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Synlett 2009(1): 92-96  
DOI: 10.1055/s-0028-1087485
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

General Synthetic Approach to 4-Substituted 2,3-Dihydrofuro[2,3-b]pyridines and 5-Substituted 3,4-Dihydro-2H-pyrano[2,3-b]pyridines

Youssef Hajbia,b, Franck Suzenet*a, Mostafa Khouilib, Said Lazarc, Gérald Guillaumet*a
a Institut de Chimie Organique et Analytique (ICOA), UMR-CNRS 6005, University of Orléans, B. P. 6759, 45067 Orléans, France
e-Mail: gerald.guillaumet@univ-orleans.fr; e-Mail: franck.suzenet@univ-orleans.fr;
b Laboratoire de Chimie Organique et Analytique, Université Sultan Moulay Slimane FST, BP 523, 23000 Beni-Mellal, Morocco
c Laboratoire de Biochimie, Environnement et Agroalimentaire, University Hassan II-Mohammedia FST, BP 146, 20800 Mohamedia, ­Morocco
Fax: +33(2)38417281;
Further Information

Publication History

Received 21 July 2008
Publication Date:
12 December 2008 (online)

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Abstract

An efficient strategy for the synthesis of functionalised 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines is reported. The strategy is based on an intramolecular inverse-electron-demand Diels-Alder reaction starting from 1,2,4-triazines appropriately functionalised with alkynes, followed by various cross-coupling reactions (Suzuki, Stille, and Sonogashira).

Key words

inverse-electron-demand Diels-Alder reactions - dihydrofuro[2,3-b]pyridines - dihydropyrano[2,3-b]pyridines - cycloaddition - microwave activation

    References and Notes

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5

General Procedure for the Intramolecular Inverse-Electron-Demand Diels-Alder Reaction for Compounds 10-13
Bromoalkyne 5, 6 or 8, 9 (0.33 mmol) was dissolved in chlorobenzene (2 mL) and heated at 180-200 ˚C under microwave irradiation (3-6 bar of pressure can be involved). The reaction was monitored by TLC (for reaction time and temperature, see Table  [¹] ). After complete conversion of the starting material, the reaction was purified by chromatog-raphy (eluent: PE-EtOAc, 8:2) to give the desired products 10-13.
4-Bromo-2,3-dihydrofuro[2,3- b ]pyridine (10) Yield 82%, as a colorless oil. IR (KBr): 3000, 2908, 1577, 945, 713, 698, 614 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.78 (d, J = 5.6 Hz, 1 H), 6.91 (d, J = 5.6 Hz, 1 H), 4.64 (t, J = 8.8 Hz, 2 H), 3.23 (t, J = 8.8 Hz, 2 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 168.4 (C), 147.2 (CH), 129.9 (C), 121.6 (C), 119.8 (CH), 68.4 (CH2), 29.2 (CH2). MS: m/z [M + 1] = 200 (for 79Br) and 202 (for 8¹Br). HRMS: m/z calcd for C7H7NO79Br [M + 1]+: 199.9709; found: 199.9709.

6

General Procedure for the Suzuki Cross-Coupling Reaction for Compounds 14-17
A solution of compounds 10-13 (0.73 mmol) in ethylene glycol dimethyl ether (5 mL, freshly distilled and degassed) under argon was treated with furan-2-boronic acid. A solution of Na2CO3 (154 mg, 1.45 mmol) in H2O (2.5 mL) was added before adding Pd(PPh3)4 (42 mg, 0.036 mmol), and the mixture was stirred vigorously at 75 ˚C and monitored by TLC (for reaction time, see Table  [²] ). After complete conversion of the starting material, the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried over MgSO4, evapo-rated, and purified by column chromatography (eluent:
PE-EtOAc) to give the corresponding compounds 14-17. 4-Fur-2-yl-2,3-dihydrofuro[2,3- b ]pyridine (14)
Yield 74%, as a yellow solid; mp 93-95 ˚C. IR (KBr): 2971, 1605, 1451, 1229, 1125, 1025, 807 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.97 (d, J = 5.3 Hz, 1 H), 7.56 (t, J = 1.2 Hz, 1 H), 7.05 (d, J = 5.3 Hz, 1 H), 6.74 (d, J = 3.4 Hz, 1 H), 6.56 (dd, J = 1.2, 3.4 Hz, 1 H), 4.65 (t, J = 8.4 Hz, 2 H), 3.42 (t, J = 8.4 Hz, 2 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 169.5 (C), 151.0 (C), 146.8 (CH), 143.7 (CH), 135.1 (C), 113.4 (C), 112.0 (CH), 111.5 (CH), 110.5 (CH), 68.8 (CH2), 29.1 (CH2). MS: m/z [M + 1] = 188. HRMS: m/z calcd for C11H10NO2 [M + 1]+: 188.0694; found: 188.0704.

