Enantioselective CpxRhIII-Catalyzed Carboaminations of Acrylates

Enantioselective carboaminations of olefins constitute an attractive strategy for a rapid increase in molecular complexity from readily available starting materials. Reported here is an intermolecular asymmetric carboamination of acrylates using rhodium(III)-catalyzed alkenyl C−H activations of N-enoxysuccinimides to generate the nitrogen and carbon portion for the transfer. A rhodium complex equipped with a tailored bulky trisubstituted chiral Cp^x ligand ensures carboamination chemoselectivity as well high levels of enantioinduction. The transformation operates under mild reaction conditions at ambient temperatures and provides access to a variety of α-amino esters in good yields and excellent enantiomeric ratios of >99.5:0.5.     

A Planar‐Chiral Rhodium(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand and Its Application in the Enantioselective Synthesis of Dihydroisoquinolones

The rapid development of enantioselective C?H activation reactions has created a demand for new types of catalysts. Herein, we report the synthesis of a novel planar‐chiral rhodium catalyst [(C₅H₂^tBu₂CH₂^tBu)RhI₂]₂ in two steps from commercially available [(cod)RhCl]₂ and tert‐butylacetylene. Pure enantiomers of the catalyst were obtained through separation of its diastereomeric adducts with natural (S)‐proline. The catalyst promoted enantioselective reactions of aryl hydroxamic acids with strained alkenes to give dihydroisoquinolones in high yields (up to 97 %) and with good stereoselectivity (up to 95 % ee).     

Rhodium‐Catalyzed Enantioselective Silylation of Cyclopropyl C−H Bonds

Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C?H bonds in high yields and with high enantiomeric excesses in the presence of a rhodium catalyst derived from a rhodium precursor and the bisphosphine (S)‐DTBM‐SEGPHOS. The resulting enantioenriched oxasilolanes are suitable substrates for the Tamao–Fleming oxidation to form cyclopropanols with conservation of the ee value from the C?H silylation. Preliminary mechanistic data suggest that C?H cleavage is likely to be the turnover‐limiting and enantioselectivity‐determining step.     

Enantioselective Access to Spirocyclic Sultams by Chiral Cpx–Rhodium(III)‐Catalyzed Annulations

Chiral spirocyclic sultams are a valuable compound class in organic and medicinal chemistry. A rapid entry to this structural motif involves a [3+2] annulation of an N‐sulfonyl ketimine and an alkyne. Although the directing‐group properties of the imino group for C?H activation have been exploited, the developments of related asymmetric variants have remained very challenging. The use of rhodium(III) complexes equipped with a suitable atropchiral cyclopentadienyl ligand, in conjunction with a carboxylic acid additive, enables an enantioselective and high yielding access to such spirocyclic sultams.     

Chiral Carboxylic Acid Enabled Achiral Rhodium(III)‐Catalyzed Enantioselective C−H Functionalization

Reported is an achiral Cp^xRh^III/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4‐dihydroisoquinolin‐3(2H)‐one. Secondary alkylamines as well as nonprotected primary alkylamines underwent the transformation with high enantioselectivities (up to 98.5:1.5 e.r.) by using a newly developed chiral carboxylic acid as the sole source of chirality to achieve enantioselective C?H cleavage by a concerted metalation‐deprotonation mechanism.     

Chiral Cp‐Rhodium(III)‐Catalyzed Asymmetric Hydroarylations of 1,1‐Disubstituted Alkenes

Metal‐catalyzed functionalizations at the ortho position of a directing group have become an efficient bond‐forming strategy. A wide range of transformations that employ Cp*Rh^III catalysts have been described, but despite their synthetic potential, enantioselective variants that use chiral versions of the Cp* ligand remain scarce (Cp*=pentamethyl cyclopentadienyl). Cyclopentadienyl compounds with an atropchiral biaryl backbone are shown to be suitable ligands for the efficient intramolecular enantioselective hydroarylation of aryl hydroxamates. Dihydrofurans that bear methyl‐substituted quaternary stereocenters are thus obtained by C? H functionalization under mild conditions.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Chiral Bifunctional Phosphine‐Carboxylate Ligands for Palladium(0)‐Catalyzed Enantioselective C−H Arylation

Previous enantioselective Pd⁰‐catalyzed C?H activation reactions proceeding via the concerted metalation‐deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes the development of new chiral bifunctional ligands based on a binaphthyl scaffold which incorporates both a phosphine and a carboxylic acid moiety. The optimal ligand provided high yields and enantioselectivities for a desymmetrizing C(sp²)?H arylation leading to 5,6‐dihydrophenanthridines, whereas the corresponding monofunctional ligands showed low enantioselectivities. The bifunctional system proved applicable to a range of substituted dihydrophenanthridines, and allowed the parallel kinetic resolution of racemic substrates.     

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N‐methoxy benzamides and α,α‐difluoromethylene alkynes is enabled by C?H activation with a chiral CpRh^III catalyst. Remarkably, product formation is solvent‐dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in ⁱPrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E‐configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z‐configured monofluoroalkene upon protonation in the ⁱPrCN system and into an alkyne by an unusual anti β‐F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z‐monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.     

