Electrochemical bromination of cholest-5-enes

Article abstract of DOI:10.1016/j.steroids.2005.06.002

Four 5,6-unsaturated steroids - 3β-chlorocholest-5-ene (1a), cholesterol (1b) and its acetate (1c) and benzoate (1d) - were subjected to constant current electrolysis (50 mA, 2 F mol^-1) in an electrolytic cell divided by a ceramic membrane, using a platinum foil as the anode and a graphite stick as the cathode. When electrolysis was carried out in a solution of tetraethylammonium bromide in aprotic solvents (dichloromethane, acetonitrile or acetic anhydride), the addition of electrochemically-generated elemental bromine onto the double bond of the cholesterol derivatives gave their corresponding 5α,6β-dibromosteroids - 3β-chloro-5α, 6β-dibromocholestane (2a), 5α,6β-dibromocholestan-3β-ol (2b), 5α,6β-dibromocholestan-3β-yl acetate (2c) and 5α,6β-dibromocholestan-3β-yl benzoate (2d) - as the sole products, and in good yields (58-91%). However, the electrolysis of steroids 1a-c in a solution of tetraethylammonium bromide with methanol as the solvent proceeded to give, in addition to dibromides 2a-c, the corresponding diastereomeric pairs of 5-bromo-6-methoxysteroids: 5α-bromo-3β- chloro-6β-methoxycholestane (3a) and 5β-bromo-3β-chloro-6α- methoxycholestane (4a), 5α-bromo-6β-methoxycholestan-3β-ol (3b) and 5β-bromo-6α-methoxycholestan-3β-ol (4b) and 5α-bromo-6β-methoxycholestan-3β-yl acetate (3c) and 5α-bromo-6β-methoxycholestan-3β-yl acetate (4c). The benzoate 1d was not soluble enough in methanol, even with heating. The products were characterized by physical and spectral data (IR, ¹H NMR and ¹³C NMR). Single crystal X-ray structure determinations of compounds 2a and 3a are also reported.

Full text of DOI:10.1016/j.steroids.2005.06.002

Steroids 70 (2005) 867–872
Electrochemical bromination of cholest-5-enes
a
b
b
Smiljka S. Milisavljevi c´ , Klaus Wurst , Gerhard Laus ,
c
c,∗
Mirjana D. Vuki c´ evi c´ , Rastko D. Vuki c´ evi c´
a
Technical Faculty Kosovska Mitrovica, University of Pri sˇ tina, Kneza Milo sˇ a 7, 28000 Kosovska Mitrovica, Serbia and Montenegro
b
Faculty of Chemistry and Pharmacy, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria
c
Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovi c´ a 12, 34000 Kragujevac, Serbia and Montenegro
Received 29 March 2005; received in revised form 31 May 2005; accepted 2 June 2005
Available online 21 July 2005
Abstract
Four 5,6-unsaturated steroids—3␤-chlorocholest-5-ene (1a), cholesterol (1b) and its acetate (1c) and benzoate (1d)—were subjected
−
1
to constant current electrolysis (50 mA, 2 F mol ) in an electrolytic cell divided by a ceramic membrane, using a platinum foil as the
anode and a graphite stick as the cathode. When electrolysis was carried out in a solution of tetraethylammonium bromide in aprotic sol-
vents (dichloromethane, acetonitrile or acetic anhydride), the addition of electrochemically-generated elemental bromine onto the double
bond of the cholesterol derivatives gave their corresponding 5␣,6␤-dibromosteroids—3␤-chloro-5␣,6␤-dibromocholestane (2a), 5␣,6␤-
dibromocholestan-3␤-ol (2b), 5␣,6␤-dibromocholestan-3␤-yl acetate (2c) and 5␣,6␤-dibromocholestan-3␤-yl benzoate (2d)—as the sole
products, and in good yields (58–91%). However, the electrolysis of steroids 1a–c in a solution of tetraethylammonium bromide with methanol
as the solvent proceeded to give, in addition to dibromides 2a–c, the corresponding diastereomeric pairs of 5-bromo-6-methoxysteroids:
5
3
␣-bromo-3␤-chloro-6␤-methoxycholestane (3a) and 5␤-bromo-3␤-chloro-6␣-methoxycholestane (4a), 5␣-bromo-6␤-methoxycholestan-
␤-ol (3b) and 5␤-bromo-6␣-methoxycholestan-3␤-ol (4b) and 5␣-bromo-6␤-methoxycholestan-3␤-yl acetate (3c) and 5␣-bromo-6␤-
methoxycholestan-3␤-yl acetate (4c). The benzoate 1d was not soluble enough in methanol, even with heating. The products were characterized
1
13
by physical and spectral data (IR, H NMR and C NMR). Single crystal X-ray structure determinations of compounds 2a and 3a are also
reported.
