Silver-catalyzed direct conversion of epoxides into cyclopropanes using N-triftosylhydrazones.

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.

Iridium Acylnitrenoid-Initiated Biomimetic Cascade Cyclizations: Stereodefined Access to Polycyclic δ-Lactams.

Ring-fused azacyclic compounds are important building units in the synthesis of biorelevant natural products, pharmaceutical agents, and molecular materials. Herein, we present a new approach to these condensed azacycles by a biomimetic cascade cyclization of arylalkenyl dioxazolones. This cascade reaction was found to proceed with excellent stereoselectivity and a high functional group tolerance. The substrate scope of arylalkenyl dioxazolones turned out to be highly flexible and extendable to additional terminating subunits, such as heteroaryl and alkynyl moieties. This biomimetic cyclization was elucidated to be initiated by an intramolecular transfer of the in situ generated electrophilic Ir-acylnitrenoid to the tethered olefinic double bond, leading to a key N-acylaziridine intermediate, which is in turn reacted with pendant (hetero)arenes or alkynes in a highly regio- and stereoselective manner to produce ring-fused azacyclic compounds.

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes.

In this work, we successfully employed electrochemical conditions to promote a Hofer-Moest, intramolecular Friedel-Crafts alkylation sequence. The reaction proceeds under mild conditions, employing carboxylic acids as starting materials. Notably, the electrochemical process performed in batch was adapted to a continuous flow electrolysis apparatus to provide a significant improvement. This catalyst-free, electrochemical approach produces an array of tetrahydronaphthalenes that could be used for API synthesis.

Asymmetric [2+1] cycloaddition of difluoroalkyl-substituted carbenes with alkenes under rhodium catalysis: Synthesis of chiral difluoroalkyl-substituted cyclopropanes.

Herein, we report a novel strategy for the synthesis of chiral difluoroalkyl-substituted cyclopropanes through enantioselective [2 + 1] cyclopropanation of alkenes and difluoroalkyl-substituted carbenes under rhodium catalysis, wherein the newly designed α, α-difluoro-ß-carbonyl ketone N-triftosylhydrazones are used as the difluoroalkyl-substituted carbenes precursors. This approach represents the first asymmetric cyclopropanation of alkenes with difluoroalkyl carbenes, featuring high yield, high enantioselectivity, and broad substrate scope. Gram-scale synthesis and further interconversion of diverse functional groups demonstrate the usefulness of this protocol in the preparation of diverse functionalized chiral difluoroalkyl-substituted cyclopropanes.

Chemoselective carbene insertion into the N-H bonds of NH3·H2O.

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.

Highly electrophilic silver carbenes.

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.

A New Benzothiazolthiazolidine Derivative, 11726172, Is Active In Vitro, In Vivo, and against Nonreplicating Cells of Mycobacterium tuberculosis.

Tuberculosis (TB) still poses a global menace as one of the deadliest infectious diseases. A quarter of the human population is indeed latently infected with Mycobacterium tuberculosis. People with latent infection have a 5 to 10% lifetime risk of becoming ill with TB, representing a reservoir for TB active infection. This is a worrisome problem to overcome in the case of relapse; unfortunately, few drugs are effective against nonreplicating M. tuberculosis cells. Novel strategies to combat TB, including its latent form, are urgently needed. In response to the lack of new effective drugs and after screening about 500 original chemical molecules, we selected a compound, 11726172, that is endowed with potent antitubercular activity against M. tuberculosis both in vitro and in vivo and importantly also against dormant nonculturable bacilli. We also investigated the mechanism of action of 11726172 by applying a multidisciplinary approach, including transcriptomic, labeled metabolomic, biochemical, and microbiological procedures. Our results represent an important step forward in the development of a new antitubercular compound with a novel mechanism of action active against latent bacilli. IMPORTANCE The discontinuation of TB services due to COVID-19 causes concern about a future resurgence of TB, also considering that latent infection affects a high number of people worldwide. To combat this situation, the identification of antitubercular compounds targeting Mycobacterium tuberculosis through novel mechanisms of action is necessary. These compounds should be active against not only replicating bacteria cells but also nonreplicating cells to limit the reservoir of latently infected people on which the bacterium can rely to spread after reactivation.

Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy.

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 ß,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 ß,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.

Oxo-Rhenium-Mediated Allylation of Furanoside Derivatives: A Computational Study on the Mechanism and the Stereoselectivity.

