Strategies for ortho-tert-Butylation of Phenols and their Analogues

Abstract

A new general process for constructing ortho-tert-butyl phenols is presented within the context of other known methods. All are briefly evaluated with regards to regioselectivity, efficiency, and functional group tolerance. In addition, we present an assortment of tert-butyl substrates accessed through o-QM chemistry. Our conclusion is that the o-QM process provides greater yields, flexibility, and generality than most other known methods for delivering ortho-tert-buytlated phenols and their derivatives.

1 Introduction

2 Friedel–Crafts Alkylation

3 Addition of t-Bu^– or t-Bu^• to Carbonyl Compounds

4 ipso-S_NAr Reactions of Aryl Methoxy and tert-Butylsulfoxide Moieties

5 Metal-Mediated Coupling of Aryl Bromides

6 Applications of o-Quinone Methides (o-QMs)

7 Conclusion

Key words

ortho-tert-butyl phenol - ortho-quinone methide - Friedel–Crafts Alkylation - S_NAr reactions - ipso substitution - metal-mediated aryl coupling

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• 18 Representative Procedure To dry nitrogen-flushed 10 mL Schlenk flask, equipped with a magnetic stir bar, was charged with SI-1 (100 mg) in dry Et₂O (3.8 mL, 0.1 M) and MeMgCl (0.42 mL, 2.69 M, 1.13 mmol, 3.0 equivalent) was added dropwise at –78 °C. The reaction was allowed to slowly warm to room temperature overnight. The reaction was quenched with 1 M aq. NH₄Cl (3 mL) and extracted with Et₂O (4 × 1 mL). The combined organic fractions were washed with brine (5 mL), dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate–hexane, 1:9) to yield the tert-butylated phenol 23 (56.9 mg, 84% isolated yield). ¹H NMR (500 MHz, CDCl₃): δ = 6.91 (dd, J = 6.7, 2.8 Hz, 1H), 6.82–6.74 (m, 2 H), 6.01 (s, OH), 3.89 (s, 3 H), 1.42 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 146.82, 144.43, 135.75, 119.19, 118.81, 108.58, 56.28, 34.78, 29.54. HRMS (EI+): m/z calcd for C₁₁H₁₆O₂ [M⁺]: 180.1150; found: 180.1149.
• 19 Preparations of the acetophenones are all fully described in the Supporting Information.