Catalytic hydrogenation on Raney nickel of estra-1,3,5(10),8,14-pentaenes with sterically accessible double bonds

Article abstract of DOI:10.1134/S1070428008050060

The catalytic hydrogenation of estra-1,3,5(10),8,14-pentaenes with sterically accessible double bonds in the presence of Raney nickel in 2-propanol at elevated pressure and at heating to 110-120°C resulted in prevailing formation of estrogens 8α-analogs alongside a considerable quantity of estra-5,7,9-trienes. Although the hydrogenation at 45-60°C provided a higher yield of estrogens 8α-analogs, the synthesis of steroids of this group gave better results at hydrogenation in a high purity benzene.

Full text of DOI:10.1134/S1070428008050060

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 675−680. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © S.N. Morozkinaa, S.V. Nikolaev, S.I. Selivanov, D.B. Ushakov, A.G.Shavva, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 5, pp. 685−690.
Catalytic Hydrogenation on Raney Nickel
of Estra-1,3,5(10),8,14-pentaenes
with Sterically Accessible Double Bonds
S. N. Morozkina, S. V. Nikolaev, S. I. Selivanov, D. B. Ushakov, and A. G. Shavva
St. Petersburg State University, St. Petersburg, 198504 Russia
e-mail: AGShavva@yandex.ru
Received July 10, 2007
Abstract—The catalytic hydrogenation of estra-1,3,5(10),8,14-pentaenes with sterically accessible double
bonds in the presence of Raney nickel in 2-propanol at elevated pressure and at heating to 110–120°C resulted in
prevailing formation of estrogens 8α-analogs alongside a considerable quantity of estra-5,7,9-trienes. Although
the hydrogenation at 45−60°C provided a higher yield of estrogens 8α-analogs, the synthesis of steroids of this
group gave better results at hydrogenation in a high purity benzene.
DOI: 10.1134/S1070428008050060
8α-Analogs of the naturally occurring estrogens
exhibit a considerable affinity to the corresponding
nuclear receptors [1–3] and therefore are promising
objects for preparation of new substances with refined
biological characteristics [4]. Although these properties
are inherent to many steroids of this stereochemical series
[5–23] the synthetic procedures for their preparation
have not been specially developed. The most common
method of preparation of steroids from this class is a
catalytic hydrogenation of estra-1,3,5(10),8,14-pentaenes
or similar substances containing a double bond in the
position 8(9) [5–32]. The formation of estrogens 8α-
analogs is usually ascribed to the easy approach of the
catalyst to the α-region of the molecule although this
reaction route is unfavorable due to the presence in the
forming compounds closely located β-hydrogens at C7
and C11, and also of an alkyl group at C13 [33]. The yield
of target products usually does not exceed 60%, yet the
most part of steroids of this group has been synthesized
by this method. In particular, in the patent [9] 133
examples are cited of preparation of compounds from
this stereochemical series.
altered junction of the rings that sometimes actually
occurs [29]. Besides in some cases (especially when the
double bonds are spatially shielded) the B ring suffers
aromatization that significantly hampers the purification
of the target products [24–28].
As a rule the catalytic hydrogenation is carried out
in the presence of Pd on some carrier. These catalysts
are relatively expensive, therefore attempts have been
made to apply the more accessible Raney nickel [15–
17]. We started a systematic research on the catalytic
hydrogenation of 1,3,5(10),8,14-estrapentaenes in the
presence of Raney nickel. The first objects of our study
were compounds with a system of conjugated double
bonds in positions 8(9),14(15) sterically accessible for
the catalyst.
First problem was to find a solvent suitable for
performing the reaction. Inasmuch as an information
existed on the hydrogenation of steroids with a double
bond in the position 8(9) in ethanol or a mixed solvent
containing ethanol [7, 25, 30–32], we checked the
feasibility of applying alcohols to the hydrogenation of
analogous substrates on Raney nickel at elevated pressure
by examples of compounds I–III (see the scheme). The
choice of model substances was governed by the potential
possibility to use the corresponding estrogens 8α-analogs
for the synthesis of products with refined biological
action [4]. The catalytic hydrogenation was carried out
in 2-propanol for the initial substrates were better soluble
in it than in ethanol.
Obviously the spatial shielding of the system of
conjugated double bonds in the substrate or the existence in
the reaction product of additional unfavorable interactions
between the substituents would result in decrease in the
yield of estrogens 8α-analogs. When under the action
of the catalyst a preliminary migration of a double bond
is possible the main reaction product might contain the
675

MOROZKINA et al.
676
Scheme.
