Deacylative transformations of ketones via aromatization-promoted C-C bond activation.

Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded our toolbox for organic synthesis1. By contrast, C-C activation methods that enable editing of the molecular skeleton remain limited2-7. Several methods have been proposed for catalytic C-C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force4,6 or directing groups5,7 to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes5. Here we report a general C-C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.

Mechanistic Investigation into Single-Electron Oxidative Addition of Single-Atom Cu(I)-N4 Site: Revealing the Cu(I)-Cu(II)-Cu(I) Catalytic Cycle in Photochemical Hydrophosphinylation.

Understanding the valency and structural variations of metal centers during reactions is important for mechanistic studies of single-atom catalysis, which could be beneficial for optimizing reactions and designing new protocols. Herein, we precisely developed a single-atom Cu(I)-N4 site catalyst via a photoinduced ligand exchange (PILE) strategy. The low-valent and electron-rich copper species could catalyze hydrophosphinylation via a novel single-electron oxidative addition (OA) pathway under light irradiation, which could considerably decrease the energy barrier compared with the well-known hydrogen atom transfer (HAT) and single electron transfer (SET) processes. The Cu(I)-Cu(II)-Cu(I) catalytic cycle, via single-electron oxidative addition and photoreduction, has been proven by multiple in situ or operando techniques. This catalytic system demonstrates high efficiency and requires room temperature conditions and no additives, which improves the turnover frequency (TOF) to 1507 h-1. In particular, this unique mechanism has broken through the substrate limitation and shows a broad scope for different electronic effects of alkenes and alkynes.

Prediction of flood sensitivity based on Logistic Regression, eXtreme Gradient Boosting, and Random Forest modeling methods.

Floods are one of the most destructive disasters that cause loss of life and property worldwide every year. In this study, the aim was to find the best-performing model in flood sensitivity assessment and analyze key characteristic factors, the spatial pattern of flood sensitivity was evaluated using three machine learning (ML) models: Logistic Regression (LR), eXtreme Gradient Boosting (XGBoost), and Random Forest (RF). Suqian City in Jiangsu Province was selected as the study area, and a random sample dataset of historical flood points was constructed. Fifteen different meteorological, hydrological, and geographical spatial variables were considered in the flood sensitivity assessment, 12 variables were selected based on the multi-collinearity study. Among the results of comparing the selected ML models, the RF method had the highest AUC value, accuracy, and comprehensive evaluation effect, and is a reliable and effective flood risk assessment model. As the main output of this study, the flood sensitivity map is divided into five categories, ranging from very low to very high sensitivity. Using the RF model (i.e., the highest accuracy of the model), the high-risk area covers about 44% of the study area, mainly concentrated in the central, eastern, and southern parts of the old city area.

Diborodichloromethane as Versatile Reagent for Chemodivergent Synthesis of gem-Diborylalkanes.

The development of boron reagents is crucial for synthetic chemistry. Herein, we present a scalable and practical synthesis of diborodichloromethane (DBDCM) through the reaction of trichloromethyllithium with bis(pinacolato)diboron (B2 pin2 ). The resulting DBDCM reagent serves as a basic synthetic unit for the construction of various structurally diverse gem-diborylalkanes through controllable C-Cl functionalizations. Moreover, we have developed consecutive tetra-functionalizations of DBDCM for the construction of diverse tertiary and quaternary carbon containing molecules. The use of isotopically enriched 13 C-chloroform and 10 B2 pin2 enables the synthesis of isotopically enriched 13 C-DBDCM and 10 B-DBDCM reagents, which are beneficial for the convenient synthesis of carbon-13 and boron-10 molecules.

Unraveling the Structure and Reactivity Patterns of the Indole Radical Cation in Regioselective Electrochemical Oxidative Annulations.

Oxidation-induced strategy for inert chemical bond activation through highly active radical cation intermediate has exhibited unique reactivity. Understanding the structure and reactivity patterns of radical cation intermediates is crucial in the mechanistic study and will be beneficial for developing new reactions. In this work, the structure and properties of indole radical cations have been revealed using time-resolved transient absorption spectroscopy, in situ electrochemical UV-vis, and in situ electrochemical electron paramagnetic resonance (EPR) technique. Density functional theory (DFT) calculations were used to explain and predict the regioselectivity of several electrochemical oxidative indole annulations. Based on the understanding of the inherent properties of several indole radical cations, two different regioselective annulations of indoles have been successfully developed under electrochemical oxidation conditions. Varieties of furo[2,3-b]indolines and furo[3,2-b]indolines were synthesized in good yields with high regioselectivities. Our mechanistic insights into indole radical cations will promote the further development of oxidation-induced indole functionalizations.

Electrooxidative Activation of B-B Bond in B2 cat2 : Access to gem-Diborylalkanes via Paired Electrolysis.

