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

We herein describe a general approach to 5-trifluoromethyl 1,2,4-triazoles via the [3 + 2]-cycloaddition of nitrile imines generated in situ from hydrazonyl chloride with CF3CN, utilizing 2,2,2-trifluoroacetaldehyde O-(aryl)oxime as the precursor of trifluoroacetonitrile. Various functional groups, including alkyl-substituted hydrazonyl chloride, were tolerated during cycloaddition. Furthermore, the gram-scale synthesis and common downstream transformations proved the potential synthetic relevance of this developed methodology.


Results
Our study commenced by choosing N-phenyl-benzohydrazonoyl chloride, 2a, and trifluoroacetaldehyde O- (2,4-dinitrophenyl) oxime, 1, as the model substrates (Table 1), using our previously reported optimized conditions for the synthesis of trifluoromethylated oxadiazoles [38]. To our delight, the reaction of 2a with 1 in a 1:2 ratio in the presence of 2.0 equiv of NEt3 afforded the desired product, 5-trifluoromethyl 1,2,4-triazole, 3a, in 3% and 8% yields in THF and DMSO, respectively (Entries 1 and 2). Among other solvents (Entries 3−6), the reaction worked best in CH2Cl2 (Entry 5), whereas in toluene, the reaction could not proceed (Entry 6). Notably, upon increasing the amount of 2a and keeping the other parameters constant, the yield of 3a was further improved (37% and 49% with 2a and 1 in 1:1 and 2:1 ratios, respectively; Entries 7 and 8). Gratifyingly, the yield of 3a was further improved to 75% by increasing the amount of NEt3 (3.0 equiv) (Entry 9). The best yield (83%) was obtained with the reaction of 2a with 1 in a 1.5:1 ratio in the presence of 3.0 equiv of NEt3 in CH2Cl2 (Entry 10). Subsequently, the efficacy of this developed protocol for the regioselective synthesis of 5-trifluoromethyl 1,2,4-triazoles with various hydrazonyl chlorides 2 was investigated ( Figure 2). The reaction of 3-, or 4-Me-, and 4-t-Bu-substituted on the Ar moieties of hydrazonyl chlorides 2b-2d with 1 provided annulated products 3b-3d in 98%, 75%, and 60% yields, respectively. The variation in the electronic properties of the aryl substituents in the hydrazonyl chlorides had a significant effect on the reaction efficiency. The reaction of the hydrazonyl chloride possessing a strong electron-donating group such as -OMe (2e) successfully provided the corresponding triazole, 3e, with good yield (75%). On the other hand, the substrates (2f and 2g) containing strongly electron-withdrawing substituents (-CO 2 Me, -CF 3 , and -SO 2 N(n-Pr) 2 ) furnished the desired triazoles (3f-3h) in moderate yields. These results are consistent with the previous observations in the synthesis of 1,2,4triazol-3-ones by Wu and co-workers [42]. Of note, the halogen substituents, such as fluoro, and chloro, were also tested for the cycloaddition, and to our delight, good yields (56-74%) of the corresponding triazoles products, 3i-3l, were obtained. A 2-naphthyl-substituted hydrazonyl chloride also furnished the desired product, 3m, in 75% yield. Likewise, 2thienyl substituted hydrazonyl chloride also smoothly underwent a reaction with 1, giving the desired product, 3n, in a 55% yield.   Meanwhile, cycloaddition was tested with different substituents at the Ar moieties of the hydrazonyl chlorides. Under the optimized conditions, a wide range of hydrazonyl chlorides contained different functional groups, such as methyl, tert-butyl, benzyloxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, and bromo groups, which were well tolerated and afforded triazole products 3o-3ab in good yields (40-65%). 2-naphthylsubstituted hydrazonyl chloride was also efficient as a substrate to produce corresponding product 3ac in a 67% yield.
The structures of products 3a-3ac were confirmed by the IR spectroscopy, and 1 H, 13 C{ 1 H}, 19 F NMR spectroscopy (Supplementary Materials). Additionally, the structure of 3s was unambiguously confirmed via single-crystal X-ray diffraction analyses (Figure 3). Meanwhile, cycloaddition was tested with different substituents at the Ar moieties of the hydrazonyl chlorides. Under the optimized conditions, a wide range of hydrazonyl chlorides contained different functional groups, such as methyl, tert-butyl, benzyloxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, and bromo groups, which were well tolerated and afforded triazole products 3o−3ab in good yields (40%−65%). 2-naphthyl-substituted hydrazonyl chloride was also efficient as a substrate to produce corresponding product 3ac in a 67% yield.
