A two-step continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles under metal- and azide-free conditions

Abstract

A green, general and efficient I₂/TBHP mediated synthetic method toward 1,4-disubstituted 1,2,3-triazoles via the reactions of acetophenones, tosylhydrazine and anilines within 35 min in a two-step continuous flow system has been developed. The reaction proceeds smoothly to afford 1,4-disubstituted 1,2,3-triazoles in moderate to good yield under metal- and azide-free conditions by using I₂ as a catalyst.

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Introduction

The formation of heterocyclic frameworks is an important part of programs in drug discovery. As important compounds, 1,2,3-triazoles have been widely used in organic synthesis,¹ biochemistry,² and materials science.³ Therefore, it is important to develop general and efficient methods for their synthesis.⁴ The pioneering work on the synthesis of 1,2,3-triazole can be dated back to the 1960s; Huisgen and co-workers reported the approach for the synthesis of these compounds through thermal dipolar cycloaddition between alkynes and azides.⁵ However, the regioselectivity of this method is poor, which limits its application. Afterward, Sharpless⁶ and Meldal⁷ reported a Cu-catalyzed azide–alkyne cycloaddition (CuAAC) method for the synthesis of 1,2,3-triazole, which was high efficiency and had excellent regioselectivity. And 1,2,3-triazoles can also be prepared by RuAAC,⁸ IrAAC,⁹ and Pd-catalyzed reactions of alkenyl bromides with azides.¹⁰ However, these reactions mentioned above shared a common drawback, which was that they utilized heavy metals, which limited its practical application.

To overcome this problem, another method was developed by using organic catalyst instead of metal catalyst.¹¹ And a lot of 1,2,3-triazoles had been readily obtained through the incorporation of azides with different reaction partners. For example the reaction of azides with enols and enamines,¹² the nitromethylene-based three-component synthesis¹³ and the Lewis based-catalyzed azide–zwitterion reaction.¹⁴ However, these reactions required sodium azides or organic azides, which were explosive and toxic. Therefore, it is important to develop an efficient and straightforward method to synthesis 1,2,3-triazoles from simple, readily accessible, and inexpensive materials.

With the striking advances of 1,2,3-triazole synthesis, the most challenge is to develop a metal- and azide-free method, which is quite attractive from the economical and green chemistry points of view. In 2013, Zhang and coworkers provided a copper-mediated method to achieve the desired 1,4-disubstituted 1,2,3-triazoles without the use of azides.¹⁵ Westermann improved Sakai's reaction and reported the synthesis of 1,4-disubstituted 1,2,3-triazoles under metal-free conditions (Scheme 1a).¹⁶ Recently, Ramasastry summarized the synthetic methods for 1,2,3-triazoles.¹⁷ To the best of our knowledge, only few literatures reported chemoselective formation of 1,4-disubstituted 1,2,3-triazoles under metal- and azide-free conditions. Ji and coworkers reported the synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles through the cycloaddition of α-chlorotosylhydrazones with arylamines under metal- and azide-free conditions (Scheme 1b).¹⁸ Wang and coworkers reported the I₂/TPBP mediated synthesis of 1,4-disubstituted 1,2,3-triazoles.¹⁹ However, the starting materials of these methods were not readily available. They were always obtained through the reaction of ketones with tosylhydrazine, which added the step to get the desired products. And the added step in multistep batch reactions was not only troublesome, but also time-consuming and less efficient.

Scheme 1 A proposed route to 1,2,3-triazoles under metal- and azide-free conditions.

The use of continuous flow microreactors provides a valuable platform for the development of multistep syntheses. Because it integrates multiple unit operations into one single operation and eliminates the handling of intermediate species.²⁰ Recently, our group had researched the oxidation amination of alcohol to amide in a two-step continuous flow reactor with metal-free catalyst.²¹ In the process, we successfully integrates alcohol oxidation and amide bond formation, which are usually accomplished separately, into a single operation. Here we report a I₂/TBHP mediated two-step continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles (Scheme 1c).

Since the continuous flow system was fit for the multistep reaction, we designed a two-step continuous flow reactor system, as shown in Fig. 1. It consists of three syringe pumps, two T-piece micromixers and two microreactors. The volume of the syringe and two microreactors are 20 mL, 2 mL and 10 mL, respectively. The mole ratio of reactants and reaction time can be modulated by changing the flow rate of syringes. And the temperature was controlled by oil bath.

Fig. 1 A two-step continuous flow reactor system.

