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Synlett 2002(12): 2095-2097
DOI: 10.1055/s-2002-35569
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Convenient Preparation of 4-Carboxamide Derivatives of Pyridazino[4,5-b]indoles and Pyridazino[4,5-b]benzo[b]furans

José C. González-Gómez*, Eugenio Uriarte
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax: +34(981)594912; e-Mail: jcgg1971@yahoo.es;
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Publication History

Received 22 August 2002
Publication Date:
20 November 2002 (online)

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Abstract

Diels-Alder reaction of indole or 3-coumaranone with 3,6-dicarbomethoxy-1,2,4,5-tetrazine followed by MgCl2-mediated C-4 regioselective amidation of the tricyclic diester and subsequent Krapcho dealkoxycarbonylation, provided a convenient route to 4-carboxamide derivatives of pyridazino[4,5-b]indoles and pyridazino[4,5-b]benzo[b]furans. 1,4-Biscarboxamide derivatives were also obtained by full amidation of diester intermediates with an excess of the amine.

Key words

Diels-Alder reaction - regioselectivity - pyridazine - indoles - benzofurans

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Preparation of 1,4-dicarbomethoxypyridazine[4,5-f]benzo[b]furan(6). Benzofuran-3(2H)-one (7; 142 mg, 1.05 mmol) was added to a dioxane (4 mL) solution of 3,6-dicarbomethoxy-1,2,4,5-tetrazine (190 mg, 0.96 mmol) with a catalytic amount of p-TsOH (10 mg). The reaction mixture was refluxed for 6 h until the red color of the tetrazine had disappeared. The solvent was removed under vacuum and the residue was purified by flash chromatography using 1:2 Hex-EtOAc as eluent, giving pure 6; yield: 200 mg (73%).

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Amidation of 6 in the absence of MgCl2 afforded mixtures of monocarboxamides C-4/C-1 in 65/35 for pyrrolidine and
70/30 for N,N-dimethylethylenediamine, as determined by 1H NMR integration of H-9.

