Catalytic hydrogenation of halosteroidal derivatives by bipyridine or phenanthroline complexes of copper(II) in hydrazine aqueous media

Article abstract of DOI:10.1080/00397910500408522

We report two synthetic systems, Cu(Bpy)²⁺ and Cu(Phen) ²⁺, for catalytic hydrogenation of steroidal haloalkenes in the presence of hydrazine and air. These studies demonstrated that the selective hydrogenation is faster for the 1,10-phenanthroline-Cu(II) system because forming more stable copper complex are formed, leaving fewer free copper ions in solution. Evidence also supports that the catalytic power of Cu(II) ions can be tuned moderately through the addition of bidentate ligand, Bpy or Phen. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500408522

Synthetic Communicationsw, 36: 621–630, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500408522
Catalytic Hydrogenation of Halosteroidal
Derivatives by Bipyridine or Phenanthroline
Complexes of Copper(II) in Hydrazine
Aqueous Media
Huang-Chi Du, Kung-Cheng Liu, and Wen-Shan Li
Institute of Chemistry, Academia Sinica, Taipei, Taiwan
Abstract: We report two synthetic systems, Cu(Bpy)2þ and Cu(Phen)2þ, for catalytic
hydrogenation of steroidal haloalkenes in the presence of hydrazine and air. These studies
demonstrated that the selective hydrogenation is faster for the 1,10-phenanthroline–
Cu(II) system because forming more stable copper complex are formed, leaving fewer
free copper ions in solution. Evidence also supports that the catalytic power of Cu(II)
ions can be tuned moderately through the addition of bidentate ligand, Bpy or Phen.
Keywords: Catalytic hydrogenation, dehalogenation, 17b-halosteroids, ligand, steroidal
haloalkenes
INTRODUCTION
Several steroidal haloalkanes are well known as antiestrogens for the
treatment of human breast tumors and probes for nuclear imaging of
estrogen receptors.[1–4] Recently, new types of steroidal estrogen-based
antagonists were developed because of the side effects of the partial estrogenic
activity of Tamoxifen,[5] the most widely used drug in breast cancer patients
for more than 30 years. For example, the compound EM-139[6,7] and ICI
182,780 (FaslodexTM),[8–12] bearing either a chlorine at the 16a-position or
a pentafluoropentylsulfinyl group at the 7a-position, demonstrate complete
Received in Japan July 7, 2005
Address correspondence to Wen-Shan Li, Institute of Chemistry, Academia Sinica,
Taipei 11529, Taiwan. Tel.: þ 886-2-27898662; Fax: þ886-2-27831237; E-mail:
wenshan@chem.sinica.edu.tw
621

622
H.-C. Du, K.-C. Liu, and W.-S. Li
endocrine blockade and activity against Tamoxifen-resistant estrogen
receptor-positive tumors. In addition, steroidal haloalkanes substituted with
halogens in the D-ring also serve as imaging agents to monitor the hormone
responsiveness of the tumor cell and provide early detection and accurate
assessment of the disease.[13–18] Similarly, steroids bearing a halogen in
the D-ring at C-17b may have the broad range of biological activity to act
as new halosteroidal antiestrogens or imaging agents.
Preparation of 17b-fluoro compounds is easily constructed by replacing
the oxygen function (triflate) at C-17b by nBu4NF; however, synthesis of
17b-chloro, 17b-bromo, and 17b-iodo by halogen substitution at C-17b
generates alkenes from elimination instead of substitution of the 17a-
triflate. Furthermore, construction of 17b-chloro, 17b-bromo, and 17b-iodo
by metal-mediated hydrogenation of vinyl halide is quite complicated
because of low yields and production of dehalogenation side products. For
instance, palladium-catalyzed hydrogenation of 17-bromo-5a-androstan-
16-ene resulted in 5a-androstane (85%) as a major product and 17b-bromo-
5a-androstane at low yield (10%).[19] Lately, we demonstrated a mild and
selective method to synthesize 17b-halosteroids through Cu(II)/Fe(III)-
mediated hydrogenation of steroidal haloakenes in the presence of
hydrazine hydrate. This methodology avoids side products from dehalogena-
tion or competing substitution and provides the desired 17b-halosteroids in
high yields (90–98%).[20]
However, the Cu(II)/Fe(III) system has a drawback: it consumes 2 equiv.
of Fe(III) during the reaction. For environmental reasons, it is more practical
to conduct the system with only a catalytic amount of Cu(II) without the assist-
ance of excess Fe(III). To accomplish this goal, we have to enhance the selec-
tivity of catalytic power of Cu(II) through the aid of coordination chemistry,
which already exists in nature. From enzymatic point of view, nature uses the
amino nitrogen and the carboxylate oxygen to coordinate the Cu(II) ion at the
active site of many metalloenzymes.[21] Because of the hydrophobic and
hydrophilic environment of the amino acid network, copper metal in the
active site of enzyme can preferentially promote catalytic reactions, such as
hydrolysis and coupling reactions, from one course and prevent the
undesired contact from the other direction. In the Cu(II)/Fe(III)-mediated
hydrogenation system, however, the role of free Cu(II) is still ambiguous,
and it is very attractive to explore how free Cu(II) or ligand Cu(II)

