Copper-Catalyzed Regiodivergent Borylation of Fluorinated Alkynes and Palladium-Catalyzed Regiospecific Suzuki–Miyaura Cross-Coupling

Abstract

Alkenylboranes are key intermediates in modern organic synthesis, and they are usually obtained by the borylation of alkynes. We report herein highly regio- and stereoselective syntheses of α,Z- and β,Z-trifluoromethylated alkenylboranes by copper-catalyzed borylation reactions. Further functionalizations by palladium-catalyzed Suzuki–Miyaura cross-couplings have been developed and, interestingly, a marked difference in reactivity between the α- and β-borylated isomers has been identified.

Key words

borylation - trifluoromethyl alkenylboranes - alkynes - copper catalysis - regiodivergence

Publication History

Received: 31 August 2023

Accepted after revision: 16 October 2023

Accepted Manuscript online:
16 October 2023

Article published online:
16 November 2023

• References and Notes

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Sn:
• 4h
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• 9 Conditions A: General Procedure A dry Schlenk tube equipped with a magnetic stirrer bar was charged under N₂ with CuCl (3 mol%, 0.6 mg, 0.006 mmol), t-BuONa (6 mol%, 1.15 mg, 0.012 mmol), and N-XantPhos (3 mol%, 3.3 mg, 0.006 mmol) in dry THF (2 mL), and the mixture was stirred for 30 min at rt. The mixture was then cooled to 0 °C and pinacolborane (1.1 equiv, 0.22 mmol, 28.2 mg) was added. The resulting mixture was stirred for 10 min, and then the appropriate CF₃-alkyne 1 (1 equiv, 0.2 mmol) was added at 0 °C. The mixture was then stirred at 50 °C overnight. When the reaction was complete, the mixture was filtered through a plug of silica gel and washed with EtOAc. The solution was concentrated under reduced pressure and purified by column chromatography (silica gel). 4,4,5,5-Tetramethyl-2-[(1Z)-1-(trifluoromethyl)dec-1-en-1-yl]-1,3,2-dioxaborolane (2a) Prepared from 1,1,1-trifluoroundec-2-yne (1a; 41.2 mg, 0.2 mmol) and isolated by column chromatography [silica gel, PE–EtOAc (95:5)] to give a colorless oil; yield: 54 mg (81%). IR (neat): 2926, 2857, 1635, 1357, 1113, 983, 854, 704 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.26–1.33 (m, 22 H), 1.42–1.48 (m, 2 H), 2.35–2.41 (m, 2 H), 6.79 (t, J = 7.6 Hz, 1 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 14.3, 22.8, 24.8, 28.8, 29.3, 29.5, 29.6, 30.5, 32.0, 84.2, 125.3 (q, J = 274.4 Hz), 128.5 (q, J = 32.2 Hz), 158.5 (q, J = 5.2 Hz). ¹⁹F{¹H} NMR (471 MHz, CDCl₃): δ = –56.2 (s, 3 F). ¹¹B NMR (160 MHz, CDCl₃): δ = 29.1 (s, 1 B). MS (ESI): m/z [M + H]⁺ calcd C₁₇H₃₁BF₃O₂: 335.24; found: 335.24.
• 10 Conditions B: General Procedure A dry Schlenk tube equipped with a magnetic stirrer bar was charged under N₂ with CuCl (3 mol%, 0.6 mg, 0.006 mmol), t-BuONa (12 mol%, 2.4 mg, 0.024 mmol), and PMe₃·HBF₄ (6 mol%, 2.0 mg, 0.012 mmol) in dry THF (2 mL), and the mixture was stirred for 15 min at rt. The mixture was then cooled to 0 °C and bis(pinacolato)diboron (1.1 equiv, 0.22 mmol, 55.8 mg) was added. The resulting mixture was stirred for 10 min at 0 °C, and then the appropriate CF₃-alkyne 1 (1 equiv, 0.2 mmol) was added, followed by MeOH (2 equiv, 0.4 mmol, 16.2 μL). The mixture was then stirred at rt until the alkyne was fully consumed. After the completion of the reaction, the mixture was filtered through a plug of silica gel and washed with EtOAc. The solution was concentrated under reduced pressure and purified by column chromatography (silica gel). 