Synthesis of Alkyl Aryl Ethers by O-Arylation of Alcohols with Diaryliodonium Salts: Scope, Limitations, and Mechanism

This manuscript is dedicated to the memory of Professor Keith Fagnou.

Abstract

We describe the development of a C–O coupling reaction between aryl(2,4,6-trimethoxyphenyl)iodonium salts and aliphatic alcohols under weak base conditions. The scope of the reaction is presented, with 16 examples ranging in yield from moderate to high (54–96%). The limitations of the reaction are also presented. Mechanistic experiments reveal a complex network of reactions that include side reactions that generate arynes and oxidize the alcohol nucleophile.

Key words

arylation - ethers - alcohols - diaryliodonium compounds - ligand coupling - C–O coupling

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• 18 C–O Coupling; General Procedure The appropriate aryl(TMP)iodonium tosylate 1a–l (0.5 mmol, 1 equiv), Cs₂CO₃ (1.5 mmol, 3 equiv), alcohol 2a–f (0.75 mmol, 1.5 equiv), and toluene (2.5 mL) were added to an 8 mL vial, equipped with a magnetic stirrer bar and sealed with a cap. The vial was placed in a preheated aluminum block set to 55 °C, and the mixture was stirred vigorously for 2 h. The vial was removed from the block and the mixture was partitioned between CH₂Cl₂ and sat. aq NH₄Cl. The resulting organic solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0–3% EtOAc–hexane).
• 19 Benzyl 4-Chlorophenyl Ether (3a) White solid; yield 82.3 mg (75%). ¹H NMR (400 MHz, CDCl₃): δ = 7.42–7.32 (m, 5 H), 7.22 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 2 H), 5.02 (s, 2 H). ¹³C {¹H} NMR (101 MHz, CDCl₃): δ = 157.4, 136.6, 129.4, 128.7, 128.1, 127.5, 125.8, 116.2, 70.3. 4-Nitrophenyl Pentyl Ether (3g) Yellow oil; yield: 102.8 mg (98%). ¹H NMR (400 MHz, CDCl₃): δ = 8.19–8.15 (m, 2 H), 6.96–6.92 (m, 2 H), 4.04 (t, J = 6.5 Hz, 2 H), 1.86–1.79 (m, 2 H), 1.49–1.35 (m, 4 H), 0.94 (t, J = 7.1 Hz, 3 H). ¹³C {¹H} NMR (101 MHz, CDCl₃): δ = 164.3, 141.2, 125.8, 114.4, 68.9, 28.7, 28.0, 22.4, 14.0. 4-Bromophenyl 2,2,2-Trifluoroethyl Ether (3m) Off-white solid; yield: 89.8 mg (70%). ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (d, J = 9.0 Hz, 2 H), 6.82 (d, J = 8.9 Hz, 2 H), 4.31 (q, J = 8.1 Hz, 2 H). ¹³C {1 H} NMR (101 MHz, CDCl₃): δ = 156.5, 132.6, 123.2 (q, J = 278.1 Hz), 116.8, 115.0, 66.0 (q, J = 35.8 Hz).