Green Suzuki coupling reaction for synthesis of abiraterone acetate and its analogues

Article abstract of DOI:10.3184/174751916X14604710386405

An eco-friendly efficient method was developed for the synthesis of abiraterone acetate and analogues in water-PEG-400 (6:1; v/v) at 75°C from various arylboronic acids and 17-(trifluoromethanesulfonyl)oxy-3β-acetoxylandrosta-5,16-diene obtained from the 3-acetate of dehydroepiandrosterone.

Full text of DOI:10.3184/174751916X14604710386405

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 MAY, 289–292
RESEARCH PAPER 289
Green Suzuki coupling reaction for synthesis of abiraterone acetate and
its analogues
Xiaoqin Biana,b, Lizhong Wangb, Jinliang Liua and Cunde Wanga*
aSchool of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P.R. China
bSchool of Pharmacy, Taizhou Polytechnic College, Taizhou 225300, P.R. China
An eco-friendly efficient method was developed for the synthesis of abiraterone acetate and analogues in water-PEG-400 (6:1; v/v) at
75 °C from various arylboronic acids and 17-(trifluoromethanesulfonyl)oxy-3ß-acetoxylandrosta-5,16-diene obtained from the 3-acetate
of dehydroepiandrosterone.
Keywords: abiraterone acetate, dehydroepiandrosterone, green Suzuki reaction, PEG-400, arylboronic acid
For many years, the modification of natural steroids has drawn
considerable attention from medicinal and synthetic organic
chemists. Among them, various derivatives involving chemical
modification of the steroidal D ring have shown biologically
important properties.1–4 For example, 3α,5α-17-phenylandrost-
16-en-3-ol is a neurosteroid antagonist,5 which can antagonise
selectively the GABA-modulatory and GABA-mimetic effects
of 3α,5α-tetrahydroprogesterone and related 5α-pregnane
steroids.5–6 Another important modified D-ring steroid is
3β-acetoxy-17-(pyridin-3-yl)androsta-5,16-diene (abiraterone
acetate) which is a potent inhibitor of human cytochrome
P45017α (steroidal 17α-hydroxylase-C17,20-lyase) that has been
approved for use together with prednisone or prednisolone,
for the treatment of metastatic castration-resistant prostate
cancer.7–8 Due to the pharmacological importance of abiraterone
acetate and analogues, a number of methods for the preparation
of abiraterone acetate and analogues have been developed.9–10
The classical preparation of the abiraterone acetate utilised
followed by esterification to give abiraterone acetate.17 In view
of the remarkable importance from a pharmacological and
synthetic point, the development of abiraterone acetate and new
analogues with possible biological activity by new synthetic
approaches using mild reaction conditions remains an active
research area.
Recently, water as a safe and green reaction medium has
been used for various organic reactions in which it was an
important partner in improving the catalyst activity,18–22
especially in the palladium-catalysed coupling reactions. These
reaction systems offered an attractive alternative to the existing
methods since the reaction proceeds in water under mild
conditions with operational simplicity, and gave the products
in high yields.23–27 Recent investigations found that polyethylene
glycol (PEG) which possesses low toxicity and solubility in
both aqueous and nonaqueous media,28–30 is advantageous
over toxic organic solvents, providing a greener alternative in
various organic reactions. Several reports have used water as
an environmentally benign solvent in the presence of PEG for
