Nickel-Catalyzed Cross-Electrophile Coupling of 2-Chloropyridines with Alkyl Bromides

Everson, Daniel A.; Buonomo, Joseph A.; Weix, Daniel J.

doi:10.1055/s-0033-1340151

Cited by 28 publications

(7 citation statements)

References 51 publications

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“… 21 After an examination of several different ligands, we found that bathophenanthroline enhanced the yield of product formed from 2-chloropyridines and alkyl bromides (Scheme 6 ). 32 Intriguingly, the very slow coupling of 2-chloro-4-trifluoromethylpyridine with an alkyl bromide could be dramatically accelerated by adding 10 mol % AIBN (from 48 to 19 h). This experiment had been informed by our ongoing mechanistic studies (vide infra) and is consistent with a radical initiation process.…”

Section: Coupling Of 2-chloropyridines With Alkyl Halidesmentioning

confidence: 99%

Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

2015

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ConspectusCross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C–H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions.Although the coupling of two different electrophiles under reducing conditions often leads primarily to symmetric dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop.A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addition to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C–C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain.Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form β-aryl alcohols, and coupling of benzyl sulfonate esters with aryl halides to form diarylmethanes. Arylnickel(II) intermediates can insert carbon monoxide to form acylnickel(II) intermediates that react with alkyl halides to form ketones, demonstrating the connection between the mechanisms of reactions of aryl halides and acid chlorides with alkyl halides. The low reactivity of epoxides with nickel can be overcome by the use of either titanium or iodide cocatalysis to facilitate radical generation and this can also be extended to enantioselective arylation of meso-epoxides. The high reactivity of benzyl bromide with nickel, which leads to the formation of bibenzyl in attempted reactions with bromobenzene, can be overcome by using a benzyl mesylate along with cobalt phthalocyanine cocatalysis to convert the mesylate into an alkyl radical.

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Section: Coupling Of 2-chloropyridines With Alkyl Halidesmentioning

confidence: 99%

Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

2015

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“…A recent result from our own laboratories has demonstrated a new, general strategy for the coupling of two electrophiles that differentiates the substrates based upon heterolytic and homolytic reactivity trends. We had previously reported the nickel-catalyzed XEC of aryl halides with alkyl halides (Figure 7 ), which can be run on large scale (>25 mmol), 13 , 34 and the extension of this concept to reactions of alkyl halides with 2-chloropyridines 35 and allylic acetates. 36 In all of these examples, we reported detailed selectivity data to demonstrate that the reactions were selective for the cross-coupled products.…”

Section: Strategies For Achieving Useful Yields Of Cross-coupled Prodmentioning

confidence: 99%

Cross-Electrophile Coupling: Principles of Reactivity and Selectivity

2014

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A critical overview of the catalytic joining of two different electrophiles, cross-electrophile coupling (XEC), is presented with an emphasis on the central challenge of cross-selectivity. Recent synthetic advances and mechanistic studies have shed light on four possible methods for overcoming this challenge: (1) employing an excess of one reagent; (2) electronic differentiation of starting materials; (3) catalyst–substrate steric matching; and (4) radical chain processes. Each method is described using examples from the recent literature.

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“…In the first of these, we were inspired by the scholarly contributions of Weix, 26 Gong, 27 and Molander 28 relying on well-precedented Ni-catalyzed reductive cross-coupling reactions involving alkyl (sp 3 ) and aryl or heteroaryl (sp 2 ) reacting partners. 29 …”

Section: Introductionmentioning

confidence: 99%

Ni-Catalyzed Reductive and Merged Photocatalytic Cross-Coupling Reactions toward sp³/sp²-Functionalized Isoquinolones: Creating Diversity at C-6 and C-7 to Address Bioactive Analogues

et al. 2020

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Naturally occurring isoquinolones have gained considerable attention over the years for their bioactive properties. While the late-stage introduction of various functionalities at certain positions, namely, C-3, C-4, and C-8, has been widely documented, the straightforward introduction of challenging sp 3 carbon-linked acyclic aminoalkyl or aza- and oxacyclic appendages at C-6 and C-7 remains largely underexplored. Interest in 6-substituted azacyclic analogues has recently garnered attention in connection with derivatives exhibiting anticancer activity. Reported here is the first application of the versatile and recently emerging field of Ni-catalyzed reductive cross-coupling reactions to the synthesis of 6- and 7- hetero(cyclo)alkyl-substituted isoquinolones. In a second and complementary approach, a new set of C-6- and C-7-substituted positional isomers of hetero(cyclo)alkyl appendages were obtained from the merging of photocatalytic and Ni-catalyzed coupling reactions. In both cases, 6- and 7-bromo isoquinolones served as dual-purpose reacting partners with readily available tosylates and carboxylic acids, respectively.

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Nickel-Catalyzed Cross-Electrophile Coupling of 2-Chloropyridines with Alkyl Bromides

Cited by 28 publications

References 51 publications

Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

Cross-Electrophile Coupling: Principles of Reactivity and Selectivity

Ni-Catalyzed Reductive and Merged Photocatalytic Cross-Coupling Reactions toward sp³/sp²-Functionalized Isoquinolones: Creating Diversity at C-6 and C-7 to Address Bioactive Analogues

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Nickel-Catalyzed Cross-Electrophile Coupling of 2-Chloropyridines with Alkyl Bromides

Cited by 28 publications

References 51 publications

Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles

Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles

Cross-Electrophile Coupling: Principles of Reactivity and Selectivity

Ni-Catalyzed Reductive and Merged Photocatalytic Cross-Coupling Reactions toward sp3/sp2-Functionalized Isoquinolones: Creating Diversity at C-6 and C-7 to Address Bioactive Analogues

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Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

Ni-Catalyzed Reductive and Merged Photocatalytic Cross-Coupling Reactions toward sp³/sp²-Functionalized Isoquinolones: Creating Diversity at C-6 and C-7 to Address Bioactive Analogues