Bioorthogonal Cycloadditions of C3-Trifluoromethylated 1,2,4-Triazines with trans-Cyclooctenes.

1,2,4-triazines are a valuable class of heterodienes that can be employed in inverse electron-demand Diels-Alder reactions. However, their broader application in bioorthogonal chemistry is limited due to their low reactivity. This article focuses on 3-(trifluoromethyl)-1,2,4-triazines, which can be efficiently prepared in a one-pot reaction from NH-1,2,3-triazoles. These triazines are highly reactive in reactions with strained cyclooctenes, giving second-order rate constants as high as 230 M-1 s-1. Despite their high reactivity, the compounds remain sufficiently stable under biologically relevant conditions. We show that some of the compounds are fluorogenic, a property of potential use in bioimaging. In addition, we demonstrate the successful application of the triazines in labeling model biomolecules. Our work shows that the reactivity of 1,2,4-triazines can be enhanced by the 3-CF3-substitution, which we consider an important step toward the wider use of this promising class of reagents.

Lewis acid-mediated transformations of 5-acyl-N-fluoroalkyl-1,2,3-triazoles to cyclopentenones, indenones, or oxazoles.

We present a transition metal-free approach to 2-N-substituted indenones, cyclopentenones, and 4-carbonyl oxazoles, based on the reaction of 5-acylated N-fluoroalkyl substituted 1,2,3-triazoles (prepared by a three-component click reaction of copper acetylides, fluoroalkyl azides, and acyl chlorides) with Lewis acids aluminium trichloride or boron trifluoride etherate, proceeding via the generation and cyclization of vinyl cations.

Photocatalytic Generation of Trifluoromethyl Nitrene for Alkene Aziridination.

N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N-trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe-to-use precursor, by visible light photocatalysis. The addition of CF3 N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N-trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N-trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N-CF3 compounds with possible applications in the life sciences.

NH-1,2,3-triazoles as versatile building blocks in denitrogenative transformations.

The utilization of NH-1,2,3-triazoles as easily accessible building blocks in denitrogenative ring cleavage transformations with electrophiles to provide multifunctionalized nitrogen heterocycles and N-alkenyl compounds is reviewed. Leveraging the ready availability of NH-1,2,3-triazoles, these processes provide a convenient route to a range of pharmaceutically relevant heterocyclic cores and N-alkenyl compounds. The synthetic usefulness of in situ acylated NH-1,2,3-triazoles as viable alternatives to widely explored N-sulfonyl-1,2,3-triazoles in ring cleavage processes is highlighted.

Synthesis and Cycloaddition Reactions of 1-Azido-1,1,2,2-tetrafluoroethane.

A new fluorinated azidoethane─1-azido-1,1,2,2-tetrafluoroethane─was prepared in quantitative yield by the addition of an azide anion to tetrafluoroethylene in a protic medium. The title azide was shown to be thermally stable and insensitive to impact. Copper(I)-catalyzed [3 + 2] cycloaddition with alkynes afforded 4-substituted N-tetrafluoroethyl-1,2,3-triazoles which underwent rhodium(II)-catalyzed transannulation with nitriles to novel N-tetrafluoroethylimidazoles or the reaction with triflic acid to enamido triflates. [3 + 2] Cycloaddition of the title azide with primary amines afforded novel 5-difluoromethyl tetrazoles.

Correction: Rhodium(II)-catalyzed transannulation approach to N-fluoroalkylated indoles.

Correction for 'Rhodium(II)-catalyzed transannulation approach to N-fluoroalkylated indoles' by Olga Bakhanovich et al., Org. Biomol. Chem., 2023, https://doi.org/10.1039/d3ob01415k.

Rhodium(II)-catalyzed transannulation approach to N-fluoroalkylated indoles.

Copper(I)-catalyzed cycloaddition of substituted cyclohexenyl acetylenes with azido(per)fluoroalkanes afforded 4-cyclohexenyl-substituted N-(per)fluoroalkylated 1,2,3-triazoles. Their rhodium(II)-catalyzed transannulation led to fused N-(per)fluoroalkyl pyrroles and subsequent oxidation provided N-(per)fluoroalkyl indoles.

N-Acyl-1,2,3-triazoles - key intermediates in denitrogenative transformations.

Elusive N-acyl-1,2,3-triazoles formed by direct acylation of NH-1,2,3-triazoles were isolated and fully characterized, including X-ray crystallography. A preference for the formation of thermodynamic N2 isomers was established. Direct evidence of interconversion between N1- and N2-acyltriazoles confirmed their value in denitrogenative transformations. Efficient synthesis of enamido triflates from NH-triazoles via the intermediacy of N2-acyl-1,2,3-triazoles was developed.

