Intermolecular selective carboacylation of alkenes via nickel-catalyzed reductive radical relay

Abstract

The development of catalytic carboacylation of simple olefins, which would enable the rapid construction of ketones with high levels of complexity and diversity, is very challenging. To date, the vast majority of alkene carboacylation reactions are typically restricted to single- and two-component methodologies. Here we describe a three-component carboacylation of alkenes via the merger of radical chemistry with nickel catalysis. This reaction manifold utilizes a radical relay strategy involving radical addition to an alkene followed by alkyl radical capture by an acyl-nickel complex to forge two vicinal C-C bonds under mild conditions. Excellent chemoselectivity and regioselectivity have been achieved by utilizing a pendant weakly chelating group. This versatile protocol allows for facile access to a wide range of important β-fluoroalkyl ketones from simple starting materials.

Fig. 1

Design of an intermolecular, selective carboacylation of alkenes. a Three-component carboacylation of olefins via nickel-catalyzed reductive radical relay. b Selectivity guided by a chelating group

Fig. 2

Substrate scope. a Scope of alkenes. b Scope of acyl chlorides. c Scope of fluoroalkyl iodides. Reaction conditions: NiCl₂•glyme (10 mol%), dtbbpy (20 mol%), alkene (1.0 equiv.), R_fI (1.0 equiv.), acyl chloride (1.5 equiv.), Mn (3.0 equiv.), CH₃CN [0.1 M], 25 ^oC, 20 h, see Supplementary Methods. All cited yields are isolated yields. Ar = 4-tert-butylphenyl, R = C₆H₁₃CO₂. ^a Performed with 20 mol% NiCl₂•glyme. ^b Reaction concentration is 0.05M CH₃CN. ^cPerformed in CH₃CN/DME (4:1) [0.1 M]

Fig. 3

Chemoselectivity guided by pendant chelating groups. a Reactivity tuned by the chelating group. b Chemoselectivity in the presence of multiple double bonds. Reaction conditions: NiCl₂•glyme (10 mol%), dtbbpy (20 mol%), alkene (1.0 equiv.), C₄F₉I (1.0 equiv.), acyl chloride (1.5 equiv.), Mn (3.0 equiv.), CH₃CN [0.1 M], 25 ^oC, 20 h, see Supplementary Methods. All cited yields are isolated yields. Ar = 4-tert-butylphenyl. ^a36% of C₄F₉-alkene byproduct isolated. ^bAlkene consumed. ^cAlkene remained. ^dPerformed with 2 equiv. of alkene. ^e140% of alkene recovered. ^fPerformed in 4:1 CH₃CN/DME [0.05 M]. ^g41% of alkene recovered. ^h17% of alkene recovered. ⁱ48 h

Fig. 4

Derivations of compound 3. See Supplementary Methods. Ar = 4-tert-butylphenyl. PMB = 4-methoxybenzyl

Fig. 5

Mechanistic studies. a Proposed mechanism. b Radical inhibition experiment. c Radical clock experiment. d Stoichiometric reaction of isolated Ni(II) complex. See Supplementary Discussion. Ar = 4-tert-butylphenyl. alkene = allyl heptanoate