Download PDF
Synlett 2015; 26(09): 1195-1200
DOI: 10.1055/s-0034-1380348
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Antimicrobial/Cytotoxic Assessment of Ferrocenyl Oxazinanes, Oxazinan-2-ones, and Tetrahydropyrimidin-2-ones

Anka Pejović
a   SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
b   Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia
,
Barbara Danneels
c   Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
,
Tom Desmet
c   Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
,
Ba Thi Cham
d   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
,
Tuyen Van Nguyen
d   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
,
Niko S. Radulović
e   Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Visegradska 33, 18000 Niš, Serbia
,
Rastko D. Vukićević*
b   Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia
,
Matthias D’hooghe*
a   SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
› Author Affiliations
Further Information

Publication History

Received: 12 January 2015

Accepted after revision: 16 February 2015

Publication Date:
19 March 2015 (online)

    Permissions and Reprints All articles of this category


Abstract

3-Arylamino-1-ferrocenylpropan-1-ones, prepared through aza-Michael addition of aromatic amines to 1-ferrocenylpropenone, were transformed into the corresponding 1,3-amino alcohols upon NaBH4-mediated carbonyl reduction. The latter amino alcohols were deployed as eligible substrates for the synthesis of a variety of ferrocene-containing heterocycles including 1,3-oxazinanes, 1,3-oxazinan-2-ones, and tetrahydropyrimidin-2-ones, which were subsequently evaluated for their antimicrobial and cytotoxic activities.

Key words

ferrocenes - heterocycles - oxazinanes - oxazinan-2-ones - tetrahydropyrimidin-2-ones - cyclization - amino alcohols
 

