Selective reduction of α,β-unsaturated steroidal carbonyl compounds by NaBH4in presence of guanidine hydrochloride in dioxane

Article abstract of DOI:10.14233/ajchem.2014.16363

A selective hydrogenation of α,β-unsaturated steroidal carbonyl compounds with NaBH₄in the presence of guanidine hydrochloride in dioxane in good to excellent yields are described.

Full text of DOI:10.14233/ajchem.2014.16363

Asian Journal of Chemistry; Vol. 26, No. 19 (2014), 6331-6334
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16363
Selective Reduction of α,β-Unsaturated Steroidal Carbonyl Compounds
by NaBH in Presence of Guanidine Hydrochloride in Dioxane
4
1
,*
1,2
SALMAN AHMAD KHAN and ABDULLAH M. ASIRI
1
2
Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
*
Corresponding author: Fax: +966 2 6952292; Tel: +966 2 6952293; E-mail: sahmad_phd@yahoo.co.in
Received: 13 September 2013; Accepted: 19 February 2014; Published online: 16 September 2014;
AJC-15912
A selective hydrogenation of α,β-unsaturated steroidal carbonyl compounds with NaBH
dioxane in good to excellent yields are described.
4
in the presence of guanidine hydrochloride in
Keywords: Guanidine, Steroids, Dioxane, Reduction.
operation it is termed a direct reductive alcohal reaction.A variety
of reducing agents, such as hydrogen in the presence of metal
INTRODUCTION
2
catalysts , Bu
0
21
22
23
Hydrogen-transfer reactions are advantageous with
3
3 3
SnH-DMF , NaBH CN , NaBH(OAc) ,
25
1
24
respect to other reduction methods because of several reasons
the hydrogen donor is easy to handle (no gas containment or
pressure vessels are necessary), low-cost and environmentally
3 4 3 12
pyridine-BH NaBH -H P O40 have been developed. How-
ever, in terms of functional group tolerance, side reactions
and reaction conditions such reducing agents have many limita-
tions. For example, catalytic hydrogenation is attractive from
economical and ecological viewpoints, despite its incompa-
tibility with compounds containing other reducible functional
groups such as carbon-carbon double or triple bond, cyano
2
3
friendly (e.g., isopropanol) possible hazards are minimized ,
the mild reaction conditions applied can afford enhanced
4
selectivity , catalytic asymmetric transfer hydrogenation can
5,6
be applied in the presence of chiral ligands . The transfer
hydrogenation of ketones has been mostly accomplished using
isopropanol as hydrogen donor under homogeneous conditions
in the presence of noble metal complexes (e.g., Ru, Rh, Ni and
26
and furyl groups .
The direct reaction (a one-pot three component conden-
sation reaction) is interesting and important, not only because
two bonds are formed in one-pot, but in many cases, also offers
considerable synthetic advantages in terms of broad variety
of compounds and simplicity of the reaction procedure. Usually
7,8
Ir) . In this field, ruthenium complexes have been by far the
most studied catalysts, especially for the asymmetric transfer
9-11
hydrogenation of aromatic ketones and from the mechanistic
point of view. It is worthwhile, however, developing new hetero-
that, generally, can simplify the catalytic
3 3
NaBH CN and NaBH(OAc) from commercial sources are
12-14
geneous catalysts
utilized to carry out this transformation. It can be carried out
under mild conditions and is compatible, in some cases, with
many functional groups. However, the processes based on such
system, use low-cost transition metals, simplify the purification
step and be recycled and reused without significant loss of
activity. In this sense, nickel appears as a potential alternative
to the above expensive transition metal complexes but very
less studied in hydrogen transfer reactions with isopropanol.
3
reducing agents have many limitations. NaBH CN is expensive
and highly toxic and it may contaminate the product with
27
NaCN and generate toxic HCN upon work-up . Consequently,
the selection of the reagents and conditions is very crucial.
But no work on α,β-unsaturated steroidal carbonyl compounds.
If one can perform the direct reduction of carbonyl compounds
in air, it would be of considerable interest. Consequently,
introduction of new procedure that alleviates or eliminates the
above mentioned problems it should be a useful contribution
in organic synthesis. We have approached this challenge to
1
5
It has been used either under homogeneous (NiBr - NaOH
2
16
and a macrocyclic nickel complex-NaOH ) or heterogeneous
18
conditions (NiCl -i-PrOLi , Ni-stabilized zirconia-KOH and
2
17
19
mesoporous NiMCM-KOH ) mainly for aromatic substrates.
In all these cases, the addition of an external base was manda-
tory for the reaction to take place. When a mixture of carbonyl
compound is treated with appropriate reducing agent in a single