organic transformations.31
palladium-catalysed
cross-coupling
reaction
between
diethyl(3-pyridyl)borane and the 17-enol triflate generated
from 3-acetate of dehydroepiandrosterone. The synthesis
involved the conversion of the carbonyl at the 17 position of
dehydroepiandrosterone acetate to the corresponding enol
triflate by treatment with trifluoromethanesulphonic anhydride
and 2,6-di-tert-butyl-4-methyl pyridine.11–12 A similar synthesis
comprised sulphonation of the enol of dehydroepiandrosterone
acetate with p-toluenesulfonic acid to obtain (3β)-
acetoxyandrost-5,16-dien-17-yl-p-toluenesulfonate. Coupling
with diethyl(3-pyridyl)borane in the presence of bis(tri-Ph
phosphine)palladium dichloride as catalyst was then used to
generate the product.13
Another improved method involved replacement of the 17-
enol triflate by the vinyl iodide of dehydroepiandrosterone
in the palladium-catalysed Suzuki cross-coupling step. The
vinyl iodide of dehydroepiandrosterone was prepared from
the corresponding 17-hydrazone in the presence of iodine
and guanidine base.14–15 On the basis of the above method,
Hong and coauthors described an improved preparation of
abiraterone acetate using a pyridyl Grignard reagent which
was coupled with the vinyl iodide of dehydroepiandrosterone
in the palladium catalyst system using either [Pd(dppf)Cl2,
Pd(PPh3)4, PdCl2(dppe), Pd/C and Pd(CH3CN)Cl2] or nickel
catalyst system [Ni(dppp)Cl2 or NiCl2(dppe)].16 Wang and
coauthors also reported a similar method in which 17-iodo-
androsta-5,16-dien-3β-ol was subjected to a Negishi cross-
coupling with 3-pyridylzinc bromide obtained by successive
reaction of 3-bromopyridine with n-BuLi and ZnBr2. This was
In light of the biological activity of abiraterone acetate, and
in continuation of our research work on the formation of C–C,
C–O, and C–N multiple bonds in water-PEG-400 (6:1, v/v),32
we considered that 17-enol triflate generated from 3-acetate
of dehydroepiandrosterone and arylboronic acid represented a
suitable candidate for Suzuki cross-coupling for synthesis of
abiraterone acetate and new analogues in water-PEG-400.
Results and discussion
We synthesised a series of 3β-acetoxyl-17-arylandrosta-5,16-
dienes with dehydroepiandrosterone (1) as the starting material
(Scheme 1). Compound 2 was synthesised by the standard
procedure in our laboratory, by treating 1 with acetic anhydide
and DMAP in pyridine at room temperature in a good yield.
According to reported methods,7 compound 3 was prepared by
treating compound 2 with trifluoromethanesulfonic anhydride
and dry triethylamine in dry CH2Cl2 at 0 °C and separated by
column chromatography. The yield was not very good and was
only 52%.
In order to establish the optimum reaction conditions of
the subsequent Suzuki coupling reaction, we examined the
reaction
between
17-(trifluoromethanesulfonyl)-oxy-3β-
acetoxylandrosta-5,16-diene (3) and phenylboronic acid
(Table 1). Initially, we examined the coupling reaction of
17-(trifluoromethanesulfonyl)oxy-3β-acetoxylandrosta-5,16-
diene (3) with phenylboronic acid in pure water using PdCl2/
CuI/Na2CO3 as a catalyst system at room temperature, but the
* Correspondent. E-mail: wangcd@yzu.edu.cn

290 JOURNAL OF CHEMICAL RESEARCH 2016
O
O
Tf2O, CH2Cl2
,
(CH3CO)2O, Py,
DMAP, rt, 6 h,
97%
Et3N, 0 oC, 2 h
52%
HO
AcO
1
2
Ar
OTf
PdCl2/CuI, ArB(OH)2
,
2M Na2CO3, PEG-400,
Water, 75 oC, N2, 6 h
75–92%
AcO
AcO
–
4a
i
3
Scheme 1 Synthesis of abiraterone acetate and analogues via green Suzuki reaction.
