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Comprehensive Summary Over the past few decades, N‐sulfonyl hydrazones have been recognized as alternative precursors for hazardous diazo compounds in organic synthesis, allowing for diverse innovative and original chemical transformations that were otherwise difficult to achieve. This critical review summarizes the major advancements in the carbene chemistry of N‐sulfonyl hydrazones. The contents of this review are organized based on research conducted by leading scientists who have made significant contributions to this field. The individual carbene transfer reactions and their mechanisms, as well as the potential applications in the synthesis of natural products and complex bioactive molecules, are thoroughly discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Catalytic carbene transfer reactions are fundamental transformations in modern organic synthesis, which enable direct access to diverse structurally complex molecules. Despite diazo precursors playing a crucial role in catalytic carbene transfer reactions, most reported methodologies take into account only diazoacetates or related compounds. This is primarily because diazoalkanes, unless they contain a resonance stabilizing group, are more susceptible to violent exothermic decomposition. In this feature article, we present an alternative approach to carbene-transfer reactions based on the formation of highly electrophilic silver carbenes from N-sulfonylhydrazones, where the high electrophilicity of silver carbenes stems from the weak interaction between silver and the carbenic carbon. These precursors are readily accessible, stable, and environmentally sustainable. Using the strategy that employs highly electrophilic silver carbenes, it is possible to develop novel intermolecular transformations involving non-stabilized carbenes, including C(sp3)–H insertion, C(sp3)–C(O) insertion, cycloaddition, and defluorinative functionalization. The silver-catalyzed carbene transfer reactions described here have high efficiency, unusual reactivity, exceptional selectivity, and a reaction pathway that differs from typical transition metal-catalyzed reactions. Our research provided fundamental insight into silver carbene chemistry, and we hope to apply this mode of catalysis to other more general transformations, including asymmetric transformations. [ABSTRACT FROM AUTHOR]

The insertion of carbenes into the α-C–H bonds of ethers represents one of the most powerful approaches to access polysubstituted α-branched ethers. However, intermolecular carbene insertions remain challenging, since current approaches are generally limited to the use of toxic and potentially explosive α-diazocarbonyl compounds. We now report a silver-catalyzed α-C–H benzylation of ethers using bench-stable N-triftosylhydrazones as safe and convenient carbene precursors. This approach is well suited for both inter- and intramolecular insertions to deliver medicinally relevant homobenzylic ethers and 5–8-membered oxacycles in good yields. The synthetic utility of this strategy is demonstrated by its easy scalability, broad scope with valuable functional groups, high regioselectivity, and late-stage functionalization of complex oxygen-containing molecules. The relative reactivities of different types of silver carbenes and C−H bonds were also investigated by experments and DFT calculations. A state-of-the-art tool in synthetic organic chemistry is a rhodium diazocarbene species, which despite its flexibility, is derived from expensive and highly reactive species. Here the authors present a methodology for C–H benzylation of ethers via an analogous silver carbene species, obtained from a more common metal and a more stable starting material. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Fluoroalkyl 1,2,3-triazoles have great potential as medicinal chemistry building blocks. However, only a few synthetic routes to these compounds are currently available. Herein, we report on a novel method to access 5-fluoroalkyl 1,2,3-triazoles from easily prepared bench-stable perfluoroalkyl N-mesylhydrazone (PFHZ-Ms), a reagent that can transform amines to 5 fluoroalkyl 1,2,3-triazoles via defluorinative [4 + 1] annulation. The simple reaction protocol can be applied to a variety of amines containing a range of functional groups, delivering 1,2,3-triazoles in good to excellent yield. The utility of this method was demonstrated in the late-stage modification of bioactive molecules. [ABSTRACT FROM AUTHOR]

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 CF 3 -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., (© 2024 Wiley-VCH GmbH.)

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., (© 2023 Wiley-VCH GmbH.)

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-β-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., (© 2023 Wiley-VCH GmbH.)

(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., (© 2023 Wiley-VCH GmbH.)

The construction of allylic quaternary sp 3 -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., (© 2022 Wiley-VCH GmbH.)

Here we report a silver-catalyzed alkynyl carbene insertion into β-ketocarbonyls using alkynyl N -nosylhydrazones as alkynyl carbene precursors, which provides access to trisubstituted allenyl ketones. This reaction represents the first example of an alkynyl carbene insertion into a C-C σ bond, affording products homologated with an sp 2 carbon center. The products are useful substrates for further transformations. Experimental investigations and theoretical calculations suggest the reaction proceeds through a stepwise enol cyclopropanation/retro-aldol pathway.