Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Electrochemical Enantioselective C-H Annulation by Achiral Rhodium(III)/Chiral Brønsted Base Domino Catalysis.

Rhodium(III)-catalyzed enantioselective C-H activation has emerged as a powerful tool for assembling enabling chiral molecules. However, this approach is significantly hampered by the cumbersome synthetic routes for preparing chiral rhodium catalysts. In sharp contrast, we herein report on an electrochemical domino catalysis system that exploits an achiral Cp*-rhodium catalyst along with an easily accessible chiral Brønsted base for an enantioselective C-H activation/annulation reaction of alkenes by benzoic acids. Our strategy offers an environmentally benign and most user-friendly approach for assembling synthetically useful chiral phthalides in good enantioselectivity, employing electricity as the sustainable oxidant.

Direct Synthesis of C4-Acyl Indoles via C-H Acylation.

The direct synthesis of C4-acyl indoles deprived of C2 and C3 substituents has proven to be challenging, with scarce efficient synthetic routes being reported. Herein, we disclose a highly site-selective palladium-catalyzed C-H acylation for the construction of C4-acyl indoles via a Catellani-Lautens cyclization strategy. In addition, we systematically studied the ortho C-H acylation mechanism of iodoaniline through density functional theory (DFT) calculations and combined experimental results to elucidate the principle of high chemoselectivity brought by triazine benzoate as an acylation reagent.

Iron-catalyzed stereoselective C-H alkylation for simultaneous construction of C-N axial and C-central chirality.

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C-H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C-N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity.

Palladium-Catalyzed Electrooxidative Double C-H Arylation.

The electrochemical transition metal-catalyzed cross-dehydrogenative reaction has emerged as a promising platform to achieve a sustainable and atom-economic organic synthesis that avoids hazardous oxidants and minimizes undesired byproducts and circuitous functional group operations. However, a poor mechanistic understanding still prevents the widespread adoption of this strategy. In this regard, we herein present an electrochemical palladium-catalyzed oxidative coupling strategy to access biaryls in the absence of a stoichiometric chemical oxidant. The robust palladaelectrocatalysis considerably suppresses the occurrence of homocoupling and oxygenation, being compatible even with electron-deficient arenes. Late-stage functionalization and Boscalid precursor synthesis further highlighted the practical importance of our electrolysis. Remarkably, mechanistic studies including the evaluation of the reaction order of each component by variable time normalization analysis (VTNA) and initial rate analysis, H/D exchange experiment, kinetic isotope effect, and stoichiometric organometallic experiments provided strong support for the involvement of transmetalation between two organopalladium complexes in the turnover limiting step. Therefore, matching the concentrations or lifetimes of two distinct organopalladium intermediates is revealed to be a pivot to the success of electrooxidative catalysis. Moreover, the presence of cationic copper(II) seems to contribute to the stabilization of the palladium(0) catalyst instead of playing a role in the oxidation of the catalyst.

Template Synthesis to Solve the Unreachable Ortho C-H Functionalization Reaction of Aryl Iodide.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho-site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Data-driven design of new chiral carboxylic acid for construction of indoles with C-central and C-N axial chirality via cobalt catalysis.

Challenging enantio- and diastereoselective cobalt-catalyzed C-H alkylation has been realized by an innovative data-driven knowledge transfer strategy. Harnessing the statistics of a related transformation as the knowledge source, the designed machine learning (ML) model took advantage of delta learning and enabled accurate and extrapolative enantioselectivity predictions. Powered by the knowledge transfer model, the virtual screening of a broad scope of 360 chiral carboxylic acids led to the discovery of a new catalyst featuring an intriguing furyl moiety. Further experiments verified that the predicted chiral carboxylic acid can achieve excellent stereochemical control for the target C-H alkylation, which supported the expedient synthesis for a large library of substituted indoles with C-central and C-N axial chirality. The reported machine learning approach provides a powerful data engine to accelerate the discovery of molecular catalysis by harnessing the hidden value of the available structure-performance statistics.

Cobalt-catalyzed radical-mediated carbon-carbon scission via a radical-type migratory insertion.

