Nickel-Catalyzed C−I-Selective C(sp2)−C(sp3) Cross-Electrophile Coupling of Bromo(iodo)arenes with Alkyl Bromides

Despite several methodologies established for C(sp²)−I selective C(sp²)−C(sp³) bond formations, achieving arene-flanked quaternary carbons by cross-coupling of tertiary alkyl precursors with bromo(iodo)arenes in a C(sp²)−I selective manner is rare. Here we report a general Ni-catalyzed C(sp²)−I selective cross-electrophile coupling (XEC) reaction, in which, beyond 3° alkyl bromides (for constructing arene-flanked quaternary carbons), 2° and 1° alkyl bromides are also demonstrated to be viable coupling partners. Moreover, this mild XEC displays excellent C(sp²)−I selectivity and functional group compatibility. The practicality of this XEC is demonstrated in simplifying the routes to several medicinally relevant and synthetically challenging compounds. Extensive experiments show that the terpyridine-ligated Ni^I halide can exclusively activate alkyl bromides, forming a Ni^I−alkyl complex through a Zn reduction. Attendant density functional theory (DFT) calculations reveal two different pathways for the oxidative addition of the Ni^I−alkyl complex to the C(sp²)−I bond of bromo(iodo)arenes, explaining both the high C(sp²)−I selectivity and generality of our XEC.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

Substrate-Mediator Duality of 1,4-Dicyanobenzene in Electrochemical C(sp2)−C(sp3) Bond Formation with Alkyl Bromides

Electrochemical approaches to form C(sp²)−C(sp³) bonds have focused on coupling C(sp³) electrophiles that form stabilized carbon-centered radicals upon reduction or oxidation. Whereas alkyl bromides are desirable C(sp³) coupling partners owing to their availability and cost-effectiveness, their tendency to undergo radical-radical homocoupling makes them challenging substrates for electroreductive cross-coupling. Herein, we disclose a metal-free regioselective cross-coupling of 1,4-dicyanobenzene, a useful precursor to aromatic nitriles, and alkyl bromides. Alkyl bromide reduction is mediated directly by 1,4-dicyanobenzene radical anions, leading to negligible homocoupling and high cross-selectivity to form 1,4-alkyl cyanobenzenes. The cross-coupling scheme is compatible with oxidatively sensitive and acidic functional groups such as amines and alcohols, which have proven difficult to incorporate in alternative electrochemical approaches using carboxylic acids as C(sp³) precursors.     

Photoinduced Metal-Free Decarboxylative Transformations: Rapid Access to Amines,Alkyl Halides,and Olefins

Herein, we report an efficient photocatalytic strategy for the decarboxylative transformations of redox-active esters to construct C=C, C(sp³)−N, and C(sp³)−X bonds in a single-step. This operationally simple method provides a straightforward access to a variety of protected alkyl amines, alkyl halides and olefins under mild conditions in the absence of metals and photocatalysts. The method can successfully be applied to primary, secondary, and tertiary aliphatic carboxylic acid derivatives. Mechanistic studies indicate that the charge transfer complex (CTC) was formed by ⁿBu₄NI with redox-active esters, in which the ⁿBu₄NI acted as both an iodine source and an efficient electron donor.     

Copper‐Catalyzed Decarboxylative Radical Silylation of Redox‐Active Aliphatic Carboxylic Acid Derivatives

A decarboxylative silylation of aliphatic N ‐hydroxyphthalimide (NHPI) esters using Si−B reagents as silicon pronucleophiles is reported. This C(sp³)−Si cross‐coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional‐group tolerance is generally excellent, and α‐heteroatom‐substituted substrates also participate well. This enables, for example, the synthesis of α‐silylated amines starting from NHPI esters derived from α‐amino acids. The new method extends the still limited number of C(sp³)−Si cross‐couplings of unactivated alkyl electrophiles.     

An extension of nickel-catalyzed reductive coupling between tertiary alkyl halides with allylic carbonates

The nickel catalyzed reductive coupling of allylic carbonates with chloro-cyclotryptamine analogs to construct sterically congested all C(sp³) quaternary centers has been achieved with emphasis on the substrate scope. And the using of dienyl methyleneyl carbonates coupling with a variety of tertiary alkyl halides furnished the dienylated products improved the reaction's applicability.     

