N-Acyl-1,2,3-triazoles – key intermediates in denitrogenative transformations

Abstract

Elusive N-acyl-1,2,3-triazoles formed by direct acylation of NH-1,2,3-triazoles were isolated and fully characterized, including X-ray crystallography. A preference for the formation of thermodynamic N2 isomers was established. Direct evidence of interconversion between N1- and N2-acyltriazoles confirmed their value in denitrogenative transformations. Efficient synthesis of enamido triflates from NH-triazoles via the intermediacy of N2-acyl-1,2,3-triazoles was developed.

---

1,2,3-Triazoles are important heterocyclic compounds with various biological activities and high synthetic value.¹ There are two general synthetic routes to N-substituted 1,2,3-triazoles – cycloaddition reactions of azides with alkynes,² activated ketones,³ or nitroalkenes,⁴ and nitrogen functionalization of NH-1,2,3-triazoles with electrophiles.⁵ Whereas the cycloaddition reaction is widely investigated and established as an efficient and robust method, functionalization of NH-1,2,3-triazoles containing three nucleophilic nitrogen atoms is considered problematic because of unpredictable regioselectivity.^1a,5 However, NH-1,2,3-triazoles are available starting materials that can be efficiently prepared from inexpensive NaN₃⁶ or TMSN₃⁷ and alkynes, or NaN₃, aldehydes and nitroalkanes via tandem Henry reaction/[3+2] cycloaddition.⁸ Recently, a number of regioselective protocols for the synthesis of either N2⁹ or N1-substituted¹⁰ isomers of 1,2,3-triazoles have been developed. Thus, alkylation, arylation, vinylation and Michael addition with NH-1,2,3-triazoles as nucleophiles have been described and extensively studied.^5,9,10 Sulfonylation of NH-1,2,3-triazoles, which would be a tempting route to synthetically useful N1-sulfonyl-1,2,3-triazoles, is not regioselective (Scheme 1B),¹¹ and only regioselective N2-sulfonylation via radical reaction is known.¹²

Scheme 1 Synthetic approaches to N-EWG-substituted 1,2,3-triazoles.

In contrast to a broad variety of known N-alkyl-, N-fluoroalkyl, N-aryl- and N-sulfonyl-1,2,3-triazoles (Scheme 1A), N-acyl-1,2,3-triazoles are almost unexplored, and only rare and scattered examples have been reported.¹³ Indeed, a click reaction with acyl azide is not a viable route because of the low stability of acyl azides in the presence of a Cu(I) catalyst, resulting in nitrene formation.¹⁴N-Carbamoylation of NH-1,2,3-triazoles was studied giving a mixture of N1- and N2-isomers.¹⁵ These compounds possess significant application potential in biological studies. For example, 2-carbamoyl-4-aryl-1,2,3-triazole derivatives were used for site-selective incorporation into proteins,^15a as selective chemical probes of endocannabinoid biosynthesis enzymes.^15b,c Very recently, the formation of N2-alkoxycarbonyl-1,2,3-triazoles was observed in click reaction of carbamoyl azides with alkynes due to spontaneous carbamoyl group migration to N2-position.¹⁶ The resulting N2-carbamoyl triazoles were highly sensitive to hydrolysis to NH-triazoles (Scheme 1C).

1,2,3-Triazoles bearing an electron-withdrawing group at position N1 are useful starting materials in denitrogenative ring opening transformations.^1,17 Among them, N-sulfonyl-1,2,3-triazoles are the most widely explored in denitrogenative transformations, which are possible under metal catalysis¹⁷ or by the action of Lewis or Brønsted acids (Scheme 2A).¹⁸ The transannulation process was recently extended by us to N-fluoroalkylated triazoles.¹⁹ Moreover, there was one report about denitrogenative cleavage of N-(1,2,4-triazolyl)-1,2,3-triazoles.²⁰ However, it is remarkable that N-acyltriazoles have never been used as substrates in denitrogenative transformations. This can be attributed to the low stability and propensity to deacylation.¹⁶ Also, reactions of N-acylbenzotriazoles with nucleophiles (amines, alcohols) result in acyl group transfer as well.²¹ Only recently, the first reports of efficient monocyclic 1,2,3-triazole ring cleavage starting from NH-triazoles via in situ acylation were published by us (Scheme 2B)²² and Li's group (Scheme 2C).²³ The formation of unstable N-acyltriazoles as intermediates in these processes has been proposed. Indeed, the utilization of readily available NH-triazoles is more atom-economical compared to N-sulfonyl- and N-fluoroalkyl-triazoles. However, the formation, stability and reactivity of N-acyl-1,2,3-triazoles remains unexplored. A high efficiency of NH-triazole ring cleavage transformations could support the hypothesis of regioselective N1-acylation,²³ while it is well-established that in reactions of NH-triazoles with electrophiles the formation of N2-substituted isomers is preferred.^9h–j We hypothesized that a rapid interconversion between N1 and N2-acyltriazoles in the presence of an excess of acylation agent might enable the conversion of N-acyltriazole into ring cleavage products. Herein we report on our systematic study on N-acylation of 1,2,3-NH-triazoles and their regioselectivity, as well as on our study of ring cleavage reactions of N-acyltriazoles with Brønsted and Lewis acids.

