Regioselective β-organoseleno/α-,N²-tetrazole addition to alkenes

Abstract

A method for the regioselective β-organoseleno/α-,N²-tetrazole addition to alkenes is reported. PhSeCl acts dually as a selenylating agent and a bridging agent for blocking the N¹ position of tetrazoles, thereby directing selectivity towards the N² position. The reactions show a broad substrate scope, accommodating various tetrazoles and alkenes, and are executed under mild conditions.

---

Both nitrogen- and selenium-containing molecules have found widespread applications in the fields of organic synthesis, materials science, and pharmaceutical chemistry.¹ Consequently, continuous efforts have been dedicated to devising novel and efficient methods for incorporating both selenium and nitrogen moieties into organic compounds.² Among established methods, the intermolecular aminoselenation of alkenes stands out as one of the most effective methods for the assembly of this ubiquitous framework, enabling the concurrent formation of vicinal C–N and C–Se bonds. Aminoselenation of alkenes has been extensively studied in recent decades, with several nitrogen-containing reagents employed as nitrogen nucleophiles, including amines, nitriles, phthalimide and sulfamides, sulfoximines, azides and azoles.³ Methods employing tetrazoles as the nitrogen sources for the aminoarylselenation have drawn significant interest.⁴ This stems from the broad utility of the tetrazole motif itself, which serves as an important synthetic scaffold in medicine, biochemistry, pharmacology, and materials science.⁵ For example, Sun and co-workers reported the aminoselenations of alkenes with tetrazole as the nitrogen source, mediated by K₂S₂O₈ and O₂, respectively (Scheme 1A).^4a,b Additionally, the Meng group developed a three-component electrochemical aminoselenation reaction of 1,3-dienes, azoles, and diselenide derivatives, achieving selenium-containing allylazoles with exclusive 1,2-regioselectivity (Scheme 1B).^4c Under the methodologies described above, the N¹ position of tetrazoles acts as an exclusively nucleophilic site, thus affording N¹-selective tetrazole functionalization. Controlling regioselectivity remains a fundamental challenge for tetrazole functionalization.⁶ The dynamic N¹/N² tautomerism presents a distinct obstacle to regiocontrol, as both N¹- and N²-selective pathways are theoretically possible.⁷ Generally, diselenides represent preferable selenylation agents due to their bench stability, ready availability, and ease of handling. Mechanistically, external oxidants have been used for the in situ generation of a reactive electrophilic selenium species, e.g. phenylselenium ion (⁺SePh), that participates in the aminoselenation of alkenes. However, under the conditions reported previously,⁴ tetrazole functionalization predominantly occurs at the N¹ position, likely due to the absence of directing interactions between the tetrazole and alkene substrates. This is again revealed by our initial experimental results. When N-(phenylselenenyl)phthalimide (NPSP) was introduced as the selenylation source, the desired N²-β-selenoalkylated tetrazole product 3a was nearly not formed (Scheme 1C). Therefore, new strategies other than through the phenylselenium ion (⁺SePh) have attracted our attention.

Scheme 1 Strategies for regioselective β-organoseleno/α-,N^1/2-tetrazole addition to alkenes.

We recognized that the high density of nitrogens in tetrazoles offers significant potential for hydrogen bonding, analogous to carboxylic acids as hydrogen bond donors,⁵ and the inherent nature of tetrazoles results in a negative charge delocalized among N², N³ and N⁴ atoms. Inspired by these features, we hypothesized that introducing a suitable selenylation source capable of bridging the N¹–H position of tetrazoles could block nucleophilic attack from N¹, thereby redirecting selectivity towards the N² position (Scheme 1D). In our previous work,⁸ we have found that intermolecular hydrogen bonding critically governs N²-selectivity in triazole functionalization.^8a,b We hypothesize herein that PhSeCl could serve as both selenylating agent and linking agent for blocking the N¹ position of tetrazoles. If this works, the desired regioselective N²-tetrazole addition could occur smoothly (Scheme 1D). With these mechanistic considerations in mind, we started our studies on this regioselective β-organoseleno/α-,N²-tetrazole addition to alkenes.

