6-Chloro- and 6-bromo-substituted steroids in the Suzuki-Miyaura cross-coupling reaction. A convenient route to potential aromatase inhibitors

Article abstract of DOI:10.1055/s-2006-926270

Chlorine at an sp²-carbon in steroids has been shown to be reactive in Suzuki-Miyaura cross-coupling reactions with either Ni or Pd catalysts. The coupling of analogous 6-bromo derivatives has also been demonstrated to be applicable to a wider scope of substrates. The Suzuki-Miyaura arylation of 6-bromo-Δ^3,5-steroid enol ethers with subsequent hydrolysis is a useful route to 6-arylated steroids bearing aryl at a saturated carbon. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926270

PAPER
533
6-Chloro- and 6-Bromo-Substituted Steroids in the Suzuki–Miyaura Cross-
Coupling Reaction. A Convenient Route to Potential Aromatase Inhibitors
6
-Chloro- and 6-B
i
romo-S
k
ubstituted S
o
S
u
l
a
iyaur
a
Cro
y
a
Chemistry Department, Moscow State Lomonosov University, Vorobievy Gory, 119992, Moscow, Russia
Fax +7(495)4223297; E-mail: nvluk@org.chem.msu.su
b
Ambiotech Inc., 300 E Lombard St. STE 1400, Baltimore, MD 21202, USA
Received 19 August 2005; revised 22 August 2005
position of incoming aryl group by the availability of keto
derivatives and are not applicable to compounds with
more than one carbonyl group.
Abstract: Chlorine at an sp2-carbon in steroids has been shown to
be reactive in Suzuki–Miyaura cross-coupling reactions with either
Ni or Pd catalysts. The coupling of analogous 6-bromo derivatives
has also been demonstrated to be applicable to a wider scope of sub-
strates. The Suzuki–Miyaura arylation of 6-bromo-D3,5-steroid enol
ethers with subsequent hydrolysis is a useful route to 6-arylated ste-
roids bearing aryl at a saturated carbon.
Earlier we described a simple route to 4-aryl-substituted
steroids via the Suzuki–Miyaura coupling of 4-bromoster-
oids.9 Though the Suzuki–Miyaura arylation of steroid vi-
nyl bromides affords high yields of arylsteroids, the use of
vinyl chlorides would allow for a more practical synthe-
sis. Of particular interest is the arylation of commercially
available chlormadinone acetate (1) (17-acetoxy-6-chlo-
ro-pregna-4,6-diene-3,20-dione), a synthetic progestin
used as oral contraceptive. Unfortunately, little is known
about the Suzuki–Miyaura coupling of vinyl chlorides.
Though the coupling with highly activated substrates such
as b-chloroketones takes place relatively readily,10 unacti-
vated substrates remain a challenging problem.
Key words: cross-coupling, palladium, steroids, Suzuki reaction,
nickel
Breast cancer is the most commonly detected form of can-
cer in women and one of the major causes of cancer-relat-
ed deaths.1 Approximately 66% of patients have steroid
receptor positive (ER/PR+) tumors. The endocrine thera-
py has shown significant efficacy in such cases compared
with that of cytotoxic chemotherapy, with less toxicity
and fewer side effects.2 The anticancer effect of the endo-
crine therapy is based on the decrease of stimulating ef-
fects of estrogens on the proliferation of cancer cells. The
aromatase inhibitors lower the estrogen level in the tumor
by blocking the aromatase enzyme, which is responsible
for the conversion of androgens (mainly androst-4-ene-
3,17-dione) to estrogens. Thus, they can be useful in the
treatment of breast cancer along with well-established but
rather toxic antiestrogens and progestines.3 Of particular
interest are the steroidal aromatase inhibitors, which are
capable of the irreversible inhibition of the aromatase by
covalent binding to the enzyme active center.
O
O
OAc
OAc
ArB(OH)2
Pd or Ni catalyst base
O
O
Hal
Ar
1
2
Hal = Cl
Hal = Br
3a–f
Scheme 1
The nickel catalysts were actively used for activation of
‘inert’ aryl chlorides in the Suzuki–Miyaura coupling.11
Therefore we investigated the nickel-catalyzed coupling
of 1 with 4-anisylboronic acid (Scheme 1, where Ar = p-
methoxyphenyl). The best results were achieved in the
Ni(dppe)Cl2-catalyzed reaction in anhydrous dioxane
with K3PO4 as base (Table 1, entry 2). The use of the
bulky and electron-rich Cy3P as ligand was less effective.
The main factor affecting the activity of the catalyst is
probably the ligand bite angle, since the electronic factors
are roughly equal for the ligands used (Table 1, entries 1,
2, 4, and 5).
A variety of potential aromatase inhibitors has been syn-
thesized and evaluated so far.4 However, little is known
about the synthesis of arylated steroid derivatives. The
commonly used ring opening of steroid epoxides with
Grignard reagents requires the protection of almost all
functionalities, both in the organometallic reagent and the
steroid.5 The introduction of palladium-catalyzed cross-
coupling reactions in steroid syntheses allowed for the
simple and efficient attachment of aryl, vinyl, and alkynyl
groups to the steroid core.6 The coupling of steroid enol
triflates and vinyl iodides with organozinc7 and
organoboron7c,8 compounds is a well-established way of
introduction of aryl groups in 3- and 17-position. Al-
though operationally simple, these methods restrict the
The coupling was most efficient in dioxane. The yield of
the Ni(dppe)Cl2-catalyzed reaction in toluene was much
lower (21%), and high amounts of unidentified byprod-
ucts were detected in acetonitrile or DMF. K2CO3 can be
used instead of K3PO4, but no arylated product was detect-
ed with other bases (Table 2).