Migratory insertions of alkenes into metal-carbon (M-C) bonds are elementary steps in diverse catalytic processes. In the present work, a radical-type migratory insertion that involves concerted but asynchronous M-C homolysis and radical attack was revealed by computations. Inspired by the radical nature of the proposed migratory insertion, a distinct cobalt-catalyzed radical-mediated carbon-carbon (C-C) cleavage mechanism was proposed for alkylidenecyclopropanes (ACPs). This unique C-C activation is key to rationalizing the experimentally observed selectivity for the coupling between benzamides and ACPs. Furthermore, the C(sp2)-H activation in the coupling reaction occurs via the proton-coupled electron transfer (PCET) mechanism rather than the originally proposed concerted metalation-deprotonation (CMD) pathway. The ring opening strategy may stimulate further development and discovery of novel radical transformations.

Bridging Chemical Knowledge and Machine Learning for Performance Prediction of Organic Synthesis.

Recent years have witnessed a boom of machine learning (ML) applications in chemistry, which reveals the potential of data-driven prediction of synthesis performance. Digitalization and ML modelling are the key strategies to fully exploit the unique potential within the synergistic interplay between experimental data and the robust prediction of performance and selectivity. A series of exciting studies have demonstrated the importance of chemical knowledge implementation in ML, which improves the model's capability for making predictions that are challenging and often go beyond the abilities of human beings. This Minireview summarizes the cutting-edge embedding techniques and model designs in synthetic performance prediction, elaborating how chemical knowledge can be incorporated into machine learning until June 2022. By merging organic synthesis tactics and chemical informatics, we hope this Review can provide a guide map and intrigue chemists to revisit the digitalization and computerization of organic chemistry principles.

Ruthenium(II)/Imidazolidine Carboxylic Acid-Catalyzed C-H Alkylation for Central and Axial Double Enantio-Induction.

Enantioselective C-H activation has surfaced as a transformative toolbox for the efficient assembly of chiral molecules. However, despite of major advances in rhodium and palladium catalysis, ruthenium(II)-catalyzed enantioselective C-H activation has thus far largely proven elusive. In contrast, we herein report on a ruthenium(II)-catalyzed highly regio-, diastereo- and enantioselective C-H alkylation. The key to success was represented by the identification of novel C2-symmetric chiral imidazolidine carboxylic acids (CICAs), which are easily accessible in a one-pot fashion, as highly effective chiral ligands. This ruthenium/CICA system enabled the efficient installation of central and axial chirality, and featured excellent branched to linear ratios with generally >20 : 1 dr and up to 98 : 2 er. Mechanistic studies by experiment and computation were carried out to understand the catalyst mode of action.

Cobalt-Catalyzed Enantioselective C-H Arylation of Indoles.

Atropoisomeric (hetero)biaryls are scaffolds with increasing importance in the pharmaceutical and agrochemical industries. Although it is the most obvious disconnection to construct such compounds, the direct enantioselective C-H arylation through the concomitant induction of the chiral information remains extremely challenging and uncommon. Herein, the unprecedented earth-abundant 3d-metal-catalyzed atroposelective direct arylation is reported, furnishing rare atropoisomeric C2-arylated indoles. Kinetic studies and DFT computation revealed an uncommon mechanism for this asymmetric transformation, with the oxidative addition being the rate- and enantio-determining step. Excellent stereoselectivities were reached (up to 96% ee), while using an unusual N-heterocyclic carbene ligand bearing an essential remote substituent. Attractive dispersion interactions along with positive C-H---π interactions exerted by the ligand were identified as key factors to guarantee the excellent enantioselection.

Enantioselective palladaelectro-catalyzed C-H olefinations and allylations for N-C axial chirality.

Enantioselective palladaelectro-catalyzed C-H alkenylations and allylations were achieved with easily-accessible amino acids as transient directing groups. This strategy provided access to highly enantiomerically-enriched N-C axially chiral scaffolds under exceedingly mild conditions. The synthetic utility of our strategy was demonstrated by a variety of alkenes, while the versatility of our approach was reflected by atroposelective C-H allylations. Computational studies provided insights into a facile C-H activation by a seven-membered palladacycle.

Rhodaelectro-catalyzed access to chromones via formyl C-H activation towards peptide electro-labeling.

Chromones represent a privileged scaffold in medicinal chemistry and are an omnipresent structural motif in natural products. Chemically encoded non-natural peptidomimetics feature improved stability towards enzymatic degradation, cell permeability and binding affinity, translating into a considerable impact on pharmaceutical industry. Herein, a strategy for the sustainable assembly of chromones via electro-formyl C-H activation is presented. The rational design of the rhodaelectro-catalysis is guided by detailed mechanistic insights and provides versatile access to tyrosine-based fluorogenic peptidomimetics.

