N-Hydroxyphthalimide catalyzed allylic oxidation of steroids with t-butyl hydroperoxide

Article abstract of DOI:10.1016/j.steroids.2014.12.004

A new and optimized procedure for the allylic oxidation of Δ⁵-steroids with t-butyl hydroperoxide in the presence of catalytic amounts of N-hydroxyphthalimide (NHPI) under mild conditions was developed, showing excellent regioselectivity and chemoselectivity (functional group compatibility). It was found that Co(OAc)₂ could enhance the catalytic ability of NHPI resulting in better yields and shorter reaction times. The reaction mechanism and the scope of the reaction with a variety of Δ⁵-steroidal substrates were also investigated.

Full text of DOI:10.1016/j.steroids.2014.12.004

Steroids 94 (2015) 1–6
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
N-Hydroxyphthalimide catalyzed allylic oxidation of steroids
with t-butyl hydroperoxide
⇑
Qian Zhao, Chao Qian, Xin-Zhi Chen
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang University, China
Department of Chemical and Biological Engineering, Zhejiang University, China
a r t i c l e i n f o
a b s t r a c t
D
5-steroids with t-butyl hydroperoxide in the
Article history:
A new and optimized procedure for the allylic oxidation of
Received 18 September 2014
Received in revised form 4 November 2014
Accepted 2 December 2014
Available online 16 December 2014
presence of catalytic amounts of N-hydroxyphthalimide (NHPI) under mild conditions was developed,
showing excellent regioselectivity and chemoselectivity (functional group compatibility). It was found
that Co(OAc)2 could enhance the catalytic ability of NHPI resulting in better yields and shorter reaction
times. The reaction mechanism and the scope of the reaction with a variety of
were also investigated.
D
5-steroidal substrates
Keywords:
Ó 2014 Published by Elsevier Inc.
Allylic oxidation
t-Butyl hydroperoxide
N-Hydroxyphthalimide
D
5-Steroids
1. Introduction
use of tert-butyl hydroperoxide (TBHP) combined with different
type of metal catalysts. Despite the good yields reported with
Allylic oxidation belongs to an important group of olefin oxida-
tions and remains a reaction of considerable importance in organic
chemistry with applications in areas ranging from agricultural
products to pharmaceutical [1]. The allylic oxidation of steroids is
a particularly important subject and has attracted interest as highly
useful synthetic conversions over many years. Among the most fre-
RuCl3 [21] to prepare allylic oxidation products from D
5-steroids,
the high cost of the ruthenium catalyst, along with the high risk
of the strongly exothermic reaction can result from the accumula-
tion of TBHP in larger scale reactions renders the procedures
unsuitable for commercialization and led other researchers to find
some new methods for this type of oxidation. To complete such
modifications in a more environmentally friendly yet still effica-
cious manner, many other metal complexes/salts have been
employed, such as sodium chlorite, [22] copper catalyst, [23,24]
dirhodium caprolactamate, [25] cobalt acetate, [26,27] and manga-
nese (III) acetate [28]. However, numerous limitations remain. All
of the available methods must strike a balance between good
yields and compatibility with sensitive functionalities near allylic
sites (e.g., hydroxyl group). Furthermore, the long reaction time
requirements and difficult catalyst preparation are additional dis-
advantages which often make such processes unattractive.
Recently, a new organic catalyst, N-hydroxyphthalimide (NHPI),
has been introduced as an effective catalyst for CAH bond activa-
tion by hydrogen abstraction [29], which is a cheap and non-toxic
compound easily prepared by the reaction of phthalic anhydride
with hydroxylamine [30]. The protagonist, NHPI, catalyzes a wide
variety of free radical autoxidations, improving both activities
and selectivities by increasing the rate of chain propagation and/
or decreasing the rate of chain termination. It is believed that its
active catalytic species, phthalimide N-oxyl radical (PINO), which
is formed in situ from NHPI via one electron transfer, initiates the
quently encountered oxidation products of
D
5-steroids are those
with a ketone function at C-7. These compounds, which have been
found in animal tissues and foodstuffs [2], are known to be inhibi-
tors of sterol biosynthesis [3,4] and with some use in cancer chemo-
therapy, since they inhibit aromatase activity, [5] cell replication,
and are more toxic towards tumor than non-tumor cells [6–8].
