Copper-catalyzed Radical Research Articles

Cu-Catalyzed Asymmetric Three-Component Radical Acylarylation of Vinylarenes with Aldehydes and Aryl Boronic Acids.

The direct use of readily available aldehydes as acyl radical precursors has facilitated diverse three-component acylative difunctionalization reactions of alkenes, offering a powerful route to synthesize β-branched ketones. However, asymmetric three-component acylative difunctionalization of alkenes with aldehydes still remains elusive. Here we report a copper-catalyzed asymmetric three-component radical acylarylation of vinylarenes with aldehydes and aryl boronic acids. This method begins with acyl radical formation from an aldehyde via hydrogen atom transfer. The acyl radical adds to the alkene, forming a new benzylic radical that then undergoes copper-catalyzed enantioselective arylation. A chiral binaphthyl-tethered bisoxazoline ligand is essential for achieving high stereocontrol. This strategy enables the direct synthesis of a range of synthetically valuable chiral β,β-diaryl ketones from aldehydes and vinylarenes.

Copper-Catalyzed Asymmetric Radical Oxysulfonylation of 2-Vinylbenzoic Acids to Access Chiral Sulfonyl Phthalides.

This study presents the development of a radical enantioselective alkene oxysulfonylation approach for the synthesis of enantioenriched sulfonyl phthalides via a catalyst system consisting of a copper salt and an OPPA ligand. The reaction proceeded under mild conditions with a wide range of substrates, good yields, and excellent enantioselectivities. Mechanistic studies suggested that the reaction proceeded through a radical-mediated process. Scalable synthesis and transformation experiments also demonstrated the applicable potential of this method.

Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams

Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams

Modular Synthesis of gem-Difluorotetrahydrocarbazolone Scaffolds via Copper-Catalyzed Cascade Reaction of Bromodifluoroacetyl Indoles and Olefins.

A novel and efficient modular synthesis of gem-difluorotetrahydrocarbazolone scaffolds via copper-catalyzed radical cascade cyclization of bromodifluoroacetyl indoles and olefins has been reported. This operationally simple protocol provides straightforward and practical access to a series of privileged gem-difluorotetrahydrocarbazolone scaffolds from readily available starting materials, with the feature of broad functional group tolerance and mild reaction conditions. Moreover, the method could be used for the late-stage functionalization of bioactive molecules, which opens up the possibility for practical applications.

Copper-Catalyzed Vicinal Thiocyanosulfonylation of Alkenes and Alkynes.

Efficient copper-catalyzed radical thiocyanosulfonylation of alkenes and alkynes with potassium thiocyanate and sodium phenylsulfinate is described. The reactions provide general and convenient methods toward the synthesis of β-thiocyanoalkyl sulfones and β-thiocyanoalkenyl sulfones, respectively, in satisfactory yields. Based on conducted mechanistic experiments, a mechanism involving oxidative generation of sulfonyl radicals and subsequent addition to alkenes followed by Cu-assisted thiocyanation is proposed. Moreover, the practicability of the reaction is successfully demonstrated by its successful application on a gram scale.

Photoinduced Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Azidooxygenation of 1,3-Dienes.

Radical-involved multicomponent difunctionalization of 1,3-dienes has recently emerged as a promising strategy for rapid synthesis of valuable allylic compounds in one-pot operation. However, the expansion of radical scope and enantiocontrol remain two major challenges. Herein, we describe an unprecedented photoinduced copper-catalyzed highly enantioselective three-component radical 1,2-azidooxygenation of 1,3-dienes with readily available azidobenziodazolone reagent and carboxylic acids. This mild protocol exhibits a broad substrate scope, high functional group tolerance, and exceptional control over chemo-, regio- and enantioselectivity, providing practical access to diverse valuable azidated chiral allylic esters. Mechanistic studies imply that the chiral copper complex is implicated as a bifunctional catalyst in both the photoredox catalyzed azidyl radical generation and enantioselective radical C-O cross-coupling.

