Regioselective Synthesis of Substituted Tetrahydrofurans through Prins Cyclization

Abstract

The synthesis of functionalized tetrahydrofurans was ­accomplished through the TfOH-catalyzed Prins cyclization. The reaction proceeded regioselectively at the internal alkene carbon in the presence of catalytic amounts of TfOH to afford the five-membered ring, rather than the typical six-membered ring. Another attractive feature of this protocol is the metal catalyst-free characteristic of the cyclization process.

Key words

alcohols - aldehydes - furans - cyclization - regioselectivity

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• 9 Representative Procedure for the Synthesis of 3a To a solution of 1-(4-bromophenyl)-4-methylpent-3-en-1-ol (1a, 255 mg, 1 mmol) and 4-bromobenzaldehyde (2a, 185 mg, 1 mmol) in CH₂Cl₂ (4 mL) was added dropwise TfOH (9 μL, 0.1 mmol) in CH₂Cl₂ (1 mL) at 0 °C. The reaction mixture was warmed to 40 °C and stirred for 3 h. Then it was quenched with sat. aq NaHCO₃. The organic layer was extracted with CH₂Cl₂, washed with brine, dried with MgSO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (PE–EtOAc = 60:1, v/v) to afford 3a as a yellow oil (384 mg, 91% yield). ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (d, J = 8.4 Hz, 2 H), 7.43(d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.14 (d, J = 8.4 Hz, 2 H), 5.19 (t, J = 2.9 Hz, 1 H), 4.95 (dd, J = 9.6, 6.0 Hz, 1 H), 3.21 (ddd, J = 16.0, 6.0, 1.6 Hz, 1 H), 2.72 (ddd, J = 16.0, 9.6, 2.8 Hz, 1 H), 1.55 (s, 3 H), 1.46 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.8, 141.1, 136.5, 131.6, 131.5, 129.7, 129.7, 127.8, 121.5, 120.5, 118.7, 84.0, 77.4, 40.7, 29.2, 27.3. ESI-HRMS: m/z calcd for C₁₉H₁₈Br₂ONa [M + Na]⁺: 442.9622; found: 442.9623.