Highly para‐Selective C−H Alkylation of Benzene Derivatives with 2,2,2‐Trifluoroethyl α‐Aryl‐α‐Diazoesters

Compared to the most popular directing‐group‐assisted strategy, the “undirected” strategy for C−H bond functionalization represents a more flexible but more challenging approach. Reported herein is a gold‐catalyzed highly site‐selective C(sp²)−H alkylation of unactivated arenes with 2,2,2‐trifluoroethyl α‐aryl‐α‐diazoesters. This protocol demonstrates that high site‐selective C−H bond functionalization can be achieved without the assistance of a directing group. In this transformation, both the gold catalyst and trifluoroethyl group on the ester of the diazo compound play vital roles for achieving the chemo‐ and regioselectivity.     

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.     

Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α‐Arylation of Alcohols through Photoredox,HAT, and Nickel Catalysis

The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α‐hydroxy C−H bonds. This approach employs zinc‐mediated alcohol deprotonation to activate α‐hydroxy C−H bonds while simultaneously suppressing C−O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn‐based Lewis acids also deactivates other hydridic bonds such as α‐amino and α‐oxy C−H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3‐step synthesis of the drug Prozac exemplifies the utility of this new method.     

Palladium‐Catalyzed Oxidative Difunctionalization of Alkenes with α‐Carbonyl Alkyl Bromides Initiated through a Heck‐type Insertion: A Route to Indolin‐2‐ones

The oxidative interception of various σ‐alkyl palladium(II) intermediates with additional reagents for the difunctionalization of alkenes is an important research area. A new palladium‐catalyzed oxidative difunctionalization reaction of alkenes with α‐carbonyl alkyl bromides is described, in which the σ‐alkyl palladium(II) intermediate is generated through a Heck insertion and trapped using an aryl C(sp²)? H bond. This method can be applied to various α‐carbonyl alkyl bromides, including primary, secondary, and tertiary α‐bromoalkyl esters, ketones, and amides.     

Synthesis of Substituted 2‐Amino‐1,3‐oxazoles via Copper‐Catalyzed Oxidative Cyclization of Enamines and N,N‐Dialkyl Formamides

A facile synthesis of 2‐amino‐1,3‐oxazoles via Cu^I‐catalyzed oxidative cyclization of enamines and N ,N ‐dialkyl formamides has been developed. The reaction proceeds through an oxidative C−N bond formation, followed by an intramolecular C(sp²)−H bond functionalization/C−O cyclization in one pot. This protocol provides direct access to useful 2‐amino‐1,3‐oxazoles and features protecting‐group‐free nitrogen sources, readily available starting materials, a broad substrate scope and mild reaction conditions.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Nucleophilic Arylation of N,O‐Ketene Acetals with Triaryl Aluminum Reagents: Access to α‐Aryl Amides through an Umpolung Process

A novel approach for the umpolung α‐arylation of amides is presented. By the nucleophilic phenylation of O‐silyl N,O‐ketene acetals, generated in situ from N‐alkoxy amides, a phenyl group can be introduced onto the α‐carbon atom of amides through N−O bond cleavage in a two‐step, one‐pot process. The asymmetric synthesis of α‐aryl amides through the diastereoselective arylation of a chiral N,O‐ketene acetal is also described.     

Site‐Selective Remote Radical C−H Functionalization of Unactivated C−H Bonds in Amides Using Sulfone Reagents

A general and practical strategy for remote site‐selective functionalization of unactivated aliphatic C?H bonds in various amides by radical chemistry is introduced. C?H bond functionalization is achieved by using the readily installed N‐allylsulfonyl moiety as an N‐radical precursor. The in situ generated N‐radical engages in intramolecular 1,5‐hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C?H functionalized amides. The generality of the approach is documented by the successful remote C?N₃, C?Cl, C?Br, C?SCF₃, C?SPh, and C?C bond formation. Unactivated tertiary and secondary C?H bonds, as well as activated primary C?H bonds, can be readily functionalized by this method.     

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.     

Utilizing Carbonyl Coordination of Native Amides for Palladium‐Catalyzed C(sp3)−H Olefination

Pd^II‐catalyzed C(sp³)?H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp³)?H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α‐H‐containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp³)?H activation. The method enables direct C(sp³)?H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.     

Intramolecular Redox‐Mannich Reactions: Facile Access to the Tetrahydroprotoberberine Core

Cyclic amines such as pyrrolidine undergo redox‐annulations with 2‐formylaryl malonates. Concurrent oxidative amine α‐C?H bond functionalization and reductive N‐alkylation render this transformation redox‐neutral. This redox‐Mannich process provides regioisomers of classic Reinhoudt reaction products as an entry to the tetrahydroprotoberberine core, enabling the synthesis of (±)‐thalictricavine and its epimer. An unusually mild amine‐promoted dealkoxycarbonylation was discovered in the course of these studies.     

