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 .

Keywords: continuous flow; flash chemistry; halogen dance; lithiation; pyridines.

Scheme 1

State of the art and this work.

Scheme 2

A) Study of the temperature effect – proof of concept. Ø 1 mm PFA tubing. [a] Determined by ¹H NMR with nitromethane as internal standard. B) Optimization of the halogen dance on 2‐chloro‐3‐bromopyridine. [a] Determined with MeNO₂ as ¹H NMR internal standard. [b] Isolated yield. [c] [Electrophile]=0.3 M, Q _C=5 mL min⁻¹, V _C=3 mL. [d] Q _C=4 mL min⁻¹ (2 equiv.). C) Batch vs. continuous‐flow experiments; Ar=3,4,5‐(OMe)₃−C₆H₂.

Scheme 3

Continuous‐flow halogen dance on 2‐chloro‐3‐bromopyridine.^[a] The same yield was obtained by using commercially available LDA 1.0 M in THF/hexanes.

Scheme 4

Continuous‐flow deprotolithiation with LDA on 2‐chloro‐3‐bromopyridine.

Scheme 5

Continuous‐flow halogen dance on 2‐fluoro‐3‐iodopyridine (4) and 3‐fluoro‐4‐iodopyridine (6). [a] [Electrophile]=1.67 M, t${}^{\mathrm{R}{}_2}$ =29.4 s. [b] Compound 6 was used.

Scheme 6

Large‐scale, continuous‐flow halogen dance on 2‐fluoro‐3‐iodopyridine trapped with 3,4,5‐trimethoxybenzaldehyde.