Synthesis of 3-substituted bicyclic imidazo[1,2-d][1,2,4]thiadiazoles and tricyclic benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles.
A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent S(N)Ar substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.
Leung-Toung
Regis
R
Medicinal Chemistry Department, ApoPharma, Inc., 400 Ormont Drive, Toronto, ON M9L 1N9, Canada. rleung@apotex.ca
Tam
Tim F
TF
Zhao
Yanqing
Y
Simpson
Craig D
CD
Li
Wanren
W
Desilets
Denis
D
Karimian
Khashayar
K
D000588:Amines / Q000737:chemistry; D001554:Benzene / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003500:Cyclization; D003545:Cysteine / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000588:Amines; D007093:Imidazoles; D013830:Thiadiazoles; C029899:imidazole; D001554:Benzene; D003545:Cysteine