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Article

Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction

by
Tinghong Tang
,
Cuiting Chen
,
Xin Fu
,
Huilan Xu
,
Luyong Wu
* and
Wenhao Chen
*
Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(6), 1191; https://doi.org/10.3390/molecules29061191
Submission received: 31 January 2024 / Revised: 20 February 2024 / Accepted: 27 February 2024 / Published: 7 March 2024
(This article belongs to the Special Issue Fluorinated Compounds: Access to Building Blocks and Their Transformation)
Browse Figures
Versions Notes

Abstract

:
Incorporation of a trifluoromethyl group with 1,2,3-triazoles motifs was described. We explored a click reaction approach for regioselective synthesis of 1-susbstituted-4-trifluoromethyl-1,2,3-triazoles in which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reacts with commercial 2-bromo-3,3,3-trifluoropropene (BTP) to form 3,3,3-trifloropropyne (TFP) in situ. Arising from merits associated with the availability and stability of BTP, and the high efficiencies of CuI/1,10-Phenanthroline (Phen)-catalyzed cycloaddition reactions of azides with alkynes, this readily performed click process takes place to form the target 1,2,3-triazoles in high yields, and with a wide azide substrate scope. The potential value of this protocol was demonstrated by its application to a gram-scale reaction.

1. Introduction

Since the time of its discovery in strategies to optimize the pharmacological properties of drug candidates [1,2,3,4], incorporation of the trifluoromethyl group has become a promising approach to discover new and/or improve existing bioactive compounds [5,6,7,8]. Although several valuable methods have been developed for the synthesis of trifluoromethyl-substituted compounds [9,10,11,12,13,14,15,16,17,18,19,20], methods that incorporate this group in an efficient and regiospecific manner remain in high demand [21,22,23,24,25,26,27], especially in the case of heterocyclic compounds [28,29,30,31,32,33,34,35].
In the past 20 years, 1,2,3-triazoles have been shown to be superior substances in drug discovery and biochemical applications [36,37,38,39,40,41]. As a result, considerable interest exists in devising strategies to prepare C4-, C5- or 1-trifluoromethyl-substituted 1,2,3-triazoles [42,43,44,45,46,47,48,49,50,51,52,53,54,55]. Currently, several noteworthy reactions exist that regioselectively generate 5-trifluoromethyl-1,2,3-triazoles [44,45,46,47,48,49,50,51,52], including trifluoromethylation of 5-iodotriazole [44,45]/5-stannyl triazoles [46], copper(I)-catalyzed interrupted click reaction [47,48], 1,3-dipolar cycloaddition [53] and annulation of perfluoroalkyl N-mesylhydrazones [49] or trifluoroacetimidoyl chlorides [50]. In contrast, much less attention has been given to the development of concise methods to produce 4-trifluoromethyl-1,2,3-triazoles. Among efforts aimed at this goal is the 2015 study by Ma and coworkers that demonstrated that silver-catalyzed cycloaddition reactions of arylisocyanides with 2,2,2-trifluorodiazoethane can be used to prepare 1-substituted-1,2,3-triazoles possessing a trifluoromethyl group at C4 (Scheme 1a) [54]. Unfortunately, use of alkylsubstituted isocyanides in this process gave rise to the formation of the corresponding 1,2,3-triazoles in low 28–54% yields. In 2021, Panish’s group developed a method to generate 4-trifluoromethyl-1,2,3-triazoles through copper-catalyzed reaction of 4,4,4-trifluoro-3-(2-tosylhdrazineylidene)butanoate with aromatic amines (Scheme 1b) [55]. The scope of substrate explored in this effort suggests that alkyl amines are not compatible with this approach. Although other multistep routes have been devised to prepare 4-trifluoromethyl-1,2,3-triazoles (Scheme 1c,d) [54,56,57,58,59], a facile method to produce 1-aryl- and 1-alkyl-substituted 4-trifluoromethyl-1,2,3-triazoles from low cost and commercially available CF3-building blocks is still lacking.
Click (cycloaddition) reactions of azides with alkynes are well-known, versatile protocols for construction of 1,2,3-triazoles [60,61,62]. Our continuing interest in the chemistry of 1,2,3-triazoles [63,64,65,66,67] and the importance of trifluoromethyl-substituted 1,2,3-triazoles encouraged us to evaluate the possibility of performing click reactions of 3,3,3-trifluoropropyne (TFP) with aryl- and alkyl-azides under mild and practical conditions. In contemplating possible methods to carry out these click reactions, we recognized that 2-bromo-3,3,3-trifluoropropylene (BTP) is a commercially available reagent [68,69,70,71,72], and that its [3+2]-cycloaddition reactions have been employed to produce CF3-substituted pyrazoles [73,74,75,76], -isoxazoles [77] and -pyrroles [78]. Particularly informative are the observations that BTP can be readily transformed to TFP by treatment with bases [79,80,81,82,83] like i-Pr2NLi and 1,8-diazabicyclo[5.4.0]undec-7-ene DBU, and that compared to gaseous TFP, BTP is an inflammable, storage-stable and easily handled liquid. Regrettably, it was inscrutably neglected to utilize BTP in click reactions to synthesize the 4-trifluoromethyl 1,2,3-triazoles.
Based on this information, we investigated copper-catalyzed click reactions of azides with BTP in the presence of DBU. In these processes, we expected that in the presence of DBU, BTP would be transformed to TFP, which then would undergo copper-catalyzed cycloaddition with azides to form the target 4-trifluoromethyl substituted-1,2,3-triazoles (Scheme 1e).

