Sterics vs Electronics: Revisiting the Catalytic Regioselective Hydrodebromination of 2,3,5-Tribromothiophene

Abstract

The application of sterically hindered palladium catalysts to the regioselective hydrodebromination of 2,3,5-tribromothiophene has been studied in detail, including the effects of catalyst choice, solvent, reaction time, and temperature, as well as the method of NaBH 4 addition and the role of chelating additives to effect NaBH 4 solubility. Ultimately it was determined that the background reaction between NaBH 4 and bromothiophenes is too facile to allow both total conversion and high selectivity. Optimized conditions finally allowed a selectivity of ca. 16:1 with overall conversion of 100%. However, complications of overdebromination under these conditions still limit the yield of the desired 2,3-dibromothiophene to 65%.

Synthesis of Brominated Thiazoles via Sequential Bromination–Debromination Methods

“…Although one would assume that such bromothiazoles could be efficiently produced via analogous methods to the more commonly applied bromothiophenes, there are some important differences between the two sulfur-based heterocycles. Bromothiophenes are typically generated by various sequential bromination and debromination steps in which bromination is accomplished via electrophilic aromatic substitution using either Br 2 or N -bromosuccinimide (NBS) . While bromothiazoles can also be produced via direct bromination, thiazole is both less aromatic and considerably less electron rich than thiophene.…”

“…Bromothiophenes are typically generated by various sequential bromination and debromination steps in which bromination is accomplished via electrophilic aromatic substitution using either Br 2 or N-bromosuccinimide (NBS). 10 While bromothiazoles can also be produced via direct bromination, thiazole is both less aromatic 11 and considerably less electron rich than thiophene. As a consequence, electrophilic aromatic substitution of thiazole is much less facile, typically requiring much more aggressive reaction conditions.…”