Synthesis of Azidodifluoromethyl Phenyl Sulfone and Its Use as a Synthetic Equivalent of the Azidodifluoromethyl Anion.

Azidodifluoromethyl phenyl sulfone, a new stable fluorinated azide, was synthesized on a multi-gram scale from difluoromethyl phenyl sulfone. The synthetic utility of the title azide in the preparation of N-difluoro(phenylsulfonyl)methyl-1,2,3-triazoles was demonstrated on examples of azide-alkyne cycloaddition reactions. Subsequent reductive desulfonylation/silylation afforded N-difluoro(trimethylsilyl)methyl-1,2,3-triazoles, and rhodium(II)-catalyzed transannulation with nitriles provided N-difluoro(phenylsulfonyl)methyl-substituted imidazoles. The title azide thus represents a synthetic equivalent of the azidodifluoromethyl anion.

Synthesis of N-vinyl isothiocyanates and carbamates by the cleavage of NH-1,2,3-triazoles with one-carbon electrophiles.

Metal-free cascade reaction of NH-1,2,3-triazoles with one-carbon electrophiles, such as thiophosgene and triphosgene, led to N-vinylated ring cleavage products. Using this approach the synthesis of N-vinylisothiocyanates from NH-triazoles and thiophosgene was achieved. A variety of multifunctional compounds, such as N-vinylcarbamates, unsymmetrical vinylureas, carbamothioates, etc. was prepared by a one-pot method from NH-triazoles, triphosgene and nucleophiles.

Lewis-Acid-Mediated Intramolecular Cyclization of 4-Aryl-5-allyl-1,2,3-triazoles to Substituted Cyclopentene Derivatives.

4-Aryl-5-allyl-N-fluoroalkyl-1,2,3-triazoles available by a three-component reaction of fluoroalkyl azides, copper acetylides, and allyl halides underwent aluminum halide-mediated transformation to N-(4-halo-2-aryl-cyclopentenyl) imidoyl halides by cyclization of vinyl cation intermediates, followed by halide capture. Utilization of the cyclic products was demonstrated by the synthesis of N-alkenyl amides, amidines, isoquinolines, and tetrazoles or by the subsequent modification of the cyclopentene ring.

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives.

The only known sulfur-containing karrikin, 3-methyl-2H-thiopyrano[3,4-b]furan-2-one, has been recently identified as an extremely efficient neuroprotective butenolide. Herein, we report the targeted synthesis of this compound as well as new synthetic protocols toward a class of compounds derived from 2H-furo[2,3-c]pyran-2-ones (karrikins) via bioisosteric exchange of oxygen with sulfur. In particular, we present synthetic procedures toward bioisosteres of karrikins with one or two sulfur heteroatoms incorporated into the core backbone together with evaluation of their biological activity in inhibition of acetylcholinesterase.

Access to Fluoroalkylated Azoles and 2-Acylaminoketones via Fluorinated Anhydride-Mediated Cleavage of NH-1,2,3-Triazoles.

NH-1,2,3-Triazoles undergo a ring cleavage in reactions with fluorinated acid anhydrides (trifluoroacetic, difluoroacetic, chlorodifluoroacetic, and pentafluoropropionic anhydrides) by nitrogen acylation and acid-mediated triazole ring opening. Structurally diverse fluoroalkylated oxazoles were prepared from 4,5-disubstituted-1,2,3-triazoles. Efficient synthesis of 2-acylaminoketones was achieved from 4-substituted 1,2,3-triazoles. Finally, easy access to fluoroalkylated imidazoles and 1,2,4-triazines was developed by a one-pot two-step route from NH-triazoles, fluorinated anhydrides, and amines or hydrazine.

Fast Fluoroalkylation of Proteins Uncovers the Structure and Dynamics of Biological Macromolecules.

Covalent labeling of proteins in combination with mass spectrometry has been established as a complementary technique to classical structural methods, such as X-ray, NMR, or cryogenic electron microscopy (Cryo-EM), used for protein structure determination. Although the current covalent labeling techniques enable the protein solvent accessible areas with sufficient spatial resolution to be monitored, there is still high demand for alternative, less complicated, and inexpensive approaches. Here, we introduce a new covalent labeling method based on fast fluoroalkylation of proteins (FFAP). FFAP uses fluoroalkyl radicals formed by reductive decomposition of Togni reagents with ascorbic acid to label proteins on a time scale of seconds. The feasibility of FFAP to effectively label proteins was demonstrated by monitoring the differential amino acids modification of native horse heart apomyoglobin/holomyoglobin and the human haptoglobin-hemoglobin complex. The obtained data confirmed the Togni reagent-mediated FFAP is an advantageous alternative method for covalent labeling in applications such as protein footprinting and epitope mapping of proteins (and their complexes) in general. Data are accessible via the ProteomeXchange server with the data set identifier PXD027310.

