in 67 70 and 71 and the PhS in 72 (with hard nucleophiles) draw nucleophiles to the site of substitution. This same e§ect has been used in the cycloheptadienyl series with eucarvone-derived Fe(CO) 2 (PhO) 3 P complexes.322 Intermediate acyclic pentadienyl structures are responsible for a new organoiron mediated route to trans-1,3-disubstituted 1,4-dioxanes,323 and dienylic fluorides.324 With acyclic dienyl complexes cisoid or transoid intermediates are possible and with the fluoride addition procedure good results were obtained by in situ replacement of a leaving group by fluoride while the corresponding reaction of an isolated dienyl salt failed.214 G.R. Stephenson MeO OMe Fe(CO)2L L = CO 70 L = PPh3 71 Fe(CO)3 + + PhS Fe(CO)3 + PhS O O 72 73 Neutral diene complexes can themselves impart important stereocontrol as in aldol chemistry at an aldehyde adjacent to the g4-complex. Reduction of the ketone in the product a§ords a 1,3-diol unit needed for a C-7–C-20 fragment of macrolactin A.325 Homoallylic alcohols have been used as a starting point to address this structural feature in a C-11–C-24 fragment.326 Access to substituted piperidines completes tricarbonyliron mediated syntheses of dienomycin C and its C-4 epimer.327 Dihydroxylation 328 cycloaddition329,330 and radical addition330 have also been examined. Functionalisation of imines next to the g4-Fe(CO) 3 unit has been used in the synthesis of a dipeptide isostere.331 Friedel–Crafts acylations form cyclic ketones in which a portion of the metal-bound diene lies within the ring.332 E§ects arising from the presence of Fe(CO) 3 can be subtle; an example of enhanced macrolactonisation has been described.333 Neutral cyclohexadiene g4-complexes have also received attention in studies of 1,3-diacetoxy substitution patterns334 and with furanyl substituents.335 The latter give convenient access to 1,4-dicarbonyl-2-ene functionality by ring opening.Dipolar cycloaddition at an exocyclic alkene,336 oxidation of alkenyl side-chains,337 and palladium catalysed replacement of OTf at C-1 of the g4-unit338 have been described. A rhodium catalysed diazo ester insertion (vide supra) has been reported adjacent to the g4-complex.339 The precursor was obtained by a dianion addition an example of the successful use of an unusually basic nucleophile.4-Bromotropylium complexes of Fe(CO) 3 interconvert.340 Moving to small rings intramolecular trapping of cyclobutadiene liberated from its Fe(CO) 3 complex forms polycyclic structures.341 There is also an important g3 chemistry of Fe(CO) 3 complexes and progress has been particularly marked in the ferralactone series available by iron mediated opening of alkenyl epoxides. Aldehydes342 and ketones343 besides the allyl complex react diastereoselectively with nucleophiles. The ferralactone carbonyl group can also be exploited and has been converted into the alkoxycarbene 74.344 Me O (CO)3Fe OMe + 74 Special notice should be taken of the strategically important reactions that remove the metal with C–C bond formation.Intramolecular procedures currently show most promise. Deprotonation of the ester 75 brings about macrocyclisation when performed at room temperature but the protonation step lacks regiocontrol a§ording a 3:4 mixture of 76 and 77 (Scheme 23).345 Deprotonation followed by oxidation e§ects 215 Organometallic chemistry the transition metals O O H (CO)3Fe 75 O O 76 O O 77 + CO2Et (CO)3Fe HO2C CO2Et 78 58% i ii i iii Scheme 23 Reagents i LDA CO; ii H`; iii O 2 carbonyl insertion as illustrated in the cyclisation that makes 78. Similar nitrile mediated cyclisations start with addition of a Cu–Zn reagent to a pentadienyliron complex followed by cyclisation upon decomplexation.346 A similar start exploits a cycloheptadienyl complex to end with the introduction of a formyl substituent by carbonyl insertion and protonation of the anionic acyl intermediate.347 Nucleophiles can also add to cycloheptadienyl complexes for form g3,g1-products with a r-bond to the metal which can directly undergo carbonyl insertion.A sequence of two cycloheptadienyliron mediated bond-formations has been performed before carbonylative decomplexation makes 79 a regioisomer which results from double bond migration (Scheme 24).348 The g3,g1-intermediates can also be accessed by opening alkenylcyclopropanes. 349 Insertion of CO in this system can be promoted with ceric ammonium nitrate.350 Investigations into the formation of non-racemic tricarbonyliron complexes have focussed particularly on improved methods of asymmetric induction during the complexation of prochiral diene ligands.Terpene-derived a,b-unsaturated imines351 and binaphthyl-based systems352 have been described. In the latter case asymmetric catalysis has been achieved. Covalently attached auxiliaries can also induce chirality during complexation and the use of esters and amides,353 and sulfinyl groups,354 have been described. Tricarbonyliron complexes have been separated by HPLC on cyclodextrin-based columns.355 Trimethylenemethane complexes have been resolved by temporary covalent attachment of lactate esters.356 Resolution using ephedrine adducts of aldehydes has provided labelled enantiopure substrates to examine the selectivity of yeast reduction of functionality in the presence of the Fe(CO) 3 group.357 The desymmetrisation of meso structures is possibly the neatest of the methods that use preformed g4-complexes.Alkyl group transfer from a dialkylzinc reagent in the presence of an amino alcohol auxiliary gives 80 in high ee (Scheme 25).358 The absolute configurations and CD curves of methyl-substituted butadiene complexes have been examined.359 A crystal structure of the symmetrical 2,4-dimethylpentadienyl complex has been described,360 and the electrochemistry of cyclohexadienyliron complexes has been examined.361 Mechanistic details in the chemistry of heterodiene tricarbonyliron complexes have 216 G.R. Stephenson But Fe(CO)2P(OPh)3 + But Fe(CO)2P(OPh)3 Ph O But Ph 79 i ii Scheme 24 Reagents i PhLi; ii CO O O Fe(CO)3 O Et Fe(CO)3 N OH Ph Ph Me i 53% 98% yield ee > 80 OH Scheme 25 Reagents i Et 2 Zn Me3Si Li Me3Si • O OEt Fe(CO)3 81 i ii Scheme 26 Reagents i Fe(CO) 5 ; ii EtOS(O) 2 CF 3 been elucidated.Vinyl ketone complexes are converted into vinylketene complexes with retention of configuration ruling out the possibility of symmetrical carbene complexes as intermediates.362 Vinylketene complexes form vinylketenimines by heating with isonitriles. Again there is retention of configuration.363 Photochemical isomerisation during complexation brings alkenes into conjugation with esters to form g4-2-alkoxyoxadiene structures.364 Vinylimine complexes with C-2 methyl substituents are converted into 2-aminodiene complexes by a rearrangement initiated by deprotonation with PhNHLi.365 Fluxionality in vinylimine complexes has been studied,366 as has the activation energy for bond-shift isomerism in g4-complexes of OCH–CH––CH–CDO.367 Vinylketene structures have been synthesised by a double carbonyl insertion in yields as high as 55%.Like decomplexation with concomitant C–C bond formation (discussed above) reactions that form g4-tricarbonyliron complexes during the process that fashions the p-bound ligand are also strategically important. The formation of 81 (Scheme 26) and the PPh 3 analogue has provided a nice example.368 When cationic g4-complexes are required CpMo(CO) 2 is a popular choice. Kno� lker has extended his organoiron routes to carbazoles to employ this Mo system in total syntheses of mukonal369 and murrayacine.370 Lactone and bicyclic amine products can also be obtained from the metal removal step.371 Organocopper–zinc nucleophiles with g4-electrophiles provide a convenient entry.The regiodirecting e§ect of a C-2 PhS group has been defined as x (i.e. nucleophiles add at C-4).372 A related molybdenum structure bound to cyclopentadienone has been employed with nucleophiles. 373 A (C 5 Me 5 )Mo(CO) 2 g3-c-lactonyl complex has been investigated in 217 Organometallic chemistry the transition metals N O NC Cr(CO)3 N O H NC i ii 82 Scheme 27 Reagents i LDA; ii I 2 reactions with nucleophiles and protons,374 and sugar-derived allylic acetates have been converted into TpMo(CO) 2 complexes by oxidative addition [Tp\hydridotris( 1-pyrazolyl)borate].375 g6-complexes Tricarbonylchromium chemistry Intramolecular nucleophilic additions to complexed arenes have been shown to be reversible but the cyclised product 82 can be trapped by aromatisation of the g5-anion upon oxidation with iodine (Scheme 27).376 Oxazoline substituents promote meta nucleophile addition which can be followed by alkylation of the anion.377 Prochiral imine and oxazoline systems have been used with asymmetrically modified organolithium reagents.378 Leaving groups can be displaced from Cr(CO) 3 -activated arenes to form biaryl379 and arylalkyne380 complexes.Methyl381 and isopinocamphenyl or fenchyl382 auxiliaries attached as aryl ethers have induced asymmetry in the addition of LiMe 2 CCN. The complex of boron heterocycle 83 reacts with acetylides at boron displacing PMe 3 .383 A cationic analogue 84 of benzene(tricarbonyl)chromium has been prepared. 384 B Cr(CO)3 PMe3 83 Cr(CO)2NO 84 + The chemistry of benzylic cation complexes has been taken up by Corey’s group to gain stereocontrol in the synthesis of cetirizine a second generation histamine antagonist.385 Benzoxanthiane386 and benzyl fluoride387 compounds have been synthesized. Benzyl anion complexes feature in the elaboration or aryl acetals,388 and fluorenes.389 When two methyl groups are placed 2,3 to a tert-butyl ester the C-2 group has been shown to be more readily deprotonated.390 Benzylic deprotonation has been used to a§ord desymmetrisation of 85 (Scheme 28).391 Chirality next to the g6-complex is induced by asymmetric deprotonation of benzyl ether complexes392 and secondary ether structures.393 Acetals can be used in the place of ethers.394 Enzymic methods395 and palladium catalysed asymmetric alkoxycarbonylation396 have been employed.Organometal catalysed processes at functionality attached to the g6-unit are interesting in their own right. Other examples include Suzuki coupling with boromoarene 218 G.R. Stephenson O (CO)3Cr O (CO)3Cr SiMe3 Ph N Li Ph 82% 76% yield ee 85 Scheme 28 Cl (CO)3Cr NHBoc CO2Me Zn NHBoc CO2Me I i ii 86 Scheme 29 Reagents i Pd 2 (dba) 3 (o-Tol) 3 P; ii hm Cr(CO)3 Me N Br Cr(CO)3 Me N Br O H (+)-87 Me N O H H (–)-88 OMe OTMS ii iii i Scheme 30 Reagents i SnCl 4 ; ii Bu 3 SnH AIBN; iii air hm complexes to form complexed biaryls,397 and incorporation of the iodoserine-derived organozinc reagent 86 in the synthesis of substituted aromatic amino acids (Scheme 29).398 The chromium influences conventional reactions at adjacent positions in the formation of unsymmetrical acetals,399 1,2-diols,400 (which has been applied to ([)- goniofupyrone401) and amines from imines by reduction402 and addition of Reformatsky reagents.403 Cycloadditions at imines404,405 can be stereocontrolled and in the case of 87 the product has been taken on in a stereoselective radical cyclisation to a§ord the ([)-isomer of 88 (Scheme 30).405 Cyclopropanation,406 elaboration of enones by Grignard reagents (followed by a stereocontrolled oxy-Cope rearrangement) or directly by Lewis acid mediated addition of allylsilanes,407 radical cyclisations of groups introduced through the exploitation of benzyl anions,408 and double functionalisations of (1,2-dioxobenzocyclobutene)Cr(CO) 3 have all been exam- 219 Organometallic chemistry the transition metals ined.409,410 The resulting bis-alkoxides also rearrange by an oxy-Cope mechanism when alkenyllithium reagents are used.Ring opening to form a quinodimethane complex and trapping by cycloaddition,411 and photochemical intramolecular cycloaddition to cycloheptatriene412 and tropone413 complexes make polycyclic products. Intermolecular addition of dienes to cycloheptatriene414,415 and g6-thiepine 1,1-dioxide415,416 complexes are performed under conditions that detach the metal during skeletal bond formation.416 Cycloaddition with alkyl isocyanates also removes the metal,417 and with alkynes a sequence of two cycloadditions and four C–C bond formations occurs during detachment of the chromium.418 A further variant uses an g5-chromium–tin adduct (arising from anion trapping) as the precursor for cycloaddition.419 Besides the specialist ‘expert’ tricarbonylchromium research teams the adoption of this chemistry this year by widely acclaimed general synthesis groups of the stature of those led by Corey385 and Paquette410 is itself a testament to the growing importance of the methodology.Tricarbonylmanganese chemistry Nucleophile addition to the cationic (and hence powerfully electrophilic) tricarbonylmanganese complexes remains the main focus of attention with cine and tele processes described for hydride addition.420 For C–C bond formation LiCH(CN)SiMe 3 can pick up two arene complexes. In the 1,2,3-trimethoxybenzene case described each addition occurs at C-4.421 Mn(CO) 2 phosphine and phosphite systems have been used with LiC(Me) 2 CN.422 With a thiophene Mn(CO) 3 complex nucleophile addition (from organocuprates) occurs at sulfur.423 (Benzothiophene)Mn(CO) 3 ` carries Mnon the arene ring and in a strange reaction an additional manganese complex has been inserted into the arene–sulfur bond.424 An g6-hydroquinone complex has been prepared.425 Reduction dimerises arene manganese complexes.426 Neutral g5-manganese complexes can themselves be elaborated by nucleophile addition,427 for cycloaddition with alkynes.428 Cyclopentadienyliron and ruthenium chemistry Cationic CpRu arene complexes play a key role in Pearson’s route to OF4949 III forming the diaryl ether 89 (Scheme 31) which was then cyclised in a formal total synthesis of the cyclic peptide target.429 Two halides can be displaced from dichloroarenes. 