I₂/TBPB mediated oxidative reaction of aryl acetaldehydes with amidines: synthesis of 1,2,5-triaryl-1H-imidazoles

Abstract

A direct method for the synthesis of 1,2,5-triaryl-1H-imidazoles was achieved easily from cyclization of aryl acetaldehydes with amidines catalyzed by I₂. Various substitued groups can be employed, and this reaction proceeds smoothly in moderate to good yields.

---

Introduction

As one of the most valuable types of N-heterocyclic compound, imidazoles have been found in numerous natural products¹ and functional materials.² They also have good biological activities, such as antitumor,³ antimicrobial,⁴ antihypertensive⁵ and protein kinase inhibitory activities.⁶ In addition, they can also act as organocatalysts,⁷ ionic liquids,⁸ and precursors of N-heterocyclic carbenes.⁹

Due to their indisputable importance and great application prospects, more and more researchers are dedicating effort to constructing imidazoles. As for tri-substituted imidazoles, a number of methods have been developed. The existing synthetic methodologies have mostly focused on 1,2,4-triarylated imidazoles¹⁰ and 2,4,5-triarylated imidazoles.¹¹ The most common route for producing 1,2,4-triarylated imidazoles is combining amidines with terminal alkynes and nitroolefins with ketones. Besides, most of the reported methods for obtaining 2,4,5-triarylated imidazoles involve the condensation of 1,2-diketones and aldehydes with amines or ammonia. However, until now only a few methods have been developed for making 1,2,5-triarylated imidazoles.¹² Therefore, it is a big challenge for organic chemists to find an efficient and simple way to construct 1,2,5-triarylated imidazoles.

Our group is dedicated to the efficient synthesis of 1,2,4-triarylated imidazoles by employing amidines and alkynes via metal-catalyzed oxidative processes.¹³ In recent years, our group has been interested in the synthesis of 1,2,4-triarylated imidazoles by employing amidines and aldehydes¹⁴/nitroolefins¹⁵/ketones.¹⁶ We herein report a more environment-friendly and efficient methodology to construct 1,2,5-triaryl-1H-imidazoles¹⁷ which uses I₂/TBPB mediated oxidative formal [3 + 2] cycloaddition of aryl acetaldehydes with amidines Scheme 1.¹⁸

Scheme 1 Synthesis of imidazole from amidine.

Results and discussion

To elucidate the optimal reaction conditions, we initially studied the reaction of N-phenylbenzimidamide 1a (0.20 mmol) with phenylacetaldehyde 2a (0.24 mmol) in the presence of I₂ (20 mol%) in dioxane at 100 °C in air for 5 h. As expected, the desired product 1,2,5-triphenyl-1H-imidazole 3aa was obtained in 40% yield (Table 1, entry 1). In order to improve the yield of 3aa, we further screened different oxidants, such as TBHP, TBPB, DTBP, H₂O₂, K₂S₂O₈ and O₂ for this reaction in the presence of iodine (Table 1, entries 2–7). Among them, TBPB was found to be the most optimal oxidant for the transformation. Next, the reaction proceeded less efficiently in other iodine-containing catalysts such as KI, TBAI, NIS, and PIDA (Table 1, entries 8–11). Then, the reaction did not give a superior result with variations in temperature (80, 110 °C, Table 1, entries 12–13). Furthermore, different solvents such as DMF, DMSO, toluene and DCB were failed to improve the yield (Table 1, entries 14–17). After several experimental iterations, the optimal reaction conditions emerged with N-phenylbenzimidamide 1a (0.20 mmol) with phenylacetaldehyde 2a (0.24 mmol) in the presence of I₂ (20 mol%) and TBPB (1 eq.) in dioxane (2 mL) at 100 °C in air for 5 h (Table 1, entry 3)