Properly substituted tetrahydrofuran (THF) rings are important building blocks in the synthesis of many natural metabolites. Having reliable procedures to control the stereoselectivity at the THF core while decorating it with different substituents is a fundamental requirement to achieve and fulfill the complexity of nature. We recently reported a new chemical approach to control the stereochemistry in the alkylation and arylation of furanoside derivatives by using a rhenium(V) complex to form an intermediate oxo-carbenium species able to react with proper soft nucleophiles. Here, we describe theoretical calculations, performed at the DFT B3LYP level, to disclose the important mechanistic features which regulate the entire catalytic cycle of the reaction of mono- and disubstituted furanosides with allyltrimethylsilane catalyzed by Re(O)Cl3(OPPh3)(Me2S). Moreover, the key factors governing the allylation step were investigated, confirming that the stereoselectivity, which is independent of the anomeric configuration of starting acetal, mainly arises from the orientation of the substituent at C-4, with only marginal contribution of the substituent at C-5. Finally, puckering Cremer-Pople parameters were used to take trace of the structural modifications throughout the catalytic cycle.

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.

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.

Synthetic exploration of sulfinyl radicals using sulfinyl sulfones.

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.

Highly Stereoselective Glycosylation Reactions of Furanoside Derivatives via Rhenium (V) Catalysis.

A novel approach for the formation of anomeric carbon-functionalized furanoside systems was accomplished through the employment of an oxo-rhenium catalyst. The transformation boasts a broad range of nucleophiles including allylsilanes, enol ethers, and aromatics in addition to sulfur, nitrogen, and hydride donors, able to react with an oxocarbenium ion intermediate derived from furanosidic structures. The excellent stereoselectivities observed followed the Woerpel model, ultimately providing 1,3-cis-1,4-trans systems. In the case of electron-rich aromatic nucleophiles, an equilibration occurs at the anomeric center with the selective formation of 1,3-trans-1,4-cis systems. This anomalous result was rationalized through density functional theory calculations. Different oxocarbenium ions such as those derived from dihydroisobenzofuran, pyrrolidine, and oxazolidine heterocycles can also be used as a substrate for the oxo-Re-mediated allylation reaction.

Fluorocyclization of Allyl Alcohols and Amines to Access 3-Functionalized Oxetanes and Azetidines.

An efficient method to prepare 3-functionalized oxetanes and azetidines has been realized by fluorocyclization of readily available 2-azidoallyl/2-alkoxyallyl alcohols and amines. Notably, this is the first example applying the fluorocyclization strategy to construct four-membered heterocycles. The pendant electron-donating group (-N3 or -OR) plays a crucial role in polarizing the C═C double bond and facilitating the cyclization process, as verified by DFT and experimental studies.

Transition Metal Promoted Cascade Heterocycle Synthesis through C-H Functionalization.

Sequential, domino and tandem reactions could be defined as a sequence of synthetic transformations that occur one after the other, in the same reaction flask. This Review highlights recent advances at the overlap of two worlds: transition-metal mediated C-H activation as a trigger of cascade reaction, for the heterocycles synthesis. To shed some light on this intricate "middle-earth", focus was put on the reaction mechanism rather than the type of metal or the chronological order of the reaction. The aim is to separate, and then highlight, the true domino reactions initiated by C-H activation, compared to other examples of C-H functionalization for heterocycle syntheses.

Overriding ortho selectivity by template assisted meta-C-H activation of benzophenones.

An orthogonal selectivity for distal meta-C-H activation of benzophenone is acheived by overriding the inherent proximal ortho-selectivity through a template assisted metalation approach. This strategy has been successfully utilized in Pd-catalyzed regioselective C-C and C-Si bond formation.

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.

Recent advances in cobalt-catalysed C-H functionalizations.

Ready availability, low cost and low toxicity of cobalt salts have redirected the attention of researchers away from noble metals, such as Pd, Rh, and Ir, towards Co in the field of C-H functionalization. In this context, the examples of Co-catalysed functionalization have exponentially grown over the last few decades. This present review focuses on the most recent developments on Co-catalysed C(sp2)-H and C(sp3)-H functionalizations. Included is also a comprehensive overview of enantioselective transformations.

Cobalt-Catalyzed C(sp2)-H Allylation of Biphenyl Amines with Unbiased Terminal Olefins.

Unactivated olefins usually react poorly in conventional alkenylation reactions. Their introduction via C-H activation is limited to aromatic acids. Herein, we disclose a C-H functionalization protocol of aromatic amines with unactivated olefins, which shows exclusive allylic selectivity for the distal ring of the biphenyl system by exploiting a readily available cobalt(II) catalyst. The allylation proceeds smoothly involving a broad set of unbiased olefins and biaryls, giving access to the functionalization of the biphenyl scaffold.