430 Combining 1,2-dichloro and 1,2-dihydroxy substitution patterns affords benzodioxin derivatives,431 and a range of related heterocycles.432 The CpFe system was useto make functionalised p-phenylenediamine compounds by replacement of Cl from 1,4-dichlorobenzene complexes.433 A kinetic study of chlorine replacement has been reported.434 Dicobalthexacarbonyl Nicholas chemistry The focus of attention in recent years on the chemistry of enediyne natural products has provided an important platform for the development of applications of cobalt alkyne chemistry in particular the use of carbocations a to the cobalt-bound alkyne a process now widely referred to as the Nicholas reaction.The diastereoselective conversion of 90 into 91 (Scheme 32) provides a fine example and is drawn from a substantial full paper setting out recent progress in the research of the Magnus group.435 Kinetic 220 G.R.Stephenson MeO OH CO2 Br ZNH Cl CO2Me NH O BocHN NH2 O RuCp PF6 – + OMe HNZ CO2H O NH CO2Me O HN O NH2 89 + i–iv Boc Scheme 31 Reagents i NaO(But) 2 C 6 H 4 ; ii hm CH 3 CN; iii NaI; iv SmI 2 TBSO O OBBu2 O Co Co(CO)3 90 TBSO OH OBBu2 O 91 H 82% i ii OTBDPS (CO)3Co Co(CO)3 H O CO2Me OTBDPS (CO)3Co Co(CO)3 CO2Me H OH 92 91% iii OTIPS O Me TBSO PhS (CO)3Co Co(CO)3 93 OMOM OMOM TBSO Me SPh CO2TIPS 94 60% iv v (CO)3 Scheme 32 Reagents i Bun 2 BOTf Et 3 N; ii cyclohexa-1,4-diene; iii (MeO)MeAlCl; iv 23 °C 24 h; v NMNO 221 Organometallic chemistry the transition metals Me3Si Co(CO)3 (CO)3Co OAc OH O Me3Si Me O O i ii 95 Scheme 33 Reagents i BF 3 ·OEt; ii CAN H H O O (CO)3Co Co (CO)3 O O H H i ii iii O H H 96 Scheme 34 Reagents i C 2 H 4 9 equiv.TMANO·2H 2 O 40 °C 25–30 atm PhMe–MeOH 81%; ii PPh 3 CBr 4 ; iii steps control gives a mixture of diastereoisomers but these equilibrate so 91 can be isolated in 82% yield. Cobalt alkyne chemistry is used the opposite way round to prepare 92 (94% erythro) which was taken on by conventional chemistry to form an enediyne which spontaneously cyclised.436 Temporary attachment of Co 2 (CO) 6 has been used as a protection strategy for enediynes.437 Bending of alkynes by complexation helps the cyclisation that forms 91 and has also been used to influence the transition state geometry in the Ireland–Claisen rearrangement of 93. The preparation of 91 and 94 illustrates the excellent ways438 now available to remove the cobalt when its role in the synthesis is over. The course of deallylcarboxylation has been adjusted by complexation of an alkyne to suit the needs of a synthesis of a carbacyclin derivative which also employs rhodium catalysed diazoester insertion (see Section 1).439 The 1,2-shift of alkynyl groups has been facilitated by complexation.440 Cycloaddition of nitrile oxides to alkenes next to the complexed alkyne is controlled by the stabilisation of charge by the cobalt and so gives excellent regioselectivity.441 Studies of enol ethers in aldol chemistry continue 442 and a case has been developed where a chiral auxiliary associates with the aldehyde.443 With simple leaving group displacement (the original Nicholas reaction) the process has been extended to include the use of alkenes as the nucleophile.This generates a carbocation which will deprotonate to form enyne products or can be intercepted as in the tandem process that forms 95 (Scheme 33).444 Pauson–Khand reaction The formation of monosubstituted cyclopentenones by means of the Pauson–Khand reaction requires the use of ethene.A much improved autoclave procedure employing nine equivalents of trimethylamine N-oxide at an optimum temperature of 40 °C has been developed and demonstrated in a synthesis of (])-taylorione 96 (Scheme 34).445 In a synthesis of (])-b-cupareneone a temporary tether was used in the cyclisation of 97 (Scheme 35).446 An 8 1 ratio of diastereoisomers was obtained. Slightly better (12 1) diastereoselectivity can be obtained at the expense of yield by omitting the 222 G.R. Stephenson Ph O S Ph S O H O i 97 Scheme 35 Reagents i Co 2 (CO) 8 NMO 16 equiv.N-methylmorpholineN-oxide. Better diastereoselectivity has been obtained by carrying out asymmetric Pauson–Khand reactions on a carbohydrate template.447 The use of a chiral ligand on cobalt to induce asymmetry is an attractive alternative approach but requires routes to unsymmetrical Co 2 (CO) 5 L complexes. Amine Noxide448 and photochemical449 methods have been described. Solid-phase supports have been used for the Pauson–Khand reaction,450 and photochemical451 and chemical (CF 3 CO 2 H)452 promotion have been examined. Applications to polyquinane synthesis have exploited the phenylcyclohexanol auxiliary illustrated in 97.453 In a tandem approach two Pauson–Khand reactions have been performed back-to-back in the cyclisation of 98,454 and sequentially with 99.455 The Pauson–Khand process can be interrupted by allowing oxygen to intervene.The intramolecular case a§ords monocyclic enones in place of the normal bicyclic products.456 O O Me3Si 98 OSiMe3 99 SiMe3 Cyclopentadienylcobalt chemistry oligomerisation combined with complexation The cyclotrimerisation of two alkynes and an alkene produces a diene cobalt complex with the diene at the location corresponding to the original alkynes. Under thermodynamic conditions with strained products rearrangement can occur as in the formation of 100 (Scheme 36). The factors influencing selectivity have been examined. 457 Rearrangement is also required to account for 101 which is formed together with a metal-free structure with an exocyclic double bond.458 Enynes have been cyclised to a§ord exocyclic 1,3-dienes their g4-complexes and structures in which the metal-bound region has moved into the ring.459 Cobalt is not the only metal that can be employed.g1-Mn(CO) 4 complexes have been elaborated by insertion of alkynes to provide intermediates that are eventually converted into metal-complexed pyrylium salts.460 Pentacarbonylchromium carbene chemistry the Do� tz reaction Double Do� tz cyclisation with a butadiyne gives a 23% yield of the chiral binaphthyl structure 102 which is formed as a single isomer (Scheme 37).461 Precursors for conventional biaryl formation have been obtained by an application of the Do� tz 223 Organometallic chemistry the transition metals CoCp CoCp 100 C O O But O O CoCp But 101 i i Scheme 36 Reagents i CpCo(CH 2 –– CH 2 ) 2 O O (CO)5Cr Cr(CO)5 Me Me HO Ph O O Me Me Ph OH 102 i Scheme 37 Reagents i PhC–– – C-C–– – CPh THF reaction.462 Cyclisation with prop-2-ynyl alcohols can be modified to a§ord lactones.463 The Do� tz cyclisation initially forms an g6-arene complex. Such products can themselves be important intermediates (see above) and there has been an extensive investigation of their isolation by in situ trapping of the phenol with silylating reagents. 464 Products of this type include naphthalenes with cyclopropyl groups next to the chromium-bound arene,465 and unusually substituted indole complexes.466 Indolines have also been obtained.467 Just as the Pauson–Khand reaction can be interrupted so too can the Do� tz process which makes five-membered rings when intercepted before the carbonyl insertion. In the case reported468 tautomerisation not oxidation interrupts the reaction.3 Organometallic compounds New applications of organometallic complexes Organometallic rods and dipoles Some striking structures have been reported this year with long oligoalkyne rods linking organometallic centres. The crystal structure of the tetrayne 103 shows ferro- 224 G.R. Stephenson FeCp FeCp FeCp N W(CO)4PPh3 103 104 Me Me Me Me Me Fe PPh2 Ph2P Me Me Me Me Me Ph2P PPh2 Fe + 105 Cp(CO)3W W(CO)3Cp 106 Cp1 2Ti FeCp FeCp Pt Et3P Et3P Pt PEt3 PEt3 109 108 C C Ru Ph2P PPh2 Ru Me Me Me Me Me Me Me Me Me Me Ph2P PPh2 107 C C FeCp FeCp FeCp FeCp FeCp FeCp 110 + 225 Organometallic chemistry the transition metals cenyl groups pointing both up and down. The W(CO) 4 PPh 3 pyridine adduct 104 has mixed alkene–arene link and in the corresponding 4-pyridyltriyne the crystal structure showed large thermal ellipsoids at the second sp carbon out from the pyridine ring.469 Direct attachment of the tetrayne to metals is also possible and in 105 mie FeII–FeIII centres are linked to form a structure described as a ‘molecular wire’ with the strongest electronic coupling through nine bonds observed to date.470 Some long structures of this type are easily made.Two Cp(CO) 3 W–C–– – C–C–– – C–H units are linked in 85% yield by oxidation with Cu(tmeda)Cl/O 2 to form 106. The same building block with PtCl 2 (dppe) forms a bent rod with Pt(dppe) in the centre.471 The same bent structure is encountered in a quite di§erent trimetal complex 107 which when oxidised with Ag` is converted via a bis-ferrocenium species into 103 and Cp@2 Ti2` in 90–98% yield.472 The unusual organic link in 108 was introduced by direct complexation of the pentayne with PtCl 2 (Et 3 P) 2 .473 Bending at carbon is introduced when a methine link is present in the chain as in 109.This complex originates from HC–– – C–CHOH–C–– – CH and a ruthenium chloride complex which are joined by AgBF 4 .474 The drawing of 109 represents one of two equivalent canonical forms. The issue of bonding in polyalkyne substructures in organometallic complexes has been addressed in a treatment that relates to a hypothetical organometallic net which has a degree of complexity that currently transcends synthetic capabilities.475 Allenes are interesting links because they introduce a twist into structures as in 110 which is isolated in low (4%) yield from triferrocenylallenium tetrafluoroborate.476 When three carbons are bound end-on to a metal the allene motif becomes an allenylidene ligand.In 111 two allenylidene g1-ruthenium complexes are joined by thiophene. This is a dication but the mixed RuII–RuI structure is accessible electrochemically. 477A 2,5-dialkynylthiophene has been used to joinMoand Fe centres in bis g1-complexes.478 Other links include anhydrides,479 Me 2 SiOSiMe 2 ,480 COMe481 and PPh 2 .482 This last case features a Co 2 (CO) 6 complexed alkyne as a substituent at phosphorus. The analogous CH-linked (prop-2-ynyl) situation has been examined with bis-CpMo(CO) 2 in a cationic structure.483 Linking by CH 2 interrupts the conjugation but a more extended range of structures has been reported in this series.The polymetallic prop-2-ynylferrocene structures have been combined in hexametal dimers by joining the CH 2 positions. Alternatively both Cp rings in ferrocene can carry prop-2-ynyl complexes and in one case these too have been joined.484 Larger clusters are combined by a variety of strategies.485–487 In 112 the cluster metallates pyridine producing a more direct attachment than in 104.487 Alkene and diene links lie between a Cr(CO) 3 arene complex and cationic arene or thiophene complexes of Mn(CO) 3 .488 An alkene between Cp ligands is transformed into the CH–CH connection between pentfulvadiene ligands by oxidation of Ru(C 5 Me 5 ) centres.489 Short links can illustrate important issues. The simple ferrocenylethynyllithium or its Ru counterpart can be combined with MnBr(CO) 5 to give bimetallic structures.490 The corresponding ferrocene with CpFe(dppm) in place of Mn(CO) 5 has been oxidised to give another example of a mixed valence complex.491 The mixed valence/canonical form issue is encountered with a three atom (cyclobutenyl) link in a bis-CpFe(CO) 2 complex and its (C 5 Me 5 )ReNO(PPh 3 ) counterpart.492 A 1,3-bisalkynylcyclobutadiene tricarbonyliron complex has been described in the continuation of the Bunz group’s remarkable work towards highly elaborate polyorganometallic assemblies.493 The possibility of nonlinear optical (NLO) properties in bimetallic structures with 226 G.R.Stephenson FeCp S C C Ru Cl Ph2P PPh2 Ph2P PPh2 C C Ru Cl PPh2 Ph2P PPh2 Ph2P 111 N Ru(CO)3 (CO)2Ru Ru(CO)4 H 112 Cr+(CO)3 FeCp BF4 – Cp(PMe3)2Ru NO2 113 114 Mn(CO)3 – – – – – 115 2+ conjugation through the link is a major motivation in this field of research (e.g.Tessier Youngs et al.,473 Dixneuf et al.,477 Fischer et al.,492 Cooke and Schultz,494 Toma et al.495). There are now excellent examples. Neutral and cationic metal centres are combined in 113 giving good polarisability and polarisation to the p-system and a very high hyperpolarisability (b\570]10~30 esu) measured by hyper-Rayleigh scattering.496 The parameter b is a useful measure of success because it is determined in solution and so does not su§er from complications di§erences in crystal form. Fieldinduced second-harmonic generation (EFISH) is another important technique. Even monometallic structures can give large values of kb e.g. 9700]10~48cm5 esu~1 for 114 in which Cp(PMe 3 ) 2 RuCCC 6 H 4 C–– – C– has been introduced497 in place of the ferrocene of Green’s original NLO organometallic.Considerable e§ort has been devoted to these lengthened systems.498 Another variant of the Green compound has a CH 2 OCH 2 strap to disturb the parallel planes of the two Cp rings.499 The role of the nitroarene is simply as a polarisable electron withdrawing group. A 4-substituted N-methylquinolinium ion has been used for this purpose giving improved hyperpolarisability and EFISH measurements.500 A dimethylazulene has also been put at this position.501 NLO measurements on structures containing individual end-groups from the more elaborate assemblies 103–113 o§er a guide to separate contributions of organometallic and metallo-organic (i.e. heteroatom linked) moieties.NLO properties have been reported for Schi§-base complexes of Ni Zn and Cu,502 Pt(polyyne) (PPY),503 nickel dithiolene complexes,504 and molybdenum or tungsten clusters with copper or sil- 227 Organometallic chemistry the transition metals ver.505 Measurements have also been made on metallo-organic thin films.506 (For more examples of thin film structures see the next section of this Report.) Metallo-organic links through two tripyrazol-1-yl borate substituents have joined two ferrocenes with a third iron atom.507 PdCl 2 bound by two substituted pyridines also fulfils this role.508 A nitrile has linked iron and molybdenum centres in a paramagnetic structure.509 Some eye-catching monometallic structures have been reported. The first linear Ph 2 C–– C––C––C––C–– iridium complex was described,510 and vinylidene complexes of manganese have cyclic tetra- or hexa-silanes at the end of the C––C unit not attached to the metal.511 Two studies of sesquifulvalene complexes from Tamm’s group explore stabilisation e§ects.512,513 Monometallic analogues of 113 were reported.These had Mn(CO) 3 Mn(CO) 2 P(OMe) 3 and Mn(CO) 2 (PPh 3 ) groups in place of FeCp and a metal-free tropylium cation at the other end of the alkyne.511 Resonance e§ects in canonical structures were examined and b values were reported though these were a factor of ten smaller than that of 113. With so many metals and ligands available to choose from a great many di§erent structural forms are available. Three-,514,515 four-,516,517 five-516 and six-armed518 structures with the metals on the outside,514–516 or the centre,516–518 ranging from monocations514,517,518 to the remarkable pentaanion 115,516 illustrate this point.The pentalithium salt prepared quantitatively from a pentacyclopentadiene derivative with butyllithium in THF is itself a potentially important building block for still greater structures. At the opposite extreme metals can be pressed close together when they share a ligand,519–521 or when the ‘ligand’ that joins them is composed of two directly linked ‘classic ligands’ as in bis-Cp,522–524 and aryl-Cp525 structures. Some structures of this type contain important metal–metal bonds that can be manipulated (broken and re-formed) without loss of the metals from the ligand.522–524 Organometallic liquid crystals films and dendrimers Ferrocene is still the most popular organometallic moiety for applications in liquid crystals and micelles.Often it is chosen because of its extreme stability and its well understood organic chemistry. Attention is now turning to the exploitation of the redox chemistry of the ferrocene group and here unique benefits for the inclusion of organometallic units can be anticipated. Oxidation of a neutral and hence non-polar nonamethylferrocene head-group in a rod-like structure has been used to place a cation at the end of the rod promoting the formation of a smectic A phase. The product 116 is the first ferrocenium-containing thermotropic liquid crystal.526 With ferrocene groups at both ends of a linker oxidation now gives rise to vesicle formation. 527 Electrochemistry was used to determine that both head-groups had been oxidised and is consistent with a spacing between the groups of about 20 Å in vesicles formed with 117.Similar results were obtained with a rigid steroid as the link but were distinct from results with a single ferrocene on a long alkyl chain. The electrochemistry of aryl diether-linked ferrocenium ions has been examined.528 Two long alkyl chains have been attached to ferocene in 118 which contains 1,3-dicarbonyl units in the enol form.529 Bis(arylimino)ferrocenes have also been examined,530 and with amide-linked amino acid esters as the substituents ordered conformations are observed.531 Chemistry that manipulates mono- and di-substitution on ferrocene will pave the way for more ambitious liquid crystal structures. 