Synthesis of steroidal oxazolidine thiones in the cholestane series

Article abstract of DOI:10.1081/SCC-200034819

Steroidal α-epoxides (I, III, and VIII) on reaction with 4-fluorophenyl-isothiocyanate give the corresponding oxazolidine thiones (II, V, VI, VII, and XI) along with other products (IV and IX). Characterization of the compounds is based on spectral proper

Full text of DOI:10.1081/SCC-200034819

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Synthesis of Steroidal
Oxazolidine Thiones in the
Cholestane Series
Mohammad Mushfiq a , Thresiamma Manuel a &
Rakhshanda Rehman a
a Department of Chemistry , Aligarh Muslim
University , Aligarh, 202002, India
Published online: 10 Jan 2011.
To cite this article: Mohammad Mushfiq , Thresiamma Manuel & Rakhshanda
Rehman (2004) Synthesis of Steroidal Oxazolidine Thiones in the Cholestane Series,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:21, 3989-3996, DOI: 10.1081/SCC-200034819
To link to this article: http://dx.doi.org/10.1081/SCC-200034819
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 21, pp. 3989–3996, 2004
Synthesis of Steroidal Oxazolidine Thiones
in the Cholestane Series
*
Mohammad Mushfiq, Thresiamma Manuel,
and Rakhshanda Rehman
Department of Chemistry, Aligarh Muslim University, Aligarh, India
ABSTRACT
Steroidal a-epoxides (I, III, and VIII) on reaction with 4-fluorophenyl-
isothiocyanate give the corresponding oxazolidine thiones (II, V, VI,
VII, and XI) along with other products (IV and IX). Characterization of
the compounds is based on spectral properties and elemental analysis.
Key Words: Epoxides; Isothiocyanates; Steroidal oxazolidine thiones.
Epoxides are well recognized, useful intermediates for organic synthesis.[1–4]
Reported useful biological activities[5–9] with nitrogen and sulphur containing
heterocycles generated interest for the synthesis of simple oxazolidine-20-
thiones by the reaction of epoxides with isothiocyanates.[10]
*
Correspondence: Mohammad Mushfiq, Department of Chemistry, Aligarh Muslim
University, Aligarh-202002, India; E-mail: mushfigs@reddif.com.
3989
DOI: 10.1081/SCC-200034819
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3990
Mushfiq, Manuel, and Rehman
Such epoxides in the steroidal substrates have also been prepared and
used for obtaining other derivatives,[11,12] and our continued interest in the
field of steroids prompted us to try such reactions in order to obtain steroidal
oxazolidine derivatives. In the content for the present studies, easily accessible
epoxides 5,6a epoxy-5a-cholestane (I)[13] and its 3b-acetoxy and 3b hydroxy
analogues (III)[14] and (VIII)[15] were subjected to the reaction with easily
available and previously studied p-fluorophenyl isothiocyanate in DMF with
LiBr as the catalyst. We report the formation and characterization of
corresponding oxazolidine thiones (II, V, VI, VII, and XI) along with other
products.
The characterization is based on elemental analysis in each new com-
1
pound formed (Table 1) and spectral properties including IR and HNMR
(Table 2).
The epoxide (I), when allowed to react with 4-fluorophenylisothiocynate,
on usual workup and column chromatography afforded a pure solid with m.p.
1318 (II) along with unresolved mixture, which could not be pursued further.
The compound m.p. 1318 showed ir bands at 1520–1500 cm21 characteristic
of oxazolidine ring[10] along with peaks at 1570, 830 cm21 for the aromatic
ring. This clearly indicated the incorporation of the reagent. On the basis of

