Hydrazinopyrazines

Relatively few new papers have appeared on synthetic procedures for the title ring system. Some of these follow established methodologies. Thus, three reports appeared where 2-hydrazinopyrazines - or their derivatives - were subjected to ring closure to give [l,2,4]triazolo[4,3- ]pyrazines. These products - with yields and references - are shown in Table 14. 

Table 14 [1,2,4]Triazolo[4,3-a]pyrazines prepared from 2-hydrazinopyrazines or their derivatives Entry Product Yield (%) Reference...

A number of 3-amino-s-triazolo[4,3-a]pyrazines (122) have been prepared by the action of cyanogen chloride on hydrazinopyrazines. The latter compounds also undergo ring closure to s-triazolo[4,3 a]-pyrazines on treatment with phosgene, carbon disulfide, and triethyl orthoformate.331-336... 

Dichloropyrazine 4-oxide (93, R = Cl) gave 2-chloro-6-hydrazinopyrazine 4-oxide (93, R = NHNH2) (H2NNH2.H20, EtOH, 20°C, 24 h 69%).891 Also other examples.78,80,276... 

The major preparative routes to hydrazinopyrazines have been covered already by primary synthesis (see Chapters 1 and 2) and by hydrazinolysis of halogenopy-razines (see Sections 4.2.1 and 4.4). Minor routes (like the hydrazinolysis of alkylthio-, alkylsulflnyl-, alkylsulfonyl-, or mercaptopyrazines) appear to be unrepresented in the recent literature. 

The reactions of hydrazinopyrazines often lead to intermediates for subsequent cyclization to heterobicyclic products. The reactions and some resulting cycliza-tions are illustrated in the following classified examples ... 

Hydrazinopyrazine 4-oxide (204) gave l,2,4-triazolo[4,3-a]pyrazine 7-oxide (206) by loss of AcOH from the unisolated intermediate (205) [neat... 

Chloro-6-hydrazinopyrazine (207) gave 2-(2-benzamidoethylidene)hydrazino-6-chloropyrazine (208) [C1CH=C(NHBz)C02H, Et3N, EtOH, reflux, 11 h ... 

Chloro-3-hydrazinopyrazine (217) gave 2-chloro-3-[4-(ethoxycarbonylmethyl)-(thiosemicarbazido)]pyrazine (218) (Et02CCH2NCS, CHC13, reflux, 1 h 63%), which underwent cyclization with loss of HC1 to afford 3-ethoxycar-... 

The major and recently used preparative routes to azidopyrazines have been covered already by azidolysis of halogenopyrazines (Sections 4.2.6 and 4.4) and by treatment of hydrazinopyrazines with nitrous acid (Section 7.4). In addition, direct C-azidation of pyrazines has been used for example, the lithio intermediate (225), generated in THF by treatment of 2-methoxypyrazine (224) with lithium 2,2,6,6-tetramethylpiperidine, gave 2-azido-3-methoxypyrazine (226) (87%) on subsequent treatment with p-toluenesulfonyl azide.232... 

Acetylpyrazine gave its semicarbazone, 2-(l-semicarbazonoethyl)pyrazine (298) (H2NHNC0NH2.HC1, AcONa, EtOH—H20, 95°C, 15 min 90%)mo 2-[2-(Pyrazin-2-yl)acetyl]pyrazine (299) and 2-hydrazinopyrazine (300) gave 2-[2-(pyrazin-2-yl)-1 -(pyrazin-2-ylhydrazono)ethyl]pyrazine (301) (EtOH, reflux, 3 h %) 730 analogues likewise.730,731 Also other examples.283,866... 

Chloro-3,6-difluoro-5-hydrazinopyrazine 2-Chloro-3,6-difluoro-5-methoxypyrazine 2-Chloro-3,6-diisobutyl-5-methoxypyrazine 2-Chloro-3,6-diisobutylpyrazine 2-Chloro-3,6-diisobutylpyrazine 1, 4-dioxide... 

The most efficient method of preparation of (31) and its alkyl derivatives was reported (62JOC3243) to be via ring closure of 2-hydrazinopyrazines with ortho esters (Scheme 58). 

As in the other fused tetrazoles, the pyrazines have been prepared from diazotization of a 2-hydrazinopyrazine (71JOC446) or via azide substitution on a 2-halopyrazine (66JHC435,80JHC11). Likewise, the quinoxalines can be synthesized by the diazotization of 2-hydrazinoquinoxalines or the azide-halide displacement (78ZC92). 

Trifluoropyrazine has been prepared from tetrafluoropyrazine through 2,3,5-trifluoro-6-hydrazinopyrazine by removal of the hydrazino substituent with aqueous copper sulfate (885). Fluorination of tetrafluoropyrazine in nitrogen in the presence of cobalt(lll) fluoride and calcium fluoride at 80° gave perfluoro-1,4-diazocyclohexa-13-diene (IS) (886). 

Tetrafluoropyrazine has been converted to 2,3,5-trifluoro-6-hydrazinopyrazine and thence to 2-chloro- and 2-bromo-3,5,6-trifluoropyTazine by reaction with ferric chloride in concentrated hydrochloric acid and cupric bromide in aqueous... 

Tetrafluoropyrazine with hydrazine gives 2,3,5-trifluoro-6-hydrazinopyrazine which on warming with aqueous copper sulfate gave trifluoropyrazine and 2,3-difluoro-5-hydrazino-6-methoxypyrazine similarly treated gave 2,3-difluoro-5-methoxypyrazine (885), but 2,3,5-trichloropyrazine could not be prepared from... 

Dichloropyrazine with hydrazine in ethanol gave 2-chloro-3-hydrazino-pyrazine (828, 919) and 2,6-dichloropyrazine with hydrazine hydrate in ethanol gave 2-chloro-6-hydrazinopyrazine (919, 973). 2,3,5-Trichloropyrazine with hydrazine gave 2,5-dichloro-3-hydrazinopyrazine (919). 

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