Palladium‐Catalyzed CH Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³)? H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.     

Cascade One‐Pot Synthesis of Orange‐Red‐Fluorescent Polycyclic Cinnolino[2,3‐f]phenanthridin‐9‐ium Salts by Palladium(II)‐Catalyzed C−H Bond Activation of 2‐Azobiaryl Compounds and Alkenes

Quaternary ammonium salts were synthesized in moderate to good yields through double oxidative C?H bond activation on azobenzenes. The mechanism of the highly regioselective reaction of 2‐azobiaryls with alkenes to give orange‐red‐fluorescent cinnolino[2,3‐f]phenanthridin‐9‐ium salts and 15H‐cinnolino[2,3‐f]phenanthridin‐9‐ium‐10‐ide is proposed to involve ortho C?H olefination of the 2‐azobiaryl compound with the alkene, intramolecular aza‐Michael addition, concerted metalation–deprotonation (CMD), reductive elimination, and oxidation.     

Rhenium(I)‐Catalyzed ortho‐C−H Addition to Bicyclic Alkenes

Hydroarylation of bicyclic alkenes has been developed using a low‐valent Re^I‐catalyzed, directing group‐assisted C?H bond activation strategy. The addition of sodium acetate significantly improves the reaction efficiency; moreover, bicyclic alkenes such as 7‐oxa and aza benzonorbornadienes worked efficiently under this reaction condition. Preliminary mechanistic studies suggest that, after the alkene insertion, the rhenacycle preferentially undergoes protonolysis rather than reductive elimination.     

Phosphite‐Catalyzed C−H Allylation of Azaarenes via an Enantioselective [2,3]‐Aza‐Wittig Rearrangement

A phosphite‐mediated [2,3]‐aza‐Wittig rearrangement has been developed for the regio‐ and enantioselective allylic alkylation of six‐membered heteroaromatic compounds (azaarenes). The nucleophilic phosphite adducts of N‐allyl salts undergo a stereoselective base‐mediated aza‐Wittig rearrangement and dissociation of the chiral phosphite for overall C?H functionalization of azaarenes. This method provides efficient access to tertiary and quaternary chiral centers in isoquinoline, quinoline, and pyridine systems, tolerating a broad variety of substituents on both the allyl part and azaarenes. Catalysis with chiral phosphites is also demonstrated with synthetically useful yields and enantioselectivities.     

Benzylic Fluorination of Aza‐Heterocycles Induced by Single‐Electron Transfer to Selectfluor

A selective and mild method for the benzylic fluorination of aromatic azaheterocycles with Selectfluor is described. These reactions take place by a previously unreported mechanism, in which electron transfer from the heterocyclic substrate to the electrophilic fluorinating agent Selectfluor eventually yields a benzylic radical, thus leading to the desired C?F bond formation. This mechanism enables high intra‐ and intermolecular selectivity for aza‐heterocycles over other benzylic components with similar C?H bond‐dissociation energies.     

Tuned C?H Functionalization to Construct Aza‐Podophyllotoxin/Aza‐Conidendrin Derivatives by Means of Domino Cyclization

An efficient domino cyclization method for the construction of aza‐podophyllotoxin/aza‐conidendrin derivatives has been established. Reactions of different dienes with aryl halides in the presence of a palladium catalytic system produced different kinds of podophyllotoxin derivatives through a highly regioselective C? H functionalization. Treatment of dienes with aryl halides that have electron‐withdrawing substituents on the phenyl ring created aza‐podophyllotoxin derivatives by means of the functionalization of the C? H bonds ortho to the C? halide bonds of the incoming aryl halides. The reaction of dienes with 1‐iodobenzene or aryl halides that incorporate electron‐donating groups produced aza‐conidendrin derivatives by means of the functionalization of both sp³ C? H and sp² C? H bonds. The regioselective C? H functionalization for the formation of different pseudo‐podophyllotoxin/‐conidendrin derivatives is proven by analyses of the ¹H NMR spectra of the products and selective X‐ray analyses of the structures of the products. Thus, the palladium‐catalyzed domino cyclization of 1,6‐dienes for the preparation of aza‐podophyllotoxin/aza‐conidendrin derivatives can be controlled by selectively controlling the C? H functionalization.     

Iron‐Carbonyl‐Catalyzed Redox‐Neutral [4+2] Annulation of N−H Imines and Internal Alkynes by C−H Bond Activation

Stoichiometric C?H bond activation of arenes mediated by iron carbonyls was reported by Pauson as early as in 1965, yet the catalytic C?H transformations have not been developed. Herein, an iron‐catalyzed annulation of N?H imines and internal alkynes to furnish cis‐3,4‐dihydroisoquinolines is described, and represents the first iron‐carbonyl‐catalyzed C?H activation reaction of arenes. Remarkablely, this is also the first redox‐neutral [4+2] annulation of imines and alkynes proceeding by C?H activation. The reaction also features only cis stereoselectivity and excellent atom economy as neither base, nor external ligand, nor additive is required. Experimental and theoretical studies reveal an oxidative addition mechanism for C?H bond activation to afford a dinuclear ferracycle and a synergetic diiron‐promoted H‐transfer to the alkyne as the turnover‐determining step.     

