Practical synthesis of 16α-bromo-17α-hydroxysteroids via a Raney Ni-catalyzed bromide exchange reaction

Article abstract of DOI:10.1016/j.tetlet.2019.05.049

D-ring modified glucocorticoids are attractive synthetic targets owing to their broad application in medicinal chemistry. Herein, we reported a practical synthesis of 16α-bromo-17α-hydroxysteroids from easily available 16β-bromo isomers via a Raney Ni-catalyzed bromide exchange reaction. The catalytic Finkelstein-type reaction features high yield, mild reaction condition, short reaction time and simple operation. The method provided an efficient approach to prepare 17α-hydroxy-15-pregnen-20-ones.

Full text of DOI:10.1016/j.tetlet.2019.05.049

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical synthesis of 16
a-bromo-17a-hydroxysteroids via a Raney
Ni-catalyzed bromide exchange reaction
b,
Fei-Fei Xu a,1, Hong-Ping Li a,1, Mao-Chang Wang c, Hai-Yan Ma a, Mei-Xin Zhao a, , Kai Ding
⇑
⇑
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, China
b CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
c Shanghai University, Shanghai 200444, China
a r t i c l e i n f o
a b s t r a c t
Article history:
D-ring modified glucocorticoids are attractive synthetic targets owing to their broad application in
Received 5 May 2019
Revised 22 May 2019
Accepted 27 May 2019
Available online xxxx
medicinal chemistry. Herein, we reported a practical synthesis of 16a-bromo-17a-hydroxysteroids from
easily available 16b-bromo isomers via a Raney Ni-catalyzed bromide exchange reaction. The catalytic
Finkelstein-type reaction features high yield, mild reaction condition, short reaction time and simple
operation. The method provided an efficient approach to prepare 17
a-hydroxy-15-pregnen-20-ones.
Ó 2019 Published by Elsevier Ltd.
Keywords:
Raney Ni
Bromide exchange
Steroid
Finkelstein reaction
Glucocorticoids are of great interest in medicinal chemistry
owing to their various biological activities [1]. A strong demand
has been created for developing efficient methods to prepare
new bioactive molecules with reduced side effects and enhanced
efficacy. Substituents and stereochemistry in D ring have been
proved to greatly affect the bioactivity of glucocorticoids [2]. For
examples, many marketed glucocorticoids have a substituent at
O
O
H2O2,Base
O
Br
Br
Zn,CuI
the 16-position, such as, dexamethasone (16
betamethasone (16b-methyl) and budesonide (16 -hydroxyl).
Several of 17 -hydroxy-15-pregnen-20-ones (I) have revealed
a-methyl),
NBS
a
a
O
O
antiandrogenic activity [3a] and used as key intermediates in the
synthesis of natural products [3d–h]. However, further
exploration has been hampered by the lack of convenient
NaH/O2(40 atm)
OH
synthetic methods (Fig. 1).
A one-step preparation of 17a-
hydroxy-16-pregnen-20-ones (I) from corresponding 15-pregnen-
20-ones (II) by treatment with oxygen in the presence of strong
base was first reported by Gardner in 1968 [3a], but the method
suffers from low yield and harsh reaction conditions [3a–c]. To
prepare the key intermediate (II) for the total synthesis of
natural products, Fuchs reported a multi-step route by using
allylic bromination as a key step [3d,3e] and Trost developed an
(II)
(I)
1) H2O2,base
2) HBr
elimination
O
O
this work
OH
Br
OH
Br
alternative synthesis with
a
dihydroxylation/dehydration
⇑
Corresponding authors.
E-mail addresses: mxzhao@ecust.edu.cn (M.-X. Zhao), dingkai@mail.sioc.ac.cn
(IV)
(III)
(K. Ding).
1
These authors contributed equally to the work.
Fig. 1. Synthesis of 17a-hydroxy-15-pregnen-20-ones (I).
https://doi.org/10.1016/j.tetlet.2019.05.049
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: F.-F. Xu, H. P. Li, M. C. Wang et al., Practical synthesis of 16
exchange reaction, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.049
a-bromo-17a-hydroxysteroids via a Raney Ni-catalyzed bromide