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	Oxidant (equiv.)	Solvent (mL)	T (°C)	Yield^b (%)
a Reaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), catalyst (20 mol%), oxidant (1 eq), solvent (2 mL), in air for 5 h; TBHP = tert-butyl hydroperoxide (70% in water); TBPB = tert-butyl peroxybenzoate; DTBP = di-tert-butyl peroxide; TBAI = tetrabutylammonium iodide; NIS = niodosuccinimide; PIDA = iodosobenzene diacetate.b Isolated yield.
1	I2(20)	—	Dioxane	100	40
2	I2(20)	TBHP(1)	Dioxane	100	78
3	I2(20)	TBPB(1)	Dioxane	100	93
4	I2(20)	DTBP(1)	Dioxane	100	38
5	I2(20)	H2O2(1)	Dioxane	100	42
6	I2(20)	K2S2O8(1)	Dioxane	100	12
7	I2(20)	O2	Dioxane	100	41
8	KI(20)	TBPB(1)	Dioxane	100	69
9	TBAI(20)	TBPB(1)	Dioxane	100	54
10	NIS(20)	TBPB(1)	Dioxane	100	65
11	PIDA(20)	TBPB(1)	Dioxane	100	31
12	I2(20)	TBPB(1)	Dioxane	80	66
13	I2(20)	TBPB(1)	Dioxane	110	68
14	I2(20)	TBPB(1)	DMF	100	42
15	I2(20)	TBPB(1)	DMSO	100	50
16	I2(20)	TBPB(1)	Toluene	100	88
17	I2(20)	TBPB(1)	DCB	100	85

---

With the optimized conditions in hand, we proceeded to examine the substrate scope (Table 2). First, we studied the R¹-substituted arylamidines. A variety of 1,2,5-trisubstituted imidazoles could be obtained by employing various arylamidines (1) and phenylacetaldehyde (2a) giving 44–85% yields (Table 2, entries 1–5). Generally, electron donating groups substituents (4-Me, 4-MeO) as well as some electron withdrawing groups (4-CF₃, 2-Cl) provided moderate yields (Table 2, entries 1–4). In addition, the substrate N-p with the pyridine ring could also be applied to this strategy, even with a relatively low yield (Table 2, entry 5).

Table 2 Reactions of amidines 1 with phenylacetaldehyde 2a^a

Entry	R^1	R^2	Product	Yield^b (%)
a Reaction conditions: 1 (0.20 mmol), 2a (0.24 mmol), I2 (20 mol%), TBPB(1 eq.), dioxane (2 mL), 100 °C in air for 5 h, unless otherwise stated.b Isolated yields.
1	4-MeOC6H4	Phenyl	3ba	81
2	4-Me C6H4	Phenyl	3ca	85
3	4-CF3 C6H4	Phenyl	3da	78
4	2-Cl C6H4	Phenyl	3ea	79
5	2-Pyridyl	Phenyl	3fa	44
6	Phenyl	4-MeO C6H4	3ga	95
7	Phenyl	4-Me C6H4	3ha	92
8	Phenyl	2-Me C6H4	3ia	90
9	Phenyl	3,4-diMe C6H3	3ja	91
10	Phenyl	2-Et C6H4	3ka	86
11	Phenyl	4-F C6H4	3la	86
12	Phenyl	4-Cl C6H4	3ma	89
13	4-MeO C6H4	4-Me C6H4	3na	92
14	4-Me C6H4	4-Me C6H4	3oa	91
15	(3-Br,4-Me)C6H3	4-Me C6H4	3pa	78
16	4-Cl C6H4	4-Me C6H4	3qa	76
17	4-Br C6H4	4-Me C6H4	3ra	72

---

We next examined the substrate scope of this reaction using R²-substituted arylamidines. Electron-rich-substituted arylamidines such as 4-OMe, 4-Me, 2-Me, 3,4-diMe were easily converted into the corresponding products in excellent yields (Table 2, entries 6–9). Moreover, the substrate with ethyl at the ortho-position afforded the corresponding product 3ka in 86% yield (Table 3, entry 10). Electron-deficient arylamidines bearing halide (4-F, 4-Cl) groups reacted under the standard conditions to afford the desired products in moderate yields (Table 2, entries 11–12).

Table 3 Reactions of N-phenylbenzimidamide 1a with aryl acetaldehydes 2^a

Entry	R^3	Product	Yield(%)^b
a Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), I2 (20 mol%), TBPB(0.2 mmol), dioxane (2 mL), 100 °C in air for 5 h, unless otherwise stated.b Isolated yields.
1	4-MeO C6H4	3ab	85
2	4-Me C6H4	3ac	83
3	3-Me C6H4	3ad	81
4	2-Me C6H4	3ae	78
5	3,4-diMe C6H3	3af	80
6	4-Et C6H4	3ag	81
7	4-F C6H4	3ah	78
8	2-F C6H4	3ai	72

---

In addition, bifunctional amidines were also studied, and were well compatible in this transformation in 72–92% yields (Table 2, entries 13–17).

