ISSN:0069-3030    

DOI:10.1039/OC99289FX001

出版商:RSC    

年代:1992

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC99289BX003

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

2 Physical Methods and Techniques Part (ii) Computer Graphics (Computer Aids to Organic Chemistry) By C. I. DE MATTEIS D. E. JACKSON and N. RAJ Department of Pharmaceutical Sciences University of Nottingham Nottingham NG7 ZRD UK 1 Introduction This is the third in a series of Reports describing the use of computer graphics in organic chemistry and follows on from the previous Reports in 1988 and 1990. As one might expect the last two years have witnessed an increased use of computer graphics in a number of applications including ‘windowed’ interfaces both to a variety of modelling software and also as a powerful visualization tool within the research environment. Graphically orientated applications such as database and data retrieval systems expert chemical systems and molecular modelling software responsible for calculating and displaying molecular structure and properties have all developed significantly over this period.In addition the potential of the computer graphics image as a means of displaying large quantities of data and in helping understand complex three dimensional problems is increasingly recognized.’ Integration of these various applications into a single graphical system allowing ease of use and greater efficiency in data management continues and a number of commercial software companies now provide such open interfaces. Additionally newly developed computer based tech- niques whereby colour graphics video animation and sound are integrated into a single computer display are being widely exploited in computer aided learning thus introducing computer graphics into the teaching environment.2 Increasingly easy access to powerful computing facilities at ever declining prices has fuelled the observed growth in computer graphics applications.It is estimated that CPU speed is doubling every 18 months,1c1 and that the ratio of price to performance is decreasing by an order of magnitude every 5-7 years3 Also graphical displays will continue to improve in clarity and realism as hardware power develops. Additionally the increasing speed of network hardware will allow graphics images and animations to be sent very rapidly to locations around the world. SuperJANET (Joint Academic Network) which is being installed in UK universities in 1993 will initially carry 140 ((I) A.J. Olson and D. S. Goodsell Scient$c American. Nov. 1992 44:(h)J. Petts. Lob. Pructicr. 1991. 40(7).9. * ‘Multimedia The CTISS File’. ed. J. Darby. CTISS Publications. Oxford. 1992. W. F. van Gunsteren and H. J.C. Berendsen. Angeat. Chem.. Int. Ed. Engl. 1992 29 992. 21 C.I. de Matteis D. E. Jackson and N. Raj million bits of information per second compared to 2 million bits per second delivered by the original JANET.4 The last two years have consequently seen an increase in the number of specialized research journals describing the use of computer aids in chemical and biological research reflecting increasing recognition of the value of these research tools. The Journal of Computer- Aided Materials Design,’ Molecular Modelling and Computational Chemistry Results,6 and Perspectives in Drug Discovery and Design’ are new journals in this field.Protein Science’ is published with a new interactive graphics supplement on diskette which allows the display and manipulation of graphical data. A number of text books have been published in this field’ and certain texts e.g. ‘Reviews in Computational Chemistry’ are now produced annually.’’ This Report will attempt to provide an update to the previous Annual Report of 1990. Given the enormous breadth of the field no attempt will be made to provide a thorough review of the literature but rather to provide an insight into the important developments in computer graphics applications over the last two years.2 Molecular Modelling Drug Design.-It is estimated that in 1989 US pharmaceutical companies spent $5.71 billion on domestic Research and Development to produce a total of 23 new US approved drugs.” The need to increase the role of rational drug design in the drug discovery process is obvious and molecular modelling is used increasingly within this process. Examples of the successful use of molecular modelling in drug design have been published,I2 and there are an increasing number of examples of its use in the de now design of protein^.'^ A number of articles and books reviewing the methods and applications of molecular modelling in the design process have a~peared,’~ together with those describing the use of these techniques to improve our understanding of biological events.’” Molecular modelling approaches to rational drug design utilize available informa- tion about the interaction of active substrate molecules with the biological macro- molecule target site.Depending on whether the three dimensional structure of the biological target molecule is available or not two distinct approaches to the design E. Geake New Scientist 1992 1848 18. Journal of Computer-Aided Materials Design ESCOM Science Publishers Leiden The Netherlands. Molecular Modelling and Computational Chemistry Results MMCC Publishing Massachusetts USA. ’ Perspectives in Drug Discovery and Design ESCOM Science Publishers Leiden The Netherlands. Protein Science Cambridge University Press Cambridge UK. (a) ‘Computer Simulation of Biomolecular Systems’ ed.W. F. van Gunsteren and A. J. Wilkinson ESCOM Leiden 1993 vol. 2; (h) ‘MOTECC-Modern Techniques in Computational Chemistry’ ed. E. Clement] ESCOM Leiden 1991. ‘Reviews in Computational Chemistry’ ed. D. B. Boyd and K. B. Lipkowitz VCH Publishers Weinheim 1992 vol. 3. M.E. Wolff and E.T. Maggio Med. Chem. Res. 1991 1 101. (a)A. Olson and D. Goodsell Curr. Opin. Struct. Biol. 1992,2 193; (b)J. Hodgson BiolTechnoloqy 1991 9 19. l3 A. Pessi E. Bianchi A. Crameri. S. Venturini A. Tramontano and M. Sollazzo Nature (London) 1992 362 367. I4 (a) W.C. Ripka and J.M. Blaney Top. Stereochem. 1991 20 1; (b) Y:C. Martin in ‘Methods in Enzymology’ ed. J. N. Abelson and M. I. Simon Academic Press 1991 vol. 203 p. 587; (c)J. S. Dixon Trends Biotech.1992 10,357; (d)J. P. Snyder Med. Res. Rev. 1991 11(6) 641; (e)‘A Textbook of Drug Design and Development’ ed. P. Krogsgaard-Larsen and H. Bundgaard Harwood 1991. Physical Methods and Techniques -Part (ii) Computer Graphics process are available. These have been referred to respectively as 'direct' or 'indirect' ligand design. In those cases where the three dimensional structure of the target site is known the drug design process involves three components. Initially the position of the binding site must be ascertained followed by an understanding of the mode of association of the ligand within this target site and finally using this information either de nouo ligand design or lead optimization is attempted. Examples of the use of NMR15 and X-ray crystallography' to study macromolecule-ligand complexes have appeared and it is claimed that once the structure of a biological macromolecule has been solved crystallographically the structure of the complex can be ascertained in a number of days.' 6*14aExamples of multiple ligand binding modes have been observed experimen- tally.' 4* The incorporation of crystallographic studies of ligand binding into enzyme inhibitor design strategies has been reported resulting in four structurally distinct novel inhibitors of Escherichia coli thymidylate synthase.Rational de nouo drug design methods generally involve the analysis of the target binding site and based on this information the prediction of compounds which may bind. A number of computational methods have been developed that locate favoured positions for ligand functional groups within the binding site.For example GRID locates the positions where particular ligand atoms or functional groups will prefer to bind by calculating the interaction energy of this functional group with the receptor at various positions around the active site using a potential energy function which considers van der Waals electrostatic and hydrogen bonding interactions.' This method has recently been upgraded to consider more accurately the possibility of the ligand functional group forming more than one hydrogen bond to the active site.'' HSITE produces a map of hydrogen bonding regions within an enzyme active site." A method for determining and displaying the position of hydrophobic and hydrogen bonding areas in ligand binding sites has been described.20 Once favourable positions for these ligand fragments have been located three dimensional databases can be screened for molecules that match these pharmacophore requirements.2 ' Alternatively fragments may be pieced together with a trial-and-error approach using either molecular graphics facilities or techniques that have been developed to assemble fragments in the required orientation for biological activity.A number of database methods have been developed that search for substructures which can act as templates and hold functional groups in the required orientations.2' CAVEAT uses a database of cyclic compounds that can be used as 'spacers' to connect the fragments required for ligand activity.22 LUDI calculates the position of interaction sites where l5 S.W.Fesik J. Med. Chem. 1991 34 2937. l6 K. Appelt R. J. Bacquet C.A. Bartlett C. L. J. Booth S.T. Freer M. A. M. Fuhry M. R. Gehring S. M. Herrmann E. F. Howland C.A. Janson T. R. Jones C.-C. Kan V. Kathardekar K. K. Lewis G.P. Marzoni D.A. Matthews,C. Mohr E. W. Moomaw,C. A. Morse,S. J.Oatley R. C. Ogden M. R. Reddy S.H. Reich W. S.Schoettlin W. W. Smith M.D. Varney J. E. Villafranca R. W. Ward S. Webber S.E. Webber K.M. Welsh and J. White J. Med. Chem. 1991.34 1925. l7 (a) P. J. Goodford J. Med. Chem. 1985,28 849; (h)D. J. Boobbyer P. J. Goodford P. M. McWhinnie and R.C. Wade J. Med. Chem. 1989 32 1083. l8 R.C. Wade K.J. Clark and P.J. Goodford J. Med. Chem.1993 36 140. l9 (a)D. J. Danziger and P. M. Dean Proc. R. SOC.London Ser. B. Biol.Sci. 1989,236,101;(b) ibid. 1989,236 115. 'O R.S. Bohacek and C. McMartin J. Med. Chem. 1992 35 1671. " Y.C. Martin J. Med. Chem. 1992 35 2145. " 'CAVEAT' G. Lauri G. T. Shea S. Waterman S.J. Telfer,and P. A. Bartlett University of California at Berkeley USA. 24 C.I. de Matteis D. E. Jackson and N. Raj hydrogen bonding and hydrophobic fragments should be placed using rules derived from an analysis of non-bonded contacts found in the Cambridge Crystallographic Database and will also use the output from GRID calculations. Up to four of these resulting interaction sites are then built into fragments using a library of approximately 600 ‘linkers’ and these fragments are then joined up into the complete molecule using small ‘bridging’ fragments which include methylene and carboxylate.This method has been used to generate improved inhibitors for dihydrofolate reductase and HIV pr~tease.’~ A structure generation algorithm that will build structurally diverse three dimen- sional chains joining fragments of defined positions within a constricted site for example an enzyme active site has been de~cribed.’~ BUILDER is a modelling program that combines automatic structure generation with database searching approaches to generate lead molecules in which the required fragments are joined.25 Chau and Dean have reported the generation of a database of small organic fragments which may be used in the future for automated site-directed drug design.26 Alternative methods for designing ligands to fit a known active site include the following DOCK which carries out a steric search of three dimensional databases to locate compounds that are geometrically and electrostatically complementary to the binding site;” LEGEND which attempts to grow a ligand within the binding site by building up the structure sequentially from random atom types and dihedral angles;28 and GROW which aims to determine the optimal peptide ligand for a given enzyme by gradually building the ligand using a library of amino acid conformation^.^^ Interactive molecular modelling approaches involving the docking of novel ligands into the target site using distance constraints to position the ligand have been rep~rted.~’ Free Energy Perturbation methods are now well established for calculating the difference in free energy of the binding of related ligands to a given target ~ite.~~v~~~ In those cases where the three dimensional structure of the target molecule is not known a variety of approaches are available for inferring the structure of the target site.If the protein of interest has homology with a protein of known three dimensional structure modelling techniques have been developed that will generate a three dimensional structure for this protein,31 although it is recognized that this model is less reliable than an experimentally determined str~ture.~~~ The use of the binding site from an enzyme with the same mechanism of action has been re~0rted.l~~ Antibody technology is being used in a variety of ways to provide information about the target site structure.By raising antibodies to the substrate or drug molecule a receptor mimic is produced and structural analysis of the relevant part of the antibody will provide information about the receptor structure.32 Another approach has been to produce an 23 (a)H. J. Bohm J. Cornput.-Aided Mol. Design 1992 6 61; (b) ibid. 1992 6 593. 24 R.A. Lewis J. Mol. Graph. 1992 10 131. 25 R. A. Lewis D. C. Roe C.Huang T. E. Ferrin R. Langridge and I. D. Kuntz J. Mol. Graph. 1992,10,66. 26 (a)P.-L. Chau and P. M. Dean J. Cornput.-Aided Mol. Design 1992,6,385; (b)ibid. 1992,6,397; (c)ibid. 1992 6 401. 27 R. L. DesJarlais R. P. Sheridan. G. L. Seibel J. S. Kuntz and R.Venkataraghavan J. Med. Chem. 1988 31 122. Y. Nishibata and A. Itai Tetrahedron 1991 47 8985. 29 J.B. Moon and W.J. Howe Proteins Struct. Funct. Genet. 1991 11 314. 30 T.J. Mitchell J. Mol. Graph. 1992 10 53. 31 S. Kawakita R. Kuroki. and T. Yao J. Mol. Graph. 1992 10 58. 32 M. A. Sherman and M.B. Bolger J. Bid. Chem. 1988 263 4064. Physical Methods and Techniques -Part (ii) Computer Graphics 25 antibody to the target site which will produce a mirror image of the target site structure. This antibody can then be analysed structurally to obtain pharmacophoric information or used as an antigen to another antibody so that structural analysis of this antibody will provide information about the target site structure." AbM is a program allowing antibody three-dimensional structure modelling from sequence information using a knowledge base of structural information combined with computational methods.33 Receptor mapping represents another approach for inferring the structure of the target site but requires no information about the location or structure of the target macromolecule By systematically altering the structure of the lead compound and ascertaining its activity the functional groups or atoms required for binding or activity can be identified and the three dimensional orientation of these molecular features provides a pharmacophore or receptor map.Deciding how to superimpose the individual molecules so as to align the pharmacophoric groups represents a considerable problem particularly if the molecules are structurally diverse and have considerable conformational flexibility.14' Both an automatic method for positioning two molecules so that the similarity between their molecular electrostatic potentials is at a maximum34 and molecular matching using simulated annealing have been de~cribed.~' SUPER matches the van der Waals surfaces and charge distributions of two molecules to produce optimum overlap whilst OVID finds the best surface overlap of user-defined atoms in two rnolec~les.~~ A method which superimposes structures on the basis of similarity of molecular shape hydrogen bonds and electrostatic interactions and additionally considers the conformational flexibility of the molecules has been rep~rted.~ Molecular similarity calculations have also been used as a method for screening large structural data sets obtained from three dimensional databases and has been shown to provide a rapid screening method.38 Quantitative structure activity relationships (QSAR) where biological activity in a series of congeneric compounds is described by a series of molecular descriptors continue to be used and developed for drug design application^.^^ Novel parameters continue to be developed for example parameters derived from theoretical chemistry4' and a novel hydrophobic parameter4' have been reported.Neural networks have been found to produce superior statistical results in QSAR when compared to regression analysis.42 Force Fields.-The motivation for molecular modelling is to try to predict physical properties of molecular systems based on the interactions that determine their behaviour.This is achieved at the most fundamental level by invoking quantum mechanics through use of the Schrodinger equation. Such ab initio or first principle 33 'AbM' Oxford Molecular Limited The Magdalen Centre Oxford Science Park Sandford-on-Thames Oxford OX4 4GA UK. 34 F. Manaut F. Sanz J. Jose and M. Nilesi J. Cornput.-Aided Mol. Design 1991 5 371. 35 (a)M. T. Barakat and P.M. Dean J. Cornput.-Aided Mol. Design 1990,4 295; (b) ibid. 1990,4 317; (c) ibid. 1991,5 107; (d)M. C. Papadopoulos and P. M. Dean J. Cornput.-Aided Mol. Design 1991 5 119. 36 R. B. Hermann and D. K. Herron J. Cornput.-Aided Mol. Design 1991 5 51 1. 37 Y. Kato A. Inoue M.Yamada N. Tomioka and A. Itai J. Cornput.-Aided Mol. Design 1992 6 475. '13 A.C. Good E.E. Hodgkin and W.G. Richards J. Cornput.-Aided Mol. Design 1992 6 513. 39 E.J. Ariens Quant. Struct.-Act. Relat. 1992 11 190. 40 L.Y. Wilson J. Med. Chern. 1991 34 1668. 41 Y.-Z. Da K. Ito and H. Fujiwara J. Med. Chern. 1992 35 3382. 42 S.4. So and W.G. Richards J. Med. Chern. 1992,35 3201. 26 C.I. de Matteis D. E. Jackson and N. Raj calculations rapidly become unfeasible however as the atomic system size starts growing. In contrast to the more theoretically based Molecular Orbital methods classical approaches such as Metropolis Monte Car10,~~ Molecular Mechanics (or energy minirni~ation),~~ Molecular dynamic^,^' and Distance Geometry46 utilize empirical or semi-empirical potential-energy functions.Such a function describes intramolecular forces and consists of terms to include bonded and non-bonded interactions. For the bonded interactions there are two-body bond length vibrations three-body angle bending vibrations and four-body dihedral rotations. The non-bonded terms usually incorporated into the force field include electrostatic and van der Waals interactions. Hydrogen-bonding may or may not be explicitly included. In cases where it is not appropriate adjustments to atomic charges may be made. An energy function of this type is easily differentiable and so allows forces on each particle to be evaluated as a function of position coordinates. The total Hamiltonian of the system is then given by the sum of various potential energy contributions plus the kinetic energy of each constituent.Equation 1 shows a typical potential energy form. V,, = Z bond stretching + E angle bending + E dihedral rotation + C (VDW + electrostatic) A wide variety of functional forms for each of the terms in equation 1have been used. In the case of bond stretching the most common is the Hooke’s law harmonic potential. This form is however only valid for small deviations of the bond from its ‘reference’ length and away from this alternatives such as the Morse47 potential are more appropriate. For angle bending again harmonic potentials are most commonly used but for greater accuracy higher order terms in the Taylor expansion for the potential are required. Dihedral angles exhibit multiple minima and it is necessary to use a periodic cosine function to describe these potentials.This usually takes the form of a truncated Fourier series involving one- two- and three-fold terms. For non-bonded atomic pairs the majority of current molecular mechanics force fields use a combina- tion of van der Waals and Coulombic energy terms. The other factor determining the success of a force field is the parameter set chosen to be used within the potential functional form. Such parameters are required for equilibrium bond lengths and bond angles with their respective force constants; dihedral barrier heights and phases; out-of-plane terms; van der Waals radii and energy well depths; partial atomic charges or bond dipoles; and perhaps a variety of cross-linking terms.Further these parameters must be chosen for all atom types comprising the class of molecules to be studied. It should always be possible to reproduce experimental results to a high degree of accuracy given arbitrarily complex analytical potential functions and highly specific atom types; however such a force field is probably only of limited use. Another approach is to sacrifice accuracy for ” N. Metropolis A. W. Rosenbiuth M. N. Rosenbluth and A.H. Teller 1.Chem. Phys. 1953 21 1087. 44 J. A. McCammon and S.C. Harvey ‘Dynamics of Proteins and Nucleic Acids’ Cambridge University Press Cambridge 1987. 45 M. P. Allen and D. J. Tildesley ‘Computer Simulation of Liquids’ Clarendon Oxford 1987. 46 G. M. Crippen and T. F. Havel ‘Distance Geometry and Molecular Conformation’ Research Studies Press Taunton 1988.47 S.D. Morley R.J. Abraham I.S. Haworth D.E. Jackson M.R. Saunders and J.G. Vinter J. Cornput.-Aided Mol. Design 1991 5 475. Physical Methods and Techniques -Part (ii) Computer Graphics 27 greater transferability and wider range of application. Below we describe recent advances in force field development together with their range of application. In addition we also review some articles dealing with the important topic of electrostatics. The standard force fields are limited to particular combinations of atoms and have been devised to be used in modelling specific molecular systems. Rappe and co-workers have recently reported on a new force-field called the Universal force field (UFF),4s in which the functional forms parameters and generating formulae are intended for the full periodic table.The set of fundamental parameters within UFF is based on the element its hybridization and its connectivity; in total UFF includes 126 atom types. Detailed comparisons are made of conformational energetics and molecular structures with experimental and published MM2 and MM3 results for organic molecules.49 The ability of UFF to reproduce the structures of a variety of main group molecules is also examined.” Whilst UFF represents a new force field the long-standing ones continue to be updated and refined. One such case is the study of the MM2 force field concerning electrostatic corrections proposed by Allinger and Lii,’ and independently by Pettersson and Liljefors.s2 Modelling was performed on a set of compounds containing phenyl groups and polar substituents on neighbouring carbon atoms with the inclusion of dipole moments for Csp2-Csp3 and Csp2-H bonds.s3 The resulting conformations with these modifications show significant improvements though a lower value for the V parameter for the torsional unit C,p2-Csp3-Csp3-Csp2 was used instead of the MM2 value.The potential functions for simple amides several peptides and the small protein Crambin was recently reported for the MM3 force field.s4 The force field for simple amides gives good results for either gas-phase or crystal structures and fair results for vibrational spectra. For peptides and the protein Crambin structural results are comparable to more specialized protein force fields.Results of calculations on aldehydes and ketones using MM3 have also recently been reported.” An alternative to the all-atom modelling of peptides and proteins is the approach taken by Gerbe~-’~ in which entire residues are the smallest units. In this description each amino acid is represented by a single point in space taken to be the position of the a-carbon atom. Additional degrees of freedom are the torsional angles + and t,b to account for the orientation of the peptides links. This ‘peptide mechanics’ force field is reported to reproduce secondary structure elements with high accuracy. Hoops et a1.57 describe application of a systematic method for incorporating a metal ion and its ligand into a classical force field.In particular reference 57 extends the AMBER force field to model the Zinc ion in human carbonic anhydrase I1 in both high and low pH forms. The approach should be transferable to computational studies of other metalloproteins at fixed coordination numbers. 48 A. K. Rappe C. J. Casewit K. S. Colwell W. A. Goddard and W. M. Skiff J. Am. Chem. SOC. 1992,114 10024. 49 C.J. Casewit K.S. Colwell and A.K. Rappe J. Am. Chem. Soc. 1992 114 10035. ’O C. J. Casewit K. S. Colwell and A. K. Rappe J. Am. Chem. Soc. 1992 114 10046. ” N. L. Allinger and J. H. Lii J. Comput. Chem. 1987 8 1146. ’* I. Pettersson and T. Liljefors J. Comput. Chem. 1987 8 1139. ’3 P. M. Ivanov and T. G. Momchilova J. Mol. Strucr. (Theochern) 1991 233 115.54 J. H. Lii and N. L. Allinger J. Comput. Chem. 1991 12 186. ” N. L. Allinger K. Chen M. Rahman and A. Pathiaseril J. Am. Chem. SOC. 1991 113 4505. ’6 P. R. Gerber Biopolymers 1992 32 1003. ” S.C. Hoops K. W. Anderson and K.M. Merz J. Am. Chem. Soc. 1991 113 8262. 28 C.I. de Matteis D. E. Jackson and N. Raj The COSMIC force field developed by Vinter and co-workers over the past fifteen years has primarily been used for modelling relatively small organic molecules. Over this period of software development the potential functions parameters and atom types have been kept as simple as possible with neither cross-terms nor higher-order terms to describe bond or angle distortions. Atom types describe little more than the hybridization and basic geometry of each atom.Morley et have recently reported a number of modifications to COSMIC. These include a two-parameter Morse potential in place of the Hill potential to describe non-bonded interactions; the introduction of a simple iterative Huckel n-electron molecular orbital calculation to allow modelling of conjugated systems; the use of explicit hydrogen-bonding potentials; and the introduction of new atom types. First generation force fields were restricted in their complexity of the analytic representation of the energy surface due to the limited amount of experimental data available for parameterization. The solution to the sparseness of such data came through the advance of high-quality ab initio generated potential-energy surfaces.The approach is to perform ab initio calculations on a number of distorted structures of a given system and so generate large amounts of data describing the full anharmonic potential-energy surface. The aim of Class I1 force fields then is to reproduce structures energies vibrational frequencies and other observables to a high degree of accuracy using a single set of parameters even for problem systems such as highly strained rings. Current Class I1 force fields include Allinger’s MM3’* and Biosym’s CFF91.” The CFF91 force field which now allows modelling of amides and amines,60 employs a quartic polynominal for bond stretching and angle bending; torsions are described by a three-term Fourier expansion and an out-of-plane term is also included. There are seven off-diagonal terms together with a Coulombic interaction between atomic charges.Finally a 9-6 potential is used for van der Waals interactions. Determination of forcefield parameters has been done by Aleman et ~1.~’ by use of quantum mechanic calculations. The approach has been incorporated into a computer program called PAPQMD (Program for Approximate Parameterization from Quan- tum Mechanical Data) which is developed to provide a tool for the determination of approximate bonded force parameters. In a following paper6’ the authors examine the reliability of the semi-empirical RHF (Restricted Hartree-Fock) wavefunction com- puted from MIND0/3,63 MND0,64 and AM 1 65 Hamiltonians to correctly represent the molecular characteristics in its perturbed geometries.Force field parameters derived semi-empirically are then compared to experimentally determined values used in the most popular force fields. An alternative to deriving parameters by optimizing agreement between experimen- 58 (a) N.L. Allinger Y.H. Yuh and J.H. Lii J. Am. Chem. SOC. 1989 111 8551; (b)J.H. Lii and N.L. Allinger J. Am. Chem. SOC. 1989,111,8566; (c)J. H. Lii and N. L. Allinger J. Am. Chem. SOC. 1989,111 8576. 59 (a)J. R.Maple U. Dinur and A. T. Hagler Proc. Nat. Acad. Sci. USA 1988,85,5350; (b)J. R. Maple T. S. Thacher U. Dinur and A.T. Hagler Chem. Design Aut. News.,1990 5(9) 5. 60 ‘DISCOVER 2.8’ Biosym Technologies Inc. 9685 Scranton Road San Diego CA 92121 USA. 61 C. Aleman E.I. Canela R. Franco and M. Orozco J. Comput.Chem. 1991 12 664. 62 C. Aleman and M. Orozco J. Cornput.-Aided Mol. Design 1992 6 331. 63 R.C. Bingham M. J. S. Dewar and D. H. Lo J. Am. Chem. SOC. 1975 97 1285. 64 M. J.S. Dewar and W. Thiel J. Am. Chem. SOC. 1971 99,4899. 65 M. J. S. Dewar E.G. Zoebisch E. F. Healy and J. J. P. Stewart J. Am. Chem. SOC. 1985 107 3902. Physical Methods and Techniques -Part (ii) Computer Graphics 29 tal and potential energy predictions is to compare experiment with free energy. The free energy perturbation (FEP) is given by AG = G -C; = -RTln<exp( -AH/RT)> (21 where AG is the free energy difference between states A and B AH is the difference between the Hamiltonians representative of these states R is the gas constant and T the temperature. Pearlman and Kollman66 use FEP in conjunction with a constraint method to generate torsion maps for comparison with potential energy torsion maps.The two maps for nucleosides are qualitatively similar but display significant quantitative differences. This indicates the significant role entropy can play in stabilizing various conformers. In the abstracts of the 204th American Chemical Society (ACS) National Meeting a number of works were presented concerning force field development. For instance recent developments of the Chem-X67 and MM368 force fields. Also given is the form scope parameterization and performance of the Merck Molecular force field.69 A systematic method for estimating MM2 parameters is given by Liu and P~rvis.’~ Cornell et al.” present a second-generation force field for proteins nucleic acids and small molecules.The development of a force field for modelling organometallics is presented by Gilbert et At earlier meetings the modelling of carbohydrates and polysaccharides was presented by brad^'^ and the derivation of QSAR parameters from quantum mechanical and force field calculations was presented by Hemken and Lehmann.74 For molecules in solution calculations are complicated due to the presence of solvent interactions which significantly affect conformational energies. An article by Teeter,75 for example discusses the theory and experiment behind water-protein interactions. Explicit inclusion of solvent molecules is practised but such an approach is computationally demanding. It is therefore desirable to have a potential function which accounts for solvent effects without the need to incorporate solvent molecules into the modelling system.Gilson and Honig76 have introduced a new pairwise energy term which accounts for charge-solvent interactions and can easily be incorporated into existing force fields. The POLARIS77 software which allows modelling of proteins in their solvent environment has been developed to allow free energy perturbation (FEP) calculations. BOSS7*is a program for performing Monte Carlo simulations for solutions containing a small number of solute molecules in either a solvent or in a dielectric continuum. 66 D. A. Pearlman and P. A. Kollman J. Am. Chem. Soc.. 1991 113 7167. ’’ K. Davies and M. Baird Ah. Papers.Am. Chem. Soc.. 1992 204. 41. ‘* J. P. Bowen P. C. Fox G. Y. Liang G. McGaughey. J. Y. Shim. and E. L. Stewart .4hs. Papers Am. Chem. Soc. 1992 204 39. 69 T.A. Halgren Ahs. Papers Am. Chem. SOL..,1992 204. 38. ’’ S.Y. Liu and G. D. Purvis Ahs. Papers Am. Chem. Soc. 1992. 204 33. 71 W. D. Cornell P. Cieplak I. R. Gould K. M. Merz J. W. Caldwell D. C. Spellmeyer. and P. A. Kollman Abs. Papers Am. Chem. Soc. 1992 204 40. 72 K. E. Gilbert J. J. Gajewski. and T. Kreek. Abs. Papers Am. Chem. Soc.. 1992. 204 379. 73 J. W. Brady Ah. Papers Am. Chem. Soc. 1992 203 4. 74 H.G. Hemken and P. A. Lehmann Ahs. Papers Am. Chem. Soc.. 1991. 202. 44. l5 M. M. Teeter Annu. Rev. Biophys. Biophys. Chem. 1991 20. 577. 76 M.K. Gilson and B. Honig J. Compur.-Aided Mol. Design 1991.5. 5. ” ‘POLARIS’ Molecular Simulations Inc. 200 Fifth Avenue Waltham MA 02154 USA. 78 ‘BOSS’ Tripos Associates Inc. 1699 South Hanley Road Suite 303 St Louis MO 63144 IJSA. 30 C.I. de Matteis D.E. Jackson and N. Raj An important feature in molecular modelling is the treatment of electrostatics. Interactions involving electrostatics are crucial in such cases as the understanding of conformations of solutes in highly dielectric solvents and also the recognition process of ligands by biological receptors. Most electrostatic calculations rely on the assumption that partial charges may be placed at atomic nuclei. These charges may be calculated rigorously by evaluating the Molecular Electrostatic Potential (MEP) from the wavefunction of a particular molecule in a given conformation.Fitting procedures are then used to assign partial charges so as to obtain the required MEP. Such an approach is clearly a function of molecular conformation and different MEP applications in drug design are discussed by Pepe et A technique for calculating partial charges given just initial nuclear coordinates is used in the CHARGE2 program. CHARGE2 is an empirical procedure for the rapid evaluation of partial charges with the original paper" concerned solely with haloalkanes. Since the first publication CHARGE has continued to develop and is now widely used in the modelling community. CHARGE2 is based on two fundamental chemical concepts the inductive effect in saturated molecules and Hiickel Molecular Orbital calculations for n-systems.The inductive effect operates uia the atomic electronegativity and polarizability and the Hiickel scheme works through appropriate Coulomb and resonance integrals. Parameterization of CHARGE2 is based on the observed molecular dipole moments. In a recent article" the authors consider the problems of including silicon together with methods of overcoming them. Also partial atomic charges for all the natural amino acids and the nucleic acids adenine cytosine guanine and thymine are given. In reference 82 the charge scheme of reference 80 is subjected to major re-parameterization in order to obtain a more general series of parameters describing the bonding interactions in saturated organic molecules. Mullays3 reports on a simple method for calculating atomic charges in charged molecular systems.The method is based on the orbital electronegativity (EN) concept and utilizes an EN equalization principal. Results show that the method compares well with high level theoretical calculations for a variety of charged molecules including alanine and protonated adenine. A recent development in modelling software is HYPERCHEM84 3D which offers four molecular mechanics force fields MM' AMBER BIO' and OPLS. MM' supplements the standard MM2 force field by providing additional parameters and BIO' is an implementation of CHARMm. This modelling system can be run on either 386/486 PC or UNIX platforms. Bays has given a broad overview of five molecular modelling programs for the Macintosh.85 The packages reviewed are Alchemy 11,86 Nemesis,87 PC-Model,88 79 G.Pepe D. Siri and J. P. Reboul J. Mol. Struct. (Theochem) 1992 88 175. 'O R.J. Abraham L. Griffiths and P.J. Loftus J. Cornput. Chern. 1982 3 407. " R. J. Abraham G. H. Grant I. S. Haworth and P. E. Smith J. Cornput.-Aided Mol. Design 1991 5 21. " R. J. Abraham and G. H. Grant J. Cornput.-Aided Mol. Design 1992 6 273. '3 J. Mullay J. Comput. Chern. 1991 12 369. 84 'HYPERCHEM' developed and licensed from Hypercube Inc. Supplied by C.E. Systems Unit 55 Suttons Park London Road Reading RG6 lAZ UK. *5 J. P. Bays J. Chern. Educ. 1992 69 209. '6 'Alchemy II' Tripos Associates Inc. 1699 South Hanley Road Suite 303 St Louis MO 63144 USA. 87 'NEMESIS' Oxford Molecular Ltd The Magdalen Centre Oxford Science Park Sandford-on-Thames Oxford OX4 4GA UK." 'PC-MODEL' Serena Software Box 3076 Bloomington IN 47 402-3076 USA. Physical Methods and Techniques -Part (ii) Computer Graphics 31 MacMimic,*’ and Chem3D P~US.’~ The review describes features such as how structures are constructed and then displayed and manipulated. The software also allows molecular mechanics computations with each package having its own force field. Alchemy I1 uses SYBYL; MacMimic uses MM2(87); PC-model and Chem-3D Plus force fields are based upon modified MM2; and Nemesis uses COSMIC-90. Molecular Simulations.-In energy minimization the task is to find the set of independent variables x = (x,,x,,x, . . .,x,,) for which the function V = V(x)has its minimum value.In the case of a molecular system comprising N atoms the 3N components of x are the atomic coordinates and Vis the potential energy. It should be pointed out that the problem of finding the global minimum of a general non-linear function with a realistic number of independent variables is extremely difficult. In molecular energy minimization the two algorithms most commonly used are steepest-descent and conjugate-gradient . Kini and Evans’ have reported on their work to develop a procedure which may routinely be used to build models of homologous proteins starting from the experimental structure of a closely related protein. Energy minimization strategies were performed on melittin and cardiotoxin by both constrained and unconstrained pathways. In addition the effects of the steepest-descent and conjugate-gradient algorithms for energy minimization were compared.Based on these results molecular modelling was applied to lysozyme mutants. In reference 92 a molecular mechanics energy minimizer ORAL is presented whose main features include ‘floating blocks’ and ‘isles’. The blocks are sets of atoms grouped together by the user and isles allow interactions between groups of atoms to be ‘switched-off ’. The program possibilities are presented by examples of molecular docking energy barrier estimation modelling of infinite structures and DNA bending simulations. Morley et al.’ have developed a hybrid conformational search algorithm Dynamic Monte Carlo (DMC) that combines a modified form of molecular dynamics with Metropolis Monte Carlo sampling.In DMC trial configurations are generated by short bursts of high-temperature dynamics in which the initial kinetic energy is focused into single bond rotations or ‘corner-flapping’ motions in ring systems. Constant temperature and simulated annealing protocols were then applied to conformational analysis of several model hydrocarbons. The work in reference 93 has since been extended to allow modelling of multi-fragment systems. This is achieved by incorporat- ing additional motions to focus energy into fragment translates and rotates. The complexes of macrocyclic hosts with suitable guest molecules are of great current intere~t,’~ both in their own right and also as model systems for studying molecular recognition and the binding interactions of larger systems such as enzyme-substrate complexes95 and macromolecule-water interaction^.^^ Molecular 89 ‘MacMimic’ Instar Software AB Research Park IDEON $22 370 Lund Sweden.9” Them-3D PLUS’ Cambridge Scientific Computing Inc. 875 Massachusetts Avenue Suite 41 Cambridge MA 02139 USA. 91 R. M. Kini and H. J. Evans. J. Biomol. Struct. Dyn. 1991 9 475. 92 K. Zimmermann J. Comput. Chem. 1991 12 310. 93 S. D. Morley D. E. Jackson M. R. Saunders. and J. G. Vinter J. Comput. Chem. 1992 13 693. 94 (a)J. M. Lehn Angew. Chem..Int. Ed. Engl. 1988,27 89; (6) D. J. Cram. Angew. Chem..Int. Ed. Engl. ’’ (a) 1988 27 1009. J. Blaney P.Weiner. A. Dearing P. Kollman E. Jorgensen,S. Oatley,J. Burridge,and C. Blake J. Am. Chem.Soc. 1982,104,6424; (6)G.Wipff A. Dearing P. Weiner J. Blaney and P. Kollman J. Am. Chem. Soc. 1983 105. 997. 32 C.1.de Matteis D. E. Jackson and N. Raj modelling has been applied to host-guest or receptor-ligand complexation to study the influence of steric-fit and electrostatic interactions. A recent article by Harris96 gives an interesting account of the nature of 'Inclusion Complexes' in which two types of confinement are described. In one type the host is the molecule with a form of cavity able to enclose a suitable guest. In the other type of complex the guest is embedded within well-defined cavities of a crystalline host. Hart and Read9' present the Multiple-Start Monte Carlo Docking Method to search for possible binding modes of molecular fragments at a specific site of a potential drug target.An MC run is first performed in which the energy in the Metropolis algorithm is replaced by a score function that measures the average distance of the probe to the target surface. This has the effect of making buried probes move toward the target surface and allows enhanced sampling of deep pockets. In the second stage an energy-driven MC is used to recover all favourable states of the bound complex. Protein-protein docking simulations have been reported by Cherfils et Anti-body-lysozyme and protease-inhibitor complexes are reconstituted by docking lysozyme as a rigid body onto the combining site of the antibodies and the inhibitor onto the active site of the proteases. The proteins are modelled with one sphere per residue and subjected to simulated annealing using a crude energy function.Five out of six of the resulting complexes retained the X-ray crystallography structures. A further docking algorithm based on graph theoretical techniques is presented by Kasinos et Results are given for the molecular recognition problem where given information concerning particular atoms involved in the binding for one molecule the algorithm correctly identifies the corresponding atoms of the approaching molecule. Gussio et a/.'00point out the importance of dielectric effects in their study of the docking of 4,5-a-epoxymorphinans into an Asp-Lys-His-Phe pseudoreceptor. Kostense et a!. report on modelling of B-cyclodextrins hosts with a variety of guest molecules by rigid body docking.Inclusion of a guest inside the cyclodextrin cavity causes the cavity to elliptically distort and the amount of distortion is related to the van der Waals volume of the guest. This enabled the authors to develop a procedure to construct fi-cyclodextrin molecules that are able to encompass guest molecules with a given van der Waals volume. Morley et a!.'02 have performed a number of complexation studies using their multi-fragment DMC algorithm. The simulations were performed with no constraints applied to host or guest molecules. Successful docking with good agreement with crystallographic data was obtained for p-tert-butylcalix[4]arene with toluene and dibenzo-34-crown-10 with [Methyl viologen12 + . In addition modelling results are presented for inclusion complexes studied experimentally by Cram et ~1."~of crown ether hosts with chiral amino acid-derivative guests.96 K. D. M. Harris Chem. Br. 1993 29 132. 97 T. M. Hart and R. J. Read Proteins Struct. Funct. Gene. 1992 13 206. 98 J. Cherfils S. Duquerroy and J. Janin Proteins Struct. Funct. Gene. 1991 11 271. 99 N. Kasinos G. A. Lilley N. Subbarao and I. Haneef Prot. Eng. 1992 5 69. *Oo R. Gussio S. Pou J.H. Chen and G. W. Smythers J. Cornput.-Aided Mol. Design 1992 6 149. lo' A. S. Kostense S.P. van Helden and L. H. M. Janssen J. Cornput.-Aided Mol. Design 1991 5 525. lo' S.D. Morley. N. Raj D. E. Jackson and P. M. Williams in 'Computer Aided Innovation of New Materials II' ed. M. Doyama J. Kihara M. Tanaka and R. Yamamoto Elsevier Amsterdam 1993 p.835. lo3 (a)D. J. Cram R.C. Helgeson S.C. Peacock L. J. Kaplan L.A. Domeier P. Moreau K. Koga J. M. Mayer Y. Chao M.G. Siege] D. H. Hoffman and G. D. Y. Sogah J. Org. Chem. 1978,43 1930; (b)C. B. Knobler F. C. A. Gaeta and D. J. Cram J. Chem. Soc. Chem. Cornmun. 1988 330. Physical Methods and Techniques -Part (ii) Computer Graphics 3 Chemical Databases The number and size of chemical information databases continues to increase together with the development of more sophisticated search and retrieval software. ‘Beilstein’s Current Facts in Chemistry’ is a database of chemical literature which can be queried using a number of data fields and is available on CD-ROM.lo4 ‘Comprehensive Heterocyclic Chemistry’ is a database of reactions involving heterocyclic compounds and can be searched by 2D structure or substructure and by a variety of textual data fields.lo5 ‘Beilstein Online’ now contains over 6.2 million preparations and reac- tions,lo6 whilst the Chemical Abstracts Registry database now contains 4.5 million substances.lo’ Chemical Abstracts is developing a new information service where concept searching and browsing facilities will be available.Text and pictures will be integrated and Hypertext navigation will allow easy access to related textual information at the touch of a button.”* The increasing availability and use of three dimensional structural data from experimental and theoretical techniques has fuelled the development of new databases and the expansion of existing ones allowing the storage and retrieval of three dimensional information.The Cambridge Structural Database now contains atomic coordinates for more than 100000 organic and organometallic compounds and 10000 new additions are predicted annually. The version V database allows searches by 3D and 2D structures and substructures together with intramolecular and intermolecular sear~hes.’~’ The Brookhaven Protein Data Bank contains three dimensional atomic coordinates for proteins nucleic acids and polysaccharides and the number of complete structures in January 1993 was 1055. The database cannot be searched at present although developments are underway to develop more intelligent retrieval software.’ lo ‘Iditis’ is a database that stores structural data calculated from Brook- haven Protein Data Bank structures and allows searching through these data for structural features of interest.In total 370 different fields of information are calculated for each protein including descriptions of motifs secondary structure amino acid and atomic structure positions of hydrogen bonds and positions of disulfide bridges.’ CAST-3D is an online database developed by Chemical Abstracts containing the three dimensional coordinates for a growing number of substances within the ‘Chemical Abstracts Registry File’. The atomic coordinates have been obtained using CON-CORD. This database can be searched three dimensionally and using Registry numbers for the compounds located allows direct querying of other Chemical Abstracts databases.’ l2 SYBYL/3DB UNITY is a commercially available three ‘Beilstein’s Current Facts in Chemistry’.Springer-Verlag Electronic Media Department 175 Fifth Avenue New York NY 10010 USA. In5 ‘Comprehensive Heterocyclic Chemistry’ Molecular Design Ltd. 10Armstrong Mall. Southwood Summit Centre Farnborough Hampshire GU14 ONR UK. Io6 ‘Beilstein Online’ Springer-Verlag Electronic Media Department 175 Fifth Avenue New York NY 10010. USA. lo’ ‘CAS Registry System’ Chemical Abstracts Services. Io8 M. Withers Chem. Br. 1993 29 274. F. H. Allen and 0.Kennard Chem. Des. Auto. News. 1993 8 1. ‘Io ‘Protein Data Bank’ Chemistry Department Building 555 Brookhaven National Laboratory Upton NY 11 973 USA. ’ ’ ‘Iditis’ Oxford Molecular Ltd. The Magdalen Centre Oxford Science Park Sandford-on-Thames Oxford OX4 4GA UK.‘I2 ‘CAST-3D’ Chemical Abstracts Services. C.I. de Matteis D.E. Jackson and N. Raj dimensional data storage and retrieval system which can import data from a number of commercial and public domain databases together with storing in-house data.’ l3 Pharmastructures is a PC based 3D structure database at present containing 4000 structures.’ l4 Further MDL and ICI are developing software which will incorporate conformationally flexible searching into the 3D search software MACCS-3D and ISIS/3D. This is achieved by allowing rotation about single bonds to create the conformation necessary to match a query.’ ‘I3 ‘SYBYL-3DB UNITY’ Tripos Associates Inc. 1699 South Hanley Road Suite 303 St Louis MO 63 144 USA.‘Pharmastructures’ 18-20 Hill Rise Richmond Surrey TW 10 6UA UK. ‘I5 B.F. Graham Chern. Des. Aut. Nrris. 1993 8 30.