  • References and Notes


      • For recent reviews, see:
    • 1a Noel T, Van der Eycken J. Green Processing and Synthesis 2013; 2: 297
    • 1b Schaarschmidt D, Lang H. Organometallics 2013; 32: 5668
      Crossref
  • 2 For a review, see: Fouda MF. R, Abd-Elzaher MM, Abdelsamaia RA, Labib AA. Appl. Organomet. Chem. 2007; 21: 613
    Crossref
  • 3 For a recent review, see: Quirante J, Dubar F, Gonzalez A, Lopez C, Cascante M, Cortes R, Forfar I, Pradines B, Biot C. J. Organomet. Chem. 2011; 696: 1011
    Crossref
  • 4 For a review, see: Scutaru D, Tataru L, Mazilu I, Vata M, Lixandru T, Simionescu C. Appl. Organomet. Chem. 1993; 7: 225
    Crossref
  • 5 For a recent review, see: Braga SS, Silva AM. S. Organometallics 2013; 32: 5626
    Crossref
  • 6 For a recent review, see: Pereira CM. P, Venzke D, Trossini GH. G. Quim. Nova 2013; 36: 143
    Crossref
    • 7a Damljanović I, Stevanović D, Pejović A, Vukićević M, Novaković SB, Bogdanović GA, Mihajlov-Krstev T, Radulović N, Vukićević RD. J. Organomet. Chem. 2011; 696: 3703
      Crossref
    • 7b Pejović A, Denić MS, Stevanović D, Damljanović I, Vukićević M, Kostova K, Tavlinova-Kirilova M, Randjelović P, Stojanović NM, Bogdanović GA, Blagojević P, D’hooghe M, Radulović NS, Vukićević RD. Eur. J. Med. Chem. 2014; 83: 73
    • 7c Radulović NS, Zlatković DB, Mitić KV, Randjelović PJ, Stojanović NM. Polyhedron 2014; 80: 134
      Crossref
    • 7d Pejović A, Damljanović I, Stevanović D, Vukićević M, Novaković SB, Bogdanović GA, Radulović N, Vukićević RD. Polyhedron 2012; 31: 789
      Crossref
    • 7e Damljanović I, Vukićević M, Radulović N, Palić R, Ellmerer E, Ratković Z, Joksović MD, Vukićević RD. Bioorg. Med. Chem. Lett. 2009; 19: 1093
      Crossref
    • 7f Ilić D, Damljanović I, Stevanović D, Vukićević M, Blagojević P, Radulović N, Vukićević RD. Chem. Biodiversity 2012; 9: 2236
      Crossref
    • 7g Radulović NS, Mladenović MZ, Stojanović-Radić Z, Bogdanović GA, Stevanović D, Vukićević RD. Mol. Diversity 2014; 18: 497
      Crossref
    • 7h Damljanović I, Stevanović D, Pejović A, Ilić D, Živković M, Jovanović J, Vukićević M, Bogdanović GA, Radulović NS, Vukićević RD. RSC Adv. 2014; 4: 43792
      Crossref
    • 8a Dolfen J, Kenis S, Van Hecke K, De Kimpe N, D’hooghe M. Chem. Eur. J. 2014; 20: 10650
      CrossrefPubMed
    • 8b De Vreese R, Verhaeghe T, Desmet T, D’hooghe M. Chem. Commun. 2013; 3775
    • 8c Kenis S, D’hooghe M, Verniest G, Reybroeck M, Dang ThiT. A, Pham The C, Thi Pham T, Törnroos KW, Van Tuyen N, De Kimpe N. Chem. Eur. J. 2013; 19: 5966
      CrossrefPubMed
    • 8d Mollet K, Goossens H, Piens N, Catak S, Waroquier M, Törnroos KW, Van Speybroeck V, D’hooghe M, De Kimpe N. Chem. Eur. J. 2013; 19: 3383
      CrossrefPubMed
    • 8e Mollet K, D’hooghe M, De Kimpe N. Mini-Rev. Org. Chem. 2013; 10: 1
    • 8f Vervisch K, D’hooghe M, Törnroos KW, De Kimpe N. Org. Biomol. Chem. 2012; 10: 3308
      Crossref
    • 8g Vervisch K, D’hooghe M, Rutjes FP. J. T, De Kimpe N. Org. Lett. 2012; 14: 106
      Crossref
    • 8h Mollet K, Catak S, Waroquier M, Van Speybroeck V, D’hooghe M, De Kimpe N. J. Org. Chem. 2011; 76: 8364
      Crossref
    • 8i Vervisch K, D’hooghe M, Törnroos KW, De Kimpe N. J. Org. Chem. 2010; 75: 7734
      Crossref
  • 9 For a review, see: Lait SM, Rankic DA, Keay BA. Chem. Rev. 2007; 107: 767
    CrossrefPubMed
  • 10 6-Ferrocenyl-3-phenyl-1,3-oxazinane (6a) Yield 78%, dark yellow solid; mp 86 °C. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 2 H), 7.13–7.09 (m, 2 H), 6.93–6.87 (m, 1 H), 5.30 (dd, J = 10.7, 2.3 Hz, 1 H), 4.74 (d, J = 10.7 Hz, 1 H), 4.48 (dd, J = 11.2, 2.4 Hz, 1 H), 4.22 (ca. dt, J = 2.5, 1.3 Hz, 1 H), 4.17 (ca. dt, J = 2.5, 1.3 Hz, 1 H), 4.15–4.07 (m, 2 H), 4.12 (s, 5 H), 3.91 (ddt, J = 13.5, 4.3, 2.3 Hz, 1 H), 3.49 (ddd, J = 13.5, 12.7, 2.9 Hz, 1 H), 2.02 (dddd, J = 13.1, 12.7, 11.2, 4.3 Hz, 1 H), 1.78 (ddt, J = 13.1, 2.9, 2.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 148.9, 129.1, 120.5, 118.4, 88.9, 81.3, 76.0, 68.6, 68.0, 67.8, 67.3, 66.0, 49.9, 29.2. MS (ES+): m/z = 348.1 [MH+]. Column chromatography (SiO2): hexane–EtOAc, 8:2 (v/v). ESI-HRMS: m/z calcd for C20H22FeNO [M + H]+: 348.1050; found: 348.1041.
  • 11 Cassady JM, Chan KK, Floss HG, Leistner E. Chem. Pharm. Bull. 2004; 52: 1
    Crossref
  • 12 Meyers AI, Roland DM, Comins DL, Henning R, Fleming MP, Shimizu K. J. Am. Chem. Soc. 1979; 101: 4732
