SciELO - Scientific Electronic Library Online

 
vol.59 issue3DEVELOPMENT OF A NEW ANALYTICAL METHODOLOGY BASED ON THE CATALYTIC EFFECT OF AG(I) IN A NEW FUCHSIN-PEROXODISULFATE-1,10-PHENANTROLINE SYSTEM: APPLICATION TO THE DETERMINATION OF TRACE AMOUNTS OF SILVERMONO-, TRINUCLEAR NICKEL(II) AND COPPER(II) DIOXIME COMPLEXES: SYNTHESIS, CHARACTERIZATION, CATECHOLASE AND CATALASE-LIKE ACTIVITIES, DNA CLEAVAGE STUDIES author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

  • On index processCited by Google
  • Have no similar articlesSimilars in SciELO
  • On index processSimilars in Google

Share


Journal of the Chilean Chemical Society

On-line version ISSN 0717-9707

J. Chil. Chem. Soc. vol.59 no.3 Concepción Sept. 2014

http://dx.doi.org/10.4067/S0717-97072014000300002 

 

SYNTHESIS OF STEROIDAL DIAZOLIDINONE, DIAZOLIDINTHIONE AND DIAZOLES: REACTION OF STEROIDAL DIBROMOKETONES WITH NUCLEOPHILIC NITROGEN

 

SHAMSUZZAMAN*, KHAN AAFTAB ALAM ABDUL BAQI

Department of Chemistry, Aligarh Muslim University, Aligarh-202 002, India
* e-mail: shamsuzzaman9@gmail.com


ABSTRACT

Reaction of 5,6β-dibromo-5α-cholestan-3-one 1 with thiourea, urea and guanidine hydrochloride provided 3-hydroxycholest-3-eno [5α,6α-d] 1',3'-diazolidin-2'-thione 2, 3-hydroxycholest-3-eno [5α,6α-d] 1',3'-diazolidin-2'-one 3 and 3-hydroxycholest-3-eno [5α,6α-d] 2'-amino-1',3'-diazole 4 respectively. The structures of these products have been established on the basis of their elemental analysis and spectral data (IR, 1H NMR and MASS).

Keywords: Steroidal dibromoketone, Diazolidinone, Diazole, Thiourea, Urea, Guanidine hydrochloride.


 

INTRODUCTION

In the light of the reported biological activities of nitrogen containing heterocycles1-3 an attempt has been made to prepare steroidal compounds incorporating diazolidinone and diazole moieties in their frame work which is in continuation of our earlier studies of steroidal heterocyclic compounds.4-6 The chemistry of these heterocycles has become more important because of the discovery of the varied biochemical properties, industrial uses and analytical applications associated with them. Steroidal dibromoketones have been important starting materials for the construction of heterocycles and they can be easily prepared in good yields. The concept of nucleophilic reagent proposed, can be manipulated to yield heterocycles.

EXPERIMENTAL

General Remarks

The reactions were carried out in ethanol with urea, thiourea and guanidine hyrochloride. The starting steroidal dibromoketone was prepared in the laboratory by known method7. All melting points were recorded on a Kofler apparatus and are uncorrected. Infrared (IR) spectra were determined (KBr/Neat) with Perkin Elmer 1600 FTIR spectrophotometer. The 1H NMR spectra were recorded by using CDCl3 as solvent on a Brucker 300 MHz spectrometer with TMS as an internal standard and its values are given in ppm (δ). The mass spectra were run on Jeol JMS D-300 spectrometer.

Synthesis of 3-hydroxycholest-3-eno [5α,6α-d] 1',3'-diazolidin-2'-thione 2.

