Continuous‐Flow Divergent Lithiation of 2,3‐Dihalopyridines: Deprotolithiation versus Halogen Dance

Abstract

We describe herein the first halogen dance (HD) in continuous flow on 2‐chloro‐3‐bromopyridine by selectively trapping a (pyridin‐4‐yl)lithium species that is known to undergo the halogen‐dance process. In addition, this lithiated intermediate was trapped at lower temperature before the HD occurs. The HD process was extended to fluoro‐iodopyridines by using various electrophiles to afford 28 examples with yields ranging from 42 to 97 % with very short residence times. Finally, scale up of the reaction was demonstrated, affording a promising space‐time yield (STY) of 4.2 kg.h ⁻¹.L ⁻¹.

Abstract

The divergent lithiation of 2,3‐dihalopyridines is reported. Taking advantage of continuous‐flow technology, either the deprotolithiation or the halogen dance is carried out. After subsequent trapping with various electrophiles, 25 examples of both regioisomers were obtained in excellent yields and selectivities. Finally, this methodology was scaled up and a promising space‐time yield was obtained.