Ring Selective Lithiation of 3,5-Lutidine. A New Route to Heterocyclic Building Blocks.

Abstract

The first direct ring lithiation of 3,5-lutidine has been performed by the BuLi-LiDMAE reagent. Successful sequential metallations and electrophilic condensations have been performed giving access to new useful polysubstituted pyridines.

Key words

pyridines - lithiation - carbanions - chemoselectivity - regioselectivity

References

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• 8b

  In this paper, 2f was prepared from 3,5-lutidine by a two-step procedure in 44% overall yield.

6

This result was in agreement with observations that we made during metallation of 2-methoxypyridine see ref. [1b]

7

Preparation of 2e is given as a typical procedure. To a solution of 2-dimethylaminoethanol (0.8 mL; 8 mmol) in hexane (5 mL) cooled at 0 °C, was added dropwise BuLi (16 mmol; 10 mL of a 1.6 M solution in hexanes). After 15 min, a solution of 1 (214 mg; 2 mmol) in hexane (5 mL) was added dropwise and the orange solution stirred for 1 h at 0 °C. After cooling at -78 °C, a solution of C₂Cl₆ (0.95 g; 10 mmol) in hexane (10 mL) was added dropwise. The reaction mixture was maintained at -78 °C for 0.5 h then allowed to warm to r.t. Hydrolysis at 0 °C with water (15 mL) was followed by extraction with diethyl ether (20 mL) and drying over MgSO₄. After evaporation of solvents, the crude product was purified by column chromatography using hexane-EtOAc (70:30). 2e was obtained as an oil (212 mg; 75%). ¹H NMR (CDCl₃, TMS): δ = 2.13 (s, 3 H), 2.17 (s, 3 H), 7.23 (d, 0.8 Hz, 1 H), 7.86 (d, 0.5 Hz, 1 H). ¹³C NMR (CDCl₃, TMS): δ = 17, 18.9, 131.4, 132.0, 140.0, 146.5, 148.1. MS (EI): m/z (%) = 141(100) [M⁺], 106(37), 77(19). Anal. Calcd for C₇H₈ClN: C, 59.38%; H, 5.69%; N, 9.89%. Found: C, 59.52%; H, 5.48%; N, 9.72%.

9

The procedure was identical as described in ref. [7] excepted that 1.6 mL (16 mmol) of 2-dimethylaminoethanol and 20 mL (32 mmol) of BuLi were used and that the electrophile (20 mmol) was added at -30 °C with 2a and 2e and at -78 °C with 2b and 3. Data given for 4b: ¹H NMR (CDCl₃, TMS): δ = 2.31 (s, 6 H), 7.42 (s, 1 H). ¹³C NMR (CDCl₃, TMS): δ = 18.4, 130.9, 142.2, 146.7. MS (EI) m/z (%) = 177(48) [M⁺ + 1], 175(76) [M⁺ - 1], 140(71), 104(68), 77(88), 62(63), 51(100). Anal. Calcd for C₇H₈ClN: C, 47.76%; H, 4.01%; N, 7.96%. Found: C, 47.94%; H, 3.87%; N, 8.02%.