Copper-mediated regio- and stereoselective 12β-hydroxylation of steroids with molecular oxygen and an unexpected 12β-chlorination

Article abstract of DOI:10.1016/j.tet.2004.10.055

It is shown, that copper(I) complexes of 17-(2-iminomethyl)pyridino steroids (17-IMPY steroids) can react with molecular oxygen followed by a regio- and stereoselective γ-hydroxylation in 12β-position. After decomplexation and hydrolysis of the IMPY group 12β-hydroxy-17-ketones are available in practical useful yields. IMPY compounds are simple to prepare by condensation of oxo compounds with (2-aminomethyl)pyridine. In the cases of 17-IMPY steroids the yields in the hydroxylation procedure of an unactivated CH₂ group are higher by starting with copper(II) complexes, reduction with benzoin/triethylamine in acetone and reaction with molecular oxygen in comparison to the direct reaction of copper(I) complexes with molecular oxygen in acetone. Employing the procedure in dichloromethane as solvent starting with copper(II) complexes surprisingly the 12β-chloro compound could be isolated next to the hydroxylation product. This regio- and stereoselective γ-chlorination takes place also in acetone, when triethylammonium chloride is added to the reaction mixture. Oxygen is necessary for this reaction. The mechanistic and stereochemical aspects of these new reactions are discussed. Comparison of the different yields of steroids with different A-ring [3-methoxy-estra-1,3,5(10)-triene and 3β-hydroxy-androst-5-ene] pointed out to a subtle influence of the molecular structure far from the reaction centre on these reactions. The successful hydroxylation of the IMPY derivative of 3β-hydroxy-androst-5-ene-17-one shows the tolerance of a homoallylic system against this oxidation procedure. By Oppenauer oxidation 12β-hydroxy- androst-4-ene-3,17-dione is available. The hydroxylation procedure opens a short way to 12β-hydroxy-17-oxo steroids, which are difficult to obtain by other routes. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.055

Tetrahedron 61 (2005) 103–114
Copper-mediated regio- and stereoselective 12b-hydroxylation
of steroids with molecular oxygen and an
unexpected 12b-chlorination
a,
Bruno Schonecker, Corinna Lange,a,b Tatjana Zheldakova,c Wolfgang Gu¨nther,a
*
¨
d
Helmar Gorls and Gavin Vaughan
e
¨
a
¨ ¨
Institut fur Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universitat Jena, Humboldtstrasse 10,
D-07743 Jena, Germany
Hans-Knoll-Institut fur Naturstoff-Forschung, Beutenbergstr. 11a, D-07745 Jena, Germany
b
¨
¨
cInstitute of Bioorganic Chemistry of the National Academy of Sciences of Belarus, Minsk, Belarus
d
¨
Institut fur Anorganische und Analytische Chemie der Friedrich-Schiller-Universitat Jena, Lessingstr. 8, D-07743 Jena, Germany
¨
eEuropean Synchroton Radiation Facility (ESRF), BP220, F-38043 Grenoble Cedex, France
Received 18 June 2004; revised 1 October 2004; accepted 18 October 2004
Dedicated to Professor D. Walther on the occasion of his 65th birthday
Abstract—It is shown, that copper(I) complexes of 17-(2-iminomethyl)pyridino steroids (17-IMPY steroids) can react with molecular
oxygen followed by a regio- and stereoselective g-hydroxylation in 12b-position. After decomplexation and hydrolysis of the IMPY group
12b-hydroxy-17-ketones are available in practical useful yields. IMPY compounds are simple to prepare by condensation of oxo compounds
with (2-aminomethyl)pyridine. In the cases of 17-IMPY steroids the yields in the hydroxylation procedure of an unactivated CH2 group are
higher by starting with copper(II) complexes, reduction with benzoin/triethylamine in acetone and reaction with molecular oxygen in
comparison to the direct reaction of copper(I) complexes with molecular oxygen in acetone. Employing the procedure in dichloromethane as
solvent starting with copper(II) complexes surprisingly the 12b-chloro compound could be isolated next to the hydroxylation product. This
regio- and stereoselective g-chlorination takes place also in acetone, when triethylammonium chloride is added to the reaction mixture.
Oxygen is necessary for this reaction. The mechanistic and stereochemical aspects of these new reactions are discussed. Comparison of the
different yields of steroids with different A-ring [3-methoxy-estra-1,3,5(10)-triene and 3b-hydroxy-androst-5-ene] pointed out to a subtle
influence of the molecular structure far from the reaction centre on these reactions. The successful hydroxylation of the IMPY derivative of
3b-hydroxy-androst-5-ene-17-one shows the tolerance of a homoallylic system against this oxidation procedure. By Oppenauer oxidation
12b-hydroxy-androst-4-ene-3,17-dione is available. The hydroxylation procedure opens a short way to 12b-hydroxy-17-oxo steroids, which
are difficult to obtain by other routes.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Despite considerable success in inducing intramolecular
hydroxylations of aromatic3 and benzylic4 C–H bonds,
analogous hydroxylations of nonactivated C–H bonds is
much more difficult and only now is becoming possible.
