Munchnones 1,3-dipolar cycloadditions

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>. 

Merlic demonstrated the direct, non-photochemical insertion of carbon monoxide from acylamino chromium carbene complexes 14 to afford a presumed chromium-complexed ketene 15 <00JA7398>. This presumed metal-complexed ketene leads to a munchnone 16 or munchnone complex which undergo dipolar cycloaddition with alkynes to yield the pyrroles 17 upon loss of carbon dioxide. 

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

Munchnones 298 obtained in situ by N-alkylation of 5(4/f)-oxazolones undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate to give Al-alkylpyr-roles 299. 1,3-Dipolar cycloaddition of munchnones with triphenylvinylphos-phonium bromides affords tri- and tetrasubstituted pyrroles 300. In this case, the interaction of the phosphonium group with the carbonyl group leads to high levels of regioselectivity (Scheme 7.99 Table 7.27, Fig. 7.29). ... 

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>. 

Mesoionic compounds have been known for many years and have been extensively utilized as substrates in 1,3-dipolar cycloadditions.158-160 Of the known mesoionic heterocycles, munchnones and sydnones have generated the most interest in recent years. These heterocyclic dipoles contain a mesoionic aromatic system i.e. 206) which can only be depicted with polar resonance structures.158 Although sydnones were extensively investigated after their initial discoveiy in 1935,160 their 1,3-dipolar character was not recognized until the azomethine imine system was spotted in the middle structure of (206). C-Methyl-N-phenylsydnone (206) combines with ethyl phenylpropiolate to give the tetrasub-... 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

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. 

The l,3- dipolar cycloaddition of alkynes to anhydro-5-hydroxyoxazolium hydroxides leads to pyrroles (equation 66). Electron-withdrawing substituents in the alkyne are activating and DMAD reacts 48 times faster with compound (235) than does methyl propiolate, which in turn is 7000 times more reactive than oct-l-yne. The reaction has many ramifications and it is frequently used to trap unisolable munchnones with or without substituents on the nitrogen atom by an in situ reaction in which the betaine is generated in the presence of the dipolarophile (equation 67). It has become an important method for constructi ng the pyrrole ring of fused heterocyclic systems, as in the example of equation (68). 

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. 

Dipolar cycloadditions involving azomethine ylides or munchnones provide access to fused pyrroles and highly functionalized pyrroles. Recent pyrrole syntheses that involve 1,3-dipolar cycloadditions include syntheses of pyrrolo[2,l,5-tfe]quinolizines <07JOC2015>, cy c lo pen ta [ 6 ] py rro le s <07JOC1104>, oligopyrroles <07AG(I)9261>, pyrrolo[2,l-... 

The role of acid in influencing the cyclization of 14 with imines towards imidazolines products is at present unclear. One possibility is suggested by the work of Ferraccioli and Croce (16), who have shown that the electronic nature of the imine can have a significant influence upon its reactivity with Munchnone. In particular, while N-alkyl substituted imines react with Munchnones to form (3-lactams, more electron poor imines, such as the N-tosyl substituted substrates, have been found to undergo a 1,3-dipolar cyclization with 14 to form imidazoles. (16) In our case, the role of acid may be in protonation of the imine substrate, thereby creating a more electrophilic C=N which can undergo a dipolar cycloaddition with 14 (path A, Scheme 2). Subsequent heterolysis of the C-0 bond in 18, would yield the observed imidazoline-carboxylate 17. 

Oxazolones are simply cyclic anhydrides of A-acyl-a-amino acids, and are constructed in the way that this implies. If the nitrogen also carries an alkyl group, cyclisation can only lead to an overall neutral product by its adopting a zwitterionic structure, for which no neutral canonical form can be written - a mesoionic structure. Mesoionic oxazolones (named munchnones by Huisgen after their discovery at the University of Munchen, Germany) undergo ready dipolar cycloadditions, with loss of carbon dioxide from initial adduct the examples show the conversion of a miinchnone into a mesoionic thiazolone and into an imidazole. 

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... 

Yamanaka and co-workerseffected the 1,3-dipolar cycloaddition between munchnones and polyfluoro-2-aIkynoic acid esters to afford the corresponding 4-(polyfluoroalkyl)pyrrole-3-carboxylates 144 (Fig. 4.50). The reaction proceeds... 

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. 

Coppola and co-workers studied extensively the dipolar cycloaddition of methyl propiolate with unsymmetrical munchnones. In addition to their own results,... 

Intramolecular 1,3-dipolar cycloadditions represent a powerful synthetic tool. Kato and co-workers were apparently the first to report an intramolecular munchnone-alkyne cycloaddition. Thus munchnones 184, as generated from iV-acylamino acids 183, yield the corresponding benzopyrano[4,3-f ]pyrroles 186 after extrusion of carbon dioxide from adduct 185 (Fig. 4.65). The yields shown are for high-dilution reaction conditions. Under normal conditions of concentration, the yields are stiU about 60%. Interestingly, attempts to divert the intramolecular cycloaddition by the addition of A -phenylmaleimide had no effect on the reaction pathway. 

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