Download PDF
Synlett 2016; 27(11): 1669-1673
DOI: 10.1055/s-0035-1561429
letter
© Georg Thieme Verlag Stuttgart · New York

An Unexpected Diastereoselective Synthesis of Novel Substituted Pyridines via One-Pot, Four-Component Reaction

Mahdieh Zangouei
a   Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 917751436, Iran   Email: abesmaeili@um.ac.ir
,
Abbas Ali Esmaeili*
a   Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 917751436, Iran   Email: abesmaeili@um.ac.ir
,
Joel T. Mague
b   Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
› Author Affiliations
Further Information

Publication History

Received: 19 January 2016

Accepted after revision: 18 March 2016

Publication Date:
13 April 2016 (online)

    Permissions and Reprints All articles of this category


Abstract

An efficient diastereoselective approach for the preparation of novel substituted pyridines has been developed through a one-pot, four-component reaction of easily available aromatic aldehydes, malononitrile, and 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidine-4-one, in appropriate alcohols at reflux in the presence of diisopropylethylamine (DIPEA) as organic base catalyst. Unexpected products were obtained in high to excellent yields using a simple workup procedure. The products synthesized showed high diastereoselectivity, and the stereochemistry was confirmed by X-ray diffraction analysis.

Key words

multicomponent reaction - diastereoselective synthesis - 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidine-4-one - malononitrile - 2-oxo-4-phenyl-1,2,3,4-tetrahydropyridine

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561429.
  • Supporting Information
 