Results and discussion

At the beginning, a model reaction of acetophenone (1a), tosylhydrazine and p-aminotoluene (2a) to form 4-phenyl-1-p-tolyl-1H-1,2,3-triazole (3a) were chosen to identify the reaction system. Firstly, we optimized the first step of the reaction in continuous flow reactor. The results were summarized in Table 1. Before we started the experiment in microreactor, a solvent screen in batch experiment was needed, which indicated that 1,4-dioxane was the optimal solvent due to the solubility of product. From Table 1 we can see that the reaction temperature and reaction time of the first step were 50 °C (Table 1, entries 1–3) and 10 min (Table 1, entry 2, 4, 5), respectively.

Table 1 Optimization of the reaction conditions of the first step^a

Entry	Equiv. number	T1 (°C)	t (min)	Yield^b (%)
a Reaction conditions: solution A: 0.1 M of 1a in dioxane, flow rate 0.1 mL min^−1; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.1 mL min^−1, unless otherwise noted.b Isolated yield.c Solution A: 0.1 M of 1a flow rate 0.2 mL min^−1; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.2 mL min^−1.d Solution A: 0.1 M of 1a flow rate 0.05 mL min^−1; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.05 mL min^−1.e Solution A: 0.1 M of 1a flow rate 0.1 mL min^−1; solution B: 0.12 M of tosylhydrazine in dioxane, flow rate 0.1 mL min^−1.f Solution A: 0.12 M of 1a, flow rate 0.1 mL min^−1; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.1 mL min^−1.
1	1 : 1	25	10	86
2	1 : 1	50	10	98
3	1 : 1	80	10	96
4^c	1 : 1	50	5	95
5^d	1 : 1	50	20	98
6^e	1 : 1.2	50	10	96
7^f	1.2 : 1	50	10	94

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Then we continued to optimize the second step which was initiated by treating acetophenone (1a), tosylhydrazine and p-aminotoluene (2a) with I₂ (10 mol%) in the presence of TBHP (2.0 equiv.), 80 °C for 35 min. The yield of the product 3a was 41%. To improve the yield of the product, different catalysts, oxidants, reaction temperature and reaction time were tested. And the results were shown in Table 2. The reaction proceeded less efficiently in other iodine-containing catalysts such as KI and NIS (Table 2, entries 1–3). And when other oxidants were used instead of TBHP, the results were really bad (Table 2, entries 1, 4–7). Next, the temperature was investigated and we observed that when increasing the temperature to 100 °C, it led to a significant improvement in the amount of product 3a. Thus, 100 °C was regarded as the optimum temperature (Table 2, entry 1, 8, 9). The reaction time (Table 2, entry 1, 10, 11) and equiv. number of catalyst (Table 2, entry 1, 12, 13) were also investigated, which led to best reaction conditions.

Table 2 Optimization of the reaction conditions of the second step^a

Entry	Catalyst (mol%)	Oxidant (equiv.)	T1 (°C)	T2 (°C)	t1 (min)	t2 (min)	Yield^b (%)
a Reaction conditions: solution A: 0.1 M of 1a in dioxane, flow rate 0.1 mL min^−1; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.1 mL min^−1; solution C: 0.06 M of 2a, 0.005 M of catalyst, 0.1 M of oxidant in dioxane, flow rate 0.2 mL min^−1 unless otherwise noted.b Isolated yield.c NP = no product.d Solution C: 0.03 M of 2a, 0.5 mM of I2, 0.05 M of TBHP in dioxane, flow rate 0.4 mL min^−1.e Solution C: 0.12 M of 2a, 0.01 M of I2, 0.1 M of TBHP in dioxane, flow rate 0.1 mL min^−1.f Solution C: 0.06 M of 2a, 0.01 M of I2, 0.1 M of TBHP in dioxane, flow rate 0.2 mL min^−1.g Solution C: 0.06 M of 2a, 0.025 M of I2, 0.1 M of TBHP in dioxane, flow rate 0.2 mL min^−1.
1	I2 (10)	TBHP (2)	50	80	10	25	41
2	KI (10)	TBHP (2)	50	80	10	25	23
3	NIS (10)	TBHP (2)	50	80	10	25	38
4	I2 (10)	H2O2 (2)	50	80	10	25	Trace
5	I2 (10)	m-CPBA (2)	50	80	10	25	NP^c
6	I2 (10)	TEMPO (2)	50	80	10	25	NP
7	I2 (10)	—	50	80	10	25	Trace
8	I2 (10)	TBHP (2)	50	50	10	25	25
9	I2 (10)	TBHP (2)	50	100	10	25	64
10^d	I2 (10)	TBHP (2)	50	100	10	16.7	48
11^e	I2 (10)	TBHP (2)	50	100	10	33.3	64
12^f	I2 (20)	TBHP (2)	50	100	10	25	85
13^g	I2 (50)	TBHP (2)	50	100	10	25	86

