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

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

• 1a Boger DL. Chem. Rev.  1986,  86:  781 
• 1b Boger DL. Tetrahedron  1983,  39:  2869 
• 1c Sauer J. Heldmann DK. Hetzenegger J. Krauthan J. Sichert H. Schuster J. Eur. J. Org. Chem.  1998,  2885 
• 2a Hajbi Y. Suzenet F. Khouili M. Lazar S. Guillaumet G. Tetrahedron  2007,  63:  8286 
• 2b Lindsley CW. Layton ME. In Science of Synthesis   Vol. 17:  Weinreb SM. Thieme; NewYork: 2003.  p.357-447  
• 2c Branowska D. Ostrowski S. Rykowski A. Chem. Pharm. Bull.  2002,  50:  463 
• 2d Sauer J. Heldmann DK. Pabst GR. Eur. J. Org. Chem.  1999,  313 
• 2e Taylor EC. Macor JE. French LG. J. Org. Chem.  1991,  56:  1807 
• 2f Taylor EC. Macor JE. J. Org. Chem.  1987,  52:  4280 
• 2g Taylor EC. Macor JE. Tetrahedron Lett.  1986,  27:  2107 
• 2h Taylor EC. Macor JE. J. Org. Chem.  1989,  54:  4984 
• 2i Taylor EC. Pont JL. J. Org. Chem.  1987,  52:  4287 
• 2j Seitz G. Görge L. Dietrich S. Tetrahedron Lett.  1985,  26:  4355 
• 2k Buysens KJ. Vandenberghe DM. Toppet SM. Hoornaert GJ. Tetrahedron  1995,  51:  12463 
• 2l Taylor EC. Macor JE. Tetrahedron Lett.  1986,  27:  431 
• 2m Taylor EC. Macor JE. Pont JL. Tetrahedron  1987,  43:  5145 
• 2n Taylor EC. Bull. Soc. Chim. Belg.  1988,  97:  599 
• 2o Haenel F. John R. Seitz G. Arch. Pharm.  1992,  325:  349 
• 2p Frissen AE. Marcelis ATM. Buurman DG. Pollmann CAM. van der Plas HC. Tetrahedron  1989,  45:  5611 
• 2q Seitz G. Dietrich S. Gorge L. Richter J. Tetrahedron Lett.  1986,  27:  2747 
• 2r Seitz G. Dietrich S. Arch. Pharm.  1985,  318:  1048 
• 2s Seitz G. Dietrich S. Arch. Pharm.  985,  318:  1051 
• 2t Lipińska T. Branowska D. Rykowski A. Chem. Heterocycl. Compd.  1999,  35:  334 
• 3a Sammes PG. Taylor JB. Comprehensive Medicinal Chemistry   Vol. 6:  Pergamon Press; Oxford: 1990. 
• 3b Lochead A, Jegham S, Galli F, and Gallet T. inventors; WO  9842713.  ; Chem. Abstr. 1998, 672553
• 3c Van Lommen GRE, Fernandez-Gadea FJ, Andres-Gil JI, and Matesanz-Ballesteros ME. inventors; WO  9505381.  ; Chem. Abstr. 1995, 557282
• 3d Comoy C. Marot C. Podona T. Baudin ML. Morin-Allory L. Guillaumet G. Pfeiffer B. Caignard DH. Renard P. Rettori MC. Adam G. Guardiola-Lemaitre B. J. Med. Chem.  1996,  39:  4285 
• 3e Podona T. Guardiola-Lemaitre B. Caignard D.-H. Adam G. Pfeiffer B. Renard P. Guillaumet G. J. Med. Chem.  1994,  37:  1779 
• 4 Li L.-S. Wu Y.-L. Tetrahedron Lett.  2002,  43:  2427 

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.