Using tri- or bidendate ligands with N-donor atoms for
copper complexation, resulted in a hydroxylation at the
b-position relative to the central N-atom in relatively low
yields (Fig. 1).5–9 Recently, we have successed, for the first
time, in obtaining g-hydroxylations of nonactivated C–H
bonds in preparative useful yields (Fig. 2).7,10
The activity of copper-containing enzymes (tyrosinase,
dopamine-b-hydroxylase and bacterial particulate methane
monooxygenase) for binding and activating molecular
oxygen with a following insertion into C–H bonds of
organic substrates under mild conditions is very remark-
able.1 Developing the ability to mimic this behavior with
simpler copper(I) complexes and molecular oxygen has thus
become an interesting research topic in the last few years.2
Using the sterically more constrained bidentate imino-
methylpyridine (IMPY)10,11 and aminomethylenepyridine
(AMPY)10–12 ligands that possess a conformationally
Keywords: C–H activation; Hydroxylation; Chlorination; Copper; Steroids.
* Corresponding author. Tel.: C49 3641 948225; fax: C49 3641 948292;
e-mail: c8scbr@uni-jena.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.055

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
104
Figure 1. Examples for b-hydroxylation of nonactivated C–H bonds.
Figure 2. Examples for g-hydroxylation of nonactivated C–H bonds.
well-defined steroid skeleton, we could develop a stereo-
chemical model for this hydroxylation reaction.7,10 Assum-
ing a dinuclear complex with the well-known central
[Cu2O2] structure motive in which the four lone pairs of
the coordinating nitrogens lie in a plane, we discovered that
a hydrogen atom at a g-C atom must also be in this plane
and, in addition, be near a oxygen atom in order for a
successful H abstraction followed by hydroxylation at the
g-C atom to take place (Fig. 3). In this way, a seven-
membered transition state can be formulated. Six atoms are
nearly in a plane. This could also confirmed by force field
calculations.10
Using 17-IMPY-3-methoxy-estra-1,3,5(10)-triene 17 as our
model, the corresponding 17a-D-homo compound as well as
the 13a-derivatives could be regio- and stereoselective
hydroxylated in the 12b-position.10 In addition, the 10-
methyl group of (1R)-IMPY-camphor was hydroxylated.10
Starting from 17a-AMPY-3-methoxy-estra-1,3,5(10)-triene
2 or 3a-AMPY-5a-cholestane, the g-methine groups could
be hydroxylated to the 14a-hydroxy and the 5a-hydroxy
derivatives, respectively.10
Several aspects of this reactions are of interest from the
practical point of view. IMPY and AMPY compounds are

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
105
As Itoh and co-workers could demonstrate, two methods are
successful for the hydroxylation of benzylic groups.4b,d
Starting with copper(I) complexes followed by the addition
of molecular oxygen (method A) the active dinuclear
[Cu2O2] species has been formed. Only one oxygen was
transferred to generate the C–O bond. In this way, only 50%
of ligand hydroxylation is possible; the other part should be
unchanged. To improve the yield, Itoh and co-workers
started with copper(II) complexes and an excess of benzoin
and triethylamine [reducing agent for copper(II)]. After
reaction with molecular oxygen, the hydroxylation took
place in the same way. The excess of reducing agent can
now reduce the formed copper(II) complex to copper(I) and
further reaction with oxygen gave a complete ligand
hydroxylation (method B).4b,d Reglier and co-workers
found that unactivated CH2 groups undergo b-hydroxylation
only with method B.6 However, we as well as Masuda et al.
could recently demonstrate, that unactivated CH2 groups
can also be hydroxylated in b-position with method A.8,9
We have now employed both methods to investigate the
possibility of g-hydroxylation of unactivated C–H bonds
with IMPY and AMPY ligands.10 An unexpected strong
dependence on the structure of the compounds could be find.
g-Methine groups of AMPY ligands can be hydroxylated
much more efficiently with method A than with method B.
In contrast to this 17-IMPY-3-methoxy-estra-1,3,5(10)-
triene 1 could be better hydroxylated with method B.
Surprisingly enough, method A is considerably better for the
other IMPY compounds. The active species for the
hydroxylationprocedureisprobablyabis(m-oxo)dicopper(III)
Figure 3. 17-IMPY-estra-1,3,5(10)-triene as a model for g-hydroxylations.
quite easy to prepare by the condensation of oxo compounds
with 2-(aminomethyl)pyridine or primary amines with
pyridine-2-carboxaldehyde.10,11 After the simple hydroxyl-
ation procedure (copper complexation and reaction with
molecular oxygen at room temperature in an organic
solvent) is performed, three variants become possible. In
most cases the IMPY and AMPY groups could be
hydrolyzed under the conditions of decomplexation (with
aqueous ammonia) and chromatography. In this way
3-hydroxy-1-ones7,10 or 3-hydroxy-1-primary amines10 are
available (Fig. 4, variant B). Using of (1R)-IMPY-camphor,
10-hydroxy-2-IMPY-camphor could be isolated (Fig. 4,
variant A).10 A third variant consists in the direct reduction
of the C]N double bond of the hydroxylation product with
NaBH4 to give 3-hydroxy-1-(N-2-pyridylmethyl)amino
compounds (Fig. 4, variant C).7,10
Figure 4. Synthesis of IMPY and AMPY compounds and their possible g-hydroxylation products.

