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Epoxides, as a prominent small ring O-heterocyclic and the privileged pharmacophores for medicinal chemistry, have recently represented an ideal substrate for the development of single-atom replacements. The previous O-to-C replacement strategy for epoxides to date typically requires high temperatures to achieve low yields and lacks substrate range and functional group tolerance, so achieving this oxygen-carbon exchange remains a formidable challenge. Here, we report a silver-catalyzed direct conversion of epoxides into trifluoromethylcyclopropanes in a single step using trifluoromethyl N-triftosylhydrazones as carbene precursors, thereby achieving oxygen-carbon exchange via a tandem deoxygenation/[2 + 1] cycloaddition. The reaction shows broad tolerance of functional groups, allowing routine cheletropic olefin synthesis in a strategy for the net oxygen-carbon exchange reaction. The utility of this method is further showcased with the late-stage diversification of epoxides derived from bioactive natural products and drugs. Mechanistic experiments and DFT calculations elucidate the reaction mechanism and the origin of the chemo- and stereoselectivity. Epoxides are prominent small-ring O-heterocycles found in a variety of bioactive natural products and pharmaceuticals. Here, the authors report a silver carbene strategy to achieve O-to-C atom exchange of epoxides in a single step, affording diverse fluoroalkylcyclopropanes. [ABSTRACT FROM AUTHOR]

The conversion of inexpensive aqueous ammonia (NH3·H2O) into value-added primary amines by N−H insertion persists as a longstanding challenge in chemistry because of the tendency of Lewis basic ammonia (NH3) to bind and inhibit metal catalysts. Herein, we report a chemoselective carbene N−H insertion of NH3·H2O using a TpBr3Ag-catalyzed two-phase system. Coordination by a homoscorpionate TpBr3 ligand renders silver compatible with NH3 and H2O and enables the generation of electrophilic silver carbene. Water promotes subsequent [1,2]-proton shift to generate N−H insertion products with high chemoselectivity. The result of the reaction is the coupling of an inorganic nitrogen source with either diazo compounds or N-triftosylhydrazones to produce useful primary amines. Further investigations elucidate the reaction mechanism and the origin of chemoselectivity. Converting low-cost inorganic chemicals into value-added organic chemicals is a longstanding goal in chemistry. Here the authors describe a silver-catalysed chemoselective carbene N−H insertion reaction, providing access to primary amines from aqueous ammonia and diazo compounds. [ABSTRACT FROM AUTHOR]

The C–F bond cleavage and C–C bond formation (i.e., carbodefluorination) of readily accessible (per)fluoroalkyl groups constitutes an atom-economical and efficient route to partially fluorinated compounds. However, the selective mono-carbodefluorination of trifluoromethyl (CF3) groups remains a challenge, due to the notorious inertness of C–F bond and the risk of over-defluorination arising from C–F bond strength decrease as the defluorination proceeds. Herein, we report a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones with β,γ-unsaturated alcohols to provide skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated ketones. The reaction starts with the formation of silver carbenes from fluoroalkyl N-triftosylhydrazones, followed by nucleophilic attack of a β,γ-unsaturated alcohol to form key silver-coordinated oxonium ylide intermediates, which triggers selective C–F bond cleavage by HF elimination and C–C bond formation through Claisen rearrangement of in situ generated difluorovinyl ether. The origin of chemoselectivity and the reaction mechanism are determined by experimental and DFT calculations. Collectively, this strategy by an intramolecular cascade process offers significant advances over existing stepwise strategies in terms of selectivity, efficiency, functional group tolerance, etc. The selective functionalization of trifluoromethyl groups is challenging due to the inertness of the C–F bonds. Here the authors report a method for the carbodefluorination of C–F bonds of fluoroalkyl ketones via a carbene-initiated rearrangement strategy. [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]

Fluoroalkyl N-sulfonyl hydrazones are versatile reagents that can be used to synthesize a wide range of diverse fluoroalkylated organic molecules. Although it has been known since 1975, the chemistry of fluoroalkyl N-sulfonyl hydrazones has recently only received great attention from the scientific community. Generally, they are used as either safe and bench-stable diazo precursors in carbene transfer reactions or as 1,3-dipoles in cycloaddition and cyclization reactions. Notably, fluoroalkyl N-sulfonyl hydrazones to replace toxic fluoroalkyl diazo compounds in carbene transfer reactions reduce the risk of rapid accumulation of explosive diazo compounds and improve functional group compatibility and substrate scope. Given the growing importance of fluoroalkyl N-sulfonyl hydrazones in chemical synthesis, a comprehensive review of this topic in the literature is essential to demonstrate their synthetic potential. In this review, we critically summarize and comprehensively analyze the publications in various literatures on the chemistry of fluoroalkyl N-sulfonyl hydrazones starting from 1990 to date. The classification of the different reactivity profiles of fluoroalkyl N-sulfonyl hydrazones and the efficiencies of similar types of reactions or substrates with fluoroalkyl diazo compounds are compared. [ABSTRACT FROM AUTHOR]