SYNTHESIS 2006, No. 3, pp 0533–0539
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926270; Art ID: Z16005SS
© Georg Thieme Verlag Stuttgart · New York

534
N. V. Lukashev et al.
PAPER
Table 1 The Effect of the Ni Catalyst on the Arylation of 1a
Table 3 The Effect of the Pd Catalyst on the Arylation of 1a
Entry
Catalyst
Yieldb (%)
Catalyst
Yieldb (%) Catalyst
Yieldb (%)
1
2
3
4
5
Ni(dppm)Cl2
Ni(dppe)Cl2
Ni(Cy3P)2Cl2
Ni(Ph2PMe)2Cl2
Ni(dppb)Cl2
32
60
26
38
31
Pd(PPh3)2Cl2
Pd(MeCN)2Cl2/dppe
Pd(dppb)Cl2
0
55
Pd(Cy3P)2Cl2
69
92
65
Pd(dppf)Cl2
c
100
PdL2Cl2
a Conditions: 5 mol% ‘Pd’, 2 equiv K2CO3, dioxane, 100 °C, 24 h.
b 1H NMR yield.
c L = 2-MeOC6H4P(t-Bu)i-Pr.
a Conditions: 10 mol% catalyst, 1.5 equiv 4-MeOC6H4B(OH)2, 3
equiv K3PO4, dioxane, 100 °C, 48 h.
b 1H NMR yield.
Table 4 The Effect of Solvent on the Pd-Catalyzed Arylation of 1a
Solvent
Me2CO
DMF
Yieldb (%)
Solvent
THF
Yieldb (%)
Table 2 The Effect of Base on the Ni-Catalyzed Arylation of 1a
0
31
43
76
Base
Yieldb (%)
Base
Yieldb (%)
0
MeCN
Toluene
NaOAc
KOt-Bu
K3PO4
0
0
Li2CO3
K2CO3
Cs2CO3
0
53
0
Dioxane
30
a Conditions: 5 mol% Pd(dppb)Cl2, K2CO3, 100 °C, 4 h in a sealed
tube.
60
b 1H NMR yield.
a Conditions: 10 mol% Ni(dppe)Cl2, 3 equiv base, 100 °C, 48 h.
b 1H NMR yield.
The choice of base greatly affects the yield of the arylated
product (Table 5). The use of K2CO3 gave the fastest con-
version and highest yield, but only traces of product were
detected with Na2CO3, Cs2CO3, or Et3N.
Though the nickel catalyst allowed for activation of 1 in
the Suzuki–Miyaura coupling, the process was rather slow
and the yield was moderate.
To determine the scope and limitations of this process, the
reaction of 1 with various arylboronic acids was investi-
gated under optimized conditions (Table 6).
The palladium-catalyzed Suzuki–Miyaura cross-coupling
often provides excellent results in mixtures of organic sol-
vents with water.12 However, aqueous solvents are not the
best choice for 1, as it possesses hydrolysis-sensitive ace-
tate groups. Indeed, we have found that the Pd(PPh3)2Cl2-
catalyzed coupling of 1 with anisylboronic acid in aque-
ous dioxane afforded arylated product 3a . However, the
yield was low and a substantial amount of deacetylated
17-hydroxyprogesterone derivatives was formed. It is im-
portant that no arylated product was detected in the same
reaction in anhydrous dioxane.
Recently palladium catalysts with bulky phosphine13 or
phosphite14 ligands were proposed for activation of vinyl
chlorides. The competitive experiments showed that cy-
clopentenyl chloride is less active in the Suzuki–Miyaura
coupling than chlorobenzene.13
The coupling with 4-fluorophenylboronic acid was faster
in dioxane than in toluene. Surprisingly, only 11% yield
of the arylated steroid was detected in the reaction with 3-
tolylboronic acid in dioxane, compared with 91% in tolu-
ene. While the reaction with electron-rich arylboronic ac-
ids afforded the products in high yields, the coupling with
3-acetylphenylboronic acid led to 43% yield of 3e, and
only traces of product were detected in the reaction with
4-carboxyphenylboronic acid. Besides, less than 10% of
the product was formed in the reaction with 2-thienylbo-
ronic acid.
While the coupling of 1 with nucleophilic arylboronic ac-
ids gave excellent yields of arylated products, the proce-
dure proved to be unsuitable for the preparation of 6-
We showed that unlike Pd(PPh3)2Cl2, palladium catalysts
with electron-donating and bidentate ligands do catalyze
the cross coupling of 1 with 4-anisylboronic acid at
100 °C in dioxane. Pd(dppb)Cl2 and Pd(dppf)Cl2 were
found to be the most active catalysts (Table 3).
Table 5 The Effect of Base on the Pd-Catalyzed Arylation of 1a
Base
Yield,% b
Base
Yieldb (%)
To improve the catalyst activity, various solvents and
bases were screened in Pd(dppb)Cl2-catalyzed reactions at
incomplete conversion. While no reaction was detected in
acetone or DMF, the coupling with 4-anisylboronic acid
was faster in MeCN and especially in toluene than in di-
oxane (Table 4). The cross-coupling rates were almost
equal in dioxane and THF.
