Directed Functionalization of Cyano-Substituted Furans and Thiophenes with TMPMgCl·LiCl

Dedicated to Prof. João L. Callegari Lopes in the occasion of his 70^th birthday

Abstract

A number of novel difunctionalized furans and thiophenes has been prepared by the reaction of the cyano-substituted substrates with TMPMgCl·LiCl followed by the reaction with electrophiles. The crucial metalation step takes place under mild conditions allowing the isolation of desired derivatives in reasonable to good yields.

Key words

organomagnesium reagents - ortho metalation - density functional theory - furan - thiophene - nitrile

• References and Notes

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• 14 Synthesis of 3c In a flame-dried flask flushed with nitrogen, substrate 1c (93 mg, 1 mmol) was dissolved in THF (1.5 mL). TMPMgCl·LiCl (1.0 M in THF, 1.8 mL, 1.8 mmol) was added dropwise at 25 °C, and the mixture was stirred for 2 h. After that, a solution of iodine (507.6 mg, 2 mmol) in THF (2 mL) was added dropwise at 0 °C, and the reaction was stirred for 1 h at 25 °C. The reaction mixture was quenched with sat. aq NaHSO₃ solution (5 mL), extracted with EtOAc (3 × 15 mL), and dried over anhydrous MgSO₄. After the filtration, solvent was evaporated in vacuo. Purification by flash-chromatography column (hexane–EtOAc, 95:5) furnished the product 3c as a yellow solid (197 mg, 90%); mp 67–69 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 2.0 Hz, 1 H), 6.60 (d, J = 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.9, 113.7, 113.2, 108.3, 100.2. IR (KBr): 3425, 3143, 2233, 1485, 1344, 1160, 1018, 877, 747, 629 cm^–1. MS (EI, 70 eV): m/z (%) = 219 (43) [M⁺], 190 (7), 127 (29), 64 (100). ESI-HRMS: m/z calcd for C₅H₃INO [M + H]⁺: 219.9259; found: 219.9258.
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• 19 Synthesis of 3o In a flame-dried vial flushed with nitrogen, substrate 1d (109 mg, 1 mmol) was dissolved in THF (1.5 mL), and a solution of ZnCl₂ (1.0 M in THF, 1 mL, 1 mmol) was added. The mixture was stirred for 10 min at 25 °C then TMPMgCl·LiCl (1.0 M in THF, 1.2 mL, 1.2 mmol) was added dropwise, and the mixture was heated for 20 min at 60 °C in a microwave reactor. After that, Pd(PPh₃)₄ (58 mg, 0.05 mmol) in THF (0.5 mL) and 1-chloro-4-iodobenzene (330 mg, 1.4 mmol) in THF (0.5 mL) were added to the reaction mixture which was then heated for 40 min at 60 °C in the microwave reactor. The mixture was then cooled to 25 °C, quenched with sat. aq. NH₄Cl solution (5 mL), extracted with EtOAc (3 × 15 mL), and dried over anhydrous MgSO₄. After the filtration, solvent was evaporated in vacuo. Purification by flash-chromatography column (hexanes–EtOAc, 95:5) furnished the product 3o as a white solid (186 mg, 85%); mp 83–85 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.69 (m, 2 H), 7.45 (m, 2 H), 7.35 (d, J = 5.3 Hz, 1 H), 7.29 (d, J = 5.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 152.4, 135.9, 130.5, 129.8, 129.5, 129.0, 125.8, 115.64, 106.50. MS (EI, 70 eV): m/z (%) = 219 (100) [ M⁺], 184 (43), 140 (41), 113 (7), 92 (6), 75 (8), 58 (12), 45 (12). ESI-HRMS: m/z calcd for C₁₁H₇ClNSNa [M + Na]⁺: 241.9807; found: 241.9800.