©
2005 Elsevier Inc. All rights reserved.
Keywords: Electrolysis; Electrochemical bromination; 5,6-Unsaturated steroid; 5␣,6␤-Dibromosteroid; Bromomethoxysteroid
1
. Introduction
[5]. Since preparation of the dichlorides has required the
handling of chlorine gas [1,6–10], the conversion of unsatu-
rated steroids into their corresponding dibromides has been
the approach most frequently employed in steroid chemistry
[11].
In continuation of our earlier studies on the electrochem-
ical generation of electrophilic species [12,13], we recently
reported on the electrochemical chlorination of some steroids
[14,15]. The conversion was carried out by the constant
current electrolysis of a solution of tetraethylammonium
chloride in dichloromethane, using an undivided electrolytic
cell under uncontrolled electrode potential. The reaction
resulted in the corresponding 5␣,6␤-dichloro derivatives
as the sole products. Quite different results were obtained
by others using tetrabutylammonium tetrafluoroborate as
Among steroids, cholesterol and its derivatives have
probably been used most widely for the synthesis of other
important steroids. The main limitation of this approach,
however, is the potential participation of the double bond
in the 5,6-position in many reactions. To prevent this, one
of the most frequently used techniques is the conversion of
the unsaturated steroids into 5,6-dihalogenides [1,2], from
which the double bond can be later regenerated with a variety
of reagents, such as zinc dust in boiling acetic acid [2],
sodium iodide [3], ferrous chloride [4] or chromous chloride
∗
Corresponding author. Tel.: +381 34 300268; fax: +381 34 335040.
E-mail address: vuk@kg.ac.yu (R.D. Vuki c´ evi c´ ).
0
039-128X/$ – see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2005.06.002

8
68
S.S. Milisavljevi c´ et al. / Steroids 70 (2005) 867–872
the electrolyte and ferric chloride as an additive [16]. This
prompted us to examine the possible electrochemical con-
version of 5,6-unsaturated steroids into their corresponding
dibromo derivatives in different solvents. It seemed to be of
interest to study the isomer distribution obtainable by this
process. For this purpose, we chose four 5,6-unsaturated
steroids, namely 3␤-chlorocholest-5-ene (1a), cholesterol
Table 1
Electrochemical bromination of cholest-5-enes in aprotic solvents
Substrate
Product
Solvent
Yield (%)
1a
2a
CH Cl
2
2
91
87
86
CH3CN
Ac2O
1b
1c
2b
2c
2d
CH2Cl2
CH3CN
Ac2O
61
58
60
(
(
1b), cholesteryl acetate (1c) and cholesteryl benzoate
1d) as the substrates. Here, we describe the results of our
efforts at synthesis, and discuss aspects of the reaction
mechanism.
