Silver-Catalyzed Dearomative Skeletal Editing of Indazoles by Donor Carbene Insertion.

Given the prevalence of heterocyclic scaffolds in drug-related molecules, converting these highly modular heterocyclic scaffolds into structural diversified and dearomatized analogs is an ideal strategy for improving their physicochemical and pharmacokinetic properties. Here, we described an efficient method for silver carbene-mediated dearomative N-N bond cleavage leading to skeletal hopping between indazole and 1,2-dihydroquinazoline via a highly selective single-carbon insertion procedure. Using this methodology, a series of dihydroquinazoline analogues with diarylmethylene-substituted quaternary carbon centers were constructed with excellent yields and good functional group compatibility, which was further illustrated by the late-stage diversification of important pharmaceutically active ingredients. DFT calculations indicated that the silver catalyst not only induces the formation of the silver carbene, but also activates the diazahexatriene intermediate, which plays a crucial role in the formation of the C-N bond.

Rhodium-Catalyzed One-Carbon Ring Expansion of Aziridines with Vinyl-N-triftosylhydrazones for the Synthesis of 2-Vinyl Azetidines.

Azetidines, being four-membered N-heterocycles, possess significant potential in contemporary medicinal chemistry owing to their favorable pharmacokinetic properties. Regrettably, the incorporation of functionalized azetidines into pharmaceutical lead structures has been impeded by the absence of efficient synthetic methods for their synthesis. In this study, a Rh-catalyzed one-carbon ring expansion of aziridines with vinyl-N-triftosylhydrazones is presented, which facilitates the synthesis of high value-added 2-alkenyl azetidine products. This research represents the first example of ring expansion of aziridines enabled by vinyl carbenes. Additionally, a one-pot two-step protocol, initiated from cinnamaldehyde, was successfully achieved, offering a step-economical and facile approach for the synthesis of these compounds. The pivotal aspect of this successful transformation lies in the in situ formation of an alkenyl aziridinium ylide intermediate. Experimental investigations, coupled with computational studies, suggest that a diradical pathway is involved in the reaction mechanism.

Controllable Skeletal and Peripheral Editing of Pyrroles with Vinylcarbenes.

The skeletal editing of azaarenes through insertion, deletion, or swapping of single atoms has recently gained considerable momentum in chemical synthesis. Here, we describe a practical skeletal editing strategy using vinylcarbenes in situ generated from trifluoromethyl vinyl N-triftosylhydrazones, leading to the first dearomative skeletal editing of pyrroles through carbon-atom insertion. Furthermore, depending on the used catalyst and substrate, three types of peripheral editing reactions of pyrroles are also disclosed: α- or γ-selective C-H insertion, and [3+2] cycloaddition. These controllable molecular editing reactions provide a powerful platform for accessing medicinally relevant CF3-containing N-heterocyclic frameworks, such as 2,5-dihydropyridines, piperidines, azabicyclo[3.3.0]octadienes, and allylated pyrroles from readily available pyrroles. Mechanistic insights from experiments and density functional theory (DFT) calculations shed light on the origin of substrate- or catalyst-controlled chemo- and regioselectivity as well as the reaction mechanism.

Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center.

The skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable because of their broad applications in medicinal chemistry. Herein, we report a general strategy for the dearomative one-carbon insertion of azoles using fluoroalkyl N-triftosylhydrazones as fluoroalkyl carbene precursors, resulting in ring-expanded heterocycles in excellent yields with good functional-group compatibility. The broad generality of this methodology in the late-stage diversification of pharmaceutically interesting bioactive molecules and versatile transformations of the products has been demonstrated.

N-Triftosylhydrazones: A New Chapter for Diazo-Based Carbene Chemistry.

