Synthesis of 1,2,4-triazine derivatives via [4 + 2] domino annulation reactions in one pot

Abstract

Simple and efficient [4 + 2] domino annulation reactions have been developed for the synthesis of 1,2,4-triazine derivatives. The strategies exhibit high performance with moderate to high yields, using easily available materials including ketones, aldehydes, alkynes, secondary alcohols and alkenes, representing a powerful tool for the formation of potentially biologically active derivatives.

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Introduction

The 1,2,4-triazine moiety represents an important class of heterocycles, and 1,2,4-triazine derivatives have been reported to possess a broad spectrum of biological activities, including anti-convulsant,^1a anti-cancer,^1b anti-cytokine,^1c anti-tumor,^1d anti-viral,^1e anti-hypertensive^1f and anti-malarial^1g activities. In addition, some important metal coordinating ligands contain the 1,2,4-triazine skeleton.² These classes of compounds are significant and useful; however, there is a shortage of systemic, operable and versatile strategies to construct 1,2,4-triazine skeletons to meet the demand of synthetic chemistry. Among the known methods for the synthesis of 1,2,4-triazines, the reactions of amidrazones and 1,2-diketone compounds are the most available protocols to form 3,5-disubstituted or 3,5,6-trisubstituted 1,2,4-triazines.³ Otherwise, the multi-component reactions (MCR) of hydrazides, dicarbonyl compounds and ammonium acetate also represent a pathway to synthesize 3,5-disubstituted 1,2,4-triazines.⁴ Nevertheless, considerable scope for improvement remains in terms of the availability of the starting materials, the tedious nature of the process and the poor functional group tolerance.

In the past years, our group reported a method to obtain the imidazole skeleton by employing amidines and ketones/nitroolefins.⁵ To the best of our knowledge, the units of ketones, acetaldehydes, alkynes and alkenes are useful building blocks providing two carbon atoms to construct five- or six-membered rings.⁶ Based on our previous works, we shifted our attention to develop six-membered nitrogen heterocyclics using simple operations, the high utilization of atoms and good yields. Herein, we report SeO₂- or iodine source-catalyzed [4 + 2] domino annulation reactions for making 1,2,4-triazine derivatives without the addition of transition metal catalysts, and the works systematically study the reactions of ketones/alkynes and amidrazones⁷ to synthesize 1,2,4-triazine derivatives. These strategies may be an highly efficient alternative to the synthesis of 1,2,4-triazine compounds in pharmaceutical chemistry and other fields.

Results and discussion

Initially, we examined the reaction of acetophenone 1a and benzimidohydrazide 2a as a model reaction, as shown in Table 1. A mixture of 1a (0.2 mmol), 2a (0.2 mmol), CuO (0.24 mmol) and I₂ (0.24 mmol) were reacted in DMSO under air at 110 °C for 2 h, and the desired product (3aa) was isolated in 14% yield (Table 1, entry 1). The structure was identified by X-ray crystallography (Fig. 1). Encouraged by this result, we continued to explore other iodine sources, but only inferior results were obtained (Table 1, entries 2–4). Noteworthily, when the reaction was completed, we found that the byproduct of 1,2,4-triazole was formed by TLC, and this side reaction had been documented in previous reports.⁸ In order to avoid the loss of 2a, we then introduced 2a into the reaction system after the acetophenone reacted for 2 hours in the presence of I₂. To our delight, a 60% yield of 3aa was obtained (Table 1, entry 5). Other oxidants, such as MnO₂, CuO and SeO₂, were also evaluated, and SeO₂ showed a better catalytic activity (Table 1, entries 6–8). When the reaction time was prolonged to 4 hours before the addition of 2a, the yield improved to 80% (Table 1, entry 9). In the screening of solvents including DMF, toluene, dioxane and H₂O, no better results were obtained (Table 1, entries 10–13).

