Alumina-Promoted Michael Addition of Imidazo[1,2-a]pyridines with α,β-Unsaturated Ketones

doi:10.6023/cjoc202503008

Abstract

A direct Michael addition reaction between imidazo[1,2-a]pyridines and α,β-unsaturated ketones using acidic alumina as a C(sp³)—H acid catalyst has been developed. The abundant C(sp³)—H acid sites (Al³⁺) on the acidic alumina surface effectively activate the carbonyl group of α,β-unsaturated ketones, significantly enhancing the electrophilicity of the β-carbon and thereby facilitating selective alkylation at the C3 position of imidazo[1,2-a]pyridines. This method demonstrates excellent functional group compatibility, mild reaction conditions, low reagent costs, and operational simplicity, providing a novel strategy for the efficient synthesis of alkylated imidazo[1,2-a]pyridine derivatives.

Key words: C(sp³)—H acid, imidazo[1,2-a]pyridine, α,β-unsaturated ketone, Michael addition

Cite this article

Yadong Sun, Hai Zhou, Tucai Zheng, Shoucai Wang, Fanghua Ji. Alumina-Promoted Michael Addition of Imidazo[1,2-a]pyridines with α,β-Unsaturated Ketones[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3361-3369.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 6

References 16

[1]	(a) Meng, F.; Wang, R.; Huang, H.; Gong, S.; Li, Q.; Zhang, S.; Ma, C.; Li, C.; Du, J. Org. Chem. Front. 2019, 6, 3929.
	(b) Zhu, F.; Guo, X.; Zhang, F.; Zhang, X.; Wang, H.; Tu, Y. Org. Lett. 2020, 22, 2076.
	(c) Kang, T.; Hou, L.; Ruan, S.; Cao, W.; Liu, X.; Feng, X. Nat. Commun. 2020, 11, 3869.
	(d) Chang, F.; Shen, B.; Wang, S.; Lin, L.; Feng, X. Chem. Commun. 2020, 56, 13429.
	(e) Schöbel, J.; Liang, W.; Wöll, D.; Bolm, C. J. Org. Chem. 2020, 85, 15760.
	(f) Huang, H.; Zhang, T.; Sun, J. Angew. Chem. Int. Ed. 2021, 60, 2668.
[2]	(a) Srinivasulu, V.; Schilf, P.; Ibrahim, S.; Shehadi, I. A.; Malik, O. G.; Sieburth, S.; Khanfar, M. A.; Hamad, M.; Abu-Yousef, I. A.; Majdalawieh, A. F.; Al-Tel, T. H. J. Org. Chem. 2020, 85, 10695.
	(b) Shee, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2020, 22, 5407.
	(c) Mukherjee, S.; Shee, S.; Poisson, T.; Besset, T.; Biju, A. T. Org. Lett. 2018, 20, 6998.
	(d) Li, S.; Wan, Q.; Kang, Q. Org. Lett. 2018, 20, 1312.
[16]	(b) Alotaibi, N.; Babaahmadi, R.; Pramanik, M.; Das, S.; Kariuki, B. M.; Richards, E.; Wirth, T.; Melen, R. L. Eur. J. Org. Chem. 2024, 27, e202400022.
	(c) Bosica, G.; Abdilla, R. Molecules 2016, 21, 815.
[2]	(e) Silva, S.; Matsuo, B. T.; Silva, R. C.; Pozzi, L. V.; Correa, A. G.; Rollin, P.; Zukerman-Schpector, J.; Ferreira, M. A. B.; Paixão, M. W. J. Org. Chem. 2018, 83, 1701.
	(f) Li, H.; Li, X.; Yu, Y.; Li, J.; Liu, Y.; Li, H.; Wang, W. Org. Lett. 2017, 19, 2010.
	(g) Zhang, X.; Jones-Mensah, E.; Deobald, J.; Magolan, J. Adv. Synth. Catal. 2019, 361, 5548.
[3]	(a) Li, H.; Yu, J.; Ge, Q.; Liu, M.; Tao, Z.; Cong, H. ChemCat- Chem 2020, 12, 5727.
	(b) Tao, L.; Wei, Y.; Shi, M. Org. Chem. Front. 2020, 7, 2634.
	(c) Bering, L.; Paulussen, F. M.; Antonchick, A. P. Org. Lett. 2018, 20, 1978.
	(d) Lei, S.; Cao, H.; Chen, L.; Liu, J.; Cai, H.; Tan, J. Adv. Synth. Catal. 2015, 357, 3109.
[4]	(a) Li, Z.; Shi, Z.; He, C. J. Organomet. Chem. 2005, 690, 5049.
	(b) Arcadi, A.; Bianchi, G.; Chiarini, M.; Anniballe, G. D.; Marinelli, F. Synlett 2004, 6, 944.
	(c) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Chem. Commun. 2005, 41, 789.
	(d) Azizi, N.; Arynasab, F.; Saidi, M. R. Org. Biomol. Chem. 2006, 4, 4275.
	(e) Manabe, K.; Aoyama, N.; Kobayashi, S. Adv. Synth. Catal. 2001, 343, 174.
	(f) Gu, Y.; Ogawa, C.; Kobayashi, S. Org. Lett. 2007, 9, 175.
[5]	Rajabi, F.; Razavi, S.; Luque, R. GreenChem. 2010, 12, 786.
[6]	(a) Trabanco, A. A.; Tresadern, G.; Macdonald, G. J.; Vega, J. A.; Lucas, A. I. d.; Matesanz, E.; García, A.; Linares, M. L.; DiegoS, A. A.; Alonso, J. M.; Oehlrich, D.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Andrés, J. I.; Lavreysen, H.; Cid, J. M. ; J. Med. Chem. 2012, 55, 2688.
	(b) Ducray, R.; Jones, C. D.; Jung, F. H.; Simpson, I.; Curwen, J.; Pass, M. Bioorg. Med. Chem. Lett. 2011, 21, 4702.
	(c) Marson, C. M. Chem. Soc. Rev. 2011, 40, 5514.