Na2CO3
K2CO3
Cs2CO3
0
76
1
Et3N
1
8
NaOAc
K3PO4
41
a Conditions: 5 mol% Pd(dppb)Cl2, toluene, 100 °C, 4 h.
b 1H NMR yield.
Synthesis 2006, No. 3, 533–539 © Thieme Stuttgart · New York

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6-Chloro- and 6-Bromo-Substituted Steroids in Suzuki–Miyaura Cross-Coupling
535
Table 7 Yields of Arylation of 2 with Arylboronic Acidsa
Table 6 Yields of Arylation of 1 with Arylboronic Acidsa
Yieldb (%)
93
Product Ar
Solvent
Toluene
Time (h)
12
Yieldb (%)
(93)
Product
Ar
3a
3a
MeO
MeO
3b
3c
3d
Toluene
Dioxane
Toluene
13
24
12
(100)
(97)
91c
3b
3c
3f
82
93
F
F
94c
S
3e
3f
Dioxane
24
43
a Conditions: 5 mol% Pd(dppf)Cl2, 2 equiv K3PO4, MeCN, 100 °C, 5
h.
b Isolated yield.
O
c 1H NMR yield, determined at 24 h.
Dioxane or 48
toluene
<10
S
A substantial acceleration of the Suzuki coupling can be
achieved by addition of water. Thus the reaction of 6-bro-
moandrosta-4,6-diene-3,17-dione 4, lacking the sensitive
acetate group, affords 6-arylated androstadienes 5a–e
within 3–4 hours in aqueous dioxane at 100 °C
(Scheme 2, Table 8).
a Conditions: 5 mol% Pd(dppb)Cl2, 1.5 equiv RB(OH)2, 3 equiv
K2CO3, 100 °C.
b 1H NMR yield; isolated yield in parentheses.
c Inseparable mixture with 9% of 1.
arylsteroids containing heterocyclic and electron-with-
drawing aryl groups. Therefore, we investigated the utility
of more reactive 17-acetoxy-6-bromopregna-4,6-diene-
3,20-dione (2) in this reaction (Table 7). The coupling
proceeds smoothly within five hours (instead of 12–24
hours for 1) with Pd(dppf)Cl2 as catalyst in absolute ace-
tonitrile and with K3PO4 as base.
O
O
"Pd"
+
R-B(OH)2
K2CO3 or K3PO4
dioxane–H2O,
100 °C
O
O
R
Br
5a–e
4
R = aryl, hetaryl
Unlike 1, the Suzuki coupling of 2 with 2-thienylboronic
acid affords a high yield of the arylated product 3f, though
prolonged heating is required to accomplish the reaction.
Scheme 2
Table 8 Yields of 6-Aryl-androsta-4,6-diene-3,17-diones 5a
Product
Ar
Catalyst (2 mol%)
Pd(PPh3)2Cl2
Base
Time (h)
3
Yieldb (%)
93
5a
2 equiv K2CO3
2 equiv K2CO3
F
5b
Pd(PPh3)2Cl2
3
99
O
5c
Pd(PPh3)2Cl2
Pd(dppf)Cl2
3 equiv K2CO3
2 equiv K3PO4
3
3
90c
87
HO2C
5d
Pd(dppf)Cl2
76
N
N
5e
Pd(dppf)Cl2
2 equiv K3PO4
4
84
Ts
a Conditions: dioxane–H2O (3:1), 100 °C.
b Isolated yield.
c As inseparable mixture with 4% Ph3PO.
Synthesis 2006, No. 3, 533–539 © Thieme Stuttgart · New York

536
N. V. Lukashev et al.
PAPER
However, the use of Pd(PPh3)2Cl2 as palladium source should be conducted in anhydrous acetonitrile with K3PO4
sometimes led to the contamination of the arylsteroid with as base.
triphenylphosphine oxide. We found that coupling in the
presence of Pd(dppf)Cl2 can be used in these cases with-
out any significant decrease of yield. These conditions can
be applied successfully for the coupling with poorly nu-
cleophilic aryl(hetaryl)boronic acids with good to excel-
lent yields of products 5b–e.
The a-configuration of the 6-aryl group was assigned for
all products by 1H NMR. The presence of 10% of the 6-b
epimer was detected for 6-thienyl-substituted product
10d.
In conclusion, we described a versatile and efficient way
for the introduction of aryl(hetaryl) groups in 6-position
The catalytic synthesis of 6-arylated steroids 10 with an
of D4,6-steroids via the palladium catalyzed Suzuki–
aryl group attached to the sp3-hybridized C6 atom implies
Miyaura coupling of 6-chloro- or 6-bromosteroids. The
the coupling of the allylpalladium complex obtained from
arylation of 6-bromo-D3,5-steroid enol ethers with subse-
quent hydrolysis is a useful route to 6-arylated steroids
readily available 6-halosteroids with an ‘aryl carbanion’.