Table 1 The optimization of reaction conditions of acetophenone and benzimidohydrazide^a

Entry	Oxidant	Solvent	Yield^b
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), oxidant (1.2 equiv.), solvent (2 mL), 110 °C, under air.b Isolated yield based on 1a.c Iodine source (0.1 equiv.), TBHP (6 equiv.).d 2a was added 2 hours after the reaction was initiated.e 2a was added 4 hours after the reaction was initiated.
1	CuO/I2	DMSO	14
2	I2	DMSO	27
3	I2/TBHP^c	DMSO	24
4	TBAI/TBHP^c	DMSO	12
5	I2^d	DMSO	60
6	MnO2^d	DMSO	0
7	CuO^d	DMSO	0
8	SeO2^d	DMSO	71
9	SeO2^e	DMSO	80
10	SeO2^e	DMF	Trace
11	SeO2^e	Tolene	12
12	SeO2^e	Dioxane	0
13	SeO2^e	H2O	0

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Fig. 1 The X-ray crystal structure of 3aa.

With the optimized conditions in hand, the scope of this domino annulation reaction was expanded. A variety of different substituted ketones 1 were examined under optimal conditions, and the results are summarized in Table 2. The reaction tolerated well both electron-withdrawing and electron-donating groups on the aromatic ring, and the expected products were obtained in moderate to high yields. Generally, the substrates with electron rich groups provided better yields than the ones with electron deficient groups (Table 2, entries 1–10). Furthermore, the steric effect had no remarkable influence on the yields (Table 2, entries 1–6), and the substrates with sterically bulky groups on the ketones, such as 1-(naphthalen-1-yl)ethanone (1m) and 1-([1,1′-biphenyl]-4-yl)ethanone (1n), and with heterocycles, such as 1-(furan-2-yl)ethanone (1o), were well tolerated, affording good yields in the range 75–78% (Table 2, entries 12–14). Somewhat disappointingly, when aliphatic ketones and substrates with amino groups were investigated in the catalytic system, the desired products were not found (Table 2, entries 11 and 15).

Table 2 Investigation of scope in the reaction of arylketones with 2a^a

Entry	R^1	Product	Yield^b
a Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), SeO2 (0.24 mmol), DMSO (2 mL), 110 °C, 2a was added 4 hours after the reaction was initiated.b Isolated yield based on 1.
1	4-MeO-C6H4, 1b	3ab	80
2	3-MeO-C6H4, 1c	3ac	77
3	2-MeO-C6H4, 1d	3ad	89
4	4-Me-C6H4, 1e	3ae	77
5	3-Me-C6H4, 1f	3af	85
6	2-Me-C6H4, 1g	3ag	73
7	3,4-MeO-C6H4, 1h	3ah	75
8	4-F-C6H4, 1i	3ai	76
9	4-Cl-C6H4, 1j	3aj	72
10	3,4-Cl-C6H4, 1k	3ak	69
11	4-NH2-C6H4, 1l	3al	0
12	1-Nap, 1m	3am	75
13	4-C6H5-C6H4, 1n	3an	76
14	2-Furan, 1o	3ao	78
15	Propyl, 1p	3ap	0

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To further investigate the reaction scope, various amidrazones (2b–h) were employed to react with acetophenone (1a), as shown in Table 3. Those transformations displayed good functional group tolerance, including methyl, methoxyl, fluoro, chloro and bromo groups, and amidrazones with electron-donating or electron-withdrawing groups had no remarkable difference in yields and gave the corresponding 1,2,4-triazines in good yields (Table 3, entries 1–7). Notably, picolinimidohydrazide (2h) also proceeded smoothly and produced a yield of 58% (Table 3, entry 7).

Table 3 Investigation of scope in the reaction of amidrazones with 1a^a

Entry	R^2	Product	Yield^b
a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), SeO2 (0.24 mmol), DMSO (2 mL), 110 °C, 2 was added 4 hours after the reaction was initiated.b Isolated yield based on 1a.
1	4-Me-C6H4, 2b	3ba	85
2	3-Me-C6H4, 2c	3bb	79
3	4-MeO-C6H4, 2d	3bc	88
4	4-F-C6H4, 2e	3bd	75
5	4-Cl-C6H4, 2f	3be	74
6	4-Br-C6H4, 2g	3bf	82
7	2-Py, 2h	3bg	58

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Inspired by the above results, we shifted our attention to explore the reaction feasibility of alkynes and amidrazones. The reaction conditions were also investigated (for details, see ESI†), and it was found that the reactions of 4a (0.4 mmol) and 2a (0.2 mmol) in the presence of N-iodosuccinimide (NIS) (0.24 mmol) and p-toluenesulfonic acid (TsOH, 0.02 mmol) in DMSO (2 mL) furnished the desired product in a yield of 62% at 110 °C. Then, the substrate scopes were investigated in detail. Arylalkynes with different functional groups, such as methoxyl, methyl, fluoro, chloro, bromo and phenyl groups, could all provide the corresponding products in good yields ranging from 51 to 82% (Table 4, entries 1–9). Notably, the substrates with electron-donating groups tended to attain better yields, and the steric effect was not critical for those transformations (Table 4, entries 7 and 9).

