Alkyl substituted 3-nitropyridines

An unusual vicarious nucleophilic substitution of alkyl substituted 3-nitropyridines was observed (Scheme 28) (93KGS136). 

The nitro group in the ortho- or para-positions is one of the strongest electron-withdrawing substituent, activating an aromatic ring for a nucleophilic attack [5]. No wonder that a great deal of both oxidative and eliminative Sn reactions have been observed in the series of nitroaromatic compounds [11, 15-18, 25, 27, 28, 30-32, 36, 37, 97-100]. The VNS protocol has been particularly effective for the Sn reactions of a large number of nitro-substituted aromatic and heteroaromatic compounds [11-18, 25, 27, 28, 30-32, 36, 37, 45, 98-100], as illustrated by nucleophilic alkylation of 3-nitropyridine with vicarious methyl chloroacetate (Scheme 22) [100]. 

A similar VNS cyanomethylation of 3-nitropyridine and subsequent hydrogena-ti(Mi of the so-formed ort/io-nitropyridyl-substituted acetonitriles provided 4- and 6-azaindoles. The VNS of hydrogen in 2-methoxy-5-nitropyridine with the carb-anion of aiyloxyacetonitrile leads to pyridylacetonitrile. Alkylation of the latter with hromoacetOTiitrile followed by a two-step reduction efficiently results in the formation of 5-azamelatonin (Scheme 69) [187]. Condensation of pyridyl-substituted acetonitriles with aromatic aldehydes followed by catalytic reduction gave 3-benzyl-4-azaindoles [187],... 

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