Gold‐Catalyzed C(sp3)H/C(sp)H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C? H/C? H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³)? H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.     

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.     

Palladium‐Catalyzed Cross‐Dehydrogenative Functionalization of C(sp2)H Bonds

The catalytic cross‐dehydrogenative coupling (CDC) reaction has received intense attention in recent years. The attractive feature of this coupling process is the formation of a C? C bond from two C? H moieties under oxidative conditions. In this Focus Review, recent advances in the palladium‐catalyzed CDC reactions of C(sp²)? H bond are summarized, with a focus on the period from 2011 to early 2013.     

Catalyst‐Free Three‐Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid,Amides, and DMSO by a Pummerer‐Type Rearrangement

A catalyst‐free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three‐component tandem CDC cyclization by a Pummerer‐type rearrangement to afford biologically relevant isoindolinones from aromatic acids, amides, and DMSO, is described. This intermolecular tandem reaction undergoes a C(sp²)?H/C(sp³)?H cross‐dehydrogenative coupling, C?N bond formation, and intramolecular amidation. A notable feature of this novel protocol is avoiding a catalyst and additive (apart from oxidant).     

Cobalt(III)‐Catalyzed Intramolecular Cross‐Dehydrogenative C−H/X−H Coupling: Efficient Synthesis of Indoles and Benzofurans

An efficient cobalt(III)‐catalyzed intramolecular cross‐dehydrogenative C?H/N?H coupling of ortho‐alkenylanilines has been developed utilizing O₂ as a terminal oxidant. The developed reaction tolerates various reactive functional groups and allows the synthesis of diverse indole derivatives in good to excellent yields. The method was successfully extended to the synthesis of benzofurans through the intramolecular cross‐dehydrogenative C?H/O?H coupling of ortho‐alkenylphenols.     

Copper‐Catalyzed Dehydrogenative Cross‐Coupling Reaction between Allylic CH Bonds and α‐CH Bonds of Ketones or Aldehydes

A dehydrogenative cross‐coupling reaction between allylic C?H bonds and the α‐C?H bond of ketones or aldehydes was developed using Cu(OTf)₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ‐unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)₂ as a Lewis acid catalyst was also proposed (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Tf=trifluoromethanesulfonate).     

Synthesis of 2‐Indolyltetrahydroquinolines by Zinc(II)‐Catalyzed Intramolecular Hydroarylation‐Redox Cross‐Dehydrogenative Coupling of N‐Propargylanilines with Indoles

An intramolecular hydroarylation‐redox cross‐dehydrogenative coupling (CDC) of propargylic anilines with indoles proceeded in the presence of zinc(II) catalysts to give 2‐indolyltetrahydroquinolines in good to high yields. Three C?H bonds (two sp² and one sp³) are activated in one shot and these hydrogen atoms are trapped by a propargylic triple bond in the molecule.     

Iron‐Catalyzed Direct Oxidative Alkylation and Hydroxylation of Indolin‐2‐ones with Alkyl‐Substituted N‐Heteroarenes

Presented herein is the first direct alkylation and hydroxylation reaction between two different C(sp³)?H bonds, indolin‐2‐ones and alkyl‐substituted N‐heteroarenes, through an oxidative cross‐coupling reaction. The reaction is catalyzed by a simple iron salt under mild ligand‐free and base‐free conditions. The reaction is environmentally benign, employs air (molecular oxygen) as the terminal oxidant and oxygen source for the synthesis of O‐containing compounds, and produces only water as the byproduct.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

Photoinduced Copper‐Catalyzed Asymmetric Decarboxylative Alkynylation with Terminal Alkynes

We describe a photoinduced copper‐catalyzed asymmetric radical decarboxylative alkynylation of bench‐stable N‐hydroxyphthalimide(NHP)‐type esters of racemic alkyl carboxylic acids with terminal alkynes, which provides a flexible platform for the construction of chiral C(sp³)?C(sp) bonds. Critical to the success of this process are not only the use of the copper catalyst as a dual photo‐ and cross‐coupling catalyst but also tuning of the NHP‐type esters to inhibit the facile homodimerization of the alkyl radical and terminal alkyne, respectively. Owing to the use of stable and easily available NHP‐type esters, the reaction features a broader substrate scope compared with reactions using the alkyl halide counterparts, covering (hetero)benzyl‐, allyl‐, and aminocarbonyl‐substituted carboxylic acid derivatives, and (hetero)aryl and alkyl as well as silyl alkynes, thus providing a vital complementary approach to the previously reported method.     