Table 1 Optimisation of the coupling-reaction conditionsa
OTf
When PEG-600 was used the model reaction was not promoted
Ph
(Table 1, entry 7). Further increase of the amount of Na2CO3
had no significant beneficial effect on the reaction (Table 1,
entry 8). Replacement of Na2CO3 by K2CO3 or Cs2CO3 gave
the product 4a in yield of 92% and 90% respectively (Table 1,
entries 9–10). The results showed the various carbonate bases
had an insignificant influence on the reaction. The ratio 10:1 of
water-PEG-400 was tested for the reaction. The result showed
that part of the starting material did not dissolve in the mixed
solvent, and the product was only obtained in 69% yield (Table
1, entry 11). Encouraged by the above-mentioned results, we
investigated the different Pd catalyst systems to optimise the
Suzuki coupling reaction. Various Pd catalyst systems were
screened (Table 1, entries 12–15). The results revealed that
the reaction was quite sensitive to the Pd catalyst systems. The
highest yield was observed when the simple Pd salt was used
and the water-PEG-400 was used as a mixed solvent.
A series of experiments revealed that the best results were
obtained when the reaction of 17-(trifluoromethanesulfonyl)
oxy-3β-acetoxylandrosta-5,16-diene (3), 2 equiv. phenylboronic
acid, 1% equiv. PdCl2 and CuI together with 1 equiv. Na2CO3
was carried out in a mixture of PEG-400 and H2O (1:6, v/v), the
resultant mixture was stirred for 6 h at 75 °C, whereby the yield
of 4a reached 92% (Table 1, entry 5).
Selected conditions
AcO
AcO
Entry Base/mmol
4a
T/°C T/h Yield/%b
3
Solvent/v/v
H2O
H2O
1
Na2CO3(1 equiv.)
Rt
60
60
60
75
85
75
75
75
75
75
75
75
75
75
10
10
8
8
6
6
6
6
6
6
6
6
6
6
6
0
32
55
72
92
91
90
92
92
90
69
91c
80d
88e
51f
2
3
4
5
6
7
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
H2O/PEG200(6/1)
H2O/PEG400(6/1)
H2O/PEG400(6/1)
H2O/PEG400(6/1)
H2O/PEG600(6/1)
8
Na2CO3(1.5 equiv.) H2O/PEG400(6/1)
9
K2CO3(1 equiv.)
Cs2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
Na2CO3(1 equiv.)
H2O/PEG400(6/1)
H2O/PEG400(6/1)
H2O/PEG400(10/1)
H2O/PEG400(6/1)
H2O/PEG400(6/1)
H2O/PEG400(6/1)
H2O/PEG400(6/1)
10
11
12
13
14
15
Withtheoptimisedreactionconditionsinhandweexploredthe
Suzuki coupling reaction of 17-(trifluoromethanesulfonyl)oxy-
3β-acetoxylandrosta-5,16-diene (3) with various arylboronic
acids affording the products 4a–i in good to excellent yields
(75−92%) (Scheme 1). The results were summarised in Table
2. Substrates bearing fluoro, methoxy and trifluoromethyl
substituents on the aryl or heterocyclic ring displayed similar
reactivity (Table 2, 4a–h), but the substrate bearing fluoro at
the 2-position of the phenyl showed poor reactivity to furnish
the products in moderate yield (Table 2, 4i).
aReaction conditions: 3 mmol 3, 3/PhB(OH)2/PdCl2/CuI/Na2CO3 = 1/2/0.01/0.01/1(mol),
solvent: H2O (8.4 mL)/PEG (1.4 mL) (6/1, v/v). bYields were isolated.
cPd catalyst: Pd(OAc)2.
dPd catalyst: Pd(PPh3)4.
ePd catalyst: Pd(PPh3)2Cl2.
fPd catalyst: Pd/C.
desired product 4a was not obtained (Table 1, entry 1). After
increasing the reaction temperature to 60 °C, we performed
the model reaction under similar conditions, and obtained the
desired product 4a in 32% yield (Table 1, entry 2). Although
the higher temperature slightly improved the reaction using
water as a solvent, there was still a solubility problem for the
starting materials. In order to make the reaction more efficient,
the low molecule weight polyethylene glycol (PEG) was used
to solubilise organic starting materials in water as a water
soluble polyether. We investigated the model reaction in various
molecule weight PEG and water (1/6, v/v) at 60 °C, and to our
delight the desired product was obtained in 55%, 72% yield
within 8 h, respectively (Table 1, entries 3–4). Since a higher
temperature might improve the reaction, the model reaction was
carried out at 75 °C and 85 °C, and the product 4a was obtained
in 92%, 91% yield within 6 h, respectively (Table 1, entries 5–6).