CH2Cl2
CH3CN
Ac2O
83
75
81
1d
CH2Cl2
CH3CN
Ac2O
72
63
72
2
. Experimental
All chemicals were commercially available and used as
washed with a solution of NaHSO3 (10%, 40 ml) to remove
residual amounts of bromine, then with saturated NaHCO3
received, except that the solvents were purified by distilla-
tion. A Uniwatt Beha Labor-Netzger a¨ t (NG 394) was used
as a direct current source for the electrolysis. A cylindrical
glass vessel equipped with a magnetic stirrer, a cylindrical
platinum foil as the anode (Ø = 2.5 cm), a ceramic tube as the
membrane (Ø = 1.5 cm), and a graphite stick as the cathode
Ø = 0.5 cm) was assembled as the divided electrochemical
cell. IR measurements were carried out with a Perkin-Elmer
57 grating FT instrument in KBr tablets. NMR spectra were
(40 ml), brine (40 ml) and H2O (40 ml). After drying with
anhydrous Na2SO4 overnight, the solvent was evaporated,
and the crude reaction mixture was subjected to column chro-
matography on SiO2 (20 g). The elution (solvents are given
below) was monitored by TLC. Yields are given in Table 1;
physical and spectral data are reported below.
(
4
2.2. 5α,6β-Dibromo-3β-chlorocholestane (2a)
recorded on a Varian Gemini (200 MHz) spectrometer, using
CDCl3 as the solvent. Chemical shifts are expressed in δ
◦
◦
20
Petroleum ether; mp 130–131 C (130 C) [17]; [α]
D
(ppm) using Me4Si as an internal standard. Melting points
◦ −1 −1
53.4 (CHCl3, c 1.07 g l ); IR (cm ): 2949, 1729, 1465,
−
were determined on a Kofler hot-plate apparatus. For TLC,
silica gel 60 on Al plates, layer thickness 0.2 mm (Merck),
1
7
64, 738; H NMR (characteristic signals) δ: 1.47 (s, 3H, 19-
1
3
2
0
Me), 4.66 (m, 1H, 3␣-H), 4.81 (t, J = 2.1 Hz, 1H, 6␣-H);
C
was used. Measured [α] values were obtained in a 1 dm
D
◦
NMR δ: 12.2, 18.7, 20.3, 21.2, 22.6, 22.8, 23.8, 24.0, 28.0,
tube at 20 C on a Perkin-Elmer SP polarimeter. Diffrac-
2
4
8.1, 30.8, 31.7, 35.7, 36.1, 37.3, 38.0, 39.5, 39.6, 41.8, 42.7,
6.8, 47.4, 55.1, 55.5, 56.1, 57.4, 89.5.
tion intensity data of single crystals were collected by means
of a Nonius Kappa CCD with graphite-monochromated Mo
K␣ radiation via φ and ω scans. The structures were solved
by direct methods (SHELXS-86) and by full-matrix least
2
.3. 5α,6β-Dibromocholestan-3β-ol (2b)
2
squares refined against F (SHELXL-97). Tables of bond
◦
◦
Toluene/ethyl acetate (9:1); mp 110–112 C (112–114 C)
lengths, angles, fractional coordinates and thermal parame-
ters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC).
20
◦
−1
◦
[
18]; [α] −42.5 (CHCl3, c 3.03 g l ) (−44 ) [18]; IR
D
−
1
1
(cm ): 3369, 2950, 1617, 1466, 735; H NMR (characteris-
tic signals) δ: 1.45 (s, 3H, 19-Me), 4.45 (m, 1H, 3␣-H), 4.81
(
t, J = 2.1 Hz, 1H, 6␣-H); 13C NMR δ: 12.2, 18.7, 20.4, 21.3,
2
.1. General procedure for electrochemical bromination
2
3
8
2.5, 22.8, 23.8, 24.0, 28.0, 28.2, 30.3, 30.9, 35.7, 36.1, 36.7,
7.2, 39.5, 39.6, 42.0, 42.7, 45.8, 47.4, 55.2, 56.1, 56.2, 69.2,
9.8.