Though allylpalladium complexes of steroids are well
bearing aryl at a saturated carbon.
known15 they have only been used in stoichiometric reac-
tions with ‘soft nucleophiles’. Moreover, the Stille cou-
NMR spectroscopy was performed on a Varian VXR400 (400
pling
of
6-bromotestosterone
acetate
with
MHz) spectrometer. Melting points were recorded on an Electro-
thermal Engineering IA9100 melting point apparatus and are uncor-
rected. MALDI-TOF spectra were recorded on a Bruker Daltonics
Proflex III spectrometer.
alkynylstannane was shown to afford a complex mixture
of unidentified products.16 We found that the Suzuki cou-
pling of 6-bromo-androst-4-ene-3,17-dione (6) with ani-
sylboronic acid yields only androstadiene 7 due to fast
dehydrobromination. So we tried to ‘mask’ the active ha-
lide by converting 6 to methyl enol ether 8 (Scheme 3).
Arylation of Chlormadinone Acetate (1); General Procedure
In a vial with a screw cap, 1 (40.5 mg, 0.100 mmol), arylboronic
acid (0.18 mmol), K2CO3 (41.4 mg, 0.300 mmol), and Pd(dppb)Cl2
(3.0 mg, 5 mmol, 5 mol%) were mixed under Ar atmosphere in tol-
uene (2 mL). The mixture was stirred at 100 °C for 12–24 h, then
diluted with CHCl3 (10 mL) and H2O (10 mL), and the aq layer was
extracted with CHCl3 (3 × 5 mL). The combined organic layers
were dried with Na2SO4. The arylated products 3a–d were isolated
by column chromatography on silica gel (CHCl3–Et2O, 4:1).
The enol ethers 8 should probably be less active substrates
for the Suzuki–Miyaura coupling than 2 due to electron-
donating properties of the methoxy group. However, al-
most quantitative yields of arylated products 9 were ob-
tained in Pd(PPh3)2Cl2- or Pd(dppf)Cl2-catalyzed
reactions with various (hetero)arylboronic acids.
17-Acetoxy-6-(4-methoxyphenyl)pregna-4,6-diene-3,20-dione
(3a)
White solid, yield: 44.3 mg (93%); mp 132–135 °C.
1H NMR (400 MHz, CDCl3): d = 7.04 (m, 2 H), 6.83 (m, 2 H), 5.97
(d, 1 H, J = 2.2 Hz, H4), 5.64 (s, 1 H, H7), 3.79 (s, 3 H), 2.98 (m, 1
H), 2.59 (m, 1 H), 2.39 (m, 2 H), 2.11 (s, 3 H), 2.05 (s, 3 H), 2.09–
1.71 (m, 7 H), 1.62 (m, 1 H), 1.45 (m, 3 H) 1.21 (s, 3 H, CH3), 0.73
(s, 3 H, CH3).
The subsequent ‘unmasking’ of 9 affords 6-aryl-androst-
4-ene-3,17-diones 10a–g. Thus the hydrolysis of 9a (ob-
tained with 85% yield by Suzuki coupling) with concen-
trated HCl in aqueous ethanol affords 72% of 10a. This
procedure can be accomplished without isolation of inter-
mediate 9 by addition of excess of concentrated HCl to the
crude reaction mixture after cross-coupling. This method
can also be applied for the preparation of 6-aryl pregnane
derivative 10h (Table 9), though the cross coupling
Anal. Calcd for C30H36O5: C, 75.60; H, 7.61. Found: C, 75.45; H,
7.63.
X
Y
X
X
Y
O
7
Y
ArB(OH)2
[Pd]
O
O
base
Br
Ar
X
X
6a,b
HC(OMe)3
H+
10a–h
Y
Y
HCl
ArB(OH)2
[Pd]
MeO
MeO
base
Br
Ar
9a–h
8a,b
X,Y = O
X = Ac, Y = OAc
6a, 8a, 9a–g, 10a–g
6b, 8b, 9h, 10h
Scheme 3
Synthesis 2006, No. 3, 533–539 © Thieme Stuttgart · New York

PAPER
6-Chloro- and 6-Bromo-Substituted Steroids in Suzuki–Miyaura Cross-Coupling
537
Table 9 Yields of 6a-Aryl-D4-steroids 10
Product
Ar
X, Y
O
Catalyst
Base
Time (h)
3
Yielda (%)
72
10a
Pd(PPh3)2Cl2
K2CO3
10b
10c
O
O
Pd(dppf)Cl2
Pd(PPh3)2Cl2
K2CO3
K2CO3
3
3
84
90
O
F
10d
10e
O
O
Pd(dppf)Cl2
Pd(dppf)Cl2
K2CO3
K2CO3
4.5
3
80
69
S
HO2C
Ac
10f
O
O
Pd(dppf)Cl2
Pd(dppf)Cl2
K2CO3
K3PO4
3
4
85
83
10g
N
Ts
b
10h
Ac, OAc
Pd(dppf)Cl2
K3PO4
5
70
a Isolated yield, from 8.
b Reaction in absolute MeCN.
17-Acetoxy-6-(4-methylphenyl)pregna-4,6-diene-3,20-dione
(3b)
Anal. Calcd for C30H36O4: C, 78.23; H, 7.88. Found: C, 78.36; H,
7.88.
White solid, yield: 46.1 mg (100%); mp 138–141 °C.
Arylation of 17-Acetoxy-6-bromopregna-4,6-diene-3,20-dione
(2); General Procedure
1H NMR (400 MHz, CDCl3): d = 7.11 (m, 2 H), 7.00 (m, 2 H), 5.99
(d, 1 H, J = 2.2 Hz, H4), 5.62 (s, 1 H, H7), 2.98 (m, 1 H), 2.58 (m, 1
H), 2.39 (m, 2 H), 2.33 (s, 3 H), 2.11 (s, 3 H), 2.05 (s, 3 H), 2.09–
1.71 (m, 7 H), 1.62 (m, 1 H), 1.44 (m, 3 H), 1.21 (s, 3 H, CH3), 0.73
(s, 3 H, CH3).