Synthesis of Fused-Ring Pyrrolizine Derivatives via a Copper-Catalyzed Radical Cascade Cyclization

AbstractHerein, an atom-economic method for the synthesis of fused-ring pyrrolizine derivatives by a cycloaddition reaction of easily accessible N-substituted pyrrole-2-carboxaldehydes with N-substituted maleimides in the presence of di-tert-butyl peroxide has been successfully developed. A total of 23 compounds were obtained by using this method, with a maximum yield of 72%, providing a practical and efficient method for the synthesis of tricyclic pyrrolizine frameworks.

Copper-Catalyzed Radical Relay 1,3-Carbocarbonylation across Two Distinct C═C Bonds.

The radical relay provides an effective paradigm for intermolecular assembly to achieve functionalization across remote chemical bonds. Herein, we report the first radical relay 1,3-carbocarbonylation of α-carbonyl alkyl bromides across two separate C═C bonds. The reaction is highly chemo- and regioselective, with two C(sp3)-C(sp3) bonds and one C═O bond formed in a single orchestrated operation. In addition, the synthesis method under mild conditions and using inexpensive copper as the catalyst allows facile access to structurally diverse 1,3-carbocarbonylation products. The plausible mechanism is investigated through a series of control experiments, including radical trapping, radical clock experiments, critical intermediate trapping, and 18O labeling experiment.

Macrocyclic Copper(II) Complexes as Catalysts for Electrochemically Mediated Atom Transfer.

Copper-catalyzed electrochemical atom transfer radical addition (eATRA) is a new method for the creation of new C-C bonds under mild conditions. In this work, we have explored the reactivity of an analogous series of N4 macrocyclic CuII complexes as eATRA precatalysts, which are primed by reduction to their monovalent oxidation state. These complexes were fully characterized structurally, spectroscopically, and electrochemically. A spectrum of radical activation reactivity was found across the series [CuI(Me4cyclen)(NCMe)]+ (Me4cyclen = 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane), [CuI(Me4cyclam)(NCMe)]+ (Me4cyclam = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), and [CuI(Me2py2clen)(NCMe)]+ (Me2py2clen = 3,7-dimethyl-3,7-diaza-1,5(2,6)-dipyridinacyclo-octaphane). The rate of radical production by [Cu(Me2py2clen)(NCMe)]+ was modest, but rapid radical capture to form the organocopper complex [CuI(Me2py2clen)(CH2CN)] led to a dramatic acceleration in catalysis, greater than seen in any comparable Cu complex, but this led to rapid radical self-termination instead of radical addition.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.

Copper-Catalyzed Enantioselective Radical Esterification of Propargylic C–H Bonds

AbstractThe copper-catalyzed enantioselective radical esterification of propargylic C–H bonds with tert-butyl peroxybenzoate (TBPB) as an oxidizing agent and an oxygenated nucleophile is reported. This variant of the Kharasch–Sosnovsky oxidation allows for the asymmetric esterification of open-chain carbon radicals without excessive amounts of alkyne substrates under mild reaction conditions, achieving a one-step conversion of simple alkynes into chiral propargylic esters.

Copper-Catalyzed Enantioselective C(sp3 )-SCF3 Coupling of Carbon-Centered Benzyl Radicals with (Me4 N)SCF3.

In contrast with the well-established C(sp2 )-SCF3 cross-coupling to forge the Ar-SCF3 bond, the corresponding enantioselective coupling of readily available alkyl electrophiles to forge chiral C(sp3 )-SCF3 bond has remained largely unexplored. We herein disclose a copper-catalyzed enantioselective radical C(sp3 )-SCF3 coupling of a range of secondary/tertiary benzyl radicals with the easily available (Me4 N)SCF3 reagent. The key to the success lies in the utilization of chiral phosphino-oxazoline-derived anionic N,N,P-ligands through tuning electronic and steric effects for the simultaneous control of the reaction initiation and enantioselectivity. This strategy can successfully realize two types of asymmetric radical reactions, including enantioconvergent C(sp3 )-SCF3 cross-coupling of racemic benzyl halides and three-component 1,2-carbotrifluoromethylthiolation of arylated alkenes under mild reaction conditions. It therefore provides a highly flexible platform for the rapid assembly of an array of enantioenriched SCF3 -containing molecules of interest in organic synthesis and medicinal chemistry.