Steroidal dibromoketone 1 (1.0 g, 1.838 mmol) was taken in ethanol (30ml) followed by thiourea8-12 (0.286 g, 3.763 mmol). The reaction mixture was refluxed for two h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure and the residue was taken in diethyl ether. The ethereal solution was washed with water and dried over anhydrous sodium sulphate. The crude product obtained after removal of solvent was purified by column chromatography over silica gel column (Petroleum ether-diethyl ether, 19:1). The compound was recrystallized from methanol, m.p 63-64 °C, Yield 83 % (Beilstein negative). Anal. Found: C, 73.28; H, 10.06; N, 6.12 %. C28H46N2OS required: C, 73.30; H, 10.10; N, 6.10 %. IR (KBr, cm-1): ν 3450 (NH), 3300 (OH), 1680 (NHCS), 1610 (C=C), and 1040 cm-1 (C-O). 1H NMR (CDCl3): δ 7.3 (s, 2H, 2 x NH, exchangeable with D2O), 5.7 (s, 1H, C4-H), 4.8 (s, 1H, OH, exchangeable with D2O), 3.9 (dd, 1H, J = 8.4, 3.6 Hz, C6β-H), 1.10 (C10-CH3), 0.71 (C13-CH3), 0.93 and 0.81 (other methyl protons). MS: m/z 458 (M+ C28H46N2OS), 414 (M-CS), 399 (M-NHCS), 384 (M-NHCSNH), 345 (M-C8H17).

Synthesis of 3-hydroxycholest-3-eno [5α,6α-d] 1',3'-diazolidine-2'-one 3.

To a solution of steroidal dibromoketone 1 (1.0 g, 1.838 mmol) in ethanol, urea9-12 (0.22 g, 3.666 mmol) was added and the reaction mixture was refluxed for 1½ h. Progress of the reaction was monitored by TLC. After completion of reaction it was usually worked up and purified by column chromatography ( Petroleum ether- diethyl ether, 15:1) provided a non-crystallizable oily compound 3 (yield 70 %). Anal. Found: C, 75.92; H, 10.44; N, 6.34 %. C28H46N2O2 required: C, 75.96: H, 10.47; N, 6.32 %. IR (Neat, cm-1): ν 3445 (NH), 3210 (OH), 1690 (NHCO), 1616 (C=C) and 1045 cm-1 (C-O). 1H NMR (CDCl3): δ 6.9 (s, 2H, 2 x NH, exchangeable with D2O), 5.6 (s, 1H, C4-H), 4.9 (s, 1H, OH, exchangeable with D2O), 3.87 (dd, 1H, J = 7.5, 2.8 Hz, C6β-H), 1.11 (C10-CH3), 0.71 (C13-CH3), 0.93 and 0.81 (other methyl protons). MS: m/z 442 (M+ C28H46N2O2), 414 (M-CO), 399 (M-NHCO), (M-NHCONH), 329 (M-C8H17).

Synthesis of 3-hydroxycholest-3-eno [5α,6α-d] 2'-amino-1',3'-diazole 4.

Steroidal diromoketone 1 (1.0 g, 1.838 mmol) was similarly treated with guanidine hydrochloride13-15 (0.22 g, 3.666 mmol) in ethanol (30 ml). The reaction mixture was refluxed for 2½ h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was similarly worked up and purified by column chromatography (Petroleum ether-diethyl ether, 14:1) which provided a non- crystallizable oily compound 4, (yield 80 %). Anal. Found: C,76.09; H, 10.68; N, 9.54 %. IR (Neat cm-1): ν 3500 (NH2), 3440 (NH), 3250 (OH), 1618 (C=C), 1540 (C=N), and 1045 cm-1 (C-O). 1H NMR (CDCl3): δ 7.4 (s, 1H, NH, exchangeable with D2O), 5.6 (br, s, NH2, exchangeable with D2O), 5.1 (s, 1H, C4-H), 4.7 (s, 1H, OH, exchangeable with D2O), 3.98 (dd, 1H, J = 7.8, 3.2 Hz, C6β-H), 1.15 (C10-CH3), 0.70 (C13-CH3), 0.95 and 0.90 (other methyl protons). MS: m/z 441 (M+ C28H47N3O), 425 (M-NH2), 399 (M-NH2CN), 384 (M-NHCNNH2), 328 (M-C8H17).