This report describes the unprecedented electrooxidation of a solvent (e.g., DMF)-ligated B2 cat2 complex, whereby a solvent-stabilized boryl radical is formed via quasi-homolytic cleavage of the B-B bond in a DMF-ligated B2 cat2 radical cation. Cyclic voltammetry and density functional theory provide evidence to support this novel B-B bond activation strategy. Furthermore, a strategy for the electrochemical gem-diborylation of gem-bromides via paired electrolysis is developed for the first time, affording a range of versatile gem-diborylalkanes, which are widely used in synthetic society. Notably, this reaction approach is scalable, transition-metal-free, and requires no external activator.

Triflylpyridinium Enables Rapid and Scalable Controlled Reduction of Carboxylic Acids to Aldehydes using Pinacolborane.

Building up new and efficient methods for the controlled conversion of carboxylic acids to aldehydes is important. Herein, we report a rapid, modular and scalable method for the conversion of carboxylic acids to aldehydes using pinacolborane at ambient temperature, in which a triflylpyridinium reagent is used. The conversion of carboxylic acid to intermediate acylpyridinium by triflylpyridinium is new. A binary pyridine-coordinated boronium complex is generated after reduction. The unprecedented reduction of the acylpyridinium by HBpin opens up a practically direct synthesis of aldehydes from carboxylic acids. Theoretical studies indicate that the reduction of acylpyridinium requires a lower activation free energy than that of the product aldehyde. The synthetic advantage of this protocol is further highlighted by the scalable synthesis of aldehyde via continuous flow process. Configuration retention for chiral acids are presented in those syntheses.

Palladium/Norbornene-Catalyzed Direct Vicinal Di-Carbo-Functionalization of Indoles: Reaction Development and Mechanistic Study.

Methods that can simultaneously install multiple different functional groups to heteroarenes via C-H functionalizations are valuable for complex molecule synthesis, which, however, remain challenging to realize. Here we report the development of vicinal di-carbo-functionalization of indoles in a site- and regioselective manner, enabled by the palladium/norbornene (Pd/NBE) cooperative catalysis. The reaction is initiated by the Pd(II)-mediated C3-metalation and specifically promoted by the C1-substituted NBEs. The mild, scalable, and robust reaction conditions allow for a good substrate scope and excellent functional group tolerance. The resulting C2-arylated C3-alkenylated indoles can be converted to diverse synthetically useful scaffolds. The combined experimental and computational mechanistic study reveals the unique role of the C1-substituted NBE in accelerating the turnover-limiting oxidative addition step.

Electroreduction Enables Regioselective 1,2-Diarylation of Alkenes with Two Electrophiles.

Precisely introducing two similar functional groups into bulk chemical alkenes represents a formidable route to complex molecules. Especially, the selective activation of two electrophiles is in crucial demand, yet challenging for cross-electrophile-coupling. Herein, we demonstrate a redox-mediated electrolysis, in which aryl nitriles are both aryl radical precursors and redox-mediators, enables an intermolecular alkene 1,2-diarylation with a remarkable regioselectivity, thereby avoiding the involvement of transition-metal catalysts. This transformation utilizes cyanoarene radical anions for activating various aryl halides (including iodides, bromides, and even chlorides) and affords 1,2-diarylation adducts in up to 83 % yield and >20 : 1 regioselectivity with more than 80 examples, providing a feasible approach to complex bibenzyl derivatives.

Iridium-Catalyzed Intramolecular ß-C-H Alkenylation of Ketones with Alkynes via a Hydride-Transfer Approach.

Direct functionalization of carbonyl ß C-H bonds without using directing groups has not been a trivial task, and it is even more challenging to realize the corresponding atom-economical transformations with common alkenes or alkynes as the coupling partner. Here, we describe the development of an iridium-catalyzed intramolecular direct ß-alkenylation of ketones with regular alkynes. The reaction is redox neutral, avoids strong acids or bases, and tolerates various functional groups. The combined experimental and computational mechanistic studies reveal a hydride-transfer pathway, involving ketone α,ß-desaturation, iridium-hydride-mediated alkyne insertion, conjugate addition, and α-protonation.

Epoxide Electroreduction.

Selective hydrogenation of epoxides would be a direct and powerful approach for alcohol synthesis, but it has proven to be elusive. Here, electrochemically epoxide hydrogenation using electrons and protons as reductants is reported. A wide range of primary, secondary, and tertiary alcohols can be achieved through selective Markovnikov or anti-Markovnikov ring opening in the absence of transition metals. Mechanistic investigations revealed that the regioselectivity is controlled by the thermodynamic stabilities of the in situ generated benzyl radicals for aryl-substituted epoxides and the kinetic tendency for Markovnikov selective ring opening for alkyl-substituted epoxides.

