The synthesis of pyrazino[2,3‐d]pyridazine and some of its derivatives

Abstract

Pyrazino[2, 3-dlpyridazine (I) w a s synthesized by two different routes. 5.8-Dihydroxypyrazino[2,3-d]pyridazine (IV) was converted to 5,8-dichloropyrazino[2,3-d]pyridazine (V) and 5,8-dibromopyrazino[2,3-d]pyridazine (Va). When V w a s treated with various benzyl mercaptans and alkoxides the corresponding disubstituted derivatives were obtained. Compound V when allowed to react with a r o m a t i c a m i n e s gave 5,8-bisaminopyrazino[2,3-d]pyridazines, however, with aliphatic a m i n e s only mono substituted products w e r e obtained substituted in the 8 -position.The reaction of pyrazine-2,3-dinitrile with hydrazine gave 5,8-diaminopyrazino[2,3-d]pyridazine (X).In the pyrazino[2,3-d]pyridazine (I) ring system only two compounds have previously been reported in the literature namely 5 , 8 -dihydroxyp,yrazino-[2,3-d]pyridazine (IV) (1,2) and 5,U-bis(P-methoxyphenyl)pyrazino[2,3-d]pyridazine (3). T h i s ring is of interest because of the close structural similarity to the pteridine ring system. The title compound (I) was synthesized by two different methods. These w e r e (a) condensation of 4,5-diaminopyridazine (II) (4) with glyoxal in methanol (5) and (b) by dehalogenation of 5 , 8dichloropyrazino[2,3dpyridazine (V) with palladium on charcoal. 2-Methylpyrazino-[ 2 , 3dlpyridazine (111) w a s similarly prepared by allowing I1 to react with pyruvaldehyde.Compound N w a s prepared by a slight modification of Hammerich's procedure (2) by using hydrazine dihydrochloride and water (6) instead of hydrazine hydrate and acetic acid. Similarly Jones' procedure (1) w a s also modified since in o u r hands e r r a t i c results w e r e obtained. We have allowed dimethylpyrazine-2,3-dicarboxylate to react with hydrazine hydrate in methanol under reflux for a longer period of time and the insoluble hydrazonium s a l t w a s dissolved in water and IV w a s precipitated by acid ( 7 ) .Compound N failed to give the diacetate as w a s the case with 5,8-dihydroxypyridino[2,3-d ]pyridazineobserved by Gheorghiu (8), but it gave the monoacetate (ma). Similarly, a monotosylate (IVb) w a s obtained when IV w a s treated with P-toluenesulfonyl chloride in pyridine. The spectroscopic data suggest that IVa and IVb exist in the keto forms. 5 ,U-Dichloropyrazin0[2,~djpyridazine w a s obtained when IV was allowed to r e a c t with a mixture of phosphorus oxychloride and phosphorus pentachloride ( 9 ) . Similarly the 5 , 8dibromopyrazino[2,3 -d ]pyridazine w a s the product when IV w a s treated with phosphorus oxybromide and bromine (10). When V was treated with sodium alkoxides the corresponding 5,U -dial koxypyrazino[ 2 ,Sd] py ridazines (VIa-c) w e r e obtained in good yields (11). Attempts to p r e p a r e 5,8-dimercaptopyrazino[2,3-d]pyridazine CHO 8 1 I CHO Ill 5 4 I Pd -C /Hp CI V OH OH 0-R IVO, R -CHsCOb. R -Tosyl

Synthesis of Pyrazino [2, 3-<i>d</i>] pyridazines and Their Bioactivities

“…In addition, we reacted four kinds of 2, 3-disubstituted dicyanopyrazines (1) with hydrazine, thus obtaining total thirty-two compounds. Among them 2-a, 10) 2-d, 6 4-b, 8) 4-d, 6 5-b, 8) 10-d12) 11-b8) and 12-b8) have been so far reported by other researchers. The rest were new compounds, some of which showed protective activity against downy mildew of cucumber.…”