FeCl₃-Promoted Facile Synthesis of Multiply Arylated Nicotinonitriles

Abstract

Many biologically active nicotinonitriles have been reported to date. Consequently, the development of synthetic methods for multiply arylated/alkylated nicotinonitriles remains a sought-after field of research. In the present work, a new synthetic strategy for multi-substituted nicotinonitriles is described. A FeCl₃-promoted condensation–cyclization reaction of an enamino nitrile and α,β-unsaturated ketones proceeded efficiently with a wide range of substrates. It is noteworthy that this method facilitates access to fully and differently substituted nicotinonitriles, including tetra-arylated nicotinonitriles, in only three steps. Using the functionality of the cyano group, the copper-catalyzed annulation reaction of the nicotinonitrile was achieved to yield benzo­[c][2,7]naphthyridin-5(6H)-one.

Key words

polysubstituted nicotinonitrile - iron(III) chloride - enamino nitrile - α,β-unsaturated ketone

Publication History

Received: 09 December 2021

Accepted after revision: 05 January 2022

Accepted Manuscript online:
05 January 2022

Article published online:
09 February 2022

• References

• 1 For a review, see: Gouda MA, Attia E, Helal MH, Salem MA. J. Heterocycl. Chem. 2018; 55: 2224
• 2a Saito K, Shinozuka T, Nakao A, Kiho T, Kunikata T, Shiiki T, Nagai Y, Naito S. Bioorg. Med. Chem. Lett. 2019; 29: 1769
• 2b Ryu H, Seo S, Cho SH, Kim HS, Jung A, Kang DW, Son K, Cui M, Hong SH, Sharma PK, Choi S, Blumberg PM, Frank-Foltyn R, Bahrenberg G, Stockhausen H, Schiene K, Christoph T, Frormann S, Lee J. Bioorg. Med. Chem. Lett. 2014; 24: 4039
• 2c Nair AG, Wong MK. C, Shu Y, Jiang Y, Jenh CH, Kim SH, Yang DY, Zeng Q, Shao Y, Zawacki LG, Duo J, McGuinness BF, Carroll CD, Hobbs DW, Shih NY, Rosenblum SB, Kozlowski JA. Bioorg. Med. Chem. Lett. 2014; 24: 1085
• 2d Ha TH, Ryu H, Kim SE, Kim HS, Ann J, Tran PT, Hoang VH, Son K, Cui M, Choi S, Blumberg PM, Frank R, Bahrenberg G, Schiene K, Christoph T, Frormann S, Lee J. Bioorg. Med. Chem. 2013; 21: 6657
• 2e Kim MS, Ryu H, Kang DW, Cho SH, Seo S, Park YS, Kim MY, Kwak EJ, Kim YS, Bhondwe RS, Kim HS, Park S, Son K, Choi S, DeAndrea-Lazarus IA, Pearce LV, Blumberg PM, Frank R, Bahrenberg G, Stockhausen H, Kögel BY, Schiene K, Christoph T, Lee J. J. Med. Chem. 2012; 55: 8392
• 2f Santilli AA, Scotese AC, Bauer RF, Bell SC. J. Med. Chem. 1987; 30: 2270
• 3a Liu C, Wang Q. Org. Lett. 2016; 18: 5118
• 3b Hansen HM, Lysen M, Begtrup M, Kristensen JL. Tetrahedron 2005; 61: 9955
• 3c Tagata T, Nishida M. J. Org. Chem. 2003; 68: 9412
• 3d Zhang N, Thomas L, Wu B. J. Org. Chem. 2001; 66: 1500
• 4a Kim K, Hong SH. Adv. Synth. Catal. 2017; 359: 2345
• 4b Zheng S, Yu C, Shen Z. Org. Lett. 2012; 14: 3644
• 4c Anbarasan P, Neumann H, Beller M. Chem. Eur. J. 2011; 17: 4217
• 4d Wu Y, Limburg DC, Wilkinson DE, Hamilton GS. Org. Lett. 2000; 2: 795