Rhodium‐Catalyzed Synthesis of Chiral Spiro‐9‐silabifluorenes by Dehydrogenative Silylation: Mechanistic Insights into the Construction of Tetraorganosilicon Stereocenters

Mechanistic insight into the construction of quaternary silicon chiral centers by rhodium‐catalyzed synthesis of spiro‐9‐silabifluorenes through dehydrogenative silylation is reported. The C₂‐symmetric bisphosphine ligand, BINAP, was effective in controlling enantioselectivity, and axially chiral spiro‐9‐silabifluorenes were obtained in excellent yields with high enantiomeric excess. Monitoring of the reaction revealed the presence of a monohydrosilane intermediate as a mixture of two constitutional isomers. The reaction proceeded through two consecutive dehydrogenative silylations, and the absolute configuration was determined in the first silylative cyclization. Competitive reactions with electron‐rich and electron‐deficient dihydrosilanes indicated that the rate of silylative cyclization increased with decreasing electron density on the silicon atom of the starting dihydrosilane. Further investigation disclosed a rare interconversion between the two constitutional isomers of the monohydrosilane intermediate with retention of the absolute configuration.     

Rhodium(III)‐Catalyzed Enantio‐ and Diastereoselective C−H Cyclopropylation of N‐Phenoxylsulfonamides: Combined Experimental and Computational Studies

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio‐ and diastereoselective construction of cyclopropanes through C?H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing‐group‐assisted C?H activation strategy was used to realize mild and redox‐neutral Rh^III‐catalyzed C?H activation and cyclopropylation of N‐phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a Rh^V nitrenoid intermediate, and Noyori‐type outer sphere concerted proton‐hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Enantioselective C−H Activation with Earth‐Abundant 3d Transition Metals

Molecular syntheses largely rely on time‐ and labour‐intensive prefunctionalization strategies. In contrast, C?H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C?H bonds has emerged as a transformative tool for the step‐ and atom‐economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C?H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C?H activation by 3d base metals up to April 2019.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

Asymmetric Synthesis of Isoindolones by Chiral Cyclopentadienyl‐Rhodium(III)‐Catalyzed CH Functionalizations

Directed Cp*Rh^III‐catalyzed carbon–hydrogen (C? H) bond functionalizations have evolved as a powerful strategy for the construction of heterocycles. Despite their high value, the development of related asymmetric reactions is largely lagging behind due to a limited availability of robust and tunable chiral cyclopentadienyl ligands. Rhodium complexes comprising a chiral Cp ligand with an atropchiral biaryl backbone enables an asymmetric synthesis of isoindolones from arylhydroxamates and weakly alkyl donor/acceptor diazo derivatives as one‐carbon component under mild conditions. The complex guides the substrates with a high double facial selectivity yielding the chiral isoindolones in good yields and excellent enantioselectivities.     

Enantioselective Copper(I)/Chiral Phosphoric Acid Catalyzed Intramolecular Amination of Allylic and Benzylic C−H Bonds

Radical‐involved enantioselective oxidative C?H bond functionalization by a hydrogen‐atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched products, while asymmetric C(sp³)?H bond amination remains a formidable challenge. To address this problem, described herein is a dual Cu^I/chiral phosphoric acid (CPA) catalytic system for radical‐involved enantioselective intramolecular C(sp³)?H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4‐methoxy‐NHPI (NHPI=N‐hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.     

Rhodium‐Catalyzed C(sp2)‐ or C(sp3)−H Bond Functionalization Assisted by Removable Directing Groups

In recent years, transition‐metal‐catalyzed C?H activation has become a key strategy in the field of organic synthesis. Rhodium complexes are widely used as catalysts in a variety of C?H functionalization reactions because of their high reactivity and selectivity. The availability of a number of rhodium complexes in various oxidation states enables diverse reaction patterns to be obtained. Regioselectivity, an important issue in C?H activation chemistry, can be accomplished by using a directing group to assist the reaction. However, to obtain the target functionalized compounds, it is also necessary to use a directing group that can be easily removed. A wide range of directed C?H functionalization reactions catalyzed by rhodium complexes have been reported to date. In this Review, we discuss Rh‐catalyzed C?H functionalization reactions that are aided by the use of a removable directing group such as phenol, amine, aldehyde, ketones, ester, acid, sulfonic acid, and N‐heteroaromatic derivatives.     

Intermolecular 1,4‐Carboamination of Conjugated Dienes Enabled by Cp*RhIII‐Catalyzed C−H Activation

A protocol for the three‐component 1,4‐carboamination of dienes is described. Synthetically versatile Weinreb amides were coupled with 1,3‐dienes and readily available dioxazolones as the nitrogen source using [Cp*RhCl₂]₂‐catalyzed C?H activation to deliver the 1,4‐carboaminated products. This transformation proceeds under mild reaction conditions and affords the products with high levels of regio‐ and E‐selectivity. Mechanistic investigations suggest an intermediate Rh^III–allyl species is trapped by an electrophilic amidation reagent in a redox‐neutral fashion.     

Low‐Pressure Cobalt‐Catalyzed Enantioselective Hydrovinylation of Vinylarenes

An efficient and practical protocol for the enantioselective cobalt‐catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L₂CoCl₂] complexes are employed that are activated in situ with Et₂AlCl. A modular chiral TADDOL‐derived phosphine–phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH₂, CN, and CO₂R, are tolerated.