Synthesis of 17α-4-amino- and 4-iodophenylestradiols

Article abstract of DOI:10.1016/S0040-4039(00)01238-7

17α-(4-aminophenyl) estradiol 4 was prepared in three steps starting from commercial estrone. The key step is the addition of aryllithium 2 to the carbonyl at C17 on a protected estrone, which is only possible by activation. The adduct 3b can be transform

Full text of DOI:10.1016/S0040-4039(00)01238-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8089–8092
Synthesis of 17a-4-amino- and 4-iodophenylestradiols
Nicolas Foy, Elie Ste´phan* and Ge´rard Jaouen
Laboratoire de chimie organome´tallique-Ecole Nationale Supe´rieure de Chimie et CNRS,
11 rue Pierre et Marie Curie, 75005 Paris, France
Received 15 June 2000; accepted 21 July 2000
Abstract
17a-(4-aminophenyl) estradiol 4 was prepared in three steps starting from commercial estrone. The key
step is the addition of aryllithium 2 to the carbonyl at C17 on a protected estrone, which is only possible
by activation. The adduct 3b can be transformed into 17a-(4-iodophenyl) estradiol 7 by a Sandmeyer-type
reaction with concomitant deprotection. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: arylation; biologically active compounds; lithiation; steroids; triazenes.
We have recently proposed a method to obtain 17a-arylestradiols in yields of 55–80% by the
addition of aryllithiums to a protected estrone at the sterically hindered C17 carbonyl, in the
presence of BF3–Et2O at low temperature.1 A rigid structure of the arene type in the 17a
position does not negatively affect estrogen hormone-receptor recognition2 and we were
particularly interested in preparing compounds substituted on the aromatic ring by amino and
iodo functionalities, which are widely used in coupling and bioconjugation reactions.3 The
present study concerns first of all the synthesis of 17a-(4-aminophenyl)-estradiol 4 (Scheme 1),
Scheme 1.
* Corresponding author. E-mail: stephan@ext.jussieu.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01238-7

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in three steps starting from commercial estrone. We now describe herein the efficient addition
of aryllithium 2 to protected estrones 1, in the presence of TMEDA at low temperature. The
product 3a gives estradiol 4 directly, by deprotecting both the phenol and the amine, in one step.
The synthesis of the aryllithium 2 has been described earlier by Gross.4 This synthesis uses a
halogen–metal exchange during the reaction of the bromo compound 5, the latter being
accessible in one step starting from 4-bromoaniline, with an excess of sec-BuLi (2.2 equiv.), in
ether at −65°C (Scheme 2). We were constrained by the solubility of the steroids to use either
THF or mixtures of solvents (such as THF or ether+toluene). Faced with reproducibility
problems for the addition of the organo-lithium 2 prepared from sec-BuLi, we studied the
exchange with tert-BuLi in an attempt to perturb the equilibrium with 2-tert-BuLi, according to
Corey5 and Seebach.6
Scheme 2.
The exchange shown in Scheme 2 occurs satisfactorily with one equivalent of tert-BuLi, as
1
shown by the H NMR spectrum of the crude reaction product obtained after treatment of the
medium with D2O (D incorporated para to the hydrogen). Using an excess of alkyllithium (2
equiv.) however gives a low rate of incorporation of D into the same position, and leads to side
reactions.
The protected estrones 1a and 1b are easily prepared by standard methods. Estrone benzyl
ether (EBE)7, prepared by reaction of its conjugated base (estrone+1 equiv. KOH) with BnBr (1
equiv.) at room temperature for 24 h in a dioxane/water (90/10) medium, is obtained in a yield
of 88% after crystallization from ether. Tetrahydropyranyl estrone8 is obtained in a yield of 80%
after recrystallization from methanol.
Aryllithium 2 does not react with the estrones 1 unless activated. Activation of aryllithiums
for addition onto the carbonyl of EBE was previously achieved using boron trifluoride, and with
aryllithium 2 the adduct was obtained in 57% yield.1 We also tested the activation by
tetramethylethylenediamine, which gives a comparable yield of 60% (with 3 equiv. TMEDA per
tert-BuLi). The procedure below describes the results obtained under optimal conditions.
Triazene 5 (2.57 g, 10.1 mmol) was dissolved in 150 mL anhydrous THF under an argon
atmosphere. The medium was cooled to −90°C, then 10.1 mmol tert-BuLi (commercial solution
in pentane) were added drop-wise while stirring. The reaction medium was stirred at −90°C for
3.5 h. TMEDA (4.57 mL, 30.3 mmol) was then added, followed by progressive addition of a
solution of 1.3 g estrone benzyl ether (3.6 mmol) in 100 mL THF. Stirring was continued for 1.5
h at low temperature before hydrolysis. The THF was evaporated and the reaction medium
extracted with dichloromethane. The crude product obtained after normal treatment was then
chromatographed on a neutral alumina column using dichloromethane as an eluent. After
evaporation of the solvent, 1.1 g estradiol 3a was obtained as a solid (m.p. 134°C) in 60% yield.
1H NMR (ppm) in CDCl3: 7.4 (m, H arom.); 7.06 (1H, d, H-1); 6.72 (2H, m, H-2 and H-4); 5.02
(2H, s, CH2ꢀPh); 3.8 (4H, m, CH2ꢀN); 1.08 (3H, s, CH3-18).

