Efficient Synthesis of Functionalized 1 , 2 , 3-Triazoles by Catalyst-Free 1 , 3-Dipolar Cycloaddition of Nitroalkenes with Sodium Azide

Five-membered nitrogen heterocycles play an important role in biological systems. Among these, the 1,2,3-triazoles and their derivatives are of considerable interest as they possess a wide range of biological properties, such as anti-HIV, anti-allergic, anti-fungal, anti-viral and anti-microbial activity. 1,2,3-Triazoles are important in pharmacological applications due to its stability toward light, moisture, oxygen, and metabolism in the body. In addition, these moieties are widely applied as photosensitizers, dyes, and commercially employed as anti-corrosive agents in industry. Owing to the importance of these compounds, a variety of methods are known in the literature for the synthesis of pyrazoles, which include the thermal 1,3-dipolar cycloaddition of azide with various alkynes and cycloaddition reactions of terminal alkynes with alkyl azides using Cu(I) as catalyst. In addition, these molecules can also be prepared in one-pot procedure from alkynes with azides. In fact, a straightforward approach to 1,2,3-triazoles is interesting and catalystfree intermolecular 1,3-dipolar cycloaddition azides with electron-deficient alkenes to afford 1,2,3-triazoles, has been the subject of intensive research. Recently, sodium azide has been used as a 1,3-dipole in 1,3-dipolar cycloaddition for the synthesis of 1,2,3-triazoles. Considering the above reports and encouraged by the good results, we envisaged that 1,3-dipolar cycloaddition would be possible between the α-carbonyl-β-aryl analogs of nitroethene with sodium azide, as outlined in Scheme 1. First, the reaction was happened via 1,3-dipolar cycloaddition of nitroalkenes with sodium ion as the key step. Then, elimination of the NaNO2 and migration of hydrogen atom afford 1,2,3-triazoles.


Introduction
Five-membered nitrogen heterocycles play an important role in biological systems.Among these, the 1,2,3-triazoles and their derivatives are of considerable interest as they possess a wide range of biological properties, such as anti-HIV, 1 anti-allergic, 2 anti-fungal, 3 anti-viral 4 and anti-microbial activity. 51,2,3-Triazoles are important in pharmacological applications due to its stability toward light, moisture, oxygen, and metabolism in the body. 6In addition, these moieties are widely applied as photosensitizers, dyes, 7 and commercially employed as anti-corrosive agents 8 in industry.Owing to the importance of these compounds, a variety of methods are known in the literature for the synthesis of pyrazoles, which include the thermal 1,3-dipolar cycloaddition of azide with various alkynes 9 and cycloaddition reactions of terminal alkynes with alkyl azides using Cu(I) as catalyst. 10In addition, these molecules can also be prepared in one-pot procedure from alkynes with azides. 11In fact, a straightforward approach to 1,2,3-triazoles is interesting and catalystfree intermolecular 1,3-dipolar cycloaddition azides with electron-deficient alkenes to afford 1,2,3-triazoles, has been the subject of intensive research. 12Recently, sodium azide has been used as a 1,3-dipole in 1,3-dipolar cycloaddition for the synthesis of 1,2,3-triazoles. 12Considering the above reports and encouraged by the good results, we envisaged that 1,3-dipolar cycloaddition would be possible between the α-carbonyl-β-aryl analogs of nitroethene with sodium azide, as outlined in Scheme 1. First, the reaction was happened via 1,3-dipolar cycloaddition of nitroalkenes with sodium ion as the key step.Then, elimination of the NaNO 2 and migration of hydrogen atom afford 1,2,3-triazoles.

Results and Discussion
Coumarins are important heterocycles widely present in natural products exhibiting a broad range of biological and therapeutic activities and have been the subject of intensive research. 13Recently, we have demonstrated the usefulness of the catalyst-free intermolecular 1,3-dipolar cycloaddition of 3-nitrocoumarins in the synthesis of functionalized pyrazoles with good yields. 14We considered that the incorporation of a 1,2,3-triazole heterocyclic unit into 3-nitrocoumarins might provide 1,2,3-triazole derivatives that have important biological and pharmaceutical activities.Thus, we turned our attention to the possible synthesis of 1,2,3-triazoles using 3-nitrocoumarins 1 as dipolarophiles for the electron-poor 3-nitrocoumarins is a good dipolarophile with a good leaving group NO 2 .The initial investigation started from the reaction between sodium azide and 3-nitrocoumarin 1a (Table 1).It is known from the literature that the optimal medium for the reaction of sodium azide with nitroalkenes is DMSO. 13Then we studied the reaction at different temperatures in DMSO, and found out that the best yield was obtained at 80 o C after 1 h (Table 1, entry 3).The structure was determined on the basis of 1 H NMR in comparison with the literature data. 15der the optimized conditions, these findings could be extended to the application of various other 3-nitrocoumarins 1a-1e, and the 1,3-dipolar cycloaddition of 3-nitrocoumarins 1 to sodium azide proceeded smoothly to afford the chromeno [3,4-d][1,2,3]triazol-4(3H)-ones 2a-2e as single regioisomers.The reaction's scope proved to be broad with respect to the 3-nitrocoumarins 1. Good yields were obtained in the reactions of electron-withdrawing substituent on the aryl ring of 3-nitrocoumarins 1 with sodium azide (Table 2).In addition, an electron-donating substituent on the aryl ring of 3-nitrocoumarins 1 substrates tended to decrease their reactivity (Table 2, entry 5).

