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Synlett 2002(3): 0453-0457
DOI: 10.1055/s-2002-20464
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Efficient Approaches to Functionalized 2-Substituted Furopyridines

Antonio Arcadi*a, Sandro Cacchi*b, Sabrina Di Giuseppea, Giancarlo Fabrizib, Fabio Marinellia
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facoltà di Scienze, Università di L’Aquila, Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy
Fax: +39(862)433753; e-Mail: arcadi@univaq.it;
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ”La Sapienza", P.le A. Moro 5, 00185 Rome, Italy
e-Mail: sandro.cacchi@uniroma1.it;
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Received 18 December 2001
Publikationsdatum:
05. Februar 2007 (online)

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Abstract

2-Ethynyl-3-pyridinols and 3-ethynyl-2-pyridinols, readily available from halopyridinols, have been treated with aryl/heteroaryl halides or vinyl triflates to give 2-substituted furo[3,2-b]pyridines and 2-substituted furo[2,3-b]pyridines through a coupling/cyclization process. Two catalyst systems have been used: PdCl2(PPh3)2-CuI and Pd2(dba)3-P(t-Bu)3. Halopyridinols have been employed for an alternative approach to 2-substituted furo[2,3-b]pyridines and 2-substituted furo[2,3-c]pyridines via 2-(trimethylsilyl)furopyridines, 2-iodofuropyridines, palladiumcatalyzed reactions.

Key words

furopyridines - palladium - halopyridinols - alkynes - coupling

8

A typical procedure for the preparation of 5 is as follows: To a solution of 3a (0.047 g, 0.395 mmol), 4b (0.155 g, 0.592 mmol) in THF-Et3N (2.0 mL/2.0 mL) under nitrogen, PdCl2(PPh3)2 (0.011 g, 0.016 mmol) and CuI (0.003 g, 0.016 mmol) were added. The mixture was stirred at room temperature for 3 h. After cooling, the reaction mixture was diluted with ethyl acetate and concentrated under vacuum. The residue was chromatographed on silica gel eluting with n-hexane-ethyl acetate (75:25 v/v) to afford 5b (0.084 g, 84% yield); mp 181-182 °C; IR (KBr) 1730, 1610, 1560
cm-1; 1H NMR 8.55 (m, 1H), 8.13 (d, J = 8.6 Hz, 2 H), 7.86 (d, J = 8.6 Hz, 2 H), 7.32 (m, 1 H), 7.24 (s, 1 H), 7.21 (m, 1 H), 3.94 (s, 3 H); 13C NMR δ 166.4, 158.1, 148.5, 148.2, 146.4, 133.5, 130.5, 130.1, 124.9, 119.4, 118.0, 104.3, 52.2; MS m/z (relative intensity) 253 (M+, 100), 222(81).

13

Typical procedure for the preparation of compounds 10: To a solution of 1b (1.0 g, 4.25 mmol) and trimethylsilylacetylene (0.54 g, 5.53 mmol) in dioxane-Et3N (2.5 mL/2.5 mL) PdCl2(PPh3)2 (0.045 g, 0.042 mmol) and CuI (0.016 g, 0.084 mmol) were added under nitrogen. The mixture was stirred at 45 °C for 3 h. After cooling, the reaction mixture was diluted with ethyl acetate, washed with HCl 0.1 M, dried over Na2SO4, and concentrated under vacuum. The residue was chromatographed on silica gel eluting with n-hexane-ethyl acetate (90:10 v/v) to afford 9a (0.688 g, 79% yield); IR(neat) 1590, 1570 cm-1; 1H NMR δ 7.47 (d, J = 8.8 Hz, 1 H), 6.97 (s, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 2.52 (s, 3 H), -0.24 (s, 9 H); 13C NMR δ 155.8, 151.5, 146.9, 121.0, 120.9, 118.2, 25.8, 0,0; MS m/z (relative intensity) 205 (M+, 59), 190(100).
To a solution of 9a (0.14 g, 0.683 mmol) in CH3OH (15 mL), NIS (0.305 g, 1.36 mmol) and KF (0.118 g, 2.04 mmol) were added. The mixture was stirred at 60 °C for 8 h. After cooling, the reaction mixture was diluted with ethyl acetate, washed with HCl 0.1 M, dried over Na2SO4, and concentrated under vacuum. The residue was chromatographed on silica gel eluting with n-hexane-ethyl acetate (90:10 v/v) to afford 10a (0.120 g, 80% yield); mp 99-100 °C; IR (KBr) 1600, 1570 cm-1; 1H NMR δ 7.59 (d, J = 8.5 Hz, 1 H), 7.11 (s, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 2.63 (s, 3 H); 13C NMR δ 154.8, 147.7, 119.8, 119.3, 117.2, 115.8, 101.5, 23.8; MS m/z (relative intensity) 259 (M+, 100).