Scheme 2 Transformations of N-EWG-substituted 1,2,3-triazoles and denitrogenative reactions of NH-1,2,3-triazoles with acylating reagents.

We initiated our study of the acylation of the model 1,2,3-triazole 1a with different acylating agents in the presence of stoichiometric amount of base (Et₃N). Acylation of 1a proceeded quickly at ambient temperature, with nearly quantitative yields (Table 1). In the case of benzoyl chloride or benzoic anhydride, mostly N2-acylated triazole 3a formed (entries 1 and 2). The more electron-deficient 4-nitrobenzoyl chloride led to the exclusive formation of N2-substituted acyl triazole 3b (entry 3), while 4-methoxybenzoylchloride, by contrast, showed a preference for N1-isomer 2c (entry 4). The presence of halogen atoms in ortho-positions, exerting steric hindrance, also favoured the formation of N1-isomers (entries 5 and 6). Acetic anhydride and fluorinated acid anhydrides afforded almost exclusively N2-isomers (entries 7–9). However, ethyl chloroformate gave a nearly 1 : 1 mixture of isomers (entry 10). Thus, the general observation is that N2-acylation is favoured and that only soft, weak and bulky acylating reagents favour N1-acylation. Solvent effects and effects of substituents at position 4 affect only slightly the reaction outcome, compared to the remarkable effect of acylating agents (see the ESI† for full details).

Table 1 Acylation of NH-triazole 1a^a

Entry	RCOX	Products	Yield^b (%) 2 + 3	Acylation ratio^c2/3
a Reaction conditions: 1a (0.10 mmol) and RCOX (0.10-0.11 mmol) mmol), Et3N (0.10-0.11 mmol), DCE (0.5 ml), rt, 1 h. b Isolated yield. c Determined by ^1H NMR. d Yield of crude products, not purified from triethylammonium salt.
1	PhCOCl	2a + 3a	>98	14 : 86
2	(PhCO)2O	2a + 3a	>98	8 : 92
3	4-O2N–C6H4COCl	3b	quant.^d	<1 : 99
4	4-MeO–C6H4COCl	2c + 3c	>98	73 : 27
5	2-Cl–C6H4COCl	2d + 3d	94	80 : 20
6	2-Br–C6H4COCl	2e + 3e	96	79 : 21
7	Ac2O	2f + 3f	98	5 : 95
8	(HCF2CO)2O	3g	quant.^d	<1 : 99
9	(CF3CO)2O	3h	quant.^d	<1 : 99
10	ClCO2Et	2i + 3i	97	45 : 55

---

X-ray diffraction analysis of N1-isomer 2c and N2-isomer 3f confirmed their structure (Fig. 1). Surprisingly, acylated triazoles 2 and 3 are stable enough to be isolated by solvent extraction using aqueous workup and to be fully characterized spectroscopically. Products 3b, 3g and 3h were found to be hydrolytically very unstable and aqueous workup could not be used. All acylated triazoles underwent partial or full decomposition during silica gel column chromatography.

Fig. 1 X-ray crystal structures of 2c (left, CCDC 2244997) and 3f (right, CCDC 2244996). Ellipsoids are set at a 50% probability level.

