N -Fluoroalkylated 1,2,3-triazoles underwent a microwave-heating-assisted ring opening, nitrogen molecule elimination and concomitant group rearrangement to form isolable N -fluoroalkylketenimines.

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.

Azomethine imines are valuable substrates for chemical synthesis in organic solvents that often require anhydrous conditions. Here, we introduce C,N-cyclic-N'-acyl azomethine imines (AMIs) to bioorthogonal reactions in an aqueous environment. These AMIs are stable under physiological conditions and react rapidly (k2 = 0.1-250 M-1 s-1, depending on pH) and chemoselectively with isonitriles in the presence of biological nucleophiles, including thiols. Live-cell imaging of cell-surface-bound isonitriles underlines the biocompatibility of the AMI-isonitrile ligation, and simultaneous one-pot triple-protein labeling demonstrates its orthogonality to commonly used bioorthogonal reactions, such as the SPAAC and iEDDA ligations.

Fluorinated azidoalkanes have emerged recently as novel and surprisingly stable azides. Their easy preparation and commercial availability have opened up new possibilities for their application in organic synthesis. This review is focused on the use of fluorinated azidoalkanes in cycloaddition reactions leading to N-fluoroalkyl-1,2,3-triazoles. It also covers the rhodium-catalyzed and acid-mediated transformations of the triazoles to afford a variety of new N-fluoroalkyl nitrogen heterocycles and N-alkenyl compounds.

The front cover picture illustrates the reaction of N-fluoroalkylated-1,2,3-triazoles with aluminum trihalide, proceeding via a vinyl cation (illustrated as the structure in brackets in the middle) to afford structurally diverse N-haloalkenyl imidoyl halides. These products are formed in a stereoselective fashion on both double bonds and have been utilized in the synthesis of various N-alkenyl compounds, such as enamides, enamidines, enimines, N-alkenyl tetrazoles, and other. In this work, Beier and co-workers show a new, mild and efficient 1,2,3-triazole denitrogenative ring-opening process mediated by easily available Lewis acids. Details can be found in the Full Paper by Beier and co-workers (A. Markos, L. Janecký, T. Chvojka, T. Martinek, H. Martinez-Seara, B. Klepetářová, P. Beier, Adv. Synth. Catal. 2021, 363, 3258–3266; DOI: 10.1002/adsc.202100009).

N-Alkenyl compounds are versatile synthetic building blocks and their stereoselective transformations are key processes in the synthesis of many prominent classes of natural products, pharmaceuticals, and agrochemicals. However, a large structural variety of known N-alkenyl compounds and their diverse reactivity have so far precluded the development of a general method for their stereoselective synthesis. Herein we present an aluminum halide-mediated, highly stereoselective, efficient and scalable transformation of commercially available N-fluoroalkyl-1,2,3-triazoles to N-haloalkenyl imidoyl halides, and demonstrate their use in the synthesis of stereodefined N-alkenyl amides, amidines, imines, hydrazonoamides, imidothioates, iminophosphonates, 1,2,4-triazoles and tetrazoles. The reaction is of wide scope on both the triazole substrate and aluminum halide, providing highly functionalized products. Mechanistic and computational investigations suggest a reaction mechanism involving the triazole ring opening, initiated by the coordination of nitrogen one of the triazole ring to the Lewis acid, N-2 elimination and the formation of a vinyl cation intermediate, which reacts with nitrogen-bound aluminum halide, followed by a series of halide exchange reactions on C-X and Al-X bonds.

The stereoselective Suzuki–Miyaura cross-coupling of (Z)-β-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 β,β-diaryl-substituted enamides is observed. Thus, the method provides synthetic access to both isomers of the target enamides from (Z)-β-enamido triflates.

A reaction of N-sulfonyl-1,2,3-triazole with boron trifluoride etherate afforded a (Z)-β-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)-β-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.

Here, we have identified the interaction site of the contraceptive drug gamendazole using computational modeling. The drug was previously described as a ligand for eukaryotic translation elongation factor 1-α 1 (eEF1A1) and found to be a potential target site for derivatives of 2-phenyl-3-hydroxy-4(1 H)-quinolinones (3-HQs), which exhibit anticancer activity. The interaction of this class of derivatives of 3-HQs with eEF1A1 inside cancer cells was confirmed via pull-down assay. We designed and synthesized a new family of 3-HQs and subsequently applied isothermal titration calorimetry to show that these compounds strongly bind to eEF1A1. Further, we found that some of these derivatives possess significant in vitro anticancer activity.

N-Fluoroalkylated 1,2,3-triazoles in the presence of triflic acid or fluorosulfonic acid underwent a cascade reaction consisting of triazole protonation, ring opening, nitrogen elimination, sulfonate addition, HF elimination, and hydrolysis to furnish novel trifluoromethanesulfonyloxy- or fluorosulfonyloxy-substituted enamides, respectively, in a highly stereoselective fashion. The vinyl triflates underwent cross-coupling reactions to a variety of substituted enamides and serve as sources of the aminovinyl cations. In reactions with triflic acid, electron-rich triazoles afforded 2-fluoroalkylated oxazoles.

Synthesis of 2-fluoroalkyl imidazoles, oxazoles and thiazoles fromN-fluoroalkyl-1,2,3-triazoles was developed.

A rhodium-catalyzed transannulation via ring-opening of N-(per)fluoroalkyl-substituted 1,2,3-triazoles followed by cycloaddition with different nitriles, enol ethers, isocyanates and silyl ketene acetals under microwave heating provided a highly efficient route to previously unreported N-(per)fluoroalkyl-substituted imidazoles, pyrroles, imidazolones and pyrrolones, respectively. These reactions were found to be applicable to the synthesis of a variety of 5-membered heterocycles bearing different (per)fluoroalkyl substituents as well as both electron-donating and electron-withdrawing groups attached to the heterocyclic core.