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Synlett 2010(19): 2918-2922  
DOI: 10.1055/s-0030-1259014
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

New Methodology for the Synthesis of 3-Substituted Coumarins via Palladium-Catalyzed Site-Selective Cross-Coupling Reactions

Sérgio Martinsa, Paula S. Brancob, María C. de la Torrec, Miguel A. Sierrad, António Pereira*a
a Centro de Química, Departamento de Química,, Universidade de Évora, 7000-671 Évora, Portugal
Fax: +351(266)745303; e-Mail: amlp@uevora.pt;
b REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, FCT, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
c Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (CSIC), 28006 Madrid, Spain
d Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
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Publication History

Received 21 July 2010
Publication Date:
03 November 2010 (online)

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Abstract

A particularly useful, easy, and concise synthesis of diversified 3-aryl coumarin was achieved using Heck coupling reactions between coumarin and aryliodides. The introduction of the aryl moiety occurred regioselective at the 3-position of the heteroaromatic ring.

Key words

coumarin - Heck reaction - palladium - coupling reaction - 3-aryl coumarin

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General Procedure for the Pd-Catalyzed Coupling of Coumarin with Aryliodides
Under a nitrogen atmosphere, a mixture of coumarin (146 mg, 1.0 mmol, 3.0 equiv), aryl iodide (1.0 equiv), Pd(PPh3)4 (10 mol%), and MeCO2Ag (1.1 equiv) in DMF (2.0 mL) was stirred at 80 ˚C for a period of 72 h. The reaction mixture was diluted with EtOAc and washed with H2O. The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chroma-tography on silica gel (230-400 mesh; hexane-CH2Cl2 gradient). 3-(4-Bromophenyl)coumarin (3b) ¹H NMR (400 MHz, CDCl3): δ = 7.31 (1 H, dd, J = 7.5, 7.4 Hz, H-6), 7.37 (1 H, d, J = 8.5 Hz, H-8), 7.53-7.61 (6 H, m, H-5, H-7, H-2′, H-3′, H-5′, H-6′), 7.82 (1 H, s, H-4). ¹³C NMR (100 MHz, CDCl3): δ = 116.6 (C-8), 119.5 (C-4a), 123.2 (C-4′), 124.6 (C-6), 127.2 (C-3), 128.0 (C-5), 130.1 (C-2′, C-6′), 131.7 (C-7, C-3′, C-5′), 133.6 (C-1′), 139.9
(C-4), 153.6 (C-8a), 160.3 (C-2). MS (EI+): m/z (%) = 299 [M79Br - H]+(100), 273 [M8¹Br - CO]+(71). HRMS (EI+):
m/z calcd for C15H9BrO2 [M]+: 299.9786; found: 299.9790.
3-(4-Ethylphenyl)coumarin (3c) ¹H NMR (400 MHz, CDCl3): δ = 1.27 (3 H, t, J = 7.6 Hz, CH2CH3), 2.70 (2 H, q, J = 7.6 Hz, CH2CH3), 7.29 (2 H, d, J = 8.2 Hz, H-3′, H-5′), 7.30 (1 H, dd, J = 7.7, 7.7 Hz, H-6), 7.37 (1 H,d, J = 8.0 Hz, H-8), 7.52 (1 H, dd, J = 8.0, 7.7 Hz, H-7), 7.54 (1 H, d, J = 7.7 Hz, H-5), 7.63 (2 H, d, J = 8.2 Hz, H-2′, H-6′), 7.80 (1 H, s, H-4). ¹³C NMR (100 MHz, CDCl3): δ = 15.5 (CH2CH3), 28.7 (CH2CH3), 116.4 (C-8), 119.8 (C-4a), 124.4 (C-6), 127.8 (C-5), 128.0 (C-3′, C-5′), 128.5 (C-3, C-2′, C-6′), 131.2 (C-7), 132.0 (C-1′), 139.2 (C-4), 145.2 (C-4′), 153.4 (C-8a), 160.7 (C-2). MS (EI+): m/z (%) = 250 [M]+ (99.5), 235 [M - CH3]+(100), 222 [M - CO]+ (17.87), 207 [M - CO2 + H]+(77). HRMS (EI+): m/z calcd for C17H14O2 [M]+: 250.0994; found: 250.0993.