OAc
OAc
OAc
H2/Ni-Ra
H
+
H
H
H
O
O
O
I
IV
V
OAc
OAc
OAc
H
H
+
+
+
H
H
H
H
H
O
VIII
VII
VI
OAc
OAc
OAc
OAc
H
H2/Ni-Ra
+
+
H
H
H
H
O
O
O
IX
X
XI
II
OAc
OAc
H2/Ni-Ra
H
O
O
OAc
OAc
+
H
+
H
H
H
O
O
products impeded their purification. The hydrogenation of
compound I at 45–60°C resulted in the formation of lesser
amounts of products of methoxy group hydrogenolysis.
It turned out that the catalytic hydrogenation of
a typical Torgov steroid I at 110–120°C led to the
formation of a complex mixture of substances that was
subjected to HPLC to provide compounds IV–VIII.
Their structure was deduced from mass spectra and
1H and 13C NMR spectra (the procedure of establishing
the structure of modified estrogens was described in [34]).
Although the 8α-analogs of steroid estrogens formed in
relatively high yields the presence of numerous reaction
Similarresultswereobtainedalsoonthehydrogenolysis
of steroid II: at 110–120°C the yields of estra-5,7,9-
trienes and 8α-analog X were comparable, at 45–60°C
the hydrogenolysis products virtually did not form.
Although the yield of the estrogens of the 8α-series
somewhat increased in the process carried out at lower
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

CATALYTIC HYDROGENATION ON RANEY NICKEL
677
temperature, the use of 2-propanol as the only solvent for
hydrogenation of substrates of similar structure would
be limited because of the low solubility of the initial
compounds.
(164–165°C [44]). 13C NMR spectrum, δ, ppm: 129.9
(C1), 112.0 (C2), 157.2 (C3), 113.0 (C4), 137.5 (C5), 31.5
(C6), 21.0 (C7), 40.2 (C8), 41.3 (C9), 134.0 (C10), 28.1
(C11), 37.5 (C12), 37.7 (C13), 46.5 (C14), 24.2 and 25.7 (C15
and C16), 27.3 (C17), 81.8 (C17a), 13.5 (C18), 55.0 (CH3O),
21.1 (CH3CO), 170.7 (CH3CO). Found, %: C 77.18; H 8.87.
C22H30O3. Calculated, %: C 77.16; H 8.83.
Formerly at the Chair of the natural compounds of the
Chemical Faculty of Saint-Petersburg State University
an efficient synthesis was performed by catalytic
hydrogenation of estra-1,3,5(10),8,14-pentaenes on Raney
nickel in benzene [13, 14, 35–42]. Taking into account
the results of these studies and the findings described
above we tested the feasibility of using for the catalytic
hydrogenation the Raney nickel thoroughly washed
from 2-propanol that was usually used for its storage.
It proved that the yield of steroid estrogens 8α-analogs
significantly grew, but the reaction should proceed at the
temperature not exceeding 80°C; at higher temperature
side products formed and hampered the purification of
the target substances.
The compounds retained in the mother liquor
were purified by HPLC on a column Lichrosorb RP-18
5 μm (Merck) with a gradient elution by the mixture
acetonitrile–water (80–95%) for 15 min. From the
most polar fraction we obtained 0.089 g (9%) of 17aβ-
acetoxy-3-methoxy-D-homoestra-5,7,9(10)-triene (V),
mp 146–149°C (after recrystallization from a mixture
1
ethanol–benzene, 25:1). H NMR spectrum, δ, ppm:
0.82 s (3H, C18H3), 2.10 s (3H, CH3CO), 3.45 s (3H,
CH3O), 4.62 m (1H, C3H), 4.68 d.d (1H, H17a, J17βH,17aαH
11.1, J17αH,17aαH 4.6 Hz), 6.94 d and 7.05 d (пO 1H, H6
and H7, J 8.1 Hz). 13C NMR spectrum, δ, ppm: 10.4,
21.1, 23.1, 23.5, 23.6, 24.5, 26.2, 27.9, 33.4, 35.4, 36.2,
44.9, 55.7, 75.4, 80.2, 123.0, 126.9, 131.7, 133.4, 133.8,
135.3, 162.1, 170.8. Mass spectrum, m/z (Irel, %): 342
(49) [M]+, 310 (100), 284 (8), 267 (16), 250 (22), 235
(29), 221 (11), 215 (14), 195 (26), 183 (21), 169 (19), 155
(19). Found, %: C 77.08; H 8.80. C22H30O3. Calculated,
%: C 77.16; H 8.83.
From the compounds synthesized the most interesting
biological properties were found in compound X
exhibiting a high hypocholesteremic action and a
considerable osteoprotective effect. The analysis of
experimental data on the biological properties of new
compounds will be published elsewhere.
