INTRODUCTION:
The ring opening reactions of epoxides are intriguing
research area that can still be considered interesting. Halohydrins are of
considerable importance in the synthesis of natural products and many organic
transformations. The isolation of some chlorinated
withanolides from the plants Withania and Actinus species was reported1 and suggested that the chlorine atom in these molecules
was derived from sodium chloride present in
the plants. Therefore, they performed a model reaction on withanolide ‘D’ using
sodium chloride on active support (silica gel) and the chlorohydrins was
obtained along with some other products. Various ring opening reactions
of epoxides with different reagents were also reported2,3. Alumina4-9
and silica gel10 provide a reaction site for various interesting
transformations. It also provides a reactive surface for the chromatographic
conversion of one functional group into another. The use of sodium chloride and
silica gel based reaction system are our current interest. In continuation of
the above work we describe the use of sodium chloride and silica gel for the
transformation of steroidal epoxides I11 and II12
to get chlorohydrins and other products.
EXPERIMENTAL:
Melting points were recorded
on a Kofler hot block apparatus and are uncorrected. IR spectra were determined
in KBr with Perkins Elmer 237 Spectrophotometer.
1HNMR spectrum were run in CDCl3 on
Bruker AV 400 instrument with TMS as internal standard and its values are given
in ppm (δ) 13C NMR were also
run in CDCl3 on Bruker DRX 300 and its values are given in
ppm (δ). TLC plates were coated with silica gel and spots were developed
in iodine chamber.
Synthesis of epoxides. Cholesterol or b-sitosterol (4gm) in chloroform (35ml) was treated with
a chloroform solution of perbenzoic acid (1.1mole) and kept at 0oC
for twenty hours. The mixture was then washed with water, sodium bicarbonate
solution (5%), water, sodium thiosulphate solution and again with water.
Removal of the solvent and crystallization from acetone gave 3b- hydroxy- 5,6α- epoxy- 5α-
cholestane(I), 2.5 gm, m.p 141oC, reported13
m.p. 142o C or 3b-
hydroxy- 5,6α- epoxy- 5α- stigmastane (II), 2.2 gm, m.p. 138o
C.
The epoxide I or II (500mg, 1.2
mmoles) in absolute methanol (200ml) was adsorbed over a powdered mixture of
silica gel and NaCl (125g, 2:1).The solvent was evaporated and the dry residue
was heated at 100oC for twenty four hours. The product was desorbed
over ethyl acetate and the residue was chromatographed over silica gel (20g). Elution
with petroleum ether/ether gave the compounds III- VIII (Fig. 1) which
were analysed on the basis of their elemental and spectral studies (Table 1and
2).
RESULTS AND DISCUSSION:
The reaction product of epoxide I on
elution with petroleum ether/ ether (50:1) gave a compound which was analysed
for C27H43OCl (positive Beilstein test). The composition
indicated that chlorine was incorporated while three hydrogen and oxygen were
lost during the reaction. This can be accommodated if we consider epoxide ring
opening with addition of HCl followed by loss of a water molecule and oxidation
by removal of 2H (oxidation of alcohol to ketone). This leads to various
possibilities such as III, IIIa, IIIb or IIIc.
The IR spectrum of the compound showed absorption bands at 1710, 1600 and 800
cm-1 and indicated the presence of a nonconjugated carbonyl group,
double bond and a carbon chlorine bond. No other significant band was observed.
The structure IIIa could be discarded on the basis of IR spectrum as
carbonyl group present was nonconjugated in nature. The NMR spectrum showed,
complex multiplet centered at δ2.01, with no clear integration, and methyl
protons at δ 1.16, 0.76 and 0.68. The absence of any vinylic proton in the
region δ 5.60 easily discarded the possibility of IIIa, IIIb
or IIIc (Fig. 2). This also suggested that the double
present (IR band at 1600) was tetrasubstituted and halogen is vinylic in
nature. These observations go in favour of the structure III, which can
account for the multiplet centered at δ 2.01 as ascribed to the C2, C4 and
C7 methylene protons. 13C NMR spectrum showed peaks at δ199.64
for C3, δ 123.56 for C5 and δ132.67
for C6. On the basis of above spectral data
the compound is characterized as 3-oxocholest-5-en-6-yl chloride (III).
Fig. 1. Reaction of epoxides I & II
using NaCl / silica gel gave the compounds III- VIII
Fig. 2. Possible structures of compound III are IIIa,
IIIb or IIIc
Further elution with petroleum ether/ ether (7:1) gave
a compound IV, which was analysed for C27H44O2
(negative Beilstein test). The IR spectrum of the compound IV showed a
band at 1710 cm-1, the broad signal could suggest the presence of
two carbonyl groups. No other significant band was observed in the IR spectrum.
The NMR spectrum of the compound was also devoid of any peak in the lower field
region. A complex multiplet centered at δ2.32 observed as methylene
envelope could be assigned to seven methylene protons at C2, C4, C7 and C5
which were α - to carbonyl groups. 13C NMR spectrum showed
peaks at δ 189.97 for C3 and δ 180.58 for
C6. By comparison with the authentic sample (m.p, mixed m.p, and TLC)14
the compound was identified as 3, 6-dioxo-5α-cholestane (IV).
