Solid-supported syntheses of 3-thio-1,2,4-triazoles

Michael W. Wilson, Andrés S. Hernández, John C. Hodges
Exploratory Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105, U.S.A.

Alain P. Calvet
Biomolecular Structure and Drug Design, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105, U.S.A.

Abstract
Two solid-supported synthesis strategies for the preparation of 3-thio-1,2,4-triazoles are described. In the first, Rink amide resin is combined with Fmoc-protected w-amino acids, acid hydrazides, and alkyl halides to provide diverse sets of starting materials from which numerous triazoles may be prepared. The second employs t-alkylcarbamate resin (Boc resin) which permits the use of additional pools of starting materials, including isothiocyanates and a- and w-amino esters, resulting in triazoles with patterns of functional groups that are not possible from the initial route. The combination of multiple resins and resin attachment sites allows the preparation of a diverse library based upon the 3-thio-1,2,4-triazole scaffold and avoids the pitfall of having a single linker functionality present at the same position in all library members. General synthetic procedures and representative products from each route are presented. A similarity analysis of representative sublibraries from each synthesis strategy concludes that variation of the solid-phase linker chemistry and attachment site can enhance molecular diversity of the combined triazole library.

Keywords
combinatorial library, molecular similarity, parallel synthesis, solid-supported synthesis, Tanimoto coefficient, 1,2,4-triazole