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

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.

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).

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-dime-Scheme 1.The synthesis of 4-CF 3 -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).

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,Ndimethylformamide (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-1,2,3triazole (3a) in a highly regioselective manner and <50% yields ( 1 H-and 13 C-NMR analysis) (entry 2).Moreover, when the copper ligand 1,10-phenanthroline (Phen) is included and CH 3 CN 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 , CuSO 4 •5H 2 O), 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 CH 3 CN at 65 • C for 4 h. 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 (1 H-and 13 C-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 sub-  65 mol% Phen CH 3 CN 65 4 87 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.2Phen = 1,10-Phenanthroline. 3 Isolated yield after column chromatography.4L1 = 4,7-Dimethoxy-1,10-phenanthroline.5L2 = 3,4,7,8-Tetramethyl-1,10-phenanthroline. 65 mmol% of CuI was loaded.
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-, metaand 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-4trifluoromethyl-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.stituents 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 stituents 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
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. 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.Table 3. Substrate Scope of 1-Alkyl-4-CF3-1,2,3-Triazoles 1,2 .
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 [81-84], 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.
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.Table 3. Substrate Scope of 1-Alkyl-4-CF3-1,2,3-Triazoles 1,2 .
creasing 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.

General Information
Melting points were measured with a Beijing-Taike X-4 apparatus without correction. 1H NMR, 19 F NMR and 13 C 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 (CDCl 3 : δ H = 7.26 ppm, δ C = 77.16ppm).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). 1 H NMR, 19 F NMR and 13 C NMR spectra shown in the Supplementary Materials.

Table 1 .
Optimization of the Reaction Conditions 1 .

Table 1 .
Optimization of the Reaction Conditions 1 .