    Crossref
  • 13 Gormley GJr, Chan YY, Fried J. J. Org. Chem. 1980; 45: 1447
    Crossref
  • 14 Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y, Goldmacher VS, Xie H, Steeves RM, Lutz RJ, Zhao R, Wang L, Blaettler WA, Chari RV. J. J. Med. Chem. 2006; 49: 4392
    Crossref
  • 15 D’hooghe M, Dekeukeleire S, Mollet K, Lategan C, Smith PJ, Chibale K, De Kimpe N. J. Med. Chem. 2009; 52: 4058
    CrossrefPubMed
    • 16a Singh H, Singh K. Tetrahedron 1989; 45: 3967
      Crossref
    • 16b Alberola A, Alvarez MA, Andres C, Gonzalez A, Pedrosa R. Synthesis 1990; 1057
      Article in Thieme Connect
    • 16c Singh K, Deb PK, Venugopalan P. Tetrahedron 2001; 57: 7939
      Crossref
  • 17 6-Ferrocenyl-3-phenyl-1,3-oxazinan-2-one (8a) Yield 64%, yellow solid; mp 148 °C. 1H NMR (400 MHz, CDCl3): δ = 7.43–7.38 (m, 2 H), 7.37–7.33 (m, 2 H), 7.29–7.24 (m, 1 H), 5.31 (dd, J = 9.5, 3.0 Hz, 1 H), 4.36 (ca. dt, J = 2.5, 1.3 Hz, 1 H), 4.28 (ca. dt, J = 2.5, 1.3 Hz, 1 H), 4.23–4.19 (m, 2 H), 4.24 (s, 5 H), 3.81 (ddd, J = 11.7, 10.2, 4.9 Hz, 1 H), 3.70 (ddd, J = 11.7, 5.5, 4.1 Hz, 1 H), 2.45 (dddd, J = 13.8, 4.9, 4.1, 3.0 Hz, 1 H), 2.28 (dddd, J = 13.8, 10.2, 9.5, 5.5 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 152.8, 143.1, 129.4, 126.9, 126.0, 86.3, 76.2, 69.1, 68.5, 68.4, 67.4, 66.1, 47.9, 28.9. IR (ATR): ν = 1685 (C=O) cm–1. MS (ES+): m/z = 362.1 [MH+]. Column chromatography (SiO2): hexane–EtOAc, 8:2 (v/v). ESI-HRMS: m/z calcd for C20H20FeNO2 [M + H]+: 362.0844; found: 362.0834.
    • 18a Fujiwara M, Baba A, Matsuda H. J. Heterocycl. Chem. 1989; 26: 1659
    • 18b Shibata I, Nakamura K, Baba A, Matsuda H. Bull. Chem. Soc. Jpn. 1989; 62: 853
      Crossref
    • 18c Baba A, Shibata I, Fujiwara M, Matsuda H. Tetrahedron Lett. 1985; 26: 5167
      Crossref
    • 18d Rice GT, White MC. J. Am. Chem. Soc. 2009; 131: 11707
      CrossrefPubMed
    • 18e Nahra F, Liron F, Prestat G, Mealli C, Messaoudi A, Poli G. Chem. Eur. J. 2009; 15: 11078
      CrossrefPubMed
    • 18f Mangelinckx S, Nural Y, Dondas HA, Denolf B, Sillanpää R, De Kimpe N. Tetrahedron 2010; 66: 4115
      Crossref
  • 19 Davies SG, Garner AC, Robert PM, Smith AD, Sweet MJ, Thomson JE. Org. Biomol. Chem. 2006; 4: 2753
    Crossref
    • 20a Park M, Lee J. Arch. Pharmacol. Res. 1993; 16: 158
      Crossref
    • 20b Li X, Wang R, Wang Y, Chen H, Li Z, Ba C, Zhang J. Tetrahedron 2008; 64: 9911
      Crossref
    • 20c McElroy CR, Aricò F, Benetollo F, Tundo P. Pure Appl. Chem. 2012; 84: 707
      Crossref
    • 20d Wang G, Ella-Menye J.-R, Sharma V. Bioorg. Med. Chem. Lett. 2006; 16: 2177
      CrossrefPubMed
    • 20e Xu ZR, Tice CM, Zhao W, Cacatian S, Ye YJ, Singh SB, Lindblom P, McKeever BM, Krosky PM, Kruk BA, Berbaum J, Harrison RK, Johnson JA, Bukhtiyarov Y, Panemangalore R, Scott BB, Zhao Y, Bruno JG, Togias J, Guo J, Guo R, Carroll PJ, McGeehan GM, Zhuang LH, He W, Claremont DA. J. Med. Chem. 2011; 54: 6050
      CrossrefPubMed
  • 21 4-Ferrocenyl-3-isopropyl-1-phenyltetrahydropyrimidin-2-one (10a) Yield 61%, orange liquid. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 2 H), 7.25–7.20 (m, 2 H), 7.16–7.09 (m, 1 H), 4.46 (t, J = 3.9 Hz, 1 H), 4.24 (d × t, J = 2.4, 1.2 Hz, 1 H), 4.20–4.09 (m, 3 H), 4.16 (s, 5 H), 4.13–4.10 (m, 1 H), 3.62–3.46 (m, 2 H), 2.33–2.15 (m, 2 H), 1.37 (d, J = 6.8 Hz, 3 H), 1.28 (d, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 154.5, 144.3, 128.8, 126.0, 125.2, 91.2, 69.4, 68.9, 68.4, 66.7, 66.0, 53.0, 50.9, 45.2, 31.7, 21.3, 20.9. IR: ν = 1636 (C=O) cm–1. MS (ES+): m/z = 403.2 [M + H]+. Preparative chromatography (SiO2): hexane–EtOAc, 6:4 (v/v). ESI-HRMS: m/z calcd for C23H27FeN2O [M + H]+: 403.1473; found: 403.1475.
  • 22 Natarajan SR, Doherty JB. Curr. Top. Med. Chem. 2005; 5: 987
    Crossref
  • 23 James CA, DeRoy P, Duplessis M, Edwards PJ, Halmos T, Minville J, Morency L, Morin S, Simoneau B, Tremblay M, Bethell R, Cordingley M, Duan JM, Lamorte L, Pelletier A, Rajotte D, Salois P, Tremblay S, Sturino CF. Bioorg. Med. Chem. Lett. 2013; 23: 2781
    Crossref
    • 24a NCCLS. Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline. NCCLS document M44-A [ISBN 1-56238-532-1]. 24, (NCCLS, NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2004)
    • 24b CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Eleventh Edition. CLSI document M02-A11. Wayne, 32, (Clinical and Laboratory Standards Institute, 2012)