Insights into Recent Nickel-Catalyzed Reductive and Redox C-C Coupling of Electrophiles, C(sp3)-H Bonds and Alkenes.

ConspectusTransition metal-catalyzed reductive cross-coupling of two carbon electrophiles, also known as cross-electrophile coupling (XEC), has transformed the landscape of C-C coupling chemistry. Nickel catalysts, in particular, have demonstrated exceptional performance in facilitating XEC reactions, allowing for diverse elegant transformations by employing various electrophiles to forge C-C bonds. Nevertheless, several crucial challenges remain to be addressed. First, the intrinsic chemoselectivity between two structurally similar electrophiles in Ni-catalyzed C(sp3)-C(sp3) and C(sp2)-C(sp2) cross-coupling has not been well understood; this necessitates an excess of one of the coupling partners to achieve synthetically useful outcomes. Second, the substitution of economically and environmentally benign nonmetal reductants for Zn/Mn can help scale up XEC reactions and avoid trace metals in pharmaceutical products, but research in this direction has progressed slowly. Finally, it is highly warranted to leverage mechanistic insights from Ni-catalyzed XEC to develop innovative thermoredox coupling protocols, specifically designed to tackle challenges associated with difficult substrates such as C(sp3)-H bonds and unactivated alkenes.In this Account, we address the aforementioned issues by reviewing our recent work on the reductive coupling of C-X and C-O electrophiles, the thermoredox strategy for coupling associated with C(sp3)-H bonds and unactivated alkenes, and the use of diboron esters as nonmetal reductants to achieve reductive coupling. We focus on the mechanistic perspectives of the transformations, particularly how the key C-NiIII-C intermediates are generated, in order to explain the chemoselective and regioselective coupling results. The Account consists of four sections. First, we discuss the Zn/Mn-mediated chemoselective C(sp2)-C(sp2) and C(sp3)-C(sp3) bond formations based on the coupling of selected alkyl/aryl, allyl/benzyl, and other electrophiles. Second, we describe the use of diboron esters as versatile reductants to achieve C(sp3)-C(sp3) and C(sp3)-C(sp2) couplings, with an emphasis on the mechanistic consideration for the construction of C(sp3)-C(sp2) bonds. Third, we discuss leveraging C(sp3)-O bonds for effective C(sp3)-C bond formation via in situ halogenation of alcohols as well as the reductive preparation of α-vinylated and -arylated unusual amino esters. In the final section, we illustrate the thermoredox functionalization of challenging C(sp3)-H bonds with aryl and alkyl halides to afford C(sp3)-C bonds by taking advantage of the compatibility of Zn with the oxidant di-tert-butylperoxide (DTBP). Furthermore, we discuss a Ni-catalyzed and SiH/DTBP-mediated hydrodimerization of terminal alkenes to selectively forge head-to-head and methyl branched C(sp3)-C(sp3) bonds. This process, conducted in the presence or absence of catalytic CuBr2, provides a solution to a long-standing challenge: site-selective hydrocoupling of unactivated alkenes to produce challenging C(sp3)-C(sp3) bonds.

Expeditious preparation of ß-sec-alkyl vicinal amino alcohols used for chiral ligand synthesis.

An economical route providing quick access to chiral ß-amino alcohols bearing one ß-sec-alkyl group was developed. This protocol starts with commercially available and cheap chiral sources such as derivatives of L-serine and L-threonine. A series of vicinal amino alcohols with high optical purity were prepared in good yields through 4 or 6 operationally simple steps. Two different strategies (three routes) were designed for the synthesis of amino alcohols bearing ß-sec-alkyl groups with various steric hindrance.

Retraction: Deoxygenative cross-electrophile coupling of benzyl chloroformates with aryl iodides.

Retraction of 'Deoxygenative cross-electrophile coupling of benzyl chloroformates with aryl iodides' by Yingying Pan et al., Org. Biomol. Chem., 2019, 17, 4230-4233, https://doi.org/10.1039/C9OB00628A.

Ni-Catalyzed Reductive Coupling of Heteroaryl Bromides with Tertiary Alkyl Halides.

We disclose here a nickel-catalyzed reductive coupling of bromopyridines with tertiary alkyl bromides for the synthesis of alkylated pyridines bearing an all-carbon quaternary center. This strategy features mild conditions, broad substrate scope, and high functional group tolerance. The method reported here offers an alternative solution to the challenging task of forging sterically congested alkylpyridines, which we believe will significantly benefit the synthetic community and pharmaceutical industry.

Nickel-Catalyzed Thermal Redox Functionalization of C(sp3 )-H Bonds with Carbon Electrophiles.

C(sp3 )-H bond coupling with carbon electrophiles remains rarely explored under thermo-driven hydrogen atom transfer (HAT) conditions due to the challenge of integrating oxidation and reduction in a single operation. We report here a Ni-catalyzed arylation and alkylation of C(sp3 )-H bonds with organohalides to forge C(sp3 )-C bonds by merging economical Zn and tBuOOtBu (DTBP) as the external reductant and oxidant. The mild and easy-to-operate protocol enables facile carbofunctionalization of N-/O-α- and cyclohexane C-H bonds, and preparation of a few intermediates of bioactive compounds and drug derivatives. Preliminary mechanistic studies implied addition of an alkyl radical to a NiII salt.

