Synthesis of Benzyl Alcohol Building Blocks Bearing an Aldehyde, Pinacol Borane or Carboxylic Acid Motif via Lithium–Bromide Exchange

Abstract

A range of useful disubstituted benzyl alcohol building blocks have been synthesised in multigram quantities in a lithium–bromide exchange to give aldehyde, carboxylic acid and pinacol ­boranes in high yields.

Key words

aldehyde - carboxylic acid - lithiation - pinacol borane - protection groups - exchange reaction

• References and Notes

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• 8 General Procedure: (3-Bromo-4-methylbenzyloxy)(tert-butyl)dimethylsilane (19.2 g, 60.9 mmol) was dissolved in THF (250 mL) and cooled to –78 °C, and n-butylithium (1.6 M in hexanes, 40.0 mL, 63.9 mmol) was added over 10 min. The pale-yellow mixture was stirred at –78 °C for 10 min, then the anion was quenched by bubbling carbon dioxide (472 mL, 6089 mmol) through the reaction for 30 min. The reaction was allowed to warm to r.t., quenched with 0.5 M HCl (100 mL), extracted with EtOAc (3 × 100 mL), and the organic layer was dried over MgSO₄, filtered and evaporated to afford 5-[(tert-butyldimethylsilyl-oxy)-methyl]-2-methylbenzoic acid (15.0 g, 88%) as a colourless gum. ¹H NMR (400 MHz, CDCl₃, 30 °C): δ = 0.09 (s, 6 H), 0.93 (s, 9 H), 2.61 (s, 3 H), 4.71 (s, 2 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.94 (s, 1 H); COOH proton missing. ¹³C NMR (100 MHz, CDCl₃): δ = 139.7, 139.1, 131.8, 130.5, 129.1, 128.8, 64.4, 26.0, 21.7, 18.4, –5.2; COOH missing. MS (ES+): m/z = 279 [M – H]^–; MS: m/z [M – CH₃]⁺ calcd for C₁₅H₂₄O₃Si: 265.1260; found: 265.1264.
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