7

General Procedure for the Stille Cross-Coupling Reaction for Compounds 18-21
To a suspension of freshly prepared Pd(PPh3)4 (25 mg, 0018 mmol) and LiCl (42 mg, 0.99 mmol) in dry DMF was added a solution of compounds 14-17 (0.36 mmol) and tributyl-2-propenylstannane (169 µL, 0.54 mmol) in dry DMF under argon. After 2-3 h (see Table  [³] ) under reflux at 90 ˚C, the reaction mixture was cooled to r.t. and quenched with brine (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), the organic phase were collected, dried over MgSO4, and the solvents were removed under reduced pressure. Flash column chromatography (eluent: PE-EtOAc, 9:1) of the crude gave the desired products 18-21. 4-Allyl-2,3-dihydrofuro[2,3- b ]pyridine (23)
Yield 62%, as a yellow oil. IR (KBr): 2976, 2906, 1639, 1608, 1588, 1227 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.90 (d, J = 5.3 Hz, 1 H), 6.62 (d, J = 5.3 Hz, 1 H), 5.95-5.79 (m, 1 H), 5.16-5.03 (m, 2 H), 4.60 (t, J = 8.4 Hz, 2 H), 3.30 (d, J = 6.6 Hz, 2 H), 3.17 (t, J = 8.4 Hz, 2 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 168.8 (C), 146.7 (CH), 146.3 (C), 134.0 (CH), 118.3 (C), 117.2 (CH2), 117.1 (CH), 68.8 (CH2), 37.3 (CH2), 26.8 (CH2). MS: m/z [M + 1] = 162. HRMS: m/z calcd for C10H12NO [M + 1]+: 162.0906; found: 1162.0919.

8

General Procedure for the Sonogashira Cross-Coupling Reaction for Compounds 22-25
A solution of the aryl bromide 12 or 13 (1.11 mmol) in anhyd ethylene glycol dimethyl ether (2.0 mL) was treated with the appropriate alkyne (1.11 mmol) and Et3N (3 mL). After 5 min, CuI (0.021 g, 0.11 mmol) and Pd(PPh3)2Cl2 (0.04 mg, 0.06 mmol) were added. The mixture was then stirred vigorously at 60 ˚C and monitored by TLC. After 24 h, the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, and dried over MgSO4, evaporated and purified by column chromatography (eluent: PE-EtOAc, 9:1) to give the corresponding compounds 22-25. 7-Phenyl-4-[2-(trimethylsilyl)ethynyl]-3,4-dihydro-2 H -pyrano[2,3- b ]pyridine (25)
Yield 44%, as a dark oil. IR (KBr): 3049, 2248, 1580, 1428, 1352, 1233, 904, 742 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.96 (d, J = 8.2 Hz, 2 H), 7.43-7.33 (m, 4 H), 4.34 (t, J = 5.2 Hz, 2 H), 3,30 (t, J = 6.5 Hz, 2 H), 2.06 (m, 2 H), 0.26 (s, 9 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 161.1 (C), 153.8 (C), 138.2 (C), 133.5 (C), 129.0 (CH), 128.6 (CH), 126.7 (CH), 117.6 (C), 116.4 (CH), 103.7 (C), 100.9 (C), 67.3 (CH2), 23.6 (CH2), 21.8 (CH2), -0.01 (CH3). MS: m/z [M + 1] = 308. HRMS: m/z calcd for C19H22NOSi [M + 1]+: 308.1468; found: 308.1471.

9

General Procedure for the Stille Reaction with 3-Bromopyridine
Compounds 32 and 33 were prepared in 70% yield, according to the procedure used for the synthesis of 18-21. The purification was carried out by flash chromatography over SiO2 (eluent: PE-EtOAc, 8:2 to 6:4). 7-Phenyl-5-pyrid-3-yl-3,4-dihydro-2 H -pyrano[2,3- b ]pyridine (33)
Yield 68%, as a clear yellow oil. IR (KBr): 3160, 2970, 2253, 1574, 1444, 1002, 906, 740 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 8.64 (s, 1 H), 8.63 (d, J = 1.2 Hz, 1 H), 8.00 (d, J = 6.5 Hz, 2 H), 7.68 (dd, J = 1.2 Hz, J′ = 5.7 Hz, 1 H), 7.43-7.23 (m, 4 H), 7.23 (s, 1 H), 4.40 (t, J = 5.0 Hz, 2 H), 2.67 (t, J = 6.2 Hz, 2 H), 2.00-1.94 (m, 2 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 161.3 (C), 154.3 (C), 149.5 (CH), 149.3 (CH), 148.8 (C), 138.3 (C), 136.0 (CH), 134.7 (C), 129.1 (CH), 128.7 (CH), 126.8 (CH), 123.4 (CH), 114.9 (C), 113.6 (CH), 67.3 (CH2), 23.8 (CH2), 22.0 (CH2). MS: m/z [M + 1] = 289. HRMS: m/z calcd for C19H17N2O [M + 1]+: 289.1350; found: 289.1341.