EXPERIMENTAL
The less polar oily fraction (85 mg) contained two
components: 20% of steroid V and 80% of 17aβ-acetoxy-
3-methoxy-D-homo-9β-estra-1,3,5(10)-triene (VI).
1H NMR spectrum, δ, ppm: 0.97 s (3H, C18H3), 2.04 s
(3H, CH3CO), 2.94 br.s (1H, H9), 3.79 s (3H, CH3O),
4.36 m (1H, H17a), 6.64 d (1H, H4, J 2.5 Hz, ), 6.72 d.d
(1H, H2, J2,4 2.5, J1,2 8.6 Hz), 7.23 d (1H, H1, J1,2 8.6 Hz).
13C NMR spectrum, δ, ppm:127.0 (C1), 111.8 (C2), 157.1
(C3), 113.8 (C4), 138.5 (C5), 25.3 (C6), 25.4 (C7), 33.3
(C8), 37.6 (C9), 130.0 (C10), 23.4 (C11), 31.8 (C12), 38.2
(C13), 39.8 (C14), 23.0 (C15), 23.8 (C16), 26.6 (C17), 81.0
(C17a), 11.4 (C18), 55.1 (CH3), 20.9 (CH3CO), 170.8
(CH3CO).
All compounds synthesized were racemic. Their
purity was checked by HPLC on a chromatographAltex.
Mass spectra were taken on MKh-1321 instrument at
the ionization chamber temperature 200–210°C and the
1
energy of ionizing electrons 70 eV. H and 13C NMR
spectra were registered at 295 K on a spectrometer Bruker
DPX-300 at operating frequencies 300.130 and 75.468
MHz respectively from solutions in 0.6 ml of CDCl3 of
1
5–7 mg of compound for registering H NMR spectra,
30–50 mg for 13C NMR spectra. Chemical shifts are
reported with respect to TMS and have been measured
from the signals of the solvent (CDCl3–CHCl3,99.9:0.1),
7.26 ppm (1H) and 76.90 ppm (13C).
We obtained additionally 175 mg (17%) of compound
IV, mp 172.5–174°C. Overall yield of steroid IV was
68%.
Catalytic hydrogenation of 17aβ-acetoxy-3-
methoxy-D-homoestra-1,3,5(10),8,14-pentaene (I). a.
To a solution of 1 g of compound I [43] in 270 ml of 2-
propanol was added 3 g of freshly prepared Raney nickel,
the hydrogenation was carried out for 1 h at 110–120°C
and at the pressure 120 at. After a common workup the
reaction products were crystallized from ethanol. We
obtained 0.52 g (51%) of 17aβ-acetoxy-3-methoxy-D-
homo-8α-estra-1,3,5(10)-triene (IV), mp 172.5–174°C
From the fraction with the retention time 10 min by
means of crystallization from methanol we isolated
33 mg (4%) of 17aβ-acetoxy-D-homo-8α-estra-1,3,5-
1
(10)-triene (VII), mp 95–96°C. H NMR spectrum, δ,
ppm: 0.98 s (3H, C18H3), 2.04 s (3H, CH3CO), 4.51 m
(1H, H17a), signals of 4 aromatic protons. 13C NMR
spectrum, δ, ppm: 13.6 (2C), 21.2 (2C), 24.2, 25.7,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

MOROZKINA et al.
678
27.3, 28.0, 31.2, 37.6, 37.7, 40.0, 42.0, 46.5, 81.8, 125.4,
125.5, 128.7, 129.1, 136.4, 141.7, 170.8. Mass spectrum,
m/z (Irel, %): 312 (64) [M]+, 252 (46), 237 (6), 223 (12),
210 (7), 197 (66), 183 (16.5), 169 (14.5), 156 (40), 142
(82), 141 (43), 130 (100). Found, %: C 80.63; H 9.11.
C21H28O2. Calculated, %: C 80.73; H 9.03.
recrystallization from methanol). 1H NMR spectrum, δ,
ppm: 0.72 s (3H, C18H3), 2.08 s (3H, CH3CO), 3.43 s
(3H, CH3O), 3.61 m (1H, H3), 4.82 d.d (1H, H17,
J 6.96, 6.90 Hz), 6.83 d and 6.92 d (1H each, H6 and H7,
J 7.8 Hz). 13C NMR spectrum, δ, ppm: 11.2, 21.1, 23.4,
24.5 (2C), 27.8, 28.1, 34.1, 35.5, 41.9, 46.1, 55.7, 75.4,
81.8, 123.3, 126.8, 131.8, 133.5, 133.8, 136.1, 171.2.