In our preliminary investigations, we examined the reaction among tetrazole (1a), styrene (2a), and PhSeCl in CHCl₃ at room temperature (25 °C) for 24 h. The reaction proceeded smoothly to provide the desired N²-product 3a in 73% yield with high N²-selectivity (>20/1) (Table 1, entry 1). Increasing the temperature to 65 °C reduced the reaction time to 1.5 h while improving both yield (85%) and N²-selectivity (>25/1) (Table 1, entry 2). While diamines effectively promoted N²-alkylation of triazoles in prior work,^8c their inclusion here in this reaction significantly diminished N²-selectivity, with various bases, including K₂CO₃, KO^tBu, Cs₂CO₃, N,N′-dimethylpiperazine (DMP), N,N,N′,N′-tetramethylethylenediamine (TMEDA) and Et₃N (Table 1, entries 3–8). This suggested that HCl, generated in situ from tetrazole and PhSeCl, might participate in governing the N²-selectivity. Solvent screening (DCE, ethyl acetate, 1,4-dioxane, toluene, DMF and CH₃OH) identified toluene as optimal, providing excellent yield (Table 1, entries 9–14). When the reaction was carried out under an inert atmosphere (argon), both the yield and N²-selectivity remained comparable to those observed in air. These results indicated that the reaction was not sensitive to oxygen (SI, Table S1, entry 13). Moreover, the reaction tolerated aqueous conditions, and afforded 3a in 86% yield employing H₂O as a solvent (Table 1, entry 15). In addition, lowering the temperature to 25 °C severely diminished the yield (33%) even after 36 h (Table 1, entry 16). Reducing the loading of 2a to 1.5 equivalents led to a dramatic decrease in the yield to 46%, while still maintaining a high N²-selectivity (>20 : 1) (Table 1, entry 17).

Table 1 Optimization of reaction conditions^a

Entry	Deviation	Solvent	Yield of 3a ^b	3a/3a′ ^c
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), PhSeCl (0.3 mmol), CHCl3 (1 mL), 1.5 h, air. ND implies that no product was detected by ^1H NMR analysis. b Isolated yield of the N^2-selective product 3a. c N^2/N^1 ratios were determined by ^1H NMR analysis of the crude mixtures. d The reaction was carried out with 0.3 mmol of 2a.
1	25 °C, 24 h	CHCl3	73	>20/1
2	—	CHCl3	85	>25/1
3	K2CO3	CHCl3	82	14/1
4	KO^tBu	CHCl3	75	7/1
5	Cs2CO3	CHCl3	Trace	—
6	Et3N	CHCl3	40	2/1
7	TMEDA	CHCl3	38	2/1
8	DMP	CHCl3	55	2/1
9	—	DCE	90	>25/1
10	—	Ethyl acetate	71	9/1
11	—	1,4-Dioxane	65	20/1
12	—	Toluene	94	>25/1
13	—	DMF	57	4/1
14	—	CH3OH	ND	—
15	—	H2O	86	>25/1
16	25 °C, 36 h	Toluene	33	>20/1
17^d	—	Toluene	46	>20/1

---

With the optimized conditions established, we explored the reaction scope primarily by varying tetrazole substrates (Scheme 2). Evaluation commenced with para-substituted aryl tetrazoles. Remarkably, these substrates exhibited excellent compatibility, affording exclusive N²-products (3a–3j) in yields up to 94%, highlighting a key advantage of this protocol. The structure of 3a was unequivocally confirmed by X-ray crystallography (CCDC 2468172). Iodo-, bromo-, chloro-, and fluoro-substituted substrates also proved viable, delivering 3e–3h in good yields with high N²-selectivities (>25/1). Furthermore, electron-donating (–OMe) or electron-withdrawing (–NO₂ and –CF₃) groups did not impede the reaction, providing products 3c, 3i and 3j in good yields. Substituents at the ortho- or meta-positions were equally tolerated, furnishing products 3k–3o in good to excellent yields (80–94%) with exceptional N²-selectivity. The free hydroxyl (3k) group was well tolerated. Both α- and β-naphthyl tetrazoles performed effectively under the standard conditions, with no significant electronic or positional effects observed on the aromatic moiety (3p and 3q). Aliphatic tetrazoles underwent smooth conversion to products 3r–3t in satisfactory yields (63–66%), albeit with reduced N²-selectivity (>3/1). This diminished selectivity likely stems from the absence of stabilizing π–π interactions between the tetrazole ring and aryl groups in 5-alkyl tetrazoles.⁵ Moreover, a gram-scale application further demonstrated synthetic utility; the reaction of 1a afforded 3a (2.44 g) in 86% yield without compromising N²-selectivity.

