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

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
• 2 For a review, see: Fouda MF. R, Abd-Elzaher MM, Abdelsamaia RA, Labib AA. Appl. Organomet. Chem. 2007; 21: 613
• 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
• 4 For a review, see: Scutaru D, Tataru L, Mazilu I, Vata M, Lixandru T, Simionescu C. Appl. Organomet. Chem. 1993; 7: 225
• 5 For a recent review, see: Braga SS, Silva AM. S. Organometallics 2013; 32: 5626
• 6 For a recent review, see: Pereira CM. P, Venzke D, Trossini GH. G. Quim. Nova 2013; 36: 143
• 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
• 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
• 7d Pejović A, Damljanović I, Stevanović D, Vukićević M, Novaković SB, Bogdanović GA, Radulović N, Vukićević RD. Polyhedron 2012; 31: 789
• 7e Damljanović I, Vukićević M, Radulović N, Palić R, Ellmerer E, Ratković Z, Joksović MD, Vukićević RD. Bioorg. Med. Chem. Lett. 2009; 19: 1093
• 7f Ilić D, Damljanović I, Stevanović D, Vukićević M, Blagojević P, Radulović N, Vukićević RD. Chem. Biodiversity 2012; 9: 2236
• 7g Radulović NS, Mladenović MZ, Stojanović-Radić Z, Bogdanović GA, Stevanović D, Vukićević RD. Mol. Diversity 2014; 18: 497
• 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
• 8a Dolfen J, Kenis S, Van Hecke K, De Kimpe N, D’hooghe M. Chem. Eur. J. 2014; 20: 10650
• 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
• 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
• 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
• 8g Vervisch K, D’hooghe M, Rutjes FP. J. T, De Kimpe N. Org. Lett. 2012; 14: 106
• 8h Mollet K, Catak S, Waroquier M, Van Speybroeck V, D’hooghe M, De Kimpe N. J. Org. Chem. 2011; 76: 8364
• 8i Vervisch K, D’hooghe M, Törnroos KW, De Kimpe N. J. Org. Chem. 2010; 75: 7734
• 9 For a review, see: Lait SM, Rankic DA, Keay BA. Chem. Rev. 2007; 107: 767
• 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
• 12 Meyers AI, Roland DM, Comins DL, Henning R, Fleming MP, Shimizu K. J. Am. Chem. Soc. 1979; 101: 4732
• 13 Gormley GJr, Chan YY, Fried J. J. Org. Chem. 1980; 45: 1447
• 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
• 15 D’hooghe M, Dekeukeleire S, Mollet K, Lategan C, Smith PJ, Chibale K, De Kimpe N. J. Med. Chem. 2009; 52: 4058
• 16a Singh H, Singh K. Tetrahedron 1989; 45: 3967
• 16b Alberola A, Alvarez MA, Andres C, Gonzalez A, Pedrosa R. Synthesis 1990; 1057
• 16c Singh K, Deb PK, Venugopalan P. Tetrahedron 2001; 57: 7939
• 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
• 18c Baba A, Shibata I, Fujiwara M, Matsuda H. Tetrahedron Lett. 1985; 26: 5167
• 18d Rice GT, White MC. J. Am. Chem. Soc. 2009; 131: 11707
• 18e Nahra F, Liron F, Prestat G, Mealli C, Messaoudi A, Poli G. Chem. Eur. J. 2009; 15: 11078
• 18f Mangelinckx S, Nural Y, Dondas HA, Denolf B, Sillanpää R, De Kimpe N. Tetrahedron 2010; 66: 4115
• 19 Davies SG, Garner AC, Robert PM, Smith AD, Sweet MJ, Thomson JE. Org. Biomol. Chem. 2006; 4: 2753
• 20a Park M, Lee J. Arch. Pharmacol. Res. 1993; 16: 158
• 20b Li X, Wang R, Wang Y, Chen H, Li Z, Ba C, Zhang J. Tetrahedron 2008; 64: 9911
• 20c McElroy CR, Aricò F, Benetollo F, Tundo P. Pure Appl. Chem. 2012; 84: 707
• 20d Wang G, Ella-Menye J.-R, Sharma V. Bioorg. Med. Chem. Lett. 2006; 16: 2177
• 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
• 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
• 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
• 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)