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  • Intramolecular Dipolar Cycloaddition Reactions of Azomethine Ylides

    Iain Coldham*, and Richard Hufton

    Department of Chemistry, University of Sheffield, Sheffield S3 7HF, U.K., and Tripos Discovery Research Ltd., Bude-Stratton Business Park,Bude EX23 8LY, U.K.

    Received September 13, 2004

    Contents1. Introduction 27652. Ylides from Aldehydes 2768

    2.1. With Secondary R-Amino-Esters 27682.2. With Secondary R-Amino Acids 27722.3. Dipolarophile Tethered to the Amine 2777

    3. Ylides from Imines 27783.1. By Prototropy 27783.2. By Metalation 27823.3. By Alkylation 2784

    4. Ylides from Aziridines 27874.1. Cycloadditions onto Alkenes to Form 5,5 and

    5,6 Ring Systems2788

    4.2. Cycloadditions onto Alkenes to Form LargeRing Systems


    4.3. Auxiliary-Controlled Cycloadditions 27944.4. Cycloadditions onto Alkynes 2794

    5. Ylides from Heterocycles 27955.1. Ylides from Oxazolines and Isoxazolines 27955.2. Ylides from Munchnones 27985.3. Ylides from Pyridines and Pyrazines 2802

    6. Other Methods of Ylide Formation 28057. Summary and Outlook 28078. References 2807

    1. Introduction

    It was in 1963 that Huisgen laid out the classifica-tion of 1,3-dipoles and the concepts for 1,3-dipolarcycloaddition reactions, although it was not until1976 that the first intramolecular 1,3-dipolar cy-cloaddition reaction of an azomethine ylide wasreported. Since then, impressive developments havebeen described in this area, with the establishmentof various useful methods for the formation of azo-methine ylides and the determination of the require-ments for a successful intramolecular cycloadditionreaction. Use of this methodology for the synthesisof pyrrolidine- and pyrrole-containing natural prod-ucts has been expanding rapidly. This review aimsto describe the background and mechanisms ofazomethine ylide formation and intramolecular cy-cloaddition, giving a critical account including the

    very first example and covering to early 2005. It ishoped that this review will be a useful resource forchemists interested in cycloaddition reactions andwill inspire further exciting developments in thisarea.

    Cycloaddition reactions are one of the most impor-tant class of reactions in synthetic chemistry. Within

    * Corresponding author. Tel: +44 (0)114 222 9428. Fax: +44 (0)-114 222 9346. E-mail: University of Sheffield. Tripos Discovery Research Ltd.

    Iain Coldham (b. 1965) is a Reader in Organic Chemistry at the Universityof Sheffield. He obtained his undergraduate degree and Ph.D. from theUniversity of Cambridge, completing his Ph.D. in 1989 under thesupervision of Stuart Warren. After postdoctoral studies at the Universityof Texas with Philip Magnus, he joined the staff in 1991 at the Universityof Exeter, U.K. In 2003, he moved to the University of Sheffield where heis involved in research on chiral organolithium compounds and on dipolarcycloaddition reactions in synthetic organic chemistry.

    Richard Hufton (b. 1970) is a Senior Research Scientist and Project Leaderwithin the Lead Discovery division at Tripos Discovery Research Ltd. Heobtained his undergraduate degree from the University of Oxford in 1993and his Ph.D. from the University of Exeter in 1996, where he studiednew methodology for the synthesis of cyclic amines under the guidanceof Iain Coldham. Prior to joining Tripos, he carried out postdoctoral studiesat the University of Nottingham and at Imperial College, London.

    2765Chem. Rev. 2005, 105, 27652809

    10.1021/cr040004c CCC: $53.50 2005 American Chemical SocietyPublished on Web 06/25/2005

  • this class, the 1,3-dipolar cycloaddition reaction hasfound extensive use as a high-yielding and efficient,regio- and stereocontrolled method for the synthesisof many different heterocyclic compounds.1-12 Indeed,the 1,3-dipolar cycloaddition reaction has been de-scribed as the single most important method for theconstruction of heterocyclic five-membered rings inorganic chemistry.13 Placing the ylide dipole and thealkene or alkyne dipolarophile within the samemolecule provides direct access to bicyclic (or poly-cyclic) products of considerable complexity.14,15 Theproximity of the reactants and the conformationalconstraints often lead to ready cycloaddition withvery high or complete selectivity. For the preparationof five-membered cyclic amines, in particular pyrro-lidines, dihydropyrroles, and pyrroles, cycloadditionof azomethine ylides with alkenes or alkynes is veryeffective and has been studied widely.16-23 Thisreview describes dipolar cycloaddition reactions ofazomethine ylides that have been carried out in-tramolecularly. Such reactions have been gainingincreasing popularity as a highly stereoselectivemethod for natural product synthesis. Despite this,previous reviews of 1,3-dipolar cycloaddition reac-tions, with two recent exceptions,22,23 have given verylittle or no attention to intramolecular cycloadditionswith azomethine ylides. This review aims to providea thorough coverage of these reactions, includingreactivity and stereochemical issues and applicationsin synthesis. Cycloaddition reactions of 2-azaallyl-lithium species, which provide an alternative ap-proach to pyrrolidine products, are not included, andreaders should refer to a recent account of this area.24

