Metal-free synthesis of 3-trifluoromethyl-1,2,4-triazoles via multi-component reaction of trifluoroacetimidoyl chlorides, hydrazine hydrate and benzene-1,3,5-triyl triformate

A convenient approach for the construction of pharmaceutically valuable 3-trifluoromethyl-1,2,4-triazoles has been developed, which employs the readily available trifluoroacetimidoyl chlorides, hydrazine hydrate and benzene-1,3,5-triyl triformate (TFBen) as starting materials. The multi-component reaction features broad substrate scope, high efficiency, and scalability, providing a facile and straightforward route to the biologically important 3-trifluoromethyl-1,2,4-triazole scaffolds in moderate to good yields. Considering its broad-spectrum pharmaceutical activity, the method offers the opportunity for the further study towards the toxicity risk assessment and structure-activity relationship of the pharmaceuticals containing trifluoromethyl-1,2,4-triazole cores.


General Information
Unless otherwise noted, all reactions were carried out under N2 atmosphere. All reagents were from commercial sources and used as received without further purification. All solvents were dried by standard techniques and distilled prior to use. Column chromatography was performed on silica gel (200-300 meshes) using petroleum ether (bp. 60~90 °C ) and ethyl acetate as eluent. 1 NMR spectra were recorded on a Bruker Avance operating at for 1 H NMR at 400 MHz, 13 C NMR at 100 MHz and spectral data were reported in ppm relative to tetramethylsilane (TMS) as internal standard and CDCl3 ( 1 H NMR δ 7.26, 13 C NMR δ 77.16) or DMSO-D6 ( 1 H NMR δ 2.50, 13 C NMR δ 39.52) as solvent. All coupling constants (J) are reported in Hz. The following abbreviations were used to describe peak splitting patterns when appropriate: s = singlet, d = doublet, dd = double doublet, ddd = double doublet of doublets, t = triplet, dt = double triplet, q = quatriplet, m = multiplet, br = broad. Mass spectroscopy data of the products were collected on an HRMS-TOF instrument or Waters TOFMS GCT Premier using EI or ESI ionization. Melting points were measured with WRR digital point apparatus and not corrected.

Preparation of Trifluoroacetimidoyl Chlorides 1
A 100 mL two-necked flask equipped with a septum cap, a condenser, and a Teflon-coated magnetic stir bar was charged with PPh3 (9.84 g, 37.5 mmol), Et3N (2.1 mL, 15 mmol), CCl4 (20.0 mL), and TFA (1.2 mL, 15 mmol). After the solution was stirred for about 10 min (ice bath), amine (15 mmol) dissolved in CCl4 (20.0 mL) was added. The mixture was then refluxed under stirring (3 h). After the reaction was completed, residual solid Ph3PO, PPh3 and Et3N-HCl were washed with petroleum ether several times. Then the petroleum ether was filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel or neutral alumina to afford the corresponding trifluoroacetimidoyl chloride products.

Preparation of Trifluoroacetimidohydrazide 1e'
A 15 mL In-Ex tube equipped with a diaphragm cover, a condenser and a Teflon-coated magnetic stir bar was charged with trifluoroacetimidoyl chloride 1e (3.0 mmol) and hydrazine hydrate (80%) (0.375 g, 6.0 mmol). The solution was stirred at 60 o C for about 20 minutes.
The crude product is then purified directly by column chromatography on silica gel to obtain the corresponding trifluoroacetimidohydrazide 1e' in almost quantitative yield.

General Procedure for the Synthesis of Products 2
Under air atmosphere, trifluoroacetimidoyl chloride 1 (0.2 mmol, 1.0 equiv), hydrazine hydrate (80%) (0.3 mmol, 1.5 equiv), TFBen (0.1 mmol, 0.5 equiv), TFA (22.8 mg, 0.2 mmol, 1.0 equiv) and toluene (2.0 mL) were added to an oven-dried 15 mL In-Ex tube. Then the tube was sealed and the mixture was stirred at 100 °C (oil bath) for 12 h. After the reaction was completed, the mixture was slowly cooled to room temperature, and extracted with EtOAc for three times (3×10 mL). The extract was combined and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to yield the 3-trifluoromethyl-1,2,4-triazole products 2.

Control Experiments
Eq. a: Under air atmosphere, trifluoroacetimidoyl chloride 1e (52.6 mg, 0.2 mmol, 1.0 equiv), hydrazine hydrate (80%) (18.7 mg, 0.3 mmol, 1.5 equiv), (HCHO)n (12 mg, 0.4 mmol, 2.0 equiv), TFA (22.8 mg, 0.2 mmol, 1.0 equiv) and toluene (2.0 mL) were added to an oven-dried 15 mL In-Ex tube. Then the tube was sealed and the mixture was stirred at 100 °C (oil bath) for 12 h. After the reaction was completed, the mixture was slowly cooled to room temperature, and extracted with EtOAc for three times (3×10 mL). The extract was combined and concentrated under vacuum. The desired product 2e was not observed. was stirred at 100 °C (oil bath) for 12 h. After the reaction was completed, the mixture was slowly cooled to room temperature, and extracted with EtOAc for three times (3×10 mL).
The extract was combined and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to yield the 3-trifluoromethyl-1,2,4-triazole products 2e as a white solid in 90% yield.
Eq. e: Under air atmosphere, trifluoroacetimidoyl chloride 1e (52.6 mg, 0.2 mmol, 1.0 equiv), HCONHNH2 (12 mg, 0.2 mmol, 1.0 equiv), TFA (22.8 mg, 0.2 mmol, 1.0 equiv) and toluene (2.0 mL) were added to an oven-dried 15 mL In-Ex tube. Then the tube was sealed and the mixture was stirred at 100 °C (oil bath) for 12 h. After the reaction was completed, the mixture was slowly cooled to room temperature, and extracted with EtOAc for three times (3×10 mL). The extract was combined and concentrated under vacuum. The desired product 2e was not observed.