Conclusions
In conclusion, an efficient method for the synthesis of functionalized 1,2,3-triazoles by catalyst-free 1,3-dipolar cycloaddition of nitroalkenes with sodium azide has been investigated.The 1,3-dipolar cycloaddition can proceed smoothly under mild conditions and provides pure 1,2,3-triazole derivatives in good yields.The reaction's scope proved to be quite broad.Notably, we incorporated a 1,2,3-triazole heterocyclic unit into coumarins and provided substituted chromeno [3,4-d][1,2,3] triazol-4(1H)-one that might have important biological and pharmaceutical  activities in the future.This novel methodology should be of great interest for natural product synthesis for the mild reaction conditions.

Experimental
All commercially available reagents and solvents were obtained from commercial providers and used without further purification.Reactions were monitored by TLC using silica gel 60 UV254 Macherey-Nagel pre-coated silica gel plates; detection was by means of a UV lamp.Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether.Organic layers were dried over anhydrous MgSO 4 or Na 2 SO 4 prior to evaporation on a rotary evaporator. 1 H NMR spectra were recorded at 400 MHz, and 13 C NMR spectra were recorded at 100 MHz (Bruker Avance).Chemical shifts (d) are reported in ppm downfield from CDCl 3 (d 7.26 ppm) for 1 H NMR and relative to the central CDCl 3 resonance (d 77.0 ppm) for 13 C NMR spectroscopy.Coupling constants (J) are given in Hz.ESI-HRMS spectrometer was measured with a Finnigan LCQ DECA ion trap mass spectrometer.2-Aryl-1-carboethoxy-1-nitroethenes 1 were prepared according to reported procedure. 22Triazoles 2a, 2c, 2e, 2f and 2g are known compounds. 15Triazoles 2b, 2d and 2h-j are new compounds and their physical and spectral properties are reported in Supplementary Information section.
General procedure for the synthesis of 1,2,3-triazoles 2 under the optimized conditions To the solution of the nitroalkenes 1 (1 mmol) in DMSO (2 mL) was added sodium azide (2 mmol).The mixture was then heated at 80 o C until the starting material was totally consumed as indicated by TLC.After cooling, water was added and the resulting precipitate was filtered, washed with excess of water, and dried to give the desired triazole, which was recrystallized.When no precipitate was observed, the triazole was isolated after extraction with ethylacetate.Further purification was done by column chromatography using ethylacetate/petroleum ether as eluent.

General methods
All commercially available reagents and solvents were obtained from commercial providers and used without further purification.Reactions were monitored by TLC using silica gel 60 UV254 Macherey-Nagel pre-coated silica gel plates; detection was by means of a UV lamp.Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether.Organic layers were dried over anhydrous MgSO 4 or Na 2 SO 4 prior to evaporation on a rotary evaporator. 1 H NMR spectra were recorded at 400 MHz, and 13 C NMR spectra were recorded at 100 MHz (Bruker Avance).Chemical shifts (d) are reported in ppm downfield from CDCl 3 (d 7.26 ppm) for1 H NMR and relative to the central CDCl 3 resonance (d 77.0 ppm) for 13 C NMR spectroscopy.Coupling constants (J) are given in Hz.ESI-HRMS spectrometer was measured with a Finnigan LCQ DECA ion trap mass spectrometer.Triazoles 2a, 2c, 2e, 2f and 2g are known compounds. 1Triazoles 2b, 2d and 2h-j are new compounds and their physical and spectral properties are reported below.

A typical procedure for synthesis of 2a-2e
To the solution of the nitroalkenes 1 (1 mmol) in DMSO (2 mL) was added sodium azide (2 mmol).The mixture was then heated at 80 o C until the starting material was totally consumed as indicated by TLC.After cooling, water was added and the resulting precipitate was filtered, washed with excess of water, and dried to give the desired triazole, which was recrystallized.When no precipitate was observed, the triazole was isolated after extraction with ethylacetate.
Further purification was done by column chromatography using ethylacetate/petroleum ether as eluent.

Table 1 .
Catalyst-free 1,3-dipolar cycloaddition of nitroalkenes with sodium azide under different conditions a a Otherwise noted, reactions performed with 0.1 mmol of 1a, 0.1 mmol of NaN 3 in 1 mL solvent.b Isolated yield.

Table 2 .
Reaction scopes of 3-nitrocoumarins 1 with sodium azide in DMSO at 80 o C a