The molecular structure of products 4a–i was elucidated from
its spectroscopic analyses as described herein for compound
4a. In the IR spectrum of compound 4a, one sharp absorption
band at 1732 cm–1, three bands at 1603, 1492, and 1371 cm–1,
could be assigned to CO and C=C stretching frequencies. The
high resolution mass spectrum of compound 4a displayed the
molecular ion peak at m/z = 413.2459 (M + Na), which is in
1
good agreement with the proposed structure. The H NMR
spectrum of compound 4a exhibited two signals at 5.91 (s, 1H),
5.42 (d, J = 4.5 Hz, 1H) for C16-H and C6-H of the double bond,
respectively, three singlet signals at 2.04 (s, 3H), 1.08 (s, 3H),
1.06 (s, 3H) and one multiplot at 4.69–4.55 (m, 1H) for CH3CO,
1
C19-CH3, C18-CH3 and C3-H respectively. Characteristic H
chemical shift of C6-H, C16-H, CH3CO, C19-CH3, C18-CH3

JOURNAL OF CHEMICAL RESEARCH 2016 291
Table 2 Preparation of target compounds (4a–i)
white solids: 3β-acetoxyandrost-5-en-17-one (5.72 g, 98% in yield).
M.p.: 170–171 °C [169–171 °C (PE/AcOEt)]; 33 IR (KBr, cm–1): 2950,
2898, 1738, 1455, 1375, 1239, 1023.
Compound -Ar
Yield/%a Compound -Ar
Yield/%a
88
N
Preparation of 17-trifluoromethanesulfonyloxy-3β-acetoxyandrosta-
5,16-diene (3)
4a
92
79
83
79
83
4f
OCH3
A mixture of 3β-acetoxyandrost-5-en-17-one (2) (3.3 g, 0.01 mol) and
dried triethylamine (2.1 mL, 0.014 mol) in dry CH2Cl2 (25 mL) was
treated with trifluoromethanesulfonic anhydride (2.12 mL, 0.012 mol)
at 0 °C. The resultant mixture was stirred at the same temperature for
2 h, and the completion of reaction was confirmed by TLC (EtOAc/
hexanes 1:8). After water (10 mL) was added to the mixture, the
organic phase was separated, and the water phase was extracted with
CH2Cl2 (25 mL). The combined organic phase was washed with water
(15 mL) and brine (15 mL), and dried over anhydrous sodium sulphate.
After removal of dichloromethane, the crude product was purified
by flash chromatography (silica gel, EtOAc/hexane, 1/40) to give the
desired 17-trifluoromethanesulfonyl-3β-acetoxyandrosta-5,16-diene
(3) (2.6 g, 52% in yield).7 Light yellow solid, m.p.: 75–76 °C (PE/
AcOEt); 1H NMR (600 MHz, CDCl3) δ (ppm): 5.58 (d, J = 0.8 Hz, 1H),
5.38 (s, 1H), 4.88–4.28 (m, 1H), 2.01 (s, 3H), 1.06 (s, 3H), 1.00 (s, 3H);
13C NMR (150 MHz, CDCl3) δ (ppm): 170.51, 159.19, 140.15, 121.77,
119.65, 117.52, 114.48, 73.71, 54.22, 50.36, 44.65, 38.08, 36.81, 32.65,
30.53, 29.92, 28.58, 27.66, 21.39, 20.10, 19.17, 15.07; IR (KBr, cm–1):
2932, 2857, 1741 (C=O), 1629 (C=C), 1534, 1421, 1376, 1244, 1212,
1142 (OSO2); HRMS (ESI) for C22H29F3O5S [M + Na] calcd 485.1584;
found: 485.1580.