Halosteroidal Derivatives
623
complexes manipulate the metal-catalyzed hydrogenation of steroidal haloalk-
enes. To unravel these questions, we report here a detailed investigation of
2,20-bipyridine (Bpy)–Cu(II) and 1,10-phenanthroline (Phen)–Cu(II)
systems in comparison with the free Cu(II) or Cu(II)/Fe(III) catalytic
method described earlier in our laboratory.
RESULTS AND DISCUSSION
Previously, metal-mediated hydrogenation of steroidal haloakenes showed
that free Cu(OAc)2 (0.1 equiv) is capable of catalyzing hydrogenation of
17-bromo-3b-hydroxy-5a-androstan-5,16-ene (1.0 equiv) into 17b-bromo-
3b-hydroxy-5a-androstan-5-ene (9%) and 3b-hydroxy-5a-androstan-5-ene
(43%).[20] However, the desired hydrogenation product is minor, and the deha-
logenation one is the major. On the other hand, exclusive K3Fe(CN)6 (1.5
equiv) as a metal catalyst is very inert at the same condition. Despite of
problems of using the metal catalyst individually, metal complex Cu(II)/
Fe(III) (0.01 equiv:2.0 equiv) has higher catalytic activity for production of
17b-halosteroids without any concomitant formation of dehalogenation
products.[20] Obviously, K3Fe(CN)6 is able to adjust the catalytic power of
Cu(II) and regulate the ratio of final products (hydrogenation/dehalogena-
tion). It is very interesting to see whether the addition of Bpy or Phen
ligand[22–24] in Cu(II) is capable of doing the same function in this catalytic
system (Scheme 1). The structures of steroidal haloakenes and the correspond-
ing products described in this study are presented in Scheme 1.
We first examined the efficacy of 10 mol% of Cu(Bpy)2þ or Cu(Phen)2þ
as a catalyst to carry out the hydrogenation of 17-chloroalkenes (1a and 3a).
The bidentate Bpy or Phen ligand (1 equiv) was mixed with 1 equiv of
Scheme 1.

