8-Aminoimidazo[1,2-a]pyridine-Directed Nickel-Catalyzed β-C(sp ²)–H Arylation and Alkylation: Implementation for Late-Stage C–H Activation towards Biologically Relevant Compounds

Abstract

We herein report an efficient and convenient protocol for the Ni(II)-catalyzed ortho-C(sp ²)–H arylation as well as alkylation using 8-aminoimidazo[1,2-a]pyridine (8-AIP) as a unique directing group in the absence of any external ligand and oxidant. This protocol is scalable, has excellent yield, exhibits high levels of β-site selectivity, and tolerates a broad spectrum of functional groups. A kinetic study was also undertaken to establish a plausible reaction pathway. Single-crystal XRD analysis was carried out to determine one of the structures. Furthermore, late-stage functionalization of the synthesized derivatives demonstrates the methodology’s synthetic adaptability and showcases the use of 8-AIP as an inbuilt directing group.

Key words

C–H activation - Ni catalysis - 8-AIP - β-C(sp ²)–H arylation - β-C(sp ²)–H alkylation

Publication History

Received: 02 April 2025

Accepted after revision: 09 May 2025

Accepted Manuscript online:
09 May 2025

Article published online:
11 June 2025

• References

• 1a Chen Z, Wang B, Zhang J, Yu W, Liu Z, Zhang Y. Org. Chem. Front. 2015; 2: 1107
• 1b Sambiagio C, Schönbauer D, Blieck R, Dao-Huy T, Pototsching G, Schaaf P, Wiensinger T, Zia MF, Wencel-Delord J, Besset T, Maes BU. W, Schnürch M. Chem. Soc. Rev. 2018; 47: 6603
• 1c Rao W.-H, Shi B.-F. Org. Chem. Front. 2016; 3: 1028
• 1d Chen F.-J, Liao G, Li X, Wu J, Shi B.-F. Org. Lett. 2014; 16: 5644
• 1e Yin X.-S, Li Y.-C, Yuan J, Gu W.-J, Shi B.-F. Org. Chem. Front. 2015; 2: 115
• 1f Zhao S, Liu Y.-J, Yan S.-Y, Chen F.-J, Zhang Z.-Z, Shi B.-F. Org. Lett. 2015; 17: 3338
• 1g Rao W.-H, Shi B.-F. Org. Lett. 2015; 17: 2784
• 1h Li Y, Liu Y.-J, Shi B.-F. Adv. Synth. Catal. 2017; 359: 4117
• 2a Wencel-Delord J, Dröge T, Liu F, Glorius F. Chem. Soc. Rev. 2011; 40: 4740
• 2b Kuhl N, Hopkinson MN, Wencel-Delord J, Glorius F. Angew. Chem. Int. Ed. 2012; 51: 10236
• 2c Hartwig JF, Larsen MA. ACS Cent. Sci. 2016; 2: 281
• 2d Gensch T, Hopkinson MN, Glorius F, Wencel-Delord J. Chem. Soc. Rev. 2016; 45: 2900
• 2e Santoro S, Ferlin F, Luciani L, Ackermann L, Vaccaro L. Green Chem. 2017; 19: 1601
• 2f Gensch T, James MJ. M. J, Dalton T, Glorius F. Angew. Chem. Int. Ed. 2018; 57: 2296
• 2g Meyer TH, Finger LH, Gandeepan P, Ackermann L. Trends Chem. 2019; 1: 63
• 2h Gandeepan P, Kaplaneris N, Santoro S, Vaccaro L, Ackermann L. ACS Sustainable Chem. Eng. 2019; 7: 8023
• 2i Gandeepan P, Müller T, Zell D, Cera G, Warratz S, Ackermann L. Chem. Rev. 2019; 119: 2192
• 2j Yu C, Sanjosé-Orduna J, Patureau FW, Pérez-Temprano MH. Chem. Soc. Rev. 2020; 49: 1643
• 2k Gandeepan P, Finger LH, Meyer TH, Ackermann L. Chem. Soc. Rev. 2020; 49: 4254
• 3a Daugulis O, Roane J, Tran LD. Acc. Chem. Res. 2015; 48: 1053
• 3b Rouquet G, Chatani N. Angew. Chem. Int. Ed. 2013; 52: 11726
• 3c Rej S, Ano Y, Chatani N. Chem. Rev. 2020; 120: 1788
• 3d Roane J, Daugulis O. J. Am. Chem. Soc. 2016; 138: 4601
• 4a Guo X.-X, Gu D.-W, Wu Z, Zhang W. Chem. Rev. 2015; 115: 1622
• 4b Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
• 4c Li S, Qin L, Dong L. Org. Biomol. Chem. 2016; 14: 4554
• 4d Arockiam PB, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879
• 4e Pan S, Shibata T. ACS Catal. 2013; 3: 704
• 5 Genchi G, Carocci A, Lauria G, Stefania M, Catalano SA. Int. J. Environ. Res. Public Health 2020; 17: 679