Over recent decades, N-sulfonylhydrazones have attracted significant attention in academic and industrial contexts owing to their ease of preparation, versatile reactivity, high stability, and practicality. In particular, the use of N-sulfonylhydrazones as precursors for diazo compounds has paved the way for innovative and original organic reactions that are otherwise difficult to achieve. Three key developments are noteworthy in the history of N-sulfonylhydrazone chemistry: (1) Bamford and Stevens initially disclosed the application of N-tosylhydrazones as a diazo source in 1952; (2) Aggarwal and co-workers investigated N-tosylhydrazone salts as diazo precursors for sulfur ylide-mediated asymmetric epoxidation and aziridination in 2001; and (3) Barluenga, Valdés and co-workers first reported Pd-catalyzed cross-coupling reactions with N-tosylhydrazones in 2007, thus introducing the direct use of N-tosylhydrazones in carbene transfer reactions. In the past 2 decades, the synthetic exploration of N-sulfonylhydrazones in carbene chemistry has increased remarkably. N-Tosylhydrazones are the most commonly used N-sulfonylhydrazones, but they are not easy to decompose and normally need relatively high temperatures (e.g., 90-110 °C). Temperature, as a key reaction parameter, has a significant influence on the selectivity and scope of organic reactions, especially the enantioselectivity. Aggarwal and co-workers have addressed this issue by using N-tosylhydrazone salts and achieved a limited number of asymmetric organic reactions, but the method is greatly limited because the salts must be freshly prepared or stored in the dark at -20 °C prior to use. Hence, easily decomposable N-sulfonylhydrazones, especially those capable of decomposing at low temperature, should open up new opportunities for the development of N-sulfonylhydrazone chemistry. Since 2014, our group has worked toward this goal and eventually identified N-2-(trifluoromethyl)benzenesulfonylhydrazone (i.e., N-triftosylhydrazone) as an efficient diazo surrogate that can decompose at temperatures as low as -40 °C. This allowed us to carry out a range of challenging synthetic transformations and to broaden the applications of some known reactions of great relevance.In this Account, we report our achievements in the application of N-triftosylhydrazones in carbene chemistry. On the basis of the reaction types, such applications can be categorized as (i) C(sp3)-H insertion reactions, (ii) defluorinative reactions of fluoroalkyl N-triftosylhydrazones, (iii) cycloaddition reactions with alkenes and alkynes, and (iv) asymmetric reactions. Additional applications in Doyle-Kirmse rearrangements and cross-coupling with isocyanides (ours) and benzyl chlorides (from the group of Xia) are also summarized in this Account concerning miscellaneous reactions. In terms of reaction efficiency, selectivity, and functional group tolerance, N-triftosylhydrazones are generally superior to traditional N-tosylhydrazones because of their easy decomposition. Mechanistic investigations by theoretical calculations provide insights into both the reaction mechanisms and the origin of selectivity. We hope that this Account will inspire broad interest and promote new progress in the synthetic exploration of easily decomposable N-sulfonylhydrazones.

Skeletal Editing of (Hetero)Arenes Using Carbenes.

(Hetero)arenes continue to prove their indispensability in pharmaceuticals, materials science, and synthetic chemistry. As such, the controllable modification of biologically significant (hetero)arenes towards diverse more-potent complex molecular scaffolds through peripheral and skeletal editing has been considered a challenging goal in synthetic organic chemistry. Despite many excellent reviews on peripheral editing (i. e., C-H functionalization) of (hetero)arenes, their skeletal editings via single atom insertion, deletion, or transmutations have received less attention in the review literature. In this review, we systematically summarize the state-of-the-art skeletal editing reactions of (hetero)arenes using carbenes, with a focus on general mechanistic considerations and their applications in natural product syntheses. The potential opportunities and inherent challenges encountered while developing these strategies are also highlighted.

Defluorinative 1,3-Dienylation of Fluoroalkyl N-Triftosylhydrazones with Homoallenols.

A silver-catalyzed regioselective defluorinative 1,3-dienylation of trifluoromethyl phenyl N-triftosylhydrazones using homoallenols as 1,3-dienyl sources provides a variety of α-(di)fluoro-ß-vinyl allyl ketones with excellent functional group tolerance in moderate to good yields. The reaction proceeds through a silver carbene-initiated sequential etherification and Claisen type [3,3]-sigmatropic rearrangement cascade. The synthetic utility of this protocol was demonstrated through the downstream synthetic elaboration toward diverse synthetically useful building blocks.

New Strategies for the Synthesis of Aliphatic Azides.

Aliphatic azides are a versatile class of compounds found in a variety of biologically active pharmaceuticals. These compounds are also recognized as useful precursors for the synthesis of a range of nitrogen-based scaffolds of therapeutic drugs, biologically active compounds, and functional materials. In light of the growing importance of aliphatic azides in both chemical and biological sciences, a vast array of synthetic strategies for the preparation of structurally diverse aliphatic azides have been developed over the past decades. However, to date, this topic has not been the subject of a dedicated review. This review aims to provide a concise overview of modern synthetic strategies to access aliphatic azides that have emerged since 2010. The discussed azidation reactions include (a) azidation of C-C multiple bonds, (b) azidation of C-H bonds, (c) the direct transformation of vinyl azides into other aliphatic azides, and (d) miscellaneous reactions to access aliphatic azides. We critically discuss the synthetic outcomes and the generality and uniqueness of the different mechanistic rationale of each of the selected reactions. The challenges and potential opportunities of the topic are outlined.

