N-Substituted 1,2,3-triazoles have aroused considerable research interests in recent years and have widespread applications in biological science ^[1-4],material chemistry ^[5-9] and medicinal chemistry ^[10-13]. N¹-substituted 1,2,3-triazoles could be prepared either by a thermo- or by metal-mediated ^[14-17] (Cu(I)-catalyzed for 1,4-disubstituted ^{[15, 18-20]} and Ru(Ⅱ)-catalyzed for 1,5-disubstituted ^{[21, 22]}) 1,3-dipolar cycloaddition reaction,whereas the synthesis of N²-substituted 1,2,3-triazoles has been far less explored to date. Many recent efforts have been made to prepare N²-aryl ^[23-25] and N²-allyl ^[26-29] 1,2,3-triazoles with high N²-selectivity through a palladium catalyzed coupling reaction by using suitable bulky phosphine ligands ^{[25, 29]}. However,N²-alkyl-1,2,3-triazoles can only be obtained by the conversion of non-substituted NH-triazoles with appropriate electrophiles through nucleophilic substitution ^[30-33].

Recently,some researchers reported the synthesis of N²-alkyl 1,2,3-triazoles through the nucleophilic reaction of alkyl halides with bulky C-4- and C-5-disubstituted NH-1,2,3-triazoles ^[30-32],in which,the synthetic utilities were therefore restricted by the substrate’s steric requirements (Scheme 1,Eq. (1)). A general,simple and scalable method for the synthesis of the N²-alkyl 1,2,3-triazoles,especially for 4-monosubstituted or 4,5-unsubstituted 1,2,3- triazoles is still not available. In the course of our research on triazole chemistry ^{[34, 35]},we were wondering if N²-substituted triazoles could be synthesized from their N¹-substituted isomers with the incorporation of labile N¹-substitutents (Scheme 1,Eq. (2)). Because the preparation of N¹-substituted 1,2,3- triazoles has been well documented in previous research,we envisioned that this new strategy would be flexible and improve the ability to construct N²-susbstituted 1,2,3-triazoles.

Brönsted acid-mediated alkene addition is one of the basic organic transformations in synthetic chemistry,and has been widely utilized for the functionalization of olefins. However,the addition of NH-1,2,3-triazole to olefins has been seldom explored before except an example of michael addition of NH-1,2,3-triazole onto α,β-unsaturated ester to provide N¹-alkyl triazole products ^[36]. Herein,we report the synthesis of N²-alkyl 1,2,3-triazole with high N²-selectivity through acid mediated addition of NH-1,2,3-triazole to olefins.

In a preliminary trial,N¹-substituted 1,2,3-triazole 1a with different substitution patterns was chosen as the substrate for our initial investigation. As shown in Table 1,the reaction of 1aH (R=H) with 4-tertbutyl styrene 2a in the presence of 1 equivalent of toluenesulfonic acid (TsOH) in CH₂Cl₂ gave no desired transformation at room temperature (Table 1,entry 1). However,when the reaction temperature was increased to 65 °C in chloroform,the desired N²-substituted coupling adduct 3a was obtained in 30% yield with N²/N¹ = 3/1. The structure of 3a was confirmed by X-ray chromatography,as shown in Fig. 1,which shows that the triazole group connects with the alkyl group at the N-2 nitrogen atom. In previously reported examples,including acetylation ^[37],Michael addition ^[38] and S_N2 substitution reaction for the conversion of unsubstituted NH-triazoles ^[9],the N¹-substituted triazoles were usually the dominant products. Therefore,this result was very interesting. Various R substituents were then evaluated (Table 1,entries 3-5),in which the toluenesulfonyl (Ts) group performed much better than the other counterparts. The labile 1,1- dimethylbenzyl group gave only a trace amount of 3a. Other Brönsted acid catalysts were also tested. It was found that TsOH performed much better than CF₃SO₃H,concentrated HCl and CH₃COOH (Table 1,entries 6-8). Increasing the equivalents of 2a and TsOH enhanced the yield of 3a (Table 1,entries 9-12). In the control experiments,the Lewis acid BF₃·Et₂O and the metal catalyst AuCl₃ gave no desired transformation (Table 1,entries 13 and 14).

