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Synlett 2008(9): 1371-1375  
DOI: 10.1055/s-2007-1072751
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Pyrido[3,2-b]carbazolequinones Involving N-Arylation of 5,8-Dimethoxy-6-nitroquinolines by Aryl Grignard Reagents and a New One-Pot, Palladium-Promoted Oxidative Coupling-Oxidative Demethylation Sequence

Juan Domingo Sánchez, 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;
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Publication History

Received 1 February 2008
Publication Date:
07 May 2008 (online)

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Abstract

The reaction between a 5,8-dimethyxy-6-nitrocarbostyril derivative and arylmagnesium bromides gave 6-arylaminocarbostyrils as the major products. Their subsequent treatment with palladium acetate in refluxing acetic acid gave linear pyrido[3,2-b]carbazolequinones in one step, involving the unprecedented oxidative demethylation of 1,4-dimethoxybenzene systems to the corresponding quinones by palladium acetate. A palladium-calalyzed oxidative functionalization of an unactivated C-H bond was also observed.

Key words

N-arylation - organomagnesium reagents - palladium catalysts - oxidative demethylation - oxidative C-H activation

12

Representative Procedure
To a solution of 1,4-dimethyl-5,8-dimethoxy-6-nitro-2 (1H)-quinolin-2-one (1 g, 3.59 mmol) was added p-tolylmagnesium bromide (10.8 mL of a 1 M soln in THF, 10.8 mmol). The reaction mixture was stirred at -48 ˚C for 1 h and poured onto a sat. aq soln of NH4Cl (15 mL), which was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over Na2SO4, and evaporated. Chromatography of the residue on silica gel, eluting with a PE-EtOAc gradient, gave 534 mg (44%) of 1,4-dimethyl-5,8-dimethoxy-6-(p-tolylamino)-2 (1H)-quinolin-2-one (5c), as a pale brown oil, and 218 mg (18%) of 1,4-dimethyl-8-methoxy-6-nitro-5-(p-tolyl)-2 (1H)-quinolin-2-one (6c), as a pale brown solid.
5c: IR (KBr): 3365, 2922, 1646, 1599, 1516, 1455 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.12 (d, 2 H, J = 8.3 Hz, H-2′, H-5′), 7.06 (s, 1 H, H-7), 7.01 (d, 2 H, J = 8.3 Hz, H-3′, H-5′), 6.50 (d, 1 H, J = 1.0 Hz, H-3), 5.98 (br s, 1 H, NH), 3.81 (s, 3 H, NCH3), 3.75 (s, 3 H, C5-OCH3), 3.67 (s, 3 H, C8-CH3), 2.60 (d, 3 H, J = 1.0 Hz, C4-CH3), 2.31 (s, 3 H, C4′-CH3) ppm. ¹³C NMR (62.9 MHz, CDCl3): δ = 163.18 (CO), 145.95 (C-1′), 145.93 (C-4), 141.15 (C-8), 140.71 (C-5), 131.31 (C-6), 130.48 (C-3′, C-5′), 127.15 (C-4′), 123.82 (C-3), 118.74 (C-2′, C-6′), 118.63 (C-4a), 113.15 (C-8a), 105.93 (C-7), 61.93 (C5-OCH3), 57.48 (C8-OCH3), 36.39 (NCH3), 23.68 (C4-CH3), 21,08 (C4′-Me) ppm. Anal. Calcd for: C, 70.99; H, 6.55; N, 8.28. Found: C, 69.83; H, 6.53; N, 7.95.
6c: Mp 181-183 ˚C. IR (KBr): 3141, 1665, 1607, 1567, 1522 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.36 (s, 1 H, H-7), 7.18-7.14 (m, 4 H, H-2′, H-3′, H-5′, H-6′), 6.52 (d, 1 H, J = 0.9 Hz, H-3), 3.99 (s, 3 H, OCH3), 3.85 (s, 3 H, NCH3), 2.41 (s, 3 H, C4′-CH3), 1.63 (d, 3 H, J = 0.9 Hz, C4-CH3) ppm. ¹³C NMR (62.9 MHz, CDCl3): δ = 162.87 (CO), 148.43 (C-8), 148.27 (C-4), 139.17 (C-6), 136.17 (C-4 ′), 133.17 (C-1′), 130.48 (C-3′, C-5′), 129.30 (C-2′, C-6′), 127.00 (C-8a), 125.66 (C-3), 124.10 (C-5), 123.20 (C-4a), 106.84 (C-7), 57.03 (OCH3), 37.28 (NCH3), 24.99 (C4-CH3), 21,80 (C4′-CH3) ppm. Anal. Calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found: C, 67.83; H, 5.53; N, 7.95.