The structures of the obtained N1- and N2-acyltriazoles were additionally confirmed by ¹H-¹⁵N HMBC NMR data. ¹H-¹⁵N HMBC data values, namely δ(¹⁵N) and J_HN were compared with calculated values for 4-phenyl-N-difluoroacetyl-1,2,3-triazoles, which confirmed the presence of a difluoroacetyl group at the N2 position (see ESI†). Importantly, ¹H–¹⁵N HMBC NMR of 2c confirmed the presence of an acyl group at position N1; this result is corroborated by single crystal X-ray analysis data (Fig. 1). Regarding ¹H NMR of N-acyltriazole mixtures, the isomers could be identified by their chemical shifts of H5, which was shifted by 0.2–0.4 ppm downfield for N1-acyltriazoles (δ_H5 = 8.4–8.7 ppm) compared to N2-acyltriazoles (δ_H5 = 8.1–8.3 ppm). This tendency corresponds to literature δ_H5 shifts observed for N1- and N2-tosyl-4-phenyl-1,2,3-triazoles.^12,24

N1- and N2-isomers of acylated triazoles convert to one another. The N1- to N2-acyltriazole interconversion (Scheme 3) can be driven by thermodynamics, as in the case of the slow conversion of 2c to 3c at room temperature, or by the formation of a crystal lattice during crystallization of sterically hindered N2-isomer 3e (Scheme 3). By contrast, we succeeded in isolating pure N1-isomer 2c by recrystallization of a 2c/3c mixture. The process of N1- to N2-interconversion depends on solvent, the concentration and even the reaction scale, which complicated its detailed study.

Scheme 3 Evidence of N1- to N2-acyltriazole interconversion process (Ar = p-tolyl).

Nevertheless, denitrogenative triazole ring cleavage can only take place from N1 isomers. We demonstrated that the reverse process of N2- to N1-acyltriazole interconversion is crucial for the success of N-acyltriazole cleavage with the involvement of N2-isomers in denitrogenative transformations. In situ formed N2-acylated triazoles 3 react efficiently with triflic acid to produce enamido triflates 4 (Scheme 4). Previously, trifluoroacetylated enamido triflates were prepared by the reaction of N-perfluoroalkyl-1,2,3-triazoles with triflic acid,^19e but the present methodology benefits from the use of readily available NH-triazoles and trifluoroacetic anhydride. The reaction was found to be applicable for the synthesis of products 4, bearing neutral aryl substituents (4a, 4b, 4d) or a bromine atom (4c), in good yields. Electron-withdrawing and bulky substituents on the aryl ring were also tolerated (4e–4h). Importantly, the method broadens the scope of enamido triflates to compounds with other fluoroalkyl groups than trifluoromethyl (CF₂Cl, CF₂CF₃, CF₂H; 4j–4l), as well as the trichloroacetyl group (4m). 4-Alkyltriazoles giving unstabilized vinyl cation afforded complex mixtures.

Scheme 4 Formation of enamido triflates 4 from NH-triazoles 1. Reaction conditions: 1 (0.3 mmol), (RCO)₂O (0.33 mmol), Et₃N (0.33 mmol) in DCE (1 ml) stirred for 1 h, then TfOH (0.45–0.54 mmol), 50–80 °C, 3–20 h.

For the above-mentioned transformations, the following mechanism of acyltriazole cleavage to form enamido triflates is proposed: Protonation of acyltriazoles 2 or 3 can theoretically lead to six protonated species, which are in equilibrium due to acyl group and proton shifts. By analogy to our earlier investigations and DFT calculations^19f only species A undergoes N1–N2 cleavage to give the diazo/diazonium intermediate B. Diazonium B undergoes denitrogenation to vinyl cation C, and recombination with the triflate anion gives enamido triflate 4 (Scheme 5).

Scheme 5 Mechanism of β-enamido triflate formation.

Acylated triazoles can be also cleaved with Lewis acids. In situ-formed acylated triazoles 2 and 3 reacted with an equimolar amount of AlX₃ to produce β-haloenamides 5, presumably via cleavage of forming N1-acyltriazole to a vinyl cation (Scheme 6). The less electron-deficient N1- or N2-acylated triazoles 2c, 3c, or 3e cyclized to give oxazoles 6, showing that both isomers can be converted to the same ring-cleavage and cyclization products.

Scheme 6 Ring cleavage of acylated triazoles using Lewis acids.

In conclusion, N-acylation of 1,2,3-NH-triazoles was investigated and N2-acyltriazoles were found to be the main products; however, electron-rich and bulky acylating reagents induced the formation of a mixture of N1- and N2-acylated triazoles. Interconversion between regioisomers of N-acyltriazoles under thermodynamic conditions, during crystal formation, or in the presence of Brønsted or Lewis acids was observed. Triazole denitrogenative ring cleavage starting from N2-acyltriazoles is reported for the first time. Efficient synthetic access to valuable vinyl triflates from NH-triazoles was developed.