2. Results

The initial phase of this study was designed to evaluate the feasibility of the process described above. We observed that reaction of phenyl azide (2a) and BTP (1) in N,N-dimethylformamide (DMF) containing DBU or other bases at 100 °C did not generate the desired 1,2,3-triazole 3a (Table 1, entry 1). The result indicated that 1,3-dipolar cycloaddition of BTP with azide with bases could not construct 1,2,3-triazoles. However, when CuI was included in the mixture, reaction occurred to form 1-phenyl-4-trifluoromethyl-1,2,3-triazole (3a) in a highly regioselective manner and <50% yields (1H- and 13C-NMR analysis) (entry 2). Moreover, when the copper ligand 1,10-phenanthroline (Phen) is included and CH3CN is utilized as solvent, the 3a-forming click process takes place at temperatures >35 °C for 4 h but with a low 37% yield (entry 3). Importantly, at 65 °C, this reaction generates 3a at an excellent 95% yield (entry 6). The results of a screening study showed that when less expensive copper salts (CuBr, CuCl, Cu(OAc)2, CuSO4·5H2O), and other ligands (see in SI), solvents (entries 10–11, Table 1) or bases (see in SI) are utilized, the process takes place with lower yields. As in the results of other copper-catalyzed click reactions, Cu(I)/Phen was shown to have high catalytic efficiency in this process. Two substituted 1,10-phenanthrolines are included in the mixture as ligands to give similar yields (entries 12 and 13). Furthermore, reduction in the amount of DBU to 2.0 eq. does not impact the yield (entry 15), and a decrease in the amount of Phen to 5 mol% lowers the yield only slightly (entry 16). The survey showed that the optimized condition for the process forming 3a involves the use of CuI (10 mol%), Phen (10 mol%) and DBU (2.0 eq.) in CH3CN at 65 °C for 4 h.
Next, the aryl azide scope of this process carried out under the optimized conditions was evaluated. Firstly, aryl azides bearing both electron-donating and -withdrawing substituents at para-, meta- and ortho-positions react to produce corresponding 4-trifluoromethyl-1,2,3-triazoles in high to excellent yields (75–99%, Table 2). These results indicate that the efficiency of this transformation is not sensitive to electronic density and steric hindrance of the aromatic substituents. Furthermore, disubstituted aromatic azides participate efficiently in the click protocol (3u–3aa, 80–91%), and α-napththyl azide reacts smoothly to form triazole 3ab in 84% yield.
To reveal its versatility, we determined if the scope of the click reaction includes alkyl azides. In the effort, we observed that a wide variety of alkyl azides react with BTP under the optimized reaction conditions to generate the corresponding 1-alkyl-4-trifluoromethyl-1,2,3-triazoles in modest to high yields (Table 3). Of particular interest was the contrast between the earlier finding that 4-trifluoromethyl-1-adamantyl-1,2,3-triazole is generated at 52% by reaction of trifluorodiazoethane and adamantyl isonitrile [53] and our observation that this substance (4d, Table 3) is produced at a 91% yield by reaction of BTP with adamantyl azide. Obviously, this copper-catalyzed click process is more efficient to produce 4-trifluoromethyl 1,2,3-triazoles with high compatibility with functional groups. In addition, both (1-azidoethyl) benzene and (2-azidoethyl) benzene react to form the corresponding triazoles 4e and 4f, and reactions of arylmethyl azides with BTP produce the corresponding products in excellent yields. Exceptions to this trend are found in reactions of 4-pyridylmethyl and N-phthalimidylethyl azide that take place less efficiently. The decreasing yields might be attributed to the coordination of the nitrogen-containing substrates with the copper catalyst to affect the catalytic capacity.
To illustrate the value of the newly developed method further, a gram-scale reaction of 2a with BTP was carried out under the standard conditions. Notably, this process formed 1,2,3-triazole 3a at a relatively high isolated yield of 88% (Scheme 2).
When heating the mixture of phenyl azide (2a), BTP (1) and bases, the product 3a was not observed. We speculated that this process is not 1,3-dipolar cycloaddition of BTP with azide. Based upon experiments and the literature [81,82,83,84], a possible pathway was proposed as Scheme 3. Firstly, BTP is converted to TFP by treatment with DBU as the base. Then, TFP undergoes copper-catalyzed cycloaddition with azide to form trifluoromethyl 1,2,3-triazoles 3 or 4.

3. Materials and Methods

3.1. General Information

Melting points were measured with a Beijing-Taike X-4 apparatus without correction. 1H NMR, 19F NMR and 13C NMR spectra were recorded using a Bruker Advance 400 MHz (Bruker, Faellanden, Switzerland) or a JEOL RESONANCE ECZ600R spectrometer (Akishima, Tokyo, Japan). Chemical shifts were reported in ppm from the solvent resonance as the internal standard (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm). Coupling constants (J) are reported in Hertz (Hz). The following abbreviations are 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. HRMS was obtained on an LCMS-IT-TOF (Thermo Fisher Scientific, Waltham, MA, USA). Reagents were received from commercial sources. Solvents were freshly dried and degassed according to the published procedures prior to use. Isolation was performed by column chromatography on silica gel (200~300 mesh) (Qingdao, China). 1H NMR, 19F NMR and 13C NMR spectra shown in the Supplementary Materials.