Alkenylation and Arylation of Peptides via Ni-Catalyzed Reductive Coupling of α-C-Tosyl Peptides with Csp2 Triflates/Halides.

A Ni-catalyzed reductive cross-coupling between α-C-tosyl peptides and Csp2 triflates/halides has been developed. This protocol enables the formation of various unnatural di- and tripeptides containing vinyl and aryl side chains, and it expands the applications of Ni-catalyzed reductive cross-coupling in late-stage diversification of peptides.

Nickel-catalyzed asymmetric reductive arylation of α-chlorosulfones with aryl halides.

We report an asymmetric Ni-catalyzed reductive cross-coupling of aryl/heteroaryl halides with racemic α-chlorosulfones to afford enantioenriched sulfones. The reaction tolerates a variety of functional groups under mild reaction conditions, which complements the current methods. The utility of this work was demonstrated by facile late-stage functionalization of commercial drugs.

Nickel-catalyzed reductive 1,3-diene formation from the cross-coupling of vinyl bromides.

Facile construction of 1,3-dienes building upon cross-electrophile coupling of two open-chain vinyl halides is disclosed in this work, showing moderate chemoselectivities between the terminal bromoalkenes and internal vinyl bromides. The present method is mild and tolerates a range of functional groups and can be applied to the total synthesis of a tobacco fragrance solanone.

Ni-Catalyzed Cross-Electrophile Coupling of Aryl Triflates with Thiocarbonates via C-O/C-O Bond Cleavage.

A nickel-catalyzed reductive coupling of aryl triflates with thiocarbonates is reported here. Both electron-rich and -deficient aryl C(sp2)-O electrophiles as well as a class of O-tBu S-alkyl thiocarbonates are compatible with the optimized reaction conditions, as evidenced by 49 examples. The reaction also proceeds with good chemoselective cleavage of the C-O bond with regard to thioesters. This work broadens the scope of nickel-catalyzed reductive cross-electrophile coupling reactions.

Nickel-Catalyzed Reductive Vinylation of Chloro-hexahydropyrroloindoline Derivatives with Vinyl Triflates.

This work emphasizes facile construction of C-3a vinyl substituted hexahydropyrrolidinoindolines based upon Ni-catalyzed reductive coupling of chloro-hexahydropyrroloindoline derivatives with a wide range of alkyl-decorated vinyl triflates. The remarkable compatibility of sterically hindered branched vinyl groups is highlighted.

Nickel-catalyzed formation of quaternary carbon centers using tertiary alkyl electrophiles.

Transformation of sterically hindered tertiary alkyl electrophiles under nickel-catalyzed conditions to forge C(sp3)-C bonds and simultaneously create challenging all-carbon quaternary centers has received growing attention in the recent years. The unique nature of nickel featuring flexible oxidation states ranging from Ni0 to NiIV, allows the effective activation of tertiary alkyl electrophiles through ionic (2e) or radical pathways. In nickel-catalyzed coupling of tertiary alkyl electrophiles, the competitive ß-H elimination upon the resulting alkyl-Ni intermediate is relatively slow, thus benefiting the C-C bond forming process. Meanwhile, nickel-catalyzed radical addition of tertiary alkyl electrophiles to unsaturated C-C bonds has also advanced rapidly due to the successful incorporation of carboxylic acid and alcohol derivatives as radical precursors, and more importantly due to further interception of the intermediate radical adducts with nucleophiles and electrophiles to accomplish three-component cascade reactions. This review highlights these state-of-the-art nickel-catalyzed transformations of tertiary electrophiles, organized by reaction types with emphasis on the reaction mechanisms.

Diverse Synthesis of Chiral Trifluoromethylated Alkanes via Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Fluoroalkylation.

The trifluoromethyl group represents one of the most functional and widely used fluoroalkyl groups in drug design and screening, while the drug candidates containing chiral trifluoromethyl-bearing carbons are still few due to the lack of efficient methods for the asymmetric introduction of trifluoromethyl group into organic molecules. Herein, we described a nickel-catalyzed asymmetric trifluoroalkylation of aryl iodides, for the first time, by utilizing reductive cross-coupling in enantioselective fluoroalkylation. This novel method has demonstrated high efficiency, mild conditions, and excellent functional group tolerance, especially for substrates containing diverse pharmaceutical and bioactive molecules moieties. This strategy provided an efficient and facile way for diversity-oriented synthesis of chiral trifluoromethylated alkanes.

Zn- and Cu-Catalyzed Coupling of Tertiary Alkyl Bromides and Oxalates to Forge Challenging C-O, C-S, and C-N Bonds.