Switchable Radical Carbonylation by Philicity Regulation.

Carbonylation reactions involving CO as readily available C1 synthons have become one of the most important tools for the construction of carbonyl compounds from feedstock chemicals. Despite numerous catalytic methods for carbonylation reactions proceeding via ionic or radical pathways, an inherent limitation to these methods is the need to control switchable single and double carbonylative formation of value-added products from the same and simple starting materials. Here, we describe a new strategy that exploits photoredox catalysis to regulate the philicity of amine coupling partners to drive switchable radical carbonylation reactions. In double carbonylation, amines were first transformed into nitrogen radical cations by single-electron transfer-oxidation and coupled with CO to form carbamoyl radicals, which further underwent radical cross-coupling with the incipient cyanoalkyl acyl radicals to afford the double carbonylation products. Upon the addition of stoichiometric 4-dimethylaminopyridine (DMAP), DMAP competitively traps the initially formed cyanoalkyl acyl radical to form the relatively stabilized cyanoalkyl acyl-DMAP salts that engaged in the subsequent substitution with the nucleophilic amines to produce the single carbonylation products. The reaction proceeded smoothly with excellent selectivity in the presence of various amine nucleophiles at room temperature, generating valuable amides and α-ketoamides in a versatile and controlled fashion. Combined experimental and computational studies provided mechanistic insights into the possible pathways.

Remote Enantioselective [4 + 1] Annulation with Copper-Vinylvinylidene Intermediates.

The first copper-catalyzed enantioselective [4 + 1] annulation of yne-allylic esters with 1,3-dicarbonyl compounds was realized through an elegant remote stereocontrol strategy. The very remote ε regioselective nucleophilic substitution was developed by employing a novel chiral copper-vinylvinylidene species from the new C4 synthon yne-allylic esters. Thus, greatly diverse spirocycles were obtained with ample scope and excellent levels of chemo-, regio-, and enantioselectivities. Moreover, detailed mechanistic studies suggest an yne-allylic substitution and Conia-ene cascade pathway on the remote stereochemical induction progress.

Catalytic Asymmetric Vinylogous and Bisvinylogous Propargylic Substitution.

Distinct regio- and enantioselectivity control in copper-catalyzed vinylogous and bisvinylogous propargylic substitution has been accomplished by using a novel chiral N,N,P ligand. The developed method provides an efficient and selective approach to an array of highly enantioenriched alkynyl unsaturated carbonyl compounds. Salient features include excellent functional group tolerance and broad substrate scope. The synthetic utility of the developed method is further demonstrated by a gram-scale synthesis and by application to a range of transformations including enantioselective synthesis of unique challenging compounds.

Chemical Recycling of Polystyrene to Valuable Chemicals via Selective Acid-Catalyzed Aerobic Oxidation under Visible Light.

Chemical recycling is one of the most promising technologies that could contribute to circular economy targets by providing solutions to plastic waste; however, it is still at an early stage of development. In this work, we describe the first light-driven, acid-catalyzed protocol for chemical recycling of polystyrene waste to valuable chemicals under 1 bar of O2. Requiring no photosensitizers and only mild reaction conditions, the protocol is operationally simple and has also been demonstrated in a flow system. Electron paramagnetic resonance (EPR) investigations and density functional theory (DFT) calculations indicate that singlet oxygen is involved as the reactive oxygen species in this degradation process, which abstracts a hydrogen atom from a tertiary C-H bond, leading to hydroperoxidation and subsequent C-C bond cracking events via a radical process. Notably, our study indicates that an adduct of polystyrene and an acid catalyst might be formed in situ, which could act as a photosensitizer to initiate the formation of singlet oxygen. In addition, the oxidized polystyrene polymer may play a role in the production of singlet oxygen under light.

Recent Advances in Theoretical Studies on Transition-Metal-Catalyzed Carbene Transformations.

