Simple synthesis of 1-substituted-4-vinyl-1,2,3-triazoles based on polystyrene-supported sulfonyl chloride

ABSTRACT Polystyrene-supported but-3-ynyl sulfonate reagent has been developed and applied to the traceless solid-phase organic synthesis of 1-substituted-4-vinyl-1,2,3-triazoles by CuI-promoted 1,3-dipolar cycloaddition reaction with various organic azides and subsequent cleavage from the polymer support through elimination reaction mediated by 1.8-diazabicyclo[5,4,0]undec-7-ene (DBU). The advantages of this new synthetic method include simple operation and moderate to good yields of the products, as well as good stability of the reagent. GRAPHICAL ABSTRACT

Initially, polystyrene-supported sulfonyl chloride 1 was conveniently prepared from a commercially available 2% cross-linked benzenesulfonic acid resin by treating it with thionyl chloride in N,N-dimethylformamide according to a previous reported procedure. [11] In the presence of triethylamine, 3-butyn-1-ol was reacted with sulfonyl chloride resin 1 at room temperature almost quantitatively to afford but-3-ynyl sulfonate resin 2 (no chlorine was found by microanalysis of resin 2 and its loading was estimated gravimetrically to be 3.52 mmol/g), which were monitored by Fourier transfer (FTIR), exhibiting the infrared absorption band at 1365 cm À 1 (-S-O stretch of -SO 2 Cl for resin 1), which shifted to 1352 cm À 1 (-SO 2 -O-), and appearing a characteristic absorption peak of carbon-carbon triple bond absorption at 2120 cm À 1 .
Next, the 1,3-dipolar cycloaddition reaction of resin 2 with various azides, the key for the success of this protocol was then investigated. Different catalysts have been reported to promote the CuAAC reaction. Among them, copper(I) salts can be used directly or generated in situ by reduction of Cu(II) salts with reducing agents to catalyzed this process smoothly for the preparation of 1,4-disubstituted-1H-1,2,3-triazoles exclusively. [3][4][5] By this way, the CuAAC reaction can be smoothly performed under milder conditions avoiding the use of an inert atmospheres. Based on these studies and inspired by our previous work on the SPOS of 1-vinyl-1,2,3-triazoles, benzyl azide was chosen here for the template reaction with resin 2, and reaction conditions such as several solvents including tetrahydrofuran (THF), dimethylfuran (DMF), dimethylsulfoxide (DMSO), and CH 2 Cl 2 , and their combinations in Scheme 1. Solid-phase synthetic route to 1-substituted-4-vinyl-1,2,3-triazoles. the presence of copper(I) catalysts like CuI, CuCl, CuBr, and CuSO 4 /sodium ascorbate, amounts of catalyst, and reaction time were evaluated. After this, the 1,3-dipolar cycloaddition of resin 2 with benzyl azide proceeded smoothly in DMF/THF in the presence of diisopropylethyl amine (DIPEA) and catalytic amounts of CuI at room temperature for 12 h to afford the 2-(4-triazolyl)ethyl sulfonate resin (3a), which can also be monitored by the IR spectrum conveniently and precisely in which the characteristic signal of the carbon-carbon triple bond absorption (2120 cm À 1 ) has been distinctly shrunk after 6 h of reaction time, and then disappeared completely for another 10 h of reaction time.
Finally, the cleavage conditions with different bases [triethylamine, pyridine, 1.8diazabicyclo [5,4,0]undec-7-ene (DBU), and potassium carbonate], various solvents (MeCN, DMF, THF, 1,4-dioxane), as well as different reaction temperatures and times were examined, and the optimal result was obtained by treating resin 3a in DMF with DBU in the presence of NaI at 120 °C for 1 h, resulting in the exclusive formation of 1-benzyl-4-vinyl-1H-1,2,3-triazole (4a) in 90% total yield based on the loading of resin 2 (entry 1, Table 1). The 1 H NMR spectrum of 4a displayed a distinct singlet at δ ¼ 7.45 ppm for the triazolyl C 5 -H proton, a singlet signal for the N-CH 2 protons appearing at δ ¼ 5.49 ppm. The signals of the vinyl protons as a double doublet were also observed at δ ¼ 6.65 (dd, J ¼ 17.8, 11.2 Hz), 5.85 (d, J ¼ 17.8 Hz), and 5.30 ppm (d, J ¼ 11.2 Hz), respectively. In addition, the melting point of this compound is in agreement with the reported value. [8a] With the optimized conditions (CuAAC reaction and base-catalyzed elimination) in hand, the generality of the method was further evaluated using a variety of azides and the resin 2, and the corresponding target compounds 4-vinyl-1,2,3-triazoles (4a-4 m) were obtained. As observed in Table 1, a range of benzylic azides (entries 1-3, Table 1) and primary azides (entries 4-6, Table 1) were found to react readily to form the desired triazole products in good yields (80-90%). Of the azides investigated in this study, aryl azides carrying either an electron-donating substituent (entries 8-10, Table 1) or an electron-withdrawing group (entries 11-13, Table 1) could also perform efficiently with moderate to excellent yields. Furthermore, greater yields were obtained when the substrates had an electron-donating or electron-withdrawing substituent both at meta-and parapositions. However, the more sterically hindered aryl azides bearing an ortho-group (entries 10 and 11, Table 1) afforded the products in lower yields. In conclusion, we have developed a facile method for the traceless solid-phase synthesis of 1-substituted-4-vinyl-1H-1,2,3-triazoles by CuI-catalyzed 1,3-dipolar cycloaddition reaction of polymer-bound but-3-ynyl sulfonate with organic azides such as benzylic azides, primary azides, and aryl azides and subsequent DBU-promoted elimination reaction. This method provides novel access to 4-vinyl-1H-1,2,3-triazoles in moderate to excellent yields with simplification of product workup.

