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.     

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.     

Rhodium(III)‐Catalyzed Directed C−H Amidation of N‐Nitrosoanilines and Subsequent Formation of 1,2‐Disubstituted Benzimidazoles

An efficient rhodium‐catalyzed direct C−H amidation of N ‐nitrosoanilines with 1,4,2‐dioxazol‐5‐ones as amidating agents has been developed. This method featured mild reaction conditions, a wide substrate scope and satisfactory yields. Besides, the amidated products could be readily converted to pharmaceutically valuable 1,2‐disubstituted benzimidazoles via an HCl‐mediated deprotection/cyclization process in one pot.     

Rhodium(III)‐Catalyzed Annulation of 2‐Alkenyl Anilides with Alkynes through C−H Activation: Direct Access to 2‐Substituted Indolines

A Rh^III complex featuring an electron‐deficient η⁵‐cyclopentadienyl ligand catalyzed an unusual annulation between alkynes and 2‐alkenyl anilides to form synthetically appealing 2‐substituted indolines. Formally, the process can be viewed as an allylic amination with concomitant hydrocarbonation of the alkyne. Mechanistic experiments indicate that this transformation involves an unusual rhodium migration with a concomitant 1,5‐H shift.     

Rhodium(III)‐Catalyzed Redox‐Neutral Coupling of α‐Trifluoromethylacrylic Acid with Benzamides through Directed C−H Bond Cleavage

A rhodium(III)‐catalyzed redox‐neutral coupling of α‐trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide‐directed C?H bond cleavage to produce β‐[2‐(aminocarbonyl)phenyl]‐α‐trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox‐neutral coupling of α‐trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen‐containing directing group can also be conducted under similar conditions.     

Mechanochemical Rhodium(III)‐ and Gold(I)‐Catalyzed C−H Bond Alkynylations of Indoles under Solventless Conditions in Mixer Mills

Mechanochemical activations in Rh^III‐ and Au^I‐catalyzed C?H alkynylations lead selectively to C₂‐ and C₃‐alkynylated indoles. The processes show excellent functional group tolerance, do not require additional heating and proceed under solventless conditions. Compared to solvent‐based standard protocols, the reaction times are shorter and the catalyst quantities lower resulting in high product yields under ambient atmosphere in mixer mills.     

Rhodium(III)‐Catalyzed Asymmetric Access to Spirocycles through C−H Activation and Axial‐to‐Central Chirality Transfer

Axial‐to‐central chirality transfer is an important strategy to construct chiral centers, where the axially chiral reagents are mostly limited to atropomerically stable ones. Reported herein is a Rh^III‐catalyzed enantioselective spiroannulative synthesis of nitrones. The coupling proceeds via C?H arylation to give an atropomerically metastable biaryl, followed by intramolecular dearomative trapping under oxidative conditions with high degree of chirality transfer.     

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by Rh^III‐catalyzed C?H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2‐substituted 1‐alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox‐neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio‐ and enantioselectivity.     

Nitrone Directing Groups in Rhodium(III)‐Catalyzed C−H Activation of Arenes: 1,3‐Dipoles versus Traceless Directing Groups

Functionalizable directing groups (DGs) are highly desirable in C?H activation chemistry. The nitrone DGs are explored in rhodium(III)‐catalyzed C?H activation of arenes and couplings with cyclopropenones. N‐tert‐butyl nitrones bearing a small ortho substituent coupled to afford 1‐naphthols, where the nitrone acts as a traceless DG. In contrast, coupling of N‐tert‐butyl nitrones bearing a bulky ortho group follows a C?H acylation/[3+2] dipolar addition pathway to give bicyclics. The coupling of N‐arylnitrones follows the same acylation/[3+2] addition process but delivers different bicyclics.     

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.     

Construction of Hexahydrophenanthrenes By Rhodium(I)‐Catalyzed Cycloisomerization of Benzylallene‐Substituted Internal Alkynes through C−H Activation

The treatment of benzylallene‐substituted internal alkynes with [RhCl(CO)₂]₂ effects a novel cycloisomerization by C(sp²)?H bond activation to produce hexahydrophenanthrene derivatives. The reaction likely proceeds through consecutive formation of a rhodabicyclo[4.3.0] intermediate, σ‐bond metathesis between the C(sp²)?H bond on the benzene ring and the C(sp²)?Rh^III bond, and isomerization between three σ‐, π‐, and σ‐allylrhodium(III) species, which was proposed based on experiments with deuterated 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.     

Highly Stereoselective Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition Cascade

A highly stereoselective three‐component C(sp²)?H bond addition across alkene and polarized π‐bonds is reported for which Co^III catalysis was shown to be much more effective than Rh^III. The reaction proceeds at ambient temperature with both aryl and alkyl enones employed as efficient coupling partners. Moreover, the reaction exhibits extremely broad scope with respect to the aldehyde input; electron rich and poor aromatic, alkenyl, and branched and unbranched alkyl aldehydes all couple in good yield and with high diastereoselectivity. Multiple directing groups participate in this transformation, including pyrazole, pyridine, and imine functional groups. Both aromatic and alkenyl C(sp²)?H bonds undergo the three‐component addition cascade, and the alkenyl addition product can readily be converted into diastereomerically pure five‐membered lactones. Additionally, the first asymmetric reactions with Co^III‐catalyzed C?H functionalization are demonstrated with three‐component C?H bond addition cascades employing N‐tert‐butanesulfinyl imines. These examples represent the first transition metal catalyzed C?H bond additions to N‐tert‐butanesulfinyl imines, which are versatile and extensively used intermediates for the asymmetric synthesis of amines.     

Axially Chiral Dibenzazepinones by a Palladium(0)‐Catalyzed Atropo‐enantioselective C−H Arylation

Atropo‐enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo‐enantioselective palladium(0)‐catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio‐determining CMD to yield configurationally stable eight‐membered palladacycles.     

Micellar Catalysis for Ruthenium(II)‐Catalyzed C−H Arylation: Weak‐Coordination‐Enabled C−H Activation in H2O

Chemoselective C?H arylations were accomplished through micellar catalysis by a versatile single‐component ruthenium catalyst. The strategy provided expedient access to C?H‐arylated ferrocenes with wide functional‐group tolerance and ample scope through weak chelation assistance. The sustainability of the C?H arylation was demonstrated by outstanding atom‐economy and recycling studies. Detailed computational studies provided support for a facile C?H activation through thioketone assistance.     

Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

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.     

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.     

Copper‐Catalyzed Direct Sulfoximination of Heteroaromatic N‐Oxides by Dual C−H/N−H Dehydrogenative Cross‐Coupling

A dual C?H/N?H dehydrogenative coupling of quinoline‐type N‐oxides with sulfoximines that leads to N‐(hetero)arylsulfoximines in high yields has been realized by using a catalytic amount of CuBr in air. The method does not require any additional ligand, base, reactivity modifier or oxidant and provides a practical route towards a series of sulfoximidoyl‐functionalized quinolines and derivatives.     

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

Palladium‐catalyzed regio‐ and diastereoselective C?H functionalization with bromoalkynes and electronically unbiased olefins is reported. The picolinamide directing group enables the formation of putative 5 and 6‐exo‐metallacycles as intermediates to afford monoalkynylated products in up to 91 % yield in a stereospecific fashion. The systematic study reveals that substrates with a wide range of substituents on the olefin and bromoalkyne coupling partners are tolerated. Chemoselective transformations were demonstrated for the obtained amides, olefins, and alkynes.