2-Alkyl-6-aminopyrazines

Monooximes of a-diketones have found applicability in the synthesis of 2-aminopyrazine 1-oxides by condensation with a-aminonitriles, and this reaction was used by White and coworkers in an approach to the synthesis of Cypridina etioluciferamine (Scheme 66 R = 3-indoloyl) (73T3761). In this instance, the use of TiCU as a catalyst was essential, since the carbonyl group in 3-acylindoles is normally deactivated and the required amine/carbonyl condensation is impractically slow. Under normal circumstances the carbonyl group in simple alkyl-substituted monoximes of a-diketones is the more reactive site and the reaction is rapid, requiring no catalysis (69LA(726)loo). 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

The direct alkylation of aminopyrazines is usually unsatisfactory as a synthetic method because it mainly takes place at the most basic ring nitrogen. However, 3,6-diamino-2,5-dicyanopyrazines are successfully alkylated by treatment with alkyl iodide or bromide in protic solvent in the presence of alkali such as NaOH in dimethylacetamide (DMA) to form bis(dialkylamino)pyrazines <1998DP(39)49>. Reaction of 2,6-diamino-3,5-diarylpyrazine with methylglyoxal in aqueous HCl-ethanol led to -alkylation but no formation of the expected bicyclic imidazolo[l,2- z]pyrazine <2001S768>. 

Pyrolysis and thermal stabilities of aminopyrazines have been studied mass spectrometrically. 2-Aminopyrazine was thermally stable at 280°. Its alkyl derivatives were less stable monoalkylation on the amino group destabilized the molecule more strikingly than dialkylation (668a). Attempts to resolve 3-amino-2,5-di-s-butylpyrazine were unsuccessful (89). 

Many arylsuifonamidopyrazines have been prepared, most usually by the reaction of the (p-acetamido)aryisulfonyl chloride, and aminopyrazine in pyridine (the 7V-acetyl group may be removed by acid or alkaline hydrolysis). In this way the following have been synthesized 2-(A( -acetylsulfanilamido)pyrazine (29) (400, 1175, 1204, 1205) [hydrolyzed by acid (400,1204)and alkali (1205) to 2-sulfanil-amidopyrazine], and various C-alkyl (and C-phenyi) derivatives (420, 535) 2-(p-... 

Aminopyrazine was alkylated with ethyl methyl ketone and sodium in liquid ammonia (in the absence of a catalyst) to 2-amino-6-butylpyrazine, and a similar reaction occurred with isobutyraldehyde (614) and 2-cyano-3-(A, A -dimethylamino-methyleneamino)-5-methylpyrazine was deprotonated with lithium diisopropyl-amide (from butyllithium and diisopropylamine) and alkylated with ethyl iodide followed by removal of the protecting group by acid hydrolysis to give 3-amino-2-cyano-5-propylpyrazine (1031). 

All tables include relevant C-alkyl derivatives of the type of pyrazine listed. For example, Table A.2 (aminopyrazines) contains aminopyrazines and A -substituted analogues, as well as C-alkyl derivatives and Table A.21 (carboxy halogenopyrazines) lists 2,6-dichloro-3 -cyano-5 -methylpyrazine. 

Pyrazinecarboxylic acids undergo decarboxylation at high temperatures above 200°C. By this procedure, alkyl- or arylpyrazines <78JOC3367>, pyrazinones <78JHC665>, and aminopyrazines <80JHC143> are effectively prepared from the corresponding carboxylic acids. 

Isoalloxazines. This heterocyclic system ie.g., 4) is of interest because it is the basic structure of riboflavin and lumiflavins. A new synthetic approach has been developed by reaction of isocyanates with l-alkyl-2-aminopyrazines (1). An example is formulated in equation (I). ... 

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