Deuterated Aryl Alkyl Ethers Synthesis via Nucleophilic Etherification of Aryl Alkyl Ethers and Thioethers with Deuterated Alcohols

Abstract

A transition-metal-free etherification protocol that is capable of synthesizing deuterated ethers is described. A wide range of aryl alkyl ethers and thioethers were suitable for this transformation owing to the mild reaction conditions. Besides, a series of sterically bulky deuterated alcohols were successfully incorporated into cyano-substituted arenes. The results of mechanistic studies suggested this reaction might take place via nucleophilic aromatic substitution pathway.

Key words

deuterium - ether - thioether - etherification - nucleophilic aromatic substitution

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• 16 Experimental Procedures General Procedure 1 An oven-dried vial (4 ml) equipped with a magnetic stir bar was charged with 2-(methoxy)benzonitrile (1a, 0.2 mmol, 26.6 mg). The vial was then moved into a N₂-filled glovebox. KOt-Bu (0.4 mmol, 44.8 mg), 4-phenylcyclohexan-1-d-1-ol (2a, 0.4 mmol, 46.8 mg), and 1,4-dioxane (0.2 mL) were added to the vial. The vial was capped, and the resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was then allowed to cool to room temperature, diluted with Et₂O (3 ml), and then filtered through a plug of silica gel, washing with THF. The crude mixture was concentrated in vacuo and purified by flash column chromatography on silica gel to provide the corresponding product 3a (43.1 mg, 78% yield) as a white solid (eluent: hexanes/EtOAc = 30:1); mp 138.6 ℃ . ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (d, J = 7.7 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.36 (t, J = 7.4 Hz, 2 H), 7.27 (t, J = 8.1 Hz, 3 H), 7.07 (d, J = 8.5 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 2.66 (t, J = 11.8 Hz, 1 H), 2.33 (d, J = 12.1 Hz, 2 H), 2.08 (d, J = 12.1 Hz, 2 H), 1.78 (t, J = 13.0 Hz, 2 H), 1.67 (t, J = 12.9 Hz, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 159.98, 146.09, 134.19, 134.03, 128.55, 126.84, 126.35, 120.83, 116.80, 114.23, 103.35, 77.43 (t, J = 21.5 Hz), 43.33, 32.22, 32.03 ppm. HRMS (ESI): m/z calcd for C₁₉H₁₈DNONa [M + Na]: 301.1422; found: 301.1414. IR (neat): 3057, 2944, 2890, 2225, 1597, 1488, 1454, 1292, 746 cm^–1. General Procedure 2 An oven-dried vial (4 ml) equipped with a magnetic stir bar was charged with 2′-methoxy-3-(methylthio)-(1,1′-biphenyl)-4-carbonitrile (4h, 0.2 mmol, 51 mg). The vial was then moved into a N₂-filled glovebox. KOt-Bu (0.4 mmol, 44.8 mg), cyclooctan-1-d-1-ol (5h, 0.4 mmol, 51.4 mg), and 1,4-dioxane (0.2 mL) were added to the vial. The vial was capped, and the resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was then allowed to cool to room temperature, diluted with Et₂O (3 mL), and then filtered through a plug of silica gel, washing with THF. The crude mixture was concentrated in vacuo and purified by flash column chromatography on silica gel to provide the corresponding product 6h (55.7 mg, 83% yield) as a rose-red solid (eluent: hexanes/Et₂O = 10:1); mp 85.8 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 7.9 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.26 (s, 1 H), 7.10 (d, J = 10.6 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 1 H), 3.84 (s, 3 H), 2.01–1.93 (m, 4 H), 1.89–1.78 (m, 2 H), 1.67 (dd, J = 13.2, 6.4 Hz, 1 H), 1.58 (dt, J = 12.8, 7.6 Hz, 6 H), 1.28 (d, J = 11.5 Hz, 1 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 159.49, 156.42, 144.82, 133.33, 130.63, 129.93, 129.20, 121.75, 121.17, 117.16, 115.47, 111.56, 101.37, 79.18 (t, J = 21.6 Hz), 55.69, 31.47, 27.15, 25.72, 23.03 ppm. HRMS (ESI): m/z calcd for C₂₂H₂₄DNO₂Na [M + Na]: 359.1840; found: 359.1838. IR (neat): 3025, 2925, 2853, 2223, 1605, 1556, 1465, 1405, 1244, 754 cm^–1.