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A New Route to 2,3-Disubstituted Pyrazines; Regioselective Metalation of Chloropyrazine
20 August 2002 (online)
Chloropyrazine is regioselectively metalated by lithium amides in tetrahydrofuran to give 3-chloro-2-lithiopyrazine. The reaction of this lithio derivative with electrophiles can either be performed in situ (with the electrophile, e. g., chlorotrimethylsilane, present in the mixture already during metalation), i. e., by the "equilibrium shift" procedure, or with the solution of the preformed lithio derivative, i. e., by the "accumulation" procedure. With aldehydes and benzophenone, the "accumulation" procedure affords 3-chloro-2-(1-hydroxyalkyl)pyrazines in good yields. The secondary alcohols thus obtained can be oxidized to 2-acyl-3-chloropyrazines with manganese(IV) oxide and these ketones can be converted into 3-acyl-2-aminopyrazines by reaction with ammonia in ethanol; cyclization of 3-chloro-2-(2-methoxybenzoyl) pyrazine using pyridine hydrochloride at 210°C affords 10-oxo-10H- benzopyrano[2,3-b]pyrazine (1,4-diazaxanthone) in high yield. 3-Chloro-2-formylpyrazine is obtained by reaction of the lithio derivative with ethyl formate and 3-chloropyrazine-2-carboxylic acid by reaction with carbon dioxide.