Table 4 Investigation of scope in the reaction of arylalkynes with 2a^a

Entry	R^3	Product	Yield^b
a Reaction conditions: 4 (0.4 mmol), 2a (0.2 mmol), NIS (0.24 mmol), TsOH (0.02 mmol), DMSO (2 mL), 110 °C, 2a was added 4 hours after the reaction was initiated.b Isolated yield based on 2a.
1	4-MeO-C6H4, 4b	3ab	82
2	3-MeO-C6H4, 4c	3ac	77
3	4-Me-C6H4, 4e	3ae	59
4	3-Me-C6H4, 4f	3af	67
5	4-F-C6H4, 4i	3ai	66
6	4-Br-C6H4, 4r	3ar	57
7	4-Cl-C6H4, 4j	3aj	60
8	3-F-C6H4, 4s	3as	51
9	2-Cl-C6H4, 4t	3at	58
10	4-C6H5-C6H4, 4n	3an	79

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In order to investigate the scope and generality of amidrazones, different amidrazones were employed to react with ethynylbenzene (4a). As expected, the reactions of the amidrazone substrates 2a–h and 4a proceeded smoothly to give the corresponding coupling products 3ba–3bg in moderate to good yields (Table 5, entries 1–7, 65–79%). Regardless of the electronic nature, the functional groups had no remarkable impact on the yields. It was noteworthy that the picolinimidohydrazide (2h) also afforded the desired products in a 64% yield (Table 5, entry 7).

Table 5 Investigation of scope in the reaction of amidrazones with 4a^a

Entry	R^2	Product	Yield^b
a Reaction conditions: 4a (0.4 mmol), 2 (0.2 mmol), NIS (0.24 mmol), TsOH (0.02 mmol), DMSO (2 mL), 110 °C, 2 was added 4 hours after the reaction was initiated.b Isolated yield based on 2.
1	4-Me-C6H4, 2b	3ba	78
2	3-Me-C6H4, 2c	3bb	77
3	4-MeO-ph, 2d	3bc	71
4	4-F-C6H4, 2e	3bd	65
5	4-Cl-C6H4, 2f	3be	79
6	4-Br-C6H4, 2g	3bf	77
7	2-Py, 2h	3bg	64

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To gain more insight into the diversity of synthetic strategies to produce 1,2,4-triazine derivatives, the building blocks including styrene (5a), 1-phenylethanol (6a), 1,2-diphenylethyne (7a) and 2-phenylacetaldehyde (8a) were introduced into this class of reactions. A reaction of styrene (5a) and 2a was carried out in the presence of iodine (1 equiv.) and DMSO (2 mL) at 110 °C, and the desired product 3aa was isolated in 38% yield (Scheme 1a). Moreover, 1-phenylethanol (6a) and 1,2-diphenylethyne (7a) were reacted with 2a in presence of iodine (1 equiv.), 2-iodoxybenzoic acid (IBX) (0.75 equiv.) and DMSO (2 mL) at 110 °C (Scheme 1b and c), and we were pleased to obtain the corresponding products 3aa and 8aa in 74% and 51% yields, respectively. To our surprise, 2-phenylacetaldehyde (8a) was also compatible in the reaction to form the desired product 3aa in 53% yield (Scheme 1d). These reactions are attractive, making a range of interesting 1,2,4-triazine scaffolds through a useful, efficient and simple procedure by using easily available starting materials.

Scheme 1 Alternative transformations to construct 1,2,4-triazine derivatives starting from styrene, 1-phenylethanol, 1,2-diphenylethyne and phenylacetaldehyde.

Regarding a probable mechanism for these kinds of reactions, some works had reported that the starting materials, such as arylketones⁹ and arynes,¹⁰ converted into corresponding diketones B. Similarly, the arylacetaldehydes, 1-arylethanol¹¹ and alkenes¹² might follow a parallel procedure. Subsequently, the diketones combined with amidrazones via a [4 + 2] annulation reaction to obtain the final 1,2,4-triazine products 3 (Scheme 2).¹³

Scheme 2 Plausible reaction pathway.