    Azomethine ylides have four electrons spreadover the three-atom C-N-C unit; as such, they mustbe represented by a zwitterionic (or diradical) form.Four zwitterionic resonance forms can be drawn, asshown in Chart 1. The most common representationhas a positive charge located on the nitrogen atomand a negative charge distributed over the two carbonatoms.25 The extent of negative charge on each carbonatom is determined by the nature and number ofsubstituents at these carbons. Alternatively, tworesonance forms with the positive and negativecharges on the carbon atoms can be drawn torepresent the 1,3-dipole.

    Cycloaddition of an azomethine ylide with a -sys-tem involves a total of six electrons [4s + 2s] andtakes place by a thermally allowed, suprafacialprocess according to the Woodward-Hoffmannrules.26-28 For a suprafacial process, the two carbon-carbon bonds are formed to the same face of theazomethine ylide and to the same face of the di-polarophile. It is generally accepted that the cycload-dition is concerted with both carbon-carbon -bondsbeing formed at the same time, although not neces-sarily to the same extent. Evidence in favor of theconcerted nature comes from the stereospecificity ofthe cycloaddition, in which the relative stereochem-

    istry of the alkene dipolarophile is maintained in thepyrrolidine product. In addition, stereospecific inter-molecular cycloadditions using azomethine ylidesderived from cis and trans aziridines have beenreported (however, compare with examples in section4.1).29 Depending on the electronic nature of thedipole and dipolarophile, a concerted process may notalways be operative and a stepwise pathway, involv-ing diradical or zwitterionic intermediates, cannot beruled out.30

    In terms of frontier molecular orbital (FMO) theory,in which reaction takes place by maximizing overlapof the HOMO and the LUMO,31 azomethine ylidescan be considered to be electron-rich, and the domi-nant interaction involves the HOMO of the azo-methine ylide with the LUMO of the -system (Chart2).32,33 This is borne out by the general preference forreaction of azomethine ylides with electron-pooralkenes. However, particularly in intramolecularcycloadditions, reaction can take place readily withan unactivated alkene and the best frontier orbitalinteraction is not necessarily obvious.

    Calculations have been carried out by CNDO/2 andan estimation has been made of the energies of thefrontier orbitals.33,34 The parent azomethine ylide(CH2NHCH2) has approximate energies for the HOMOof -6.9 eV and for the LUMO of +1.4 eV. The relativeenergies of the frontier orbitals are illustrated inChart 3. The most favorable interaction will bebetween the HOMO of an unstabilized azomethineylide dipole and the LUMO of an electron-deficientdipolarophile (Z substituent), a conjugated dipolaro-phile (C substituent), or an alkyl-substituted di-polarophile (R substituent); however, the extent ofinteraction is similar between that of the HOMO ofthe dipole and the LUMO of an electron-rich di-polarophile (X substituent) and that of the LUMO ofthe dipole and the HOMO of the electron-rich di-polarophile and either could dominate. Such unsta-bilized ylide dipoles should react best with electron-deficient dipolarophiles, and examples in this reviewattest to this. The substitution pattern of the ylideor the presence of metal ions can alter the relativeenergies of the molecular orbitals, and care must betaken if invoking this theory. For example, the moreelectron-deficient azomethine ylide RO2CCHdN(Ar)-CHCO2R has approximate energies for the HOMOof -7.7 eV and for the LUMO of -0.6 eV. Hence withthis dipole, reaction should occur readily with anytype of dipolarophile. Intramolecular dipolar cycload-dition reactions are common with electron-poor andwith electron-rich alkenes and numerous examplesare provided in this review. In addition to these

    Chart 1

    Chart 2

    2766 Chemical Reviews, 2005, Vol. 105, No. 7 Coldham and Hufton

  • studies, other theoretical calculations using semi-empirical and ab initio methods have been investi-gated, providing evidence for concerted or stepwiseprocesses, depending on the substitution pattern ofthe dipole and dipolarophile.35-45

    If the relative sizes of the atomic orbitals areknown for the frontier orbitals of both the azomethineylide and the dipolarophile, then a prediction of theregioselectivity in the cycloaddition reaction of anunsymmetrical dipole and dipolarophile can be made.34The preferred transition state will involve interactionof the larger terminal


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