ISSN:0069-3030    

DOI:10.1039/OC9928900021

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

3 Theoretical Organic Chemistry By J. J. W. McDOUALL Department of Chemistry University of Manchester Manchester M 13 9PL UK 1 Methods The high level of activity in the area of density functional theory continues and a number of useful assessments of various aspects have appeared. Notable amongst these is a detailed review of the methodology of the DGauss program' and its application to many organic systems. Fan and Ziegler2 also provide an assessment of their density functional formalism through its application to the calculation of activation energies for elementary organic reactions the results of which are very encouraging. Applica- tion of density functional theory to the calculation of 27 homolytic dissociation reactions using generalized valence bond (GVB) reference wavefunctions3 and a modest basis set (&3 lG(D)) show an average error of 4kcal mol- '.The use of the same basis set and Hartree-Fock reference wavefunctions with a density function treatment of exchange and correlation4 for a set of 106 experimentally well established atomization energies ionization potentials and proton affinities show a mean absolute deviation of only 4.18 kcal mol- '.Other tests of density functional using the large G1 database of Pople and co-workers' have also shown these approaches to provide accurate and computationally efficient methods for studying chemical reactions.Though not directly related to density functional theory an interesting analysis of the effect of electron correlation on charge density distributions in molecules has been carried out for the widely used MP2 CISD and QCISD wavefunctions.8 Compared to the QCI density MP2 is found to consistently exaggerate the loss in charge density in bonding regions leading to an increase in bond length whereas CISD is found to underestimate the shift.Pople and co-workers have provided a detailed overview of their approach to the molecular orbital theory ofexcited states.' The method is now applicable to quite large 1 cal = 4.1845 J. Andzelm and E. Wimmer J. Chem. Phys. 1992 96 1280. L. Fan and T. Ziegler J. Am. Chem. Soc. 1992 114 10890. E. Kraka Chem. Phys. 1992 161. 149. P. M. W. Gill B.G. Johnson J. A. Pople and M. J. Frisch Chem. Phys. Lett. 1992 197 499. ' A. Becke J. Chern. Phys. 1992 96 2155.'A. Becke J. Chem. Phys. 1992 97 9173. 'J. A. Pople M. Head-Gordon D.J. Fox K. Raghavachari and L. A. Curtiss,J. Chem. Phys. 1989,97,9173; L.A. Curtiss K. Raghavachari G. W. Trucks and J. A. Pople J. Chem. Phys. 1992 97 9173. K. B. Wiberg C. M. Hadad T.J. LePage C. M. Breneman and M. J. Frisch J. Phys. Chem. 1992,96,671. 'J. B. Foresman M. Head-Gordon J. A. Pople and M. J. Frisch J. Phys. Chem. 1992 96 135. J. J. W. McDouall systems as demonstrated by calculations on the excited states of formaldehyde ethylene pyridine and porphin. 2 Bonding and Molecular Structure It seems appropriate to begin this section by mentioning a review entitled 'The VSEPR Model Revisited'.'' An up-to-date account of the model with emphasis on an improved reformulation of some of the basic ideas together with some examples of new applications is given.As a qualitative method for predicting molecular geometries it remains hard to beat! The effects of sulfur and nitrogen substituents on the properties of 23 analogues of monoanionic methylphosphonates and methylphosphinates have been studied.' Pv compounds with oxygen bound to phosphorus are generally the most stable analogues and consecutive substitution by sulfur and nitrogen makes these compounds less stable. The sulfur analogues of PI" compounds were found to be the most stable while compounds with P=NH groups were calculated to be the most unstable analogues. A study of the structures of 12 phosphonium ylides (l),shows that they can be classified as (i) non-stabilized and (ii) stabilized ylides.'' All examples of non-stabilized ylides have non-planar ylidic carbon geometries while stabilized ylides have planar ylidic carbons.These structures have been used to support the notion that the dominant resonance structure is the ylide form. Mide Ylene (1) Molecular electrostatic potentials have been used to determine the effect of the substituent groups -F -NH, -OH -CH, CH,=C- HCEC-on the carbon- phosphorus triple bond in phosphaalkynes.' In spite of the varying electronegativity of the groups studied a characteristic feature found is the weak sensitivity of the C-P bond length to the substituent at the carbon atom. The electrostatic potential reflects the relative electronegativity of these groups and their ability to attract the polarizable charge from the carbon-phosphorus triple bond.This also suggests that these derivatives of phosphaalkynes are most likely to attract incoming electrophiles to the n-electron region of the carbon-phosphorus triple bond. Transition metals are coordinated 'sideways' with phosphaalkynes and in this configuration the lone-pair electrons of the phosphorus atom are unlikely to interact with the metal. A number of studies of tautomeric equilibria in the gas phase and solution have appeared. These include the keto-enol tautomerism of 3-and 5-hydroxyisoxazole,'4 lo R. J. Gillespie Chem. SOC.Rev. 1992 21 59. l1 M. Perakyla T. A. Pakkanen J.-P. Bjorkroth E. Pohjala and H. 0.Leiras J. Chem. SOC.,Perkin Trans. 2 1992 1167.l2 S.M. Bachrach J. Org. Chem. 1992 57 4367. '' K. Jayasuriya Int. J. Quantum Chem. 1992 44,321. l4 S. Woodcock D. V. S. Green M. A. Vincent I. H. Hillier and M. F. Guest J. Chem. SOC., Perkin Trans. 2 1992 2151. Theoretical Organic Chemistry three tautomers of 3-amino- 1,2,4-triazole,' and tautomerism in cytosine.' Note also a high-level gas-phase study of the four most important tautomers of uracil' and the infrared spectrum of the dioxo form.'* The structures and energies of MeCH,NO (2) and MeNHNO (3) and their tautomeric (E,Z)-and (Z,Z)-nitronic acids (4) and (5) respectively have been investigated." Also the nitroanions MeCH=NO; (6)and MeN=NO; (7) which are intermediates in the transformations (2) -P (4) (3) -,(5) have been determined.(Z,Z)- (4)and (Z,Z)-(5) were calculated to be 18.4 kcal mol -' and 14.0 kcal mol- ' less stable than (2) and (3) respectively (the (Z,Z)-isomers being the most stable); (3)was found to be essentially nonplanar. Ab initio calculations of tautomerism between formhydroxamic acid (8) and formhydroximic acid (9)20 H(C=O)NHOH eHC(OH)=NOH (81 (91 show that formhydroxamic acid is more stable by 40.7 kJ mol- '. The activation energy for the tautomerism via a 1,3-intramolecular hydrogen shift is 15 1.4 kJ mol- '. The formhydroximic acid is predicted to have a possibility of existence in conditions of low temperature and pressure. The structures of the fluoromethylplumbanes CH,PbF (lo) (CH,),PbF (1 l) and CH,PbF (12) show that the bond angles in all of the unsymmetrically substituted species deviate significantly from the idealized tetrahedral values.' F-Pb-F angles are less than 109.5 O C-Pb-C angles are considerably larger. The most extreme case being (11) with a C-Pb-C of 135". In (10) the C,Pb unit approaches planarity. Pb" compounds are destabilized by electronegative substituents in contrast to alkanes and silanes which are stabilized by geminal fluorine substitution. Transition metal activation of C-C bonds in ethane and cyclobutane have been studied for the entire second row of transition metals. For cyclobutane the first transition metal series has also been studied,22 and cyclopropane has also been studied for rhodium and palladium. Palladium is found to have the smallest barriers for the IS O.G.Parchment I. H. Hillier D. V. S. Green N.A. Burton. J. 0.Morley. and H. F. Schaefer 111 J. Chem. SOC.,Perkin Trans. 2 1992. 1681. 16 I. R. Gould. D. V. S. Green P. Young and I. H. Hillier J. Org. Chem. 1992 57. 4434. 17 J. Leszczynski J. Phys. Chern. 1992 96 1649. I8 I. R. Gould. M. A. Vincent and I. H. Hillier J. Chem. Soc.. Perkin Trans. 2 1992 69. 19 V.G. Arakyan and O.V. Fateyev THEOCHEM 1992 262. 39. 20 D. Wengui. Int. J. Quunturn Chem. 1992 44 319. 21 M. Kaupp and P. von R. Schleyer. Angeu.. Chern. Inr. Ed. Engl. 1992 31 1224. 22 P. E. M. Siegbahn and M. R. A. Blornberg J. Am. Chem. Sac.. 1992 114 10548. 38 J.J. W. McDouall C-C breaking reaction with the bond in cyclopropane being the easiest to break.The binding energy curve between ethene and all second row transition metals from yttrium to palladium has been ~alculated.~~ The strongest bonds are formed by the atoms to the right for which covalent and donation-back-donation bonding is optimally mixed. The atoms to the left form metallocyclopropanes in which the C-C n-bond is fully broken. Theoretical binding energies have also been obtained for all of the first row and selected members of the second row transition metal ion-benzene complexes.24 Although the bonding is found to be predominantly electrostatic a significant enhancement to the bonding does arise from metal donation into the n* orbitals of benzene. The structure of azole-X+ (X = Na K Al) complexes show the A1 complex closely resembles the corresponding protonated species while those of Na' and K+ are similar to that found for Li+.25 The Al+-azole interaction has a non-negligible covalent character due to the low lying p orbitals of Al'.It is suggested that this interaction is responsible for the enhanced stability of some A1 complexes. + The acid-strengthening and base-weakening effect of the acetylenic linkage as illustrated by a comparison of ethyneamine (HC-CNH,) and etheneamine (H2C=CHNH,)26 shows ethyneamine to have a very high relative acidity due to the relative stabilization of the ethynylamide anion. The corresponding low basicity is due to the relative destabilization of the ethynylammonium cation. For both ethyneamine and etheneamine the preferred site of protonation is on carbon rather than nitrogen due to strong stabilization of the carbon-protonated species.In the geometries of diethers diketones and diamines and their protonated species a good correlation is found between proton affinity and the hydrogen bond angles.27 As the alkyl size increases the angles and the ring strain at the sp3 carbons become larger which leads to a levelling-off of proton affinity values. The splitting between the two lowest energy cation states and the two lowest energy anion states have been investigated for a series of rigid non-conjugated dienes with the two double bonds separated by 4-12 carbon-carbon a-bonds. The dependence of the n+,n-splittings on the number of carbonxarbon a-bonds separating the ethylenic groups is found to have an exponential dependence for dienes with bridge^^^^^^ containing 8,10 and 12 C-C bonds.When four- and six-bond bridges are included the dependence is no longer a simple exponential; the origin of this effect is suggested to be due to multiple through-bond interactions. A high level ab initio study of the structure of acetamide finds that the lowest energy conformer in the gas phase and condensed media has a nonplanar geometry. One of the methyl C-H bonds is almost perpendicular to the plane of the non-hydrogen atoms and the amino group is slightly ~yramidal.~' The preference for this non-planar structure is attributed to the favourable interaction of the nitrogen lone-pair and one of the methyl hydrogens. A recent theoretical study of the diketene (13) produced an equilibrium 23 M.R. A. Blomberg P. E.M. Siegbahn and M. Svensson J. Phys. Chem. 1992 96 9794. 24 C. W. Bauschlicher Jr. H. Partridge and S. R. Langhoff J. Phys. Chem. 1992 % 3273. 25 M. Alcami 0.Mo and M. Yanez J. Phys. Chem. 1992 % 3022. 26 B. J. Smith and L. Radom J. Am. Chem. SOC. 1992 114 36. 27 S. Yamabe K. Hirao and H. Wasada J. Phys. Chem. 1992 % 10261. K. D. Jordan and M. N. Padden-Row J. Phys. Chem. 1992,% 1188. 29 K. D. Jordan and M.N. Padden-Row Chem. Rev. 1992 92 395. 30 M.W. Wong and K.B. Wiberg J. Phys. Chem. 1992,96 668. 31 (a)E. T. Seidl and H. F. Schaefer 111 J. Phys. Chem. 1992,% 657; (b)J. Am. Chem.SOC.,1990,112,1493. Theoretical Organic Chemistry geometry quite different from that determined experimentally by either electron diffraction or X-ray crystallography.An improved level of theory has been applied 31b and the predicted rotational constants are in much better agreement with microwave experiments than are those derived from electron diffraction and crystal structures. A case is put forward that there are serious deficiencies in the experimental molecular structures for diketene. The geometries electron distribution and spin distribution for three oxidation forms of lumiflavin (14) (15) and (16) and the 2+ and 2-charged species have been obtained.32 The reduced form (1,5-dihydrolumiflavin) is found to have a non-planar structure. H3C’ (14) Lumiflavin (oxidized form) (15) 5-hydrolumiflavin (radical form) (1 6) 1,5-dihydrolumiflavin (reduced form) Calculations of various protonation states of DNA base and DNA radical-ions including each of the protonation states important to proton-transfer reactions in base pair radical-ions found in irradiated DNA have been perf~rmed.~~,~~ Evidence is provided for proton transfer in guanine-cytosine base pair radical-anions.Conforma- tional features of amrinone (1 7) and milrinone (18) and their molecular electrostatic 32 S.A. Vasquez J.S. Andrews C. M. Murray R. D. Amos and N.C. Handy J. Chem. SOC.,Perkin Trans. 2 1992 889. 33 A.-0. Colson B. Besler D. M. Close and M. D. Sevilla J. Phys. Chem. 1992 96,661. 34 A.-0. Colson B. Besler D. M. Close and M. D. Sevilla J. Phys. Chem. 1992 % 9787. J. J. W. McDouall potentials have been studied.35 It is suggested that the twisted conformers of these molecules are responsible for their observed cardiotonic properties.H HH HH Nmo:wo H HH NH2 H HH CN Finally there have been a number of studies of the geometries and singlet-triplet energy gaps in ~henylnitrene,~~ (in which the ground state is a triplet) rn-q~inone~~ and tetramethyleneethane38~3gand its cyclic analogue^.^' 3 Reactivity Pericyclic Reactions.-A new secondary orbital interaction has been suggested4l for the Diels-Alder reactions of butadiene with vinyl boranes. In these systems the archetypal [4 + 21 cycloaddition appears to take place via a [4 + 3) transition state in which the distance of the boron atom in the vinyl borane is closer to the terminal carbon atom of the butadiene moiety than is the carbon atom in the vinyl borane.The reaction path for the Diels-Alder reaction of s-cis-1,3-butadiene cation-radical with ethene yielding the cyclohexene cation-radical has been studied42 and found to follow a concerted but non-synchronous path which proceeds without a barrier in the gas phase. In Diels-Alder and nitrile oxide intramolecular cycloadditions it has been found that when the addends are linked by three CH groups (leading to the formation of a five-membered ring) the strain in the transition state causes the addends to twist about the forming bonds resulting in a skewed transition state compared to the intermolecular transition state.43 However when the addends are linked by four CH groups (forming a six-membered ring) there is little strain and the addends do not twist.The different reactivity of oxazole and isoxazole in Diels-Alder cycloadditions is ascribed to the higher energy of activation (13 kcal mol- ') and endothermicity of the isoxazole reactions.44 The activation energies and asynchronicities of the Diels-Alder reactions of 2-azabutadiene with alkenes and alkynes follow the same trends as that of b~tadiene.~' The effect of the aza group in the diene is very small. In the dimerization of silaethylene to form 1,3-disilacyclobutane and 1,2-disilacyclobutane the 1,3 product is formed via a concerted [2s + 2s] mechanism with a barrier of 5.2 kcal mol- '. The 35 A. K. Bhattacharjee D. Majumdar and S. Guha J. Chem. Soc. Perkin Trans. 2 1992 805. 36 D.A.Hrovat E. E. Waali and W.T. Borden J. Am. Chem. SOC. 1992 114 8698. R. C. Fort Jr. S.J. Getty D. A. Hrovat P.M. Lahti and W. T. Borden J. Am. Chem. Soc. 1992,114,7549. 38 P. Nachtingall and K. D. Jordan J. Am. Chem. Soc. 1992 114 4743. 39 P. Nachtingall P. Dowd and K.D. Jordan J. Am. Chem. Soc. 1992 114,4747. 40 J.J. Nash P. Dowd and K.D.Jordan J. Am. Chem. Soc. 1992 114 10071. " D.A. Singleton J. Am. Chem. Soc. 1992 114 6563. 42 N.L. Bauld J. Am. Chem. Soc. 1992 114 5800. 43 F. K. Brown U. C. Singh P. A. Kollman L. Raimondi K. N. Houk and C. W. Bock J.Org. Chem. 1992 57 4862. 44 J. Gonzalez E.C. Taylor and K. N. Houk J. Org. Chem. 1992 57 3753. 45 J. Gonzalez and K. N. Houk J. Org. Chem. 1992 57 3031. Theoretical Organic Chemistry 41 1,2-product is higher in energy by 19.8 kcalmol-' and is formed via a two-step mechanism involving a diradical intermediate.46 The [2s + 2s] cycloaddition of ethylene is a classical forbidden Woodward-Hoffman process.The reaction lends itself to catalysis via complexation with metal radical- cation^.^' In the case of Be-+ the reaction proceeds via a metallocyclopentane (see Scheme 1 ) radical cation intermediate and two successive 1,2-hydrogen shifts to form the isomeric acyclic butenes. No points on the reaction path have an energy higher than the starting materials. Be" + C2H4 -4be.+ + C2H4 -[[::Bet511 -Scheme 1 The dimerization of carbodiimides (HN=C=NH) to 1,3-diazetidinediimines (19) appears to favour an asynchronous pathway.48 For the case of N-amino-"methyl carbodiimide 12 asynchronous transition structures have been located which lead to isomeric products.The mechanism of the cycloaddition of ketene and imine is found to H I I H be a two-step process with a zwitterionic intermediate.49 The electrocyclic conrotatory closure of this intermediate is predicted to be the rate determining step. The conrotatory ring opening in phospha- and azacyclobutenes is found to be thermoneut- ral or very slightly endothermic for dihydrophosphates but exothermic for dihyd- r~azetes.~'The energies of activation for the opening of 2,3-dihydrophosphete and 3,4-dihydroazete are 41 and 37 kcal mol -',respectively. The opening of 1,2-dihyd- rophosphete and 1,2-dihydroazete can occur via two diastereomeric pathways.Inward rotation of the heteroatom lone pair is favoured for both systems. The barriers are 25 and 30 kcal mol- ' for 1,2-dihydrophosphete and 2,3-dihydrophosphete respectively. The conrotatory ring opening of dihydrodiphosphetes is endothermic while the opening of the dihydrodiazetes is ex other mi^.^' Inward rotation of the heteroatom lone pair is favoured in all cases. A detailed study of the transition structures of pericyclic hydrocarbon reactions finds common features in the geometries energies and electronic characteristics.s2 General- " E.T. Seidl R. s. Grev and H. F. Schaefer 111 J. Am. Chem. Soc. 1992 114. 3643. '' A. Alex and T. Clark 1. Am. Chem. SOC.. 1992 114 506. '' J. Bertran A. Oliva J. Jose M. Duran P. Molina M. Alajarin C.L. Leonardo and J. Elguero J. Chem. SOC.,Perkin Trans 2 1992 299. 49 J.A. Sordo J. Gonzalez. and T. L. Sordo. J. Am. Chem. Soc. 1992. 114 6249. " S.M. Bachrach and M. Liu J. Org. Chem. 1992 57 209. " S.M. Bachrach and M. Liu J. Org. Chem. 1992 57 2040. " K.N. Houk Y. Li and J. D. Evanseck Angew. Chem.. Int. Ed. Enyl.. 1992 31 682. 42 J.J. W. McDouall ization permits the prediction of other transition state geometries and energies. At the same time a great diversity of electronic structure is observed from rigid closed shells to floppy diradicals. Other interesting results on pericyclic processes include evidence for the photo- chemical addition of halo(trifluoromethy1)carbenes to dinitr0ge1-1~~ and a study of the thermal and photochemical cycloaddition of Dewar benzene.54 Oxygen Transfer.-A study of the oxygen transfer from an oxaziridine to the lithium enolate of acetaldehyde shows it to proceed by S,2 attack of the p-carbon on the enolate along the 0-N bond of the parent ~xaziridine.~~ In the transition structure the Li' cation is coordinated to both the enolate and the oxaziridine oxygen atoms.A review of the structure and mechanism of formation of ozonides studies a number of questions regarding the three step Criegee mechanism including evidence for intermediates and whether cycloaddition and cycloreversion are ~oncerted.~~ A study of the reaction of organic sulfides with singlet oxygen57 finds only a peroxy sulfoxide as an intermediate at the Hartree-Fock level of theory.However another intermediate thiadioxirane is found at the MP2 level. In the gas phase these are essentially isoenergetic but peroxy sulfoxide may be preferred in solution. The energy of activation for their interconversion is 20 kcal mol- *. A study on the mechanism of oxidation of sulfides and sulfoxides by dioxirane suggests that the oxidation of sulfoxide to sulfone by parent dioxirane in the gas phase is greatly favoured over the oxidation of sulfide to sulf~xide.~~ Using a simple electrostatic model of solvent the sulfide to sulfoxide oxidation is shown to be stabilized by the presence of solvent while the sulfoxide to sulfone oxidation is destabilized. Hence the difference in the predicted reactivity of dioxiranes with sulfides and sulfoxides in solution may be quite small and solvent dependent.The relative reactivity of dioxirane and its isomeric form carbonyl oxide have been investigated at a number of levels of theory regarding their ability to transfer oxygen to ethylene and ammonia.59 The question of the intermediacy of diradical structures in the transition states of these reactions is analysed and rejected. Unsaturated Systems.-An elaborate calculation of the energy barrier for the isomerization of vinylidene6' finds this system to violate the Hammond postulate. The barrier found is 2.2 kcal mol-' and the reaction exothermicity is 43.9kcal mol-'. In spite of the small barrier and highly exothermic nature of the reaction the transition structure is located halfway between reactant and product.The result is rationalized by considering the two components of the process the location of the transition state is determined by hydrogen migration which has a significant barrier whereas the exothermicity results from the conversion of the lone pair of vinylidene to a 7t bond in acetylene. Each process individually satisfies the Hammond postulate. A study of the mechanism and selectivity of electrophilic aromatic nitration finds '' J.E. O'Gara and W. P. Dailey J. Am. Chem. SOC.,1992 114 3581. 54 I. J. Palmer M. Olivucci F. Bernardi and M.A. Robb J. Org. Chem. 1992 57 5081. 55 R.D. Bach J.L. Andres and F.A. Davis J. Org. Chem. 1992 57 613. 56 R.L. Kuczkowski Chem. SOC.Rev. 1992 21 79. '' F. Jensen J. Org. Chem. 1992 57 6478. 58 J. J. W. McDouall J.Ory. Chem. 1992 57 2861. 59 R. D. Bach J. L. Andres A. L. Owensby H. B. Schlegel and J. J. W. McDouall J. Am. Chem. SOC.,1992 114 7207. 6o G. A. Peterson T.G. Tensfeldt and J.A. Montgomery Jr. J. Am. Chem. SOC. 1992 114 6133. Theoretical Organic Chemistry that unsolvated nitronium ion reacts with benzene to form the Wheland intermediate without an activation barrier.61 However solvated nitronium ion (protonated methyl nitrate) reacts with an activation barrier that is substituent dependent and also dependent on the solvating species. The conversion of diazafulvenone to cyanovinyl isocyanate according to Scheme 2 is predicted to have a barrier to reaction of 44kcal mol- '. The oxocarbene (20)is not an intermediate but the transition state corresponding to the rate determining step.This process constitutes a retro-Wolff rearrangement.62 Scheme 2 In the elimination of molecular hydrogen from 1,4-cyclohexadiene to form benzene it is found that the reactant carbon framework is planar and the transition state has a C, symmetry boat-like conformation. The transition structure has the H moiety located centrally over the ring.63 The predicted barrier is 60.1 kcalmol-' and the exothermicity is 9.3 kcal mol- '. Analysis of relative reactivity in radical addition reactions of the type A-D A-A and D-D (A = acceptor and D = donor) in 1,1-disubstituted ethenes and related monosubstituted ethene and 2-substituted propenes have been perf~rmed.~~ Ground state effects in the 1,1-disubstituted ethene were evaluated using the isodesmic scheme H,C=CXY + H,C=CH -+ H,C=CHX + H,C=CHY (Y X = F OH NH, C1 SH CN CHO BH,).The mechanism of ferrocene formation from atomic iron and cyclopentadiene is found to proceed by insertion of iron into a C-H bond of cyclopentadiene. The resulting high-spin complex then binds another molecule of cyclopentadiene and undergoes conversion to a low-spin complex. Elimination of hydrogen from the final complex is predicted to be facile.65 The bifunctional catalysis by HF of the hydrogenation of ethylene has been studied.66 The presence of the catalyst makes possible a HOMO-LUMO interaction leading to the formation of the two new C-H bonds. The bifunctional catalyst provides an alternative path to the direct charge transfer from ethylene to hydrogen by acting as an electronic bridge (2 1).(21) 61 K. J. Szabo A.-B. Hornfeldt and S. Gronowitz J. Am. Chem. SOC. 1992 114 6827. M.T. Nguyen M. R. Hajnal T.-K. Ha L. G. Vanquickenborne and C.Wentrup J. Am. Chem. SOC.,1992 114 4387. 63 R.J. Rico M. Page and C. Doubleday Jr. J. Am. Chem. SOC. 1992 114 1131. 64 D.J. Pasto J. Org. Chem. 1992 57 1139. 65 M.L. McKee J. Phys. Chem. 1992 % 1683. 66 M. I. Menendez J. A. Sordo and T. L. Sordo J. Phys. Chem. 1992 % 1185. J. J. W. McDouall Transition structures for the syn and anti attack of diazomethane on cis-3,4-dichlorocyclobutene have been The syn attack is predicted to be dominant. General.-There have been a great many excellent studies on the subtleties of reactivity and mechanism.The following is an incomplete list rather than a general discussion of some of them hydration of carbon dioxide by carbonic anhydrase a comparison of the Lipscomb and Lindskog mechanisms including a treatment of solvent effects;68 the reaction path for the alkaline hydrolysis of ester via a hydrogen bonded intermediate;69 a detailed analysis of the reaction of L-ascorbic acid with OH radical including a discussion of the site of attack and mechanism of dehydrati~n;~' the decarboxylation and dehydration reactions of monomeric formic acid;71 dissociation pathways of formic acid;72 molecular orbital calculations on the mechanisms of repair of alkylated n~cleosides;~ modelling of receptor-ligand interactions in proteins specifically for asparagine glutamine serine threonine and tyro~ine;~~ a theoretical study and comparison with experiment of the structure and n-facial regioselectivity of 9-chloro-l,4,5,8-tetrahydro-4a,8a-methanonaphthalene (22);75an investigation of the effects of P-substituents on C-OX bond length in Y-C-C-OX systems (Y = F H SIR,; X = CH, CHO NO,);76pyramidal inversion energies of hypervalent selenox- ides R,SeO (R = H F CH3);77 the mechanism of photolysis and solvolysis of arylvinyl halides;78 primary and secondary hydrogen abstraction from propane by CN radical;79 homolytic substitution by hydrogen atom and methyl radical in alkyl sulfides and sulfoxides;80 quantitative valence-bond curve-crossing calculations for S,2 reactions;' secondary kinetic isotope effects and transition structure geometries for the Cope rearrangement.82 67 M.Bagatti A. Ori A. Rastelli M. Burdisso and R. Gandolfi J. Chem. SOC.,Perkin Trans. 2 1992 1657. 68 M. Sola A. Lledos M. Duran and J. Bertran J. Am. Chem. SOC. 1992 114 869. 69 K. Hori J. Chem. SOC.,Perkin Trans. 2 1992 1629. 70 Y. Abe S.Okada R. Nakao,T. Horii H. Inoue S.Taniguchi,and S. Yamabe,J. Chem. SOC.. Perkin Truns. 2 1992 2221. 71 J. D. Goddard Y. Yamaguchi and H. F. Schaefer 111 J. Chem. Phys. 1992,96 1158. 72 J. S. Francisco J. Chem. Phys. 1992 96,1167. 73 R. H. D. Lyngdon J. Chem. SOC..Perkin Trans. 2 1992 1173. 74 J. Lindroos M. Perakyla J.-P. Bjorkroth and T. A. Pakkanen J. Chem. SOC.,Perkin Trans. 2 1992,2271. 75 B. Halton R. Boese and H.S. Rzepa J. Chem. SOC.,Perkin Trans. 2 1992 447. 16 R. D. Amos N. C. Handy P. G. Jones A. J. Kirby J. K. Parker J. M. Percy and M. D. Su J. Chem.SOC.. Perkin Trans. 2 1992 549. 77 H. Fueno S. Ikuta H. Matsuyama and N. Kamigata J. Chem. SOC.,Perkin Trans. 2 1992 1925. 78 K. Hori H. Kamada T. Kitamura S. Kobayashi and H. Taniguchi J. Chem. SOC.,Perkin Trans. 2 1992 871. 79 J. J. W. McDouall THEOCHEM 1992 255 35. no J. E. Lyons and C. H. Schiesser J. Chem. SOC. Perkin Trans. 2 1992 1655. 81 G. Sini S. Shaik and P.C. Hiberty J. Chem. SOC.,Perkin Trans. 2 1992 1019. 82 K. N. Houk S. M. Gustafson and K.A. Black J. Am. Chem. SOC. 1992 114 8565.

ISSN:0069-3030    

DOI:10.1039/OC9928900035

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (i) Pericyclic Reactions By N. G. RAMSDEN Glaxo Group Research Berkeley Avenue Green ford Middlesex UB6 OHE UK 1 Cycloadditions The topological approach to chemical reactivity in terms of second order similarity indices has been applied to a detailed analysis of correlation effects in pericyclic reactions.' A theoretical study of the intramolecular Diels-Alder reaction suggests that reactions leading to 6,s systems have considerable skew strain in the transition state. This is not seen in 6,6-forming reactions2 MM2 force field calculations have shown that transition state flexibility and conformational effects are the most important factors in determining the stereochemical outcome of these reaction^.^ y-N,N-Dibenzylamino-cr,p-didehydroaminoacid esters undergo cycloaddition reactions with diastereoselectivity opposite to that predicted by the principle of 1,3-allylic strain with addition to the most hindered face being refer red.^ Diastereofacial selectivity in Diels-Alder reactions of z,P-unsaturated esters with stereogenic functions containing oxygen occurs in an anti-Felkin-Ahn sense due to a combination of steric and electronic fact01-s.~ Methylene-lactones (1) undergo highly em selective Diels-Alder reactions with cyclopentadiene to give products with >99% enantiomeric excess; the exo selectivity may result from dipolar interactions.6 The Diels-Alder reaction of phthalimide (2)with enol ethers shows a very large increase in stereoselectivity towards the cis adduct as the pressure is increased.' The rate constant for the cis reaction appears to be under a far greater influence from substituents.The electronic effect of the trifluoromethyl group in (3) on the stereochemical outcome of the reaction is important as replacement with other substituents alters the stereochemistry of the product.* The Diels-Alder reaction of 2H-1,4-0xazin-2-ones with substituted olefins occurs with endo selectivity due to both secondary orbital interactions and repulsion ' R. Ponec and M. Strnad Int. J. Quantum Chem.. 1992 42 501. ' F. K. Brown U. C. Singh P. A. Kollman L. Raimondi K. N. Houk and C. W. Bock J. Org. Chern. 1992 57 4862. L. Raimondi F. K. Brown J. Gonzalez and K.N. Houk J. Am. Chem. SOC. 1992 114 4796. M.T. Reetz F. Kayser and K.Harms Tetrahedron Lett. 1992 33 3453. R. Casas T. Parella V. Branchadell A. Oliva R. M. Ortuno and A. Guingant Tetrahedron 1992,48,2659. ' W. R. Roush and B. B. Brown J. Org. Chem. 1992 57 3380. ' L. F. Tietze T. Huebsch J. Oelze C. Ott W. Tost G. Woerner and M. Buback Chem. Ber. 1992 125 2249. M. Suzuki T. Okada T. Taguchi Y. Hanzawa and Y. Iitaka J. Fluorine Chem. 1992 57 239. 45 N. G. Ramsden between the lactone and olefin substituents in the exo transition state.' The transannular Diels-Alder reaction of (4) occurs with high diastereoselectivity that can be rationalized by MM2 modelling of the transition state." A study of the reaction of (5) with cyclopentadienes both experimentally and theoretically indicates that steric factors alone cannot account for the stereoselectivity in asymmetric thermal Diels-Alder reactions.'' Electronic factors in the transition state must be important. Reactions of acroleins with cyclopentadiene catalysed by the chiral oxazaborolide (6) have been studied by NMR spectroscopy.'2 The structure of the complex of the catalyst with 2-methylacrolein shows that both indole and tosyl rings are crucial to enantioselectivity. The Diels-Alder reaction of (7) catalysed by (8) occurs via a 1 1 complex of aluminium and acryloyl oxygen.13 The C symmetric chiral enamine (9) undergoes cycloadditions with very high enantioselectivity. The intramolecular Diels-Alder reaction of silyl tethered reagents such as (10) is highly stereoselective and the geometry of the transition state appears to be constrained by the dienophile stereocentre.' [(Trimethylsilyl)ethynyl]-9-BBNreacts with acyclic dienes to give cyclohexadienes such as (1 1) with a meta relationship of diene- and boron-substituents.'6 Ab initio 0 +H RH Bu C. Fannes L. Meerpoel S. Toppet and G. Hoornaert Synthesis 1992 705. lo T. Takahashi Y. Sakamoto and T. Doi Tetrahedron Lett. 1992 33 3519. I' B. Stammen U. Berlage R. Kindermann W.S. Sheldrick P. Welzel W.R. Roth M. Kaiser and B. Guenther J. Org. Chem. 1992 57 6566. E. J. Corey,T. P. Loh T. D. Roper M. D. Azimioara and M. C.Noe J. Am. Chem. SOC.,1992,114,8290. l3 E.J. Corey S. Sarshar and J. Bordner J. Am. Chem. SOC. 1992 114 7938. l4 J. E. Backvall C. Lofstrom M. Maffei and V.Langer Tetrahedron Lett. 1992 33 2417. D. Craig and J.C. Reader Tetrahedron Lett. 1992 33 6165. l6 D. A. Singleton and S.W. Leung J. Ory.Chem. 1992 57 4796. Reaction Mechanisms -Part (i) Pericyclic Reactions Ph I CF$OzN NS02CF3 Al‘ I (9) calculations suggest that a [4 + 31 transition state with advanced bonding of boron to C-1 of the butadiene is involved. A further study on the reaction of butadiene with vinyl boranes suggests that the reaction proceeds via an endo transition state with very little charge separation or diradical character. ’’Furthermore calculations do not support the presence of Woodward-Hoffman type secondary orbital interactions. Ynamine esters and a$-unsaturated- 1,3-dicarbonyl compounds give funtionalized pyrans in a formal Diels-Alder reaction.’ Chemoselectivity is governed by steric factors.The heterocyclic Diels-Alder reaction between 1 -0xabutadienes and enol ethers gives dihydropyrans.” The reaction of ethylene with aza-and phos-phabutadienes has been examined with the aid of ab initio calculations.” The reactions of phosphabutadienes are characterized by lower activation energies and higher exothermicity. The difference between activation energy of (E)-and (2)-azabutadienes is greater than that for phosphabutadienes possibly due to the less diffuse phosphorus lone pair leading to less repulsion in the transition state. The transition state for the reaction of l-aza-l,3-butadiene with ethene has been compared with that for butadiene and ethene.21 The transition state for the reaction of 2-aza-1,3-butadiene has also been calculated and the effect of the aza group shown to be negligible.22 The rate and stereoselectivity of the reaction of cyclopentadiene and (-)-menthylacrylate has been measured in a variety of solvent~,~~ The empirical parameter a accounts for rate and diastereoselectivity changes but TC*and 6 need to be included to account for changes in the endolexo ratio.Solvent effects in the retro-Diels-Alder reaction suggest that the solvent acts as an electrophile lowering the activation energy of the reaction.24 The effect is similar to that in the Diels-Alder reaction suggesting D.A. Singleton J. Am. Chem. Soc.. 1992 114 6563. C. P. Dell Tetrahedron Lett. 1992 33 699. A. Celli M.Scotton and A. Sega Tetrahedron 1992 48 5883. lo S.M. Bachrach and M. Liu J. Org. Chem. 1992 57 6736. M. E. Tran Huu Dau J. P. Flamant J. M. Lefour C. Riche and D. S. Grierson Tetrahedron Lett. 1992,33 2343. *’ J. Gonzalez and K. N. Houk J. Org. Chem. 1992 57 3031. 23 C. Cativiela J. I. Garcia J. A. Mayoral A. J. Royo L. Salvatella X. Assfeld and M. F. Ruiz-Lopez J. Phys. Orq. Chem. 1992 5 230. 24 G. Desirnoni G. Faita D. Pasini and P. P. Righetti Tetrahedron 1992 48 1667. 48 N. G. Ramsden that the retro-Diels-Alder reaction has a late transition state and solvent effects derive from specific interactions. The Gibbs Free Energy profile of initial state and transition state for the reaction between cyclopentadiene and methyl vinyl ketone has provided an explanation for the enhancement of the rates of Diels-Alder reactions in the presence of water.25 The initial state appears to be destabilized as the transition state is relatively insensitive to changes in the solvent.The rate of Diels-Alder reactions in sodium and guanidinium salt solutions decreases as anion size increases approximat- ing to a Hofmeister series.26 It is surmised that contact between the organic solute and the electrolyte may be involved. The K-10 catalysed Diels-Alder reaction in the presence of polar water miscible solvents would appear to occur in the bulk solvent as the endolexo selectivity is However excellent selectivity is observed with non-polar solvents. Catalytic activity is very dependent upon the Lewis acidity of the cation exchanged onto the clay.The regioselectivity of the reaction between surfactant dienes and surfactant dienophiles appears to be controlled by alignment of reactants at a micelle-water interface.28 Semi-empirical and ab initio calculations for the reaction of indole radical-cations with cyclohexa-l,3-dienes suggest that attack occurs at the 3-position of the indole and have allowed the rationalization of experimentally observed regiosele~tivities.~~ The path of the Diels-Alder reaction between 173-butadiene cation-radical and ethene appears to be concerted non-synchronous and without activation in the gas phase.30 AM 1 and PM3 SCF-MO transition states for reactions involving carbodiimides reveal that the specificity of the reactions is due to substituent stereoelectronic,entropic and steric factor^.^' Ab initio calculations suggest that the reaction between isoxazole and ethene has an activation energy some 13 kcalt mol -greater than that for oxazole possibly explaining the lack of reactivity of isoxazoles in cycloadditions.32 An axiomatic model of the intramolecular Diels-Alder reaction of furans has been created based on the energetics of implicit transition states deduced from explicit conformations of products and reactants.33 The behaviour of pentadienoic acids in cycloaddition reactions together with the effect of cross conjugation has been in~estigated.~~ The mechanism of the Staudinger reaction continues to be a subject of debate. The reaction of ketene and methylenimine has been studied by RHF/3-21G and IRC and results point to a non-synchronous concerted reaction via a twisted transition state.35 Four n-orbitals are involved in a 2 x [I1 + 11 type cycloaddition and rotation is of the methylene rather than the oxygen of the ketene.However other studies suggest that the reaction is not concerted and proceeds via a zwitterionic intermediate formed by nucleophilic addition of the imine to the ketene.36 The cycloaddition of ketene and 1kcal = 4.184kJ. 25 W. Blokzijl and J. B. F.N. Engberts J. Am. Chem. Soc. 1992 114 5440. 26 C. J. Rizzo J. Org. Chem. 1992 57 6382. 27 C. Cativiela J. M. Fraile J. I. Garcia J. A. Mayoral F. Figueras L. C. De Menorval and P. J. Alonso J. Catal. 1992 137 394. D.A. Jaeger and J. Wang Tetrahedron Lett.1992 33 6415. 29 0.Wiest E. Steckhan and F. Grein J. Org. Chem. 1992 57,4034. 30 N.L. Bauld J. Am. Chem. Soc. 1992 114 5800. 31 H. S. Rzepa P. Molina M. Alajarin and A. Vidal Tetrahedron 1992 48 7425. 32 J. Gonzalez E.C. Taylor and K.N. Houk J. Org. Chem. 1992 57 3753. 33 D. P. Dolata and L. M. Harwood J. Am. Chem. Soc. 1992 114 10738. 34 V. Branchadell A. Oliva R. M. Ortuna S. Rafel and M. Ventura Tetrahedron 1992 48 9001. 35 D. Fang and X. Fu Int. J. Quantum Chem. 1992 43 669. 36 J.A. Sordo J. Gonzalez and T. L. Sordo J. Am. Chem. SOC. 1992 114 6249. Reaction Mechanisms -Part (i) Pericyclic Reactions formaldehyde to give 2-oxetanone proceeds by a non-synchronous but concerted mechanism involving a four-membered transition state.37 The reaction of allenes with tert-butylthioacrylonitrile (BTA) suggests that a diradical intermediate is formed by an allene-HOMO-BTA-LUMO intera~tion.~~ Formation of the diradical intermediate is irreversible but closure is not as product distribution appears to be under thermodynamic control.The cycloaddition of methyl propiolate with enantioenriched 1,3-dimethylallene results in 40% of the enantiomeric excess being transferred to the cycloadd~cts.~~ This has been explained by initial formation of the anti syn diradical intermediate (12) which then preferentially closes to the syn-methyl-substituted end of the ally1 radical. The most reasonable interpretation for the results of the reaction between 1,3-dimethylallene and 1,l-dichloro-2,2-difluoroethene involves reaction uia one major continuous low energy pathway uia a similar intermediate.40 Reaction of 1,l-diphenylethene with 1,3-dimethylallene does not lead to cycloadducts but racemization of the allene occurs suggesting that radical formation is reversible.The trapping of zwitterionic intermediates in [2 + 21 cycloadditions has been reported. Phenylselenide (13) reacts with activated alkenes under Lewis acid catalysis to give the cyclobutanes (14) with selenium and acyl substituents cis.41 However in the presence of water Me,SiCO(CH,),COR is formed. The cycloaddition of (15) with HC-CCO,Me occurs via a 1,4-dipole that has been trapped with both methyl propiolate and tert-b~tanol.~’ 37 D.C. Fang and X. Y. Fu Chin. Chem. Lett.1992 3 367. D.J. Pasto and W. Kong J. Phys. Org. Chem. 1992 5 160. 39 D. J. Pasto K. D. Sugi and D. E. Alonso J. Org. Chem. 1992 57.1146. 40 D. J. Pasto and K. D. Sugi J. Org. Chem. 1992 57 12. 41 S. Yamazaki H. Fujitsuka S. Yamabe and H. Tamura J. Ory. Chem. 1992 57 5610. 42 M. L. Graziano M. R.Iesce F. Cermola and G. Cimminiello J. Chem. SOC.,Perkin Trans. I 1992 1269. N. G. Ramsden Molecular fluorine adds to ethylenes in a cis fashion and a mechanism based on HOMO-LUMO interactions of the weak fluorine bond has been proposed.43 (Me,CCO),C=C=O usually dimerizes to give a [2 + 41 dimer. However in the presence of DMSO Bu3P0 or pyridine dimerization occurs across the C=O of the ketene.44 Carbocation-activated olefins add to unactivated olefins in a [2 + 21 cycloaddition to give cycl~butanes.~’ These reactions support the formation of the second C-C bond in the stepwise cycloaddition of allyl cations to 1,3-dienes in a formal Diels-Alder sense.The synchronicity regioselectivity and transition states for the reaction of CH,=N+H-O-with alkenes have been obtained by MO calculation^.^^ Force field models for nitrile oxide cycloadditions account for the observed diastereoselectivity in reactions controlled by steric factors.47 MM2 parameters based on ab initio transition states for intramolecular addition of nitrile oxides to allyl ethers have been developed.48 The regiospecificity of the intramolecular cyclization of N-3 butenyl nitrones is determined by the contribution of activation enthalpy and entropy to two similar parallel reaction pathway^.^' The regiochemical course of cycloadditions of C,N-diary1 nitrones to a,B-unsaturated esters and lactones has been explained.’’ A transition state for the reaction of non-stabilized azomethine ylids with olefins has been pr~posed.~’ It is suggested that chelation to lithium forms a rigid transition state with the largest substituent anti to the approaching olefin.Reactions of substituted 1,2,3-triazolin-1 -imides with dipolarophiles are dipole-HOMO controlled concerted cycl~additions.~~ Benzyl cations react with styrenes in a formal [3 + 21 cy~loaddition.’~ This occurs uia a transition state (16) which minimizes non-bonded interactions and allows some degree of n-n interaction. Methylene cyclopropene (17) reacts in a [3 + 21 cycloaddi- tion with electron deficient 01efins.’~ The stereochemical outcome suggests that the reaction occurs via an endo transition state.The loss of stereoselectivity in polar 43 T. Iwaoka H. Ichikawa and C. Kaneko Chem. Pharm. Bull. 1992,40 1969. 44 C.O. Kappe G. Faerber C. Wentrup and G. Kollenz J. Org. Chem. 1992 57 7078. 45 P. G. Gassman and A. C. Lottes Tetrahedron Lett. 1992 33 157. 46 Y. L. Pascal J. Chanet-Ray R. Vessiere and A. Zeroual Tetrahedron 1992 48 7197. 47 F.K. Brown L. Rairnondi Y. D. Wu and K.N. Houk Tetrahedron Lett. 1992 33,4405. 48 L. Raimondi Y. D. Wu F. K. Brown and K.N. Houk Tetrahedron Lett. 1992 33 4409. 49 S. Ma and X. Fu Huaxue Xuebao 1992,50 811. A. Banerji and S. Basu Tetrahedron 1992 48 3335.G. Negron G. Roussi and J. Zhang Heterocycles 1992 34 293. 52 R.N. Butler F. A. Lysaght and L. A. Burke J. Chem. Soc. Perkin Trans. 2 1992 1103. 53 S.R.Angle and D. 0.Arnaiz J. Org. Chem. 1992 57 5937. 54 S. Ejiri S. Yamago and E. Nakamura J. Am. Chem. Soc. 1992 114 8707. Reaction Mechanisms -Part (i) Pericyclic Reactions solvents suggests that this transition state is polar. 2-Substituted oxazoles react with ethenetetracarbonitrile in a formal [3 + 21 cycloaddition.’’ The reaction is suggested to proceed uia oxazole opening and a zwitterionic intermediate. 2 Sigmatropic Reactions The pericyclic module of CAMEO has been expanded to include both ene and retro-ene reactions 56 whilst the MM2 force field has been modified to rationalize and predict the stereochemical outcome of intramolecular ene reactions.57 Predictions are good for all except activated enophiles. The effect of pressure on the rate constants of ene reactions can be described by a linear free-energy type relationship.’* This points to the reaction being non-concerted. Ene reactions of substrates such as RO,CCOOCOCO,R with olefins give the expected products whose stereochemistry suggests a stepwise ionic me~hanism.’~ This view is supported by a study of intermolecular primary and secondary isotope effects in the ene reaction of tiglic acid derivatives with N-phenyl-l,2,4-triazoline-3,5-dione or singlet oxygen.60 Product ratios in the rearrangement of (18) and (19) to (20) and (21) vary significantly indicative of a substantial isotope effect in this ene reaction.61 MeCH=C(SMe)CH,OTBDMS reacts with aldehydes under Lewis acid catalysis to give syn or anti adducts with high stereoselectivity.62 It is proposed that the reaction proceeds uia a 6-membered chair-like transition state.55 T.Ibata ‘. Isogami H. Nakawa H. Tamura H. Suga X. Shi and H. Fujieda Bull. Chem.SOC.Jpn. 195 65. 1771. 56 G.’D. Paderes and W. L. Jorgensen J. Org. Chem. 1992 57 1904. ” B. E. Thomas IV R. J. Loncharich and K. N. Houk J. Org. Chem. 1992,57 1354. ’’ B. El’yanov E. M. Gonikberg and G. Jenner J. Chem. SOC.,Perkin Trans. 2 1992 137. 59 P. Bleak Z. Song and J.E. Resek J. Org. Chem. 1992 57 944. “ Y. Elemes and C. S. Foote J. Am. Chem. SOC. 1992 114 6044. 61 J.A. Marshall and M.W.Andersen J. Org. Chem. 1992,57 5851. T. Nakamura K. Tanino and I. Kuwajima Chem. Lett. 1992 1425. N. G. Ramsden Two theoretical studies on the rate acceleration of the Claisen rearrangement of allyl vinyl ethers in aqueous solvents have been reported. The free-energy-of-hydration profile obtained by Monte Carlo methods suggests that the transition state is some 3.85 kcal mol- better hydrated than reactant due to the presence ofan extra hydrogen bond.63 This does not reflect charge transfer to an enolate/allyl cation pair but rather increased exposure of the oxygen to the solvent. An SCF solvation method has also been used.64 Similar findings were made and the reaction energetics appear to be very sensitive to substituent effects. The organoaluminium promoted Claisen rearrange- ment of allyl vinyl ethers has also been studied e~perimentally.~~ The observed (E)and (2) stereoselectivity is best explained by two chair-like transition states with substituents axial or equatorial.Both (22)66 and 1,2,6,7-cyclodecatetraene6'have been investigated as substrates in the Cope rearrangement. In each case the d,l-isomer must react via a chair-like transition state whilst the meso isomer is constrained to react via a boat-like transition state. For (22) kd,,/k,,, = 7 x lo6 and it appears that secondary orbital interactions are of little importance in determining this ratio. The d,l-isomers may react via competing non-concerted and concerted processes. Compound (23) reacts on treat- ment with base via a p-dienone intermediate.68 Geometrically pure 1,5-heptadiene- 3-01s undergo anionic oxy-Cope rearrangement^.^' The stereochemistry is under exclusive control of oxyanion orientation with -60% preference for equatorial oxygen due to disfavoured 1,3-diaxiaI interactions.The phospha-Cope reaction of (24) appears to be preceded by a pre-equilibrium between tetra- and pentacoordinate phosph~rus.~' OH 0 I R 63 D. L. Severance and W. L. Jorgensen J. Am. Chem. SOC. 1992 114 10966. 64 C.J. Cramer and D.G. Truhlar J. Am. Chem. Soc. 1992 114 8794. 65 K. Nonoshita K. Maruoka and H. Yamamoto Bull. Chem. SOC. Jpn. 1992 65 541. 66 K. J. Shea G. J. Stoddard W. P. England and C.D. Haffner J. Am. Chem. SOC. 1992 114 2635. 67 W.R. Roth T. Schaffers and M. Heiber Chem.Ber. 1992 125 739. 68 S. Raghavan and G.S. R. Subba Rao Tetrahedron Lett. 1992 33 119. 69 L.A. Paquette and G. D. Maynard J. Am. Chem. SOC.,1992 114 5018. 'O T. Kawashima D. J. Park S. Murata R. Okazaki and N. Inamoto Chem. Lett. 1992 1607. Reaction Mechanisms -Part (i) PericycIic Reactions Electrocyclic openings of cyclobutenes have been studied by both theoretical and experimental techniques. Opening of benzocyclobutene to o-xylyene has been examined by ab initio MO techniques and torqueselectivity theories appear to be applicable.’ Torqueselectivity results in cyclobutene (25) opening in a formyl-in ester-out mode.72 Cyclobutene (26) opens to give the expected product (27)together with the hexahydronapthalene (28).73This product does not arise by a concerted 1,3-shift.1,5-Sigmatropic rearrangements of CH,=CHCH=CHCH,X investigated by MO theory suggest that when X does not possess a lone pair the shift is suprafacial but when X does possess a lone pair the antarafacial pathway is electronically favoured.74 Upon heating benzylidene cyclobutanols undergo electrocyclic ring opening to allenes. Subsequent reactions are dependant upon starting material structure.75 71 C. W. Jefford G. Bernardinelli. Y. Wang D. C. Spellmeyer A. Buda and K. N. Houk J. Am. Chem. Soc. 1992 114 1157. ’’ S. Niwayama and K. N. Houk Tetrahedron Lett.. 1992 33 883. 73 G.C. Paul and J. J. Gajewski J. Org. Chem. 1992 57. 1970. l4 I. Lee B.S. Lee N. D. Kim and C. K. Kim Bull. Koreun Chem. Soc,.. 1992 13 565. ’’ J.E. Ezcurra C. Pham and H.W. Moore J. Org. Chem. 1992 57 4787.