624
H.-C. Du, K.-C. Liu, and W.-S. Li
Cu(OAc)2 and in situ generated mononuclear complex Cu(Bpy)2þ or
Cu(Phen)2þ, which was examined for its catalytic hydrogenation in the
presence of hydrazine hydrate and air in methanol. Thus, 17-chloroalkenes
(1a and 3a) were the first interesting targets to investigate because of their
higher heterolytic bond dissociation energy of C–Cl bond; that is, the hetero-
lytic bond dissociation energy is greater for the C–Cl bond than for the
C–Br/C–I bonds. In comparison to the absence and presence of Bpy or
Phen ligand with Cu(OAc)2 (Table 1, entries 1–3), the ratio of products
(hydrogenation/dehalogenation) increased from 0.7 (without ligand) to 7.3
(with Phen ligand), indicating that enhancement of catalytic hydrogenation
occurs in the presence of Bpy or Phen. In other words, the abilities of
catalytic hydrogenation displayed by Cu(Bpy)2þ and Cu(Phen)2þ for 1a were
increased three- to ten-fold when compared with Cu(OAc)2 itself. Similarly,
the relative yields of 4a listed in Table 1 (entries 4–6) were found to increase
from 66% to 97% with an addition of ligand in the following order: no ligand ,
Bpy , Phen. The Cu(Bpy)2þ or Cu(Phen)2þ complex exhibited enhancements
in the abilities of catalytic hydrogenation by factors of four to 17-fold relative to
those of Cu(OAc)2. The increasing propensity of the catalytic hydrogenation
based on the ratio of products is in accordance with the tendency of stability
constants of Cu(Bpy)2þ and Cu(Phen)2þ complexes, where their overall
Table 1. Catatlytic hydrogenation of 1a and 3a by Cu(OAc)2 in the presence or
absence of ligandsa
Yield
(%)b
Entry
1
Ligand
—
Substrate
Product
Ratioc
1a
2a
dehalogenation
42
58
67
33
88
12
66
34
87
13
97
3
0.7
2.0
7.3
1.9
6.7
32
2
3
4
5
6
Bpy
Phen
—
1a
1a
3a
3a
3a
2a
dehalogenation
2a
dehalogenation
4a
dehalogenation
4a
Bpy
Phen
dehalogenation
4a
dehalogenation
aReactions were performed at room temperature in methanol (3 mL) for 27 h with
substrate 1a or 3a (70 mmol), Cu(OAc)2 (7 mmol), and ligands (7 mmol) in the
presence of hydrazine hydrate and air.
1
bDetermined from the integral ratio of H NMR.
cThe value of ratio is the yield of hydrogenation product/yield of dehalogenation
product.

Halosteroidal Derivatives
625
formation constants are about 1017 and 1020 in solution respectively.[25] This
evidence suggests that more free Cu(II) in solution results in less hydrogenation
product and additional formation of dehalogenation. Meanwhile, Cu(Bpy)2þ
and Cu(Phen)2þ complexes entice induction of thermodynamic stability and
promote desired orientation for a selective catalytic pathway by a coordination
chemistry approach.
In the case of 17-iodoalkenes (1c and 3c), under typical hydrogenation con-
ditions, dehalogenation products (Table 2, entries 1, 4, 12) are usually generated
because of the low dissociation energy of C–I bond. Thus, it is necessary to
explore various reaction conditions for hydrogenation of 1c/3c using Cu(II)–
ligand complex in the presence of K3Fe(CN)6 to scrutinize the influence of
Bpy or Phen on selective hydrogenation. Obviously, with the addition of
different amounts of K3Fe(CN)6 in solution the desired hydrogenation product
2c had been consistently increased with less formation of dehalogenation
product. After optimization, we were able to build up a suitable and practical
condition (entry 8) for the catalytic hydrogenation of 1c (entries 2, 3, 5–7,
8–10). The reaction with Cu(OAc)2/Bpy/K3Fe(CN)6 (the molar ratio is
0.1:0.1:0.4) yielded 17b-iodoalkane 2c in 50% yield with an equal amount of
the deiodomination compound (entry 8). Similarly, we then examined the
efficacy of Cu(OAc)2/Phen/K3Fe(CN)6 as a catalyst for the formation of 17b-
iodoalkane 4c (entries 11–18). We found that the best protocol for the catalytic
hydrogenation of 3c was obtained using the same molar ratio (0.1:0.1:0.4) of
Cu(OAc)2/Phen/K3Fe(CN)6 in the presence of hydrazine hydrate and air
(entry 16). In this event, 4c was detected in 72% yield, and the other deiodomina-
tion product was observed in 12% yield only. Elongationof the reactiontime defi-
nitely increased the yield of hydrogenation product 4c up to 87% (entry 19).
Using this protocol, we were able to evaluate the efficacy of Bpy or Phen
as a part of the catalyst to catalyze hydrogenation of bromo- and iodo-steroidal
compounds (1b, 3b, 1c, and 3c). Interestingly, the catalyst with Phen ligand
also displayed a higher ratio of hydrogenation products than those of Bpy
ligand (Table 3). For example, the ratios of hydrogenation/dehalogenation
increased from 2.6 to 3.5 in the cases of entries 1 and 2, from 4.3 to 7.4 in
the cases of entries 3 and 4, from 1.0 to 2.0 in the cases of entries 5 and 6,
and from 1.1 to 6.0 in the cases of entries 7 and 8. These results are consistent
with the observations in Table 1 in the absence of K3Fe(CN)6 as the catalyst.
In addition, evidence demonstrates that the catalytic ability of the Cu(II) ion
in hydrogenation of steroidal haloalkenes can be tuned comparatively by
adding the Bpy or Phen ligand.
CONCLUSIONS
In conclusion, a practical protocol has been developed that allowed us to
evaluate the roles of Bpy and Phen ligands toward Cu(II) metal through the
manipulation of thermodynamic stability and reconstruction of the catalytic