Electro-oxidative Intermolecular Allylic C(sp3)-H Aminations.

The oxidative intermolecular nitrogenation of C(sp3)-H bonds represents one of the most straightforward strategies to construct nitrogen-containing molecules. However, a sacrificial chemical oxidant is generally required. Herein, we describe electrochemical oxidative intermolecular allylic C(sp3)-H aminations in an undivided cell by electric current. The cross-dehydrogenative amination proceeded efficiently with ample scope under metal- and chemical oxidant-free reaction conditions, giving molecular H2 as the only byproduct.

Rhoda-Electrocatalyzed Bimetallic C-H Oxygenation by Weak O-Coordination.

Rhodium-electrocatalyzed arene C-H oxygenation by weakly O-coordinating amides and ketones have been established by bimetallic electrocatalysis. Likewise, diverse dihydrooxazinones were selectively accessed by the judicious choice of current, enabling twofold C-H functionalization. Detailed mechanistic studies by experiment, mass spectroscopy and cyclovoltammetric analysis provided support for an unprecedented electrooxidation-induced C-H activation by a bimetallic rhodium catalysis manifold.

Enantioselective Ruthenium-Catalyzed C-H Alkylations by a Chiral Carboxylic Acid with Attractive Dispersive Interactions.

Asymmetric ruthenium-catalyzed C-H alkylations were enabled by a chiral C2-symmetric carboxylic acid. The mild cooperative ruthenium(II) catalysis set the stage for the assembly of chiral tetrahydrocarbazoles and cyclohepta[b]indoles with high levels of enantioselectivity at room temperature. Mechanistic studies by experiment and computation identified a fast C-H ruthenation, along with a rate- and enantio-determining proto-demetalation. The asymmetric induction was governed by weak attractive secondary dispersion interactions as found in NCI analysis of the key transition states.

Electrooxidative Rhodium-Catalyzed [5+2] Annulations via C-H/O-H Activations.

Electrooxidative annulations involving mild transition metal-catalyzed C-H activation have emerged as a transformative strategy for the rapid construction of five- and six-membered heterocycles. In contrast, we herein describe the first electrochemical metal-catalyzed [5+2] cycloadditions to assemble valuable seven-membered benzoxepine skeletons by C-H/O-H activation. The efficient alkyne annulation featured ample substrate scope, using electricity as the only oxidant. Mechanistic studies provided strong support for a rhodium(III/I) regime, involving a benzoxepine-coordinated rhodium(I) sandwich complex as the catalyst resting state, which was re-oxidized to rhodium(III) by anodic oxidation.

Enantioselective Pallada-Electrocatalyzed C-H Activation by Transient Directing Groups: Expedient Access to Helicenes.

Asymmetric pallada-electrocatalyzed C-H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C-H activations were realized with high position-, diastereo-, and enantio-control under mild reaction conditions to obtain highly enantiomerically-enriched biaryls and fluorinated N-C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.

Electroreductive Cobalt-Catalyzed Carboxylation: Cross-Electrophile Electrocoupling with Atmospheric CO2.

The chemical use of CO2 as an inexpensive, nontoxic C1 synthon is of utmost topical interest in the context of carbon capture and utilization (CCU). We present the merger of cobalt catalysis and electrochemical synthesis for mild catalytic carboxylations of allylic chlorides with CO2 . Styrylacetic acid derivatives were obtained with moderate to good yields and good functional group tolerance. The thus-obtained products are useful as versatile synthons of γ-arylbutyrolactones. Cyclic voltammetry and in operando kinetic analysis were performed to provide mechanistic insights into the electrocatalytic carboxylation with CO2 .

Insights into Cobalta(III/IV/II)-Electrocatalysis: Oxidation-Induced Reductive Elimination for Twofold C-H Activation.

The merger of cobalt-catalyzed C-H activation and electrosynthesis provides new avenues for resource-economical molecular syntheses, unfortunately their reaction mechanisms remain poorly understood. Herein, we report the identification and full characterization of electrochemically generated high-valent cobalt(III/IV) complexes as crucial intermediates in electrochemical cobalt-catalyzed C-H oxygenations. Detailed mechanistic studies provided support for an oxidatively-induced reductive elimination via highly-reactive cobalt(IV) intermediates. These key insights set the stage for unprecedented cobaltaelectro two-fold C-H/C-H activation.