The structures of products 3a−3ac were confirmed by the IR spectroscopy, and 1 H, 13 C 1 H , 19 F NMR spectroscopy (Supplementary Materials). Additionally, the structure of 3s was unambiguously confirmed via single-crystal X-ray diffraction analyses (Figure 3). Next, we attempted the cycloaddition of alkyl-substituted hydrazonyl chlorides 4 with 1 (Figure 4). Under the optimized conditions, both methyl, ethyl, and n-propyl-substituted hydrazonyl chlorides furnished the desired products, 5a−5c, in only moderate yields (22%−40%), which could be a result of the inherent instability of the hydrazonyl chloride substrates with an alkyl substituent. However, ester-substituted hydrazonyl chloride 4d did not result in the desired cyclized product, 5d, under our standard or modified reaction conditions, probably due to the resulting decreased nucleophilicity of the nitrogen atom through the conjugated system from the nitrile imine intermediates. Nevertheless, a hydrazonyl chloride with a t-butyl substituent on the nitrogen atom reacted with 1 to produce the corresponding product, 5e, in a 26% yield (Scheme 2). Next, we attempted the cycloaddition of alkyl-substituted hydrazonyl chlorides 4 with 1 ( Figure 4). Under the optimized conditions, both methyl, ethyl, and n-propyl-substituted hydrazonyl chlorides furnished the desired products, 5a-5c, in only moderate yields (22-40%), which could be a result of the inherent instability of the hydrazonyl chloride substrates with an alkyl substituent. However, ester-substituted hydrazonyl chloride 4d did not result in the desired cyclized product, 5d, under our standard or modified reaction conditions, probably due to the resulting decreased nucleophilicity of the nitrogen atom through the conjugated system from the nitrile imine intermediates. Meanwhile, cycloaddition was tested with different substituents at the Ar moieties of the hydrazonyl chlorides. Under the optimized conditions, a wide range of hydrazonyl chlorides contained different functional groups, such as methyl, tert-butyl, benzyloxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, and bromo groups, which were well tolerated and afforded triazole products 3o−3ab in good yields (40%−65%). 2-naphthyl-substituted hydrazonyl chloride was also efficient as a substrate to produce corresponding product 3ac in a 67% yield.
The structures of products 3a−3ac were confirmed by the IR spectroscopy, and 1 H, 13 C 1 H , 19 F NMR spectroscopy (Supplementary Materials). Additionally, the structure of 3s was unambiguously confirmed via single-crystal X-ray diffraction analyses (Figure 3). Next, we attempted the cycloaddition of alkyl-substituted hydrazonyl chlorides 4 with 1 (Figure 4). Under the optimized conditions, both methyl, ethyl, and n-propyl-substituted hydrazonyl chlorides furnished the desired products, 5a−5c, in only moderate yields (22%−40%), which could be a result of the inherent instability of the hydrazonyl chloride substrates with an alkyl substituent. However, ester-substituted hydrazonyl chloride 4d did not result in the desired cyclized product, 5d, under our standard or modified reaction conditions, probably due to the resulting decreased nucleophilicity of the nitrogen atom through the conjugated system from the nitrile imine intermediates. Nevertheless, a hydrazonyl chloride with a t-butyl substituent on the nitrogen atom reacted with 1 to produce the corresponding product, 5e, in a 26% yield (Scheme 2). Nevertheless, a hydrazonyl chloride with a t-butyl substituent on the nitrogen atom reacted with 1 to produce the corresponding product, 5e, in a 26% yield (Scheme 2). Nevertheless, a hydrazonyl chloride with a t-butyl substituent on the nitrogen atom reacted with 1 to produce the corresponding product, 5e, in a 26% yield (Scheme 2).