Mass spectrum, m/z (Irel, %): 328 (56) [M]+, 296 (100),
253 (27), 236 (37.5), 221 (47), 210 (17.5), 195 (42), 183
(22), 165 (16.5), 155 (26). Found, %: C 76.69; H 8.71.
C21H28O3. Calculated, %: C 76.79; H 8.59.
From the most polar fraction by means of crystallization
from methanol we isolated 78 mg (8%) of 17aβ-acetoxy-
1
D-homoestra-5,7,9-triene (VIII), mp 145–147°C. H NMR
spectrum, δ, ppm: 0.81 s (3H, C18H3), 2.09 s (3H, CH3CO),
4.67 d.d (1H, H17a, J1 11, J2 4.6 Hz), 6.92 d and 7.04 d
(1H each, H6 and H7, J 8.1 Hz). 13C NMR spectrum, δ,
ppm: 10.4, 21.2, 22.7, 23.0, 23.6, 23.7, 26.2, 26.3, 29.8,
33.5, 36.2, 45.0, 80.3, 122.4, 126.6, 133.8, 134.5, 134.9
(2C), 157.0, 170.9. Mass spectrum, m/z (Irel, %): 312
(100) [M]+, 252 (35), 237 (50), 223 (13), 209 (13), 197
(31), 185 (58), 171(8), 155 (13), 143 (16), 141 (14), 129
(15).Found, %: C 80.85; H 9.12. C21H28O2. Calculated,
%: C 80.73; H 9.03.
From the fraction with the retention time 10.5 min
we obtained 0.335 g (33%) of 17β-acetoxy-3-methoxy-
8α-estra-1,3,5(10)-triene (X), mp 112–112.5OC (after
recrystallization from methanol). Mass spectrum, m/z
(Irel, %): 328 (100) [M]+, 285 (2), 268 (14.5), 253 (3),
239 (17), 227 (9), 211 (5.5), 199 (5.5), 186 (41.5), 173
(19.5), 160 (39), 147 (11). Found, %: C 76.73; H 8.64.
C21H28O3. Calculated, %: C 76.79; H 8.59.
b. The hydrogenation of 0.50 g of compound I was
performed in 270 ml of 2-propanol at the pressure of
100 at and temperature 45–60°C for 45 min, the reaction
products were purified in the same way as in the procedure
a. We obtained 0.009 g (2%) of compound V, mp 144–
147°C, 0.035 g (7%) of oily 9β-analog VI, and 0.34 g
(67%) of steroid IV, mp 171–173°C. The respective
1H and 13C NMR spectra were the same as cited above.
From the fraction with the retention time 12.8 min
we isolated 0.14 g(15%) of 17β-acetoxyestra-5,7,9(10)-
triene (XI), mp 131–133.5°C (after recrystallization
from methanol). 1H NMR spectrum, δ, ppm: 0.73 s
(3H, C18H3), 2.10 s (3H, CH3CO), 4.84 d.d (1H, H17,
J
16a,17a = J16β,17a = 6.93 Hz), 6.81 d and 6.92 d (1H each,
H6 and H7, J 7.7 Hz). 13C NMR spectrum, δ, ppm: 11.1,
21.1, 22.7, 23.3, 23.4, 24.3, 26.4, 28.1, 30.0, 34.1, 41.9,
46.1, 81.8, 122.7, 126.5, 133.9, 134.5, 134.8, 135.6,
171.1. Mass spectrum, m/z (Irel, %): 298 (100) [M]+, 238
(24), 223 (60), 210 (16), 197 (22), 185 (12.5), 165 (5).
Found, %: C 80.44; H 8.81. C20H26O2. Calculated, %:
C 80.50; H 8.78.
c. To a solution of 7.0 g of compound I in 270 ml
of benzene was added 10 g of freshly prepared Raney
nickel W-6 [45] thoroughly washed with benzene. The
hydrogenation was carried out at 60–70°C and hydrogen
pressure 120–160 at. After consumption of 100–120 l of
hydrogen the hydrogenation was stopped, the products
were subjected to usual workup, the target compound
was isolated by crystallization from methanol, yield
b. The catalytic hydrogenation of 0.5 g of estrapentaene
II and the purification of the reaction products was
performed as in procedure a, but the temperature of
the process was maintained in the range 45–60°C. We
obtained 0.042 g (8%) of steroid IX, mp 125–127 °C,
0.29 g (57%) of acetate X, mp 112–113°C, and 0.02 g (4%)
of compound XI, mp 201–203°C (201–203°C [47]).