3.2. General Procedure for the Synthesis of Triazoles 3 and 4

A 10 mL crimp-seal veal was charged with an azide (2) (0.50 mmol), 2-bromo-3,3,3-trifluoropropylene (1) (219 mg, 1.25 mmol), acetonitrile (4.0 mL), CuI (9.5 mg, 10 mol%), 1,10-phenanthroline (9.0 mg, 10 mol%) and DBU (152 mg, 1.0 mmol). The mixture was then stirred at 65 °C for 4 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (40 mL), and then washed with water (10 mL × 4). The organic phase was washed with saturated brine, dried by anhydrous Na2SO4 and concentrated in vacuo to give a residue that was subjected to silica gel column chromatography (petroleum ether/ethyl acetate) (V:V = 20:1 − 1:1.2) to give 1-substituted-4-trifluoromethyl-1,2,3-triazoles.

3.3. Data for Compounds of 4-Trifluoromethyl-1,2,3-Triazole

1-Phenyl-4-(trifluoromethyl)-1H-1,2,3-triazole (3a) [53].
White solid (101 mg, mp: 77–78 °C, yield: 95%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.29 (s, 1H), 7.74 (dd, J = 7.5, 2.1 Hz, 2H), 7.61–7.49 (m, 3H). 19F NMR (377 MHz, CDCl3, ppm) δ −61.19 (s). 13C NMR (101 MHz, CDCl3, ppm) δ 139.57 (q, J = 39.6 Hz), 136.26, 130.10, 129.89, 121.73, 120.99, 120.49 (q, J = 267.9 Hz).
1-(o-Tolyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3b) [53].
Pale red oil (94 mg, yield: 83%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (400 MHz, CDCl3, ppm) δ 8.08 (s, 1H), 7.45 (td, J = 7.2, 1.6 Hz, 1H), 7.41–7.37 (m, 1H), 7.36–7.30 (m, 2H), 2.20 (s, 3H). 19F NMR (377 MHz, CDCl3, ppm) δ −61.01 (s). 13C NMR (101 MHz, CDCl3, ppm) δ 138.85 (q, J = 39.5 Hz), 135.56, 133.81, 131.28, 126.60, 124.81, 120.57 (q, J = 267.8 Hz), 17.75.
1-(m-Tolyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3c) [53].
Yellowish solid (109 mg, mp: 59–61 °C, yield: 96%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (400 MHz, CDCl3, ppm) δ 8.30 (d, J = 2.5 Hz, 1H), 7.56 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H). 19F NMR (377 MHz, CDCl3, ppm) δ −61.20 (s). 13C NMR (101 MHz, CDCl3, ppm) δ 139.31 (q, J = 39.2 Hz), 136.23, 130.63, 129.87, 121.67 (d, J = 5.3 Hz), 120.52 (q, J = 267.8 Hz), 118.07, 21.42. HRMS (ESI): calcd. for C10H8F3N3 [M + Na]+: 250.0563, found: 250.0557.
1-(p-Tolyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3d) [53].
Yellowish solid (113 mg, mp: 94–95 °C, yield: 99%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.26 (s, 1H), 7.63–7.57 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 2.43 (s, 3H). 19F NMR (377 MHz, CDCl3, ppm) δ −61.18 (s). 13C NMR (101 MHz, CDCl3, ppm) δ 140.23, 139.48 (q, J = 39.4 Hz), 134.00, 130.61, 121.61, 120.92, 120.54 (q, J = 267.8 Hz), 21.22.
1-(2-Fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3e) [53].
White solid (87 mg, mp: 57–58 °C, yield: 75%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.41 (s, 1H), 7.99–7.92 (m, 1H), 7.55–7.48 (m, 1H), 7.40–7.30 (m, 2H). 19F NMR (377 MHz, CDCl3, ppm) δ −61.25 (s), −123.77–123.86 (m). 13C NMR (101 MHz, CDCl3, ppm) δ 153.51 (d, J = 251.5 Hz), 139.44 (q, J = 39.8 Hz), 131.42 (d, J = 8.0 Hz), 125.66 (d, J = 3.8 Hz), 125.12, 124.61 (dd, J = 8.5, 2.9 Hz), 124.49 (q, J = 267.8 Hz), 117.43, 117.23.
1-(3-Fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3f) [53].
White solid (90 mg, mp: 87–88 °C, yield: 78%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.34 (d, J = 0.8 Hz, 1H), 7.57–7.53 (m, 3H), 7.24–7.21 (m, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.23 (s), −108.75 (dd, J = 14.0, 7.4 Hz). 13C NMR (151 MHz, CDCl3, ppm) δ 163.24 (d, J = 250.0 Hz), 139.89 (q, J = 39.8 Hz), 137.37 (d, J = 9.9 Hz), 131.71 (d, J = 8.9 Hz), 121.70, 120.34 (q, J = 268.0 Hz), 116.95 (d, J = 21.2 Hz), 116.37, 108.96 (d, J = 26.4 Hz).
1-(4-Fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3g) [53].
White solid (112 mg, mp: 84–85 °C, yield: 97%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.21 (s, 1H), 7.69–7.64 (m, 2H), 7.22–7.17 (m, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.16 (s), −110.16–−110.24 (m). 13C NMR (151 MHz, CDCl3, ppm) δ 163.15 (d, J = 250.9 Hz), 139.76 (q, J = 39.7 Hz), 132.57, 123.22 (d, J = 8.8 Hz), 121.90, 120.41 (q, J = 267.9 Hz), 117.21 (d, J = 23.4 Hz).
4-(Trifluoromethyl)-1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (3h).
White solid (136 mg, mp: 87–89 °C, yield: 97%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.41 (s, 1H), 8.04 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.26 (s), −62.86 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 140.13 (q, J = 39.8 Hz), 136.67, 132.93 (q, J = 33.6 Hz), 131.07, 126.63 (d, J = 3.5 Hz), 124.20, 121.77 (d, J = 3.1 Hz), 121.48 (q, J = 90.9 Hz), 120.31 (q, J = 273.0 Hz), 118.09 (d, J = 3.8 Hz). HRMS (ESI): calcd. for C10H5F6N3 [M + H]+: 282.0460, found: 282.0454.
