CuBr-Catalyzed Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles Through Cycloaddition of Azides to Alkenes

GRAPHICAL ABSTRACT Abstract We developed a CuBr-catalyzed synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with moderate to good yields via azide–alkene cycloaddition and oxidative aromatization using air as oxidant. The reaction is simple and easily handled with inexpensive and readily available copper catalysis.

Scheme 1. The scope of this transformation.

RESULTS AND DISCUSSION
(E)-Chalcone and (azidomethyl)cyclohexane were chosen as the substrates for this reaction.
(1-(Cyclohexylmethyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone (3aa) could be obtained in 40% yield in the presence of 1 mol% CuBr catalyst in 80°C (Table 1, entry 1). When the temperature was raised to 110°C, the yield could be improved to 61% (Table 1, entry 2). Some other copper and iron catalysts gave poor yields for this transformation (Table 1, entries 3-5). Finally, the optimized result was realized when 5 mol% CuBr was used and the yield could be achieved in 81% (Table 1, entries 6 and 7). Only 38% yield was obtained when no catalyst was used and 50% (E)-chalcone (1a) was recovered (Table 1, entry 8). Also little by-product could be detected by thin-layer chromatographic (TLC) monitoring. Unfortunately, it could not be isolated and identified successfully. The result shows that the copper catalyst is necessary for this transformation. We assume that a triazoline intermediate, which could be generated via 1,3-dipolar cycloaddition, undergoes oxidation under copper and air conditions. [8] With the optimized reaction conditions in hand, the scope of this 1,2,3-triazole synthesis was investigated (Scheme 1). To our delight, various substituted internal olefins could react with (azidomethyl)cyclohexane to give corresponding 1,2,3-triazol successfully with moderate to good yields. When 1-azidononane was used instead of (azidomethyl)cyclohexane, the desired products also could be obtained with moderate to good yields. The results indicate that the present reaction system has wide substrate scope.

CONCLUSION
In summary, we developed a CuBr-catalyzed synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via azide-alkene cycloaddition and oxidative aromatization using air as oxidant. The present method is simple and convenient for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with moderate to good yields. The catalyst amount is low and additive is unnecessary for this transformation. Further exploration of the mechanism and synthetic application is ongoing in our group.

EXPERIMENTAL
All manipulations were conducted under an air atmosphere. 1 H NMR spectra were recorded on a Bruker Avance III-400 spectrometer. Chemical shifts (in ppm) were referenced to tetramethylsilane (δ ¼ 0 ppm) in CDCl 3 as an internal standard. 13 C NMR spectra were obtained by using the same NMR spectrometers and were calibrated with CDCl 3 (δ ¼ 77.00 ppm). High-resolution mass spectra were recorded using a Fourier transform ion cyclotron resonance mass spectrometer (APEX IV, Bruker).

FUNDING
This work was supported by the financial support from PLA General Hospital, which is greatly appreciated.

SUPPORTING INFORMATION
Full experimental details and 1 H and 13 C NMR spectra can be accessed on the publisher's website.