Copper‐Catalyzed Oxidative Amination and Allylic Amination of Alkenes

Enamines and enamides are useful synthetic intermediates and common components of bioactive compounds. A new protocol for their direct synthesis by a net alkene C? H amination and allylic amination by using catalytic Cu^II in the presence of MnO₂ is reported. Reactions between N‐aryl sulfonamides and vinyl arenes furnish enamides, allylic amines, indoles, benzothiazine dioxides, and dibenzazepines directly and efficiently. Control experiments further showed that MnO₂ alone can promote the reaction in the absence of a copper salt, albeit with lower efficiency. Mechanistic probes support the involvement of nitrogen‐radical intermediates. This method is ideal for the synthesis of enamides from 1,1‐disubstituted vinyl arenes, which are uncommon substrates in existing oxidative amination protocols.     

Copper‐Catalyzed Oxidative Dimerizations of 3‐N‐Hydroxy‐aminoprop‐1‐enes to form 1,4‐Dihydroxy‐2,3‐diaminocyclohexanes with C2 Symmetry

This work describes the one‐step construction of complex and important molecular frameworks through copper‐catalyzed oxidations of cheap tertiary amines. Copper‐catalyzed aerobic oxidations of N‐hydroxyaminopropenes to form C₂‐symmetric N‐ and O‐functionalized cyclohexanes are described. Such catalytic oxidations proceed with remarkable stereocontrol and high efficiency. Reductive cleavage of the two N? O bonds of these products delivers 1,4‐dihydroxy‐2,3‐diaminocyclohexanes, which are important skeletons of several bioactive molecules.     

Copper‐Catalyzed Oxyboration of Unactivated Alkenes

The first regiodivergent oxyboration of unactivated terminal alkenes is reported, using copper alkoxide as a catalyst, bis(pinacolato)diboron [(Bpin)₂] as a boron source, and (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) as an oxygen source. The reaction is compatible with various functional groups. Two regioisomers are selectively produced by selecting the appropriate ligands on copper. The products may be used as a linchpin precursor for various other functionalizations, and net processes such as carbooxygenation, aminooxygenation, and dioxygenation of alkenes can be achieved after C?B bond transformations. Mechanistic studies indicate that the reaction involves the following steps: 1) Transmetalation between CuOtBu and (Bpin)₂ to generate a borylcopper species; 2) regiodivergent borylcupration of alkenes; 3) oxidation of the thus‐generated C?Cu bond to give an alkyl radical; 4) trapping of the resulting alkyl radical by TEMPO.     

Electrochemical Intramolecular Aminooxygenation of Unactivated Alkenes

An electrochemical approach to the intramolecular aminooxygenation of unactivated alkenes has been developed. This process is based on the addition of nitrogen‐centered radicals, generated through electrochemical oxidation, to alkenes followed by trapping of the cyclized radical intermediate with 2,2,6,6‐tetramethylpiperidine‐N‐oxyl radical (TEMPO). Difunctionalization of a variety of alkenes with easily available carbamates/amides and TEMPO affords aminooxygenation products in high yields and with excellent trans selectivity for cyclic systems (d.r. up to>20:1). The approach provides a much‐needed complementary route to existing cis‐selective methods.     

Enantioselective Copper‐Catalyzed Carboetherification of Unactivated Alkenes

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper‐catalyzed cyclization of γ‐unsaturated pentenols which terminates in C? C bond formation, a net alkene carboetherification. Both intra‐ and intermolecular C? C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused‐ring and bridged‐ring oxabicyclic products. Transition‐state calculations support a cis‐oxycupration stereochemistry‐determining step.     

Copper‐Catalyzed Stereoselective Aminoboration of Bicyclic Alkenes

A copper‐catalyzed aminoboration of bicyclic alkenes, including oxa‐ and azabenzonorbornadienes, has been developed. With this method, amine and boron moieties are simultaneously introduced at an olefin with exo selectivity. Subsequent stereospecific transformations of the boryl group can provide oxygen‐ and nitrogen‐rich cyclic molecules with motifs that may be found in natural products or pharmaceutically active compounds. Moreover, a catalytic asymmetric variant of this transformation was realized by using a copper complex with a chiral bisphosphine ligand, namely (R,R)‐Ph‐BPE.     

Ligand‐Controlled Regiodivergent Copper‐Catalyzed Alkylboration of Alkenes

A novel copper‐catalyzed regiodivergent alkylboration of alkenes with bis(pinacolato)diboron and alkyl halides has been developed. The regioselectivity of the alkylboration was controlled by subtle differences in the ligand structure. The reaction thus enables the practical, regiodivergent synthesis of two different alkyl boronic esters with complex structures from a single alkene.     

