Phosphorus oxide (P4O10) → 3-(p-Tolyl)isonicotinonitrile

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Reaction Steps

Synthetic Scheme XXVI shows the 6-step preparation of the alkylating reagent 3-(4bromomethylphenyl)-4-cyanopyridine (66) from 4-picoline (67) (Aldrich). In step 1, 4-picoline was brominated with bromine in fuming sulfuric acid at high temperatures to give 3-bromo-4-picoline (68). In step 2, the picoline 68 was oxidized to the corresponding carboxylic acid 69 with KMnO4. In step 3, the acid 69 was first converted to its acid chloride with oxalyl chloride and subsequently treated with condensed ammonia to give the amide 70. In step 4, the amide 70 was converted to 3-bromo-4-cyanopyridine (71) by treatment with P2O5 at high temperatures. In step 5, the nitrile 71 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 4-cyano-3-(4-methylphenyl)pyridine (72). In step 6, 72 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 66.

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