228 G.R. Stephenson FeC5Me5 O O O O O + FeCp O + O FeCp + 116 117 TsO– Ferrocene and isoquinolinium groups linked by a rigid 9,10-diarylnaphthalene centre form inverse micelles and Langmuir–Blodgett films with non-centrosymmetric Z-type layers.532 Two ferrocenes linked with unsaturated rigid spacers o§er a more disk-like structure.The example 119 forms Langmuir monolayers on the surface of water.533 Metal carbonyls can also be applied in work of this type. The tricarbonylchromium chloresteryl benzoate complex and the corresponding tricarbonyliron hexadienoate derivative 120 are cholesteric mesogens.534 In the tricarbonylchromium case the complex exhibited its mesophase at a lower temperature than the free ligand.535 A tricarbonylchromium group has been placed at the centre of a much longer and more flexible rod combining arene and long-chain alkyl components with imine ester and ether links.Smectic C and nematic phases have been observed.536 The repeat unit 121 lies at the surface of an organometallic fourth generation dendrimer containing all 48 ruthenium atoms in the surface layer.537 As many as 64 ferrocenes occupy the surface of a poly(propylenimine) dendrimer.538 Organometallic polymers Linking ferocenes by monosubstitutions on each ring can produce structures with the iron atoms within in the polymer chain. Alternating ferrocene and SiMe 2 units have been combined in this way.539 With SiMeCl in the repeat unit the polymer can be elaborated after formation.540 SnMe 2 -541 and S 2 -542 linked polymers have also been described as have the Se 2 - and Te 2 - linked counterparts.542 In 122 a rigid rod is combined with ferrocene and (PBu 3 ) 2 Pd centres.The palladium centre and a Ru(dppe) 2 centre have been joined in polymers by acetylide links developed from HC–– – C–C 6 H 4 –C–– – CH.543 This same acetylide strategy has been employed with –(C–– – C) 2 –C 6 H 4 –(C–– – C) 2 – as the linker.544 A cymantrene-containing organometallic polymer has been made by Suzuki coupling.545 When the connection is by two substitution sites on one ligand the metal stands aside from the chain as in the tetrayne-linked oligomer 123.546 An unusual polymerisation exploits thermally induced loss of methane to form the polymeric zirconacycle 124.547 Gold,548 manganese549 and platinum550 have been inserted directly into the polymer backbone by a variety of techniques e.g. coordination by pyridine,548 in Schi§ base complexes,549 and much more weakly linked hydrogen bonded structures.550 Conventional polymers can be elaborated to introduce ligand sites for complexation.229 Organometallic chemistry the transition metals Fe O O H O O H 118 Fe Fe O O O chloresterol O Fe(CO)3 119 120 O O O Ru(CO)2Cp Ru(CO)2Cp 121 PBu3 Pd PBu3 Fe n 122 Me3Si Me3Si CoCp n 123 230 G.R. Stephenson SiMe3 Cp2Zr Me Zr Me3Si Cp Cp n i 83% 124 Scheme 38 Reagents i heat Cyclopentadiene introduced onto a polystyrene support has been complexed by rhodium.551 Polymethacrylates from copolymerisation carry ferrocene-containing thermotropic liquid crystal side-chains.552 Peptides are rather specialised polymers but since they can be made on supports it is possible to develop exotic supported catalysts with ligand sites introduced on unnatural amino acids themselves built up on resin beads.The key is the use of phosphine sulfides to protect phosphine ligands from oxidation during solid phase synthesis.553 Ru Rh and Pd complexes have been immobilised on solid supports.554 Both these and the peptide-based systems have been shown to be functional hydrogenation catalysts. A polymer-modified electrode with Rh(C 5 Me 5 ) complexes has been prepared.555 Organometallic sensors and receptors Selectivity in response to dihydrogen phosphate makes the diferrocene derivative 125 an exceptional sensor. This selective luminescent anion sensor shows a 20-fold increase in emission intensity at 690nm when the analyte is bound in the diamide pocket.556 Less selective neutral ferrocene-based anion receptors have also been shown to bind dihydrogen phosphate.557 Chiral recognition of camphor-10-sulfonate has been achieved with a cobaltocenium-based receptor.558 Work with crown ether binding sites continues.Electrochemical sensing of sodium and magnesium ions has been studied with a di(aminobenzo)crown equipped with two ferrocene carbaldehydes attached by Schi§ base links.559 A cobaltocenium structure links two indenyl ligands with azacrown ethers as substituents. Complexation of lithium and sodium is studied by cyclic voltametry.560 The same indenyl azacrown as a tricarbonylmanganese complex allows the detection of binding of alkali metal ions by FTIR although the shifts are small. A much larger shift is observed upon protonation of the nitrogen. Protonation e§ects of this type have been developed for use in IR-active organometallic pH probes.Since the vibrational bands are narrow and intense several independent responses can be measured in the same spectroscopic experiment allowing dual or multiple sensing.561 This IR-readout approach has also been developed to detect p-stacking of aromatic rings and the binding of organic analytes in crowns by ammonium ion recognition.562 A cyclic tetramer with two ferrocenes and two decaalkylferrocenes in the ring has been prepared.563 The same paper reports the formation of the monocobalt analogue 126. Complexation of cobalt between two cyclopentadienes strategically placed at the ends of a trimer of ferrocene-based building blocks closes the ring. Two ferrocenes have been placed at opposite sides of a polycyclic macrocycle with diazacrowns joining pairs of cyclopentadienyl ligands.564 A rigid aromatic hydrophobic pocket has been 231 Organometallic chemistry the transition metals Fe N N (bipy)2Ru O NH FeCp O NH FeCp 125 Me Me Me Me Me Me Me Me Co Me Me Me Me Me Me Me Me Fe + PF6 – 126 Fe 2+ closed with a ferrocene attached by an amide on each ring.565 The opposite is achieved in ferrocene-closed ring containing four pyrazoles.566 An alternative structure was also prepared in which a tertiary amine closed the ring but two of the pyrazoles bore ferrocenes as substituents.Four ferrocenes have been attached to a porphyrin at the methines joining the pyrroles. The tetraruthenocenyl analogue and a corresponding metal carbonyl structure with four tricarbonylmanganese centres have also been prepared.567 Receptors are not only important in analytical chemistry; e¶cient recognition of specific features is also pertinent to selective catalysis and organometallic structures have a role to play here too.An azacrown system with a ferrocenyldiphosphine ligand as a substituent has been used in enantioselective allylation.568 Bioorganometallic chemistry A ferrocenyl derivative of hydroxytamoxifen has been prepared as an estradiol receptor site-directed cytotoxic agent and tested against a human breast cancer cell line.569 In a continuation of work on steroid-based compounds the aryloxy group of 17-a- ethynylestradiol has been derivatised with an MeC 6 H 4 FeCp marker but in this case a¶nity for the receptor was lost.570 Oxorhenium metallo-organic estradiol-derived compounds have been prepared,571 and two strategies for metal containing steroid look-alikes have been described.572,573 Supramolecular Rh(C 5 Me 5 ) nucleoside and nucleotide complexes have been used in molecular recognition studies with amino acids.574 Organocobalt complexes have been developed for selective tagging of biological macromolecules by exploiting the chemistry of amino ester substituents,575 or other activated esters.576 Peptide hydrolysis has been promoted by platinum and palladium complexes.577 The radionuclide technetium-99 has been incorporated into peptides with a high a¶nity for the somatostatin receptor.578 The chemistry of ferrocene building blocks The increased focus on ferrocene derivatives in new applications has revitalised e§orts in the oldest branch of organometallic chemistry.Making unsymmetrical CpFeCp@ 232 G.R. Stephenson structures,579 or selectively substituted rings in symmetrical forms,580 will open the way to new functionalised systems. In the latter case enol ethers provide the source for the cyclopentadienyl rings. A conventional acylation strategy has been used to introduce perfluoroalkyl chains.581 Monolithiation of ferrocene is a di¶cult problem. A revised procedure has been o§ered.582 Mono-bromine–lithium exchange with 1,1- dibromoferrocene constitutes an alternative.583 Chloromethylenetriphenylphosphonium ylide e§ects an alkenylation of ferrocene carbaldehyde to a§ord a mixture of E- and Z-isomers that can be converted without separation into ethynylferrocene by treatment with butyllithium.584 An ingenious trick allows temporary attachment of a diamine to ferrocene carbaldehyde to relay metallation to the unsubstituted ring.585 Asymmetric functionalisation is important if the goal is a ligand for use in asymmetric synthesis.Approaches based on metallation directed by chiral auxiliaries are popular. Metallation in the presence of chiral oxazoline substituents has been followed by trapping with Me 3 Si,586 Bu 3 Sn,587 and Ph 2 PCl.588 The combination of sparteine with a ferrocene carboxamide also gives good ee values in the induced planar chirality. 589 A chiral 1,2-diamine with a dimethylaminomethyl substituent on the ferrocene was less e§ective but in this case trapping with DMF introduced a formyl group.590 Chirality in side-chains is also valuable. (S)-1-Amino-2-methoxymethylpyrrolidine has been used to form chiral ferrocenylalkylamines.591 Asymmetric reduction of diacyl ferrocenes is also e§ective.592 Functional changes in side-chains include replacement of OH in CH 2 OH by reaction with triphenylphosphite to form a phosphonate,593 aldol functionalisation of acylferrocene with aromatic aldehydes (a reaction performed in the presence of cyclodextrin which induced a slight asymmetric bias),594 and Lewis acid catalysed displacement of OMe from CH 2 OMe substituents.595 Organometallic complexes as ligands Many bimetallic structures both with separated metals and with metal–metal bonding can be regarded as containing organometallic structures as ligands but the description is of greatest value when applied to organometallic auxiliaries that are employed as ligands in other processes most typically asymmetric catalysis.There is an increasingly large number of examples and ligands of this type o§er geometries which may be advantageous and will certainly be unusual. The use of the aminophosphine 127 as a ligand in Grignard cross-coupling,596 or the diamine 128 in asymmetric hydrosilylation,597 provide typical examples. Levels of asymmetric induction can be very high. (S)-DIPOF 129 gives 96% ee in a quantitative asymmetric hydrosilylation catalysed by [Ir(COD)Cl] 2 .598 The ligand 130 has been used in asymmetric palladium catalysed allylic substitution.599 More elaborate ligands can provide more than one binding site. This seems likely to be a growth area in future years because of the extra benefit of holding catalyst and substrates together with separate recognition features.With an aminoalkyl substituent to dock an alkene substrate with an organoboron centre in 131 an intermolecular hydrogenation or hydroformylation can be rendered intramolecular.600 Organometallic mechanisms C–H activation in methane has been studied by perturbation and hybrid density functional theory comparing Co Rh and Ir. Only the Rh and Ir complexes should be reactive towards alkanes.601 Oxidative addition of methane to palladium clusters has 233 Organometallic chemistry the transition metals CpFe NMe2 PPh 127 Me N Se Se CpFe CpFe N Me 128 N O Ph Ph Ph2P 129 CpFe Fe CO2Me PPh2 CO2Me PPh2 130 Fe PPh2 PPh2 N B O Me Me 131 also been examined.602 Reductive elimination of C–H from ruthenium clusters changes from a CO-associative mechanism to a CO-dissociative mode when other ligands are varied.603 An alkane-associative mechanism has been identified in the activation of cyclooctane by IrClH 2 (Pr* 3 P) 2 to form cyclooctene.604 Hydrogen migration in Ir–ketene complexes has been shown by NMR to proceed in a stepwise fashion.605 Non-linear temperature dependence has been observed in asymmetric hydrogenation.606 A mechanism for arene exchange in g6-rhodium complexes involves a square planar cis-phosphine cis-ether intermediate a conclusion based on NMR EXSY experiments.607NMR is a powerful tool for mechanism research 19F–19F COSY has given evidence for g2-arene intermediates on the way to C–H and C–F insertion products.608 para-Hydrogen induced polarisation has allowed the detection of intermediates at low concentrations in a study of ligand exchange in iridium complexes.609 Femtosecond IR experiments allowed the direct observation of a reactive solvated monocarbonyl intermediate in C–H activation by a rhodium complex.610 Time-resolved IR spectroscopy makes good use of the IR time-scale and has been applied to the photochemical rearrangement of a dirhenium MeO 2 CC–– – CCO 2 Me complex in which the ligand spans the rhenium atoms.Evidence was obtained for a bis-carbene intermediate.611 Palladium catalysed alkene dimerisation has been studied.612 and mass transfer of ethylferrocene from water to a droplet has been shown to be limited by di§usion. In contrast,OHor NMe 2 groups on the alkylferrocene were also governed by adsorption at the interface. Electrochemical methods were used in this investigation.613 234 G.R.Stephenson A kinetic study of the Tebbe reaction supports the role of Cp 2 Ti––CH 2 as the reactive species.614 Kinetics have been applied to the transfer of tricarbonyliron between benzylideneacetone and azadienes.615 In some cases calculations o§er the best guide. Nucleophile addition to g3-palladium complexes,616 hydrogen exchange coupling in Cp 2 MoH 3 ,617 and isomerisation of osmium hydride complexes have been subjected to ab initio treatments.618 Molecular mechanics calculations have been applied to properties of iron acyl complexes.619 Organometallic structures and bonding C 60 is undoubtedly an eye-catching ligand. The lattice dynamics and hyperfine interactions of its Fe(CO) 4 complex have been reported.620 Extending out from C 60 provides larger ligand sites and an Fe(CO) 3 adduct has been prepared in this way.621 An unusual small ligand in 132 contains a run of cumulated carbon atoms.622 This is reminiscent of the rod structures discussed earlier except that the metal is bound side-on.C–C links between metals have also been the subject of structural study.623 Three PC–– – NPr* 2 units are combined in the unusual nickel complex 133.624 This complex contained a side-on P–– – C triple bond. A P–– – C double bond is coordinated in 134.625 C C C C Ph Ph Ph Ph Pri 3P Rh Cl PPri 3 P C NPri 2 Ni P P Pri 2N NPri 2 132 133 P (CO)2W Me Ar Cp 134 Co 2 (CO) 6 is an important fragment. It has been stabilised by a bridging ligand in 135. Carbon monoxide scrambling in 135 has been examined.626 Charge stabilisation is the issue in the dication 136,627 and the di(azulenyl)ferrocenylcarbenium ion 137.628 Three di§erent aromatic substituents are present in the pyrylium complex formed from 138.629 Bond-lengthening in dihydrogen complexes,630 linkage isomerism in o-xylylene complexes,631 aromatic ring currents in bis-Cr(CO) 3 complexes of dibenzannulene632 and hapticity interconversion in cycloheptatrienyl complexes633 illustrate other contemporary structural issues.Correlation of Hammett constants with NMR chemical shifts is useful with 1-aryl substituted palladium allyl complexes.634 Ligand e§ects on reactivity have been examined,616 and a theoretical study probed the influence of ancillary ligands.635 The final citation in this section identifies a feature article that may herald a new age in organometallic chemistry. Issues of intermolecular interactions and supramolecular organisation take the subject beyond its normal bounds.With great structural variety and increasingly well understood functional utility available in organometallic solids examining how they organise together is likely to grow into a major field supraorganometallics. 636 Note This will be the last year of this catch-all survey of the organic chemistry of the transition elements. The subject has now become too large. When the 1997 literature is 235 Organometallic chemistry the transition metals O P P (CO)2Co Co(CO)2 O O 135 (CO)2Mo Mo(CO)2 H2C CH2 + + 2 BF4 – 136 + FeCp PF6 – 137 O CF3 Cl Mn(CO)3 138 reviewed separate Reports on catalytic and stoichiometric bond-formation and structural/ mechanistic aspects of organometallic chemistry will be presented.The organisation of material in this 1996 Report looks ahead to the need to review these features independently. References 1 Y. Hamada N. Seto H. Ohmori and K. 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Klug and J. Schaefer Organometallics 1996 15 4678.554 V. Isaeva A. Derouault and J. Barrault Bull. Soc. Chim. Fr. 1996 133 351. 555 E. Ho� fer E. Steckhan B. Ramos W. R. Heineman J. Electroanal. Chem. 1996 402 115. 556 P. D. Beer A. R. Graydon and L. R. Sutton Polyhedron 1996 15 2457. 557 Z. Chem. A. R. Graydon and P. D. Beer J. Chem. Soc. Faraday Trans. 1996 92 97. 558 N. Komatsuzuaki M. Uno K. Shirai Y. Takai T. Tanaka M. Sawada and S. Takahashi Bull. Chem. Soc. Jpn. 1996 69 17. 559 P. D. Beer and K. Y. Wild Polyhedron 1996 15 775. 560 H. Plenio and D. Burth Organometallics 1996 15 1151. 561 C. E. Anson T. J. Baldwin C. S. Creaser M. A. Fey and G. R. Stephenson Organometallics 1996 15 1451. 