4-(Trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (3i) [53].
White solid (122 mg, mp: 137–138 °C, yield: 87%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.39 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.24 (s), −62.70 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 140.17 (q, J = 39.7 Hz), 138.72, 132.02 (q, J = 32.8 Hz), 127.56 (d, J = 3.4 Hz), 125.28 (q, J = 272.6 Hz), 123.82 (q, J = 261.38 Hz), 121.65, 121.16.
1-(4-(Trifluoromethoxy)phenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3j) [59].
White solid (127 mg, mp: 115–116 °C, yield: 86%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.26 (s, 1H), 7.77–7.72 (m, 2H), 7.36 (d, J = 8.7 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −57.94 (s), −61.24 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 149.95, 139.97 (q, J = 39.8 Hz), 134.61, 123.04 (q, J = 259.7 Hz), 122.68, 122.61, 122.14 (q, J = 268.8 Hz), 121.79 (d, J = 3.0 Hz).
1-(4-Methoxyphenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3k) [53].
Pale yellowish solid (104 mg, mp: 120–122 °C, yield: 86%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.21 (s, 1H), 7.62 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.05 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 160.69, 139.42 (q, J = 39.5 Hz), 129.60, 122.73, 121.73, 120.55 (q, J = 267.7 Hz), 115.13, 55.79.
1-(2-Chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3l) [53].
Yellowish oil (99 mg, yield: 80%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm δ 8.32 (s, 1H), 7.65–7.60 (m, 2H), 7.55–7.47 (m, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.98 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.89 (q, J = 39.7 Hz), 134.02, 131.78, 131.08, 128.79, 128.33, 127.96, 125.45 (d, J = 2.4 Hz), 120.45 (q, J = 267.9 Hz).
1-(3-Chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3m) [53].
White solid (105 mg, mp: 76–78 °C, yield: 85%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.33 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 11.4 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.19 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.89 (q, J = 39.7 Hz), 137.10, 136.07, 131.26, 130.05, 121.67, 121.37, 120.33 (q, J = 268.0 Hz), 119.03.
1-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3n) [53].
White solid (100 mg, mp: 126–128 °C, yield: 81%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.32 (s, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 19F NMR (565 MHz, CDCl3, ppm) δ −61.17 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.83 (q, J = 39.7 Hz), 135.89, 134.75, 130.35, 122.24, 121.68, 120.36 (q, J = 267.9 Hz).
1-(2-Bromophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3o).
Yellowish oil (126 mg, yield: 86%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.27 (s, 1H), 7.78 (dd, J = 8.1, 1.3 Hz, 1H), 7.57–7.51 (m, 2H), 7.46 (td, J = 8.1, 1.8 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.93 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.77 (q, J = 39.7 Hz), 135.62, 134.21, 132.15, 128.88, 128.33, 125.51 (d, J = 2.0 Hz), 120.44 (q, J = 267.9 Hz), 118.67. HRMS (ESI): calcd. for C9H5BrF3N3 [M + Na]+: 313.9511, found: 313.9506.
1-(3-Bromophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3p).
White solid (140 mg, mp: 77–79 °C, yield: 96%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.32 (s, 1H), 7.94 (s, 1H), 7.70 (dd, J = 8.1, 1.2 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.17 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.89 (q, J = 39.8 Hz), 137.16, 132.99, 131.47, 124.19, 123.70, 121.69, 120.32 (q, J = 268.0 Hz), 119.54. HRMS (ESI): calcd. for C9H5BrF3N3 [M + Na]+: 313.9511, found: 313.9504.
1-(4-Bromophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3q) [53].
White solid (120 mg, mp: 134–136 °C, yield: 82%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.31 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 9.0 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.15 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.87 (q, J = 39.7 Hz), 135.24, 133.35, 123.81, 122.45, 121.59, 120.34 (q, J = 268.0 Hz).
4-(4-(Trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzonitrile (3r) [59].
White solid (105 mg, mp: 160–161 °C, yield: 88%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.42 (s, 1H), 7.98–7.94 (m, 2H), 7.92–7.89 (m, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.26 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 140.32 (q, J = 40.1 Hz), 139.07, 134.30, 121.93 (q, J = 265.1 Hz), 121.59, 121.28, 117.45, 113.81.
1-(3-Nitrophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3s).