In a vial with a screw cap, 2 (67.4 mg, 0.150 mmol), arylboronic
acid (0.195 mmol), K3PO4 (95.4 mg, 0.450 mmol), Pd(dppf)Cl2 (5.5
mg, 7.5 mmol, 5 mol%) were mixed under Ar atmosphere in MeCN
(2 mL). The mixture was stirred at 100 °C for 5 h, then diluted with
CHCl3 (10 mL) and H2O (10 mL), and the aq layer was extracted
with CHCl3 (3 × 5 mL). The combined organic layers were dried
with Na2SO4. The arylated products 3a–c were isolated by column
chromatography on silica gel (CHCl3–Et2O, 4:1) (Table 7).
Anal Calcd for C30H36O4: C, 78.23; H, 7.88. Found: C, 78.65; H,
7.86.
17-Acetoxy-6-(4-fluorophenyl)pregna-4,6-diene-3,20-dione (3c)
Reaction in dioxane; white solid, yield: 44.9 mg (97%); mp 132–
134 °C.
6-Bromoandrosta-4,6-diene-3,17-dione (4)
1H NMR (400 MHz, CDCl3): d = 7.08 (m, 2 H), 6.99 (m, 2 H), 5.98
(d, 1 H, J = 2.2 Hz), 5.56 (s, 1 H, H7), 2.99 (m, 1 H,), 2.59 (m, 1 H),
2.40 (m, 2 H), 2.11 (s, 3 H), 2.06 (s, 3 H), 2.09–1.71 (m, 7 H), 1.63
(m, 1 H), 1.45 (m, 3 H) 1.21 (s, 3 H), 0.74 (s, 3 H).
In a two-necked flask, equipped with reflux condenser, NBS (583
mg, 3.28 mmol) was slowly added to a suspension of 6-bromo-3-
methoxyandrosta-3,5-diene-17-one (1.20 g, 3.16 mmol) in 96% aq
acetone (9.3 mL) at 0 °C under flow of Ar. After stirring at 0 °C for
20 min, LiBr (504 mg, 5.80 mmol), Li2CO3 (497 mg, 6.73 mmol),
and DMF (4.8 mL) were added and the mixture was stirred at 80 °C
for 6 h. The reaction mixture was extracted with CH2Cl2 (50 mL),
washed with H2O (6 × 20 mL), and dried with MgSO4. The product
was isolated by column chromatography on silica gel (CH2Cl2–
Et2O, 20:1).
Anal. Calcd for C29H33FO4: C, 74.98; H, 7.16. Found: C, 74.85; H,
7.24.
17-Acetoxy-6-(3-methylphenyl)pregna-4,6-diene-3,20-dione
(3d)
White solid, yield: 41.7 mg (91%); mp 125–127 °C.
1H NMR (400 MHz, CDCl3): 7.19 (m, 1 H), 7.09 (m, 1 H), 6.91 (m,
2 H), 5.99 (d, J = 2.2 Hz, 1 H), 5.62 (s, 1 H), 2.98 (m, 1 H), 2.59 (m,
1 H), 2.39 (m, 2 H), 2.32 (s, 3 H), 2.11 (s, 3 H), 2.06 (s, 3 H), 2.09–
1.71 (m, 7 H), 1.63 (m, 1 H), 1.44 (m, 3 H), 1.22 (s, 3 H), 0.74 (s, 3
H).
White solid, yield: 977 mg (85%); mp 155–157 °C (dec.).
1H NMR (400 MHz, CDCl3): d = 6.63 (d, 1 H, J = 2.3 Hz, H4), 6.31
(s, 1 H, H7), 2.50 (m, 4 H), 2.16 (m, 2 H), 2.02 (m, 1 H), 1.90 (m, 1
H), 1.73 (m, 3 H), 1.58–1.28 (m, 4 H), 1,17 (s, 3 H, CH3), 0.95 (s, 3
H, CH3).
Synthesis 2006, No. 3, 533–539 © Thieme Stuttgart · New York

538
N. V. Lukashev et al.
PAPER
Anal. Calcd for C19H23BrO2: C, 62.82; H, 6.38. Found: C, 62.53; H,
6.61.
mL), NBS (7.64 g, 42.9 mmol) was slowly added. After stirring for
30 min at r.t. the solution was concentrated at reduced pressure. The
residue was dissolved in CH2Cl2 (100 mL) and the organic layer
was washed with H2O (6 × 50 mL) and dried over MgSO4. The sol-
vent was removed in vacuo to give a 2:1 mixture of b:a epimers
(11.85 g, 97%), which was used without further purification for the
preparation of 8a.
1H NMR (400 MHz, CDCl3): d = 6.44 (d, 1 H, J = 1.8 Hz, H4)a, 5.91
(s, 1 H, H4)b, 5.01 (m, 1 H, H6)a, 4.89 (m, 1 H, H6)b, 2.60–1.07 (m,
17 H), 1.56 (s, 3 H, CH3)a, 1.24 (s, 3 H, CH3)b, 0.97 (s, 3 H, CH3)a,
0.91 (s, 3 H, CH3)b. a 6a-bromoandrost-4-ene-3,17-dione. b 6b-bro-
moandrost-4-ene-3,17-dione.