Examination of the literature showed that a variety of chro-
mium (VI) compounds have been used in the allylic oxidation
[9–20]. However, complications in applying these methods remain
because of the harsh reaction conditions required and difficult
workup and purification procedures. In addition, the accumula-
tions of chromic acid or chromium salt wastes that are the side
products of these reactions are of great environmental concern.
A variety of catalytic methods for allylic oxidation have been
reported and generally peroxide-based oxidants have been the
reagents of choice. Of greater preparative interest has been the
⇑
Corresponding author at: Key Laboratory of Biomass Chemical Engineering of
Ministry of Education, Zhejiang University, China. Tel./fax: +86 (571) 87951615.
E-mail address: xzchen@zju.edu.cn (X.-Z. Chen).
http://dx.doi.org/10.1016/j.steroids.2014.12.004
0039-128X/Ó 2014 Published by Elsevier Inc.

2
Q. Zhao et al. / Steroids 94 (2015) 1–6
radical propagation of autoxidation. The oxidation by molecular
oxygen in the presence of NHPI and an organic free-radical initiator
such as dibenzoyl peroxide (BPO) or azodiisobutyronitrile have
been reported to be suitable for the allylic oxidation of steroids,
49.00, 48.96, 44.41, 43.40, 42.14, 40.84, 37.73, 37.29, 35.47,
35.38, 34.67, 30.19, 28.31, 28.23, 27.55, 25.30, 20.23, 19.81,
17.85, 16.31, 10.98.
13 [29]: Isolated as a white solid; mp: 158.3–159.8 °C (lit. mp:
154–155 °C). 1H NMR (CDCl3, 400 MHz): d 5.63 (d, J = 1.6 Hz, 1H),
4.65 (m, 1H), 1.98 (s, v3H), 1.14 (s, 3H), 0.85 (d, J = 6.5 Hz, 3H),
as it gives moderate yields of
D
5-7-keto-steroids, and the catalyst
can be recovered almost completely thereby avoiding the use of
metal compounds and consequently the contamination of product
by metal compounds [31–34]. Despite these benefits, the stoichi-
ometric amounts of NHPI must be used and the application of this
method to the laboratory scale is restricted due to the technical
and safety problems related to a reaction under an oxygen atmo-
sphere. Herein, we report the use of inexpensive and commercially
available cobalt acetate and NHPI (catalytic amounts) as the cata-
lyst and of tert-butyl hydroperoxide (TBHP) as the cooxidant for
mild, efficient, regioselective, chemoselective (functional group
0.80 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H), 0.61 (s, 3H).13
C
NMR (CDCl3, 100 MHz): d 200.98, 169.29, 162.85, 125.69, 71.20,
53.74, 48.93, 48.78, 44.40, 42.09, 38.45, 37.63, 37.29, 36.72,
35.15, 34.97, 34.70, 27.52, 26.97, 26.33, 25.29, 22.80, 21.79,
21.54, 20.25, 20.14, 17.84, 16.24, 10.9.
14 [35]: Isolated as a white solid; mp: 168.5–170.5 °C (lit. mp:
169–171 °C). 1H NMR (CDCl3, 400 MHz): d 5.62 (d, J = 1.6 Hz, 1H),
3.60 (m, 1H), 1.13 (s, 3H), 0.85 (d, J = 6.5 Hz, 3H), 0.80 (d,
J = 6.5 Hz, 3H), 0.79 (d, J = 6.5 Hz, 3H), 0.61 (s, 3H). 13C NMR (CDCl3,
100 MHz): d 201.39, 164.24, 125.06, 69.47, 53.78, 48.95, 48.92,
44.40, 42.09, 40.80, 38.46, 37.69, 37.27, 35.33, 35.17, 34.69,
30.15, 27.52, 26.98, 25.30, 22.81, 21.79, 21.54, 20.20, 17.85,
16.29, 10.95.
15 [23]: Isolated as a white solid; mp: 148.8–150.1 °C (lit. mp:
150–153 °C). 1H NMR (CDCl3, 400 MHz): d 5.65 (d, J = 1.6 Hz, 1H),
4.66 (m, 1H), 2.06 (s, 3H), 1.99 (s, 3H), 1.15 (s, 3H), 0.59 (s,
3H).13C NMR (CDCl3, 100 MHz): d 208.67, 200.14, 169.28, 163.17,
125.50, 71.08, 61.26, 48.98, 48.65, 44.23, 43.37, 37.37, 36.76,
36.63, 35.01, 30.60, 26.30, 25.44, 22.60, 20.23, 20.08, 16.25, 12.24.