Yellowish solid (110 mg, mp: 141–142 °C, yield: 88%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.64 (t, J = 2.1 Hz, 1H), 8.44 (s, 1H), 8.40 (dd, J = 8.2, 1.9 Hz, 1H), 8.21 (dd, J = 8.1, 2.0 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.23 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 149.15, 140.66 (q, J = 39.3 Hz), 137.01, 131.54, 126.55, 124.45, 121.95 (q, J = 271.6 Hz), 121.72, 115.96. HRMS (ESI): calcd. for C9H5F3N4O2 [M + H]+: 259.0437, found: 259.0435.
Methyl 2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzoate (3t).
Yellowish oil (114 mg, yield: 84%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 8:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.17 (s, 1H), 8.07 (dd, J = 7.7, 1.6 Hz, 1H), 7.71 (td, J = 7.7, 1.6 Hz, 1H), 7.66 (td, J = 7.7, 1.3 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 3.70 (s, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.87 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 164.91, 138.61 (q, J = 39.5 Hz), 135.40, 133.26, 131.77, 130.94, 127.34, 125.66 (d, J = 2.1 Hz), 120.53 (q, J = 267.7 Hz), 52.73. HRMS (ESI): calcd. for C11H8F3N3O2 [M + Na]+: 294.0461, found: 294.0454.
1-(3-Fluoro-4-methylphenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3u).
White solid (100 mg, mp: 111–113 °C, yield: 82%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.29 (s, 1H), 7.47 (d, J = 9.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 2.35 (s, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.20 (s), −112.68–−112.79 (m). 13C NMR (151 MHz, CDCl3, ppm) δ 161.46 (d, J = 248.3 Hz), 139.71 (q, J = 39.7 Hz), 135.05 (d, J = 9.9 Hz), 132.79 (d, J = 6.0 Hz), 127.16 (d, J = 17.3 Hz), 121.61, 120.40 (q, J = 268.0 Hz), 116.06 (d, J = 3.6 Hz), 108.52 (d, J = 27.4 Hz), 14.47 (d, J = 2.9 Hz). HRMS (ESI): calcd. for C10H7F4N3 [M + H]+: 246.0649, found: 246.0644.
1-(3-Bromo-4-methylphenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3v).
Yellowish solid (139 mg, mp: 87–89 °C, yield: 91%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.28 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.2, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.13 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 140.20, 139.74 (q, J = 39.7 Hz), 134.85, 131.91, 125.80, 124.77, 121.62, 120.38 (q, J = 268.0 Hz), 119.69, 22.79. HRMS (ESI): calcd. for C10H7BrF3N3 [M + Na]+: 327.9668, found: 327.9661.
1-(3-Chloro-4-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3w) [53].
White solid (112 mg, mp: 70–71 °C, yield: 84%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.31 (s, 1H), 7.87 (dd, J = 6.1, 2.7 Hz, 1H), 7.66 (ddd, J = 8.9, 3.8, 2.8 Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.22 (s), −112.22 (dd, J = 13.1, 7.3 Hz). 13C NMR (151 MHz, CDCl3, ppm) δ 158.75 (d, J = 253.5 Hz), 139.99 (q, J = 39.8 Hz), 132.79 (d, J = 3.2 Hz), 123.77, 123.16 (d, J = 19.4 Hz), 122.04 (q, J = 268.18 Hz), 121.87, 120.96 (d, J = 7.8 Hz), 118.13 (d, J = 23.0 Hz).
1-(3-Bromo-4-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3x).
Yellowish solid (126 mg, mp: 95–98 °C, yield: 81%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.30 (s, 1H), 8.01 (dd, J = 5.7, 2.7 Hz, 1H), 7.71 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 7.33 (dd, J = 8.8, 7.7 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.19 (s), −104.28 (dd, J = 13.0, 6.5 Hz). 13C NMR (151 MHz, CDCl3, ppm) δ 159.78 (d, J = 252.0 Hz), 139.98 (q, J = 39.8 Hz), 133.04, 126.55, 122.01–121.62 (m), 120.26 (q, J = 268.0 Hz), 117.98, 117.82, 110.80 (d, J = 23.0 Hz). HRMS (ESI): calcd. for C9H4BrF4N3 [M + H]+: 309.9597, found: 309.9592.
1-(4-Bromo-3-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3y).
Yellowish solid (127 mg, mp: 115–117 °C, yield: 82%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.34 (s, 1H), 7.77 (dd, J = 8.6, 7.1 Hz, 1H), 7.64 (dd, J = 8.5, 2.5 Hz, 1H), 7.47 (ddd, J = 8.7, 2.4, 1.1 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.25 (s), −101.84 (t, J = 8.6 Hz). 13C NMR (151 MHz, CDCl3, ppm) δ 159.68 (d, J = 250.9 Hz), 140.08 (q, J = 39.9 Hz), 136.33 (d, J = 8.9 Hz), 135.10, 121.59 (d, J = 2.9 Hz), 120.21 (q, J = 268.1 Hz), 117.26 (d, J = 3.8 Hz), 110.72 (d, J = 21.1 Hz), 109.75 (d, J = 27.3 Hz). HRMS (ESI): calcd. for C9H4BrF4N3 [M + Na]+: 331.9417, found: 331.9411.
1-(3-Bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3z).
Yellowish solid (137 mg, mp: 111–113 °C, yield: 84%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.33 (d, J = 0.8 Hz, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.69 (dd, J = 8.7, 2.5 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.20 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 140.04 (q, J = 39.8 Hz), 136.34, 135.16, 131.66, 126.00, 124.07, 121.87–121.67 (d, J = 2.0 Hz), 120.69, 120.22 (q, J = 268.2 Hz). HRMS (ESI): calcd. for C9H4BrClF3N3 [M + K]+: 363.8861, found: 363.8876.
