New Efficient Approaches to Functionalized 2-Substituted Furopyridines

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

References

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• 7a

  Typical procedure for the preparation of compounds 3a,b: 3-Acetoxy-2-[2-(trimethylsilyl)ethynyl]pyridine 2a (2.36 g, 10.1 mmol) (prepared according to ref. [7b] ) was dissolved in CH₃OH (20 mL) and KF (2.11 g, 36.4 mmol) was added. The reaction mixture was stirred at room temperature until TLC indicated complete consumption of 2a. Then, the reaction mixture was concentrated under vacuum and the residue was chromatographed on silica gel eluting with an 80:20 (v/v) n-hexane-ethyl acetate mixture to give 3a (0.83g, 70% yield); mp 144-145 °C; IR (KBr) 3280, 2100 cm^-1; ¹H NMR δ 9.88 (bs, 1 H), 7.53 (dd, J = 5.8 and 1.8 Hz, 1 H), 6.77 (m, 2 H), 3.83 (s, 1 H); ¹³ C NMR δ 155.7, 140.7, 130.7, 124.7, 122.6, 83.7, 80.5; MS m/z (relative intensity) 119 (M⁺, 100), 91(53). Compound 3c was prepared from 3-iodo-5-ethoxycarbonyl-2-pyridinol according to ref. [1a]

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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 Na₂SO_4, 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 Na₂SO_4, 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).