Pyrido pyrazines, reduction

Nitro groups have been reduced to amino groups, whilst amino groups in the 3- and 6-positions of pyrido[2,3-f ]pyrazines and in the 5-position of the [3,4-f ] isomers have been hydrolyzed to the corresponding hydroxy derivatives with alkali. Protected amino groups have been liberated by hydrolysis or reduction in deazapteridine syntheses. 

Racemic or optically active perhydropyrido[l,2-a]pyrazines were obtained by reduction of 9a5-perhydropyrido[l,2-u]pyrazin-4-one with LAH in Et20 at room temperature (99H(51)2065) and by reduction of perhydropyr-ido[l,2-u]pyrazine-l,4-diones with LAH in boiling THF (97USP5703072, 00JAP(K)00/86659). Treatment of (9uS)-2-(fcrf-butoxycarbonyl)perhydro-pyrido[l,2-u]pyrazin-4-one with LAH in Lt20 afforded (9uS)-2-fcrf-butox-ycarbonyl-l,6,7,8,9,9a-hexahydro-2//-pyrido[l,2-a]pyrazine (99H(51)2065). 

Selective reduction of the 7-oxo group in pyrido[23-synthetic approach to 5,10-dideazatetrahydrofolic acid <00H(53)1207>. Cycloaddition of pyrimido[4,5-c][l,2,5]oxadiazine 96 with 2,3-dihydrofuran affords a new synthesis of dimethyllumazine derivative 97 which undergoes a ring-opening reaction to give pyrazine derivative 98 <00JHC419>. 

Derivatives of pyrido[2,3-f>]pyrazine were prepared from pyridyl-substituted AAs. Reductive cyclization afforded 115 (79CZ387), whereas cyclization with potassium carbonate gave the dione 116 (87TL6363). 

Pyrido[2,3-6]pyrazines are reduced349,350 in aqueous-ethanolic medium initially to the 1,4-dihydro derivative. Just as in the reduction of quinox-alines, the dihydropyridopyrazines may isomerize to 3,4-dihydro derivatives, but, surprisingly, some also isomerize to 5,8-dihydropyridopyrazines, which add ethanol to give a tetrahydro derivative. In acetonitrile in the presence of acetic anhydride, 3-phenylpyrido[2,3-h]pyrazine (215) is reduced to the 1,4-diacetyl-1, 4-dihydro derivative 216 [Eq. (122)], whereas the 2,3-diphenyl-pyrido[2,3-fc]pyrazine (217) under these conditions gives 5-acetyl-5,8-di-hydropyridopyrazine (218) [Eq. (123)]. 

Reduction of cis-6H,9aH-, 4-d ioxoperhyd ropyridoLl, 2-aJpyrazine-6-carboxylate with LAH yielded quantitatively 6-hydroxymethylperhydro-pyrido[l,2-a]pyrazine (07USA2007/037816, 07USA2007/037817). 

Hydrogenation of 2-bromopyrido[l,2-n]pyrazin-5-ium bromide and its 2-oxide over Pt02 gave pyrido[l,2-a]pyrazin-5-ium bromide and its 2-oxide [67JCS(C)2391], Reduction of 7-oxo-2-(2-pyrimidinyl)perhydropyrido[l,2-a]pyrazine with 10% NaBH4 on alumina in MeOH afforded 7-hydroxy derivative (96MIP4). 

Reduction of 2-benzyl-2,3,4,6,7,8-hexahydro-l//-pyrido[l,2-a]pyrazin-l-one (73CPB1248) and l-oxo-l,2,3,4-tetrahydropyrazino[l,2-b]isoquinolinium bromide (73CPB2039) with NaBH4 yielded perhydropyrido[l,2-fl] pyrazin-1-one and l,3,4,6-tetrahydro-2//-pyrazino[l,2-6]isoquinolin-l- one, respectively. 

Pyrido[2,3-Z7]pyrazines [359] form on reduction in aprotic medium primarily a 1,4-dihydro derivative, which may tautomerize into the 1,2- or 5,8-dihydro derivative in the presence of acetic anhydride, a 5-acetyl-5,8-dihydro derivative is isolated. 

Pyrido[2,3-Zj]pyrazine (451) is reduced rapidly and regiospecifically by NBH in trifluoroacetic acid to the 1,2,3,4-tetrahydropyrazine 452. ° No reduction of the pyridine ring was observed. Reduction with LAH on this and pyrido[3,4-Zj]pyrazines leads to tetrahydropyrazines. ... 

The reduction by sodium borohydride in the presence of trifluoroacetic acid90 9 has also been applied to pyrido[2,3-6]pyrazine (9).92... 

Applied to pyrido[2,3-6]pyrazine, the method of reductive alkylation using alkali borohydride and a carboxylic acid90 yields the 1,4-dialkyl products.93 Thus, treatment of pyrido[2,3-6]pyrazine (9) with potassium borohydride in the presence of formic, acetic or propionic acid... 

Lithium aluminum hydride reduction has also been applied to pyrido[2,3-fr]pyrazines. 

The electrochemical reduction of pyrido[2,3-h]pyrazines bearing methyl or phenyl substituents in the 2/3-positions has been studied in hydroorganic or aprotic media.35 The 1,4-dihydro compounds thus formed then in most cases isomerize to give the 1,2-, 3,4-, or 5,8-dihydro compounds. 

Polarographic reduction of the parent gave a value for the half-wave potential (E1/2 = -0.85 v) which is intermediate between the values for quinoxaline ( 1/2 =-1.09 v) and pteridine ( 1/2 =-0.52 v). The electrochemical reduction of substituted pyrido[2,3-fc]pyrazines has been the subject of a recent study. Along with other fused pyrazine systems, the... 

Recently electrochemical reduction of pyrido[2,3-h]pyrazines has been shown to give l,2-(or possibly 3,4-)dihydro derivatives. These partially reduced compounds are isolated in good yield under controlled conditions. It is suggested that 1,4-dihydro compounds are initially formed, and these rapidly isomerize before they can be isolated. 

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