16 [26]: Isolated as a white solid; mp: 205.9–207.0 °C (lit. mp:
207–208 °C). 1H NMR (CDCl3, 400 MHz): d 5.64 (d, J = 1.7 Hz, 1H),
3.61 (m, 1H), 2.06 (s, 3H), 1.14 (s, 3H), 0.59 (s, 3H).13C NMR (CDCl3,
100 MHz): d 208.81, 200.57, 164.64, 124.84, 69.37, 61.29, 49.00,
48.77, 44.22, 43.40, 40.84, 37.34, 36.67, 35.37, 30.59, 30.10,
25.46, 22.60, 20.13, 16.31, 12.24.
17 [26]: Isolated as a white solid; mp: 182.9–184.5 °C (lit. mp:
184–185 °C). 1H NMR (CDCl3, 400 MHz): d 5.69 (d, J = 1.4 Hz, 1H),
4.65 (m, 1H), 2.76 (m, 1H), 1.99 (s, 3H), 1.17 (s, 3H), 0.83 (s,
3H).13C NMR (CDCl3, 100 MHz): d 219.23, 199.72, 169.26, 163.82,
125.51, 70.95, 48.95, 46.84, 44.72, 43.34, 37.44, 36.82, 34.95,
34.62, 29.67, 26.27, 23.15, 20.22, 19.53, 16.37, 12.74.
18 [26]: Isolated as a white solid; mp: 221.4–223.6 °C (lit. mp:
229–232 °C). 1H NMR (CDCl3, 400 MHz): d 5.68 (d, J = 1.4 Hz, 1H),
3.63 (m, 1H), 2.75 (m, 1H), 1.16 (s, 3H), 0.83 (s, 3H). 13C NMR
(CDCl3, 100 MHz): d 219.42, 200.08, 165.19, 124.89, 69.28, 49.08,
46.86, 44.73, 43.32, 40.85, 37.40, 35.29, 34.63, 30.09, 29.70,
23.16, 19.57, 16.42, 12.74.
19 [29]: Isolated as a white solid; mp: 184.5–185.5 °C (lit. mp:
183.8–184 °C). 1H NMR (CDCl3, 400 MHz): d 5.71 (d, J = 1.3 Hz, 1H),
4.72 (m, 1H), 4.48 (m, 1H), 3.44 (m, 2H), 2.87 (m, 1H), 2.49 (m, 3H),
2.05 (s, 3H), 1.23 (s, 3H), 0.98 (d, J = 7.0 Hz, 3H), 0.80 (s, 3H) 0.79 (s,
3H).13C NMR (CDCl3, 100 MHz): d 201.36, 170.28, 164.08, 126.50,
109.19, 80.93, 72.14, 66.80, 61.09, 49.65, 49.46, 44.89, 41.58,
40.97, 38.66, 38.46, 37.79, 35.99, 33.71, 31.44, 30.31, 28.80,
27.33, 21.24, 20.90, 17.26, 17.12, 16.43, 14.65.
20 [36]: Isolated as a white solid; mp: 192.4–194.5 °C (lit. mp:
198–203 °C). 1H NMR (CDCl3, 400 MHz): d 5.63 (d, J = 1.6 Hz, 1H),
4.39 (m, 1H), 3.36 (m, 2H), 2.80 (m, 1H), 2.39 (m, 3H), 1.15 (s,
3H), 0.91 (d, J = 7.0 Hz, 3H), 0.73 (s, 3H) 0.72 (s, 3H).13C NMR
(CDCl3, 100 MHz): d 200.71, 164.40, 124.87, 108.20, 79.93, 69.42,
65.79, 60.07, 48.78, 48.47, 43.85, 40.85, 40.56, 39.94, 37.70,
37.40, 35.32, 32.69, 30.41, 30.13, 29.30, 27.77, 19.93, 16.31,
16.11, 15.42, 13.63.
compatible), allylic oxidation of different
D
5-steroids. As far as
we are aware, it is the first demonstration of allylic oxidation by
tert-butyl hydroperoxide (TBHP) in cooperation with NHPI. This
allylic oxidation process, requiring fewer reagents, shorter reaction
time, no specialty chemicals, no expensive anhydrous solvents and
employing mild reaction conditions and easy work-up, has pro-
vided a milder and inexpensive approach for the synthesis of this
important class of compounds.