RESULTS AND DISCUSSION

Steroidal dibromoketone 17 on treatment with thiourea8-12 in ethyl alcohol afforded a solid compound which was analyzed for C28H46N2OS (M+ 458). Negative Beilstein test, elemental analysis, MS and absence of C-Br absorption band in the IR spectrum clearly suggested the absence of bromine in the product. The IR spectrum exhibited characteristic absorption bands at 3450 (N-H), 3300 (OH), 1680 (NHCS), 1610 (C=C) and 1040 cm-1 (C-O). The 1H NMR spectrum of the compound displayed a singlet (exchangeable with D2O) for two (2 x NH) protons at δ 7.3, another singlet for one proton at 5.7 assignable to C4-olefinic proton. Hydroxyl proton appeared at δ 4.8 (exchangeable with D2O), a double doublet for one proton was observed at 3.9 (J = 8.4, 3.6 Hz) which was assignable for C6β-proton. Angular and side-chain methyl protons were observed at δ 1.10 (C10-CH3), 0.71 (C13-CH3), 0.93 and 0.81 (side-chain methyl protons). Additional support to the structure 2 was provided by its mass spectrum which gave a prominent molecular ion peak at m/z 458 (M+ C28H46N2OS) along with M+2 peak. Other significant peaks were observed at m/z 414 (M-CS), 399 (M-NHCS), 384 (M-NHCSNH), 345 (M-C8H17).

The same steroidal ketone 1 on similar treatment with urea9-12 and guanidine hydrochloride13-15 provided 3-hyroxycholest-3-eno [5α,6α-d] 1',3'-diazolidine-2'-one 3 and 3-hyroxycholest-3-eno [5α,6α-d] 2'-amino-1',3'-diazole 4, respectively. Both the products showed negative Beilstein test. Compound 3 was analyzed for C28H46N2O2 (M+ 442). The IR spectrum of the compound showed absorption bands at 3445 (NH), 3210 (OH), 1690 (NHCO),16 1616 (C=C) and 1045 cm-1 (C-O). The 1H NMR spectrum of the compound exhibited a singlet (exchangeable with D2O) for two (2 x NH) protons at δ 6.9 and another singlet for one protons at 5.6 for C4-H. Hydroxyl proton appeared at δ 4.9 (exchangeable with D2O) as a singlet and C6β-proton at 3.87 (J = 7.5, 2.8 Hz) as a double doublet. Angular and side-chain methyl protons were observed at δ 1.11 (C10-CH3), 0.71 (C13-CH3), 0.93 and 0.81 (other methyl protons). The structure of the compound was further supported by its mass spectrum which showed the molecular ion peak at m/z (M+ C28H46N2O2). The other important fragment ions were observed at m/z 414 (M-CO), 399 (M-NHCO), 384 (M-NHCONH), 329 (M-C8H17).

The oily compound 4 was analyzed for C28H47N3O (M+ 441). The IR spectrum of the compound exhibited characteristic bands at 3500 (NH2), 3440 (NH), 3250 (OH), 1618 (C=C), 1540 (C=N) and 1045 cm-1 (C-O). The 1H NMR spectrum of the compound displayed characteristic peaks at δ 7.4 (s, 1H, NH, exchangeable with D2O), 5.6 (br, s, 2H, NH2, exchangeable with D2O), 5.1 (s, 1H, C4-H). Hydroxyl proton appeared at δ 4.7 (exchangeable with D2O) and C6β-proton at 3.98 (J = 7.8, 3.2 Hz) as a double doublet. Angular and side-chain methyl protons were observed at 1.15 (C10-CH3), 0.70 (C13-CH3), 0.95 and 0.90 (other methyl protons). The structure of the compound was further supported by its mass spectrum, which showed the molecular ion peak at m/z 441 (M+ C28H47N3O). The other important fragments ions were observed at m/z 425 (M-NH2), 399 (M-NH2C=N), 384 (M-NHCNNH2), 328 (M-C8H17).

