Gold-Catalyzed Diastereoselective Synthesis of α-Fluoroenones from Propargyl Acetates

Abstract

A diastereoselective preparation of α-fluoroenones from propargyl acetates has been developed proceeding via a gold-catalyzed rearrangement-fluorination cascade. Control reactions are consistent with a mechanism involving a gold-mediated 3,3-sigmatropic shift followed by a direct, nongold-catalyzed electrophilic fluorination of the allenyl acetate intermediate.

Key words

gold - fluorine - catalysis - diastereoselectivity - rearrangement

References and Notes

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1

New address: A. D. Gee, Division of Imaging Sciences, School of Medicine, King’s College London, The Rayne Institute, 4th Floor Lambeth Wing, St Thomas’ Hospital, Lambeth Palace Rd., London, SE1 7EH, UK.

14

Compounds (E)-2a and (Z)-2a were stable towards isomerization under the reaction conditions implying that the observed diastereoselectivity is under kinetic control.

15

General Procedure for Rearrangement-Fluorination Process
Selectfluor (2 equiv), SIPrAuCl (5 mol%), and silver trifluoromethanesulfonate (12.5 mol%) were added to a solution of the propargyl acetate (1 equiv) in MeCN (0.05 M). The mixture was stirred at r.t. or 40 ˚C until TLC showed consumption of the propargyl acetate (1.5-72 h). H₂O was added, and the mixture was extracted with EtOAc (3×). The combined organic fractions were washed with brine, dried with anhyd MgSO₄, filtered, and the solvents removed in vacuo. The crude mixture was purified by column chromatography on silica gel.
Preparation of 2a
The general procedure was followed using 1a (500 mg, 1.94 mmol), Selectfluor (1.37 g, 3.87 mmol), SIPrAuCl (60 mg, 0.10 mmol), and AgOTf (62 mg, 0.24 mmol) in MeCN (39 mL). The reaction was stirred for 48 h at r.t. ^¹9F NMR analysis on the crude reaction mixture indicated an E/Z ratio of 12.5:1. Purification by column chromatography on silica gel (hexane-Et₂O = 20:1) afforded the product (E)-2a as a yellow oil (290 mg, yield 64%) as well as (Z)-2a as a yellow solid (24 mg, yield 6%).
( E )-2-Fluoro-1-phenylnon-1-en-3-one [( E )-2a] R _f = 0.50 (hexane-Et₂O = 9:1). ^¹H NMR (400 MHz, CDCl₃): δ = 7.60-7.64 (m, 2 H), 7.35-7.40 (m, 3 H), 6.70 (d, 1 H, J = 25.3 Hz), 2.65 (dt, 2 H, J = 7.1, 3.5 Hz), 1.63 (tt, 2 H, J = 7.3, 7.1 Hz), 1.27-1.36 (m, 6 H), 0.90 (dd, 3 H, J = 6.8, 6.5 Hz). ^¹³C NMR (101 MHz, CDCl₃): δ = 195.6 (d, J = 38 Hz), 153.1 (d, J = 258 Hz), 130.9 (d, J = 10 Hz), 130.0 (d, J = 2 Hz), 129.2, 128.2, 119.7 (d, J = 27 Hz), 40.2 (d, J = 2 Hz), 31.6, 28.8, 23.2 (d, J = 2 Hz), 22.5, 14.0. ^¹9F NMR (377 MHz, CDCl₃): δ = -114.9 (dt, J = 25, 4 Hz). IR (neat): 1708 (C = O). HRMS (ESI⁺): m/z calcd for C₁₅H₁₉FNaO⁺ [M + Na]⁺: 257.1314; found: 257.1312.
( Z )-2-Fluoro-1-phenylnon-1-en-3-one [( Z )-2a] Mp 30 ˚C. R _f = 0.42 (hexane-Et₂O = 9:1). ^¹H NMR (400 MHz, CDCl₃): δ = 7.66-7.70 (m, 2 H), 7.38-7.44 (m, 3 H), 6.83 (d, 1 H, J = 36.9 Hz), 2.74 (dt, 2 H, J = 7.3, 2.3 Hz), 1.69 (tt, 2 H, J = 7.5, 7.3 Hz), 1.27-1.41 (m, 6 H), 0.91 (dd, 3 H, J = 7.0, 6.8 Hz). ^¹³C NMR (101 MHz, CDCl₃): δ = 195.1 (d, J = 32 Hz), 154.1 (d, J = 272 Hz), 131.2 (d, J = 4 Hz), 130.6 (d, J = 9 Hz), 129.7 (d, J = 3 Hz), 128.8, 114.9 (d, J = 6 Hz), 38.0, 31.6, 28.8, 23.5 (d, J = 2 Hz), 22.5, 14.0. ^¹9F NMR (377 MHz, CDCl₃): δ = -125.0 (d, J = 37 Hz). IR (CH₂Cl₂): 1697 (C = O). HRMS (FI⁺): m/z calcd for C₁₅H₁₉FO [M]⁺: 234.1420; found: 234.1414.

19

Allenyl acetate 4l was isolated as the only acetylated product during the attempted preparation of the corresponding propargyl acetate 1l according to the procedure of ref. 11a. This compound is presumably formed via a spontaneous
3,3-sigmatropic rearrangement of 1l.