2. Experimental
Melting points were determined using WRR melting point appa-
ratus. 1H and 13C NMR spectra were recorded on Bruker AV-400
spectrometer (Bruker Corporation, America) at working frequencies
400 and 100 MHz respectively in CDCl3 and with TMS as the inter-
nal standard. Chemical shifts are expressed in ppm downfield from
TMS and observed coupling constants (J) are given in Hertz (Hz).
Starting materials were commercially purchased. The progress of
the reactions was monitored by thin-layer chromatography (TLC)
Analytical thin-layer chromatography (TLC) was conducted using
silica gel plates (200 microns) containing a fluorescent indicator
(silica gel 60 F254). Detection was performed by spraying with
phosphomolybdic acid (5%) and heating at 120 °C. Column
chromatography was performed using silica gel, 200–300 mesh,
and elution was performed with n-hexane/ethyl acetate.
2.1. General procedure for allylic oxidation of the
substrates
D
5-steroidal
In a typical experiment, to a solution of 25-hydroxycholesteryl
acetate (0.428 g, 1 mmol) in acetone (10 mL), NHPI (0.0163 g,
0.1 mmol), Co(OAc)2 (0.002 g, 0.01 mmol) and TBHP (0.515 g,
4 mmol) were added. After 12 h under magnetic stirring at ambient
temperature (TLC monitoring), the solution was poured into sodium
sulfite solution (10% aq.) and extracted with dichloromethane. The
extract was washed with an aq. saturated solution of NaHCO3,
water, dried over anhydrous sodium sulfate, and evaporated.
The final products were isolated using column chromatography
(absorbent: silica gel, mobile phase: n-hexane/EtOAc (8:1, v/v)).
11 [19]: Isolated as a white solid; mp: 148.2–149.7 °C (lit. mp:
150 °C). 1H NMR (CDCl3, 400 MHz): d 5.63 (d, J = 1.5 Hz, 1H), 4.64
(m, 1H), 0.87 (d, J = 6.5 Hz, 3H), 0.61 (s, 3H). 13C NMR (CDCl3,
100 MHz): d 200.93, 169.28, 162.86, 125.68, 71.19, 70.07, 53.69,
48.92, 48.76, 44.38, 43.36, 42.10, 37.63, 37.29, 36.72, 35.41,
34.97, 34.67, 28.23, 26.33, 25.27, 20.25, 20.14, 19.78, 17.81,
16.24, 10.95.
3. Results and discussion
12 [19]: Isolated as a white solid; mp: 178.4–180.5 °C (lit. mp:
183.5–184 °C). 1H NMR (CDCl3, 400 MHz): d 5.62 (d, J = 1.4 Hz, 1H),
3.60 (m, 1H), 0.87 (d, J = 6.5 Hz, 3H), 0.61 (s, 3H). 13C NMR
(CDCl3, 100 MHz): d 201.26, 164.25, 125.07, 70.10, 69.47, 53.79,
In a first set of experiments, 25-hydroxycholesterol acetate was
used as a model substrate under various experimental conditions
(Table 1). Acetone was chosen as solvent to dissolve steroids.

Q. Zhao et al. / Steroids 94 (2015) 1–6
3
A generally increasing trend of isolated yield was observed as
the amount of NHPI was increased from 0.1 equiv to 2 equiv. The
highest yield was achieved when 1.0 equiv of NHPI was used,
and the additional amount of NHPI did not result in a higher yield
(Table 1, entries 1–4). To ensure that the reaction gives the desired
yield, stoichiometric amount of NHPI must be used. Lesser
amounts of catalysts and higher yields of products were always
the ultimate goal in industrial application. Thus it is crucial for
the oxidation of 25-hydroxycholesterol acetate using a catalytic
amount NHPI in high yield. However, as shown in Table 1, when
the amount of NHPI was dropped to 0.5 equiv, both the reaction
rate and yield significantly decreased.
Solvent was an important variable for this oxidation. Among the
screened solvents, acetone was found to be the best solvent
(Table 2, entry 2). No significant changes were seen when the
reaction temperatures changed from 50 °C to 25 °C (Table 2, entries
1 and 2). A generally increasing trend of isolated yields was
observed as the oxidant ratio was increased from 1 equiv to 6
equiv. The highest yield was achieved when 4 equiv of TBHP was
used, and the additional amount of oxidant did not result in a
higher yield. Compared to other reported TBHP-mediated
oxidation, [21,23,24,26,27] fewer reagents were used.
The scope of the present procedure was further indicated by the
results summarized in Table 3 for a variety of
substrates (Scheme 1).
