Copper-Catalyzed Enantioconvergent Radical C(sp3)−N Cross-Coupling: Access to α,α-Disubstituted Amino Acids

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C−N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C−N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm. An array of α,α-disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α-fully substituted amine building blocks.     

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.     

Visible-Light-Driven Intermolecular Reductive Ene–Yne Coupling by Iridium/Cobalt Dual Catalysis for C(sp3)−C(sp2) Bond Formation

A new methodology to form C(sp³)−C(sp²) bonds by visible-light-driven intermolecular reductive ene–yne coupling has been successfully developed. The process relies on the ability of the Hantzsch ester to contribute in both SET and HAT processes through a unified cobalt and iridium catalytic system. This procedure avoids the use of stoichiometric amounts of reducing metallic reagents, which is translated into high functional-group tolerance and atom economy.     

Dual Benzophenone/Copper-Photocatalyzed Giese-Type Alkylation of C(sp3)−H Bonds

Photocatalyzed Giese-type alkylations of C(sp³)−H bonds are very attractive reactions in the context of atom-economy in C−C bond formation. The main limitation of such reactions is that when using highly polymerizable olefin acceptors, such as unsubstituted acrylates, acrylonitrile, or methyl vinyl ketone, radical polymerization often becomes the dominant or exclusive reaction pathway. Herein, we report that the polymerization of such olefins is strongly limited or suppressed when combining the photocatalytic activity of benzophenone (BP) with a catalytic amount of Cu(OAc)₂. Under mild and operationally simple conditions, the Giese adducts resulting from the C(sp³)−H functionalization of amines, alcohols, ethers, and cycloalkanes could be synthesized. Preliminary mechanistic studies have revealed that the reaction does not proceed through a radical chain, but through a dual BP/Cu photocatalytic process, in which both Cu^II and low-valent Cu^I/0 species, generated in situ by reduction by the BP ketyl radical, may react with α-keto or α-cyano intermediate radicals, thus preventing polymerization.     

Convenient Access to Chiral Cyclobutanes with Three Contiguous Stereocenters from Verbenone by Directed C(sp3)−H arylation

This work demonstrates how a series of complex, chiral cyclobutane derivatives can be accessed in four steps from the terpene verbenone through the application of a directed C−H functionalization approach. The developed synthetic route involved an 8-aminoquinoline-directed C(sp³)−H arylation as the key step, and this reaction could be carried out with a wide range of aryl and heteroaryl iodides to furnish a variety of cyclobutane products with three contiguous stereocenters. Moreover, it was shown that the 8-aminoquinoline auxiliary could be effectively removed from the cyclobutane derivatives using an ozonolysis-based cleavage method.     

A Chemoselective Polarity-Mismatched Photocatalytic C(sp3)−C(sp2) Cross-Coupling Enabled by Synergistic Boron Activation**

We report the development of a C(sp³)−C(sp²) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.     

Paired Oxidative and Reductive Catalysis: Breaking the Potential Barrier of Electrochemical C(sp3)−H Alkenylation**

Due to the intrinsic inertness of alkanes, strong oxidative conditions are typically required to enable their C(sp³)−H functionalization. Herein, a paired electrocatalysis strategy was developed by integrating oxidative catalysis with reductive catalysis in one cell without interference, in which earth-abundant iron and nickel are employed as the anodic and cathodic catalysts, respectively. This approach lowers the previously high oxidation potential required for alkane activation, enabling electrochemical alkane functionalization at the ultra-low oxidation potential of ≈0.25 V vs. Ag/AgCl under mild conditions. Structurally diverse alkenes, including challenging all-carbon tetrasubstituted olefins, can be accessed using readily available alkenyl electrophiles.     

Site-Selective,Remote sp3 C−H Carboxylation Enabled by the Merger of Photoredox and Nickel Catalysis

A photoinduced carboxylation of alkyl halides with CO₂ at remote sp³ C−H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.     

Amidyl Radical Directed γ-C(sp3)−H Functionalization with Silyl Enol Ethers via Photoredox Catalysis

Herein we reported an efficient photoredox-catalyzed reaction for site-selective C(sp³)−H functionalization of carboxamides with silyl enol ethers as radical acceptors. The reaction proceeded through amidyl radical-directed 1,5-hydrogen atom transfer (1,5-HAT) and C(sp³)−C(sp³) bond formation via radical addition of silyl enol ethers. The process features mild conditions and high functional-group tolerance, allowing the preparation of a series of carboxamides with pendant carbonyl moieties.     