6
332 Khan et al.
Asian J. Chem.
discover a new reagent from the viewpoint of both process
and green chemistry. After surveying many of commercially
available hydride reagents, we selected sodium borohydride
as the least expensive, safe to handle and environmentally
friendly reducing agent, which can particularly be used for
large-scale reductions.
unsaturated steroidal carbonyl compounds with using
4
guanidine hydrochloride (5 mol %)/NaBH in dioxane at room
temperature and after the usual work up alcohol was obtained
in 80-95 % isolated yield. These encouraging results prompted
us to further investigate the use of guanidine hydrochloride/
4
NaBH as reducing agent. We have been studying the use of
We report the results of our investigations for direct
reduction of α,β-unsaturated steroidal carbonyl compounds
by sodium borohydride/guanidine hydrochloride in dioxane.
In addition, reactions in aqueous medium eliminate the addi-
tional efforts of preparing anhydrous substrates and reagents
before use (Scheme-I). Unique properties of dioxan can be
utilized to realize reactivity and selectivity that attained in
organic solvents. At first, we carried out the reduction of α,β-
α,β-unsaturated steroidal carbonyl compounds for the synthesis
of the corresponding allyl alcohols. Allyl alcohols are impor-
tant intermediates in the production of pharmaceuticals,
agrochemicals and fragrances. Chemo selective reduction of
conjugated carbonyl compounds is a common reaction exten-
sively used in synthetic chemistry and industry. Many useful
methodologies for selective 1,2-reduction of α,β-unsaturated
carbonyl compounds have been developed through metal
HO
Thionyl chloride
Acetic anhydride Pyridine
Na
amyl alcohol
Cl
AcO
(2)
(
3)
(
1)
t-Butyl chromate
t-Butyl chromate
t-Butyl chromate
O
(
6)
Cl
O
AcO
O
(
5)
(
4)
NaBH4
Gu. HCl
Gu. HCl
NaBH4
Gu. HCl
NaBH
4
OH
Cl
OH
AcO
OH
(8)
(9)
(
7)
Scheme-I