D
5-steroidal
Early research indicated that NHPI can efficiently oxidate sub-
strate by adding a small amount of radical starters, such as diben-
zoyl peroxide (BPO). However, stoichiometric amount of NHPI was
still needed (Table 1, entries 5 and 6). In combination with transi-
tion metal salts co-catalysts, notably cobalt, the reactivity of NHPI
can be enhanced. [37] Thus, transition metal salts was added to the
reaction as co-catalyst. The improved yields and shorter reaction
times were obtained only with catalytic amounts of NHPI (Table 1,
entries 7–11). Interestingly, we noticed that the yields were
improved to some extent no matter what kind of metal salt was
used. Among the screened co-catalyst, the yields were lower when
trivalent metal salts were used, while the higher yields were
obtained when bivalent metal salts were used. NHPI acts as a pre-
cursor of the phthalimido-N-oxyl (PINO) radical, generated with
the assistance of metal salts. The transition metal ions worked by
forming oxo-transition metal intermediates. This required the
transition metal ions have the ability to lose one electron (e.g.,
Co(II)–Co(III)), which may explain why bivalent metal salts are
more effective than trivalent ones that are far more reluctant to
lose electrons. [38] Blank experiments revealed that Co(OAc)2 as
the sole catalyst led to a longer reaction time. No significant reac-
tion occurred in the absence of catalyst (Table 1, entries 12 and 13).
To find the best catalytic system, allylic oxidation of 25-hydroxy-
cholesterol acetate in the presence of other nitroxy radicals under
the same conditions was studied. 2,2,6,6-Tetramethylpiperidinel-
oxyl (TEMPO), being a widely used catalyst for the oxidation of
alcohols, was used in our allylic oxidation system, had no catalytic
activity under these conditions (Table 1, entry 14). The use of N-
hydroxysuccinimide (NHSI) in place of NHPI led an increase in
the reaction time and lower yield (Table 1, entry 15). Based on
the above-mentioned results, NHPI was revealed to be a key cata-
lyst proved efficient both with respect to the final yields and the
reaction times.
In most cases examined, the reactions proceeded smoothly
using the optimized condition with 10 mol% of NHPI, 4 equiv of
TBHP, 1 mol% of Co(OAc)2 and acetone as the solvent at ambient
temperature. The allylic oxidation products were obtained in
isolated yields, in the range 59.9–93.7%. The excellent chemoselec-
tivity of the reaction was noteworthy. High selectivity was found
towards the formation of steroidal enones even when a free
secondary hydroxyl group was present. The more challenging
oxidation of 3-hydroxy-D
5-steroids can be successfully realized
with a small decrease in yields. Interestingly, we found that even
when the same method was applied for different substrates, a
fluctuant degree of yields and reaction time were achieved.
For
D
5-steroids, the two allylic sites do not have much differ-
ence in reactivity at first glance. However, only 7-keto products
were obtained exclusively. From the resonance structures, the
difference became clear (Fig. 1). Species bearing a radical at the
7-position will have two possible resonance structures, one of
which is a tertiary radical that can significantly lower the energy,
Table 2
Oxidation of 25-hydroxycholesterol acetate by TBHP/NHPI/Co(OAc)2 in different
conditions.a
Entry
TBHP/mmol
Solvent
T/°C
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
9
4
4
1
2
6
4
4
4
4
Acetone
Acetone
Acetone
Acetone
Acetone
THF
1,2-Dioxane
EtOAc
CH2Cl2
50
25
25
25
25
25
25
25
25
11
12
24
15
12
48
48
24
24
69.1
74.3
24.6
50.0
73.0
–
–
35.1
15.0
a
Reaction conditions: 25-hydroxycholesterol acetate (1 mmol), solvent (10 mL),
Table 1
Allylic oxidation of 25-hydroxycholesterol acetate.a
NHPI (0.1 mmol), Co(OAc)2 (0.01 mmol).
b
Isolated yield.