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
106
complex [in equilibrium with previously generated (m–h2:h2–
peroxo)dicopper(II) complexes] (Fig. 5).4b,c,d As discussed by
Reglier and co-workers a mixed bis (m-oxo)Cu(II), Cu(III)
complex6 is also possible (method B).
of benzoin/triethylamine to give a yellow copper(I) complex
solution (method B). Reaction with pure oxygen then
yielded a dark-green solution. After decomplexation and
chromatography, DHEA 4 and two new polar compounds
could be isolated in 25 and 19% yields, respectively (6 and
7, Scheme 1).
The more polar compound 6 was the expected 12b-hydroxy
compound [comparison with 3 from the estra-1,3,5(10)-
triene series]. Similarities in the 1H and 13C NMR spectra of
6 and 7 pointed to a 12b-substitution of 7. MS spectra and
elemental analysis of 7 indicated a 12b-chlorine substitution
which could be confirmed by an X-ray analysis (Fig. 6).
This result was completely unexpected, because the only
source for chlorine was the solvent (dichloromethane). To
confirm this reaction, we reinvestigated the hydroxylation
procedure of the IMPY derivative 1 of the estra-1,3,5(10)-
triene series in CH2Cl2. Indeed, we could isolate, after
careful chromatography (MPLC), the new 12b-chloro
compound 8 in a yield of 14% in addition to the known
12b-hydroxy compound 3. To exclude chlorine sources we
changed the solvent to acetone. Using method B for the
hydroxylation of 5 under these conditions yielded solely 6
which could be isolated in a yield of 35% after the work-up
procedure (next to 4). From compound 1, only 3 was
obtained in acetone in a yield of 50%. 6 could be
transformed by an Oppenauer oxidation to the desired
12b-hydroxy-androst-4-ene-3,17-dion 9 (Scheme 2).
Interestingly enough, hydroxylation of 5 using method A in
CH2Cl2 [Cu(CH3CN)4PF6, O2, decomplexation, chroma-
tography] gave only compound 6 in nearly 20%. The same
yield of 6 could be obtained with method A in acetone.
Using method A for 1 in CH2Cl2 only 3 could be obtained
(29%). We assume that the basic conditions of method B in
CH2Cl2 (benzoin/triethylamin) are responsible for the
generation of chloride ions. We could thus demonstrate,
that triethylammonium chloride is indeed a source for the
chlorination procedure. Adding three equivalents of
triethylammonium chloride (method B) to the reaction of
5 in acetone resulted in a mixture of 7 and 6; both in very
low yields (5% of 6 and 10% of 7). Method A in acetone
with triethylammonium chloride gave the same (see
Table 1).
Figure 5. Structures of copper-O2-complexes.
Our results indicate that a fine tuning by varying the
surrounding of the ligand at the copper center10,13 influences
the structures of the active copper-oxygen species. The
method employed (A or B) also directly affect the results.
For these reasons, we decided to investigate additional
g-hydroxylations of the 12b-position of steroids. We chose
3b-hydroxy-androst-5-ene-17-one as the target, since
different conformational effects of the estra-1,3,5(10)-triene
and the androst-5-ene skeleton could be awaited. Further-
more, we were interested in the stability of the 3b-hydroxy-
androst-5-ene system (a homoallyl alcohol) towards our
hydroxylation procedure. The biological activity of, until
now, difficult to obtain 12b-hydroxy-androstenes14 is also of
interest. After a successful 12b-hydroxylation it should be
possible to transform the 3b-hydroxy-5-ene system into the
3-oxo-4-ene system by an Oppenauer oxidation.
It should be mentioned, that copper(I) complexes of tris(N-
benzylaminoethyl)amine, tris(N-benzyl-N-methylamino-
ethyl)amine and tris(2-pyridylmethyl)amine are able to
react with CH2Cl2 to generate copper(II)chloro complexes.
1,2-Dichlorethane (coupling product) can also be obtained
under these conditions.15 Copper(I) chloride coordinated
with 1,1,4,7,10,10-hexamethylethylentetramine can act in
DMF as a atom-transfer radical polymerization catalyst for
poly(vinylchloride) and polyethylene glycol monometha-
crylate.16 In addition, other metal complexes are able to
react with CH2Cl2 under oxidative addition.17 Our experi-
mental results (Table, entry 3 and 7) show that no
chlorination product could be detected with method A in
CH2Cl2. When chloride ions are added, a chlorination takes
place (entry 9). Method B in acetone with added of chloride
ions also results in chlorination (entry 5). Chlorination takes
place only when pure oxygen is involved in the reaction. It
2. Results and discussion
The IMPY compound 5 was synthesized by heating 3b-
hydroxy-androst-5-ene-17-one 4 (dehydroepiandrosterone,
DHEA) with 2-(aminomethyl)pyridine and p-toluensulfonic
acid in toluene. 5 could be obtained in a yield of 87% and
was reacted in CH2Cl2 with copper(II)triflate. The green
complex thus obtained was directly reduced with an excess

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
107
Scheme 1. g-Hydroxylation and chlorination of 17-IMPY steroids. (a) PyCH2NH2, p-toluenesulfonic acid, refluxing toluene; (b) 1. Cu(CF3SO2)2, CH2Cl2 or
acetone; 2. benzoin, N(C2H5)3, Ar; 3. O2; (c) NH4OH/H2O; (d) chromatography on silica gel.