ISSN:0069-3030    

DOI:10.1039/OC9928900045

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (ii) Polar Reactions By J.M. PERCY School of Chemistry University of Birmingham Edgbaston Birmingham B 15 2TT UK 1 Introduction The whole 1992 volume of Advances in Physical Organic Chemistry will interest readers of this chapter. Reviews by Williams,'" Lee,'b Bernasconi," and Ta-Shma and Rappoport Id covered respectively the relationship between effective charge and transition-state structure the use of cross interaction coefficients in the diagnosis of reaction mechanisms the principle of non-perfect synchronization and solvent- induced changes in the selectivity of solvolysis reactions. The first issue of Accounts of Chemical Research contained a number of relevant articles one described Bunnett's work on the dehalogenation of aryl halides by SET processes;2 mechanisms of amide hydrolysis in aqueous media were also disc~ssed.~ Elsewhere the conceptual basis of face-selectivity in carbonyl-group addition reactions was apprai~ed,~ and aspects of aromatic chemistry were reviewed including the electrophilic substitution reactions of heterocyclic compoundsS and vicarious nucleophilic substitutions.6 The roles of ion-pair exchange processes and their manifestation in salt effects were reviewed,' and scales of solvent ionizing power based upon the solvolyses of benzylic substrates were surveyed.8 A number of aspects of nucleophilic aliphatic substitution were summarized and discussed including the intervention of single electron transfer (SET) processes' and theoretical aspects of the S,2 reaction." Other topics which received attention included mechanisms for the formation of ozonides," and the use of the endocyclic restriction test for the elucidation of transition-state geometries.' A set of guidelines for the publication of results in (a)A.Williams Advances in Physical Organic Chemistry 1992,28 1 ;(b)I. Lee ibid.,57; (c)C. Bernasconi ibid. 119; (d) R. Ta-Shma and Z. Rappoport ibid. 239. J. F. Bunnett Acc. Chem. Res. 1992 25 2. R.S. Brown A. J. Bennett and H. Slebocka-Tilk Acc. Chem. Res. 1992 25 481. W. J. LeNoble Red. Trav. Chim. Pays-Bas 1992 111 199. A. R. Katritzky and W. Q. Fan Heterocycles 1992 34 2179. M. Makosza Pol. J. Chem. 1992 66 3. A. Loupy B. Tchoubar and D. Astruc Chem. Rev.1992 92 1141. D.N. Kevill and M.J. D'Souza J. Phys. Org. Chem. 1992 5 287. J.M. Saveant New J. Chem. 1992 16 304. lo S. S. Shaik H. B. Schlegel and S. Wolfe 'Theoretical Aspects of Physical Organic Chemistry. The S,2 Reaction' Wiley New York 1992. R. L. Kuczowski Chem. Soc. Rev. 1992 21. 79. P. Beak Ace. Chem. Res. 1992 25 215. 55 56 J.M. Percy physical organic chemistry was defined.' Books of general interest included the fourth edition of a well-known clas~ic'~ and a short but highly accessible text on polar rearrangements.' A survey of the reactions of C, may prove a useful source work for physical organic chemists wishing to bring the rigour of a quantitative approach to bear on this fascinating and challenging new molecule.'6 2 Solvolysis and Carbocations Diarylmethyl and triarylmethyl cations were generated in aqueous acetonitrile solutions containing amine nucleophiles using the laser flash photolysis technique.' In highly aqueous media amine desolvation became rate determining.Evidence for this included a change of sign (from positive to negative) in fiN with increasing amine basicity. A good correlation was observed between fiN and pK,+ demonstrating that amine nucleophiles do not adhere to the N + constant selectivity relationship. X Id" / + (1) Y = OTS,OBZ,N3 (2) A significant piece of work has bridged the divide between cations that follow the reactivity-selectivity principle and those for which Ritchie's N + scale applies.' * Varying X in (1) allowed precise control of cation reactivity; at the most stable extreme (X = NMe,) behaviour comparable to that of the least stable triarylmethyl cations was detected.As X became less powerfully electron-donating nucleophilic selectivities became increasingly dependent on the electrophile. A recommendation was made' concerning the 9-fluorznyl cation (2). Using combined theoretical and experimental approaches it was shown that the anticipated destabilizing effect of antiaromaticity was very small. The authors concluded that we should no longer refer to (2) as antiaromatic. A number of publications described cations containing cyclopropyl groups. Olah and co-workers2' demonstrated that (3a) and (4a) co-exist at -90 "C while (3b) only commences reorganization to (4b) at -70 "C.The presence of a second cyclopropyl group strongly stabilizes (3c); (4c) only becomes detectable above -20 "C. The authors were unable to detect participation by the C-1-C-6 a-bond in any of these cases. In contrast protonation2 of alkene (5)afforded the symmetrically-bridged cation (6). l3 W. Drenth Pure Appl. Chem. 1992 64 989. 14 J. March 'Advanced Organic Chemistry Reactions Mechanisms and Structure' 4th Edn. Wiley New York 1992. L. Harwood 'Polar Rearrangements' Oxford University Press Oxford 1992. l6 F. Wudl A. Hirsch K.C. Khemani T. Suzuki P. M. Allemand A. Koch H. Eckert G. Srdanov and H. M. Webb ACS Symp. Ser. 1992 481 161. R. A. McClelland V. M. Kanagasabapathy N. S. Banait and S. Steenken J. Am. Chem. SOC.,1992,114 1816.J. P. Richard T.L. Amyes and T. Vontor J. Am. Chem. SOC. 1992 114 5626. l9 T. L. Amyes J. P. Richard and M. Novak J. Am. Chem. SOC.,1992 114 8032. 2o G. A. Olah V. Prakash Reddy G. Rasul and G. K. Surya Prakash J. Ory. Chem. 1992 57 11 14. W. Kirmse H. Landscheidt. and A. Schleich J. Phys. Org. Chem. 1992 5 19. Reaction Mechanisms -Part (ii) Polar Reactions The 1-ferrocenyl- 1 -cyclopropyl cation (7) was observed by NMR spectroscopy and showed extensive charge delocalization into the ferrocenyl moiety.22 (3) a R = Me; (4) a,R=Me; (5) (6) b R = Ph; b R = Ph; c R = cyclopropyl C,R = cyclopropyl The importance of hyperconjugative interactions by the p-silyl group in cation (8) was probed by NMR experiments and ab initio calculation^.^^ The search for observable trivalent silicenium cations was reviewed by two gro~ps.*~*~~ Both concluded that all attempts to generate these species as long-lived intermediates in solution have been unsuccessful.The reduction of carbenium ions by hydrosilanes forms the basis of a useful synthetic reaction. Mayr and co-workers26 have compiled a quantitative scale of hydrosilane reactivity which parallels the anticipated ease of formation of carbenium (and by implication) silicenium-type species. A Hammett correlation was reported (p = -2.46 with up)for the reduction of diarylmethyl cations by aryldimethyl silanes. H Aspects of polyenyl chemistry included the electrocy~lizations~~ of (9a) and (9b) which occurred in dichloromethane at -70 “Cupon treatment with fluorosulfuric acid to afford (10a) and (lob).The cyclizations traversed dicationic intermediates formed via protonation at oxygen. High activation entropy (AS) values were measured and a strong dependence of reactivity upon acid strength was detected consistent with the dicationic mechanism. These reactions are related to the synthetically-useful Nazarov cyclization. Laser flash photolysis was employed to study the reactions of pentadienyl cation (1 1) with nucleophiles. Picosecond laser experiments allowed the detection of contact ion 22 G. K. Surya Prakash H. Bucholz V. Prakash Reddy A. de Meijiere and G.A. Olah J. Am. Chem. Soc. 1992 114 1097. 23 H.-U. Siehl F.-P. Kaufmann and K. Hori J. Am. Chem. Soc. 1992 114 9343. 24 P. D. Lickiss J.Chem. SOC.,Dalton Trans. 1992 1333. ” G. A. Olah G. Rasul L. Heiliger J. Bausch and G. K. Surya Prakash. J. Am. Chem. Soc. 1992,114,7737. 26 H. Mayr N. Basso and G. Hagen J. Am. Chem. Soc. 1992. 114 3060. ” G.R. Elia R. F. Childs and G.S. Shaw Can. J. Chrm. 1992 70 2065. J. M. Percy pairs which dissociated to free ions at longer reaction times in polar solvents. The free carbenium ion obeyed the reactivity-selectivity principle displaying good correlations with Swain-Scott n values.28 The slopes of the correlations were strongly solvent dependent decreasing in magnitude as the water content of the photolysis medium was reduced. An unusual 1,3-hydride shift was claimed to explain the outcome of the annulation reaction depicted in Scheme 1.Isotopic labelling studies allowed an alternative explanation based on consecutive 1,2-shifts to be eliminated.29 OMEMBu SiMe 1.3-shift ' SiMe3 -Aru -bz, TiCb SiMe Scheme 1 3 Other Nucleophilic Substitutions The mechanisms of nucleophilic substitution at allylic and primary alkyl carbon centres were found to have many features in common. A study of ally1 arenesulfonates '' N.J. Pienta and R. J. Kessler J. Am. Chem. Soc. 1992 114 2419. 29 S. R. Angle and H. L. Mattson-Arnaiz J. Am. Chem. SOC. 1992 114,9782. Reaction Mechanisms -Part (ii) Polar Reactions (12) failed to show the anticipated similarities with benzylic species. Lee and co-workers3' reached this conclusion from a study of linear free-energy relationships and derived cross-in teraction coefficients.Cyclophane hosts (13a) and (13b) were shown to be effective catalysts for the methylation of quinolines and the demethylation of dialkylsulfonium cation^.^ Catalysis was attributed to a favourable interaction between these highly-polarizable hosts and the delocalized sN2 transition states. co -02c' The balance between intramolecular SN2 and E2 reactions was investigated to elucidate the controlling effect of strain energy on reaction pathways.32 Scheme 2 shows two systems which straddle the borderline between the two pathways. The determinant quantity is the excess enthalpy differential (EED) the extra strain-energy difference between the acyclic starting material and the cyclic product incurred upon cyclization.A limiting value of 160 kJ mol-was proposed; cyclizations incurring a higher EED were not observed. Nucleophilic displacements at silicon were studied33 in aryloxysilane (14) which undergoes substitution by carboxylate anions in DMF solution. Brsnsted coefficients (& = 1.O PL = 1.9) were reported and despite cross interaction coefficients of zero a concerted mechanism was preferred to a stepwise addition4imination via a penta- covalent intermediate. The effective charge at silicon was calculated for the reaction. Two-electron mechanisms were claimed34 for the nucleophilic ring-opening of cyclic peroxides (15). Thiocyanate anion attacked at the less-substituted oxygen to afford an unstable adduct. Products arising from intramolecular attack at carbon (16) and sulfur (17) were isolated.Other nucleophilic reactions at sulfur include the methan~lysis~~ of H. K. Oh H. J. Koh and I. Lee J. Chem. SOC..Perkin Trans. 2 1992 1981. 3' A. McCurdy L. Jiminez D.A. Stauffer and D.A. Dougherty J. Am. Chem. SOC.,1992 114 10314. 32 S. M. Jeffery S. Niedoba and C.J. M. Stirling J. Chem. Soc.. Chem. Commun.. 1992 650. 33 P. E. Dietze. J. Org. Chem. 1992 57 1042. 34 W. Adam and M. Heil J. Am. Chern. SOC.,1992 114 5591. 35 J. L. Kice and A.G. Kutateladze J. Org. Chem. 1992 57 3298. J. M. Percy PhSO B~OK B~OH 100% 0% EED = 138 kJ mole-’ PhSO2 B~OK B~OH phso20 0% 100% EED = 212 k~ mole-’ Scheme 2 sulfenamides (18). A sulfuramide intermediate (19)was proposed to lie on the pathway for this reaction.0 It Nucleophilic attack at phosphorus by water is an important biological process. It was shown that synthetic host (20),modelled on the active site of on the arginine diad of staphyloccocal nuclease bound the pentacovalent intermediate of phosphodiester hydrolysis more strongly than the phosphodiester monoanion and additionally eased leaving group departure by acting as a general-acid catalyst. An acceleration of phosphodiester hydrolysis was thus achieved.36 36 V. Jubian R. P. Dixon and A. D. Hamilton J. Am. Chem. Soc. 1992 114 1120. Reaction Mechanisms -Part (ii) Polar Reactions 4 Elimination Reactions Alkenes were formed3' as the sole products upon solvolysis of the esters (21) in 80% aqueous acetone.However p-deuterium isotope effects were too small to be consistent with a pericyclic elimination mechanism. Instead an explanation in which proton-loss occurs from an ion-pair intermediate was proposed. A nitrile-forming elimination was proposed38 as the key step in the hydrolysis of carcinogen MNNG (22). A curved region in the pH-rate profile above pH 6.5 required a term that was first-order in hydroxide ion and the conjugate base of MNNG consistent with the mechanism shown in Scheme 3. /I OH-Scheme 3 Decomposition of potassium-(E)-methane diazoate (23) involves an elimination of methanol across an N=N bond from the diazoate (24).The pH-rate profile an uncatalysed region below pH 7 and allowed an apparent pK of 8.63 to be determined for the conjugate acid of (23).Sulfene intermediate (25) was detected during the hydrolyses of methylsulfonyl ~hloride.~' At low pH (56.7) direct attack at sulfur by water was the dominant 37 X. Creary H.N. Hatoum A. Barton and T. E. Aldridge J. Org. Chem. 1992 57. 1887. 38 C. L. Galtress P. R. Morrow S. Nag. T. L. Smalley M. F. Tschantz J.S. Vaugh D. N. Wickens. S. K. Ziglar and J. C. Fishbein J. Am Chem. Soc. 1992. 114. 1406. 3y J. Horvinen and J.C. Fishbein .I. Am. Chem. Soc. 1992 114. 366. 40 J. F King J. Y. L. Lam and S. Skonieczny J. Am. Chern. Soc.. 1992. 114 1743. J. M. Percy pathway. However at high pH (26.7) sulfene formation by elimination of HCl became rate-determining while above pH 11 sulfene formation and interception by hydroxide occurred at comparable rates.The measurement of isotope effects allowed (ElcB),, and (ElcB)irrev mechanisms to be discounted in favour of an E2 process. The choice between concerted and stepwise pathways was encountered41 in the base-catalysed ring opening of (26)to (27). The base-catalysed elimination occurred by the rare (ElcB) mechanism. In acid the (ElcB) mechanism was observed with loss of the neutral phenolic leaving group at rates close to the encounter limit. Both acid and base catalysed eliminations occurred oia transition states that were very early with respect to C-0 bond breaking. The data allowed the nucleofugacity of the phenolic leaving group to be ranked using Stirling’s approach. 5 Addition Reactions The relief of steric strain energy has been implicated as a driving force in many important types of reaction.Shea and Kim42 have quantified the influence of strain release on the rates of alkene epoxidation by mCPBA. A good correlation was obtained between relative epoxidation rates and the calculated (MM2)strain energy released in each reaction (ASE). Attempts to use alkene frontier orbitals to predict reaction rates gave poor results. Transannular cyclizations of acetylenic ketones are useful reactions formally involving an addition reaction across an alkyne. Harding and King43 have addressed the mechanism via a study of an acyclic system and proposed that the cyclization follows the pathway depicted in Scheme 4.Isotopic labelling and careful product analysis studies were conducted to support the claim that the oxete species (28) was the key intermediate.0 Scheme 4 A number of publications dealt with addition reactions of substituted alkenes. Solvent isotope effects indicated that enol phosphate (29)underwent hydrolysis in acid 41 R.G. Button and P.J. Taylor J. Chem. SOC. Perkin Trans. 2 1992 1571. 42 K. J. Shea and J.-S. Kim J. Am. Chem. SOC. 1992 114 3044. 43 C.E. Harding and S.L. King J. Org. Chem. 1992 57 883. Reaction Mechanisms -Part (ii) Polur Reactions 63 uia rate-limiting protonation of the double bond,44 rather than the P-0 cleavage observed for simple alkyl or aryl phosphates. The general acid catalysed hydrolyses of highly nucleophilic ketene acetals (30) and (31) were studied; average Brsnsted a-values were reported for a set of eight ketene acetals (a = 0.44 & 0.08) including (30) and (3 1).The average exponent for a similar set of vinyl ethers had a higher value (a = 0.67 0.08) consistent with lower hydrolytic reactivity. However these suggested that the ketene acetal hydrolysis reactions have an intrinsically higher barrier and that this arises from more extensive charge delocalization in the more highly-oxygenated series. Meo-foMe OMe OMe R\”’ (29) (30) (31) (32) a X = COT b X = CO2H c X = C02Me Vinyl ethers bearing an a-carboxyl function (32a-c) were in~estigated,~~ using excess acidity (X)functions as models for 5-enolpyruvylshikimate-3-phosphate, EPSP (33). The nature of the carboxyl function controlled the hydrolytic reactivity.All the compounds were less reactive than methyl vinyl ether with (32a) being the most reactive suggesting that this is the form of EPSP maintained by the EPSP synthase enzyme. Addition reactions to ketenes continued to attract attention and a number of studies were described. Analysis of the activation parameters and substituent effects for the hydrolyses of a series of ketenes (34) supported a transition state with significant enolate character (35),developed uia attack at the carbonyl group and not at the C=C bond.47 The methylthio group in (36a) slowed the rate of uncatalysed hydration by a factor of 36 relative to phenylketene (36b) whereas a hydroxyl group at the same position (36c) accelerated the same reaction by a factor of 140.It was concluded that the hydroxyl substituent raised the ground-state energy of the ketene and that the bulkier methylthio group sterically hindered the attack of water.48 The reaction of diphenyl ketene with water in the presence of base resulted in direct attack by the base at the carbonyl group rather than general-base catalysed addition of water.49 Nitrone (37) underwent hydrolysis via direct attack by water between pH 4.5 and 10. Acid and base-catalysed pathways were detected and Hammett correlations were reported. 50 Arylnitroso compounds have been identified as active metabolites of arylnitro species and aromatic amines and their reactions with biological nucleophiles have been implicated in a range of toxic effects. Kazanis and McClellandsl have studied the 44 A.S. Kearney and V. J. Stella Pharm. Res. 1992 9 378. 45 A. J. Kresge and M. Leibovitch J. Am. Chem. Soc. 1992 114 3099. 46 A.J. Kresge M. Leibovitch and J.A. Sikorski J. Am. Chem. SOC. 1992 114 2618. 47 A.D. Allen J. Andraos A. J. Kresge M. A. McAllister and T.T. Tidwell J. Am. Chem. SOC.,1992 114 1878. 48 J. Jones and A. J. Kresge J. Urg. Chem. 1992 57 6467. 49 J. Andraos and A. J. Kresge J. Am. Chem. SOC. 1992 114 5643. 50 S. W. Lee C.G. Kwak I. Kwang and K.C. Lee J. Korean Chem. SOC. 1992. 36. 584. 51 S. Kanzanis and R. A. McClelland J. Am. Chrm. Soc. 1992 114 3052. 64 J. M. Percy reaction of nitrosobenzene with glutathione and proposed the mechanism depicted in Scheme 5. Monothioacetal (38) underwent reduction in the presence of glutathione anion via attack at sulfur to afford the corresponding hydroxylamine.In addition a co, I (34) R = alkyl alkynyl alkenyl (33) trifluoromethyl (35) R (36) a R=MeS (37) b,R=H C R = HO rearrangement pathway led to sulfinanilide (39). Uncatalysed and specific and general-acid catalysed pathways were detected for the latter reaction. Cleavage of the N-0 bond was found to be rate determining and isotope tracer and linear free-energy relationship studies (p' = -3.5) implied that nitrenium ion (40) was the key intermediate. This is unlike the course of the Bamberger rearrangement in which nucleophilic attack at the ring precedes N-0 cleavage. SG GSH GSSG H GSH ' L-L' * ArON,OH Ar/"OH GSH = Glutahone (38) H (40) Scheme 5 6 Aromatic Addition and Substitution Rate constants (105-109M-I s-' ) were reported for the reactions between the photogenerated 9-fluorenyl cation and a number of substituted benzenes in CF,CH(OH)CF,.These are formal models for Friedel-Crafts alkylation reactions.52 52 F. Cozens J. Li R.A. McClelland. and S. Steenken Anqew. Chem. Int. Ed. Engl. 1992 31 743. Reaction Mechanisms -Part (ii) Polar Reactions Second-order rate constants ranged from 3.3 x lo5M-Is-for benzene to 1.7 x lo9M-s-' for cation capture by meta-xylene which marked the upper rate limit for these reactions. The reaction with toluene showed high para-selectivity (0:m:p 5 5:90) despite the high reactivity of the nucleophile (k = 1.1 x lo7M-' s-'). A Hammett correlation with a,'(p+ = -5.0) was reported that was consistent with the accepted mechanism via a cyclohexadienyl cation.For arene nucleophiles more reactive than toluene a-adducts were observed directly. Marcus theory has been applied to the nitration and nitrosation reactions of aromatic compounds and allowed some conclusions concerning the nature of the active electrophiles to be drawn.53 The SET model for nitration predicted that H,NO and not NO was the reactive nitrating agent in nitric acid mixtures. The intervention of the electron transfer mechanism has regiochemical consequences; for example attack at C-1 in naphthalene becomes a favoured pathway. Activity coefficient (M,) and excess acidity (X) methods have been applied to diagnose desulfonation mechanisms for aromatic compounds.54 Isotopic exchange in N-aryl-2,5-dimethyl pyrroles (41) showed a low electronic sensitivity (p = -0.90)to substitution in the aromatic ring due to steric impedence of conjugation.Methylation at C-2' and C-6' increased the rate of detritiation by differentially inhibiting solvation of the conjugate acid but not the transition state for the detritiation step.55 Metal-coordinated (q2)-pyrroles showed some interesting acid-base and tautomeric behaviour. Coordination to pentaamineosmium(I1) facili- tated the 1H-to 2H-pyrrole equilibrium (42) to (43) (Keq= 1) and directed the attack of electrophiles to C-fi.It followed that the uncomplexed portion of the ligand was behaving as an enamine with one strongly-screened face resulting in highly stereo- and regioselective protonations.A number of pK values for the various tautomers were reported.56 The reactions of n-excessive heteroaromatics with 4,6-dinitrobenzofuroxan (DNBF) (44) showed that this carbon electrophile is more reactive than either p-nitrobenzene diazonium cation or the pr~ton.~ The reactions with indole 2-methylindole and s3 J.P. B. Sandall J. Chem. SOC.,Perkin Trans 2 1992 1689. 54 E.N. Krylov Zh. Obsch. Khim. 1992 62 147. 55 J. R. Jones S. Hunt F. Terrier and E. Buncel J. Chem. SOC..Perkin Truns. 2 1992 295. 56 W. H. Myers J. I. Koontz and W. D. Harman J. Am. Chem. SOC. 1992 114 5684. " F. Terrier E. Kizilian J.-C. Halle and E. Buncel J. Am. Chem. SOC.. 1992 114 1740. J. M. Percy 1,2,5-trimethyIpyrrole involved rate determining attack at C-7 to afford zwitterionic o adducts from which proton loss was facile.A number of aspects of the S,Ar mechanism were discussed. Even substrates that would normally be considered unreactive undergo substitution at reasonable rates. No2 Hengge used "0 labelling to show that the hydroxyl group of 4-nitrophenol exchanged in dilute (0.55 M) alkaline solution at an observable rate (t+ = 74minutes at 1000C).58Gandler and co-workersS9 measured rate constants for the reactions of picryl chloride and chloro-2,4-dinitrobenzenewith nucleophiles in aqueous and methanolic solutions. A modified Ritchie equation (equation 1 ) logk = S'N + logk (1) was used to treat the results. The electrophile-dependent parameter S+ varied from (0.79 a 0.1 1) for the more reactive picryl halide to (0.95 f0.13)for the less reactive halide consistent with the reactivity-selectivity principle.The reactions of 2,4,6-trinitroanisole with hydroxide methoxide and phenoxide in mixed aqueous/dipolar aprotic solvents afforded a diverse array of products.60 However allowing the systems to reach thermodynamic product mixtures led to simplification. With phenoxide anion the final irreversibly-formed product was (45) whereas with methoxide (46) dominated the equilibrium mixture. A range of kinetic thermodynamic and stereoelectronic factors were discussed to rationalize these observations. Hydrolysis of the C-4 methoxy group in (47) occurred very readily in aqueous sulfuric acid at 25 "C.Protonation of the diazo group was followed by ips0 attack by water at C-4.Rate determining protonation at C-6 initiated the considerably slower hydrolysis of the C-3 methoxy group.61 Excess acidity methods were employed A.C. Hengge J. Am. Chem. SOC. 1992 114 2747. 59 J. R.Gandler 1. U. Setiarakardjo C. Tufon and C. Chen J. Org. Chem. 1992 57 4169. 6o E. Buncel J. M. Dust A. Jouczyk R. A. Manderville and I. Onyido J. Am. Chem. SOC.,1992,114,5610. 61 R.A. Cox I. Onyido and E. Buncel J. Am. Chem. SOC. 1992 114 1358. Reaction Mechanisms -Part (ii) Polar Reactions allowing a number of pKIH and m* values to be obtained for the protonated phenylazopyridines. The mechanism of amino-migration in 0-phenylhydroxylamine was studied.62 In trifluoroacetic acid ortho-rearranged products predominated unlike the Bamberger OMe 6 (47) rearrangement which leads to para-isomers.A Hammett correlation (0') with a large negative slope (p' = -7.8) indicated that initial N-0 cleavage occurred to generate a phenoxenium cation with extensive charge delocalization into the aromatic ring. Recombination of the ion-molecule pair led to ortho-aminophenols; interception of the ion-molecular pair by trifluoroacetate led to catechols and hydroquinones. 7 Proton Transfer and Carbanions Stabilized carbanions reported in 1992 included the conjugate bases of tris(tri- fluoromethanesu1fonato)methane (48) and 4,6-dinitro-7-methylbenzofuroxan(49).A pK of -12 was measured for (48) which is a sufficiently strong acid to protonate diethyl ether.63 The extraordinary charge delocalizing ability of the benzofuroxan system was demonstrated by the low pK (2.50) for C-H ionization exhibited by (49).This was confirmed by the very high intrinsic barrier for the deprotonation reaction (AGt = 85.5 kJ mol- ') consistent with the extensive molecular electronic and solva- tional reorganization required to form a highly delocalized anion.64 I 0-I N+ H+S02CF3 Stable cyclopropyl anions present a synthetic challenge; two groups reported their efforts in the area. Crispino and Bres10w~~ have described several air and water-stable tris(pyridiniumy1)propenyl anions (which are in effect actually dications) including (50). The presence of a cyclopropyl anion intermediate was inferred in the reaction of (51) with cyanide to afford ring-opened products.66 62 N.Haga Y. Endo K. Kataoka K. Yamaguchi and K. Shudo J. Am. Chem. So(..,1992 114 9795. 63 Y. L. Yagupol'skii T. I. Savina N. 0. Pavlenko A. A. Pankov. and S. A. Pazenok Zh. Ohshch. Khim. 1991 61 1512. 64 F. Terrier D. Croisat A. P. Chatrousse M. J. Pouet and J.-C. Halle J. Org. Chem. 1992 57 3684. G. R. Crispino and R. Breslow J. Org. Chem. 1992 57 1849. 66 A. S. Feng S.G. DiMagno M. S. Konings and A. Streitweiser J. Org. Chem. 1992 57 2902. J.M. Percy Me The formal antiaromatic carbanion (52) was generated via an unusually facile photochemical decarboxylation rea~tion.~’ This may prove an interesting method for revealing fundamental properties of carbanions in the way that laser flash photolysis has enriched our knowledge of carbocations.An unusual carbanionic rearrangement occurred upon treatment of (53)with LDA. Vinylsilane (54) was obtained as a mixture of E and 2 isomers following a 1,2-migration of the silyl group with concerted leaving group departure. An alternative mechanism involving migration of the phenyl group was discounted on the basis of labelling studies.68 The question of how enzymic systems deal with proton transfers to and particularly from carbon remains the subject of dispute. There are two main areas of contention and they concern the nature of the intermediates arising from formal proton transfer at enzyme active sites and how enzymes achieve high reaction rates for proton transfers.Two contrasting observations were reported concerning the status of enolates. Gerlt and Gassman concluded that enzyme-catalysed p-elimination reactions to afford a$-unsaturated carbonyl compounds (vinylogous E2 elimination) occurred via the formation of en01s.~~ A combination of enforced concerted general-acid and general- base catalysis from active site residues was proposed to prevent the formation of unstable intermediates. The conclusions arose from considerations of the pK,s of substrates and active site residues and the general model was discussed with reference to a number of specific enzyme-catalysed reactions. An alternative approach sought to generate simple models of putative intermediates away from the enzyme and establish their chemical stability.This approach led Amyes and Richard to generate thioester enolate (55) in quinuclidine-buffered aqueous ~olution.’~ A pK was estimated (20.4-2 1.5) and an 6’ E. Krogh and P. Wan J. Am. Chem. SOC.,1992 114 705. 68 S. Menichetti and C.J. M. Stirling J. Chem. SOC..Perkin Trans. 2 1992 741. 69 J.A. Gerlt and P.G. Gassman J. Am. Chem. SOC. 1992 114 5928. ’O T. L. Amyes and J.P. Richard J. Am. Chem. SOC. 1992. 114 10297. Reaction Mechanisms -Part (ii) Polar Reactions 69 intimate ion pair with the quinuclidinium cation of lifetime 10-9-10-10 s was detected. The authors therefore concluded that enzyme-catalysed Claisen condensa- tions do not occur by enforced concerted mechanisms. On the question of efficiency an effective molarity of 104-105 M was estimated for exchange of the methine proton in (56) an extremely facile reaction even at -80 "C in toluene.71 Examination of the crystal structure of (56) revealed a close contact between 0-the nitrogen atom and the exchanging proton; the authors concluded that the combination of proximity and reactivity supported the concept of spatiotemporal control.8 Carbonyl Derivatives The molybdate dianion was shown to be a more reactive nucleophilic catalyst for the hydrolysis of 4-nitrophenyl acetate and thioacetate than the basicity of the dianion would lead one to predict. It was suggested that either the anion was weakly solvated or that the carbonyl oxygen coordinated to the molybdenum atom providing some Lewis-acid activation.A more complex synthetic catalyst (57)was described by Breslow and Zhang.73 The B-cyclodextrin units provided a binding site for the adamantyl group holding the carbonyl group of ester (58) close to the divalent zinc ion which acted as a Lewis acid and as a source of nucleophile via a coordinated water molecule. The catalyst achieved a rate enhancement of 2.2 x 105-fold over the uncatalysed hydrolysis at pH 7 and a turnover of at least 50. p-CDX p-CDX OpNP (57) p-CDX = P-cyclodextrin (58) pNP = paranitrophenol The aminolysis of 4-nitrophenyl acetate in chlorobenzene was accelerated by glyme co-solvents. Recognition of the zwitterionic tetrahedral intermediate (59)is possible in triglyme via the formation of bifurcated hydrogen bonds to the ammonium protons.Proton transfer to the aryloxide leaving group occurred in a subsequent and non-rate-determining 71 F. M. Menger and K. Gabrielson .I. Am. Chem. SOL... 1992 114 3574. '' B. Wikjord and L.D. Byers J. Am. Chem. SOL..,1992 114 5553. '' R. Breslow and B. Zhang J. Am. Chem. Soc. 1992 114 5882. 74 J.C. Hogan and R. D. Gandour J. Org. Chem. 1992 57. 55. J. M. Percy The presence of divalent barium or strontium cations accelerated the ethanolysis of (60)700-fold. It was proposed that metal cations were bound strongly by the transition state but only weakly by the reactant and that the catalysis arose from the utilization of this differential binding energy.75 Hengge studied the hydrolysis of 4-nitrophenyl acetate using a 5Nisotopic probe in the nitro It was argued that the size of the observed isotope effect was consistent only with a mechanism in which leaving group departure occurred in the rate-determining step.A mechanism involving tetrahedral intermediate formation and breakdown would not satisfy this criterion. The author therefore favoured an AND description for this mechanism. Acyl phosphate (61)was synthesized by a novel proton pump system. The transfer of citraconic anhydride from acid solution (pH 0.3) across a chloroform 'membrane' into alkaline solution (pH 10)drove the synthesis of the high-energy intermediate by the transfer of two protons.77 The hydrolyses of orthocarbonates (62a and b) were studied and shown to be subject to general-acid catalysis. The hydrolysis of (62a) occurred ten times more slowly than that of triphenyl orthoformate while the latter compound and (62b) hydrolysed at the same rate and with very similar sl values.The authors argued that the slow orthocarbonate hydrolysis was due to the instability of trioxacarbenium ions. Stabilization was provided by the electron-releasing methoxy groups in (62b) raising the hydrolysis rate.78 0 (61) (62) a X = H b X = OMe '' D. Kruft R. Cacciapaglia V. Bohrner A.A. El-Fadl S. Harkema L. Mandolini D. N. Reinhoudt W. Verboorn and W. Vogt J. Org. Chem. 1992 57 826. 76 A. Hengge J. Am. Chem. SOC.,1992 114 6515 77 I. J. Colton and R. J. Kazlauskas J. Org. Chem. 1992 57 7005. 70 P. Kandaanarachchi and M. L. Sinnott J. Chem. SOC..Chem. Commun.1992 777. Reaction Mechanisms -Part (ii) Polar Reactions Keto-enol equilibria in the pyruvic acid system have been studied. Acidity constants for ionization of the pyruvate enol (63) (pK = 11.55) at the hydroxyl group and pyruvic acid (64) (pKf = 16.58) ionizing at carbon were rep~rted.'~ The enol was generated directly in aqueous solution by hydrolysis of bis(trimethylsily1) precursor (65)or by rapid dilution of a DMSO solution of (64). The second method exploited the relatively high stability of simple enols in DMSO a good hydrogen-bond accepting solvent. Ketonization of the enol accounts for 47% of the free energy liberated by the conversion of phosphenol pyruvate to pyruvic acid. 9 Other Reactions The mechanism of the Wittig reaction was studied using isotope effects and Hammett correlations.For the reaction between substituted benzaldehydes and benzylidene triphenyl phosphorane (66) in THF large reaction constants (p = 2.77) were obtained when lithium bromide was absent. In the presence of the salt the reaction constant was lower (p = 1.38) leading to the conclusion that the reaction passed through an earlier transition state in the presence of the salt." Azomethine ylides are useful species for the construction of nitrogen-containing heterocycles by dipolar cycloaddition. A method for the generation of these 1,3-dipoles involved' an iodide-catalysed intramolecular alkylation of oxazole (67) in the presence of cyanide anion which then attacked at the hard immonium carbon of (68). Fragmentation of the heterocyclic ring then occurred to generate the ylide (69).Softer nucleophiles (thiophenolate thiocyanate) attacked directly at the S,2 centre in (67).A number of publications dealt with processes related to the Favorskii rearrange- ment. Cordes and Berson described the thermal interconversion of diastereoisomeric 79 Y. Chiang A.J. Kresge and P. Pruszynski J. Am. Chem. SOC. 1992 114 3103. 8o H. Yamataka K. Nagareda K. Ando and T. Hanafusa J. Org. Chem. 1992 57 2865. 81 A. Hassner and B. Fischer J. Org. Chem. 1992 57 3070. J. M. Percy cyclopropanones (70a and b) via oxyallyl (71) (only one rotamer shown).82 Recycliz- ation with inversion of the spiro centre completed the interconversion which was facile (70) a X = CH2 Y = C=O; (71) b X= C=O Y = CH2 in dichloromethane at -80 “C (tt = 80 minutes).A related process occurreds3 in the conversion shown in Scheme 6. Mechanisms involving [3,3]-rearrangement or &2‘ displacement of mesylate from (72) were excluded. Interception of nitrogen-containing oxyallyl (73) with other anionic nucleophiles was possible. a NMe -% NMe NMe Y I Y I Y I OH OMS OMS (72) Y NHMe C1 (73) Scheme 6 A novel functionahzation of c-3 of the /?-lactam ring occurred via the sN2’ displacement of an arenesulfonate leaving group as shown in Scheme 7.84 However it appears possible that the reaction may have proceeded via (74). In any case this mechanistically-interesting transformation may find extensive application in /?-lactam chemistry.An unusual example of a reaction in which a sulfonyl oxygen acted as a nucleophile was reported.85 Treatment of bissulfone (75) with bromine and silver tetrafluoroborate afforded an epimeric mixture of y-sultinium ions (76).The cyclic adducts were opened readily by nucleophiles to afford em-syn products. Attempts to deprotect enantiomeri- cally pure ketal (77) in acid lead to racemization.86 The problem was traced to a pseudo-Smiles rearrangement of diol (78) shown in Scheme 8 activated by N-protonation of the heterocycle. This had implications for the correct choice of deprotection conditions; brief exposure of the ketal to strong acid allowed deprotec- ” M.H. Cordes and J.A. Berson J. Am. Chem. Soc. 1992 114 11 010. 83 R.V. Hoffmann N. K. Kayyar and B.W. Klinekole J. Am. Chrm. Soc. 1992 114 6262. 84 C. M. Gasparski M. Teng and M. J. Miller J. Am. Chem. SOC. 1992 114 2741. 85 V. Lucchini G. Modena and L. Pasquato J. Chem. SOC.,Chem. Commun. 1992 293. 86 J. J. Barlow M. H. Block J. A. Hudson. A. Leach J. L. Londridge. B.G. Main and S. Nicholson J. Org. Chem. 1992 57 5158. 73 Reaction Mechanisms -Part (ii) Polar Reactions -TsN~ EtjN 0'~TS -0 OTs &-N "FI' NpwR-N3gR -0 0 -0 (74) Scheme 7 PhO& pho& ' &?,-0 S0,Ph 0 tion with minimal racemization. This exploited the specific-acid catalysed pathway for ketal hydrolysis which is rapid at very low pH. Below the pK of the heterocycle racemization became pH independent allowing the rate difference between wanted and unwanted reactions to be maximized.(77) R-(+) Scheme 8 In a similar vein a method allowing the yields of certain important reactions to be maximized was prescribed.*' Ketone alkylation and Schotten-Baumann reactions formed the subject of the study which showed how control of pH allowed mono- or dialkylations to be performed or similar functional groups to be acylated selectively. J.F. King R. Rathore J.Y. L. Lam Z. R. Guo and D. F. Klassen. J. Ory. Chem. 1992 57. 3028. J. M. Percy 10 Probes of Polar Reactions Bentley and Jones88 have described new rate-product correlations for reactions in binary solvent mixtures involving general-base catalysis. The selectivities (S) for a number of well-known systems were derived allowing deviations due to mechanistic change to be identified in solvolysis studies.A refinement in the Grunwald-Winstein procedure was proposed which took account of variations in the solvation of groups adjacent to the reaction centre. A Ysimparameter was therefore derived for a range of binary solvent mixtures by measuring solvolysis rates for compounds with alkyl alkenyl aryl and alkynyl groups next to the reaction ~entre.~’ These parameters are anticipated to aid the prediction of changes in reaction rates caused by changing the solvolysis medium. Advantages were claimed for aqueous acetonitrile as the binary mixture of choice for the study of solvolysis reactions over aqueous acetone and aqueous dioxan mixtures. Four different solvent structures were detected in aqueous acetonitrile.” Changes in the structure of aqueous acetonitrile were also detected during the reaction of 4-nitrophenyl acetate with anionic nucle~philes.~~ Solvent effects on the solvolyses of neophyl tosylates were summarized in a new solvent scale (Y,) for P-aryl assisted (k,) solv01yses.~~ The new scale was shown to be more suitable than the more established YoTsfor dealing with processes of this type.Multiparameter approaches to the correlation of solvent effects were described by Gaje~ski’~ and drag^,'^ while Blokzijl and Engberts described a quantitative approach to understanding the hydrophobic acceleration of organic reactions in water and aqueous solvent mixture^.^' Substituent effects were discussed by a number of groups.Lee related the magnitude of cross-interaction coefficients to differences in force constants (AFI) between reactant and product state~,’~ while Hoz presented a non-traditional interpretation of LFER data.97 Exner and co-workers reported that the nature of the effects exerted by meta- and para-substituents on reaction centres are quite different and advised caution in the use of small sets of compounds for constructing Hammett correlations when both positional isomers were present.98 A new fast electrochemical technique was described which allowed SET and S,2 mechanisms to be distinguished.” Bethel1 and Parker showed that predictive relationships exist between charge-transfer transition energies and the reactivity of electrophile-nucleophile reactions.O0 ’’ T. W. Bentley and R.O. Jones J. Chem. SOC.,Chem. Commun. 1992 743. 89 T.W. Bentley J.-P. Dau-Schmidt G. Llewllyn and H. Mayr J. Org. Chem. 1992 57 2387. 90 A. Wakisaka Y. Shirnizu K. Nishi K. Tokurnaru and H. Sakuragi J. Chem. Soc.,Faraday Trans. 1992 88 1129. 9’ I.H. Urn G.J. Lee H. W. Yoon and D.S. Kwon Tetrahedron Lett. 1992 33 2023. 92 M. Fujio M. Goto K. Funatsu T. Yoshino Y. Saeki K. Yatsugi and Y. Tsuno Bull. Chem. SOC.Jpn. 1992 65 46. 93 J.J. Gajewski J. Org. Chem. 1992 57 5500. 94 R.S. Drago J. Org. Chem. 1992 57 6547. 95 W. Blokzijl and J. B. F. N. Engberts Process Technol. 1992 2 49. 9h I. Lee J. Phys. Org. Chem. 1992 5 736. 97 S. Hoz Acta Chem. Scand. 1992 46 503. 98 M. Ludwig S. Wold and 0.Exner Acta Chem. Scand.1992 46 549. 99 D. L. Zhou P. Walder R. Scheffold and L. Walder Helv. Chim. Acta 1992 75 995. loo D. Bethel1 and V.D. Parker J. Phys. Org. Chem. 1992 5 317.