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The estradiol 3b was prepared (and purified) under similar conditions, starting from estrone
1b. Compound 3b was obtained in 57% yield after chromatography (solid, m.p. 118°C).
1H NMR (ppm) in CDCl3: 7.38 (m, H arom.), 7.08 (d, H-1), 6.79 (m, H-2 and H-4), 5.37 (m,
OꢀCHꢀO), 3.8 (m, CH2ꢀN), 1.08 (s, CH3-18).
Use of an NiꢀAl alloy9 has been proposed for reduction of triazenes to amines. Therefore
hydrogenolysis of the triazene 3a in the presence of an NiꢀAl alloy was tested, however, this did
not give satisfactory results in various solvents. The estradiol 4 was prepared by hydrogenation
of 3a in the presence of palladium on charcoal. Simultaneous debenzylation and reduction of the
triazene function to amine was observed in the methanol–THF solution.
Steroid 3a (0.13 g, 0.24 mmol) was dissolved in a mixture of methanol (10 mL) and THF (3
mL). Pd/C at 10% (0.13 g) was added and the medium hydrogenated under atmospheric
pressure for 21 h. After filtration and evaporation of the solvents, the estradiol 4, crystallized
from a THF/pentane mixture, was obtained in a 67% yield. This is a solid (m.p.=220°C) with
1
low solubility in various solvents. H NMR (ppm) in CD3OD: 7.14 (d, H meta to NH2), 7.0 (d,
H-1), 6.70 (d, H ortho to NH2), 6.44 (m, H-2 and H-4), 1.05 (s, CH3-18).
Hydrogenation of 3a was also carried out in the presence of PdCl2(CH3CN)2, in ethanol/ethyl
acetate (50/50; v/v). The triazene was then reduced selectively since the 3-O-benzyl ether of
17a-(4-aminophenyl) estradiol precipitated in this medium.
Barrio has previously described the halogenation of 1-aryl-3,3-dialkyltriazenes either in an
acid medium10 or in the presence of trimethylsilyl halides.11 The second method was applied to
the steroids 3 in order to obtain the 4-iodophenylated compounds 6 (Scheme 3).
Scheme 3.
The reaction shown above was first carried out with benzylated triazene. The estradiol
formed, 6a has a great tendency to dehydrate with heating. The dehydration can be limited at
room temperature, and 6a was thus obtained in 75% yield after purification by chromatography
on a neutral alumina column.
Hydrogenolysis of the 3-O-benzyl ether of 6a was difficult and deprotection by ethanethiol in
the presence of BF3ꢀetherate12 caused side reactions. The reaction shown in Scheme 3 was
therefore carried out with the tetrahydropyranylated steroid 3b. The Sandmeyer-type reaction is
accompanied by deprotection of the phenol function in situ. In this way 17a-(4-
iodophenyl)estradiol was prepared directly from 3b according to the following method:

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NaI (0.19 g, 1.26 mmol) was dissolved under an argon atmosphere in 1.5 mL acetonitrile,
,
previously dried on a 4 A filter. TMSꢀCl (0.080 mL, 0.63 mmol) was added and the solution
stirred at room temperature for several minutes. A solution of the steroid 3b (0.15 g, 0.28 mmol)
in 9 mL acetonitrile was then added and the mixture stirred for 17 h. After hydrolysis (saturated
NaHCO3) and evaporation of the acetonitrile, the residue was extracted with dichloromethane.
After the usual treatment, the estradiol 7 was obtained as a solid (m.p.>300°C) in 90% yield.
1H NMR (ppm) in DMSO-d6: 8,9 (s, OH), 7.65 (d, H ortho to I), 7.15 (d, H meta to I), 6.89
(d, H-1), 6.4 (m, H-4), 0.95 (s, CH3-18).
In summary, two new 17a-arylestradiols, 4 and 7, have been prepared in three steps starting
from commercial estrone. The key step is the condensation of a protected 4-lithioaniline onto a
protected estrone, either in the presence of BF3ꢀEt2O1, or TMEDA as shown here. The
intermediate triazene can be reduced to an amine or undergo a Sandmeyer-type reaction which
permits access to a 4-iodophenylated estradiol at the 17 position. The compounds 3 undergo a
Sandmeyer-type reaction with trimethylsilyl iodide to give 4-iodophenylated estradiols 6
(Scheme 3). 17a-(4-Iodophenyl) estradiol 7 is obtained by reaction of the tetrahydropyranylated
compound 3b with TMSI prepared in situ by reacting trimethylsilyl chloride with NaI. This
synthesis therefore opens the way to the preparation of an estradiol 7 containing radioactive
iodine, which, using isotopes such as 125I or 131I,11 could be a good candidate for use as a
readily-accessible radiopharmaceutical. To our knowledge, estradiols 4 and 7 have not been
previously described in the literature. Measurements of biological affinity of the newly prepared
estradiols for estradiol receptors are underway.
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