is therefore plausible, that an active complex with a [Cu2O2]
core is a common intermediate for both hydroxylation and
chlorination. Similar to the recently calculated b-hydroxyl-
ation of benzylic groups,18 abstraction of a hydrogen atom
in g-hydroxylation by one oxygen of the [Cu2O2] core is an
important step followed by creation of the C–O bond
(Fig. 7). If chloride ions are present, it could be possible that
the [Cu2O2] core reacts to form a [Cu2O2Cl] core containing
an additional chloro bridge (Fig. 8). In this case, a five-
coordinated copper intermediate similar to the oxidation
product of L2[Cu2Br2] possessing a [Cu2Br2O] core19 could
Figure 6. Molecular structure of 12b-chloro-3b-hydroxy-androst-5-ene-17-
be present. The assumed [Cu2O2Cl] core should have two
one 7.
Scheme 2. Synthesis of 12b-hydroxy-androst-4-ene-3,17-dione 9.

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
108
Table 1. Hydroxylation and chlorination in dependence of reaction conditions
Entry
1
IMPY compound
Method
B
Solvent
CH2Cl2
Addition
–
Yields
1
3: 38% (OH
8: 14% (Cl)
3: 50% (OH)
3: 29% (OH)
6: 25% (OH)
7: 19% (Cl)
6: 35% (OH)
6: 5% (OH)
7: 10% (Cl)
6: 22% (OH)
6: 20% (OH)
6: 6% (OH)
7: 9% (Cl)
2
3
4
1
1
5
B
A
B
Acetone
CH2Cl2
CH2Cl2
–
–
–
5
6
5
5
B
B
Acetone
Acetone
–
[HNEt3]CClK
7
8
9
5
5
5
A
A
A
CH2Cl2
Acetone
Acetone
–
–
[HNEt3]CClK
Figure 7. Mechanism for g-hydroxylation.
possibilities for reaction after the H abstraction: reaction
with the O-brigded oxygen to a hydroxylated product or
reaction with the bridged chlorine to a chlorinated product.
Whether the primary attack of the hydrogen is caused by an
oxygen or the chlorine is an open question. Possible
mechanisms are given in Figures 7 and 8.
yields, a great potential for the functionalization of
unactivated g-CH2 (maybe CH and CH3 as well) groups
in a regio- and stereoselective manner. Further investi-
gations especially optimization of the reaction conditions
(copper salts, source of chloride, solvent, temperature, etc.)
is, however, necessary to improve this chlorination process.
In addition, use of bromide or other bridging anions for
functionalizations should be interesting.
This chlorination reaction has, in spite of the relatively low

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
109
Figure 8. Mechanisms for g-chlorination.
The regio- and stereoselective chlorination of unactivated
CH bonds is not a process that is simple to achieve. Breslow
and co-workers have described the chlorination of
unactivated CH groups using suitable esters or silylethers
of steroidal 3a- or 17a-alcohols and a chloride source
(SOCl2, PhICl2). In this way, selective chlorination of the
tertiary positions 9, 14 and 17 are possible.20–22
products.25 However, their synthesis is a difficult problem.
19-nor-3,17-dioxo-4-androstane can be converted in two
microbial steps (12b-hydroxylation and aromatization) to
12b-hydroxy-estrone.26 Cholanic acids with a 12a-hydroxy
group serve as starting materials for multistep chemical
syntheses to 12b-hydroxylated estra-1,3,5(10)-trienes.27
Intermediates are 12-oxo-androstenes. 12b-Hydroxylated
androstenes have been synthesized also in a multistep
chemical procedure starting with the steroid alkaloid
jervine.28 Polyoxypregnanes with a 12b-hydroxy group
are important natural products.29 A remote oxidation in the
12-position of the androstane skeleton (12a-OH and 12-
oxo) has been reported by P. A. Grieco and T. L. Shuk.30 In
addition the 14a-position has been hydroxylated. A 3a-
phenylacetic ester with a synthetic manganeseporphyrin in
meta-position of the phenyl ring and iodosylbenzene as
oxygen source are responsible for the oxygen transfer.30
With the corresponding 3a-benzoic acid ester, a tertiary
17a-hydroxy group could be introduced.30 Recently,
Breslow et al reported on manganeseporphyrin catalysts
linked by spacers to cyclodextrin which are able to achieve
a selective hydroxylation of steroids in 6a- and 9a-
position.31
Selective C-chlorination of ligands with metal complexes
are quite rare. As an examples, the C-chlorination of the
pyrazole ring of a CuCl2 complex with 3-phenyl-5-(6-
methyl-2-pyridyl)pyrazole in DMF to a dinuclear copper
complex containing chloride bridges23 or a similar chlori-
nation of a (2-pyridyl)pyrazol complex with VOCl3 and
tert.-BuOOH24 need to be mentioned. The active chlorine
species in the latter case should be formed in a vanadium
haloperoxidase-like reaction.24
Similar to the regio- and stereoselective 12b-chlorination
observed to 17-IMPY compounds (forms 7 and 8) the 12b-
hydroxylation to form the new compounds 6 and 3 is a
practical useful procedure. 12b-hydroxylated estra-
1,3,5(10)-trienes and androst-4-enes are metabolic

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
110
We could demonstrate that, with our procedure, the IMPY
derivatives of 3-methoxy-estra-1,3,5(10)-triene-17-one 1
and 3b-hydroxy-androst-5-ene-17-one 5 can be regio- and
stereoselective hydroxylated in the 12b-position using
method B [starting with Cu(II) complexes in acetone,
reduction with benzoin/triethylamine, reaction with
molecular O2, hydrolysis] in yields of 50 and 35%. The
difference in the yields points to a subtle influence of the
molecular structure. In principle, the hydroxylation pro-
cedure is also successful for molecules possessing an
homoallylic alcohol group (as compound 4).
