Ni-catalyzed regio- and stereo-defined intermolecular cross-electrophile dialkylation of alkynes without directing group

Yi-Zhou Zhan,Nan Xiao,Wei Shu

doi:10.1038/s41467-021-21083-w

Yi-Zhou Zhan, Nan Xiao + Show 1 more

Open Access

https://doi.org/10.1038/s41467-021-21083-w

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Abstract

The development of straightforward synthesis of regio- and stereodefined alkenes with multiple aliphatic substituents under mild conditions is an unmet challenge owing to competitive β-hydride elimination and selectivity issues. Herein, we report the nickel-catalyzed intermolecular cross-dialkylation of alkynes devoid of directing or activating groups to afford multiple aliphatic substituted alkenes in a syn-selective fashion at room temperature. The combination of two-electron oxidative cyclometallation and single-electron cross-electrophile coupling of nickel enables the syn-cross-dialkylation of alkynes at room temperature. This reductive protocol enables the sequential installation of two different alkyl substituents onto alkynes in a regio- and stereo-selective manner, circumventing the tedious preformation of sensitive organometallic reagents. The synthetic utility of this protocol is demonstrated by efficient synthesis of multi-substituted unfunctionalized alkenes and diverse transformations of the product.

Highlights

The development of straightforward synthesis of regio- and stereodefined alkenes with multiple aliphatic substituents under mild conditions is an unmet challenge owing to competitive β-hydride elimination and selectivity issues
We demonstrate the Ni-catalyzed intermolecular cross-dialkylation of alkynes without organometallic reagents
After extensive evaluation of a series of reaction parameters, we identified the use of NiBr2·DME (10 mol%), 4cyanopyridine (5 mol%, A1), cerium chloride (0.8 equiv), potassium iodide (2.0 equiv), zinc (4.5 equiv) in the presence of water (1.5 equiv) in N,N-dimethylformamide (0.1 M) at room temperature as the optimal conditions, affording the desired threecomponent sequential dialkylation product 4a in 66% yield (Table 1, entry 1)

Summary

Introduction

The development of straightforward synthesis of regio- and stereodefined alkenes with multiple aliphatic substituents under mild conditions is an unmet challenge owing to competitive β-hydride elimination and selectivity issues. We envisioned a fully intermolecular oxidative cyclometallation of alkyne with alkene[50,51,52,53,54,55,56], followed by cross-electrophile coupling of alkyl halide to sequentially forge two Csp2-Csp[3] bonds to deliver general tri- and tetrasubstituted alkenes (Fig. 1c) This conceptual strategy arises several significant challenges: the nucleophilic addition of organonickel/zinc species onto enones, β-H elimination of alkylnickel intermediate, homocoupling/ dehalogenation of alkyl halides and oligomerization of enone under reductive conditions, and isomerization of the desired product to conjugated enone. This mild method allows for the regio- and stereo-selective conversion of both terminal and internal alkynes into tri- and tetrasubstituted alkenes with up to four aliphatic substituents in the absence of any directing group

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