Nitriles reactions with arynes

Although acetonitrile is a common solvent in aryne chemistry, it is rarely involved as a reactant in the coupling reactions with arynes. Recently, a three-component coupling of arynes, N-heteroaromatic compounds, and nitriles was reported by Jeganmohan and Cheng (Scheme 12.18) [42] where the reachon was initiated by a nucleophilic attack of the N-heteroaromatic on the aryne, leading to a zwitterionic species 50. The zwitterion 50 then abstracted a proton from acetonitrile (or other nitrile) to afford intermediate 51, alongside anion 52. Anion 52... 

In connection with the substituent effects, the kinetic stability of benzyne is suggested to be increased by electron withdrawal (-/) and decreased by electron release (+/).73 However, the inference cannot be extrapolated to selectivity of substituted arynes in general. For example, in additions involving competition between phenyllithium and lithium piperidide, the methyl substituents (+/) on benzyne increase its selectivity, whereas methoxy groups (-/) decrease it (Scheme 6). On the other hand, in reactions of car-banions derived from acetonitrile in alkylamine solvents both +/ and -/ benzyne substituents lower selectivity and cause predominant amination. Thus, the method was found unsuitable for preparation of many substituted benzyl nitriles.74 In symmetrically disubstituted arynes there is partial cancellation of polarization, and in fact acceptable yields of acetonitrile adducts could be obtained from 3,6-dimethoxy-benzyne.75 The selectivity of substituted arynes varies with the set of nucleophiles in the competition and no comprehensive theory or simple generalization is available on this point. 

In addition to the examples discussed above, arynes have also been found to insert into C-C single bonds. The reaction of either 2- or 3-bromophenol with arylacetonitriles in the presence of a strong base, such as lithium 2,2,6,6-tetramethylpiperidide (LiTMP), led to the same major products, 2-arylmethyl-6-hydroxybenzenecarbonitriles 23 (Scheme 12.9) [26]. In both cases, lithium 2,3-didehydrophenoxide (21) was generated. The anion of nitrile 20 then adds solely at the 3-position of 21 to afford adduct 22, which subsequently leads to the final product 23 after intramolecular rearrangement. When 2-bromo-l-naphthol was used instead of 2-bromophenol, a similar reachvity was observed [27]. 

More recently, the coupling of a nitrile with two molar equivalents of an aryne under mild conditions, has been reported by Yoshida et al. (Scheme 12.12) [29]. The fluoride anion used in this case acted not only as an aryne generator but also as a base to deprotonate the nitrile. This reaction proceeds in a manner similar to... 

Both 1,2,4 or better 1,2,3-benzotriazines, 49d and 49c, respectively, loose Nj and nitriles on thermolysis to give arynes. The triazinones 49f undergo a similar minor fragmentation with expulsion of nitrogen and isocyanates. The major reaction leads to azetinones 54 which were shown not to be precursors of arynes. 

One of the best routes to arynes is the oxidation of aminotriazoles (49j) with lead tetraacetate. Variations involve generating the intermediate nitrene 57 or nitrenoid with other oxidizing agents or from other precursors (49k-49n). By analogy the nitrene 58 or nitrenoid obtained by oxidation of 1-aminoindazole (59) might be expected to fragment to arynes by loss of Nj and a nitrile. In fact this reaction constitutes an excellent synthesis of the previously discussed aryne precursors, the 1,2,3-benztriazines (49e). A vibrationally excited form of 49c is presumably an intermediate in the pyrolysis of sulfoximides of 2-aminoindazoles (60) to arynes. 

Insertion into Carbon-Carbon o-Bonds. First examples of this concept were reported with anionic nucleophiles in the context of the addition of a-lithioalkyl and a-lithioarylacetonitriles to arynes. In 1984, Meyers and Pansegrau proposed a cyclization rearrangement mechanism to account for the formation of products 77 in the reaction of a-lithioacetonitriles to 3-oxazolylbenzyne. Initial attack of the nucleophile takes place at C-2 probably due to chelation of the lithium atom from the lithiated nitrile to the oxazoline moiety (Scheme 12.40) [67]. 

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