Short synthesis of new 13,16-diazaestrone and 13,16-diazaequilenin analogs

SHORT REPORT

Short synthesis of new 13,16-diazaestrone and 13,16-diazaequilenin analogs

J. A. Parihar; M. M. V. Ramana^*

Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai-400098, India

ABSTRACT

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

RESUMO

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.

Introduction

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 reported^13,14 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 -dione¹³1a 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-diones^13,141b-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.

Experimental

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) n_max/ 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) l_max/ 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) n_max/ 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) l_max/ 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) n_max/ 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) l_max/ 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) n_max/ 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) l_max/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) n_max/ 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) l_max/ 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) n_max/ 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) l_max/ 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) n_max/ 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) l_max/ 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) n_max/ 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) l_max/ 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.

Acknowledgements

We are very much thankful to reviewers for their very helpful suggestions. JAP is thankful to UGC, New Delhi for the financial assistance.

Received: October 29, 2004

Published on the web: June 09, 2005

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Publication Dates

• Publication in this collection
  25 Aug 2005
• Date of issue
  Aug 2005

History

• Received
  29 Oct 2004
• Accepted
  09 June 2005