Synthesis of α-Quaternary β-Lactams via Copper-Catalyzed Enantioconvergent Radical C(sp3)−C(sp2) Cross-Coupling with Organoboronate Esters

The copper-catalyzed enantioconvergent radical C(sp³)−C(sp²) cross-coupling of tertiary α-bromo-β-lactams with organoboronate esters could provide the synthetically valuable α-quaternary β-lactams. The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N-ligand catalyst to forge the sterically congested chiral C(sp³)−C(sp²) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross-coupling reactions.     

Photoredox-Controlled Mono- and Di-Multifluoroarylation of C(sp3)−H Bonds with Aryl Fluorides

A controllable mono- and di-multifluoroarylation of acyclic and cyclic N-aryl amines with aryl fluorides by photocatalyzed dual C(sp³)−H/C(sp²)−F functionalization has been developed, providing new access to a wide array of valuable α-fluoroarylated amines. In addition, the one-pot consecutive hetero-di-multifluoroarylation of N-aryl pyrrolidines and N,N-dimethylanilines was achieved with high to excellent diastereoselectivity. This new defluorinative C(sp³)−C(sp²) coupling is distinguished by a broad scope, good regioselectivity, and mild conditions as well as gram-scale and late-stage applicability, and thus constitutes a significant advance in the arylation of unactivated C(sp³)−H bonds with aryl fluorides.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

Cobalt(II)-Catalyzed C(sp3)−C(sp3) Coupling for the Direct Stereoselective Synthesis of 2-Deoxy-C-Glycosides from Glycals

We report a ligand-controlled Co^II-catalyzed C(sp³)−C(sp³) coupling hydroalkylation for direct and β-selective synthesis of 2-deoxy-C-glycosides from glycals. This reaction proceeds by a radical pathway for alkyl halide activation and is β-selective through ligand control. This approach may inspire the development of further stereoselective coupling reactions with potential application in the field of carbohydrates.     

Copper‐Catalyzed Bromination of C(sp3)−H Bonds Distal to Functional Groups

Selective bromination of γ‐methylene C(sp³)−H bonds of aliphatic amides and δ‐methylene C(sp³)−H bonds of nosyl‐protected alkyl amines are developed using NBS as the brominating reagent and catalytic amount of Cu^II/phenanthroline complexes as the catalyst. Aryl and benzylic C−H bonds at other locations remain intact during this directed radical abstraction reaction.     

Direct C(sp2)C(sp3) Cross‐Coupling of Diaryl Zinc Reagents with Benzylic,Primary, Secondary,and Tertiary Alkyl Halides

The direct C(sp²)? C(sp³) cross‐coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²)? C(sp³) cross‐coupling showed excellent functional‐group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²)? C(sp³) bonds.     

Direct C(sp2)?C(sp3) Cross‐Coupling of Diaryl Zinc Reagents with Benzylic,Primary, Secondary,and Tertiary Alkyl Halides

The direct C(sp²) C(sp³) cross‐coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²) C(sp³) cross‐coupling showed excellent functional‐group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²) C(sp³) bonds.     

Nickel‐Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic Carbonates

The construction of all C(sp³) quaternary centers has been successfully achieved under Ni‐catalyzed cross‐electrophile coupling of allylic carbonates with unactivated tertiary alkyl halides. For allylic carbonates bearing C1 or C3 substituents, the reaction affords excellent regioselectivity through the addition of alkyl groups to the unsubstituted allylic carbon terminus. The allylic alkylation method also exhibits excellent functional‐group compatibility, and delivers the products with high E selectivity.     

Cross-Electrophile Coupling between Two Different Tosylates Enabled by Nickel/Palladium Cooperative Catalysis

Cross-electrophile coupling reactions are efficient for the construction of carbon-carbon bonds under relatively mild conditions, and hence widely used for making new molecules. Among various electrophiles, the cross-electrophile coupling reaction between two different tosylates has been rarely studied. Herein, we present a cross-electrophile coupling of gem-difluoroalkenyl tosylate (C(sp²)−OTs) and α-CF₃ benzyl tosylate (C(sp³)−OTs) by nickel/palladium cooperative catalysis. Mechanistic investigation indicated that the activation of C(sp²)−OTs bond and C(sp³)−OTs bond was facilitated by nickel and palladium respectively.     