ISSN:0069-3030    

DOI:10.1039/OC9928900055

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (iii) Free- Radical Reactions By S.A. HEWLINS and J.A. MURPHY Department of Chemistry University of Nottingham Nottingham NG7 2RD UK 1 Oxidative Initiation/Termination of Radical Chemistry The advantages of performing radical reactions without loss of functionality have led to numerous investigations of both oxidative and reductive terminations of free radical reactions. Now results of attempts to effect stereochemical control in manganese(rI1) induced cyclization'"Yb of dicarbonyl derivatives (la-) inter alia are reported." Of these substrates (la) gave the best results with a 90% yield of (2a) formed with 86% diastereomeric excess. Notably (1b) did not react under these conditions. 00 XivI *% Studies on regiochemical control have also appeared from Snider's laboratories.The regiochemistry of these cyclizations is very sensitive to the substituents on the alkene. Thus the chloroalkene (3) directs the exclusive formation2 of the endo-cyclization (a) B. B. Snider and Q. Zhang Tetrahedron Lett. 1992,33,5921; (b)P. A. Zoretic X. Weng C. K. Biggers M. S. Biggers and M. L. Caspar Tetrahedron Lett. 1992 33 2637. B. B. Snider Q. Zhang and M. A. Dombroski J. Org. Chem. 1992 57 4195. 75 S. A. Hewlins and J. A. Murphy intermediate (4) while the isomer (5) causes exclusive exo-cyclization to (6). Whereas alkyl substituents have also been found to control regiochemistry the easy displace- ment of the chlorine group makes it uniquely useful. A study of intermolecular reactions between dicarbonyl radicals and haloalkenes shows that the chlorine acts by decelerating the addition of a radical to the atom bearing the chlorine rather than by accelerating the addition to the neighbouring atom.0 C02Me Cl c1 c1 -products GHCl (6) The use of chloroalkenes is also advantageous in other ways.3 In attempts to form the tricyclic ring system (8) the reactions of the alkynes (7) with Mn"'/Cu" were explored. In the terminally unsubstituted alkyne (7a) no desired product was seen. With the silyl substituted alkyne (7b) only the dimer (9) was obtained. The desired product is thought to form but the speed of desilylation was so rapid that it left (8 R = H) exposed to the oxidizing conditions for a sufficient length of time to produce the oxidatively coupled product (9).Attempts to slow the desilylation by buffering the reaction were unsuccessful. However use of the chloroalkene (10) produced (8a) in 86% via the chlorotricycle (11). The method was subsequently extended to the preparation of the dimethoxy derivative (8b) which bears the aromatic substitution pattern present in the aureolic acid antibiotics. ' B. B. Snider and T. Kwon J. Org. Chem. 1992 57 2399. Reaction Mechanisms -Part (iii) Free-Radical Reactions (8) a R = H b R=OMe Extending this oxidative chemistry to molecules other than fl-dicarbonyl com- pounds is an obviously worthwhile goal and several investigations have moved in this direction. Snider,3 Matta~,~ and Lopez' have studied the oxidative radical chemistry of enol ethers of monocarbonyl compounds but from different perspectives.In Snider's case the aim was initially to see if enolyl radicals (i.e. radicals derived from enols themselves) could cyclize onto alkenes. This reaction could not compete with intermolecular couplings but oxidation of silyl enol ethers such as (12) was successful. Cyclizations to cyclopentanones or cyclohexanones (15)were observed with appropri-ate substrates but the phenyl group is crucial to the success of the reaction. From clever mechanistic investigations Snider has concluded that it is the cation radicals such as (13)and (14)which are performing the cyclizations. Although aminium salts have also been studied in this work oxidation with copper salts and ceric ammonium nitrate (CAN)are preferred.Mattay has investigated a similar reaction but with photochemi- cal initiation of the reaction by electron transfer to the excited singlet state of 9,lO-dicyanoanthracene. In this case it is not necessary to use phenyl ketones. 0SiBu'Me~ OSiBu'MeZ OSiBu'Mez I I I (12) n= 1,2 t . \ A. Heidbreder and J. Mattay Tetruhedron Lett. 1992 33 1973. L. Lopez and L. Troisi Tetrahedron 1992 48 7321. S. A. Hewlins and J. A. Murphy Lopez however has studied the reaction of vinyl ethers (16) with dioxygen to form dioxetanes (17) catalysed at -78 "C in dichloromethane with tris-p-bromo-phenylaminium hexachloroantimonates. The dioxetanes form in good yield. In similar chemistry,6 but induced by ceric salts enamines (18) have been coupled to silyl enol ethers (19)in good yield.The enamine is thought to be converted into its radical cation to trigger this process; notably however the chemistry also works on the less electron rich enamines (20). Aminium salts have been extensively used in the pioneering studies of Bauld on the cation-radical cycloaddition reactions mentioned in previous reports. This work is now being extended7 with kinetic studies to see how fast such intramolecular cyclizations occur. A number of probes were synthesized and their cyclization rate constants determined. For example the rate constant for the cyclobutanation of (21)to (22) via cation radical chemistry is 23 x 109s-'. This probe was then used to investigate the mechanism of metalloporphyrin-induced epoxidations of alkenes which have previously been reported to occur via the intermediacy of cation radicals.The fact that no cyclobutanation was seen in the epoxidation of (21) allowed Bauld to state a maximum lifetime for a free radical cation in this reaction. According to his calculations a cation-radical process with a decay rate-constant up to 6 x 10' s-would have been detectable and concludes that cation-radicals are not intermediates in these epoxidations. On the other hand cation radicals are proposed as intermediates in a novel oxidative cleavage of carbon-tin bonds developed by Hanessiam8 Here trimethyltin radicals add to an alkene (23) triggering a 5-exo cyclization. The product (24) is oxidized with K.Narasaka T. Okauchi K. Tanaka and M. Murakami Chem. Lett. 1992 2099. ' G.A. Mirafzal T. Kim J. Liu and N. L. Bauld J. Am. Chem. SOC. 1992 114 10968. a S. Hanessian and R. Leger J. Am. Chem. SOC. 1992 114 31 15. Reaction Mechanisms -Part (iii) Free-Radical Reactions ceric ammonium nitrate in methanol giving a dimethyl acetal (25). The mechanism of this transformation is speculative but it is proposed that the tin-carbon bond in (24) fragments after formation of the radical cation to give a carbon radical which is trapped by ceric ammonium nitrate. Hanessian proposes that this nitrate undergoes (presumably heterolytic) fission giving an aldehyde which is then converted under the conditions of the reaction to the dimethyl acetal.Mention must be made of a radical cation with 'non-classical cation' character.' The benzhydrylidenenorbornene (26) behaves as an electron donor to an excited state of phenanthrene. The resulting radical cation (27) is trapped with complete stereoselectiv- ity by methanol ultimately yielding (28). The authors propose that this selectivity is due to a strong homoconjugative interaction between the 3n electrons of the radical cation. $ Me3SnvPh MeOvPh OMe \/ -MesSnCl. NaBH3CN AlBN EtO2C C02Et Et02C CO2Et EtO2C CO2Et 2 Reductive Initiation/Termination of Radical Chemistry Electrochemical reductive coupling between ketones and nitriles has been announced by Shono." The chemistry works both intra- and intermolecularly. In an elegant demonstration of its potential he has synthesized guaiazulene (29) ( -)-valeranone (30) polyquinanes e.g.(31) methyldihydrojasmonate (32) and rosaprostol (33). T. Hitano S. Shiina and M. Ohashi J. Chem. SOC..Chem. Commun. 1992 1544. lo T. Shono N. Kise T. Fujimoto N. Tominaga and H. Morita J. Org. Chem. 1992 57 7175. S. A. Hewlins and J. A. Murphy The reactions of samarium iodide continue to excite interest. A Japanese report' details the reductive coupling of N,N-disubstituted amides (34) to form 1,2-diarninoal- kenes (35) using a mixture of samarium and samarium iodide. It is proposed that the reduction starts with formation of the radical anion of the amide. Stereospecific trapping of the reactive intermediate by an alkene suggests that a carbene is formed on further reduction of this intermediate.Both samarium and samarium iodide are required so this is a very potent reducing agent. I 0 The intramolecular reactions of ketyls with alkenes have been previously reported however a current study12 shows strange events can take place in certain such reactions. Thus the products of reaction of substrates (36) and (37) include (38) and (40) resulting from trapping of ethene. The ethene arose from the original generation of samarium iodide from reaction of samarium metal with diiodoethane. These products were not seen when the solution was degassed after generation of samarium iodide. Also seen in the reaction of (36) is 1-methylcyclooctanol (39)from a curious 8-endo trig cyclization. A range of electrophiles has been tested with the organosamarium intermediates generated by this method.Curran has also treated' 3,14 organosamarium reagents with a range of electrophiles to test the scope of their chemistry. In this case the samarium reagents were generated from iodides such as (42). The organosamarium l1 A. Ogawa N. Takami M. Sekiguchi I. Ryu N. Kambe and N. Sonoda J. Am. Chem.SOC.,1992,114,8729. l2 G.A. Molander and J.A. McKie J. Org. Chem. 1992 57 3132. l3 M. J. Totleben D. P. Curran and P. Wipf J. Org. Chem. 1992 57 1740. l4 D. P. Curran and M. J. Totleben J. Am. Chem. SOC. 1992 114 6050. Reaction Mechanisms -Part (iii) Free-Radical Reactions compounds (43) could be converted into organ~copper'~ compounds (44)which are capable of performing conjugate additions in the manner of more traditional cuprates.[~-~CuSmX12]-cux (44) 3 Atom Transfer Reactions Linking into the theme of the previous section remote functionalization has been achieved by treating suitable iodoarenes (45) with samarium iodide.' Radical formation followed by hydrogen atom abstraction occurs prior to trapping by a second equivalent of samarium iodide; the organosamarium intermediate (46) was then successfully reacted with ketones isocyanates and isonitriles. M. Murakarni M. Hayashi and Y. Ito J. Org. Chern. 1992 57 793. S. A. Hewlins and J. A. Murphy f f f &I (LjJ"Y s'-bNL2 0 -0 -0 -0 (45) (46) The above reactions involve the expected 1,Shydrogen atom transfer to aryl radicals. However a number of investigations have been launched to determine the detailed regioselectivity of such abstractions.Thus naphthyl amides such as (47) have been subjectedI6 to reaction with tributyltin deuteride and AIBN. Extensive amounts of 1,6 and 1,7-hydrogen atom transfer occurred as judged by the sites of deuteration in the products (48).This is curious since earlier studies had demonstrated an absence of 1,6 and 1,7-transfers in the amines (49). Curran has sought to functionalize by 1 $transfer from cleavable protecting groups. Hence the silyl ethers (50) and (51) gave F3cY0 F3cY0 -I I (1.5) 40% 1.6) 30% (1,7) 10% (1.7) (13 (47) (48) H R R' 24% 65% I Bu3SnD ____) Ph-OSiRR'Ph I 11% (49) Ph (50) R,R' = Me (51) R,R' = (CH2)4 deuterated products on treatment' with tributyltin deuteride and AIBN.Again the regioselectivity was only moderate. The figures shown represent the extent of deuterium incorporation starting from (50). In a different application" of hydrogen atom transfer the bromotrityl ether was used as a self-oxidizing protecting group. This has particular uses; for example selective oxidation of the primary alcohol was achieved in (52). l6 D. Denenmark T. Winkler A. Waldner and A. De Mesmaeker Tetrnhedron Lett. 1992 33 3613. D. P. Curran K.V. Somayajula and H. Yu Tetrahedron Lett. 1992 33 2295. Is D. P. Curran and H. Yu Synthesis 1992 123. Reaction Mechanisms -Part (iii) Free-Radical Reactions Parsonslg has used 1,5-hydrogen atom abstraction of an allylic hydrogen followed by cyclization for the construction of hydrindanes (54).This full paper details the benefits of starting with vinyl iodides and having an electron-poor alkene as in (53),as the radical acceptor in the final step.A fresh example of the rare 1,4-hydrogen atom abstraction is witnessed in the complicated chemistry of the vinyl radical (55)studied by Malacria.20 Thus following the transfer ring expansion results giving (56). Both alkenes (57)and (58)formed in this case are stereochemically pure. i BySnH c ii. Hz% HO Hok (57) (55) (56) A most unusual regiochemistry was observed in some hydrogen atom abstraction reactions studied by Kraus2' Substrate (59) on photoexcitation underwent 1,9-I' A. D. Borthwick S.Caddick and P.J. Parsons Tetrahedron 1992,48 10655. 2o M. Journet and M. Malacria Tetrahedron Lett. 1992 33 1893. S. A. Hewlins and J. A. Murphy hydrogen atom abstraction. Although it might immediately be supposed that the product results from two sequential 1 ,Sabstractions labelling studies have disproved this. This study on a-ketoesters raises a number of interesting questions particularly concerning the rates of the competing processes. Thus the cyclopropane (60)is cleanly transformed via a 1,5-transfer into (61) indicating that the fragmentation of the acyl-oxygen bond is extremely rapid. Changing from hydrogen transfers to iodine atom transfers an intriguing revelation has been made about the differences between the atom-transfer additions to alkenes of iodomalonates and iodomalononitriles.It has previously been reported that iodo- malonate (62) undergoes addition to alkenes when irradiated in the presence of hexabutylditin giving the cyclic product (63).However the corresponding annulation with the dinitrile (64)went in very poor yield,22 with the iodide (65) being isolated as the principal product of a dirty reaction. Omitting the ditin however and using thermal activation in the dark for prolonged reaction times led to good yields of the desired cyclic compound (66).Evidence suggests that this is indeed a radical process. It is proposed that the reason that the reaction does not proceed well with irradiation is that photochemical activation generates too high a concentration of reactive inter- mediates which react with each other rather than with the alkene.The hexabutylditin is thought to thwart successful reaction by reacting directly with the iodomalononitrile -by a polar mechanism. The dinitrile reaction appears to generate iodine from the start < + hv. A fBU %Sn2 * Me02C Me02C C02Me C02Me '' G. A. Kraus and Y. Wu J. Am. Chem. SOC. 1992 114 8705. 22 D. P. Curran and C. M. Seong Tetrahedron 1992 48 2157. Reaction Mechanisms -Part (iii) Free-Radical Reactions of the reaction and it is possible that iodine (as well as iodomalononitrile) may act as a very efficient quencher for the intermediate radical (67) before cyclization can occur. The dinitrile radical successfully adds to di- and trisubstituted alkenes unlike the diester radical.This considerably extends the synthetic potential of electrophilic radicals. Bu NCGBU-'b CN NCQBu CN NC CN Ally1 iodomalononitriles23 also lead to two stage annulation reactions. However in this case a nitrile transfer can occur. The geometric constraints imposed on intermediates in these reactions can lead to remarkable control of stereochemistry. For example cyclization of (68) with cyclopentene leads to the single isomer (69) being formed in 68% yield. The only other isolated product is the reduced bicyclic product (70). Starting from two simple achiral precursors five stereogenic centres have been constructed with excellent selectivity! NC CN 'Cr> NcY Nd NC A variant of these atom-transfer ideas is seen in the one-pot syntheses of azabicyclo~ctanes.~~ Here the initial radical cyclization of (71) is coupled with a subsequent polar displacement on the intermediate (72) giving good yields of the bicyclic products (73).These products have been used to develop agonists at a newly discovered serotonin receptor. 23 D. P. Curran and C. M. Seong Tetrahedron 1992. 48 2175. 24 D. L. Flynn D. P. Becker R. Nosal and D. L. Zabrowski. Tetrahedron Lett.. 1992 33 7283; D. L. Flynn. D. L. Zabrowski and R. Nod ihid. 1992 33 7281. S. A. Hewlins and J. A. Murphy H I + eNR BbSn2 &-IQ hv t Me02C C02Me Me02C C02Me Me02C C02Me 4 Large and Small Rings Large Rings.-Three communications and one full paper have appeared this year describing reactions which take advantage of the reluctance of amides and esters to adopt suitable conformations for cyclizations to 5- and 6-membered rings.The slowing of this process allows cyclization to larger rings to compete. Amide25 (74) has been used for a 10-endo dig cyclization in a very novel approach to isoquinoline alkaloid synthesis. Expoxidation with rn-chloroperoxybenzoic acid followed by acid treatment led via the ketoamide (79 to the tetracycle (76). H WNV0 n (74) li mCPBA 14-to 16-endo cyclizations onto propiolate alkynes are witnessed in the work of Baldwin.26 Whereas in many cases direct reduction of the halide competes with the cyclization a 63% yield of (78) was obtained from the iodoester (77). This method does not produce smaller rings.A cuprous chloride/2,2’-bipyridine complex has been used2’ to trigger formation of 8-membered ring lactones e.g. (79) by an atom-transfer reaction in moderate to excellent yields. The authors suggest that the terminal alkene may be coordinated to the copper during the reaction favouring the reaction by a template effect. 25 C. Lamas C. Saa L. Castedo and D. Dominguez Tetrahedron Lett. 1992 33 5653. 26 J. E. Baldwin R. M. Adlington and S. H. Ramcharitar Tetrahedron 1992 48 3413. 27 F.O.H. Pirrung W. J. M. Steeman H. Hiemstra W. N. Speckamp B. Kaptein W. H. J. Boesten H. E. Schoemaker and J. Kamphuis Tetrahedron Lett. 1992 33 5141. Reaction Mechanisms -Part (iii) Free-Radical Reactions 0 (77) When monobromoacetates e.g. (80),were treated with tributyltin hydride a similar 8-end0 cyclization28 to (82) was found.Direct reduction product (81) was also observed. One remarkable observation was the isolation of 25% of lactone (84) from the reaction of (83).The mechanism proposed for the formation of this bicyclic lactone features a carbon radical attack upon a lactone carbonyl group as shown. Whereas attack on ketone and aldehyde carbonyl groups are now common this reaction at a lactone carbonyl is to our knowledge unique. The proposed conformations required for 5-exo (85) and 8-end0 (86)attack for radical (83) are shown. Once again it is the reluctance to adopt the s-cis conformation that leads to the eight-membered rings. The attack by a carbon radical on a ketone carbonyl group to give an alkoxyl radical (87) that then fragments with cleavage of the ring-junction to leave a larger ring continues to be e~plored.~~-~~ Dowd long an exponent of this chemistry has reported the fragmentation of radicals derived from spiro- and fused-cycl~butanones~~*~~ such as (88) and (89).The fused compounds are easily synthesized by photochemical ” E. Lee C. H. Yoon and T. H. Lee J. Am. Chem. Soc. 1992 114 10981. 29 P. Dowd and S.-C. Choi Tetrahedron 1992 48 4773. 30 J. E. Baldwin R. M. Adlington and R. Singh Tetrahedron 1992 48 3385. 31 W. R. Bowman and P.J. Westlake Tetrahedron 1992 48 4027. 32 D. Batty and D. Crich J. Chem. Soc.. Perkin Trans. I 1992 3205. 33 W. Zhang and P. Dowd Tetrahedron Letr. 1992 33 3284. 34 P. Dowd and W. Zhang J.Orq. Chem. 1992 57 7163. S. A. Hewlins and J.A. Murphy Oy' 0 0-S-~~UU (86) s-cis (85) (89) 0 87 % Reaction Mechanisms -Part (iii) Free-Radical Reactions cycloaddition. The presence of the chlorine atom in these molecules is no real disadvantage since it is ultimately removed by tributyltin radical reduction. It has the beneficial effect of preventing hydrogen atom abstraction in those cases where this would otherwise be likely. Some curious rearrangements are seen in this work. The formation of decalone (92),from (90),is rationalized as fragmentation/recyclization of the radical (93). (93) (92) A great deal of synthetic effort has been dedicated to synthesis of taxol (94).In a novel appr~ach,~’ Pattenden has shown that selective macrocyclization (12-endo)of (95) followed by transannular ring formation (6-exo) leads to the tricyclic taxane skeleton as a mixture of epimers (96)and (97).Byproducts were also produced in this reaction from reduction of radical intermediates on the path to these epimers but the direct assembly of the carbon framework is appealing. AcO n 0 Ph OH (94)(94) OAc In another synthetic venture36 from the same laboratories an approach to lophotoxin (98) via a macrocyclization using acyl radicals was employed. Selenoester (99)gave successful cyclization to the diketone (loo),which could be converted into the furan (101).Interestingly an alternative approach to the acyl radical using acylcobalt precursors proved problematic.A final intriguing example37of macrocyclization with radicals is in the formation of macrocycle (102) in 74% yield. The authors report little if any uncyclized material. In 35 S. A. Hitchcock and G. Pattenden Tetrahedron Letr. 1992 33 4843. 36 M.P. Astley and G. Pattenden Synrhesis 1992 101. 37 K. J. Shea R. O’Dell and D.Y. Sasaki Tetrahedron Lett. 1992 33 4699. S. A. Hewlins and J.A. Murphy 0 0 (95) I $0 ??@ 0 0 (97) CHO / BugSnH TsOH AlBN this case molecular conformation must play a significant role in boosting the efficiency of the cyclization. Small Rings.-We have previously made mention of the polarity-reversal catalysis developed by Roberts. This year sees a useful application of this phenomenon.t-Butoxyl radical abstracts hydrogen atoms from esters either adjacent to the carbonyl group or adjacent to the alkyl oxygen atom but shows little selectivity between these Reaction Mechanisms -Part (iii) Free-Radical Reactions Bu3SnH AlBN sites. However by adding an amine-borane complex R3N -+ BH,R hydrogen is rapidly abstracted from the borane. The resulting radical is highly nucleophilic and will show a kinetic preference for reaction at a site which will leave an electrophilic radical. In the case of an ester this means reaction ct to the carbonyl. Thus when methyl acetate and the ally1 t-butylperoxide (103)react in the presence of this catalyst the ester is specifically fun~tionalized~~ to (104). The synthetic utility of epoxide cleavages has been further explored.39 Rawal has developed a photochemical conversion of epoxy enol acetates (105)to alcohols (106) utilizing diphenyl disulfide as the catalyst.Many of these reactions proceed in good yield. One strange fact emerges. Although it might be imagined that photocleavage of diphenyl disulfide would permit the reactions to be well initiated they do not proceed cleanly unless 10% AIBN is added to the reaction. Similar results using silyl enol ethers in place of enol acetates and tributyltin hydride plus AIBN as a thermally activated radical source have also been rep~rted.~’ It is not necessary to use enol acetates or silyl enol ethers in these reactions h~wever;~”~~ Kim has shown that keto-epoxides (107) also perform well in the 38 H.S.Dang and B. P. Roberts Tetrahedron Lett. 1992 33 4621 6169. 39 V. H. Rawal and V. Krishnamurthy Tetrahedron Lett. 1992 33 3439. 40 S. Kim and J.S. Koh Tetrahedron Lett. 1992 33 7391. 41 S. Kim and J. S. Koh J. Chem. Soc. Chem. Commun. 1992 1377. 42 E. Hasegawa K. Ishiyama T. Kato T. Horaguchi T. Shimizu S. Tanaka and Y. Yamashita J.Org.Chem. 1992 57 5352. S. A. Hewlins and J. A. Murphy presence of tributyltin radicals. This reaction is very interesting since the initially formed radical can react as above i.e. as an oxyl radical (108) or it can undergo a tributyltin shift to an enolyl radical (109). Kim has demonstrated that the latter reacting through the carbon atom can undergo cyclizations onto alkenes. The mechanism of radical-induced epoxide cleavage has inspired further study.Here,43 the effect of stereoelectronic factors on the regioselectivity of cleavage has been addressed. The rigid spiroepoxides (110) and (111) were subjected to cleavage with tributyltin radicals. If stereoelectronic factors operate and if the reaction is irreversible one would expect to see C-0 bond cleavage for (11 1) and C-C bond cleavage for (1 lo) because of the overlap between the carbon radical orbital and the adjacent epoxide bonds. However only products (112) and (1 13) resulting from C-C bond cleavage were observed. Hence this reaction either disregards stereoelectronic factors or it is reversible. One curious side-reaction seen in this study was the formation of methyl ether (114) and thioacetal (1 15) as a result of a reluctance of an intermediate radical to fragment..-"r..4Lr-Ar 43 W. R. Bowman D. S. Brown C. A. Burns B. A. Marples and N.A. Zaidi Tetrahedron. 1992 48 6883. Reaction Mechanisms -Part (iii) Free-Radical Reactions 93 Epoxides are not the only small rings which have received wide attention. Cyclobutanes and cyclopropanes are widely represented in the literature of 1992. An excellent study of the homolytic reactions of cubanes attests to the strange chemistry of these carbo~ycles.~~ Cubyl bromides (116) react with triethylsilyl radicals to give the cubyl radicals (117) which were expected to abstract hydrogen from the Si-H bond of triethylsilane; this does happen but it is in competition with abstraction from the carbon adjacent to silicon giving radical (118) as attested by ESR studies.Another notable observation was that t-butoxyl radicals appear from ESR to selectively abstract hydrogens from the ring carbons in methylcubane in preference to the methyl group hydrogens. This is counter to expectations based on bond strength calculations. When an equilibrium exists between a ring-opened form and a cyclic molecule for a three- or four-membered ring the ring-opened form normally predominates. Counter- examples have been highlighted in previous Annual Reports but more have come to light recently. Thus the bromoketal(ll9)cyclizesin72% yield to thecyclobutane (120); the authors suggest an enhanced Thorpe-Ingold effect4' operates for the two alkoxy substituents since the effect is stronger than for the case with two alkyl substituents.On the other hand it is the stability of the cyclic radical (122) which drives the equilibrium with (121) to the side of the cy~lobutane,~~ allowing good conversion to (123). EtO OEt EtO OEt 'C02Et %.,,I SMe Unexpected formation of cyclopropane (124) occurred during Dowd's investiga- tions of cyclobutanone rearrangements4' (fiide supra) when the precursor side-chains contained vinyl bromides. " E. W. Della. N. J. Head P. Mallon and J. C. Walton. J. Am. Chem. Sot,. 1992. 114. 10 730. 45 M. E. Jung. I. D. Trifunovich. and N. Lensen Tetrahedron Lett.. 1992 33 6719. 46 K. Ogura. N. Sumitani A. Kayano. H. Iguchi. and M. Fujita. Chern. Lett.. 1992 1487. '7 W. Zhang and P.Dowd. Tetrahedron Lett. 1992. 33 7307. S. A. Hewlins and J. A. Murphy Cyclopropane cleavages were probed from a novel viewpoint by Kilb~rn.~~ Methylenecyclopropanes (125) with reactive side-chains undergo initial exo-cycliz- ation and then fragmentation leading to cyclohexane (126) derivatives. (124) 40% 5 Probes The chemistry of small ring cleavage has been deployed in synthetic studies but it has also found application in kinetics in particular in the use of probes to determine the mechanisms of reactions. Both Tanner49 and Tanko” have proved false the assumption that use of the ring opening reaction of cyclopropylcarbinyl radicals as a mechanistic probe can be extended to cyclopropylketyls (127). They have shown that the ring opening is reversible and Tanko has estimated the equilibrium constant for ring opening of the ketyl(l27) as 2 x Hence ketyl can be present in test solutions without ring opening being observed.The reactions of the ketyls have been further investigated. The principal product isolated when phenylcyclopropyl ketone is subjected to bulk electrolytic reduction is the alcohol (128) arising by a coupling of ring-opened and ring-closed forme and an intramolecular hydride transfer. Newcomb’ has discovcxd ultra fast radical probes. The mono- and diphenylcyc- 48 C. Destabel and J.D. Kilburn J. Chem. SOC. Chem. Commun. 1992 596. 49 D. D. Tanner J. J. Chen C. Luelo and P. M. Peters J. Am. Chem. SOC.,1992 114 713. J.M. Tanko and R. E. Drurnright J. Am. Chem. SOC. 1992 114 1844.M. Newcornb C.C. Johnson M.B. Manek and T.R. Varick J. Am. Chem. SOC. 1992 114 10915. Reaction Mechanisms -Part (iii) Free-Radical Reactions lopropylcarbinyl radicals (129) all undergo ring opening with rate constants in excess of 10" s-Appropriate prescursors can therefore probe the extremely fleeting existences of these radicals in chemical or biological reactions. (127) I *<R1 R2 (129) a R' = H R2= Ph b R' = R2= Ph 6 Biological Applications of Radicals Cyclopropane cleavages have been exploited by Silverman in investigations of the mode of action of monoamine oxidaseS2 (MAO). This enzyme causes an initial electron transfer from amines (130). The question is what happens next? There are two possibilities (a) proton loss occurs from the neighbouring carbon,.followed by electron loss or (b) loss of hydrogen atom occurs.The product of a proton loss would be a carbon radical (131) and to test for this the phenylcyclopropyl amine (132) was treated with the enzyme. It acted as a good substrate and only one product emerged from the reaction; this was phenylcyclopropylcarboxaldehyde(134). Silverman deduced that if a carbon radical (133) was present it either had a very short lifetime or the cyclopropylcarbinyl radical was more stable than the ring-opened form (vide supra) due to stabilization from nitrogen. To probe these questions further the radical was produced by non-enzymatic routes; here the isolated product was exclusively the result of ring cleavage demonstrating that the cyclopropane cleavage was thermodynami- cally favourable.The mechanism of action of general acyl coenzyme A dehydrogenase (GAD) is now 52 R. B. Silverman and Y. Zelechonok J. Org. Chem. 1992 57 6373 5787. S. A. Hewlins and J.A. Murphy -H' I ,p- -,m -,b-,D-c;" 0 P~ NH2 Pi NH2 Pi yH2 Pi thought to proceed through radical chemistry.53 This enzyme is responsible for converting coenzyme A esters of medium length fatty acids to their @-unsaturated counterparts. It is inhibited by (methylenecyclopropy1)acetyl coenzyme A (MCPA- CoA) (135) a metabolite of hypoglycin A that causes Jamaican vomiting sickness. The realization that radicals are involved comes from isolation of the epoxide turnover product (136) from MCPA-CoA.The proposed mechanism of formation of this compound is shown. (135) &SCoA c--~SC A SCoA O -0-0 0 0-0. 0 0 FAD' 1 Dowd has revisited the chemistry of methylmalonyl-CoA rn~tase.~~ He has prepared the first model compound in which the rearrangement to a succinate (138a) is triggered by hydrogen atom abstraction from an unactivated carbon in (137) as in the enzyme reaction. The investigation has produced some uncertainty over the mechanism however since performing the reaction in MeOD led to incorporation of deuterium giving (138b) and (139b and 139c). If the process were purely radical in nature no s3 M.T. Lai and H.-W. Liu J. Am. Chem. Soc. 1992 114 3161. s4 P. Dowd B. Wilk and B. K. Wilk. J. Am. Chem. SOC. 1992 114 7949.Reaction Mechanisms -Part (iii) Free-Radical Reactions incorporation of deuterium would be expected; the observed levels of deuterium incorporation were very high. f yosE3 C02Et - EtO2C C02Et COzEt R C02Et (138) a R= H I b R=D (137) EtO2C LEt SOC The mechanism of DNA fragmentation resulting from hydrogen atom abstraction from C-4’ of deoxyribose has been studied by Giese.” By adding phenylthiyl radicals to the alkene (140) Giese has generated an intermediate resembling the resulting radical. Loss of phosphate occurs to leave a radical cation (141). Although similar radical cations have been seen in previous work by other authors the loss is surprising here since the reaction is performed in the presence of thiophenol which is one of the most effective hydrogen atom donors known.This shows that the phosphate loss is extremely rapid. 0 0 I I 0=P(OR)2 0=P(OR)2 One of the most enlightening investigations published this year concerned the action of the anti-tumour antibiotic quin~carcin.~~ When pure quinocarcin (142) was allowed to stand in the absence of oxygen it underwent a spontaneous disproportionation to 55 B. Giese J. Burger T. W. Kang C. Kesselheim and T. Wittmer J. Am. Chem. Soc. 1992 114 7322. 56 R. M. Williams T. Glinka M. E. Flanagan R. Gallegos H. Coffman and D. Pei J. Am. Chem. Soc. 1992 114 733. 98 S. A. Hewlins and J. A. Murphy two products (143) and (144).When quinocarcin was allowed to stand in the presence of oxygen it was noted that superoxide was produced.Williams proposes a mechanism consistent with the available facts where quinocarcin undergoes an electron transfer to its ring-opened form (145) giving product radicals (146) and (147). A second electron transfer from (146) leads via the cation (148) to the amide (144) while (147) is either converted into quinocarcinol (143) or reacts with dioxygen ultimately yielding superoxide and quinocarcin. DNA cleavage mediated by this drug is completely inhibited by superoxide dismutase and also strongly inhibited (84%) by conducting the reaction under anaerobic conditions. The superoxide produced is proposed to undergo reduction with traces of adventitious redox metals to produce a diffusible oxidant thought to be hydroxyl radical which cleaves DNA by established routes.The authors produce evidence of C-4’ hydrogen atom abstraction from deoxyriboses as the trigger for at least one of the operative mechanisms. Bleomycin also acts as an anti-tumour agent by abstraction of the (2-4’ hydrogen from deoxyriboses. A great deal of research has been conducted into the chemistry of modified bleomycins but it is particularly pertinent to mention one of these in this review of radical mechanisms. This concerns the report by Mascharak5’ on DNA cleavage reactions of cobalt(Ii1) analogues of bleomycin. Here under anaerobic conditions and under photochemical activation DNA cleavage is observed. ESR analysis of such solutions in the presence of dimethylpyrroline-N-oxide (DMPO) and in the absence of DNA shows a spectrum reminiscent of the hydroxyl radical adduct of DMPO.Further investigation suggests that the hydroxyl radical is not the first radical formed in solution but is preceded by another radical which gives a more complex spectrum. This is therefore assigned to a carbon- or nitrogen-centred radical. However the authors suggest that this initial radical abstracts hydrogen from water to give the hydroxyl radical which is then trapped. This is very strange as water features very strong 0-H bonds. Acetonitrile (with varying amounts of added water) is the solvent in which these ESR studies were conducted and if simple hydrogen atom abstraction were occurring one would expect that acetonitrile would be a better donor. Hence the possibility cannot be ruled out that the formation of the hydroxyl radical occurs through a less direct mechanism.Several metal-dependent oxidation systems have appeared over the last few years which are capable of destroying nucleic acids by attack on the deoxyribose hydrogens. A question which always arises is whether the intermediate is a freely diffusing oxyl radical or a metal-bound oxidant. With a molecule which shows recognition of DNA e.g.bleomycin the sequence selectivity indicates that free hydroxyl radicals are not the principal oxidants. However for molecules which do not show DNA recognition alternative methods must be found. A method which has been used by a number of authors is the quenching of the hydroxyl radical with dimethyl s~lfoxide.~~,~~ The nature of the intermediates formed in the presence of metals and oxidants is of interest also in the chemistry of methane monooxygenase which has many facets in common with Gif oxidants developed by Barton.In investigations into the nature of ’’ J. D. Tan S. E. Hudson S.J. Brown M. M. Olmstead and P. K. Mascharak J. Am. Chem.SOC.,1992,114 3841. 58 S. Hashimoto R. Yamashita and Y. Nakamura Chem. Lett. 1992 1639. 59 R. E. Shepherd T.J. Lomis and R.R. Koepsel J. Chem. SOC.. Chem. Commun. 1992 222. Reaction Mechanisms -Part (iii) Free-Radical Reactions O2+ (142) S. A. Hewlins and J.A. Murphy intermediates in these oxidations Barton6' has produced evidence that one of his intermediates can be trapped by tetramethylpiperidinoxyl (Tempo) even though it is not a free radical.This provides a caveat for those seeking to prove radical mechanisms in organometallic chemistry. One of the fastest biological reactions known is the oxygenation carried out by cytochromes P-450. This year has seen the first report of dioxygen cleavage followed by hydrocarbon hydroxylation with a strapped porphyrin acting as a P-450model bearing a thiolate ligand (149a -+ 149b). Although the site of oxygenation in the polymethylene strap is not yet established this is a very useful advance for future understanding of these important cytochromes.61 X (149a) X=H (149b) X=OH 7 Radical Chemistry of Silicon Sulfur and Selenium The search continues for new radical reducing agents with advantageous properties.The toxicity of tin derivatives has encouraged investigations into silanes and the new silane bis(trimethylsilyl)methylsilane62(Me,Si),SiMeH is now reported. It functions as expected but delivers a hydrogen atom to carbon radicals some ten times more slowly than tris(trimethylsily1)silane and some one hundred times more slowly than tributyltin hydride. The variation in chemoselectivity of different silanes is considerable and the more electrophilic tris(methylthio)silane (MeS),SiH shows a substantial tendency to add to alkenes in competition with abstraction of a bromine atom by a (MeS),Si' radical. Thus reaction with 6-bromohexene yielded 25% of tris(methy1thio)hexylsilane as well as 62% methyl~yclopentane.~~ The addition of tris(trimethylsily1)silane to the alkene in (150) was also competitive with attack on the acid chloride.64 A further difference between tributyltin hydride and silane reducing reagents is the inability of the silanes to reduce tertiary alkylnitro R,CNO compounds to the 6o D.H. R. Barton. S. D. Beviere W. Chavasiri E. Csuhai D. Doller and W.-G. Liu J.Am. Chem.SOC.,1992 114 2147. 61 H. Patzelt and W.-D. Woggon Helv. Chim. Acta 1992 75 523. 62 C. Chatgilialoglu A. Guerrini and M. Lucarini J. Org. Chem. 1992 57 3405. 63 C. Chatgilialoglu M. Guerra A. Guerrini G.Seconi K. B. Clark D. Griller J. Kanabus-Kaminska and J.A. Martinho-Simoes J. Org. Chem. 1992 57 2427. 64 M. Ballestri C. Chatgilialoglu N. Cardi and A. Sommazzi Tetrahedron Lert. 1992 33 1787. Reaction Mechanisms -Part (iii) Free-Radical Reactions 101 corresponding alkanes R,CH.The reason for this has now been el~cidated.~’ A nitroalkane (151) initially forms the nitroxide (152). Whereas the corresponding tin adduct would undergo C-N cleagave for cases where R was a tertiary alkyl group in this case N-0 cleavage occurs. The radical (153) then undergoes an exothermic rearrangement to (154) which adds to the nitroalkane giving (155). (Me3Si)3Si 0-Si(SiMe,) +I? (Me$i)+i’ R-N\ * R-N -R-lV ‘0-Si(SiMe& 0-0’ 0 (153) (151) (152) SiMe I d I O-Si(SiMe3)2 Me3% RNOz 1 R-N\ c-O-?i(SiMe& 0’ (1 54) (155) A different type of rearrangement featuring attack on silicon by a carbon radical has been reported.66 Here cyclization of enyne (156) leads to the formation of three products.The cyclic silane (157) results from vinyl radical attack on the tris(trimethylsily1)silyl group in (1 58). This attack on silicon has parallels in the and chemistry of seleni~m~’.~~ Theoretical interest in the nature of the reaction pathway^^'.^^ has been accompanied by experimental work as in the formation of selenium heterocycles (159) and (160). M~therwell’~ has discovered a novel way of appending a functionalized vinyl group onto an arene. The homopropargyl aryl sulfonates (161) suffer attack by tributyltin radical and (1,6)-ipso substitution of the sulfonate group follows. The resulting sulfur radical (162) then substitutes for the tin on the vinyl stannane giving sultones (163). 65 M.Ballestri C. Chatgilialoglu M. Lucarini. and G. F. Pedulli. J. Orq. Chem. 1992 57 948. 66 K. Miura K. Oshima and K. Utimoto Chem. Lett. 1992. 2477. ‘’ C. H. Schiesser and K. Sutej. J. Chem. Soc.. Chem. Cornmun. 1992. 57. “ C.H. Schiesser and K. Sutej Tetrahedron Lett.. 1992 33. 5137. 69 M. Tada and H. Nakagiri Tetrahedron Lett. 1992 33 6657. ’O K. F. Ferris J. Franz C. Sossa and R.J. Bartlett J. Org. Chem. 1992. 57. 777. J. E. Lyons and C. H. Schiesser J. Chem. Soc.. Perkin Trans. 2. 1992 1655. ’’ W. B. Motherwell A. K. M. Pennell. and F. Ujjainwalla J. Chem. Soc. Chem. Commun.. 1992 1067. S. A. Hewlins and J.A. Murphy EtOzC R OH ! Reaction Mechanisms -Part (iii) Free-Radical Reactions 8 Radical Chemistry of Nitrogen Barton has announced73 a novel means of introducing an amine by radical means.Thus a carbon radical (164)formed by decarboxylation of a Barton ester or by other means reacts with 3-phenyl-3-trifluoromethyldiazirine(165)to yield the imine (166) hydrolysis of which affords the amine (167). F3cxph ,R N-N-N-N ix (165) R F3C Ph Warkentin has examined74 the exolendo cyclization competition in aryl radicals derived from bromides (168). There are cases where 6-end0 does prevail but the products resulting from attack on nitrogen i.e. indolines (169),are also observed. The bizarre fact is that the ratio of products varies with the relative concentration of tributyltin hydride. The relative amount of (169) increases at higher tin hydride concentrations and the proposal is made that tributyltin radicals can attack at the nitrogen of the imine giving N-stannylamine (170) as an intermediate and that this would be followed by homolytic displacement of tin from nitrogen during the formation of the five-membered ring.This proposal is speculative at present although precedents are quoted for addition of triethyltin radicals to the nitrogen of an imine. 73 D. H. R. Barton J. C. Jaszberenyi and E. A. Theodorakis J. Am. Chern. SOC. 1992 114 5904. '' M. J. Tomaszewski and J. Warkentin Tetrahedron Lett. 1992 33 2123. S. A. Hewlins and J. A. Murphy 9 Polycyclization Chemistry One of the most active areas of research in radical chemistry is that of multiple cyclizations; the stereo- and regioselectivity afforded determines the applicability to syntheses of natural molecules.A total synthesis of (k) dihydrois~codeine~~ (172) results from (171) by a tandem 5-exo-trig-6-endo-trig cyclization and elimination with stereocontrol. The ready further conversion of this product to dihydrocodeinone (173) completes an attractive formal total synthesis of (k)-morphine. NMe Ts The tetracyclic anti-tumour agent ( )-camptothecin (175) has been ~ynthesized~~ in short order by reaction of hexabutylditin and phenylisonitrile with vinyl bromide (174).The isonitrile group acts as radical acceptor and then radical donor to form the B and c rings. -9 A/---0 C02Me Br Et (174) C0,Me Et I i ’’ K.A. Parker and D. Fokas J. Am. Chrm.SOC. 1992 114 9688.’‘ D.P. Curran and H. Liu J. Am.Chem. SOC. 1992 114 5863. Reaction Mechanisms -Part (iii) Free-Radical Reactions Multiple cyclizations also result from molecules related to the antibiotic enediynes. 1,6-Didehydro[lO]annulene (176) has been synthesized by the Myers group” at Pasadena. This molecule is highly unstable but can be observed at -90 “Cby NMR. The 13Cspectrum shows two CH signals and one signal due to quaternary carbon indicating that the electron distribution for this molecule lies between the ‘Kekule’ forms (176a) and (176b). Rapid cyclization occurs on warming above -90 “Cto give naphthalene. This rearrangement is therefore analogous to the neocarzinostatin cyclization. Diyl cyclizations are now beginning to be extended to the synthesis of more varied molecules.Thus trapping of one of the radicals from a Bergman cyclization by a pendant alkene has been accomplished by two research gro~ps.’*~’~ Note that the conversion of diyne (177) into (178) requires very forcing conditions. Interestingly the omission of cyclohexadiene leads to formation of no desired product. (176a) (176b) e ‘ I (178) 58% OTBS (177) 77 A.G. Myers and N.S. Finney J. Am. Chem. Soc.. 1992 114 10986. 78 Y. W. Andemichael Y. Gui Gu and K. K. Wang J. Org. Chem. 1992 57 794. 79 J. W. Grissom and T. L. Calkins Tetruhedron Lett. 1992. 33. 2315.