Arylation of 6-Bromoandrosta-4,6-diene-3,17-dione (4); Gener-
al Procedure
In a vial with a screw cap, 4 (54.5 mg, 0.150 mmol), arylboronic
acid (0.165 mmol), K2CO3 (41.4 mg, 0.300 mmol), and
Pd(PPh3)2Cl2 or Pd(dppf)Cl2 (3 mmol, 2 mol%) were mixed under
Ar atmosphere in dioxane (1.5 mL) and H2O (0.5 mL). The mixture
was stirred at 100 °C for 3–4 h, then diluted with CHCl3 (10 mL)
and H2O (10 mL), and the aq layer was extracted with CHCl3 (3 × 5
mL). The combined organic layers were dried with Na2SO4. The
arylated products 5 were isolated by column chromatography on sil-
ica gel (CH2Cl2–Et2O, 20:1 or CH2Cl2–MeOH, 2:1).
6-Bromo-3-methoxyandrosta-3,5-diene-17-one (8a)
To a mixture of 6-bromoandrost-4-ene-3,17-dione (6a) (2.00 g,
5.47 mmol) and sulfosalicylic acid (24 mg, 0.11 mmol), toluene (6
mL) and trimethyl orthoformate (1.31 mL, 12.0 mmol) were added
under the flow of Ar. The mixture was stirred at r.t. for 1 h, then
Et3N (0.1 mL) was added. The solution was cooled to 0 °C and 2%
NaOH soln (10 mL) was added, while stirring vigorously. The prod-
uct was extracted with CH2Cl2 (20 mL) and dried with Na2SO4. The
solvents were evaporated and the residue was treated with cold i-
PrOH, washed with cold Et2O, and dried in vacuo.
6-(4-Fluorophenyl)androsta-4,6-diene-3,17-dione (5a)
White solid, yield: 53 mg (93%); mp 139–140 °C.
1H NMR (400 MHz, CDCl3): d = 7.08 (m, 2 H,), 7.00 (m, 2 H), 6.06
(d, 1 H, J = 2.1 Hz, H4), 5.56 (s, 1 H, H7), 2.51 (m, 4 H), 2.11 (m, 3
H), 1.92 (m, 1 H), 1.74 (m, 3 H), 1.60–1.33 (m, 4 H), 1.23 (s, 3 H,
CH3), 0.98 (s, 3 H, CH3).
Anal. Calcd for C25H27FO2: C, 79.26; H, 7.13. Found: C, 79.50; H
7.00.
White solid, yield: 1.89 g (91%); mp 174–175 °C (dec.).
6-(3-Acetylphenyl)androsta-4,6-diene-3,17-dione (5b)
White solid, yield: 60 mg (99%); mp 110–112 °C.
1H NMR (400 MHz, CDCl3): d = 7.88 (m, 1 H), 7.72 (m, 1 H), 7.43
(m, 1 H), 7.32 (m, 1 H), 6.10 (d, 1 H, J = 2.1 Hz, H4), 5.48 (s, 1 H,
H7), 2.60 (s, 3 H), 2.52 (m, 4 H), 2.12 (m, 3 H), 1.93 (m, 1 H), 1.76
(m, 3 H), 1.62–1.33 (m, 4 H), 2.16 (s, 3 H, CH3), 0.99 (s, 3 H, CH3).
1H NMR (400 MHz, CDCl3): d = 5.59 (d, 1 H, J = 1.5 Hz, H4), 3.64
(s, 3 H, OCH3), 2.71 (m, 1 H), 2.46 (m, 1 H,), 2.29 (m, 2 H), 2.05
(m, 4 H), 1.82 (m, 2 H), 1.70 (m, 1 H), 1.57 (m, 1 H), 1.34 (m, 4 H),
1.16 (m, 1 H), 1.01 (s, 3 H, CH3), 0.89 (s, 3 H, CH3).
Anal. Calcd for C20H27BrO2: C, 63.33; H, 7.17. Found: C, 63.40; H,
7.43.
Anal. Calcd for C27H30O3: C, 80.56; H, 7.51. Found: C, 80.27; H,
7.42.
6a-Aryl-D4-steroids; General Procedure
In a vial with a screw cap, 8a or 8b (0.15 mmol), arylboronic acid
(0.165 mmol), K2CO3 or K3PO4 (0.3 mmol), Pd(PPh3)2Cl2 or
Pd(dppf)Cl2 (3.0–7.5 mmol, 2 mol%) were mixed under Ar at-
mosphere in dioxane (1.5 mL) and H2O (0.5 mL) or MeCN (2 mL)
for 10 h. After stirring at 100 °C for 3–5 h, the mixture was cooled
to r.t. and 37% HCl soln (0.25 mL) was added. The reaction was
stirred for 2–3 h, then diluted with CHCl3 (10 mL) and H2O (10
mL), and the aq layer was extracted with CHCl3 (3 × 5 mL). The
combined organic layers were dried with Na2SO4. The arylated
products 10a–h were isolated by column chromatography on silica
gel (CH2Cl2–Et2O, 20:1 or CH2Cl2–EtOAc, 2:1).
6-(4-Carboxyphenyl)androsta-4,6-diene-3,17-dione (5c)
White solid, yield: 53 mg (87%); mp 255–256 °C.
