Services on Demand
- Cited by SciELO
- Access statistics
Print version ISSN 0103-5053On-line version ISSN 1678-4790
J. Braz. Chem. Soc. vol.16 no.4 São Paulo July/Aug. 2005
J. A. Parihar; M. M. V. Ramana*
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai-400098, India
Different 3-[2-(3,4-dihydro-1-naphthyl)ethyl]imidazolidine-2,4-diones and 3-[2-(1-naphthyl)ethyl]imidazolidine-2,4-diones, when heated in polyphosphoric acid at 150 °C, underwent chemoselective intramolecular cyclization to afford the 13,16-diazaestrone steroids and 13,16- diazaequilenin steroids respectively.
Keywords: polyphosphoric acid, chemoselective cyclization, 13,16-diazaestrone steroids, 13,16- diazaequilenin steroids
Diferentes 3-[2-(3,4-diidro-1-naftil)etil]imidazolidina-2,4-dionas e 3-[2-(1-naftil)etil]- imidazolidina-2,4-dionas, quando aquecidas em ácido polifosfórico a 150 °C, sofrem ciclização quimioseletiva intramolecular resultado nos respectivos esteróides 13,16-diazaestrona e 13,16- diazaequilenina.
Azasteroids are known to exhibit various biological properties which include analgesic,1 antiandrogenic,2 antiphlogistic,3 antimicrobial,4 antileukemic,5 antifungal,6 bactericide,7 antiestrogenic,8 antifertility,9 and cardiotonic and hypotensive activities.10 Moreover, some azasteroids act as neuromuscular blockers11 and inhibitors of 5-a reductase and androgen receptor binding.12 Recently we have reported13,14 the syntheses of 13,16-diazaestrone and 13,16-diazaequilenin analogs from the intramolecular cyclization of the corresponding 5-hydroxyimidazolidin-2-ones. We now wish to report a new synthesis of the title compounds from intramolecular cyclization of the corresponding imidazolidine-2,4-diones.
Results and Discussion
Towards this end, the intramolecular cyclization of 3-[2-(3,4-dihydro-1-naphthyl)ethyl]imidazolidine-2,4 -dione13 1a was undertaken. All our attempts to cyclize 1a employing POCl3 and P2O5 in different solvents such as benzene, dichloroethane, toluene and xylene were unsatisfactory and gave the starting material back. Heating 1a with POCl3 in refluxing tetralin gave a brown solid, which was insoluble in all organic solvents and hence could not be characterized. Attempts to cyclize 1a in polyphosphoric acid (PPA) at 100 °C gave starting material back. When the temperature increased to 120 °C the TLC (CHCl3-MeOH, 96:4) showed the formation of a new spot but the bulk of starting material remained intact even after 12h. The reaction was then carried out at 150 °C, which led to consumption of the starting material in 6h to give a yellow solid in 44% yield after aqueous work-up (Scheme 1). IR spectrum of the yellow solid showed the N-H band at 3250 cm-1 and the 1H NMR spectrum displayed a 1H broad singlet due to N-H at d 8.91 and 1H singlet due to vinylic proton at d 6.70 thus confirming the chemoselective formation of 13,16-diazaestrone 2a and not the corresponding 13,15-diazasteroids. This may be explained on the basis of more electrophilic nature of carbonyl carbon of amide than urea.15,16 Proposed mechanism for intramolecular cyclization of 1a to give 2a is shown in Scheme 2. Following the above standardized protocol, intramolecular cyclization of other imidazolidine-2,4-diones13,14 1b-h were carried out to afford the corresponding 13,16-diazasteroids 2b-h in 42-59 % yields (Scheme 1). It is important to notice that the earlier attempts by Schleigh et al.17 to synthesize 13-azaestrone and 13-azaequilenin analogs by such one-step intramolecular cyclization of the corresponding pyrrolidine-2,5-diones under various acidic conditions were unsuccessful and gave either starting material back or a trace amount of uncharacterized solid material melting over a wide range.
In conclusion, the present work describes a new synthesis of 13,16-diazasteroids 2a-h by chemoselective cyclization of 1a-h in PPA. The method is short, general and utilizes easily accessible materials for the synthesis of the new 13,16-diazasteroids.
