Dipolar Cycloaddition-Based Multicomponent Reactions in Ionic Liquids: A Green, Fully Stereoselective Synthesis of Novel Polycyclic Cage Systems with the Generation of Two New Azaheterocyclic Rings

Abstract

Two libraries of novel, bifunctional polycyclic cage structures have been synthesized for the first time in an ionic liquid, 1-butyl-3-methylimidazolium bromide ([bmim]Br), employing a sustainable microwave-assisted, one-pot, three-component [3+2] cycloaddition–annulation protocol in good to excellent yields. The ring systems thus generated contain as structural elements bridged, fused and spiro rings and were obtained with complete regio- and stereoselectivity through the creation of two C–C and two C–N bonds, which led to the generation of two azaheterocyclic rings and five adjacent stereogenic carbons, three of which are quaternary.

Key words

azomethine ylides - [3+2] cycloadditions - ionic liquids - stereoselective synthesis - spiro compounds

• References

• 1 Geldenhuys WJ, Malan SF, Bloomquist JR, Marchand AP, Van der Schyf CJ. Med. Res. Rev. 2005; 25: 21
• 2 Boros E, Rybak-Akimova E, Holland JP, Rietz T, Rotile N, Blasi F, Day H, Latifi R, Caravan PJ. Mol. Pharmaceutics 2014; 11: 617

For a review of the concept of multiple bond-forming transformations, see:
• 3a Coquerel Y, Boddaert T, Presset M, Mailhol D, Rodriguez J. Ideas in Chemistry and Molecular Sciences . In Advances in Synthetic Chemistry . Vol. 1. Pignataro B. Chap. 9 Wiley-VCH; Weinheim: 2010: 187-202

For a special issue on the use of multiple bond-forming reactions in the synthesis of heterocycles, see:
• 3b Curr. Org. Chem. 2013; 17: 1919 ; Editor: Menéndez, J. C. (issue 18)
• 4 Dömling A. Curr. Opin. Chem. Biol. 2002; 6: 306
• 5a Ganem B. Acc. Chem. Res. 2009; 42: 463
• 5b Dömling A. Chem. Rev. 2006; 106: 17
• 5c Ramón DJ, Yus M. Angew. Chem. Int. Ed. 2005; 44: 1602
• 5d Orru RV. A, de Greef M. Synthesis 2003; 1471
• 5e Zhu JP. Eur. J. Org. Chem. 2003; 1133
• 5f Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
• 6 Zanze IA. Curr. Opin. Chem. Biol. 2008; 12: 324
• 7a Elders N, van der Born D, Hendrickx LJ. D, Timmer BJ. J, Krause A, Janssen E, de Kanter FJ. J, Ruijter E, Orru RV. A. Angew. Chem. Int. Ed. 2009; 48: 5856
• 7b Groenendaal B, Ruijter E, Orru RV. A. Chem. Commun. 2008; 5474
• 7c Elders N, Ruijter E, Kanter FJ. J, Lutz M, Spek AL, Orru RV. A. Chem. Eur. J. 2009; 15: 6096
• 8a Schreiber SL. Science 2000; 287: 1964
• 8b Weber L. Curr. Med. Chem. 2002; 9: 2085
• 8c Bienayme H, Hulme C, Oddon G, Schmitt P. Chem. Eur. J. 2000; 6: 3321
• 8d Abboub F, Amari M, Kolli B. J. Soc. Alger. Chim. 2001; 11: 223
• 9a Forsyth SA, Fröhlich U, Goodrich P, Gunaratne HQ. N, Hardacre C, McKeown A, Seddon KR. New J. Chem. 2010; 34: 723
• 9b Gao J, Song Q.-W, He L.-N, Liu C, Yang Z.-Z, Han X, Li X.-D, Song Q.-C. Tetrahedron 2012; 68: 3835
• 9c Narayana Kumar GG. K. S, Aridoss G, Laali KK. Tetrahedron Lett. 2012; 53: 3066
• 10a Welton T. Chem. Rev. 1999; 99: 2071
• 10b Petkovic M, Seddon KR, Rebelo LP. N, Pereira CS. Chem. Soc. Rev. 2011; 40: 1383
• 10c Yao Q. Org. Lett. 2002; 4: 2197
• 10d Kumar A, Pawar SS. J. Org. Chem. 2004; 69: 1419
• 10e Fukumoto K, Yoshizawa M, Ohno H. J. Am. Chem. Soc. 2005; 127: 2398
• 11 Isambert N, Duque MM. S, Plaquevent J.-C, Genisson Y, Rodriguez J, Constantieux T. Chem. Soc. Rev. 2011; 40: 1347
• 12a Microwaves in Organic Synthesis . De la Hoz A, Loupy A. Wiley-VCH; Weinheim: 2012
• 12b Kappe CO, Dallinger D. Mol. Diversity 2009; 13: 71
• 12c DiMauro EF, Kennedy JM. J. Org. Chem. 2007; 72: 1013
• 12d Kremsner JM, Stadler A, Kappe CO. Top. Curr. Chem. 2006; 266: 233
• 12e Kappe CO. Angew. Chem. Int. Ed. 2004; 43: 6250
• 12f Tye H, Whittaker M. Org. Biomol. Chem. 2004; 2: 813
• 12g Hoel AM. L, Nielsen J. Tetrahedron Lett. 1999; 40: 3941
• 13a Polshettiwar V, Varma RS. Acc. Chem. Res. 2008; 41: 629
• 13b Martins MA. P, Frizzo CP, Moreira DN, Zanatta N, Bonacorso HG. Chem. Rev. 2008; 108: 2015
• 13c Miao W, Chan TH. Acc. Chem. Res. 2006; 39: 897
• 13d Green Techniques for Organic Synthesis and Medicinal Chemistry. Zhang W, Cue BW. John Wiley & Sons; Chichester: 2012
• 14 Kumar RS, Osman H, Perumal S, Menéndez JC, Ali MA, Ismail R, Choon TS. Tetrahedron 2011; 67: 3132
• 15a Kumar RS, Almansour AI, Arumugam N, Basiri A, Kia Y, Kumar RR. Aust. J. Chem. 2015; 68: 863
• 15b Kia Y, Osman H, Kumar RS, Basiri A, Murugaiyah V. Bioorg. Med. Chem. 2014; 22: 1318
• 15c Kumar RS, Almansour AI, Arumugam N, Osman H, Ali MA, Basiri A, Kia Y. Med. Chem. 2014; 10: 228
• 15d Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Hooda A, Parsons RB. Bioorg. Med. Chem. 2014; 22: 906
• 15e Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Perumal S, Wahab HA, Bing CS. Bioorg. Med. Chem. 2013; 21: 1696
• 15f Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Ali MA. Bioorg. Med. Chem. 2013; 21: 3022
• 15g Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Perumal S, Razak IA. Bioorg. Med. Chem. Lett. 2013; 23: 2979
• 15h Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Awang KB, Ali MA. Eur. J. Med. Chem. 2013; 67: 221
• 15i Arumugam N, Almansour AI, Kumar RS, Perumal S, Ghabbour HA, Fun H.-K. Tetrahedron Lett. 2013; 54: 2515
• 15j Kumar RS, Ramar A, Perumal S, Almansour AI, Arumugam N, Ali MA. Synth. Commun. 2013; 43: 2763
• 15k Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS. Bioorg. Med. Chem. Lett. 2013; 23: 1383
• 15l Ali MA, Ismail R, Choon TS, Kumar RS, Asad M, Almansour AI, Yoon YK, Wei AC, Elumalai K, Pandian S. Med. Chem. (Sharjah, United Arab Emirates) 2012; 2: 007 ; DOI: 10.4172/2161-0444.1000106