Conclusions

In conclusion, we have reported effective and simple strategies to synthesize 1,2,4-triazine derivatives through [4 + 2] domino annulations in one pot. These transformations employ SeO₂ or iodine sources as oxidants without using a transition metal catalyst and show good functional group tolerance with moderate to high yields. Moreover, the reactions can access the important 1,2,4-triazine skeleton, which can be potentially applied to afford a series of biologically active derivatives.

Experimental

Typical procedure for the preparation of 1,2,4-triazine derivatives 3.

Procedure A

The reaction was carried out in a round-bottom side-arm flask (10 mL). 1 (0.2 mmol), SeO₂ (0.24 mmol) and DMSO (2 mL) were added to the flask with a magnetic stirring bar at 110 °C under air. After 4 h of stirring at this temperature, 2 (0.2 mmol) was introduced into the catalytic system. 2 hours later, the flask was then removed and cooled to room temperature. The mixture was washed with 20 mL water and extracted with ethyl acetate (3 × 50 mL). The oil layer was combined and concentrated under reduced pressure to distill ethyl acetate, which was further purified by silica gel chromatography (petroleum/ethyl acetate = 5/1 as eluent) to obtain the product 3.

Procedure B

The reaction was carried out in a round-bottom side-arm flask (10 mL). 4 (0.4 mmol), NIS (0.24 mmol), TsOH (0.02 mmol) and DMSO (2 mL) were added to the flask with a magnetic stirring bar at 110 °C under air. After 4 h of stirring at this temperature, 2 (0.2 mmol) was introduced into the catalytic system. The following processing method was referred to in procedure A.

¹H NMR and ¹³C NMR spectra were recorded on 300 MHz and 75 MHz in CDCl₃. Unknown products were further characterized by HRMS (TOF-ESI), and the melting points of solid products were determined on a microscopic apparatus.

Acknowledgements

We are grateful to the project sponsored by the National Science Foundation of P. R. China (No. J11003307 and 21372102).

