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. 2020 Nov 6;10(21):12642-12656.
doi: 10.1021/acscatal.0c03237. Epub 2020 Sep 29.

A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies

David J Charboneau  1 , Emily L Barth  1 , Nilay Hazari  1 , Mycah R Uehling  2 , Susan L Zultanski  3
Affiliations

A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies

David J Charboneau et al. ACS Catal. .

Abstract

A dual catalytic system for cross-electrophile coupling reactions between aryl halides and alkyl halides that features a Ni catalyst, a Co cocatalyst, and a mild homogeneous reductant is described. Mechanistic studies indicate that the Ni catalyst activates the aryl halide, while the Co cocatalyst activates the alkyl halide. This allows the system to be rationally optimized for a variety of substrate classes by simply modifying the loadings of the Ni and Co catalysts based on the reaction product profile. For example, the coupling of aryl bromides and aryl iodides with alkyl bromides, alkyl iodides, and benzyl chlorides is demonstrated using the same Ni and Co catalysts under similar reaction conditions but with different optimal catalyst loadings in each case. Our system is tolerant of numerous functional groups and is capable of coupling heteroaryl halides, di-ortho-substituted aryl halides, pharmaceutically relevant druglike aryl halides, and a diverse range of alkyl halides. Additionally, the dual catalytic platform facilitates a series of selective one-pot three-component cross-electrophile coupling reactions of bromo(iodo)arenes with two distinct alkyl halides. This demonstrates the unique level of control that the platform provides and enables the rapid generation of molecular complexity. The system can be readily utilized for a wide range of applications as all reaction components are commercially available, the reaction is scalable, and toxic amide-based solvents are not required. It is anticipated that this strategy, as well as the underlying mechanistic framework, will be generalizable to other cross-electrophile coupling reactions.

Keywords: cross-electrophile coupling; mechanism; medicinal chemistry; nickel; synthetic methods.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(a) General depiction and (b) mechanism of conventional nickel-catalyzed cross-electrophile coupling reactions using a heterogeneous reductant. (c) Cross-electrophile coupling reactions described in this work with a dual catalyst system and a homogeneous reductant.
Figure 2.
Figure 2.
Potential reactions of LNiII(Ar)X in catalysis and an envisioned strategy for system development.
Figure 3.
Figure 3.
Proposed mechanism for the cross-electrophile coupling of aryl and alkyl halides in the presence of CoII(Pc).
Figure 4.
Figure 4.
Substrate scope for dual-catalyzed cross-electrophile coupling between aryl halides and alkyl halides or pseudohalides. Values outside of parentheses are isolated yields and values inside of parentheses are NMR yields, which were determined by integration of 1H NMR spectra against a hexamethylbenzene external standard. a1.6 equiv. of alkyl substrate, 140 mol % TDAE. b2.0 equiv. of alkyl substrate, 160 mol % TDAE. c36 h. d48 h. e1-iodo-3-phenylpropane used as an alkyl substrate. fN-(3-bromopropyl)phthalimide used as an alkyl substrate instead of 1-bromo-3-phenylpropane.
Figure 5.
Figure 5.
Substrate scope for dual-catalyzed cross-electrophile coupling between MSD Aryl Halide Informer Library and 1-bromo-3-phenylpropane. Values outside of parentheses are NMR yields, which were determined by integration of 1H NMR spectra against a hexamethylbenzene external standard, and values inside of parentheses are isolated yields on 0.10 mmol scale. a2 equivalents of 1-iodo-3-phenylpropane alkyl substrate, 160 mol % TDAE, 48 h.
Figure 6.
Figure 6.
Dual-catalyzed cross-electrophile coupling reactions between 5f and a series of benzyl chlorides, alkyl iodides, and alkyl bromides. Values are reported as the conversion to product relative to all known species derived from 5f determined by UV–vis spectroscopy (see Supporting Information for details). NMR yields were determined by integration of 1H NMR spectra against a hexamethylbenzene external standard.
Scheme 1.
Scheme 1.
Cross-Electrophile Coupling of Aryl Iodides with Benzyl Chlorides Using TDAE Reported by Weix et al
Scheme 2.
Scheme 2.
Cross-Electrophile Coupling of Iodobenzene with 1-Iodo-3-Phenylpropane
Scheme 3.
Scheme 3.
Cross-Electrophile Coupling of 1-Bromo-2-Methyl-1-Propene with N-(3-bromopropyl)Phthalimide
Scheme 4.
Scheme 4.
Single-Step Three-Component Cross-Electrophile Coupling of 1-Bromo-4-Iodo-2-Methoxybenzene with Benzyl Chloride and 1-Bromo-3-Phenylpropane
Scheme 5.
Scheme 5.
3.0 mmol Scale Cross-Electrophile Coupling of 5f with 1-Iodo-3-Phenylpropane
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