Reagents were of LR grade and were used without further purification. Column chromatography was carried out using silica gel (S. D. Fine Chemicals, India) 60-120 mesh. Boiling point of Petroleum ether used was in the range of 60-80 °C. The melting points (uncorrected) were determined on a Gallenkamp melting apparatus. The IR spectra (wavenumbers in cm-1) were recorded on a Shimadzu FTIR-4200 spectrometer either as oil film or KBr discs. UV spectra were recorded on a Shimadzu UV-Visible spectrophotometer UV-2100. 1H NMR spectra were recorded on Varian EM-360L (60 MHz), Varian 200 (200 MHz), Bruker 300 (300 MHz) and Varian VR (500 MHz) instruments in CDCl3 with tetramethylsilane as internal standard. Chemical shifts are given in ppm and coupling constants (J) in Hz. Elemental analyses were carried out on a Carlo Erba EA-1108 elemental analyser. The electron impact spectrum was recorded on a Katros MS-80.
General procedure for the synthesis of 13,16-diazasteroids 2a-h
A mixture of compound 1a-h (50 mg) and PPA (2 g) was heated at 150 °C for 6h. The reaction mixture was poured onto ice. It was extracted with EtOAc (3 ´ 25 mL). The combined EtOAc extracts were washed with 10% Na2CO3 (2 ´ 25 mL), water (2 ´ 25 mL) and then dried (anhydrous Na2SO4). Evaporation of solvent gave a brown residue, which was purified by column chromatography (basic alumina, CHCl3-MeOH, 95:5) to afford the corresponding compound 2a-h.
4,5,10,11-Tetrahydro-2H-benzo[f]imidazo- [5,1-a]isoquinolin-1-one (2a). Yield 44%, mp 242-245 °C (decomp.). IR (KBr) nmax/ cm-1: 1680 (C=C), 1715 (C=O), 3250 (N-H). 1H NMR (CDCl3, 300 MHz): d 2.43 (t, 2H, J 6.5, H-4), 2.86 (t, 2H, J 6.5, H-5), 3.44 (t, 2H, J 7.8, H-10), 4.01 (t, 2H, J 7.8, H-11), 6.70 (s, 1H, C=C-H), 7.45-7.80 (m, 4H, Ar-H), 8.91 (s, 1H, N-H). UV (CHCl3) lmax/ nm (log e): 288 (3.97), 307 (3.89), 322 (3.81). Analysis calc. for C15H14N2O: C, 75.61; H, 5.92; N, 11.76; Found: C, 75.53; H, 5.97; N, 11.72.
8-Methyl-4,5,10,11-tetrahydro-2H-benzo[f]imidazo[5,1-a]isoquinolin-1-one (2b). Yield 52%, mp 220-222 °C (decomp.). IR (KBr) nmax/ cm-1: 1680 (C=C), 1716 (C=O), 3270 (N-H). 1H NMR (CDCl3, 300 MHz): d 2.33 (s, 3H, CH3), 2.39 (t, 2H, J 6.5, H-4), 2.84 (t, 2H, J 6.5, H-5), 3.41 (t, 2H, J 7.6, H-10), 3.87 (t, 2H, J 7.6, H-11), 6.30 (s, 1H, C=C-H), 7.50-7.72 (m, 3H, Ar-H), 8.54 (s, 1H, N-H). MS (EI, m/z (rel.%)): 252 (M+, 80%), 251 (20), 250 (35), 223 (20), 184 (17), 168 (40), 155 (16), 141 (42), 128 (33), 115 (58), 77 (100). UV (CHCl3) lmax/ nm (log e): 288 (3.79), 307 (3.85), 322 (3.98). Analysis calc. for C16H16N2O: C, 76.16; H, 6.39; N, 11.10; Found: C, 76.19; H, 6.34; N, 11.14.
