Synlett 2014; 25(12): 1692-1696
DOI: 10.1055/s-0033-1339105
letter
© Georg Thieme Verlag Stuttgart · New York

α,β-Epoxy Esters in Multiple C–O/C–N Bond-Breaking/Formation with 2-Aminopyridines; Synthesis of Biologically Relevant (Z)-2-Methylene­imidazo[1,2-a]pyridin-3-ones

Sankar K. Guchhait*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Sector 67, Mohali, Punjab 160062, India   Fax: +91(172)2214692   Email: skguchhait@niper.ac.in
,
Garima Priyadarshani
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Sector 67, Mohali, Punjab 160062, India   Fax: +91(172)2214692   Email: skguchhait@niper.ac.in
,
Neha Hura
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Sector 67, Mohali, Punjab 160062, India   Fax: +91(172)2214692   Email: skguchhait@niper.ac.in
› Author Affiliations
Further Information

Publication History

Received: 04 March 2014

Accepted after revision: 09 April 2014

Publication Date:
23 May 2014 (eFirst)

Abstract

A new reaction of aryl 2,3-epoxy esters with 2-aminopyridines has been developed that involves multiple C–O/C–N bond-breaking/formation reactions in one chemical step. Compared with known reactions of α,β-epoxy esters, which take place through oxiranyl C–O or C–C bond cleavage, the present reaction exploits the tendency of the oxirane ring to act as a bi-electrophile. Thus, the reaction follows a unique cascade pathway of epoxide C–O bond cleavage, formation of an α-enamine ester, and intramolecular transamidation with chemo-, regio- and diastereoselectivity. The reaction allows access to biologically relevant (Z)-2-methyleneimidazo[1,2-a]pyridin-3-ones. Water and ethanol are the only by-products. The reaction is flexible, and aryl 2,3-epoxy esters as well as 2-aminopyridines possessing either electron-donating or -withdrawing functionalities, can be used. In contrast to various Brønsted and Lewis acid catalysts, polyphosphoric acid plays a multifunctional role in this intermolecular cascade reaction.

Supporting Information,

 
  • References and Notes

    • 1a Tietze LF. Chem. Rev. 1996; 96: 115
    • 1b Nicolaou KC, Edmonds DJ, Bulger PG. Angew. Chem. Int. Ed. 2006; 45: 7134
    • 2a Corey EJ, Russey WE, Montellano PR. O. D. J. Am. Chem. Soc. 1966; 88: 4750
    • 2b Vilotijevic I, Jamison TF. Angew. Chem. Int. Ed. 2009; 48: 5250
  • 3 For important building blocks with multiple functionalities in proximity, such as Baylis–Hillman adducts, see: Deevi B, Gorre V. Chem. Soc. Rev. 2012; 41: 68
  • 4 Crotti P, Ferretti M, Macchia F, Stoppioni A. J. Org. Chem. 1986; 51: 2159
    • 5a Mordant C, Andrade CC, Touati R, Vidal VR, Hassine BB, Genet JP. Synthesis 2003; 2405
    • 5b Vega JA, Cueto S, Ramos A, Vaquero JJ, Navio JG, Builla JA, Ezquerra J. Tetrahedron Lett. 1996; 37: 6413
    • 6a Hodgson DM, Pierard FY. T. M, Stupple PA. Chem. Soc. Rev. 2001; 30: 50
    • 6b Mehta G, Muthusamy S. Tetrahedron 2002; 58: 9477
  • 7 Zhang J, Chen Z, Wu H, Zhang J. Chem. Commun. 2012; 48: 1817
  • 8 Liu R, Zhanga M, Zhang J. Chem. Commun. 2011; 47: 12870
  • 9 Wang GW, Yang HT, Wu P, Miao CB, Xu Y. J. Org. Chem. 2006; 71: 4346
  • 10 Xu HW, Fan W, Li MY, Jiang B, Wang SL, Tu SJ. Org. Biomol. Chem. 2013; 11: 3603
  • 11 Suzuki M, Watanabe A, Noyori R. J. Am. Chem. Soc. 1980; 102: 2095
  • 12 Concellón JM, Bardales E. Org. Lett. 2002; 4: 189

