One-Pot, Three-Component Synthesis of Novel 4-Phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]pyrimidine Libraries via Michael Addition, Cyclization, and C–C Coupling Reactions: A New MCR Strategy

Abstract

Privileged medicinal scaffolds based on the structures of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines have been synthesized via a single-step, three-component reaction­ of 3-(dimethylamino)-1-phenylprop-2-en-1-one (enaminone), 3-bromobenzimidamide hydrochloride, and various alkynes/alkenes/arylboronic acids. The mechanism of this multi-component reaction (MCR) involves a Michael addition, cyclization, isomerization, and dehydration, followed by Sonogashira, Heck or Suzuki coupling. This new MCR strategy afforded a new compound library based on pyrimidine framework.

Key words

multi-component reactions (MCRs) - Michael addition - Pd catalyst - C–C coupling reactions

• References


The term ‘privileged scaffolds or structures’ was originally introduced by Merck researchers in their work on benzodiazepines:
• 1a Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, Lundell GF, Veber DF, Anderson PS. J. Med. Chem. 1988; 31: 2235
• 1b Patchett AA, Nargund RP. Ann. Rep. Med. Chem. 2000; 35: 289
• 2a Press JB, McNally JJ, Keiser JA, Offord SJ, Katz LB, Giardino E, Falotico R, Tobia AJ. Eur. J. Med. Chem. 1989; 24: 627
• 2b Alam O, Khan SA, Siddiqui N, Ahsan W, Verma SP, Gilani SJ. Eur. J. Med. Chem. 2010; 45: 5113
• 2c Amin KM, Awadalla FM, Eissa AA. M, Abou-Seri SM, Hassan GS. Bioorg. Med. Chem. 2011; 19: 6087
• 3a Bruno O, Schenone S, Ranise A, Barocelli E, Chiavarini M, Ballabeni V, Bertoni S. Arzneim.-Forsch./Drug Res. 2000; 50: 140
• 3b Bruno O, Brullo C, Schenone S, Bondavalli F, Ranise A, Tognolini M, Ballabeni V, Barocelli E. Bioorg. Med. Chem. 2004; 12: 553
• 4 Wyrzykiewicz E, Bartkowiak G, Kedzia B. Farmaco 1993; 48: 979
• 5 Sharma P, Rane N, Gurram VK. Bioorg. Med. Chem. Lett. 2004; 14: 4185
• 6 Elkholy YM, Morsy MA. Molecules 2006; 11: 890
• 7 Holla BS, Mahalinga M, Karthikeyan MS, Akberali PM, Shetty NS. Bioorg. Med. Chem. 2006; 14: 2040
• 8 Ingarsal N, Saravanan G, Amutha P, Nagarajan S. Eur. J. Med. Chem. 2007; 42: 517
• 9 Zhao X.-L, Zhao Y.-F, Guo S.-C, Song H.-S, Wang D, Gong P. Molecules 2007; 12: 1136
• 10 Cordeu L, Cubedo E, Bandrés E, Rebollo A, Sáenz X, Chozas H, Domínguez MV, Echeverría M, Mendivil B, Sanmartin C, Palop JA, Font M, García-Foncillas J. Bioorg. Med. Chem. 2007; 15: 1659
• 11 Sondhi SM, Singh N, Johar M, Kumar A. Bioorg. Med. Chem. 2005; 13: 6158
• 12 Amin KM, Hanna MM, Abo-Youssef HE, George RF. Eur. J. Med. Chem. 2009; 44: 4572
• 13a Baumgarth M, Beier N, Gericke R. J. Med. Chem. 1997; 40: 2017
• 13b Ramesh LS, Varsha IS, Ganesh DJ, Jyoti BW. Med. Chem. Res. 2012; 21: 1825
• 14 Nega S, Aionso J, Diazj A, Junquere F. J. Heterocycl. Chem. 1990; 27: 269
• 15 Shishoo CJ, Jain KS. J. Heterocycl. Chem. 1992; 29: 883
• 16 Peters JU, Hunziker D, Fischer H, Kansy M, Weber S, Kritter S, Muller A, Ricklin F, Boehringer M, Poli SM, Csato M, Loeffler BM. Bioorg. Med. Chem. Lett. 2004; 14: 3575
• 17 Peters JU, Weber S, Kritter S, Weiss P, Wallier A, Zimmerli D, Boehringer M, Steger M, Loeffler BM. Bioorg. Med. Chem. Lett. 2004; 14: 3579

For reviews, see:
• 18a Undheim K, Benneche T In Comprehensive Heterocyclic Chemistry II . Vol. 6. Katritzky AR, Rees CW, Scriven EF. V, McKillop A. Pergamon; Oxford: 1996: 93
• 18b Lagoja IM. Chem. Biodiversity 2005; 2: 1
• 18c Michael JP. Nat. Prod. Rep. 2005; 22: 627
• 18d Joule JA, Mills KI. Heterocyclic Chemistry . 4th ed. Blackwell Science Ltd; Cambridge: 2000: 194
• 18e Hill MD, Movassaghi M. Chem.–Eur. J. 2008; 14: 6836

For reviews, see:
• 19a Turck A, Ple N, Mongin F, Queguiner G. Tetrahedron 2001; 57: 4489
• 19b Chinchilla R, Najera C, Yus M. Chem. Rev. 2004; 104: 2667
• 19c Schroder S, Stock C, Bach T. Tetrahedron 2005; 61: 2245
• 19d Martin R, Buchwald SL. Acc. Chem. Res. 2008; 41: 1461
• 19e Surry DS, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 6338

Passerini three-component and Ugi four-component condensations are the most popular among many other reactions for their wide scope and synthetic utility. For reviews, see:
• 20a Bienayme H, Hulme C, Oddon G, Schmitt P. Chem. Eur. J. 2000; 6: 3321
• 20b Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168

For recent reviews, see:
• 21a Toure BB, Hall DG. Chem. Rev. 2009; 109: 4439
• 21b Balme G, Bossharth E, Monteiro N. Eur. J. Org. Chem. 2003; 4101
• 21c Hulme C, Gore V. Curr. Med. Chem. 2003; 1051
• 21d Zhu J. Eur. J. Org. Chem. 2003; 1133
• 22 Weber L, Illgen K, Almstetter M. Synlett 1999; 366
• 23a Lin Y-i, Lang SA. Jr. J. Heterocycl. Chem. 1977; 14: 345
• 23b Bredereck H, Effenberger F, Botsch H. Chem. Ber. 1964; 97: 3397
• 23c Junek H, Schmidt A. Monatsh. Chem. 1968; 99: 635
• 23d Junek H, Stolz G. Monatsh. Chem. 1970; 201: 1234
• 24 Medwid JB, Rolf P, Baker JS, Brockman JA, Du MT, Hallett WA, Hanifin WJ, Hardy RA, Ernestine TM. Jr, Torley LW, Wren S. J. Med. Chem. 1990; 33: 1230