Two-Carbon Homologation of Aldehydes: An Efficient Route to Difluoromethyl Alkynes

Abstract

We report a simple and efficient two-carbon homologation method to directly convert aldehydes into difluoromethyl alkynes by using readily accessible and stable diphenyl(2,2,2-trifluoroethyl)phosphine oxide [Ph₂P(=O)CH₂CF₃]. The conditions for this reaction are compatible with a broad range of aldehydes. Deuterium-labeling experiments suggest that the reaction probably involves a key rearrangement of aryl difluoroallenes generated in situ.

Key words

two-carbon homologation - difluoromethyl alkynes - aldehydes - difluoroallenes - rearrangement

• References and Notes

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• 20 (3,3-Difluoroprop-1-yn-1-yl)arenes 3a–r; General Procedure Under an N₂ atmosphere, a flame-dried 8 mL reaction vial was charged with Ph₂P(=O)CH₂CF₃ (2; 0.25 mmol, 71.0 mg), the appropriate aldehyde (0.1 mmol), and DMSO (0.05 M, 2 mL). When the dissolution of the substrates was complete, t-BuOK (0.5 mmol, 56.0 mg) was added with vigorous shaking. When the reaction was complete (~10 min), the reaction was quenched with H₂O and the mixture was extracted with Et₂O (3 × 10 mL). The extracts were washed with sat. brine (3 × 10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pentane). 1-tert-Butyl-4-(3,3-difluoroprop-1-yn-1-yl)benzene (3a) ^11d Colorless liquid; yield: 14.8 mg (71%). ¹H NMR (400 MHz, CDCl₃): δ = 7.45 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 6.41 (t, J = 55.2 Hz, 1 H), 1.32 (s, 9 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –104.89 (d, J = 55.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 153.64, 131.95 (t, J = 2.6 Hz), 125.56, 116.81, 104.32 (t, J = 231.7 Hz), 88.80 (d, J = 7.3 Hz), 79.25 (t, J = 33.8 Hz), 34.97, 31.09. 2-(3,3-Difluoroprop-1-yn-1-yl)-1-benzothiophene (3l) Colorless oil; yield: 16.2 mg (78%). ¹H NMR (400 MHz, CDCl₃): δ = 7.80 (dd, J = 7.1, 2.2 Hz, 2 H), 7.65–7.60 (m, 1 H), 7.50–7.37 (m, 2 H), 6.46 (t, J = 54.7 Hz, 1 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –106.02 (d, J = 54.7 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 140.84, 138.43, 131.89, 126.46, 125.11, 124.43, 122.16, 104.08 (t, J = 232.9 Hz), 84.50 (t, J = 34.3 Hz), 82.31 (t, J = 7.4 Hz). HRMS (EI): m/z [M + H]⁺ calcd for C₁₁H₇F₂S: 208.0153; found: 208.0158.