To further study the scope and generality of the present protocol, various aryl acetaldehyde 2 were studied for the cycloaddition reactions with N-phenylbenzimidamide 1a under the optimized reaction conditions (Table 3). Substrates bearing electron-donating groups (4-OMe, 4-Me, 3-Me, 2-Me, 3,4-diMe and 2-Et) at the aromatic ring produced the corresponding products in moderate yields (Table 3, entries 1–6). The presence of electron-withdrawing substituents (2-F, 4-F) reduced the efficiency of the reaction, as the corresponding products could be isolated in slightly lower yields (Table 3, entries 7–8).

Based on the results and the literature reports,¹⁹ a plausible mechanism was proposed as shown in Scheme 2. Initially, the intermediate A is produced by the condensation reaction of N-phenylbenzamidine 1a with phenylacetaldehyde 2a. Subsequently, the iodo compound B is formed from the A after attack by a molecule of iodine, at the same time with release of H⁺. There follows an intramolecular cyclization of the iodo compound B to form the immediate C by leaving of I⁻ along with a catalytic cycle of I⁻ being oxidized to I₂ by TBPB. Then, a subsequent oxidation of C to give the desired product 3aa.

Scheme 2 Plausible reaction pathway.

Conclusion

In conclusion, we have successfully described a practical and efficient strategy for one-pot synthesis of 1,2,5-triaryl-1H-imidazoles which uses I₂/TBPB mediated oxidative formal [3 + 2] cycloaddition of aryl acetaldehydes with amidines. The reaction is carried out smoothly and the corresponding products are formed in good to excellent yields with excellent regioselectivity. Importantly, operational simplicity, inexpensive catalysts, an excellent functional groups tolerance to the desired compounds from easily available starting materials. And further studies with respect to the details on the subject remain in progress.

Acknowledgements

We are grateful to the project sponsored by the National Science Foundation of P. R. China (No. 21372102 and 21403256).