Notes and references

1. (a) P. Ahuja and N. Siddiqui, Eur. J. Med. Chem., 2014, 80, 509–522; (b) M. Anjomshoa, H. Hadadzadeh, M. Torkzadeh-Mahani, S. J. Fatemi, M. Adeli-Sardou, H. A. Rudbari and V. M. Nardo, Eur. J. Med. Chem., 2015, 96, 66–82; (c) M. Khoshneviszadeh, M. H. Ghahremani, A. Foroumadi, R. Miri, O. Firuzi, A. Madadkar-Sobhani, N. Edraki, M. Parsa and A. Shafiee, Bioorg. Med. Chem., 2013, 21, 6708–6717; (d) L. Yurttaş, Ş. Demirayak, S. Ilgın and Ö. Atlı, Bioorg. Med. Chem., 2014, 22, 6313–6323; (e) V. L. Rusinov, I. N. Egorov, O. N. Chupakhin, E. F. Belanov, N. I. Bormotov and O. A. Serova, Pharm. Chem. J., 2012, 45, 655–659; (f) W. P. Heilman, R. D. Heilman, J. A. Scozzie, R. J. Wayner, J. M. Gullo and Z. S. Riyan, J. Med. Chem., 1979, 22, 671–677; (g) A. Agarwal, K. Srivastava, S. K. Puri and P. M. S. Chauhan, Bioorg. Med. Chem. Lett., 2005, 15, 531–533.
2. (a) F. Marandi, M. Jangholi, M. Hakimi, H. A. Rudbari and G. Bruno, J. Mol. Struct., 2013, 1036, 71–77; (b) E. WoliNska, Tetrahedron, 2013, 69, 7269–7278; (c) F. W. Lewis, L. M. Harwood, M. J. Hudson, A. Geist, V. N. Kozhevnikov, P. Distler and J. John, Chem. Sci., 2015, 6, 4812–4821; (d) G. L. Guillet, I. F. D. Hyatt, P. C. Hillesheim, K. A. Abboud and M. J. Scott, New J. Chem., 2013, 37, 119–131; (e) V. Maheshwari, D. Bhattacharyya, F. R. Fronczek, P. A. Marzilli and L. G. Marzilli, Inorg. Chem., 2006, 45, 7182–7190; (f) M. J. Hudson, C. E. Boucher, D. Braekers, J. F. Desreux, M. G. B. Drew, M. R. S. J. Foreman, L. M. Harwood, C. Hill, C. Madic, F. Marken and T. G. A. Youngs, New J. Chem., 2006, 30, 1171–1183.
3. (a) G. R. Pabst and J. Sauer, Tetrahedron Lett., 1998, 39, 6687–6690; (b) M. Altuna-Urquijo, S. P. Stanforth and B. Tarbitb, Tetrahedron Lett., 2005, 46, 6111–6113; (c) B. M. Culbertson and G. R. Parr, J. Heterocycl. Chem., 1967, 4, 422–424.
4. R. Ghorbani-Vaghei, A. Shahriari, Z. Salimia and S. Hajinazari, RSC Adv., 2015, 5, 3665–3669.
5. (a) D. Tang, P. Wu, X. Liu, Y. X. Chen, S. B. Guo, W. L. Chen, J. G. Li and B. H. Chen, J. Org. Chem., 2013, 78, 2746–2750; (b) X. Liu, D. Wang and B. Chen, Tetrahedron, 2013, 69, 9417–9421; (c) D. Tang, X. L. Li, X. Guo, P. Wu, J. H. Li, K. Wang, H. W. Jing and B. H. Chen, Tetrahedron, 2014, 70, 4038–4042.
6. (a) K. K. D. R. Viswanadham, M. P. Reddy, P. Sathyanarayana, O. Ravi, R. Kant and S. R. Bathula, Chem. Commun., 2014, 50, 13517–13520; (b) Y. Zhu, F. Jia, M. Liu and A. Wu, Org. Lett., 2012, 14, 4414–4417.
7. (a) K. Veejendra, K. Yadavand and G. Babu, Eur. J. Org. Chem., 2005, 2005, 452–456; (b) É. Bokor, A. Fekete, G. Varga, B. Szőcs, K. Czifrák, I. Komáromi and L. Somsák, Tetrahedron, 2013, 69, 10391–10404.
8. (a) H. M. Cheng, D. R. Zhu, W. Lu, R. H. Xu and X. Shen, J. Heterocycl. Chem., 2010, 47, 210–213; (b) M. O’rourke, S. A. Lang Jr and E. Cohen, J. Med. Chem., 1977, 20, 723–726.
9. (a) H. Z. Li, W. J. Xue and A. X. Wu, Tetrahedron, 2014, 70, 4645–4651; (b) H. Batchu and S. Batra, Eur. J. Org. Chem., 2012, 15, 2935–2944.
10. (a) Z. Wan, C. D. Jones, D. Mitchell, J. Y. Pu and T. Y. Zhang, J. Org. Chem., 2006, 71, 826–828; (b) H. P. Kalmode, K. S. Vadagaonkar and A. C. Chaskar, Synthesis, 2015, 47, 429–438; (c) K. D. R. Viswanadham, M. P. Reddy, P. Sathyanarayana, O. Ravi, R. Kant and S. R. Bathula, Chem. Commun., 2014, 50, 13517–13520; (d) P. Daw, R. Petakamsetty, A. Sarbajna, S. Laha, R. Ramapanicker and J. K. Bera, J. Am. Chem. Soc., 2014, 136, 13987–13990; (e) X. F. Xia, Z. Gu, W. Liu, N. Wang, H. Wang, Y. Xia, H. Gao and X. Liu, Org. Biomol. Chem., 2014, 12, 9909–9913.
11. (a) Y. P. Zhu, Q. Cai, Q. H. Gao, F. C. Jia, M. C. Liu, M. Gao and A. X. Wu, Tetrahedron, 2013, 69, 6392–6398; (b) H. P. Kalmode, K. S. Vadagaonkar and A. C. Chaskar, Synthesis, 2015, 47, 429–438.
12. S. Dutta, S. S. Kotha and G. Sekar, RSC Adv., 2015, 5, 47265–47269.
13. (a) S. C. Benson, J. L. Gross and J. K. Snyder, J. Org. Chem., 1990, 55, 3257–3269; (b) G. L. Guillet, I. D. Hyatt, P. C. Hillesheim, K. A. Abboud and M. J. Scott, New J. Chem., 2013, 37, 119–131.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1415846. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra26638f

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