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

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.

bromine-lithium exchange - ortholithiation - bromopyridines - regioselectivity

References

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5

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

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TMSCl is known to display some compatibility towards hindered bases. See:

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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).

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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.

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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%.