Metal-free synthesis of imidazopyridine from nitroalkene and 2-aminopyridine in the presence of a catalytic amount of iodine and aqueous hydrogen peroxide

Abstract

We have developed a metal-free synthetic method for 3-nitroimidazo[1,2-a]pyridines from nitroalkenes and 2-aminopyridines using catalytic amounts of iodine and aqueous hydrogen peroxide as a terminal oxidant.

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Imidazo[1,2-a]pyridines are of great importance for their remarkable biological properties, and they are found in many pharmaceutical compounds, including zolpidem, saripidem, zolimidine, and olprinone.¹ Thus, there are various synthetic reactions that include the use of 2-aminopyridine combined with phenacyl halide,² propynal,³ aldehyde and alkyne,⁴ aldehyde and isonitrile,⁵ Morita–Baylis–Hillman acetate of nitroalkene,⁶ and 1,3-oxoester.⁷ In addition, intramolecular amination has also been used for the construction of imidazopyridines.⁸ Recently, nitroalkenes have been adopted as a reaction partner of 2-aminopyridine. When FeCl₃ ⁹ or FeCl₂ ¹⁰ were used as catalysts, denitrated imidazopyridines were obtained. On the other hand, CuBr¹¹ and NaICl₂ ¹² yielded 3-nitroimidazo[1,2-a]pyridines under oxidative reaction conditions. Furthermore, three-component reactions using nitromethane and aldehyde rather than nitroalkene have also been reported.¹³ Although these reactions are highly practical because 3-nitroimidazo[1,2-a]pyridine can be converted to various imidazopyridine derivatives,¹⁴ such reactions require a transition metal catalyst or a reagent which is not available commercially. Therefore, the development of a facile catalytic metal-free reaction is required from the viewpoint of green chemistry.

We have developed various aerobic photooxidative reactions with iodine sources using molecular oxygen.¹⁵ During the course of our study, we developed an oxidative C–C bond formation between tertiary amines and carbon nucleophiles using a combination of catalytic amounts of iodine and hydrogen peroxide as a terminal oxidant.¹⁶ We then examined the metal-free synthetic reaction of 3-nitroimidazo[1,2-a]pyridines from nitroalkene and 2-aminopyridine using an iodine source combined with hydrogen peroxide. Here, we report the details of this reaction (Scheme 1).

Scheme 1 Synthesis of 3-nitroimidazo[1,2-a]pyridine in the presence of catalytic iodine and aqueous hydrogen peroxide.

Table 1 shows the results of the optimization of reaction conditions for the synthesis of imidazopyridines using trans-β-nitrostyrene and 2-aminopyridine as a test substrate. Among the solvents and iodine sources examined, dimethyl sulfoxide (DMSO) and I₂, which are more atom efficient and inexpensive than N-iodosuccinimide, were found to be the most suitable for the reaction (entries 1–13). Note that 3a was obtained in good yield (entry 14) by increasing the amount of 2-aminopyridine to 1.2 equiv. Conversely, changing the reaction temperature and amounts of hydrogen peroxide resulted in lower yields of 3a (entries 15–18).

Table 1 Study of reaction conditions^a

Entry	Solvent	Iodine source	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), iodine source, and 35% aq H2O2 (4 equiv.) in solvent (3 mL) were stirred at 70° for 20 h.b ^1H NMR yields. Number in parentheses is isolated yield.c The reaction was carried out with 2a (1.2 equiv.).d The reaction was carried out at 60 °C.e The reaction was carried out at 80 °C.f The reaction was carried out with 35% aq H2O2 (3 equiv.).g The reaction was carried out with 35% aq H2O2 (5 equiv.).
1	Toluene	I2	9
2	EtOAc	I2	20
3	2-PrOH	I2	21
4	MeCN	I2	26
5	DMF	I2	63
6	DMSO	I2	71
7	DMSO	NIS	71
8	DMSO	55% aq HI	66
9	DMSO	KI	66
10	DMSO	Cal2	57
11	DMSO	Nal	45
12	DMSO	Lil	29
13	DMSO	TBAI	11
14^c	DMSO	I2	87 (75)
15^c^,^d	DMSO	I2	38
16^c^,^e	DMSO	I2	38
17^c^,^f	DMSO	I2	46
18^c^,^g	DMSO	I2	56

