Regiodivergent Synthesis of Brominated Pyridylthiophenes by Overriding the Inherent Substrate Bias

Abstract

Regiocontrolled functionalization of a pyridylthiophene scaffold was accomplished. Regioselectivity for deprotonation of pyridylthiophene was switched by the reaction conditions, including organometallic base and solvent. Subsequently, in situ transmetalation and halogen dance on the corresponding organometallic species were controlled by additives and the reaction temperature as well as the above reaction conditions. This method successfully enabled the synthesis of four iodinated constitutional isomers from a single starting material, 2-(5-bromothiophen-2-yl)pyridine.

Ultrafast Halogen Dance Reactions of Bromoarenes Enabled by Catalytic Potassium Hexamethyldisilazide

“…However, although halogen dance reactions of thiophene, [6] pyridine, [7] and ferrocene [8] are well known, there are few examples of their successful application to other arenes [9] . Recently, much of our efforts have been devoted to extending the limited substrate scope and utilizing the hitherto unutilized arylmetal species of the halogen dance reaction of thiophene, [10a,b] azole, [10c] pyrrole, [10d–g] and benzene [10h,i] . Nevertheless, the general conditions remain underdeveloped, even for bromopyridines, which are the most investigated halogen dance reaction substrates.…”