V. Snieckus, Michael E. Dalziel
Oct 1, 2016
Citations
0
Influential Citations
36
Citations
Journal
Synfacts
Abstract
Significance: Reported is the sp2–sp2 coupling of bromoazoles 1–3 with (het)arenes via a presumed 2-azolyl radical. In preliminary studies, protodebrominated 3 was identified as the major side product. The solubility of the amine in acetonitrile was critical for limiting this side reaction: the use of i-BuCy2N (0.01 mmol/mL) greatly enhanced the 6a/desbromo-3a ratio compared with DIPEA (1.30 mmol/mL). The scope of azoles explored included thiazoles, benzoxazoles, and benzimidazoles. Exploration of the (het)aryl coupling partner showed efficient reaction occurred with a variety of sterically congested aryl counterparts, as well with as electron-rich heteroaromatics. Unfortunately, bare pyridine moieties were not tolerated (6k and 6l). Comment: The outlined methodology provides a general and competitive protocol toward the synthesis of these bisheteroaromatic motifs (see Review below). The method was applied in the latestage functionalization of the purine analogue 4a and a derivative of the commercially available oral contraceptive mestranol 6e. A major drawback of this method is that an excess of the (het)arene component is required for efficient reaction (2.5– 5.0 equiv), which significantly limits its utility with expensive late-stage intermediates. Furthermore, because all reactions were performed on a milligram scale and at high dilution, the scalability is questionable. A plausible anti-Minisci radical mechanism is proposed without supporting evidence.