Synlett 2007(18): 2805-2808  
DOI: 10.1055/s-2007-990957
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Juan Domingo Sánchez, Pilar Cledera, Subbu Perumal, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax: +34(91)3941822; e-Mail: josecm@farm.ucm.es;
Further Information

Publication History

Received 28 March 2007
Publication Date:
19 October 2007 (online)

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.

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1

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

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.