Scheme 2. Synthesis of 5e.
To assess the scale-up of the procedure, the reaction of 2a with 1 as the representative example was investigated on a 10.0 mmol scale (Scheme 3). Under the optimized reaction conditions, the cycloaddition occurred to give 3a in a 56% (1.63 g) yield.
To assess the scale-up of the procedure, the reaction of 2a with 1 as the representative example was investigated on a 10.0 mmol scale (Scheme 3). Under the optimized reaction conditions, the cycloaddition occurred to give 3a in a 56% (1.63 g) yield.

Scheme 3. Gram-scale synthesis of 3a.
To further demonstrate the synthetic utility of the products, Heck reaction and Sonogashira coupling of bromide 3l were carried out with p-methylstyrene and phenylacetylene to afford the corresponding products, 6 and 7, in 62% and 71% yields, respectively (Scheme 4a). Finally, the bromination of the C−H bond of 3e was performed under oxidative conditions to furnish product 8 in a 74% yield (Scheme 4b). To further demonstrate the synthetic utility of the products, Heck reaction and Sonogashira coupling of bromide 3l were carried out with p-methylstyrene and phenylacetylene to afford the corresponding products, 6 and 7, in 62% and 71% yields, respectively (Scheme 4a). Finally, the bromination of the C-H bond of 3e was performed under oxidative conditions to furnish product 8 in a 74% yield (Scheme 4b).
To assess the scale-up of the procedure, the reaction of 2a with 1 as the representative example was investigated on a 10.0 mmol scale (Scheme 3). Under the optimized reaction conditions, the cycloaddition occurred to give 3a in a 56% (1.63 g) yield.

Scheme 3. Gram-scale synthesis of 3a.
To further demonstrate the synthetic utility of the products, Heck reaction and Sonogashira coupling of bromide 3l were carried out with p-methylstyrene and phenylacetylene to afford the corresponding products, 6 and 7, in 62% and 71% yields, respectively (Scheme 4a). Finally, the bromination of the C−H bond of 3e was performed under oxidative conditions to furnish product 8 in a 74% yield (Scheme 4b). Based on the results obtained from these experiments and literature reports [38,43], a plausible mechanism for the formation of 5-trifluoromethyl 1,2,4-triazole (3) was proposed (Scheme 5). The nitrile imine generated in situ from hydrazonyl chloride 2 in the presence of a base underwent regioselective [3 + 2] cycloaddition with the in situ-generated CF 3 CN from 1 to generate the desired product, 3. presence of a base underwent regioselective [3 + 2] cycloaddition with the in situ-generated CF3CN from 1 to generate the desired product, 3.

Scheme 5.
Proposed mechanism for the formation of 3.

Materials and Methods
1 H NMR, 19 F NMR, and 13 C NMR spectra were recorded using a Bruker AVIII 400 spectrometer. 1 H NMR and 13 C NMR chemical shifts were reported in parts per million (ppm) downfield from tetramethylsilane, and 19 F NMR chemical shifts were determined relative to CFCl3 as the external standard; low field was positive. Coupling constants (J) are reported in Hertz (Hz). The residual solvent peak was used as an internal reference: 1 H NMR (CDCl3 δ 7.26), 13 C NMR (CDCl3 δ 77.0). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. The infrared (IR) spectra were recorded using Nicolet iS50 at room temperature. HRMS were obtained from State Key Discipline Testing Center for Physical Chemistry of Fuzhou University. Trifluoroacetaldehyde O-(2,4-dinitrophenyl) oxime 1 [38], and N'-phenylacylhydrazides and hydrazonoyl chlorides [44,45] were prepared according to the published procedures. Starting materials and solvents that were received from commercial sources were used without further purification. Column chromatography purifications were performed via flash chromatography using Merck silica gel 60.
Caution: It is known that trifluoroacetonitrile is a highly toxic gas (boiling point, −64 °C) and must be handled with care. The rapid evolution of CF3CN gas occurs when this precursor reacts with base. All operations were performed in a fume hood under good conditions.