ISSN:0069-3030    

DOI:10.1039/OC9928900075

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

5 Aliphatic and Alicyclic Chemistry By P. QUAYLE Department of Chemistry University of Manchester Manchester M 13 9PL UK 1 Introduction The year started off in contemplative mood. Berson’s narrative lo ‘Discoveries missed discoveries made’ provides an interesting insight into how reactions are discovered lost and sometimes rediscovered under different names. Equally thought provoking were two articles by Eschenmoser one concerned with the origins of pre-biological natural products,2 and an account of the synthetic efforts directed towards the synthesis of homo-DNA oligonucleotides. As noted previ~usly,~ the current resurgence in interest in the chemistry of molecules of ‘theoretical interest’ (or non-natural products) has been manifested in the number of reviews appearing in this area.Interest in the chemistry of C, (Buckminsterfullerene) continues ~nabated.~ Related areas of chemistry have received exhaustive coverage and include an introduction to ‘Molecular Lego’,6 overviews of supermolecular chemistry,’ cycloalkadiyne chemistry,8 polymeric carbon allotrope^,^ ‘radialenes’,’’ oxocarbons,’ ’cyclobutanes,’ 2a cubanes,’ 2b and dendritic macromolecules.’ Numer-ous reviews and appraisals of current synthetic methodology have appeared. A most interesting c~mpilation’~ entitled ‘New Synthetic Methods’ provides a useful forum for emerging synthetic methodology. In a similar vein a collection of papers’ concerning (a) J.A. Berson Tetrahedron 1992 48 3; (b) For a personal account on how to invent a reaction see D.H.R.Barton and D. Doller Acc. Chem. Res. 1992 25 504. A. Eschenrnoser and E. Loewenthal Chem. SOC.Rev. 1992 21 1. A. Eschenrnoser and M. Dobler Helu. Chim. Acta. 1992 75 218. P. Quayle Ann. Rep. Sect. B 1991 88 103. H. W. Kroto Angew. Chem. Int. Ed. Engl. 1992,31,11;F. W. McLafferty (Ed.) Acc. Chem. Res. 1992,25 98. J. P. Mathias and J. F. Stoddart Chem. Soc. Rev. 1992 21 215. ’ C. See1 and F. Vogtle Angew. Chem. Int. Ed. Engl. 1992,31 528; E. Constable Tetrahedron 1992,48 10013. R. Gleiter Angew. Chem. Int. Ed. Engl. 1992,31 1;K. C. Nicolaou and A. L. Smith,Acc. Chem. Res. 1992 25 497. F. Diederich and Y. Rubin Angew. Chem. Int. Ed. Engl. 1992,31 1101. lo H. Hopf and G. Maas Angew. Chem. Int. Ed. Engl. 1992 31 931.P. Seitze and P. Imming Chem. Reu. 1992 92 1227. l2 (a)T. Tada and P. Garratt Chem. Rev. 1992,92 1685; (b)P. E. Eaton Angew. Chem. Int. Ed. Engl. 1992 31 1421. l3 G. R. Newkome C. N. Moorfield and G. R. Baker Aldrichimica Acta 1992 25 33. l4 S. E. Denmark (guest editor) Tetrahedron 1992 48 1959. I5 M.T. Reetz (guest editor) Tetrahedron 1992 48 5557. 107 108 P. Quayle the use of titanium reagents in organic synthesis provides much useful information. Cascade reactions,I6 enantioselective Rh” catalysed reactions,’ desymmeterization of meso-epoxides,’ transition metal catalysed reactions of organozinc reagents ’ fluorinated organometallics,20 asymmetric carbonyl reductions,21 chromium(11) re- agents,22 palladium catalysed reactions of organometallic~,~~ asymmetric-ene reac- tion~,~~ rhodium catalysed asymmetric hydrogenation^,^^ intramolecular carbenoid reactions in organic synthesis,26 asymmetric Michael reaction^,^ and asymmetric dihydroxylation reactions2 have been reviewed.A critical discussion of palladium- catalysed allylic substitution reactions29 has appeared as has an update on the anomeric effect.30 It is fitting some twenty-five years after the promulgation3’ of the Wood- ward-Hoffmann rules that a reappraisal of pericyclic reactions be published.32 Two comprehensive reviews on stereocontrolled organic synthesis have a~peared;~ the use of enzymes in this particular endeavour continues to expand.34 Of particular note are the use in multi-step synthesis of highly functionalized but readily available homochiral substrates such as cyclohexa-3,5-diene- 1,2-diok3’ Exploitation of sulfox- ides in asymmetric synthesis continues to produce much new synthetic meth~dology.~~ Similarly target-orientated synthesis by necessity generates new synthetic methodol- ogy as demonstrated by the variety of routes now available for the synthesis of forskolin and its analogues37 and C-glyco~ides.~~ The quest for carbocyclic nucleosides has generated much new chemistry,39 as has the search for reliable methods for the preparation of g-40 and ‘unusual’41 amino acids.Sugars remain popular as chiral auxiliarie~.~’ Overviews of contemporary organic synthesis and metal-assisted organic synthesis are to be found in articles edited by Richer43” and van K~ten~~~ respectively.l6 H. M.R. Hoffmann Angew. Chem. Int. Ed. Enyl. 1992 31 1332. l7 H. Brunner Angew. Chem. Int. Ed. Engl. 1992 31 1183. l8 (a) I. Patterson and D. J. Berrisford Angew. Chem. Int. Ed. Engl. 1992 31 1178; (b)W. A. Nugent J. Am. Chem. Soc. 1992 114 2768. l9 E. Erdik Tetrahedron 1992 48 9577. ’O D. J. Burton and Z.-Y. Yang Tetrahedron 1992 48 189. ” V. K. Singh Synthesis 1992 605; S. Wallbaum and J. Martens Tetrahedron Asymmetry 1992 3 1475. 22 P. Cintas Synthesis 1992 248. 23 T. N. Mitchell Synthesis 1992 803. 24 E. Mikami M. Tereda S. Narisawa and T. Nakai SYNLETT 1992 255. 25 K. Inoguchi S. Sakarabu and K. Achiwa SYNLETT 1992 169. 26 A. Padwa and K. E. Krumpe Tetrahedron 1992 48 5385. ” J. d’Angelo D. Desmaele F.Dumas and A. Guingent Tetrahedron Asjwmetry 1992 3 459. ” B.B. Lohray Tetrahedron Asymmetry 1992 3 1317. 29 C. G. Frost J. Howarth and J. M. J. Williams Tetrahedron Asymmetry 1992 3 1089. 30 E. Juarista and G. Cueras Tetrahedron 1992 48 5019. 31 R. B. Woodward Chemical Society Special Publn. 1967 21 217. 32 K.N. Houk Y. Li J.D. Evanseck Anyew. Chem. Int. Ed. Engl. 1992 31 681. 33 J. A. Gladysz and J. Michl (eds.) Chem. Rev. 1992,92,741; D. J. Ager and M. B. East Tetrahedron 1992 48 2803. 34 V. S. Parmar (ed.) Pure and Applied Chem. 1992 64 1055. 35 H. A. Carless Tetrahedron Asymmetry 1992 3 795. 36 A. J. Walker Tetrahedron Asymmetry 1992 3 961. 37 M. I. Colombo J. Zinczuk and E.A. Ruveda Tetrahedron 1992 48 963. 38 M. H. D. Postena Tetrahedron 1992 48 8545.39 A.D. Borthwick and K. Biggadike Tetrahedron 1992 48 571. 40 R. M. Williams Aldrich Chim. Acta 1992 25 11. 41 Y. Ohfume Acc. Chem. Res. 1992 25. 360. 42 H.-U. Reissig Anyew. Chem. Int. Ed. Enyl. 1992 32 288. 43 (a) J.-C. Richer Pure Appl. Chem. 1992 64 1809; (6) G. van Koten Pure Appl. Chem. 1992 64 315. Aliphatic and Alicyclic Chemistry 109 Overman has reviewed the concept of charge in organic synthesis.44 Finally in a most revealing article Collum dispels some of the myths associated with the use of TMEDA in fundamentally important processes such as metalation reaction^.^' 2 Aliphatic Chemistry The synthesis and reactivity of alkynyl- and allenyl-(pheny1)iodonium compounds46 and vinyl-pho~phonates~~ have been reviewed.A much-needed compilation of copper-mediated coupling reactions has appeared.48 Once again palladium-mediated ‘Heck’ and ‘Stille’ coupling reactions have been used extensively for the synthesis of functionalized olefins and arenes. In this context the use of novel C,-symmetric ligand systems for asymmetric alkylations has enjoyed a major breakthrough this year.490 Heck reaction of aryl halides and 4H-1,3-dioxin provides ready access to functionalized cinnamaldehydes (Scheme 1). In addition Reagents i Pd(OAc), P(Ph,), Ag,CO, DMF 60°C; ii H30’ (1 1 Reagents i Ag,CO, DMF Pd(OAc), (R)-BINAP; ii H,-Pd/C; iii H,O+ Scheme 1 reaction of 4H- 1,3-dioxin with iodobenzene in the presence of Pd(OAc),-(R)-BINAP using Ag,CO, as base afforded the product (1) in 62% yield with 43% e.e.49b Stille coupling (Scheme 2) of the bis-stannane (2) provides rapid access to polyenes of defined Me3Sn SnMe3 1 Reagents i Pdo Scheme 2 44 L.E. Overman Acc. Chem. Res. 1992 25 352. 45 D. B. Collum Acc. Chem. Res. 1992 25 448. 46 P. J. Stang Angew. Chem. Int. Ed. Engi. 1992 31 274. 47 T. Minami and J. Motoyoshiya Synthesis 1992 332. 48 B.H. Lipshutz and S. Sengupta Org. React. 1992 41 135. 49 (a)B. M. Trost D. L. Van Vranken and C. Bingel J. Am. Chem.Soc. 1992,114,9327;F. Ozawa. A. Kubo and T. Hayashi Tetrahedron Lett. 1992,33,1485;U. Leutenegger G. Umbricht C. F. Matt and A. Pfaltz Tetrahedron 1992,48,2143; (b)T.Sakamoto Y. Kondo. and H. Yamanaka Tetrahedron Lett. 1992,33 6845. 110 P.Quayle stereochemistry ." Moriarty' has described a versatile coupling reaction between alkenyl-iodonium salts and a variety of organotin substrates Scheme 3. Vinyl-zinc R' = vinyl alyl ally1 53-8096 Reagents i Pd(CH,CN),CI (cat.) Scheme 3 reagentss2 in many cases prove to be superior to the corresponding stannanes in Stille reactions Scheme 4. Vinyl and aryl triflates are often used in palladium catalysed 0 Bzov -Bzov 70% BzO BzO Reagents i CF,y ZnC1; ii Pd(PPh3) (cat.) Scheme 4 coupling reactions. corn in^'^ has demonstrated that the pyridine-derived triflating agents (3) are superior to N-phenyltriflimide which is commonly used in the preparation of these substrates Scheme 5. SoderquistS4 has amply demonstrated the 0 OTf Reagents i L-Selectride; ii (3) Scheme 5 50 A.Kiehl A. Eberhardt M. Adam V. Enkelmann and K. Mullen Angew. Chem. Int. Ed. Engl. 1992,31 1588. 51 R. M. Moriarty and W. R. Epa Tetrahedron Lett. 1992 33 4095. 52 B. Jiang and Y. Xu Tetrahedron Lett. 1992 33 511; A. Pimm P. Kocienski and S. D. A. Street SYNLETT 1992 886. 53 D. L. Comins and A. Dehghani Tetrahedron Lett. 1992 33 6299. 54 I Rivera J. C. Colberg and J. A. Soderquist Tetrahedron Lett. 1992 33 6919. Aliphatic and Alicyclic Chemistry viability of alkyl- and alkenyl-boranes in Suzuki coupling reactions as exemplified in his synthesis of (k)-ibuprofen Scheme 6. A fundamental ob~ervation~~ is that the Y Reagents i Bu'-9-BBN Pd' NaOH (94%); ii Tf,O/py (87%); iii B Pd' K,PO (68%) Q Scheme 6 rate of migration of alkyl groups from tin to palladium in such coupling reactions is enhanced via intramolecular coordination with a proximal amino residue.Also of note is Grigg'~~~ observation that the rate of tandem cyclization-carbonylation reactions can be enhanced by the addition of thallium acetate Scheme 7. ___) Ph 0 Ph 0 Reagents i CO (1 atm.) MeOH PdCI,(PPh,) (5mol.%) TlOAc Scheme 7 Homoenolates derived from gly~ine~~" have been coupled with a variety of electrophiles without the requirement for full protection of the amino moiety Scheme 8. A 'three component coupling' in a related sequence nicely demonstrates the synthetic utility of such processes Scheme 9.57b NHBoc E+* IZn-EYNHBOC C02Bn k02Bn Scheme 8 55 E.Vedejs A. R. Haight and W. 0.Moss J. Am. Chem. Soc. 1992 114,6556; J. M. Brown M. Pearson T. B. H. Jastrzebski and G. van Koten J. Chem. SOC. Chem. Commun. 1992 1440. 56 R. Grigg P. Kennewell and A. J. Teasdale Tetrahedron Lett. 1992 33 7789. 57 (a)R. F.W. Jackson N. W. Stuart A. Wood K. Jarnesw and M. J. Wythes J. Org. Chem.,1992.57,3397; (6)Y. Tamura K. Yasui H. Takanabe S. Tanaka and K. Fugami Angew. Chem..Int. Ed. Engl. 1992,31 645. 112 P. Quayfe Reagents i Pd(PPh3), CO HMPA 25 "C Scheme 9 Hydrosilylation-oxidation of mew olefins affords a rapid entry to the bicyclic alcohols in a near optically pure state Scheme lo.'* The synthesis of the vinyLS9 89% (95% e.e.) Reagents i HSiCI, [PdCI(n-C,H,)], (R)-MOP; ii KF KHCO, H,O Scheme 10 and allyl-stannanes6' continues to attract much attention.A number of novel transformations of these substrates has been documented this year including a synthesis of vinyl-silanes via a 1,2-migration-destannylationsequence6' (Scheme 11) SiMe3 Me3Si 0 ___c UR1 R'COCl Reagents i AlCI, -78"C CH,Cl Scheme 11 and a stereoselective stannyl-Pummerer reaction.62 Thomas63 has developed a remarkably efficient 1,5-asyrnmetric induction strategy for the synthesis of olefinic diols Scheme 12. LCHO -BnOL C H BnO + Bu3Sn-OBn OBIl 70% (> 96%d.e.) Reagents i SnCl, CH,CI, -78 "C Scheme 12 58 (a)Y.Uozumi S.-y. Lee and T. Hayashi Tetrahedron Lett. 1992,33,7185;(b)1. Matsuda J. Sakakibara H. Inoue and H. Nagashima Tetrahedron Lett.1992 33 5799. s9 J. P. Marino M. V. M. Emonds P. J. Stengel A. R. M. Oliveira F. Simonelli and J. T. B. Ferreira Tetrahedron Lett. 1992 33 49; D. M. Hodgson Tetrahedron Lett. 1992 33 5603. 6o Y. Tsuji and T. Kakehi J. Chem. SOC. Chem. Commun. 1992 1OOO. 61 K.-T. Kang J.C. Lee and J. S. U.. Tetrahedron Lett. 1992 33 4953. 62 R. L. Beddoes D. McLeod D. Moorcroft P. Quayle and Y. Zhao. Tetrahedron Lett. 1992 33 417. 63 A. H. McNeill and E. J. Thomas Tetrahedron Lett. 1992 33 1369. Aliphatic and Alicyclic Chemistry The use of N-lithioimidazole as a dummy ligand in cuprate reactions has been described.64 The preparation of functionalized vinylic lithiocyanocuprates should prove to be a useful de~elopment,~’ Scheme 13. Complementary approaches to I 0 0 Reagents i Cp,Zr(H)CI; ii Me,Cu(CN)Li,; iii BF,.OEt Scheme 13 functionalized copper66 and bimetallic reagents67 have been described providing ready access to a variety of reactive intermediates.The synthesis of polyenes continues as an area of much interest. Jeffery6* has described a facile route to skipped polyenes and Trod9 has developed a general synthesis of buta-l,3-dienes from readily available acetylenic ketones Scheme 14. Palladium7’ and ruthenium7 catalysed acetylene and olefin isomerization reactions provide rapid access to a variety of synthetically useful intermediates Scheme 15. The use of silanes as masked OH groups continues to gain acceptance in synthetic Scheme 16. A facile synthesis of the synthetically useful (E)-1-iodoalkenes from aldehydes has been de~eloped.’~ Hypervalent alkenyliodonium salts are emerging as useful synthetic intermediates.Stang74 has for example demonstrated that readily available bis-iodonium salts undergo displacement reactions under mild conditions to afford the vinyl-cyanides (4),Scheme 17. New methods have appeared for 64 B. H. Lipshutz P. Fatheree W. Hagen. and K. L. Stevens Terrahedron Lett. 1992 33 1041. 65 B. Lipshutz and R. Keil J. Am. Chem. Soc. 1992. 114 7919. 66 F.C. Tucci. A. Chieffi and J.V. Cornasseto Tetrahedron Lett. 1992 33. 5721; A.R. Sidduri and P. Knochel J. Am. Chem. SOC.,1992,114.7579; D. E. Stack and R. D. Rieke. Tetrahedron Lett. 1992,114 6575. 67 J. R. Waas A. R. Sidduri and P. Knochel Tetrahedron Lett..1992,33,3717 B. H. Lipshutz. R. Kell. and J.C. Barton Tetrahedron Lett. 1992 33 5860. 68 T. JetTery S. Gueugnot and G. Linstrumelle Tetrahedron Lett. 1992 33 5757. 69 B. M. Trost and U. Kazrnaier J. Am. Chem. Soc. 1992 114 7933. 70 B. M. Trost and C. Pedregal J. Am. Chem. SOC. 1992 114. 7292. 71 B. M. Trost and J. A. Flygare J. Am. Chem. SOC. 1992 114 5476. 72 J. Legeune and J. Y. Lallernand Tetrahedron Lett. 1992,33,2977;T. Harada S.Imanaka. Y. Ohyama Y. Matsuda and A. Oku Tetrahedron Lett. 1992 33 5807. 73 A. G. Martinez R. M. Alvarez S. M. Gonzalez L. R. Subramanian. and M. Conrad Tetrahedron Lett.. 1992,33 2043. 74 P. J. Stang A. Schwartz T. Blurne. and V.V. Zhdankin. Tetrahedron Lett.. 1992 33. 6759. 114 P. Quayle M%Si =--(Ref.68) 83% --0 --0 (Ref. 69) Reagents i CuI/DMF/Na,CO,/Bu:NCI; ii Ni(OAc),.4H2O EtOH NH,(CH,),NH, H,; iii Ph,P/Tol-uene/llO "C Scheme 14 OMe (Ref. 70) OMe (Ref. 71) 57% + -OH Reagents:i Pd,(dba), CHCI, TPP; ii Cp(Ph,P),RuCI (O.leq.) NH,PF (0.2eq.) 100 "C;iii RhCI, THF 100 "C Scheme 15 Aliphatic and Alicyclic Chemistry -*Lp i ii OH Reagents i Bu,SnH AIBN; ii H,O, NaHCO, MeOH Scheme 16 IPh CN (4) Reagents NaCN CuCN CH,CN Scheme 17 the synthesis of vinyl-sulfides7 and -~ilanes.~~ Davis77 has developed a 'super silylating' agent (Me,SiB(OTf),) for use in allylation reactions of aldehydes with allylsilanes. The Motherwell reaction78 has been reinvestigated resulting in the realization of a general carbonyl coupling reaction Scheme 18.A highly efficient Reagents Zn Scheme 18 functionalization of acetylenes leading to the generation of tetrasubstituted olefins has been described,79 Scheme 19. The first asymmetric selenoxide elimination" reaction R-CO,Et -RT:: I HO Reagents i TaCI, Zn; ii THF Py; iii R'CHO; iv I Scheme 19 7s N. A. Petasis and I. Akritopolou SYNLETT 1992 665. 76 S. Takano Y. Sugihara and K. Ogasawara SYNLETT 1992 668. l7 A. P. Davis and M. Jaspars Angew. Chem. Int. Ed. Engl. 1992 31 470. 78 C.A. M. Afonso W. B. Motherwell D. M. O'Shea and L. R. Roberts Tetrahedron Lett. 1992,33 3899. 79 Y. Katuoka J. Miyai M. Tezuka K. Takai and K. Utimoto J. Org. Chem. 1992 57 6796. 8o N. Komatsu Y. Nishibayashi T.Sugita and S. Urmura J. Chem. SOC..Chem. Commun. 1992 46. 116 P. Quayle has been reported affording allenes with modest levels of optical purity (2-21 % e.e.). Gree" has developed a highly efficient method for the preparation of allenes in a nearly optically pure state based upon the efficient transfer of chirality from metal to 'ligand' in optically pure (irontricarbony1)diene complexes (Scheme 20). A facile synthesis of Et I (> 95% d.s.) R (major) Reagents 1 ClC(O)OPh Py; ii (EtCuBr)MgBr; iii CAN/MeOH Scheme 20 internal acetylenes from readily available 1,1-dibromoallene should prove to be of some synthetic utility.82 The use of sulfoxides as chiral auxiliaries continues to be an area ofintense Full details concerning the preparation of diastereomerically pure sugar-derived sulfoxides have appeared.84 Caution must be exercised when the Anderson procedure is adopted for the preparation of optically enriched sulfoxides; in one case at least when using a sterically hindered alkyl-lithium reagent retention at sulfur rather than inversion has been observed.85 Phenylsulfonyl- 1,3-86 and 1,4-dieness7 are an interesting class of polyfunctionalized dienes.Recent studies by Backvall have further extended their synthetic utility Scheme 21. The sulfone group continues to find use both as an activating and stereocontrolling element.88 2 dR1 j-iii R\ R\ \ Reagents i R'CH,NO, DBU; ii KMnO,; iii Bu'OK THF Reagents i 0, PhSH; ii Oxone; iii PhSCI Et,N; iv Et,N; v H,O, HOAc Scheme 21 K.Nunn P. Mosest R. Gree K. Pelem R.W. Saadfrank and H.G. von Schering Angew. Chem. Int. Ed. Engl. 1992 31 224. 82 M. Kunishima K. Hioki T. Ohara and S. Tani J. Chern. SOC. Chem. Commun. 1992 219. 83 M. Casey I. Mukhurgee and H. Trabsa Tetrahedron Lett. 1992 33 127; G. Solladie N. Maugein I. Morreno A. Almario M. Marino and 5. L. Garcia-Ruano Tetrahedron Lett. 1992,33,4561;D. Barros M. Carmen Carreno J. L. Garcia-Ruano and M. C. Maestro Tetrahedron Lett. 1992 33 2733. 84 1. Fernandez N. Khiar J. M. Llera and F. Alcudia J. Org. Chem. 1992 57 6789. R5 J. Draowicz B. Budzinski and M. Mikolajczyk J. Chem. SOC..Chem. Commun. 1992 1500. J.-E. Backvall A.M. Ericsson N.A. Plobeck and S. K. Juntunen Tetrahedron Lett. 1992 33 131. *' Z. Ni X. Wang A. Rodriguez and A.Padwa Tetrahedron Lett. 1992 33 7303. 88 H.-J. Gais and G. Hellman J. Am. Chem. SOC.,1992,114,4439;C. M. Rodriguez M. A. Ramirez and V. S. Martin Tetrahedron Lett. 1992 33 3039. Aliphatic and Alicyclic Chemistry The diastereoselective synthesis of 2,3-epo~y-sulfoxides,~~ -silanesgO and -phos- phines’l has been reported. NugentI8’ has developed a chiral Lewis acid catalyst which enables the facile desymmeterization of meso-epoxides Scheme 22. Asymmetric 78% (88% e.e.) Reagents 1 [(Zr(OBu‘),) 31-TMSN3. 0 C N t)3 Scheme 22 dihydroxylation of olefins continues to be a focus of much methodological attenti~n.’~ A practical demonstration of this powerful process is outlined in a three-step synthesis of (-)-or ( +)-muricatacin Scheme 23.93 (Camphory1)sulfonyl oxaziridines are versatile epoxidizing agents and the publication of a method suitable for their large H’M~B~-92% HO C12H25 0 HO‘ a (+)-Muricatacin Reagents i.CH3(0Et), EtC0,H (cat.) A; ii AD-mix-x Scheme 23 89 C. M. Rayner and A. D. Westwell Tetruhedron Lett.. 1992,33. 2409; C. M. Rayner. M. S. Sin and A. D. Westwell Tetrahedron Lett. 1992 33. 7237. 90 P. Mohr Tetrahedron Lett. 1992 33 2455. 91 J. Clayden E. W. Collington and S. Warren Tetrahedron Lett. 1992 33 7043. 92 K.-S. Jeong P. Sjo and K. B. Sharpless Tetrahedron Lett. 1992. 33 3833; G. A. Crispino and K. B. Sharpless Tetrahedron Lett. 1992 33 4273; J. A. Turpin and L. 0.Weigel Tetruhrdron Lett.. 1991. 33 6563; L. Wang and K. B. Sharpless J.Am. Chem. Soc. 1992 114 7568; D. Xu G.A. Cripino and K. B. Sharpless J. Am. Chem. Soc. 1992. 114,7570; K. Fuji K. Tanaka and H. Miyarnoto. Tetruhedron Lett. 1992,33 402 1. 93 Z.-M.Wang X.-L. Zhang. K. B. Sharpless S. C. Sinha A. Sinha-Bagchi and E. Keinan. Trtruhedrnn Lrtt.. 1992. 33 6407. 118 P. Quayle scale preparation is most welcome.94 Ley95 has developed a new protecting group strategy for use in carbohydrate chemistry in which selective protection of diequatorial vicinal diols with the diene (5) is observed. Selective removal of the protecting group can be achieved without the disruption of other acid sensitive functionality Scheme 24. Clearly this represents a major methodological advance. Reagents i CSA CHCl, A Scheme 24 The introduction of amino groups into highly functionalized molecules is sometimes difficult to achieve using standard polar functional group manipulations.In a recurrent theme but with a novel twist Barton96 has developed a radical amination reaction sequence in which a carbon-centred radical prepared by one of several routes is efficiently trapped (ca. 100%)with a diazirene to afford upon work-up high yields of the requisite primary amine Scheme 25. The asymmetric synthesis of amines has been i-iii I Reagents i F3cx[ ; ,hv 95%; ii B(OH), EtOH H,O 87%; iii Ac,O Py 90% Ph NS I Scheme 25 OAc 94 I. Mergelsberg D. Gala D. Scherer D. DiBenedetto and M. Tanner Tetrahedron Lett. 1992 33 161. 9s S.V. Ley R. Leslie P.D. Tiffin and M. Woods Tetrahedron Lett.1992 33 161. 96 D. H. R. Barton J. Cs. Jaszberenyi and E.A. Theodorakis J. Am. Chem. Sac. 1992 114 5904. Aliphatic and Alicyclic Chemistry achieved uia the diastereoselective conjugate addition reactions of amide anions to en~lates,~' and by the dia- by catalytic asymmetric hydrogenation of imine~,~~ stereoselective addition of carbon nucleophiles to oximes and related corn pound^.^^ Oppolzer has reported two complementary routes to the asymmetric synthesis of p-amino alcohols either uia reaction of an achiral zinc enolate with homochiral or-chloronitroso reagents'"" or by reaction of a homochiral enolate with an achiral aminating agent.*'Ob Both routes proceed with excellent levels of induction (~96% e.e.). Hoppe'" has shown that carbamates of B-aminoalcohols undergo highly enantioselective deprotonation-alkylation reactions in the presence of sparteine Scheme 26.Clearly methodological advances in this area rely upon the identification Reagents i Bu"Li-sparteine(3 eq.) Et,O -78°C; ii E' Scheme 26 of other complexing agents which will ensure that this sequence has greater generality. The asymmetric synthesis of alcohols has taken on a new dimension since the development of other methodology (e.g.diastereoselective allylic alcohol epoxidation reactions) which use alcohols as starting materials. In recent years a most significant advance appears to be the use of homochiral oxazaborolidines for the asymmetric reduction of ketones. Again this year this method has gained prominence resulting in a wealth'02u of examples as exemplified in Scheme 27.The structure of the catalyst employed in these reductions has been determined by X-ray crystallography' OZb enabling the definition of a mechanistic model for the reduction sequence. A variety of 97 Y. Yamamoto N. Asao and T. Uyehara J. Am. Chem. Sue. 1992 114 5427. 98 C. A. Willoughby and S. L. Buchwald J. Am. Chem. Sue. 1992,114,7562;M. J. Burk and'J. E. Feaster J. Am. Chem. Soc. 1992,114,6266;see also D. R. Williams and M. H. Osterhout J. Am. Chem. Soc. 1992 114 8750. 99 K. Higashiyama H. Inoue and H. Takagashi Tetrahedron Lett. 1992,33,235:K. Soai T. Hatouaka and T. Miyazawa J. Chem. Soc.. Chem. Commun. 1992 1097. loo (a)W. Oppolzer 0.Tamura G. Sundarababu and M. Signer J.Am. Chem. Sue. 1992 114,5900; (b)W. Oppolzer 0.Tamura and J. Deerburg Helo. Chim. Acta 1992 75 1965. lo' J. Schwerdtfeger and D. Hoppe Angew. Chem. Int. Ed. Engl. 1992 31 1505; For a mini-review see P. Knochel Angew. Chem. Int. Ed. Engl. 1992 31 1459. lo* (a)E. J. Corey K. Y. Yi and P. T. Matsuda Tetrahedron Lett.. 1992,33,2319;E. J. Corey J. 0.Link and R. B. Bakshi Tetrahedron Lett. 1992,33,7107; E. J. Corey and K. A. Cimprich Tetrahedron Lett. 1992 33,4099; E. J. Corey and J.O. Link Tetrahedron Lett. 1992,33,4141; E. J. Corey and J. 0.Link J. Am. Chem. Soc. 1992 1-14 1906; (b)E. J. Corey M. Azimioara and S. Sarshar Tetrahedron Lett. 1992 33 3429. 120 P. Quuyle i ii 92%e.e. squalene epoxide H Ph Ph eo Reagents i ; o>BH ,88% (92% e.e.); ii Pr'ONa Pr'OH 3h A 91% (92% e.e.) \.Bu' Scheme 27 novel reducing agents have been reported this year some of which [(6) to (S)] appear to have some synthetic ~tility.'~~-~~~ OMe details concerning the use of the modified Noyori asymmetric hydrogenation system have appeared together with a representative synthetic application Scheme 28. The nucleophilic addition of C-centred anions to a carbonyl group is a fundamental synthetic operation. Reactions of aldehydes possessing an a-stereogenic centre with Grignard reagents affords the 'Cram' product usually with modest levels of 1,2-induction. However by merely changing the counter-ion associated with the lo3 R. Rawson and A.I. Meyers J. Chem. SOC.,Chem. Commun. 1992 494. lo4 N. Srivatava A.Mital and A. Kuma J. Chem. SOC..Chem. Commun. 1992 493. J.-M. Brunel 0.Pardigan B. Faure and G. Buono J. Chem. Soc. Chem. Commun. 1992 281 lo6 D.F. Taber P. B. Deker and L. J. Silverberg J. Org. Chern. 1992 57 5990. Aliphatic and Alicyclic Chemistry Indolizidine 223 AB Reagents i [(R)-Ru(BINAP)CI,], NEt, 0.1 mol. YOHCI/MeOH. 5Opsi H, 90% (98% ex.) Scheme 28 Grignard reagent high levels of induction may be observed,"' Scheme 29. The direct conversion of vinyl-boranes into vinyl-zinc reagents has been achieved. These nucleophilic organometallic reagents generated in situ undergo enantioselective alkylation reactions with aldehydes in the presence of a suitable homochiral catalyst. lo* A variety of chirally modified organometallics have been observed to undergo similar reactions with aldehydes with high levels of asymmetric induction.Io9 Mechanistic evidence has been presented which implies the existence of chelated intermediates in the nucleophilic addition of organometallics to a-alkoxy ketones' lo (i.e. validation of the Cram 'cyclic model' of induction some 30 years after its OH ?H PhyCHO N~-~ F'h* + P h p CHO "Cram" Nu-= MeMgCl 70 30 Nu-= MeMg 94 6 Scheme 29 lo' M.T. Reetz N. Harmat and R. Marchwald Angew. Chem. Int. Ed. Enyl. 1992 31 342. lo' W. Oppolzer and R.N. Radinov Helv. Chim. Actu 1992 75 170. lo9 A. Hafner R.O. Duthbaler R. Marti G. Rihs P. Rothe-streit. and F. Schwarzenbach J. Am. Chem. Soc. 1992,114,2321; B. Weber and D. Seebach Angew. Chem. In[.Ed. Enyl. 1992,31,85; D. Seebach D. A. Plattner A. K. Beck Y. M. Wang and D. Hunziker. Helv. Chim. Actu 1992 75 2171. 