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Optimized reaction conditions for a two-step continuous flow synthesis of 1,2,3-triazole had been obtained. And we used the similar conditions to investigate the same reaction in batch. The yield of the product was only up to 43%, which was much lower than that in continuous flow system. And the reaction time in batch was 15 h, which was much longer than 35 min. Most importantly, the reaction in batch was much more troublesome. The two steps needed to be accomplished separately, p-aminotoluene, I₂ and TBHP in dioxane were added to the reaction liquid when acetophenone (1a) and tosylhydrazine were reacted completely and isolated, which led to time-consuming and less efficient. From these results we can see that the continuous flow system was fit for the multistep reaction.

With the optimized conditions in hand, an array of commercially available anilines was used to investigate the substrate scope of this method. And the results were shown in Table 3. Moderate to good yields were obtained in most cases. The reactions of aniline or 4-substituted anilines afforded corresponding product 3a–3d in 72–85% yields. And fluoro, chloro, and bromo group could be tolerated in the reaction conditions to generate the desired functionalized 1,4-disubstituted 1,2,3-triazoles in good yields (Table 3, 3e–3g). What's more, the reaction was not affected by the position of the substituents on the aromatic ring of anilines (Table 3, 3h–3j). When more sterically hindered substrate ([1,1′-biphenyl]-2-amine) was applied, the reaction proceeded smoothly (Table 3, 3k).

Table 3 Scope of anilines^a

a Reaction conditions: solution A: 0.1 M of 1a in dioxane, flow rate 0.1 mL min⁻¹; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.1 mL min⁻¹, T₁ = 50 °C; solution C: 0.06 M of 2, 0.005 M of I₂, 0.1 M of TBHP in dioxane, flow rate 0.2 mL min⁻¹, T₂ = 100 °C.

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Next, a wide range of acetophenones had also been used to test the substrate scope of the reaction, and the results were shown in Table 4. Both electron-deficient and electron-rich substrates could react smoothly to afford the desired products in good yields (Table 4, 3m–3s). 1-Acetonaphthone and 2-acetonaphthone were good substrates for this reaction (Table 4, 3t, 3u). Furthermore, triazoles with heterocyclic substituents, such as furyl and thiophenyl groups, were obtained in high yields (Table 4, 3w, 3x).

Table 4 Scope of acetophenones^a

a Reaction conditions: solution A: 0.1 M of 1 in dioxane, flow rate 0.1 mL min⁻¹; solution B: 0.1 M of tosylhydrazine in dioxane, flow rate 0.1 mL min⁻¹, T₁ = 50 °C; solution C: 0.06 M of 2a, 0.005 M of I₂, 0.1 M of TBHP in dioxane, flow rate 0.2 mL min⁻¹, T₂ = 100 °C.

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To show the application of this new methodology, we conducted a large-scale reaction in continuous flow system under the best reaction conditions. And the desired product was obtained successfully in 83% yield (Scheme 2).

Scheme 2 A large-scale reaction in continuous flow system.

Conclusions

In conclusion, a green, efficient and direct method for the synthesis of 1,4-disubstituted 1,2,3-triazoles in a two-step continuous flow system has been developed. This metal- and azide-free method uses commercial available starting materials and integrates multistep reactions, which are usually accomplished separately, into a single operation. And the yield of the corresponding products was good. It also clearly shows the major advantage of continuous multistep systems to allow reaction parameters to be independently adjusted.

Experimental

General details

Reaction solvents were obtained commercially, and used without further purification. Commercial reagents were used as received. Reaction were monitored by thin-layer chromatography (TLC) on 0.25 mm precoated Merck Silica Gel 60 F254, visualizing with ultraviolet light. ¹H/¹³C NMR spectra were recorded on 400′54 ascend purchased from Bruker Biospin AG, operating at 400/100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard. High-resolution mass spectra (HRMS) were obtained from an Agilent 6520 LC-MS instrument. Flash column chromatography was performed on Merck Silica Gel 60 (200–300 mesh) using petroleum ether and ethyl acetate.

