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. 2022 Dec 20;28(71):e202202286.
doi: 10.1002/chem.202202286. Epub 2022 Oct 31.

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

Thibaud Brégent  1 , Maria V Ivanova  1 , Thomas Poisson  1   2 , Philippe Jubault  1 , Julien Legros  1
Affiliations

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

Thibaud Brégent et al. Chemistry. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
State of the art and this work.
Scheme 2
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
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
Scheme 4
Continuous‐flow deprotolithiation with LDA on 2‐chloro‐3‐bromopyridine.
Scheme 5
Scheme 5
Continuous‐flow halogen dance on 2‐fluoro‐3‐iodopyridine (4) and 3‐fluoro‐4‐iodopyridine (6). [a] [Electrophile]=1.67 M, tR2 =29.4 s. [b] Compound 6 was used.
Scheme 6
Scheme 6
Large‐scale, continuous‐flow halogen dance on 2‐fluoro‐3‐iodopyridine trapped with 3,4,5‐trimethoxybenzaldehyde.
See this image and copyright information in PMC

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