1-(3-Chloro-4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3aa).
Yellowish solid (132 mg, mp: 72–74 °C, yield: 80%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.4). 1H NMR (600 MHz, CDCl3, ppm) δ 8.35 (s, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 8.9, 2.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −57.83 (s), −61.29 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 146.09, 140.19 (q, J = 39.9 Hz), 135.01, 129.55, 123.89, 123.61, 122.22 (d, J = 260.9 Hz), 121.99 (d, J = 268.3 Hz), 121.77 (d, J = 2.9 Hz), 120.30. HRMS (ESI): calcd. for C10H4ClF6N3O [M + K]+: 369.9579, found: 369.9582.
1-(Naphthalen-1-yl)-4-(trifluoromethyl)-1H-1,2,3-triazole (3ab) [53].
Pale red oil (110 mg, yield: 84%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.24 (s, 1H), 8.06 (dd, J = 7.3, 2.2 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.62–7.59 (m, 1H), 7.59–7.54 (m, 3H), 7.51 (d, J = 8.5 Hz, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.78 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.01 (q, J = 39.6 Hz), 134.24, 132.65, 131.36, 128.57, 128.45, 128.30, 127.49, 125.89, 125.02, 123.95, 121.76, 120.60 (q, J = 267.9 Hz).
1-Octyl-4-(trifluoromethyl)-1H-1,2,3-triazole (4a).
Yellowish oil (106 mg, yield: 85%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.87 (s, 1H), 4.40 (t, J = 7.3 Hz, 2H), 1.96–1.89 (m, 2H), 1.35–1.18 (m, 10H), 0.85 (t, J = 7.1 Hz, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.01 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.89 (q, J = 39.3 Hz), 123.04, 120.64 (q, J = 267.6 Hz), 50.99, 31.75, 30.23, 29.06, 28.94, 26.45, 22.65, 14.09. HRMS (ESI): calcd. for C11H18F3N3 [M + Na]+: 272.1345, found: 272.1339.
1-Nonyl-4-(trifluoromethyl)-1H-1,2,3-triazole (4b).
Yellowish oil (109 mg, yield: 83%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.87 (s, 1H), 4.40 (t, J = 7.3 Hz, 2H), 1.92 (dt, J = 14.6, 7.3 Hz, 2H), 1.35–1.18 (m, 12H), 0.85 (t, J = 7.0 Hz, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.01 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.89 (q, J = 39.2 Hz), 123.04, 120.64 (q, J = 267.5 Hz), 50.99, 31.86, 30.23, 29.36, 29.21, 28.98, 26.44, 22.70, 14.12. HRMS (ESI): calcd. for C12H20F3N3 [M + Na]+: 286.1502, found: 286.1497.
1-Cyclohexyl-4-(trifluoromethyl)-1H-1,2,3-triazole (4c) [53].
Yellowish solid (88 mg, mp: 34–36 °C, yield: 80%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.84 (s, 1H), 4.51 (tt, J = 11.9, 3.9 Hz, 1H), 2.25 (dd, J = 13.8, 2.4 Hz, 2H), 1.95 (dd, J = 11.1, 3.1 Hz, 2H), 1.76 (dt, J = 16.1, 12.4 Hz, 3H), 1.48 (dt, J = 13.2, 3.3 Hz, 2H), 1.33 (s, 1H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.93 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.63 (q, J = 39.2 Hz), 120.94, 120.74 (q, J = 267.7 Hz), 60.89, 33.59, 25.15, 25.09.
1-((3s,5s,7s)-Adamantan-1-yl)-4-(trifluoromethyl)-1H-1,2,3-triazole (4d) [53].
White solid (125 mg, mp: 146–148 °C, yield: 92%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.90–7.89 (s, 1H), 2.27 (dd, J = 21.5, 2.9 Hz, 9H), 1.84–1.76 (m, 6H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.81 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.11 (q, J = 39.0 Hz), 120.87 (q, J = 267.8 Hz), 119.78, 60.92, 43.02, 35.83, 29.50.
1-(1-Phenylethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (4e) [53].
White solid (114 mg, mp: 57–58 °C, yield: 95%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (400 MHz, CDCl3, ppm) δ 7.69 (d, J = 7.4 Hz, 1H), 7.29 (q, J = 7.2, 6.7 Hz, 3H), 7.23–7.18 (m, 2H), 5.77 (q, J = 7.1 Hz, 1H), 1.92 (d, J = 7.1 Hz, 3H). 19F NMR (377 MHz, CDCl3, ppm) δ −61.05 (s). 13C NMR (101 MHz, CDCl3, ppm) δ 138.84, 138.80 (q, J = 39.1 Hz), 129.34, 129.11, 126.69, 122.21, 120.61 (q, J = 267.8 Hz), 61.16, 21.23. HRMS (ESI): calcd. for C11H10F3N3 [M + Na]+: 264.0719, found: 264.0713.
1-Phenethyl-4-(trifluoromethyl)-1H-1,2,3-triazole (4f).
White solid (91 mg, mp: 59–61 °C, yield: 80%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 8:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.54 (s, 1H), 7.30 (dd, J = 7.9, 6.4 Hz, 2H), 7.28–7.25 (m, 1H), 7.08 (d, J = 7.0 Hz, 2H), 4.65 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 7.2 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.01 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.63 (q, J = 39.3 Hz), 136.41, 129.10, 128.71, 127.53, 123.55, 120.53 (q, J = 267.6 Hz), 52.27, 36.63. HRMS (ESI): calcd. for C11H10F3N3 [M + Na]+: 264.0719, found: 264.0715.
4-((4-(Trifluoromethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine (4g).