With the optimized reaction conditions in hand (Table 1,entry 12),we then examined the scope of this transformation by synthesizing a variety of N²-alkyl 1,2,3- triazole derivatives. As shown in Table 2,a series of 1,2,3-triazole substrates were examined by using 4-tertbutyl styrene 2a as the coupling partner. At first,several phenyl triazoles with different substitution patterns were tested,in which substrates with electron-rich substituents (Table 2,3a-c) performed better than their electron-poor counterparts (Table 2,3e-h). p-Methoxy phenyl triazole 1d gave 3d in only 34% yield (Table 2,3d). The reaction of thiophenyl triazole 1i went smoothly,affording 3i in moderate yields with a high N²-selectivity. Unsubstituted NH-1,2,3-triazole 1j worked very well,providing 3j in moderate yield with a good N²-selectivity. Notably,the benzotriazole coupling adduct 3k was obtained with good N²-selectivity (N²/N¹ = 4/1). Compared with the low N²-selectivities obtained in previous reports,this result significantly improves the potential application of the acid mediated reaction ^{[21, 22]}. Because of its instability,the N¹-Ts alkyl substrates were not explored.

The TsOH mediated reaction of 1aT with a variety of olefins was explored,wherein,aromatic olefins and diene substrates worked very well. As shown in Table 3,N²-alkyl 1,2,3-triazoles 4b and 4c were obtained in good yields with high N²-selectivities from the reactions of substituted styrene 2b and 2c. In the reactions of the bulky 2-vinylnaphthalene and 2,4,6-trimethyl styrene,the substrate’s steric hindrance affected the yields of 4d and 4e (Table 3,4d and 4e). Moreover,a low N²/N¹-selectivity was observed in the 4f (Table 3,4f). This might be because of the formation of a stabilized carbon cation intermediate. Similarly,trisubstituted olefin 2g,which would lead to a stabilized trisubstituted carbon cation intermediate,gave 4g with a low N²-selectivity (N²/N¹= 3.1/1). Cyclohexadiene was also tested,providing 4h in 88% yield with a N²/N¹ = 8/1. The reactions of the aliphatic olefins were unsuccessful,owing to the poor regioselectivity of the olefins.

Next,we explored the TsOH mediated reactions of vinyl ester 5. As shown in Table 4,a series of N²-substituted 1,2,3-triazole derivatives were obtained in moderate to good yields. Notably,only N²-isomers were obtained in these reactions. No obvious electronic effect or site preference was observed,and the N²-substituted p-methoxy phenyl triazole 6d was obtained in a low yield. The structure of 6f was determined by X-ray chromatography,as shown in Fig. 2.

As depicted in Eq. (2) in Scheme 1,the Ts protecting group in the N¹-Ts triazole substrates would act as the leaving group,which should be trapped by the trace amount of water in CHCl₃. To elucidate the detailed reaction mechanism,two equivalents of ethanol were added in the reaction of 1a and 2a (Scheme 2,Eq. (3)). It was found that the desired N²-coupling adduct 3a was obtained in 65% yield,together with the formation of CH₃CH₂OTs 7 in 62% yield. The reaction of TsOH with ethanol was performed in CHCl₃ at 65 °C as the control experiment (Scheme 2,Eq. (4)),in which no p-toluenesulfonyl ester 7 was detected.

A plausible mechanism was then proposed based on these observations. As shown in Scheme 3,a carbon cation intermediate is generated from the styrene with the addition of a proton,which is then attacked by the internal nitrogen of the N¹-Ts triazole substrate to give the desired N²-alkyl 1,2,3-triazole product. At the same time,the leaving Ts group is trapped by the trace amount of water in CHCl₃ to give TsOH as the side product. The low reactivity of 1-(p-methoxyphenyl) triazole can be rationalized by the instability of its Ts protection group under the reaction conditions (3d in Table 2,6d in Table 4). The low N²/N¹ selectivities of 4f and 4g can be explained by the reversible elimination of these N²-alkyl triazole products,owing to the improved stability of the corresponding carbon cation intermediates.

In summary,a new efficient method was developed to synthesize N²-alkyl 1,2,3-triazole products through the TsOH catalyzed addition of N¹-Ts substituted 1,2,3-triazoles to olefins. Monosubstituted and unsubstituted triazole substrates and various olefins,including vinyl esters,worked very well in this reaction. Considering the easy availability of N¹-substituted 1,2,3-triazoles using the previously reported methods,the reaction reported in this paper provides a simple method to construct various types of N²-substituted triazoles.