Nickel-Catalyzed Direct Stereoselective Alpha-Allylation Ketones with Non-conjugated Dienes

22 February 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

The development of efficient, sustainable methods for the construction of carbon-carbon bonds with the simultaneous stereoselective generation of vicinal stereogenic centers is a longstanding goal in organic chemistry. In this respect, the carbonyl group is a particularly relevant due to its ability reacting either as electrophile or pro-nucleophile at the alpha-carbon in its enolized form. The transition from precious metals to catalysts based on earth-abundant metals made impressive progress, and especially nickel became a powerful tool due to its low-cost and unique reactivity profiles. Low-valent nickel(0) complexes promote reductive couplings carbonyl compounds exploiting the electrophilic nature of the carbonyl group. In stark contrast, complementary alpha-functionalization of carbonyls leveraging its pro-nucleophilic character in conjunction with olefin acceptors are very scarce despite their attractivity. We report a Ni(0)NHC catalyst which promotes the conversion of ketones and non-conjugated dienes that are both cheap and widely accessible starting materials to synthetically highly valuable alpha-allylated products in excellent yields under mild conditions without any additional base or additive. The catalyst directly activates the alpha-hydrogen atom of the carbonyl substrates transferring it the olefin acceptor. The complete process is redox neutral and fully atom-economic. This feature contrasts typical carbonyl -functionalizations with precious metals that require functionalized substrates like a pre-formed enolate nucleophile and allyl electrophile. The transformation creates adjacent quaternary and tertiary stereogenic centers in a highly diastereoselective manner. Moreover, we introduce a chiral bulky designer NHC ligand allowing to conduct the reaction in an enantioselective manner providing the functionalized products with up to 99:1 er and >20:1 dr. Mechanistic and computational studies indicate an initial LLHT process from the ketone substrate to the olefin substrate to set the selectivity of the whole transformation. A beta-hydride elimination chain walking events is triggered until a favorable pi-allyl intermediate is reached leading by reductive elimination to the targeted products. The shown facile and selective functionalization of alpha-C-H bond of carbonyl groups by Ni(0)NHC catalysts opens new opportunities to exploit sustainable 3d-metal catalysis for a stereoselective access to valuable chiral building blocks.

Keywords

Nickel
NHC
Enantioselective Catalysis
Allylation

Supplementary materials

Title
Description
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Title
CIF Compound 6a
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X-ray crystallographic data CIF Compound 6a
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CIF Compound 8s
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X-ray crystallographic data CIF Compound 8s
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CIF Compound 8t
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X-ray crystallographic data CIF Compound 8t
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CIF Compound 8w
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X-ray crystallographic data CIF Compound 8w
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CIF Compound 9
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X-ray crystallographic data CIF Compound 9
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CIF Compound MeIPrtBu* x HBF4
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X-ray crystallographic data CIF ligand MeIPrtBu* x HBF4
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CIF Compound MeIPrtBu x HBF4
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X-ray crystallographic data CIF ligand MeIPrtBu x HBF4
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CIF Compound SIPrtBu x HBF4
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CIF Compound SIPrtBu x HBF4
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Computational data
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computational data
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