Mechanistic Insights into C(sp2)−C(sp)N Reductive Elimination from Gold(III) Cyanide Complexes

A new family of phosphine-ligated dicyanoarylgold(III) complexes has been prepared and their reactivity towards reductive elimination has been studied in detail. Both, a highly positive entropy of activation and a primary ^12/13C KIE suggest a late concerted transition state while Hammett analysis and DFT calculations indicate that the process is asynchronous. As a result, a distinct mechanism involving an asynchronous concerted reductive elimination for the overall C(sp²)−C(sp)N bond forming reaction is characterized herein, for the first time, complementing previous studies reported for C(sp³)−C(sp³), C(sp²)−C(sp²), and C(sp³)−C(sp²) bond formation processes taking place on gold(III) species.     

Intermolecular Enantioselective Benzylic C(sp3)−H Amination by Cationic Copper Catalysis**

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp³)−H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp³)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp³)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer.     

Simple Ether-Directed Enantioselective C(sp3)−H Borylation of Cyclopropanes Enabled by Iridium Catalysis

Reported here is an efficient and simple ether-directed iridium-catalyzed enantioselective C(sp³)−H borylation of cyclopropanes. Various functional groups were well-tolerated, affording a vast array of chiral cyclopropanes with high enantioselectivities. We also demonstrated that the turnover numbers of the current reaction could be up to 335.     

Electrochemical NiH-Catalyzed C(sp3)−C(sp3) Coupling of Alkyl Halides and Alkyl Alkenes

Herein, an electrochemically driven NiH-catalyzed reductive coupling of alkyl halides and alkyl alkenes for the construction of Csp³−Csp³ bonds is firstly reported. Notably, alkyl halides serve dual function as coupling substrates and as hydrogen sources to generate NiH species under electrochemical conditions. The tunable nature of this reaction is realized by introducing an intramolecular coordinating group to the substrate, where the product can be easily adjusted to give the desired branched products. The method proceeds under mild conditions, exhibits a broad substrate scope, and affords moderate to excellent yields with over 70 examples, including late-stage modification of natural products and drug derivatives. Mechanistic insights offer evidence for an electrochemically driven coupling process. The sp³-carbon-halogen bonds can be activated through single electron transfer (SET) by the nickel catalyst in its low valence state, generated by cathodic reduction, and the generation of NiH species from alkyl halides is pivotal to this transformation.     

Site- and Stereoselective C(sp3)−H Borylation of Strained (Hetero)Cycloalkanols Enabled by Iridium Catalysis

Transition metal-catalyzed site- and stereoselective C−H activation of strained (hetero)cycloalkanes remains a formidable challenge. We herein report a carbamate-directed iridium-catalyzed asymmetric β−C(sp³)−H borylation of cyclopropanol derivatives. A variety of densely functionalized cyclopropanols were obtained in good enantioselectivities via desymmetrization and kinetic resolution. In addition, site-selective C(sp³)−H borylation of methine groups furnished α-borylated (hetero)cycloalkanols in moderate to good yields. The synthetic utility of the method was further shown in a gram-scale synthesis and diverse downstream transformations of borylated products.     

Oxodealkenylative Cleavage of Alkene C(sp3)−C(sp2) Bonds: A Practical Method for Introducing Carbonyls into Chiral Pool Materials

Reported herein is a one-pot protocol for the oxodealkenylative introduction of carbonyl functionalities into terpenes and terpene-derived compounds. This transformation proceeds by Criegee ozonolysis of an alkene, reductive cleavage of the resulting α-alkoxy hydroperoxide, trapping of the generated alkyl radical with 2,2,6,6-tetramethylpiperidin-1-yl (TEMPO), and subsequent oxidative fragmentation with MMPP. Using readily available starting materials from chiral pool, a variety of carbonyl-containing products have been accessed rapidly in good yields.     

Pd(II)-Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza-Wacker Cyclization to Access β-Stereogenic γ-Lactams

Herein, we describe an unprecedented cascade reaction to β-stereogenic γ-lactams involving Pd(II)-catalyzed enantioselective aliphatic methylene C(sp³)−H alkenylation–aza-Wacker cyclization through syn-aminopalladation. Readily available 3,3′-substituted BINOLs are used as chiral ligands, providing the corresponding γ-lactams with broad scope and high enantioselectivities (up to 98 % ee).     

