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16.14.1.4.3.1 Method 1: From β,β′-Difunctional Secondary Amines (or Amides) and Ammonia

DOI: 10.1055/sos-SD-016-00919

Sato, N.Science of Synthesis, (200416773.

Treatment of (2-oxoalkylamino)acetate derivatives 84 with ammonia in methanol at room temperature affords 3,6-disubstituted pyrazinols 85 (Scheme 29).[‌180‌,‌181‌] Unlike amines 84, which are obtained by multistage synthetic routes, amide 86 is directly prepared by condensation of 2-aminoacetophenonehydrochloride complex with sodium benzoylformate in the presence of dicyclohexylcarbodiimide and benzotriazol-1-ol hydrate. Treatment of amide 86 with ammonium acetate in ethanol then gives 3-alkyl-5-arylpyrazinols 87 in 5370% overall yield from the α-oxo acids (Scheme 29).[‌40‌] Similarly, amide 86 (R1=indol-3-yl) is prepared from indol-3-ylglyoxylic chloride instead of the acylformate salt, and then undergoes cyclization to pyrazinol 87 by treatment with liquid ammonia in methanol under pressure.[‌182‌] N,N-Bis(phenacyl)-4-toluenesulfonamides 88 are also conveniently synthesized and are converted into 2,6-diarylpyrazines 89 in 6774% yield by treatment with methyl hydrazinecarboxylate (Scheme 29).[‌43‌] 3-Aminopyrazine-2-carbonitrile 91 is produced by cyclization of azadiene 90 with ammonia (Scheme 29).[‌183‌] Another synthesis in this category is the cyclization of iminodiacetonitrile (92) with hydroxylamine yielding 6-(hydroxyamino)pyrazin-2-amine 1-oxide (93),[‌184‌] which is readily converted into pyrazine-2,6-diamine 1-oxide (94) by catalytic hydrogenation (the N-oxide oxygen surprisingly survives such reductive conditions) (Scheme 29).

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