Copper‐Catalyzed Double Additions and Radical Cyclization Cascades in the Re‐Engineering of the Antibacterial Pleuromutilin

A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. Sm^II‐mediated radical cyclization cascades of dialdehydes, prepared using a new, one‐pot, copper‐catalyzed double organomagnesium addition to β‐chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non‐traditional, de novo synthetic access to analogues of the important antibacterial that can′t be prepared from the natural product by semisynthesis.     

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.     

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.     

Tandem Radical Cyclization for the Construction of Difluoro‐Containing Oxindoles and Quinoline‐2,4‐diones

Cu‐catalyzed direct difluoromethylation of activated alkenes through a difluoromethyl radical addition/cyclization to afford difluorinated oxindoles and quinoline‐2,4‐diones has been developed. This method provides convenient access to a variety of oxindoles and quinoline‐2,4‐diones under mild conditions via a proposed tandem radical cyclization process, while tolerating various functional groups well. Moreover, a facile method to construct diverse difluorinated quinoline‐2,4‐diones by visible‐light photoredox catalysis under mild conditions was presented.     

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.     

Radical Cyclization/ipso‐1,4‐Aryl Migration Cascade: Asymmetric Synthesis of 3,3‐Difluoro‐2‐propanoylbicyclo[3.3.0]octanes

A novel method for the asymmetric synthesis of 3,3‐difluoro‐2‐propanoylbicyclo‐[3.3.0]octanes involves an unprecedented intramolecular radical cyclization/ipso‐1,4‐aryl migration cascade.     

Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes

β,γ‐Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β‐γ‐unsaturated ketones through 1,2‐addition of α‐carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)‐trichostatin A, a histone deacetylase inhibitor.     

Copper‐Catalyzed One‐Pot Trifluoromethylation/Aryl Migration/Carbonyl Formation with Homopropargylic Alcohols

A novel copper‐catalyzed one‐pot functionalization of homopropargylic alcohols that involves trifluoromethylation, aryl migration, and formation of a carbonyl moiety has been developed. This reaction constitutes the first direct conversion of homopropargylic alcohols into CF₃‐containing 3‐butenal or 3‐buten‐1‐one derivatives in a regioselective manner. Mechanistic studies indicate that the 1,4‐aryl migration proceeds through a radical pathway.     

Efficient Access to Bicyclo[4.3.0]nonanes: Copper‐Catalyzed Asymmetric Silylative Cyclization of Cyclohexadienone‐Tethered Allenes

The creation of three consecutive chiral carbon centers in one step is achieved using Cu‐catalyzed asymmetric silylative cyclization of cyclohexadienone‐tethered allenes. Through regioselective β‐silylation of the allene and subsequent enantioselective 1,4‐addition to cyclohexadienone, this tandem reaction could afford cis‐hydrobenzofuran, cis‐hydroindole, and cis‐hydroindene frameworks with excellent yields (80–98 %) and enantioselectivities (94–98 % ee) bearing vinylsilane and enone substructures. Meanwhile, this mild transformation is generally compatible with a wide range of functional groups, which allows further conversion of the bicyclic products to bridged and tricyclic ring structures.     

Copper‐Catalyzed Trifluoromethylation of Trisubstituted Allylic and Homoallylic Alcohols

An efficient copper‐catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni’s reagent has been developed. This strategy, accompanied by a double‐bond migration, leads to various branched CF₃‐substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which β‐H elimination is prohibited, CF₃‐containing oxetanes are isolated as the sole product.     

Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions

Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single‐electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single‐electron transfer oxidant. Ester enolates were coupled with α‐benzylidene and α‐alkylidene β‐dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5‐exo pattern for terminally substituted olefin units to a 6‐endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6‐tetramethyl‐1‐piperidinoxyl, and two C?C bonds and one C?O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.     

Microwave‐Assisted Copper‐Catalyzed Oxidative Cyclization of Acrylamides with Non‐Activated Ketones

An operationally simple and efficient microwave‐assisted protocol for the oxidative cyclization of acrylamide derivatives with non‐activated ketones to generate 3,3‐disubstituted oxindoles is described. The reaction proceeds by a copper‐catalyzed tandem radical addition/cyclization strategy and tolerates a series of functional groups with moderate to excellent yields.     

Synthesis of Substituted Pyrroles via Copper‐Catalyzed Cyclization of Ethyl Allenoates with Activated Isocyanides

A new method for the synthesis of di‐ and trisubstituted pyrroles via copper‐catalyzed cyclization of ethyl allenoates with activated isocyanides has been developed. In contrast to related annulation reactions previously reported, this new process features a skeletal rearrangement in which the aryl sulfonyl moiety, which functions as the electron‐withdrawing group in the α‐carbon of the isocyanide, was found to migrate to the γ‐carbon of the starting allenoate in the final product for the first time.     

Copper‐Catalyzed Decarboxylative Radical Silylation of Redox‐Active Aliphatic Carboxylic Acid Derivatives

A decarboxylative silylation of aliphatic N ‐hydroxyphthalimide (NHPI) esters using Si−B reagents as silicon pronucleophiles is reported. This C(sp³)−Si cross‐coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional‐group tolerance is generally excellent, and α‐heteroatom‐substituted substrates also participate well. This enables, for example, the synthesis of α‐silylated amines starting from NHPI esters derived from α‐amino acids. The new method extends the still limited number of C(sp³)−Si cross‐couplings of unactivated alkyl electrophiles.     

Stereoselective Synthesis of cis‐2,5‐Disubstituted Pyrrolidines via Copper‐Catalyzed Cyclization of Alkenes

An efficient methodology for the stereoselective synthesis of cis‐2,5‐disubstituted pyrrolidines using copper catalyst was developed. The corresponding cis‐2,5‐disubstituted pyrrolidines could be obtained in reasonable yields and with good stereoselectivities in the presence of 4,4′‐di‐tert‐butyl‐2,2′‐bipyridine as ligand and 1‐methyl‐2‐pyrrolidinone as solvent.