• 4e Burland DM, Bjorklund GG, Alvarez DC. J. Am. Chem. Soc. 1980; 102: 7119
• 5a Xin X, Wang Y, Kumar S, Liu X, Lin Y, Dong D. Org. Biomol. Chem. 2010; 8: 3078
• 5b Katrizky RA, Denisenko A, Arend M. J. Org. Chem. 1999; 64: 6076
• 5c Dissanayake AA, Staples JR, Odom LA. Adv. Synth. Catal. 2013; 356: 1811
• 5d Bardasov NI, Alekseeva UA, Ershov VO. Tetrahedron Lett. 2018; 59: 1398
• 5e Bardasov NI, Mihailov LD, Alekseeva UA, Ershov VO. Nasakin E. O. Tetrahedron Lett. 2013; 54: 21
• 5f Evdokimov MN, Magedov VI, Kireev SA, Komieko A. Org. Lett. 2006; 8: 899
• 5g Guo K, Thompson JM, Chen B. J. Org. Chem. 2009; 74: 6999
• 5h Brandt W, Mologni L, Preu L, Lemcke T, Gambacorti-Passerini C, Kunick C. Eur. J. Med. Chem. 2010; 45: 2919
• 5i Girgis SA, Hosni MH, Kalmouch A. J. Chem. Res. 2005; 38
• 5j Alekseeva YA, Mikhailov LD, Bardasov NI, Ershov VO, Nasakin EO, Lyshchikov NA. Russ. J. Org. Chem. 2014; 50: 244
• 5k Amer AA. J. Heterocycl. Chem. 2018; 55: 297
• 6a Ding Y, Ma R, Xiao X, Wang Z, Ma Y. J. Org. Chem. 2021; 86: 3897
• 6b Bharkavi C, Gunasekaran P, Kurmar VS, Sakthi M, Perumal S. Tetrahedron Lett. 2014; 55: 5486
• 6c Wu X, Zhang J, Liu S, Gao Q, Wu A. Adv. Synth. Catal. 2016; 358: 218
• 6d Pagadala R, Maddila S, Moodley V, Zyl van EW, Jonnalagadda BS. Tetrahedron Lett. 2014; 55: 4006
• 6e Chen J, Ding Y, Gao Y, Zhou D, Hider R, Ma Y. ChemistrySelect 2019; 4: 2404
• 6f Gao Y, Zhou D, Ma Y. ChemistrySelect 2018; 3: 9374
• 6g Jiang B, Wang X, Shi F, Tu S, Li G. Org. Biomol. Chem. 2011; 9: 4025
• 7a Chikayuki Y, Miyashige T, Yonekawa S, Kirita A, Matsuo N, Teramoto H, Sasaki S, Higashiyama K, Yamauchi T. Synthesis 2020; 52: 1113
• 7b Yamaguchi Y, Katsuyama I, Funabiki K, Matsui M, Shibata K. J. Heterocycl. Chem. 1998; 35: 805
• 7c Schmidt H, Zacharias G, Junek H. Synthesis 1980; 471
• 7d Sagitullina PG, Garkushenko KA, Dushek AM, Poendaev VN, Sagitullin SR. Chem. Heterocycl. Compd. 2011; 46: 1250
• 7e Sagitullina PG, Garkushenko KA, Silina OE, Sagitullin SR. Chem. Heterocycl. Compd. 2009; 45: 948
• 8a Stetinova J, Kada R, Lesko J, Zalibera L, Ilavsky D, Bartovic A. Collect. Czech. Chem. Commun. 1996; 61: 921
• 8b Li N, Wang P, Lai S, Liu W, Lee C, Lee S, Liu Z. Adv. Mater. 2010; 22: 527
• 8c You J, Lo M, Liu W, Ng T, Lai S, Wang P, Lee C. J. Mater. Chem. 2012; 22: 5107
• 8d You J, Lai S, Liu W, Ng T, Wang P, Lee C. J. Mater. Chem. 2012; 22: 8922
• 8e Al-Matar MH, Khalil DK, Elnagdi HM. Curr. Org. Synth. 2014; 11: 922
• 8f Al-Matar MH, Khalil DK, Al-Kanderi FM, Elnagdi HM. Molecules 2012; 17: 897
• 8g Behbehani H, Ibrahim MH. Tetrahedron 2013; 69: 10535
• 8h Abdelrazek MF, Michael AF. J. Heterocycl. Chem. 2006; 43: 7
• 9a Hirai S, Horikawa Y, Asahara H, Nishiwaki N. Chem. Commun. 2017; 53: 2390
• 9b Arita M, Yokoyama S, Asahara H, Nishiwaki N. Synthesis 2019; 51: 2007
• 9c Arita M, Yokoyama S, Asahara H, Nishiwaki N. Eur. J. Org. Chem. 2020; 466
• 10 Chen Y, Wu Y, Jhan Y, Hsieh J. Org. Chem. Front. 2014; 1: 253