Synthesis of 3-Trifluoromethyl-1,2,4-triazolines and 1,2,4-Triazoles via Tandem Addition/Cyclization of Trifluoromethyl N-Acylhydrazones with Cyanamide

Abstract

A tandem addition/cyclization reaction between trifluoromethyl N-acylhydrazones and cyanamide is described, which provides a novel and efficient process for the synthesis of polysubstituted 3-trifluoromethyl-1,2,4-triazolines and their derivatives. The method has the advantages of mild reaction conditions, a broad substrate scope, good product yields, and atom economy.

K2CO3-Catalyzed (3 + 2) Cycloaddition Reaction of N-2,2,2-Trifluoroethylisatin Ketimines with Azodicarboxylates: Access to Spirooxindoles Containing Trifluoromethyl-1,2,4-triazolines

“…Spirooxindole core is an important structural motif, especially spirooxindoles bearing an N -heterocycle at the 3-position are widely found in many natural products and bioactive compounds due to their significant bioactivities, making them attractive targets in organic synthesis (Figure a–c). , Organofluorine chemistry is of great importance in the fields of agrochemicals, biology, medicine, and materials science. In the field of medicinal chemistry, the introduction of fluorine, especially trifluoromethyl, into biologically active molecules can effectively improve binding affinity, lipophilicity, metabolic stability, bioavailability, and other properties, and is therefore widely used in the design and development of new drugs. , Among a large number of trifluoromethylated drugs, trifluoromethyl-1,2,4-triazole derivatives have attracted a lot of attention in recent years due to their numerous potential uses in drug development, such as the glucose-lowering drug sitagliptin, anti-HIV-1 reagents, and Gly T1 inhibitors (Figure d–f) …”

Tandem Addition/Cyclization/Halogenation Reaction of Difluoromethylated N-Acylhydrazones with Allyltrimethylsilanes

“…In our group, we are endeavoring on the development of efficient methods to construct fluorine-containing heterocycles and find that fluoroalkylated N -acylhydrazones and nitrile imines are versatile building blocks for the synthesis of various fluorine-containing heterocycles such as pyrazoles, pyrazolines, pyrazolidines, imidazolines, imidazolidines, dihydropyridazines, oxadiazoles, triazoles, and triazolines . However, difluoromethylated N -acylhydrazones have never been synthesized and used for the construction of difluoromethylated heterocycles.…”

“…In our group, we are endeavoring on the development of efficient methods to construct fluorine-containing heterocycles and find that fluoroalkylated N-acylhydrazones and nitrile imines are versatile building blocks for the synthesis of various fluorine-containing heterocycles such as pyrazoles, 16 pyrazolines, 17 pyrazolidines, 18 imidazolines, 19 imidazolidines, 20 dihydropyridazines, 21 oxadiazoles, 22 triazoles, and triazolines. 23 However, difluoromethylated N-acylhydrazones have never been synthesized and used for the construction of difluoromethylated heterocycles. Herein, we report that difluorome- thylated N-acylhydrazones can be used as stable difluoromethyl building blocks to react with allyltrimethylsilanes in the presence of N-bromosuccinimide (NBS) to afford 3-difluoromethylpyrazolines in good yields through a one-pot tandem addition/ cyclization/halogenation reaction (Scheme 1, c).…”

Regioselective Synthesis of 5-Trifluoromethyl 1,2,4-Triazoles via [3 + 2]-Cycloaddition of Nitrile Imines with CF3CN

“…It has been well established that the introduction of trifluoromethyl into therapeutic compounds can impart beneficial effects to lipophilicity, metabolic stability, conformational preference, and bioavailability [ 9 , 10 , 11 ]. As a consequence, a broad range of protocols for the construction of trifluoromethylated 1,2,4-triazoles have been disclosed [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”