IBX in an ionic liquid: Eco-friendly oxidation of 17α- methylandrostan-3β,17β-diol, an intermediate in the synthesis of anabolic oxandrolone

Article abstract of DOI:10.1016/j.tetlet.2004.08.127

An easily available hypervalent iodine(V) reagent, 2-iodoxybenzoic acid (IBX) immobilized in the ionic liquid [bmim][Br] was found to be an efficient and eco-friendly protocol for the oxidation of 17α-methylandrostan- 3β,17β-diol (1). At ambient temperature oxidation of 1 with IBX gave mestanolone (2) in good yield and with an increased stoichiometric amount of IBX, oxidation adjacent to the carbonyl functionality (α,β- unsaturation) occurred to give dehydrogenated 17β-hydroxy-17α-methyl- Δ¹-androsten-3-one (3) as the major product in a one-pot reaction. The product is easily obtained by extraction with diethyl ether and evaporation of the solvent.

Full text of DOI:10.1016/j.tetlet.2004.08.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7585–7588
IBX in an ionic liquid: eco-friendly oxidation of
7a-methylandrostan-3b,17b-diol, an intermediate in the
synthesis of anabolic oxandrolone
1
Bhupender S. Chhikara, Ramesh Chandra and Vibha Tandon*
Medicinal Chemistry Research Laboratory, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
Received 14 April 2004;revised 6 August 2004;accepted 20 August 2004
Abstract—An easily available hypervalent iodine(V) reagent, 2-iodoxybenzoic acid (IBX) immobilized in the ionic liquid [bmim][Br]
was found to be an efficient and eco-friendly protocol for the oxidation of 17a-methylandrostan-3b,17b-diol (1). At ambient tem-
perature oxidation of 1 with IBX gave mestanolone (2) in good yield and with an increased stoichiometric amount of IBX, oxidation
1
adjacent to the carbonyl functionality (a,b-unsaturation) occurred to give dehydrogenated 17b-hydroxy-17a-methyl-D -androsten-
3
-one (3) as the major product in a one-pot reaction. The product is easily obtained by extraction with diethyl ether and evaporation
of the solvent.
2004 Elsevier Ltd. All rights reserved.
ꢀ
Oxandrolone
(17b-hydroxy-17a-methyl-2-oxa-5a-
The pentavalent iodine reagent, 1-hydroxy-1,2-benzio-
doxol-3(1H)-one-1-oxide (IBX) has been used for the
androsterone-3-one) is a well known 2-oxasteroid recog-
nized for its anabolic activity with negligible side
8
oxidation of alcohols to carbonyl compounds, oxida-
tions adjacent to carbonyl groups to form a,b-unsatu-
rated carbonyl systems and in the synthesis of various
1
effects. It is widely used in medicine as an anabolic
2
9
drug, for the promotion of weight gain following sur-
3
10
gery and to improve muscle weakness. It has also been
recommended for the treatment of osteoporosis, HIV-
wasting syndrome and HIV-associated muscle weak-
heterocyclic compounds. IBX has been known for
1
1
more than a century, although its presence in organic
synthesis has remained limited primarily due to its
12,13
remarkable insolubility in most organic solvents.
4
ness. Oxandrolone was first prepared in 1962. In its
synthesis from dehydroepiandrosterone;17 a-methyl-
androstan-3b,17b-diol (1), mestanolone (2) and 17b-
Very recently, Desai et al. reported the conversion of 2
1
4
into 3 using IBX in dimethyl sulfoxide (DMSO), the
only solvent in which IBX is appreciably soluble. As
the recovery of product from this solvent is very difficult
due to its high boiling point, it is an inconvenient solvent
for the synthesis.
1
hydroxy-17a-methyl-D -androsten-3-one (3) are impor-
tant intermediates. The synthesis of 3 from mestanolone
is a regioselective transformation. In earlier reports bro-
mination with molecular bromine followed by dehydro-
bromination was used to achieve this transformation,
but the isomers were formed with poor regioselectivity.
In another report, selective bromination with the bulky
brominating agent phenyltrimethylammonium tribro-
mide (PTT) was performed to improve the regioselectiv-
Ambient temperature ionic liquids especially those
based on 1,3-dialkylimidazolium cations, are attracting
growing interest as alternative reaction media for chem-
1
5,16
ical and biochemical transformations.
Since they are
5
ity. In all these earlier reported procedures hazardous
6
molecular bromine was used in the synthesis.
nonvolatile in nature without any detectable vapor pres-
sure, they have gained wide popularity in recent years
as environmentally benign solvents and have been
employed as reaction media for various organic reac-
In the last two decades, hypervalent iodine reagents
7
have enjoyed increasing popularity in organic synthesis.
17
18
tions such as alkylation, Heck reactions, Suzuki
21
reactions, oxidation and heterocyclization.
1
9
20
Keywords: Steroid;Oxidation;IBX;Mestanolone;Dehydrogenation;
Oxandrolone;Ionic liquid;[bmim][Br].
In our efforts to synthesize anabolic steroids via eco-
friendly methods with improved yields, we found that
*
Corresponding author. E-mail: vibhadelhi@hotmail.com
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.127

