Heterocyclic compounds reactions with arynes

Prior to 1960 little work had been done on reactions of heterocyclic compounds involving hetarynes, i.e. intermediates with a triple bond in the nucleus containing the hetero atom. Since then interest in hetarynes has grown and investigations in this area are developing rapidly using information available from carbocyclic aryne chemistry. Therefore, a short survey of the chemistry of arynes is presented before summarizing typical problems encountered in hetaryne chemistry. 

The reactions of benzyne with various kinds of heterocyclic compounds has been reviewed " . Aromatic five-membered heterocycles 241 (X = O, N, S, Si, Ge, etc.) react with benzynes to give [4 + 2] cycloadducts (and sometimes other products) 242, from which the X-bridge can be eliminated or rearranged in various ways, often with aromatization of the bicyclic ring. The methodology permits a new aromatic ring to be fused to an already existing one (in the aryne). Some recent examples are described here. 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

Despite the fact that the history of hetarynes is older than that of the benzynes (cf. 2), physical data on these compounds are scarce. Numerous trapping experiments furnished evidence for the formation of brradicaloid intermediates in the field of five-membered heterocycles (didehydrofurans, -thiophenes, and -pyrroles)." Direct spectroscopic data on these species, however, do not exist, which may be attributable to the increased ring strain in the five-membered o-arynes, associated with a strong tendency to undergo ring-opening reactions. 

The very reactive arynes have also been used as dienophiles in Diels-Alder cycloadditions with vinyl heterocycles and are included here, after the acetylenic esters, because of the similarity of their reactive functions. This reaction is of considerable importance because of its application in the synthesis of polycyclic compounds. 

Although nucleophilic substitution of 3-halo-1,2,5-thiadiazoles is known, the symmetry of the heterocyclic nucleus prevents the detection of the aryne 567 by cine-substitution in the absence of isotopic labeling. An attempt to trap this species with anthracene (147) from the aprotic diazotization " of the amino acid 568 gave, instead of the heterotriptycene 569, a mixture of 9-nitro- (341) and 9-thiocyanoanthracene (570). The former compound is also observed in a similar reaction in the thiophene series (Section III.3.A.d) and could arise by direct nitration of anthracene with nitrous acid " present in the alkyl nitrite. 

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