The respective substrate (0.4 mmol) and a 0.05 M solu-
tion of Et4NBr in the appropriate solvent (20 ml) were placed
in the anodic compartment of the cell (outside the ceramic
tube). The same solution of Et4NBr (2.5 ml) was used as the
catholyte. The CH2Cl2 solution was vigorously stirred and
electrolysed at a constant current (50 mA) at room temper-
ature. When MeCN, Ac2O or MeOH was used, the mixture
2.4. 5α,6β-Dibromocholestan-3β-yl acetate (2c)
◦
◦
Toluene/ethyl acetate (9:1); mp 112–113 C (112–114 C)
20
◦
−1
◦
[18]; [α] −44.5 (CHCl3, c 3.59 g l ) (−46 ) [18]; IR
D
◦
−1
1
was heated to 55 C to dissolve the substrate. The electrol-
(cm ): 2250, 1736, 1239, 1031; H NMR (characteristic
ysis was stopped after about 30 min (exactly calculated to
signals) δ: 1.39 (s, 3H, 19-Me), 1.98 (s, 3H, OAc), 4.75 (t,
J = 2.1 Hz, 1H, 6␣-H), 5.41 (m, 1H, 3␣-H); C NMR δ: 12.2,
18.6, 20.1, 21.3, 22.5, 22.8, 23.8, 24.0, 26.2, 28.0, 28.1, 29.7,
30.8, 35.7, 36.1, 36.5, 37.2, 39.5, 39.6, 41.8, 41.9, 42.7, 47.2,
55.1, 56.1, 72.0, 88.1, 170.3.
−
1
13
provide 2.05 F mol charge). The solvent was removed by
rotary evaporation, H2O (15 ml) was added to the residue,
and the mixture was extracted with three portions of Et2O
(3 × 15 ml). The organic layers were first collected and

S.S. Milisavljevi c´ et al. / Steroids 70 (2005) 867–872
869
2
.5. 5α,6β-Dibromocholestan-3β-yl benzoate (2d)
◦
Petroleum ether/acetone (95:5), mp 133–135 C
◦
20
−1
(
(
135–136 C) [18]; [α] −35.5◦ (CHCl3, c 1.47 g l
)
D
◦
−1
−33 ) [18]; IR (cm ): 3066, 2947, 1716, 1278, 1109, 713;
1
H NMR (characteristic signals) δ: 1.45 (s, 3H, 19-Me), 4.79
t, J = 2.1 Hz, 1H, 6␣-H); 5.58 (m, 1H, 3␣-H); 13C NMR
δ: 12.2, 18.6, 20.2, 21.3, 22.5, 22.8, 23.8, 24.0, 26.3, 28.0,
(
Fig. 1. ORTEP view of 5␣,6␤-dibromo-3␤-chlorocholestane 2a. Displace-
ment ellipsoids are drawn at the 50% probability level, and hydrogen atoms
are omitted for clarity.
2
4
1
8.2, 30.8, 35.7, 36.1, 36.5, 37.2, 39.5, 39.6, 41.9, 42.0,
2.7, 47.3, 55.1, 56.0, 56.1, 72.7, 88.1, 128.3, 129.6, 130.5,
32.8, 165.9.
2
.6. 5α-Bromo-3β-chloro-6β-methoxycholestane (3a)
reaction conditions, it yielded two products with very close
Rf values. After column chromatography (SiO2/petroleum
ether), only the major product was isolated in a pure state
(61%, see Scheme 1 and Table 1), identified on the basis
of its physical data as 5␣,6␤-dibromocholestan-3␤-ol (2b).
However, electrochemical bromination of cholesteryl esters
1c and 1d under these conditions gave the corresponding
dibromo derivatives, 5␣,6␤-dibromocholestan-3␤-yl acetate
(2c) and 5␣,6␤-dibromocholestan-3␤-yl benzoate (2d), as
the sole products, in high yields (Scheme 1 and Table 1).
