CrO3/NHPI adsorbed on activated clay: A new supported reagent for allylic selective oxidation of Δ5-sterols

Article abstract of DOI:10.1080/00397910802484114

Chromium trioxide and N-hydroxyphthalimide (NHPI) supported on activated clay could serve as an efficient and mild oxidant for allylic selective oxidation of Δ5-sterols. Thus, a ketone group could be easily introduced into the allylic position of Δ5-sterols with the existence of a sensitive 3β-hydroxyl group. The oxidant residue can be removed easily from the reaction mixture by filtration and reused after reactivation at 120δC for 4-6 h. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802484114

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CrO3/NHPI Adsorbed on
Activated Clay: A New
Supported Reagent for Allylic
Selective Oxidation of Δ5-
Sterols
Jin Liu a , Hong-You Zhu a & Xiao-Hong Cheng a
a Department of Chemistry , Key Laboratory of
Medicinal Chemistry for Natural Resources (Ministry
of Education), Yunnan University , Kunming, China
Published online: 25 Feb 2009.
To cite this article: Jin Liu , Hong-You Zhu & Xiao-Hong Cheng (2009) CrO3/
NHPI Adsorbed on Activated Clay: A New Supported Reagent for Allylic Selective
Oxidation of Δ5-Sterols, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:6, 1076-1083, DOI:
10.1080/00397910802484114
To link to this article: http://dx.doi.org/10.1080/00397910802484114
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Synthetic Communications1, 39: 1076–1083, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802484114
CrO3/NHPI Adsorbed on Activated Clay: A New
Supported Reagent for Allylic Selective
Oxidation of D5-Sterols
Jin Liu, Hong-You Zhu, and Xiao-Hong Cheng
Department of Chemistry, Key Laboratory of Medicinal Chemistry for
Natural Resources (Ministry of Education), Yunnan University,
Kunming, China
Abstract: Chromium trioxide and N-hydroxyphthalimide (NHPI) supported on
activated clay could serve as an efficient and mild oxidant for allylic selective oxi-
dation of D5-sterols. Thus, a ketone group could be easily introduced into the
allylic position of D5-sterols with the existence of a sensitive 3b-hydroxyl group.
The oxidant residue can be removed easily from the reaction mixture by filtration
and reused after reactivation at 120 ꢀC for 4–6 h.
Keywords: Activated clay, allylic oxidation, CrO3=NHPI, 7-keto-D5-sterols,
supported reagents
7-Keto-D5-sterols are found in animal tissues, food products, and certain
folk medicines and are reported as inhibitors of sterol biosynthesis,
HMG-CoA reductates, and cell replication.[1] Therefore, a great number
of oxidants for allylic oxidation of D5-sterols are developed to obtain 7-
keto-D5-sterols. The most common allylic oxidants used are CrO3
complexes, such as Collins reagent,[2] pyridinium chlorochromate
(PCC),[3] pyridinium dichromate (PDC),[4] CrO3-3,5-dimethylpyrazole,[5]
Received June 24, 2008.
Address correspondence to Xiao-Hong Cheng, Department of Chemistry,
Key Laboratory of Medicinal Chemistry for Natural Resources (Ministry of
Education), Yunnan University, Kunming, Yunnan 650091, China. E-mail:
xhcheng@ynu.edu.cn
1076

