Electronically diverse carbenes.

Metal carbenes with different polarities are generated from a single class of precursor.

Universal Reagent for Mild and Stereospecific Nucleophilic Substitution of Alcohols with Amines.

A user-friendly reagent for mild and general activation of alcohols towards bimolecular nucleophilic substitution (S2) leveraging diverse nucleophiles, including primary and secondary amines is reported herein. The new ion-paired reagent discovery was based upon the putative zwitterionic betaine intermediate of the Mitsunobu reaction and enabled the one-step conversion of enantioenriched alcohols to valuable chiral C-X bonds (where X=N, C, S, O or halide). The described activating reagent has also been applied to a one-step methylation reaction using methanol and to an intermolecular amination/intramolecular cyclization sequence that generates heterocycles, such as tetrahydroisoquinolines.

On-Demand Continuous Flow Synthesis of Pentafluorosulfanyl Chloride (SFCl) Using a Custom-Made Stirring Packed-Bed Reactor.

The pentafluorosulfanyl (SF-) group has been the subject of a surge of interest in the past decade, but there is still little practicality associated with its synthesis and installation. Herein is reported the first continuous flow synthesis of pentafluorosulfanyl chloride (SFCl), the most common reagent for the synthesis of SF-substituted compounds. The synthesis is based on inexpensive and easy-to-handle reagents: sulfur powder (S), trichloroisocyanuric acid (TCCA) and potassium fluoride (KF).

1,3-Dipolar Cycloaddition of SF-Alkynes with Nonstabilized Diazo: Synthesis of Highly Substituted SF-3-Pyrazoles.

This work presents the 1,3-dipolar cycloaddition of SF-alkynes with nonstabilized diazo compounds under mild conditions, producing highly substituted SF-3-pyrazoles. Eighteen examples are given, with yields of up to 91%. The two regioisomers were obtained in ratios ranging from 27:73 to 73:27.

Asymmetric Synthesis of (-)-Cannabidiol (CBD), (-)-Δ-Tetrahydrocannabinol (Δ-THC) and Their Analogs Using an Enantioselective Organocatalyzed Diels-Alder Reaction.

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (-)--CBD and psychoactive (-)--Δ-THC, as well as their synthetic diastereomers. The key step is an enantioselective Diels-Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.

Synthesis of 2-substituted bicyclo[1.1.0]butanes zincocyclopropanation using bromoform as the carbenoid precursor.

Through a revisited Simmons-Smith type zincocyclopropanation using bromoform as the carbenoid source, the synthesis of 2-, 2,2- and 2,4-substituted bicyclo[1.1.0]butanes is reported.

Rhodium-Catalyzed Intramolecular Cyclopropanation of Trifluoromethyl- and Pentafluorosulfanyl-Substituted Allylic Cyanodiazoacetates.

The synthesis of trifluoromethyl (CF)- and pentafluorosulfanyl (SF)-substituted cyclopropane-fused γ-lactones was carried out through Rh(esp)-catalyzed intramolecular cyclopropanation in up to 99% yields. Twelve examples of this interesting scaffold are reported, as well as postfunctionalizations that provide access to highly functionalized CF- and SF-substituted cyclopropanes. These novel SF-substituted analogues join the very short list of available pentafluorosulfanyl intermediates.

Organocatalyzed Visible Light-Mediated -Borosilylcyclopropanation.

The borosilylcyclopropanation of styrene derivatives using a (diiodo(trimethylsilyl)methyl)boronic ester carbene precursor is reported herein. The key reagent was synthesized in a 4-step sequence using inexpensive and commercially available starting materials. This method enabled the preparation of novel 1,1,2-tri- and 1,1,2,2-tetrasubstituted borosilylcyclopropanes up to excellent yields and diastereoselectivity.

Access to hexahydroazepinone heterocycles palladium-catalysed C(sp)-H alkenylation/ring-opening of cyclopropanes.

In this communication, we describe the synthesis of novel hexahydroazepinone derivatives starting from two simple building blocks in presence of a readily available palladium catalyst. The reaction proceeds through a selective C(sp)-H alkenylation/ring-opening process to obtain the seven-membered ring products in good to excellent yields on a wide variety of substrates under batch, microwave, and continuous flow conditions.

Catalytic Asymmetric Syntheses of Alkylidenecyclopropanes from Allenoates with Donor-Acceptor and Diacceptor Diazo Reagents.

The first diastereo- and enantioselective cyclopropanation reactions of electron-deficient allenes with donor-acceptor and diacceptor diazo reagents are described. The desired enantioenriched alkylidenecyclopropanes (ACPs) were obtained in high yields with high diastereo- and enantioselectivities in the presence of Rh ((S)-TCPTAD) or Rh ((R)-BTPCP) catalysts (up to 95 % yield, >95 : 5 d.r.

Fluorocyclopropane-Containing Proline Analogue: Synthesis and Conformation of an Item in the Peptide Chemist's Toolbox.

Over the years, numerous modifications to the structure of proline have been made in order to tune its effects on bioactive compounds. Notably, the introduction of a cyclopropane ring or a fluorine atom has produced interesting results. Herein, we describe the synthesis of a proline containing fluorocyclopropane.

Asymmetric Synthesis of Fluoro, Fluoromethyl, Difluoromethyl, and Trifluoromethylcyclopropanes.

Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH bond with fluorine or a fluorinated group (such as CF or CFH) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent.

Synthesis of Fluoro-, Monofluoromethyl-, Difluoromethyl-, and Trifluoromethyl-Substituted Three-Membered Rings.