2
F.-F. Xu et al. / Tetrahedron Letters xxx (xxxx) xxx
sequence [3f–h]. However, these methods generally suffer from
limited substrate scope and unsatisfactory yields. Therefore, it is
still highly desirable to develop a convenient method to prepare
perature. The unusual Raney Ni-catalyzed bromide-exchange reac-
tion can occur under mild condition without additional inorganic
bromide in spite of the low yield. The result prompted us to inves-
17a-hydroxy-15-pregnen-20-ones with broad substrate scope,
tigate the possibility to prepare 16a-bromosteroids (IV) from
mild conditions and high yields.
easily available 16b-isomer (III). Herein, we reported a Raney
Ni-catalyzed bromide exchange reaction, which featured high
yields, mild reaction condition and simple operation. On the basis
Julian and van Dorp developed a three-step process [4] to intro-
duce 17
trial scale from easily available 16-dehydropregnenolone acetate
(16-DPA, 18), in which 16b-bromo-17 -hydroxysteroids (III) are
key intermediates. However, our attempt to prepare 17
a-hydroxyl group to produce corticosteroids on an indus-
of the method, 17a-Hydroxy-15-pregnen-20-one was efficiently
a
synthesized on a 5-g scale from easily available raw material.
To explore the feasibility of the bromide-exchange, we initiated
our studies with bromide 1 and Raney Ni purchased from a com-
mercial supplier. Methanol is the most popular solvent for Raney
Ni-debromination reaction, however, only provided desired bro-
mide-exchange product in low yield. A brief screening of solvents
revealed acetone as the optimal solvent for the bromide-exchange
reaction. Substrate 1 was treated at room temperature with 5
a
-
hydroxy-15-pregnen-20-ones (I) via direct elimination of the
16-bromo-steroid (III) was unsuccessful due to the formation of
corresponding epoxides. In our previous study on the debromina-
tion of 16b-bromo-17-
was observed that the product was often contaminated with a
small amount of 16 -bromo isomer (IV) (5–10%). Conventional
a-hydroxysteroid (III) with Raney Ni, it
a
Finkelstein halogen exchange reaction [5] often suffers from a large
equiv of Raney Ni to offer desired 16-a-bromo isomer 2 in 21%
excess of the halide salt, long reaction time and high reaction tem-
yield (Table 1, entry 1). A small amount of epoxide 4 was simulta-
Table 1
Optimization of bromide-exchange reaction.a
O
O
O
O
OH
Br
OH
O
OH
Raney-Ni
Br
O
O
1
2
3
4
Entry
Acid
(equiv)
Raney-Ni
(wt)
Time
(h)
Yieldb
2:3:4
1
2
3
4
5
6
——
5
5
5
5
3
1
4
2
2
2
14
2
1:3.3:0.5
1:2.5:0
1:0.4:0
<20% conv.
1:0.04:0
NR
0.5(HOAc)
0.5(HBr)
1.0(HBr)
0.5(HBr)
0.5(HBr)
a
0.25 mmol substrate, 6 mL of acetone, 25 °C.
NMR yield.
b
Table 2
Optimization of bromide-exchange reaction.a
O
O
O
OH
Br
OH
O
OH
Br
Raney-Ni
HBr, acetone
O
O
1
2
3
Entrya
1
Raney-Ni
(wt)
Time
(h)
Solvent
(ml)
Yield
(%)
3
3
0.5
2
6
6
83
NR
b
2
3
4
5
2
1.5
2
2
2
10
14
6
3
2
6
6
4.5
3
3
95
68(72c)
96
6
91
7d
—(27c)
a
b
c
0.25 mmol substrate, 0.5 equiv of HBr, acetone, W2 grade Raney-Ni, rt, HPLC yield.
W1 grade Raney-Ni.
Conversion (%).
18 °C.
d
Please cite this article as: F.-F. Xu, H. P. Li, M. C. Wang et al., Practical synthesis of 16
exchange reaction, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.049
a-bromo-17a-hydroxysteroids via a Raney Ni-catalyzed bromide