For a recent review of Ni-catalyzed C–H bond functionalization, see:
• 6a Yamaguchi J, Muto K, Itami K. Eur. J. Org. Chem. 2013; 1: 19
• 6b Harry NA, Saranya S, Ujwaldev SM, Anilkumar G. Catal. Sci. Technol. 2019; 9: 1726
• 7a Hachiya H, Hirano K, Satoh T, Miura M. Org. Lett. 2009; 11: 1737
• 7b Canivet J, Yamaguchi J, Ban I, Itami K. Org. Lett. 2009; 11: 1733
• 8a Aihara Y, Chatani N. J. Am. Chem. Soc. 2013; 135: 5308
• 8b Honeycutt AP, Hoover JM. ACS catal. 2017; 7: 4597
• 9 Yokota A, Aihara Y, Chatani N. J. Org. Chem. 2014; 79: 11922
• 10a Zhao S, Liu B, Zhan BB, Zhang WD, Shi BF. Org. Lett. 2016; 18: 4586
• 10b Liu B, Zhang ZZ, Li X, Shi BF. Org. Chem. Front. 2016; 3: 897
• 11a Mondal B, Ghosh P, Kundu MK, Das TK, Das S. Org. Biomol. Chem. 2021; 19: 360
• 11b Mondal B, Ghosh P, Kundu MK, Das S. Org. Biomol. Chem. 2021; 19: 1604
• 11c Hajra AK, Ghosh P, Roy C, Kundu M, Ghosh S, Das S. Org. Biomol. Chem. 2024; 22: 6617
• 12 Garamvölgyi R, Dobos J, Sipos A, Boros S, Illyés E, Baska F, Kékesi L, Szabadkai I, Szantai-Kis C, Kéri G, Őrfi L. Eur. J. Med. Chem. 2016; 108: 623
• 13 Hamaguchi W, Koganemaru Y, Sekiyoka R, Kaneko O, Kato K. PCT Int. Appl 2012108490, 2012
• 14 Liscio P, Carotti A, Asciutti S, Karlberg T, Bellocchi D, Macchiarulo LL. A, Aaronson SA, Schüler H, Pellicciari R, Camaioni E. J. Med. Chem. 2014; 57: 2807
• 15 Blair VL, Carrella LM, Clegg W, Conway B, Harrington RW, Hogg LM, Klett J, Mulvey RE, Rentschler E, Russo L. Angew. Chem. Int. Ed. 2008; 47: 6208
• 16a Bergman RG. Nature 2007; 446: 391
• 16b Hong B, Luo T, Lei X. ACS Cent. Sci. 2020; 6: 622
• 16c Moir M, Danon JJ, Reekie TA, Kassiou M. Expert Opin. Drug Discov. 2019; 14: 1137
• 16d Guillemard L, Kaplaneris N, Ackermann L, Johansson MJ. Nat. Rev. Chem. 2021; 5: 522
• 16e Castellino NJ, Montgomery AP, Danon JJ, Kassiou M. Chem. Rev. 2023; 123: 8127
• 17 Garamvolgyi R, Dobos J, Sipos A, Boros S, Illyes E, Baska F, Kekesi L, Szabadkai I, Szantai-Kis C, Keri G, Orfi L. Eur. J. Med. Chem. 2016; 108: 623
• 18a Li Y, Zou L, Bai R, Lan Y. Org. Chem. Front. 2018; 5: 615
• 18b Omer HM, Liu P. J. Am. Chem. Soc. 2017; 139: 9909