Ligand-dependent stereoselective Suzuki-Miyaura cross-coupling reactions of ß-enamido triflates.

The stereoselective Suzuki-Miyaura cross-coupling of (Z)-ß-enamido triflates is demonstrated. Depending on the nature of the ligand in the palladium catalyst, either retention or inversion of the configuration during the synthesis of ß,ß-diaryl-substituted enamides is observed. Thus, the method provides synthetic access to both isomers of the target enamides from (Z)-ß-enamido triflates.

Stereoselective Synthesis of (Z)-ß-Enamido Fluorides from N-Fluoroalkyl- and N-Sulfonyl-1,2,3-triazoles.

A reaction of N-sulfonyl-1,2,3-triazole with boron trifluoride etherate afforded a (Z)-ß-ensulfonylamido fluoride instead of the previously erroneously assigned E isomer. The correction of the stereochemistry was based on a ge-1D ROESY NMR experiment and X-ray crystal structure analyses. Application of the reaction to N-fluoroalkyl-1,2,3-triazoles afforded new (Z)-ß-enamido fluorides in a stereoselective manner. A mechanism involving coordination of BF3 with the triazole ring and vinyl diazonium and vinyl cation intermediates was proposed.

Synthesis of N-perfluoroalkyl-3,4-disubstituted pyrroles by rhodium-catalyzed transannulation of N-fluoroalkyl-1,2,3-triazoles with terminal alkynes.

The rhodium-catalyzed transannulation of N-perfluoroalkyl-1,2,3-triazoles with aromatic and aliphatic terminal alkynes under microwave heating conditions afforded N-perfluoroalkyl-3,4-disubstituted pyrroles (major products) and N-fluoroalkyl-2,4-disubstituted pyrroles (minor products). The observed selectivities in the case of the reactions with aliphatic alkynes were high.

Preparation of 1-Azido-2-Bromo-1,1,2,2-Tetrafluoroethane and Its Use in the Synthesis of N-Fluoroalkylated Nitrogen Heterocycles.

A straightforward synthesis of 1-azido-2-bromo-1,1,2,2-tetrafluoroethane on a multigram scale from 1,2-dibromotetrafluoroethane and sodium azide in a novel process initiated by organomagnesium compounds (i-PrMgCl·LiCl, turbo Grignard) is reported. Synthetic utility of the title azide in the preparation of N-tetrafluoroethylated and N-difluoromethylated five-membered nitrogen heterocycles was demonstrated with azide-alkyne cycloaddition to N-bromotetrafluoroethyl 1,2,3-triazoles, subsequent reduction to N-tetrafluoroethyl triazoles, rhodium-catalyzed transannulation with nitriles to N-tetrafluoroethylated imidazoles and rhodium-catalyzed ring-opening, and cyclization to N-difluoromethylated oxazoles and thiazoles.

Protonation of CH3 N3 and CF3 N3 in Superacids: Isolation and Structural Characterization of Long-Lived Methyl- and Trifluoromethylamino Diazonium Ions.

The methylamino diazonium cations [CH3 N(H)N2 ]+ and [CF3 N(H)N2 ]+ were prepared as their low-temperature stable [AsF6 ]- salts by protonation of azidomethane and azidotrifluoromethane in superacidic systems. They were characterized by NMR and Raman spectroscopy. Unequivocal proof of the protonation site was obtained by the crystal structures of both salts, confirming the formation of alkylamino diazonium ions. The Lewis adducts CH3 N3 ⋅AsF5 and CF3 N3 ⋅AsF5 were also prepared and characterized by low-temperature NMR and Raman spectroscopy, and also by X-ray structure determination for CH3 N3 ⋅AsF5 . Electronic structure calculations were performed to provide additional insights. Attempted electrophilic amination of aromatics such as benzene and toluene with methyl- and trifluoromethylamino diazonium ions were unsuccessful.

Synthesis, Stability and Reactivity of α-Fluorinated Azidoalkanes.

Organic α-fluorinated azidoalkanes appeared in the literature for the first time half a century ago. However, for a long time they remained undeveloped and were regarded as chemical curiosities. Recent advances in the preparation of α-fluorinated azidoalkanes as well as studies on their stability and reactivity opened up their broader synthetic potential for the preparation of valuable fluorinated and non-fluorinated compounds.