Pyrazinones reduction

Bicychc pyrazinones foimd in several natural products were synthesized via Michael addition of heterocyclic amines to nitro olefin followed by reduction/cyclization of the nitro group of the adduct [20] (Scheme 5). Further elaboration of the C-6 methoxycarbonyl group in pyrazinone to the n-propyl guanidine group could result in the synthesis of indoloperamine. 

The dechlorination of the C-3 and C-5 position of the pyrazinone system was described to be fast under microwave irradiation [29]. Contrary to the reported de-chlorination [26] via palladium-catalyzed reaction with sodium formate 100 °C for 2-4 h and at the C-5 position in 2-3 days, a dramatic rate enhancement was observed under microwave irradiation (Scheme 12). The mono-reduction at C-3 was performed at 190 °C in DMF in merely 5 min, and the reduction of C-5, starting from the mono-reduction product, was performed in n-butanol in 55 min to afford the fois-reduction product in good overall yield. 

V-(l-Acetyl-l-methylethyl)-2-chloro-(V-hydroxyacetamide (69) gave 1-hydroxy-5,6,6-(rimc(hyl-3,6-dihydro-2( I //(-pyrazinone (70) (NH4OH—I (OH—dioxane, 20°C, 3 days 8%) likewise one homologue.424 Aldehydes gave better results under reductive conditions.1768... 

Reductive debenzylation. 2-Benzyloxy-3,6-diisobutyl-5-methoxypyrazine 4-oxide (21) gave 3,6-diisobutyl-5-methoxy-2(l//)-pyrazinone 4-oxide (22) (H2, Pd/C, EtOH, h 90% structure confirmed by X-ray analysis) 310 2,5-dibenzy-loxy-3,6-diphenylpyrazine likewise gave 5-hydroxy-3,6-diphenyl-2(l//)-pyrazinone (23) (43%).82... 

The polarographic reduction of 6-methyl-3-phenyl-2(l//)-pyrazinone (105) has been studied.983... 

This minor route to pyrazine N-oxides involves either reductive or hydrolytic debenzylation of l-benzyloxy-2(l//)-pyrazinones, often available by primary synthesis. 

Ethylthio-l-methyl-3-(2,4,5-trimethoxy-3-methylbenzyl)-3,6-dihydro-2(l//)-pyrazinone (60) gave l-methyl-3-(2,4,5-trimethoxy-3-methylbenzyl)-2-piperazinone (61) (A1—Hg, THF—H20, 0°C, 4 h 59% note concomitant nuclear reduction).103... 

In contrast, l-benzyl-6-m-methoxybenzyl-2(l//)-pyrazinone gave only 6-m-mcihoxybcnzyl-2(l//)-pyrazinone on reductive debenzylation (liquid NHj—THF, Na 49%). ... 

Nitrodiphenyiamine is reductively cyclized with sodium borohydride in the presence of a base. A primary amino group and a carbon of ano er ring may be annulated by reaction with ethyl chloroformate to give the pyrazinone. 

Pyrazine- and quinoxalinethiones have been synthesized by treatment of halogeno compounds with sodium or potassium hydrogen sulfide, sodium polysulfide, phosphorus pentasulfide, or thiourea . Pyrazinethiones are directly prepared by treating 2(177)-pyrazinones with Lawesson s reagent (2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulfide) <83H(20)797>. They are also obtained by treatment of (4-methoxybenzylthio)pyrazines with mer-cury(II) acetate and successive reduction <93JCS(P1)15>. 

Nitrogen containing heterocycles can he reduced by NaBH3CN under acidic conditions. Two recent examples involved the stereoselective reduction of pyrazines to piperazines (eq 43) and pyrazinones to piperazinones (eq 44). The effectiveness of the ongoing use of sodium cyanoborohydride in reduction of cyclic imine derivatives was demonstrated by these reactions. In both cases only a single diastereomer of product was detected and isolated. 

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