No other isomers could be detected.
◦
20
D
◦
Petroleum ether; mp 130–132 C; [α] −53 (CHCl3, c
− −1
1
1
.07 g l ); IR (cm ): 2933, 1634, 1466, 1081, 768, 737;
1
H NMR (characteristic signals) δ: 1.23 (s, 3H, 19-Me), 3.32
s, 3H, OMe) 3.60 (t, J = 2.1 Hz, 1H, 6␣-H), 4.55 (m, 1H,
(
3
2
4
␣-H); 13C NMR δ: 12.2, 17.5, 18.7, 21.2, 22.6, 22.8, 23.8,
4.1, 28.0, 28.2, 29.6, 30.9, 31.9, 35.8, 36.1, 36.2, 39.5, 39.7,
0.5, 42.7, 43.6, 47.6, 55.7, 56.1, 57.9, 58.5, 85.3, 88.2.
2
.7. 6β-Bromo-3β-chloro-5α-methoxycholestane (4a)
1H NMR (characteristic signals from the mixture with 3a)
In the course of the present investigations, we also tested
two additional polar aprotic solvents (acetonitrile and acetic
anhydride) as possible reaction media for the electrochemical
bromination of cholesterol and its derivatives. Since the cho-
sen substrates were only negligibly soluble in these solvents
δ: 1.36 (s, 3H, 19-Me), 3.13 (s, 3H, OMe) 3.96 (m, 1H, 3␣-H),
.32(t, J = 2.1 Hz, 1H, 6␣-H);13CNMR(signalsthatcouldbe
distinguished from those of 3a) δ: 19.9, 21.0, 30.4, 30.8, 32.3,
4
◦
3
7
4.1, 36.3, 37.3, 39.9, 42.8, 44.6, 47.9, 50.7, 55.2, 56.3, 56.7,
9.6 (non-protonated carbon atom bearing methoxy group).
at room temperature, the reaction was performed at 55 C. As
the data in Table 1 show, the corresponding dibromides 2a–d
were obtained in comparable yields as when dichloromethane
was used as the solvent.
3
. Results and discussion
The mechanism of the reaction deserves some comment.
Anodic oxidation of the bromide gives elemental bromine,
which, as an electrophilic agent, attacks the ␲-electron
system of the substrate’s double bond, preferably from the
less hindered side. In many brominations, it is fairly certain
that a tricentric bromonium ion is an intermediate. Since
the subsequent nucleophilic attack of the bromide ion must
occur from the backside, the overall addition must be anti.
On the basis of the final product stereochemistry, of the
5␣,6␤-dibromides 2a–d, the following conclusions may be
drawn: (i) if the electrophilic attack of bromine happens from
the ␤-side of the steroid molecule, the reaction must proceed
in agreement with Markovnikov’s rule; (ii) on the other hand,
if the attack occurs from the ␣-side, the reaction must violate
Markovnikov’s rule, otherwise, the 5␤,6␣-diastereomers
would appear as the products. In order to gain insight into
the operative mechanism, we conducted the electrolysis in
methanol, expecting that methanol might compete with bro-
mideduringthesecondstepoftheaddition[19], leadingtothe
production of the corresponding bromomethoxy derivatives.
We started with the constant-current electrolysis (50 mA,
−1
2
F mol ) of 3␤-chlorocholest-5-ene (1a) at room tempera-
ture, in a dichloromethane solution of tetraethylammonium
bromide, using an undivided electrochemical cell supplied
with a cylindrical platinum foil as the anode and a graphite
stick as the cathode. Contrary to our expectations based
on past experience with electrochemical chlorination under
these same conditions [15], this reaction gave a complex mix-
ture of products difficult to separate, containing the starting
substrate 1a, 3␤-chloro-5␣,6␤-dibromocholestane (2a), and
several unidentified compounds. In the next experiment, we
used an electrochemical cell divided by a ceramic diaphragm.
