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Synlett 2004(13): 2319-2322  
DOI: 10.1055/s-2004-831337
LETTER
© Georg Thieme Verlag Stuttgart · New York

Unusual t-BuLi Induced Ortholithiation versus Halogen-Lithium Exchange in Bromopyridines: Two Alternative Strategies for Functionalization

Philippe Pierrat, Philippe Gros*, Yves Fort*
Synthèse Organométallique et Réactivité, UMR CNRS-UHP 7565, Faculté des Sciences, Université Henri Poincaré, 54506 Vandoeuvre-lès-Nancy, France
Fax: +33(3)83844785; e-Mail: Yves.Fort@sor.uhp-nancy.fr; e-Mail: Philippe.Gros@sor.uhp-nancy.fr;
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Publication History

Received 13 May 2004
Publication Date:
08 September 2004 (online)

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Abstract

The reaction of lithiating agents with various 3-bromopyridines has been investigated. An unprecedented selectivity was observed with t-BuLi, which effected a clean lithiation at C-4. With 3-bromo and 2-chloro-3-bromo pyridines, the ortholithiation-exchange ratio was strongly electrophile and addition order dependent while 2-chloro-5-bromopyridine always gave exclusive C-4 substitution.

Key words

bromine-lithium exchange - ortholithiation - bromopyridines - regioselectivity

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5

Temperatures below -78 °C did not change the selectivity.

8

Compound 1-d4 was obtained in 70% yield (d >98%, 1H NMR) by reaction of 1 with LDA (3 equiv) in THF at -78 °C for 0.5 h and condensation with MeOD (5 equiv).

10

General Procedure for Ortholithitaion of 4 with t -BuLi.
A solution of 2-chloro-5-bromopyridine (386 mg, 2 mmol) in THF (6 mL) was cooled to -78 °C and t-BuLi (1.17 mL, 2 mmol) was added dropwise under nitrogen. After 5 min at -78 °C, the brown solution was treated with a solution of the appropriate electrophile (3 mmol) in THF (4 mL). The reaction medium was then allowed to warm to r.t. (1 h) and the mixture was hydrolyzed at 0 °C with H2O (10 mL). The aqueous layer was then extracted with Et2O. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography. Selected data for compound 10c obtained as an orange oil, (358 mg, 75%), eluent: hexane-EtOAc (90:10). 1H NMR (200 MHz, CDCl3): δ = 2.5 (s, 3 H), 6.9 (s, 1 H), 8.3 (s, 1 H). 13C NMR (50 MHz, CDCl3): δ = 14.8, 117.7, 118.8, 149.8, 150.4, 154.4. MS (EI):
m/z (%) = 241 (28), 239 (100) [M+], 237 (74), 206 (18), 143 (19), 81 (16). Anal. Calcd for C6H5BrClNS (%): C, 30.21; H, 2.11; N, 5.87. Found: C, 30.33; H, 2.12; N, 5.78.

13

Under these reaction conditions (1 equiv, -78 °C in THF), t-BuLi did not metallate pyridine even after 1 h, and gave only 2-tert-butylpyridine in 10-15%.