626
H.-C. Du, K.-C. Liu, and W.-S. Li
Table 2. Selected optimization conditions for 17b-iodosteroids (2c and 4c)
formationsa
Yield (%)b
Reaction 2c or Dehalo-
4cc
Entry
Substrate Metal oxidant
Ratio (nmol)
time (h)
genation
1
2
1c
1c
Cu(II)/Bpy
Cu(II)/Bpy/
Fe(III)
0.01:0.01
0.01:0.01:0.02
1.0
1.0
8
12
86
11
3
1c
Cu(II)/Bpy/
Fe(III)
0.01: 0.01: 0.1
1.0
9
7
4
5
1c
1c
Cu(II)/Bpy
Cu(II)/Bpy/
Fe(III)
0.1:0.1
0.1:0.1:0.02
2.0
4.0
0
14
100
74
6
7
1c
1c
1c
1c
1c
3c
Cu(II)/Bpy/
Fe(III)
0.1:0.1:0.2
0.1:0.1:0.4
0.1:0.1:0.4
0.1:0.15:0.4
0.1:0.15:1.0
0.01:0.01:0.1
4.0
4.0
9.0
4.0
6.0
1.0
22
47
50
28
20
15
40
28
50
39
51
16
Cu(II)/Bpy/
Fe(III)
8
Cu(II)/Bpy/
Fe(III)
9
Cu(II)/Bpy/
Fe(III)
10
11
Cu(II)/Bpy/
Fe(III)
Cu(II)/Phen/
Fe(III)
12
13
3c
3c
Cu(II)/Phen
Cu(II)/Phen/
Fe(III)
0.1:0.1
0.1:0.1:0.2
2.0
4.0
2
55
11
25
14
15
16
17
18
19
3c
3c
3c
3c
3c
3c
Cu(II)/Phen/
Fe(III)
0.1:0.2:0.2
0.1:0.1:0.4
0.1:0.1:0.4
0.1:0.1:1.0
0.2:0.2:0.4
0.1:0.1:0.4
4.0
4.0
53
47
72
29
29
87
31
8
Cu(II)/Phen/
Fe(III)
Cu(II)/Phen/
Fe(III)
9.0
12
13
39
13
Cu(II)/Phen/
Fe(III)
9.0
Cu(II)/Phen/
Fe(III)
4.0
Cu(II)/Phen/
Fe(III)
14.0
aReactions were performed at room temperature in methanol (3 mL) for different
time with substrate 1c or 3c (70 mmol), Cu(OAc)2 (7 mmol), ligands (7 mmol), and
various amounts of K3Fe(CN)6 in the presence of hydrazine hydrate and air.
1
bDetermined from the integral ratio of H NMR.
c2c is the product for entries 1–10; 4c is the product for entries 11–19.