electron impact (DEI) with 70 eV and electro spray
ionization (ESI). Elemental analyses were performed with
a CHNS-932 (LECO) instrument. 1H and 13C NMR spectra
were recorded on either a Bruker AC 250 or a DRX-400
spectrometer (1H NMR 250 MHz, 400 MHz, 13C NMR
62.5 MHz, 100 MHz). Signals were assigned by DEPT,
COSY, TOCSY, NOESY and HMQC experiments. All
reactions were carried out under inert conditions. The
reactions were monitored by TLC aluminium sheets, silica
gel 60 F254 (Merck.), 0.2 mm, detection by UV (254 nm)
and spraying with methanolic sulfuric acid (methanol/H2-
SO4 4:1) and heating at 170 8C. For flash chromatography,
silica gel 60 (Lichroprep Si 60, 40–63 mm, Merck.) was
used. MPLC was performed on Lichroprep Si 60, 15–
25 mm, Merck). Solvents were purified, dried and distilled
according to convential methods.
3. Conclusion
The regio- and stereoselective 12b-hydroxylation of 17-(2-
iminomethyl)pyridino steroids (IMPY compounds) via
copper complexation and reaction with molecular oxygen
described here is a model reaction for a hydroxylation of
unactivated C–H bonds in g-position to the IMPY nitrogen.
The simple preparation of IMPY compounds from oxo
compounds and their easy hydrolysis after the hydroxylation
procedure allows the synthesis of 3-hydroxy-1-oxo com-
pounds in a simple procedure and in satisfactory yields.
Starting with the IMPY compounds of 3-methoxy-estra-
1,3,5(10)-triene-17-one and 3b-hydroxy-androst-5-ene-17-
one and using copper(II) triflate for complexation in acetone
followed by reduction with benzoin/triethylamine and
reaction with molecular oxygen, the 12b-hydroxy-17-
ketones could be obtained after hydrolysis in yields of 50
and 35%, respectively. Using copper(I) salts for complexa-
tion the yields are clearly lower. This is in contrast to the
recently described g-hydroxylations of IMPY compounds
of a D-homo-17a-ketone, a 13a-17-ketone, (1R)-camphor
and 17a-, 16a- and 3a-aminomethylene steroids (AMPY
steroids),10 all of which react better with copper(I)
complexes and molecular oxygen as compared to the use
of copper(II) complexes and reduction. In summary, these
results, point to subtle influences of the molecular structure
on the reactive centre;32 the yields maybe also be due to
different active species.
4.2. Crystal structure analysis
Compound measurements were carried out at beamline
ID11 at the European Synchrotron Radiation Facility
(ESRF). Data were collected using a Bruker ‘Smart’
CCD-camera system at fixed 2q, while the sample was
rotated over 0.18 intervals during 2 s exposures, using
˚
monochromated radiation from lZ0.38745 A. Data were
corrected for Lorentz and polarization effects, but not for
absorption.33 The structures were solved by direct methods
(SHELXS34) and refined by full-matrix least squares
techniques against Fo2 (SHELXTL97-235). The hydrogen
atoms were located by difference Fourier synthesis and
refined isotropically. All non-hydrogen atoms were refined
anisotropically.35 XP (SIEMENS Analytical X-ray
Instruments, Inc.) was used for structure representations.
4.3. Synthesis of 17-IMPY steroids
4.3.1. 17-(N-2-Pyridylmethyl)imino-3-methoxy-estra-
1.3.5(10)-triene (1). 3-Methoxy-estra-1,3,5(10)-triene-17-
one (1.3 g, 4.5 mmol), 2-(aminomethyl)pyridine (0.97 mL,
9.0 mmol) and triethyl orthoformate36 (25 mL) were heated
at 808 for 5 h. After removing the liquids under reduced
pressure the yellowish solid was crystallized from ethyl
acetate giving white crystals of 1 (1.47 g, 86%). Mp 124–
126 8C; [a]2D4ZC81.7 (cZ0.9 in CH2Cl2); 1H NMR
(CDCl3): dZ0.89 (s, 3H, 18-H3), 2.86 (m, 2H, 6-H2), 3.76
(s, 3H, OCH3), 4.60 (m, 2H, CH2N), 6.60–6.65 (s, m, 2H,
4-H and 2-H), 7.10 (m, 3H, 1-H, 3-Hpy and 5-Hpy), 7.58
(m, 1H, 4-Hpy), 8.52 (m, 1H, 6-Hpy), 8.52 (m, 1H, 6-Hpy).
