Hydrogen-Bond-Promoted Friedel–Crafts Reaction of Secondary Propargylic Fluorides: Preparation of 1-Alkyl-1-aryl-2-alkynes

Dedicated to Prof. Victor Snieckus on the occasion of his 80^th birthday

Abstract

We report that aromatic propargylation is achievable with secondary propargylic fluorides, thus affording 1-alkyl-1-aryl-2-alkynes. In the present case, hydrogen bonding is responsible for the activation of the C–F bond. A large excess of arene nucleophile is shown to be necessary to achieve good yields.

Key words

alkynes - arenes - C–F bond activation - Friedel–Crafts reaction - HFIP - hydrogen bond - propargylation - propargylic fluoride

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• 25 All our efforts towards the preparation of an (α-aryl)propargylic fluoride failed as spontaneous decomposition kept occurring upon purification. Since decomposition only occurred after purification, a sample of crude (α-aryl)propargylic fluoride was directly engaged in a Friedel–Crafts reaction. However, decomposition still prevailed over the desired reactivity when using CH₂Cl₂/HFIP (30:1) as the solvent.

At this point, the reasons for the absence of reaction with alcohol 20 are not understood. Our current hypothesis is that 20 is involved in a strong hydrogen-bond network, as an alcohol is capable, at the same time, of accepting and donating hydrogen bonds, with HFIP and/or TFA, which would overall protect it from further reaction. For examples of hydrogen bonded complexes with HFIP, see:
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• 26c Further experiments were performed and no reaction was observed when running the reaction at r.t. or 40 °C using either 5 or 50 mol% of TFA. At best, a low conversion (ca. 13%) to the trifluoroacetate of 20 was observed under more forcing conditions (i.e., TFA (50 mol%), DCE/HFIP (9 :1), 70 °C, 18 h).
• 27 Compound 21 principally led to side reactions even under reaction conditions where HFIP was omitted, affording 2 in 29% NMR yield (o/p = 1:7.7). It should also be mentioned that 21 was also subject to rapid decomposition during column chromatography or during evaporation postpurification.
• 28 Representative Procedure for the Friedel–Crafts Reaction of Propargylic Fluorides – Synthesis of 1-Methyl-4-(1-phenylhex-1-yn-3-yl)benzene (2) A solution of TFA (8.7 μL, 0.114 mmol) in CH₂Cl₂ (13 mL) was prepared. 3-(Fluorohex-1-ynyl)benzene (1, 40 mg, 0.227 mmol) was then charged in a vial and dissolved in this TFA/CH₂Cl₂ solution (1.3 mL, resulting in 5 mol% of TFA). Toluene (0.60 mL, 5.68 mmol) was added, followed by HFIP (0.13 mL). The resulting solution was stirred at r.t. for 18 h. The reaction was quenched with sat. NaHCO₃ and stirred until no more gas evolved. It was then extracted with CH₂Cl₂ (3×). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The desired product (41.5 mg, 74%, o/p = 1:9.2) was isolated as a colorless oil by flash chromatography using hexanes. IR (ATR, ZnSe): ν = 2957, 2925, 2871, 1686, 1599, 1450, 1281, 812, 754, 689 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.57 (d, 0.11 H, minor, J = 7.7 Hz) 7.44–7.42 (m, 2 H), 7.31–7.24 (m, 4.89 H), 7.14 (d, 2 H, J = 7.8 Hz), 4.04 (dd, 0.11 H, minor, J = 9.1, 5.1 Hz), 3.81 (dd, 0.89 H, major, J = 8.4, 6.1 Hz), 2.39 (s, 0.32 H), 2.34 (s, 2.68 H), 1.85–1.72 (m, 2 H), 1.59–1.44 (m, 2 H), 0.99–0.93 (m, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 139.5, 136.3, 131.8, 130.6 (minor), 129.3, 128.3, 127.8, 127.7 (minor), 127.5, 126.7 (minor), 126.4 (minor), 124.0, 92.1, 83.1, 41.0, 39.4 (minor), 38.0, 34.7 (minor), 29.9 (minor), 21.2, 21.1 (minor), 20.8, 19.4 (minor), 14.0; ESI-HRMS: m/z calcd for C₁₉H₂₁[M + H]⁺: 249.1638; found: 249.1634