'lo X. Chen E.R. Hortelano. E. E. Eliel and S.V. Frye J. Am. Chem. Soc. 1992 114 1778. 122 P. Quayle introduction). In other systems the presence of a polar functional group may effect 'coordinated delivery' of a nucleophilic species to a carbonyl group,' '' Scheme 30. Clearly our understanding of such reactions remains to some extent empirical. SYn Anti 6 1 Reagents i ZnC1 Et,O -78 "C Scheme 30 The aldol reaction continues to be investigated as a vehicle for the asymmetric synthesis of P-hydroxy propionates and related systems."* A major theme this year has been concerned with the development of enantioselective catalyst systems for the Mukaiyama crossed-aldol reaction.' l3 In a rather interesting development Davis' l4 has shown that intramolecular hydrosilylation of these P-hydroxy esters followed by intermolecular allylation afforded the corresponding diols with useful levels of asymmetric induction (trans:cis = 20 :l) Scheme 31.The chemistry of 'zirconecene' continues to generate much interest. For example reaction of zirconecene with allylic or propargylic ether derivatives generates the corresponding allylic or allenic organometallics respectively which then undergo clean alkylation reactions with a variety of aldehydes,' ' Scheme 32. Unexpected-'" R. S. Coleman and A. Carpenter Tetrahedron Lett. 1992 33 1697. '" E. J. Corey D.-H. Lee and S. Choi Tetrahedron Lett.1992 33 6735 I. Paterson and R. D. Tillyer Tetrahedron Lett. 1992 33 4233; W. Oppolzer and C. Starkemann Tetrahedron Lett. 1992 33 2439; A. G. Myers S. E. Kephart and H. Chen J. Am. Chem. SOC.,1992,114,7923;A. K. Ghosh T.T. Duong and S. P. McKee J. Chem. SOC.. Chem. Commun. 1992 1673; see P.G. Willard Q.-Y. Liu and L. Lochmann J. Am. Chem. SOC.,1992 114 348 for X-ray structure of a LHMDS-ester complex. l3 e.g. W. Odenkirk J. Whelan and B. Bosnich Tetrahedron Lett. 1992,33,5729; S.4. Kiyooka Y. Kaneko and K.4. Kume Tetrahedron Lett. 1992,33,4927;E. Parmee Y. Hong 0.Tempkin and S. Masamune Tetrahedron Lett. 1992,33 1729; E. J. Corey C. L. Cywin and T. D. Roper Tetrahedron Lett. 1992,33 6907; R. C. Corcorran and J. Ma J. Am. Chem. SOC.,1992,114,4536; V. Sharma M.Sirnard and J. D. Wuest J. Am. Chem. SOC.,1992 114 7931. A.P. Davis and S.C. Hegarty J. Am. Chem. SOC. 1992 114 2745; For an example of a catalytic asymmetric ketone hydrosilylation see M.J. Burk and J. E. Feaster J. Am. Chem. SOC. 1992 114 2099. 'I5 H. Ito T. Nakamura T. Taguchi and Y. Hanzawa Tetrahedron Lett. 1992 33 3769. Aliphatic and Alicyclic Chemistry (major) Reagents i F- 0°C; ii SnCI Scheme 31 CP /cP OTBDMS ?h-( -OTBDMS 73% ii I OH OH > 98 2 Reagents i ‘Cp,Zr’; ii C,H ,CHO BF,.OEt, 50“ Scheme 32 ly,’ a-allenyl ketones undergo kinetically controlled deprotonation to afford the cumulenolates (9),which may be trapped with a variety of electrophiles producing the functionalized allenes (lo) Scheme 33.0 0 !r,H3 - R A,’ 3544% LRlR Reagents i LHMDS or LDA THF -78°C Scheme 33 ’I6 N.A. Petasis and K.A. Teets J. Am. Chem. Soc. 1992 114 10328. 124 P. Quayle The use of radical processes in organic synthesis continues to generate much interest especially for the construction of five-membered rings and polycyclic ring systems. ' ' 7a Latterly attention has also focused upon the control of relative stereochemistry in radical-mediated C-C bond formation and related reactions.' '7b Toru' * has described a three-component coupling reaction more usually associated with cuprate chemistry for the vicinal dialkylation of unsaturated ketones Scheme 34. SiMe3 70% Scheme 34 The Cieplak effect"' has come under much scrutiny and a unified model for the conjugate addition reactions of cuprates to y-alkoxyenoates has been proposed.' 2o 3 Alicyclic Chemistry Introduction.-The Birch reduction' 2' of aromatic compounds and the divinylcyclo- propane-cyclopentadiene rearrangement' 22 have been reviewed.An in-depth survey of the intramolecular S,' reaction contains much useful information relating to ring forming processes.'23 Cyc1opropanes.-Olah' 24 has described the preparation of the 1-ferrocenyl- 1-cyclo-propyl cation the first long-lived cyclopropyl cation. Doyle and Mul1e1-I~~ have 'I' (a) For an overview see W. B. Motherwell and D. Crich in 'Free-Radical Chain Reactions in Organic Synthesis'. Academic Press London 1992; (h)W. Smadja M. Zahouily and M. Malacria Tetrahedron Lett.1992,33,5511;A. Naim G. Mills and P. B. Shelvin Tetrahedron Lett. 1992,33,6779; D. P. Curran and G. Thoma J. Am. Chem. SOC.,1992,114,4436;W. Damrn B. Giese J. Hartung T. Hasskerl K. N. Houk 0.Hutler and H. Zipse J. Am. Chem.SOC.,1992,114,4067; D. P. Curran and B. Yoo Tetrahedron Lett. 1992 33 6931; N. A. Porter I. J. Rosenstein R.A. Breyer J. D. Bruhnke W.-X. Wu and A.T. McPhail J. Am. Chem. SOC. 1992 114 7664; J.G. Stack D.P. Curran S. V. Geib J. Rebek and P. Ballester J. Am. Chem. Soc. 1992 114 7007; Y.-D. Wu and K.N. Houk J. Am. Chem. Soc. 1992 114 1656; P. Erdrnan J. Schafer R. Springer H.-G. Zeitz and B. Giese Helu. Chim. Acta 1992 75 638; B. Giese W. Damm M. Roth and M. Zehnder SYNLETT 1992,441;see also D. P. Curran T. L. Fevig and M. J. Totleben SYNLETT 1992 943 for an appraisal of samarium-promoted Barbier reactions.T. Toru Y. Watanabe M. Tsuaka R. K. Gautam K. Tazawa M. Bakouetila T. Yoneda and Y. Ueno Tetrahedron Lett. 1992 33 4037. J. M. Coxon and D. Q. McDonald Tetrahedron Lett. 1992,33,651;M. N. Paddon-Row Y.-D. Wu and K. N. Houk J. Am. Chem. Soc. 1992,114 10638; A. Mukherjee E. M.M. Venter W. J. le Noble W. A. Watson and R. P. Kashap Tetrahedron Lett. 1992,33 3837; V. Vinkovic K. Mlinaric-Majerski and Z. Marinic Tetrahedron Lett. 1992,33 7441 ;see also C. Beeson N. Pham and T. A. Dix Tetrahedron Lett. 1992 33 2955; G. Mehta F. A. Khan and K. A. Laskshrni Tetrahedron Lett. 1992 33 7977. Y. Yamamoto Y. Chounan S. Nishii T. Ibuka and H. Kitahara J. Am. Chem. Soc. 1992 114 7652. P. W. Rabideau and Z.Marcinow Ory. React. 1992 42 Ch. 3. 122 T. Hudlicky R. Fan J. W. Reed and K.G. Gadamastti Org. React. 1992 41. Ch. 1. L. A. Paquette and C. J. M. Stirling Tetrahedron 1992 48 7383. G. K. S. Prakash H. Buchholz V. P. Reddy A. de Meijere and G. A. Olah J. Am. Chem. Soc. 1992,114 1097. M.N. Protopopova M. P. Doyle P. Muller and D. Ene J. Am. Chem. Soc. 1992 114 2755. Aliphatic and Alicyclic Chemistry I25 reported that the intermolecular cyclopropenation of alkynes with diazo esters catalysed by Rh,[(SR)-MEPY] can proceed with high levels of induction (98% e.e.). Padwa and Doyle’26 have studied the effect of ligand upon the chemoselectivity of catalytic carbenoid reactions. These workers concluded that cyclopropanation of a C-C double bond can be achieved with high levels of chemoselectivity when Rh,(cap) is employed as the catalyst rather than Rh,(OAc) or Rh,(pfb), Scheme 35.catalyst (A) (B) Rh*(OAc)? 52 48 Rh,@fb) 100 0 Rh2(cap) 0 100 Scheme 35 Martin’ 27 has developed an intramolecular cyclopropanation strategy for the preparation of oxabicyclo[4.1 .O]heptanes (1 1 ),which are valuable synthetic intermedi- ates. Hence reaction of the diazo-olefin (12) with Rh,[(SS)-MEPY] afforded the cyclopropanes (11) in good chemical yields (55-80%) and in up to 92% optical purity Scheme 36. KobayashiI2* has reported the first catalytic enantioselective Sim- mons-Smith cyclopropanation reactions of allylic alcohols in which a Reagents i Rh2[(SS)-MEPY],. CH2C12 Scheme 36 C2-symmetric bis-sulfonamide (13) was employed as the chiral auxiliary.To date chemical yields for this sequence are good but the optical purities are variable (13-82% e.e.) Scheme 37. M~therwell’~~ has shown that zinc carbenoids (14) may be generated from aldehydes using Zn/ClSi( Me),CH,.CH .Si(Me),Cl and trapped in situ 126 A. Padwa. D. J. Austin S. F. Hornbuckle. M. A. Semones. M. P. Doyle. and M. N. Protopopava J. Am. Chem. Soc. 1992 114. 1874. 12’ S. F. Martin C. J. Oalmann. and S. Liras Trtruhrdrori Lerr.. 1992. 33 6727. IZxH. Takahashi M. Yoshioka. M. Ohno. and S. Kobayashi Tetruhcdron Lett.. 1992 33. 2575. W. R. Motherwell and L. R. Roberts J. Chrm. SOL...Chum. Commun. 1992 1582. 126 P.Quayle Ph OH iPh A O H / 100% (80% e.e.) NHSqR Reagents i Et,Zn (2eq.) CH,I (3.0eq.) "NHS4R (13) Scheme 37 with olefins to afford the corresponding cyclopropanes in good yields.Treatment of the readily available a-(a1koxy)methyliron compounds (15) with a Lewis acid in the presence of an electron-rich olefin affords the cyclopropanes (16) in moderate to good yields'30 (44-68%) Scheme 38. De~xygenation'~'of the tertiary amide (17) with R I 1 P X Reagents i TMSOTf CH,CI, -78 "C Scheme 38 Sm/SmI generates the bicyclic species (18),in moderate overall yield. Presumably this sequence proceeds via the intermediacy of an a-amino carbene Scheme 39. Burgess'32 Reagents i SrnIJSrn THF reflux Scheme 39 I3O W. J. Seitz A. K. Saha D. Casper and M. Hossain Tetrahedron Lett.1992,33,7755;R. M. Vargas R. D. Theys and M. Mahum Hossain J. Am. Chem. SOC. 1992 114 777. 13' A. Ogawa N. Takarni M. Sekiguchi I. Ryu N. Karnbe and N. Sonada J. Am. Chem. SOC. 1992,114 8729. 13' K. Burgess and K.-K. Ho Tetrahedron Lett. 1992 33 5677. Aliphatic and Alicyclic Chemistry 127 has described an asymmetric synthesis of ornithine- and arginine-2,3-methanologues starting from the homochiral epoxy-tosylate (19) Scheme 40. Brinke~-'~~ has ri BOC-CJT~O-OXTI-O B Reagents i NaH C,H, 15-crown-5 25 "C Scheme 40 developed a facile method for the functionalization of bicyclo[n. 1 .O] systems which relies upon the activating effect of the cyclopropane ring on vicinal C-H bonds. Note that this particular C-H bond activation does not extend to the homologous bicyclo[n.2.0] system Scheme 41.81 19 Reagents i CHCI, NaOH TEBA Scheme 41 Cyc1obutanes.-Ikegami' 34 has demonstrated that by judicious choice of ligand Rh" catalysed C-H insertion reactions may be directed towards the formation of spirocyclobutanones rather than to the isomeric bicyclo[n.3.0] system Scheme 42. An asymmetric [2 +21-photocycloaddition reaction has been employed by Smith135 in the total synthesis of (-)-echinosporin. In the crucial reaction inter- molecular photocyloaddition of the enol ether (20) with cyclopent-2-enone afforded the (predicted) tetracyclic intermediate (21) as the major product in 50% isolated yield Scheme 43. An intramolecular [2 +21-cycloaddition strategy has been put to good effect by Crimmins' 36 in his total synthesis of (&)-bilobalide Scheme 44.Fleming 37 has used a silicon tether to control the regio- and stereochemical outcome of similar photocycloaddition reactions. Narasaka' 38 has developed a highly enantioselective (>80% e.e.) cyclobutane synthesis via a thermal cycloaddition reaction between electron-rich olefin and acrylamide derivatives catalysed by a homochiral titanium catalyst. Cycloaddition' 39 of the keteniminium salt (22) generated in situ 133 L. Xu W. B. Smith and U.H. Brinker J. Am. Chem. SOC. 1992 114 783. 134 S.4. Hashimoto N. Watanabe and S. Ikegami Tetrahedron Lett. 1992 33 2709. A. B. Smith G.A. Sulikowski M.M. Sulikowski and K. Fujimoto J. Am. Chem. SOC.. 1992 114 2567. M.T. Crimmins D. K. Jung and J.L. Gray J. Am. Chem. SOC.,1992 114 5445. S.A. Fleming and S.C. Ward Tetrahedron Lett. 1992 33 1013. 138 K. Narasaka Y. Hayashi H. Shimadzu and S. Niihata J. Am. Chem. SOC. 1992 114 8869. 139 C. Genicot and L. Ghosez Tetrahedron Lett. 1992 33 7357. 128 P. Quayle n O# C02Me 0 C02Me (A) (B) Reagents (i) Rhz(OAc)2 37 63 Rh2(02CCF3)4 56 44 ~~(HNAc)~ 14 86 Scheme 42 Scheme 43 Scheme 44 Aliphatic and Alicyclic Chemistry from the amide (23) with a variety of olefins affords cyclobutanones with moderate to excellent asymmetric induction (48-98% ex.) Scheme 45. 0 93% (93% e.e.) Reagents i Tf,O Base -10 'C CH,Cl,; ii H,O Scheme 45 The synthesis of C4.5.5.5lfenestrenesvia an intramolecular enone-alkyne photocyclo- addition reaction (a little-used variant) has been reported.140 Cyclobutanones serve as useful intermediates for the synthesis of y-butyrola~tones.'~~ The torquoselectivity observed in the electrocyclic conversion of cyclobutenes to their open-chain isomers has again come under in~estigation.'~' Eat~n'~~ has further investigated the nature of the cubyl cation. Della and Walt~n'~~ have generated cubyl radicals and studied their subsequent chemical functionalization. Cyc1opentanes.-A variety of organometallic approaches to cyclopentanes have been reported this year. Herndon 145 has discovered that cyclopropyl chromium carbene complex (24) unexpectedly underwent a metathesis-type reaction upon reaction with hepta-1,6-diyne to afford the phenol (25) in 51% isolated yield Scheme 46.A OMe (24) Scheme 46 molybdenum equivalent '46 of the Pauson-Khand reaction has been developed which appears to proceed in marginally higher yields than its cobalt counterpart. The Pauson-Khand 14' reaction itself has been utilized in the construction of polycyclic and 140 P. Gerber and R. Keese Tetrahedron Lett.. 1992 33. 3987 see also M. L. Graziano M. R. lesce F. Cermola and G. Cimminiello J. Chem. SOC..Perkin Trans. I 1992. 1269. 14' K. Tsushima and A. Murai Tetrahedron Lett. 1992 33 4345. 14' S. Niwayama and K. N. Houk Tetrahedron Lett. 1992,33,883; C. W. Jefford G. Bernardinelli. Y. Wang D.C. Spellmeyer A. Buda and K. N. Houk J. Am. Chem. SOC.. 1992 114. 1157. 143 P.E.Eaton and J. P. Zhou J. Am. Chem. SOC.,1992 114 3118. 144 E. W. Della N. J. Head P. Mallon and J. C. Walton. J. Am. Chem. Soc. 1992 114 10 730. 145 S.V. Tumer J. W. Herndon and L.A. McMullen J. Am. Chem. SOC.,1992 114 8394. C. Mukai M. Uchiyama and M. Hanaoka. J. Chem. Soc.,Chem. Commun. 1992 614. 14' M. E. Kraft I. L. Scott and R. H. Romero Tetrahedron Lett. 1992,33.3829; A. S. Gybin W. A. Smit R. Caple A.L. Veretenov A.S. Shashkov L.G. Vorontsova M.G. Kurella V.S. Chertkov A.A. Carapetyan A. Y. Kosnikov M. S. Alexanyan S. V. Lindeman,V. N. Panov A. V. Maleev Y. T. Strchkov. and S.M. Sharpe J. Am. Chem. Soc.. 1992. 114 5555. 14' 130 P. Quayle fused heterocyclic systems. Eat~n'~~ has reported the first catalytic iron-mediated [4+ 11 cyclopentenone synthesis Scheme 47.Fused bicyclic and spirocyclic cyclopen- ten one^'^^ are readily available by way of a Ni(CO) promoted carbonylative cycloaddition reaction of acetylenes with ally1 halides Scheme 48.Of note in this 7678% R1y?y: R' 0 Reagents i Fe(CO), 10 mol. YO,CO 25 "C Scheme 47 0 Reagents i Ni(CO), MeOH 25 "C Scheme 48 reaction sequence is the regiochemical control apparent in the incorporation of the acetylene into the product. Buchwald' 50a has demonstrated that cyclopentenones bearing reactive functionality may be prepared using Negishi-type ene-yne carbonyla- tion chemistry. Negishi'50b himself has utilized the same sequence in the preparation of ( + )-iridomyremycin (26) from the ene-yne (27). Vinyl rhodium carbenoids (28) undergo regioselective [3 + 21 annulation reac-tion~~ ' with electron-rich olefins to afford the functionalized cyclopentenes (29) in good overall yields.FSiMe3 14' B.E. Eaton B. Rollman and J.A. Kaduk J. Am. Chem. SOC. 1992 114 6245. L. Pages A. Llebaria F. Camps E. Molins,C. Miravitilles,and J. M. Moreto,J. Am.Chem.SOC.,1992,114 10449; F. Camps A. Llebaria J. M. Moreto and L. Pages Tetrahedron Lett. 1992 33 109. (a)R. B. Grossman and S. L. Buchwald J. Org. Chem. 1992,57 5804; (b)G. Agnel Z. Owczarczyk and E.4. Negishi Tetrahedron Lett. 1992 33 1543. H. M. L. Davies and B. Hu,Tetrahedron Lett. 1992 33 453. Aliphatic and Alicyclic Chemistry Suzuki’52 palladium-catalysed coupling of alkyl boranes (30)with the vinyl halides (31) has been applied in an intramolecular sense for the synthesis of carbocycles (32) possessing exocyclic alkene vinylidene groups of defined stereochemistry .A variety of palladium-catalysed cascade reactions’ 53 have been employed in the synthesis of cyclopentanes Scheme 49. Fu~hs’~~ has developed a “4 + 11’ strategy whereby sulfone dianions (33) are alkylated with o bis-electrophiles (34) to afford cyclopen- tenylsulfones (35) in a one-pot reaction. X OAc I (Ref. 153a) 0 +A(.& E+A E E / Me0 2-P EE (7 Br (Ref. 153b) E E Reagents i Pd(OAc), PPh, HCO,H CH,CN A; ii Pd(OAc), PPh, Ag,CO (2eq.) CH,CN 80°C Scheme 49 Herndon’ 55 has demonstrated that a variety of 5-hexenyltributylstannane deriva-tives undergo high yielding 5-em-cyclization upon reaction with the’modified ‘PhSe+’ reagent N-phenylselenophthalimide/tintetrachloride at -78 “C Scheme 50.Radical N. Miyayura M. Ishikawa and A. Suzuki Tetrahedron Lett. 1992 33 2571. (a)B. Burns R. Grigg V. Santhakumar V. Sridharan P. Stevenson and T. Warakua Tetrahedron 1992 48,7297; (b)F. E. Meyer J. Brandenburg P. J. Parsons and A. de Meijere J.Chem.Soc.. Chem. Commun. 1992 390. S. S. Magar and P. L. Fuchs Tetrahedron Lett. 1992 33 745. *’’J. W. Herndon and J. J. Harp Tetrahedron Lett. 1992 33 6243. 132 P. Quayle R Reagents i NSP-SnCI,. CH,Cl, -78 'C Scheme 50 processes' 56 have again been used extensively for the construction of cyclopentanes. A particularly useful development has been reported by Hanessian,' 56d who used trimethyltin radicals to initiate a cascade process and then removed the tin moiety oxidatively generating an acetal at the end of the sequence Scheme 51.Grigg' 57 has Reagents i Me,SnCl NaCNBH, AIBN Bu'OH A; ii MeOH CAN Scheme 51 shown that polycyclic systems can be rapidly constructed from simple acyclic precursors using a nitrone-based cascade process Scheme 52. Reagents i Hg(OAc),; ii A; iii I Scheme 52 Cyc1ohexanes.-The Diels-Alder reaction continues to be the premier method for the stereoselective construction of functionalized cyclohexane derivatives. Transition' 58 state structures for the JMDA reaction have been modelled using Allingers MM2 force field. Chou' 59 has evaluated the relative directing effects of 2,3-disubstituted buta- 1,3-dienes in the Diels-Alder reaction.A bewildering variety of dienes and dienophiles have again been utilized in the Diels-Alder reaction this year Figures l(a)and l(b). The development of Lewis acid catalysts such as (36) and (37)for use in the Diels-Alder 156 (a)J. S. Yadav K. T. K. Kumar and V. R. Gadgil Tetrahedron Lett. 1992,33,3687; (b)V.H. Rawal and S. Iwasa. Tetrahedron Lett.. 1992 33 4687; (c)J. M. Contelles P. R. Riiz B. Sanchez and M. L. Jimeno Tetrahedron Lett.. 1992 33. 5261; (d) S. Hanessian and R. Leger J. Am. Chem. SOC. 1992 114 3115. 151 R. Grigg M. Hadjisoteriou P. Kennewell J. Markandu and M. Thornton-Pett J. Chem. SOC.. Chem. Commun. 1992. 1308. 158 L. Raimondi F. K. Brown J. Gonzalez. and K.N.Houk J. Am. Chem. SOC.,1992 114 4796. 159 T.-S. Chou C.-Y. Chang. M.-C. Wu S.-H. Hung. H.-M. Liu and W.-Y. Yeh J. Chem. Soc. Chem. Cornmun. 1992 1643. Aliphatic and Alicyclic Chemistry 0 Ph Ph Bz0 0 (Ref. 160) (Ref. 161) (Ref. 162) R'THoyoY:e I / 0 OL '-_. (Ref. 163) (Ref. 164) (Ref. 165) (Ref. 166) n 4 0 B00 1 "I Ph (Ref. 167) (Ref. 168) (Ref. 169) NTs s^ KBR2 R*07? 0 (Ref. 170) (Ref. 171) (Ref. 172) (Ref. 173) Figure l(a) Ih0 D. Craig and J.C. Reader. Tetrahedron Lett.. 1992 33 4073. Y 161 M. Toyota. T. Seishi. M. Yokoyama K. Fukumoto and C. Kabuto Tetrahedron Lett. 1992 33 4581. 162 T. K. M. Shing and Y. Tang J. Chem. SOL... Chem. Commun. 1992 341. I63 B. Alcaide C. Biurru J. Plumet and E.Borredon. Tetrahedron 1992 48 9719. I64 A. Razaname P. Vogel and F. Claret Hek. Chim. Acta 1992 75 1087. 165 S.R. Desai V. K. Gore T. Mayelvaganan R. Padmakumar and S.V. Bhat. Tetrahedron 1992. 48 481. 166 G.H. Posner T.-C. Carry T. E. N. Anjeh and A. N. French J. Org. Chem. 1992 57 7012. I67 I. E. Mark0 and A. Chesney SYNLETT 1992 275. 168 S. Horne and R. Rodrigo J. Chem. Soc.. Chem. Commun. 1992 164. 169 K. C. Nicolaou C.-K. Hwang E. J. Sorenson and C. F. Clairborne J. Chem. Soc..Chem. Commun.. 1992 1117. 170 M.-H. Cheng G.-M. Yang J.-F. Chow G.-H. Lee and S.-M. Peng J. Chem. Soc.. Chem. Commun. 1992. 934. 171 K. Narasaka and 1. Yamamoto. Tetrahedron 1992. 48. 5743. 172 D. A. Singleton J. P. Martinez J. Watson and G. M.Nidip Tetrrihedron. 1992. 48. 5831. 173 P. Hamley G. Helmchen A. B. Holmes D. R. Marshall J. W. M. MacKinnan D. F. Smith and J. W. Ziller J. Chem. Soc.. Chem. Commun.. 1992 786. 134 P. Quayle (Ref. 174) (Ref. 175) Figure l(b) reaction have figured pr~rninently."~ An X-ray crystal of the Corey catalyst (38) has been obtained. In conjunction with NMR data the structure of one catalyst dienophile complex (39)has been formulated as shown in Figure 2. This model correctly predicts the absolute sense of induction observed in the Diels-Alder reactions of this dienophile-catalyst system. Fe ArS02/ N,~/o I Bun (36) (37) L J Figure 2 174 M. Chini P. Crotti F. Macchia M. Pineschi and L. A. Flippin Tetrahedron 1992,48 539. A.Defin A. Brouillard-Poichet and J. Streith Helv. Chim. Acta 1992 75 109. 176 E. J. Corey T.-P. Loh T. D. Roper M. D. Azimiora and M. C. Noe J. Am. Chem. SOC.,1992,114,8290; T.K. Hollis N.P. Robinson and B. Bosnich J. Am. Chem. SOC. 1992 114 5464; E.J. Corey and K. Ishihara Tetrahedron Lett. 1992 33 6807; S. Kobayashi I. Hachiya T. Takahori M. Araki and H. Ishitani Tetrahedron Lett. 1992,33,6815; W.Odenkirk A. L. Rheingold and B. Bosnich J. Am. Chem. SOC. 1992 114 6392; K. Maruoka S. Saito and H. Yamamoto J. Am. Chem. Soc. 1992 114 1089. '" E. J. Corey S. Sarshar and J. Bordner J. Am. Chem. SOC.,1992 114 7938. Aliphatic and Alicyclic Chemistry Other methods of synthesis reported this year include a manganese(III)-promoted oxidative free radical cyclization ''I3 of p-ketoimides (Scheme 53) double Michael Reagents i.Mn(OAc),.2H20 Cu(OAc),.H,O HOAc 25 "C Scheme 53 addition reactions,' 79 and a polyene cyclization sequence leading to ( & )-taxodione,' go Scheme 54. Tietze' '' utilized a tandem Sakurai carbonyl-ene sequence OMe I i -83% Reagents i BF3-CH3N02 25 "C Scheme 54 for the construction of steroidal-like tricyclic systems Scheme 55. 'Heck',' 82 'Trost',' 83 and radical' 84 cyclization reactions nicely compliment each other as SiMe Reagents i TMSOTf 1.1 eq. -78°C to -30°C Scheme 55 178 P.A. Zoretic X.Weng C. K. Biggers M. S. Biggers M. L. Caspar and D. G. Davis Tetrahedron Lett. 1992 33 2637. 179 H. Hagwara K.Kon-No and H. Uda J. Chem. SOC.,Chem. Commun. 1992 866.180 S.R.Harring and T. Livinghouse J. Chem. Soc.. Chem. Commun. 1992 502. 181 L. F. Tietze and M.Rischer Angew. Chem. fnt. Ed. Engl. 1992 31 1221. 182 J. L. Mascarenas A.M. Garcia L. Castedo and A. Mourino Tetrahedron Lett. 1992 33 4365. I63 B. M. Trost and J. Dumas J. Am. Chem. SOC.,1992 114 1924. 184 C. Chen and D. Crich Tetrahedron Lett. 1992 33 1945. 136 P. Quayle illustrated in Scheme 56 for the approaches developed to the synthesis of the A-ring of vitamin D metabolites. Ref. 184 U Scheme 56 Cycloheptanes and Cyc1ooctanes.-The chemistry of cyclooctanes has been re-viewed.*85 Smithlg6 has prepared the first trans-homotropone and studied its rearrangement chemistry. Dowdlg7 has developed a novel route to the synthesis of cycloheptenes/cyclooctenes based upon a radical cyclization-fragmentation stragegy Scheme 57.Crich’ 88 has developed a radical-based route to bicyclo[5.3.0]decan- 2-ones utilizing the intramolecular capture of acyl radicals which are generated from Reagents i Bu,SnH. AIBN 80°C; ii TMSI ZnI,; iii DBU Scheme 57 acylselenides. The intramolecular nitrile oxide cycloaddition reactions of sugar-derived nitrones have been extended by Dureau1tlg9 to the synthesis of poly- hydroxylated cycloheptane derivatives Scheme 58. The frenzied interest in taxane Is’ N. Pestasis and M. A. Patani Tetrahedron 1992 48 5755. J.L. Wood and A.B. Smith J. Am. Chem. SOL..,1992 114 10075. ‘” P. Dowd and W. Zhang J. Am. Chem. SOC.,1992 114. 10084; Tetrahedron Lett. 1992 33 3285.D. Batty and D. Crich Tetrahedron Lett. 1992 33 875. 189 0.Duclos A. Dureault and J. C. Depezay Tetrahedron Lett. 1992 33 1059. Aliphatic and Alicyclic Chemistry OBn OBn OBn HO OBn (major) Reagents i NaOCl (eq.).CH,CI, 20 C Scheme 58 chemistry has again culminated in many ‘approaches’ to the basic ring system. Wender’” has presented an elegant and viable approach to the synthesis of the basic tricyclic core starting from a-pinene Scheme 59. Fetizon”’ has also described li c &l3R RO-Reagents i htl (85%) Scheme 59 a photochemical route to the taxane skeleton whereby irradiation of the ketone (40) resulted in a Norrish type I1 cleavage generating the [5.2.1] system (41). 19’ P.A. Wender and T. P. Mucciaro.J. Am. Chem. Soc.. 1992 114. 5878. I91 M. B. le-Hocine D. D. Khac M. Fetizon. F. Guir. Y. Guo and T. Prange 7krruhedroii Lrtr.. 1992 33. 1443. 138 P. Quayle Medium and large ring~.-White'~~ has completed a total synthesis of (&)-byssochlamic acid which utilizes an intramolecular [2 +23-photocycloaddition reaction in the key C-C bond forming step Scheme 60. Marshalllg3 has developed a 0 00 0 A0 i Scheme 60 highly efficient synthesis of large ring-containing acetylenes via intramolecular alkylation of an aldehyde with an allenyl stannane Scheme 61. Numerous publications RO eH 1 - 5%93 RO Reagents i BF,.OEt, -78 "C Scheme 61 this year have again been concerned with the synthesis of ene-diynes as exemplified by the first asymmetric synthesis'94 of the ten-membered ring system (42) related to the neocarzinostatin chromophore Scheme 62.In terms of simple elegance the synthesis of cyclacenes' 95 such as Kohnkene (43) via repetitive Diels-Alder reactions is perhaps one of the most aesthetically pleasing results of the year. 19' J. D. White M. P. Dillon and R. J. Butlin J. Am. Chem. SOC. 1992 114 9673. 193 J.A. Marshall and X.-J. Wang J. Org. Chem. 1992 57 3387. 194 K. Natatani K Arai and S. Terashima J. Chem. SOC. Chem. Commun. 1992 289. 195 P. R. Ashton G.R. Brown N. S. Issacs D. Giuffrida F. H. Kohnke J.P. Mathias A.M.Z. Slawin D. R. Smith J. F. Stoddart and D.J. Williams J. Am. Chem. SOC. 1992 114 6330. Aliphatic and Alicyclic Chemistry Reagents i LiN(SiMe,), THF -78 "C BF,.OEt,; ii Ac,O Scheme 62

