No abstract

A reinvestigation of the structural assignments for the isomeric IV-1and N-2-methyl derivatives of 5-amino-3,4-dicyanopyrazole (1), obtained by direct methylation, according to the published procedure, has been accomplishéd. The higher melting isomer (2, mp 243-245°) was annulated to give 4-amino-3-cyano-l-methylpyrazolo[3,4-d]pyrimidine (4) and alkaline peroxide converted 4 into 4-amino-l-methylpyrazolo [3,4-d]pyrimidine-3-carboxamide (7a). Hydrolysis of the cyano group of 4 under more vigorous conditions gave 4-amino-l-methyipyrazolo [3,4-d]pyrimidine-3-carboxylic acid (7b), which was subsequently decarboxylated in hot sulfolane to afford 4-amino-1 -methylpyrazolo[3,4-d]pyrimidine (7c) of established structure. This established the structure of the N-methylpyrazole (mp 243-245°) as 5-amino-3,4-dicyano-l-methylpyrazole (2) and reversed the structural assignment previously reported for 2. A similar reaction sequence converted the lower melting isomer (3, mp 128-130°) into 4-amino-2-methylpyrazolo[3,4-d]pyrimidine (8d) and established the structure of 3 as 5-amino-3,4-dicyano-2-methylpyrazole. 13C NMR spectroscopy has furnished additional corroboration for these structural reassignments.

The condensation of 4‐acetamido‐3‐cyanopyrazolo[3,4‐d]pyrimidine (5) with crystalline 2,3,5‐tri‐O‐acetyl‐β‐D‐ribofuranosyl chloride (6) has furnished a good yield of nucleoside material (7) which on treatment with sodium methoxide in methanol provided a high yield of nucleoside which was subsequently established as methyl 4‐amino‐1‐(β‐D‐ribofuranosyl)pyrazolo[3,4‐d]‐pyrimidine‐3‐formimidate monohydrate (11). The formimidate function of 11 was found to be highly reactive and 11 was readily converted into the corresponding carhoxamidine (8), carboxamidoxime (14) and carboxamidrazone (15) when treated with the appropriate nucleophiles. Treatment of the imidate (11) with sodium hydrogen sulfide gave a high yield of the thiocarboxamide (12) which was then readily converted into 4‐amino‐3‐cyano‐1‐(β‐D‐ribofuranosyl)pyrazolo[3,4‐d]pyrimidine (16). Aqueous base transformed 11 into 4‐amino‐1‐(β‐D‐ribofuranosyl)‐pyrazolo[3,4‐d]pyrimidine‐3‐carboxamide (10) while more vigorous basic hydrolysis provided the corresponding carboxylic acid (9) in nearly quantitative yield. Decarboxylation of 9 proceeded smoothly in hot sulfolane to provide the known 4‐amino‐1‐(β‐D‐ribofuranosyl)pyrazolo[3,4‐d]pyrimidine (13) in 68% yield which unequivocally established the site of ribosylation and anomeric configuration for all nucleosides reported in this investigation.

A new class of tricyclic nucleosides in which the aglycon has a linear [6:5:6] geometry has been synthesized using certain pyrrolo[2,3-d]pyrimidine nucleosides as the starting materials. An adenosine-adenosine analogue (12) has been prepared from 6-aminotoyocamycin using two different synthetic routes. An adenosine-guanosine analogue (4) and several adenosine-6-mercaptopurine ribonucleoside-type tricyclic nucleoside derivatives have also been synthesized. Structural assignments have been based on 1H NMR spectral studies, as well as an unequivocal chemical proof of structure. An interesting chemical shift for the 2' hydrogen of certain tricyclic nucleosides was observed and is discussed. The in vitro cytotoxicity of these nucleosides against leukemia L-1210 has been determined. The in vivo evaluation of these tricyclic nucleosides against mouse leukemia will also be discussed.

The chemical reactivity of citraconimide (3‐methylmaleimide, 2) has been investigated with special emphasis being placed on the use of mild and selective reaction conditions. Particular attention has been focused on the theiotropic reactivity of citraconimide. The results indicate that the reaction of various mercaptans with citraconimide is highly regioselective resulting predominately in the geminally substituted products with the percentage of vicinally substituted products increasing as a function of the steric bulk of the alkyl mercaptan. Additional studies on the double bond of citraconimide have furnished 4‐halogeno‐ and the 3,4‐dihydro derivatives of citraconimide. Several N‐substituted citraconimide derivatives have also been prepared.