Synthesis of 6,6-Difluorocyclopropa[b]furo[2,3-c]pyrrole and 7-Fluoro­furo[3,2-c]pyridine Derivatives via 1,5-Electrocyclization of Carbene-Derived Azomethine Ylides

Abstract

Reaction of N-(5-R-furan-2-ylmethylidene)anilines with difluorocarbene, generated in CF₂Br₂/Pb*/Bu₄NBr/ultrasound system proceeds via 1,5-electrocyclization of intermediate azomethine ylides to give 6,6-difluorocyclopropa[b]furo[2,3-c]pyrrol-4(5H)-one or/and 4,4,6,6-tetrafluorocyclopropa[b]furo[2,3-c]pyrrole derivatives. Thermolysis of these compounds under solvent-free conditions gives rise to 2,5-disubstituted 7-fluoro-4,5-dihydrofuro[3,2-c]pyridine-4(5H)-ones in high yields.

ylides - carbenes - cylizations - fused heterocycles

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11

General Procedure for Preparation of Compounds 3 and 4.
A flask containing active lead (1.2 g, 5.8 mmol) and CH₂Cl₂ (7 mL) was charged with Bu₄NBr (2.0 g, 6.0 mmol), imine 1a-f (2.7 mmol), and CBr₂F₂ (1.95 g, 9.3 mmol). The flask was tightly stopped, and the mixture was irradiated with ultrasound at 40 °C until the lead was completely consumed. Chromatography (hexane-EtOAc, 4:1) followed by recrystallization provided compounds 4 or/and 3.
5-(4-Bromophenyl)-4,4,6,6-tetrafluoro-2-(2-fluoro-phenyl)-4,5,5a,6-tetrahydro-3a H -cyclo-propa[ b ]fu-ro[2,3- c ]pyrrole ( 3d): mp 135-140 °C dec. (hexane-Et₂O). ¹H NMR (300 MHz, CDCl₃): δ = 3.88 (t, J _HF = 7.3 Hz, 1 H, 5a-H), 4.60 (dddd, J = 13.3, 6.4, 3.9, 2.6 Hz, 1 H, 3a-H), 5.93 (dd, J = 3.9, 2.6 Hz, 1 H, 3-H), 7.01-7.69 (m, 8 H, Ar-H). ¹³C NMR (75 MHz, CDCl₃): δ = 50.5 (t, J _CF = 15.5 Hz, 1a-C), 58.4 (t, J _CF = 32.1 Hz, 3a-C), 70.0 (m, 6a-C), 98.0 (d, J _CF = 14.4 Hz, 3-C), 109.7 (ddd, J _CF = 320, 302, 9.4 Hz, 6-C), 115.3, 115.6 (d, J _CF = 21.6 Hz), 116.6 (d, J _CF = 11.6 Hz), 118.4, 123.9 (d, J _CF = 3.9 Hz), 127.3 (d, J _CF = 1.7 Hz, C_Ar), 128.6 (ddd, J _CF = 260, 247, 5.5 Hz, 4-C), 130.9 (d, J _CF = 8.8 Hz), 131.8, 137.7 (d, J _CF = 5.0 Hz, C_Ar), 152.7 (2-C), 159.9 (d, J _CF = 254 Hz, C_Ar-F). Anal. Calcd for C₁₉H₁₁BrF₅NO: C, 51.38; H, 2.50; N 3.15. Found: C, 51.41; H, 2.75; N, 2.92. 6,6-Difluoro-5-phenyl-5a,6-dihydro-3a H -cyclo-propa[ b ]furo[2,3- c ]pyrrol-4 (5 H )-one ( 4a): mp 87-88 °C (hexane-Et₂O). IR (CHCl₃): 1725 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.96 (dd, ³ J _HF = 8.2, 1.7 Hz, 1 H, 5a-H), 4.22 (dd, J = 4.5, 2.6 Hz, 1 H, 3a-H), 5.54 (dd, J = 4.5, 2.6 Hz, 1 H, 3-H), 6.62 (t, J = 2.6 Hz, 1 H, 2-H), 7.23-7.54 (m, 5 H, Ph-H). ¹³C NMR (75 MHz, CDCl₃): δ = 49.5 (dd, J _CF = 17.7, 15.5 Hz, 5a-C), 51.6 (d, J _CF = 1.7 Hz, 3a-C), 68.2 (dd, J _CF = 19.4, 11.1 Hz, 6a-C), 100.4 (d, J _CF = 1.1 Hz, 3-C), 108.5 (dd, J _CF = 319, 301 Hz, 6-C), 120.7, 125.7, 128.8, 137.3 (C_Ph), 147.5 (2-C), 170.8 (dd, J _CF = 3.9, 3.2 Hz, 4-C). Anal. Calcd for C₁₃H₉F₂NO₂: C, 62.65; H, 3.64; N, 5.62. Found: C, 62.64; H, 3.82, N, 5.73.

12

General Procedure for Preparation of Compounds 8. Compound 3 or 4 (0.52 mmol) is placed to a dry, 10 mL, one-necked round-bottomed flask and is heated at 160 °C for 10 min. Upon cooling to r.t. a brown solid forms; recrystallization from CH₂Cl₂-Et₂O mixture gives furo[3,2-c]pyridine 8 as a colorless solid.
7-Fluoro-5-phenylfuro[3,2- c ]pyridine-4 (5 H )-one ( 8a): mp 120-121 °C (CH₂Cl₂-Et₂O). IR (CHCl₃): 1630 (C=C), 1705 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.07 (dd, J _HH = 2.0 Hz, J _HF = 2.3 Hz, 1 H, 3-H), 7.28 (d, J _HF = 5.9 Hz, 1 H, 6-H), 7.39-7.52 (m, 5 H, Ar-H), 7.63 (d, 1 H, J _HH = 2.0 Hz, 2-H). ¹³C NMR (75 MHz, CDCl₃): δ = 108.2 (d, J _CF = 2.2 Hz, 3-C), 117.5 (d, J _CF = 3.3 Hz, 3a-C), 119.7 (d, J _CF = 32.6 Hz, 6-C), 126.5, 128.1, 129.0 (C_Ar), 137.8 (d, J _CF = 239 Hz, 7-C), 140.0 (C_Ar), 144.6 (2-C), 148.9 (d, J _CF = 15.5 Hz, 7a-C), 156.9 (4-C). Anal. Calcd for C₁₃H₈FNO₂: C, 68.12; H, 3.52; N 6.11. Found: C, 67.96; H, 3.55; N 6.08.