N
N
4b
4g
4h
4i
83
81
75
N
F
4c
F
N
F
4d
CF3
N
4e
F
aIsolated yields.
and C3-H unequivocally indicated the exclusive chemical
environment of compound 4a protons. The H-decoupled 13C
1
NMR spectrum of compound 4a showed 25 distinct signals in
agreement with the suggested structure. The important peaks
were related to the CO and three C=C double bonds which
appeared at δ 170.57, 154.75, 140.01, 137.32, 128.10, 127.22,
126.71, 126.70 and 122.45 ppm.
In summary, we have developed an eco-friendly efficient
method for the synthesis of abiraterone acetate and
analogues in water-PEG-400 (6:1; v/v) at 75 °C from various
arylboronic acids and 17-(trifluoromethanesulfonyl)oxy-3β-
acetoxylandrosta-5,16-diene (3) generated from 3-acetate
of dehydroepiandrosterone. The merit of this method was
highlighted by its environmentally friendly, operational
simplicity and simple workup procedure. This enabled the
rapid assembly of abiraterone acetate and analogues for the
generation of a wide range of structurally interesting and
pharmacologically significant compounds.
General procedure for preparation of abiraterone acetate and
analogues (4a–i)
The mixture of 17-trifluoromethanesulfonyl-3β-acetoxyandrosta-
5,16-diene (3) (2.0 g, 4.3 mmol), PdCl2 catalyst (7.63 mg, 0.043 mmol)
and CuI (8 mg, 0.043 mol) in PEG-400 (2 mL) and water (12 mL)
was stirred at room temperature for 5 min. The resultant mixture
was treated with the arylboronic acid (8.6 mmol) and 2 M sodium
carbonate (2.2 mL) respectively. The mixture was stirred at 75 °C for
5 h, and the completion of reaction was confirmed by TLC (EtOAc/
hexanes 1:8). The reaction mixture was then extracted with
dichloromethane (10 mL × 2). The organic phase was washed with
3% HCl (10 mL), water (10 mL) and brine (5 mL), and dried over
anhydrous sodium sulphate. After removal of dichloromethane,
the crude product was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1/40) to give the desired products 4a–i.
3β-acetoxy-17-phenylandrosta-5,16-diene (4a): White solid,
yield: 92%, m.p.: 142–143 °C (PE/AcOEt); 1H NMR (600 MHz,
CDCl3) δ (ppm): 7.37 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.22
(t, J = 7.2 Hz, 1H), 5.91 (s, 1H), 5.42 (d, J = 4.5 Hz, 1H), 4.69–4.55
(m, 1H), 2.04 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ (ppm): 170.57, 154.75, 140.01, 137.32, 128.10, 127.22, 126.71,
126.70, 122.45, 73.94, 57.58, 50.32, 47.20, 38.16, 36.93, 36.80, 35.34,
31.61, 31.57, 30.45, 27.76, 21.46, 20.89, 19.28, 16.64; IR (KBr, cm–1):
3059, 2937, 2891, 2854, 1732, 1603, 1492, 1371, 1243, 1032, 759, 667;
HRMS (ESI) calcd for C27H34O2 [M + Na] 413.2451; found: 413.2459.
3β-acetoxy-17-(pyridin-3-yl)androsta-5,16-diene (4b): White solid,
yield: 79%, m.p.: 145–146 °C (PE/AcOEt) lit.7 m.p.: 144–145 °C;
1H NMR (600 MHz, CDCl3) δ (ppm): 8.55 (s, 1H), 8.38 (d, J = 4.6
Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 7.6, 5.0 Hz, 1H), 5.92
(s, 1H), 5.35 (d, J = 4.1 Hz, 1H), 4.58–4.50 (m, 1H), 1.97 (s, 3H), 1.01
(s, 3H), 0.97 (s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 169.50,
150.60, 146.83, 146.78, 138.98, 132.68, 131.93, 128.21, 122.01, 121.26,
72.82, 56.42, 49.20, 46.27, 37.09, 35.87, 35.74, 34.15, 30.75, 30.46,
29.36, 26.69, 20.40, 19.77, 18.22, 15.54; IR (KBr, cm–1): 3045, 2936,
2890, 1734, 1601, 1408, 1244, 1034, 799, 615; HRMS (ESI) calcd for
C26H33NO2 [M + H] 392.2590; found: 392.2589.
