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. 2018 Jan 5;9(7):1795-1802.
doi: 10.1039/c7sc04916a. eCollection 2018 Feb 21.

Stereoselective cobalt-catalyzed halofluoroalkylation of alkynes

Guojiao Wu  1 , Axel Jacobi von Wangelin  1   2
Affiliations

Stereoselective cobalt-catalyzed halofluoroalkylation of alkynes

Guojiao Wu et al. Chem Sci. .

Abstract

Stereoselective additions of highly functionalized reagents to available unsaturated hydrocarbons are an attractive synthetic tool due to their high atom economy, modularity, and rapid generation of complexity. We report efficient cobalt-catalyzed (E)-halofluoroalkylations of alkynes/alkenes that enable the construction of densely functionalized, stereodefined fluorinated hydrocarbons. The mild conditions (2 mol% cat., 20 °C, acetone/water, 3 h) tolerate various functional groups, i.e. halides, alcohols, aldehydes, nitriles, esters, and heteroarenes. This reaction is the first example of a highly stereoselective cobalt-catalyzed halo-fluoroalkylation. Unlike related cobalt-catalyzed reductive couplings and Heck-type reactions, it operates via a radical chain mechanism involving terminal halogen atom transfer which obviates the need for a stoichiometric sacrificial reductant.

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Figures

Scheme 1
Scheme 1. Metal-mediated halo-fluoroalkylations of alkynes.
Scheme 2
Scheme 2. Generalized mechanistic dichotomy of radical addition reactions under low-valent cobalt catalysis.
Scheme 3
Scheme 3. Cobalt-catalyzed bromo-carboxydifluoromethylation of alkynes. Standard conditions: 1 (0.3 mmol), 2a (0.45 mmol), CoBr2 (2 mol%), dppbz (2 mol%) and Zn (5 mol%), 0.6 mL acetone/H2O, 20 °C, 3 h under N2. Isolated yields are given; E/Z ratios in parentheses (by 19F NMR). [a] 20 mol% Zn. [b] 40 mol% Zn, 8 h.
Scheme 4
Scheme 4. Reactions with alkyl-substituted terminal alkynes.
Scheme 5
Scheme 5. Cobalt-catalyzed halo-fluoroalkylation of alkynes and alkenes. Standard conditions: 1 (0.3 mmol), 2 (0.45 mmol), CoBr2 (2 mol%), dppbz (2 mol%), Zn (5 mol%), 0.6 mL acetone/H2O, 20 °C, 3 h under N2. Isolated yields given; E/Z ratios in parentheses (by 19F NMR). [a] 20 mol% Zn. [b] RF–Br (1.0 equiv.), 10 mol% Zn. [c] RF–X (3.0 equiv.), 10 mol% Zn. [d]E/Z ratio of isolated products. [e] 10 mol% Zn. [f] 6 h.
Scheme 6
Scheme 6. Post-ATRA transformations by cross-coupling reactions.
Scheme 7
Scheme 7. Key mechanistic experiments.
Fig. 1
Fig. 1. 31P NMR (top) and 1H NMR (bottom) monitoring of catalyst formation and reductive electrophile activation.
Fig. 2
Fig. 2. UV-vis absorption spectra: CoBr2/dppbz (orange); after reduction of Co(ii) with Zn to Co(i) (green); Co(i) with 1 equiv. 1a (blue); Co(i) with 1 equiv. of 2a (yellow).
Scheme 8
Scheme 8. Proposed reaction mechanism.
See this image and copyright information in PMC

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