Novel Solid-phase and Solution-phase Synthetic Methods for Trisubstituted Thieno[3,2-d]pyrimidine Derivatives

• Published in: Bulletin of the Korean Chemical Society 2016, 37(9), , pp.1406-1414
• Main Authors: Jeon, Moon-Kook, Kim, Jung-Gyu, Lee, Duck-Hyung
• Format: Article
• Language: English
• Subjects: Heterocycle; Privileged structure; Screening library; Solid-phase organic synthesis; Thienopyrimidine; 화학
• ISSN: 1229-5949; 0253-2964; 1229-5949
• DOI: 10.1002/bkcs.10878

The coupling of 7‐aryl‐3,4‐dihydro‐4‐oxothieno[3,2‐d]pyrimidine‐2‐carboxylic acid with a primary alkylamine‐loaded acid‐sensitive methoxy benzaldehyde (AMEBA) resin, a benzotriazol‐1‐yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)‐mediated amination reaction, and cleavage from the solid support yielded N‐alkyl‐4‐(alkylamino)‐7‐arylthieno[3,2‐d]pyrimidine‐2‐carboxamide derivatives. The progress of the reactions on solid phase was monitored through attenuated total reflectance‐FTIR spectroscopy and was compared with representative solution‐phase surrogates. Additionally, N‐acylation (acid chloride, InF3 , CH3CN, room temperature) and cyclization (DBN, 1,4‐dioxane, 80°C) of a 3‐amino‐4‐(4‐t‐butoxycarbonylphenyl)thiophene‐2‐carboxamide intermediate under previously unreported conditions provided 2‐substituted thieno[3,2‐d]pyrimidin‐4(3H)‐one derivatives, which were subsequently converted to 2‐substituted 4‐alkylamino‐7‐[4‐(alkylaminocarbonyl)phenyl]thieno[3,2‐d]pyrimidine derivatives through a reaction sequence consisting of a BOP‐mediated amination reaction, t‐butyl deprotection, and amide formation.