MS (EI): m/z (%): 374 (100%) [MC]; C25H30N2O (374.5)
calcd: C 80.18; H 8.07; N 7.48; found: C 80.52; H 8.16; N
7.42.
A 12b-chlorination was oberserved in addition to the 12b-
hydroxylation with the Cu(II) complexes in the presence of
benzoin/triethylamine/O2 when CH2Cl2 as solvent is
employed. This chlorination also took place in acetone
after the addition of triethylammonium chloride to the
reaction mixture, but in lower yields. A chloro-bridge
between the two copper centres together with oxygen
bridges could possibly be responsible for these reactions.
Further optimizations are necessary to improve the yields of
this new g-chlorination procedure. In addition the
possibility of functionalization with other bridged atoms
or groups should be quite interesting.
4.3.2. 17-(N-2-Pyridylmethyl)imino-3b-hydroxy-androst-
5-ene-17-one (5). A mixture of dehydroepiandrosterone 4
(2.0 g, 6.9 mmol), 2-(aminomethyl)pyridine (3.5 mL,
34.7 mmol) and a catalytic amount of p-toluenesulfonic acid
(30 mg) was dissolved in toluene (30 mL) and refluxed for 2 h
using a Dean–Stark apparatus. After cooling the reaction
mixture was diluted with ethyl acetate, washed twice with
aqueous satured NaHCO3 solution and water, dried and
separated. The solvent was evaporated and the sticky brown
residue purified by crystallization from ethyl acetate, giving
pure 17-imine 5 (2.28 g, 87%) as light yellow crystals. Mp
4. Experimental
4.1. General
¨
Melting points were measured on a Boetius micromelting
point apparatus and are corrected values. Mass spectra were
determined on an AMD 402 intectra instrument with direct

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B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
111
172–175 8C (ethylacetate); [a]2D4ZK40.8 (cZ0.9 in
CH2Cl2); 1H NMR (250 MHz, CD2Cl2): dZ0.89 (s, 3H, 18-
H3), 1.05 (s, 3H, 19-H3), 3.47 (m, 1H, 3a-H), 4.49 (m, 2H,
CH2-N), 5.37 (m, 1H, 6-H), 7.14, 7.52, 7.68 and 8.48 (4!m,
4!1H, 4!Hpy); MS (EI): m/z (%): 378 [MC]; C25H34N2O
(378.6): calcd: C 79.32; H 9.05; N 7.40; found: C 79.12; H
9.04; N 7.46.
3b,12b-Dihydroxy-androst-5-ene-17-one 6: Mp 192–
196 8C (diethyl ether); [a]2D4ZK21.9 (cZ0.9 in CH2Cl2);
1H NMR (400 MHz, CDCl3): dZ0.94 (s, 3H, 18-H3), 1.03
(s, 3H, 19-H3), 3.49 (m, 1H, 3a-H), 3.78 (m, 1H, 12a-H),
5.36 (m, 1H, 6-H); 13C NMR (100 MHz, CDCl3): dZ8.00
(CH3), 19.3 (CH3), 21.7 (CH2), 28.2 (CH2), 30.3 (CH2), 30.6
(CH), 31.6 (CH2), 35.7 (CH2), 36.7 (Cq), 37.1 (CH2), 42.1
(CH2), 49.1 (CH), 49.6 (CH), 51.4 (Cq), 71.5 (C-3), 72.7
(C-12), 120.7 (C-6), 141.0 (C-5), 222.6 (C-17); C19H28O3
(304.2): calcd C 74.95; H 9.28; found: C 73.99, H 9.17.
4.4. Hydroxylation and chlorination procedures
4.4.1. Hydroxylation and chlorination of 17-IMPY-3b-
hydroxy-androst-5-ene 5 (method B, CH2Cl2). To a
solution of 5 (756 mg, 2.0 mmol) in abs. CH2Cl2 (30 mL)
Cu(CF3SO3)2 (880 mg, 2.4 mmol) was added. The dark-
green solution was stirred at rt for about 1 h. Under an argon
atmosphere and continual stirring benzoin (850 mg,
4.0 mmol) and triethylamine (0.6 mL, 4.0 mmol) were
added. After 4 h pure oxygen was bubbled through the
mixture for 10 min. The yellow-brown solution was stirred
for further 24 h under O2 during which it turned to dark-
green. After removing the solvent a dark-sticky oil was
obtained. The crude product was dissolved in ethyl acetate
and extracted three times with aqueous NH4OH (25%). The
brown organic layer was washed with brine, dried with
Na2SO4 and evaporated. The residue was redissolved in
methanol (40 mL) and treated with acetic acid (40 mL) at
908 for 6 h. The methanol was removed and the mixture was
poured into water and extracted with ethyl acetate. The
organic phase was washed with brine and dried (Na2SO4).
Evaporation gave a dark oil which was purified by MPLC
(Lichroprep Si 60, 15–20 mm, n-hexane/ethyl acetate
70:30). Dehydroepiandrosterone 4 (121 mg, 21%), 12b-
chloro compound 7 (122 mg, 19%) and 12b-hydroxy
compound 6 (152 mg, 25%) were obtained as white
amorphous solids.
