Iron(III) Chloride Catalyzed Nazarov Cyclization of 3-Substituted Thiophene Derivatives

Abstract

The Nazarov cyclization of silicon-free 3-substituted thiophene derivatives was effectively catalyzed by 10 mol% FeCl₃, which provided the desired cyclized trans product in good yield.

Key words

iron catalyst - Nazarov cyclization - thiophene

References and Notes

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• 16 Crystallographic data for compound 2a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 673143. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail:[e-mail]]
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11

Scandium-catalyzed Nazarov cyclization of 2- or 3-substituted silicon-free thiophene substrates was reported by Frontier et al., see: ref. 10g.

12

Nazarov Reaction of 1a; Typical Procedure (Table 1, entry 2): To a solution of FeCl₃ (3.2 mg, 0.02 mmol) in toluene (0.4 mL) was added 1a (54 mg, 0.2 mmol) at r.t., and the mixture was stirred at 60 °C for 5 h. The reaction mixture was quenched with H₂O, and extracted with Et₂O. The combined organic layers were dried over anhyd MgSO₄ and concentrated in vacuo. The residue was purified by preparative silica gel TLC (hexane-EtOAc = 4:1) to give 2a (49 mg, 90%) as a white solid; R _f 0.41 (hexane-EtOAc, 4:1); mp 96-97 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.83 (s, 3 H), 3.92 (d, J = 3.0 Hz, 1 H), 5.11 (d, J = 3.0 Hz, 1 H), 7.20-7.22 (m, 3 H), 7.30-7.73 (m, 3 H), 7.42 (d, J = 5.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 46.9, 52.9, 68.2, 119.6, 127.2, 128.0, 129.2, 132.6, 140.6, 144.4, 168.4, 172.7, 189.7. IR (KBr): 642, 698, 733, 1013, 1161, 1240, 1321, 1433, 1701, 1740 cm^-1. EI-MS: m/z = 272. HRMS (EI): m/z calcd for C₁₅H₁₂O₃S: 272.0507; found: 272.0509.

13

Most combinations resulted in no reaction, except for FeCl₃ in toluene (59%), FeCl₃ in dichloroethane (32%), Fe(ClO₄)₂·6H₂O in dichloroethane (32%) or Fe(ClO₄)₃·nH₂O in CH₂Cl₂ (30%).

14

Decarbomethoxylated product 3a: ¹H NMR (500 MHz, CDCl₃): δ = 2.93 (dd, J = 2.7, 18.5 Hz, 1 H), 3.50 (dd, J = 7.1, 18.5 Hz, 1 H), 4.69 (dd, J = 2.7, 7.1 Hz, 1 H), 7.17-7.20 (m, 3 H), 7.24-7.29 (m, 1 H), 7.32-7.35 (m, 2 H), 7.38 (d,
J = 5.1 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 43.0, 52.2, 119.3, 127.0, 127.5, 129.1, 132.2, 142.5, 146.5, 173.6, 197.2.

15

This decarbomethoxylation reaction might be caused by trace amount of H₂O, because the reaction was conducted under air.