Copper‐Catalyzed Reaction Cascade of Thiophenol Hydroxylation and S‐Arylation through Disulfide‐Directed C−H Activation

Copper‐catalyzed thiophenol C?H activation is described. Through an initial attempt to conduct C‐arylation with arylboronic acid, a rather surprising sequential C?H activation and S‐arylation was discovered. Mechanistic investigation revealed the disulfide intermediate as the key component in directing C?H oxidation. The overall reaction proceeded under mild conditions with molecular oxygen as the oxidant. Discovery of disulfide as the directing group provides a potential new direction for catalytic C?H functionalization under mild conditions.     

Rhodium‐Catalyzed PIII‐Directed ortho‐C−H Borylation of Arylphosphines

Transition‐metal‐mediated metalation of an aromatic C?H bond that is adjacent to a tertiary phosphine group in arylphosphines via a four‐membered chelate ring was first discovered in 1968. Herein, we overcome a long‐standing problem with the ortho‐C?H activation of arylphosphines in a catalytic fashion. In particular, we developed a rhodium‐catalyzed ortho‐selective C?H borylation of various commercially available arylphosphines with B₂pin₂ through P^III‐chelation‐assisted C?H activation. This discovery is suggestive of a generic platform that could enable the late‐stage modification of readily accessible arylphosphines.     

Supramolecular Assemblies of (±-2,2''''-Dihydroxy-1,1''''-binaphthyl with 2,2''''-Bipyridine and Naphthodiazine

Introduction Optically active 1,1'-bi-2-naphthol (BINOL) and its derivatives have been widely used as chiral ligands of catalysts for asymmetric reactions and effective host compounds for the isolation or optical resolution of a wide range of organic guest molecules through the for-mation of crystalline inclusion complexes.1,2 The wide-ranging and important applications of these com-pounds in organic synthesis have stimulated great inter-est in developing efficient methods for their prepara-…     

Sulfilimines as Versatile Nitrene Transfer Reagents: Facile Access to Diverse Aza‐Heterocycles

We herein report the unprecedented synthesis of diverse biologically important aza‐heterocycles by employing sulfilimines as nitrene transfer reagents. This class of sulfur‐based aza‐ylides had not been successfully used for gold nitrene transfer before. This work contains an efficient generation of α‐imino gold carbenes by N?S cleavage of sulfilimines. These gold carbenes undergo C?H insertion, cyclopropanation, and nucleophilic attack to form indoles (44 examples), 3‐azabicyclo[3.1.0]hexan‐2‐imines (24 examples), and imidazoles (3 examples). Our study represents a unique gold‐catalyzed reaction between alkynes and sulfur ylides, and also includes the first aza‐heterocycle synthesis that proceeds by intermolecular nitrene transfer followed by cyclopropanation of the α‐imino gold carbenes. Moreover, an unexpected synthesis of 4‐acylquinolines (3 examples) from 2‐acylphenyl sulfilimines and propargylic silyl ether derivatives by a 1,2‐hydride shift onto the α‐imino gold carbene and a subsequent Mukaiyama aldol cyclization was discovered.     

Rhodaelectrocatalysis for Annulative C−H Activation: Polycyclic Aromatic Hydrocarbons through Versatile Double Electrocatalysis

Rapid access to structurally diversified polycyclic aromatic hydrocarbons (PAHs) in a controlled manner is of key significance in materials sciences. Herein, we describe a strategy featuring two distinct electrocatalytic C?H transformations for the synthesis of novel nonplanar PAHs. The combination of rhodaelectrooxidative C?H activation/[2+2+2] alkyne annulation of easily accessible boronic acids with electrocatalytic cyclodehydrogenation provided modular access to diversely substituted PAHs with electricity as a sustainable oxidant. The unique molecular topology as well as the photophysical and electronic properties of the thus obtained PAHs were fully analyzed. The unique power of this metallaelectrocatalysis method was demonstrated by the chemoselective assembly of synthetically useful iodo‐substituted PAHs.     

Catalytic Behavior of Mono‐N‐Protected Amino‐Acid Ligands in Ligand‐Accelerated C−H Activation by Palladium(II)

Mono‐N‐protected amino acids (MPAAs) are increasingly common ligands in Pd‐catalyzed C?H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C?H activation step. Here, it is shown that MPAA ligands exhibit a second property commonly associated with ligand‐accelerated catalysis: the ability to support catalytic turnover at substoichiometric ligand‐to‐metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C?H activation and catalytic C?H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50–100‐fold increase in rate when only 0.05 equivalents of MPAA are present relative to Pd^II. These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to Pd^II enables a single MPAA to support C?H activation at multiple Pd^II centers.     

