In this study, we explore a new approach for the mild and selective activation of C(sp3)-F bonds in fluorinated azidoalkanes. Our approach utilizes electrophilic azide groups, which promote fluoride elimination and enable nucleophilic addition to newly formed electrophilic sites. This method achieves rapid, high-yield transformations of (per)fluoroalkyl azides into novel sulfur-containing azides, imines, and triazoles under mild conditions and using inexpensive reagents. The reaction proceeds without metal catalysts or external energy input and displays broad functional group tolerance, including toward thiol-sensitive motifs. Mechanistic studies supported by spectroscopy and x-ray crystallography, corroborated by ab initio calculations, reveal key azide intermediates and establish the denitrogenation pathway via α,α-disubstituted species. This transformation provides a practical and scalable route for the conversion of (per)fluoroalkyl azides into nitrogen- and sulfur-functionalized scaffolds, advancing C─F activation processes.

2-Fluoro-6-fluoroalkylpyridines and their ring-fused analogues were synthesized from N-fluoroalkyl-4-alkenyl-1,2,3-triazoles by thermal denitrogenation, fluorine shift, cyclization, and hydrogen fluoride elimination. This reaction proceeds via ketenimine intermediates. Conversely, 2-fluoroalkylpyridines were prepared starting from N-fluoroalkyl-4-alkyl-1,2,3-triazoles and proceeded by denitrogenation, fluorine shift, hydride shift, cyclization, and hydrogen fluoride elimination. Nucleophilic aromatic substitution of 2-fluoro-6-fluoroalkylpyridines afforded highly functionalized 2-fluoroalkylpyridines.

Stable secondary N-trifluoromethylamides have been prepared and isolated by two complementary methods: from N-trifluoromethyl-1,2,3-triazoles via thermally generated ketenimines, and by thioacid ligation with azidotrifluoromethane. These transformations overcome the long-standing instability of N-trifluoromethyl amine precursor and provide direct, scalable routes to bench-stable secondary N-trifluoromethyl- and N-fluoroalkylamides, tolerating diverse functional groups and structural motifs. Detailed experimental and computational studies reveal their high thermal stability, good hydrolytic stability, significantly higher acidity, and enhanced lipophilicity and hydrogen bond donor strength compared to conventional secondary amides. The new class of compounds expands the chemical space of fluorinated amides and introduces N-(per)fluoroalkyl secondary amides as easy to handle molecules with potential applications in medicinal and material chemistry.

Strain-promoted azide-alkyne cycloaddition (SPAAC) is a cornerstone of bioorthogonal chemistry, offering metal-free and biocompatible ligation for applications ranging from bioconjugation to live-cell imaging. However, its relatively slow kinetics and limited selectivity hinder the simultaneous labelling of multiple targets. Here, we report on a systematic study of fluoroalkyl azides as SPAAC reagents that display enhanced reactivity with electron-rich cyclooctynes, while showing significantly reduced reactivity with electron-deficient dipolarophiles. Kinetic measurements revealed over 100-fold rate differences depending on the azide-alkyne pair, enabling orthogonal bioconjugation in both purified proteins and living cells. Quantum chemical calculations support the feasibility and qualitative trends of these SPAAC reactions while highlighting the limitations of simple frontier-orbital descriptors and inverse-electron-demand arguments. Fluorescently labelled fluoroalkyl and alkyl azide probes demonstrate the selective labeling of modified antibody trastuzumab and protein concanavalin A in vitro and the selective labelling of organelles in living cells. This dual-selectivity strategy enables orthogonal SPAAC labeling.

Twelve model amino-based linear D-pi-A and tripodal D-(pi-A)3 chromophores bearing electron-withdrawing SF5-group(s) at different peripheral positions were designed and prepared in a straightforward way. The influence of the position and the number of SF5-groups was studied with the aid of single crystal X-ray analysis, thermal and electrochemical measurements, (non)linear steady-state and time resolved spectroscopies, and DFT calculations. Significant property tuning can be achieved when modulating the number and position of the (peripheral) SF5-group(s), e.g. increase of the thermal robustness from 300 to 420 degrees C, the HOMO-LUMO gap is tuned through an exclusive manipulation of the LUMO, and the absorption/emission maxima can be red-shifted. The para-positioning allowing their hyperconjugation and the increasing number of the appended SF5-groups along with a polar environment support the intramolecular charge-transfer and open a non-radiative deexcitation channel, while the two-photon absorption cross-section is generally enhanced for the para-substituted octupolar chromophores. Thus, properly placing the SF5-group(s) along the pi-conjugated backbone allows a principal tuning of the push-pull chromophore fundamental function(s).