Representative examples: For antitumour activity, see:
• 16a Dimmock JR, Padmanilayam MP, Puthucode RN, Nazarali AJ, Motaganahalli NL, Zello GA, Quail JW, Oloo EO, Kraatz HB, Prisciak JS, Allen TM, Santos CL, Balzarini J, De Clercq E, Manavathu EK. J. Med. Chem. 2001; 44: 586

For nociceptin agonism, see:
• 16b Jenck F, Wichmann J, Dautzenberg FM, Moreau JL, Ouagazzal AM, Martin JR, Lundstrom K, Cesura AM, Poli SM, Roever S, Kolczewski S, Adam G, Kilpatrick G. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 4938

For nociceptin antagonism, see:
• 16c Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Azuma T, Ichikawa D, Nambu H, Iguchi T, Iwasawa Y, Ohta H. Eur. J. Pharmacol. 2000; 402: 45
• 16d Zaratin PF, Petrone G, Sbacchi M, Garnier M, Fossati C, Petrillo P, Ronzoni S, Giardina GA, Scheideler MA. J. Pharmacol. Exp. Ther. 2004; 308: 454
• 17 Lee HK, Chun JS, Pak CS. Tetrahedron Lett. 2001; 42: 3483
• 18a Caddick S. Tetrahedron 1995; 51: 10403
• 18b Lidstrom P, Tierney J, Wathey B, Westman J. Tetrahedron 2001; 57: 9225
• 18c Santagada V, Perissutti E, Caliendo G. Curr. Med. Chem. 2002; 9: 1251
• 18d Microwaves in Organic Synthesis . Loupy A. Wiley-VCH; Weinheim: 2002
• 19 De la Hoz A, Díaz-Ortiz A, Moreno A, Langa F. Eur. J. Org. Chem. 2000; 3659
• 20 Kumar RS, Osman H, Ali MA, Hemamalini M, Fun HK. Acta Crystallogr., Sect. E 2010; 66: o2926
• 21 Kumar RS, Osman H, Abdul Rahim AS, Hemamalini M, Fun HK. Acta Crystallogr., Sect. E. 2011; 67: o2879