Sulfinyl radicals – one of the fundamental classes of S-centered radicals – have eluded synthetic application in organic chemistry for over 60 years, despite their potential to assemble valuable sulfoxide compounds. Here we report the successful generation and use of sulfinyl radicals in a dual radical addition/radical coupling with unsaturated hydrocarbons, where readily-accessed sulfinyl sulfones serve as the sulfinyl radical precursor. The strategy provides an entry to a variety of previously inaccessible linear and cyclic disulfurized adducts in a single step, and demonstrates tolerance to an extensive range of hydrocarbons and functional groups. Experimental and theoretical mechanistic investigations suggest that these reactions proceed through sequential sulfonyl and sulfinyl radical addition. Sulfinyl radicals are an underexplored synthon in organic chemistry due to the fact that they reversibly add to pi systems and undergo homodimerization. Here the authors synthesize sulfonyl sulfones, previously thought to be unstable, and demonstrate their broad use as sulfinyl radical precursors in disulfurizations of alkenes and alkynes. [ABSTRACT FROM AUTHOR]

C(CO)-alkyl bonds are ubiquitous in a variety of organic molecules, and their selective activation and functionalization are important for the reconstruction of simple ketones into valuable building blocks. However, due to the thermodynamic and kinetic stability, the cleavage and transformation of the unstrained C(CO)-alkyl bonds remain a significant challenge. Herein, we report a novel silver-catalyzed scission of the unstrained C(CO)-alkyl bond of ketones by reacting with N-isocyanoiminotriphenylphosphorane (NIITP) under mild conditions. This method could transform a variety of unstrained ketones into iminophosphoranes and nitriles in high yields. Experimental and computational studies disclosed the reaction proceeded through an unprecedented [3+2]/retro-[3+2] cycloaddition mechanism. [ABSTRACT FROM AUTHOR]

The development of azide migration reactions is a formidable challenge due to potential competition from side processes driven by the release of molecular nitrogen. Here, we show a novel neighbouring carbonyl group-assisted sequential 1,2-azide and 1,4-oxygen migration reaction of α-vinyl azides for the efficient preparation of a range of α-azido ketones. This represents the first transformation of α-vinyl azides into α-azido ketones. Notable features of this method are its high efficiency, broad substrate scope, excellent functional group compatibility, and high yields. The computational studies gave a key insights into the regioselective 1,2-azide and 1,4-oxygen migrations assisted by the neighbouring carbonyl group. Further conversions into a variety of nitrogen-containing compounds demonstrated the synthetic utility of the α-azido ketone products. Preliminary mechanistic studies disclosed a novel reaction mechanism involving neighbouring carbonyl group-assisted sequential 1,2-azide and 1,4-oxygen migrations. [ABSTRACT FROM AUTHOR]

The oxidant iodosobenzene diacetate was combined with the cheap, environment-friendly FeCl as a chloride source to produce an efficient chlorinating agent for α-chlorination of ketene dithioacetals through direct C(sp)-H chlorination. Furthermore, the synthetic utility of α-chlorinated ketene dithioacetals was verified by the intermolecular cyclization with hydrazine hydrate, leading to the synthesis of pyrazoles, in which a 1,2-sulfur migration was involved. [ABSTRACT FROM AUTHOR]

Trifluorodiazoethane (CF3CHN2), a highly reactive fluoroalkylating reagent, offers a useful means to introduce trifluoromethyl groups into organic molecules. At present, CF3CHN2 can only be generated by oxidation of trifluoroethylamine hydrochloride under acidic conditions; due to its toxic and explosive nature, its safe generation and use remains a prominent concern, hampering wider synthetic exploitation. Here we report the development of trifluoroacetaldehyde N-tfsylhydrazone (TFHZ-Tfs) as a CF3CHN2 surrogate, which is capable of generating CF3CHN2 in situ under basic conditions. The reaction conditions employed in this chemistry enabled a difluoroalkenylation of X-H bonds (X = N, O, S, Se), affording a wide range of heteroatom-substituted gem-difluoroalkenes, along with Doyle-Kirmse rearrangements and trifluoromethylcyclopropanation reactions, with superior outcomes to approaches using pre-formed CF3CHN2. Given the importance of generally applicable fluorination methodologies, the use of TFHZ-Tfs thus creates opportunities across organic and medicinal chemistry, by enabling the wider exploration of the reactivity of trifluorodiazoethane. Since fluoro-compounds are popular in industrial settings, efficient methods for incorporation of fluoride into organic molecules are desirable. Here, the authors developed trifluoroacetaldehyde N-tfsylhydrazone (TFHZ-Tfs) as a CF3CHN2 surrogate that generates CF3CHN2 in situ under basic conditions. [ABSTRACT FROM AUTHOR]