Cycloaddition reactions of munchnones

TABLE 10.4. 1,3-DIPOLAR CYCLOADDITION REACTIONS OF MUNCHNONES AND METHYLENE TRIAZOLES ... 

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. 

The higher reactivity of ring-strained olefins has been exploited by several workers in 1,3-dipolar cycloaddition reactions of munchnones. Thus Kato and co-workers reported that munchnone 42 reacts with 1,2,3-triphenyl-IH-phosphirene 269 in boiling acetonitrile to give l-methyl-2,3,4,5-tetraphenylpyrrole 270 (45%... 

Apparently independently, Markl and Regitz " discovered that 1,3-dipolar cycloaddition reactions of munchnones and phosphaalkenes or phosphaalk-ynes provide a direct synthesis of 1,3-azaphospholes 353 (Table 4.21). The intermediate cycloadducts cannot be isolated. The various phosphaalkynes were generated from phosphaalkenes or, in the case of methylidynephosphane 352... 

Because all of the work with munchnone imines that has been reported since the review by Gingrich and Baum was described by one research group and involves only cycloaddition chemistry, it is collected in this section. In a series of papers, Laude and co-workers " " examined 1,3-dipolar cycloaddition reactions of munchnone imines derived from Reissert compounds. For example, treatment of the readily assembled Reissert compounds 358 and 360 with HBF4 forms the munchnone imines 359 and 361, respectively (Fig. 4.119). " " Both 359 and 361 undergo smooth intramolecular 1,3-dipolar cycloaddition with the tethered alkyne unit to afford pyrroles 362 and 363, respectively, after extrusion of HNCO (Fig. 4.120). " " ... 

Padwa A, Burgess EM, Gingrich HL, Roush DM (1982) On the problem of regioselectivity in the 1,3-dipolar cycloaddition reaction of munchnones and sydnones with acetylenic dipo-larophiles. J Org Chem 47 786-791... 

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>. 

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>. 

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... 

Acetylation of the amide (128) produced a fused tricyclic pyrrole in 17% yield (Scheme 39).64 A munchnone intermediate was postulated and could be trapped via intermolecular cycloaddition with diethyl acetylenedicarboxylate. Presumably the direct cyclization product lost carbon dioxide, a known reaction of munchnone cycloadducts.65 An homologous munchnone with an o-(propenyl)phenyl group, rather than o-(butenyl)phenyl group, failed to cyclize, although it could again be trapped with diethyl acetylenedicarboxylate. 

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. 

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. 

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

Maryanoff and Turchi pursued a detailed theoretical study of the reaction between 1,2-dicyanocyclobutene 279 and munchnone 280, prepared by cyclodehydration of 278 and acetic anhydride (Fig. 4.100). The results from these AMI molecular orbital calculations led to the conclusions that the transition state leading to the exo cycloadduct 281 is favored electrostatically and that azomethine ylide 282 is a discrete intermediate in the formation of dihydroazepine 283. More recently, Turchi reported cycloaddition reactions between munchnone 285 and 279 to afford dihydroazepine 286 in high yield. Further cyclization of 286 gave tricycle 287. Likewise, diester 288 reacts with munchnone 42 to give dihydroazepine 289. 

Kato and co-workers also studied the cycloaddition reactions of tropone 294 with several mesoionic heterocycles. Unfortunately, despite heroic efforts, the reaction of 294 with munchnone 42 was complex and could not be unraveled (Fig. 4.102). However, as described later, the reaction of tropone with isomunch-nones was successful. 

No new examples of 1,3-dipolar cycloaddition reactions between munchnones and carbonyl compounds have been reported in the interim since the review by Gingrich and Baum. The original work by Huisgen and co-workers remains the only study of this interesting reaction. 

TABLE 4.8 1,3-DIPOLAR CYCLOADDITION REACTIONS OF IN-SITU-GENERATED MUNCHNONES AND TERMINAL ALKYNES, 502... 

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