Entry
Catalyst/mmol
Co-catalyst/mmol
Time/h
Yieldb/%
1
2
3
NHPI (0.1)
NHPI (0.5)
NHPI (1)
NHPI (2)
NHPI (1)
NHPI (0.5)
NHPI (0.1)
NHPI (0.1)
NHPI (0.1)
NHPI (0.1)
NHPI (0.1)
–
–
–
–
–
36
36
24
18
12
18
12
18
30
18
10
48
48
48
18
10.0
45.8
61.9
58.8
69.5
55.8
74.3
68.3
55.9
44.4
30.5
60.5
–
Table 3
Allylic oxidation of
D
5-steroidal substrates.a
4
5c
6c
7
BPO (0.05)
BPO (0.05)
Co(OAc)2 (0.01)
Mn(OAc)2 (0.01)
Cu(OAc)2 (0.01)
Co(acac)3 (0.01)
Fe(acac)3 (0.01)
Co(OAc)2 (0.01)
–
Entry
Substrate
Product
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
11
12
13
14
15
16
17
18
19
20
12
12
12
12
7
7
5
5
11
11
74.3
59.9
75.8
63.8
85.9
73.5
93.7
81.1
75.5
63.0
8
9
10
11
12
13
14
15
–
TEMPO (0.1)
NHSI(0.1)
Co(OAc)2 (0.01)
Co(OAc)2 (0.01)
–
51.3
10
10
a
Reaction conditions: 25-hydroxycholesterol acetate (1 mmol), acetone (10 mL),
TBHP (4 mmol), room temperature.
a
Reaction conditions: D
5-steroidal substrates (1 mmol), acetone (10 mL), TBHP
b
Isolated yield.
The reaction was heated to 50 °C.
(4 mmol), Co(OAc)2 (0.01 mmol), NHPI (0.1 mmol), room temperature.
c
b
Isolated yield.

4
Q. Zhao et al. / Steroids 94 (2015) 1–6
OH
OH
NHPI/Co(OAc)
TBHP
2
R
R
O
1
2
R=OAc
R=OH
11
12
R1
R1
R2
R2
NHPI/Co(OAc)
TBHP
2
R
R
O
3
4
5
6
7
8
R=OAc; R1=C8H17; R2=H
R=OH; R1=C8H17; R2=H
13
14
R=OAc; R1=COCH3; R2=H 15
R=OH; R1=COCH3; R2=H 16
R=OAc; R1; R2=O
R=OH; R1; R2=O
17
18
O
O
O
O
NHPI/Co(OAc)
2
TBHP
R
R
O
9
R=OAc
R=OH
19
20
10
Scheme 1. Chemical structures of the starting
D D
5-steroidal substrates and the final 5-7-keto derivatives.
The mechanism of the allylic oxidation is worth considering.
Allylic oxidation is a process involving free radicals, and it is most
likely to occur in the presence of low oxidation state transition
metal species. A plausible reaction mechanism for the allylic oxida-
tion catalyzed by NHPI and transition metal salts is shown in
Scheme 2.
The in situ generation of PINO from NHPI through redox reac-
tion of transition metal salts is a key step. Once PINO is generated
the autoxidation can proceed further by the chain propagation
steps, which involves selective allylic hydrogen abstraction to
generate the allyl radical, transfer of the tert-butyl peroxy ligand
from the metal center to the allyl radical, and the t-butoxy radical
promoted degradation of the tert-butyl peroxy ether to the
corresponding enone.
R
R
R
R
Fig. 1. Resonance structures of radical species at the 7-position or at the 4-position.
while the species bearing a radical at the 4-position also has two
possible resonance structures, but neither contributes to the lower
energy state. Meanwhile, it is to be expected that axial hydrogen
will be preferentially abstracted to equatorial hydrogen because
of the more favorable stereoelectronic situation with the develop-
In summary,
a mild, efficient, regioselective, and highly
functional group compatible allylic oxidation protocol using com-
mercially available NHPI and Co(OAc)2 as the catalyst has been
developed. Compared to other TBHP-mediated methods, this sys-
tem was proved to be efficient both with respect to the final yields
and the compatibility with sensitive functionalities near allylic
sites (e.g., hydroxyl group). This economical and environmen-
tally-friendly procedure led to good yields with a small amount
of catalyst in a relative short reaction time and can be conveniently
scaled-up for subsequent manufacturing and commercialization.
ing p-orbital and the
p system. [39] In this case, the axial hydrogen
of C-4 lies above the plane of the steroid molecule, and the angular
methyl group at C-10 would hinder the approach of the oxidizing
species. The axial hydrogen at C-7, which is below the plane of
the molecule, is free from such steric interferences. Thus the
reaction proceeded at this position to yield the corresponding
D
5-7-keto products.

