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.     

Thioamide‐Directed Cobalt(III)‐Catalyzed Selective Amidation of C(sp3)−H Bonds

A mild, oxidant‐free, and selective Cp*Co^III‐catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp³)−H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C−H amidation of a wide range of functionalized thioamides with aryl‐, heteroaryl‐, and alkyl‐substituted dioxazolones under the Cp*Co^III‐catalyzed conditions. The observed regioselectivity towards primary C(sp³)−H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate‐assisted concerted metalation/deprotonation mechanism. The reported method is a rare example of the use of a directing group other than the commonly used pyridine and quinolone classes for Cp*Co^III‐catalyzed C(sp³)−H functionalization and the first to exploit thioamides.     

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.     

Copper‐Catalyzed C(sp3)−H/C(sp3)−H Cross‐Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2‐Trifluoromethyl‐Substituted Dihydropyrrol‐2‐ols

The first oxidative C(sp³)−H/C(sp³)−H cross‐dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper‐catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2‐trifluoromethyldihydropyrrol‐2‐ol derivatives in a highly diastereoselective manner by cascade C(sp³)−C(sp³) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.     

C（sp3）-H bond functionalization of oximes derivatives via 1,5-hydrogen atom transfer induced by iminyl radical

Oximes derivatives have been vastly used in organic synthesis. In this review, C（sp³）-H bond functionalization of oximes derivatives via iminyl radical induced 1,5-hydrogen atom transfer was discussed. According to the different type of products, this review was divided into three parts:（1） C（sp³）-H bond functionalization for C-C bond formation.（2） C（sp³）-H bond functionalization for C-N bond formation.（3） C（sp³）-H bond functionalization for C-S, C-F b...     

Copper‐Catalyzed Three‐Component Carboazidation of Alkenes with Acetonitrile and Sodium Azide

A copper‐catalyzed three‐component reaction of alkenes, acetonitrile, and sodium azide afforded γ‐azido alkyl nitriles by formation of one C(sp³)−C(sp³) bond and one C(sp³)−N bond. The transformation allows concomitant introduction of two highly versatile groups (CN and N₃) across the double bond. A sequence involving the copper‐mediated generation of a cyanomethyl radical and its subsequent addition to an alkene, and a C(sp³)−N bond formation accounted for the reaction outcome. The resulting γ‐azido alkyl nitrile can be easily converted into 1,4‐diamines, γ‐amino nitriles, γ‐azido esters, and γ‐lactams of significant synthetic value.     

Iron-Catalysed Remote C(sp3)−H Azidation of O-Acyl Oximes and N-Acyloxy Imidates Enabled by 1,5-Hydrogen Atom Transfer of Iminyl and Imidate Radicals: Synthesis of γ-Azido Ketones and β-Azido Alcohols

In the presence of a catalytic amount of iron(III) acetylacetonate [Fe(acac)₃], the reaction of structurally diverse ketoxime esters with trimethylsilyl azide (TMSN₃) afforded γ-azido ketones in good to excellent yields. This unprecedented distal γ-C(sp³)−H bond azidation reaction went through a sequence of reductive generation of an iminyl radical, 1,5-hydrogen atom transfer (1,5-HAT) and iron-mediated redox azido transfer to the translocated carbon radical. TMSN₃ served not only as a nitrogen source to functionalise the unactivated C(sp³)−H bond, but also as a reductant to generate the catalytically active Fe^II species in situ. Based on the same principle, a novel β-C(sp³)−H functionalisation of alcohols via N-acyloxy imidates was subsequently realised, leading, after hydrolysis of the resulting ester, to β-azido alcohols, which are important building blocks in organic and medicinal chemistry.     

Rhodium(II)‐ or Copper(I)‐Catalyzed Formal Intramolecular Carbene Insertion into Vinylic C(sp2)−H Bonds: Access to Substituted 1H‐Indenes

A rhodium(II)‐ or copper(I)‐catalyzed formal intramolecular carbene insertion into vinylic C(sp²)−H bonds is reported herein. This method provides straightforward access to 1H ‐indenes with high efficiency and excellent functional‐group compatibility. Mechanistically, the reaction is proposed to involve the following sequence: metal carbene formation, intramolecular nucleophilic addition of the double bond to the electron‐deficient carbene carbon atom, dearomatization, and finally a 1,5‐H shift.     

C−H Activation of Unbiased C(sp3)−H Bonds: Gold(I)-Catalyzed Cycloisomerization of 1-Bromoalkynes**

Selective functionalization of non-activated C(sp³)−H bonds is a major challenge in chemistry, so functional groups are often used to enhance reactivity. Here, we present a gold(I)-catalyzed C(sp³)−H activation of 1-bromoalkynes without any sort of electronic, or conformational bias. The reaction proceeds regiospecifically and stereospecifically to the corresponding bromocyclopentene derivatives. The latter can be readily modified, comprising an excellent library of diverse 3D scaffolds for medicinal chemistry. In addition, a mechanistic study has shown that the reaction proceeds via a so far unknown mechanism: a concerted [1,5]-H shift / C−C bond formation involving a gold-stabilized vinylcation-like transition state.     

α‐Aminoxy‐Acid‐Auxiliary‐Enabled Intermolecular Radical γ‐C(sp3)−H Functionalization of Ketones

A method for site‐specific intermolecular γ‐C(sp³)?H functionalization of ketones has been developed using an α‐aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5‐hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C‐radicals thus formed at the γ‐position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding γ‐functionalized ketones.     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

Silver‐Catalyzed Oxidative C(sp3)−P Bond Formation through C−C and P−H Bond Cleavage

The silver‐catalyzed oxidative C(sp³)−H/P−H cross‐coupling of 1,3‐dicarbonyl compounds with H‐phosphonates, followed by a chemo‐ and regioselective C(sp³)−C(CO) bond‐cleavage step, provided heavily functionalized β‐ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional‐group tolerance, and exclusive selectivity.     

Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

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.     

Copper(I)‐Catalyzed Chemoselective Coupling of Cyclopropanols with Diazoesters: Ring‐Opening C−C Bond Formations

Reported herein is an exceptional chemoselective ring‐opening/C(sp³)−C(sp³) bond formation in the copper(I)‐catalyzed reaction of cyclopropanols with diazo esters. The conventional O−H insertion product is essentially suppressed by judicious choice of reaction conditions. DFT calculations provide insights into the reaction mechanism and the rationale for this unusual chemoselectivity.     

Palladium‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Copper‐Promoted Site‐Selective Acyloxylation of Unactivated C(sp3)H Bonds

The site‐selective acyloxylation of aliphatic amides was achieved via a copper‐promoted C(sp³)? H bond functionalization process directed by a bidentate ligand. The reaction showed a great preference for activating C? H bonds of β‐methyl groups over those of γ‐methyl and unactivated methylene groups.