F.-F. Xu et al. / Tetrahedron Letters xxx (xxxx) xxx
3
neously formed, which was proposed to be caused by basic Raney
Ni and can be suppressed by adding acetic acid (entry 2). When
HBr was used to replace acetic acid, the desired isomer 2 was sig-
nificantly increased (entry 3). However, a further increase in the
acidity led to a dramatic decrease of reaction rate (entry 4). The
effect of catalyst loading amount was proved to be critical for the
chemoselectivity. With 3 equiv of Raney Ni as catalyst, desired
16-a-bromo product 3 was obtained in almost quantitative yield
(entry 5). A further decrease of catalyst loading led to a complete
recovery of starting material 1 (entry 6).
Because Raney Ni purchased from different suppliers may exhi-
bit different reactivity, further optimizations were performed with
freshly-prepared Raney Ni (Table 2). The W2 grade Raney Ni [6a]
was much more active than commercial Raney Ni (0.5 h vs 14 h,
entry 1). However, W1 grade Raney Ni [6b] did not initiate the
reaction (entry 2). With freshly-prepared W2 Raney Ni as
catalyst, 2 equiv of catalyst loading provided the best results
(entries 3, 4). Increased substrate concentration led to an
increase of reaction rate (entries 5, 6). When the concentration of
substrate was set to 18 mL/mmol, the best result was obtained
Table 3
Scope of substrates.a
Entry
Substrate
Product
Time
(h)
Yield
(%)b
1
6
95
O
O
O
HO
HO
HO
Br
Br
Br
O
O
1
2
2
3
8
6
90
94
O
HO
HO
HO
Br
O
O
O
O
5
6
O
O
HO
HO
O
O
Br
Br
7
8
4
5
6
7
6
91
O
O
O
O
OAc
OAc
OH
OH
Br
Br
O
O
O
9
10
2
97
OBz
OBz
OH
OH
Br
Br
O
O
O
11
12
HO
17
96(83c)
O
O
HO
Br
Br
Br
O
O
14
13
6
NR
OH
OH
Br
16
15
a
b
c
0.5 mmol substrate, 9 mL of acetone, 2 equiv of W2 grade Raney-Ni, 25 °C.
Isolated yield.
Conversion (%).
Please cite this article as: F.-F. Xu, H. P. Li, M. C. Wang et al., Practical synthesis of 16
exchange reaction, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.049
a-bromo-17a-hydroxysteroids via a Raney Ni-catalyzed bromide

