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Synlett 2025; 36(08): 999-1002
DOI: 10.1055/a-2487-3686
DOI: 10.1055/a-2487-3686
letter
Two-Carbon Homologation of Aldehydes: An Efficient Route to Difluoromethyl Alkynes
Authors
We are grateful for financial support provided by the National Natural Science Foundation of China (22471035) and the Natural Science Foundation of Shanghai (24ZR1403600).
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 - rearrangementSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2487-3686.
- Supporting Information (PDF) (opens in new window)
Publication History
Received: 08 October 2024
Accepted after revision: 25 November 2024
Accepted Manuscript online:
25 November 2024
Article published online:
12 December 2024
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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.