Chemoselective synthesis of bridged benzo[no]tetraphen-8-one via copper-catalyzed radical dimerization of 1-alkynylnaphthols

In organic chemistry, dimerization reactions represent a synthetically powerful strategy for the rapid construction of molecular complexity. This study introduces a copper-catalyzed radical dimerization of 1-alkynylnaphthols, enabling chemo- and diastereoselective synthesis of bridged tetrahydro-benzo[no]tetraphenone products. The approach boasts the use of an economical catalyst and a green oxidant under mild conditions. Different heteroaryls, such as indole and thiophene, are well-tolerated in the reaction. Control experiments provided valuable insights, revealing a sequence involving the formation of a C1–radical intermediate, intermolecular (3+2) cyclization, and an unusual intramolecular C4–C8′ coupling.

Photo-Mediated Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Azidooxygenation of 1,3-Dienes

Photo-Mediated Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Azidooxygenation of 1,3-Dienes

Site-Selective sp2 C-H Cyanation of Allenes via Copper-Catalyzed Radical Relay.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling to Access Chiral α-Amino-β-lactams.

A copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of racemic tertiary α-bromo-β-lactams with aromatic amines is developed under mild thermal reaction conditions. The use of a sterically demanded oxazoline-derived sulfonamide N,N,N-ligand is crucial for the reaction initiation and effective enantio-discrimination of the azetidinone-derived cyclic alkyl radicals. The strategy provides an attractive approach to access chiral α-amino-β-lactams, an important structural motif in many biologically active molecules. Preliminary mechanistic studies support the formation of azetidinone-derived alkyl radicals from the L*Cu(I)-amido complex and α-bromo-β-lactams.

Copper-(Photo)Catalyzed Radical Reactions with Organic Halides

AbstractCopper is one of the most efficient and attractive metals for catalysis. In addition to their availability, low cost and limited toxicity, copper complexes are utilized to catalyze a broad variety of reactions, including examples involving radicals. For such reactions, organic halides are by far the most versatile and attractive substrates. Our contributions to the catalysis of radical reactions from organic halides with copper complexes are summarized in this account.1 Introduction2 Copper-Catalyzed Radical Cross-Coupling Reactions3 Copper-Catalyzed Radical Reactions4 Copper-Catalyzed Radical Carbonylative Cross-Coupling Reactions5 Photoinduced, Copper-Catalyzed Radical Reactions6 Conclusions and Outlook

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

Copper-Catalyzed Radical Enantioselective Synthesis of γ-Butyrolactones with Two Non-vicinal Carbon Stereocenters.

Chiral heterocycles with two or more carbon stereocenters are quite important skeletons in many fields. However, powerful strategies for the construction of such synthetically valuable heterocycles, especially with two or more remote carbon stereocenters, have largely lagged behind. We report here a powerful method for the synthesis of chiral γ-butyrolactones with two non-vicinal carbon stereocenters from readily available chemical feedstocks under mild conditions. Both of the two diastereoisomers can be obtained with good to excellent enantioselectivities. The well-designed copper/PyBox catalytic system overrides the intrinsic stereoinduction of the close chirality center generated by the previous innocent radical addition step. Nevertheless, this work has the power to selectively provide one single diastereoisomer by taking advantage of the epimerization effect but also to synthesize all four diastereoisomers with the pair of chiral ligands L2 and L2' having opposite chirality. The obtained useful chiral γ-butyrolactones can be synthetically transformed into acyclic or cyclic molecules with two non-vicinal carbon stereocenters. Mechanistic studies reveal that this radical reaction follows a linear relationship and can be well performed with a less loading amount of ligand compared to that of the copper catalyst.

Copper-Catalyzed Enantioconvergent Radical C(sp3 )-N Cross-Coupling: Access to α,α-Disubstituted Amino Acids.

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C-N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C-N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm. An array of α,α-disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α-fully substituted amine building blocks.