ISSN:0069-3030    

DOI:10.1039/OC9928900107

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

6 Aromatic Compounds By A. P. CHORLTON Zeneca Specialties Hexagon House Blackley Manchesrer M9 3DA UK 1 General and Theoretical Studies In .n systems with localized double bonds the switch from one localization pattern to another symmetry-equivalent one is generally considered to proceed via a delocalized transition state of higher symmetry. Heibrunner and Shaik have proposed a mechanism for double bond fluctuation without passing through a high energy delocalized structure. This model is based on second-order perturbation theory within the Hiickel formalism.' The structures of a number of triannulated benzenes have been studied these show no evidence of bond alternation in a 'Mills-Nixon' fashion. Bond alternation is however observed and this is postulated to arise as a consequence of the degree of 71 character of the annulated rings.2 An empirical aromaticity index has been proposed based on the reversibility of protonation of aromatic ether^.^ Liebman has also developed an experimentally convenient theoretical model for the prediction of relative ar~maticity,~ based on the thermochemical equivalence of phenyl and vinyl groups.The presence of o-benzyne has often been inferred by the observation of infra-red signals at 2085cm-' which is within the normal range associated with C=C triple bonds. Theoretical considerations have led to the conclusion that the ketene C=C plus C=O in cyclopentadienylideneketeneis responsible for this IR feat~re.~ Proof of rn-arynes has been obtained for the first time from an IR spectroscopic study of 2,4-didehydro~henoI.~ The photoelectronic spectrum of o-benzyne has been used to detect its ionization potential; this can then in turn be used as a measure of its singlet-triplet gap.7 It has been found that when benzene molecules are subjected to supersonic jet laser spectroscopy they show a sudden drop of photoionization yield at the onset of the third channel region.8 19FNMR has confirmed the existence of a new type of torsional stereoisomerism.9,10-bis(Trifluorovinyl)phenanthrenehas been shown to exist as a pair of torsional ' E. Heibronner and S. Shaik Helc. Chim. Actu 1992 75 539. K. K. Baldridge and J. S. Siege] J. Am. Chem. Soc. 1992 114. 9583. B. Capon and S. Q. Lew Tetrcihrdron. 1992 48 7823. R. S.Hosmane and J. F. Liebman Tetrahedron Lett. 1992 33 2303. ' A.C. Scheiner and H. F. Schaefer J. Am. Chem. Soc. 1992. 114 4758. ' G. Bucher W. Sander E. Kraka. and D. Cremer Angew. Chrrn.. fnt. Ed. Engl. 1992 31 1230 ' X. Zhang and P. Chen J. Am. Chem. Soc. 1992 114 3147. T. Ichimura. H. Shinohara K. Ohashi and N. Nishi. Bull. Chem. Snc,. Jpn.. 1992 65 234. 141 142 A. P. Chorlton diastereoisomers. The barriers to interconversion of these diastereoisomers is thought to be due to steric effects between the phenanthrene and vinyl moieties.' NMR data has demonstrated that the negative charge of the 2,4,3,5,6~pentamethylbenzene anion is confined to a single resonance-stabilized methylene. No evidence was found for a fluxional carbanion in which protons pass rapidly in a circular fashion from one carbon to the next." The 13C NMR substituent-induced chemical shifts of mono substituted benzene derivatives have been examined.' The structural consequences of a molecular assembly that is deficient in hydrogen bond acceptors has been studied by X-ray crystallography.It was shown that aromatic amines can remedy this unfavourable situation by the formation of weak N-H bonds to the aromatic system and through a change in hybridization of nitrogen.'* Polar/n interactions seem to affect the barrier to rotation of 1,%diary1 napthalenes.' The intramolecular hydrogen bonding in N-alkyl-o-nitroanilines has been studied by the application of solvatochromism.'4 The debate on the homoaromaticity of triquinacene has continued.The heat of hydrogenation of triquinacene (1) is anomalously low and this has been attributed to homoaromaticity caused by the overlap of its three TC orbitals. This claim has been refuted by a number of workers who claim this discrepancy is due to differential relief of strain by di- tetra- and hexahydrotriquinacene. These claims could not be verified by theoretical methods. However a recent MM3 study has given calculated heats of hydrogenation in good agreement with experimental values thus concluding that homoaromaticity in triquinacene and in other neutral hydrocarbons is vanishingly small. Scheme 1 The formation of valence isomers of benzenes from the parent aromatic generally involves their excited states and is therefore a photochemically allowed process.Miki W. R. Dolbier Jr. and K. W. Palmer Tetrahedron Lett. 1992 33 1547. lo F. M. Menger and M.G. Banaszczyk Tetrahedron Lett. 1992 33 301. 0.Exner and M. Budesinsky Coll. Czech. Chem. Commun.,1992 57 497. l2 L. R. Hanton C. A. Hunter and D.H. Purvis J. Chem. SOC..Chem. Commun. 1992 1134. l3 F. Cozzi M. Cinquini R. Anunziata T. Dwyer and J.S. Siegel J. Am. Chem. SOC. 1992 114 5729. l4 R. Cattana J.J. Silber and J. Anunziata Can. J. Chem. 1992 70 2677. '' J. W. Storer and K. N. Houk J. Am. Chem. SOC. 1992 114 1165. Aromatic Compounds has reported the first thermal example of this ‘forbidden’ reaction Scheme (l).16-17 In the rearrangement of Dewar benzene the population of singlet excited benzene is not allowed by energetic constraints.However the thermolysis of (2) is anticipated to release 334 kJ mol- in activation and reaction enthalpy. This is sufficient energy to yield the singlet state of (3) which undergoes rearrangement to quinovalene (4) albeit in low yield.’ * Further examples of this type of rearrangement in cyclophanes have been described.19920 A MC-SCF study of the thermal and photochemical cycloaddition of Dewar benzene has been described.2’ * (3) 1 0 But (5) (4) UV and NMR evidence indicate that the singlet state of 1,2,4,5-tetramethyleneben-zene biradical (5)is kinetically stable; this is contrary to previous experimental studies which favoured a triplet state.22 1,2,4-cyclohexatriene (6) an isobenzene has been generated. Its structure was proved by subsequent trapping reactions; Scheme (2).23Its [2 + 2) cycloaddition with styrene has been the subject of a theoretical 2 Preparation of Benzenes from Non-aromatic Precursors The Diels-Alder reaction is still used routinely to prepare aromatic rings; a recent application is the synthesis of musk odour type arene~.~’ There is continued popularity in the use of a-pyrones as 4n components in the Diels-Alder reaction.26 Two recent l6 S.Miki T. Katayama and Z. Yoshida Chem. Lett. 1992 41. S. Miki T. Ema R. Shimizu H. Nakatsuji and 2. Yoshida Tetrahedron Lett. 1992 33 1619. I* S. Miki 0.Kobayashi H. Kagawa Z. Yoshida and H. Nakatsuji Chem. Left. 1992 65. l9 R. Gleiter and B. Treptow Angew. Chem.. fnt. Ed. Engl. 1992 31 862. 2o S. Miki R.Shimizu and H. Nakatsuji Tetrahedron Lett. 1992 33 953. 1. J. Palmer M. Olivucci F. Bernardi and M.A. Robb J. Org. Chem. 1992 57 5081. ” J. H. Reynolds J. A. Berson K. K. Kumashiro J.C. Duchamp K. W. Zilm A. Rubello and P. Vogel J. Am. Chem. SOC. 1992 114 763. 23 M. Christ] M. Braun and G. Muller Angew. Chem.. In[. Ed. Engl. 1992 31 473. 24 R. Janoschek Angew. Chem. Int. Ed. Engl. 1992 31 477. 25 G. Shi S. Cottens S.A. Shiba and M. Schlosser Tetrahedron 1992 48 10 569. ” K. Afarinka G. H. Posner and V. Vinder J. Org. Chem. 1992 57. 4088. 144 A. P. Chorlton -30°C Scheme 2 examples demonstrated how aromatic rings can be annulated to heterocycles to form carba~oles~~ and indoles.28 o-Quinodimethanes continue to be of interest because of their synthetic utility as effective dienes in Diels-Alder reactions for the construction of polycyclic compounds.Quinodimethanes can be generated under mild conditions by the action of Pd'SmI on the propargylic acetate (7). The resulting napthoquinodimethanes (8) can be trapped with alkenes; subsequent oxidation gives 2,3-substituted anthracenes (9).29 OAc Pd(0). Sm12 -78°C OAc (9) (7) The ring opening of benzocyclobutenes is still the preeminent procedure for the generation of quinodimethanes. This method has been used to prepare 3-amino- symmetrical polymethoxy anthra~enes~~ 2-napthalene carboxylic a~id,~',~ and substituted 2-napth0ls.~~ It is very well exemplified by a one-pot synthesis of anthracenes (Scheme 3).3493 The rearrangement of 1,5-diyne-3-enes to arene- 1,4-diyls (Bergman cyclization Scheme 4) has taken on added significance with the discovery of natural toxins which appear to function by undergoing this rearrangement under mild conditions and '' P.I. Van Brueck P. E. van Duran S. M. Toppet and G. J. Hoornaert J. Chem.Soc. Perkin Trans. I 1992 415. P. M. Jackson and C.J. Moody Tetrahedron 1992 48 7447. 29 J. Inanaga Y. Sugimoto and T. Hanamoto Tetrahedron Lett. 1992 33 7035. j0 K. Kobayashi Y. Kanno S. Seko and H. Suginome J. Chem. Soc.. Prrkin Trans. I 1992 31 1 I. 31 K. Kobayashi Y. Kanno S. Seko and H. Suginome J. Chem. Soc. Chern. Commun. 1992 781. 32 J. J. Fitzgerald N. E. Drysdale and R. A. Olofson Synth. Cornmun. 1992 22 1807. 33 A. Rakeeb Deshmuhk H.Zhang L. Tran and E.R. Biehl J. Org. Chem. 1992 57 2485. 34 A. Rakeeb Deshmukh M. Morgan L. Tran and E. R. Biehl Synthesis 1992 1083. 35 E.R. Biehl M. Dutt B. Fravel and H. Zhang J. Chem. Soc. Chem. Cornmun. 1992 1520. Aromatic Compounds produce DNA strand scission. This has prompted the investigation of this reaction in a number of model CN uBrDl LDmHF--70°C R' R' Scheme 3 X X Scheme 4 The relative rates of cycloaromatization have been correlated to the distance between the terminal alkyne~.~' This assumption has been challenged it has been alternatively proposed that the rate of cycloaromatization is related to the strain release in the transition state.41 Semmelhack has highlighted the dependence of the Bergman cyclization on the nature of the trapping agent and its concentration as well as the wide variation of product distribution with reaction ternperat~re.~~ Tandem Bergman cyclizations have been utilized in a new ring annulation method43 and in the preparation of napthalene (10) from (Z,Z)-deca-3,7-diene- 1,5,9-triyne (11).44 MeOH -6 \ K.C.Nicolaou A. Liu Z. Zeng and S. McComb J. Am. Chem. Soc. 1992 114 9279. " P. Magnus R. Lewis and F. Bennett J. Am. Chem. SOC. 1992 114 2560. A.G. Meyers and P. S. Dragovich J. Am. Chem. Soc. 1992 114 5859. 39 Y. Sakai Y. Bando K. Shishido and M. Shibuya Tetrahedron Lett.. 1992 33. 957. 40 K. C. Nicolaou G. Zuccarello C. Riemer V. A. Estevez and W. M. Dai J. Am. Chem. SOC.,1992 114. 7360. 4' P. Magnus P. Carter J.Elliott R. Lewis J. Harling. T. Pitterna W. E. Bauta. and S. Fortt J. Am. Chem. SOC.,1992 114 2544. 42 M. F. Semmelhack T. Neu and F. Foubelo Tetrahedron Lett. 1992 33 3277. " J. W. Grissom and T. L. Calkins Tetrahedron Lett. 1992 33 2315. 44 K. W. Bharucha R. M. Marsh R. E. Minto and R.G. Bergman J. Am. Chem. Soc. 1992. 114 3120. 146 A. P. Chorlton Meyers has shown that allenic enediynes (12) undergo a mild thermal rearrangement to form aromatic products. This reaction is similar to the Bergman cyclization in that it may proceed via the intermediacy of a biradical (13). This biradical shows substantial polar character which is evidenced by its reaction with methanol to form benzylmethyl ether along with 2-phenylethanol formed from radical rea~tion.~’ Palladium and nickel mediated inter and intra [2 + 2 + 21 electrocylizations of alkynes and alkenes have been used to prepare polycycles containing a central aromatic ring.46-48 D-glucose is converted to aromatics by Eschevichia coli.This reaction is catalysed by a transketolase enzyme. Genetic manipulation of this enzyme has resulted in a two-fold increase in the percentage of D-Glucose which is siphoned into aromatic biosynth- e~is.~’ A Michael-induced ring closure has been effectively used for the regioselective preparation of ~yano-anilines~~ and-phenol~.~The employment of phthalides has allowed cyclohex-2-enones to be used as the Michael acceptor to give direct access to structural subunits of Olivomeyin and related antibiotics (Scheme 5).52 Reagents i Bu‘OLi; ii Raney nickel Scheme 5 In a similar process the intramolecular Wittig reaction is utilized to give 2- naphth~ates.’~ A new general route to 1,2-diarylethylenes has been developed through nucleophilic addition of Grignard reagents to cl-cinnamoyl dithioacetals followed by cationic cyclization in the presence of boron trifluoride (Scheme 6).54 ” A.G.Myers P. S. Dragovich and E.Y. Kuo J. Am. Chem. Soc. 1992 114 9369. 46 F. E. Meyer H. Henniges and A. de Meijere Tetrahedron Lett. 1992 33 8039. ‘’ E. Negishi D. S. Harring Z. Owczarczyk M. M. Mohamad and M. Ay Tetrahedron Lett. 1992,33,3253. 48 P. Bhatarah and E.H. Smith J. Chem. Soc. Perkin Trans. 1 1992 2163. 49 K. M. Draths P. L. Pomplians D. L. Conley J. W. Frost A.Berry G. L. Disbrow R. J. Staversky and J.C. Lievense J. Am. Chem. Soc. 1992 114 3956. 50 G.E. H. Elgemrie A.M. Elzanate and A. K. Mansour J. Chem. SOC.,Perkin Trans. I 1992 1073. R. S. Mali and P. G. Jagtap Tetrahedron Lett. 1992 33 1655. ” D. Mal R. Pal and K.V.S.N. Murty J. Chem. Soc.. Chem. Commun. 1992 821. 53 W. Ding J. Pu and C. Zhang Synthesis 1992 635. ’‘ C. Srinivasa Rao 0.M. Singh H. Ila and H. Junjappa Synthesis 1992 1075. Aromatic Compounds eMgBr_ & OH SMe Me \ \ Scheme 6 The Rh' catalysed reaction of acylcyclopropenes represents a new approach towards substituted phenols Scheme (7).55 OH Scheme 7 This synthesis of phenols complements the more traditional benzannulation reactions of carbene complexes (Scheme 8).563s7 __t R' R$H OH R3 Scheme 8 An alternative method for the preparation of phenols is the thermal rearrangement of cyclobutenones.This procedure has been further exploited to give p-chloro- phenols58 and pentasubstituted phenols (Scheme 9).59 Danheiser has utilized this methodology for the key annulation of the c ring in the total synthesis of Dan Shen.60 55 A. Padwa and S. L. Xu J. Am. Chem. SOC. 1992 114 5881. 56 K.H. Dotz T. Schafer F. Kroll and K. Harms Angew. Chem.. Int. Ed. Engl. 1992 31 1237. 5' D. F. Harvey K. P. Lund and D. A. Neil J. Am. Chem. SOC.,1992 114 8424. " S. L. Xu and H. W. Moore J. Org. Chem. 1992 57 326. 59 D. J. Krysan A. Gurski and L.S. Liebeskind J. Am. Chem. SOC. 1992 114 1412. 6o R. L. Danheiser D.S. Casebier and J. L. Loebach Tetrahedron Lett. 1992 33 1149. 148 A. P. Chorlton M,r&C-R -[M]=O + [MI-R [MI-C-R'0' 0' [MI = U(C5H=J2; R =Me EX,Pr' But Scheme 10 Triscyclopentadienyl uranium alkyl complexes react with carbon monoxide to give alkyl benzenes (Scheme 3 Non-aromatic Compounds from Benzene Precursors Oxidation of methoxyphenols with iodobenzene diacetate in various alcohols as solvent affords the mixed quinone monoketals. When p-methoxylphenol is oxidized in the presence of sorbyl alcohol the mixed quinone monoketal is trapped by an intramolecular Diels-Alder reaction (Scheme 1 1).62 4) -Q Me0 0 Me0 0 Scheme 11 Iodobenzene diacetate is also effective in the oxidation of phenolic-dibenzylbutyro lactones to spirodienones in the synthesis of dibenzocyclooctadiene lignan~.~~ Methoxyphenols can also be oxidized to quinone mono ketals by thallium(nI) nitrate.64 Anodic oxidation of 4-(2'-alkenylpheny1)phenolsaffords trans-dihydroben- zofurans derived from a formal 1,3-0xidative cycloaddition of the phenol to the styrene derivative (Scheme 12).65 C.Villiers R. Adam and M. Ephritikhine J. Chem. SOC.,Chem. Cornrnun. 1992 1555. 62 A. E. Fleck J.A. Hobart and G. W. Morrow Synth. Commun. 1992 22 179. 63 A. Pelter R. S. Ward and A.A. Abd-El-Ghani J. Chem. SOC.,Perkin Trans. 1 1992 2249. 64 F.T. Hong K.S. Lee and C.C. Liao Tetrahedron Lett. 1992 33 1992. 65 B.D. Gates P. Dalidowiez A. Tebben S. Wang and J.S. Swenton J. Ory. Chem. 1992 57 2135. Aromatic Compounds Anodic oxidations have also proved effective for the preparation of 1,4-66 and 1,3-~yclohexadienes.~~ Phenols can be oxidized to hydroquinone under mild condi- tions with copper a-diimine complexes as catalysts.@ Microbial oxidation of chloroaromatics gives chiral diene ~is-diols~~ which have been used in improved methods for the synthesis of (-)-cond~ritol~~ and a keto carbocylic nucleoside ~ynthon.~' ortho-Alkylated a-and /I-naphthols are oxidized with t-butyl hydroperoxide in the presence of Ti(OPr') to the corresponding a-ket~ls.~~ 1,2-dimethoxyarenes (14) can be cleaved to muconic diesters (15) by porphyrin catalysed oxidation with magnesium mon~peroxyphthalate.~ Addition of nucleophiles to an aromatic ring results in non-aromatic products.An example is the addition of alkenyl lead triacetates to 2,6-dimethylphenols (Scheme 13).74 OH 0 Scheme 13 If the aromatic contains a chiral auxiliary nucleophilic addition followed by removal of the auxiliary can give enantiomerically pure products. This methodology 66 I. Bardon and ?. Tornero Tetrahedron 1992 48 9967. 67 G. E. Hawkes J. E. Hawkes F.C. M. Comminos V. L. Pardini and H. Viertler Tetrahedron Lett. 1992 33 8133. J. Sykora E. Brandsteterova and A. Jabconova Synth. Commun. 69 T. Hudlicky E. E. Buros and C.H. Buros SYNLETT. 1992 391. 70 H. A. J. Carless J. Chem. SOC.,Chem. Commun. 1992 234. 71 T. Hudlicky M.G. Natchus and T.C. Nugent Synth. Commun. 1992 151. '' K. Krohn K. Bruggmann D. Doring and P.G. Jones Chrm. Ber.1992 125 2439. 73 I. Artaud H. Grennberg and D. Mansuy J. Chem. Soc. Chem. Commun. 1992 1036. 74 T. W. Hambley R. J. Holmes C. J. Parkinson and J. T. Pinhey J.Chem. SOC.,Perkin Trans. 1 1992,1917. 150 A. P. Chorlton has been put into good effect to give chiral tetralin derivatives (Scheme 14).75 Complexation of arynes with organo-manganese compounds allows previously inert aromatic systems to be attacked by nucleophiles. The use of the neutral hexa- fluorophosphate aryl tricarbonyl manganese complex has increased the number of nucleophiles that can be used effe~tively.~~ The addition of chiral nucleophiles to organo-manganese complexes can be stereoselective and this methodology has been used as the key step in a formal synthesis of (+ )-j~vabione.~~ NO CH2OH -[6{ RMgCl ___) NaBh mR \/ \/ \/ Scheme 14 Aromatic systems can also be broken down by reductive processes.The Birch reduction followed by alkylation of N-alkylnaphthalenes sulfonamides (16) gave the 1,4-dihydrosulfonamide (17) which on heating eliminated SO and amine to give substituted naphthalenes (18).78 9-Methoxyphenanthrene can be reductively aminated by photochemical means to give cis- and trans-9-amino- 10-methoxy-9,10-dihydrophenanthrenein a ratio of 75 :25.79Polynuclear aromatic hydrocarbons can be catalytically reduced using group 5 metal aryloxide compounds to give all-cis products.*' 2-Aryl substituted 3-benzyloxypropan-1-enesgenerally undergo meta photocyclo-addition at the 1,3-position of the benzene ring to give dihydro semibullvalenes (19).*' However aryl substituted 4-phenyloxybut-1-enes undergo [2 + 21 photoaddition to give cyclobutanes (20) which undergo ring opening to give the cyclooctatrienes (21); these can undergo subsequent electrocyclization of the diene unit to give the cyclobutenes (22).The substitution in the aryl ring markedly influences which product 75 L.N. Pridgen M. K. Mokhallalati and M. J. Wu J. Org. Chem. 1992 57 1237. 16 F. Balssa K. Aniss and F. Rose-Munch Tetrahedron Lett. 1992 33 1901. 71 W. H. Miles and H. R. Brikman Tetrahedron Lett. 1992 33 589. 78 H. J.E. Loewenthal and L. Gottlieb J. Org. Chem. 1992 57 2631. 79 M. Yasuda K.Shiomori S. Hamasuna K. Shima and T. Yamashita J. Chem. Soc..Perkin Trans. 2,1992 305.80 J. S. Yu B.C. Ankianiec M.T. Nguyen and I.P. Rothwell J. Am. Chem. Soc. 1992 114 1927. 81 D. C. Blakemore and A. Gilbert J. Chem. Soc.. Perkin Trans. I 1992 2265. Aromatic Compounds The photochemical reaction of octafluoronaphthalene and indene has is f~rmed.~~?~~ been studied and this results in all three cycloaddition modes i.e. 1,2- 1,3- and 1,4- cycloadditions take place.84 9-(5-Anilinohexy1)phenanthrene undergoes 1,3-photocycloaddition to afford a novel polycyclic nitrogen heter~cycle.~ Tetranitromethane forms 1,4-photoadducts with benzene showing that the aromaticity of even benzene can be broken down by this type of reaction.86 Monosubstituted benzene derivatives have been shown to act as a dipolarophile in reaction with tetracyanoethylene oxide (Scheme 1 5).87 Scheme 15 The photolysis of 3P-diarnidophenyl azides gives azepines and anilines the product distribution is dependent on the substituents; evidence is also presented for azirine intermediates.88 R2 S.Y. Al-Qaradawi K. B. Cosstick and A. Gilbert J. Chem. Soc.. Perkin Trans. 1 1992 1145. R3 P. J. Wagner M. Sakamoto and A. E. Madkour J. Am. Chem. Soc. 1992 114 7298. R4 N. Zupancic and B. Sket J. Chem. SOC.,Perkin Trans. 1 1992 179. R5 A. Sugimoto R. Hiraoko H. Inoue and T. Adachi J.Chem. Soc.. Perkin Trans. 1 1992 1559. R6 L. Eberson and M.P. Hartshorn J. Chem. SOC..Chem. Commun. 1992 1563. A. de la Hoz C. Pardo J. Elguero and M. L. Jimeno Monatsh. Chem. 1992 123 99. G.G. Younger and R.A. Bell J. Chem.SOC.,Chem. Commun. 1992 1359. A. P.Chorlton 4 Substitution in the Benzene Ring Electrophilic Substitution.-Aryl iodides are usually more difficult to prepare than other aryl halides and synthetic methods leading to them are relatively few. A number of procedures have been developed. Bis(pyridine)iodonium(I) tetrafluoroborate has been used as a mild source of electrophilic iodine.89 In a similar method N-iodosuccinimide and a catalytic amount of hydroxy(tosy1oxy)iodobenzene (Koser's reagent) have been used for the iodination of polyalkylbenzene~.~~ Direct iodination can also be achieved with iodine and alumina-supported copper(1r) chloride or ~ulfate.~' The search for more selective bromination continues with the use of polymer-bound tetraalkylammonium tribromide.This effects para-bromination of phenols in up to 90%.92Selective ring bromination of alkyl-substituted aromatic hydrocarbons has also been achieved using bromine adsorbed on the surface of alumina without any solvent.93 Aromatics can be chlorinated and brominated in the presence of a N-halosaccharin/pyridinium poly(hydrogen fluoride) system. This reaction avoids the use of any catalyst and takes place under mild conditions. This system is thought to generate the highly polarized halogenomonofluoride which obviates the need for polarization of the halogenation species by a Lewis acid.94 The selective introduction of fluorine into aromatics is difficult to achieve directly generally indirect methods are used of which the Balz-Schiemann is preeminent.This however has a number of limitations one of which is the need to isolate and dry the diazonium fluoroborate which can be hazardous and generally the reaction gives poor yields for carboxyl- and hydroxyl-substituted arylamines. A convenient one-pot conversion of arylamines to fluoroaromatics oia nitrosonium tetrafluoroborate has been developed which avoids these limitation^.^' A number of mild methods have been developed that introduce fluorine regioselectively . Caesium fluoroxysulfate has been used to prepare fluoroaromatics regioselectively under mild conditions by the ips0 substitution of arylboronic acids and hydroxyalkyl gro~ps.~~,~~ Fluorine can also be introduced regioselectively by the treatment of N-aryl-N-hydroxyamides with di- ethylaminosulfur trifiuoride this results in the removal of the hydroxy function and introduction of fluorine at the para position.98 The introduction of the trifluoromethyl group has been reviewed.99 The mechanism of aromatic nitration continues to be the subject of active research.Theoretical calculations have been carried out that go some way to explain the solvent effects and regioselectivity of the reaction."' Aromatic nitration has been shown to take place under very mild conditions with potassium nitrate or nitric acid and boron 89 J. Barguena J. M. Gonzalez M. A. Garcia-Martin P.J. Campos and G. Asensio J. Chem. SOC.,Chem. Commun. 1992 1016. 'O P. Bovonsombat G.J. Angara and E. McNelis SYNLETT 1992 131. " M. Kodomari N. Amanokura K.Takeuchi and S. Yoshitomi Bull. Chem. SOC.Jpn. 1992 65 306. " K. Smith D. M. James I. Matthews and M. R. Bye J. Chem. SOC. Perkin Trans. I 1992 1877. '3 B. C. Ranu D.C. Sarker and R. Chakraborty Synth. Commun. 1992 22 1095. 94 I. Mozek and B. Stek Synth. Commun. 1992 22 2513. 95 D. J. Milner Synth. Commun. 1992 22 73. 96 L. J. Diorazio D. A. Widdowson and J. M. Clough Tetrahedron 1992 48 8073. 9' S. Stauber 1. Kosir and M. Zupan J. Chem. Soc.. Chem. Commun. 1992 275. " Y. Kikugawa K. Matsumoto K. Mitsui and T. Sakamoto J. Chem. SOC.,Chem. Commun. 1992 921. 99 M. A. McClinton and D. A. McClinton Tetrahedron 1992 48 6555. loo K. J. Szdbo A. Hornfeldt and S. Gronowitz J. Am. Chem. Soc. 1992 114 6827. Aromatic Compounds 153 trifluoride monohydratelo' and with nitric acid/trifluoromethanesulfonic anhydr-ide.lo2 Friedel-Crafts alkylation of phenyltrimethylsilane gives a mixture of three regio- isomers with the absence of ipso-substitution.It has been suggested therefore that in Friedel-Crafts alkylation the trimethylsilyl group is a very slightly activating substituent but has essentially no directing effect.lo3 The use of shape selective zeolites in the Friedel-Crafts acylation gives good regioselective control and avoids the use of large quantities of aluminium ch10ride.l'~ Dihydroxy ketones such as (23) are usually obtained by a sequence involving Friedel-Crafts acylation and hydrolysis. A more direct route to these dihydroxy ketones is by a photochemical mediated reaction between an aldehyde and a quinone."' OH OH OH OH 0 (23) It had previously been reported that the persulfate oxidation of aromatic amines (Boyland-Sims oxidation) gave exclusively the o-aminoaryl sulfates (24).It has now been established that the para isomer (25) is also formed and that the arylhyd- roxylamine 0-sulfonate (26) is the probable intermediate in this reacti~n.'~~?~~~ 0+ s,o;-(yoso< + 0 A detailed study has been carried out on the reaction of sulfur trioxide with benzene derivatives containing an oxy-substituent. It was found that the reaction is solvent dependent the use of a polar complexing solvent leading predominantly to the para-sulfonic acid whereas dichloromethane or trichlorofluoromethane lead to the ortho-sulfonic acid.' 08,'09 In a further example of regiospecific sulfonation the ortho- and meta-hydroxybenzenesulfonic acids were obtained from the silylation of the lo' G.A.Olah Q. Wang X. Li and I. Bucsi Synthesis 1992 1085. Io2 G. A. Olah V. P. Reddy and G. K. Surya Prakash Synthesis 1992 1087. lo' H. Ishibashi H. Sakashita and M. Ikeda J. Chem. SOC.,Perkin Trans. 1 1992 1953. Io4 G. Harvey and G. Mader Coll. Czech. Chem. Cornmun. 1992 57 862. lo' G. A. Kraus and M. Kirihara J. Org. Chem. 1992 57 3256. Io6 E.J. Behrman J. Chem. SOC.,Perkin Trans. 1 1992 305. lo' E.J. Behrman J. Org. Chem. 1992 57 2266. lo* H. R. W. Ansink and H. Cerfontain Recl. Trav. Chim. Pays-Bas 1992 111 183. Io9 H. R. W. Ansink and H. Cerfontain Recl. Trav. Chim. Pays-Bas 1992 111 215. 154 A.P. Chorlton corresponding chlorophenols followed by ipso-sulfonation of the arylsilane intermedi- ates.' lo A one-pot synthesis of diarylsulfones has been developed. In this procedure an alkylbenzene (27) is treated with HS0,F-SbF,; this initially gives the p-sulfonylfluor- ide (28) which can be isolated but can be allowed to react in situ to give diarylsulfone (29)."' If HS0,-SbF is reacted with alkylbenzenes under an atmosphere of carbon monoxide the para-formyl compound (30) is first formed followed by further reaction to give the 2-(sulfony~fluoride)-4-formylalkylbenzene derivative (31).' ' A ready formylation of anilines has been developed using dimethyl sulfoxide/HCl 4-aminobenzaldehydes are formed in high yields. Chloromethyl methyl sulfoxide is thought to be the active species in this reaction.'13 Aromatic oximes have been prepared directly by the reaction of primary nitroalkanes with aromatics in triflic acid.The regioselectivity is in agreement with electrophilic aromatic substitution but fails for strongly deactivated aromatic^."^ The nitrile moiety can be introduced into electron-rich aromatics in moderate to good yields with activated arylcyanates using AICl,/HCl; the formation of the p-isomers is preferred.' Nucleophilic Substitution.-The mechanism of nucleophilic substitution of aromatic halides has been widely investigated. It appears that the first stage in this reaction is not the formation of a Meisenheimer adduct but an electron transfer process leading to radical intermediates.Grossi has reported the first experimental evidence from EPR spectroscopy for the radical species involved in such reactions. l6 The rate constants for the nucleophilic aromatic substitution reaction of 2,4-dinitrochlorobenzeneand picryl chloride have been measured and when used in combination with other literature data have been shown to correlate well with Ritchie's N+ parameter.'17 'lo P. Babin B. Bennetau P. Bourgeois and J. Dunogues Bull. SOC.Chim. Fr. 1992 129 25. M. Tanaka and Y. Souma J. Org. Chem. 1992 57 3738. '12 M. Tanaka J. Iyoda and Y. Souma J. Org. Chem. 1992 57 2677. '13 B. Liedholm J. Org. Chem. 1992 2235. 'I4 J. Coustard J. Jacquesy and B. Violeau Tetrahedron Lett. 1992 33 8085. K. Buttke T. Reiher and H. J. Niclas Synth. Commun.1992 22 2237. '16 L. Grossi Tetrahedron 1992 33 5645. J.R. Candler I.U. Setiarahardjo C. Tufon and C. Chen J. Org. Chem. 1992 57,4169. Aromatic Compounds Vicarious nucleophilic substitution has become more useful as the range of nucleophiles has increased. Amination of nitroarenes is now possible via the use of sulfenamides (Scheme 16).'l8 A certain degree of regioselectivity can also be achieved by variation of the base used. An intramolecular variant of the vicarious nucleophilic process has been developed which allows the synthesis of benzosultans.' l9 Scheme 16 In a similar process cyclic guanidines have been produced without the aid of a vicarious leaving group. The yields of the products are only moderate because a disproportionation reaction of the starting material is necessary for the elimination of the hydride ion.'*' The regioselectivity of intramolecular aromatic substitution to give benzodiazepines has been examined.12' A further advance has been made in nucleophilic aromatic substitution of hydrogen.Aniline in the presence of tetramethylammonium hydroxide attacks nitrobenzene to give N-(4-nitrosophenyl)phenylaminein 89% yield. In this process there is no auxiliary leaving group or external oxidant the formal oxidation takes place by an intermolecular redox process. 22 Nucleophilic aromatic substitution of isomeric chlorotoluenes can be facilitated by complexation with a cyclopentadienyl iron moiety. The resultant complexes undergo reaction with ethyl cyanoacetate followed by photolytic decomplexation to yield ethyl tolyl cyan~acetates.'~~ The position of nucleophilic attack of 4-(dimethy1amino)azobenzeneis controlled by the organometallic reagent used.Methyllithium adds ortho to the azo in the electron rich aminophenyl ring whereas organo-iron reagents add ortho to the azo in the less electron rich ring (Scheme 17).124 R'X = MeLi R' = Me R2 = H R'X = MQFeLi R' = H R2 = Me Scheme 17 M. Makosza and M. Bialecki J. Org. Chem. 1992 57 4784. K. Wojciechowski and M. Makosza Synthesis 1992 571. lZo F. Esser and K. Pook Synthesis 1992 596. K.A. Parker and C.A. Coburn J. Org. Chem. 1992 57 97. lZ2 M. K. Stern F.D. Hileman and J. K. Bashkin J. Am. Chem. SOC.. 1992 114 9237. A. S. Abd-El-Aziz and C. R. de Renus Synrh.Commun. 1992 22 581. T. Kauffmann J. Jordan and J. Sanders Chem. Ber. 1992 153. A. P. Chorlton The copper (I) halide catalysed reaction of aromatic halides with sodium alkoxides has been studied with reference to the solvent halogen temperature and rate of reaction. 12' The preparation of diphenyl ethers by the Ullmann reaction is catalysed by alkali-metal carbonates in combination with silica and aluminium silicates. The silyl ether formed from an aromatic halide and the silanol group on the surface of silica is presumed to be the intermediate of etherification.'26 The Ullmann reaction can take place at milder temperatures and gives improved yields with the use of ~1trasound.l~~ Microwave irradiation has been shown to accelerate the rate of ethoxylation of ortho and para-nitrochlorobenzenes by up to 240 fold.' 28 The ring opening reaction of (methy1enedioxy)benzenes (32) with propanethiolate in DMF leads to products (33) or (34) depending on the nature of (Z).Where Z = NO (33) is formed in 98% yield.Where Z is a more electron rich substituent e.g. CONH, nucleophilic attack takes place at the methylenedioxy carbon to give (34).129 Z 04 Z L O SPr OH (33) (34) Two groups of workers have independently reported the conversion of 1,2-dichlorobenzenes to 2-nitrophenols with nitrite in a dipolar aprotic media.' 303 '3' Nucleophilic fluorination of aromatic compounds containing suitable leaving groups is generally achieved by the use of KF or CsF in DMSO or sulfolane at high temperatures.This often leads to decomposition of base-susceptible substrates. Tetrabutylphosphonium fluoride and dihydrogen trifluoride can be used under milder conditions in polar solvents to furnish fluoroaromatics in excellent yield.' 32 A new methodology has been developed for the synthesis of a-aryl ketones (2)-Arylazo t-butyl sulfides react with ketone enolates via an S,,1 process to give a-aryl ketones.'33 Substitution via Organometallic Intermediates.-The geometry of the substitution at bromine in the bromine-lithium exchange reaction between a primary alkyllithium reagent has been evaluated by the endocyclic restriction test. The experiments have established that there is a geometrical dependence in these reactions and this combined with the failure of external bromide to become incorporated into the products appears to rule out both a four-centre concerted mechanism and a single 12' M.A. Keegstra T. H. A. Peters and L. Brandsma Tetrahedron 1992 48 3633. 126 I. Fukawa T. Tanabe and T. Dozono J. Chem. SOC.,Perkin Trans. 2 1992 377. 12' K. Smith and D. Jones J. Chem. SOC..Perkin Trans. 1 1992 407. Y. Yuncheng G. Dabin and J. Yulin Synth. Commun. 1992 22 2117. B. K. Cassels C. Radetski and M. C. Rezende Red. Trau. Chim. Pays-Bas 1992 111 448. I3O J. Zilberman D. Ioffe and I. Gozlan Synthesis 1992 659. 13' Y. Uchibori M. Umeno H. Seto Z. Qian and H. Yoshioka SYNLETT 1992 345. 132 L.R. Caswell M. Guevara L.D. Corley A.V. Martinez T. Hollis K. Largess and D.L. Thornley Synthesis 1992 823. 133 C. Dellerba M.Novi G. Petrillo and C. Tavani Tetrahedron 1992 48 325. Aromatic Compounds electron transfer mechanism. The reaction is suggested to proceed uia an ate complex or an S,2 type transition state.'34 Directed ortho metalation (DoM) has developed into a standard synthetic technique. Snieckus has continued to exploit the use of the ortho lithiated N,N-diethylbenzamide group which when reacted with a variety of electrophiles gives access to phthalides phthalic anhydrides and benzofurans all of which were only available by demanding classical methods.' 35,136 Heathcock has also used this methodology as the key step in the synthesis of Pancrastistatin models. In this example 1-nitrocyclohexene is added to in a 1,4-fashion by an ortho-lithiated benzamide.' 37 A number of other DoM groups have been investigated; these include t-butyl sulfox- ide,13* flu~rine,'~~*'~~ and thi01.l~' The anionic Fries rearrangement of esters of ortho-iodobenzyl alcohols proceeds smoothly to give isobenzofurans which can be intercepted in situ by inter- or intramolecular Diels-Alder reactions.An illustration of the usefulness of these reactions is the efficient synthesis of oestrone methyl ether and its 9p epimer (Scheme 18).'42 n BlLi Scheme 18 Aryl carbamates' 36 and phenyl tetramethyldiamid~phosphates'~~ also undergo anionic Fries rearrangements to give salicylamides and 2-hydroxyphosphonamide lJ4 P. Beak and D. J. Allen J. Am. Chem. Soc. 1992 114 3420. 135 S.0.de Silva J. N. Reed R. J. Billedeau X.Wang D.J. Norris and V. Snieckus Tetruhedron 1992 48 4863. 136 M. Tsukazaki and V. Snieckus Can. J. Chem. 1992 70 1487. 13' R. S.C. Lopes C.C. Lopes and C. H. Heathcock Tetrahedron Lett. 1992 33 6775. C. Quesnelle T. Ilhama T. Aubert H. Perrier and V. Snieckus. Tetrahedron Lett. 1992 33 2625. lJ9 A. J. Bridges A. L. Emmanuel C. Maduakor and C. E. Schwartz Tetrahedron Lett. 1992 33 7495. A. J. Bridges A. L. Emmanuel C. Maduakur and C.E. Schwartz Tetrahedron Lett. 1992 33 7499. 14' D. M. Giolando and K. Kirschbaum Synthesis 1992 451. 142 S. Horne and R. Rodrigo J. Chem. Soc.. Chem. Commun. 1992 164. L43 J.H. Nasman and N. Kopola Synth. Commun. 1992 22 2491. 158 A. P. Chorlton respectively. Protected derivatives of 3,4,5-trimethoxybenzaldehyde,when treated with alkali metals are subject to regioselective reductive elimination of the 4-methoxy The resulting anion can be quenched with a variety of electrophiles.An improved halogenation procedure has been developed for the preparation of l-halo-2,6-dimethoxybenzenes via the reaction of bis(2,6-dimethoxyphenol)dimethyl-tin and N-halogeno succinimides. '45 The palladium-catalysed coupling of aryl boronic acids has great utility in the synthesis of the unsymmetrical biphenyl natural products Biphenomcycin and Van~omycin'~~ and for the regio construction of tetraaryls quateraryls and higher order polyaryls. '47 An asymmetric variant of this reaction has been developed to give 4-aryl phenylalanines via cross coupling of aryl boronic acids and chiral tyrosine triflate.14' Suzuki has improved the original cross coupling reaction conditions thus allowing the synthesis of hindered biar~1s.l~~ Axially chiral biaryls have been obtained by the cross coupling of 2,6-disubstituted aryl Grignard reagents with chiral aryl-oxazolines. 50 Highly functionalized biaryls have also been synthesized via an intramolecular Ullmann coupling reaction directed by salicyl alcohol which acts as a tether between the two aryl moieties. After coupling the tether is removed by hydrolysis to furnish the biaryls. '' Palladium catalysed coupling of 1-iodo,-2,3-dimethylbenzene(35)gives 6H-dibenzo[b,d]pyrans (36)which results from coupling followed by a palladium catalysed CH-activation of the methoxy group.'" H3C0 ,0CH3 (35) Nio has been used for the first time for the cross-coupling of aryl carbamates and aryl triflates with Grignard reagents.' s3 The palladium-catalysed arylation of alkenes the Heck reaction is a powerful synthetic tool; its utility has been extended to the a-arylation of acyclic enol etherslS4 and the reaction can be asymmetrically catalysed with BINAP to give products with good enantiomeric purity.' s5 Two examples of homogeneous catalysis have been developed.These give advantages of higher activity and improved yields'56 and the 144 U. Azzena G. Melloni and A.M. Piroddi J. Ory. Chem. 1992 57 3101. 145 M. Wada H. Wakamuri A. Hiraiwa and T. Erabi Bull. Chern. SOC.Jpn. 1992 65 1389. 146 A. G. Brown M. J. Crimmin and P. D. Edwards J. Chem.SOC..Perkin Trans. I 1992 123. 14' C. M. Unrau M. G. Campbell and V. Snieckus Tetrahedron Lett. 1992 33 2773. 148 W.C. Shieh and J.A. Carlson J. Ory. Chem. 1992 57 379. T. Watanabe N. Miyaura and A. Suzuki SYNLETT 1992 207. 150 A. I. Meyers A. Meier and D. J. Rawson Tetrahedron Lett. 1992 33 853. 15' M. Takahashi Y. Moritani T. Ogiku H. Ohmizu K. Kondo and T. Iwasaki Tetrahedron Lett. 1992,33 5103. Is* G. Dyker Angew. Chem. Int. Ed. Engl. 1992 31 1023. S. Sengupta M. Leite D.S. Raslan C. Quesnelle and V. Snieckus J. Org. Chem. 1992 57 4066. W. Cabri I. Candiani A. Bedeschi and S. Penco J. Org. Chem. 1992 57 1481. 15' F. Ozawa A. Kubo and T. Hayashi Tetrahedron Lett. 1992 33 1485. lS6 J. P. Genet E. Blart and M. Savignac SYNLETT 1992 715. Aromatic Compounds ability to carry out the reaction in aqueous media.'" An unusual doubly substituted product has been obtained from the phase-transfer-catalysed Heck reaction of o-bromobenzaldehydes with methyl acrylate Scheme 19.It has been established that the bromine was replaced by the propionats group and the formyl group by the acrylate residue.' 58 Scheme 19 Aryl alkynes can be synthesized in good yields by the copper-catalysed coupling reaction of aryl halides with terminal alkynes.lS9 The a-and y-coupling reaction of allylic chlorides with p-methoxyphenylmagnesium bromide has been studied and it has been found that the solvent has a substantial bearing on the regio- and stereoselectivity of this reaction.16' Arylzinc reagents generated by electrochemical reduction of aryl halides have been found to be effective in the cross coupling of aryl halides.16' Electrosynthesis has also been successfully applied to the synthesis of unsymmetrical polyaryls.'62 Triarylbismuthines have been carbonylated for the first time by the use of rhodium (I) catalysts to give diarylketones. '63 Crossed carbonylation coupling has been achieved by the palladium-catalysed reaction of aryl fluorosilanes with aryl iodides. '64 Amides and azoles can be N-arylated with p-tolyllead tria~etate.'~'.'~~ Phenols can be oxidatively coupled with manganese (III) complexes.' 67 Acetal phenoxides also undergo oxidative coupling to afford 2,2'-dihydroxybiaryls with high regiochemical control.'68 Substitution via Aryl Radicals.-The rate constants of the intramolecular aryl radical cyclization of aldimines has been studied Scheme 20.It was found that there was a large preference for 6-end0 ring closure to carbon over 5-ex0 ring closure to nitrogen. This is in direct contrast to radical cyclization to alkenes. Energetic and steric postulates have been developed to explain these re~u1ts.l~~ The photostimulated reaction of 2-naphthoxide ions (37)with o-dihalobenzenes (38) in liquid ammonia gives the halosubstituted product (39) and the cyclized substituted 15' B. M. Choudary R. M. Sarrna and K. K. Rao Tetrahedron 1992 48 719. 15* S. K. Meegalla N. J. Taylor and R. Rodrigo J. Ory. Chem. 1992 57 2422. 159 K. Okaro M. Furaune M. Miura and M. Nornura Tetrahedron Lett. 1992 33 5363.160 N. H. J. Lajis and M. N. Khan Tetrahedron 1992 48 1109. 161 S. Sibille V. Ratovelornanana and J. Perichan J. Chem. SOC.,Chem. Commun. 1992 283. 162 P. Boy C. Cornbellas A. Thiebault. C. Arnatore and A. Jutand Tetrahedron Lett.. 1992 33 491. 163 C.S. Cho T. Ohe 0.Itoh and S. Uemura J. Chem. SOC.. Chem. Commun. 1992 453. 164 Y. Hatanaka S. Fukushirna and T. Hiyarna Tetrahedron 1992 48 21 13. 16' P. Lopez-Alvarado C. Avendano and J. C. Menendez Tetrahedron Lett. 1992 33 6875. P. Lopez-Alvarado C. Avendano and J. C. Menendez Tetrahedron Lett. 1992 33 659. 16' H. Nishino N. Itoh M. Nagashirna and K. Kurasawa Bull. Chem. SOC. Jpn. 1992 65 620. 168 G. Sartori R. Maggi F. Bigi A. Arienti and G. Casnati Tetrahedron Lett. 1992 33 2207. 169 M.J.Tornaszewski and J. Warkentin Tetrahedron Letr. 1992 33 2123. A. P. Chorlton Scheme 20 product (40).This is the first report of coupling of an aromatic radical with an oxygen nucleophile.' 70 It has been found that or-methyl styrene is hydrogenated by dihydroanthracene almost quantitatively at 280-310 "C in an uncatalysed H-transfer reaction. This reaction proceeds by a molecular formation of a radical by H transfer from a C-H bond.17' Aryl radicals generated from diazonium salts react with copper (11) p-diketones to give a-aryl-p-diketones in moderate yields.' 72 Flash vacuum pyrolysis of the alkyl esters (41) (X = 0 S CH,,CO) at 900°C gives dibenzofurans diben- zothiophenes fluorenes and fluorenones respectively as the major products. The mechanism involves the radical intermediate (42)which equilibrates by intramolecular hydrogen transfer via a six-membered transition state prior to cy~lization.'~~ 'x '-[O\,lo]- aco2-(41) (42) 5 Functional Group Interconversions of Benzene Derivatives Rapid reduction of nitroarenes to aromatic amines by sodium borohydride can be achieved by the enhancement of the catalytic activity of MOO with sodium ~e1enate.I~~ Sodium trimethylsilanethiolate has also been found to reduce nitroarenes to aromatic amine~.'~~ The reductive capability of sodium borohydride is also increased by the addition of nickel chloride; this system allows the facile deoxygenation M.T. Baumgartner A. B. Pierini and R. A. Ross Tetrahedron Lett. 1992 33 2323. I7l C.Ruchardt M. Gerst and M. Nolke Angew. Chem. Int. Ed. Engl. 1992 31 1523. 172 M. E. Llorus R. A. Abramovitch J. Marquet and M. Moreno-Manas Tetrahedron 1992.48 6909. 173 J. I.G. Cadogan H. S. Hutchison and H. McNab. Tetrahedron 1992 48 7747. 174 K. Yanada R. Yanada and H. Meguri Tetrahedron Lett. 1992 33 1463. 17' J.R. Huru F.F. Wong and M. Shiao J. Org. Chem. 1992 57 5254. Aromatic Compounds 161 of phenols.' 76 Aryl carboxylic acids can be reduced to benzyl alcohols with SmI and phosphoric acid.' 77 Zinc chlorochromate has been used as a mild inexpensive oxidant of benzylic carbon-hydrogen bonds.' ' Electron-rich aryl alkenes can be cleaved to aldehydes electrochemically. '79 This method should have environmental advantages over ozonolysis in large scale reactions.Methyl aromatic compounds have been photooxygenated in the presence of TiO and AgSO to give benzaldehydes and in some cases benzoic acids.'*' Aryl C-nitroso compounds can be conveniently synthesized by the pyridinium chlorochromate oxidation of hydroxylamines.' '' Two direct routes to the synthesis of aromatic nitriles via the aldehydes have been developed.' 82,183 6 Condensed Polycyclic Aromatic Compounds Methylene bridged polycyclic aromatic hydrocarbons (PAHs) are thought to be potential carcinogens. However few PAHs of this class have been synthesized. Harvey has synthesized a number of these PAHS'*~,~'~ and studied their electrophilic sub- stitution.lg6 Carbon-14 labelled dibenz[a,h]anthracene has been produced so that its biotransformations can be studied.IE7 Methyl substitution of the bay region of PAHs enhances their carcinogenicity.The trifluoromethyl analogue (43) of a potent carcin- ogen has been synthesized to examine its activity."* A number of carcinogenic nitro- nitroso- and amino-fluoranthenes have been prepared by standard methods. '89 Me0 0 + 40 0 (43) (45) Binaphthathiophene reacts with lithium to give 2,2'-disubstituted-l,1 -binaphthalene or dihydroperylene depending on the reaction condition^.^^' Both [5]-and [6]- helicenes (44) have been rapidly constructed via the Diels-Alder reaction of benzoquinone and the bis-enol ether (45).' ' 17' F. Wang K. Chiba and M. Tada J. Chem. Soc. Perkin Trans. 1 1992 1897. Y. Karnochi and T. Kudo Tetrahedron 1992 48 4303.H. Firouzabadi and A. Sharifi Synthesis 1992 999. 179 E. Steckhan and C. Kandzia SYNLETT 1992 139. E. Baciocchi G. C. Rosato C. Roi and G. V. Sebastiani Tetrahedron Lett. 1992 33 5437. la' W.W. Wood and J.A. Wilkin Syn. Commun. 1992 22 1683. la' H. Suzuki and C. Nakaya Synthesis 1992 641. la3 F. Delgao A. C. Cano 0.Garcia J. Alvarado L. Velasco C. Alvarez and R. H. Rudler Syn. Cornmun.. 1992 22 2125. C. Yang and R.G. Harvey Tetrahedron 1992 48 3735. C. Yang D.T.C. Yang and R.G. Harvey SYNLETT. 1992 799. E. Abu-shqara C. Yang and R.G. Harvey J. Org. Chem. 1992 57 3312. K. L. Platt and F. Setiabudi J. Chem. Soc. Perkin Trans. 1 1992 2005. '*' M. M. Coornbs and H. H. Zepik J. Chem. Soc. Chem. Cornmun. 1992 1376. C. J. van Haeringen N.F. Aten J. Cornelisse and J. Lugtenburg Recl. Trau. Chim. Pays-Bas 1992 111 335. I9O A. Dore S. Gladiali S. Cossu and 0.De Lucchi SYNLETT 1992 807. N. D. Willrnore L. Lui and T. J. Katz Anyew. Chem. Int. Ed. Engl. 1992 31 1093. A. P. Chorlton A domino-Heck coupling of aryl halides and dicyclopentadiene also demonstrates how simple precursors can be utilized to prepare PAHs Scheme 21.192 Triphenylene can be obtained in 66% yield from the decomposition of 1-fluoro-2-sodiobenzene ; this reaction is thought to proceed via trimerization of ben~yne.’~~ An improved procedure for the synthesis of several isomeric methoxy- nitronaphthalenes has been described.’94 Reagents i Pd(OAc), K,CO, Bu,NBr; ii I, hv; iii FVP 750°C Scheme 21 A convenient route to corannulene (46)has been developed flash vacuum pyrolysis of the fluoranthene (47)gives corannulene and its bromo derivative.The bowl to bowl inversion of corannulene dimethyl carbinol has been studied by examining the NMR of the coalescence of the diastereotopic methyl groups. From this data the barrier to bowl to bowl inversion was calculated to be G = 10 & 0.2 Kcal mol-’ at -64°C. This is remarkably close in energy to that for the conversion of cyclohexane from one chair form to the other.19’ Tetrabenzo[a,c,g,i]fluorenyl-17-methylurethane has been synthesized for use as a Nor protecting group. This group has been designed to allow adsorption onto porous graphitized carbon thus allowing facile separation of Nor-acetylated truncated peptides generated as impurities in solid phase peptide synthesis.’ 96 Angular phenylenes have been synthesized by a series of cobalt carbonyl mediated [2 + 2 + 21 cycloaddition reactions.The structures of these angular systems are best described by involving varying degrees of bond alternation. Thus (48) contains an internal ‘cyclohexatriene’ maximizing the ‘aromaticity’ of the flanking two benzene rings. Bond localization is attenuated along the series (48) (49) (50).197 K. Albrecht 0.Reiser M. Weber and A. de Meijere SYNLETT 1992 521. 193 M. Fossatelli and L. Brandsma Synthesis 1992 757. 194 C. Parkanyi H. L. Yuan A. Sappok-Stang A. R. Gutierrez and S. A. Lee Monatsh. Chem. 1992,123,637. 195 L.T. Scott M. M. Hashemi and M.S. Bratcher J. Am. Chem.SOC. 1992 114 1921. 196 R. Ramage and ?. Raphy Tetrahedron Lett. 1992 33 385. 19’ R. H. Schmidt-Radde and K.P.C. Vollhardt J. Am. Chem. SOC.,1992 114 9713. Aromatic Compounds 163 2,2'-Distyrylbiphenyl on electrochemical reduction undergoes [2 +21 cycloaddi- tion this result is compared with the photolytic [2 +21 cycl~addition.'~~~'~~ The formation of a great number of PAHs with up to a molecular weight of 604 occurs when an electric discharge from a graphite electrode is made in toluene.200 The fragmentation of PAHs observed in mass spectra supports the view that sufficiently large component PAHs probably survive in the diffuse interstellar medium.201 (48) n= 1 (49) n=2 (50) n =3 Non-benzenoid Aromatics.-Two new methods for the preparation of 1,6-meth- The ano[ lolannulene have been de~cribed.~'~.~'~ 1,6-methano[ lolannulene nucleus has also been used to demonstrate chirality due to deuterium substitution (+ )-l-(R)p-2,7-dideutero-1,6-methano[lO]annulene(51a) was prepared from the chiral dibromo-derivative (51b) by the formation of the lithio derivative followed by quenching with de~teriurn.~'~ The methanocycloundeca[6]pyrrole (52) has been synthesized and shown to be an aromatic molecule having a diatropic 14 n-electron system.205 X (51a) X = D (51b) X =Br Cyclopenta[a]azulenes (53) and (54) have been synthesized and fully characterized for the first time.The anions of these compounds (55) are not peripherally 14 n-conjugated because of the larger stabilization energy of the cyclopentadienyl anion compared to that of the azulene.206 19' A.Bohm K. Meeholz J. Heinze and K. Mullen J. Am. Chem. SOC. 1992 114 689. 199 A. Bohm and K. Mullen Tetrahedron Lett. 1992 33 611. 'O0 M.T. Beck Z. Dinya and S. Keki Tetrahedron 1992 48 4919. J. Aihara and H. Ichikawa Bull. Chem. SOC.Jpn. 1992 65 597. 'O' D. G. Barrett G. B. Liang and S. H. Gellman J. Am. Chem. SOC. 1992 114 6915. '03 R. Neidlein and G. Schroder Chem. Ber. 1992 125 2225. '04 A. Meyer and K. Schogl Monatsh. Chem. 1992 123 465. '05 N. Kanomata K. Kamae Y. Iino and M. Nitta J. Org. Chem. 1992 57 5313. '06 Y. Kitamuri M. Yasunami T. Hioki I. Kikuchi and K. Takase Bull. Chem. SOC.Jpn. 1992 65 1527. 164 A. P. Chorlton Allylic dihydroazulene (56) rearranges at room temperature to the thermodynami- cally more stable substituted azulene (57).This novel Cope-type rearrangement can be observed by the naked eye as a colour change from yellow to blue.207 The [abcl-annelation of naphthalene or phenanthrene systems has given the [18lannulene (58). This molecule is essentially non-planar consisting of 'aromatic islands' which are connected by (E)-configured alkene bridges. The absence of a diamagnetic ring current rules out a macrocyclic aromaticity.208 The reductive alkylation of the pyrene isomer (59) afforded the bridged [14]- annulene (60). This reaction has been demonstrated to take place via an electron- transfer mechanism. O9 p2-2 \ \ (56) Yellow (57) Blue ii RX (59) (60) 7 Cyclophanes Medium-sized cyclophanes have been found to undergo novel isomerization and transannular cyclization reactions.* An example of this is the iron catalysed bromination of the metacyclophane (61) which affords the corresponding tetrahydro- pyrenes oia an addition-elimination reaction." * '07 K.Hafner J. Hartung and C. Syren Tetrahedron 1992 48 4879. '08 H. Meier H. Kretzschmann and H. Kolshorn J. Org. Chem. 1992 57 6847. '09 K. Mullen J. Alexander K. U. Klabunde F. Klarner H. Lund and T. Lund Chem. Ber. 1992 125,505. 210 T. Yamato J. Matsumoto K. Tokuhisa K. Tsuji K. Suehiro,and M. Tashiro,J. Chem.SOC.,Perkin Trans. I 1992 2675. 'I1 T.Yamato J. Matsumoto K. Tokuhisa K. Suehiro and M. Tashiro,J. Chem.SOC.,Chem.Commun. 1992 865. T. Yamato J. Matsumoto,K.Tokuhisa M. Shigekui K. Suehiro,and M. Tashiro,J. Org.Chem.,1992,57 395. Aromatic Compounds Et Et + Generally cyclophanes are not prepared by direct annulation of the bridge but by ring contraction rearrangement of bridges or formation of the benzene ring in the final step. Tris(donor)-substituted 1,3,5-trinitrobenzenes generally exist in boat or twist boat conformations. This distortion has been put to good effect in the synthesis of cyclophane (62). Reduction of the nitro group in (63)eliminates the electronic bias for a boat conformation and this results in the benzene ring returning to planarity.213 The X-ray analysis of the biphenylene-cyclophane (64) illustrates how the frame- work of the biphenylene unit is bent out of plane.This distortion is caused by transannular repulsion.2 l4 (62) X=NH2 (63) X=NO2 'I3 J.J. Wolff S. F. Nelson D. R. Powell and B. Nuber Angew. Chern.. Inr. Ed. Engl. 1992 31. 882. '14 K. Saitmacher J. E. Schulz M. Nieger and F. Voglte J. Chem. SOC..Chem. Commun.. 1992 175.