4.4.2. Hydroxylation of 5 (method B, acetone). 5 (756 mg,
2.0 mmol) was reacted with CuII(CF3SO3)2 (880 mg,
2.4 mmol), benzoin (850 mg, 4.0 mmol) and triethylamine
(0.6 mL, 4.0 mmol) in absolute acetone (30 mL) as
desribed above. Separation by MPLC yielded dehydro-
epiandrosterone 4 (127 mg, 22%) and 12b-hydroxy
compound 6 (213 mg, 35%).
4.4.3. Hydroxylation and chlorination of 5 (method B,
NEt3$HCl, acetone). To a solution of 5 (756 mg, 2.0 mmol)
in absolute acetone (30 mL) CuII(CF3SO3)2 (880 mg,
2.4 mmol) and triethylamine hydrochloride (825 mg,
6.0 mmol) were added. The mixture was then treated with
benzoin (850 mg, 4.0 mmol) and triethylamine (0.6 mL,
4.0 mmol) as described above. After working up and MPLC
(Lichroprep Si 60, 15–20 mm, n-hexane/ethyl acetate 70:30)
dehydroepiandrosterone 4 (231 mg, 40%), 12b-chloro
compound 7 (64 mg, 10%) and 12b-hydroxy compound 6
(30 mg, 5%) were obtained.
4.4.4. Hydroxylation of 5 (method A, CH2Cl2). To a
solution of 5 (378 mg, 1.0 mmol) in absolute dichloro-
methane (30 mL), tetrakis(acetonitrile)copper(I)hexafluoro-
phosphate (447 mg, 1.2 mmol) was added. The resulting
brown solution was stirred at rt. After 1 h the argon
atmosphere was replaced by an O2 atmosphere. Pure oxygen
was then bubbled trough the reaction mixtures for
approximately 10 min. The solution were stirred for about
24 h under O2. During this time it turned to dark green. The
solvent was distilled off and the oily dark residue was
dissolved in ethyl acetate and extracted three times with
aqueous NH4OH (25%); the brown organic layer was
washed with brine, dried over Na2SO4 and evaporated. The
brown oil was then redissolved in methanol (20 mL) and
treated with acetic acid (20 mL) at 90 8C for 6 h. The
methanol was removed and the mixture was poured into
water and extracted with ethyl acetate. The organic phase
was washed with brine and dried (Na2SO4). Evaporation
gave a dark oil which was separated by MPLC using
Lichroprep Si 60, 15–20 mm, n-hexane/ethyl acetate 80:20
(column of 200!35 mm, rate 25 mL minK1) yielding
dehydroepiandrosterone 4 (130 mg, 45%) and 12b-hydroxy
compound 6 (72 mg, 22%). No chlorination product could
be found.
12b-Chloro-3b-hydroxy-androst-5-ene-17-one 7: Mp 189–
193 8C (diethyl ether); [a]2D4ZK60.1 (cZ0.9 in CH2Cl2);
1H NMR (400 MHz, CDCl3): dZ1.04 (s, 3H, 19-H3), 1.06
(s, 3H, 18-H3), 3.51 (m, 1H, 3a-H), 3.99 (m, 1H, 12a-H),
5.36 (m, 1H, 6-H); 13C NMR (100 MHz, CDCl3): dZ9.15
(CH3), 19.5 (CH3), 21.4 (CH2), 30.3 (CH), 30.7 (CH), 31.6
(CH2), 33.3 (CH2), 35.6 (CH2), 36.9 (Cq), 37.2 (CH2), 42.2
(CH2), 50.8 (CH), 51.4 (Cq), 52.2 (CH), 61.8 (C-12), 71.6
(C-3), 120.8 (C-6), 140.9 (C-5), 216.3 (C-17); C19H27O2Cl
(322.2): calcd C 70.77; H 8.45; Cl 10.86; found: C 68.07; H
8.62; Cl 10.04.
Crystal data for 7.37 C19H27ClO2, MrZ322.86 g molK1
,
colourless prism, size 0.04!0.04!0.03 mm3, ortho-
˚
rhombic, space group P212121, aZ5.9230 (1) A, bZ
3
˚
˚
˚
11.4755 (2) A, cZ24.8073 (4) A, VZ1686.14(5) A ,
TZK153 8C, ZZ4, rcalcdZ1.272 g cmK3
, m (lZ
0.38745 A)Z0.000 cmK1, F(000)Z696, 10,716 reflections
in h(K7/7), k(K15/14), l(K32/32), measured in the range
2.428%Q%14.978, completeness QmaxZ85.8%, 3630
independent reflections, RintZ0.031, 3440 reflections with
FoO4s(Fo), 308 parameters, 0 restraints, R1obsZ0.024,
wR2obsZ0.062, R1allZ0.027, wR2allZ0.063, GOOFZ
1.007, Flack-parameter 0.69 (6) (absolute configuration
not determined), largest difference peak and hole: 0.208/
˚
4.4.5. Hydroxylation of 5 (method A, acetone). 5 (378 mg,
1.0 mmol) was reacted with tetrakis(acetonitrile)copper-
(I)hexafluorophosphate (447 mg, 1.2 mmol) in absolute
acetone (30 mL) as described under Section 4.4.4. Separ-
ation by MPLC yielded dehydroepiandrosterone 4 (104 mg,
36%) and 12b-hydroxy compound 6 (61 mg, 20%).