3-(4-Iodophenyl)coumarin (3d) ¹H NMR (400 MHz, CDCl3): δ = 7.31 (1 H, dd, J = 7.1, 7.1 Hz, H-6), 7.37 (1 H, d, J = 8.2 Hz, H-8), 7.46 (2 H, d, J = 7.0 Hz, H-2′, H-6′), 7.53-7.56 (2 H, m, H-5, H-7), 7.79 (2 H, d, J = 7.0 Hz, H-3′, H-5′), 7.82 (1 H, s, H-4). ¹³C NMR (100 MHz, CDCl3): δ = 95.0 (C-4′), 116.5 (C-8), 119.5 (C-4a), 124.6 (C-6), 127.3 (C-3), 128.0 (C-5), 130.2 (C-2′, C-6′), 131.7 (C-7), 134.2 (C-1′), 137.6 (C-3′, C-5′), 139.9 (C-4), 153.6 (C-8a), 160.2 (C-2). MS (EI+): m/z (%) = 347 [M]+(61), 57 [C2HO2](100). HRMS (EI+): m/z calcd for C15H9IO2 [M]+: 347.9647; found: 347.9645.
4-(Coumarin-3-yl)benzaldehyde (3e) ¹H NMR [400 MHz, CO(CD3)2]: δ = 7.40 (2 H, m, H-6, H-8), 7.67 (1 H, dd, J = 7.2, 6.8 Hz, H-7), 7.80 (1 H, d, J = 6.8 Hz, H-5), 8.02 (4 H, br s, H-2′, H-3′, H-5′, H-6′), 8.31 (1 H, s, H-4), 10.10 (1 H, s, CHO). ¹³C NMR [100 MHz, CO(CD3)2]: δ = 116.9 (C-8), 120.5 (C-4a), 125.5 (C-6), 127.5 (C-3), 129.7 (C-5), 130.1 (C-2′, C-6′), 130.2 (C-3′,
C-5′), 133.0 (C-7), 137.4 (C-4′), 141.8 (C-1′), 142.4 (C-4), 154.8 (C-8a), 160.2 (C-2), 192.5 (CHO). MS (EI+): m/z (%) 249 [M - H]+ (73.71), 221 [M - CO]+ (14.6), 220 [M - CHO]+ (17.9), 57 [C2HO2](100). HRMS (EI+): m/z calcd for C16H10O3 [M]+ 250.0630; found: 250.0632.
3-(4-Nitrophenyl)coumarin (3f) ¹H NMR (400 MHz, CDCl3): δ = 7.36 (1 H, dd, J = 7.6, 6.8 Hz, H-6), 7.41 (1 H, d, J = 8.2 Hz, H-8), 7.60 (1 H, d, J = 7.6 Hz, H-5), 7.61 (1 H, dd, J = 8.2, 6.8 Hz, H-7), 7.92 (2 H, d, J = 8.8 Hz, H-2′, H-6′), 7.95 (1 H, s, H-4), 8.33 (2 H, d, J = 8.8 Hz, H-3′, H-5′). ¹³C NMR (100 MHz, CDCl3): δ = 116.7 (C-8), 119.1 (C-4a), 123.7 (C-3′, C-5′), 124.9 (C-6), 126.1 (C-3), 128.4 (C-5), 129.5 (C-2′, C-6′), 132.6 (C-7), 141.0 (C-1′), 141.6 (C-4), 147.8 (C-4′), 153.9 (C-8a), 159.8 (C-2). MS (EI+): m/z (%) = 267 [M]+(100), 239 [M - CO]+ (17.4). HRMS (EI+): m/z calcd for C15H9NO4 [M]+: 267.0532; found: 267.0533.
3-(4-Methoxyphenyl)coumarin (3g) ¹H NMR [400 MHz, CO(CD3)2]: δ = 3.84 (3 H, s, OCH3), 7.01 (2 H, d, J = 8.0 Hz, H-3′, H-5′), 7.36 (2 H, m, H-6, H-8), 7.59 (1 H, dd, J = 7.8, 7.5 Hz, H-7), 7.75 (3 H, m, H-5, H-2′, H-6′), 8.07 (1 H, s, H-4). ¹³C NMR [100 MHz, CO(CD3)2]: δ = 55.6 (OCH3), 114.5 (C-3′, C-5′), 116.7 (C-8), 120.9 (C-4a), 126.0 (C-6, C-3), 129.1 (C-5, C-1′), 130.7 (C-2′, C-6′), 131.9 (C-7), 139.4 (C-4), 154.0 (C-8a), 160.5 (C-4′), 161.1 (C-2). MS (EI+): m/z (%) = 252 [M]+(100), 209 [M - CO + CH3]+ (53.2). HRMS (EI+): m/z calcd for C16H12O3 [M]+: 252.0786; found: 252.0785.
( E )-Methyl 3-[4-(coumarin-3-yl)phenyl]acrylate (9) ¹H NMR (400 MHz, CDCl3): δ = 3.82 (3 H, s, OCH3), 6.49 (1 H, d, J = 16.0 Hz, CHCHCO), 7.32 (1 H, dd, J = 7.6, 7.6 Hz, H-6), 7.38 (1 H, d, J = 8.3 Hz, H-8), 7.55 (1 H, dd, J = 8.3, 7.6 Hz, H-7), 7.56 (1 H, d, J = 7.6 Hz, H-5), 7.60 (2 H, d, J = 8.1 Hz, H-3′, H-5′), 7.72 (1 H, d, J = 16.0 Hz, CHCHCO), 7.76 (2 H, d, J = 8.4 Hz, H-2′, H-6′), 7.87 (1 H, s, H-4). ¹³C NMR (100 MHz, CDCl3): δ = 51.8 (OCH3), 116.5 (C-8), 118.6 (CHCHCO), 119.5 (C-4a), 124.6 (C-6), 127.5 (C-3), 128.0 (C-5), 128.1 (C-3′, C-5′), 129.0 (C-2′, C-6′), 131.8 (C-7), 134.8 (C-4′), 136.5 (C-1′), 140.1 (C-4), 144.0 (CHCHCO), 153.6 (C-8a), 160.3 (C-2), 167.3 (CHCHCO). MS (EI+): m/z (%) = 306 [M]+ (63.15). HRMS (EI+): m/z calcd for C19H14O4 [M]+: 306.0892; found: 306.0896.