Experimental
General
All melting points were determined in a Yanaco melting point apparatus
and are uncorrected. IR spectra were recorded in a Nicolet FTIR 5DX
spectrometer. The 1H NMR (600 MHz) and 13C NMR (150 MHz)
spectra were recorded in a Bruker AV-600 spectrometer with TMS as
internal reference in CDCl3 solutions. The J values are given in hertz.
1
Only discrete or characteristic signals for the H NMR are reported.
The MS spectra were obtained on a ZAB-HS mass spectrometer with
70 eV. High-resolution ESI mass spectra were obtained on a UHR-TOF
maXis (ESI) mass spectrometer. Flash chromatography was performed
on silica gel (230–400 mesh) eluting with ethyl acetate-hexane mixture.
All reactions were monitored by thin layer chromatography (TLC). All
reagents and solvents were purchased from commercial sources and
purified commonly before used.
Preparation of 3β-acetoxyandrost-5-en-17-one (2)
The mixture of dehydroepiandrosterone (DHEA) (5.0 g, 17.5 mmol)
and 4-(dimethylamino)pyridine (DMAP) (0.022 g, 0.175 mmol) in
pyridine (20 mL) at room temperature was stirred for 15 min. To
the above mixture was added dropwise acetic anhydride (3.3 mL,
35 mmol), then the resultant mixture was stirred at room temperature
for 6 h, and the completion of reaction was confirmed by TLC (EtOAc/
hexanes 1:2). The reaction mixture was poured into ice-water (150 g),
filtered and washed with water, and dried in air to yield a product, the
3β-acetoxy-17-(3-fluorophenyl)androsta-5,16-diene (4c): Light
yellow solid, yield: 83%, m.p.: 109–110 °C (PE/AcOEt); 1H NMR
(600 MHz, CDCl3) δ (ppm): 7.13 (m, 1H), 7.04 (d, J = 7.8 Hz, 1H),
6.98–6.94 (m, 1H), 6.80 (m, 1H), 5.84 (dd, J = 3.1, 1.7 Hz, 1H), 5.31
(d, J = 5.2 Hz, 1H), 4.54–4.49 (m, 1H), 1.93 (s, 3H), 0.98 (s, 3H),

292 JOURNAL OF CHEMICAL RESEARCH 2016
0.95 (s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 170.47, 162.68
(d, J = 244.7 Hz), 153.65, 139.98, 139.48 (d, J = 7.6 Hz), 129.47 (d,
J = 8.2 Hz), 128.48, 122.31 (d, J = 3.8 Hz), 113.47 (d, J = 7.0 Hz), 113.33
(d, J = 7.6 Hz), 73.86, 57.53, 50.27, 47.16, 38.15, 36.90, 36.75, 35.23,
31.58, 31.51, 30.38, 27.74, 21.39, 20.85, 19.24, 16.61; IR (KBr, cm–1):
3074, 2939, 2877, 1733, 1577, 1485, 1373, 1245, 1037, 784, 692; HRMS
(ESI) calcd for C27H33FO2 [M + Na] 431.2362; found: 431.2357.