4,4,5,5-Tetramethyl-2-[(1Z)-3,3,3-trifluoro-1-octylprop-1-en-1-yl]-1,3,2-dioxaborolane (3a) Prepared from 1,1,1-trifluoroundec-2-yne (1a; 41.2 mg, 0.2 mmol) and isolated by column chromatography [silica gel, PE–EtOAc (95:5)] to give a colorless oil; yield: 66 mg (99%). IR (neat): 2926, 1380 1339, 1263, 1111, 863, 690 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 6.9 Hz, 3 H), 1.23–1.31 (m, 22 H), 1.35–1.41 (m, 2 H), 2.31–2.35 (m, 2 H), (q, J = 9.1 Hz, 1 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 14.3, 22.8, 24.8, 29.3, 29.5, 29.6, 29.7, 30.1, 32.0, 84.4, 123.2 (q, J = 273.8 Hz), 128.5 (q, J = 32.5 Hz), 158.5 (q, J = 5.0 Hz). ¹⁹F{¹H} NMR (471 MHz, CDCl₃): δ = –58.3 (s, 3 F). ¹¹B NMR (160 MHz, CDCl₃): δ = 30.1 (s, 1 B). MS (ESI): m/z [M + H]⁺ calcd for C₁₇H₃₁BF₃O₂: 335.24; found: 335.24.
• 11 See the SI for details.
• 12 For an example of borylstannylation of alkynes, see: Takemoto Y, Yoshida H, Takaki K. Chem. Eur. J. 2012; 18: 14841
• 13 For an example of 1,2-carboboration of alkynes, see: Alfaro R, Parra A, Alemán J, García Ruano JL, Tortosa M. J. Am. Chem. Soc. 2012; 134: 15165
• 14 Suzuki–Miyaura Cross-Coupling: General Procedure A dry Schlenk tube equipped with a magnetic stirrer bar was charged under N₂ with the appropriate boronic ester 2 or 3 (1 equiv, 0.2 mmol), Pd(P-t-Bu₃)₂ (5 mol%, 5.1 mg), the appropriate aryl iodide (1.5 equiv, 1.5 mmol), THF (0.25 mL), Cs₂CO₃ (3 equiv, 0.6 mmol, 195.5 mg), and H₂O (60 μL). The mixture was then stirred at rt (for 2) or at 50–75 °C (for 3) until the boronic ester was fully consumed (TLC and ¹⁹F NMR). The reaction was quenched with H₂O, and the mixture was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give products 5 (from 2) or 6 (from 3). [(1Z)-1-(Trifluoromethyl)dec-1-en-1-yl]benzene (5aa) Prepared from product 2a (0.15 mmol, 50.1 mg) and PhI (1.5 equiv, 0.23 mmol, 25 μL), and purified by column chromatography (silica gel, 100% cyclohexane) to give a colorless oil; yield: 40 mg (95%). IR (neat): 2925, 2856, 1650, 1264, 1201, 1112, 759, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.88–0.91 (m, 3 H), 1.28–1.33 (m, 10 H), 1.50 (quint, J = 7.3 Hz, 2 H), 2.41–2.44 (qq, J = 7.4 Hz, J = 2.3 Hz, 2 H), 6.03 (t, J = 7.7 Hz, 1 H), 7.28–7.32 (m, 2 H), 7.33–7.37 (m, 3 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 14.3, 22.8, 29.0 (q, J = 2.2 Hz), 29.3, 29.4, 29.5, 29.7, 32.0, 124.2 (q, J = 275.7 Hz), 128.1, 128.3 (2C), 131.6 (q, J = 29.6 Hz), 136.9 (q, J = 1.9 Hz), 142.6 (q, J = 3.2 Hz). ¹⁹F NMR (471 MHz, CDCl₃): δ = –57.1 (s, 3 F). HRMS (ESI): m/z [M⁺] calcd for C₁₇H₂₃F₃: 284.1746; found: 284.1741. [(1E)-3,3,3-Trifluoro-1-octylprop-1-en-1-yl]benzene (6aa) Prepared from product 3a (0.15 mmol, 50 mg) and PhI (1.5 equiv, 0.23 mmol, 25 μL), and purified by column chromatography (silica gel, 100% cyclohexane) to give a colorless oil; yield: 38.2 mg (90%). IR (neat) = 2626, 2856, 1650, 1263, 1110, 758, 696 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.86 (t, J = 7.0 Hz, 3 H), 1.21–1.35 (m, 12 H), 2.67–2.70 (m, 2 H), 5.73 (q, J = 8.6 Hz, 1 H), 7.34–7.39 (m, 5 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 14.2, 22.8, 28.5, 29.2, 29.3, 29.6, 31.3, 31.9, 116.1 (q, J = 33.7 Hz), 123.8 (q, J = 271.0 Hz), 126.7, 128.7, 128.9, 140.2, 154.7 (q, J = 5.6 Hz). ¹⁹F{¹H} NMR (471 MHz, CDCl₃): δ = –56.5 (s, 3 F). MS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃F₃: 284.1746; found: 284.1753.