1H NMR (400 MHz, CDCl3): d = 8.03 (m, 2 H), 7.23 (m, 2 H), 6.13
(d, 1 H, J = 1.8 Hz, H4), 5.61 (s, 1 H, H7), 2.56 (m, 4 H), 2.13 (m, 3
H), 2.93 (m, 1 H), 1.75 (m, 3 H), 1.63–1.33 (m, 4 H), 1.26 (s, 3 H,
CH3), 0.99 (s, 3 H, CH3).
MS (MALDI-TOF): m/z = 405.50 [M + H]+.
6-(3-Quinolinyl)androsta-4,6-diene-3,17-dione (5d)
White solid, yield: 46.9 mg (76%); mp 223–225 °C.
1H NMR (400 MHz, CDCl3): d = 8.67 (d, 1 H, J = 2.1 Hz), 8.10 (d,
1 H, J = 8.5 Hz), 7.92 (d, 1 H, J = 2.1 Hz), 7.78 (dd, 1 H, J = 8.3,
1.0 Hz), 7.72 (m, 1 H), 7.56 (m, 1 H), 6.21 (d, 1 H, J = 2.0 Hz, H4),
5.57 (s, 1 H, H7), 2.54 (m, 5 H), 2.15 (m, 3 H), 1.96–1.24 (m, 7 H,),
1.30 (s, 3 H, CH3,), 1.00 (s, 3 H, CH3).
6a-(4-Methylphenyl)androst-4-ene-3,17-dione (10a)
White solid, yield: 41 mg (72%); mp 105–107 °C.
1H NMR (400 MHz, CDCl3): d = 7.12 (m, 2 H), 6.98 (m, 2 H), 5.18
(d, 1 H, J = 1.5 Hz, H4), 3.55 (m, 1 H, H6), 2.38 (m, 3 H), 2.32 (s, 3
H), 2.09 (m, 3 H), 1.93 (m, 3 H), 1.76 (m, 2 H), 1.54 (m, 3 H), 1.35
(m, 2 H), 1.33 (s, 3 H, CH3), 1.15 (m, 1 H), 0.93 (s, 3 H, CH3).
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.43; H, 7.25; N, 3.17.
Anal. Calcd for C26H32O2: C, 82.94; H, 8.57. Found: C, 83.04; H,
8.44.
6-(N-Tosylindole-3-yl)androsta-4,6-diene-3,17-dione (5e)
White solid, yield: 70 mg (84%); mp 173–174 °C.
6a-(4-Methoxyphenyl)androst-4-ene-3,17-dione (10b)
1H NMR (400 MHz, CDCl3): d = 7.95 (m, 1 H), 7.76 (m, 2 H,), 7.47
(s, 1 H,), 7.25 (m, 3 H), 7.18 (m, 2 H), 6.26 (d, 1 H, J = 2.1 Hz, H4),
5.51 (s, 1 H, H7), 2.51 (m, 4 H), 2.34 (s, 3 H), 2.12 (m, 3 H), 1.92
(m, 1 H), 1.75 (m, 3 H), 1.61–1.32 (m, 4 H), 1.29 (s, 3 H, CH3), 0.98
(s, 3 H, CH3).
White solid, yield: 49 mg (84%); mp 110–111 °C.
1H NMR (400 MHz, CDCl3): d = 7.01 (m, 2 H), 6.85 (m, 2 H), 5.18
(d, 1 H, J = 1.8 Hz, H4), 3.79 (s, 3 H), 3.53 (m, 1 H, H6), 2.40 (m, 3
H), 2.09 (m, 3 H), 1.93 (m, 3 H), 1.76 (m, 2 H), 1.53 (m, 3 H), 1.35
(m, 2 H), 1.14 (m, 1 H), 1.33 (s, 3 H, CH3), 0.94 (s, 3 H, CH3).
MS (MALDI-TOF): m/z = 554.37 [M + H]+.
Anal. Calcd for C26H32O3: C, 79.56; H, 8.22. Found: C, 79.20; H,
8.31.
6-Bromoandrost-4-ene-3,17-dione (6a)
To a suspension of 3-methoxyandrosta-3,5-diene-17-one (10.0 g,
33.3 mmol) and NaOAc (2.7 g, 33 mmol) in 96% aq acetone (350
6a-(4-Fluorophenyl)androst-4-ene-3,17-dione (10c)
White solid, yield: 51 mg (90%); mp 114–115 °C.
Synthesis 2006, No. 3, 533–539 © Thieme Stuttgart · New York

PAPER
6-Chloro- and 6-Bromo-Substituted Steroids in Suzuki–Miyaura Cross-Coupling
539
1H NMR (400 MHz, CDCl3): d = 7.07 (m, 2 H), 7.01 (m, 2 H), 5.13
(d, 1 H, J = 1.5 Hz, H4), 3.58 (m, 1 H, H6), 2.40 (m, 3 H), 2.09 (m,
3 H), 1.94 (m, 3 H), 1.77 (m, 2 H), 1.53 (m, 3 H), 1.35 (m, 2 H), 1.33
(s, 3 H, CH3), 1.15 (m, 1 H), 0.94 (s, 3 H, CH3).
References
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Anal. Calcd for C25H29FO2: C, 8.84; H, 7.62. Found: C, 78.77; H,
7.42.