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Selected physical and spectroscopic data of new compounds. Compound 6: mp 218-220 ºC(dioxane). 1H NMR (CDCl3): δ = 8.87 (d, J = 7.95 Hz, 1 H, H-9), 7.82 (m, 2 H), 7.61 (dt, J = 6.60, 1.70 Hz, 1 H), 4.24 (s, 3 H, OCH3), 4.22 (s, 3 H, OCH3); 13C NMR (CDCl3): δ = 165.08, 162.57, 157.87, 155.06, 147.87, 140.02, 133.24 (CH), 127.90 (CH), 125.95 (CH), 125.82, 118.48, 113.08 (CH), 54.03 (CH3), 53.94 (CH3); MS (EI): m/z (%) = 286 (M+, 1.9), 169 (100). Compound 8a: mp 192-194 ºC. 1H NMR (CDCl3): δ = 8.89 (d, J = 8.15 Hz, 1 H, H-9), 7.82 (m, 2 H), 7.60 (dt, J = 6.60, 1.70 Hz, 1 H), 4.24 (s, 3 H, OCH3), 3.88 (t, J = 6.70 Hz, 2 H), 3.74 (t, J = 6.55 Hz, 2 H), 1.96-2.08 (m, 4 H); MS (EI): m/z (%) = 325 (M+, 23), 70 (100). Compound 8b: mp 168-171 ºC. 1H NMR (CDCl3): δ = 8.89 (d, J = 8.15 Hz, 1 H, H-9), 8.72 (s, 1 H, NH), 7.87 (m, 1 H), 7.82 (m, 1 H), 7.60 (m, 1 H), 4.23 (s, 3 H, OCH3), 3.68 (t, J = 5.75 Hz, 2 H), 2.62 (t, J = 6.10 Hz, 2 H), 2.33 (s, 6 H). Compound 9a: 1H NMR (CDCl3): δ = 11.00 (s, 1 H, NH), 8.84 (d, 1 H, J = 8.25 Hz, H-9), 7.57 (m, 2H, H-6/H-7), 7.37 (m, 1 H, H-8), 4.29 (t, J = 6.50 Hz, 2 H), 4.14 (s, 3 H, OCH3), 3.77 (t, J = 6.55 Hz, 2 H), 1.95 (m, 4 H); MS (EI): m/z (%) = 324 (M+, 15), 168 (100). Compound 9b: 1H NMR (CDCl3): δ = 10.83 (s,
1 H, NH), 8.92 (d, J = 8.25 Hz, 1 H, H-9), 8.84 (s, 1 H, NH), 7.70 (m, 2 H), 7.49 (m, 1 H), 4.22 (s, 3 H, OCH3), 3.69 (m, 2 H), 2.64 (m, 2 H), 2.34 (s, 3 H), 2.33 (s, 3 H). Compound 10a: mp 190-193 ºC. 1H NMR (CDCl3): δ = 8.42 (d, J = 7.90 Hz, 1 H, H-9), 7.75 (m, 2 H), 7.55 (m, 1 H), 3.80 (m, 8 H), 2.00 (m, 8 H); MS (EI): m/z (%) = 364 (M+, 29), 70 (100). Compound 10b: mp 161-162 ºC. 1H NMR (CDCl3): δ = 9.27 (d, J = 8.15 Hz, 1 H, H-9), 8.76 (t, J = 4.80 Hz, 1 H, NH), 8.56 (t, J = 4.80 Hz, 1 H, NH), 7.88 (d, J = 8.45 Hz, 1 H), 7.77 (dt, J = 7.20, 1.35 Hz, 1 H), 7.58 (t, J = 8.18 Hz, 1 H), 3.73 (m, 4 H), 2.63 (m, 4 H), 2.33 (s, 6 H), 2.32 (s, 6 H). Compound 11a: 1H NMR (CDCl3): δ = 8.34 (d, J = 8.10 Hz, 1 H, H-9), 7.65 (m, 2 H), 7.40 (m, 1 H), 4.35 (t, J = 6.40 Hz, 2 H), 3.88 (m, 4 H), 3.56 (t, J = 6.50 Hz, 2 H), 2.00 (m, 8 H); MS (EI): m/z (%) = 363 (M+, 4), 70 (100). Compound 11b: 1H NMR (CDCl3): δ = 10.86 (s, 1 H, NH), 9.35 (d, J = 8.20 Hz, 1 H), 8.73 (m, 2 H, 2NH), 7.65 (m, 2 H), 7.44 (m, 1 H), 3.75 (m, 2 H), 3.68 (m, 2 H), 2.67 (m, 2 H), 2.63 (m, 2 H), 2.35 (s, 6 H), 2.34 (s, 6 H). Compound 12: 1H NMR (CDCl3): δ = 9.86 (s, 1 H, H-1), 8.13 (d, J = 7.80 Hz, 1 H, H-9), 7.75 (m, 2 H), 7.56 (m, 1 H), 3.86 (t, J = 6.80 Hz, 2 H), 3.76 (t, J = 6.50 Hz, 2 H), 2.00 (m, 4 H); 13C NMR (CDCl3): δ = 162.29, 156.91, 152.28, 146.09, 145.02, 131.80 (CH), 125.45 (CH), 124.49, 122.66 (CH), 119.56 (CH), 113.67 (CH), 49.11 (CH2), 46.99 (CH2), 26.67 (CH2), 24.56 (CH2). Compound 13: 1H NMR (CDCl3): δ = 10.62 (s, 1 H, NH), 9.76 (s, 1 H, H-1), 8.15 (d, J = 7.95 Hz, 1 H, H-9), 7.57 (m, 2 H), 7.36 (m, 1 H), 4.30 (t, J = 6.40 Hz, 2 H), 3.77 (t, J = 6.50 Hz, 2 H), 1.90 (m, 4 H); 13C NMR (CDCl3): δ = 163.25, 143.07, 140.42, 138.96, 135.26, 128.66 (CH), 121.06 (CH), 120.88, 120.21 (CH), 118.41 (CH), 111.55 (CH), 49.16 (CH2), 46.98 (CH2), 25.90 (CH2), 22.57 (CH2).