The Directed Lithiation Route to 2-Amino-3-alkylquinones: Highly Regioselective Introduction of Electrophiles at the C-7 Position of 2(1H)-Quinolinones

Abstract

An ortho-directed lithiation strategy starting from 2-amino-1,4-dimethoxybenzene derivatives allowed the efficient preparation of 2-amino-3-alkylbenzoquinone derivatives. This method was also successful in the case of 6-pivaloylamino-4-methyl-5,8-dimethoxycarbostyril derivatives, in spite of the fact that two other modes of lithiation are possible, and allowed the preparation of derivatives containing alkyl chains or functional groups at the highly hindered C-7 position. A reaction starting from 4-methyl-5,8-dimethoxy-2-pivaloyloxyquinoline was regioselectively directed to the C-4 methyl group.

Key words

assisted lithiation - alkylation - regioselectivity - quinolin-2-ones - aminoquinones

References and Notes

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1

Permanent address: Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India.

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Representative Procedure
To a cooled (0 °C) solution of 4-methyl-5,8-dimethoxy-6-pivaloylamino-2 (1H)-quinolinone (12, 636 mg, 2 mmol) in anhyd THF (25 mL), under an argon atmosphere, was added dropwise a solution of BuLi in hexanes (5 mL, 8 mmol) and the resulting yellow solution was stirred at 0 °C for 2 h. Methyl iodide (1.13 g, 8 mmol) was added dropwise at the same temperature and stirring was maintained at 0 °C for 1 h, and then the reaction was left to warm to r.t. for 13 h. The reaction mixture was poured onto sat. aq NH₄Cl (25 mL) and extracted with CHCl₃ (3 × 50 mL). The combined extracts were dried over anhyd Na₂SO₄ and evaporated, and the residue was purified by column chromatography on silica gel, eluting with a PE-EtOAc gradient, to give 432 mg (65%) of compound 14a as a white solid; mp 241-243 °C. IR (KBr): 3299 (NH), 1666 (CO) cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 9.19 (br s, 1 H, N₁-H), 7.38 (br s, 1 H, NH), 6.40 (s, 1 H, H-3), 3.80 (s, 3 H, OCH₃), 3.66 (s, 1 H, OCH₃), 2.62 (s, 3 H, C₄-CH₃), 2.20 (s, 3 H, C₇-CH₃), 1.37 (s, 9 H, t-Bu) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 177.6 (CON), 161.6 (C-2), 149.6 (C-4), 148.9 (C-8), 140.9 (C-5), 132.5 (C-6), 131.5 (C-8a), 124.9 (C-7), 122.2 (C-3), 113.2 (C-4a), 62.0 (OCH₃), 61.2 (OCH₃), 39.5 [C(CH₃)₃], 27.8 [C(CH₃)₃], 22.8 (C₄-CH₃), 12.1 (C₇-CH₃) ppm. Anal. Calcd for C₁₈H₂₄N₂O₄: C, 65.04; H, 7.28; N, 8.43. Found: C, 64.95; H, 7.20; N, 8.16.