Q. Zhao et al. / Steroids 94 (2015) 1–6
5
O
O
N
OH
N
O
O
O
NHPI
PINO
PINO
tBuO
tBuOOH
tBuOO
R
tBuOH
tBuOH
NHPI
CoIIIOOtBu
R
R
H2O
tBuOOH
+
CoII
CoIIIOH
OOtBu
R
O
tBuO
tBuOOH
Scheme 2. A plausible mechanism for the allylic oxidation of
D
5-steroidal substrates catalyzed by NHPI and Co(OAc)2.
[17] Pearson AJ, Chen YS, Hsu YS, Ray T. Oxidation of alkenes to enones using tert-
butyl hydroperoxide in the presence of chromium carbonyl catalysts.
Tetrahedron Lett 1984;25:1235.
Acknowledgments
The authors are grateful for the financial support from the Nat-
ural Science Foundation of China (21376213), the Research Fund
for the Doctoral Program of Higher Education of China
(20120101110062) and the Low Carbon Fatty Amine Engineering
Research Center of Zhejiang Province (2012E10033).
[18] Pearson AJ, Chen YS, Hang SY, Hsu YS, Ray T. A new method for the oxidation of
alkenes to enones. An efficient synthesis of
Perkin Trans 1 1985;267.
D
5-7-oxo steroids. J Chem Soc
[19] Schmidt AW, Doert T, Goutal S, Grunner M, Mende F, Kurzchalia TV, Knolker
HJ. Regio-and stereospecific synthesis of cholesterol derivatives and their
hormonal activity in caenorhabditis elegans. Eur
3687–706.
J Org Chem 2006:
[20] Saini R, Boland S, Kataeva O, Schmidt AW, Kurzchalia TV, Knolker HJ.
Stereoselevtive synthesis and hormonal activity of novel dafachronic acids
and naturally occurring steroids isolated from corals. Org Biomol Chem
2012;10:4159.
[21] Miller RA, Li WJ, Humphrey GR. A ruthenium catalyzed oxidation of steroidal
alkenes to enones. Tetrahedron Lett 1996;37:3429–32.
Reference
[1] Sheldon RA, Kochi JK. Metal-catalyzed oxidations of organic compounds. New
York, NY, London, Toronto, Sydney, San Francisco, CA: Academic; 1981.
[2] Smith LL. Cholesterol autoxidation. New York: Plenum Press; 1981.
[3] Schroepfer Jr GJ. Sterol biosynthesis. Ann Rev Biochem 1981;50:585–621.
[4] Taylor FR, Saucier SE, Shown EP, Parish EJ, Kandutsch AA. Correlation between
oxysterol binding to a cytosolic binding protein and potency in the repression
of hydroxymethylglutaryl coenzyme
12382–7.
[5] Numazawa M, Tachibana M. Studies directed toward a mechanistic evaluation
of aromatase inhibition by androst-5-ene-7,17-dione. Steroids 1997;62:
516–22.
[6] Cheng KP, Nagano H, Bang L, Ourisson G. Chemistry and biochemistry of
Chinese drugs. Part I. Sterol derivatives cytotoxic to hepatoma cells, isolated
from the drug Bombyx cum Botryte.. J Chem Res (S) 1977;217.
[7] Nagano H, Poyser JP, Cheng KP, Ourisson G. Chemistry and biochemistry of
Chinese drugs. Part II. Hydroxylated sterols, cytotoxic towards cancerous cells,
synthesis and testing. J Chem Res (S) 1977;218.
[22] Silvestre SM, Salvador JAR. Allylic and benzylic oxidation reactions with
sodium chlorite. Tetrahedron 2007;63:2439–45.
[23] Salvador JAR, Melo MLS, Neves ASC. Copper-catalysed allylic oxidation of D5
steroids by t-butyl hydroperoxide. Tetrahedron Lett 1997;38:119–22.
-
A reductase. J Biol Chem 1984;259:
[24] Li YC, Wu XG, Lee TB, Isbell EK, Parish EJ, Gorden AEV. An effective method for
allylic oxidation of
2010;75:1807–10.
[25] Doyle MP, Choi H. Optimal TBHP allylic oxidation of
D
5-steroids using t-butyl hydroperoxide.
5-steroids catalyzed by
J Org Chem
D
dirhodium caprolactamate. Org Lett 2007;9:5349–52.
[26] Salvador JAR, Clark JH. The allylic oxidation of unsaturated steroids by tert-
butyl hydroperoxide using surface functionalized silica supported metal
catalysts. Green Chem 2002;4:352–6.