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Table 2 presents the scope and limitations of the reactions between nitroalkenes (1) and 2-aminopyridines (2) under the optimized reaction conditions.¹⁷ The corresponding imidazopyridines were obtained in good to high yield regardless of an electron-donating or -withdrawing group at the para- and meta-positions of the aromatic nucleus of nitroalkenes (3b–f, and 3l). On the other hand, ortho-substituted nitroalkene 1g gave low yield due to steric hindrance. 3, 4, or 5 substituted 2-aminopyridines, including methyl, chloro, and ester groups, were good substrates in this reaction (3h–l).

Table 2 Scope and limitations^a

a Isolated yields.b Reaction was conducted with aminopyridine (1.5 equiv.).

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We performed several control experiments to resolve the reaction mechanism (Table 3). The fact that imidazopyridine was not obtained or was obtained in only low yields without iodine or hydrogen peroxide shows the necessity of these ingredients. Note that DMSO was not an oxidant in the reaction (entries 1–3). Furthermore, when we used 1 equiv. of iodine in the absence of hydrogen peroxide, 3a was obtained in only 14% yield (entry 4). The iodination of several compounds, including electron-rich aromatics, olefins, and ketones, with molecular iodine is accelerated by hydrogen peroxide,¹⁸ and hypoiodous acid (HOI) has been considered to be an active species.¹⁹ Therefore, we speculate that HOI is also involved in this reaction. Even under dark conditions, the reaction proceeded with good yields, which suggests that light is not essential for the reaction (entry 5). Since HIO₃, which is produced by disproportionate of HOI, is not good reagent, this disproportionation isn't thought to be important in this reaction (entry 6).

Table 3 Study of reaction mechanism

Entry	Change from standard conditions	Yield^a (%)
a ^1H NMR yields.
1	I2 (0 equiv.), H2O2 (0 equiv.)	0
2	I2 (0 equiv.)	0
3	H2O2 (0 equiv.)	7
4	I2 (1 equiv.), H2O2 (0 equiv.)	14
5	In the dark	78
6	HIO3 (4 equiv.), I2 (0 equiv.), H2O2 (0 equiv.)	22

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Scheme 2 shows a plausible path for this intermolecular oxidative cyclization, which we postulate after considering all of the results presented above. The path includes the following three steps. First, HOI is generated from iodine and hydrogen peroxide. Next, Michael addition of the 2-aminopyridine (2) to nitroalkene 1 followed by iodination at the α-position of the nitro group produces adduct 5.²⁰ Finally, intramolecular nucleophilic substitution and subsequent oxidation of 6 with HOI gives imidazopyridine 3.²¹ On the other hand, in situ generated HI is reoxidized to HOI in the presence of hydrogen peroxide.

Scheme 2 Plausible reaction mechanism.

Conclusions

In conclusion, we have found a metal-free synthetic method for 3-nitroimidazo[1,2-a]pyridines from nitroalkene and 2-aminopyridine in the presence of catalytic iodine and aqueous hydrogen peroxide. This reaction is interesting in keeping with the notion of green chemistry because of the use of catalytic amounts of molecular iodine and hydrogen peroxide as the terminal oxidant.

