Munchnones cycloaddition reactions

Dipolar cycloaddition reactions of thioisoraunchnones (l,3-thiazolium-4-olates) have not been as extensively studied as those of munchnones (l,3-oxazolium-5-olates) despite offering rapid access to novel heterocyclic compounds. The cycloaddition of the thioisomunchnone (52) with trans-P-nitrostyrene results in the formation of two diastereoisomeric 4,5-dihydrothiophenes (53) and (54) via transient cycloadducts. These cycloadducts then undergo rearrangement under the reaction conditions <96JOC3738>. 

TABLE 10.1. 1,3-DIPOLAR CYCLOADDITION REACTIONS OF IN SITU GENERATED MUNCHNONES AND METHYL PROPIOLATE AND METHYL 3-PHENYLPROPIOLATE"... 

Mesoionic oxazolones (munchnones) 297 can be generated by cyclodehydration of N-substituted a-amino acids 295 or by alkylation of oxazolones 296 (Scheme 7.98). These compounds are reactive and versatile 1,3-dipoles that undergo cycloaddition reactions with dipolarophiles to generate a variety of heterocyclic systems. In particular, this is an extremely versatile methodology to prepare pyrroles that result from elimination of carbon dioxide from the initial cycloadduct. Numerous examples have appeared in the literature in recent years and several have been selected for discussion. The reader should consult Part A, Chapter 4 for an extensive discussion and additional examples. 

The cycloaddition reactions of isoquinolinium species produce fused isoquinoline products. The Af-ylide of 53, formed with base addition, couples with alkenes <99S51> or imines <99T7279> to afford tricyclic products, such as 54. Pyrrole-fused isoquinolines result from the reaction between mUnchnone imine intermediates and a,yff-ethylenic esters <99EJOC297>. N-Arylimides undergo 1,3-dipolar cycloaddition with strained frani-cyclooctenes, as opposed to common cycloalkenes, to tdford the pyrazolidine-fused ring system <99H(50)353>. 

The mesoionic heterocycles called munchnones function as cyclic azomethine ylides in cycloaddition reactions.63 The alkenyl moiety can be attached at carbon or at nitrogen. 

This section deals with the comparatively new anhydro-4-hydroxyoxazolium hydroxides (217), the isomeric 5-hydroxy compounds (218) and the amino analogues (219). The chemistry of the munchnones (218) has been intensively studied as a result of the pioneering research of Huisgen s school in Munich on 1,3-dipolar cycloaddition reactions of these compounds (B-67MI41800). There have been so many publications in this area that only the bare outlines can be presented here the reader is referred to recent reviews (76AHC(19)1, 81MI41800) for fuller accounts. 

Cycloaddition reactions of anhydro-5-hydroxyoxazolium hydroxides, e.g. (235), have been investigated thoroughly but no satisfactory comprehensive theoretical treatment to account for the orientation of the products has yet been presented. While the munchnones usually function as 1,3-dipoles (236), several reactions involving the intermediacy of the valence-isomeric ketenes (237) have come to light. 

The cyclodehydration of 2-substituted-A/-acylthiazolidine-4-carboxylic acids yields bicyclic munchnones. This mesoionic ring system acts as a cyclic azomethine ylid and can undergo 1,3-dipolar cycloaddition reactions with dipolarophiles. A range of chiral pyrrolo[l,2-c]thiazoles have been prepared by this method both intermolecularly and intramolecularly. 

As Gingrich and Baum said in their review, the most important reactions (of munchnones) from a synthetic point of view are 1,3-dipolar cycloaddition reactions. If anything, as will be seen, this is even more true today. Although the... 

Similarly, Toupet and co-workers determined the structures of the pyrrole adducts 150 from the cycloaddition of munchnones 149 with methyl phenylpro-pionate by X-ray crystallography (Fig. 4.53). These highly regioselective cycload ditions are in accord with FMO predictions. A detailed study by this same team involved cycloaddition reactions of mimchnones with methyl propiolate and methyl... 

Dalla Croce and La Rosa examined the 1,3-dipolar cycloaddition reactions of unsymmetrical munchnones with terminal alkynes to give pyrroles 156 and 157 (Table 4.8). The reaction is generally regioselective the major pyrrole isomer from the monosubstituted munchnones have adjacent hydrogens, irrespective of the munchnone substituent. With the disubstituted munchnones, the major regioisomer is derived from attachment of C-4 of the munchnone and the p-carbon of the alkyne, except for phenylacetylene, which shows the opposite regiochemistry. The authors interpreted this behavior as a consequence of the electron-rich nature of phenylacetylene as a dipolarophile with a larger LUMO coefficient on the a carbon. 

Jursic smdied the cycloaddition reaction of a munchnone with acetylene from several theoretical standpoints using density functional theory on AMI geometries. The predicted activation energy for the 1,3-dipolar cycloaddition is 11.49 kcal/mol and the elimination of carbon dioxide from the cycloadduct to give a pyrrole is 5.82 kcal/mol. Both reactions are extremely exothermic as observed experimentally. 

The 1,3-dipolar cycloaddition reactions of munchnones with olefinic dipolarophiles continues to be of enormous interest in regard to both mechanisms and synthetic applications. Unlike the comparable cycloadditions with acetylenic dipolarophiles that yield only pyrroles, reactions of munchnones with olefinic dipolarophiles can lead to a variety of interesting products. 

TABLE 4.12. 1,3-DlPOLAR CYCLOADDITION REACTIONS OF IN SITU ENERATED MUNCHNONES AND l,4-QUINONES ... 

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