  • References and Notes

  • 3 Gahlot US, Rao SS, Dulawat SS, Ameta KL, Verma BL. Afinidad 2003; 60: 558
    Search in Google Scholar
  • 5 Nofal AM, Fahmy HH, Zarea ES, El-Eraky W. Acta Pol. Pharm. 2011; 68: 507
    Search in Google Scholar
  • 6 Badshaw TD, Wrigley S, Shi DF, Schultz RJ, Paull KD, Stevens MF. G. Br. J. Cancer 1998; 77: 745
    CrossrefPubMedSearch in Google Scholar
  • 9 Storck P, Aubertinb AM, Grierson DS. Tetrahedron Lett. 2005; 46: 2919
    CrossrefSearch in Google Scholar
    • 10a Breinholt J, Ludvigesen S, Rassing BR, Rosendahl CN. J. Nat. Prod. 1997; 60: 33
      CrossrefPubMedSearch in Google Scholar
    • 10b Singh SB, Liu W, Li X, Chen T, Shafiee A, Card D, Abruzzo G, Flattery A, Gill C, Thompson JR, Rosenbach M, Dreikorn S, Hornak V, Meinz M, Kurtz M, Kelly R, Onishi JC. ACS Med. Chem. Lett. 2012; 3: 814
      CrossrefSearch in Google Scholar
  • 11 Lv Z, Sheng C, Wang T, Zhang Y, Liu J, Feng J, Sun H, Zhong H, Niu C, Li K. J. Med. Chem. 2010; 53: 660
    CrossrefSearch in Google Scholar
  • 12 Wallace EM, Lyssikatos J, Blake JF, Seo J, Yang HW, Yeh TC, Perrier M, Jarski H, Marsh V, Poch G, Livingston MG, Otten J, Hingorani G, Woessner R, Lee P, Winkler J, Koch K. J. Med. Chem. 2006; 49: 441
    CrossrefPubMedSearch in Google Scholar
  • 13 Hu E, Tasker A, White RD, Kunz RK, Human J, Chen N, Burli R, Hungate R, Novak P, Itano A, Zhang X, Yu V, Nguyen Y, Tudor Y, Plant M, Flynn S, Xu Y, Meagher KL, Whittington DA, Ng GY. J. Med. Chem. 2008; 51: 3065
    CrossrefSearch in Google Scholar
  • 14 Dragovich PS, Prins TJ, Zhou R, Johnson TO, Hua Y, Luu HT, Sakata SK, Brown EL, Maldonado FC, Tuntland T, Lee CA, Fuhrman SA, Zalman LS, Patick AK, Matthews DA, Wu EY, Guo M, Borer BC, Nayyar NK, Moran T, Chen L, Rejto PA, Rose PW, Guzman MC, Dovalsantos EZ, Lee S, McGee K, Mohajeri M, Liese A, Tao J, Kosa MB, Liu B, Batugo MR, Gleeson JP. R, Wu ZP, Liu J, Meador JW, Ferre RA. J. Med. Chem. 2003; 46: 4572
    CrossrefSearch in Google Scholar
  • 15 Li R, Xue L, Zhu T, Jiang Q, Cui X, Yan Z, McGee D, Wang J, Gantla VR, Pickens JC, McGrath D, Chucholowski A, Morris SW, Webb TR. J. Med. Chem. 2006; 49: 1006
    CrossrefSearch in Google Scholar
  • 16 Lenaerts AJ, Bitting C, Woolhiser L, Gruppo V, Marietta KS, Johnson CM, Orme IM. Antimicrob. Agents Chemother. 2008; 52: 1513
    CrossrefSearch in Google Scholar
  • 17 Cheney IW, Yan S, Appleby T, Walker H, Vo T, Yao N, Hamatake Hong RZ, Wu JZ. Bioorg. Med. Chem. Lett. 2007; 17: 1679
    CrossrefSearch in Google Scholar
  • 19 Gadekar SM. DE 2555411, 1976 ; Chem. Abstr. 1976, 85, 198163b
    • 20a Ehteshami M, Scarth BJ, Tchesnokov EP, Dash C, Le Grice SF. J, Hallenberger S, Jochmans D, Götte M. J. Biol. Chem. 2008; 283: 29904
      CrossrefSearch in Google Scholar
    • 20b Ehteshami M, Nijhuis M, Bernatchez JA, Ablenas CJ, McCormick S, Jong DD, Jochmans D, Götte M. J. Biol. Chem. 2013; 28: 17336
      Search in Google Scholar
    • 20c Jochmans DE. D, Wigerinck PT. B. P. WO 2007088214, 2007 ; Chem. Abstr. 2007, 147, 227136
    • 20d Sarkar R, Mukhopadhyay C. Tetrahedron Lett. 2014; 55: 2618
      CrossrefSearch in Google Scholar
  • 21 Ferraz AC, Angelucci ME. M, Da Costa ML, Batista IR, De Olivera BH, Da Cunha C. Pharmacol. Biochem. Behav. 1999; 63: 367
    CrossrefSearch in Google Scholar
  • 22 Kheder NA, Mabkhot YN, Farag AM. Synth. Commun. 2008; 38: 3170
    CrossrefSearch in Google Scholar
  • 24 Güllü M, Dinçsönmez A, Özyavaş Ö. Eur. J. Org. Chem. 2010; 2113
  • 25 General Procedure for the Synthesis of 4 A mixture of aromatic aldehyde (1, 1 mmol), malononitrile (2, 1 mmol, 660 mg), 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3, 1 mmol, 192 mg), and DIPEA (5 mol%) was heated to reflux in the requisite alcohol (6 mL) for 2 h (the progress of the reaction was monitored by TLC). After completion of reaction, the mixture was allowed to cool to room temperature, and the precipitate was filtered off and washed with cold alcohol to afford the pure alkyl 6-amino-5-cyano-2-oxo-4-phenyl-1-pyrimidin-2-yl-1,2,3,4-tetrahydropyridine-3-carboxylate 4 (yields 85–95%). Representative Analytical Data Ethyl 6-Amino-5-cyano-1-(4,6-dimethylpyrimidin-2-yl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyridine-3-carboxylate (4a) White powder, 355 mg (91%); mp 207 °C; Rf = 0.52 (n-hexane–EtOAc, 1:1.5). IR (KBr): ν = 3448, 3324 (NH2), 2195 (CN), 1743, 1721 (2 C=O), 1653 (C=N) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.19 (t, 3 H, J = 7.0 Hz,OCH2CH 3), 2.54 (s, 6 H, 2 CH3), 3.85 (d, 1 H, J = 7.7 Hz, CHC=O), 4.15–4.20 (m, 2 H, OCH 2CH3), 4.34 (d, 1 H, J = 7.7 Hz, CHAr), 4.91 (s, 2 H, NH2), 7.10 (s, 1 H, CH=CCH3), 7.26–7.38 (m, 5 H, HAr). 13C NMR (75 MHz, CDCl3): δ = 13.98 (OCH2 CH3), 23.84 (2 CH3), 40.28 (CHPh), 56.64 (CHC=O), 62.02 (CCN), 63.41 (CH2O), 119.16 (C≡N), 120.42 (CHAr), 127.65 (2 CH ortho ), 128.04 (CH para ), 129.02 (2 CH meta ), 138.38 (CAr), 152.20 (CNH2), 155.16 (NC=N), 165.43 (C=O), 167.05 (C=O), 170.07 (2 CCH3). MS: m/z (%) = 391 (4) [M+], 378 (69), 358 (64), 341 (18), 313 (100), 258 (68), 271 (63), 233 (62). 211 (48), 198 (63), 164 (65), 122 (66), 106 (71), 81 (61), 67 (70), 42 (64), 29 (65). Anal. Calcd for C21H21N5O3: C, 64.44; H, 5.41; N, 17.89. Found: C, 63.99; H, 5.39; N, 17.83. Ethyl 6-Amino-5-cyano-1-(4,6-dimethylpyrimidine-2-yl)-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylate(4b) White powder, 409 mg (94%); mp 211–212 °C; Rf = 0.40 (n-hexane–EtOAc, 1:1.5). IR (KBr): ν = 3452, 3350 (NH2), 2185 (CN), 1747, 1717 (2 C=O), 1632 (C=N) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.24 (t, 3 H, J = 4.5 Hz, OCH2CH 3), 2.56 (s, 6 H, 2 CH3), 3.82 (d, 1 H, J = 7.79 Hz, CHC=O), 4.21–4.25 (m, 2 H, OCH 2CH3), 4.46 (d, 1 H, J = 7.79 Hz, CHAr), 5.11 (s, 2 H, NH2), 7.12 (s, 1 H, CH=CCH3), 7.26–8.31 (m, 4 H, HAr). 13C NMR (75 MHz, CDCl3): δ = 14.02 (OCH2 CH3), 23.81 (2 CH3), 40.15 (CHPh), 56.51 (CHC=O), 61.25 (CCN), 62.50 (CH2O), 118.81 (C≡N), 120.60 (CHAr), 122.74 (CH ortho ), 123.244 (CH para ), 130.16 (CH meta ), 134.12 (CH ortho ), 140.83 (NC=N), 148.69 (CAr), 153.05 (CNH2), 154.99 (CNO2), 164.60 (C=O), 166.48 (C=O), 170.27 (2 CCH3). MS: m/z (%) = 436 (14) [M+], 422 (72), 393 (71), 346 (100), 318 (71), 304 (69), 241 (42), 212 (32), 199 (72), 150 (71), 123 (73), 107 (74), 82 (50), 67 (72), 29 (74). Anal. Calcd for C21H20N6O5: C, 57.79; H, 4.62; N, 17.26. Found: C, 57.62; H, 4.27; N, 16.95.