We describe here the facile construction of sterically hindered tertiary alkyl ethers and thioethers via the Zn(OTf)2-catalyzed coupling of alcohols/phenols with unactivated tertiary alkyl bromides and the Cu(OTf)2-catalyzed thiolation of unactivated tertiary alkyl oxalates with thiols. The present protocol represents one of the most effective unactivated tertiary C(sp3)-heteroatom bond-forming conditions via readily accessible Lewis acid catalysis that is surprisingly less developed.

Nickel-Catalyzed, Regio- and Enantioselective Benzylic Alkenylation of Olefins with Alkenyl Bromide.

A NiH-catalyzed migratory hydroalkenylation reaction of olefins with alkenyl bromides has been developed, affording benzylic alkenylation products with high yields and excellent chemoselectivity. The mild conditions of the reaction preclude olefinic products from undergoing further isomerization or subsequent alkenylation. Catalytic enantioselective hydroalkenylation of styrenes was achieved by using a chiral bisoxazoline ligand.

Metal catalyst-free photo-induced alkyl C-O bond borylation.

Metal catalyst free, blue visible light-induced C-O bond borylation of unactivated tertiary alkyl methyl oxalates has been developed to furnish tertiary alkyl boronates. From the secondary alcohols activated with imidazolylthionyl, moderate yields of boronates were attained under standard photo-induced conditions. Preliminary mechanistic studies confirmed the involvement of a (DMF)2-B2cat2 adduct that weakly absorbs light at 437 nm so as to initiate a Bcat radical. A radical-chain process is proposed wherein the alkyl radical is engaged.

Cross-Electrophile Couplings of Activated and Sterically Hindered Halides and Alcohol Derivatives.

Transition metal catalyzed cross-electrophile coupling of alkyl electrophiles has evolved into a privileged strategy that permits the facile construction of valuable C(sp3)-C bonds. Numerous elegant Ni-catalyzed coupling methods, for example, arylation, allylation, acylation, and vinylation of primary and secondary alkyl halides have been developed. This prior work has provided important mechanistic insights into the selectivity and reactivity of the coupling partners, which are largely dictated by both the catalysts and the reactants. In spite of the advances made to date, a number of challenging issues remain, including (1) achieving stereoselective syntheses of C-C bonds that rely primarily on functionalized or activated alkyl precursors, (2) diversifying the electrophiles, and (3) gaining insights into the underlying reaction mechanisms.In this Account, we summarize a number of Ni- and Fe-catalyzed reductive C-C bond forming methods developed in our laboratory, which have allowed us to couple activated, sterically hindered tertiary alkyl and C(sp3)-O bond electrophiles and to access methylated and trifluoromethylated products, esters, C-glycosides, and quaternary carbon centers. We will begin with a brief discussion of Ni-catalyzed chemoselective construction of unactivated alkyl-alkyl bonds, with focus on the effects of ligands and reductants, along with leaving group-directed reactivities of alkyl halides, and the role they play in promoting the reductive coupling of activated electrophiles, including methyl, trifluoromethyl, and glycosyl electrophiles, and chloroformates. Matching the reactivities of these electrophiles with suitable coupling partners is considered essential for success; this is something that can be tuned by means of appropriate Ni catalysts. Second, we will detail how tuning the steric and electronic effects of nickel catalysts with labile pyridine-type ligands and additives (primarily MgCl2) permits effective creation of arylated all-carbon quaternary centers through the coupling of aryl halides with sterically encumbered tertiary alkyl halides. In contrast, the use of bulkier bipyridine and terpyridine ligands permits the incorporation of relative small-sized acyl and allyl groups into acylated and allylated all-carbon quaternary centers. Finally, we will show how the knowledge gained with halide electrophiles enabled us to develop methods that permit the coupling of tertiary alkyl oxalates with allyl, aryl, and vinyl electrophiles, wherein Barton C-O bond radical fragmentation is mediated by Zn and MgCl2 and promoted by Ni catalysts. The same protocol is applicable to the arylation of secondary alkyl oxalates derived from α-hydroxyl carbonyl substrates, which involves the formation of relatively stable α-carbonyl carbon centered radicals. Thus, this Account not only summarizes synthetic methods that allow formation of valuable C-C bonds using challenging electrophiles but also provides insight into the relationship between the structure and reactivity of the substrates and catalysts, as well as the effects of additives.

Iron-Catalyzed Reductive Vinylation of Tertiary Alkyl Oxalates with Activated Vinyl Halides.

We present herein a rare and efficient method for the creation of vinylated all carbon quaternary centers via Fe-catalyzed cross-electrophile coupling of vinyl halides with tertiary alkyl methyl oxalates. The reaction displays excellent functional group tolerance and broad substrate scope, which allows cascade radical cyclization and vinylation to afford complex bicyclic and spiral structural motifs. The reaction proceeds via tertiary alkyl radicals, and the putative vinyl-Br/Fe complexation appears to be crucial for activating the alkene and enabling a possibly concerted radical addition/C-Fe forming process.

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine.

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar-Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp2) electrophile to the resultant Gly-Ni(i) intermediate gives a key Gly-Ni(iii)-Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly-Ni(i) intermediate.