Vol. 26, No. 19 (2014)
4
Selective Reduction of α,β-Unsaturated Steroidal Carbonyl Compounds by NaBH 6333
28
hydride mediated reductions . The most widely accepted of
these involves sodium borohydride in the presence of cerium
chloride. This has been optimized to give excellent selectivity
RESULTS AND DISCUSSION
The starting material 3β-acetoxycholest-6-one (1), 3β-
3
3,34
29-32
chloro-cholest-6-one (2), 5α-cholest-6-one (3)
were
under mild condition . We now report that guanidine hydro-
chloride (5 mol %)/NaBH in dioxane effects a facile and smooth
reduction of α,β-unsaturated steroidal carbonyl compounds
16
prepared according to the published methods . Reduction of
α,β-unsaturated steroidal carbonyl compounds by sodium
borohydride/guanidine hydrochloride in dioxan. as shown in
4
to produced exclusively the corresponding allylic alcohols.
17
Scheme-I . All the compounds were soluble in DMSO and
ethanol. The structures of all the compounds were established
EXPERIMENTAL
1
on the basis of spectral studies such as IR, H NMR, FAB mass
All the chemicals were purchased fromAldrich Chemical
Company (U.S.A) and were used without further purification.
The reactions were monitored by precoated aluminium silica
gel 60F 254 thin layer plates procured from Merck (Germany).
All melting points were measured with a capillary apparatus
and are uncorrected.All the compounds were routinely checked
spectra and the elemental analyses were carried out to check
the purity of the compounds.
Assignments of selected characteristic IR band positions
provide significant indication for the reduction of α,β-unsatu-
rated steroidal carbonyl compounds. All the compounds
-1
showed ν(C-OH) stretch at 3352-3344 cm and absence of
-1
absorption band at 1700-1630 cm also confirms the conver-
1
by IR, H NMR and mass spectrometry. IR spectra were
recorded in KBr on a Perkin-Elmer model 1620 FTIR spectro-
1
photometer. H NMR spectra were recorded at ambient tempe-
sion of -C=O group to -C-OH group. Further evidence for the
reduction of α,β-unsaturated Steroidal carbonyl compounds
1
was obtained from the H NMR spectra, which provide diag-
rature using a Brucker spectroscopin DPX-400 MHz spectro-
photometer in DMSO. FAB mass spectra were recorded on a
JEOL SX102 mass spectrometer using argon/xenon (6 kV, 10
mB gas). Column chromatography was performed on silica
gel (100-200 mesh). Anhydrous sodium sulfate was used as a
drying agent for the organic phase.
nostic tools for the positional elucidation of the protons.
Assignments of the signals are based on the chemical shifts
and intensity patterns. The reduction of α,β-unsaturated
steroidal carbonyl compounds all the compounds is shown as
brood singlet in the range 2.24-280 ppm, which is confirms
the conversion of -C=O group to -C-OH group. Characteristic
peaks were observed in the mass spectra of compounds 7-9,
which followed the similar fragmentation pattern. The spectrum
General procedure: To a solution containing guanidine
hydrocholiride (10 mg, 5 mol %) in dioxane (10 mL), was
added the α,β-unsaturated steroidal carbonyl (2 mmol) (4-6)
and the mixture vigorously stirred for 0.5 h at room tempe-
•+
of compound 7 showed a molecular ion peak (M ) at m/z 445,
•
compound 8 showed a molecular ion peak (M ) at m/z 423
+
rature. After, NaBH
4
(2 mmol, 1 equiv.) was added, the mixture
•+
was stirred for additional 0.5 h. Progress of the reaction was
monitored by TLC. The reaction mixture poured into ice cold
and compound 9 showed a molecular ion peak (M ) at m/z
387. Further fragmentation pattern of these compounds has
given in experimental section.
2 2 2 4
water and extracted with CH Cl , dried over Na SO , concen-
trated under vacuum and the crude mixture was purified by
column chromatography on silica gel (hexane:ethyl acetate,
ACKNOWLEDGEMENTS
2
:1) to afford pure products (7-9).
β-Acetoxycholest-5-en-7-ol (C29
This article was funded by the Deanship of Scientific
Research (DSR), King Abdulaziz University Jeddah. The
authors, therefore, acknowledged with thanks DSR technical
and financial support.
3
H
48
O
3
) (7): semi-solid
-1
yields: 88 %; IR (KBr, νmax, cm ): 3352 (OH), 2922 (C-H),
1
1
2
3
0
4
7
626 (C=C). HNMR (400 MHz, CDCl
.04 (s, 3H, CH OCO), 4.86 (br, m, w = 17 Hz, C3α-axical),
.2 (m, C7-H), 2.4 (br, s, OH) 1.4 (C10-CH ), 0.75 (C13-CH ),
.96, 0.84 (remaining methyl proton). Fab Mass (M .) at m/z
3
) δ: 5.45 (m, C6-H),
3
3
3
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