Phase-Transfer Catalysis: Mixing Effects in Continuous-Flow Liquid/Liquid O- and S-Alkylation Processes

Abstract

This article describes detailed studies on the importance of mixing effects in the O- and S-alkylation of selected phenol and thiophenol substrates. Direct comparison between various continuous-flow reactors and a batch microwave reactor demonstrates the excellent mixing properties of the flow devices, which improve the reaction outcome.

Key words

O- and S-alkylation - phase-transfer catalysis - ethers - continuous-flow - mixing

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• 19 Synthesis of 1,3,5-Trimethyl-2-[(phenylmethyl)thio]-benzene: A: Batch Microwave Conditions: Into a 5-mL microwave Pyrex process vial equipped with a magnetic stir bar organic stock solution A (2 mL; 0.2 M 2,4,6-trimethylthiophenol and 0.24 M benzyl bromide in CH₂Cl₂) and aq stock solution D [2 mL; 0.6 M K₂CO₃ and 0–2 mM (0–1 mol%) TBAB] were placed. The vial was sealed with a Teflon septum fitted in an aluminum crimp top and heated in the microwave reactor for 1–10 min (fixed hold time) at 70–100 °C (3–18 bar). After cooling to 45 °C, the reaction mixture was immediately quenched with 2 M aq HCl to reach pH <2. After 2 min of vigorous stirring the aqueous phase was separated via syringe and 10 μL aliquots of the organic phase were subjected to HPLC analysis (λ = 215 nm). 1,3,5-Trimethyl-2-[(phenylmethyl)thio]benzene was isolated by phase separation from the basic aqueous phase, followed by H₂O extraction (3 ×). The obtained organic phases were combined, dried over MgSO₄, filtrated and concentrated under vacuum to provide the S-benzyl ether (88 mg, 91% yield, yellowish plates); mp 35–36 °C (lit.³: mp 36 °C). MS (APCI, –): m/z = 242.1 [M⁺], 241.1 [M⁺ – 1], 151.1 [M⁺ – 91]. ¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 3 H), 2.37 (s, 6 H), 3.78 (s, 2 H), 6.92 (s, 2 H), 7.08–7.11 (m, 2 H), 7.22–7.25 (m, 3 H). B: Continuous Flow Conditions: For details please see the provided Supporting Information.