This work was supported by the Czech Academy of Sciences (RVO: 61388963) and the Czech Science Foundation (23-04659S).

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. (a) Chemistry of 1,2,3-triazoles, ed. W. Dehaen and V. A. Bakulev, Springer, Cham, 2015; (b) H. M. Davies and J. S. Alford, Chem. Soc. Rev., 2014, 43, 5151.
2. (a) M. Meldal and F. Diness, Trends Chem., 2020, 2, 569; (b) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302; (c) L. Liang and D. Astruc, Coord. Chem. Rev., 2011, 255, 2933; (d) F. Wei, W. Wang, Y. Ma, C.-H. Tung and Z. Hu, Chem. Commun., 2016, 52, 14188.
3. (a) R. Prakash, T. Opsomer and W. Dehaen, Chem. Rec., 2021, 21, 376; (b) J. John, J. Thomas and W. Dehaen, Chem. Commun., 2015, 51, 10797.
4. (a) C. P. Parambil, S. P. Veethil and W. Dehaen, Synthesis, 2022, 910; (b) V. A. Motornov, S. L. Ioffe and A. A. Tabolin, Targets Heterocycl. Syst., 2019, 23, 237.
5. (a) T. Opsomer and W. Dehaen, Chem. Commun., 2021, 57, 1568; (b) C. P. Parambil, S. P. Veethil and W. Dehaen, Synthesis, 2022, 910.
6. (a) D. Jankovic, M. Virant and M. Gazvoda, J. Org. Chem., 2022, 87, 4018; (b) L. Hu, C. Muck-Lichtenfield, T. Wang, G. He, M. Gao and J. Zhao, Chem. – Eur. J., 2016, 22, 911.
7. T. Jin, S. Kamijo and Y. Yamamoto, Eur. J. Org. Chem., 2004, 3789.
8. (a) R. Hui, M. Zhao, M. Chen, Z. Ren and Z. Guan, Chin. J. Chem., 2017, 35, 1808; (b) L. Wu, X. Wang, Y. Chen, Q. Huang, Q. Lin and M. Wu, Synlett, 2016, 437.
9. (a) For a review, see: Y. Zheng, L. Tian, V. Ramadoss, H. Zhang, L.-L. Zhu and Y. Wang, Synthesis, 2022, 2548 Recent representative examples: ; (b) S. Roshandel, M. J. Lunn, G. Rasul, D. S. M. Ravinson, S. C. Suri and G. K. S. Prakash, Org. Lett., 2019, 21, 6255; (c) V. Motornov, G. V. Latyshev, Y. N. Kotovschikov, N. V. Lukashev and I. P. Beletskaya, Adv. Synth. Catal., 2019, 361, 3306; (d) X. Man, Y. C. Li, X. X. Li and Z. G. Zhao, New J. Chem., 2019, 43, 14739; (e) V. A. Motornov, A. A. Tabolin, R. A. Novikov, N. E. Shepel, V. G. Nenajdenko and S. L. Ioffe, Tetrahedron, 2018, 74, 3897; (f) X. Deng, X. Lei, G. Nie, L. Jia, Y. Li and Y. Chen, J. Org. Chem., 2017, 82, 6163; (g) S. Ueda, M. Su, B. P. Fors and S. L. Buchwald, J. Org. Chem., 2012, 77, 2543; (h) Y. Chen, Y. Liu, J. L. Petersen and X. Shi, Chem. Commun., 2008, 44, 3254; (i) Y. Liu, W. Yan, Y. Chen, J. L. Petersen and X. Shi, Org. Lett., 2008, 10, 5389; (j) X. Wang, L. Zhang, H. Lee, N. Haddad, D. Krishnamurthy and C. H. Senanayake, Org. Lett., 2009, 11, 5026.
10. (a) K. Morimoto, Y. Ohnishi, A. Nakamura, K. Sakamoto, T. Dohi and Y. Kita, Asian J. Org. Chem., 2014, 3, 382; (b) C. Sun, X. Yian, Y. Li, X. Li and Z. Zhao, Org. Biomol. Chem., 2017, 15, 2721; (c) S. P. Desai and M. S. Taylor, Org. Lett., 2021, 23, 7049; (d) S. P. Desai, M. T. Zambri and M. S. Taylor, J. Org. Chem., 2022, 87, 5385.
11. T. V. Beryozkina, et al. , Tetrahedron, 2015, 71, 6189.