Asymmetric Donor–π‐Acceptor‐Type Benzo‐Fused Aza‐BODIPYs: Facile Synthesis and Colorimetric Properties

Novel aza‐diisoindolylmethene and their BF₂‐chelating complexes (benzo‐fused aza‐BODIPYs) were synthesized on a large scale and in a facile manner from phthalonitrile in tBuOK‐DMF solution. The unique asymmetric donor–π‐acceptor structure facilitates B? N bond detachment in the presence of trifluoroacetic acid (TFA) in dichloromethane, resulting in sharp color change from red to colorless, with over 250 nm hypsochromic shift in the absorption maximum. This colorimetric process can be reversed by adding a very small amount of proton‐accepting solvents or compounds. A ¹H and ¹¹B NMR spectroscopy study and also density functional theory (DFT) calculations suggest that TFA‐induced B? N bond cleavage may disrupt the whole π‐conjugation of the BODIPY molecule, resulting in significant colorimetric behavior.     

Copper‐Catalyzed Domino Synthesis of 2‐Imino‐1H‐imidazol‐5(2H)‐ones and Quinoxalines Involving CC Bond Cleavage with a 1,3‐Dicarbonyl Unit as a Leaving Group

Although 2‐imino‐1H‐imidazol‐5(2H)‐ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as “privileged scaffolds” in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper‐catalyzed domino reactions for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones and quinoxalines involving C?C bond‐cleavage with a 1,3‐dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones includes aza‐Michael addition, intramolecular cyclization, C?C bond‐cleavage, 1,2‐rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza‐Michael addition, intramolecular cyclization, elimination reaction, and C?C bond‐cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.     

Late‐Stage Peptide Diversification through Cobalt‐Catalyzed C−H Activation: Sequential Multicatalysis for Stapled Peptides

Bioorthogonal late‐stage diversification of structurally complex peptides has enormous potential for drug discovery and molecular imaging. In recent years, transition‐metal‐catalyzed C?H activation has emerged as an increasingly viable tool for peptide modification. Despite major accomplishments, these strategies largely rely on expensive palladium catalysts. We herein report an unprecedented cobalt(III)‐catalyzed peptide C?H activation, which enables the direct C?H functionalization of structurally complex peptides, and sets the stage for a multicatalytic C?H activation/alkene metathesis/hydrogenation strategy for the assembly of novel cyclic peptides.     

A syn‐Selective Aza‐Aldol Reaction of Boron Aza‐Enolates Generated from N‐Sulfonyl‐1,2,3‐Triazoles and 9‐BBN‐H

A syn‐selective aza‐aldol reaction of boron aza‐enolates, generated from N‐sulfonyl‐1,2,3‐triazoles and 9‐BBN‐H, is reported. It provides a sequential one‐pot procedure for the stereoselective construction of 1,3‐amino alcohols, having contiguous stereocenters, starting from terminal alkynes.     

Total Synthesis of (−)‐Salinosporamide A via a Late Stage C−H Insertion

The synthesis of (?)‐salinosporamide A, a proteasome inhibitor, is described. The synthesis highlights the assembly of a densely decorated pyrrolidinone core via an aza‐Payne/hydroamination sequence. Central to the success of the synthesis is a late‐stage C?H insertion reaction to functionalize a sterically encumbered secondary carbon. The latter functionalization leads to an enabling transformation where most of the prototypical strategies failed.     

Mechanistic Study on Ligand‐Controlled Cobalt‐Catalyzed Regioselectivity‐Switchable Hydroarylation of Styrenes

Density functional theory (DFT) calculations have been performed to study the mechanism of the recently reported Co‐catalyzed ligand‐controlled hydroarylation of styrenes as a means of preparing 1,1‐ or 1,2‐diarylalkanes. The present study corroborates the previously proposed three‐step mechanism, comprising C? H activation (C? H oxidative addition), styrene insertion, and reductive elimination. In the C? H activation and reductive elimination steps, our calculations suggest that styrene does not coordinate to the Co center. In the insertion step, styrene is inserted into the Co? H bond rather than the Co? C bond. Furthermore, the rate‐ and regiodetermining step is found to be C? C reductive elimination. It is significant that the regioselectivity observed experimentally has been successfully reproduced by our calculations. More importantly, in analyzing the origin of the ligand‐controlled regioselectivity, we have found that the steric effects of different ligands mainly determine the observed regioselectivity. Both the shape (i.e., “umbrella‐up” or “umbrella‐down”) and bulkiness of the ligand contribute to the steric effect.     

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.