Friedel-Crafts Cyclization of 1,1-Difluoroalk-1-enes: Synthesis of Benzene-Fused Cyclic Ketones via α-Fluorocarbocations

Abstract

1,1-Difluoroalk-1-enes bearing a phenyl group at the C-3, -4, or -5 position, readily obtained from 2,2,2-trifluoroethyl p-toluenesulfonate, are treated with FSO₃H·SbF₅ to undergo Friedel-Crafts cyclization in (CF₃)₂CHOH. The cyclization takes place via α-fluorocarbocations, followed by spontaneous hydrolysis of the C-F bond to afford bicyclic ketones including a five, six, or seven-membered ring in good yield.

Friedel-Crafts cyclization - difluoroalkene - bicyclic ketone - α-fluorocarbocation - fluoroalcohol solvent

References

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13

The configuration of 1h was assigned by ¹H NMR measurement. The ¹H NMR spectrum for the major isomer of 1h exhibits a large geminal coupling constant (J _gem = 13.4 Hz) between the protons H_ax and H_eq at C-3. H_ax is coupled to the C-2 and C-4 protons with coupling constant values of 11.3 Hz and 4.6 Hz, which are consistent with typical axial-axial and axial-equatorial values, respectively. In the ¹H NMR spectrum of the minor isomer of 1h, two large axial-axial coupling constants are observed between the C-3 axial proton and the C-2 proton and between the C-3 axial proton and the C-4 proton (J ₃₂ = 14.0 Hz, J ₃₄ = 11.9 Hz). Moreover, the observed NOEs between the C-2 axial proton and the methyl proton of the major isomer and between the C-2 axial proton and the C-4 axial proton of the minor isomer support this assignment. Stereochemistry was assigned for 2g on the basis of the proton coupling constants in a similar manner.

14

Vinyl fluoride 14 (X = F) was not detected by ¹⁹F NMR measurement of the reaction mixture.

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The spectroscopic data (¹H, ¹³C NMR and IR) of 2a,b,d are in agreement with the reported data:

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