562 C. E. Anson C. S. Creaser and G. R. Stephenson Spectrochim. Acta Part A 1996 52 1183. 563 Suo;Hare Organometallics 1996 15 3885. 564 C. D. Hall A. Leineweber J. H. R. Tucker and D. J. Williams J. Organomet. Chem. 1996 523 13. 565 R. A. Bartsch P. Kus R. A. Holwerda B. P. Czech X. Kou and N. K. Dalley J. Organomet. Chem. 1996 522 9. 566 N. Chabert-Couchouron C. Reibel C. Marzin and G. Tarrago An. Quim. Int. Edn. 1996 92 70. 567 N.M. Loin N. V. Abramova and V. I. Sokolov Mendeleev Commun. 1996 46. 568 M. Sawamura Y. Nakayama W.-M. Tang and Y. Ito J. Org. Chem. 1996 61. 9090. 569 S. Top J. Tang A. Vessie` res D. Carrez C. Provot and G. Jaouen Chem. Commun. 1996 955. 570 A. Pio� rko R. G. Sutherland A. Vessie` res-Jaouen and G. Jaouen J. Organomet. Chem. 1996 512 79. 571 F. Wu� st H. Spies and B. Johannsen Bioorg. Med. Chem. Lett. 1996 6 2729. 572 R. K. Hom D. Y. Chi and J.A. Katzenellenbogen J. Org. Chem. 1996 61 2624. 573 Y. Sugano and J. A. Katzenellenbogen Bioorg. Med. Chem. Lett. 1996 6 361. 574 H. Chen S. Ogo and R. H. Fish J. Am. Chem. Soc. 1996 118 4993. 575 S. Blanalt M. Salmain B. Male� zieux and G. Jaouen Tetrahedron Lett. 1996 37 6561. 576 H. El Amouri Y. Besace J. Vaissermann and G. Jaouen J. Organomet. Chem. 1996 515 103. 577 E. N. Korneeva M.V. Ovchinnikov and N. M. Kostic� Inorg. Chim. Acta 1996 243 9. 578 D. A. Pearson J. Lister-James W. J. McBride D.M. Wilson L. J. Martel E. R. Civitello J. E. Taylor B. R. Moyer and R. T. Dean J. Med. Chem. 1996 39 1361. 579 K. L. Cunningham and D. R. McMillin Polyhedron 1996 15 1673. 580 H. Plenio and C. Aberle Chem. Commun. 1996 2123. 581 C. Guillon and P. Vierling J. Organomet. Chem. 1996 506 211.582 R. Sanders and U. T. Mueller-Westerho§ J. Organomet. Chem. 1996 512 219. 583 T.-Y. Dong and L.-L. Lai J. Organomet. Chem. 1996 509 131. 584 J.-G. Rodriguez A. Onate R. M. Martin-Villamil and I. Fonseca J. Organomet. Chem. 1996 513 71. 585 G. Iftme C. Moreau-Bossuet E. Manoury and G. A. Balavone Chem. Commun. 1996 527. 586 T. Sammakia and H. A. Latham J. Org. Chem. 1996 61 1629. 246 G.R. Stephenson 587 K. H. Ahn C.-W. Cho H.-H. Baek J. Park and S. Lee J. Org. Chem. 1996 61 4937. 588 J. Park S. Lee K. H. Ahn and C.-W. Cho Tetrahedron Lett. 1996 37 6137. 589 M. Tsukazaki M. Tinkl A. Roglans B. J. Chapell N. J. Taylor and V. Snieckus J. Am. Chem. Soc. 1996 118 685. 590 Y. Nishibayashi Y. Arikawa K. Ohe and S. Uemara J. Org. Chem. 1996 61 1172. 591 D. Enders R. Lochtman and G.Raabe Synlett 1996 126. 592 L. Schwink and P. Kno� chel Tetrahedron Lett. 1996 37 25. 593 W. Henderson A. G. Oliver and A. J. Downard Polyhedron 1996 15 1165. 594 J.-T. Wang X. Feng L.-F. Tang and Y.-M. Li Polyhedron 1996 15 2997. 595 A. J. Locke and C. J. Richards Tetrahedron Lett. 1996 37 7861. 596 B. Jedlicka R. E. Ru� lke W. Weissensteiner R. Ferna� ndez-Gala� n F.A. Jalo� n B.R. Manzano J. Rodrý�guez-de la Fuente N. Veldman H. Kooijman and A. L. Spek J. Organomet. Chem. 1996 516 97. 597 Y. Nishibayashi K. Segawa J. D. Singh S. Fukazawa K. Ohe and S. Uemura Organometallics 1996 15 370. 598 Y. Nishibayashi K. Segawa H. Takada K. Ohe and S. Uemura Chem. Commun. 1996 847. 599 W. Zhang T. Kida Y. Nakatsuji and I. Ikeda Tetrahedron Lett. 1996 37 7995. 600 B. F. M. Kimmich C.R. Landis and D. R. Powell Organometallics 1996 15 4141. 601 P. E. M. Siegbahn J. Am. Chem. Soc. 1996 118 1487. 602 V.M. Mamaev I. P. Gloriozov V. V. Simonyan A. V. Prisyajnyuk and Y. A. Ustyuyk Mendeleev Commun. 1996 146. 603 F. J. Safarowic and J. B. Keister Organometallics 1996 15 3310. 604 J. Belli and C. M. Jensen Organometallics 1996 15 1532. 605 D. B. Grotjahn and H. C. Lo J. Am. Chem. Soc. 1996 118 2097. 606 D. Heller H. Buschmann and H.-D. Scharf Angew. Chem. Int. Ed. Engl. 1996 35 1852. 607 E. T. Singewald X. Shi C. A. Mirkin S. J. Schofer and C. L. Stern Organometallics 1996 15 3062. 608 M. Ballhorn M. G. Partridge R. N. Perutz and M. K. Whittlesey Chem. Commun. 1996 961. 609 C. J. Sleigh S. B. Duckett and B. A. Messerle Chem. Commun. 1996 2395. 610 T. Lian S. E. Bromberg H.Yang G. Proulx R. G. Bergman and C. B. Harris J. Am. Chem. Soc. 1996 118 3769. 611 C. P. Casey W.T. Boese R. S. Carino and P. C. Ford Organometallics 1996 15 2189. 612 G.M. Drienzo P. S. White and M. Brookhart J. Am. Chem. Soc. 1996 118 6225. 613 K. Nakatani M. Wakabayashi K. Chikama and N. Kiramura J. Phys. Chem. 1996 100 6749. 614 D. L. Hughes J. F. Payack D. Cai T. R. Verhoeven and P. J. Reider Organometallics 1996 15 663. 615 F. Squizani E. Stein and E. J. S. Vichi J. Braz. Chem. Soc. 1996 7 127. 616 K. I. Szabo� Organometallics 1996 15 1128. 617 S. Camanyes F. Maseras M. Moreno A. Lledo� s J.M. Lluck and J. Berbra� n J. Am. Chem. Soc. 1996 118 4617. 618 F. Maseras and A. Lledo� s Organometallics 1996 15 1218. 619 K. Wisniewski Z. Pakulski A. Zamojski and W.S. Sheldrick J.Organomet. Chem. 1996 523 1. 620 R. H. Herber E. Bauminger and I. Felner J. Chem. Phys. 1996 104 7. 621 M.-J. Arce A. L. Viado S. I. Khan and Y. Rubin Organometallics 1996 15 4340. 622 H. Werner R. Wiedemann N. Mahr P. Steinert and J. Wolf Chem. Eur. J. 1996 2 561. 623 P. Belanzoni N. Re M. Rosi A. Sgamellotti and C. Floriani Organometallics 1996 15 4264. 624 J. Grobe D. Le Van F. Immel M. Hegemann B. Krebs and M. La� ge Z. Anorg. Allg. Chem. 1996 622 24. 625 T. Lehotkay K. Wurst P. Jaitner and F. R. Kreissl J. Organomet. Chem. 1996 523 105. 626 E. M. Vogl J. Bruckmann C. Kru� ger and M. W. Haenel J. Organomet. Chem. 1996 520 249. 627 J. El Amouri and Y. Besace Organometallics 1996 15 1514. 628 S. Ito N.Morita and T. Asao J. Org. Chem. 1996 61 5077. 629 W. Tully L. Main and B. K. Nicholson J.Organomet. Chem. 1996 507 103. 630 F. Maseras A. Lledo� s M. Costas and J. M. Poblet Organometallics 1996 15 2947. 631 J. E. McGrady R. Stranger M. Brown and M.A. Bennett Organometallics 1996 15 3109. 632 R. H. Mitchell and Y. Chen Tetrahedron Lett. 1996 37 6665. 633 R. L. Beddoes Z. I. Hussain A. Roberts C. R. Barraclough and M. W. Whiteley J. Chem. Soc. Dalton Trans. 1996 3629. 634 R. Malet M. Moreno-Man8 as T. Parella and R. Pleixats J. Org. Chem. 1996 61 758. 635 K. J. Szabo J. Am. Chem. Soc. 1996 118 7818. 636 D. Braga and F. Grepioni Chem. Commun. 1996 571. 247 Organometall

ISSN:0069-3030    

DOI:10.1039/oc093197

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

8 Synthetic methods By N. J. LAWRENCE Department of Chemistry UMIST PO Box 88 Manchester UK M60 1QD 1 Introduction The predominant theme of new synthetic methods this year has been the development of cleaner reactions and transformations. Methods that detail asymmetric catalysis and selective processes have as in recent years been prominent in 1996. The importance of such methods is highlighted in two reviews covering the industrial manufacture of enantiomerically pure pharmaceuticals and agrochemicals.1,2 The number of reports describing combinatorial chemistry and organic chemistry on solid supports3 has increased this year and has included some very useful reviews.4,5 An excellent collection of reviews provides an interesting overview of many frontiers in organic synthesis.6 Specialist reference works published in 1996 include volume 487 of Organic Reactions which reviews asymmetric epoxidation of allylic alcohols the Katsuki–Sharpless epoxidation reaction,7a and radical cyclisation reactions.7b Books covering synthetic methods published this year include those on asymmetric synthesis;8,9 organic synthesis; 10 organosulfur reagents;11 total synthesis;12 b-amino acid synthesis;13 palladium reagents;14 organozinc reagents.15 2 Carbon–carbon bond formation The nucleophilic allylation of aldehydes and ketones is a reaction that has seen great attention over the period covered by this review.Many of these methods involve asymmetric allylation,16 a topic that has been reviewed this year. For example Kobayashi and co-workers have developed a very e¶cient protocol for the asymmetric allylation of aldehydes using phosphoramides as substoichiometric catalysts.17 The best results were obtained for the reaction of benzaldehyde and allyltrichlorosilane with the catalyst 1 derived from (S)-proline (Scheme 1a).Kobayashi et al. have also found that the trichloroallylsilane 3 is a useful precursor in the synthesis of a- methylene-c-lactones 5 (Scheme 1b).18 The allylsilane 3 was prepared from methyl a-(bromomethyl)acrylate 2 in the presence of copper(I) chloride and diisopropylamine. The intermediate 3 reacts with aldehydes to give the corresponding a-methylene-c- hydroxy esters 4 which readily cyclise to the lactones 5 upon treatment with acid. It is not often that reports appear describing asymmetric catalysis using a silver Royal Society of Chemistry–Annual Reports–Book B 249 Cl3Si Ph OH N P N Pri 2N O CO2Me Br CO2Me SiCl3 R OH CO2Me O O R PhCHO (10 mol%) –78 °C 168 h 83% 88% ee HSiCl3 cat.CuCl 2 3 RCHO DMF–CH3CN 0 °C 5 71% for R = Ph H+ 4 Pri 2NEt Et2O (a) (b) 1 Scheme 1 SnBu3 Ph OH PhCHO ( R)-BINAP•AgOTf (5 mol%) –20 °C THF 75% 92% ee Scheme 2 catalyst. However a particularly e¶cient process for the catalytic asymmetric allylation of aldehydes using a chiral silver(I) complex has been described by Yamamoto and co-workers.19 Having screened a range of metal catalysts and found that the e¶ciency of the silver trifluoromethanesulfonate (triflate)-catalysed allylation of benzaldehyde is greatly improved by the presence of triphenylphosphine the group developed an asymmetric process. The catalyst BINAP·AgOTf prepared from 2,2@-bis(diphenylphosphino)- 1,1@-binaphthyl (BINAP) and silver(I) triflate gives the highest enantioselectivity in the reaction of methallyltributyltin (Scheme 2).Although the catalytic mechanism has not yet been fully elucidated the BINAP·AgOTf complex is thought to act as a chiral Lewis acid rather than as a precursor to an allylsilver reagent. The enantioselective addition of tributylallylstannane to aldehydes is known to proceed particularly e¶ciently with the (R)- or (S)-BINOL (binaphthalene-2,2@-diol) and Ti(OPr*) 4 . Faller et al. have developed a cheaper alternative process that avoids 250 N. J. Lawrence Bu3Sn Ph OH Ti(OPri)4 (0.3 equiv.) PhCHO –23 °C 70 h 6 (1.1 equiv.) 7 63% 91% ee (±)-BINOL (0.2 equiv.) D-DIPT (0.3 equiv.) Scheme 3 O SiMe3 O NH Ph Ph COCF3 Me3SiO NH Ph Ph COCF3 O Sn O O Sn O O O CO2But CO2But Br HO HO CO2But CO2But 10 (1 equiv.) (2 equiv.) (2 equiv.) 11 95% de 89% TMSOTf (0.1 equiv.) TfOH (0.1 equiv.) 10 (b) DBUH+ DBU 8 9 (a) Scheme 4 the use of very expensive resolved BINOL.20 They showed that there is a non-linear relationship between the enantiomeric excess of the product and the BINOL catalyst.Exploiting this finding they showed that a catalyst prepared from racemic BINOL–Ti(OPr*) 4 and D-diisopropyl tartrate [(DIPT)–Ti(OPr*) 4 ] (both of which are poor catalysts on their own) was e§ective for the process (6]7) (Scheme 3). The addition of the (DIPT)–Ti(OPR*) 4 poison appears to deactivate the (R)-BINOLderived catalyst far more e§ectively than the (S)-BINOL-derived catalyst. Mazaleyrat and Wakselman have developed a new procedure for the resolution of BINOL and 2,2@-bis(bromomethyl)-1,1@-binaphthalene.The diastereoisomeric ethers from the Williamson reaction of these compounds can easily be separated by crystallisation or chromatography; the parent compounds can be regenerated by treatment with boron tribromide.21 The chiral allylating reagent 9 readily generated in situ from the benzodioxastannole 8 allyl bromide (])-di-tert-butyl tartrate and 1,8-diazabicyclo[5.4.0]undec-7- ene (DBU) smoothly reacts stoichiometrically with aromatic aldehydes at [78 °C in the presence of a catalytic amount of a copper salt to a§ord the corresponding homoallylic alcohols in high yields with high enantioselectivities (Scheme 4a).22 The 251 Synthetic methods BaCl Ph H NBn NHBn Ph NHBn Ph a at 0 °C 74% a:g >99:1 at –78 °C 94% a:g <1:99 g Scheme 5 new 2-amino alcohol derivative 10 and its application in the stereoselective allylation of ethyl methyl ketone has been described by Tietze et al.23 The allylation of ethyl methyl ketone with allyltrimethylsilane is catalysed by 10 allowing the synthesis of tert-homoallylic ether 11 with high enantio- and diastereo-selectivity (de 89%) (Scheme 4b).Many non-asymmetric allylation procedures have been developed in the past year. For example Aggarwal and Vennall24 have found that scandium triflate (2–10 mol%) is a highly e¶cient catalyst for the addition of allyltrimethylsilane to both aromatic and aliphatic aldehydes. Kobayashi and Nagayama have shown that scandium(III) chloride supported on Nafion (NR-50) catalyses the allylation of aldehydes with tetrallylstannane in a continuous flow system.25 Young and co-workers also describe a convenient allylation procedure.26 They have found that tetrallyltin adds to aldehydes in methanol at 30 °C with no additional catalysts.Tin-mediated addition of allylic bromides to aldehydes leads to adducts with high diastereo- and diastereo-facial selectivity in the presence of indium trichloride in water.27 Trehan and co-workers demonstrate that the Brønsted acid bis(fluorosulfuryl)imide catalyses the addition of allyltrimethylsilane to carbonyl compounds.28 The e§ective allylation of aldehydes ketones and imines is accomplished by allylic tributyltin species in the presence of SnCl 2 in acetonitrile solution.29 Aldimines are transformed into homoallylic amines by treatment with allylbarium reagents.30 The a- and c-adducts are selectively obtained by simply changing the reaction temperature; the a-adduct is favoured at 0 °C while the c-adduct is favoured at[78 °C (Scheme 5).A mild and simple zinc-promoted Barbier-type allylation of aromatic aldehydes in liquid ammonia has been published by Makosza and Grela.31 The authors comment that procedures involving liquid ammonia are often considered inconvenient; however they argue that their procedure is simple and convenient. The ammonia is introduced into a cold reaction flask (dry ice–acetone) and the reaction temperature is kept constant at [33 °C by allowing the ammonia to evaporate slowly. The use of ammonia on a large scale is also convenient since it is cheap readily available and easily recycled. Whitesell and Apodaca detail a procedure for the allylation of aldehydes with allyltributyltin in the presence of 10mol% dibutyltin dichloride and either an acid chloride or trimethylsilyl chloride.Homoallylic esters carbonates trimethylsilyl ethers and alcohols were obtained in up to 99% yield.32 The use of bis(penta- fluorophenyl)tin dibromide as a catalyst for the same reactions has been described by Otera and co-workers.33 252 N. J. Lawrence Ph H O HO Ph ButOK (10 mol%) DMSO 70% Scheme 6 The Lewis acid-mediated reaction of an aldehyde with allylstannanes and allylsilanes is usually faster than the reaction of the corresponding imine. Yamamoto and co-workers outline a reaction with the entirely opposite chemoselectivity.34 They found that imines are allylated chemoselectively in the presence of aldehydes using allylstannanes with a p-allylpalladium chloride dimer catalyst.Kang and co-workers report the palladium-catalysed carbonyl allylation of aldehydes with allylic phosphates35 and diethylzinc in the presence of catalytic Pd(PPh 3 ) 4 probably via addition of a nucleophilic allylzinc species to the aldehyde. Several new methods involving the nucleophilic addition of alkynes to carbonyl compounds have appeared this year. A useful procedure for the addition of terminal alkynes to ketones has been devised by Babler et al.36 Examination of the equilibrium acidities in DMSO of phenylacetylene (pKa \28.7) and tert-butyl alcohol (pKa \32.2) indicated that potassium tert-butoxide would be a good choice in the alkynylation reaction. This turned out to be true (Scheme 6).Indeed since the product of the addition to the ketone is initially a tertiary alkoxide the base can be used catalytically. The procedure clearly has advantages over the strong bases used traditionally to facilitate this transformation. Yoon and co-workers have found that sodium trimethyl(ethynyl)aluminate (STEA) prepared from sodium acetylide and trimethylaluminium is an excellent chemoselective reagent for the addition of acetylide anion to ketones and aldehydes.37 The reagent did not react with representative alkyl or benzyl halides epoxides amides or nitriles at room temperature or esters at 0 °C. Zwierzak and Tomassy report a procedure for the reaction of alkynylmagnesium bromides with paraformaldehyde thereby avoiding the use of gaseous formaldehyde. 