Single and Twofold Metal‐ and Reagent‐Free Anodic C−C Cross‐Coupling of Phenols with Thiophenes

The first electrochemical dehydrogenative C−C cross‐coupling of thiophenes with phenols has been realized. This sustainable and very simple to perform anodic coupling reaction enables access to two classes of compounds of significant interest. The scope for electrochemical C−H‐activating cross‐coupling reactions was expanded to sulfur heterocycles. Previously, only various benzoid aromatic systems could be converted, while the application of heterocycles was not successful in the electrochemical C−H‐activating cross‐coupling reaction. Here, reagent‐ and metal‐free reaction conditions offer a sustainable electrochemical pathway that provides an attractive synthetic method to a broad variety of bi‐ and terarylic products based on thiophenes and phenols. This method is easy to conduct in an undivided cell, is scalable, and is inherently safe. The resulting products offer applications in electronic materials or as [OSO]²⁻ pincer‐type ligands.     

Gold‐Catalyzed C(sp3)?H/C(sp)?H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C H/C H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³) H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.     

Cu‐Catalyzed Cross‐Dehydrogenative ortho‐Aminomethylation of Phenols

A highly selective Cu^II‐catalyzed cross‐dehydrogenative ortho‐aminomethylation of phenols with aniline derivatives is described. The corresponding C(sp²)?C(sp³) coupling products were obtained in moderate to excellent yields under mild reaction conditions and with a broad substrate scope. A radical mechanism is proposed.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²)? H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂?4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

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.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)?H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²) H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂⋅4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

Synthesis of C3‐Fluorinated Oxindoles through Reagent‐Free Cross‐Dehydrogenative Coupling

Reported herein is an unprecedented synthesis of C3‐fluorinated oxindoles through cross‐dehydrogenative coupling of C(sp³)‐H and C(sp²)‐H bonds from malonate amides. Under the unique and mild electrochemical conditions, the requisite oxidant and base are generated in a continuous fashion, allowing the formation of the base‐ and heat‐sensitive 3‐fluorooxindoles in high efficiency with broad substrate scope. The synthetic usefulness of the electrochemical method is further highlighted by its easy scalability and the diverse transformations of the electrolysis product.     

Stereoselective Synthesis of Trisubstituted Alkenes through Sequential Iron‐Catalyzed Reductive anti‐Carbozincation of Terminal Alkynes and Base‐Metal‐Catalyzed Negishi Cross‐Coupling

The stereoselective synthesis of trisubstituted alkenes is challenging. Here, we show that an iron‐catalyzed anti‐selective carbozincation of terminal alkynes can be combined with a base‐metal‐catalyzed cross‐coupling to prepare trisubstituted alkenes in a one‐pot reaction and with high regio‐ and stereocontrol. Cu‐, Ni‐, and Co‐based catalytic systems are developed for the coupling of sp‐, sp²‐, and sp³‐hybridized carbon electrophiles, respectively. The method encompasses a large substrate scope, as various alkynyl, aryl, alkenyl, acyl, and alkyl halides are suitable coupling partners. Compared with conventional carbometalation reactions of alkynes, the current method avoids pre‐made organometallic reagents and has a distinct stereoselectivity.     

Synthesis of [Zn(ΙΙ)BHPPDAH] as New Heterogeneous Catalyst without Being Immobilized on Any Support and Applied for Mannich Reaction

In this paper, a novel heterogeneous complex of zinc with N,N‐bis(2‐hydroxyphenyl)pyridine‐2,6‐dicarboxamide(BHPPDAH) was synthesized. The catalyst was found to be a highly effective catalyst for the three‐component coupling reactions of aldehydes, alkynes, and amines (A3 coupling) via C–H activation. The reactions could be applied to both aromatic and aliphatic aldehydes and alkynes. Nearly quantitative yields of the desired products were obtained in most cases. The reaction proceeds without any cocatalyst or activator, and water is the only byproduct. The catalyst was quantitatively recovered from the reaction by a simple filtration and reused for five cycles with almost consistent activity.     

Copper‐Catalyzed Enantioconvergent Cross‐Coupling of Racemic Alkyl Bromides with Azole C(sp2)−H Bonds

The development of enantioconvergent cross‐coupling of racemic alkyl halides directly with heteroarene C(sp²)?H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona‐alkaloid‐derived N,N,P‐ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp²)?H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α‐chiral alkylated azoles, such as 1,3,4‐oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4‐triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp²)?H bond and the involvement of alkyl radical species under the reaction conditions.