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.

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

References and Notes

1

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

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13

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.

14 In this case, compound 14b was accompanied by 14% of 4-propyl-7-ethyl-5,8-dimethoxy-6-pivaloylamino-2 (1H)-quinolinone, from dialkylation at both C-7 and at the C-4 methyl. The difference in behavior between iodides and bromides may be related to different aggregation states of the intermediate organolithium compounds, leading to an increased stability of the species alkylated at C-7 and lithiated at both NH groups and at the C-4 methyl in the presence of bromide and allowing its generation under those conditions. For an example of an abrupt change in reactivity of a carboxylic acid dilithio derivative in the presence of two different halides, which was also explained in terms of different aggregation states of the dianion, see: Gil S. Torres M. Ortúzar N. Wincewicz R. Parra M. Eur. J. Org. Chem.  2004,  2160