Reductive Deuteration of Aromatic Esters for the Synthesis of α,α-Dideuterio Benzyl Alcohols Using D₂O as Deuterium Source

Abstract

α,α-Dideuterio benzyl alcohols are important building blocks for the synthesis of deuterium-labeled medicines and agrochemicals. We have developed the first general single-electron transfer reductive deuteration of readily commercially available aromatic esters for the synthesis of α,α-dideuterio benzyl alcohols using benign D₂O and a mild single-electron donor SmI₂. This operationally convenient method features very good functional group tolerance and high deuterium incorporations (>95% D₂). The potential impact has been exemplified by the synthesis of numerous deuterium labeled building blocks of important bioactive compounds. Most crucially, the method represents the first example of selective reductive deuteration of benzylic-type ketyl radicals using mild and highly chemoselective lanthanide(II) reagents.

Key words

reductive deuteration - α,α-dideuterio benzyl alcohol - single-electron transfer - reduction - D₂O

Publication History

Received: 28 August 2020

Accepted after revision: 17 September 2020

Article published online:
16 October 2020

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• 20 Typical Procedure for the Preparation of Model Compound (4-Heptylphenyl)methan-d₂ -ol (2a) To a solution of samarium(II) iodide (0.10 M in THF; 12 mL, 1.2 mmol, 6.0 equiv) a solution of methyl 4-heptylbenzoate (46.9 mg, 0.200 mmol) in THF (2.0 mL) was added, followed by Et₃N (0.33 mL, 2.4 mmol) and D₂O (0.261 mL, 14.4 mmol) under Ar at room temperature and stirred vigorously. After 15 min, the excess of SmI₂ was oxidized by bubbling air through the reaction mixture. The reaction mixture was diluted with CH₂Cl₂ (10 mL) and NaOH (10 mL, 1 M, aq). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL), organic layers were combined, washed with Na₂S₂O₃ (2 × 20 mL, sat., aq), dried over MgSO₄, filtered, and concentrated. The crude product was purified by flash chromatography (silica, 15% EtOAc/hexane) to afford 2a (40.8 mg, 98%) as a colorless oil. Percentage of exchanged protons are determined by ¹H NMR spectroscopy indicated in square brackets in Scheme 2. ¹H NMR (300 MHz, CDCl₃): δ = 7.26 (m, 2 H), 7.16 (m, 2 H), 2.59 (t, J = 7.7 Hz, 2 H), 1.86 (br, 1 H), 1.60 (m, 2 H), 1.38–1.19 (m, 8 H), 0.87 (t, J = 6.8 Hz, 3 H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 142.6, 138.1, 128.6, 127.2, 64.6 (m), 35.7, 31.9, 31.6, 29.3, 29.2, 22.7, 14.1.