4
F.-F. Xu et al. / Tetrahedron Letters xxx (xxxx) xxx
(entry 5). It is noteworthy that a slightly lower temperature led to a
significant decrease in reaction rate (entry 7).
With the optimized reaction condition in hand, the substrate
scope was investigated (Table 3). The reaction was proved to be
(entries 1–5) even with substituents at 21-postion (entries 4 and
5). The reaction of 4-ene-3-one compound 13 was sluggish, and
required a long reaction time to provide desired product in an
acceptable conversion (entry 6). The Finkelstein reaction is an
equilibrium reaction, and the driving force of this reaction was pro-
posed to be the formation of the thermodynamically stable prod-
uct. As expectedly, substrate 15 cannot be transformed into cis-
form product 16.
Although the details of reaction mechanism are not yet clear,
control experiments showed that Raney Ni was indispensable to
the bromide exchange reaction. No reaction was observed with
HBr, nickel-aluminium alloy or nickel salt as catalyst (Scheme 1).
It is noteworthy that the exchange reaction of 16-chloro or 16-
iodo-steroids did not occur under same condition.
robust and gave corresponding 16a-bromo products in >90% yields
O
O
OH
Br
OH
Br
catalyst
O
O
1
2
With 16
a
-bromo-17a-hydroxysteroids in hand, we next
attempted to prepare 17
a
-hydroxy-15-pregnen-20-ones via direct
a) HBr, b) HBr,Al-Ni, c) NiBr2
elimination (Table 4). As expectedly, classical elimination condi-
tion with Li2CO3/LiBr [7] gave the epoxy 4 as major product
(>80%, entry 1). However, the elimination reaction did not occur
in the absence of LiBr (entry 2). The reaction with DBU at high tem-
Scheme 1. Bromide exchange reaction with other catalysts.
perature [8] offered desired 17a-hydroxy-15-pregnen-20-one 17
Table 4
Optimization of elimination reaction.a
as sole product (entry 3). Complete conversion was observed with
33 equiv of DBU after 8 h, and the desired product 17 was obtained
in 94% isolated yield (entry 4).
O
O
OH
Br
To illustrate the practical utility of our method, preparation of
17a-hydroxy-15-pregnen-20-one from commercially available
OH
DBU
16-dehydropregnenolone acetate (16-DPA, 18) was realized on a
5 g scale (Scheme 2). Raw material 18 (16-DPA) was transformed
into bromide 20 with an almost quantitatively yield according to
the conventional method [4]. The direct inversion reaction of bro-
mide 20 was unsuccessful due to its poor solubility in acetone.
After acetylation of 20, the Raney Ni-catalyzed bromide exchange
Toluene,Reflux
O
O
17
2
Entry
Reagent
(equiv)
Solvent
Temp.
Time
(h)
Conversion
(%)
reaction proceeded smoothly to afford the corresponding 16
a
-bro-
(°C)
mide 22, which reacted with DBU to furnish
D
15-steroid 23 in 69%
1
2
Li2CO3/LiBr(5)
Li2CO3(5)
DBU(5)
DMF
DMF
Toluene
Toluene
170
170
135
135
4
2
4
8
>99
<10
overall yield (5 steps).
In summary, a novel Raney Ni-catalyzed bromide exchange
reaction has been developed and applied to the synthesis of 16
bromo-17 -hydroxysteroids. The method provides an efficient
approach for the preparation of 17 -hydroxy-15-pregnen-20-ones
3
40
4b
DBU(33)
99(94c)
a-
a
a
Reaction conditions: 0.1 mmol substrate, 5 equiv of catalyst, 1 mL of solvent,
NMR yield.
a
b
0.5 mL of DBU(33equiv), 0.5 mL of toluene.
from easily available raw materials. Further investigation on the
reaction mechanism is under progress.
c
Isolated yield.
O
O
O
O
OH
Br
NaOH,H2O2
MeOH
Ac2O,DMAP
DCM
HBr
MeCN
HO
AcO
HO
19
20
18 (16-DPA)
O
O
O
OH
Br
OH
Br
OH
DBU
Raney-Ni
Toluene,reflux
AcO
HBr,acetone
AcO
AcO
21
22
23
Scheme 2. Synthesis of
D
15-steroid from 16-DPA.
Please cite this article as: F.-F. Xu, H. P. Li, M. C. Wang et al., Practical synthesis of 16
exchange reaction, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.049
a-bromo-17a-hydroxysteroids via a Raney Ni-catalyzed bromide

F.-F. Xu et al. / Tetrahedron Letters xxx (xxxx) xxx
5
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(1999) 2056;
Appendix A. Supplementary data
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(b) P.L. Julian, E.W. Meyer, W.J. Karpel, I.R. Waller, J. Am. Chem. Soc. 72 (1950)
5145.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.05.049.
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Please cite this article as: F.-F. Xu, H. P. Li, M. C. Wang et al., Practical synthesis of 16
exchange reaction, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.049
a-bromo-17a-hydroxysteroids via a Raney Ni-catalyzed bromide