(150 MHz, CDCl3) δ (ppm): 170.53, 160.20 (d, J = 246.9 Hz), 148.85,
140.02, 130.73 (d, J = 4.3 Hz), 130.15 (d, J = 3.8 Hz), 128.14 (d, J = 8.0
Hz), 125.19 (d, J = 15.5 Hz), 123.40 (d, J = 3.6 Hz), 122.41, 115.66 (d,
J = 23.6 Hz), 73.92, 57.13, 50.39, 48.27, 38.15, 36.93, 36.81, 34.94, 32.10,
31.58, 30.62, 27.76, 21.43, 20.82, 19.25, 16.27; IR (KBr, cm–1): 3029,
2966, 2854, 1734, 1665, 1568, 1447 1372, 1245, 1033, 808, 762; HRMS
(ESI) calcd for C27H33FO2 [M + Na]431.2362; found: 431.2363.
3β-acetoxy-17-(2-trifluoromethylphenyl)androsta-5,16-diene
(4d): Light yellow solid, yield: 79%, m.p.: 120–121 °C (PE/AcOEt);
1H NMR (600 MHz, CDCl3) δ (ppm): 7.52 (s, 1H), 7.45 (d, J = 7.8 Hz,
1H), 7.40 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 5.92 (dd, J = 3.0,
1.7 Hz, 1H), 5.34 (d, J = 5.1 Hz, 1H), 4.57–4.51(m, 1H), 1.96 (s, 3H),
1.01 (s, 3H), 0.99 (s, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 169.52,
152.54, 138.99, 137.01, 129.44 (q, J = 31.9 Hz), 128.79, 128.03, 127.49,
125.02 (q, J = 272.2 Hz), 124.12, 122.30 (q, J = 3.5 Hz), 121.28, 72.84,
56.53, 49.23, 46.23, 37.11, 35.88, 35.74, 34.17, 30.65, 30.47, 29.37, 26.71,
20.40, 19.80, 18.22, 15.60; IR (KBr, cm–1): 3038, 2964, 2930, 2899,
2857, 1731, 1619, 1432, 1336, 1175, 1098, 801, 701; HRMS (ESI) calcd
for C28H33O2F3 [M + Na] 481.2330; found: 481.2328.
This work was supported by generous grants from the National
Natural Science Foundation of China (NNSFC 21173181),
and the project funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions. This
work is also supported by grant TG201422 from the Taizhou
science and technology support project and by BRA2014182
from the Jiangsu 333 talents project funds to Lizhong Wang.
Received 31 January 2016; accepted 20 February 2016
Paper 1603887 doi: 10.3184/174751916X14604710386405
Published online: 19 April 2016
3β-acetoxy-17-(5-fluoropyridin-3-yl)androsta-5,16-diene
(4e):
White solid, yield: 83%, m.p.: 146–147 °C (PE/AcOEt); 1H NMR
(600 MHz, CDCl3) δ (ppm): 8.37 (s, 1H), 8.25 (s, 1H), 7.29 (dd,
J = 9.9, 1.4 Hz, 1H), 5.99 (d, J = 1.3 Hz, 1H), 5.34 (d, J = 2.6 Hz, 1H),
4.56–4.52 (m, 1H), 1.97 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ (ppm): 170.52, 159.28 (d, J = 255.7 Hz), 150.42,
143.74 (d, J = 3.7 Hz), 140.02, 135.92 (d, J = 23.3 Hz), 134.48 (d,
J = 3.5 Hz), 130.80, 122.20, 120.23 (d, J = 17.9 Hz), 73.81, 57.41, 50.18,
47.34, 38.11, 36.89, 36.75, 35.10, 31.82, 31.44, 30.34, 27.71, 21.42, 20.77,
19.23, 16.57; IR (KBr, cm–1): 3031, 2972, 2933, 2856, 2824, 1730, 1607,
1596 1416, 1376, 1246, 1193, 1136, 810, 704; HRMS (ESI) calcd for
C26H32FNO2 [M + H] 410.2495; found: 410.2494.
