SYNTHESIS OF HETEROCYCLIC SYSTEMS BY CYCLOADDITION REACTIONS

The publications that appeared up to 1975 on the transformations of oxiranes into other heterocyclic compounds are reviewed in detail in the monograph by van der Plas and the relevant chapters of other reviews. Accordingly, we merely supplement the earlier data with more recently reported results and, at the same time, present some of the varied transformations of the oxiranes. The possibility of stereoselective synthesis of heterocyclic systems was broadened considerably by 1,3-dipolar cycloaddition reactions. Heterocycles are formed if the ylide intermediates produced from oxiranes in photolytically or thermally induced reactions are made to react intramolecularly or with external dipolarophiles. Reactions of these types will be treated in Sections IV.8 and IV.9. 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

Two reactions formerly used widely in the formation of carbo-cycles have now been successfully extended to the synthesis of heterocyclic systems. Thus the intramolecular cycloaddition of the olefinic alkoxyketenes (36) leads to cyclobutanone annulated heterocycles (37), where better yields are obtained by using the... 

The synthesis of nitrogen containing heterocyclic systems by photocylo-addition processes is virtually limited to examples involving [ 2 + 2] cycloaddition of imines, nitriles, and azo compounds. Successful additions are few in number and the requirements for success uncertain. The reactions do not proceed with the facility with which carbonyl containing compounds undergo photocycloaddition to alkenes to give oxetans, and various explanations have been advanced to account for this observed lack of reactivity.226... 

In 1981 we published the first paper [22] on the synthesis of s-triazolo[4,3-a]pyridinium salts, 4, by the anodic oxidation of hydrazones 3 in the presence of pyridine (Scheme 5). In our working mechanistic scheme we proposed nitrilimine as the possible intermediate and pointed out that this reaction opens the door to a wide range of heterocyclic systems via anodic oxidation of aldehyde hydrazones through 1,3-dipolar cycloaddition reactions of the nitrilimine involved. 

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

Several fully saturated heterocyclic systems which have been formed by cycloaddition reactions have found use in natural product synthesis. Cycloadducts (27) and (28) were prepared as part of an investigation into the synthesis of the benzoxocin fragment of the antitumor anthracycline nogalomycin <9lJOCl364> and cycloadducts (245) and (248) were intermediates in the synthesis of amino sugar derivatives <84JA5598>. 

Herein an overview of the most relevant approaches for the synthesis of un-natiual heterocycles of biological and industrial potential from carbohydrates is presented the natiual heterocycles have been previously reviewed [6]. This review is hmited to heterocycles with one or more of their carbon skeletons derived from carbohydrate precursors—those formed by cycloaddition reactions are not included. Also, carbohydrates with strained ring systems, oxiranes, aziridines, and thiiranes have aheady been reviewed and are not included herein [20]. The synthetic approaches for the reviewed heterocycles are divided according to the size of the heterocychc rings and the number of hetero atoms in the ring. The bicyclic ring systems are included under the smaller ring of their skeleton. 

The various approaches to forming heterocyclic ring systems by intramolecular cyclizations were discussed in Chapter 4 and by cycloaddition reactions in Chapter 5. In Chapters 6 and 7, numerous reactions of heterocyclics were described. We will now reexamine some of this material from a different standpoint, taking a particular heterocyclic family and considering some of the methods that are useful for the construction of the family. In addition, some information on the synthesis of important heterocycles not yet considered will be presented. As was discussed in Chapter 8, great numbers of new heterocyclic compounds have been, and continue to be, synthesized in the research laboratories of the pharmaceutical industry in their search for new materials of value in medicine, and the many accomplishments from this work provide a multitude of examples that can be used to illustrate the practical application of heterocycMc chemistry. However, the presentation must be limited to a small number of examples for more in-depth discussions of important syntheses, two works by... 

A versatile method for the synthesis of a variety of five-membered heterocycles and their ring-fused analogs involves the reaction of a neutral 47r-electron-3-atom system with a 27T-electron system, the dipolarophile, which is usually electron deficient in nature. Available evidence, e.g. retention of dipolarophile stereochemistry in the product and solvent polarity exerting only a moderate influence on the reaction, indicates that the cycloaddition proceeds via a concerted mechanism 63AG(E)565, 63AG(E)633, 68JOC2291) and may be represented in general terms by the expression in Scheme 8. 

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