6-Chloro-4,5,10,11-tetrahydro-2H-benzo[f]imidazo[5,1-a]isoquinolin-1-one (2c). Yield 42%, mp 202-205°C (decomp.). IR (KBr) nmax/ cm-1: 1670 (C=C), 1713 (C=O), 3304 (N-H). 1H NMR (CDCl3, 200 MHz): d 2.40 (t, 2H, J 6.6, H-4), 2.83 (t, 2H, J 6.6, H-5), 3.41 (t, 2H, J 7.8, H-10), 4.02 (t, 2H, J 7.8, H-11), 6.62 (s, 1H, C=C-H), 7.50-7.80 (m, 3H, Ar-H), 8.60 (s, 1H, N-H). UV (CHCl3) lmax/ nm (log e): 287 (3.91), 304 (3.86), 321 (3.82). Analysis calc. for C15H13N2OCl: C, 66.06; H, 4.80; N, 10.27; Cl, 13.00; Found: C, 65.97; H, 4.82; N, 10.32; Cl, 12.94.
7,8-Dimethyl-4,5,10,11-tetrahydro-2H-benzo[f]imidazo[5,1-a]isoquinolin-1-one (2d). Yield 59%, mp 238-241 °C (decomp.). IR (KBr) nmax/ cm-1: 1670 (C=C), 1715 (C=O), 3315 (N-H). 1H NMR (CDCl3, 60 MHz): d 2.25-4.00 (m, 14H, aliphatic H), 6.43 (s, 1H, C=C-H), 7.35 (s, 1H, Ar-H), 7.60 (s, 1H, Ar-H), 8.72 (s, 1H, NH). UV (CHCl3) lmax/nm (log e): 292 (3.93), 305 (3.87). Analysis calc. for C17H18N2O : C, 76.66; H, 6.81; N, 10.52; Found: C, 76.75; H, 6.78; N, 10.50.
10,11-Dihydro-2H-benzo[f]imidazo- [5,1-a]isoquinolin-1-one (2e). Yield 47%, mp 252-255 °C (decomp.). IR (KBr) nmax/ cm-1: 1680 (C=C), 1715 (C=O), 3270 (N-H). 1H NMR (CDCl3, 300 MHz): d 3.44 (t, 2H, J 6.4, H-10), 4.01 (t, 2H, J 6.4, H-11), 6.70 (s, 1H, C=C-H), 7.46- 7.83 (m, 5H, Ar-H), 8.00 (d, 1H, J 8.41, H-9), 8.91 (br s, 1H, N-H). UV (CHCl3) lmax/ nm (log e): 288 (3.83), 307 (3.81), 321 (3.75). Analysis calc. for C15H12N2O: C, 76.25; H, 5.12; N, 11.86; Found: C, 76.15; H, 5.16; N, 11.80.
8-Methyl-10,11-dihydro-2H-benzo[f]imidazo- [5,1-a]isoquinolin-1-one (2f). Yield 55%, mp 229-231 ºC (decomp.). IR (KBr) nmax/ cm-1: 1680 (C=C), 1715 (C=O), 3250 (N-H). 1H NMR (CDCl3, 300 MHz): d 2.51 (s, 3H, CH3), 3.41 (t, 2H, J 6.3, H-10), 4.00 (t, 2H, J 6.3, H-11), 6.66 (s, 1H, C=C-H), 7.38-7.98 (m, 5H, Ar-H), 8.90 (br s, 1H, N-H). UV (CHCl3) lmax/ nm (log e): 288 (3.89), 307 (3.84), 322 (3.79). Analysis calc. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19; Found: C, 76.88; H, 5.66; N, 11.24.
6-Chloro-10,11-dihydro-2H-benzo[f]imidazo- [5,1-a]isoquinolin-1-one (2g). Yield 45%, mp 208-211 ºC (decomp.). IR (KBr) nmax/ cm-1: 1680 (C=C), 1710 (C=O), 3200 (N-H). 1H NMR (CDCl3, 300 MHz): d 3.43 (t, 2H, J 6.5, H-10), 4.03 (t, 2H, J 6.5, H-11), 6.68 (s, 1H, C=C-H), 7.60-7.92 (m, 4H, Ar-H), 8.00 (d, 1H, J 8.41, H-9), 8.97 (br s, 1H, N-H). UV (CHCl3) lmax/ nm (log e): 288 (3.92), 305 (3.90), 321 (3.85). Analysis calc. for C15H11N2OCl: C, 66.55; H, 4.10; N, 10.35; Cl, 13.10; Found: C, 66.48; H, 4.14; N, 10.31; Cl, 13.07.