This Minireview describes recent advances toward the synthesis of fluoro-, monofluoromethyl-, difluoromethyl-, and trifluoromethyl-substituted three-membered rings such as cyclopropanes, aziridines, epoxides, episulfides, cyclopropenes, and 2 H-azirines. The main synthetic methodologies since 2016 for cyclopropanes and since 2010 for the other three-membered rings are reported.

Catalytic Asymmetric Synthesis of α,α-Difluoromethylated and α-Fluoromethylated Tertiary Alcohols.

The catalytic asymmetric synthesis of α,α-difluoromethylated tertiary alcohols is described, using an asymmetric dihydroxylation reaction. This protocol using either the AD-mix-α or AD-mix-β allowed an easy access to these valuable fluorinated chiral building blocks, which have been obtained with excellent yields and er. In addition, the reaction was extended to the α-fluoromethylated analogues.

Non-stabilized diazoalkane synthesis the oxidation of free hydrazones by iodosylbenzene and application in MIRC cyclopropanation.

Electron-rich alkyl diazo compounds are powerful reagents in organic synthesis, but the risks associated with their toxicity and instability often limit their uses. Herein we describe an efficient, easy-to-handle and safe batch protocol for the generation and cyclopropanation of these highly reactive non-stabilized diazoalkanes through the oxidation of free hydrazones using iodosylbenzene. Numerous substituted cyclopropanes have been synthesized using this methodology, including various -dimethylcyclopropanes of particular interest in medicinal chemistry.

Utilization of BozPhos as an Effective Ligand in Enantioselective C-H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones.

The bisphosphine monoxide ( R, R)-BozPhos enables enantioselective C-H functionalization of cyclopropanes in a palladium-catalyzed cyclization. The synthesis of a broad spectrum of dihydroisoquinolones and dihydroquinolones in good yields and high enantiomeric excess was achieved through the use of this hemilabile ligand. Furthermore, the isolation of an intermediary palladium(II)-BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and angles through a crystal structure.

Rhodium catalysed enantioselective synthesis of mono-(halo)-methyl-cyclopropanes.

The catalytic asymmetric synthesis of mono-fluoro-, -chloro- and -bromomethyl-1,2-diaryl cyclopropane ester is described. The reaction, using Rh2((S)-BTPCP)4 as a catalyst, allowed the formation of the desired cyclopropanes in good to excellent yields (up to 99%) and excellent diastereoselectivities (up to >20 : 1) and with a high level of enantioselectivities (up to 98% ee). Finally, the synthetic utility of the chiral cyclopropanes was also demonstrated.

Iron-catalyzed synthesis of cyclopropanes by in situ generation and decomposition of electronically diversified diazo compounds.

The modular synthesis of a variety of trans 1,2-disubstituted cyclopropanes in a safe and user-friendly one-pot iron-catalyzed cyclopropanation reaction is described. Easily synthesized N-nosylhydrazones are used as diazo precursors, allowing the in situ generation of electron-rich diazo compounds under mild reaction conditions and their direct participation in the cyclopropanation reaction.

Borocyclopropanation of Styrenes Mediated by UV-light Under Continuous Flow Conditions.

Herein, we report a user-friendly and metal-free UV-A light mediated borocyclopropanation of styrenes using continuous flow technology. A broad range of styrene derivatives can be cyclopropanated in good yields within 1 h residence time to produce highly valuable cyclopropylboronate esters with modest to good diastereoselectivities. The reaction is also applicable to α-substituted styrenes.

General Catalytic Enantioselective Access to Monohalomethyl and Trifluoromethyl Cyclopropanes.

An efficient catalytic enantioselective access to chiral functionalized trifluoromethyl cyclopropanes from two classes of diazo compounds and α-trifluoromethyl styrenes using Rh ((S)-BTPCP) as a catalyst is described. This method provides an efficient and practical strategy for the synthesis of highly functionalized CF -cyclopropanes with excellent diastereoselectivities (up to 20:1) and enantioselectivities (up to 99 % ee). The depicted methodology represents, to date, the most efficient catalytic enantioselective method to access highly decorated chiral CF -cyclopropanes.

Safe and Facile Access to Nonstabilized Diazoalkanes Using Continuous Flow Technology.

Despite the high synthetic potential of nonstabilized diazo compounds, their utilization has always been hampered by stability, toxicity, and safety issues. The present method opens up access to the most reactive nonstabilized diazoalkanes. Among diazo compounds, nonstabilized alkyl diazo compounds are the least represented because of their propensity to degrade during preparation.

Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes.

The first catalytic asymmetric synthesis of highly functionalized difluoromethylated cyclopropanes is described. The method, based on a rhodium-catalyzed cyclopropanation of difluoromethylated olefins, gives access to a broad range of cyclopropanes bearing ester, ketone, or nitro functional groups. By using Rh ((S)-BTPCP) as a catalyst, the corresponding products were obtained in high yields and high diastereo- and enantioselectivities (up 20:1 d.

Engineered, highly reactive substrates of microbial transglutaminase enable protein labeling within various secondary structure elements.

Microbial transglutaminase (MTG) is a practical tool to enzymatically form isopeptide bonds between peptide or protein substrates. This natural approach to crosslinking the side-chains of reactive glutamine and lysine residues is solidly rooted in food and textile processing. More recently, MTG's tolerance for various primary amines in lieu of lysine have revealed its potential for site-specific protein labeling with aminated compounds, including fluorophores.