Regioselective Synthesis of Functionalized 3-(Methylthio)phenols by the First Formal [3+3] Cyclocondensations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with 1,1-Bis(methylthio)-1-en-3-ones

Abstract

The [3+3] cyclocondensation of 1,3-bis(silyl enol ethers) with 1,1-bis(methylthio)-1-en-3-ones results in the regioselective formation of 3-(methylthio)phenols. The products represent useful synthetic building blocks, which are not readily available by other methods.

Key words

arenes - cyclizations - regioselectivity - silyl enol ethers

References and Notes

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• 23 Typical Procedure: Synthesis of Ethyl 4-Ethyl-6-hydroxy-3-methyl-2-(methylthio)benzoate (4b) To a solution of 2b (0.190 g, 1.0 mmol) and 3b (0.549 g, 2.0 mmol) in CH₂Cl₂ (2 mL) was added TiCl₄ (0.11 mL, 1.0 mmol) at -78 ˚C under argon. The temperature of the reaction mixture was allowed to rise to 20 ˚C during 14 h, and an aq HCl solution (10%, 10 mL) was added. The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. After column chromatography (SiO₂, heptane-EtOAc = 10:1), 4b was obtained as a colorless solid (227 mg, 89%); mp 120-121 ˚C; R_f  = 0.39 (heptane-EtOAc = 3:1). ^¹H NMR (250 MHz, CDCl₃): δ = 9.06 (s, 1 H, OH), 6.78 (s, 1 H, ArH), 4.43 (q, ^³ J = 7.1 Hz, 2 H, OCH₂), 2.60 (q, ^³ J = 7.5 Hz, 2 H, ArCH₂), 2.45 (s, 3 H, ArCH₃), 2.28 (s, 3 H, SCH₃), 1.41 (t, ^³ J = 7.1 Hz, 3 H, OCH₂CH ₃), 1.18 (t, ^³ J = 7.5 Hz, 3 H, ArCH₂CH ₃). ^¹³C NMR (300 MHz, CDCl₃): δ = 170.2 (C=O), 156.9 (CO), 148.8, 136.2, 132.7, 117.3 (C_Ar), 116.9 (CH_Ar), 61.8 (OCH₂), 27.6 (ArCH₂), 20.0, 16.2, 14.0, 13.8 (CH₃). IR (ATR): ν = 3298 (OH), 1699 (C=O) cm^-¹. MS (EI, 70 eV): m/z (%) = 254 (39) [M⁺], 209 (21), 208 (100), 193 (8), 180 (27), 165 (32). Anal. Calcd for C₁₃H₁₈O₃S (254.10): C, 61.39; H, 7.13. Found: C, 61.35; H, 7.27
• 24 CCDC-685823 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; or [e-mail]