ISSN:0069-3030    

DOI:10.1039/OC9928900141

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

7 Heterocyclic Compounds By D.E. AMES Department of Chemistry Queen Mary and Westfield College London El 4NS UK 1 Introduction The significance of bond lengths and bond orders of many simple heteroaromatic molecules has been discussed.' X-ray crystallographic data were used to assess the presence of delocalization in conjugated n-systems. The importance of heteroaroma-ticity and its role in the tertiary structures of DNA are emphasized. Other topics reviewed include heterocyclic N-oxides and N-imides,2 alkaloid N-~xides,~ and the synthesis of oxygen-containing heterocycles by intramolecular ~xypalladation.~ 2 Three-membered Rings A one-pot procedure achieves efficient stereospecific transformation of 1,2-diols(1) via halogenoacetates (2) into epoxides (3) (Scheme l).5 OAc ;I' R1& R2 i.ii * R' &R2 + Rl/yR2 OH x OAc (2) iiiI Reagents i H+ MeC(OMe),; ii AcX or Me,SiX; iii K,CO,-MeOH Yield 86% (99% e.e.) when R' = 2-Ph(CH,),C6H and RZ = C0,Me Scheme 1 Direct epoxidation of chalcones (4) with dimethyldioxirane gives epoxides (5)which are acid- and base-sensitive (Scheme 2).6 ' V. G. S. Box Heterocycles 1992 34 1631. A. R. Katritzky and J. N. Lam Heterocycles 1992 33 101 1. A. Albini Heterocycles 1992 34 1973. T. Hosokawa and S. I. Murahashi Heterocycles 1992 33 1079. H.C. Kolb and K.B. Sharpless Tetrahedron 1992 48 10515. W. Adams J. Bialas L. Hadjiarapoglou and T. Patonay Synthesis 1992 49. 167 168 D.E. Ames 0 0 (4) (5) Reagents i Dimethyldioxirane Yield 100% (Ar = Ph) Scheme 2 Phenylsulfonyloxiranes (6) have been converted into a-bromoketones (7) by reaction with magnesium bromide.Desilylation and base-catalysed cyclization yields a-epoxyketones (8) (Scheme 3).' Br (7) Reagents i MgBr,; ii Bu,N+F- H,O; iii Et,N Scheme 3 A Darzens-type reaction of bromoketones (9) promoted by a tributylstannyl carbamate gives epoxyketones or epoxyesters (10) in a one-pot reaction (Scheme 4).* 0 Reagents i R'CHO Bu,SnNEtCO,Me Yield 85% (for R' = Me X = Br R2 = Ph) with cis:trans = 79:21 Scheme 4 Primary 2,3-epoxyamines e.g. (1l) react with butyl lithium and then trimethylaluminium to form the aluminium complex (12). Rearrangement and hydrolysis then gives (hydroxyalky1)aziridine (1 3) stereospecifically (Scheme 5).9 Treatment of optically active oxirane-2-carboxylic esters (14) with sodium azide yields azidoalcohols (15) which react with triphenylphosphine to form aziridine- 2-carboxylic esters (16) in good yields and high optical purity (Scheme 6).1° S.F.C. Dunn and R. F. W. Jackson J. Chem. Soc. Perkin Trans. I 1992 2863. I. Shibata H. Yamasaki A. Baba and H. Matsuda J. Org. Chem. 1992 57 6909. R. Najime S. Pilard and M. Vaultier Tetrahedron Lett. 1992 33 5351. lo J. Legters L. Thijs and B. Zwanenburg Rec. Trav. Chim. Pays-Bas 1992 111 1. Heterocyclic Cornpounds N-Chlorination followed by dehydrochlorination provides 2H-azirine-2-carboxylic esters (17). Me..+NH2 i ii ~ 69% H H Me O h N AlMe3 H (12) (13) Reagents i BuLi; ii AIMe,; iii NaF H,O Scheme 5 OH (14) (15) lii H N iii iv c- A" R C02R' (17) Reagents i NaN, NH,CI; ii Ph,P; iii Bu'OC1; iv DBU Yield 69% (R = Pr R' = Et) Scheme 6 Conversion of amides (18) into lithium enolates followed by treatment with diphenylphosphorochloridate generates ketiminium salts (19) which react with sodium azide to give the 3-amino-2-substituted-2H-azirine (20) (Scheme 7).12 (19) (20) Reagents i LiNPr;; ii CIPO(OPh),; iii NaN Yield 50% (R = Me or Ph) Scheme 7 Reactions of halodiazirines by S,2' and electron-transfer initiated processes have been reviewed.'' J. Legters L. Thijs and B. Zwanenburg Rec. Trau. Chim. Pays-Bas 1992 111 75. *'J. M. Villalgordo and H. Heimgartner Helu.Chim. Acta 1992 75 1866. l3 X. Creary Acc. Chem. Res. 1992 25 31. 170 D. E. Ames Dialkyl- and alkylarylimines are efficiently oxidized to oxaziridines by 'oxone' (potassium peroxymonosulfate) in the presence of sodium hydrogencarbonate whereas diarylimines give only nitrones. l4 3 Four-membered Rings Benzil in the lowest excited triplet state adds regio- and stereoselectively to 2-morpholinoacrylonitrile (21) to form oxetane (22) (Scheme 8).' Reagents i (PhCO), hv Scheme 8 Highly enantioselective hydrogenation of diketene (4-methyleneoxetan-2-one) in the presence of a ruthenium catalyst having an (S)-ligand gives (R)-4-methyloxetan- 2-one in up to 97% selectivity and 92% e. e.I6 Trans-disubstituted p-lactones such as (23) have been synthesized using a titanium chloride-mediated enantioselective aldol condensation reaction.' Chiral ester (24) was converted into silyl enol ether (25) which was condensed with an aldehyde-amide to obtain the aldol(26).Hydrogenolytic cleavage of the chiral group and double-bond reduction gave acid (27) which was cyclized to trans-oxetanone (23) (Scheme 9). iv 95% 1 R2 = CH2(CH2),Me 78% HO& (CH2),CONEt2 0 OH Reagents i LiNPr;; ii Me,SiCl; iii TiCl, trans-OCHCH=CH(CH,),CONEt,;iv H, Pd-C; v PhSO,Cl pyridine Scheme 9 A. R. Hajipour and S.G. Pyne J. Chem. Res. (S) 1992 388. D. Dopp H. R. Memarian M. A. Fischer A. M. J. van Eijk and C. A. G. 0.Varma Chem. Ber. 1992,125 983. l6 T. Ohta T. Miyake and H. Takaya J. Chem. Soc..Chem. Commun. 1992 1725. S. Cardani C. De Toma C. Gennari and C. Scolastico Tetrahedron 1992 48 5557. Heterocyclic Compounds 171 Obafluorin (28) an antibacterial agent from Pseudomonas jluorescens is a cis-disubstituted fi-lactone. Its synthesis is summarized in Scheme 10.l8 The amino acid (29; R = H) reacted with 2-nitrophenylsulfenyl chloride to give (29; R = 2-O,NC,H,S) which was cyclized to give lactone (30). Removal of the arylthiol group and an acylation process led to obafluorin in an optically pure form. i ___) 24% (30) ii. iiii iv 39% I HO OH 0 Reagents i 4-BrC,H,S02C1 pyridine; ii TsOH; iii 2,3-(OSO,)C,H3COC1; iv H,O Scheme 10 In an efficient synthesis of 3-oxetanones a,fi-epoxy diazo-methyl ketones (31) are treated with tin(1v) chloride at -78 "Cto form chlorohydrins (32) in a syn manner with retention of configuration at C,.Cyclization of the diazomethyl a-hydroxyalkyl ketone (32) with boron trifluoride then gives the 3-oxetanone (33) (Scheme 1l).l9 (31) (32) (33) Reagents i SnC1,; ii NaHCO, H20; iii BF,-Et,O Yield 37% overall (R'= Ph R2 = R3 = H) Scheme 11 Photolysis of thiolactone (34) yields thiete (35) (Scheme 12).20 Oxidation of 3,4-di(t-butyl)-2,5-dimethylthiophene1,l-dioxide (36) with m-chloro- perbenzoic acid gives the acylthiete (37) but in the presence of base epoxide (38) is produced (Scheme 1 3).21 l8 C. Lowe Y. Pu and J.C. Vederas J. Org. Chem. 1992 57 10. l9 L. Thijs P. J. M. Cillissen and B. Zwanenburg Tetrahedron 1992 48 9985. 2o H.Hinrichs and P. Margaretha Chem. Ber. 1992 125 2311. 21 J. Nakayama and H. Kamiyama Tetrahedron Lett. 1992 33 7539. 172 D.E. Ames Me Me CH2Ph hv CH2Ph -31% Bu' But Scheme 12 COMe i i ii -s,r 0 Me Me 0 Me // \\ Me Me J 'b 00 (37) (36) Reagents i 3-C1C,H4C0,H; ii Na,CO Scheme 13 The thietanone (39)has been obtained by a photochemical ring contraction reaction (Scheme 14).22 Ketoester (40) gave thiapyrandione (41) by an internal Claisen condensation. The derived enol ether (42; R = OEt) was reduced to dihyd-rothiapyranone (42; R = H) the substrate for the photochemical reaction to produce (39). COMe /CM% --of I i ii iii. iv,v vi s\ 68% 50% 96% y2 C02Et (40) Reagents i NaOEt; ii HCl H,O; iii EtOH TsOH A; iv LiAlH,; v H,SO, H,O; vi hv Scheme 14 1-Alkyl-3-hydroxy-2-phenylazetidines(43)are obtained by reaction of 2-( l-bro-mobenzy1)oxirane (44)with aliphatic primary amines (Scheme 15).23 RNH2 PhL 65% (R = Pr") -ph&=-oH 0 Scheme 15 22 E.Er and P. Margaretha Helv. Chim. Acta 1992 75 2265. 23 T. Toda M. Karikomi M. Ohshima and M. Yoshida Heterocycles 1992 33 511. Heterocyclic Compounds 173 Oxa-and thiaphosphetanes azaphosphetidines and diphosphetanes have been reviewed.24 In a synthesis of 1,2-azaphosphetidines (45) the a-diazo-p-ketophosphonamidate (46) was heated with rhodium acetate to effect cyclization by carbene attack upon an isopropyl group (Scheme 16).25 i,ii 334b EtO-P EtO' II 0 Reagents i Rh,(OAc), A; ii H,O Scheme 16 fLLactams.-Ring enlargement of the alkyl-N-tosylaziridine (47)has been effected first by reaction with methanolic potassium cyanide to form acyclic nitrile (48) then by hydrolysis and cyclization to give p-lactam (49) (Scheme 17).26 I? r!y I? Y mCH2OR i y C H 2 0 R ii.iii,iv,v 828 CN NHTs 608 * 0 mCH20R Ts Me Me Ts Me (47) (48) (49) R = CH2Ph Reagents i KCN MeOH A; ii NaOH H,O A; iii HC1 H,O; iv 4-pyrrolidino-pyridine dicyclohexylcar-bodiimide; v H,O Scheme 17 When diketene is heated with an imine (R'N=CHR2) and imidazole p-lactam (50) is produced.27Anodic fluorination of 2-aryl-4-thiazolidinones (51; R' = H) is highly regioselective.28Oxidation of the product (51;R' = F),followed by thermolysis of the corresponding sulfone gives monofluoro-&lactams (52).4-Sulfinylazetidin-2-ones (53; R2 = SOPh) react with tributyltin alkoxides in the presence of trimethylsilyl trifluoromethanesulfonate to give the 4-alkoxyazetidin-2-ones (53; R2 = OR).29 A photochemical reaction of chromium carbene complexes with iminodithiocarbon-ates (54) produces 4,4-bis(methylthio)-p-lactams (55). These are oxidized by N-bromosuccinimide to azetidine-2,4-diones (56) (Scheme 18).30 Turning to fused-ring p-lactams tricyclic 3-azadethiacepham (57)has been prepared " K. Afarinkia Heterocycles 1992 34 369. 25 K. Afarinkia J.I.G. Cadogan and C. W. Rees J. Chem. Soc. Chem. Commun. 1992 285. D. Tanner and H. M. He Tetrahedron 1992 48 6079. 27 A. Sasaki K.Goda M. Enemoto and M. Sunagawa Chem. Pharm. Bull. 1992,40 1095. T. Fuchigami S. Narizuka and A. Konno J. Org. Chem. 1992 57 3755. 29 Y. Kita N. Shibata N. Yoshida and T. Tohjo Chem. Pharm. Bull. 1992 40 1044. 30 B. Alcaide G. Dominguez J. Plumet and M. A. Sierra J. Org. Chem. 1992 57 447. 174 D.E. Ames by condensation of the aminoalkyl lactam (58) with the vinyl vicinal tricarbonyl compound (59) (Scheme 19).31 Reagents i (CO),Cr=CRzR3 hv; ii N-bromosuccinimide H,O Yield 70% (R' = Ph RZ= OMe R3 = Me) Scheme 18 Reagents i pyridinium tosylate Scheme 19 2-exo-Methylenepenam (60) a promising intermediate has been prepared from the unsaturated ester (61 ). Ozonolysis conversion into enol triflate (62) and elimination of trifluoromethanesulfonic acid led to allene (63).Reduction of the S-sulfonyl group by a zinc-bismuth(II1) chloride bimetal redox system was followed by cyclization to form (60) (Scheme 20).32 A synthesis of isocephem analogues (64) is based on conversion of alkenyl lactam (65) into tosylate (66) by ozonolysis reduction and tosylation. Base-catalysed condensation with carbon disulfide followed by ethylation gave ester (64; R2 = 4-O,NC,H,CH,) and then by palladium-catalysed hydrogenolysis the acid (64; R2 = H) (Scheme 21).33 31 H. H. Wasserman S. L. Henke and E. Nakanishi J. Org. Chem. 1992 57 2641. 32 H. Tanaka Y. Kameyama T. Yamauchi and S. Torii J. Chern. SOC. Chem. Cornrnun. 1992 1793. 33 S. Shakaya and T. Durst Heterocycles 1992 34 67. Heterocyclic Compounds (63) iv 41% 1 Reagents i 0,;ii (CF,SO,),O Et,N; iii Et,N A; iv Zn BiCI Scheme 20 SEt Reagents i O, Me,S; ii Na(CN)BH,; iii TsCl pyridine; iv LiN(SiMe,), CS,; v NaH EtI Scheme 21 A route to the potent penem antibacterial agent sulopenem (67; R' = R2 = H) has been described.34 Condensation of chlorolactam (68) with thiocarbonate salt (69) and acylation gave the trithiocarbonate ester (70).Cyclization with triethyl phosphite yielded penem analogue (67; R' = SiMe2Bu' R2 = CH2CCl=CH2) and removal of the protecting groups gave the hydroxy acid (67; R' = R2 = H) (Scheme 22). 4 Five-membered Rings The boron trifluoride-catalysed condensation of aldehydes with 1,6-di(trirnethyl- silyl)hexa-2,4-diene (71) yields 2,5-dialkyl-3,4-divinyltetrahydrofurans(72) (Scheme 23).35 A polymer-supported synthesis of 2,5-disubstituted tetrahydrofurans (73) (Scheme 24)36 has been developed based on the construction of an isoxazole as in (74).34 R.A. Volkrnann P. R.Kelbaugh D. M. Nason and V. J. Jasys J. Org. Chem. 1992 57 4352. 3s C. Brouard J. Pornet and L. Miginiac Tetrahedron 1992 48 2385. 36 X.Beebe N.E. Schore and M.J. Kurth J. Am. Chem. SOC. 1992 114 10061. 176 D.E. Awes Reaction with iodine monochloride then effects ring cleavage recyclization and removal from the polymer to produce (73). i ii COC02CH2CCl=CH2 Reagents i H,O; ii FCOCO,CH,CCI=CH, PriNEt; iii P(OEt) Scheme 22 Reagents i RCHO BF,.OEt Yield 51% (R = Me) 75% (R = CH,Ph) Scheme 23 OSiMe3 Polymer-CHO -Polymer-1 CH-CH2N02 iii1 OSiMe3 I Polymer -c,H iv N-0 c- Reagents i MeNO, Et,N; ii Me,SiCl Et,N; iii PhNCO Et,N CH,=CH(CH,),CH=CH, A; iv ICl Overall yield 29% Scheme 24 Heterocyclic Compounds 177 2,5-Cis- or trans-substituted tetrahydrofurans can be obtained from either (E)-or (2)-alkenols (75) and (76) respectively by choosing the appropriate electrophile as shown in Scheme 25.37 Addition of 2-(metallomethyl)-2-alkenylethers (77; M = ZnBr or MgCl) to aldehydes or ketones generates metal alkoxides (78) which undergo palladium(0)- catalysed cyclization to form 3-methylenetetrahydrofurans (79) (Scheme 26).38 Imines react similarly to give 3-methylenepyrr0lidines.~~ (75) (76) Reagents i I, CF,CO,Ag; ii PhSeCl Scheme 25 -MOR~ ii ~ "I>""'-R20 ~T-J$ R20 R4 R4 MO (77) (79) Reagents i R3R4CO; ii Pd(PPh,), A Scheme 26 A new route to 3,4-disubstituted furans involves addition of bis(tributy1stan- ny1)ethyne (80) to phenyl isoxazole (81) to form furans (82; 190/,) and (83; R = H; 23%) with elimination of benzonitrile (Scheme 27).Palladium-catalysed replacement of the substituents in (82) by reaction with aryl iodides gives 3,4-diar~lfurans.~~ When (82)is treated with butyllithium the metal derivative (83; R = Li) is generated and this reacts with electrophiles to form various products (83; R = alkyl acyl etc.) (Scheme 27).40 3' B. H. Lipshutz and J.C. Barton J. Am. Chem. Soc. 1992 114 1084. J. van der Louw J. L. van der Baan H.Stichter G.J. J. Out F. J. J. de Kanter F. Bickelhaupt and G. W. Klumpp Tetrahedron 1992 48 9877. 39 Y. Yang and H.N.C. Wong J. Chem. Soc. Chem. Commun. 1992 656. 40 Y. Yang and H. N.C. Wong J. Chem. SOC..Chem. Commun.. 1992 1723. 178 D. E. Ames Scheme 27 5-Substitution of 3-furanaldehyde can be effected by protection with lithium morpholide followed by metallation at C-5 and reaction with an electrophile (Scheme 28).41 OLi Reagents i Lithium morpholide; ii Bu'Li; iii electrophile Yield 70% (E = Me,Si from Me,SiCl); 30% (E = C,H,,CH(OH) from C,H,,CHO} Scheme 28 Michael addition of P-ketoesters to alkenyl sulfoxides (84) followed by Pummerer rearrangement of sulfoxides (85) provides an efficient route to dihydrofurans (86) (Scheme 29).Oxidation with peracid leads to syn-elimination from the corresponding sulfoxide to give substituted furans (87).42 R' x-73 i(c" R~~ jiR1 i I1 PhSO PhSO 0 PhS 0 R2 iii 1 CO,R~ R2 (87) Reagents i R2COCH,C0,R3 NaOR3; ii CI,CCO,H (CH,CO),O A; iii 3-CIC,H,C03H Scheme 29 The furanocyclohexadienone subunit (88) is present in some antifungal antibiotics. The first synthesis of this highly reactive system has been reported.43 The sequence 41 G.C.M. Lee J.M. Holmes D.A. Harcourt and M.E. Garst J. Ore. Chem. 1992 57 3126. 42 W. H. Chan A. W. M. Lee and E.T. T. Chan J. Chem. SOC.. Perkin Trans. 1 1992 945. 43 C.A. Broka and B. Ruhland J. Orq. Chem. 1992,57,4888. Heterocyclic Compounds summarized in Scheme 30 is based on the protected hydroxyaldehyde (89).Removal of the silyl group yields hydroxypyran (90) which is oxidized to the corresponding lv 0 ~ vi,vii HO MezN&$ @ 0 0 0 Reagents i Bu,N+F- H,O; ii pyridinium dichromate mol. sieves; iii H+-H,O; iv Fetizon's Reagent; v HC(NMe,),; vi Cu(OAc),; vii HCI-H,O Scheme 30 lactone. Hydrolysis of the isopropylidene ketal and oxidation of the diol with Fetizon's reagent leads to ketol(91). This is condensed with tris(dimethy1amino)methane to give enamine (92). Oxidation of the ketol group to a dione and acid-catalysed cyclization then produces the furan system.43 Oxidative thermolysis of cyclic a-azohydroperoxides (93) provides a convenient route to 3-hydroxy- 1,2-dioxolanes (hemi-perketals) (94) (Scheme 3 1).44 Scheme 31 Reaction of potassium p-toluenethiosulfonate (TsSK) with two molecules of acetylenedicarboxylic ester unexpectedly yielded tetramethyl thiophenetetracar- boxylate in good yield.45 Conjugated polythiophenes have been reviewed.46 44 A.L. Baumstark and P.C. Vasquez J. Org. Chem. 1992 57 393. 45 T.G. Kutateladze J. L. Kice and N. S. Zefirov J. Org. Chem. 1992 57 5270. 46 J. Roncali Chem. Rev. 1992 92 711. 180 D. E. Ames Lithiation of fluorobenzenes (95) and reaction with N,N-dimethylformamide provide the reactive fluoroaldehydes (96). Displacement of fluoride using methyl thioglycolate and base constitutes a general preparation of benzothiophene-2- carboxylate esters (97) (Scheme 32).47 (95) (96) Reagents i LiNPri HCONMe,; ii HSCH,CO,Me NaH Scheme 32 Use of cerium(1v) ammonium nitrate for oxidative demethylation of 4,7-dimethoxybenzo[b] thiophene -selenophene and 4,7-dimethoxyindole (98) affords the corresponding quinones (99).In contrast the benzofuran (98; X = 0) gives the bisquinone (100) (Scheme 33).48 Reagents i (NH,),Ce(NO,) Scheme 33 Rearrangement of alkynyl sulfone (101) generates allene (102) which undergoes intramolecular addition across the furan unit to form (103). Base-catalysed rearrange- ment yields 5-hydroxy-ly3-dihydrobenzo[c]thiophene2,2-dioxide (104) (Scheme 34).49 Sterically-congested ly9-di(ary1thio)dibenzothiophenescan be obtained by a ring contraction process (Scheme 35).50 In a general synthesis of bridged bicyclic disulfides a dibromoketone e.g.(105; R = Br) is converted into the di(thio-cyanate) (105; R = SCN) by reaction with potassium thiocyanate. Reduction to the hydroxy-dithiol(l06) followed by oxidation with iodine gave the bridged disulfide (107) (Scheme 36).5' Trans-1-benzyl-2,5-di(benzyloxymethyl)pyrrolidine(108) has been prepared by A. J. Bridges A. Lee E. C. Maduakor and C. E. Schwartz Tetrahedron Lett. 1992 33 7499. 48 M. Cherif P. Cotelle and J.-P. Catteau Heterocycles 1992 34 1749. 49 K. Kanematsu and I. Kinoyama J. Chem. SOC. Chem. Commun. 1992 735. T. Kimura Y. Horie S. Ogawa H. Fujihara F. Iwasaki and N. Furukawa Hererocycles 1992,33 101. P. L. Folkins and D.N. Harpp J. Org. Chem. 1992 57 2013. Heterocyclic Compounds cACH2S02CH2GCH ,502 Reagents i A1,0,; ii A; iii KOBu‘ Scheme 34 SAr 0-SAr SAr SAr Scheme 35 Reagents i KSCN; ii LiAlH,; iii I, NaOAc Yield 50% overall Scheme 36 heating benzylamine with ditosylate (109) which had been obtained from D-mannitol by a number of steps (Scheme 37).52 A radical route to (2S)-4-exo-methyleneproline (110) is based on a favoured 5-exo-dig cyclization of the radical derived from acetylenic bromide (1 1 1 ) to form the pyrrolidine derivative (112).The product (110) is then obtained by removal of the protecting groups (Scheme 38).53 When alkene (113) is oxidized with peracid and heated the epoxide undergoes 5-em-tet ring closure (Scheme 39) to form pyrrolidine derivatives (114 and 115; 52 M. Marzi P. Minetti and D. Misiti Tetrahedron 1992 48 10 127.53 R. M. Adlington and S.J. Mantell 7etrahedron 1992 48 6529. 182 D. E. Ames OTs 58% -'[F02CH2Ph -Y-eHzPh 76% N "H SOzPh SOzPh H (1 11) (112) (110) Reagents i Bu,SnH AIBN (azoisobutyronitrile); ii Na/Hg K,HPO, MeOH Scheme 38 NHTs Reagents i 3-chloroperbenzoic acid; ii A Scheme 39 R' = Ts R2 = CH,Ph; R3= CH,OH). Oxidation and removal of the benzyl and tosyl groups using ruthenium(II1) chloride and sodium periodate gives cis-and trans-pyrrolidine-2,5-dicarboxylic acids (114and 115; R' = R2 = H R3= C02H).54 N-Allylarylamines (1 16) react with carbon monoxide and sodium borohydride in the presence of catalytic amounts of the zwitterionic rhodium complex (117) to form pyrrolidines (118) (Scheme 40).55 R I ArNHCH2C=CH2 + Reagents i CO NaBH, A Yield 83% (Ar = Ph R = n-C,H,,) Scheme 40 54 J.E. Baldwin C. Hulme and C. J. Schofield J. Chem. Res. (S) 1992 173. 55 J.-Q. Zhou and H. Alper J. Org. Chem. 1992 57 3328. Heterocyclic Compounds In another rhodium-catalysed reaction alkyl- or arylpropargylamines (119) carbon monoxide and hydrogen produce pyrroles (120) (Scheme 41).56 Condensation of /!I-trifluoroacetylvinyl ethers (1 2 1) with 2,2-dimethoxyethylamine followed by acid-catalysed cyclodehydration yields 3-trifluoroacetylpyrroles (122j (Scheme 42).57 Reagents i H, CO Rh(OAc), PPh, A Yield 78% (R' = Ph R2 = Me) Scheme 41 COCF EtOCR=CHCOCF3 2(MeOhCHCH,NHCR=CHCOCF (121) H Reagents i (MeO),CHCH,NH,; ii CF,CO,H Yields 87% (R = H) 100% (R = Me) Scheme 42 1-(t-Butoxycarbony1)indolinesare regioselectively lithiated at the 7-position by s-butyl lithium with tetramethylethylenediamine at low temperature.The lithiated species react with electrophiles to give 7-substituted in do line^.^^ Treatment of indole with butyl lithium and carbon dioxide gives the indole- 1-carboxylic acid salt. Addition of t-butyllithium then gives the 2-lithio derivative which reacts with hexachloroethane to produce after hydrolysis 2-chloroindole (90%j. The bromo- and iodo- analogues can be obtained similarly. They are stable at -20°C but not at room temperat~re.~' The cyclohepta[c,d lindole (123) has been prepared from 4-iodo- 1 -methylindole- 3-carboxaldehyde (1 24) by a palladium-catalysed condensation with but-3-enonit- rile.60A useful alumina-mediated C-alkylation of indoles and pyrroles is exemplified by the synthesis of dithyreanitrile (125).This indole alkaloid which is an insect-feeding inhibitor was prepared by condensation of 7-methoxyindole with chlorodi(methy1- thio)acetonitrile in the presence of alumina.61 56 E. M. Campi G. D. Fallon W. R. Jackson and Y. Nilsson Aust. J. Chem. 1992 45 1167. 57 E. Okada R. Masuda M. Hojo and R. Yoshida Heterocycles 1992 34 1435. M. Iwao and T. Kuraishi Heterocycles 1992 34 1031. 59 J. Bergman and L. Venemalm J. Org. Chem. 1992 57 2495. 6o I. Moldval C. Szantay and C. Szantay Heterocycles 1992 34 219. 61 H. Ishibashi N. Mita N. Matsuba T. Kubo M. Nakanishi and M. Ikeda,J.Chem. Soc.,Perkin Trans. I 1992 2821. 184 D.E. Awes CN 4-Iodo-1-(triisopropylsilyl)indole(126) undergoes a palladium-catalysed condensa- tion with methyl (trimethylstanny1thio)acetate to form ester (127). An aldol condensa- tion then gives the thioacrylate intermediate (128). Ring-closure by a novel fluoride ion catalysed process yields methyl ester (129) (Scheme 43).62 A mixture of cis-and trans-isomers is produced. The free acid (cis-isomer) is the ( )-form of chuangxin- mycin an antibiotic produced by the soil microorganism Actinuplanes jinanensis. Reagents i Me,SnSCH,CO,Me Pd(PPh,), A; ii LiNPr';; iii MeCHO; iv Bu,N+F- H,O A Scheme 43 Ellipticine (130; R = H) reacts with hexamethylene tetraamine in hot trifluoroacetic acid to give aldehyde (130; R = CHO).Baeyer-Villiger oxidation and hydrolysis using aqueous hydrogen peroxide and sulfuric acid then provides 9-hydroxyellipticine (130; R = 0~1.63 Condensation of arylamines with l,l-bis(methylthio)-2-nitroetheneyields al- kenylamines (13l).Cyclization by treatment with cold trifluoromethanesulfonic acid produces 2-methylthio-3H-indol-3-one oximes (132).64 Thionyl chloride pyridine and phthalaldehyde react to form the azinium salt (133) which condenses with primary amines to give 2-aryl- l-arylimino-2,3-dihydro-1H- isoindoles (134) (Scheme 44).65 A palladium-catalysed tandem cyclization of 4,6- and 5,7- diene amides e.g. (135) provides a new route to pyrrolizidine and indolizidine structures. Thus (135) is converted into pyrrolidinone (136) which on hydrogenation gives ketone (137; 62 M.J. Dickens T. J. Mowlem D. A. Widdowson A. M. Z. Slawin. and D. J. Williams J. Chem. Soc. Perkin Trans. 1 1992 323. 63 J.M. Plug G.-J. Koomen and U.K. Pandit Synthesis 1992 1221. 64 T. Kearney J. A. Joule and A. Jackson Heterocycles 1992 33 757. 65 J.-J. Van den Eynde A. Mayence A. Maquestiau and E. Anders Bull. SOC. Chim. Belg. 1992,101 509. Heterocyclic Compounds X = 0)stereospecifically. Reduction with lithium aluminium hydride then yields (f)-heliotridane (137; X = H2) (Scheme 45).66 c1 I+ RNH2 93% (R = ph) CH-NCtjHS @y-j I Cl (133) (134) Scheme 44 Reagents i Pd(OAc), CuCI, 0, A; ii PtO, H Scheme 45 In another palladium-catalysed reaction alkynyl N-acylenamine ( 138) undergoes cycloisomerization to produce the indolizinone derivative (139) (Scheme 46).67 Pr Reagents i Pd(OAc), bis(benzy1idene)ethylenediamine Scheme 46 66 P.G.Anderson and J.-E. Backvall J. Am. Chem. SOC.,1992 114 8696. 67 B. M. Trost and C. Pedregal J. Am. Chem. SOC. 1992 114 7292. 186 D. E. Ames A short highly stereocontrolled asymmetric synthesis68 of allopumiliotoxin A an indolizine alkaloid from Dendrobatid frogs is summarized in Scheme 47. N-Hydroxymethylation of keto-amine salt (140) by reaction with methanal followed by heating with p-toluenesulfonic acid yields indolizinone (141). Condensation of the lithium enolate with (R)-2-methylhexanal leads to the hydroxyalkyl derivative (142). Dehydration and selective reduction of the carbonyl group then affords only the isomer (143) ( + )-allopumiliotoxin A.68 %COMe 1'''OH I!l I'"0H" fi I'"0H" Me Me Me v vi I O'"OH H G Me (143) Reagents i HCHO H,O; ii TsOH A; iii Ph,CLi; iv (R)-BuCH(CH,)CHO; v (F,CCO),O DBU; vi [Me,N][BH(OAc),] HOAc Scheme 47 An interesting synthesis of indoli~ine-5~8-dione (144) is based on condensation of 1-lithiopyrrole with a cyclobutenedione (145) to form (146; R = H).Pyrolysis of the protected derivative (146; R = SiMe,) generated ketene (147) which cyclized to indolizine (148). Oxidation then yielded the quinone (144) (Scheme 48).69 Addition of monoalkylhydrazines to acetylenic esters e.g. (149) having either elec tron-wi t hdrawing or bulky P-subs ti tuents affords 3-hydroxypyrazoles with isomers (1 50) being the major regioisomeric product^.^' In contrast the cycloconden- sation of b-ketoesters with alkylhydrazines gives isomers (1 51) (Scheme 49)." Jmidazolophanes (152) bridged by short chains (n= 5 or 6) are readily accessible by the [3 + 21 cycloaddition of imines with azaallenyl radical cations (153) generated from bicyclic azirines (154) under electron transfer conditions (Scheme 50).71 A regiospecific palladium-catalysed cycloaddition reaction of aziridines (1 55) with carbodiimides (ArN=C=NAr) yields 2-aryliminoimidazolines (156).72 68 S.W. Goldstein L. E. Overrnan and M. H. Rabinowitz J. Ory. Chem. 1992 57 1179 69 B.R. Yerxa and H. W. Moore Tetrahedron Lett. 1992 33 7811. 70 B. C. Hamper M.L. Kurtzweil and J. P. Beck J. Org. Chem. 1992 57 5680. 71 F. Miiller and J. Mattay Angew. Chem.. Int. Ed. Engl. 1992 31 209. " J.-0. Baeg and H. Alper J. Org. Chem. 1992 57 157. Heterocyclic Compounds t 0 OH 0 OSiMq (144) (148) Reagents i 1-lithiopyrrole; ii Me,SiCl; iii A; iv air or FeCI Scheme 48 (1501 (151) Product ratio 150:151 = 94:6 Scheme 49 Condensation of an arylmethylamine with formaldehyde and glyoxal (molar ratio 4 :2 :1) in the presence of formic acid gives 2,4,6,8-tetraazabicyclo[3.3.O]octanes (157) in high yields (e.g. 84% when Ar = Ph).73 An interesting paper74 describes a versatile regiospecific synthesis of di- and (154) n=5or6 Reagents i hv 1,4-dicyanonaphthalene; ii PrCH=NPr Scheme SO 73 A.T. Nielsen R.A. Nissan A. P. Chafin R. D. Gilardi and C. F. George J. Org. Chem. 1992,57 6756. 188 D.E. Ames R2b (?i?Y R2XKAr N N N R’ R’ CH2Ar CH2Ar trimethyl-2-aminoimidazoquinoxalineswhich are potent mutagens formed when protein foods are cooked at high temperatures. Key steps in the process are photocyclization to obtain the fused ring system and introduction of the required 2-amino group. In the photocyclization the pyrazinylalkenyl(bromoimidazo1e)(1 58) is converted into the tricyclic structure (159; R2 = SMe). The latter transformation is achieved by permanganate oxidation to the sulfone (159; R2 = SO,Me) reaction with benzylamine to give (159; R2 = NHCH,Ph) and debenzylation by catalytic hydro- genolysis using ammonium formate and a palladium catalyst to produce the target molecule (159; R2 = NH,) (Scheme 51).74 (158) (159) Scheme 51 Guanine 7-oxide (160; R = H) and some 9-substituted derivatives which show anti-leukemic activity have been prepared (Scheme 52).75Condensation of the chloro compound (161) with phenacylamines gave (162) and base-catalysed cyclization with elimination of benzoic acid yielded the N-oxide (160).Reagents i PhCOCH,NHR.HCl; ii NaOH Scheme 52 ’’ D. E. Bierer J. F. O’Connell J. R. Parquette C. M. Thompson and H. Rapoport J. Org. Chem.,1992,57 1390. 75 K. Ogawa M. Nishi J.4. Inagaki F. Nohara T. Saito,T. Itaya and T. Fujii Chem. Pharm. Bull. 1992,40 343. Heterocyclic Compounds Unsaturated oximes e.g. (163) react with phenylselenyl bromide to give the cyclic nitrone (164) which on heating undergoes a diastereospecific cycloaddition to form the tricyclic system (165) (Scheme 53).76 0-iii I CH(Et)SePh @?; Reagents i PhSeBr; ii K,CO,; iii A Scheme 53 2,4,6-Cycloheptatriene-1-thione ( 166) and p-toluenesulfonyl isocyanate react by an [8 + 21 type cycloaddition to produce the fused-ring thiazolone (167) (Scheme 54).77 Scheme 54 2-Vinyl-1,3-thiazetidine(168) rearranges to thiazolidine (169) in good yield on hydrogenation in the presence of a platinum catalyst (Scheme 55).78 COzEt I 76 R.Grigg M. Hadjisoteriou P. Kennewell and J. Markandu J. Chem. Soc. Chem. Commun. 1992. 1537. ” K. Ito K. Saito S. Takeuchi and K. Takahashi Heterocycles 1992 34 1415.18 N. K. Capps G. M. Davies D. Loakes. and D. W. Young Tetrahedron 1992 48 10 149. 190 D. E. Arnes 5 Six-membered Rings In a synthesis of 2-dialkylaminochromones the boron complex (1 70) obtained from 2-hydroxyacetophenone and boron trifluoride was condensed with a Vilsmeier reagent to form salt (171). Hydrolysis of the borate group and cyclization yielded the chromone (1 72) (Scheme 56).79 0 r Me I ii -78% (170) (171) (172) Reagents i Cl,C=hMe,; ii H,O A Scheme 56 Treatment of 3-ethylphthalides (1 73) or 2-(prop-1 -enyl)benzoic acids (1 74) with aluminium chloride gives 8-hydroxy-3-methyl-3,4-dihydroisocoumarins(175) (Scheme 57).80 E3 (173) Scheme 57 The palladium catalysed C-H activation of methoxy groups in aryl iodides provides an efficient route to 6H-dibenzo[b,d]pyrans (Scheme 58).81 Iodo-2,3-dimethoxyben- zene (176; R = OMe) self-condenses to form the dibenzopyran (177) but when the blocking 3-methoxy group is absent as in (176; R = H) another condensation step occurs to give (178).Oxidation of enamines (179) with anhydrous dimethyldioxirane generates the epoxides (180) which dimerize to form 1,4-dioxanes (181) in excellent yields (Scheme 59).82 A synthesis of trioxanesB3 is based on photochemical oxidation of tetraallyltin (182) to tetra(ally1dioxy)tin (183) which reacts with ethanal to form (184). Cyclization of the alkoxide units using mercury(x1) acetate yields the acetoxymercuriotrioxane (1 85; R = HgOAc). Reduction with alkaline sodium borohydride solution then gives 79 J.Morris D.G. Wishka and Y. Fang J. Org. Chem. 1992 57 6502. R. S. Mali P.G. Jagtap S. R. Patil and P. N. Pawar J. Chem. Soc. Chern. Commun. 1992 883. G. Dyker Angew. Chrm. Int. Ed. Engl. 1992 31 1023. 82 W. Adam E.-M. Peters K. Peters H.G. von Schnering and V. Voerckel Chem. Ber. 1992 125 1263. 83 J. Cai and A.G. Davies J. Chem. Soc.. Perkin Truns. I 1992 3383. Heterocyclic Compounds 3,5-dimethyl-l,2,4-trioxane (185; R = H)as a mixture of cis-and trans-isomers (Scheme 60).83 MeO c--v Me0 R=H 90% Me0 (176) (177) Reagents i Pd(OAc), Bu,fSBrf HCONMe, A Scheme 58 (179) (180) Reagents i Dry dimethyldioxirane Yield 91% (R’ = Bu’ R = Me) Scheme 59 Sn(CH2CH=CH2) ASn(02CCH2CH=CH,) (182) (1 83) ] ii iii -Sn(O-C(Me)H-0-O-CH2CH=CH2) RH2c (1 84) (185) Reagents i 0,,hv tetraphenylporphine; ii MeCHO; iii Hg(OAc) Scheme 60 The literature on the antimalarial drug artemisinin (Qinghaosu) (186) which is the only known natural 1,2,4-trioxane has been reviewed.84 6-Thiashikimic acid has been prepared as its racemic ethyl ester acetate (187) A.R.Butler and Y.-L. Wu Chem. SOC.Rev. 1992 21 85. 192 D.E. Ames 0 (186) (Scheme 61).85 Ethyl thioxoacetate (188) generated by pyrolysis of its anthracene adduct added to 1,4-diacetoxybuta-l,3-diene to give a mixture of thiopyrans (189) and (190). Hydroxylation using osmium tetraoxide furnished diol(19l) and elimination of acetic acid by heating with pyridine yielded the acetoxy-ester (187).C02Et -HO”’ OAc OH OH Reagents i 1,4-diacetoxybuta-l,3-diene; ii OsO, H,O; iii pyridine A Scheme 61 Oxoenaminoketones obtained from 1,3-diketones and N,N-dimethylformamide dimethyl acetal yield 2-thiopyrans by a regioselective one-pot thionation-[4 + 21 cycloaddition sequence (Scheme 62).86 Condensation of ethyl formate with thiochroman-4-one gives 3-hydroxy-methylenethiochroman-4-one (192). Treatment with N-chlorosuccinimide (1 molar equivalent) produces 3-chlorothiochroman-4-one (193) whereas when two equival- ents are used chlorinated thiochromones (194; X = H and X = C1) are obtained (Scheme 63).s7 85 D. Adam A. A. Freer N. W. Isaacs G.W. Kirby A. Littlejohn and M. S. Rahman .I.Chem. SOC.,Perkin Trans.1 1992 1261. 86 C.D. Gabbutt J. D. Hepworth and B. M. Heron J. Chem. SOC.,Perkin Trans. I 1992 2603. ’’ P.R.Giles and C. M. Marson Aust. J. Chem. 1992 45,439. Heterocyclic Compounds Reagents i Me,NCH(OMe),; ii Lawesson's reagent; iii CH,=CHCHO Scheme 62 (193) (192) (194) Reagents i N-chlorosuccinimide Scheme 63 An asymmetric synthesis of piperidine alkaloids is based on the diastereoselective reaction of 1,3-0xazolidine (195) with Grignard reagents. The oxazolidine derived from carbinolamine (196) undergoes a ring cleavage reaction with pent-4-enylmag- nesium bromide to form (197). Palladium-catalysed oxidation of the alkene produces methyl ketone (198) with 87% of the product having the configuration shown at C*. Hydrogenolysis to remove the benzyl-type N-substituents followed by cyclization completed the synthesis of (2R,6S)-(-)-dihydropinidine (199) (Scheme 64).88 (199) (198) Reagents i PrCHO MgSO,; ii CH,=CH(CH,),MgBr; iii PdCl,(MeCN), CuCI, 0,;iv H, Pd/C; v HCI "20 Scheme 64 K.Higashiyama K. Nakahata and H. Takahashi Heterocycles 1992 33 17. 194 D. E. Ames Tetrahydropyridines are produced by an intramolecular [2 + 2) cycloaddition of Group IV metal-imido complexes of alkyn-amines e.g. (200) is converted into (201) (Scheme 65).89 Reagents i CpTiCI, PrzNEt; ii H,O Scheme 65 Thermal cyclization of alkyne-hydroxylamines provides a route to cyclic nitrones. Thus (202) yields the tetrahydropyridine N-oxide (203) (Scheme 66).90 Scheme 66 The 3-lithio derivative is obtained exclusively by reaction of 4-methoxy- 1 -methyl- 2-pyridone with butyllithium at -78 "C.The 3-carboxylic acid (80%) and other 3-substituted products can then be obtained by reaction with electr~philes.~ Ruthenium-catalysed transformation of b-ketonitriles gives ene-lactams.'* The examples (Scheme 67) show the preparation of two hexahydroquinolinones.c02et wco R CQEt *ace +a"""" R =85% H H Reagents i RuH,(PPh,), H,O A Scheme 67 4-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols (204) are obtained by an internal Barbier reaction when halogenoketones (205) are treated with butyllithium (Scheme 68).93 Cobalt and ruthenium carbonyls catalyse a novel rearrangement of heterocyclic side-chain ketones to lactams. For example decahydroisoquinoline derivative (206) is converted into lactams (207; 90%) and (208; 9%) (Scheme 69).94 89 P.L. McGrane M. Jensen and T. Livinghouse J. Am. Chem. SOC.,1992 114 5459. 90 M. E. Fox A. B. Holmes I. T. Forbes and M. Thompson Tetrahedron Lett, 1992 33 7421. 91 J. Buck J. P. Madeley and G. Pattenden J. Chem. SOC.,Perkin Trans. 1 1992 67. 92 S.-I. Murahashi S. Sasao E. Saito and T. Naota J. Org. Chem. 1992 57 2521. 93 M. Kihara M. Kashimoto and Y. Kobayashi Tetrahedron 1992 48 67. 94 M.D. Wang and H. Alper J. Am. Chem. SOC. 1992 114 7018. Heterocyclic Compounds 195 BuLi \ (205) Yield 69% (R = CO,Et Ar = Ph) Scheme 68 Reagents i CO Co,(CO), Ru,(CO),, A Scheme 69 2-Formylation of N-(2,2-diethoxyethyl)benzylamine(209; R = H) is effected by reaction with butyllithium and N,N-dimethylformamide.The product (209; R = CHO) undergoes acid-catalysed hydrolysis and cyclization to form 2-methyl- 1,2-dihydroisoquinoIine-3-aldehyde(2 10). Borohydride reduction then gives 2-methyl-3-hydroxymethyl-l,2,3,4-tetrahydroisoquinoline (21 1) (Scheme 70).95 (209) (210) Reagents i HCI H,O; ii NaBH, MeOH Scheme 70 Asymmetric syntheses of three quinolizidine alkaloids have been accomplished with a high degree of stereoc~ntrol.~~ For example the (-)-8-phenylmenthyl ester of 4-methoxy-3-(triisopropylsilyl)pyridinium- 1 -carboxylate chloride (212) was treated with 4-chlorobutylmagnesium bromide to obtain the conjugate addition product (213). Methanolysis of the N-carboxylate group and cyclization yielded (214) and addition of a methyl group to the enone system gave (+)-myrtine (215) (Scheme 71).96 A synthesis of 3,4-dihydro-l,6-naphthyridin-2( 1H)-ones (216) is based on nuc-leophilic displacement of the methoxy group of 5-cyan0-3~4-dihydro-6-rnethoxy-2(1H)-pyridone (217).Thus (217) reacts with malononitrile to form (218) which is cyclized by hydrogen chloride to produce the chloro compound (216; X = Cl). 95 G. Sirnig J. Chem. SOC..Perkin Trans. 1 1992 1613. 96 D.L. Cornins and D.H. LaMunyon J. Org. Chem. 1992 57 5807. 196 D. E. Ames -i ii ___) Cl(H2C)d' I c1-C02R* (212) (213) (214) (215) R* = (-)-8-phenylmenthyl Reagents i Cl(CH,),MgBr; ii H,O+; iii KOMe; iv oxalic acid; v MeMgCl Scheme 71 Reduction with zinc and acetic acid then yields the dihydronaphthyridinone (216; X = H) (Scheme 72).97 (217) (218) (216) Reagents i CH,(CN),; ii dry HCI Scheme 72 Recent advances in pyridazine chemistry have been reviewed." 3-Chloro-pyridazines react with hydrazine in hot butanol to form 3-hydrazinopyridazines which can be reduced to 3-aminopyridazines by nickel-aluminium alloy and aqueous alkali .99 Condensation of acids with propane- 1,3-diamine by heating with alumina yields the 2-alkyltetrahydropyrimidines (219).By dehydrogenating over a palladium catalyst the 2-alkylpyrimidines can be obtained. loo Simple diazines and benzodiazines react with benzyloxycarbonyl chloride and sodium cyanoborohydride to give tetra- or hexahydro-N-benzyloxycarbonyl deriva-tives."' For example pyrimidine yields the tetrahydro compound (220) (37%).SMe MeS/c=c/CN Meo2ctJ \C02Me 5 H Me C02C H2Ph 97 P.J. Victory J. Teixido and J. I. Borrell Heterocycles 1992 34 1905. 98 G. Heinisch Bull. SOC. Chim. Belg. 1992 101 579. 99 J.-M. Sitamze M. Schmitt and C.G. Wermuth J. Org. Chem. 1992 57 3257. 100 J. W. Hull and K. Otterson J. Org. Chem. 1992 57 2925. 101 J. R. Russell C. D. Garner and J. A. Joule J. Chem. SOC.,Perkin Trans. 2 1992 409. Heterocyclic Compounds Reaction of the ketene dithioacetal (221) with sodium hydride and thioacetamide gives methyl 2-methyl-6-methylthio-4-thioxopyrimidine-S-carboxylate (222).lo2 173-Diaza-1,3-dienes (223) undergo a [4 + 21 cycloaddition with acetylenic ketones (224) to form pyrimidines (225).The trichloromethyl group can either be reduced to methyl or displaced by methoxide ion to give the 2-methoxy analogue (Scheme 73).'03 5,8-Quinoxalinediones can be obtained by oxidative demethylation of 5,8-dimethoxyquinoxalines using cerium(1v) nitrate.lo4 Aza-Wittig reaction of bis(iminophosphorane) (226) with phenyl isocyanate gives the pyrido[2.3.4-d7e]quinazoline (227) (Scheme 74). lo' Yield 98% (R' = H RZ= CO,Me R3 = OMe) Scheme 73 Me Me I I 1 N= PPh3 .YNPh (226) NHPh Scheme 74 The chemistry of 172,4-triazinium salts has been reviewed. lo6 A synthesis of 1,2,4-triazine-5-carboxylate esters (228) from diazo-ketoesters (229; X = N,) has been developed. Reaction with triphenylphosphine gave (229; X = NN=PPh,) which was hydrolysed to hydrazone (229; X = NHNH,).Condensation with amide ketal (230) yielded (231) which was cyclized by reaction with ammonium acetate to produce the triazine (228) (Scheme 75).'07 Substituted 3,4-dihydro-2H-l,3-oxazines(232; X = Ac; Y = Me) have been pre- pared by condensation of acetylacetone with aryl aldehydes and ammonium acetate. Similar reaction of o-sulfonylacetophenone gives (232; X = PhSO,; Y = Ph).lo8 Io2 A. Lorente M. L. Garcia M. Fernandez and J. L. Soto Heterocycles 1992 34 1573. Io3 A. Guzman M. Romero F. X. Talamas and J. M. Muchowski Tetrahedron Lett. 1992 33 3449 lo4 Y. Kitahara S. Nakahara T. Tanaka and A. Kubo Heterocycles 1992 34 1623. lo' P. Molina M. Alajarin and A. Vidal J.Org. Chem. 1992 57 6703. Io6 0.Chupakhin S. Alexeev B. Rudakov and V. Charushin Heterocycles 1992 33 931. lo' T. Ohsumi and H. Neunhoeffer Tetrahedron 1992 48 5227. K. Pandiarajan and J. C. N. Benny J. Chem. Soc. Perkin Trans. I 1992 2055. 198 D. E. Ames R2 I MQN-C(OMe)2 (230) -+ X II R'-C -COCOzEt (229) Reagents i NH~OAC-, HOAc A Scheme 75 3-Methyl-5,6-dihydro-S,S-dimethyl-l,4-oxazin-2-one (233; X = H) is converted by action of t-butyl hypochlorite into the 3-chloromethyl compound (233; X = Cl). This undergoes self-condensation in the presence of ethyl diisopropylamine to form the green bis(oxazino)pyrazine (234).'09 It has been shown by X-ray studies that condensation of the benzopyran derivative (235) with 2-trifluoroacetylpyrrole involves the formation of a morpholine ring in the product (236) (Scheme 76).' lo (235) (236) Reagents i KOBu' tetramethylethylenediamine,2-trifluoroacetylpyrrole A Scheme 76 A stereocontrolled synthesis of tetrahydro-1,4-thiazinesis based on the ring- cleavage reaction of epoxide (237) with sodium methoxide and methyl thioglycolate to form the thioether (238).Conversion into chloro-amide (239) followed by cyclization lo9 D. J.R. Brook R.C. Haltiwanger and T.H. Koch J. Am. Chem. SOC. 1992 114 6017. 'lo D. R. Buckle S.C. Connor D. S. Eggleston A. Faller I. L. Pinto S.A. Readshaw and D.G. Smith J. Chem. SOC.,Perkin Trans. 1 1992 769. Heterocyclic Compounds gave thiazanone (240; X = 0)which was reduced to thiazane (240; X = H,H) by sodium borohydride and acetic acid (Scheme 77)." Reagents i NaOMe HSCH,CO,Me; ii NH,; iii SOCI Scheme 77 The benzo-1,2-selenazin-3-one(241) has been obtained by action of bromine and a base on the methylselenoamide (242).l1 Ring expansion of 1,3-dithiolium cations (243) by reaction with iodine and aqueous ammonia yields 1,4,2-dithiazines (244).' l3 (241) (242) (243) (244) Carbonyl oxides (245) derived by ozonolysis of vinyl ethers (246) readily undergo [3 + 3lcycloaddition reactions with nitrones (247) to form dihydro-l,2,4,5-trioxazines (248) (Scheme 78).Il4 C=CH-OR3R ,C-0-0-+ R' \+ R6 R4 ,N=C,\+ I R2 R2 -0 R5 (246) R6 (248) Scheme 78 l1 J. L. G.Ruano M. C. Martinez J. H. Rodriguez E. M. Olefirowicz and E.L. Eliel J. Org. Chem. 1992,57 4215. 'I2 P. V. Jacquemin L. E. Christiaens M. J. Renson M. J. Evers and N. Dereu Tetrahedron Lett. 1992,33 3863. 'I3 M. R. Bryce G. R. Davison J. A. K. Howard and A. S. Batsanov J. Chem. SOC.,Chem. Commun. 1992 478. M. Mori,T. Sugiyama M. Nojima S. Kusabayashi and K. J. McCullough,J. Org. Chem. 1992,57,2285. 200 D. E. Ames 6 Sevenmembered Rings A general molybdenum-catalysed process for the cyclization of dialkenyl ethers to unsaturated oxygen heterocycles having five six or seven-membered rings with elimination of a small aliphatic alkene is indicated in Scheme 79 (X = O)." N-Alkyl N-heterocycles can be obtained by a similar process (Scheme 79; X = NR).l16 PhCMe;! RO OR 'FY where R = CMe(CF3)2 Scheme 79 Anodic oxidation of tributylstannylmethyl ethers containing an alk-4-enyl group in the presence of tetrabutylammonium fluoborate leads to intramolecular C-C bond formation with introduction of a fluorine atom.For example ether (249) gives a mixture of fluorohexahydrooxepine (250) and the tetrahydrooxepine (251) (Scheme 80).' 4-Fluoropyrans can be prepared similarly. snBu3 I (250; 61%) (251; 28%) Reagents i Bu,&BF, electrolysis Scheme 80 The first total synthesis of hemibrevetoxin B (252) a 'red tide' marine neurotoxin from Gyrnnodinium breve has been reported.' l8 This outstanding achievement in heterocyclic synthesis is however too long and elaborate to discuss here. The ester (253; X = CO,Me) obtained by addition of methyl acrylate to a chloroalkenyl toluene-p-sulphonamide reacts with methylmagnesium iodide to give 'I5 G.C.Fu and R. H. Grubbs J. Am. Chem. SOC.,1992 114 5426. G.C. Fu and R.H. Grubbs J. Am. Chem. Soc. 1992 114 7324. J.-i. Yoshida Y. Ischichi and S. hoe J. Am. Chem. SOC. 1992 114 7594. K.C. Nicolaou K.R. Reddy G. Skokotas F. Sato and X.-Y. Xiao J. Am. Chem. SOC. 1992,114,7935. Heterocyclic Compounds 201 carbinol (253; X = CMe,OH). Cyclization under acidic conditions yields 53-dimethyl- l-tosylazepan-3-one (254) (Scheme 8 1).' (253) (254) Reagents i 90% H,SO Scheme 81 In a synthesis of 1,3-benzoxazepines (255) (Scheme 82)l2' azido-ester (256; X = 0 Y = N3) was treated with triphenylphosphine to generate iminophosphorane (256; X = 0 Y = NzPPh,) which cyclized by an internal Wittig reaction to form the heterocycle (255).1,3-Benzodiazepines (257) were obtained similarly from the azido-amide (256; X = NH Y = N3). ,CO,Et 11 -X=NH R (255) (257) Reagents i Ph,P; ii A Scheme 82 Pyrrolo[2,1-c][ 1,4]benzodiazepines e.g. (258) have been prepared by the process shown in Scheme 83.121 Acid chloride (259) was condensed with pyrrolidine- 2-aldehyde diethyl dithioacetal and reduction of the nitro-group then gave amino-amide (260). Mercury(l1)-catalysed cyclization led to the tricyclic product (258). 119 F.A. Fraser G. R. Proctor and J. Redpath J. Chem. SOC..Perkin Trans. 1 1992 445. 12" J. Kurita T. Iwata S. Yasuike and T. Tsuchiya J. Chem. SOC. Chem. Commun.1992 81 lZ1 D.S. Bose G. B. Jones and D. E. Thurston Tetrahedron 1992 48 751. 202 D.E. Ames Me0 cocl Me0 0 (259) iii 83% 1 0 Reagents i pyrrolidine-2-aldehyde diethyl thioacetal; ii SnCl, A; iii HgCl, CaCO, H,O Scheme 83 1l-Phenyl-5H,11H-pyrrolo[2,l-c][1,4]benzothiazepine (261) has been prepared from sulfide (262). Oxidation to the sulfoxide followed by treatment with acetic anhydride led to an intramolecular electrophilic cyclization onto the pyrrole producing (261) (Scheme 84).’22 Ph Reagents i 3-C1C,H,CO3H; ii Ac,O A Scheme 84 7 Larger Rings Thermal cycloaddition of dimethyl acetylenedicarboxylate to the tetrahydropyridine (263) leads to (264) which undergoes a ring cleavage to form the tetrahydroazocine derivative (265) (Scheme 85).lZ3 3,4-Dihydro-2H- 1,2-benzothiazin-3-0ne 1,l-dioxide (266) reacts with the azirine (267) at ambient temperatures to give adduct (268) which rearranges spontaneously to 1,2,5-benzothiadiazonin-6-0ne1 ,l-dioxide (269).This structure was indicated by X-ray studies (Scheme 86). 24 ”’ A. Garafolo G. Campiani V. Nacci and 1. Fiorini Heterocycles 1992 34 51. lZ3 P. Sanna A. Carta and G. Paglietti J. Chem. Res. (S) 1992 16. lZ4 A. S. Orahovats A. Linden and H. Heimgartner Helv. Chim. Acta 1992 75 2515. Heterocyclic Compounds CH2CH2NEt2 (264) (265) Reagents i MeO,CCECCO,Me Yield 79% (R = C0,Me) Scheme 85 00 Flash vacuum pyrolysis of the o-vinyl esters (270) generates thione (271) by elimination of cyclopentadiene.Cyclization leads to (272; mixed isomers) which can be reduced using ‘diimide’ to 3-thianonanolide (273) (Scheme 87).12’ The process is applicable to the preparation of thialactones with 7- to 1 l-membered rings. 1,4-Dihydr0-2,3-benzodithiin(274) reacts with 2,3-dimethylbuta- 1,3-diene in the presence of boron trifluoride etherate to effect 1,4-addition with concomitant S-S bond cleavage thus forming heterocycle (275) which has a 10-membered ring (Scheme 88).’26 C02(CHz)sCH=CH2 H-!-C02(CH2)&H=CH2 [ 1 163% Reagents i Flash vacuum pyrolysis; ii KO,CN=NCO,K HOAc H,O Scheme 87 125 S.S.-M. Choi G. W. Kirby and M.P. Mahajan J. Chem. SOC.,Perkin Trans. I 1992 191. R. Sato J. Kumagai K. Yonesaka and S.4. Satoh Tetrahedron Lett. 1992 33 947.204 D.E. Ames Reagents i BF,.Et,O CH,=CMeCMe=CH Scheme 88 Oxidation of bithiazolium salt (276) with potassium superoxide-18-crown-6 gives 1,2,5,8-dithiadiazecin-6,7-dione (277) (Scheme 89).12’ L N-C-C-N Me II I100 Me (276) (277) Reagents i KO, 18-crown-6 MeCN Scheme 89 Intramolecular palladium(0)-catalysed cross-coupling of structures terminating in an acyl chloride and a /3-stannyl alkenoate e.g. (278) provides a new and efficient route to 10-to 20-membered y-oxo-a,B-unsaturated macrolides. Monomers (279) and dimers (280) are produced (Scheme 90).’* Both (2)-and (E)-/3-stannylalkenoatesgive identical macrocycles indicating thermodynamic equilibration during the reaction. Ii RT&o 0 + (279) Reagents i CO trans-benzylchlorobis(triphenylphosphine)palladiurn(o),A Scheme 90 ’” T.Itoh K. Nagata M. Okada K. Yarnaguchi and A. Ohsawa TetrahedronLett. 1992 33,6983. lZ8 J. E. Baldwin R. M. Adlington and S. H. Ramcharitar Tetrahedron,1992. 48. 2957. Heterocyclic Compounds 205 In the crown ether field reviews have dealt with macrocyclic polyethers (cages) and related compounds'29 and crown ethers with sidearms (lariat ethers).' 30 A convenient one-pot synthesis of tropocoronands (28 1) is based on a heterocycle exchange reaction occurring when benzo[b]cyclohepta[e][ 1,4]oxazine (282) is heated with x,m-diaminoalkanes (Scheme 91).' 31 (282) (281) Reagents i H2N(CH,),NH, A Scheme 91 The use of metalloporphyrins as catalysts for oxidation reactions including DNA cleavage has been reviewed.' 32 Octaethylporphyrin can be fluorinated at its rneso-positions by heating with N-fluoropentachloropyridinium trifluoromethanesulfonate.'33 The tetrafluoro de- rivative (20%) is obtained together with small amounts of monosubstitution products.Tolyporphin (283) is a novel multidrug resistance reversing agent isolated from an alga. It potentiates the cytotoxicity of adriamycin or vinblastine at low doses. The structure (283) was established mainly by NMR studies.'34 Me 0 Me Ho+p$ OAc \> AcO I OH 0 Me (283) Finally oxidative thermolysis of (1,19-dimethyloctadehydrocorrinato)nickel(11) chloride (284)occurs surprisingly easily (Scheme 92).'35The corrin frame is expanded one angular methyl group becomes a methine bridge and the furanoid ring is formed.lZ9 H. An J.S. Bradshaw and R.M. Izatt Chem. Rev. 1992 92 543. 130 G. W. Gokel Chem. SOC.Rev.,1992 21 39. 13' T. Nozoe K. Shindo H. Wakabayashi and S. Ishikawa Heterocycles 1992 34 881. B. Meunier Chem. Rev. 1992 92 1411. 133 Y. Naruta F. Tani and K. Maruyama Tetrahedron Lett. 1992 33 1069. 134 M. R. Prinsep F.R. Caplan R. E. Moore G. M. L. Patterson and C. D. Smith J. Am. Chem. SOC.,1992 114 385. 135 C. K. Chang W. Wu S.S. Chern and S. M. Peng Angew. Chem. Int. Ed. Engl. 1992 31 70. 206 D. E. Ames The structure of the green pigment (285)formed was indicated by X-ray studies; the 18 n-electron system has only three pyrrolic components. The corresponding free base was also obtained from the nickel compound (285).Scheme 92

ISSN:0069-3030    

DOI:10.1039/OC9928900167

出版商:RSC    

年代:1992

数据来源: RSC