Synthesis of acylated steroidal olefins and their derivatives

Article abstract of DOI:10.1080/00397910903098714

Acylation of cholest-5-ene and cholest-5-ene 3-one with anhydrides in the presence of zinc chloride and characterization of products thus obtained on the basis of elemental analysis, spectral data, and chemical transformations are reported. Copyright Tayl

Full text of DOI:10.1080/00397910903098714

This article was downloaded by: [New York University]
On: 01 June 2015, At: 04:54
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Acylated Steroidal Olefins
and Their Derivatives
M. Mushfiq a , A. R. Khan a , Afreen Shamim a , Rakhshanda Rehman a
& Sultanat a
a Department of Chemistry , Aligarh Muslim University , Aligarh,
India
Published online: 23 Apr 2010.
To cite this article: M. Mushfiq , A. R. Khan , Afreen Shamim , Rakhshanda Rehman & Sultanat
(2010) Synthesis of Acylated Steroidal Olefins and Their Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:10, 1508-1515,
DOI: 10.1080/00397910903098714
To link to this article: http://dx.doi.org/10.1080/00397910903098714
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 40: 1508–1515, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903098714
SYNTHESIS OF ACYLATED STEROIDAL OLEFINS AND
THEIR DERIVATIVES
M. Mushfiq, A. R. Khan, Afreen Shamim,
Rakhshanda Rehman, and Sultanat
Department of Chemistry, Aligarh Muslim University, Aligarh, India
Acylation of cholest-5-ene and cholest-5-ene 3-one with anhydrides in the presence of zinc
chloride and characterization of products thus obtained on the basis of elemental analysis,
spectral data, and chemical transformations are reported.
Keywords: Acetic anhydride; anhydrous sodium sulfate; Baeyer–Villiger oxidation; carbon tetrachloride;
sodium bicarbonate solution (5%); zinc chloride
Acylation has shown interesting results,[1–3] and in the Friedel–Crafts method, the
b,c-unsaturated ketone is the main product.[4–6] No attempt has been reported of
similar studies on steroidal olefins, and our continued interest in oxygen-containing
steroids[7–9] prompted us to investigate similar reactions with steroidal olefins.
Cholest-5-ene(1),[10] on treatment with acetic anhydride and zinc chloride,
afforded two products with melting points of 92 ꢀC (3) and 125 ꢀC (4) (Figure 1),
which were almost identical in terms of composition and infrared (IR) spectral
values (Table 1). Distinguishing the isomeric products was made possible with the
1
help of H NMR spectra. Compound 3 showed a distorted doublet at d2.94 with
J ¼ 5.5 Hz for one proton ascribable to C6-aH (equatorial),[11] making the acetyl
group b (axial) oriented. For compound 4, the peak for the C6-proton was observed
at d 3.25 with J ¼ 11.9 Hz (b, axial-H), making the acetyl group a-oriented.
The chemical shift for the C4-vinylic proton is influenced by the orientation of
the C6-acetyl group. In compound 3, the proton appears at d5.67 (C6b-acetyl),
whereas in its isomer (4), the same proton appeared at relatively upfield d4.99
because of the carbonyl cone effect possible when the acetyl group is equatorially
oriented.[11]
This stereochemical assignment of the acetyl group in compounds 3 and 4 is
strongly supported by the observation that under electron-impart mass spectrometry
(EI-MS), the loss of the b-oriented acetyl group in compound 3 is much faster than
the same loss in compound 4.
Received March 19, 2009.
Address correspondence to Rakhshanda Rehman, Department of Chemistry, Aligarh Muslim
University, Aligarh 202002, India. E-mail: rakhshandaorg@rediffmail.com
1508

ACYLATED STEROIDAL OLEFINS AND THEIR DERIVATIVES
1509
Figure 1.
The same substrate (1) under similar conditions, using propanoic anhydride
and zinc chloride, furnished only one compound (mp 99 ꢀC) characterized as 6b-
propionyl cholest-4-ene (5). The stereochemical assignment of the propionyl group
(axial) is based on the observation of a multiplet at d2.88 (W1=2 ¼ 3 Hz) for one pro-
ton at C6 (equatorial). The elemental analysis and IR spectral values (Table 1) for
the compound are in full agreement with the structure (5).
The formulations 3, 4, and 5 find further support on the basis of preparation of
simple derivatives. The compounds 3–5 afforded the corresponding oximes 6, 7, and
8, respectively.