General procedure for synthesis of compound 3. 5 mmol of acetophenones (1) was dissolved in 50 mL dioxane, which was placed into syringe A. And 5 mmol of tosylhydrazine was dissolved in 50 mL dioxane, which was placed into syringe B. Anilines (2, 3 mmol, 1.2 eq.), I₂ (0.25 mmol, 0.2 eq.) and TBHP (70 wt% in water, 5 mmol, 2 eq.) were dissolves in 50 mL dioxane, which was placed into syringe C. The flow rate of syringes A, B and C were 0.1 mL min⁻¹, 0.1 mL min⁻¹, and 0.2 mL min⁻¹, respectively. And the temperature of the two oil baths was set in 50 °C and 80 °C, respectively. The reaction liquid was collected, and then quenched by NaHSO₃ solution and extracted with ethyl acetate, washed with H₂O. The organic layer was dried over anhydrous sodium sulfate and solvent was removed under vacuum. And the crude product was purified by flash chromatography on silica gel by gradient elution with ethyl acetate in petroleum ether to obtain the product 3.
4-Phenyl-1-p-tolyl-1H-1,2,3-triazole (3a). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.36 (dd, J = 14.0, 7.8 Hz, 3H), 2.44 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 146.25, 137.90, 129.26, 128.43, 127.90, 127.35, 124.84, 119.46, 117.79, 116.59, 20.11; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃ [M + H]⁺ 236.1182, found 236.1195.
1,4-Diphenyl-1H-1,2,3-triazole (3b). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.81 (d, J = 7.7 Hz, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.47 (t, J = 6.5 Hz, 3H), 7.38 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 147.42, 136.09, 129.24, 128.79, 127.93, 127.78, 127.44, 124.87, 119.56, 116.61; HRMS (ESI) m/z calcd for C₁₄H₁₁N₃ [M + H]⁺ 222.1047, found 222.1053.
1-(4-Isopropylphenyl)-4-phenyl-1H-1,2,3-triazole (3c). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.94–7.88 (m, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (dd, J = 15.2, 7.9 Hz, 3H), 3.00 (dt, J = 13.8, 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 148.25, 130.29, 128.92, 128.39, 127.73, 125.87, 120.64, 117.66, 33.87, 23.91; HRMS (ESI) m/z calcd for C₁₇H₁₇N₃ [M + H]⁺ 264.1495, found 264.1509.
1-(4-Methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (3d). Light yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.93–7.88 (m, 2H), 7.71–7.65 (m, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 130.38, 128.92, 128.35, 125.85, 122.24, 117.86, 114.83, 55.66; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃O [M + H]⁺ 252.1131, found 252.1146.
1-(4-Fluorophenyl)-4-phenyl-1H-1,2,3-triazole (3e). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.78 (dd, J = 8.8, 4.5 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 147.56, 129.10, 127.95, 124.86, 121.57, 121.48, 116.72, 115.87, 115.64; HRMS (ESI) m/z calcd for C₁₄H₁₀N₃F [M + H]⁺ 240.0932, found 240.0958.
1-(4-Chlorophenyl)-4-phenyl-1H-1,2,3-triazole (3f). Light yellow solid; ¹H NMR (400 MHz, DMSO) δ 7.97–7.93 (m, 4H), 7.66–7.60 (m, 2H), 7.54–7.48 (m, 4H); ¹³C NMR (101 MHz, DMSO) δ 167.82, 132.82, 130.75, 129.91, 129.22, 129.02, 128.53, 125.32, 121.65, 119.71; HRMS (ESI) m/z calcd for C₁₄H₁₀N₃Cl [M + H]⁺ 256.0636, found 256.0664.
1-(4-Bromophenyl)-4-phenyl-1H-1,2,3-triazole (3g). White solid; ¹H NMR (400 MHz, DMSO) δ 9.36 (s, 1H), 7.99–7.90 (m, 4H), 7.90–7.82 (m, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO) δ 145.20, 135.82, 132.84, 130.07, 129.02, 128.33, 125.33, 121.87, 119.65; HRMS (ESI) m/z calcd for C₁₄H₁₀N₃Br [M + H]⁺ 300.0131, found 300.0131.