Notes and references

1. (a) Z. Jin, Nat. Prod. Rep., 2005, 22, 196–229; (b) Z. Jin, Nat. Prod. Rep., 2006, 23, 464–496; (c) Z. Jin, Nat. Prod. Rep., 2009, 26, 382–445; (d) M. Roue, I. Domart-Coulon, A. Ereskovsky, C. Djediat, T. Perez and M. L. Bourguet-Kondracki, J. Nat. Prod., 2010, 73, 1277–1282.
2. (a) Y. Yuan, J.-X. Chen, F. Lu, Q.-X. Tong, Q.-D. Yang, H.-W. Mo, T.-W. Ng, F.-L. Wong, Z.-Q. Guo, J. Ye, Z. Chen, X.-H. Zhang and C.-S. Lee, Chem. Mater., 2013, 25, 4957–4965; (b) N. Nagarajan, G. Velmurugan, A. Prakash, N. Shakti, M. Katiyar, P. Venuvanalingam and R. Renganathan, Chem.–Asian J., 2014, 9, 294–304; (c) T. H. Chiang, Y.-C. Lin, Y.-F. Chen and E.-Y. Chen, J. Appl. Polym. Sci., 2016, 133; (d) J. J. Huang, Y. H. Hung, P. L. Ting, Y. N. Tsai, H. J. Gao, T. L. Chiu, J. H. Lee, C. L. Chen, P. T. Chou and M. K. Leung, Org. Lett., 2016, 18, 672–675.
3. (a) C. D. Mohan, V. Srinivasa, S. Rangappa, L. Mervin, S. Mohan, S. Paricharak, S. Baday, F. Li, M. K. Shanmugam, A. Chinnathambi, M. E. Zayed, S. A. Alharbi, A. Bender, G. Sethi, Basappa and K. S. Rangappa, PLoS One, 2016, 11, e0153155; (b) S. Subramanian, H.-S. Yang, M. Manickam, J. Yun and S.-H. Jung, Bull. Korean Chem. Soc., 2016, 37, 632–637; (c) J. Yong, C. Lu and X. Wu, Lett. Org. Chem., 2016, 13, 283–288.
4. (a) S. Q. Wen, P. Jeyakkumar, S. R. Avula, L. Zhang and C. H. Zhou, Bioorg. Med. Chem. Lett., 2016, 26, 2768–2773; (b) Y. A. Ammar, M. A. El-Sharief, M. M. Ghorab, Y. A. Mohamed, A. Ragab and S. Y. Abbas, Curr. Org. Synth., 2016, 13, 466–475.
5. B. Hanumantha Rao, I. V. Subramanyeswara Rao, V. Ravi Kanth, K. V. Prasada Rao, K. Balamurali Krishna and B. Syama Sundar, Sci. Pharm., 2015, 83, 465–478.
6. L. Z. Bendjeddou, N. Loaec, B. Villiers, E. Prina, G. F. Spath, H. Galons, L. Meijer and N. Oumata, Eur. J. Med. Chem., 2017, 125, 696–709.
7. L. Hojabri, A. Hartikka, F. M. Moghaddam and P. I. Arvidsson, Adv. Synth. Catal., 2007, 349, 740–748.
8. J. Dupont, R. F. de Souza and P. A. Z. Suarez, Chem. Rev., 2002, 102, 3667–3692.
9. (a) F. E. Hahn and M. C. Jahnke, Angew. Chem., Int. Ed., 2008, 47, 3122–3172; (b) K. M. Hindi, M. J. Panzner, C. A. Tessier, C. L. Cannon and W. J. Youngs, Chem. Rev., 2009, 109, 3859–3884; (c) B. Alič and G. Tavčar, J. Fluorine Chem., 2016, 192, 141–146.
10. (a) M. Adib, S. Ansari, S. Feizi, J. Damavandi and P. Mirzaei, Synlett, 2009, 2009, 3263–3266; (b) L. Hong, Y. Shao, L. Zhang and X. Zhou, Chem.–Eur. J., 2014, 20, 8551–8555; (c) J. Cao, X. Zhou, H. Ma, C. Shi and G. Huang, RSC Adv., 2016, 6, 57232–57235; (d) Y. Li, Y. Fu, C. Ren, D. Tang, P. Wu, X. Meng and B. Chen, Org. Chem. Front., 2015, 2, 1632–1636.
11. (a) X. Guo, J. Shao, H. Liu, B. Chen, W. Chen and Y. Yu, RSC Adv., 2015, 5, 51559–51562; (b) C. Y. Chen, W. P. Hu, P. C. Yan, G. C. Senadi and J. J. Wang, Org. Lett., 2013, 15, 6116–6119; (c) J. Banothu, R. Gali, R. Velpula and R. Bavantula, Arabian J. Chem., 2013 DOI:10.1016/j.arabjc.2013.10.022; (d) X. Xu and Y. Li, Res. Chem. Intermed., 2014, 41, 4169–4176; (e) H. Ramezanalizadeh and F. Manteghi, Monatsh. Chem., 2016 DOI:10.1007/s00706-016-1776-9.
12. (a) X. Zhou, Z. Jiang, L. Xue, P. Lu and Y. Wang, Eur. J. Org. Chem., 2015, 2015, 5789–5797; (b) J. Zhang, Q. Gao, X. Wu, X. Geng, Y. D. Wu and A. Wu, Org. Lett., 2016, 18, 1686–1689; (c) B. Sezen and D. Sames, J. Am. Chem. Soc., 2003, 125, 10580–10585; (d) A. R. Katritzky, L. Zhu, H. Lang, O. Denisko and Z. Wang, Tetrahedron, 1995, 51, 13271–13276; (e) J. Grimshaw and S. A. Hewitt, J. Chem. Soc., Perkin Trans. 1, 1990, 2995–2998,  10.1039/p19900002995.
13. J. Li and L. Neuville, Org. Lett., 2013, 15, 1752–1755.
14. X. Liu, D. Wang, Y. Chen, D. Tang and B. Chen, Adv. Synth. Catal., 2013, 355, 2798–2802.
15. (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.
16. J. Qu, P. Wu, D. Tang, X. Meng, Y. Chen, S. Guo and B. Chen, New J. Chem., 2015, 39, 4235–4239.
17. D. El Abed, C. Adiche and M. Hamadouche, Heterocycles, 2016, 92, 1614.
18. (a) J. Li and L. Neuville, Org. Lett., 2013, 15, 6124–6127; (b) J. Li, S. Benard, L. Neuville and J. Zhu, Org. Lett., 2012, 14, 5980–5983; (c) R. Navratil, J. Tarabek, I. Linhart and T. Martinu, Org. Lett., 2016, 18, 3734–3737.
19. (a) X. Zhang, M. A. Campo, T. Yao and R. C. Larock, Org. Lett., 2005, 7, 763–766; (b) G. Bharathiraja, S. Sakthivel, M. Sengoden and T. Punniyamurthy, Org. Lett., 2013, 15, 4996–4999; (c) S. K. Lee and J. K. Park, J. Org. Chem., 2015, 80, 3723–3729.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ra01966a

---