Strategies for successful Suzuki-Miyaura cross-couplings with thienylboronic acids: From model studies to dye structures

Suzuki-Miyaura cross-coupling is a convenient way for preparing thienyl containing dyes and bioactive mole-cules. However, reactions with thienylboronic acids can be troublesome. To understand these reactions in more depth, we herein present our investigation into the cross-coupling of (5-formylthiophen-2-yl)boronic acid with 4-bromoanisole as a model reaction. The study includes variations of catalyst, base, aryl halide type, temperature and reaction medium. A key to succeed with such cross-couplings is a highly active catalyst, and sufficient solubility of both the boronic acid and the aryl halide. XPhos precatalysts proved to be the best system for the model reaction, while other catalysts might be applicable provided that more boronic acid is added, or an aryl iodide is used as cross-coupling partner. The XPhos 4th generation precatalyst was also efficient for the con-struction of mono-and di-thiophene-2-carbaldehyde substituted phenothiazines and a triarylamine dye pre-cursor. However, each cross-coupling pair needs fine tuning of the reaction medium to maximize yield.

Automated summary

The Suzuki-Miyaura cross-coupling reaction is a convenient method for preparing thienyl-containing dyes and bioactive molecules. However, using thienylboronic acids in these reactions can present challenges. In this study, we investigated the cross-coupling of (5-formylthiophen-2-yl)boronic acid with 4-bromoanisole as a model reaction to gain a deeper understanding. We explored variations in catalyst, base, aryl halide type, temperature, and reaction medium. The results showed that a highly active catalyst and sufficient solubility of both the boronic acid and the aryl halide were crucial for successful cross-coupling reactions. XPhos precatalysts were found to be the most effective system for the model reaction, and other catalysts could also be used with higher amounts of boronic acid or an aryl iodide as the cross-coupling partner. The XPhos 4th generation precatalyst was also efficient for constructing various compounds such as mono- and di-thiophene-2-carbaldehyde substituted phenothiazines and a triarylamine dye precursor. However, fine tuning of the reaction medium was necessary for each cross-coupling pair to maximize the yield.