The allylic oxidation of unsaturated steroids by tert-butyl hydroperoxide using
homogeneous and heterogeneous cobalt acetate†
Jorge A. R. Salvador and James H. Clark
Clean Technology Centre, Chemistry Department, University of York, York, UK YO10 5DD
Received (in Liverpool, UK) 8th September 2000, Accepted 14th November 2000
First published as an Advance Article on the web 11th December 2000
Cobalt acetate is an effective catalyst for the selective allylic
oxidation of unsaturated steroids using tert-butyl hydro-
peroxide especially when used in a supported form when it
can be easily recovered and reused.
Allylic oxidation is a reaction of fundamental importance in
organic chemistry with applications in areas ranging from
agricultural products to pharmaceuticals.1,2
5
The allylic oxidation of unsaturated steroids such as D -
steroids has traditionally been carried out with chromium
reagents such as CrO3–pyridine complex,3 chromium trioxide
and 3,5-dimethylpyrazole,4 pyridinium chlorochromate,
(PCC),5,6 pyridinium dichromate (PDC),6 sodium chromate,7
sodium dichromate in acetic acid8 and pyridinium fluoro-
chromate.9 However the large excess of reagent used in these
procedures along with a difficult work-up and production of
extract was washed with aq. saturated solution of NaHCO3,
environmentally hazardous chromium residues, makes these
water, dried and evaporated to dryness to give 7,17-dioxo-
reactions increasingly unacceptable on a commercial scale. Of
androst-5-en-3b-yl acetate. These reactions are very selective
greater preparative interest has been the use of hydroperoxides
compared to those carried out using Fe(acac)3 as catalyst
combined with different types of catalysts.10–17 Despite the
reported by Kimura et al.15,16 Mo(CO)6 has also been described
good yields reported with CrO3,10 hexacarbonylchromium
as catalyst for this reaction, but this led to epoxidation of the
Cr(CO)6,11,12 pyridinium dichromate13 and RuCl314 to prepare
cholesteryl acetate under similar oxidative conditions.16
5
allylic oxidation products from D -steroids, the toxicity of the
While the product yields of the allylic oxidations are very
chromium compounds and the high cost of the ruthenium
similar under homogeneous and heterogeneous conditions, the
catalyst renders the procedures unsuitable for commercialisa-
easier recovery of the catalyst in the heterogeneous reactions
tion and led us to recently report the use of cuprous salts, CuBr,
make these more environmentally friendly processes. Fur-
CuCl, Cul, and a cupric salt CuCl2, as well as copper metal as
thermore using the heterogeneous catalysts 2 and 3 it was
catalysts for this type of reaction.17
possible to reuse the catalyst with only a small reduction in the
Allylic oxidation of steroids, particularly at the 7-position,
product yields, under similar experimental conditions (80% for
5
has attracted interest over many years. The D -steroids can be
recycled catalyst 2 and 81% for recycled catalyst 3, Table 1).
oxidised to 5-en-7-ones, which are known as inhibitors of sterol
Our catalytic method is also effective for other unsaturated
biosynthesis and have some use in cancer chemotherapy.18 This
4
steroids. Thus the D -steroid 14 gives the testosterone acetate
has encouraged us to find new, more environmentally accept-
15, in a yield of 70% (Scheme 2). Furthermore, the method is
able methods for this reaction. The heterogenisation of
also effective in the presence of an oxidatively vulnerable
inorganic reagents and catalysts useful in organic reactions is a
secondary alcohol group. The steroid 16 is oxidised to the
very important area in clean technology.19 In this communica-
alcohol product 17 with impressive selectivity (71%) (Scheme
tion we report the use of cobalt acetate in homogeneous,
2).
(Co(OAc)2·4H2O), and more importantly, heterogeneous forms
In summary we have discovered a new efficient and
(catalysts 1, 2, and 3 prepared as reported previously20,21) for
relatively environmentally friendly method for the preparation
this type of allylic oxidation reaction.
5
Using D -steroids 4–7 and 12 as substrates (Scheme 1) allylic
oxidation products 8–11 and 13 were obtained in very high,
isolated yields, 70–86% (Table 1). Apart from the reaction with
substrate 6 which required benzene as solvent and a temperature
of 70 °C all the reactions were performed in acetonitrile using a
milder temperature of 50–55 °C. The best results were obtained
using the supported catalyst 3 which may be a result of its
greater organophilic character. No significant reaction occurs in
the absence of catalyst or in the presence of the catalyst support
only.
In a typical reaction to a solution of 17-oxoandrost-5-en-3b-
yl acetate 4 (660.90 mg 2 mmol) in acetonitrile (12 ml) under
nitrogen, catalyst 3 (60 mg, cobalt loading 0.41 mmol g21) and
tert-butyl hydroperoxide (ca. 2.4 ml 12 mmol) were added.
After 24 h under magnetic stirring at 50 °C, the catalyst was
removed by filtration and the solution was poured into sodium
sulphite solution (10% aq.) and extracted with diethyl ether. The
† UK Patent applied for.
Scheme 1
DOI: 10.1039/b007447k
Chem. Commun., 2001, 33–34
33
This journal is © The Royal Society of Chemistry 2001
Salvador
