Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination Enabled by a Transient Chiral Auxiliary

Atroposelective synthesis of axially chiral biaryls by palladium-catalyzed C−H olefination, using tert-leucine as an inexpensive, catalytic, and transient chiral auxiliary, has been realized. This strategy provides a highly efficient and straightforward access to a broad range of enantioenriched biaryls in good yields (up to 98 %) with excellent enantioselectivities (95 to >99 % ee). Kinetic resolution of trisubstituted biaryls bearing sterically more demanding substituents is also operative, thus furnishing the optically active olefinated products with excellent selectivity (95 to >99 % ee, s-factor up to 600).     

Chiral Phosphoric Acid Catalyzed Atroposelective C−H Amination of Arenes

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C−H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C–N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C–N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.     

Rhodium-Catalyzed Intermolecular Silylation of Csp−H by Silacyclobutanes

The signature reactivity of silacyclobutane (SCB) is their cycloaddition reactions with various π bonds. Recently, the first cases were disclosed where SCBs reacted with both C_sp2−H and C_sp3−H σ bonds in an intramolecular fashion. Herein, it is reported that SCB is also an efficient reagent for C_sp−H bond silylation. Thus, rhodium-catalyzed intermolecular reactions between SCBs and terminal alkynes produced a series of symmetrical and unsymmetrical tetraorganosilicons bearing a C_sp−Si functionality. Preliminary studies suggested that the reaction did not involve a cycloaddition pathway, but instead a direct activation of C_sp−H bonds.     

Synthesis of Axially Chiral Biaryl-2-amines by PdII-Catalyzed Free-Amine-Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II-catalyzed atroposelective C−H olefination. A broad range of axially chiral biaryl-2-amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram-scale synthesis. The resulting axially chiral biaryl-2-amines also provide a platform for the synthesis of a set of chiral ligands.     

Cobalt-Catalyzed Dehydrogenative C−H Silylation of Alkynylsilanes

Herein, we report that a cobalt catalyst permits the general synthesis of substituted alkynylsilanes through dehydrogenative coupling of alkynylsilanes and hydrosilanes. Several silylated alkynes, including di- and trisubstituted ones, were prepared in a one-step procedure. Thirty-seven compounds were synthesized for the first time by applying our catalyst system. The alkynylsilanes bearing hydrosilyl moieties provide an opportunity for further functionalization (e. g., hydrosilylation). The use of primary silanes as substrates and precatalyst activators permits the use of inexpensive and easily accessible 3d metal precatalysts, and avoids the presence of additional activators.     

Synthesis of Axially Chiral Biaryls through Cobalt(II)-Catalyzed Atroposelective C−H Arylation

Highly efficient synthesis of axially chiral biaryl amines through cobalt-catalyzed atroposelective C−H arylation using easily accessible cobalt(II) salt and salicyloxazoline ligand has been reported. This methodology provides a straightforward and sustainable access to a broad range of enantioenriched biaryl-2-amines in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). The synthetic utility of the unprecedented method is highlighted by its scalability and diverse transformations.     

Enantioselective Synthesis of C−O Axially Chiral Diaryl Ethers by NHC-Catalyzed Atroposelective Desymmetrization**

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C−O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C−O axis remains a significant challenge. Herein, we demonstrate the first N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. Mechanistically, the reaction proceeds via NHC-catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C−O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C−O bonds are also presented.     

Synthesis of Chiral Sulfoximines via Iridium-Catalyzed Regio- and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand

Transition metal-catalyzed enantioselective C−H activation of prochiral sulfoximines for non-annulated products remains a formidable challenge. We herein report iridium-catalyzed enantioselective C−H borylation of N-silyl diaryl sulfoximines using a well-designed chiral bidentate boryl ligand with a bulky side arm. This method is capable of accommodating a broad range of substrates under mild reaction conditions, affording a vast array of chiral sulfoximines with high enantioselectivities. We also demonstrated the synthetic utility on a preparative-scale C−H borylation for diverse downstream transformations, including the synthesis of chiral version of bioactive molecules. Computational studies showed that the bulky side arm of the ligand confers high regio- and enantioselectivity through steric effect.     

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.     

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Expanding the toolbox of C−H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.     

Palladium-Catalyzed Atroposelective Kinetic C−H Olefination and Allylation for the Synthesis of C−B Axial Chirality

The direct C−H functionalization of 1,2-benzazaborines, especially asymmetric version, remains a great challenge. Here we report a palladium-catalyzed enantioselective C−H olefination and allylation reactions of 1,2-benzazaborines. This asymmetric approach is a kinetic resolution (KR), providing various C−B axially chiral 2-aryl-1,2-benzazaborines and 3-substituted 2-aryl-1,2-benzazaborines in generally high yields with excellent enantioselectivities (selectivity (S) factor up to 354). The synthetic potential of this reaction is showcased by late-stage modification of complex molecules, scale-up reaction, and applications.     