White solid (60 mg, mp: 104–105 °C, yield: 53%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.63 (s, 2H), 7.90 (s, 1H), 7.13 (d, J = 5.4 Hz, 2H), 5.61 (s, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.07 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 150.89, 142.43, 139.70 (q, J = 39.6 Hz), 123.62, 122.33, 120.30 (q, J = 267.9 Hz), 53.24. HRMS (ESI): calcd. for C9H7F3N4 [M + H]+: 229.0696, found: 229.0692.
1-(Thiophen-3-ylmethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (4h).
White solid (100 mg, mp: 82–83 °C, yield: 86%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.76 (s, 1H), 7.40 (dd, J = 5.0, 3.0 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 5.0, 1.3 Hz, 1H), 5.61 (s, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.99 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.26 (q, J = 39.3 Hz), 133.86, 128.09, 127.08, 125.39, 122.98, 120.49 (q, J = 267.8 Hz), 49.55. HRMS (ESI): calcd. for C8H6F3N3S [M + Na]+: 256.0127, found: 256.0122.
1-(Benzo[b]thiophen-2-ylmethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (4i).
White solid (122 mg, mp: 127–129 °C, yield: 86%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.91 (s, 1H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H), 7.78 (dd, J = 6.5, 2.5 Hz, 1H), 7.42–7.36 (m, 4H), 5.85 (s, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.00 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 140.47, 139.45 (q, J = 39.6 Hz), 139.10, 135.38, 125.72, 125.67, 125.17, 124.28, 123.16, 122.65, 120.42 (q, J = 268.2 Hz), 49.86. HRMS (ESI): calcd. for C12H8F3N3S [M + Na]+: 306.0283, found: 306.0280.
2-(2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)ethyl)isoindoline-1,3-dione (4j).
White solid (84 mg, mp: 165–167 °C, yield: 54%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.98 (d, J = 0.9 Hz, 1H), 7.81 (dd, J = 5.4, 3.0 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 4.76 (dd, J = 12.0, 6.0 Hz, 2H), 4.19 (dd, J = 12.0, 6.0 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.01 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 167.73, 139.31 (q, J = 39.5 Hz), 134.58, 131.65, 123.79, 123.73 (d, J = 2.6 Hz), 120.41 (q, J = 267.8 Hz), 48.63, 37.57. HRMS (ESI): calcd. for C13H9F3N4O2 [M + Na]+: 333.0570, found: 333.0565.
1-(2-Phenoxyethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (4k).
White solid (102 mg, mp: 69–71 °C, yield: 80%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1, Rf = 0.3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.09 (s, 1H), 7.31 (dd, J = 8.7, 7.4 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.88 (dd, J = 8.7, 0.9 Hz, 2H), 4.83 (t, J = 4.8 Hz, 2H), 4.38 (t, J = 4.8 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.97 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 157.61, δ 139.21 (q, J = 39.7 Hz), 129.92, 124.44, 122.18, 120.54 (q, J = 267.7 Hz), 114.61, 65.98, 50.42. HRMS (ESI): calcd. for C11H10F3N3O [M + Na]+: 280.0668, found: 280.0665.
1-(2,5,8,11-Tetraoxatridecan-13-yl)-4-(trifluoromethyl)-1H-1,2,3-triazole (4l).
Yellowish oil (120 mg, yield: 73%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1.2, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 8.20 (s, 1H), 4.61 (t, J = 4.8 Hz, 2H), 3.87 (t, J = 4.8 Hz, 2H), 3.63–3.60 (m, 10H), 3.54–3.50 (m, 2H), 3.34 (s, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.86 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 138.80 (q, J = 39.3 Hz), 124.85, 120.72 (q, J = 267.6 Hz) 71.96, 70.63, 70.60, 70.55, 70.50, 69.03, 59.06, 50.75. HRMS (ESI): calcd. for C12H20F3N3O4 [M + Na]+: 350.1298, found: 350.1292.
Ethyl 4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)butanoate (4m).
Yellowish oil (80 mg, yield: 64%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.90 (s, 1H), 4.51 (t, J = 7.0 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.36 (t, J = 7.0 Hz, 2H), 2.26 (t, J = 7.0 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). 19F NMR (565 MHz, CDCl3, ppm) δ −61.01 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 172.23, 139.07 (q, J = 39.3 Hz), 123.44, 120.54 (q, J = 267.6 Hz), 61.01, 49.87, 30.60, 25.41, 14.25. HRMS (ESI): calcd. for C9H12F3N3O2 [M + Na]+: 274.0774, found: 274.0770.
1-Cinnamyl-4-(trifluoromethyl)-1H-1,2,3-triazole (4n).
White solid (102 mg, mp: 66–67 °C, yield: 81%). Isolated by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, Rf = 0.3). 1H NMR (600 MHz, CDCl3, ppm) δ 7.88 (s, 1H), 7.35 (d, J = 7.1 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 15.8 Hz, 1H), 6.29 (dt, J = 15.7, 6.9 Hz, 1H), 5.15 (dd, J = 6.8, 1.4 Hz, 2H). 19F NMR (565 MHz, CDCl3, ppm) δ −60.97 (s). 13C NMR (151 MHz, CDCl3, ppm) δ 139.29 (q, J = 39.3 Hz), 136.88, 135.17, 129.05, 128.95, 126.94, 122.96, 120.59, 120.56 (q, J = 267.8 Hz), 52.94. HRMS (ESI): calcd. for C12H10F3N3 [M + Na]+: 276.0719, found: 276.0714.