7,8-Dimethyl-10,11-dihydro-2H-benzo[f]imidazo- [5,1-a]isoquinolin-1-one (2h). Yield 60%, mp 245-247 ºC (decomp.). IR (KBr) nmax/ cm-1: 1680 (C=C), 1715 (C=O), 3260 (N-H). 1H NMR (CDCl3, 60 MHz): d 2.51 (s, 6H, 2 ´ CH3), 3.33-4.08 (m, 4H, H-10 and H-11), 6.70-7.64 (m, 5H, 4 Ar-H and C=C-H), 8.82 (br s, 1H, NH). UV (CHCl3) lmax/ nm (log e): 288 (3.98), 307 (3.92), 322 (3.84). Analysis calc. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60; Found: C, 77.15; H, 6.14; N, 10.62.
We are very much thankful to reviewers for their very helpful suggestions. JAP is thankful to UGC, New Delhi for the financial assistance.
1. Taylor, E. C.; Lenard, K.; J. Chem. Soc., Chem. Commun. 1967, 97. [ Links ]
2. Shibata, K.; Takeguwa, S.; Koizumi, N.; Yamakoshi, N.; Shimazawa, E.; Chem. Pharm. Bull. 1992, 40, 935. [ Links ]
3. Akherm, A. A.; Lakhvich, F. A.; Pshenichnyi, V. N.; Lis, L. G.; Kuzmitskii, B. B.; Mizulo, N. A.; USSR 636236 1978. (CA 90:104210t) [ Links ]
4. Norman, F. P.; Doorenbos, N. J.; J. Miss. Acad. Sci. 1976, 21, 23. (CA 86:165794a) [ Links ]
5. Anastasiou, A.; Catsoulacus, P.; Epitheor, K.; Farmakol. Farmakokinet. Intl. Ed. 1992, 6, 130. (CA 119:72911w) [ Links ]
6. Patrick, G. L.; Kinsman, O. S.; Eur. J. Med. Chem. 1996, 31, 615. [ Links ]
7. William, R. H.; Hoehn, M. M.; Michel, K. H.; US 147808 1994. (CA 123:75620u) [ Links ]
8. Greenbalatt, R. B.; Bornstan, R.; Bohler, C. S. S.; J. Reprod. Med. 1974, 13, 201. [ Links ]
9. Kierstead, R. W.; Faraone, A.; Boris, A.; J. Med. Chem. 1969, 12, 629. [ Links ]
10. Akherm, A. A.; Lakhvich, F. A.; Pshenichnyi, V. N.; Lakhvich, O. F.; Kuzmitskii, B. B.; Gorbatenko, S. F.; USSR 636235 1978. (CA 90:104211u) [ Links ]
11. Li, X.; Singh, S. M.; Lourdusamy, M.; Merand, Y.; Veitleux, R.; Labrie, F.; Bioorg. Med. Chem. Lett. 1995, 5, 1061. [ Links ]
12. Bakshi, R. K.; Patel, G. F.; Rasmussan, G. H.; US 373341, 1995. (CA 123:212693c) [ Links ]
13. Parihar, J. A.; Ramana, M. M. V.; Tetrahedron Lett. 2003, 44, 1843. [ Links ]
14. Parihar, J. A.; Ramana, M. M. V.; Chin. J. Chem. 2004, 22, 1196. [ Links ]
15. Kallies, B.; Mitzner, R.; J. Mol. Struct. (THEOCHEM). 1998, 428, 267. [ Links ]
16. Kallies, B; Mitzner, R.; J. Mol. Modeling. 1998, 4, 183. [ Links ]
17. Schleigh, W. R.; Catala, A.; Popp, F. D.; J. Heterocycl. Chem. 1965, 2, 379. [ Links ]
Received: October 29, 2004
Published on the web: June 09, 2005