[7]	(a) Muzalevskiy, V. M.; Sizova, Z. A. ; Shastin, A. V.; Nenajdenko, V. G. Eur. J. Org. Chem. 2019, 4034.
	(b) Majee, D.; Biswas, S.; Mobin, S. M.; Samanta, S. J. Org. Chem. 2016, 81, 4378.
	(c) Wang, S.; Huang, X.; Ge, Z.; Wang, X.; Li, R. RSC Adv. 2016, 6, 63532.
[8]	(a) Wen, Q.; Lu, P.; Wang, Y. Chem. Commun. 2015, 51, 15378.
	(b) Park, S.; Kim, H.; Son, J.; Um, K.; Lee, S.; Baek, Y.; Seo, B.; Lee, P. H. J. Org. Chem. 2017, 82, 10209.
	(c) Olivier, A.; Sevrin, M.; Durant, F.; George, P. Bioorg. Med. Chem. Lett. 1997, 17, 2277.
[9]	(a) Ducray, R.; Simpson, I.; Jung, F. H.; Nissink, W. M.; Kenny, P. W.; Fitzek, M.; Walker, G. E.; Ward, L. T.; Hudson, K. Bioorg. Med. Chem. Lett. 2011, 21, 4698.
	(b) Tresadern, G.; Cid, J. M.; Macdonald, G. J.; Vega, J. A.; Lucas, A. I.; García, A.; Matesanz, E.; Linares, M. L.; Oehlrich, D.; Lavreysen, H.; Biesmans, I.; Trabanco, A. A. Bioorg. Med. Chem. Lett. 2010, 20, 175.
[10]	(a) Patel, O. P. S.; Anand, D.; Maurya, R. K.; Yadav, P. P. J. Org. Chem. 2016, 81, 7626.
	(b) Kibriya, G.; Samanta, S.; Jana, S.; Mondal, S.; Hajra, A. J. Org. Chem. 2017, 82, 13722.
	(c) Guo, Y.; Lu, S.; Tian, L.; Huang, E.; Hao, X.; Zhu, X.; Shao, T.; Song, M. J. Org. Chem. 2018, 83, 338.
	(d) Semwal, R.; Ravi, C.; Kumar, R.; Meena, R.; Adimurthy, S. J. Org. Chem. 2019, 84, 792.
	(e) Joshi, A.; Semwal, R.; Suresh, E.; Adimurthy, S. Chem. Commun. 2019, 55, 10888.
	(f) Cai, Q.; Liu, M.-C.; Mao, B.-M.; Xie, X.; Jia, F.-C.; Zhu, Y.-P.; Wu, A.-X. Chin. Chem. Lett. 2015, 26, 881.
	(g) Ulloora, S.; Adhikari, A. V.; Shabaraya, R. Chin. Chem. Lett. 2013, 24, 853.
[11]	(a) Liang, Y.; Teng, L.; Wang, Y.; He, Q.; Cao, H. Green. Chem. 2019, 21, 4025.
	(b) Wang, C.; Lei, S.; Cao, H.; Qiu, S.; Liu, J.; Deng, H.; Yan, C. J. Org. Chem. 2015, 80, 12725.
	(c) Cao, H.; Zhan, H.; Lin, Y.; Lin, X.; Du, Z.; Jiang, H. Org. Lett. 2012, 14, 1688.
	(d) Gao, Y.; Yin, M.; Wu, W.; Huang, H.; Jiang, H. Adv. Synth. Catal. 2013, 355, 2263.
	(e) Li, J.; Li, C.; Yang, S.; An, Y.; Wu, W.; Jiang, H. J. Org. Chem. 2016, 81, 7771.
	(f) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem. Int. Ed. 2011, 50, 5678.
	(g) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217.
	(h) Wang, S.; Zhang, S.; Liu, M.; Zang, J.; Jiang, G.; Ji, F. Org. Chem. Front. 2020, 7, 697.
	(i) Li, X.; Wang, S.; Zang, J.; Liu, M.; Jiang, G.; Ji, F. Org. Biomol. Chem. 2020, 18, 9100.
[12]	Lei, S.; Mai, Y.; Yan, C.; Mao, J.; Cao, H. Org. Lett. 2016, 18, 3582.
[13]	(a) Nandi, S.; Islam, M. M.; Saha, M.; Mitra, S.; Khatua, S.; Pal, A. K. Syn. Commun. 2016, 46, 1461.
	(b) Bosica, G.; Abdilla, R. Molecules 2016, 21, 815.
	(c) Borah, P.; Yamashita, Y.; Kobayashi, S. Angew. Chem. Int. Ed. 2017, 56, 10330.
	(d) Luque-Agudo, V.; Padró J. M.; Román, E.; Serrano, J. A.; Gil, M. V. New J. Chem. 2018, 42, 18342.
[14]	(a) Ji, F.; Li, J.; Li, X.; Wu, W.; Jiang, H. J. Org. Chem. 2018, 83, 104.
	(b) Jiang, G.; Wang, S.; Zhang, J.; Yu, J.; Zhang, Z.; Ji, F. Adv. Synth. Catal. 2019, 361, 1798.
	(c) Wang, S.; Wang, K.; Kong, X.; Zhang, Shu.; Jiang, G.; Ji, F. Adv. Synth. Catal. 2019, 361, 3986.
	(d) Wang, S.; Li, X.; Zang,J.; Liu, M.; Zhang, S.; Jiang, G.; Ji, F. J. Org. Chem. 2020, 85, 2672.
	(e) Jiang, G.; Yang, G.; Liu, X.; Wang, S.; Ji, F. New J. Chem. 2021, 45, 104.
[15]	(a) Qin, H.; Zhang, Z.; Lekkala, R.; Alsulami, H.; Rakesh, K. P. Eur. J. Med. Chem. 2020, 193, 112215.
	(b) Huo, P.; Guan, X.; Liu, P.; Song, Y.; Sun, M.; He, R.; Zou, L.; Xue, L.; Shi, J.; Zhang, N.; Liu, Z.; Ge, G. Eur. J. Med. Chem. 2021, 209, 112856.
	(c) Arai, R.; Hirashima, S.; Nakano, T.; Kawada, M.; Akutsu, H.; Nakashima, K.; Miura, T. J. Org. Chem. 2020, 85, 3872.
	(d) Souza, A. C. A.; Mori, M.; Sens, L.; Rocha, R. F.; Tizziani, T.; Souza, L. F. S.; Chiaradia-Delatorre, L. D.; Botta, M.; Nunes, R. J.; Terenzi, H.; Menegatti, A. C. O. Bioorg. Med. Chem. Lett. 2020, 30, 127350.
	(e) Selvaraj, B.; Nguyen, U. T. T.; Huh, G.; Nguyen, D. H.; Mok, I.; Lee, H.; Kang, K.; Bae, A. N.; Kim, D. W.; Lee, J. W. Bioorg. Med. Chem. Lett. 2020, 30, 127597.
[16]	(a) Akhmetov, V.; Feofanov, M.; Sharapa, D.; Amsharov, K. J. Am. Chem. Soc. 2021, 143, 15420.