4. Conclusions

In the study chronicled above, we demonstrated an efficient protocol to produce 1-substituted-4-trifluoromethyl-1,2,3-triazoles from BTP with azides. In this reaction, copper salt and ligands were necessary to catalyze the click process, and CuI (10 mol%)/Phen (10 mol%) gave the best yield with 2.0 eq. DBU as the base in CH3CN at 65 °C. With the mild reaction conditions, both aryl azide and alkyl azides bearing a range of electronically and sterically different groups participate in this process to give good to excellent yields. Moreover, this process can be conducted readily and on modestly large scales. Further studies are in progress to develop the chemistry of 4-trifluoromethyl-1,2,3-triazoles generated using this click reaction platform.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29061191/s1, Table S1: Optimization of the Reaction Conditions; Copies of 1H NMR, 19F NMR and 13C NMR spectra [85,86,87,88,89,90,91,92,93,94].

Author Contributions

Conceptualization, resources and funding acquisition, L.W.; supervision and project administration, W.C.; methodology, validation, investigation and data curation, T.T., C.C., X.F. and H.X.; writing—original draft preparation, T.T.; writing—review and editing, L.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Hainan Province Natural Science Foundation of China, grant number 222RC656.

Data Availability Statement

1H- NMR and 13C- and 19F-NMR Data are available in section “MDPI Research Data Policies” at https://www.mdpi.com/ethics.

Acknowledgments

We are grateful to our colleagues at the Centre for Instrumental Analysis for providing instrumental services.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 01191 sch001
Scheme 1. The synthesis of 4-CF3-1,2,3-triazoles.
Scheme 1. The synthesis of 4-CF3-1,2,3-triazoles.
Molecules 29 01191 sch001
Molecules 29 01191 sch002
Scheme 2. Gram-scale synthesis of 3a.
Scheme 2. Gram-scale synthesis of 3a.
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Molecules 29 01191 sch003
Scheme 3. Proposed pathway for reaction of BTP with azides to form 1-substituted-4-trifluoromethyl-1,2,3-triazoles.
Scheme 3. Proposed pathway for reaction of BTP with azides to form 1-substituted-4-trifluoromethyl-1,2,3-triazoles.
Molecules 29 01191 sch003
Table 1. Optimization of the Reaction Conditions 1.
Table 1. Optimization of the Reaction Conditions 1.
Molecules 29 01191 i001
EntryCuILigand 2SolventTemp. (°C)Time (h)Yield 3
1nonenoneDMF10016n.d.
210 mol%noneDMF801647
310 mol%PhenCH3CN35437
410 mol%PhenCH3CN50476
510 mol%PhenCH3CN501087
610 mol%PhenCH3CN65495
710 mol%PhenCH3CN75492
810 mol%PhenCH3CN65393
910 mol%PhenCH3CN65279
1010 mol%PhenDMF65494
1110 mol%PhenDMSO65451
12 410 mol%L1CH3CN65493
13 510 mol%L2CH3CN65493
1410 mol%PhenCH3CN65469
1510 mol%PhenCH3CN65495
16 65 mol%PhenCH3CN65487
1 Standard reaction conditions: 1 (1.25 mmol, 2.5 equiv), 2a (0.5 mmol, 1.0 equiv.), CuI (0.05 mmol, 10 mol%), ligand (0.05 mmol, 10 mol%), solvent (4.0 mL), DBU (1.0 mmol, 2.0 equiv.), 65 °C, 4 h under air atmosphere. 2 Phen = 1,10-Phenanthroline. 3 Isolated yield after column chromatography. 4 L1 = 4,7-Dimethoxy-1,10-phenanthroline. 5 L2 = 3,4,7,8-Tetramethyl-1,10-phenanthroline. 6 5 mmol% of CuI was loaded.
Table 2. Substrate Scope of 1-Aryl-4-CF3-1,2,3-Triazoles 1,2.
Table 2. Substrate Scope of 1-Aryl-4-CF3-1,2,3-Triazoles 1,2.
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Molecules 29 01191 i003
1 Reaction conditions: 1 (1.25 mmol, 2.5 equiv.), 2 (0.5 mmol, 1.0 equiv.), CuI (0.05 mmol, 10 mol%), Phen (0.05 mmol, 10 mol%), CH3CN (4.0 mL), DBU (1.0 mmol, 2.0 equiv.), 65 °C, 4 h under air atmosphere. 2 Isolated yields.
Table 3. Substrate Scope of 1-Alkyl-4-CF3-1,2,3-Triazoles 1,2.
Table 3. Substrate Scope of 1-Alkyl-4-CF3-1,2,3-Triazoles 1,2.
Molecules 29 01191 i004
Molecules 29 01191 i005
1 Reaction conditions: 1 (1.25 mmol, 2.5 equiv.), 2 (0.5 mmol, 1.0 equiv.), CuI (0.05 mmol, 10 mol%), Phen (0.05 mmol, 10 mol%), CH3CN (4.0 mL), DBU (1.0 mmol, 2.0 equiv.), 65 °C, 4 h under air atmosphere. 2 Isolated yields.
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Tang, T.; Chen, C.; Fu, X.; Xu, H.; Wu, L.; Chen, W. Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction. Molecules 2024, 29, 1191. https://doi.org/10.3390/molecules29061191

AMA Style

Tang T, Chen C, Fu X, Xu H, Wu L, Chen W. Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction. Molecules. 2024; 29(6):1191. https://doi.org/10.3390/molecules29061191

Chicago/Turabian Style

Tang, Tinghong, Cuiting Chen, Xin Fu, Huilan Xu, Luyong Wu, and Wenhao Chen. 2024. "Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction" Molecules 29, no. 6: 1191. https://doi.org/10.3390/molecules29061191

APA Style

Tang, T., Chen, C., Fu, X., Xu, H., Wu, L., & Chen, W. (2024). Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction. Molecules, 29(6), 1191. https://doi.org/10.3390/molecules29061191

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