3β-acetoxy-17-(5-methoxylpyridin-3-yl)androsta-5,16-diene (4f):
White solid, yield: 88%, m.p.: 164–165 °C (PE/AcOEt); 1H NMR (600
MHz, CDCl3) δ (ppm): 8.17 (s, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.09 (s,
1H), 5.93 (s, 1H), 5.34 (d, J = 4.9 Hz, 1H), 4.58–4.51 (m, 1H), 3.79
(s, 3H), 1.97 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ (ppm): 169.51, 154.23, 150.46, 139.48, 139.00, 134.18,
132.50, 128.49, 121.26, 117.66, 72.83, 56.44, 54.49, 49.23, 46.33, 37.10,
35.88, 35.75, 34.21, 30.75, 30.47, 29.37, 26.70, 20.41, 19.79, 18.22,
15.60; IR (KBr, cm–1): 3029, 2974 2922, 2850, 1730, 1612, 1587, 1427,
1374, 1204, 1033, 810, 707; HRMS (ESI) calcd for C27H35NO3 [M + H]
422.2695; found: 422.2696.
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3β-acetoxy-17-(pyrimidin-5-yl)androsta-5,16-diene (4g): Light
yellow solid, yield: 83%, m.p.: 159–160 °C (PE/AcOEt); 1H NMR (600
MHz, CDCl3) δ (ppm): 9.00 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 1.9 Hz,
2H), 6.04 (s, 1H), 5.35 (d, J = 2.6 Hz, 1H), 4.54 (m, 1H), 1.97
(d, J = 2.3 Hz, 3H), 1.01 (s, 3H), 0.97 (s, 3H); 13C NMR (150 MHz,
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121.13, 72.77, 56.29, 49.13, 46.35, 37.08, 35.87, 35.74, 34.05, 30.98,
30.41, 29.31, 26.68, 20.41, 19.73, 18.22, 15.51; IR (KBr, cm–1): 3036,
2941, 2909, 2868, 2842, 1735, 1666, 1550, 1373, 1246, 1034, 812, 744;
HRMS (ESI) calcd for C25H32N2O2 [M + H] 393.2537; found: 393.2542.
3β-acetoxy-17-(6-fluoropyridin-3-yl)androsta-5,16-diene (4h):White
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1
solid, yield: 81%, m.p.: 140–141 °C (PE/AcOEt); H NMR (600 MHz,
CDCl3) δ (ppm): 8.12 (d, J = 1.5 Hz, 1H), 7.67 (m, 1H), 6.79 (dd, J = 8.5,
2.9 Hz, 1H), 5.87 (s, 1H), 5.34 (d, J = 4.9 Hz, 1H), 4.56–4.53 (m, 1H),
1.97 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
(ppm): 169.51, 161.59 (d, J = 238.9 Hz), 149.52, 144.23 (d, J = 14.2 Hz),
139.02, 138.16 (d, J = 7.5 Hz), 129.99, 128.21, 121.23, 107.82 (d, J = 37.3
Hz), 72.82, 56.42, 49.22, 46.31, 37.11, 35.90, 35.76, 34.18, 30.72, 30.46,
29.39, 26.71, 20.40, 19.78, 18.22, 15.46; IR (KBr, cm–1): 3031, 2945, 2911,
2850, 1729, 1666, 1583, 1473, 1248, 1030, 810; HRMS (ESI) calcd for
C26H32FNO2 [M + Na] 410.2495; found: 410.2494.
3β-acetoxy-17-(2-fluorophenyl)androsta-5,16-diene (4i): White
solid, yield: 75%, m.p.: 177–178 °C (PE/AcOEt); 1H NMR (600
MHz, CDCl3) δ (ppm): 7.23 (t, J = 7.7 Hz, 1H), 7.21–7.18 (m, 1H), 7.07
(t, J = 6.2 Hz, 1H), 7.06–7.02 (m, 1H), 5.92 (s, 1H), 5.42 (d, J = 5.0 Hz,
1H), 4.66–4.59 (m, 1H), 2.03 (s, 3H), 1.07 (s, 3H), 0.99 (s, 3H); 13C NMR
33 J. Romo, J. Am. Chem. Soc., 1957, 79, 1118.