Scheme 2 Reaction scope of tetrazoles. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), PhSeCl (0.3 mmol), 1.0 mL of toluene, 65 °C, 1.5 h, air; yields of the isolated N²-products were reported; N²/N¹ ratios were determined by ¹H NMR analysis of the crude mixtures. All products were obtained as racemic mixtures.

An excellent tolerance of substituents was also observed during the subsequent investigation of the alkene scope (Scheme 3). A broad range of substituted styrenes, featuring electron-donating or electron-withdrawing groups at the para position, underwent the transformation smoothly, leading to the desired N²-products (4a–4g) in excellent yields. A reactive benzylic chloromethyl (Ar-CH₂Cl) group was found untouched under these standard conditions (4g). The electronic and steric effects on the ortho or meta position of styrenes did not affect the reactivity and N²-selectivity of the reaction (4h–4j). Substrates containing steric hindrance, such as α-methylstyrene and β-methylstyrene, smoothly delivered the desired N²-products 4k and 4l in yields of 75% and 85%, respectively. Moreover, this protocol could also be applied to inactive aliphatic alkenes, such as (E)-hex-3-ene, from which an anti-addition process was clearly seen (4m). In the case of tert-butylethene, product 4n with reverse regioselectivity was formed due to the steric hindrance of the bulky ^tBu group. Other cyclic alkenes, such as indene, 1,2-dihydronaphthalene and cyclohexene, were also efficiently converted to 4o–4q. 1,3-Dienes are often used as versatile feedstocks to assemble structurally diverse, complex molecular architectures.^3j,4c Considering the conjugated nature of 1,3-dienes, two different reaction sites would occur simultaneously; the regioselective alkene functionalisation of 1,3-dienes is a challenging research topic. However, this protocol was expanded to cyclohexadiene and 1-aryl-1,3-diene under the standard conditions with high 1,2-regioselectivities and excellent N²-selectivities (4r and 4s). Furthermore, alkenes with various functional groups, including cinnamic alcohol, vinyl acetate and 3-vinyl pyridine, were also effective to give the desired N²-products 4t–4v in good yields. Moreover, N-glycosylation⁹ has been recognized as a powerful tool for the synthesis of essential nucleosides and has also been applied for the modification of peptide-based drugs to improve their pharmacological properties. This protocol was also applicable to sugar chemistry. When commercially available triacetyl-D-galactal and tetrazole were subjected to the standard reaction conditions, the N-glycosylated product 4w was obtained with excellent β- and N²-selectivity. The structure of 4w was assigned based on a series of 2D NMR experiments (HSQC, HMBC, COSY, and NOESY).

Scheme 3 Reaction scope of alkenes. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), PhSeCl (0.3 mmol), 1.0 mL of toluene, 65 °C, 1.5 h, air; yields of the isolated N²-products were reported; N²/N¹ ratios were determined by ¹H NMR analysis of the crude mixtures. All products were obtained as racemic mixtures, with the exception of compound 4w. ^a The reaction was carried out with alkene (0.2 mmol) and 1a (0.4 mmol).

To further elucidate the reaction mechanism, we performed a series of controlled experiments (Scheme 4). Under the optimized reaction conditions, addition of the radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT, 2.0 equiv.) afforded 3a in 91% yield without compromising N²-selectivity. This result suggested that radical intermediates were not likely involved in the reaction (Scheme 4A). Moreover, using N-(phenylselenenyl)phthalimide (NPSP) as the selenylation source, in the presence of 2.0 equivalents of concentrated HCl, the yield remarkably reached up to a quantitative level with excellent N²-selectivity. When NPSP was treated with concentrated HCl in CDCl₃ at room temperature for 1.5 hours, PhSeCl was generated and was detected by ¹H NMR analysis of the crude product. These results clearly suggested that PhSeCl apart from ⁺SePh served as an effective selenylation agent for the desired N²-selectivities.

Scheme 4 Control experiments.

Moreover, we explored the scope of selenium electrophiles (Scheme 4C). Owing to their high moisture sensitivity, these species are difficult to isolate as pure compounds. As an alternative, we opted to generate ArSeCl reagents in situ from diaryl diselenides and N-chlorosuccinimide (NCS) following a literature procedure.¹⁰ Employing this protocol, we conducted the model reaction in CHCl₃ with diphenyl diselenide (5), affording product 3a in 86% yield with excellent N²-selectivity (>25 : 1)—a result comparable to that obtained using PhSeCl (Table 1, entry 2). Selenium reagents bearing electron-donating groups (e.g., OMe, 6) enhanced the reactivity, presumably by improving the stability of the selenium species. In contrast, those with electron-withdrawing groups (e.g., acetyl, 7) led to diminished yields. The presence of a bulky substituent (naphthyl, 8) did not significantly impact the reactivity; however, a slight reduction in N²-selectivity was observed in these cases.