    • For scaffold-hopping strategies that have led to several marketed drugs, see:
    • 13a Schneider G, Neidhart W, Giller T, Schmid G. Angew. Chem. Int. Ed. 1999; 38: 2894 ; Angew. Chem. 1999, 111, 3068
    • 13b Sun H, Tawa G, Wallqvist A. Drug Discov. Today 2012; 17: 310
    • 14a Haudecoeur R, Boumendjel A. Curr. Med. Chem. 2012; 19: 2861
    • 14b Haudecoeur R, Belkacem AA, Yi W, Fortune A, Brillet R, Belle C, Nicolle E, Pallier C, Pawlotsky JM, Boumendjel A. J. Med. Chem. 2011; 54: 5395
  • 15 Hadjeri M, Barbier M, Ronot X, Mariotte AM, Boumendjel A, Boutonnat J. J. Med. Chem. 2003; 46: 2125
  • 16 Isobe M, Kuse M, Yasuda Y, Takahashi H. Bioorg. Med. Chem. Lett. 1998; 8: 2919
    • 17a Pujala B, Rana S, Chakraborti AK. J. Org. Chem. 2011; 76: 8768
    • 17b Bonollo S, Fringuelli F, Pizzo F, Vaccaro L. Synlett 2007; 2683
    • 17c Pachon LD, Gamez P, van Brussel JJ. M, Reedijk J. Tetrahedron Lett. 2003; 44: 6025
  • 18 This selectivity problem also arises because of constraints commonly associated with epoxide ring opening by amines, such as the formation of regioisomeric and undesired products, incompatibility with less nucleophilic amines, and the required use of an excess of amine.
  • 19 CCDC 959103 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
  • 20 So YH, Heeschen JP. J. Org. Chem. 1997; 62: 3552
  • 21 Synthesis of (Z)-2-(4′-Chlorobenzylidene)-2H-imidazo-[1,2-a]pyridin-3-one; Typical Procedure (Table 2): To a mixture of 2-aminopyridine (47 mg, 0.5 mmol) and ethyl 3-(4′-chlorophenyl)oxirane-2-carboxylate (113 mg, 0.5 mmol) in a round-bottom flask, was added PPA (1.5 g), and the mixture was magnetically stirred at 110 °C under open air. Upon completion of the reaction as indicated by TLC (1–1.5 h), the resultant mixture was poured into crushed ice (2 g) and neutralized with 5% aq NaOH. The mixture was extracted with CH2Cl2 (2 × 25 mL) and the organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatographic purification of the crude mass on silica gel (EtOAc–hexane, 1:6) gave (Z)-2-(4-chlorobenzylidene)-2H-imidazo[1,2-a]pyridin-3-one (3a; 106 mg, 83%) as a red solid. Mp 182–184 °C; Rf = 0.33 (EtOAc–hexane, 10%). Compounds 3ao were prepared by following a similar procedure. Data for 3a: See Figure 2 for numbering. 1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 8.3 Hz, 2 H, Hj), 7.62 (d, J = 6.8 Hz, 1 H, Ha), 7.40 (d, J = 8.3 Hz, 2 H, Hk), 7.23 (s, 1 H, Hh), 7.17 (dd, J = 6.6, 9.2 Hz, 1 H, Hc), 6.93 (d, J = 9.4 Hz, 1 H, Hd), 6.25 (dd, J = 6.6, 6.6 Hz, 1 H, Hb); 13C NMR (100 MHz, CDCl3): δ = 167.4 (Cg), 156.7 (Ce), 138.6 (Cf), 137.9 (Cc), 136.4 (Ci), 133.7 (Cj), 133.2 (Cl), 129.1 (Ck), 127.2 (Ca), 126.0 (Cd), 119.3 (Cb), 109.3 (Ch); IR (neat): 2879, 1707, 1650, 1601 cm–1; HRMS (ESI): m/z [M(35Cl) + H]+ calcd. for C14H9ClN2O: 257.0481; found: 257.0477.