Copper‐Catalyzed Alkynylboration of Alkenes with Diboron Reagents and Bromoalkynes

An efficient method for the synthesis of homopropargylboronates by copper‐catalyzed alkynylboration of alkenes with diboron reagents and bromoalkynes has been developed. The alkynylboration reaction features high selectivity and efficiency, mild reaction conditions, wide substrate scope, and functional‐group compatibility, and is a highly attractive complement to existing methods for the synthesis of homopropargylboronates. Both the boryl and alkynyl groups are good potential functional groups for the subsequent manipulations that provide access to a variety of important molecule structures.     

Efficient Copper‐Catalyzed Direct Intramolecular Aminotrifluoromethylation of Unactivated Alkenes with Diverse Nitrogen‐Based Nucleophiles

A mild, convenient, and step‐economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen‐based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligands, is described. Many different nitrogen‐based nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulfonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction. The aminotrifluoromethylation process allows straightforward access to diversely substituted CF₃‐containing pyrrolidines or indolines, in good to excellent yields, through a direct difunctionalization strategy from the respective acyclic starting materials. Mechanistic studies were conducted and a plausible mechanism was proposed.     

Copper‐Catalyzed Alkylarylation of Unactivated Alkenes: Synthesis of 3‐Alkyl Indolines from N‐Allyl Anilines and Alkanes

A rare example of C(sp³)?H functionalization of simple alkanes with unactivated alkenes is presented. In the presence of a copper salt and di‐tert‐butyl peroxide (DTBP), N‐allyl anilines underwent exo‐selective alkylation/cyclization cascade with unactivated alkenic bonds as radical acceptors and simple alkanes as radical precursors, providing a direct access to 3‐alkyl indolines. The present protocol features simple operation, broad substrate scope and great exo 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.     

Copper‐Catalyzed Borocarbonylative Coupling of Internal Alkynes with Unactivated Alkyl Halides: Modular Synthesis of Tetrasubstituted β‐Borylenones

Reported is a general procedure to synthesize tetrasubstituted enones, which are borylated in the β‐position, using a copper‐catalyzed four‐component coupling reaction of simple chemical feedstocks: internal alkynes, alkyl halides, bis(pinacolato)diboron (B₂pin₂), and CO. A broad scope of highly functionalized β‐borylated enones, a largely unknown class of organic compounds, can be accessed efficiently using this method. The synthesis of all‐carbon tetrasubstituted enones was realized by employing the β‐borylated enone unit, without purification, in a Suzuki–Miyaura coupling. The utility of the method was further demonstrated by various transformations, including halogenation, oxidation, and protodeboration, of the corresponding reduced oxaborole species to provide densely substituted allylic alcohol and ketone products.     

A Copper‐Catalyzed Decarboxylative Amination/Hydroamination Sequence: Switchable Synthesis of Functionalized Indoles

A copper‐catalyzed decarboxylative amination/hydroamination sequence of propargylic carbamates with various nucleophiles is described for the first time. It features an earth‐abundant metal catalyst, mild reaction conditions, and high efficiency. Further treatments of the resultant key intermediates using an acid or a base in one pot enable the controllable and divergent synthesis of two types of functionalized indoles. Moreover, experiments to demonstrate the synthetic potential of this methodology are performed.     

Copper‐Catalyzed Intermolecular Carboetherification of Unactivated Alkenes by Alkyl Nitriles and Alcohols

A three‐component carboetherification of unactivated alkenes has been developed allowing the rapid building of complexity from simple starting materials. A wide range of α‐substituted styrenes underwent smooth reactions with unactivated alkyl nitriles and alcohols to afford γ‐alkoxy alkyl nitriles with concomitant generation of a quaternary carbon center. A radical clock experiment provided clear‐cut evidence that the reaction proceeds through a tertiary alkyl radical intermediate.     

Copper‐Catalyzed Carbotrifluoromethylation of Unactivated Alkenes Driven by Trifluoromethylation of Alkyl Radicals

We report herein an unprecedented protocol for radical carbotrifluoromethylation of unactivated alkenes. With Cu(OTf)₂ as the catalyst, the reaction of unactivated alkenes, TMSCF₃ and activated alkyl chlorides at room temperature provides the corresponding carbotrifluoromethylation products in satisfactory yields. Directed by trifluoromethylation of alkyl radicals, the method exhibits an excellent regioselectivity that is opposite to those driven by CF₃ radical addition.