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. 2019 Sep 25;141(38):15433-15440.
doi: 10.1021/jacs.9b08185. Epub 2019 Sep 10.

Mechanistic Investigation of Enantioconvergent Kumada Reactions of Racemic α-Bromoketones Catalyzed by a Nickel/Bis(oxazoline) Complex

Haolin Yin  1 , Gregory C Fu  1
Affiliations

Mechanistic Investigation of Enantioconvergent Kumada Reactions of Racemic α-Bromoketones Catalyzed by a Nickel/Bis(oxazoline) Complex

Haolin Yin et al. J Am Chem Soc. .

Abstract

In recent years, a wide array of methods for achieving nickel-catalyzed substitution reactions of alkyl electrophiles by organometallic nucleophiles, including enantioconvergent processes, have been described; however, experiment-focused mechanistic studies of such couplings have been comparatively scarce. The most detailed mechanistic investigations to date have examined catalysts that bear tridentate ligands and, with one exception, processes that are not enantioselective; studies of catalysts based on bidentate ligands could be anticipated to be more challenging, due to difficulty in isolating proposed intermediates as a result of instability arising from coordinative unsaturation. In this investigation, we explore the mechanism of enantioconvergent Kumada reactions of racemic α-bromoketones catalyzed by a nickel complex that bears a bidentate chiral bis(oxazoline) ligand. Utilizing an array of mechanistic tools (including isolation and reactivity studies of three of the four proposed nickel-containing intermediates, as well as interrogation via EPR spectroscopy, UV-vis spectroscopy, radical probes, and DFT calculations), we provide support for a pathway in which carbon-carbon bond formation proceeds via a radical-chain process wherein a nickel(I) complex serves as the chain-carrying radical and an organonickel(II) complex is the predominant resting state of the catalyst. Computations indicate that the coupling of this organonickel(II) complex with an organic radical is the stereochemistry-determining step of the reaction.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
An overview of previous experiment-based mechanistic studies of nickel-catalyzed couplings of alkyl electrophiles with organometallic nucleophiles. For the sake of simplicity, all elementary steps are depicted as being irreversible.
Figure 2.
Figure 2.
X-ray crystal structure of NiIIBr2(Ph-BOX) (1) (thermal ellipsoids at 30% probability; for clarity, the hydrogen atoms have been omitted).
Figure 3.
Figure 3.
The yield and ee of the coupling product, as well as the ee of the unreacted electrophile, as a function of time (eq 3).
Figure 4.
Figure 4.
UV-vis spectra of a coupling in progress (eq 3) and of NiIIBr2(Ph-BOX) (1). The absorption from PhMgBr has been subtracted.
Figure 5.
Figure 5.
(a) UV-vis spectra of NiIIBr2(Ph-BOX) (1) and of the reaction of Ni(cod)2, Ph-BOX, and Ph-Br (eq 6, except in DME). (b) Absorbance at 474 nm as a function of time.
Figure 6.
Figure 6.
X-ray crystal structure of NiIIPhBr(Ph-BOXPh)•THF (2Ph•THF) (thermal ellipsoids at 30% probability; for clarity, the solvent and the hydrogen atoms have been omitted).
Figure 7.
Figure 7.
(a) UV-vis spectra of a coupling reaction in progress (eq 3), of NiIIPhBr(Ph-BOX) (2), and of NiIIPhBr(Ph-BOXPh) (2Ph). (b) Natural transition orbital (NTO) representations of the computed (B3LYP/6–31G*) lowest energy transition for NiIIPhBr(Ph-BOX) (2).
Figure 8.
Figure 8.
X-ray crystal structure of NiIBr(Ph-BOX) (3) (thermal ellipsoids at 30% probability; for clarity, the hydrogen atoms have been omitted).
Figure 9.
Figure 9.
(a) X-band EPR spectrum of NiIBr(Ph-BOX) (3) (collected in toluene glass at 77 K with ν = 9.4 GHz at 2 mW power and a modulation amplitude of 2 G) and simulated spectrum (parameters used for simulation: g1 = 2.084, g2 = 2.087, g3 = 2.329, line width = 5.28); hyperfine couplings from the nitrogen atoms were not resolved. (b) DFT-computed (B3LYP/6-31G*) spin density plot for NiIBr(Ph-BOX) (3).
Figure 10.
Figure 10.
UV-vis spectra of a coupling reaction in progress (eq 3), of NiIIBr2(Ph-BOX) (1), of NiIIPhBr(Ph-BOX) (2), and of NiIBr(Ph-BOX) (3).
Figure 11.
Figure 11.
Possible mechanism for the nickel/bis(oxazoline)-catalyzed enantioconvergent Kumada coupling of an α-bromoketone with a Grignard reagent. Intermediates that have been isolated are boxed. For the sake of simplicity, all elementary steps are depicted as being irreversible.
Figure 12.
Figure 12.
UV-vis spectra of the reaction between NiIIBr2(Ph-BOX) (1) and PhMgBr after 30 seconds, of a separate catalyzed coupling reaction in progress (eq 3), of NiIIBr2(Ph-BOX) (1), and of NiIIPhBr(Ph-BOX) (2).
Figure 13.
Figure 13.
UV-vis spectra of the reaction between NiIIPhBr(Ph-BOX) (2) and an α-bromoketone after 6 hours, of NiIIPhBr(Ph-BOX) (2), and of NiIIBr2(Ph-BOX) (1).
Figure 14.
Figure 14.
Ratio of uncyclized (U) to cyclized (C) products, as a function of the loading of NiIIBr2(Ph-BOX) (1).
Figure 15.
Figure 15.
Computed relative free energies for step 2 and for step 3 of the proposed catalytic cycle (Figure 11), calculated at (U)M06/6-311+G**,SMD(THF)//(U)B3LYP/6x-31G*) level of theory.
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