1
6.55–6.65 g (93–95%), mp 171–173°C. The H and
13C NMR spectra of the steroid isolated were identical
to those cited above.
Catalytic hydrogenation of 17β-acetoxy-3-methoxy-
estra-1,3,5(10),8,14-pentaene (II). a. To a solution of 1 g
of compound II [46] in 270 ml of 2-propanol was added
5 g of Raney nickel, the hydrogenation was carried out
for 1 h at 110–120°C and the pressure of 120 at. The
reaction products were purified by HPLC on a column
Lichrosorb RP-18 5 μm (Merck) with a gradient elution
by the mixture acetonitrile–water (80–95%) for 15 min.
c. Into a steel pressure reactor of capacity 600 ml was
charged a solution of 13 g of estrapentaene II in 260 ml
of benzene. To the solution 10 g of Raney nickel was
added. The catalyst was thoroughly washed with benzene
just before the experiment. The hydrogen pressure was
increased to 150–180 at.
The reaction mixture was heated to 45–50°C, and then
the agitator was started. The temperature was maintained
not higher than 90°C without stopping the reaction.
After consumption of 100 l of hydrogen the agitator
From the fraction with the retention time 8.3 min we
obtained 0.232 g (23%) of 17β-acetoxy-3-methoxy-
estra-5,7,9(10)-triene (IX), mp 125–127°C (after
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CATALYTIC HYDROGENATION ON RANEY NICKEL
679
was stopped, the reaction mixture was cooled to room
REFERENCES
temperature. The catalyst was filtered off through a glass
frit and washed on the filter with 100 ml of benzene, the
solutions of the hydrogenation products were combined.
The solvents were removed on a rotary evaporator.
The residue was recrystallized from methanol. Yield of
compound X 11.15 g (85%), mp 113.5–115°C. The mixed
probe with an authentic sample melted without depression
of the melting point. The 1H NMR spectrum of steroid X
was identical to that of the authentic compound.
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3-methoxyestra-1,3,5(10),8,14-pentaene (III). To
a solution of 0.50 g of compound III [46] in 270 ml
of 2-propanol was added 0.5 g of Raney nickel, the
hydrogenation was carried out at 45–65°C and the
pressure of 100–105 at for 1 h. The catalyst was filtered
off, the solvent was removed in a vacuum, the reaction
products were purified by HPLC.
From the least polar fraction we separated by
crystallization from ethanol 0.055 g (11%) of 17β-
acetoxy-2-methyl-3-methoxyestra-1,3,5,7,9-pentaene
(XII), mp 178–185°C (178–185°C [46)]). The mixed
probe with an authentic sample [46] melted without
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1
13
depression of the melting point. The H and C NMR
spectra of steroid XII was identical to that of the authentic
compound.
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From the next fraction we separated by crystallization
from ethanol 0.035 g (7%) of 17β-acetoxy-2-methyl-
3-methoxyestra-1,3,5(10),8-tetraene (XIII), mp 148–
1
150°C. H NMR spectrum, δ, ppm: 0.81 s (3H, C18H3),
2.07 C (3H, CH3CO), 2.19 C (3H, C2–CH3), 3.82 C (3H,
CH3O), 4.77 d.d (1H, H17, J1 = J2 = 6.9 Hz), 6.62 s (1H,
H4), 7.09 s (1H, H1). Mass spectrum, m/z (Irel, %): 340
(100) [M]+, 325 (6), 309 (3), 297 (4), 278 (13.5), 265
(16), 249 (5), 240 (9), 239 (9), 225 (7), 186 (22), 165
(5). Found, %: C 77.51; H 8.35. C22H28O3. Calculated,
%: C 77.61; H 8.29.
From the most polar fraction we separated by
crystallization from ethanol 0.26 g (51%) of 17β-acetoxy-
2-methyl-3-methoxy-8α-estra-1,3,5(10)-triene (XIV),
1
mp 132.5–133.5°C. H NMR spectrum, δ, ppm: 0.91 s
(3H, C18H3), 2.07 s (3H, CH3CO), 2.17 s (3H, C2–CH3),
3.79 s (3H, CH3O), 4.62 d.d (1H, H17, J1 = J2 = 8.7 Hz),
6.52 s (1H, H4), 6.91 s (1H, H1). Mass spectrum, m/z (Irel,
%): 342 (100) [M]+, 282 (10), 267 (3.5), 253 (12), 241
(4.5), 225 (4.5), 213 (4.5), 200 (32.5), 187 (13), 185 (8),
174 (24.5), 161 (8), 159 (10). Found, %: C 76.91; H 8.90.
C22H30O3. Calculated, %: C 77.16; H 8.83.
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