Further elution with petroleum ether/ ether (1:1) gave
a compound V, which was analysed for C27H45O2Cl
(positive Beilstein test). The IR spectrum of the compound V, showed absorption
bands at 3390, 1710 and 760 cm-1 , which were assigned to a hydroxyl
group, a nonconjugated carbonyl group and carbon - chlorine bond ,
respectively. Absence of any band around 1600 cm-1 suggested the
absence of carbon – carbon double bond. The NMR spectrum of the compound showed
a multiplet at δ 4.18 integrating for one proton with W1/2 =8Hz
and could be assigned to equatorial proton at C6. A broadened singlet at δ
3.35 integrating for single proton and could be assigned to hydroxy
proton. A singlet was observed at 3.03 for two protons which could be assigned
to methylene protons of C4 in compound V. These methylene protons
were adjacent to carbonyl group and other side chain was flanked by OH group. A
multiplet at δ2.25 was ascribed to two protons at C2.Other signals as
singlets were observed at δ1.17, 0.93, 0.85 and 0.67(other methyl
protons). 13C NMR spectrum showed peaks at δ197.40 for C3, δ77.33 for
C5 and δ 32.40 for C6.On the basis
of above discussion the compound has been identified as
5-hydroxy-3-oxo-5α-cholestan-6β-yl chloride (V) .The structure
was again confirmed by the mixed m.p. and TLC with the authentic sample15.
Similarly, the reaction product of epoxide II,
on elution with petroleum ether/ ether (50:1) gave a compound VI, which
was analysed for C29H47OCl (positive Beilstein test). The
IR spectrum of the VI, showed absorption bands at 1710, 1620 and 800 cm-1
and suggested the presence of unconjugated carbonyl group, double bond and a
carbon halogen bond. In the NMR spectrum absence of any peak between the
δ5.0-6.0 showed that no vinylic proton was present, which means that
carbon carbon double was tetrasubstituted. A complex multiplet centred at
δ2.05 was observed with no clear integration and was assigned to methylene
protons at C2, C4 and C7. Other signals were observed at δ1.18, 1.05,
0.96, 0.78 and 0.65(other methyl protons).13C NMR spectrum showed
peaks at δ195.26 for C3, δ122.54 for C5 and
δ135.63 for C6. On the basis of
above spectral data the compound and in analogy with the similar compound can
best be characterized as 3-oxostigmast-5-en-6-yl chloride (VI).
Further elution with petroleum ether/ ether (8:1) gave
the compound VII, which was analysed for C29H48O2
showed negative Beilstein test. The IR spectrum of the VII, showed a
band at 1710 cm-1, which was assigned to two groups. Absence of any
band above 3000cm-1 indicated the absence of OH group
and it could be assumed that the two oxygen atoms present were in the form of
carbonyl groups. The NMR spectrum of the compound was also devoid of any
significant peak except a multiplet centered at δ 2.18, with no
clear integration and could be assigned to methylene protons present at C2, C4and
C7 and a single proton at C5 ,all the protons were α to two carbonyl
groups. Other singlets were observed at d 1.12, 1.08, 0.97, 0.86 and 0.78 (other methyl protons). 13C
NMR spectrum showed peaks at δ 190.91 for C3 and δ 175.51 for C6. On the basis of above spectral data the
compound can best be characterized as 3, 6-dioxo-5 α-stigmastane (VII).
On further elution with the same solvent (1:1) gave the
compound VIII, which was analyzed for C29H49O2Cl
showed positive Beilstein test. The IR spectrum of VIII, showed
absorption bands at 3400, 1715 and 760 cm-1 for a hydroxyl group, a
carbonyl group and carbon chlorine bond. The NMR spectrum of the compound
showed a multiplet at δ 4.20 integrating for one proton with W1/2=9Hz
which could be ascribed to equatorial proton at C6. A multiplet observed at δ3.35
also integrating for single proton was assigned to hydroxy group. Another
multiplet was observed at δ 3.12, integrating for two protons
ascribable to methylene protons of C4. A multiplet centred at δ 2.13 for
two protons was assigned to C2-H2.Other singlets were observed at
δ1.15, 1.08, 0.95, 0.83 and 0.69 (other methyl protons). 13C
NMR spectrum showed peaks at δ199.16 for C3, δ71.40 for C5 and δ33.66
for C6.On the basis of above discussion and in analogy with the similar
compound V, obtained in previous case the compound can
be characterized as 5-hydroxy-3-oxo-5α-stigmastan-6β-yl chloride (VIII).
The putative mechanism of the formation of products are shown (scheme 1 and 2).
Scheme 1
Scheme 2
CONCLUSION:
We conclude that the solid characterization of reaction
products III –VIII by spectroscopic methods is a convenient,
environmentally friendly, one pot transformation of steroidal epoxides I and
II. Above results as well as the mild reaction conditions make the
method highly useful.
ACKNOWLEDGEMENT:
The authors are thankful to Chairman Department of
Chemistry, AMU, Aligarh for providing necessary research facilities.
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