Nickel-catalyzed reductive conjugate addition to enones via allylnickel intermediates

Abstract

An alternative method to copper-catalyzed conjugate addition followed by enolate silylation for the synthesis of β-disubstituted silyl enol ether products (R(1)(R(2))HCCH═C(OSiR(4)(3))R(3)) is presented. This method uses haloarenes instead of nucleophilic aryl reagents. Nickel ligated to either neocuproine or bipyridine couples an α,β-unsaturated ketone or aldehyde (R(2)HC═CHC(O)R(3)) with an organic halide (R(1)-X) in the presence of a trialkylchlorosilane reagent (Cl-SiR(4)(3)). Reactions are assembled on the benchtop and tolerate a variety of functional groups (aldehyde, ketone, nitrile, sulfone, pentafluorosulfur, and N-aryltrifluoroacetamide), electron-rich iodoarenes, and electron-poor haloarenes. Mechanistic studies have confirmed the first example of a catalytic reductive conjugate addition of organic halides that proceeds via an allylnickel intermediate. Selectivity is attributed to (1) rapid, selective reaction of LNi(0) with chlorotriethylsilane and enone in the presence of other organic electrophiles, and (2) minimization of enone dimerization by ligand steric effects.

Figure 1

Comparison of three approaches to conjugate addition reactions that highlights the advantages of this study (C).

Figure 2

The reductive Heck consensus mechanism and its relationship to the limitations of the methods.

Figure 3

A hypothetical reductive conjugate addition mechanism with an allylnickel(II) intermediate (II).

Figure 4

Reaction of (L10)Ni(cod) with Ph-I ( ), cyclohexenone + Et₃SiCl ( ), Et₃SiCl (●), and cyclohexenone ( ) as monitored by UV-Vis at 450 nm. For full UV-Vis spectra and expanded plots of all four reactions, see Figures S1–S3 in the Supporting Information.

Figure 5

Reaction of (L1)Ni(cod) with 2-bromoheptane ( ), cyclohexenone + Et₃SiCl ( ), Et₃SiCl (●), and cyclohexenone ( ) as monitored by UV-Vis at 880 nm. For full UV-Vis spectra and an expanded plot of all four reactions, see Figures S11 and S12 in the Supporting Information.

Figure 6

Optimal ligand for different substrate combinations.

Scheme 1. Acceptor and Silicon Reagent Scope^a

^a Ratio of enone : Ar-I : R₃Si-Cl : catalyst was 1.0 : 1.0 : 1.1 : 0.01. Yields reported are of isolated, pure material (average of two runs). ^b Reaction temperature was 40 °C. ^c With ligand L2 and after deprotection by KF in methanol. Yield reported is for two steps. ^d Products isolated as mixtures of diastereomers: 6, 1:1; 7, 6:1.

Scheme 2. Aryl Halide Electronic Effects^a

^a Reactions conducted as in Scheme 1. ^b With Ar-Br, 58% yield.

Scheme 3. Ortho-Substituted Arenes.^a

^a Reactions conducted as in Scheme 1. ^b With Ar-Br, 44% yield. ^c Yield based on a single run.

Scheme 4. Functional-Group Compatibility

^a Reactions conducted as in Scheme 1. ^b 1.2 Equiv of aryl iodide was used instead of 1 equiv. ^c Product contaminated with a small amount of hydrodehalogenated arene.

Scheme 5. Reaction of (L1)Ni⁰(allyl) with 2-bromoheptane.^a

^a See Supporting Information for full details. Yields of stoichiometric reactions are based upon the amount of nickel, yields of catalytic reaction is based upon the amount of 2-bromoheptane. Yields are uncorrected vs. dodecane internal standard.

Scheme 6

Unified Mechanism.