4-Phenyl-1-m-tolyl-1H-1,2,3-triazole (3h). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.95–7.89 (m, 2H), 7.64 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.50–7.34 (m, 5H), 2.47 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 140.05, 130.32, 129.56, 128.92, 128.40, 125.88, 121.24, 117.63, 21.45; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃ [M + H]⁺ 236.1182, found 236.1208.
1-(3-Methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (3i). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.92 (dd, J = 5.2, 3.3 Hz, 2H), 7.50–7.35 (m, 5H), 7.32 (dd, J = 8.0, 1.1 Hz, 1H), 6.99 (dd, J = 8.3, 1.8 Hz, 1H), 3.91 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 159.65, 147.36, 137.10, 129.54, 129.23, 127.91, 127.43, 124.87, 116.64, 113.63, 111.38, 105.38, 54.65; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃O [M + H]⁺ 252.1131, found 252.1125.
4-Phenyl-1-o-tolyl-1H-1,2,3-triazole (3j). Light yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.43 (d, J = 6.4 Hz, 1H), 7.35–7.42 (m, 3H), 2.28 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 147.6, 136.5, 133.7, 131.5, 130.3, 129.9, 128.9, 128.3, 126.8, 125.9, 125.8, 121.1, 17.9; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃ [M + H]⁺ 236.1182, found 236.1198.
1-(Biphenyl-2-yl)-4-phenyl-1H-1,2,3-triazole (3k). White solid; ¹H NMR (400 MHz, CDCl₃) δ 7.66–7.57 (m, 3H), 7.53–7.45 (m, 3H), 7.31 (dd, J = 9.4, 5.3 Hz, 3H), 7.25–7.20 (m, 4H), 7.10–7.06 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 146.40, 136.29, 135.95, 134.26, 130.13, 129.30, 128.87, 127.76, 127.74, 127.60, 127.50, 127.15, 127.04, 125.50, 124.74, 120.68; HRMS (ESI) m/z calcd for C₂₀H₁₅N₃O [M + H]⁺ 298.1339, found 298.1377.
1-(Naphthalen-1-yl)-4-phenyl-1H-1,2,3-triazole (3l). Brown oil; ¹H NMR (400 MHz, CDCl₃) δ 8.18–8.10 (m, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.98 (dd, J = 6.7, 5.2 Hz, 2H), 7.73–7.53 (m, 4H), 7.49 (dd, J = 7.8, 4.2 Hz, 3H), 7.40 (t, J = 6.8 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 147.77, 134.23, 133.76, 130.48, 130.21, 129.00, 128.48, 128.40, 128.33, 127.96, 127.13, 125.93, 125.04, 123.60, 122.33; HRMS (ESI) m/z calcd for C₁₈H₁₃N₃O [M + H]⁺ 272.1182, found 272.1196.
4-(4-Fluorophenyl)-1-phenyl-1H-1,2,3-triazole (3m). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.89 (dd, J = 8.5, 5.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 8.6 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 163.05, 160.59, 146.54, 135.98, 128.81, 127.86, 126.64, 126.56, 125.44, 125.40, 119.53, 116.38, 115.05, 114.83; HRMS (ESI) m/z calcd for C₁₄H₁₀N₃F [M + H]⁺ 240.0892, found 240.0896.
4-(4-Chlorophenyl)-1-phenyl-1H-1,2,3-triazole (3n). White solid; ¹H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 7.97 (t, J = 8.4 Hz, 4H), 7.69–7.50 (m, 5H); ¹³C NMR (101 MHz, DMSO) δ 146.20, 136.53, 132.67, 130.20, 129.96, 129.14, 129.09, 128.82, 126.99, 120.02; HRMS (ESI) m/z calcd for C₁₄H₁₀N₃Cl [M + H]⁺ 256.0563, found 256.0576.
4-(4-Bromophenyl)-1-phenyl-1H-1,2,3-triazole (3o). White solid; ¹H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 7.94 (dd, J = 16.4, 8.0 Hz, 4H), 7.73 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 7.9 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO) δ 146.27, 136.57, 131.99, 129.96, 129.48, 128.83, 127.27, 121.25, 120.02; HRMS (ESI) m/z calcd for C₁₄H₁₀N₃Br [M + H]⁺ 300.0038, found 300.0064.
1-Phenyl-4-p-tolyl-1H-1,2,3-triazole (3p). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.86–7.75 (m, 4H), 7.56 (dd, J = 10.5, 5.0 Hz, 2H), 7.46 (dd, J = 10.6, 4.3 Hz, 1H), 7.30–7.26 (m, 2H), 2.40 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 147.46, 137.32, 136.09, 128.75, 128.59, 127.69, 126.37, 124.73, 119.50, 116.21, 20.32; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃ [M + H]⁺ 236.1143, found 236.1175.