Plasmonic Silver-Nanoparticle-Catalysed Hydrogen Abstraction from the C(sp3)−H Bond of the Benzylic Cα atom for Cleavage of Alkyl Aryl Ether Bonds

Selective activation of the C(sp³)−H bond is an important process in organic synthesis, where efficiently activating a specific C(sp³)−H bond without causing side reactions remains one of chemistry's great challenges. Here we report that illuminated plasmonic silver metal nanoparticles (NPs) can abstract hydrogen from the C(sp³)−H bond of the C_α atom of an alkyl aryl ether β-O-4 linkage. The intense electromagnetic near-field generated at the illuminated plasmonic NPs promotes chemisorption of the β-O-4 compound and the transfer of photo-generated hot electrons from the NPs to the adsorbed molecules leads to hydrogen abstraction and direct cleavage of the unreactive ether C_β−O bond under moderate reaction conditions (≈90 °C). The plasmon-driven process has certain exceptional features: enabling hydrogen abstraction from a specific C(sp³)−H bond, along with precise scission of the targeted C−O bond to form aromatic compounds containing unsaturated, substituted groups in excellent yields.     

Design of New Ligands for the Palladium‐Catalyzed Arylation of α‐Branched Secondary Amines

In Pd‐catalyzed C? N cross‐coupling reactions, α‐branched secondary amines are difficult coupling partners and the desired products are often produced in low yields. In order to provide a robust method for accessing N‐aryl α‐branched tertiary amines, new catalysts have been designed to suppress undesired side reactions often encountered when these amine nucleophiles are used. These advances enabled the arylation of a wide array of sterically encumbered amines, highlighting the importance of rational ligand design in facilitating challenging Pd‐catalyzed cross‐coupling reactions.     

Anomeric Stereoauxiliary Cleavage of the C−N Bond of d-Glucosamine for the Preparation of Imidazo[1,5-a]pyridines

The targeted cleavage of the C−N bonds of alkyl primary amines in sustainable compounds of biomass according to a metal-free pathway and the conjunction of nitrogen in the synthesis of imidazo[1,5-a]pyridines are still highly challenging. Despite tremendous progress in the synthesis of imidazo[1,5-a]pyridines over the past decade, many of them can still not be efficiently prepared. Herein, we report an anomeric stereoauxiliary approach for the synthesis of a wide range of imidazo[1,5-a]pyridines after cleaving the C−N bond of d -glucosamine (α-2° amine) from biobased resources. This new approach expands the scope of readily accessible imidazo[1,5-a]pyridines relative to existing state-of-the-art methods. A key strategic advantage of this approach is that the α-anomer of d -glucosamine enables C−N bond cleavage via a seven-membered ring transition state. By using this novel method, a series of imidazo[1,5-a]pyridine derivatives (>80 examples) was synthesized from pyridine ketones (including para-dipyridine ketone) and aldehydes (including para-dialdehyde). Imidazo[1,5-a]pyridine derivatives containing diverse important deuterated C(sp²)−H and C(sp³)−H bonds were also efficiently achieved.     

Ruthenium-Catalyzed Remote Difunctionalization of Nonactivated Alkenes for Double meta-C(sp2)−H/C-6(sp3)−H Functionalization

Twofold distal C−H functionalization was accomplished by difunctionalization of nonactivated alkenes to provide rapid access to multifunctionalized molecules. The multicomponent ruthenium-catalyzed remote 1,n-difunctionalization (n=6,7) of nonactivated alkenes with fluoroalkyl halides and heteroarenes in a modular manner is reported. The meta-C(sp²)−H/C-6(sp³)−H distal functionalization featured mild conditions, unique selectivity, and broad substrate scope with a domino process for twofold remote C(sp²)−H/C(sp³)−H activation of the sequential formation of three different carbon-centered radicals. A plausible mechanism was proposed based on detailed experimental and computational studies.