Amidines aminomethylenemalonates

When these reactions were monitored by means of thin-layer chromatography, the initial formation of an amidine (see Schemes 26 and 27, 247 or 248) could be detected. The amidine then either reacted directly with diethyl malonate or was converted into another reactive intermediate, N-arylformimidate (249), which next reacted with diethyl malonate to give A,-(3-chlorophenyl)aminomethylenemalonate (250). 

AM3-Chlorophenyl)aminomethylenemalonate (250) was obtained in pure form in 94% yield when /V,A, -bis(3-chlorophenyl)formamidine (248) (1 mol), diethyl malonate (I mol), and ethyl orthoformate (1.2 mol) were reacted for 20 hr at 126°C, the ethanol evolved being continuously distilled off. More diethyl malonate (1 mol) was then added to the half-converted reaction mixture, and the reaction mixture was stirred at 126°C for 48 hr (65MIP1 66JOC4003). Under these conditions, the formation of N- 3-chlorophenyl)aminomethylenemalonamate (252, R = 3-C1) could be excluded because the 3-chloroaniline formed in the reaction of amidine and malonate was simultaneously converted to amidine by ethyl orthoformate. 

V-(3-Ethoxy-4-decyloxyphenyl)aminomethylenemalonate (309) was prepared in the reaction of the amidine (308), diethyl malonate, and ethyl orthoformate in the presence of ammonium chloride at 125-130°C for 1 hr (68FRP1531495). The crude ester (309) was applied without purification in the cyclization step. 

Starting from the appropriate amidines (254, R = 3-C1, R1 = H, and R = R1 = 3,4-diisobutyl), diethyl malonate and ethyl orthoformate, N-(3-chlorophenyl)- and N-( 3,4-diisobutylphenyl)aminomethylenemalonates (250 and 257, R = diisobutyl) were prepared in 92% yields, respectively (69M1P1). 

The reaction of aminomethylenemalonate (1558) with morpholine and with pyrrolidine gave a mixture of the amidine (1559) and the amine (1560), with an excess of the amidine (1559). In the case of N-methylpiperazine, only the amine (1560) was obtained (70IJC499). 

The treatment of dialkyl N-(3-cyanophenyl)aminomethylenemalonates with hydrogen chloride in a mixture of dioxane and an alcohol at 2-4°C for 7 days afforded imino ethers (1588) in 50-68% yields, which were then converted with ammonia in an alcohol into amidines (1589) in 70-78% yields (76PHA145). 

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