[27] Salvador JAR, Clark JH. The allylic oxidation of unsaturated steroids by tert-
butyl hydroperoxide using homogeneous and heterogeneous cobalt acetate.
Chem Commun 2001:33–4.
[28] Shing TKM, YeunG YY, Su PL. Mild manganese (III) acetate catalyzed allylic
oxidation: application to simple and complex alkenes. Org Lett 2006;8:
3149–51.
[8] Kumar V, Amann A, Ourisson G, Luu B. Stereospecific synthesis of 7b- and 7A-
hydroxycholesterols. Synth Commun 1987;7:1279–86.
[9] Krafft ME, Dasse OA, Fu Z. Synthesis of the C/D/E and A/B rings of
xestobergsterol-(A). J Org Chem 1999;64:2475–85.
[29] Ishii Y, Sakaguchi S, Iwahama T. Innovation of hydrocarbon oxidation with
molecular oxygen and related reactions. Adv Synth Catal 2001;343:
393–427.
[30] Karakurt A, Dalkara S, Ozalp M, Ozbey S, Kendi E, Stables JP. Synthesis of some
1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivatives
[10] Girous S, Corey EJ. Stereocontrolled synthesis of dafachronic acid A, the ligand
for the DAF-12 nuclear receptor of Caenorhabditis elegans. J Am Chem Soc
2007;129:9866–7.
[11] Parish EJ, Chitrakorn EJ, Wei TY. Pyridinium chlorochromate-mediated allylic
and benzylic oxidation. Synth Commun 1986;16:1371.
[12] Parish EJ, Wei TY. Allylic oxidation of
D
5-steroids with pyridinium
and their anticonvulsant and antimicrobial activities. Eur
2001;36:421.
J Med Chem
chlorochromate (PCC) and pyridinium dichromate (PDC). Synth Commun
1987;176:1227.
[31] Celine L, Chanaz S, Yves L, Jean MB. Synthesis of new 7-amisosterol squalamine
analogues with high antimicrobial activities through stereoselective
a
[13] Marshall CW, Ray RE, Laos I, Reigel B. 7-keto steroids. II Steroidal 3b-hydroxy-
D
5-7-ones and 3,5-7-ones. J Am Chem Soc 1957;79:6308.
D
titanium reductive amination reaction. Tetrahedron 2007;63:12968–74.
[32] Jean MB, Celine L, Nicolas V, Michel D, Yves L. Synthesis and antifungal activity
of oxygenated cholesterol derivatives. Steroids 2005;70:907–12.
[33] Kazuo O, Yutaka N, Seiji T, Isao K, Yoshinori F, Nobuo I. Formal synthesis of
squalamine from desmosterol. Chem Pharm Bull 2003;51:1177–82.
[34] Lardy H, Kneer N, Wei Y, Partridge B, Marwah P. Ergosteroids II: biologically
active metabolites and synthetic derivatives of dehydroepiandrosterone.
Steroids 1998;63:158–65.
[14] Amann A, Ourisson G, Luu B. Stereospecific syntheses of the four epimers of
7,22-dihydroxycholesterol. Synthesis 1987;1002.
[15] Parish EJ, Sun H, Kizito SA. Allylic oxidation of
flurochromate. J Chem Res (S) 1996;544.
D
5-steroids with pyridinium
[16] Muzart J. Synthesis of unsaturated carbonyl compounds via a chromium-
mediated allylic oxidation by 70% tert-butyl hydroperoxide. Tetrahedron Lett
1987;28:4665.

6
Q. Zhao et al. / Steroids 94 (2015) 1–6
[35] Dauben WG, Lorber M, Fullerton DS. Allylic oxidation of olefins with
chromium trioxide-pyridine complex. J Org Chem 1969;34:3587–92.
[36] Marwah P, Marwah A, Lardy HA. An economical and green approach for the
oxidation of olefins to enones. Green Chem 2004;6:570–7.
[37] Roger AS, Arends IWCE. Organocatalytic oxidations mediated by nitroxyl
radicals. Adv Synth Catal 2004;346:1051–71.
[38] Ferreira P, Hayes W, Phillips E, Rippon D, Tsang SC. Polymer-supported
nitroxyl catalysts for selective oxidation of alcohols. Green Chem 2004;6:310.
[39] Liu J, Zhu HY, Cheng XH. CrO3/NHPI adsorbed on activated clay: a new
supported reagent for allylic selective oxidation of
2009;39:1076–83.
D
5-sterols. Synth Commun