General Procedure for the Synthesis of 5-Trifluoromethyl 1,2,4-Triazoles 3
A mixture of hydrazonoyl chloride, 2 (0.30 mmol, 1.5 equiv), and trifluoroacetaldehyde O- (2,4-dinitrophenyl) oxime, 1 (54.1 mg, 0.20 mmol, 1.0 equiv), in CH2Cl2 (1.0 mL) was added to a Schlenk tube equipped with a stir bar. Then, NEt3 (60.6 mg, 83.2 μL, 0.60 mmol, 3.0 equiv) was added. The tube was immediately sealed with a Teflon cap and stirred at room temperature for 12 h. After the reaction was terminated, the solvent was removed in vacuo under reduced pressure. Product 3 was purified via flash column chromatography on silica gel with petroleum ether and CH2Cl2 as eluent.

Crystal Structure Analyses
The suitable crystals of 3s were mounted on quartz fibers and X-ray data collected on a Bruker AXS APEX diffractometer, equipped with a CCD detector at -50 ºC, using MoKα radiation (λ 0.71073 Å). The data was corrected for Lorentz and polarisation effect with the SMART suite of programs and for absorption effects with SADABS [46]. Structure solution and refinement were carried out with the SHELXTL suite of programs. The structure was solved by direct methods to locate the heavy atoms, followed by difference Scheme 5. Proposed mechanism for the formation of 3.

Materials and Methods
1 H NMR, 19 F NMR, and 13 C NMR spectra were recorded using a Bruker AVIII 400 spectrometer. 1 H NMR and 13 C NMR chemical shifts were reported in parts per million (ppm) downfield from tetramethylsilane, and 19 F NMR chemical shifts were determined relative to CFCl 3 as the external standard; low field was positive. Coupling constants (J) are reported in Hertz (Hz). The residual solvent peak was used as an internal reference: 1 H NMR (CDCl 3 δ 7.26), 13 C NMR (CDCl 3 δ 77.0). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. The infrared (IR) spectra were recorded using Nicolet iS50 at room temperature. HRMS were obtained from State Key Discipline Testing Center for Physical Chemistry of Fuzhou University. Trifluoroacetaldehyde O-(2,4-dinitrophenyl) oxime 1 [38], and Nphenylacylhydrazides and hydrazonoyl chlorides [44,45] were prepared according to the published procedures. Starting materials and solvents that were received from commercial sources were used without further purification. Column chromatography purifications were performed via flash chromatography using Merck silica gel 60.
Caution: It is known that trifluoroacetonitrile is a highly toxic gas (boiling point, −64 • C) and must be handled with care. The rapid evolution of CF 3 CN gas occurs when this precursor reacts with base. All operations were performed in a fume hood under good conditions.
General Procedure for the Synthesis of 5-Trifluoromethyl 1,2,4-Triazoles 3 A mixture of hydrazonoyl chloride, 2 (0.30 mmol, 1.5 equiv), and trifluoroacetaldehyde O-(2,4-dinitrophenyl) oxime, 1 (54.1 mg, 0.20 mmol, 1.0 equiv), in CH 2 Cl 2 (1.0 mL) was added to a Schlenk tube equipped with a stir bar. Then, NEt 3 (60.6 mg, 83.2 µL, 0.60 mmol, 3.0 equiv) was added. The tube was immediately sealed with a Teflon cap and stirred at room temperature for 12 h. After the reaction was terminated, the solvent was removed in vacuo under reduced pressure. Product 3 was purified via flash column chromatography on silica gel with petroleum ether and CH 2 Cl 2 as eluent.

Crystal Structure Analyses
The suitable crystals of 3s were mounted on quartz fibers and X-ray data collected on a Bruker AXS APEX diffractometer, equipped with a CCD detector at −50 ºC, using MoKα radiation (λ 0.71073 Å). The data was corrected for Lorentz and polarisation effect with the SMART suite of programs and for absorption effects with SADABS [46]. Structure solution and refinement were carried out with the SHELXTL suite of programs. The structure was solved by direct methods to locate the heavy atoms, followed by difference maps for the light non-hydrogen atoms. CCDC 2183507 contain the supplementary crystallographic data. These data can also be obtained free of charge at ccdc.cam.ac.uk/structures/ from the Cambridge Crystallographic Data Centre.