Entry	Al₂O₃	Solvent	T/^oC	Yield^b/%
1^a	Acidic	n-Hexane	68	85
2	Neutral	n-Hexane	68	17
3	Basic	n-Hexane	68	21
4	Acidic	Heptane	68	75
5	Acidic	PhMe	68	55
6	Acidic	DCM	68	60
7	Acidic	CH₃CN	68	20
8	Acidic	n-Butanol	68	0
9	Acidic	Ethanol	68	0
10	Acidic	THF	68	30
11	Acidic	Acetone	68	15
12	Acidic	DMSO	68	0
13	Acidic	dioxane	68	0
14	Acidic	n-Hexane	48	65
15	Acidic	n-Hexane	88	81
16	Acidic	n-Hexane	108	78
17^c	Acidic	n-Hexane	68	70
18^d	Acidic	n-Hexane	68	56
19	—	n-Hexane	68	0

Entry	Al₂O₃	Solvent	T/^oC	Yield^b/%
1^a	Acidic	n-Hexane	68	85
2	Neutral	n-Hexane	68	17
3	Basic	n-Hexane	68	21
4	Acidic	Heptane	68	75
5	Acidic	PhMe	68	55
6	Acidic	DCM	68	60
7	Acidic	CH₃CN	68	20
8	Acidic	n-Butanol	68	0
9	Acidic	Ethanol	68	0
10	Acidic	THF	68	30
11	Acidic	Acetone	68	15
12	Acidic	DMSO	68	0
13	Acidic	dioxane	68	0
14	Acidic	n-Hexane	48	65
15	Acidic	n-Hexane	88	81
16	Acidic	n-Hexane	108	78
17^c	Acidic	n-Hexane	68	70
18^d	Acidic	n-Hexane	68	56
19	—	n-Hexane	68	0

氧化铝促进的咪唑并[1,2-a]吡啶与α,β-不饱和酮的Michael加成