Regioselective Synthesis of Rare 3-Halomethylphenols Based on Formal [3+3] Cyclizations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes

Abstract

The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with halo-substituted enones afforded 3-difluorochloromethyl-, 3-difluorobromomethyl-, 3-dichloromethyl-, and 3-trichloro-methylphenols with very good regioselectivity. The hydrolysis of the dichloromethyl group gave functionalized 3-formylphenols, which are not readily available by other methods.

Key words

arenes - cyclization - regioselectivity - silyl enol ethers

References and Notes

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25

General Procedure for the Synthesis of 5a-p
To CH₂Cl₂ solution (4 mL) of 3a-e (2.0 mmol) and of 4a-i (2.0 mmol) was added TiCl₄ (2.0 mmol) at -78 °C under argon atmosphere. The temperature of the solution was allowed to rise to 20 °C during 20 h. The solution was poured into an aq solution of HCl (10%). The organic and the aqueous layer were separated and the latter was extracted (3×) with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, heptane-EtOAc = 10:1).
Methyl 6-(Dichlorofluoromethyl)-2-hydroxy-3-meth-oxybenzoate (5b)
Starting with 3a (370 mg, 2.0 mmol), 4b (581 mg, 2.0 mmol), and TiCl₄ (380 mg, 2.0 mmol), 5b was isolated as a colorless oil (261 mg, 50%); mp 50-51 °C; R _f = 0.78
(n-heptane-EtOAc = 1:1). ¹H NMR (300 MHz, CDCl₃): δ = 8.01 (s, 1 H, OH), 7.23 (d, ^³ J = 8.8 Hz, 1 H, CH), 6.94 (d, ^³ J = 8.8 Hz, 1 H, CH), 3.97, 3.96 (s, 3 H, OMe). ¹³C NMR (63 MHz, CDCl₃): δ = 167.4 (O-C=O), 149.7, 146.6 (C-O), 126.5 (t, J _C,F = 27.0 Hz, C-6), 125.3 (t, J _C,F = 289.8 Hz, CF₂Cl), 117.9 (t, J _C,F = 7.8 Hz, C-5), 115.2 (t, J _C,F = 2.8 Hz, C-1), 111.5 (C-4), 56.3, 52.7 (OMe). ¹⁹F NMR (235 MHz, CDCl₃): δ = -45.0 (CF₂Cl). IR (KBr): ν = 3466 (br, m), 2969 (w), 2843 (w), 1735 (s), 1616 (m), 1590 (m) cm^-1. MS (EI, 70 eV): m/z (%) = 268 (21) [M⁺, ³⁷Cl], 266 (62) [M⁺, ³⁵Cl], 236 (37), 234 (100), 211 (64), 198 (90). HRMS (EI, 70 eV): m/z calcd for C₁₀H₉F₂ClO₄ [M⁺, ³⁵Cl]: 266.01519; found: 266.015398.