Diazidodifluoromethane was prepared from dibromodifluoromethane, sodium azide and an alkanethiolate initiator. It represents the first example of a diazidomethane that is stable enough to be used in synthesis. The stability of (poly)azidomethanes was explored with ab initio calculations. Copper(I)-catalysed azide-alkyne cycloaddition of the title azide with alkynes afforded difluoromethylene-containing bis(1,2,3-triazoles)amenable to Rh(II)-catalysed transannulation with nitriles to difluoromethylene bis(imidazoles).

A reaction between azide, alkyne and 2H-azirine resulted in C-C bond formation at position five of 1,2,3-triazole, instead of previously misidentified C-N bond connectivity. The reaction mechanism of this C-C bond formation on the triazole ring was fully explained by employing calibrated QM(DFT-D3) calculations. Functionalization of primary products provided substituted pyrimidine, furan or 1,3-oxazepine.

A mild, rapid, and regioselective cyclization of azidofluoroalkanes with carbonyl-stabilized phosphonium ylides, resulting in the formation of 1-fluoroalkyl-5-substituted-1,2,3-triazoles, is presented. The synthetic method tolerates air and water, works at room temperature in a benign solvent, and is metal-free. Both starting materials are commercially available and easily prepared. The cyclization method was expanded to 4-halogen-substituted analogues of target triazoles, which underwent either rhodium-catalyzed transannulation with benzonitrile to yield uniquely substituted N-fluoroalkylated 4-haloimidazoles or cross-coupling reactions to produce fully substituted N-fluoroalkylated triazoles.

A highly efficient and atom-economical method for the C-H trifluoromethylation of (hetero)arenes and complex biomolecules has been developed using a substoichiometric amount of the stable tetrakis(trifluoromethyl)cuprate(iii) salt. Upon violet-light irradiation in the presence of an oxidant, all four CF3 groups are sequentially converted into trifluoromethyl radicals, enabling high-yielding transformations under mild conditions. The protocol exhibits excellent functional group tolerance and is applicable to the late-stage trifluoromethylation of pharmaceuticals, amino acids, and nucleosides. Mechanistic studies support a photoinitiated radical pathway and reveal the full utilization of the Cu(iii) species. The results presented advance the use of copper-mediated strategies for the sustainable incorporation of fluorine into complex molecules.

Trifluoromethyl nitrene generated photocatalytically from azidotrifluoromethane was added to sulfides to afford new N-trifluoromethylsulfilimines. Their methylation yielded N-methyl-N trifluoromethyl sulfonium salts and oxidation provided N-trifluoromethyl sulfoximines.

Direct N-acylation of 1,2,3-NH-triazoles aimed at obtaining elusive N-acyl-1,2,3-triazoles was investigated. A preference for the formation of thermodynamically favoured N2 isomers was established and an influence of the hard/soft character of the electrophile on the regioselectivity of acylation was found. Although N-acylated 1,2,3-triazoles are hydrolytically unstable compounds, they were isolated and fully characterized, including crystal structure determination of examples of N1 and N2 acylated products by X-ray difraction. N1- and N2-acyltriazoles interconvert in the presence of Bronsted or Lewis acids, which explained the efficiency of triazole cleavage transformations proceeding via N1-acylated triazoles. Efficient synthesis of enamido triflates from NH-triazoles proceeding via the intermediacy of N2-acyl-1,2,3-triazoles was developed.

Strain-promoted azide–alkyne cycloaddition (SPAAC) is a cornerstone of bioorthogonal chemistry, offering metal-free and biocompatible ligation for applications ranging from bioconjugation to live-cell imaging. However, its relatively slow kinetics and limited selectivity hinder the simultaneous labelling of multiple targets. Here, we report on a systematic study of fluoroalkyl azides as novel SPAAC reagents that display enhanced reactivity with electron-rich cyclooctynes, while showing significantly reduced reactivity with electron-deficient dipolarophiles. Kinetic measurements revealed over 100-fold rate differences depending on the azide–alkyne pair, enabling orthogonal bioconjugation in both purified proteins and living cells. Experimental and computational data support the rate trends and mechanistic rationale based on electronic complementarity. Fluorescently labelled fluoroalkyl and alkyl azide probes demonstrate the selective labeling of modified antibodies and lectin protein in vitro and the selective labelling of organelles in living cells. This dual-selectivity strategy enables orthogonal SPAAC labeling.