Finally, transformation of selenides was achieved via a one-pot reaction of 1a and 2a, affording the N²-olefinated tetrazole 9 in 94% yield without adjustment of the standard reaction conditions.¹¹

In summary, we have developed an efficient intermolecular regioselective β-organoseleno/α-,N²-tetrazole addition to alkenes. The in situ blocking of the N¹ position of tetrazoles has been proposed to play important roles for N²-selectivities. We expect that this new strategy for controlling N²-selectivity in tetrazole functionalization will find potential synthetic applications in the future.

Author contributions

L.-L. Zhu, H. Zhang and Y. Wang conceived this work and designed the experiments. L.-L. Zhu, L. Tian, Z. Zhang, Q. Li, Y. Tian, X. Han, J. Li, and G. Liu conducted the experiments and analyzed the data. L.-L. Zhu and Y. Wang wrote the manuscript and the SI.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5ob01622c.

CCDC 2468172 (3b) contains the supplementary crystallographic data for this paper.¹²

Acknowledgements

We acknowledge the National Natural Science Foundation of China (22001272), the Science and Technology Research Project of Henan Province (242102110035), and the University Student Scientific Research Innovation Foundation of Zhoukou Normal University (ZKNUD2025103) for financial support.

References

1. (a) C. W. Nogueira, G. Zeni and J. B. T. Rocha, Chem. Rev., 2004, 104, 6255–6285; (b) W. Hou and H. Xu, J. Med. Chem., 2022, 65, 4436–4456; (c) J. Wang, M. Chen, Z. Zhang, L. Ma and T. Chen, Coord. Chem. Rev., 2023, 493, 215278; (d) C. Morán-Serradilla, D. Plano, C. Sanmartín and A. K. Sharma, J. Med. Chem., 2024, 67, 7759–7787.
2. (a) K. Sun, X. Wang, C. Li, H. Wang and L. Li, Org. Chem. Front., 2020, 7, 3100–3119; (b) L. Lu, D. Huang, Z. Wang and X. Wu, Adv. Synth. Catal., 2023, 365, 2310–2331; (c) P. Qu, Y.-Q. Jiang, Y.-H. Wang and G.-Q. Liu, Green Chem., 2023, 25, 7485–7507.
3. (a) E. Tang, W. Wang, Y. Zhao, M. Zhang and X. Dai, Org. Lett., 2016, 18, 176–179; (b) Y. Liu, C. Li, S. Mu, Y. Li, R. Feng and K. Sun, Asian J. Org. Chem., 2018, 7, 720–723; (c) L. Sun, Y. Yuan, M. Yao, H. Wang, D. Wang, M. Gao, Y. H. Chen and A. Lei, Org. Lett., 2019, 21, 1297–1300; (d) X. Gao, L. Tang, L. Huang, Z.-S. Huang, Y. Ma and G. Wu, Org. Lett., 2019, 21, 745–748; (e) B. Huang, Y. Li, C. Yang and W. Xia, Green Chem., 2020, 22, 2804–2809; (f) G.-Q. Liu, C.-F. Zhou, Y.-Q. Zhang, W. Yi, P.-F. Wang, J. Liu and Y. Ling, Green Chem., 2021, 23, 9968–9973; (g) F. Cui, Y. Hua, Y. Lin, J. Fei, L. Gao, X. Zhao and H. Xia, J. Am. Chem. Soc., 2022, 144, 2301–2310; (h) X. Li, J. Huang, L. Xu, P. Liu and Y. Wei, J. Org. Chem., 2022, 87, 10684–10697; (i) M. Kuang, H. Li, Z. Zeng, H. Gao, Z. Zhou, X. Hong, W. Yi and S. Wang, Org. Lett., 2023, 25, 8095–8099; (j) R. Wang, N. Zhang, Y. Zhang, B. Wang, Y. Xia, K. Sun, W. Jin, X. Li and C. Liu, Green Chem., 2023, 25, 3925–3930; (k) Y.-Q. Zhang, Y.-Q. Jiang, Y.-H. Wang, C. Qi, Y. Ling, Y. Zhang and G.-Q. Liu, J. Org. Chem., 2023, 88, 7431–7447; (l) J. Ji, X. Chen, Z. Hu, C. Guan, J. Liu, Y. Deng and S. Liu, Org. Chem. Front., 2024, 11, 3066–3071.