Experimental
Melting points Are uncorrected. 1 H and 13 C NMR spectra were recorded on a Bruker Avance (400-MHz) spectrometer, using CDCl 3 as the solvent and TMS as internal reference. IR spectra were taken on a Perkin-Elmer SP One FTIR spectrophotometer. Microanalyses were performed with a Carlo Erba 1106 Elemental Analyzer, and 2% cross-linked benzenesulfonic acid resin (4.5 mequiv/g) was used for the preparation of sulfonyl chloride resin 1 (loading ¼ 4.1 mmol Cl/g) according to the reported method. [11] All organic azides are known compounds and were prepared by reaction of NaN 3 with organic halides in DMF according the literature procedure. [12] The other starting materials were purchased from commercial sources and used without further purification. THF was newly destilled from sodium benzophenone immediately before use. DMF was purified by distillation under reduced pressure over calcium hydride prior to use.

General procedure for the preparation of 4-vinyl-1,2,3-triazoles
Resin 2 (0.57 g, 2.0 mmol) was swelled in THF/DMF (15 mL, 2:1) at room temperature for 30 min under nitrogen. Then azide (8.0 mmol), CuI (19.0 mg, 0.1 mmol), and DIPEA (1.0 mL, 7.7 mmol) were added, and the mixture was stirred at room temperature. This progression of the reaction was monitored by IR spectroscopy. After disappearance of the signal near 2100 cm À 1 , the suspension was filtered through the vessel frit and the resin was washed successively with H 2 O (2 � 10 mL), DMF (2 � 10 mL), MeOH (2 � 10 mL), and CH 2 Cl 2 (2 � 10 mL) and dried in vacuo to give resin 3. The resin 3 was then swelled in DMF (15 mL) for 30 min under a nitrogen atmosphere. NaI (0.9 g, 0.6 mmol) and DBU (0.6 g, 4.0 mmol) were added this suspension mixture, which was heated to 120 °C and kept at this temperature for 1 h. Upon completion, the mixture was cooled and the resin was collected by filtration and washed with CH 2 Cl 2 (3 � 10 mL). The filtrate was washed with water (2 � 30 mL), dried over magnesium sulfate, and concentrated to afford crude products 4a-4 m, which were further purified via flash column chromatography (hexane-EtOAc, 10:1) for their structural analysis.