A Tandem Aldol/Desilylation/CuAAC Sequence of Difluoroenoxysilanes and Silyl-α-ketoalkynes to α-Fluoroketone α-1,2,3 Triazole Tertiary Alcohol

Abstract

A one-pot tandem aldol/desilylation/CuAAC sequence is developed, allowing the facile synthesis of tertiary alcohols featuring an α-difluoroketone moiety and a 1,2,3-triazole at the α position in moderate to good yields, with an operationally friendly manner. While Bi(OTf)₃ was the optimal catalyst for the Mukaiyama-aldol reaction of silyl-α-ketoalkynes and difluoroenoxysilanes, CuCl was found to efficiently mediate the alkyne–azide cycloaddition.

Keywords

Aldol/desilylation/CuAAC reaction - Difluoroenoxysilanes - Silyl-α-ketoalkynes - α-Fluoroketone α-1,2,3 triazole tertiary alcohol

Publikationsverlauf

Eingereicht: 10. Juli 2025

Angenommen nach Revision: 02. September 2025

Accepted Manuscript online:
19. September 2025

Artikel online veröffentlicht:
05. November 2025

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• 12b To a 10 mL Schlenk tube were added Bi(OTf)₃ (16.4 mg, 10 mol%) and ynones 5c (35.1mg, 0.25 mmol), followed by the addition of anhydrous DCE (2.5 mL) and difluoroenoxysilanes 4a (89.3 mg, 0.375 mmol) at 0 °C. The reaction mixture was stirred at 0 °C until full conversion of ynones 5c by TLC analysis. Subsequently, TBAF (0.375 mL, 1 M in THF) was added to the reaction mixture and stirred at room temperature. After full conversion of aldol product 2c by TLC until the solvent was evaporated and dried under vacuum to give the residue. To the Schlenk tube containing the above residue were added CuCl (2.5 mg, 10 mol%) and CH₃CN (2.5 mL) under an N₂ atmosphere, followed by the addition of benzylazide 6a (49.9 mg, 0.375 mmol). The resulting mixture was stirred at 40 °C until full conversion of 2b by TLC analysis, and then directly purified by flash column chromatography with PE/EA (3 /1, v/v) as the eluent to afford the desired tertiary alcohol 1a, in 87% yield as white solid. m.p. = 89.6–91.1 °C. ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J = 7.8 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.48–7.36 (m, 6H), 7.23–7.20 (m, 2H), 5.57–5.46 (m, 2H), 4.21 (s, 1H), 1.78 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 190.3 (t, J_CF = 30.3 Hz), 148.1, 145.6, 134.2, 130.7 (t, J_CF = 4.0 Hz), 129.2, 129.1, 128.8, 128.0, 121.9, 116.4 (t, J_CF = 264.6 Hz), 73.2 (t, J_CF = 26.3 Hz), 54.3, 22.8 (t, J_CF = 3.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −108.71 (d, J = 276.0 Hz, 1F), −110.37 (d, J = 276.0 Hz, 1F); IR (ATR): 1716, 1691, 1280, 1186, 1051, 808, 646 cm⁻¹; HRMS (ESI): Exact mass calcd for C₁₉H₁₇F₂N₃NaO₂ [M+Na]⁺: 380.1181, Found: 380.1187.