Metal-Free Intermolecular C−H Borylation of N-Heterocycles at B−B Multiple Bonds

Carbene-stabilized diborynes of the form LBBL (L=N-heterocyclic carbene (NHC) or cyclic alkyl(amino)carbene (CAAC)) induce rapid, high yielding, intermolecular ortho-C−H borylation at N-heterocycles at room temperature. A simple pyridyldiborene is formed when an NHC-stabilized diboryne is combined with pyridine, while a CAAC-stabilized diboryne leads to activation of two pyridine molecules to give a tricyclic alkylideneborane, which can be forced to undergo a further H-shift resulting in a zwitterionic, doubly benzo-fused 1,3,2,5-diazadiborinine by heating. Use of the extended N-heteroaromatic quinoline leads to a borylmethyleneborane under mild conditions via an unprecedented boron-carbon exchange process.     

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II-catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III-catalyzed enantioselective C(sp³)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity-determining step.     

Dibenzothiophenesulfilimines: A Convenient Approach to Intermolecular Rhodium-Catalysed C−H Amidation

A sulfilimine-based Group 9 transition-metal-catalysed C−H amidation procedure is reported. Dibenzothiophene-based sulfilimines were shown to constitute a class of novel amidation reagents which enable the transfer of a wide range of N-sulfonyl and N-acyl moieties. It was demonstrated that sulfilimines, which are easily accessible from cheap reagents, are safe-to-handle and represent broadly applicable amidation reagents. The dibenzothiophene can be recycled after use. The C−H amidation was shown to proceed with high selectivity and gave the mono-amidated products, mostly in good to excellent yields.     

Chiral Catalysts for Pd0-Catalyzed Enantioselective C−H Activation

In the past few decades, processes that involve transition-metal catalysis have represented a major part of the synthetic chemist′s toolbox. Recently, the interest has shifted from the well-established cross-coupling reactions to C−H bond functionalization, thus making it a current frontier of transition-metal-catalyzed reactions. Constant progress in this field has led to the discovery of enantioselective methods to generate and control various types of stereogenic elements, thereby demonstrating its high value to generate scalemic chiral molecules. The present review is dedicated to enantioselective Pd⁰-catalyzed C−H activation, which may be considered as an evolution of Pd⁰-catalyzed cross-couplings, with a focus on the different chiral ligands and catalysts that enable these transformations.     

Direct Dimesitylborylation of Benzofuran Derivatives by an Iridium-Catalyzed C−H Activation with Silyldimesitylborane

Direct dimesitylborylation of benzofuran derivatives by a C−H activation catalyzed by an iridium(I)/N-heterocyclic carbene (NHC) complex in the presence of Ph₂MeSi-BMes₂ afforded the corresponding dimesitylborylation products in good to high yield with excellent regioselectivity. This method provides a straightforward route to donor–(π-spacer)–acceptor systems with intriguing solvatochromic luminescence properties.     

Diastereoselective Double C−H Functionalization of Chiral Ferrocenes with Heteroaromatics

Diastereoselective double C−H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C−H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. ¹⁹F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.     

Chiral N-Heterocyclic Carbene Ligands Enable Asymmetric C−H Bond Functionalization

The asymmetric functionalization of C−H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral N-heterocyclic carbene (NHC) ligands have become ubiquitous in enantioselective transition-metal catalysis. Conversely, the use of chiral NHC ligands in metal-catalyzed asymmetric C−H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.     

Enantioselective Silylation of Aliphatic C−H Bonds for the Synthesis of Silicon-Stereogenic Dihydrobenzosiloles

A rhodium(I)-catalyzed enantioselective silylation of aliphatic C−H bonds for the synthesis of silicon-stereogenic dihydrobenzosiloles is demonstrated. This reaction involves a highly enantioselective intramolecular C(sp³)−H silylation of dihydrosilanes, followed by a stereospecific intermolecular alkene hydrosilylation leading to the asymmetrically tetrasubstituted silanes. A wide range of dihydrosilanes and alkenes displaying various functional groups are compatible with this process, giving access to a variety of highly functionalized silicon-stereogenic dihydrobenzosiloles in good to excellent yields and enantioselectivities.     

Regioselective C−H Functionalization of Heteroarene N-Oxides Enabled by a Traceless Nucleophile

Although N-alkenoxyheteroarenium salts have been widely used as umpoled synthons with nucleophilic (hetero)arenes, the use of electron-poor heteroarenes has remained unexplored. To overcome the inherent electron deficiency of quinolinium salts, a traceless nucleophile-triggered strategy was designed, wherein the quinolinium segment is converted into a dearomatized intermediate, thereby allowing simultaneous C8-functionalization of quinolines at room temperature. Experimental and computational studies support the traceless operation of a nucleophile, which enables the previously inaccessible transformation of N-alkenoxyheteroarenium salts. Remarkably, the generality of this strategy has been further demonstrated by broad applications in the regioselective C−H functionalization of other electron-deficient heteroarenes such as phenanthridine, isoquinoline, and pyridine N-oxides, offering a practical tool for the late-stage functionalization of complex biorelevant molecules.