Notes and references

1. (a) S. M. Hanson, E. V. Morlock, K. A. Satyshur and C. Czajkowski, J. Med. Chem., 2008, 51, 7243; (b) L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P. Rugarli, A. Biancotti, A. Gamba and W. Murmann, J. Med. Chem., 1965, 8, 305; (c) T. S. Harrison and G. M. Keating, CNS Drugs, 2005, 19, 65; (d) A. R. Katritzky, Y. J. Xu and H. Tu, J. Org. Chem., 2003, 68, 4935; (e) E. C. Gueiffier and A. Gueiffier, Mini-Rev. Med. Chem., 2007, 7, 888.
2. (a) A. J. Stasyuk, M. Banasiewicz, M. K. Cyrański and D. T. Gryko, J. Org. Chem., 2012, 77, 5552; (b) A. Herath, R. Dahl and N. D. P. Cosford, Org. Lett., 2010, 12, 412; (c) K. S. Gudmundsson and B. A. Johns, Org. Lett., 2003, 5, 1369; (d) R. J. Sundberg, D. J. Dahlhausen, G. Manikumar, B. Mavunkel and A. Biswas, J. Heterocycl. Chem., 1988, 25, 129.
3. H. Cao, X. Liu, L. Zhao, J. Cen, J. Lin, Q. Zhu and M. Fu, Org. Lett., 2014, 16, 146.
4. (a) I. R. Siddiqui, P. R. Raila, A. Srivastava and S. Shamim, Tetrahedron Lett., 2014, 55, 1159; (b) S. Mishra and R. Ghosh, Synthesis, 2011, 3463.
5. (a) H. Sun, H. Zhou, O. Khorev, R. Jiang, T. Yu, X. Wang, Y. Du, Y. Ma, T. Meng and J. Shen, J. Org. Chem., 2012, 77, 10745; (b) H. Bienayme and K. Bouzid, Angew. Chem., Int. Ed., 1998, 37, 2234; (c) A. L. Rousseau, P. Matlaba and C. J. Parkinson, Tetrahedron Lett., 2007, 48, 4079; (d) A. Domling, Chem. Rev., 2006, 106, 17; (e) J. Zhu, Eur. J. Org. Chem., 2003, 1133.
6. D. K. Nair, S. M. Mobin and I. N. N. Namboothiri, Org. Lett., 2012, 14, 4580.
7. (a) X. Wang, L. Ma and W. Yu, Synthesis, 2011, 15, 2445; (b) L. Ma, X. Wang, W. Yu and B. Han, Chem. Commun., 2011, 47, 11333.
8. (a) D. C. Mohan, S. N. Rao and S. Adimurthy, J. Org. Chem., 2013, 78, 1266; (b) S. Husinec, R. Markovic, M. Petkovic, V. Nasufovic and V. Savic, Org. Lett., 2011, 13, 2286; (c) H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang and Q. Zhu, Angew. Chem., Int. Ed., 2011, 50, 5678.
9. S. Santra, A. K. Bagdi, A. Mttee and A. Httra, Adv. Synth. Catal., 2013, 355, 1065.
10. H. Yan, S. Yang, X. Gao, K. Zhou, C. Ma, R. Yan and G. Huang, Synlett, 2012, 23, 2961.
11. R. Yan, H. Yan, C. Ma, Z. Ren, X. Gao, G. Huang and Y. Liang, J. Org. Chem., 2012, 77, 2024.
12. P. B. Jagadhane and V. N. Telvekar, Synthesis, 2014, 25, 2636.
13. H. Yan, R. Yan, S. Yang, X. Gao, Y. Wang, G. Huang and Y. Liang, Chem.–Asian J., 2012, 7, 2028.
14. (a) M. Bazin, S. Marhadour, A. Tonnerre and P. Marchand, Tetrahedron Lett., 2013, 54, 5378; (b) L. Arias, H. Salgado-Zamora, H. Cerantes, E. Campos, A. Reyes and E. C. Taylor, J. Heterocycl. Chem., 2006, 43, 565; (c) H. S. Zamora, B. Rizo, E. Campos, R. Jiménez and A. Reyes, J. Heterocycl. Chem., 2004, 41, 91.
