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 couplin...

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

Driven by the inherent synthetic potential of CO2 as an abundant, inexpensive and renewable C1 chemical feedstock, the recent years have witnessed renewed interest in devising catalytic CO2 fixations into organic matter. Although the formation of C-C bonds via catalytic CO2 fixation remained rather limited for a long period of time, a close look into the recent literature data indicates that catalytic carboxylation reactions have entered a new era of exponential growth, evolving into a mature discipline that allows for streamlining the synthesis of carboxylic acids, building blocks of utmost relevance in industrial endeavors. These strategies have generally proven broadly applicability and convenient to perform. However, substantial challenges still need to be addressed reinforcing the need to cover metal-catalyzed carboxylation area in a conceptual and concise manner, delineating the underlying new principles that are slowly emerging in this vibrant area of expertise.

Transition-Metal-Catalyzed Carboxylation Reactions with Carbon Dioxide.

ConspectusDifluoroalkylated compounds play a remarkably important role in life and materials sciences because of the unique characteristics of the difluoromethylene (CF2) group. In particular, precise introduction of a CF2 group at the benzylic position can dramatically improve the biological properties of the corresponding molecules. As a consequence, difluoroalkylation of aromatic compounds has become a powerful strategy in modulating the bioactivities of organic molecules. However, efficient strategies to selectively synthesize difluoroalkylated arenes had been very limited before 2012. Traditional synthetic methods in this regard suffer from either harsh reaction conditions or narrow substrate scope, significantly restricting their widespread applications, particularly for late-stage difluoroalkylation of bioactive molecules. To overcome these limitations, a straightforward route to access these valuable difluoroalkylated skeletons is the direct introduction of the difluoroalkylated group (CF2R) onto ...

Transition-Metal (Cu, Pd, Ni)-Catalyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides.

https://pubs.rsc.org/en/content/articlepdf/2019/cc/c9cc01047e

Recent advances of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) in photocatalytic transformations.

Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C—C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg–Backlund rearrangement, and 1,2-Wittig rearrangement, which usuall...

Recent Advances in the Chemical Synthesis of C-Glycosides

The formation of C–C bonds directly by catalytic reductive cross-coupling of two different electrophiles represents one of the practical synthetic protocols that differs from the conventional nucleophile/electrophile coupling methods. Particularly the reductive coupling of alkyl electrophiles with other electrophiles is still a challenge. This report summarizes the advances in the formation of C(sp3)–C(sp3) bonds between two alkyl electrophiles, with emphasis on the control of chemoselectivity that is exceedingly challenging to achieve due to similar structures and reactivities of two unactivated alkyl halides. The coupling of alkyl halides with aryl or acyl electrophiles was also discussed based on the chemical approach developed by our group, followed by a brief overview of the reactions of tertiary alkyl halides. In the end, a brief overview of the challenges in this exciting field was illustrated. Whereas the reaction mechanisms generating alkyl–alkyl products are proposed to involve reactions of Ni(I) species with alkyl halides to generate Ralkyl–Ni(III)–Ralkyl intermediates through a radical/Ni cage-rebound process, the obtained evidence seemingly supports that the radical chain mechanism governs the acylation and arylation of alkyl halides. The latter features a cage-escaped alkyl radical.

https://pubs.rsc.org/en/content/articlepdf/2015/qo/c5qo90045j

Nickel-catalyzed reductive coupling of alkyl halides with other electrophiles: concept and mechanistic considerations

The Ni-catalyzed reductive coupling of alkyl/aryl with other electrophiles has evolved to be an important protocol for the construction of C–C bonds. This chapter first emphasizes the recent progress on the Ni-catalyzed alkylation, arylation/ vinylation, and acylation of alkyl electrophiles. A brief overview of CO2 fixation is also addressed. The chemoselectivity between the electrophiles and the reactivity of the alkyl substrates will be detailed on the basis of different Nicatalyzed conditions and mechanistic perspective. The asymmetric formation of C(sp3)–C(sp2) bonds arising from activated alkyl halides is next depicted followed by allylic carbonylation. Finally, the coupling of aryl halides with other C(sp2)– electrophiles is detailed at the end of this chapter.

Nickel-Catalyzed Reductive Couplings

This work highlights Ni-catalyzed reductive coupling of alkyl acids with alkyl halides, particularly sterically hindered unactivated tertiary alkyl bromides for the production of all carbon quaternary ketones. The reductive strategy is applicable to α-selective synthesis of saturated, fully oxygenated C-acyl glycosides through easy manipulations of the readily available sugar bromides and alkyl acids, avoiding otherwise difficult multistep conversions. Initial mechanistic studies suggest that a radical chain mechanism (cycle B, Scheme 1) may be plausible, wherein MgCl2 promotes the reduction of NiII complexes.

Ni-Catalyzed Reductive Coupling of Alkyl Acids with Unactivated Tertiary Alkyl and Glycosyl Halides

A mild Ni-catalyzed reductive arylation of tertiary alkyl halides with aryl bromides has been developed that delivers products bearing all-carbon quaternary centers in moderate to excellent yields with excellent functional group tolerance. Electron-deficient arenes are generally more effective in inhibiting alkyl isomerization. The reactions proceed successfully with pyridine or 4-(dimethylamino)pyridine, while imidazolium salts slightly enhance the coupling efficiency.

Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides

This work illustrates the reductive coupling of electron-rich aryl halides with tertiary alkyl halides under Ni-catalyzed cross-electrophile coupling conditions, which offers an efficient protocol for the construction of all carbon quaternary stereogenic centers. The mild and easy-to-operate reaction tolerates a wide range of functional groups. The utility of this method is manifested by the preparation of cyclotryptamine derivatives, wherein successful incorporation of 7-indolyl moieties is of particular interest as numerous naturally occurring products are composed of these key scaffolds. DFT calculations have been carried out to investigate the proposed radical chain and double oxidative addition pathways, which provide useful mechanistic insights into the part of the reaction that takes place in solution.

Xuan Wang

Papers

Nickel-catalyzed reductive coupling of alkyl halides with other electrophiles: concept and mechanistic considerations

Nickel-Catalyzed Reductive Couplings

Ni-Catalyzed Reductive Coupling of Alkyl Acids with Unactivated Tertiary Alkyl and Glycosyl Halides

Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides

Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl Iodides with Tertiary Alkyl Halides