Synthesis of Steroidal Oxazolidine Thiones
3991
Table 1. Reaction of epoxides(I), (III), and VIII with p-fluorophenylisothiocyanate.
Starting
compound
Solvent
system
Crystallized
from
Yield
%
M.P.
8C/oil
Product
I
II unresolved
mixture
4 : 1
MeOH
26.86
131
1 : 1
20 : 2
20 : 6
20 : 7
10 : 2
10 : 3
—
MeOH
MeOH
—
30.00
10.63
21.64
19.34
16.66
25.36
oil
143
194
oil
III
VIII
IV
V
VI þ VII
IX
MeOH
—
184
oil
X þ XI
the mechanism reported,[10] it was formulated as 5a-cholestano [5,6a:5040]-
30(p-flourophenyl) oxazolidine-20-thione(II). The n.m.r spectrum supported
the structure proposed by a broad signal at d 6.7 for four aromatic protons.
Another signal at d 3.3 as a multiplet can be ascribed to C6-H, and the half-
band width (7 Hz) clearly suggests it to be axial b-oriented, thus rendering
nitrogen as a-oriented.
Under similar conditions, epoxides (III) provided three fractions A, B,
and C on chromatographic separation. Fraction A obtained as pure compound
on crystallization has been identified as 3b-acetoxy-7a-bromo-5a-cholestane-
6-one (IV).[16] Fraction B also obtained as pure crystalline substance showed
the presence of N, S, and O on elemental analysis. The ir spectrum of this com-
pound indicated presence of NH (3475 cm21), CH3COO (1730, 1255,
1020 cm21), and oxazolidine ring (1520–1500 cm21 [10]
but it did not show
)
any band in the aromatic proton region. On the basis of these studies, many
isomeric structures can be drawn, such as V, and Va-g in agreement with
elemental analysis and ir spectrum. The structure V is preferred on account
of the n.m.r spectrum of this compound, which accounts for all the signals
in a better way. The singlet at d 8.0 is ascribed to N-H[17] and the multiplet
d 5.1 with w 1/2 ¼ 20 Hz is ascribed to C3a axial proton, suggesting that
junction A/B is trans. The important signal at d 4.72 as broadened singlet
for one proton can be accounted for by considering it to the C6b-H, thus ren-
dering oxygen as a-oriented. Hence, this compound is characterized as 3b-
acetoxy-5a-cholestano [5, 6a: 40,50] oxazolidine-20-thione (V).
The third fraction obtained as oil showed the presence of two components
of very close Rf and could not be separated. Elemental analysis corresponds to
composition C36H53O3NSF. The i.r. spectrum showed bands at 1725, 1720
(C55O), 1625 (aromatic ring), 1520–1500 (oxazolidine ring), and 1240,

3992
Mushfiq, Manuel, and Rehman
b
a
a
b
a
a
b
b
b

Synthesis of Steroidal Oxazolidine Thiones
3993
a
b
a
a
a
b

3994
Mushfiq, Manuel, and Rehman
1205, and 1020 cm21 (C-O). Two carbonyl peaks also support it to be a
mixture and suggest that one is for equatorial acetate (A/B trans) (VI) and
the other is for axially oriented acetate (A/B cis) (VII). This is further sup-
ported by the n.m.r. spectrum displaying two multiplets d 5.12 and 5.55
each integrating for 1/2 proton with W 1/2 ¼ 20 & 7 Hz, respectively.
Another pair of signals as multiplet for 1/2 proton each is observed at d
3.5 (W 1/2 ¼ 18 Hz) and 4.12 (W 1/2 ¼ 19 Hz), both being b-oriented can be
accounted for by considering it to be C6 proton when C6 is attached to nitro-
gen as in (VI) and when C6 is attached to oxygen[17] as in (VII), respectively.
Other signals (Table 2) are observed as usual and hence this fraction can best
be characterized as a mixture of 3b-acetoxy-5a-cholestano [5, 6a: 50, 40]-30-
(p-fluorophenyl) oxazolidine-20-thione (VI) and 3b-acetoxy-5b-cholestano
[5,6a: 40,50]-30-[p-fluorophenyl) oxazolidine-20-thione (VII).
Epoxide (VIII) under similar conditions gave two fractions, which on the
basis of the similar studies as described with (III), are characterized as com-
pound (IX) and a mixture of (X) and (XI), respectively (see Table 2).
The mechanism proposed[10] can account for the formation of (II), (V),
(VI), (IX), and (X) but the products (VII) and (XI) need special mention for
their formation. It is suggested that (Sch. 1) C5 being a tertiary carbon
favors the formation of carbocation followed by nucleophilic attack by nitro-
gen in SN1 type rather than SN2 type as suggested earlier.[10] This could also
be considered as a concerted process of attack of nitrogen to C5 and the attack
Scheme 1.