15. (a) A. Kariya, T. Yamaguchi, T. Nobuta, N. Tada, T. Miura and A. Itoh, RSC Adv., 2014, 4, 13191–13194; (b) T. Nobuta, A. Fujiya, T. Yamaguchi, N. Tada, T. Miura and A. Itoh, RSC Adv., 2013, 3, 10189–10192; (c) T. Nobuta, A. Fujiya, N. Tada, T. Miura and A. Itoh, Synlett, 2012, 23, 2975–2979; (d) N. Tada, T. Ishigami, L. Cui, K. Ban, T. Miura and A. Itoh, Tetrahedron Lett., 2013, 54, 256–258; (e) N. Tada, M. Shomura, L. Cui, T. Nobuta, T. Miura and A. Itoh, Synlett, 2011, 2896–2900; (f) T. Nobuta, S. Hirashima, N. Tada, T. Miura and A. Itoh, Org. Lett., 2011, 13, 2576; (g) N. Kanai, H. Nakayama, N. Tada and A. Itoh, Org. Lett., 2010, 12, 1948; (h) T. Nobuta, S. Hirashima, N. Tada, T. Miura and A. Itoh, Synlett, 2010, 2335; (i) H. Nakayama and A. Itoh, Tetrahedron Lett., 2007, 48, 1131; (j) H. Nakayama and A. Itoh, Chem. Pharm. Bull., 2006, 54, 1620.
16. T. Nobuta, A. Fujiya, A. Kariya, N. Tada, T. Miura and A. Itoh, Org. Lett., 2013, 15, 574.
17. Typical procedure (Table 1, entry 14): a solution of trans-β-nitrostyrene (1a) (44.7 mg, 0.3 mmol), 2-aminopyridine (2a) (33.9 mg, 1.2 equiv.), iodine (7.6 mg, 0.1 equiv.), and 35% aq H₂O₂ (106 μL, 1.2 mmol) in DMSO (3 mL) in a pyrex test tube was stirred under air at 70 °C for 20 h. The reaction mixture was washed with aq Na₂S₂O₃ and H₂O, and extracted with EtOAc. Organic layer was dried over MgSO₄, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (hexane : EtOAc = 2 : 1) provided 3-nitro-2-phenylimidazo[1,2-a]pyridine (3a) (54 mg, 75%).
18. (a) J. Pavlinac, M. Zupan and S. Stavber, Org. Biomol. Chem., 2007, 5, 699; (b) J. Pavlinac, M. Zupan and S. Stavber, J. Org. Chem., 2006, 71, 1027; (c) J. Pavlinac, M. Zupan and S. Stavber, Synthesis, 2006, 2603; (d) M. Jereb, M. Zupan and S. Stavber, Chem. Commun., 2004, 2614; (e) K. Omura, J. Org. Chem., 1996, 61, 2006; (f) H. Ohta, T. Motoyama, T. Ura, Y. Ishii and M. Ogawa, J. Org. Chem., 1989, 54, 1668.
19. (a) I. Lengyel, I. R. Epstein and K. Kustin, Inorg. Chem., 1993, 32, 5880; (b) I. Barnes, K. H. Bedker and J. Starcke, Chem. Phys. Lett., 1992, 196, 578; (c) J. Paquette and B. L. Ford, Can. J. Chem., 1985, 63, 2444; (d) M. Uyanik, H. Hayashi and K. Ishihara, Science, 2014, 345, 291.
20. For iodoamination, see: (a) K. Miyamoto, O. Morikawa and H. Konishi, Bull. Chem. Soc. Jpn., 2005, 78, 886; (b) O. Kitagawa and T. Taguchi, Synlett, 1999, 1191; (c) Y. Cai, X. Liu, J. Li, W. Chen, W. Wang, L. Lin and X. Feng, Chem.–Eur. J, 2011, 17, 14916.
21. For oxidative aromatization by iodine, see: (a) C. Zhu and Y. Wei, ChemSusChem, 2011, 4, 1082; (b) B. Maleki and H. Veisi, Bull. Korean Chem. Soc., 2011, 32, 4366; (c) J. S. Yadav, B. V. S. Reddy, G. Sabitha and G. S. K. K. Reddy, Synthesis, 2000, 1532; (d) M. Filipan-Litvic, M. Litvic and V. Vinkovic, Tetrahedron, 2008, 64, 5649.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra14970j

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