4. (a) K. Sun, X. Wang, Y. Lv, G. Li, H. Jiao, C. Dai, Y. Li, C. Zhang and L. Liu, Chem. Commun., 2016, 52, 8471–8474; (b) K. Sun, X. Wang, C. Zhang, S. Zhang, Y. Cheng, H. Jiao and W. Du, Chem. – Asian J., 2017, 12, 713–717; (c) S.-Y. Ren, Q. Zhou, H.-Y. Zhou, L.-W. Wang, O. M. Mulina, S. A. Paveliev, H.-T. Tang, A. O. Terentev, Y.-M. Pan and X.-J. Meng, J. Org. Chem., 2023, 88, 5760–5771.
5. C. G. Neochoritis, T. Zhao and A. Dömling, Chem. Rev., 2019, 119, 1970–2042.
6. A. Fanourakis, Y. Ali, L. Chen, P. Q. Kelly, A. J. Bracken, C. B. Kelly and M. D. Levin, Nature, 2025, 641, 646–652.
7. For selected examples of N-substituted tetrazoles, see: (a) G. Aridoss and K. K. Laali, Eur. J. Org. Chem., 2011, 6343–6355; (b) N. Zhou, J. Zhao, C. Sun, Y. Lai, Z. Ruan and P. Feng, J. Org. Chem., 2021, 86, 16059–16067; (c) N. Zhou, J. Yu, L. Hou, X. Wu, Z. Ruan and P. Feng, Adv. Synth. Catal., 2022, 364, 35–40; (d) T. Kaszás, B. Szakács, É. Juhász-Tóth, I. Cservenyák, T. Kovács, L. Juhász, L. Somsák and M. Tóth, Eur. J. Org. Chem., 2022, e202201103; (e) S. P. Desai and M. S. Taylor, Org. Lett., 2022, 24, 7617–7621.
8. For our recent work on N²-selective functionalization of triazoles, see: (a) L.-L. Zhu, X. Xu, J. Shi, B. Chen and Z. Chen, J. Org. Chem., 2016, 81, 3568–3575; (b) L.-L. Zhu, L. Tian, H. Zhang, L. Xiao, W. Luo, B. Cai, H. Wang, C. Wang, G. Liu, C. Pei and Y. Wang, Adv. Synth. Catal., 2019, 361, 1117–1123; (c) L.-L. Zhu, L. Tian, B. Cai, G. Liu, H. Zhang and Y. Wang, Chem. Commun., 2020, 56, 2979–2982; (d) L.-L. Zhu, L. Tian, K. Sun, Y. Li, G. Liu, B. Cai, H. Zhang and Y. Wang, J. Org. Chem., 2022, 87, 12963–12974; (e) H. Zhang, L. Tian, Q. Li, H. Zheng, Y. Dai, J. Li, G. Liu, L.-L. Zhu and Y. Wang, Org. Biomol. Chem., 2025, 23, 7270–7274; (f) H. Zhang, Z. Zhang, L. Tian, Y. Han, P. Zhao, H. Yang, J. Li, G. Liu, L.-L. Zhu and Y. Wang, Org. Lett., 2025, 27, 1428–1433 and for a review on this topic, see: (g) Y. Zheng, L. Tian, V. Ramadoss, H. Zhang, L.-L. Zhu and Y. Wang, Synthesis, 2022, 2548–2560.
9. (a) Carbohydrates: The Essential Molecules of Life, ed. R. V. Stick and S. Williams, Elsevier, 2nd edn, 2009; (b) C. Xu and C. C. J. Loh, J. Am. Chem. Soc., 2019, 141, 5381–5391.
10. A. López-Francés, J. Rodrigues, S. Humbel, J. Rodriguez, M. Amatore and T. Constantieux, Eur. J. Org. Chem., 2025, e202500485.
11. A. Toshimitsu, T. Aoai, H. Owada, S. Uemura and M. Okano, J. Org. Chem., 1981, 46, 4727–4733.
12. CCDC 2468172: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2nvbgb.

---