1510

1511

1512
M. MUSHFIQ ET AL.
Compound 3 under Baeyer–Villiger oxidation conditions using m-chloroper-
benzoic acid gave four products identified as 6b-acetoxycholestan-5-ene (9),
5a-cholestan-6-one (10),[12] [normal Baeyer–Villiger (B.V.) product], 6b-acetyl-
4a,5-epoxy-5a-cholestane (11), and 6b-acetyl-5a cholestan-4-one (12). Scheme 1
explains the formation of these products starting from compound 3.
Cholest-5-ene-3-one (2)[13] on treatment with acetic anhydride in the presence
of zinc chloride afforded two products: cholest-4-en-3-one (13)[13] and 6a-acetyl
cholest-4-en-3-one (14). Compound 13 is a simple isomerized product that refuses
the Friedel–Crafts reaction because the double bond is in conjugation with the car-
bonyl group, whereas the compound 14 is obtained by the Friedel–Crafts reaction
before the isomerization can take place.
The characterization of 14 is based on the 1H NMR spectrum, which gave two
signals of interest at d3.2 (W1=2 ¼ 9 Hz) and d5.96 for one proton each. These can be
ascribed to C6b-H and C4-vinylic H, and hence the acetyl group at C6 is a-oriented
(equatorial).
Compound 14, on oximation, gave a compound with a melting point of 145 ꢀC,
which was analyzed to show two nitrogen atoms. In its IR spectrum, the carbonyl
Scheme 1.

1513

1514
M. MUSHFIQ ET AL.
band was absent; therefore, it can be formulated as 6a-acetylcholest-4-en-3-one-
10,3-dioxime (15).
Baeyer–Villiger oxidation of 6a-acetylcholest-4-en-3-one (14) afforded methyl
4
a-5-epoxy-5a-cholestan-3-oxo-6a-carboxylate (16) and methyl 3-oxo-4aa,5-
epoxy-A-homo-5-a-cholestan-4-oxo-6-a-carboxylate (17). A similar attempt using
propionic anhydride–zinc chloride with cholest-5-ene-3one (2) gave the propionoxy
derivative (18). The data (Table 1) are in full agreement with the structure being 6b-
propionoxy-cholest-4-ene-3-one (18).
Similar treatment to 3b-chlorocholest-5-ene (1a)[14] resulted in simple replace-
ment of chlorine by the acetoxy group, whereas the 3b-acetoxy cholest-5-ene (1b)[15]
completely refused to react under the conditions.
EXPERIMENTAL
General Procedure for Acylation
A solution of cholest-5-ene (1) (2.5 g, 0.007 mol) in carbon tetrachloride (40 ml)
was added in small portions to a well-stirred mixture of acetic anhydride (20 ml) and
dry zinc chloride (1 g, 0.007 mol) over a period of 40–45 min. The temperature of the
reaction mixture was maintained between 0 and 5 ꢀC by external cooling. After the
addition was complete, stirring was continued for 8 h at room temperature under
anhydrous conditions. The reaction mixture was then poured into ice-cooled water.
The organic matter was extracted with carbon tetrachloride; washed successively
with water, sodium bicarbonate solution (5%), and water; and then dried over anhy-
drous sodium sulfate. Evaporation of solvent under reduced pressure afforded an oil,
which was chromatographed over silica gel (50 g). The column was eluted with light
petroleum ether to provide different fractions with increasing proportions of ether as
shown in Table 2.
Baeyer–Villiger oxidation was carried out according to the literature
procedure,[16] and the products are given in Table 2.
Oximation of the ketones as reported was carried out following the procedure
reported in the literature,[17] and the products are listed in Table 2.
REFERENCES
1. Hoffmann, M. R.; Tsushima, T. Acylation of olefins by acetyl hexachloroantimonate:
Selective formation of b,c-unsaturated ketones under kinetic control and mechanistic
rationale as an ene reaction. J. Am. Chem. Soc. 1977, 99(18), 2008. See also Kondakov,
I. L. Zh. Russ., Fiz-Khim-O-va. 1892, 24, 309 and Blanc, G. Bull. Soc. Chim. Fr. 1898,
19, 699.
2. Olah, G. A. Friedel–Crafts and Related Reactions; John Wiley: New York, 1964; vol. 3.
3. Groves, J. K. The Friedel–Crafts acylation of alkenes. Chem. Soc. Rev. 1972, 1, 73.
4. Deno, N. C.; Chafetz, H. Acetylation of 1-methylcyclohexene. J. Am. Chem. Soc. 1952,
74, 3940.
5. (a) Groves, J. K.; Jones, N. Aliphatic Friedel–Crafts reactions, part VI: Preparation of bc
unsaturated ketones by the acetylation of substituted cyclohexenes. J. Chem. Soc. (C)
1968, 2215; (b) Groves, J. K.; Jones, N. Aliphatic Friedel–Crafts reactions, part VIII:

ACYLATED STEROIDAL OLEFINS AND THEIR DERIVATIVES
1515
Preparation of unsaturated ketones by the acetylation of 1-alkylcyclopentenes. J. Chem.
Soc. (C) 1969, 608.
6. Beak, P.; Berger, K. R. Scope and mechanism of the reaction of olefins with anhydrides
and zinc chloride to give bc-unsaturated ketones. J. Am. Chem. Soc. 1980, 102, 3848.
7. Mushfiq, M.; Mudgal, G.; Manuel, T.; Shamim, A. Synthesis of some new arylmethyli-
dene steroidal compounds. J. Chem. Res., Synop. 1997, 12, 474.
8. Mushfiq, M.; Mudgal, G. Synthesis of some steroidal 1,5 benzothiazepine derivatives in
the stigmastane series. J. Chem. Res., Synop. 1992, 5, 168.
9. Mushfiq, M.; Iqbal, N. Synthesis of some steroidal 1,5 benzothiazepine derivatives. J. Ind.
Chem. Soc. 1988, 65, 132.
10. Anagnostopoules, C. E.; Fieser, L. F. Nitration of unsaturated steroids. J. Am. Chem.
Soc. 1954, 76, 532.
11. Bahacca, N. S.; Williams, D. H. Applications of NMR Spectroscopy in Organic Chemistry;
Holden Day: San Francisco, 1964.
12. Shoppee, C. W.; Jenkins, R. H.; Summers, G. H. R. Steroids and Walden inversion, part
XXXIX: The halogenation of 5a-cholestan-6-one and pyrolysis of 5-chloro-5a-
cholestan-6-one. J. Chem. Soc. 1958, 1657.
13. Fieser, L. F. Cholestrol and companions VII: Steroidal dibromides. J. Am. Chem. Soc.
1953, 75, 5421.
14. Baker, R. H.; Squire, E. N. Derived steroids, 1: Cholesteryl ketones. J. Am. Chem. Soc.
1948, 70, 1487.
15. Fieser, L. F.; Fieser, M. Steroids; Reinhold: New York, 1959.
16. Ahmad, M. S.; Siddiqui, A. H.; Shafiullah. Baeyer–Villiger oxidation of 3b-
acetoxycholest-5 ene-7-one and cholest-5 ene-7-one. Ind. J. Chem. 1970, 8, 786.
17. Ahmad, M. S.; Shafiullah; Mushfiq, M. Azasteroids from 3a,5a-cyclocholestan-6-one and
3b-bromo-5a-cholestan-6-one. Aust. J. Chem. 1971, 24, 213.