Since bromine reacts with olefins in an equimolar ratio, the
−
1
electrolysis time was set to provide 2.05 F mol charge. The
reaction mixture was extracted (see Section 2) to give the
dibromide 2a as the sole product. Subsequent column chro-
matography (SiO2/petroleum ether) gave the pure compound
2
a in a very high, isolated yield (Table 1), followed only
◦
by traces of the substrate 1a. The structure of this product
was confirmed by comparing its physical and spectral data
with that in the literature, as well as by X-ray crystal analysis
However, the electrolysis of 1a–c in this solvent at 55 C
(1d was not soluble enough even with heating) resulted in
mixtures very difficult to separate. Besides the corresponding
dibromo derivatives, two bromomethoxy derivatives were
(Fig. 1). When cholesterol (1b) was submitted to the same

8
70
S.S. Milisavljevi c´ et al. / Steroids 70 (2005) 867–872
Scheme 1.
detected by NMR. Only when 1a was used as the substrate
was it possible to separate pure 2a (66%) from the mixture of
bromomethoxy derivatives (22%). On the basis of H NMR
spectral data, the ratio of the two bromomethoxy isomers was
found to be 75:25. The major isomer, with a slightly higher
the ␤-approach of bromine), and 6␣-bromo-3␤-chloro-5␤-
methoxycholestane (6a; the Markovnikov product with the
␣-approach of bromine). Comparing 1H and C NMR
spectra of pure 3a and the mixture with its isomer (Fig. 3),
we concluded that the second methoxylated compound must
correspond to structure 4a. In particular, the fact that the
methoxy group is attached to a non-protonated carbon atom
points to a 5-methoxy derivative, excluding structure 5a. The
1
13
R value, was isolated in pure form by repeated chromatog-
f
1
13
raphy. Spectral data (IR, H and C NMR), as well as X-ray
structure determination (Fig. 2) of this product, confirmed
the structure as the new compound, 5␣-bromo-3␤-chloro-
1
very similar coupling patterns in the H NMR spectra of 3a
6
␤-methoxycholestane (3a). Apparently, this product results
and 4a (triplet of H-6 from eq–eq and eq–ax coupling; multi-
plet of H-3 from two ax–ax and two ax–eq couplings) suggest
that both compounds have the same conformation, excluding
structures 5a and 6a. These structures could also be ruled
out because signals of their equatorial protons connected
to C-3 would have appeared at a lower field than in the
from the anti-Markovnikov reaction after initial electrophilic
attack of bromine from the ␣-side of the steroid. Here, the
terms “Markovnikov” and “anti-Markovnikov” are intended
only to describe different types of products without any
implication of a specific mechanism. Since the structure of
3
a is known, there are three theoretically possible structures
of the second methoxylated product: 6␤-bromo-3␤-chloro-
␣-methoxycholestane (4a; the Markovnikov product with
5
initial ␤-approach of bromine), 5␤-bromo-3␤-chloro-6␣-
methoxycholestane (5a; the anti-Markovnikov product with
Fig. 2. ORTEP view of 5␣-bromo-3␤-chloro-6␤-methoxycholestane 3a.
Displacement ellipsoids are drawn at the 50% probability level, and hydro-
gen atoms are omitted for clarity.
1
Fig. 3. Partial H NMR spectra of (a) pure 3a and (b) a mixture of isomeric
3
a and 4a, showing signals of protons adjacent to the newly introduced Br
and OMe substituents.