1-Phenyl-4-m-tolyl-1H-1,2,3-triazole (3q). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.83–7.76 (m, 3H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.50–7.44 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 2.43 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 137.63, 134.56, 132.62, 128.77, 128.22, 127.81, 127.76, 125.53, 121.93, 119.52, 116.56, 20.46; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃ [M + H]⁺ 236.1143, found 236.1164.
1-Phenyl-4-o-tolyl-1H-1,2,3-triazole (3r). Light yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.80–7.85 (m, 3H), 7.56 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 2.8 Hz, 3H), 2.55 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 147.81, 137.03, 135.72, 130.91, 129.84, 129.52, 129.03, 128.72, 128.42, 126.13, 120.51, 119.72, 21.43; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃ [M + H]⁺ 236.1143, found 236.1154.
4-(4-Methoxyphenyl)-1-phenyl-1H-1,2,3-triazole (3s). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 158.78, 147.25, 134.95, 128.75, 127.67, 126.16, 121.88, 119.48, 115.76, 113.31, 54.34; HRMS (ESI) m/z calcd for C₁₅H₁₃N₃O [M + H]⁺ 252.1092, found 252.1104.
4-(Naphthalen-1-yl)-1-phenyl-1H-1,2,3-triazole (3t). Brown yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J = 9.4 Hz, 1H), 8.27 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 7.0 Hz, 1H), 7.64–7.52 (m, 5H), 7.49 (t, J = 7.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 146.58, 136.02, 132.89, 130.13, 128.85, 128.19, 127.86, 127.51, 126.57, 126.42, 125.78, 125.09, 124.37, 124.33, 119.60; HRMS (ESI) m/z calcd for C₁₈H₁₃N₃ [M + H]⁺ 272.1143, found 272.1154.
4-(Naphthalen-2-yl)-1-phenyl-1H-1,2,3-triazole (3u). Light brown yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 8.33 (s, 1H), 8.04–7.98 (m, 1H), 7.97–7.90 (m, 2H), 7.90–7.81 (m, 3H), 7.61–7.45 (m, 5H); ¹³C NMR (101 MHz, CDCl₃) δ 133.95, 132.53, 132.24, 128.81, 127.83, 127.68, 127.24, 126.79, 126.52, 125.53, 125.29, 123.66, 122.82, 119.57; HRMS (ESI) m/z calcd for C₁₈H₁₃N₃ [M + H]⁺ 272.1143, found 272.1147.
4-(Biphenyl-4-yl)-1-phenyl-1H-1,2,3-triazole (3v). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.47 (t, J = 7.7 Hz, 3H), 7.38 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 128.80, 127.83, 127.82, 126.00, 126.50, 126.00, 125.24, 119.54, 117.48, 116.57; HRMS (ESI) m/z calcd for C₁₈H₁₃N₃ [M + H]⁺ 298.1300, found 298.1327.
4-(Furan-2-yl)-1-phenyl-1H-1,2,3-triazole (3w). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 7.7 Hz, 2H), 7.47 (dd, J = 13.3, 5.7 Hz, 2H), 6.94 (d, J = 3.3 Hz, 1H), 6.53 (dd, J = 3.2, 1.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 144.83, 141.30, 140.11, 135.82, 128.80, 127.88, 119.51, 116.06, 110.58, 106.16; HRMS (ESI) m/z calcd for C₁₂H₉N₃O [M + H]⁺ 212.0779, found 212.0787.
1-Phenyl-4-(thiophen-2-yl)-1H-1,2,3-triazole (3x). White solid; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.7 Hz, 2H), 7.47 (dd, J = 12.5, 5.0 Hz, 2H), 7.35 (dd, J = 5.1, 0.9 Hz, 1H), 7.12 (dd, J = 5.0, 3.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 142.91, 135.86, 131.42, 128.79, 127.89, 126.72, 124.39, 123.55, 119.54, 116.07; HRMS (ESI) m/z calcd for C₁₂H₉N₃S [M + H]⁺ 228.0551, found 228.0583.

Acknowledgements

The research has been supported by the National Natural Science Foundation of China (Grant No. 21522604, U1463201 and 21402240); the youth in Jiangsu Province Natural Science Fund (Grant No. BK20150031, BK20130913 and BY2014005-03); a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra. See DOI: 10.1039/c6ra19022g

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