An efficient one-pot microwave-assisted potassium fluoride-mediated synthesis of 1-fluoroalkyl-3-fluoroisoquinolines and fused fluoroalkylpyridines from N-fluoroalkylated 1,2,3-triazoles was developed. The reaction has a wide scope and allows the preparation of structurally diverse 3-fluoroisoquinolines with a fluoroalkyl group in position 1, a substituent in position 4 and a substituent on the fused benzene (or heteroaromatic) ring. N-Fluoroalkylated ketenimines, which undergo stereoselective formal 1,3-fluorine shift to difluoroazadienes, were identified as intermediates in the reaction sequence. The presence of fluorine in position 3 and a halogen in position 4 of the resulting isoquinolines allowed for further modification by nucleophilic aromatic substitution and cross-coupling reactions, respectively. The developed methodologies were utilized for the synthesis of derivatives of drug candidates.

A one-pot multistep methodology leading to trifluoromethylated cyclopenta[c]isoquinolines, indeno[1,2-c]isoquinolines, 6,6-difluoro-1,3-oxazines, or 1,3-oxazin-6-ones, based on the reaction of 5-acylated N-pentafluoroethyl-substituted 1,2,3-triazoles is presented. A thermal ring opening of the starting triazoles, followed by a 1,2-acyl shift formed reactive ketenimines which cyclized after a rearrangement in a substrate-specific manner to provide new trifluoromethylated heterocyclic products.

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.

Tris(trifluoromethyl)copper(III) – Cu(CF3)3 – was prepared for the first time and fully characterized in the form of weakly coordinated highly reactive solvent adducts (DMF)2Cu(CF3)3 and (MeCN)Cu(CF3)3. DFT calculation studies confirmed the superacid properties of Cu(CF3)3 molecule, exhibiting higher expected Lewis acidity than SbF5, which makes it one of the strongest Lewis acids known (pF- = -13.9). Substitution of solvent molecules with monoanionic ligands in mild conditions afforded the first Cu(III) carboxylates [Cu(CF3)3(OAc)]- and [Cu(CF3)3(OBz)]- and Cu(III) nitrito complex [Cu(CF3)3(ONO)]-. An improved synthesis of valuable Grushin’s reagents via the intermediary (MeCN)Cu(CF3)3 was developed.

Ring-fused 1,2,3-triazoles are important biologically active compounds and synthetic intermediates. Known methods for their synthesis are limited mostly to triazoles fused to six-membered or larger rings. Herein we disclose a synthetic approach to triazoles fused to five-membered rings based on copper(I)-promoted double cyclization consisting of azide-alkyne cycloaddition, followed by cross coupling to aryl iodides.

image [3802‐95‐7] CF 3 N 3 (MW 111.03) InChI = 1S/CF3N3/c2‐1(3,4)6‐7‐5 InChiKey = VTWUWWKZOBMMPO‐UHFFFAOYSA‐N Physical Data : bp −28.5 °C (at 743 torr) estimated. Solubility : soluble in THF, chloroform, and most organic solvents. Form Supplied in : solution in THF (0.5 M). Preparative Methods : azidotrifluoromethane 1,2 was prepared by the reaction of trifluoronitrosomethane with hydrazine, followed by the treatment with chlorine gas (eq 1). 3–5 Azidotrifluoromethane was also prepared starting from electrophilic azide reagent tosyl azide and TMSCF 3 activated with cesium fluoride and was isolated by distillation (eq 2). 6 image image Handling, Storage, and Precautions : CF 3 N 3 is thermally relatively stable and safe to use in laboratory in solution at temperatures <150 °C. 6 Can be stored in THF solution in a fridge or a freezer due to compound volatility. Storage in pure form in a stainless‐steel cylinder at ambient temperature at several atmospheres' pressure did not result in any significant decomposition. 5 Decomposition was reported at 1120 K to give N 2 and FCN. 7 Also, an explosion was reported at 330 °C. 4