Electrochemical Synthesis of C(sp3)-Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds.

Alkylamines form the backbone of countless nitrogen-containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three-dimensional α-substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report the design of a catalyst-free electroreductive manifold that merges amines, carbonyl compounds and carbon-based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α-amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug-like scaffolds which are inaccessible by conventional means.

Recent Advances in First-Row Transition Metal-Catalyzed Reductive Coupling Reactions for π-Bond Functionalization and C-Glycosylation.

ConspectusEfficient construction of ubiquitous carbon-carbon bonds between two electrophiles has garnered interest in recent decades, particularly if it is mediated by nonprecious, first-row transition metals. Reductive coupling has advantages over traditional cross-coupling by obviating the need for stoichiometric air- and moisture-sensitive organometallic reagents. By harnessing transition metal-catalyzed reductive coupling as a powerful tool, intricate molecular architectures can be readily assembled through the installation of two C-C bonds across π systems (alkenes/alkynes) via reaction with two appropriate electrophiles. Despite advances in reductive alkene difunctionalization, there remains significant potential for the discovery of novel reaction pathways. In this regard, development of reductive protocols that enable the union of challenging alkyl/alkynyl electrophiles in high regio- and chemoselectivity remains a highly sought-after goal.Apart from π-bond functionalization, reductive coupling has found application in carbohydrate chemistry, particularly in the synthesis of valuable C-glycosyl compounds. In this vein, suitable glycosyl donors can be used to generate reactive glycosyl radical intermediates under reductive conditions. Through elaborately designed reactions, these intermediates can be trapped to furnish pharmaceutically relevant glycoconjugates. Consequently, diversification in C-glycosyl compound synthesis using first-row transition metal catalysis holds strong appeal.In this Account, we summarize our efforts in the development of first-row transition metal-catalyzed reductive coupling reactions for applications in alkene/alkyne functionalization and C-glycosylation. We will first discuss the nickel (Ni)-catalyzed reductive difunctionalization of alkenes, aided by an 8-aminoquinoline (AQ) directing auxiliary. Next, we highlight the Ni-catalyzed hydroalkylation of alkenyl amides tethered with a similar AQ-derived directing auxiliary. Lastly, we discuss an efficient synthesis of 1,3-enynes involving site- and stereoselective reductive coupling of terminal alkynes with alkynyl halides and NHPI esters.Beyond alkene dicarbofunctionalization, we extended the paradigm of transition metal-catalyzed reductive coupling toward the construction of C-glycosidic linkages in carbohydrates. By employing an earth-abundant iron (Fe)-based catalyst, we show that useful glycosyl radicals can be generated from glycosyl chlorides under reductive conditions. These intermediates can be captured in C-C bond formation to furnish valuable C-aryl, C-alkenyl, and C-alkynyl glycosyl compounds with high diastereoselectivity. Our Ni-catalyzed multicomponent union of glycosyl chlorides, aryl/alkyl iodides, and isobutyl chloroformate under reductive conditions led to the stereoselective synthesis of C-acyl glycosides. In addition to Fe and Ni, we discovered a Ti-catalyzed/Mn-promoted synthetic route to access C-alkyl and C-alkenyl glycosyl compounds, through the reaction of glycosyl chlorides with electron-deficient alkenes/alkynes. We further developed an electron donor-acceptor (EDA) photoactivation system leveraging decarboxylative and deaminative strategies for C-glycosylation under Ni catalysis. This approach has been demonstrated to selectively activate carboxyl and amino motifs to furnish glycopeptide conjugates. Finally, through two distinct catalytic transformations of bench-stable heteroaryl glycosyl sulfones, we achieved stereodivergent access to both α- and ß-anomers of C-aryl glycosides, one of which involves a Ni-catalyzed reductive coupling with aryl iodides.The findings presented in this Account are anticipated to have far-reaching implications beyond our research. We foresee that these results will pave the way for new transformations founded on the concept of reductive coupling, leading to the discovery of novel applications in the future.

Diversification of Glycosyl Compounds via Glycosyl Radicals.

Glycosyl radical functionalization is one of the central topics in synthetic carbohydrate chemistry. Recent advances in metal-catalyzed cross-coupling chemistry and metallaphotoredox catalysis provided powerful platforms for glycosyl radical diversification. In particular, the discovery of new glycosyl radical precursors in conjunction with these advanced reaction technologies have significantly expanded the space for glycosyl compound synthesis. In this Review, we highlight the most recent progress in this area starting from 2021, and the reports included will be categorized based on different reaction types for better clarity.

N-Heterocyclic carbenes as privileged ligands for nickel-catalysed alkene functionalisation.

Alkene functionalisation is a powerful strategy that has enabled access to a wide array of compounds including valuable pharmaceuticals and agrochemicals. The reactivity of the alkene π-bond has allowed incorporation of a diverse range of atoms and functional groups through a wide variety of reaction pathways. N-Heterocyclic carbenes (NHCs) are a class of persistent carbenes that are widely employed as ancillary ligands due to their ability to act as strong σ-donors compared to widely-applied conventional phosphine-based ligands. NHCs are also unique as their molecular bulk provides steric influence for regio- and stereo-control in many alkene functionalisation reactions, illustrated by the examples covered in this review. A combination of the unique reactivity of NHC ligands and nickel's characteristics has facilitated the design of reaction pathways that show distinct selectivity and reactivity, including the activation of bonds previously considered "inert", such as C-H bonds, the C-O bond of ethers and esters, and the C-N bonds of amides. This review summarises the advancements in Ni(NHC) catalysed alkene functionalisation up to 2022, covering the following major reaction classes: Heck-type reactions, hydrofunctionalisation and dicarbofunctionalisation.

Stereoselective C-Aryl Glycosylation by Catalytic Cross-Coupling of Heteroaryl Glycosyl Sulfones.

Stereoselective C-glycosylation reactions are increasingly gaining attention in carbohydrate chemistry because they enable glycosyl precursors, readily accessible as anomeric mixtures, to converge to a single diastereomeric product. However, controlling the stereochemical outcome through transition-metal catalysis remains challenging, and methods that leverage bench-stable heteroaryl glycosyl sulfone donors to facilitate glycosylation are rare. Herein, we show two complementary nonprecious metal catalytic systems, based on iron or nickel, which are capable of promoting efficient C-C coupling between heteroaryl glycosyl sulfones and aromatic nucleophiles or electrophiles through distinct mechanisms and modes of activation. Diverse C-aryl glycosides were secured with excellent selectivity, scope, and functional-group compatibility, and reliable access to both α and ß isomers was possible for key sugar residues.

Iron-Catalyzed Regioselective Alkenylboration of Olefins.

The first examples of an iron-catalyzed three-component synthesis of homoallylic boronates from regioselective union of bis(pinacolato)diboron, an alkenyl halide (bromide, chloride or fluoride), and an olefin are disclosed. Products that bear tertiary or quaternary carbon centers could be generated in up to 87 % yield as single regioisomers with complete retention of the olefin stereochemistry. With cyclopropylidene-containing substrates, ring cleavage leading to trisubstituted E-alkenylboronates were selectively obtained. Mechanistic studies revealed reaction attributes that are distinct from previously reported alkene carboboration pathways.