Pyrrolidine-Derived Phenanthroline Diamides: An Influence of Fluorine Atoms on the Coordination of Lu(III) and Some Other f-Elements and Their Solvent Extraction.

Three pyrrolidine-derived phenanthroline diamides were studied as ligands for lutetium trinitrate. The structural features of the complexes have been studied using various spectral methods and X-ray. The presence of halogen atoms in the structure of phenanthroline ligands has a significant impact on both the coordination number of lutetium and the number of solvate water molecules in the internal coordination sphere. The stability constants of complexes with La(NO3)3, Nd(NO3)3, Eu(NO3)3, and Lu(NO3)3 were measured to demonstrate higher efficiency of fluorinated ligands. NMR titration was performed for this ligand, and it was found that complexation with lutetium leads to an approximately 13 ppm shift of the corresponding signal in the 19F NMR spectrum. The possibility of formation of a polymeric oxo-complex of this ligand with lutetium nitrate was demonstrated. Experiments on the liquid-liquid extraction of Am(III) and Ln(III) nitrates were carried out to demonstrate advantageous features of chlorinated and fluorinated pyrrolidine diamides.

Site-Selective C-H Allylation of Alkanes: Facile Access to Allylic Quaternary sp3 -Carbon Centers.

The construction of allylic quaternary sp3 -carbon centers has long been a formidable challenge in transition-metal-catalyzed alkyl-allyl coupling reactions due to the severe steric hindrance. Herein, we report an effective carbene strategy that employs well-defined vinyl-N-triftosylhydrazones as a versatile allylating reagent to enable direct assembly of these medicinally desirable structural elements from low-cost alkane feedstocks. The reaction exhibited excellent site selectivity for tertiary C-H bonds, broad scope (>60 examples and >20 : 1:0 r. r.) and good efficiency, even on a gram-scale, making it a convenient alternative to the well-known Trost-Tsuji allylation reaction for the formation of alkyl-allyl bonds. Combined experimental and computational studies were employed to unravel the mechanism and origin of site- and chemoselectivity of the reaction.

Direct gem-Difluoroalkenylation of X-H Bonds with Trifluoromethyl Ketone N-Triftosylhydrazones for Synthesis of Tetrasubstituted Heteroatomic gem-Difluoroalkenes.

The direct gem-difluoroalkenylation of X-H bonds represents the most straightforward approach to access heteroatomic gem-difluoroalkenes that, as the isostere of the carbonyl group, have great potency in drug discovery. However, the construction of tetrasubstituted heteroatomic gem-difluoroalkenes by this strategy is still an unsolved problem. Here, we report the first direct X-H bond gem-difluoroalkenylation of amines and alcohols with trifluoromethyl ketone N-triftosylhydrazones under silver (for (hetero)aryl hydrazones) or rhodium (for alkyl hydrazones), thereby providing a most powerful method for the synthesis of tetrasubstituted heteroatomic gem-difluoroalkenes. This method features a broad substrate scope, high product yield, excellent functional group tolerance, and operational simplicity (open air conditions). Moreover, the site-specific replacement of the carbonyl group with a gem-difluorovinyl ether bioisostere in drug Trimebutine and the post-modification of bioactive molecules demonstrates potential use in medicinal research. Finally, the reaction mechanism was investigated by combining experiments and DFT calculations, and disclosed that the key step of HF elimination occurred via five-membered ring transition state, and the difference in the electrophilicity of Ag- and Rh-carbenes as well as the multiple intermolecular interactions rendered the effectiveness of Rh catalyst selectively for alkyl hydrazones.

A Carbene Strategy for Progressive (Deutero)Hydrodefluorination of Fluoroalkyl Ketones.

Hydrodefluorination is one of the most promising chemical strategies to degrade perfluorochemicals into partially fluorinated compounds. However, controlled progressive hydrodefluorination remains a significant challenge, owing to the decrease in the strength of C-F bonds along with the defluorination. Here we describe a carbene strategy for the sequential (deutero)hydrodefluorination of perfluoroalkyl ketones under rhodium catalysis, allowing for the controllable preparation of difluoroalkyl- and monofluoroalkyl ketones from aryl- and even alkyl-substituted perfluoro-alkyl ketones in high yield with excellent functional group tolerance. The reaction mechanism and the origin of the intriguing chemoselectivity of the reaction were rationalized by density functional theory (DFT) calculations.

