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. 2017 Apr 7;19(7):1570-1573.
doi: 10.1021/acs.orglett.7b00386. Epub 2017 Mar 23.

Base Catalysis Enables Access to α,α-Difluoroalkylthioethers

Douglas L Orsi  1 , Brandon J Easley  1 , Ashley M Lick  1 , Ryan A Altman  1
Affiliations

Base Catalysis Enables Access to α,α-Difluoroalkylthioethers

Douglas L Orsi et al. Org Lett. .

Abstract

A nucleophilic addition reaction of aryl thiols to readily available β,β-difluorostyrenes provides α,α-difluoroalkylthioethers. The reaction proceeds through an unstable anionic intermediate, prone to eliminate fluoride and generate α-fluorovinylthioethers. However, the use of base catalysis overcomes the facile β-fluoride elimination, generating α,α-difluoroalkylthioethers in excellent yields and selectivities.

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Figures

Figure 1
Figure 1
Undesired Reactivity with Inorganic Bases.
Figure 2
Figure 2
Coupling of Aryl Thiol over Alkyl Thiol.
Scheme 1
Scheme 1
Base Catalyst Enables Nucleophilic Addition to gem-Difluoroalkenes.
Scheme 2
Scheme 2. Scope of Distinct β,β-Difluorostyrenes[a]
[a] Standard conditions: 5a–n (1.0 equiv), PhSH (2.0 equiv), TMG (5.0 mol %), DCE (0.25 M), temperature and time as indicated. Selectivity >25:1 as determined by 19F NMR analysis of the reaction mixture, unless otherwise indicated. Yields represent an average of two runs. [b] PhSH (3.0 equiv). [c] Selectivity = 13:1. [d] Selectivity = 6.6:1. [e] Selectivity = 8:1. PMB = 4-methoxybenzyl, Tf = trifluoromethylsulfonate.
Scheme 3
Scheme 3
Decomposition of Anionic Intermediate A Reduces the Selectivity for e--Deficient Substrates.
Scheme 4
Scheme 4
Scope of Heteroaromatic β,β-Difluorostyrenes.[a] [a] Standard conditions: 7a–n (1.0 equiv), PhSH (2.0 equiv), TMG (5.0 mol %), DCE (0.25 M), temperature and time as indicated. Selectivity >25:1 as determined by 19F NMR analysis of the reaction mixture. Yields represent an average of two runs. [b] PhSH (3.0 equiv). Ts = 4-toluenesulfonyl.
Scheme 5
Scheme 5
Scope of Distinct Aryl Thiols.[a] [a] Standard conditions: 1 (1.0 equiv), ArSH 9a–j (2.0 equiv), TMG (5.0 mol %), DCE (0.25 M), temperature and time as indicated. Selectivity >25:1 as determined by 19F NMR analysis of the reaction mixtures. Yields represent an average of two runs. [b] ArSH (3.0 equiv).
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