Allylic Selective Oxidation of D5-Sterols
1077
pyridinium fluorochromate (PFC),[6] and so on. However, a large excess
of oxidants (about 10–30 equiv.) must be applied in this process, which
led to a difficult workup process and production of environmentally
hazardous chromium residues. Recently, low molar ratios of the oxidants
are realized by using CrO3=NHPI in a cosolvent system of water and
organic solvents[7] however, the complicated separation procedure and
difficult disposal of the toxic chromium residues remained unsolved.
Many supported reagents were studied, and some provided particu-
larly environmentally friendly mild procedures in acceptable yields,[8]
Among them, Cr(VI)-supported reagents were used as efficient oxidants
for the transformation of hydroxyl compounds to carbonyl com-
pounds;[9] unfortunately only few are related to the allylic oxidation.[10]
In this article, we report that CrO3 and N-hydroxyphthalimide (NHPI)
adsorbed on activated clay could be applied as a new supported reagent
for allylic selective oxidation of D5-sterols. The reactions were carried out
under room temperature, the chromium residues could be easily removed
from reaction mixture by filtration and reused by reactivation at 120 ꢀC
for 4–6 h. The structures of the products were characterized by infrared
(IR) and NMR. The sensitive 3b-hydroxyl groups in the D5-sterols
remained uninfluenced.
As far as we know, reported oxidants, including CrO3 complexes or
t-butyl hydroperoxide (TBHP), combined with different types of catalysts
or cooxidations,[11] when used as allylic oxidants of 3b-hydroxyl
D5-sterols. In most cases, the 3b-hydroxyl group should be protected
before oxidation, usually as the acetate or benzoate ester[1]; if not, 3b-
hydroxyl group would be oxidized to a ketone group. For example,
oxidation of steroidal 5-en-3b-ol (via intermediate 5-en-3b-one) yielded
4-en-3,6-diones instead of 7-one-5-en-3b-ol using of Jones reagent[12] or
PCC.[13]
To demonstrate the validity and regioselectivity of the
CrO3=NHPI-activated clay system developed herein, some model com-
pounds were tested, and the results are summarized in Table 1. In all
cases, the 7-keto-D5-sterols were synthesized successfully in acceptable
yields by using this supported oxidizing system; the 3b-hydroxyl group
remained uninfluenced as concluded from the IR and NMR spectra of
the corresponding oxidized products (compounds 1a–1e) (Scheme 1).
For D5-steroid with the protected 3b-hydroxyl group (compound 1f),
the allylic oxidation remained similar, but increasing reaction rate and
oxidizing yield were observed (Scheme 2). The oxidant residue can be
recovered by reactivation at 120 ꢀC for 4–6 h and reused for the
new oxidizing reaction. For example, oxidizing compound 1f with the
recovered oxidant still gave 2f in good yield (60%). Note that for com-
pound 1g, after the oxidizing reaction, the acetal protecting group was

1078

1079

1080
J. Liu, H.-Y. Zhu, and X.-H. Cheng
Scheme 1. Allylic selective oxidation of compounds 1a–e to compounds 2a–e.
1
cleaved to 2a (as concluded from H NMR and 13C NMR). Probably
the oxidizing conditions used here are not mild enough for the acid-sen-
sitive acetal protecting group in 1g to survive the transformation
(Scheme 3).
In summary, CrO3=NHPI-activated clay in CH2Cl2 proved to be an
effective oxidant for allylic oxidation of D5-sterols. In this way, allylic
hydrogen atoms of D5-sterols could be oxidized to a ketone group with
the existence of the sensitive 3b-hydroxyl group, and the chromium
residues can be removed easily by filtration after the reaction and reused
after reactivation at 120 ꢀC for 4–6 h.
Scheme 2. Allylic selective oxidation of compound 1f with protected 3b-hydroxyl
group to compound 2f.

Allylic Selective Oxidation of D5-Sterols
1081
Scheme 3. Allylic selective oxidation of compound 1g to compound 2a
accompanied by cleavage of the acetal protecting group.
The reactions can be carried out under mild condition with moderate
yields. This procedure expands the utility of supported reagents as an
efficient method for allylic selective oxidation of D5-sterols.
EXPERIMENTAL
Preparation of CrO3/NHPI-Activated Clay-Supported Oxidant
Solid chromium trioxide (10 g, 100 mmol) was dissolved in water (15 ml)
at 40 ꢀC; NHPI (5 g, 260 mmol) was added. The mixture was stirred for
20 min; then water (15 ml) and activated clay (/ < 75 mm) (45 g) were
added. The mixture was further stirred for 10 min and then dried in
vacuum. The dry mixture was ground with a mortar and obtained finally
as a kind of brown powder.
Oxidation of 3b-Hydroxyl-D5-Sterols: Typical Procedure
To a solution of 3b-hydroxyl-D5-sterols (5 mmol) in CH2Cl2 (120 ml), the
CrO3=NHPI-activated clay-supported oxidant (5.8 g, CrO3 content,
8 mmol) was added at rt with stirring. After 10 h to 24 h, an additional
amount of CrO3=NHPI-activated clay-supported oxidant (5.8 g, CrO3
content, 8 mmol) was added portionwise during a period of 10 h. After
that, the reaction mixture was further stirred until the reaction completed
(thin-layer chromatography, TLC, control) (about 24 h to 48 h). The mix-
ture was filtered through a bed of activated clay and washed with dichlor-
omethane. The combined filtrate was washed repetitively with saturated
Na2CO3 solution until no orange color was observed in the organic layer
(at this moment, almost all the NHPI residues were removed). The
organic layers were then washed with brine and water and dried over
MgSO4; the solvent was evaporated in vacuum. Purification of the

1082
J. Liu, H.-Y. Zhu, and X.-H. Cheng
product was done by column chromatography (eluent: petroleum=ethyl
acetate 3=1).
ACKNOWLEDGMENTS
Thanks are due to Prof. Fu-Chu Liu (Yunnan University) for helpful
criticism of the manuscript. This work was supported by the National
Natural Science Foundation of China (No. 20472070) and the Yunnan
Science Foundation (No. 2005E008M).
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