38 An excellent method for the enantioselective synthesis of alcohols involves the asymmetric catalytic addition of an organometallic reagent usually organozinc to an aldehyde.This area of research is proving as popular as ever (Fig. 1). Some of the new catalysts used to promote the addition of diethylzinc to aldehydes include the diselenide 11 the proline-derived b-amino disulfide 12,39 the oxazolidine derivative 13,40 the oxazolidine 14 derived from the natural product abrine41 and the zinc alkoxide 15.42 While much research has focused on the catalytic asymmetric addition of dialkylzinc species to aldehydes much less attention has been paid to the corresponding addition to imines. This is somewhat surprising in view of the synthetic importance of enantio pure amines. This year Andersson et al. have investigated the addition of diethylzinc to the diphenylphosphinoylimine 16.43 The aziridino alcohol 18 was the ligand that gave the best enantioselectivity in the synthesis of the phosphinoylamine 17 (Scheme 7).The use of alkylzinc chemistry for the highly e¶cient enantioselective catalytic asymmetric automultiplication of chiral pyrimidine alcohol 20 has been impressively described by Soai and co-workers.44 This is a rare case of a catalytic reaction that uses 253 Synthetic methods Se)2 N S S N Me N Me NH O Ph Ph HO NH MeN O nPr Ar Ar O O Ph Ph Zn 11 ( S) 1 mol% 91% 98% ee 12 ( R) 2.5 mol% 76% 86.6% ee 13 ( S) 6 mol% 95% 100% ee 14 ( S) 10 mol% 58% 60% ee 15 ( R) 10 mol% 89% 98% ee Fig. 1 Selectivity in the addition of ZnEt 2 to PhCHO [configuration of PhCH(OH)Et catalyst mol% yield ee] Ph O P N Ph Ph Ph O P HN Ph Ph N OH CH2Ph 16 17 63% 94% ee Et2Zn 18 (1 equiv.) 18 Scheme 7 the product as catalyst.In such reactions separation of the product and catalyst is clearly not an issue. In addition once the first reaction has been performed the catalyst will be readily available. Soai and his group found that the addition of diisopropylzinc to pyrimidine-5-carbaldehyde is catalysed by the product of the reaction the alcohol 20. When the reaction is performed with enantio-enriched 20 (93.4% ee) the stereoreplication is highly e¶cient giving the product 20 with the similar enantio purity (90.8% ee) (Scheme 8a). The process recently highlighted,45 has been described as a paradigm for the origin of the homochirality of natural biomolecules since it was found that when 20 (5% ee) is used as the catalyst the product alkanol has an enantiomeric excess of 39%.46 The process therefore provides a mechanism by which a small initial imbalance in chirality can become overwhelming.The same principle of asymmetric autocatalysis has been demonstrated in the reaction of diisopropylzinc with quinoline- 3-carbaldehyde.47,48 Another organozinc reagent the carbenoid species XZnCFBr 2 prepared by treatment of tribromofluoromethane with diethylzinc reacts smoothly and chemoselectively with aldehydes (Scheme 8b).49 The method described by Shimizu and co-workers is a good one for the synthesis of a a-dibromofluoromethyl alcohols. Secondary and 254 N. J. Lawrence N N H O N N N N OH Bun H O O Bun CFBr2 O OH 20 (93.4% ee) (20 mol%) Pri 2Zn 0 °C 19 20 79% (90.8% ee) CFBr3 Et2Zn (a) 69% (b) OH DMF –60 °C 14 h Scheme 8 Scheme 9 tertiary alkylzinc bromides have been found to add conjugatively to a,b-unsaturated ketones in the presence of trimethylsilyl chloride and BF 3 ·OEt 2 without a copper catalyst.50 Greeves and Pearce have illustrated in two reports that novel organocerium reagents incorporating TADDOL (a,a,a@,a@-tetraaryl-1,3-dioxolane 4,5-dimethanol) can be used to generate enantiomerically enriched alcohols from aldehydes.It was found that the tris(TADDOL) derivative 21 can be used to add a butyl group to aldehydes with enantioselectivity (Scheme 9)51 much higher than when the complex 22 with only one TADDOL ligand is used.52 Procedures that involve organocerium reagents are somewhat capricious. This behaviour is associated with the activity of anhydrous CeCl 3 which depends strongly on the drying procedure.Two reports illustrate this particularly well. Dimitrov et al. have shown that deactivation of CeCl 3 occurs during the drying process as a result of hydrolysis by the hydrate water when heating above 90 °C. The highly active CeCl 3 prepared by an improved drying procedure (sequential heating at 50 °C 4 h; 60 °C 4 h; 70 °C 5 h; 80 °C 7 h; and 140 °C for 20 h at 0.05–0.01 Torr) is demonstrated to activate rapidly (in catalytic and stoichiometric amounts) ketones at room temperature providing excellent addition of 255 Synthetic methods R OSO2CF3 O O O H O O R OH i. CrCl2 (15 mol%) ii. TBAF 80% Mn TMSCl Scheme 10 Scheme 11 organometallic reagents.53 Dehydration of CeCl 3 (H 2 O) 7 by the usual procedures (150 °C at 0.03 Torr for 12 h) has been shown by X-ray di§raction studies to produce [CeCl 3 (H 2 O)]n.54 The evident di¶culties in obtaining anhydrous CeCl 3 may explain the unpredictable reactivity sometimes encountered in its use.The Nozaki–Hiyama–Kishi coupling of organochromium compounds to aldehydes provides a powerful method for the synthesis of alcohols. However the toxicity of chromium salts greatly reduces the attractiveness of this reaction for large-scale applications. Fu� rstner and Shi have devised a modified process that involves a catalytic amount of chromium chloride [doped with nickel(II) chloride] and stoichiometric manganese (Scheme 10).55 Many important procedures concerning the aldol reaction have been published in the past year. Denmark et al.report a new system for e§ecting catalytic asymmetric aldol reactions. They have found that trichlorosilyl enolates (derived from tributylstannyl enolates and silicon tetrachloride) are highly reactive in the chiral phosphoramide- catalysed asymmetric aldol reactionScheme 11).56 For example the trichlorosilyl enolate 23 derived from cyclohexanone reacts in the presence of the phosphoramide 25 with (E)-cinnamaldehyde to give the anti-aldol product 24 with excellent diastereoselectivity and high enantioselectivity. Evans et al. have developed an excellent asymmetric variant of the Mukaiyama aldol reaction of a-benzyloxy aldehydes 26 (Scheme 12).57 This type of aldehyde reacts with trimethylsilylketene acetals in the presence of the C 2 -symmetric copper(II) complex 27 with exceptionally high enantioselectivity.The success of the reaction is due in part to coordination of the copper atom in a bidentate fashion by the aldehyde. The 256 N. J. Lawrence BnO H O OEt OTMS BnO OH O OEt N N Cu N O O Ph Ph 99% 98% ee 27 (0.5 mol%) –78 °C 26 2+ (SbF5)2 27 Scheme 12 O HN R1 O O HN R1 O R OH N N O Ph O N N O Ph O Ph OH i ii 28 29 74% anti:syn 95:5 30 31 de 84% iii iv (b) (a) R1 = p-MeC6H4SO2 R = Ph Scheme 13 Reagents i TiCl 4 Pr* 2 NEt 23°C; ii RCHO TiCl 4 CH 2 Cl 2 [78°C; iii TiCl 4 Pr* 2 NEt 0°C; iv PhCHO,[78°C. indium trichloride-catalysed Mukaiyama aldol reaction has been reported by Loh et al.58 They found that ketone trimethylsilyl enol ethers react in water with aldehydes in the presence of indium(III) chloride (20 mol%) to a§ord the corresponding aldol products in good yields.The ever e§ective Lewis acid scandium triflate catalyses the aldol reaction of polymer-supported silyl enol ethers with aldehydes providing a convenient method for the preparation of b-hydroxy ester libraries.59 The use of the cis-1-aminoindan-2-ol as an auxiliary for the synthesis of enantiomerically pure anti-aldol products (Scheme 13a) has been described by Ghosh and Onishi.60 The reaction of the (Z)-titanium enolate of 28 with aldehydes is both highly diastereo- and enantio-selective. The methodology provides convenient access to either anti-aldol enantiomer 29 since both enantiomers of cis-1-aminoindan-2-ol from which 28 is derived are commercially available. Palomo et al. have shown that the chiral imide acetamide 30 reacts on lithium and titanium enolate formation with 257 Synthetic methods OMe OMe O SMe MgBr N MeO O Cl Me MeS O Cl Br Ph O (a) (PriO)2Ti(NTf2)2 (5 mol%) (b) 34 90% i.ii. 2 M HCl 33 32 i. Zn Et2O ii. PhCH2COCl (c) 92% Ac2O MeNO2 room temp 10 min Scheme 14 aldehydes in a stereoselective manner (Scheme 13b).61 For example the reaction of the lithium enolate with benzaldehyde (30]31) provides a rare example of a stereoselective reaction of a chiral enolate that bears no a-substituents other than hydrogen. An important carbon–carbon bond forming reaction involves the acylation of carbon nucleophiles. Tillyer et al. report62 a simple high yielding synthesis of a-chloro ketones 34 by the reaction of organometallic reagents with N-methoxy-N-methylchloroacetamide a process pioneered by Wienreb. Addition of Grignard and organolithium reagents to N-methoxy-N-methylchloroacetamide 32 prepared by the Schotten–Baumann reaction of N,O-dimethylhydroxylamine and chloroacetyl chloride gives after acidic work-up the corresponding chloro ketone (e.g.33]34) (Scheme 14a). The e¶ciency of the procedure was greatly increased by the regeneration of the chloroacetamide directly by chloroacetylation of the aqueous phase using chloroacetyl chloride–K 2 CO 3 . The procedure is also e§ective for the synthesis of a-fluoro ketones from N-methoxy-N-methylfluoroacetamide. Metal bis(trifluoromethylsulfonyl)amides have been used by Mikami et al. as highly e¶cient Lewis acid catalysts for the Friedel–Crafts acylation of arenes (Scheme 14b).63 Unlike most of the existing catalysts used to accomplish this type of reaction the bistriflylamides of aluminium titanium and ytterbium can be used in substoichiometric quantities.The same research group have also found that lithium perchlorate greatly accelerates the scandium or ytterbium triflate-catalysed Friedel–Crafts reactions. The mixture of rare-earth triflate and lithium perchlorate is easily recovered from the reaction mixture by simple extraction and can be reused without a decrease in its catalytic activity.64 The combined catalyst system TiCl(OTf) 3 and TfOH developed by Izumi and Mukaiyama also e§ects e¶cient Friedel–Crafts acylation of aromatic compounds.65 The reaction of an acid chloride allyl bromide and commercial zinc dust in diethyl ether conveniently generates b,c-unsaturated ketones (Scheme 14c).66 A facile synthesis of conjugated acetylenic ketones involving copper(I)-catalysed acyla- 258 N.J. Lawrence Ph OH O Ph O O O O Ph O Et Ph Li (5.6 equiv.) naphthalene (10 mol%) BusCl (1.2 equiv.) 75% (a) EtMgBr CH2Cl2 (b) 88% Scheme 15 O O CHO N N OMe i. TDSOTf THF –78 °C 35 ii. TBAF iii. HCl 78% >98% ee Scheme 16 tion of terminal alkynes with acyl halides is reported by Chowdhury and Kundu.67 The synthesis of a variety of ketones in moderate yield by the lithium-mediated coupling of carboxylic acids and alkyl or aromatic chlorides has been detailed by Yus and co-workers (Scheme 15a).68 Rapoport and Mattson have also devised a method for the conversion of carboxylic acids to ketones.69 They found that the addition of a Grignard reagent (100 mol%) to an acyl hemiacetal in dichloromethane generates the corresponding ketone with little tertiary alcohol formation (Scheme 15b).If desired the formation of the acyl hemiacetal and Grignard addition can be carried out in the same pot. An interesting synthesis of enantio-enriched b-formyl ketones from a,b-unsaturated ketones (Scheme 16) has been reported by Lassaetta et al.70 This is achieved by an enantioselective Michael addition of the neutral formyl anion equivalent 35. The addition of the formaldehyde (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone 35 is promoted by dimethylthexylsilyl (TDS) triflate. Trehan and co-workers have found thatN-trimethylsilyl bis(fluorosulfonyl)imide 36 is an e¶cient catalyst for the addition of trimethylsilyl cyanide to ketones and aldehydes to give cyanohydrins (Scheme 17).71 In the presence of 36 (1 mol%) trimethylsilyl cyanide adds e¶ciently to carbonyl compounds to give the corresponding O-trimethylsilyl cyanohydrin.The imide 36 is a more e§ective catalyst for the reaction than trimethylsilyl triflate. A combination of dibutyltin dichloride and diphenyltin dichloride also functions as an e§ective catalyst for the trimethylsilylcyanation of aldehydes and ketones.72 Numbered among the various catalysts that have been used for the asymmetric trimethylsilylcyanation of aldehydes are the (salen) complexes 3773 and 38;74 (Fig. 2) both of which are used in combination with Ti(OPr*) 4 . 259 Synthetic methods O 36 (1 mol%) TMSCN (1.1 equiv.) –78°C TMSO CN FSO2 SO2F N TMS 36 98% Scheme 17 OH N N HO Ph Ph N N HO OH 38 ( R) 84% ee 37 ( S) 68% ee Fig. 2 Enantioselectivities in the addition of TMSCN to PhCHO with Ti(OPr*) 4 (configuration of the product TMS cyanohydrin ee) A convenient method for the synthesis of enantiomerically enriched bicyclic alcohols has been described by Hodgson and Lee.75 They found that the enantioselective a-deprotonation–rearrangement of medium-sized cycloalkene oxides can be achieved using organolithium reagents in the presence of stoichiometric amounts of ([)-sparteine (e.g 39]40) (Scheme 18a).The methylaluminoimidazoline 43 has been used by Kocienski and co-workers to catalyse the enantioselective [2]2] cycloaddition of (trimethylsilyl)ketene to aldehydes (Scheme 18b).76 The process (41]42) is a useful asymmetric route to b-lactones. Alkene and alkyne synthesis Several reports have appeared this year detailing new ways to make alkenes via Wittig methods.An interesting review of asymmetric Wittig-type reactions has also appeared. 77 Patil and Ma� vers found that the Wittig reaction between aldehydes and ethoxycarbonylmethylene(triphenyl)phosphorane can be carried out in hexane in the presence of silica gel.78 This protocol is a convenient method for the synthesis of (E)-a,b-unsaturated esters. The silica gel both accelerates the reaction a absorbs the triphenylphosphine oxide by-product. The product ester can be obtained pure by simply filtering the reaction mixture. The use of ethylmagnesium bromide as the base in the Wittig reaction has been investigated by Shen and Yao.79 The reaction of benzylidene(triphenyl)phosphorane derived in this manner with the a variety of aldehydes has been shown to be highly stereoselective in the synthesis of (E)-alkenes.Two complementary methods for the conversion of an aldehyde to its corresponding N-alkenyl-N-methylformamide derivative 44 (Scheme 19) have been disclosed by Paterson et al.80 The first method involves a Wittig reaction of the phosphonium salt 45 to produce the (Z)-formamide 44 as the major product (E:Z 1.4 to 1 10). Isomerisa- 260 N. J. Lawrence (a) (b) O H H OH R H O O O SiMe3 R Ph Ph N Al N X X Me Me3Si C O 39 PriLi (2.4 equiv.) 40 97% 77% ee (0.3 equiv.) 