S.S. Milisavljevi c´ et al. / Steroids 70 (2005) 867–872
871
Table 2
Summary of crystal data and details of structure refinement for 2a and 3a
2a
3a
Molecular formula
Formula weight
Crystal system
Space group
C27H45Br2Cl
564.90
Orthorhombic
P2(1)2(1)2(1)
C28H48BrClO
516.02
Monoclinic
P2(1)
◦
◦
◦
˚
◦
a = 6.9913(1) A; α = 90
Unit cell dimensions
a = 12.0559(2) A˚ ; α = 90
b = 12.1699(2) A˚ ; β = 90
c = 18.2735(4) A˚ ; γ = 90
˚
◦
b = 11.1143(3) A; β = 96.618(1)
˚
◦
c = 17.6327(5) A; γ = 90
Volume ( A˚ 3)
Z
2681.07(9)
4
1360.99(6)
2
Temperature (K)
Calculated density (Mg m
Absorption coefficient (mm 1)
233(2)
1.399
3.136
233(2)
1.259
1.626
−
3
)
−
F (0 0 0)
1176
552
Color, habit
Crystal size (mm)
θ Range for data collection ( )
Colorless prism
0.35 × 0.25 × 0.20
2.01–26.00
Colorless plate
0.42 × 0.35 × 0.12
2.33–25.99
◦
Index ranges
−14 < h < 12,
−8 < h < 8,
−
15 < k < 12,
22 < l < 21
−13 < k < 13,
−21 < l < 21
−
Reflections collected
Independent reflections
Reflections with I > 2σ(I)
Data/restraints/parameters
Flack parameter
15230
5250 (Rint = 0.0366)
4886
5250/0/272
0.002(7)
1.025
9270
5109 (Rint = 0.0193)
4865
5109/1/281
0.016(7)
1.053
2
Goodness-of-fit on F
Final R indices [I > 2σ(I)]
R indices (all data)
R1 = 0.0264, wR2 = 0.0590
R1 = 0.0307, wR2 = 0.0604
R1 = 0.0295, wR2 = 0.0707
R1 = 0.0322, wR2 = 0.0721
case of 3a. Connectivities were also corroborated by a two-
dimensional H,C-correlated spectrum of 3a. Finally, the fact
that bromination of cholest-5-enes in aprotic solvents gave
only 5␣,6␤-products supports this conclusion. Crystallo-
graphic data and details of the refinement are summarized
in Table 2.
classic bromination reaction but avoids the use of hazardous
brominating reagents. Bromomethoxylation also yielded
solely 5␣,6␤-products. In contrast, electrolytical experi-
ments in an undivided cell gave only complex mixtures. The
necessary equipment is very simple, inexpensive and readily
available.
The structures of compounds 3a and 4a demonstrate that
electrochemical bromomethoxylation starts with both the
␣
- and ␤-approach of bromine during the first stage of the
reaction, giving ␣- and ␤-bromonium ions, respectively. The
-cation undergoes further addition to the anti-Markovnikov
Acknowledgements
␣
This work was supported by the Ministry of Science and
Environmental Protection of the Republic of Serbia (grant
1245). The authors are also grateful to Prof. V. Pavlovi
Faculty of Chemistry, University of Belgrade, Serbia, for the
generous supply of some substrates.
product 3a, whereas the ␤-cation is transformed in agreement
with Markovnikov’s rule to 4a. The 75:25 ratio of 3a–4a
demonstrates that the initial ␣-approach (from the less
hindered side) of the electrophile predominates, as expected.
c´ ,
4
. Conclusion
Supplementary data
In conclusion, we have shown that 5,6-unsaturated
CCDC 258873 (2a) and 258874 (3a) contain the sup-
plementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, United Kingdom; fax: +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
steroids can be smoothly brominated by electrochemically-
generated bromine derived from bromides in a divided
electrolytic cell. This methodology allows for the prepara-
tion of the corresponding 5␣,6␤-dibromosteroids in good
to high yields when aprotic solvents are used. The process
compares favorably in yield and ease of operation with the

8
72
S.S. Milisavljevi c´ et al. / Steroids 70 (2005) 867–872
[11] As a recent report see Yu B, Liao J, Zhang J, Hui Y. The first
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