Cross‐Coupling of α‐Carbonyl Sulfoxonium Ylides with C−H Bonds

The functionalization of carbon–hydrogen bonds in non‐nucleophilic substrates using α‐carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross‐coupling reactions of sulfoxonium ylides with C(sp²)−H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C−H activation, migratory insertion of the ylide into the carbon–metal bond, and protodemetalation, the last step being turnover‐limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium‐catalyzed dehydrative cyclization.     

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

A new iron‐facilitated silver‐mediated radical 1,2‐alkylarylation of styrenes with α‐carbonyl alkyl bromides and indoles is described, and two new C?C bonds were generated in a single step through a sequence of intermolecular C(sp³)?Br functionalization and C(sp²)?H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.     

Enantioselective Intermolecular Radical Amidation and Amination of Benzylic C−H Bonds via Dual Copper and Photocatalysis

A method for direct access to enantioenriched benzylic amides and carbamate-protected primary benzylamines by C−H functionalization is reported. The C−H substrate is used as limiting reagent with only a small excess of the unactivated amide or carbamate nucleophile. The enantioselective intermolecular dehydrogenative C−N bond formation is enabled by a combination of a chiral copper catalyst, a photocatalyst, and an oxidant, and it takes place under mild conditions, which allow for a broad substrate scope. The method is compatible with late-stage C−H functionalization, and it provides easy access to ¹⁵N-labeled amides and amines starting from cheap ¹⁵NH₄Cl.     

NiH‐Catalyzed Remote Asymmetric Hydroalkylation of Alkenes with Racemic α‐Bromo Amides

Reported here is a terminal‐selective, remote asymmetric hydroalkylation of olefins with racemic α‐bromo amides. The reaction proceeds by NiH‐catalyzed alkene isomerization and subsequent alkylation reaction, and can enantioconvergently introduce an unsymmetrical secondary alkyl group from a racemic α‐bromo amide onto a terminal C(sp³)?H position along the hydrocarbon chain of the alkene. This mild process affords a range of structurally diverse chiral α‐alkylalkanoic amides in excellent yields, and high regio‐ and enantioselectivities. In addition, the synthetic utility of this protocol is further highlighted by the regioconvergent conversion of industrial raw materials of isomeric olefin mixtures into enantioriched α‐alkylalkanoic amides on large scale.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α‐Arylation of Alcohols through Photoredox,HAT, and Nickel Catalysis

The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α‐hydroxy C?H bonds. This approach employs zinc‐mediated alcohol deprotonation to activate α‐hydroxy C?H bonds while simultaneously suppressing C?O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn‐based Lewis acids also deactivates other hydridic bonds such as α‐amino and α‐oxy C?H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3‐step synthesis of the drug Prozac exemplifies the utility of this new method.     

Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)‐Catalyzed C−H Alkylation of Azacycles

The development of new and practical 3‐pentoxythiocarbonyl auxiliaries for Ir^I‐catalyzed C−H alkylation of azacycles is described. This method allows for the α‐C−H alkylation of a variety of substituted pyrrolidines, piperidines, and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate‐type auxiliaries is underscored by the ease of installation and removal, the method's utility is demonstrated in its ability to functionalize biologically relevant l ‐proline and l ‐trans ‐hydroxyproline, delivering unique 2,5‐dialkylated amino acid analogues that are not accessible by other C−H functionalization methods.     

Regioselective Insertion of o‐Carborynes into the α‐CH Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C? H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C? H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Gold‐Catalyzed [3+2]/Retro‐[3+2]/[3+2] Cycloaddition Cascade Reaction of N‐Alkoxyazomethine Ylides

A novel cascade reaction has been developed for the synthesis of 2,6‐methanopyrrolo[1,2‐b]isoxazoles based on the gold‐catalyzed generation of an N‐allyloxyazomethine ylide. This reaction involves sequential [3+2]/retro‐[3+2]/[3+2] cycloaddition reactions, thus providing facile access to fused and bridged heterocycles which would be otherwise difficult to prepare using existing synthetic methods. Notably, this reaction allows the efficient construction of three C−C bonds, one C−O bond, one C−N bond and one C−H bond, as well as the cleavage of one C−C bond, one C−O bond and one C−H bond in a single operation. The intermolecular cycloaddition of an N‐allyloxyazomethine ylide and the subsequent application of the product to the synthesis of tropenol is also described.