6-(2-Thienyl)androst-4-ene-3,17-dione (10d)
White solid, yield: 44 mg (80%); mp 106–108 °C.
1H NMR (400 MHz, CDCl3): d = 7.20 (m, 1 H), 6.97 (m, 1 H), 6.81
(m, 1 H), 6.02 (s, 1 H, H4)2, 5.37 (d, 1 H, J = 1.8 Hz, H4)1, 3.98 (m,
1 H, H6)2, 3.92 (m, 1 H, H6)1, 2.37 (m, 4 H), 2.10 (m, 2 H), 1.93 (m,
3 H), 1.76 (m, 2 H), 1.53 (m, 3 H), 1.34 (m, 2 H), 1.32 (s, 3 H, CH3)1,
1
1.16 (m, 1 H), 0.93 (s, 3 H, CH3)1. 6a-(2-thienyl)androst-4-ene-
3,17-dione. 2 6b-(2-thienyl)androst-4-ene-3,17-dione.
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Anal. Calcd for C23H28O2S: C, 74.96; H, 7.66. Found: C, 74.70; H,
7.45.
6a-(4-Carboxyphenyl)androst-4-ene-3,17-dione (10e)
White solid, yield: 42 mg (69%); mp 202–203 °C.
1H NMR (400 MHz, CDCl3): d = 8.04 (m, 2 H), 7.22 (m, 2 H), 5.16
(d, 1 H, J = 1.5 Hz, H4), 3.67 (m, 1 H, H6), 2.44 (m, 3 H), 2.13 (m,
3 H), 1.93 (m, 3 H), 1.79 (m, 2 H), 1.57 (m, 3 H), 1.39 (m, 2 H), 1.36
(s, 3 H, CH3), 1.19 (m, 1 H), 0.95 (s, 3 H, CH3).
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Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.;
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MS (MALDI-TOF): m/z = 407.45 [M + H]+.
6a-(3-Acetylphenyl)androst-4-ene-3,17-dione (10f)
White solid, yield; 52 mg (85%); mp 117–118 °C.
(8) (a) Gravett, E. C.; Hilton, J. P.; Jones, K.; Romero, F.
Tetrahedron Lett. 2001, 42, 9081. (b) Ciattini, P. G.;
Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 4815.
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G. A.; Beletskaya, I. P. Synthesis 2005, 1578.
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1H NMR (400 MHz, CDCl3): d = 7.83 (m, 1 H), 7.73 (m, 1 H), 7.43
(m, 1 H), 7.33 (m, 1 H), 5.07 (d, 1 H, J = 1.5 Hz, H4), 3.67 (m, 1 H,
H6), 2.59 (s, 3 H), 2.41 (m, 3 H), 2.10 (m, 3 H), 1.93 (m, 3 H), 1.78
(m, 2 H), 1.58 (m, 3 H), 1.37 (m, 2 H), 1.36 (s, 3 H, CH3), 1.18 (m,
1 H), 0.94 (s, 3 H, CH3).
Anal. Calcd for C27H32O3: C, 80.16; H, 7.97. Found: C, 79.97; H,
7.96.
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6a-(N-Tosylindol-3-yl)androst-4-ene-3,17-dione (10g)
White solid, yield: 69 mg (83%); mp 184–185 °C.
1H NMR (400 MHz, CDCl3): d = 7.94 (m, 1 H), 7.73 (m, 2 H), 7.39
(s, 1 H), 7.23 (m, 4 H), 7.15 (m, 1 H), 5.12 (d, 1 H, J = 1.2 Hz, H4),
3.81 (m, 1 H, H6), 2.38 (m, 3 H), 2.33 (s, 3 H), 2.12 (m, 3 H), 1.94
(m, 3 H), 1.77 (m, 2 H), 1.56 (m, 3 H), 1.38 (s, 3 H, CH3), 1.35 (m,
2 H), 1.17 (m, 1 H), 0.94 (s, 3 H, CH3).
MS (MALDI-TOF): m/z = 556.28 [M + H]+.
(13) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
17-Acetoxy-6a-(4-methylphenyl)pregn-4-ene-3,20-dione (10h)
White solid, yield: 50.0 mg (70%); mp 137 °C.
4020.
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1H NMR (400 MHz, CDCl3): d = 7.11 (m, 2 H), 6.97 (m, 2 H), 5.17
(d, 1 H, J = 1.6 Hz, H4), 3.52 (s, 1 H, H6), 2.92 (m, 1 H), 2.36 (m, 2
H), 2.31 (s, 3 H), 2.11 (s, 3 H), 2.06 (m, 3 H), 2.04 (s, 3 H), 1.82–
1.16 (m, 11 H), 1.31 (s, 3 H, CH3), 0.69 (s, 3 H, CH3).
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Anal. Calcd for C30H38O4: C, 77.89; H, 8.28. Found: C, 77.65; H,
8.47.
(16) Sperandio, A.; Tuozzi, A.; Bocelli, G.; Sterzo, C. L.
Tetrahedron 1999, 55, 461.
(17) Kashirskoe shosse 9, b. 3, Moscow, 115230, Russia. Tel/
Fax:+7(095)7778495.
Acknowledgment
We are grateful to the Russian Foundation for Basic Research (grant
04-03-32995) for financial support. Dr. A. N. Andresyuk of Chim-
med Co.17 kindly provided us with the samples of arylboronic acids.
Synthesis 2006, No. 3, 533–539 © Thieme Stuttgart · New York