Rhodium(III)-Catalyzed Oxidative Cross-Coupling of N-Pyrimidylindoles with Cyclic ß-Keto Esters for Accessing All-Carbon Quaternary Centers.

Rh(III)-catalyzed direct oxidative C-H/C-H cross-coupling between N-pyrimidylindoles and ß-ketoesters is presented. Easily available ß-ketoesters are used as an alkylating agent for the facile construction of all-carbon quaternary centers under mild conditions. The ester group in the product can undergo decarboxylation or decarboxylative amination.

Cobalt- or rhodium-catalyzed synthesis of 1,2-dihydrophosphete oxides via C-H activation and formal phosphoryl migration.

A highly stereo- and chemoselective intermolecular coupling of diverse heterocycles with dialkynylphosphine oxides has been realized via cobalt/rhodium-catalyzed C-H bond activation. This protocol provides an efficient synthetic entry to functionalized 1,2-dihydrophosphete oxides in excellent yields via the merger of C-H bond activation and formal 1,2-migration of the phosphoryl group. Compared with traditional methods of synthesis of 1,2-dihydrophosphetes that predominantly relied on stoichiometric metal reagents, this catalytic system features high efficiency, a relatively short reaction time, atom-economy, and operational simplicity. Photophysical properties of selected 1,2-dihydrophosphete oxides are also disclosed.

Rhodium-catalyzed enantioselective and diastereodivergent access to diaxially chiral heterocycles.

N-N axially chiral biaryls represent a rarely explored class of atropisomers. Reported herein is construction of diverse classes of diaxially chiral biaryls containing N-N and C-N/C-C diaxes in distal positions in excellent enantioselectivity and diastereoselectivity. The N-N chiral axis in the products provides a handle toward solvent-driven diastereodivergence, as has been realized in the coupling of a large scope of benzamides and sterically hindered alkynes, affording diaxes in complementary diastereoselectivity. The diastereodivergence has been elucidated by computational studies which revealed that the hexafluoroisopropanol (HFIP) solvent molecule participated in an unusual manner as a solvent as well as a ligand and switched the sequence of two competing elementary steps, resulting in switch of the stereoselectivity of the alkyne insertion and inversion of the configuration of the C-C axis. Further cleavage of the N-directing group in the diaxial chiral products transforms the diastereodivergence to enantiodivergence.

Rhodium-catalyzed atroposelective access to trisubstituted olefins via C-H bond olefination of diverse arenes.

The atroposelective synthesis of axially chiral acyclic olefins remains a daunting challenge due to their relatively lower racemization barriers, especially for trisubstituted ones. In this work, atroposelective C-H olefination has been realized for synthesis of open-chain trisubstituted olefins via C-H activation of two classes of (hetero)arenes in the coupling with sterically hindered alkynes. The employment of phenyl N-methoxycarbamates as arene reagents afforded phenol-tethered olefins, with the carbamate being a traceless directing group. The olefination of N-methoxy-2-indolylcarboxamides afforded the corresponding chiral olefin by circumventing the redox-neutral [4 + 2] annulation. The reactions proceeded with excellent Z/E selectivity, chemoselectivity, regioselectivity, and enantioselectivity in both hydroarylation systems.

Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones.

The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3-dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched. Herein, we report asymmetric 1,4-oxyamination of gem-difluorodiene by chiral rhodium-catalyzed three-component coupling with readily available carboxylic acid and dioxazolone, affording gem-difluorinated 1,4-amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4-regio- and enantioselectivity with utility in the late-stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π-allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.

O-Allylhydroxyamine: A Bifunctional Olefin for Construction of Axially and Centrally Chiral Amino Alcohols via Asymmetric Carboamidation.

Difunctionalization of olefins offers an attractive approach to access complex chiral structures. Reported herein is the design of N-protected O-allylhydroxyamines as bifunctional olefins that undergo catalytic asymmetric 1,2-carboamidation with three classes of (hetero)arenes to afford chiral amino alcohols via C-H activation. The C═C bond in O-allylhydroxyamine is activated by the intramolecular electrophilic amidating moiety as well as a migrating directing group. The asymmetric carboamidation reaction pattern depends on the nature of the (hetero)arene reagent. Simple achiral (hetero)arenes reacted to give centrally chiral ß-amino alcohols in excellent enantioselectivity. The employment of axially prochiral or axially racemic heteroarenes afforded amino alcohols with both axial and central chirality in excellent enantio- and diastereoselectivity. In the case of axially racemic heteroarenes, the coupling follows a kinetic resolution pattern with an s-factor of up to >600. A nitrene-based reaction mechanism has been suggested based on experimental studies, and a unique mode of induction of enantio- and diastereoselectivity has been proposed. Applications of the amino alcohol products have been demonstrated.

Rhodium-Catalyzed Atroposelective Access to Axially Chiral Olefins via C-H Bond Activation and Directing Group Migration.

Axially chiral open-chain olefins represent an underexplored class of chiral platform. In this report, two classes of tetrasubstituted axially chiral acyclic olefins have been accessed in excellent enantioselectivity and regioselectivity via C-H activation of (hetero)arenes assisted by a migratable directing group en route to coupling with sterically hindered alkynes. The coupling of indoles bearing an N-aminocarbonyl directing group afforded C-N axially chiral acrylamides with the assistance of a racemic zinc carboxylate additive. DFT studies suggest a ß-nitrogen elimination-reinsertion pathway for the directing group migration. Meanwhile, the employment of N-phenoxycarboxamide delivered C-C axially chiral enamides via migration of the oxidizing directing group. Experiments suggest that in both cases the (hetero)arene substrate adopts a well-defined orientation during the C-H activation, which in turn determines the disposition of the alkyne in migratory insertion. Synthetic applications of representative chiral olefins are demonstrated.

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 RhIII -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.

Rhodium-Catalyzed Enantioselective Oxidative [3+2] Annulation of Arenes and Azabicyclic Olefins through Twofold C-H Activation.

C-H bond activation is mostly limited to ortho selectivity. Activation of both ortho and meta C-H bonds constitutes a particularly important strategy for annulation, but has rarely been studied in enantioselective systems. Reported herein is rhodium(III)-catalyzed asymmetric [3+2] transannulation of arenes with 7-azabenzonorbornadienes. Two distinct classes of arenes have been identified as substrates, and the coupling proceeded with high enantioselectivity and excellent diastereoselectivity through sequential activation of ortho and meta C-H bonds.

Rhodium(III)-Catalyzed Meta-Selective C-H Alkenylation of Phenol Derivatives.

Rhodium(III)-catalyzed remote meta-selective-C-H alkenylation of phenol derivatives has been developed using a traceless organosilicon template as the directing group. This transformation proceeds smoothly with good yields and high meta-selectivities toward a series of phenol and alkene substrates. In addition, this protocol provides an effective strategy for late-stage transformations of various meta-alkenylated aromatic compounds.

A meta-selective-C-H alkenylation of phenol-derivatives employing a traceless organosilicon template.

A traceless organosilicon template-directed meta-selective-C-H alkenylation of phenols was realized with good yields and high selectivities. The template was readily removable through F--promoted O-Si cleavage under extremely mild conditions or recyclable through a p-TSA catalyzed process. The product was successfully applied in the preparation of a series of meta-alkenylated aromatic compounds.