7586
B. S. Chhikara et al. / Tetrahedron Letters 45 (2004) 7585–7588
2
2
HO
HO
to form a homogeneous mixture. We report herein
the synthesis of mestanolone (2) and 17b-hydroxy-17a-
Me
O OH
Me
Me
Me
I
1
O
methyl-D -androsten-3-one (3), important intermediates
Me
Me
N
in the synthesis of the anabolic drug oxandrolone, by the
oxidation and dehydrogenation of 17a-methylandro-
stan-3b,17b-diol (1) with 2-iodoxybenzoic acid (IBX)
using 1-butyl-3-methylimidazolium bromide ([bmim]-
O
[
6
2 h
bmim]Br
o
0-70 C
HO
O
1
2
2
[
Br]) as the reaction medium (Scheme 1).
Br -
N
[
bmim]Br =
In a systematic study, we investigated the efficacy of the
oxidation of cyclic secondary alcohols with IBX in an
ionic liquid (Table 1). The reactions were performed un-
der different conditions by dissolving the alcohol in
Scheme 1. Oxidation of 1 with 1.2equiv of IBX in ionic liquid.
[
bmim]Br followed by addition of IBX. The representa-
ionic liquids were excellent reaction media for the oxida-
tion and dehydrogenation of steroids with 2-iodoxyben-
zoic acid. IBX dissolves in the ionic liquid [bmim][Br]
tive substrates cyclohexanol (entry 3) and cyclooctanol
(entry 4) were oxidized at room temperature with
1.2equiv of IBX to give cyclohexanone and cycloocta-
Table 1. Oxidative transformations with IBX in the ionic liquid [bmim]Br
a
Yield (%)
Entry
1
Substrate
Product
Conditions
1
2
IBX (1.2equiv), 65ꢁC, 2h
88
8
b
2
c
2
3
1
3
IBX (2.4equiv), 65ꢁC, 22h
IBX (1.2equiv), 25ꢁC, 2.5h
74
71
87
b,c
O
OH
OH
O
4
5
IBX (1.2equiv), 25ꢁC, 6h
IBX (3equiv), 80ꢁC, 4h
92
82
OH
O
O
O
6
7
IBX (1.4equiv), 75ꢁC, 7h
IBX (1.8equiv), 75ꢁC, 8h
84
86
O
O
OH
O
8
9
IBX (2.6equiv), 75ꢁC, 8h
IBX (2.8equiv), 75ꢁC, 14h
IBX (2.5equiv), 75ꢁC, 11h
IBX (2.5equiv), 85ꢁC, 11h
78
82
80
74
O
OH
O
1
0
1
OH
1
HO
O
a
b
c
Yield determined by gas chromatography.
Reaction repeated in recovered ionic liquid.
Methyltestosterone (8–10%) is also present.

B. S. Chhikara et al. / Tetrahedron Letters 45 (2004) 7585–7588
HO
HO
7587
HO
Me
Me
Me
Me
Me
Me
Me
H
IBX (2.4 eq.)
Me
Me
+
[
bmim]Br
o
6
5-70 C,
HO
O
O
24 h
H
1
74 %
3
8-10 %
4
Scheme 2. One-pot synthesis of 3 via IBX-mediated oxidation of 1 in the ionic liquid [bmim][Br].
none as the sole products. Further additional portion-
wise addition of IBX at the same temperature did not
lead to further oxidation of the product. However, dehy-
drogenation adjacent to the carbonyl functionality
occurred at elevated temperature. Replacing the alcohol
reaction mixture with pure cyclohexanone (entry 6) also
led to a similar observation. When the initial tempera-
ture of the reaction mixture was kept at 70–80ꢁC, the
portionwise continuous addition of 1.2equiv of IBX
yielded the corresponding ketone in much reduced time,
although a minor amount of the a,b-unsaturated ketone
was obtained due to further oxidation. With a stoichio-
metric increase of IBX with respect to the reactant, oxi-
dation with simultaneous dehydrogenation occurred
giving the corresponding a,b-unsaturated ketone
directly from the alcohols (entries 8–10). Having gained
the key information regarding the scope of this method-
ology, we turned our attention to more complex sub-
strate, the steroid alcohol 1. Steroid molecules were
considered to be the best testing ground for evaluation
of the efficacy of the developed system. Mestanolone
was the product ketone obtained on oxidation of 17a-
methylandrostan-3b,17b-diol (1) with 1.2equiv of IBX.
Previously this transformation was achieved with
secondary alcohols using the mild and inexpensive rea-
gent IBX at ambient temperature in the environmentally
benign ionic liquid [bmim][Br]. With the prospect of
recycling the ionic liquid and excellent yield of the prod-
ucts, this protocol will be potentially beneficial for
chemists for the synthesis of other steroid drugs.
2
5
Acknowledgements
The authors are thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for providing a
senior research fellowship to one of the authors (B.S.C.).
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