43 41 R = p-MeOC6H4CH2 42 X = 2,6-(CH3)2-4-Bu tC6H2SO2 77% 83% ee (–)-sparteine (2.5 equiv.) Scheme 18 Scheme 19 tion to the (E)-alkene is achieved by treating the alkene with molecular iodine (5 mol% CH 2 Cl 2 20 °C) in the absence of light. The second method involves the acid-catalysed condensation of the aldehyde with the N-methylformamide.Phosphorus pentoxide is the best catalyst serving both as acid and dehydrating agent. An excellent review of the stereocontrol imparted by the diphenylphosphoryl group in the Horner–Wittig olefination was published this year.81 The Horner–Wittig reaction has been used by Liu and Schlosser in the synthesis of trans alkenes. They found that the reaction of the anions derived from alk-2-enyldiphenylphospine oxides react with aldehydes with excellent trans selectivity (e.g. 46]47) (Scheme 20).82 The same excellent trans selectivity was also observed in the Horner–Wittig reaction of alk-2- enylphosphonates.83 An Organic Syntheses article describing the synthesis of bis(trifluoroethyl)phosphonate a Horner–Wadsworth–Emmons reagent particularly useful for the synthesis of (Z)-alkenes appeared this year.84 Miyaura and co-workers85 have used the boron–Wittig reaction to prepare alkenes from aldehydes and Knochel-like (dialkoxyboryl)methylcopper reagents (Scheme 21).The in situ preparation of 49 from Knochel’s (dialkoxyboryl)methylzinc reagent 48 and 261 Synthetic methods Ph2P O CHO i. Bu nLi ii. 46 47 71% E:Z 96:4 Scheme 20 B O O IZn(CN)Cu CHO B O O F2BO HO OH 48 BF3•OEt2 heat H2O2 NaOH 50 84% 51 90% 49 Scheme 21 CuCN·2LiCl in THF followed by its addition to aldehydes in the presence of boron trifluoride–diethyl ether yielded the rather stable b-hydroxyalkylboronate derivative 49. The thermally promoted boron–Wittig reaction or the alkaline hydrogen peroxide oxidation of 49 gave the corresponding alkenes 50 or alkane-1,2-diol 51 in high yields.The reaction provides a very simple procedure for the olefination or the hydroxymethylation of aldehydes. A general and convenient synthetic method to produce geometrically pure (Z)-1- bromoalk-1-enes 53 has been developed by Uenishi et al. (Scheme 22).86 Palladiumcatalysed hydrogenolysis of 1,1-dibromoalk-1-enes 52 by tributyltin hydride proceeds smoothly to give (Z)-1-bromoalk-1-enes 53 with excellent stereoselectivity in good yields. Dibromomethylenation of aldehydes by a combination of CBr 4 and PPh 3 in methylene chloride and the successive hydrogenolysis a§ords the (Z)-1-bromoalk-1- enes 53 in a one-pot procedure. The protocol has been applied to the stepwise and one-pot synthesis of enediynes and dienynes.87 262 N. J.Lawrence R Br Br R Br cat. Pd(Ph3)4 52 53 Z E >98 2 Bu3SnH Scheme 22 R1 R2 N N Ph R1 R2 R1 R2 N N Ph Li R1 R2 Li LDA (0.3 equiv.) –20 °C 1 h; 0 °C 3 h 54 84% cis:trans 99.4:0.6 55 R1 = n-CH3(CH2)4 R2 = n-CH3(CH2)3 56 Scheme 23 An intriguing synthesis of alkenes from the N-(2-phenylaziridin-1-yl)imine derivative of ketones is illustrated in Scheme 23.88 This catalytic Shapiro reaction devised by Yamamoto and co-workers is e§ected by a substoichiometric quantity of LDA. The high levels of cis stereoselectivity and regioselectivity are explained by a-deprotonation of the hydrazone 54 to give the organolithium derivative 55 which decomposes to the vinyllithium species 56 with the extrusion of styrene and nitrogen. The LDA is regenerated from the diisopropylamine formed in the first step and the vinyllithium 56.Taber et al. have shown that a-diazo ketones undergo b-hydride elimination with rhodium(II) trifluoroacetate to produce (Z)-a,b-unsaturated ketones in high yield (57]58) (Scheme 24a).89 This constrasts with the rhodium(II) acetate-catalysed reaction which also produces carbocycles from a competing 1,5-insertion process. Terminal alkenes can be prepared in useful yields via a [2,3]-Wittig type fragmentation by the treatment of benzyl ethers with n-butyllithium (e.g. 59]60) (Scheme 24b).90 Bandgar and co-workers have found that the Envirocat EPZG' is also an e¶cient and environmentally benign catalyst for the synthesis of conjugated nitroolefins via the Henry reaction of aldehydes and nitroalkanes (Scheme 24c).91 Alkenes are obtained via b-elimination of water when tertiary alcohols are treated with oxalyl chloride triethylamine and dimethyl sulfoxide.92 Unfortunately the process shows little regioselectivity.It has long been known that the addition of the anion of dimethyl diazomethylphosphonate 61 (which has seen an improved synthesis this year93) to aldehydes generates alkynes. Bestmann and co-workers94 have developed an improved one-pot procedure for the synthesis of terminal alkynes (62]63) from aldehydes using the phosphonate 64 (Scheme 25). The one-pot procedure is high yielding under very mild conditions without requiring low temperatures or inert gas techniques and avoids the use of strong bases. The anion of 61 is generated in situ by mild base-promoted acyl cleavage 263 Synthetic methods Envirocat EPZG® 90% O O H O NO2 (c) n-C7H15 O N2 n-C7H15 O Rh2(O2CCF3)4 58 92% Z:E >95:5 57 (a) Bn O (CH2)8OTBS 90% (CH2)8OTBS BunLi 59 60 (b) CH2Cl2 –78 °C MeNO2 100 °C Scheme 24 Scheme 25 of 64.The procedure is likely to be a valuable alternative to the commonly used Corey–Fuchs dibromomethylenation–elimination protocol. 3 Reduction The development of new reagents for the e¶cient reduction of aldehydes and ketones has featured widely this year. For example Kobayashi et al. report that a combination of trichlorosilane and dimethylformamide e¶ciently reduces aldehydes and imines.95 The reagent system also e§ects reductive amination of aldehydes under mild conditions. Hypervalent hydridosilicates generated by the coordination ofDMFto Cl 3 SiH are the active reducing species and enable e¶cient and selective reduction under mild conditions.An aryl chloride and nitro groups and carbon–carbon double and triple bonds are tolerated by the system. Uemura and co-workers also describe the reduction 264 N. J. Lawrence Ph O Ph OH Ph OH PPh2 N O Ph Ph ( R) 100% 91% ee ( S) 100% 96% ee Ph2SiH2 [Rh(COD)Cl]2 ( S)-DIPOF 65 Et2O 25 °C Ph2SiH2 [Ir(COD)Cl]2 ( S)-DIPOF 65 Et2O 25 °C Fe ( S)-DIPOF 65 Scheme 26 of ketones using a silane but in this case the reaction is asymmetric. They found that the chiral oxazolylferrocenylphosphine hybrid ligand (DIPOF) 65 is a very e¶cient ligand for the iridium(I)-catalysed asymmetric hydrosilylation of simple ketones (Scheme 26).96 Iodotrichlorosilane prepared in situ from SiCl 4 –NaI e§ects the chemoselective reduction of a,b-unsaturated ketones to their saturated counterparts.97 Similarly Cu–SiO 2 can be conveniently used for the hydrogenation of conjugated enones to saturated ketones in the presence of isolated alkene functionality present within the same molecule.98 Molecular hydrogen or propan-2-ol can also be used as the hydrogen source. The H 2 –Lindlar catalyst system has been found to be highly e§ective for the reduction of carbon–carbon double bonds of a,b-unsaturated carbonyl compounds.99 Both Williams100 and Helmchen101 and their co-workers have described the rhodium- catalysed asymmetric reduction of ketones using phosphorus-containing oxazoline ligands. The rhodium-catalysed hydrosilylation of acetophenone in the presence of the oxazolinyl phosphine ligand 66 proceeds with good enantioselectivity (Scheme 27).Asymmetric protocols using oxazaborolidine catalysts have seen widespread use for the borane reduction of ketones. Among many new catalysts introduced over the past year are the pinene-derived oxazaborolidine 67,102 the oxazaphospholidine oxide 68103 and the thiol 69 (Fig. 3).104 The use of diphenyloxazaborolidine for enantioselective reduction of ketones has been reviewed.105,106 The same monograph contains a comparative review of the use of tartrate TADDOL and binaphtholate-derived ligands for the enantioselective LiAlH 4 reduction of ketones.107 The asymmetric hydrosilylation of ketones using triethoxysilane and (R)-BINOL–Ti(OPr*) 2 as a catalyst occurs in excellent yield and moderate enantioselectivity (70]71) (Scheme 28a).108 The combination of BINOL–Ti(OPr*) 4 provides an excellent catalyst for the reduction of aldehydes with Bu 3 SnD (Scheme 28b).109 The method provides an excellent way for the synthesis of chiral primary alcohols.265 Synthetic methods 66 Ph O Ph OH i. [Rh(COD)Cl]2 (1 mol%) 66 (10 mol%) Ph2SiH2 (4 equiv.) THF –78 °C 86% 82% ee PPh2 O N ii. HCl MeOH Scheme 27 i. 10 mol% [( S)-BINOL–Ti(OPri)4] HSi(OEt)3 70 71 (a) Ph O Ph OSi(OEt)3 ii. 92% 94% ee Ph H O DSnBu3 HO D Ph (b) ( R)-BINOL–Ti(OPri)2 Et2O Scheme 28 Fig. 3 Selectivity in the borane reduction of PhCOMea or PhCOEtb (configuration of product catalyst mol% yield ee) Prasad and Joshi have shown that the oxazaborolidinone-catalysed borane reduction of diaryl-1,2-diones leads to the corresponding enantiomerically pure 1,2-diol.110 For example benzil 72 gives (1S,2S)-dihydrobenzoin 73 (ee[99%) when treated with borane–dimethyl sulfide and the oxazaborolidine catalyst 74 (Scheme 29a).In this case the ratio of threo to erythro diastereoisomers is 88 12. The asymmetric reduction of diacylaromatic compounds has also been achieved with the B-chlorodiisopinocampheylborane provides the product diols in excellent diastereoisomeric and enantiomeric purity.111 These procedures provide useful alternatives to the Sharpless asymmetric dihydroxylation protocol. Parker and Ledeboer have revealed that the related oxazaborolidine 75 is an excellent catalyst for the borane reduction of alkynyl ketones (Scheme 29b).112 The ketones are reduced rapidly with high enantioselectivities. The process was particularly e§ective where other procedures (BINAL-H and Alpine-borane') were ine§ective due to the associated long reaction times.266 N. J. Lawrence Ph Ph O O Ph Ph HO OH N B O Ph Ph R O HO Me2S•BH3 74 (10 mol%) 72 73 85% (ee >99%) 74 R = H 75 R = Me Me2S•BH3 75 (2 equiv.) –30 °C (a) 81% (ee 98%) (b) Scheme 29 79 O N N O O O O Co O OH MeO MeO O OH 78 78 (2.5 mol%) NaBH4 EtOH 79 CHCl3 77 98% 93% ee 76 Scheme 30 The enantioselective borohydride reduction of ketones catalysed by the optically active (b-oxoaldiminato) cobalt(II) complex 78 has been remarkably improved by using a borohydride species modified with the tetrahydrofurfuryl alcohol 79 and ethanol (Scheme 30). In the presence of the complex catalyst 78 the asymmetric reduction of aromatic ketones proceeds smoothly to give the corresponding optically active alcohols in quantitative yields within 6–12 h with high enantiomeric excesses (e.g.76]77).113,114 Diisopropoxytitanium(III) tetrahydroborate is an excellent reducing agent for the chemoselective reduction of ketones.115 With this reagent cyclic ketones are reduced with excellent axial hydride delivery. a,b-Unsaturated aldehydes are reduced e¶ciently to give allylic alcohols. The reagent is prepared in situ by the reaction of diisopropoxytitanium dichloride with benzyltriethylammonium borohydride (2 equiv.). An- 267 Synthetic methods O OH N Me Me N O O NHPh PhNH Ph Ph O Ph Ph OH 80 (b) 87% 80% ee [Rh(COD)Cl]2 (5 mol%) 80 (50 mol%) PriOH ButOK 60 °C (a) syn:anti 96:4 H2 RuCl2[( p-MeOC6H4)3P]3 (0.2 mol%) H2N(CH2)2NH2 KOH Scheme 31 other borohydride reagent methyltriphenylphosphonium borohydride reduces aldehydes and ketones in dichloromethane to their corresponding alcohols in high yield; a,b-unsaturated carbonyl compounds undergo 1,2-reduction.116 A ruthenium(II) catalyst formed in situ from RuCl 2 (PPh 3 ) 3 a 1,2-diamine and potassium hydroxide in 1 1 2 molar ratio e§ects easy reduction of various ketones in propan-2-ol in 1–8 atm of hydrogen.117 The process developed by Noyori and coworkers represents a good method for the diastereoselective synthesis of alcohols.For example the reduction of 4-tert-butylcyclohexanone occurs with excellent cis selectivity (cis trans 4-tert-butylcyclohexanol 98.4 1.6). The reducing system shows excellent Cram selectivity when tris(p-methoxyphenyl)phosphine is part of the catalyst (Scheme 31a). Lemaire and co-workers found that the ligand 80 containing two urethane groups gave the best enantioselectivity in the rhodium-catalysed reduction of propiophenone using propan-2-ol as the hydrogen source (Scheme 31b).118 Rubidium- and strontium-modified L-zeolite-supported platinum catalysts are highly selective for the chemoselective hydrogenation of cinnamaldehyde to cinnamyl alcohol.119 A convenient asymmetric synthesis of a-1-arylalkylamines has been described by Burk et al.For example hydrogenation of the enamide 81 in the presence of a rhodium catalyst and the DuPHOS ligand 83 gave the amide 82 quantitatively and with excellent enantioselectivity (Scheme 32).120 Several reductive methods involving substituted tin hydrides as the active reducing species have appeared in the past year. A useful method for the conjugate reduction of a,b-unsaturated ketones using catalytic tributyltin hydride (Scheme 33a) has been disclosed by Fu and co-workers.121 A combination of phenylsilane and tributyltin hydride (cat.) in the presence of a radical initiator reduced the enone 84 to the silyl enol ether 85 from which the corresponding ketone could be generated by alkaline hydrolysis.The process has the obvious advantage of involving substoichiometric quan- 268 N. J. Lawrence NHAc NHAc P P Me Me Me Me (Me-DuPHOS)-Rh+OTf– ( S,S)-Me-DuPHOS 83 H2 (60 psi) 81 82 95.4% ee Scheme 32 O OSiPhH2 O Ph OH Ph Ph Ph O Ph Ph O Ph OH 84 85 80% i. Bu3SnH (cat.) PhSiH3 (1.2 equiv.) AIBN PhH heat Bu3SnH (10 mol%) 88 (a) 86 87 trans:cis 1.2:1 Bu2SnIH 89 47% syn:anti 4:1 (b) (c) PhCHO ii. TBAF PhSiH3 (1.2 equiv.) ButOOBut PhMe heat Scheme 33 tities of the toxic tin hydride.The same workers have also shown that the Bu 3 SnH(cat.)–PhSiH 3 system can be used to e§ect the reductive cyclisation of enals and enones (e.g. 86]87) (Scheme 33b).122 Baba and co-workers describe the use of dibutyliodotin hydride for the reduction of a,b-unsaturated ketones.123 The reagent reduces aldehydes in poor yield. This chemoselectivity can be exploited to enable aldol reactions to be carried out between a,b-unsaturated ketones and aldehydes (e.g. 88]89) (Scheme 33c). The conjugate reduction of a,b-unsaturated ketones and 269 Synthetic methods Ar H O Ar Ar HO OH Ti Cl THF Ph Et O Ph Ph Et Me Me Et (a) 88% ( dl:meso 94:6) when Ar = p-OMe 90 i. MeMgBr VCl2(TMEDA)2 91 89% meso:dl 1:1 THF:H2O (4:1) 0 °C (b) ii. O2 (0.2 equiv.) THF reflux 15 h iii.H2O Scheme 34 aldehydes is also e§ected by the combined action of the Lewis acid aluminium tris(2,6- diphenylphenoxide) and the complex DIBAlH–n-BuLi.124 The pinacol coupling of aldehydes and ketones is a particularly useful route to glycols. However most methods require rigorously dry reaction conditions and are incompatible with the protic functionality. A procedure that avoids these restrictions has been developed by Barden and Schwartz.125 They have found that reaction of titanocene chloride with the aromatic aldehydes in a mixture of THF and brine yields the corresponding 1,2-diol with very high stereoselectivity (Scheme 34a). A simple and rapid procedure for e§ecting the pinacol reaction of aromatic aldehydes has been devised by Khurana et al. The pinacol reaction is e§ected by the inexpensive combination of aluminium powder and potassium hydroxide in methanol at room temperature.126 Hindered ketones are reduced to the corresponding alcohols by the same reagent.A reaction related to the pinacol coupling reported by Kataoka and Tani and co-workers involves a new C–C single bond-forming reaction by reductive coupling mediated by a system consisting of a Grignard reagent low-valent vanadium and a catalytic amount of oxygen (Scheme 34b).127 For example the coupled product 91 is formed by reaction of the ketone 90 with methylmagnesium bromide in the presence of vanadium(II) dichloride (TMEDA) 2 . The intermediate alkoxyvanadium species undergoes reductive coupling by the action of oxygen to give 91. Examples of the synthesis of aldehydes and ketones via reductive methods are rarer than those involving the oxidation of alcohols.One example involves the use of catecholalane 92 prepared by the reaction between catechol and aluminium hydride in THF at 0 °C. It is an excellent reagent for the partial reduction of nitriles to aldehydes (Scheme 35).128 The reagent reduces aldehydes ketones esters and acid chlorides to the corresponding alcohols and primary amides to the corresponding amines.129 Several new methods for the reductive amination of aldehydes and ketones have been reported in the past year. A very useful full paper130 and review131 describing various methods for the reductive amination of aldehydes and ketones with sodium triacetoxyborohydride have been published by Abdel-Magid and co-workers. An 270 N. J. Lawrence O Al O H CN CHO 92 ii.H3O+ THF 25 °C 72 h 95% i. Scheme 35 (b) (c) R H N Ph Ph R N Ph Ph Ph H N Ph Ph Ph N Ph Ph Ph ButOK (1.2 equiv.) 97 92% ButOK (0.1 equiv.) 