Synthesis of Steroidal Oxazolidine Thiones
3995
of oxygen to carbon of isothiocyanate moiety, but with this one would expect
a-attack on C5 more favorable. Hence, the stepwise mechanism is preferred in
this case for formation of product with ring junction A/B cis.
EXPERIMENTAL
Melting points determined on a Kofler block are uncorrected, i.r. spectra
were determined in KBr/CCl4 with a 408-Shimadzu spectrophotometer, and
n.m.r spectra were run in CDCl3 on a Varian FT 8 A instrument with TMS
as internal standard. T.l.c. plates were coated with silica gel and spots were
developed in iodine chamber.
Reaction of steroidal epoxide with p-flurophenylisothiocyanate: General
Procedure — A solution of the epoxide (1 g, 2.59 mmol) in dimethyl form-
amide (20 mL) was mixed with an equimolar quantity of p-flurophenyl isothio-
cyanate and catalytic amount of lithium bromide at room temperature. The
reaction mixture was then refluxed under anhydrous conditions and the pro-
gress of the reaction was monitored by t.l.c. After completion of the reaction
the mixture was poured into water and extracted with ether. The ethereal
extract was washed with water, sodium bicarbonate (5%), and water, and
then dried over anhydrous sodium sulphate. Evaporation of the solvent gave
an oily residue (ca. 0.95 g), which was chromatographed over a column of
silica gel (25 g). Elution with light petroleum (b.p. 60–808C): diethyl ether
gave the products as shown in Table 1. Analytical and spectral data of the pro-
ducts are given in Table 2.
REFERENCES
1. Elderfield, R.C. Heterocyclic Compounds; John Wiley and Sons, Inc.:
New York, 1950; Vol. I.
2. Feinauer, R.; Jacobi, M.; Hamann, K. Ber. 1965, 98, 1782.
3. Etalis, V.S.; Sinekov, A.P.; Razuvaev, G.A.; Zh. Obshih. Khim. 1975, 62,
9132.
4. Ansari, M.H.; Saeed, M.T.; Ahmad, M. J. Chem. Res(s) 1990, 126.
5. Spencer, R.P.; Husain, H. Med. Hypothesis 1980, 6, 190.
6. Duff, D.A.; Price, S.C.; Snell, K. Biochem. Soc. Trans. 1980, 8, 574.
7. Kinoshita, T.; Watanabe, H.; Tamura, C.; Nishimura, T. Jap. P. 79, 132,
571/1979; Chem. Abstr. 1980, 92, 111016.
8. Takeuchi, H.; Yokai, I.; Kurono, M. Neuropharmacology 1977, 16, 849.
9. Ancher, J.F.; Bourger, G.; Dostert, P.; Douzon, C.; Guerret, L.A.;
Langlois, M. Fr P 2, 458, 547/1981; Chem. Abstr., 1981, 95, 132868.

3996
Mushfiq, Manuel, and Rehman
10. Ansari, M.H.; Ahmad, M. J. Chem. Research (M) 1990, 1733–1743.
11. Mushfiq, M.; Mudgal, G. J. Chem. Research(s) 1992, 168.
12. Mushfiq, M.; Mudgal, G.; Manuel, T.; Shamim, A. J. Chem. Res(s) 1997,
474.
13. Robert, E.I.; Wringly, T.I.; Young, W.G. J. Amer. Chem. Soc. 1958, 80,
4604.
14. Fieser, L.F.; Fieser, M. Steroids; Reinbold: New York, 1959.
15. Westphalen, T. Ber. 1915, 48, 1064.
16. Heilburon, I.M.; Jones, E.R.H.; Spring, F.S. J. Chem. Soc. 1987, 801.
17. Bhacca, N.S.; Williams, D.H. Application of NMR Spectroscopy in
Organic Chemistry; Holden-Day: San Francisco, 1964.
Received in India May 7, 2004