Silver-Catalyzed Activation of Terminal Alkynes for Synthesizing Nitrogen-Containing Molecules.

Alkynes are one of the most abundant chemicals in organic chemistry, and therefore the development of catalytic reactions to transform alkynes into other useful functionalities is of great value. In recent decades, extraordinary advances have been made in this area with transition-metal catalysis, and silver-based reagents are ideal for the activation of alkynes. This high reactivity is probably due to the superior π-Lewis acidic, carbophilic behavior of silver(I), allowing it to selectively activate carbon-carbon triple bonds (C≡C) through the formation of a silver-π complex. Within this field, we have been interested in the activation and subsequent reactions of readily accessible terminal alkynes for the synthesis of nitrogen-containing compounds, which has generally received less attention than methods involving internal alkynes. This is possibly due to the lack of suitable reactive reaction partners that are compatible under transition metals. Therefore, a thorough understanding of the factors that influence homogeneous silver catalysis and the identification of the appropriate reaction partners can provide a powerful platform for designing more efficient silver-catalyzed reactions of terminal alkynes. In this context, we envisioned that using readily available, environmentally benign, and inexpensive trimethylsilyl azide (TMSN3) or an isocyanide as the nitrogen-donor would be the key to develop novel reactions of terminal alkynes.This Account describes our efforts since 2013 toward the development of novel silver-catalyzed tandem reactions of terminal alkynes with either TMSN3 or isocyanides for the assembly of various nitrogen-containing compounds. The first section of this Account discusses the initial developments in the silver-catalyzed hydroazidation of terminal alkynes with TMSN3 and the subsequent advances made in our laboratory. We first describe the discovery and experimental and computational mechanistic investigations of silver-catalyzed hydroazidation reactions, which is the most efficient strategy reported to date for accessing vinyl azides. Mechanistic study of this hydroazidation reaction provides an alternative activation mode for terminal alkyne conversion in transition metal catalysis. We then present the chemistry of in situ generated vinyl azides, including one-pot tandem radical addition/cyclization or migration reactions of terminal alkynes to access a variety of nitrogen-containing molecules. Finally, we discuss the one-pot, multistep tandem hydroazidation and 1,2-azide migratory gem-difluorination of terminal alkynes for the synthesis of ß-difluorinated alkyl azides. The second section describes the silver-catalyzed coupling reactions between terminal alkynes and isocyanides, which offer a straightforward method for accessing synthetically useful building blocks, such as pyrroles, allenamides, benzofuran, vinyl sulfones, indazolines, propiolonitriles, and pyrazoles. The high efficiency, mild conditions, low cost, broad substrate scope, high chemo- and regioselectivity, step economy, and ecofriendliness of the developed approaches make them attractive and practical. The progress in this area provides guiding principles for designing new reactions of terminal alkynes that can be extended to various nitrogen-containing molecules of interest to medicinal and materials chemists.

Computational Insights into Different Mechanisms for Ag-, Cu-, and Pd-Catalyzed Cyclopropanation of Alkenes and Sulfonyl Hydrazones.

The [2+1] cycloaddition reaction of a metal carbene with an alkene can produce important cyclopropane products for synthetic intermediates, materials, and pharmaceutical applications. However, this reaction is often accompanied by side reactions, such as coupling and self-coupling, so that the yield of the cyclopropanation product of non-silver transition-metal carbenes and hindered alkenes is generally lower than 50 %. To solve this problem, the addition of a low concentration of diazo compound (decomposition of sulfonyl hydrazones) to alkenes catalyzed by either CuOAc or PdCl2 was studied, but side reactions could still not be avoided. Interestingly, however, the yield of cyclopropanation products for such hindered alkenes were as high as 99 % with AgOTf as a catalyst. To explain this unexpected phenomenon, reaction pathways have been computed for four different catalysts by using DFT. By combining the results of these calculations with those obtained experimentally, it can be concluded that the efficiency of the silver catalyst is due to the barrierless concerted cycloaddition step and the kinetic inhibition of side reactions by a high concentration of alkene.

AgN3-Catalyzed Hydroazidation of Terminal Alkynes and Mechanistic Studies.

