Subsupercritical Water Generated by Inductive Heating Inside Flow Reactors Facilitates the Claisen Rearrangement

Abstract

Claisen rearrangement of electron-deficient O-allylated phenols, including fluorine-modified phenols, is facilitated in aqueous media at high temperatures and pressures under flow conditions, as opposed to organic solvents. The O-allylation of phenols can be coupled with the Claisen rearrangement in an integrated flow system.

Key words

Claisen rearrangement - flow chemistry - fluorobenzenes - inductive heating - supercritical water

Publication History

Received: 14 August 2020

Accepted after revision: 16 September 2020

Article published online:
27 October 2020

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• 18 Two-Step Flow Synthesis of 2-Allyl-4,6-difluorophenol (23) An allyl bromide solution in benzene (1 M) was combined with a 0.1 M aqueous sodium phenolate solution (7, sodium salt) via a static mixer. An additional 0.5 mol/L of sodium hydroxide was added to the aqueous sodium phenolate solution. Both reagents were pumped at a flow rate of 0.3 mL/min through a 1/8′′ steel reactor (coiled, V = 3.4 mL). The reactor was heated to 110 °C in an oscillating electromagnetic high-frequency field. The reaction mixture was then passed through a second reactor (3.2 mL), which was heated to a temperature of 265 °C at a pressure of 183–184 bar. The reaction mixture was collected over a period of 25 min and extracted with diethyl ether (3 × 10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure and co-evaporated with methanol. The residue obtained was purified by flash chromatography (pentane to pentane/diethyl ether 10%). 2-Allyl-4,6-difluorophenol (24) Yellow oil (80.2 mg, 0.47 mmol; 64%). ¹H NMR (600 MHz, CDCl₃, CHCl₃ = 7.26 ppm): δ = 6.75–6.71 (1 H, m, H-7), 6.68–6.66 (1 H, m, H-5), 5.98–5.92 (1 H, m, H-2), 5.14–5.10 (2 H, m, H-1), 4.99 (1 H, br s, OH), 3.41–3.40 (2H, m, H-3). ¹³C NMR (150 MHz, CDCl₃, CDCl₃ = 77.16 ppm): δ = 156.5–154.8 (q, dd, J = 240.6 Hz, 11.5 Hz, C-6), 151.4–149.7 (q, dd, J = 238.7 Hz, 12.7 Hz, C-8), 138.0–137.9 (q, dd, J = 14.0 Hz, 3.5 Hz, C-9), 135.3 (t, C-2), 129.6–129.5 (q, dd, J = 8.3 Hz, 2.6 Hz, C-4), 116.9 (s, C-1), 112.0–111.8 (t, dd, J = 22.6 Hz, 3.4 Hz, C-5), 102.0–101.7 (t, dd, J = 27.2 Hz, 23.0 Hz, C-7), 34.0–33.9 (s, dd, J = 3.1 Hz, 1.4 Hz C-3). HRMS (EI): m/z calcd for C₉H₈OF₂: 170.0543; found: 170.0543; R_f = 0.24 (pentane/Et₂O = 9:1).