N-Boc-Protected α-Amino Acids by 1,3-Migratory Nitrene C(sp3)−H Insertion

N-Boc-protected α-amino acids are synthesized in two steps from linear or branched carboxylic acid feedstocks. In the first step, the carboxylic acid is coupled with tert-butyl aminocarbonate (BocNHOH) to generate azanyl ester (acyloxycarbamate) RCO₂NHBoc. In the second step, this azanyl ester undergoes a stereocontrolled iron-catalyzed 1,3-nitrogen migration to generate the N-Boc-protected non-racemic α-amino acid. This straightforward protocol is applicable to the catalytic asymmetric synthesis of α-monosubstituted α-amino acids with aryl, alkenyl, and alkyl side chains. Furthermore, α,α-disubstituted α-amino acids are accessible in an enantioconvergent fashion from racemic carboxylic acids. The new method is also advantageous for the synthesis of α-deuterated α-amino acids. N-Boc-protected α-amino acids synthesized using this two-step protocol are ready-to-use building blocks.     

Chiral Iron Porphyrins Catalyze Enantioselective Intramolecular C(sp3)−H Bond Amination Upon Visible-Light Irradiation

Iron-catalyzed asymmetric amination of C(sp³)−H bonds is appealing for synthetic applications due to the biocompatibility and high earth abundance of iron, but examples of such reactions are sparse. Herein we describe chiral iron complexes of meso- and β-substituted-porphyrins that can catalyze asymmetric intramolecular C(sp³)−H amination of aryl and arylsulfonyl azides to afford chiral indolines (29 examples) and benzofused cyclic sulfonamides (17 examples), respectively, with up to 93 % ee (yield: up to 99 %) using 410 nm light under mild conditions. Mechanistic studies, including DFT calculations, for the reactions of arylsulfonyl azides reveal that the Fe(NSO₂Ar) intermediate generated in situ under photochemical conditions reacts with the C(sp³)−H bond through a stepwise hydrogen atom transfer/radical rebound mechanism, with enantioselectivity arising from cooperative noncovalent interactions between the Fe(NSO₂Ar) unit and the peripheral substituents of the chiral porphyrin scaffold.     

Palladium-Catalyzed Decarboxylative Alkynylation of α-Acyloxyketones by C(sp3)−O Bond Cleavage

Palladium-catalyzed decarboxylative alkynylation of α-acyloxyketones triggered by C(sp³)−O bond cleavage is disclosed. The decarboxylation strategy featuring a neutral reaction condition enabled an unprecedent catalytic alkynylation of a ketone enolate. The reaction was applied to a variety of substrates, giving desired products in good yields. We successfully obtained X-ray crystallography of a new palladium–enolate intermediate that was synthesized by a reaction of [Pd(cod)(CH₂TMS)₂] with XPhos and α-acyloxyketone at room temperature, indicating facile C(sp³)−O bond disconnection.     

Organocatalyzed Double C(sp3)−H Alkylation of Cyclic N-Sulfonyl Ketimines with 3-Chloropropiophenones: Selective Access to 2,3,6-Trisubstituted Pyridines

An efficient sequential one-pot, two-step pseudo-four-component reaction between 3/4-methyl N-sulfonyl ketimines with 3-chloropropiophenones triggered by DIPEA/NaHCO₃ as a cooperative base and subsequent aza-cyclization using NH₄OAc is reported. This transition-metal-oxidant-free technique concocts new C−C/C=C/C=N−C bonds selectively, guaranteeing acceptable yields of 2,3,6-trisubstituted pyridines possessing ortho-hydroxyaryl/benzenesulfonamide and propiophenone moieties at C2 and C3 positions, respectively. Interestingly, while replacing methyl-substituents with straight alkyl chains of N-sulfonyl ketimines, only a monoalkylation reaction happened with in situ-generated vinyl ketones to deliver promising yields of 3-picoline derivatives. Moreover, the synthetic transmutation of prepared pyridine derivative led to several important classes of pyridocoumarin, 5H-chromenopyridine, and di(pyridin-3-yl) methane derivatives.