The hydroazidation of alkynes is the most straightforward way to access vinyl azides-versatile building blocks in organic synthesis. We previously realized such a fundamental reaction of terminal alkynes using Ag2CO3 as a catalyst. However, the high catalyst loading seriously limits its practicality, and moreover, the exact reaction mechanism remains unclear. Here, on the basis of X-ray diffraction studies on the conversion of silver salts, we report the identification of AgN3 as the real catalytic species in this reaction and developed a AgN3-catalyzed hydroazidation of terminal alkynes. AgN3 proved to be a highly robust catalyst, as the loading of AgN3 could be as low as 5 mol %, and such a small proportion of AgN3 is still highly efficient even at a 50 mmol reaction scale. Further, the combination of experimental investigations and theoretical calculations disclosed that the concerted addition mechanism via a six-membered transition state is more favored than the classical silver acetylide mechanism.

Cleavage of carbon-carbon bonds by radical reactions.

In recent years, radical C-C bond cleavage reactions have been increasingly understood and used to perform transformations that complement traditional ionic processes. However, to date radical C-C bond cleavage/functionalization reactions have not been the subject of a dedicated review. Herein we summarize the most recent and significant developments in the radical activation and functionalization of carbon-carbon bonds, with an emphasis on both synthetic outcomes and reaction mechanisms, and highlight how these radical C-C bond cleavage reactions enable challenging transformations.

Difluoroacetaldehyde N-Triftosylhydrazone (DFHZ-Tfs) as a Bench-Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane.

Despite the growing importance of volatile functionalized diazoalkanes in organic synthesis, their safe generation and utilization remain a formidable challenge because of their difficult handling along with storage and security issues. In this study, we developed a bench-stable difluoroacetaldehyde N-triftosylhydrazone (DFHZ-Tfs) as an operationally safe diazo surrogate that can release in situ two low-molecular-weight diazoalkanes, diazoacetaldehyde (CHOCHN2 ) or difluorodiazoethane (CF2 HCHN2 ), in a controlled fashion under specific conditions. DFHZ-Tfs has been successfully employed in the Fe-catalyzed cyclopropanation and Doyle-Kirmse reactions, thus highlighting the synthetic utility of DFHZ-Tfs in the efficient construction of molecule frameworks containing CHO or CF2 H groups. Moreover, the reaction mechanism for the generation of CHOCHN2 from CF2 HCHN2 was elucidated by density functional theory (DFT) calculations.

Direct Transformation of Terminal Alkynes into Amidines by a Silver-Catalyzed Four-Component Reaction.

An unprecedented conversion of terminal alkynes into N-sulfonimidamides (amidines) is reported by a silver-catalyzed, one-pot, four-component reaction with TMSN3, sodium sulfinate, and sulfonyl azide. The reaction scope includes both aromatic and aliphatic alkynes. A possible cascade reaction mechanism, consisting of alkyne hydroazidation, sulfonyl radical addition, 1,3-dipolar cycloaddition by TMSN3, and retro-1,3-dipolar cycloaddition, is proposed. TMSN3 is found to play an essential role in each step of the reaction.

Directed Copper-Catalyzed Intermolecular Aminative Difunctionalization of Unactivated Alkenes.

A diverse collection of copper-catalyzed intermolecular aminative difunctionalizations of unactivated alkenes with N-halodialkylamines as the terminal dialkylamino source is reported. A bidentate auxiliary tethered on the alkene substrates is crucial, which can promote the migratory insertion of nonactivated alkenes into the aminyl radical-metal complex and stabilize the resultant high-valent copper intermediate to allow for further transformations. By employing this strategy, the intermolecular aminohalogenation reactions and a three-component aminoazidation reaction of unactivated alkenes with dialkylamino source were successively achieved in a remarkable regio- and stereoselective manner. These reactions were performed under neutral conditions and maintained excellent functional group tolerance toward a wide range of N-halodialkylamines and unactivated alkenes. Further mechanistic studies and DFT calculations supported a concerted migratory insertion of the C-C double bond into the aminyl radical-metal complex to form a Cu(III) intermediate.

Directed Copper-Catalyzed Intermolecular Heck-Type Reaction of Unactivated Olefins and Alkyl Halides.

A new type of intermolecular alkylative olefination of unactivated olefins and alkyl halides has been realized for the first time. This copper-promoted Heck-type reaction employs a directing-group strategy to efficiently produce the coupled alkyl olefin products with excellent regio- and stereoselectivity. A broad substrate scope including 1°, 2°, and 3° alkyl bromides and various nonactivated alkenes could be well tolerated. DFT calculations disclosed a dimethyl sulfoxide assisted concerted H-Br elimination process of a conformationally strained Cu(III) cyclic transition state.