Metal carbene plays a vital role in modern organic synthesis. The neutral divalent carbon of metal carbene renders it an active intermediate throughout a range of reactions. In experiments, diverse metal carbene-related transformation reactions have been established, including transition-metal-catalyzed cross-coupling reactions using N-heterocyclic carbenes as ligands, metal carbene insertion into σ bonds, cyclopropanations, ylide formation, and so forth. The remarkable progress achieved in synthetic chemistry, in turn, has increased the demand for mechanistic studies of carbene chemistry. A thorough understanding of reaction mechanisms can extend the application scope of metal carbene compounds and inspire the rational design of new carbene transformation reactions.Density functional theory (DFT) calculations have been performed in our group to gain more mechanistic insights into metal carbene-related reactions. This account focuses on computational studies of transition-metal-catalyzed carbene transformation reactions with nucleophiles. The generation of metal carbene or metal-ligated free carbene and subsequent carbene transformation pathways is discussed. According to our mechanistic studies of carbene transformation with nucleophiles, three generalized reaction models are summarized, including the intramolecular migratory insertion of metal carbene, intermolecular nucleophilic addition toward metal carbene, and outer-sphere nucleophilic addition to the metal-ligated free carbene.In general, the intermolecular nucleophilic addition mechanism is commonly proposed since metal carbene has an electrophilic carbene carbon. From a mechanistic point of view, the intramolecular migratory insertion mechanism is also widely used because metal carbene insertion into σ bonds formally occurs through this mechanism. An outer-sphere nucleophilic addition mechanism is proposed for reactions that form a metal-ligated free carbene complex instead of the commonly proposed metal carbene. The metal-ligated free carbene complex contains a naked carbene carbon that is not coordinated with the metal center. In this case, a transition-metal catalyst is used only as a Lewis acid, and nucleophilic addition occurs directly at the free carbene carbon. Our computational results suggested that outer-sphere nucleophilic addition is a facile step because metal ligation could stabilize the transition state as well as the generated intermediate. The intramolecular migratory insertion mechanism also has a low energy barrier due to the lack of an entropy penalty. Carbene formation from carbene precursors is usually the rate-determining step, except in intermolecular nucleophilic addition, and the reactivity of nucleophiles has a significant influence on the overall reaction rate. We can also envision that the weak nucleophilicity of nucleophiles would suppress outer-sphere nucleophilic addition. These computational studies showcase the characteristics of three carbene transformation models, and we hope that it will spur the development of mechanistic studies of carbene chemistry.

ProPhenol Derived Ligands to Simultaneously Coordinate a Main-Group Metal and a Transition Metal: Application to a Zn-Cu Catalyzed Reaction.

A new bifunctional ligand bearing chiral N-heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero-bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto-homoenolates, leading to the formation of various γ-vinyl ketones with good regio- and enantio-selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN 2' addition and the ligand-substrate steric interactions account for the stereoselective outcome.

Diastereoselective Transfer of Tri(di)fluoroacetylsilanes-Derived Carbenes to Alkenes.

Stereoselective cyclopropanation reaction of alkenes is usually achieved by metal complexes via singlet-metal-carbene intermediates. However, previous transition-metal-catalyzed cyclopropanation of alkenes with acylsilanes afforded low diastereoselectivity. Herein, we report the first visible-light-induced transition-metal-free cyclopropanation reaction of terminal alkenes with trifluoroacetylsilanes and difluoroacetylsilanes. Both aromatic and aliphatic alkenes as well as electron-deficient alkenes are suitable substrates for the highly cis-selective [2+1] cyclization reaction. A combination of experimental and computational studies identified triplet carbenes as being key intermediates in this transformation. The gram scale reaction and late-stage functionalization demonstrated the synthetic potential of this strategy.

From Esters to Ketones via a Photoredox-Assisted Reductive Acyl Cross-Coupling Strategy.

A method was developed for ketone synthesis via a photoredox-assisted reductive acyl cross-coupling (PARAC) using a nickel/photoredox dual-catalyzed cross-electrophile coupling of two different carboxylic acid esters. A variety of aryl, 1°, 2°, 3°-alkyl 2-pyridyl esters can act as acyl electrophiles while N-(acyloxy)phthalimides (NHPI esters) act as 1°, 2°, 3°-radical precursors. Our PARAC strategy provides an alternative and reliable way to synthesize various sterically congested 3°-3°, 3°-2°, and aryl-3° ketones under mild and highly unified conditions, which have been otherwise difficult to access. The combined experimental and computational studies identified a Ni0 /NiI /NiIII pathway for ketone formation.

Photoinduced Copper-Catalyzed Asymmetric C(sp3 )-H Alkynylation of Cyclic Amines by Intramolecular 1,5-Hydrogen Atom Transfer.

The development of a mild and general method for C(sp3 )-H functionalization of cyclic amines has been an ongoing challenge. In this work, we describe the copper-catalyzed enantioselective C(sp3 )-H alkynylation of unactivated cyclic 2-iodo-benzamide under photo-irradiation by intramolecular 1,5-hydrogen atom transfer (HAT). The employment of a new bisoxazoline diphenylamine ligand, in conjunction with 1,1'-bi-2-naphthol, which significantly improved the reduction potential of the copper complex, was the key to success of this chemistry. Mechanistic and computational studies supported that the new copper complex served the dual role as a photoredox and coupling catalyst, the reaction went through a radical process, and the intramolecular 1,5-HAT process was involved in the rate-limiting step. Apart from the broad substrate scope including unprecedented benzocyclic amines, this method also showed excellent diastereoselectivity in 2-monosubstituted cyclic amines via substrate control.