17

Representative Procedure
A solution of compound 5a (120 mg, 0.37 mmol) and Pd(OAc)2 (166 mg, 0.74 mmol) in AcOH (15 mL) was heated at 120 ˚C for 16 h, under an argon atmosphere. The reaction mixture was evaporated to dryness and the residue was chromatographed on silica gel, eluting with an EtOAc-PE gradient, to give 29 mg (25%) of 5,11-dimethoxy-1,4-dimethyl-1H-pyrido[3,2-b]carbazol-2 (6H)-one (7a), as an orange solid, and 64 mg (59%) of 1,4-dimethyl-1H-pyrido[3,2-b]carbazole-2,5,11 (6H)-trione (8a), as a red solid.
7a: Mp 270-272 ˚C. IR (KBr): 3202, 2930, 1635, 1587, 1550, 1484, 1437, 1230 cm-¹. ¹H NMR (250 MHz, DMSO-d 6): δ = 8.36 (s, 1 H, NH), 7.96 (d, 1 H, J = 7.9 Hz, H-10), 7.51-7.57 (m, 2 H, H-7 and H-9), 7.40-7.26 (m, 1 H, H-8), 6.54 (s, 1 H, H-3), 3.99 (s, 6 H, 2 OMe), 3.85 (s, 3 H, N1-Me), 2.73 (s, 3 H, C4-Me) ppm. ¹³C NMR (62.9 MHz, CDCl3): δ = 160.56 (C-2), 146.25 (C-4), 140.28 (C-11), 139.12 (C-5), 130.72 (C-6a), 128.92 (C-10a), 127.79 (C-5a), 124.02 (C-9), 122.52 (C-10), 122.29 (C-8), 120.91 (C-3), 120.63 (C-11a), 116.49 (C-7), 111.25 (C-10b), 62.35 (C5-OCH3), 61.81 (C11-OCH3), 36.08 (NCH3), 23.72 (C4-CH3) ppm. Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.70; H, 5.71; N, 8.50.
8a: Mp >300 ˚C. IR (KBr): 3424, 2941, 1647, 1575, 1542, 1484 cm-¹. ¹H NMR (250 MHz, DMSO-d 6): δ = 12.94 (br s, 1 H, N6-H), 8.06 (d, 1 H, J = 7.5 Hz, H-10), 7.56 (d, 1 H, J = 7.5 Hz, H-7), 7.40-7.30 (m, 2 H, H-8, H-9), 6.58 (s, 1 H, H-3), 3.84 (s, 3 H, N1-CH3), 2.56 (s, 3 H, C4-Me) ppm. ¹³C NMR (62.9 MHz, CDCl3): δ = 178.01 (C-11), 177.33 (C-5), 161.37 (C-2), 149.13 (C-4), 145.89 (C-6a), 137.78 (C-10a), 136.24 (C-5a), 126,43 (C-10a), 123.99 (C-4a), 123.67 (C-9), 122.42 (C-10), 121.81 (C-8), 116.04 (C-3), 114.87 (C-10b), 113.87 (C-7), 30.68 (NCH3), 22.59 (C4-CH3) ppm. MS:
m/z = 292 [M+], 263, 169, 44. Anal. Calcd for C17H12N2O3: C, 69.86; H, 4.14; N, 9.58. Found: C, 69.53; H, 3.97; N, 9.24.