12. R. J. Reddy, A. Shankar, Md Waheed and J. B. Nanubolu, Tetrahedron Lett., 2018, 59, 2014.
13. For inconsistent data regarding regioselectivity of triazole acylation, see: (a) Y. Takanashi, et al. , J. Org. Chem., 2017, 82, 11370; (b) I. S. Odin, S. Cao, D. Hughes, E. V. Zamaratskii, Yu. P. Zarubin, P. P. Purygin, A. A. Golovanov and S. S. Zlotskii, Dokl. Chem., 2020, 492, 89; (c) R. Birkofer and P. Wegner, Chem. Ber., 1967, 100, 3485; (d) F. Politano, A. L. Sandoval, M. L. Witko, K. E. Doherty, C. M. Schroeder and N. E. Leadbeater, Eur. J. Org. Chem., 2022, 38.
14. E. Haldon, M. Besora, I. Cano, X. C. Cambeiro, M. A. Pericas, F. Maseras, M. C. Nicasio and P. J. Perez, Chem. – Eur. J., 2014, 20, 3463.
15. (a) Q. Lin, A. Rahim and Y. Xu, Angew. Chem., Int. Ed., 2022, 61, e202202657; (b) K. van Rooden, et al. , Chem. – Asian J., 2018, 13, 3491; (c) K.-L. Hsu, K. Tsuboi, L. R. Whitby, A. E. Speers, H. Pugh, J. Inloes and B. F. Cravatt, J. Med. Chem., 2013, 56, 8257; (d) L. Chen, L. J. Keller, E. Cordasco, M. Bogyo and C. S. Lentz, Angew. Chem., Int. Ed., 2019, 58, 5643.
16. B. Chakraborti, T. Mandal, C. P. Roy and J. Dash, Chem. Commun., 2021, 57, 7970.
17. (a) M. Akter, K. Rupa and P. Anbarasan, Chem. Rev., 2022, 122, 13108; (b) B. Chattopadhyay and V. Gevorgyan, Angew. Chem., Int. Ed., 2012, 51, 862; (c) P. Anbarasan, D. Yadagiri and S. Rajasekar, Synthesis, 2014, 3004.
18. (a) Z.-F. Xu, H. C. Dai, L. H. Shan and C.-Y. Li, Org. Lett., 2018, 20, 1054; (b) D. Yang, L. Shan, Z.-F. Xu and C.-Y. Li, Org. Biomol. Chem., 2018, 16, 1461.
19. (a) V. Motornov, A. Markos and P. Beier, Chem. Commun., 2018, 54, 3258; (b) V. Motornov and P. Beier, J. Org. Chem., 2018, 83, 15195; (c) V. Motornov, V. Košťál, A. Markos, D. Taffner and P. Beier, Org. Chem. Front., 2019, 6, 3776; (d) O. Bakhanovich, V. Khutorianskyi, V. Motornov and P. Beier, Beilstein J. Org. Chem., 2021, 17, 504; (e) A. Markos, S. Voltrová, V. Motornov, D. Tichý, B. Klepetářová and P. Beier, Chem. – Eur. J, 2019, 25, 7640; (f) A. Markos, L. Janecký, T. Chvojka, T. Martinek, H. Martinez-Seara, B. Klepetářová and P. Beier, Adv. Synth. Catal., 2021, 363, 3258.
20. M. Zibinsky and V. V. Fokin, Org. Lett., 2011, 13, 4870.
21. (a) A. R. Katritzky, H.-Y. He and K. Suzuki, J. Org. Chem., 2000, 65, 8210; (b) A. R. Katritzky, A. A. A. Abdel-Fattah and M. Wang, J. Org. Chem., 2003, 68, 1443; (c) A. R. Katritzky, A. A. Shestopalov and K. Suzuki, Synthesis, 2004, 1806.
22. (a) V. Motornov and P. Beier, Org. Lett., 2022, 24, 1958; (b) V. Motornov and P. Beier, New J. Chem., 2022, 46, 14318.
23. T. Wang, Z. Tang, H. Luo, Y. Tian, M. Xu, Q. Lu and B. Li, Org. Lett., 2021, 23, 6293.
24. Q. Xing, C. Zhou, S. Jiang, S. Chen and G.-J. Ding, Org. Biomol. Chem., 2021, 19, 7838.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, compound characterization and copies of NMR spectra. CCDC 2244996 and 2244997. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3cc00987d

---