A Novel Cascade Benzyne Nucleophilic Addition/Fries Rearrangement for Entry into 2,3-Disubstituted Phenols

Abstract

A cascade benzyne Fries rearrangement is reported that offers facile access to 2,3-disubstituted phenols, allowing for two points of diversity on the benzyne adduct. The methodology utilizes an o-(trimethylsilyl)triflate phenol as a common intermediate, from which substitution of the phenolic oxygen readily yields benzyne precursors that undergo the requisite rearrangement in the presence of an amine nucleophile, base, and a fluoride source.

Key words

benzyne - aryne - Fries rearrangement - reactive intermediate - silyltriflate

• References and Notes

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• 13 Representative Procedure: Benzyne Adduct 3a To an oven dried 10 mL vial was added NaH (60% in mineral oil; 8.6 mg, 0.22 mmol, 2.0 equiv), TBAT (89.8 mg, 0.161 mmol, 1.50 equiv), 4-methyl-N-phenylbenzenesulfonamide (2a, 53.2 mg, 0.215 mmol, 2.00 equiv), and anhydrous THF (6.2 mL). The mixture was stirred at r.t. for 15 min, and then a solution of [2-(trifluoromethylsulfonyloxy)-3-trimethylsilylphenyl]benzoate (1a, 45.0 mg, 0.108 mmol, 1.00 equiv) in THF (1.0 mL) was added. The vial was sealed and the mixture was heated to 60 °C for 16 h under a nitrogen atmosphere. The reaction was not monitored during the course of the reaction as frequent monitoring was found to result in decreased yields. After cooling to r.t., the crude mixture was concentrated under reduced pressure, and diluted with CH₂Cl₂ (5.0 mL) and aq HCl (0.5 M, 5.0 mL). The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 5.0 mL). The combined organic layers were dried over Na₂SO₄, filtered, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (100% heptane to 20% i-PrOAc in heptane gradient) to give the title compound (36.5 mg, 0.0824 mmol, 77% yield) as a white solid. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.10 (s, 1 H), 7.65–7.60 (m, 2 H), 7.60–7.54 (m, 1 H), 7.42 (app. t, J = 7.7, 2 H), 7.36 (d, J = 8.2, 1 H), 7.29 (s, 2 H), 7.29–7.26 (m, 2 H), 7.20–7.09 (m, 3 H), 7.04–6.98 (m, 2 H), 6.96 (dd, J = 8.5, 0.9, 1 H), 6.87 (dd, J = 8.1, 0.8, 1 H), 2.36 (s, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 194.5, 156.1, 144.4, 140.7, 139.3, 137.3, 136.4, 133.6, 131.0, 130.1, 129.6, 129.1, 128.7, 128.3, 128.3, 128.1, 127.6, 120.3, 116.2, 21.5. HRMS (ESI⁺): m/z calcd for C₂₆H₂₂NO₄S [M + H]⁺: 444.1264; found: 444.1259.
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