K3
˚
K0.137 e A
.

¨
B. Schonecker et al. / Tetrahedron 61 (2005) 103–114
112
4.4.6. Hydroxylation and chlorination of 5 (method A,
NEt3$HCl, acetone). To a solution of 5 (378 mg, 1.0 mmol)
triene-17-one (87 mg, 49%) and 12b-hydroxy compound 3
(55 mg, 29%).
in
absolute
acetone
(30 mL)
tetrakis(aceto-
nitrile)copper(I)hexafluoro-phosphate (447 mg, 1.2 mmol)
and triethylamine hydrochloride (412 mg, 3.0 mmol) were
added. The reaction and working up procedures were
performed as described under Section 4.4.4. After separ-
ation by MPLC dehydroepiandrosterone 4 (155 mg, 54%),
12b-chloro compound 7 (29 mg, 9%) and 12b-hydroxy
compound 6 (18 mg, 6%) were obtained.
4.5. Oppenauer oxidation of 6
To a solution of 6 (200 mg, 0.7 mmol) in anhydrous toluene
(20 mL) and cyclohexanone (2 mL) a suspension of
aluminium isopropoxide (200 mg, 1 mmol) in toluene
(1 mL) was added. The reaction mixture was refluxed
while stirring for 4 h. After cooling to room temperature the
reaction mixture was washed with diluted sulfuric acid and
water, dried over Na2SO4 and evaporated. The oily crude
product was purified by MPLC on silica gel with n-hexane-
ethyl acetate (50:50) giving pure 12b-hydroxy-androst-4-
ene-3,17-dione 9 (100 mg, 50%) as white crystals. Mp 149–
152 8C (n-hexane-ethyl acetate); 1H NMR (400 MHz,
CDCl3): dZ0.94 (s, 3H, 18-H3), 1.16 (s, 3H, 19-H3), 3.74
(m, 1H, 12a-H), 5.70 (m, 1H, 4-H); 13C NMR (100 MHz,
CDCl3): dZ8.19, 17.2, 21.6, 27.9, 30.2, 31.4, 32.4, 33.8,
34.2, 35.6, 38.5, 48.5, 51.4, 52.2, 72.3, 124.4, 169.3, 199.1,
222.1; HRMS (EI): m/z found 302.2062, calcd C19H26O3
(MC) 302.2065.
4.4.7. Hydroxylation and chlorination of 17-IMPY-3-
methoxy-estra-1.3.5(10)-triene 1 (method B, CH2Cl2). 1
(374 mg, 1.0 mmol) was reacted with Cu(CF3SO3)2
(440 mg, 1.3 mmol), benzoin (425 mg, 2.0 mmol) and
triethylamin (0.3 mL, 2.0 mmol) in abs. CH2Cl2 (20 mL)
as desribed under Section 4.4.1. Also the working up
procedure was performed as described. MLPC using
Lichroprep Si60, 15–20 mm, n-hexane/ethyl acetate 75:25
(column of 200!35 mm, rate 25 mL minK1) yielded
3-methoxy-estra-1.3.5(10)-triene (57 mg, 20%) and 12b-
chloro compound 8 (45 mg, 14%) and 12b-hydroxy
compound 3 (114 mg, 38%) as white amorphous solids.
Acknowledgements
12b-Chloro-3-methoxy-estra-1.3.5(10)-triene-17-one 8: Mp
166–171 8C (CH3OH); [a]2D4ZC33.4 (cZ0.9 in CH2Cl2);
1H NMR (400 MHz, CDCl3): dZ1.08 (s, 3H, 18-H3), 2.88
(m, 2H, 6-H2), 3.76 (s, 3H, CH3O), 4.14 (m, 1H, 12a-H),
6.63 (d, 1H, JZ2.7 Hz, 4-H), 6.70 (dd, 1H, JZ2.7, 8.6 Hz,
2-H), 7.13 (d, 1H, JZ8.6 Hz, 1-H); 13C NMR (100 MHz,
CDCl3): dZ9.3 (C-18), 20.9, 25.8, 29.4, 35.3, 37.4, 37.8,
43.8, 50.7, 51.6 (C-13), 55.2 (H3CO), 61.0 (C-12), 111.7
(C-2), 114.1 (C-4), 126.0 (C-1), 130.2 (C-10), 137.5
(C-5), 157.9 (C-3), 215.8 (C-17); MS (ESI): m/z (%): 341
(100) [MCCNa]; HRMS (ESI): m/z found 341.1278, calcd
C19H23O2ClNa (MCCNa) 341.1287.
This work was supported by the Deutsche Forschungs-
gemeinschaft (Sonderforschungsbereich 436), the
Thuringian Ministerium fu¨r Wissenschaft, Forschung und
Kunst and the Fonds der Chemischen Industrie. We thank
the Schering AG and the Jenapharm GmbH for the gift of
¨
steroids and M. Kotteritzsch for experimental assistance.
References and notes
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CH2Cl2); H NMR (CDCl3): 0.96 (s, 3H, 18-H3), 2.89 (m,
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