 
Scheme 1

It is proposed that the reaction proceeds via nucleophilic attack of nitrogen at C5 and C6 position of steroidal dibromoketone 1 . The formation of cis product was supported by the proposed mechanism (Scheme 2) in which SN2 inversion takes place at C6. Notice that the product of HBr elimination provided 6β-bromocholest-4-en-3-one which is rate determining step with thiourea, urea and guanidine hydrochloride. It is also supported by Dreiding model which indicate that molecule is under less strain with a trans A/B ring junction as is commonly observed.17

 
Scheme 2

ACKNOWLEDGEMENT

We are thankful to the Chairman, Department of Chemistry for providing necessary facilities and also to the U.G.C., New Delhi for financial support in the form of Major Research Project [UGC-Scheme-F.No 33-263/2007(SR)].

 

REFERENCES

1. M. Sekar, K.J. Prasad, Indian J. Chem. 37B, 314, (1998).         [ Links ]

2. M.B. Deshmukh, P.V. Anbhule, S.D. Jadhav, S.S. Jagtap, D.R. Patil, S.M. Salunkhe, S.A. Sankpal, Indian J. Chem. 47B, 792, 2008.         [ Links ]

3. M.S. Chande, M.S. Pankhi, V.V. sugdare, S.B. Ambaikar, Indian J. Chem. 38B, 925, (1999).         [ Links ]

4. Shamsuzzaman, A. Salim, M.K. Akram, Indian J. Chem. 38B, 1218, (1999); Shamsuzzaman, A. Salim, M. Aslam, F. Naqvi, Synth. Commun. 27 (12), 2171, (1997); Shamsuzzaman, A. Salim, K. Saleem, M.A. Khan, Indian J. Chem. 36B, 617, (1997).         [ Links ]

5. Shamsuzzaman, K.A.A. Abdul Baqi, Synth. Commun., 40(15), 2278 (2010); Shamsuzzaman, M.S. Khan, M. Alam, J. Chilean Chem. Soc., 54, 372 (2009); Shamsuzzaman, T. Siddiqui, M.G. Alam, Chinese J. Chem., 26(7), 1339 (2008); Shamsuzzaman, T. Siddiqui, M.G. Alam, Chinese Chem. Lett., 20(2), 153 (2009).         [ Links ]

6. Shamsuzzaman, M.S. Khan, M. Alam, Z. Tabassum, A. Ahmad, A.U. Khan. European J. Med. Chem., 45, 1094 (2010); Shamsuzzaman, M.G. Alam, T. Siddiqui, Synth. Commun., 39, 2161 (2009); Shamsuzzaman, N. Siddiqui, A. Salim, M.K. Akram, Chinese J. Chem., 27(8), 1523 (2009); Shamsuzzaman, T. Siddiqui, M.G. Alam, Indian J. Chem., 46B, 2068 (2007).         [ Links ]

7. L.F. Fieser, J. Am. Chem. Soc. 75, 5421, (1953).         [ Links ]

8. H.H. Sayed, Indian J. Chem. 37B, 1054, (1998).         [ Links ]

9. D. Anshu, G. Alpana, J. Indian Chem. Soc. 72, 833, (1995).         [ Links ]

10. V. Padmavathi, A. Balaiah, V. Reddy, A. Padmaja B. Reddy, Indian J. Chem. 41B, 1670, (2002).         [ Links ]

11. K.M. Mahadevan, V.P. Vaidya, J. Indian Council Chemists 18, 78, (2001).         [ Links ]

12. F.G. Baddar F.H. Ai-Hajjar, N.R. El-Rayyes, J. Heterocycl. Chem. 13, 257, (1976).         [ Links ]

13. R. Harode, T.C. Sharma, J. Indian Chem. Soc. 79, 190, (2002).         [ Links ]

14. N.R. El-Rayyes, F.H. Al-Hajjar, J. Heterocycl. Chem. 14, 367, (1977).         [ Links ]

15. K.M. Dawood, Z.E. Kandeel, A.M. Farag, J. Chem. Research (S) 208, (1998).         [ Links ]

16. L.J. Bellamy, The infrared spectra of complex molecules, (John Wiley, New York) 223, (1958).         [ Links ]

17. N.S. Bhacca, D.H. Williams, Application of NMR spectroscopy in organic chemistry (Holden Day San Fransisco) 79, (1964).         [ Links ]

 

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License