95 96 O OMe OMe MeO MeO OMe OMe MeO MeO NH O H HCONH2 HCO2H microwave irradiation 94 75% 93 (a) THF room temp. PhCH2Br (1.2 equiv.) THF room temp. Scheme 36 intriguing example of reductive amination has been described by Turnbull and coworkers. Treatment of 4-substituted aroyl azides with NaBH 4 –TFA leads to the corresponding novel 4-substituted N,N-bis(2,2,2-trifluoroethyl)aniline derivatives in excellent yield except where electron-withdrawing groups are present.132 The classical transformation of ketone 93 to its corresponding formamide derivative 94 the Leuckart reaction has been significantly improved by Loupy et al.133 They found that the formamides were obtained rapidly and in excellent yield when the ketone is heated with a mixture of formamide and formic acid in a microwave reactor (Scheme 36a).An e¶cient transamination protocol under mild conditions has been revealed by Cainelli Giacomini and co-workers.134 This is not really a reduction but is included here since it represents a reaction equivalent to the reductive amination of an aldehyde. The method is ideal for the transformation of aldehydes to amines via their imines 95 derived from aminodiphenylmethane (Scheme 36b). Treatment of the imine 95 with a catalytic amount of potassium tert-butoxide generates the isomerised product 96 in excellent yield. Subsequent hydrolysis with hydrochloric acid generated the amine. When the aldehyde is benzaldehyde or 2-furaldehyde the intermediate 2-azaallyl anion can be trapped with a variety of electrophiles to generate a secondary 271 Synthetic methods N H O N O Et Et MeO OMe N H N F3C OH OH F3C O O Ph OMe O 98 (DHQD)2AQN Ph OMe O (DHQD)2AQN OsO4 [O] 99 TsNH OH 100 81% ee with 98 64% ee with (DHQD)2PHAL (DHD)2PHAL K2OsO2(OH)2 102 66% 81% ee 101 (a) (b) TsNClNa•3H2O Scheme 37 amine derivative 97 (Scheme 36c).The corresponding reaction of ketones has only been reported for 1,2-diones. A review of the selective catalytic reduction of aromatic nitro compounds has been published this year.135 A new method for the chemoselective reduction of azides with iron powder and nickel(II) chloride hexahydrate has been disclosed by Sandhu and co-workers.136 Azides can also be reduced to amines in good yields and under mild conditions with SmI 2 or Cp 2 TiCl 2 –Sm systems.137 4 Oxidation One of the most successful oxidative synthetic methods of recent years the Sharpless asymmetric dihydroxylation (AD) reaction has been refined and exploited extensively this year.Whilst much attention has focused on the mechanism of the reaction138–142 the process has inter alia been applied to the synthesis of tetraols,143 dendrimers144 and pyrrolizidine natural products.145 Several examples of the reaction using polymer- supported ligands have been reported this year.146–148 A new class of anthraquinone- based ligands [e.g. (DHQD) 2 AQN 98] has been found to give superior enantioselectivities in the Sharpless asymmetric dihydroxylation of olefins that bear only alkyl substituents (99]100) (Scheme 37a).149 Chang and Sharpless have syn- 272 N.J. Lawrence thesised enantiopure 2-amino alcohols from the corresponding diols by activation of the diols as cyclic carbonates azide ring-opening of the carbonates and hydrogenation of the resulting azido alcohols.150 Sharpless and co-workers have also developed a more direct route to derivatives of 2-amino alcohols–the catalytic asymmetric aminohydroxylation of alkenes a close relative of the asymmetric dihydroxylation reaction.151 For example ethyl cinnamate 101 when treated with chloramine-T a cinchona alkaloid ligand and a source of osmium tetroxide gives the hydroxy sulfonamide 102 (Scheme 37b). The ligand a§ects not only the enantioselectivity of the process but also the regioselectivity.The procedure has been used to prepare the side-chain of taxol.152 By far the most commonly used method for the synthesis of aldehydes and ketones is the oxidation of alcohols. Many new oxidative methods have been described over the period covered in this review. Several are variants of well studied oxidising agents. For example Khadilkar and co-workers153 report the preparation of silica gel-supported chromium trioxide and describe its use in the selective oxidation of alcohols. The reagent oxidises alcohols to their corresponding carbonyl compound; primary alcohols are not over-oxidised to the carboxylic acid. The oxidation is carried out in 1,2-dichloroethane and is complete after 15 min at room temperature. The product of the reaction is obtained simply by filtration of the reaction mixture.Another chromium- based reagent quinolinium chlorochromate (ACC) has been shown to be an e¶cient reagent for the selective oxidation of primary and secondary alcohols.154 The related quinolinium bromochromate reported by OÆ zgu� n and Degirmenbasi and co-workers,155 is also a new reagent for the oxidation of alcohols to carbonyl compounds. The reagent also functions as a brominating agent for aromatic compounds. An improved protocol for the oxidation of secondary alcohols by copper permanganate is described by Craig and Ansari. The reaction is carried out in a homogeneous medium (acetic acid) a§ording rapid and complete conversion of the alcohols to ketones.156 Chromium trioxide and tricapryl(methyl)ammonium chloride (Aliquot 336) also serves as an e¶cient system for the oxidation of alcohols.157 Hexadecyl silica-supported cupric nitrate in carbon tetrachloride oxidises alcohols to their corresponding carbonyl compounds.It oxidises primary alcohols in the presence of secondary alcohols with absolute chemoselectivity in high yields.158 The catalytic activity of cerium(IV) doped Weakley-type heteropolyoxometalates for the H 2 O 2 oxidation of primary and secondary alcohols has been evaluated for the first time. It was found that this catalyst exhibits mild and selective activity especially for benzyl alcohols.159 Delaude and Laszlo160 describe full details of the use of another oxidising reagent potassium ferrate(VI) and K10 Montmorillonite clay. The reagent is a strong and environmentally benign oxidant for the oxidation of benzyl alcohols. Bis(trimethylsilyl) chromate generated from chromic anhydride and hexamethyldisiloxane in chloromethane has been supported on silica gel and was excellent for oxidising alcohols of various types to the corresponding carbonyl compounds.161 The development of other clean oxidising systems has seen much activity this year.Systems that use only a catalytic quantity of a metal complex are particularly attractive. A practical procedure for the molybdenum-catalysed oxidation of alcohols by sodium percarbonate is detailed by Muzart and co-workers.162 The oxidation is carried out at reflux in acetonitrile or 1,2-dichloroethane in the presence of catalytic molybdenyl acetylacetonate and Adogen 464. The process is generally applicable for the synthesis 273 Synthetic methods 103 laccase–ABTS(NH4)2 103 O2 87–100% R R OH N S NH4O3S Et N N S N Et SO3NH4 Scheme 38 of a wide range of carbonyl compounds.Catalytic amounts of cis-dioxomolybdenum( VI) complexes in association with sulfoxides can be used to oxidise alcohols to carbonyl compounds.163 For primary alcohols the oxidation to aldehydes is selective no further oxidation to carboxylic acid being observed. The oxidation is most e§ective for benzylic and allylic alcohols. Processes that have no metal catalyst and use oxygen or air as the terminal oxidant have even greater potential as clean synthetic methods. One such process a simple and convenient method for the oxidation of secondary alcohols using molecular oxygen and benzaldehyde in 1,2-dichloroethane in the absence of metal catalysis is described by Choudary and Sudha for the first time.164 Rodrigues and co-workers have found that acyl nitrates can be used to oxidise primary and secondary alcohols to aldehydes and ketones.165 Acetyl nitrate supported on Montmorillonite clay gives the best results.The reaction is explained by a mechanism involving the formation of an intermediate alkyl nitrate which decomposes to give the carbonyl compound. Although the authors do not report any problems with this procedure they do not present any safety analysis which would have been welcome considering the known hazards associated with the use of acetyl nitrate. Chen and co-workers also describe an environmentally benign and potentially useful enzymemediated molecular oxygen oxidation of substituted benzyl alcohols to the corresponding aldehydes (Scheme 38).166 The enzyme used laccase requires an artificial co-factor diammonium 2,2@-azinobis(3-ethylbenzothiazoline-6-sulfonate) [ABTS(NH 4 ) 2 ] 103.The reaction proceeds under physiological conditions to yield the product aldehydes quantitatively. A new procedure for the oxidation of primary and secondary alcohols with tertbutyl hydroperoxide employing catalytic Zr(OBu5) 4 or Zr(OPrn) 4 –3Å molecular sieves has been reported by Krohn et al.167 Secondary alcohols–if not severely sterically hindered–are usually converted quantitatively to the corresponding ketones. Aldehydes are obtained from primary alcohols in good yield by lowering the reaction temperature decreasing the amount of ButOOH or replacing ButOOH by cumene hydroperoxide (CHP) and/or exchanging the catalyst Zr(OBut) 4 by Zr(OPrn) 4 or silica gel-supported zirconium(IV).In certain cases a remarkable selectivity for equatorial alcohol groups is observed in contrast to chromium(VI)-based oxidations. tert-Butyl hydroperoxide has also been used as the oxidant for converting benzylic alcohols into the corresponding carbonyl compounds; the process requires the use of chromium(VI)-incorporated zeolite CRS-2 as a catalyst.168 274 N. J. Lawrence N O Cl OH Cl OH NaOCl (0.6–0.7 equiv.) 104 (1 mol%) 104 70% conversion 89% ee Scheme 39 RO O PdCl2(CH3CN)2 (5 mol%) DMF–acetone–water 110 °C R = Me2(Bu t )Si PPh3 (22 mol%) 2-bromomesitylene (1.1 equiv.) 110 °C 76% i. ii. Scheme 40 An intriguing and e¶cient enantioselective protocol for the oxidation of secondary alcohols is reported by Rychnovsky et al. (Scheme 39).169 They used the optically pure nitroxide catalyst 104 which is essentially a ‘chiral version’ of 2,2,6,6-tetramethylpiperidine- N-oxyl (TEMPO) a well studied oxidation catalyst.The azepine 104 oxidises activated secondary alcohols in the presence of the terminal oxidant sodiumhypochlorite (0.6–0.7 equiv.). The resolution of the benzylic alcohol is e¶cient; the (S) isomer is oxidised six times faster than the (R) enantiomer. A procedure for the one-pot desilylation–oxidation of aliphatic tert-butyldimethylsilyl ethers using a palladium(II) catalyst is reported by Wilson and Keay.170 The desilylation involves heating the silyl ether in acetone–DMF containing water (5 equiv.) in the presence of PdCl 2 (CH 3 CN) 2 (5 mol%). Once the desilylation is complete triphenylphosphine (22 mol%) and 2-bromomesitylene (1.08 equiv.) are added and the mixture heated at 110 °C (Scheme 40) to e§ect the oxidation of the alcohol.A review of the use of stable organic nitroxyl radicals for the oxidation of primary and secondary alcohols has appeared this year.171 The e¶cient and highly selective oxidation of primary alcohols to aldehydes using one such nitroxyl radical is described by Einhorn et al.172 They found that TEMPO catalyses the e¶cient oxidation of primary alcohols to aldehydes by N-chlorosuccinimide in a biphasic dichloromethane –aqueous pH8.6 bu§er system in the presence of tetrabutylammonium chloride. Aliphatic benzylic and allylic alcohols are readily oxidised with no over-oxidation to carboxylic acids. Secondary alcohols are oxidised to ketones with much lower e¶ciency.(Arene)tricarbonylchromium alcohols are oxidised to aldehydes or ketones by either DMSO–TFAA (trifluoroacetic anhydride) or DMSO–SO 3 -pyridine reagents with minimal complications from decomplexation.173 275 Synthetic methods Ph Ph O Ph Ph O O Et2N NEt2 NEt2 Ph Ph O Ph Ph O O O (a) 105 106 99% NaOCl aq. CH2Cl2 107 Cl– 107 poly-L-leucine H2O2–NaOH– CH2Cl2 (b) ee > 98% Scheme 41 Several methods for the epoxidation of alkenes have appeared over the past year. For example Mioskowski and co-workers have found that sodium hypochlorite is a convenient oxidant for the epoxidation of a,b-unsaturated ketones (105]106) (Scheme 41a).174 This is made possible by employing a two-phase system and hexaethylguanidinium chloride 107 as a phase-transfer agent. An intriguing asymmetric process for the epoxidation of a,b-unsaturated ketones and dienones has been disclosed by Roberts and co-workers (Scheme 41b).175 In these reactions poly-L-leucine and poly-D-leucine are used as asymmetric catalysts.Noyori and co-workers describe a particularly e¶cient method for the epoxidation of terminal olefins with the 30% hydrogen peroxide using conditions that are both organic and inorganic halide-free. The catalytic system consists of Na 2 WO 4 (aminomethyl)phosphonic acid and methyl(tri-n-octyl)ammonium hydrogensulfate under halide-free conditions.176 A non-transition metal-catalysed process for the catalytic asymmetric oxidation of unfunctionalised alkenes has been disclosed by Aggarwal and Wang.177 They found that just 5mol% of the binaphthyl-based iminium salt 108 is su¶cient to catalyse the oxidation of alkenes to epoxides with moderate to good enantioselectivity (Scheme 42a).The active epoxidising agent in this process is an oxaziridinium salt derived from the iminium salt 108 via oxidation by Oxone. An optimised process for the direct asymmetric epoxidation of aldehydes using an ingenious reagent system with a catalytic sulfide is also described by Aggarwal et al.178 A mixture of aldehyde diazo compound catalytic enantiopure sulfide 111 and copper(II) acetylacetonate provides an e¶cient route to epoxides (109]110) with trans selectivity. The sulfur ylide is generated from the copper-catalysed reaction of the sulfide and diazo compound. The ylide reacts with the aldehyde to provide the epoxide of exceptionally high enantiopurity and returns the sulfide to the catalytic cycle (Scheme 42b).The use of the C 2 -symmetric chiral ketone 112 for the asymmetric epoxidation of unfunctionalised olefins (Scheme 37) has been described by Yang et al.179 The axially chiral ketone 112 is particularly e§ective for the asymmetric epoxidation of stilbene derivatives 113. The reaction is carried out using Oxone in an homogeneous acetonitrile –water solvent system. This was until recently the highest enantioselectivity reported for the epoxidation of an alkene via a chiral dioxirane. However Shi and co-workers have found that the fructose-derived ketone 114 surpasses the ketone 112 as an e§ective asymmetric epoxidation catalyst for a variety of trans-alkenes (Scheme 43).180 276 N. J. Lawrence N Me Ph Ph O O H O Ph Ph O S Me 108 108 (5 mol%) Oxone (1 equiv.) NaHCO3 (4 equiv.) MeCN–H2O 80% 71%ee (a) 111 (0.2 equiv.) Cu(acac)2 (5 mol%) PhCHN2 73% trans:cis >98:2 110 109 111 Scheme 42 Hiegel et al.report the potentially useful direct oxidative conversion of an aldehyde to its corresponding methyl ester in the absence of metals (Scheme 44).181 Treatment of the aldehyde with a solution of methanol pyridine and trichloroisocyanuric acid in acetone acetonitrile or dichlormethane e¶ciently gives the methyl ester. The complex HOF·MeCN has also been used to e§ect non-metal-mediated oxidations. The complex made directly by bubbling fluorine through aqueous acetonitrile reacts quickly and e¶ciently with the enolic forms of ketones to produce a-hydroxy ketones.182 5 Protection and functional group interconversion Several excellent reviews describing protecting group strategies in organic-synthesis have appeared this year.183,184 Alcohols and thiols An excellent review focuses on the selective deprotection of silyl ethers in the presence of other like and unlike silyl ethers.185 Deprotection of structurally di§erent trimethylsilyl ethers to their corresponding alcohols can be achieved rapidly in refluxing benzene in the presence of tris[trinitratocerium(IV)] paraperiodate M[(NO 3 ) 3 Ce] ·3H 2 IO 6N.The reagent has also been used successfully for the direct oxidation of trimethylsilyl ethers to their corresponding carbonyl compounds. Benzylic double 277 Synthetic methods Scheme 43 Ph O H N N N O Cl Cl Cl O O Ph O OMe MeOH pyridine 67% Scheme 44 bonds are prone to cleavage reactions with this method.186 tert-Butyldimethylsilyl and tetrahydropyranyl (THP) ethers are also cleaved oxidatively by catalytic ceric ammonium nitrate in methanol.187 TBDMS ethers of primary alcohols are deprotected more rapidly than THPethers and ketals.The deprotection of trimethylsilyl ethers can also be e§ected by the action of the modified borohydride agents BAAOTB (1-benzyl- 