Halosteroidal Derivatives
627
Table 3. Optimized catalytic hydrogenation of 1b, c and 3b, c by Cu(OAc)2 in the
a
presence of ligand and K3Fe(CN)6
Yield (%)b
Catalyst/
ligand
Reaction
time (h)
Hydro-
genation
Dehalo-
genation
Entry
1
Substrate
Ratioc
2.6
1b
Cu(II)/Bpy/
Fe(III)
18
18
18
18
9
72 (2b)
78 (2b)
81 (4b)
74 (4b)
50 (2c)
62 (2c)
47 (4c)
72 (4c)
28
22
19
10
50
31
42
12
2
3
4
5
6
7
8
1b
3b
3b
1c
1c
3c
3c
Cu(II)/Phen/
Fe(III)
3.5
4.3
7.4
1.0
2.0
1.1
6.0
Cu(II)/Bpy/
Fe(III)
Cu(II)/Phen/
Fe(III)
Cu(II)/Bpy/
Fe(III)
Cu(II)/Phen/
Fe(III)
9
Cu(II)/Bpy/
Fe(III)
9
Cu(II)/Phen/
Fe(III)
9
aReactions were performed at room temperature in methanol (3 mL) for 9 or 18 h
with substrate 1b, 3b, 1c, or 3c (70 mmol), Cu(OAc)2 (7 mmol), ligands (7 mmol),
and K3Fe(CN)6 (28 mmol) in the presence of hydrazine hydrate and air.
1
bDetermined from the integral ratio of H NMR.
cThe value of ratio is the yield of hydrogenation product/yield of dehalogenation
product.
orientation. The catalyst with Phen ligand displays more catalytic power
during selective hydrogenation of halosteroidal compounds. Studies to facili-
tate the selectivity between hydrogenation and dehalogenation by Cu(OAc)2
using more rigid ligands are under way in our laboratory.
EXPERIMENTAL
General
1H spectra were recorded on a Bruker AMX400 spectrometer. Proton
chemical shifts (d) are reported in parts per million (ppm) relative to the
methine singlet at 7.24 ppm for the residual CHCl3 in the deuteriochloroform.
The water used in this study was deionized and doubly distilled. All chemicals
and solvents were purchased from Sigma, Aldrich, or Acros Organics.

628
H.-C. Du, K.-C. Liu, and W.-S. Li
Synthesis of steroidal haloalkenes (1a–c and 3a–c) was conducted in two
steps as described previously.
General Hydrogenation Method
Vinyl halide (70 mmol) was added to a stirred solution of Cu(OAc)2 (1.3 mg,
7.0 mmol) and ligand (7.0 mmol) in methanol (3 mL) under an atmosphere of
air at room temperature, then N2H4 ꢀ H2O (200 mL). N2H4 ꢀ H2O (200 mL)
was slowly added every 2 h, and the solution was allowed to stir continuously.
We stopped the reaction when TLC analysis showed that starting material was
gone. The precipitate was filtered and washed thoroughly with dichloro-
methane. The organic layer was evaporated, and dilute aqueous HCl was
added to the remaining aqueous phase adjust the pH to 8–8.5. The resulting
water solution was extracted with CH2Cl2 (6 mL), and the combined
organic phases were dried (Na2SO4). The solvent was evaporated, and the
small amount of mixture was then directly analyzed by 1H NMR to
determine the ratio of hydrogenation product. The pale yellowish residue
was purified by chromatography on silica gel. Elution with hexane first and
then a mixture of EtOAc/hexane (1:10 v/v) yielded the corresponding
products in order of increasing polarity: the dehalogenation product
followed by hydrogenation product as a colorless solid.
ACKNOWLEDGMENTS
We thank the National Science Council (NSC93-2113-M-001-035) and
Academia Sinica for financial support.
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