4-aza-1-azoniabicyclo[2.2.2]octane tetrahydroborate) and TBATB (tetrabutylammonium tetrahydroborate) in refluxing ButOH.188 An e§ective method for the cleavage of tert-butyldimethylsilyl ethers using a 1% solution of iodine in methanol is described.189 E¶cient tert-butyldimethylsilylation of alcohols including tertiary and sterically hindered secondary alcohols using N,O-bis(tert-butyldimethylsilyl)acetamide in the presence of catalytic amounts (1 mol%) of TBAF has been disclosed by Johnson and Taubner.190 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is commonly used to deprotect various methoxy substituted benzyl ethers.One drawback with this method is the need for a stoichiometric amount of DDQ. A solution to this problem has been disclosed by Yadav and co-workers who found that 4-methoxy- and 3,4-dimethoxy-benzyl ethers can be deprotected with the catalytic amounts of DDQ by oxidative recycling of the by-product DDHQ by iron(III) chloride.191 The same research group have found that the cleavage of O-allyl ethers of primary alcohols can also be e§ected with DDQ.192 Several new methods for the manipulation of acetal-based alcohol protecting groups have been described. THP ethers can be prepared from an alcohol and tetrahydropyran using heteropoly acids [e.g.H 3 [PMo 12 O 40 )] as catalysts.193 A mild and e¶cient method for selective deprotection of THP ethers has been reported by Maiti and Roy194 and simply involves heating in water and dimethyl sulfoxide at 90 °C in the presence of excess lithium chloride. Oriyama et al. have developed a variety of methods for the manipulation of THP ethers.195 For example THP ethers are 278 N. J. Lawrence N Ph OH Bn N Ph HN Bn CHO 115 116 70% Me3SiCN H2SO4 Scheme 45 transformed into trialkylsilyl ethers by the action of trialkylsilyl trifluoromethanesulfonate. When the triflate is trimethylsilyl trifluoromethanesulfonate the THP ether is cleaved to the corresponding alcohol. Silyl ethers are also produced by the reaction of THP ethers with a trialkylsilane and catalytic tin(II) triflate.A new procedure for cleavage of benzylidene acetals from glycopyranosides using tin(II) chloride is described which does not a§ect other protecting groups such as benzoyl acetyl benzyl or acetonide.196 The highly versatile 1-[(2-trimethylsilyl)ethoxy]ethyl (SEE) group readily obtainable from an alcohol and 2-(trimethylsilyl)ethyl vinyl ether in the presence of a catalytic amount of PPTS has been developed for the protection of hydroxy groups. Deprotection can be achieved under virtually neutral conditions with the use of a fluoride ion source thus allowing for e§ective protection of hydroxy groups of compounds that contain acid- and/or base-sensitive functional groups.197 Alcohols protected as their methoxyacetates can easily be regenerated by the action of ytterbium(III) triflate in methanol.198 Several useful functional group interconversions of alcohols have been disclosed this year.For example a convenient synthesis of aromatic thiols from phenols has been described by Arnould et al.199 Aromatic thiols were synthesised from phenols in good yield and under mild conditions by reaction of the corresponding triflates with sodium triisopropylsilanethiolate (NaSTIPS) and subsequent deprotection. The e¶cient inversion of a variety of secondary alcohols can be achieved by the reaction of their chloromethanesulfonates with caesium acetate in the presence of 18-crown-6. Basecatalysed or reductive hydrolysis of the product acetate gives the alcohol with the opposite stereochemical configuration.200 A novel modification of the Ritter reaction described by Goel and co-workers uses trimethylsilyl cyanide and sulfuric acid to convert alcohols to their corresponding formamides in high yields (e.g.115]116) (Scheme 45).201 Ketones and aldehydes By far the most common method for the protection of aldehydes and ketones involves the synthesis of acetals and thioacetals. Much research has focused on milder methods for their synthesis and removal. For example Bandgar and co-workers202 have found that the Envirocat EPZG' is an excellent heterogeneous catalyst for the thioacetalisation of ketones and aldehydes with the ethane-1,2-dithiol. The process o§ers high yields and easy separation of products and catalyst by filtration. The same transformation is catalysed by Fe3`-exchanged Montmorillonite,203 and kaolinitic clay.204 Schmittel and Levis205 describe the use of the one-electron oxidant iron(III) tris(phenanthrolinehexafluorophosphate) in the deprotection of benzyl-substituted 1,3-dithianes.Scandium bis(trifluoromethanesulfonamide) has been shown to be a highly e¶cient Lewis acid catalyst for the synthesis of ketals from ketones and 1,2- or 279 Synthetic methods Ph O H O O O Ph OH HO O Sc(NTf2)3 MgSO4 CH2Cl2 23 °C 20 h 83% cis:trans 93:7 Scheme 46 1,3-diols.206 The catalyst can also be used for the diastereoselective preparation of 1,3-dioxolanes from aldehydes (Scheme 46). A novel method for the deprotection of S,S-acetals using air and catalytic bismuth( III) nitrate has been reported by Komatsu et al.207 Both cyclic and acyclic S,S-acetals of ketones and aldehydes are smoothly deprotected to regenerate the parent carbonyl compound and diphenyldisulfide.Curini and co-workers have found that layered zirconium sulfophenyl phosphonate [e.g. Zr(O 3 PCH 3 ) 1.2 (O 3 PC 6 H 4 SO 3 H) 0.8 ] is an e¶cient heterogeneous catalyst for mild hydrolysis of oximes semicarbazones and tosylhydrazones.208 The same research group have also found that ketones and aldehydes can be regenerated from their corresponding 1,3-dithiolanes and 1,3-dithianes using Oxone' and wet alumina.209 Triphenylphosphine and carbon tetrabromide have been used to promote the selective deprotection of ketals and acetals under mild neutral anhydrous reaction conditions.210 An exceptionally simple and convenient method for dethioacetalization has been described by Mehta and Uma.211 Thioacetals of aldehydes and ketones give the parent carbonyl compound upon treatment with a solution of ‘oxides of nitrogen’ in dichloromethane.The ‘oxides of nitrogen’ are prepared by treating arsenious oxide with conc. HNO 3 . A number of 1,3-dithianes have been e¶ciently converted to the parent carbonyl compounds in good yields by treatment with 1.5 equiv. of DDQ in MeCN–H 2 O (9 1).212 A variety of derivatives of ketones and aldehydes are converted to the parent carbonyl compound by new protocols. For example ketone dimethylhydrazones undergo easy cleavage to the corresponding ketones using a catalytic amount of Pd(OAc) 2 –SnCl 2 .213 Sankararaman and co-workers have shown that 5M lithium perchlorate in diethyl ether is an excellent Lewis acid medium for the conversion of epoxides to carbonyl compounds (e.g.117]118) (Scheme 47). The reagent appears to be more regio- and chemo-selective than the commonly used boron trifluoride.214 Carboxylic acids and derivatives Several new methods for the manipulation of esters have been described. For example trimethylsilyl trifluoromethanesulfonate has been used as a catalyst to e§ect the fast clean and e¶cient esterification of alcohols with carboxylic acid anhydrides.215 Treatment of a variety of aromatic carboxylic acids with alcohols in the presence of thionyl chloride results in excellent yields of corresponding esters.216 The transesterification of a,x-dicarboxylic acids gives the corresponding monoesters in high yields when the reaction is catalysed by strongly acidic ion exchange resins in an ester–octane biphasic mixture.217 It has been shown that prop-2-ynyl esters are useful protecting groups for carboxylic acids and that they are selectively deprotected in the presence of other esters on treatment with tetrathiomolybdate under mild conditions.218 280 N.J. Lawrence Ph O Ph O 117 75% 118 LiClO4 Et2O Scheme 47 The easy deprotection of allyl esters is achieved by allyl group transfer to anisole using the catalytic action of the superacid sulfated SnO 2 .219 The use of magnesium methoxide for the deprotection of alkyl esters has been described. This mild reagent provides a good method to cleave esters e¶ciently and more importantly allows for e§ective di§erentiation between two di§erent esters. The order of the reactivity of this reagent towards acyl cleavages was found to be p-nitrobenzoate[acetate[benzoate [pivaloate?acetamide.220 Amines and phosphines The tert-butoxycarbonyl protecting group for amines alcohols and thiols is removed e¶ciently (90–99% yields) by use of catalytic of ceric ammonium nitrate (0.20 equiv.) in refluxing acetonitrile.221 The cleavage of N-Boc groups in the presence of either TBDMS or TBDPS ethers is successfully achieved by use of a saturated solution of HCl in ethyl acetate.222 An e¶cient and high-yield method for the N-tert-butoxycarbonyl protection of sterically hindered a-amino-acids has been developed by Johnson and co-workers.223 The amino acid is treated with tetramethylammonium hydroxide and (Boc) 2 Oin acetonitrile.TheN-2,4-dimethylpent-3-yloxycarbonyl (Doc) group has been used as a new protecting group for tryptophan that is stable to nucleophiles and trifluoroacetic acid suppresses alkylation side reactions and is cleaved by strong acid along with other protecting groups used in Boc solid-phase peptide synthesis.224 The tetrachlorophthaloyl group has been used as a versatile amine protecting group.225 It can be removed to reveal the parent amine by treatment with the ethylenediamine in ethanol at 60 °C.The conditions required to remove a phthaloyl group in a similar way are much harsher. Zmijewski and co-workers have developed an enzymatic method for the selective deprotection of phthalyl protected amines.226,227 Phthalyl amidase selectively deprotects phthalimido groups under very mild aqueous conditions in a one-pot reaction to produce phthalic acid and the free amine. The enzyme has been shown to deprotect several primary amines of distinctly di§erent structure and exhibits chiral selectivity when the substrate contains extensive beta-branching.6 Organo halides Fluoro compounds Many new methods for the selective fluorination of organic compounds have appeared this year. Auseful review summarises the use of cobalt trifluoride for the fluorination of organic compounds.228 Katzenellenbogen and co-workers have developed an e¶cient route to trifluoromethyl ketones 122 via trifluoromethyl-substituted imidazolines (Scheme 48).229 The imidazolines 121 were prepared by the reaction of the silyl-N- 281 Synthetic methods Ph N Ph Ph N Ph N N CF3 R O Ph Ph Ph CF3 HN O R O SiMe3 i. LDA ii. TMSCl RCOCl CF3CN THF MeOH–H2O HCl 119 120 74% Scheme 48 benzylidenebenzylamine 120 (made from 119) with acid chlorides and trifluoroacetonitrile.The reaction proceeds via a 1,3-dipolar cycloaddition between the N-acylazomethine ylide generated from the acid chloride and the silylimine. Mild acid hydrolysis of the imidazoline generates the trifluoromethyl ketone 122. The process can also be used to generate trifluoromethyl ketones that are incorporated in bioactive peptides. A description of the synthesis of aryl trifluoromethyl ketones by a Friedel–Crafts acylation reaction has appeared from Simchen and Schmidt.230 They used 4-dimethylamino-1-trifluoroacetylpyridinium trifluoroacetate as an e§ective easy to handle and stable trifluoroacetylation agent. Arenes are converted to their corresponding trifluoromethyl ketones by its action in the presence of aluminium chloride.The use of several highly selective electrophilic fluorinating agents has been reviewed this year.231,232 a,a-Difluoro ketones are prepared from hydroxy-substituted aromatic derivatives by reaction with the 1-fluoro-4-hydroxy-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [AccufluorTM NFTh] 123 in methanol or acetonitrile (Scheme 49a).233 The same reagent has also been used for the high-yield direct a-fluorination of ketones234 and polycyclic aromatic hydrocarbons. 235 Iodotoluene difluoride can also be used to selectively fluorinate b-keto esters in the a-position.236 Similarly dialkyl fluoromalonates have been prepared by treating the sodium derivatives of the parent dialkyl malonates with elemental fluorine.237 Yokoyama and Mochida have developed a useful procedure for the formation of the trifluoromethyl anion from phenyl trifluoromethyl sulfide by the use of Et 3 GeNa.Various aldehydes were transformed into the corresponding a-trifluoromethylated alcohols in good to excellent yields (e.g. RCHO]124) (Scheme 49b).238 Acyl fluorides are prepared e¶ciently by the oxidation of aliphatic and alicyclic alcohols with the commercial reagent BrF 3 .239 Bromo compounds A useful method for the transformation of ketones and aldehydes to gem-dibromides has been developed by Takeda et al.240 The ketone or aldehyde is first converted to its corresponding hydrazone 125 which is then treated with copper(II) bromide–lithium tert-butoxide to give the gem-dibromide in good yield (Scheme 50). The bromination of 282 N. J. Lawrence OH O F F N+ N+ OH F Et3GeNa CF3Na RCHO 124 86–96% (b) (a) (BF4 –)2 123 123 MeCN room temp.0.5 h SCF3 R CF3 OH Scheme 49 Scheme 50 1,3-diketones can be achieved using a mixture of potassium bromate and potassium bromide in the presence of Dowex' 50X2-200 ion-exchange resin.241 The regiospecific bromination of benzene derivatives can be achieved by using Me 2 SO–HBr.242 Reactions of mono-substituted aromatic substrates of moderate activity with bromine in the presence of stoichiometric amounts of zeolite NaY proceed in high yield and with high selectivity to the corresponding p-bromo products; the zeolite is easily regenerated by heating.243 7 Miscellaneous preparations Mioskowski and co-workers report an interesting procedure for the conversion of primary amides to nitriles (126]127) (Scheme 51)244 involving aldehyde- and acidcatalysed water transfer from the amide to acetonitrile.Whilst various aldehydes are e§ective as catalysts only formic acid serves as a successful acid catalyst. The proposed catalytic cycle involves the formation of the nitrilium salt 128 from the aldehyde formic acid and acetonitrile. Reaction of this salt with the primary amide is thought to give the intermediate 129 which collapses with the release of the nitrile 127 to the b-hydroxy amide 130. The aldehyde is regenerated from the b-hydroxy amide 130 and at the same time produces acetamide. The mild reaction conditions should render the process useful. A potentially useful method for the synthesis of phthalimidine derivatives from o-phthalaldehyde and an amine has been revealed by Takahashi and co-workers (Scheme 52).245 They found that the reaction is e¶cient when 1,2,3-1H-benzotriazole and 2-mercaptoethanol are present in the reaction mixture.Pinacolborane (PBH) is an excellent stoichiometric hydroboration reagent for alkenes and alkynes in the presence of catalytic amounts of transition metal complexes 283 Synthetic methods R1 NH2 O R1 C N R N HO R1 NH2 O R N HO O N H R1 R N H HO O 126 RCHO HCO2H CH3CN heat 126 127 RCHO HCO2H CH3CN 128 HCO2 – 129 – R1CN 130 – MeCONH2 Scheme 51 H H O O NH N N HO SH N O R 80% R = p-CO2Me-C6H4 RNH2 Scheme 52 (Zr and Rh).246,247 While Wilkinson’s catalyst causes isomerisation of internal alkenes Rh(CO)(PPh 3 ) 2 Cl gives the internal alkyl pinacolboronates with excellent regioselectivity. Rhodium and also nickel are extremely e§ective catalysts for the hydroboration of alkynes with PBH.Dicarbonyltitanocene is also an e¶cient and highly selective catalyst for alkyne hydroborations by catecholborane and dimethyltitanocene is an e¶cient and highly selective catalyst for alkene hydroborations.248 These results contrast hydroboration chemistry with other early transition metal complexes that simply lead to decomposition of catecholborane to form diborane. The simple hydroboration of olefins with catecholborane in the absence of metal catalysts at room temperature is greatly accelerated by the presence of N,N-dimethylacetamide. 249 The removal of organotin residues from reaction mixtures particularly those from radical reactions is often problematic. 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ISSN:0069-3030    

DOI:10.1039/oc093249

出版商:RSC    

年代:1997

数据来源: RSC