An improved synthesis of 3-aminoestrone

Article abstract of DOI:10.1016/j.tetlet.2005.08.105

An efficient Pd(0)-catalyzed protocol for the rapid and efficient preparation of 3-aminoestrone via 3-benzylaminoestrone from estrone-triflate is described. The three step synthesis proceeds with an overall yield of about 55% using X-Phos as optimal ligan

Full text of DOI:10.1016/j.tetlet.2005.08.105

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7111–7115
An improved synthesis of 3-aminoestrone
Uwe Schon,a,* Josef Messinger,a Monika Buchholz,a Uwe Reinecker,a Hubert Thole,a
¨
Manoj K. S. Prabhub and Ashok Kondab
aSolvay Pharmaceuticals Research Laboratories, Hans-Bo¨ckler-Allee 20, 30173 Hannover, Germany
bResearch Support International Limited, S. V. Road, Majiwada, Thane west 400 607, India
Received 26 July 2005; revised 10 August 2005; accepted 22 August 2005
Abstract—An efficient Pd(0)-catalyzed protocol for the rapid and efficient preparation of 3-aminoestrone via 3-benzylaminoestrone
from estrone–triflate is described. The three step synthesis proceeds with an overall yield of about 55% using X-Phos as optimal
ligand for the Pd(0)-catalyzed Buchwald–Hartwig amination.
Ó 2005 Elsevier Ltd. All rights reserved.
3-Aminoestrone (4), a non-natural C-18 steroid, has
been described as a key intermediate for the synthesis
of biologically active steroid derivatives which can be
used, for example, for the treatment of prostate and
breast cancers.1 Unfortunately, the compound is not
commercially available and the classical and the recent
synthetic methods described so far2–4 have some draw-
backs, such as high reaction temperature, long reaction
time, poor yields, low product purity and high costs.
Thus, we were interested to develop a simple and effi-
cient way to overcome these drawbacks.
efficient pathway starting with estrone–triflate (2). To
introduce the nitrogen atom at position C-3 of estrone,
they used benzophenone imine as a convenient ammonia
equivalent. Their optimized conditions required three
days of reaction time at 120 °C in a Schlenk tube
[estrone–triflate, benzophenone imine, Pd2(dba)3, S(À)-
BI-NAP, Cs2CO3, toluene (74%)] and, finally, by acidic
hydrolysis 3-aminoestrone was isolated in 87% yield.
In 2003, Zhang and Sui reported5 the preparation of
3-aminoestrone by using benzylamine as ammonia
equivalent and slightly modified amination conditions
[Pd(OAc)2, BINAP, and NaO-t-Bu in toluene at 100 °C,
24 h] (Scheme 2). However, the reaction resulted in very
low yield of desired amino derivative (4) (ꢀ15%) with
mostly recovering estrone, generated by the hydrolysis
In two recent publications about the transformation of
estrone (1) into 3-aminoestrone (4), Pd(0)-catalyzed
amination was used as a key reaction. In 2002, as shown
in Scheme 1, Poirier and co-workers4 reported a new
O
O
O
H
H
H
a)
b)
H
H
H
H
H
H
N
O
H2N
87%
74%
O
S
O
CF3
2
3
4
Scheme 1. 3-Aminoestrone synthesis via benzophenone imine. Reagents and conditions: (a) benzophenone imine, Pd2(dba)3, S(À)-BINAP, Cs2CO3,
toluene, Schlenk tube, 120 °C, 3 days; (b) cat. HCl, wet THF, rt.
Keywords: Microwave; Buchwald–Hartwig amination; X-Phos; Palladium; 3-Aminoestrone; Steroids.
*
Corresponding author. Tel.: +49 511 857 2311; fax: +49 511 857 2195; e-mail: uwe.schoen@solvay.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.105

7112
U. Scho¨n et al. / Tetrahedron Letters 46 (2005) 7111–7115
O
O
O
H
H
H
a)
b)
H
H
H
H
H
H
H
N
O
S
H2N
82%
65%
O
O
(CF2)3CF3
5
6
4
Scheme 2. 3-Aminoestrone synthesis via nonaflate. Reagents and conditions: (a) Pd(OAc)2, BINAP, NaO-t-Bu, benzylamine, toluene, 100 °C, 24 h;
(b) H2, Pd/C.
of triflate (2) under alkaline reaction conditions. As a con-
sequence, the authors replaced triflate by the correspond-
ing nonaflate (5) possessing stronger stability toward base
hydrolysis. Finally, 3-aminoestrone (4) was obtained by
hydrogenation of the benzyl-protected amino derivative
(6) in 82% yield.
O
O
H
H
H
H
H
H
H
H
O
N
H
estrone
Scheme 3. Goal optimization.
3-aminoestrone
As we were interested in larger amounts of 3-amino-
estrone for different research programs, we wanted to
improve this method, especially because of the high cost
of CF3(CF2)3SO2F, by using triflic anhydride.
ence of five different phosphine ligands, Cs2CO3 in tolu-
ene at 120 °C for 15 h using benzylamine as a NH2
equivalent (Scheme 4).
In recent years, the Pd(0)-catalyzed amination of aryl
halides, triflates or tosylates (independently developed
by the groups of Buchwald and Hartwig) has been widely
used as methodology of choice for the synthesis of substi-
tuted anilines.6 Thus, given the distinct advantages of
Pd(0)-catalyzed amination reaction, we started a pro-
gram to optimize the reaction conditions for the trans-
formation of estrone–triflate to 3-benzylamino estrone
using different ligands, palladium sources, solvents and
bases at different temperatures. Our experimental results
are presented and discussed below (Scheme 3).
The results of the ligand screening are depicted in Figure 1
and it can be seen that the extent of amination depends
on the ligand used. Of the five ligands screened, the
highest isolated yield was achieved by using X-Phos
(L4) while the other ligands such as BINAP (L2) and
DPPF (L3) gave much lower yields and P(C6H5)3 (L1)
and the bidentate ligand Xantaphos (L5) were observed
to be highly ineffective.
Our work began with the intention to identify the best
phosphine ligand required in the synthesis of 3-benzyl-
amino estrone. In a typical experiment, estrone–triflate
was subjected to Pd(0)-catalyzed amination in the pres-
Recently, Buchwald and co-workers reported that
X-Phos (L4) was an excellent supporting ligand for the
Pd-catalyzed amination of arylbenzene sulfonates as
well. They also reported that the catalyst system based
O
O
H
H
Pd(OAc)2
H
H
H
H
H
N
ligand L
Cs2CO3
O
O
S
O
toluene
120°C
CF3
5
6
Ligands
PPh2
PCy2
i-Pr
PPh2
PPh2
Fe
P
i-Pr
O
PPh2
PPh2
PPh2
i-Pr
L1
L2
L3
L4
L5
Scheme 4. Ligand screening.

U. Scho¨n et al. / Tetrahedron Letters 46 (2005) 7111–7115
7113
Table 3. Effect of ligand amount on palladium-catalyzed amination of
60
50
40
30
20
10
0
estrone–triflate with BnNH2 in toluenea
X-Phos
(mol %)
Pd(OAc)2
(mol %)
Temp
(°C)
Time
(h)
6 (%)b
2 (%)b
5
10
10
10
120
120
15
15
60
74.5
29.4
17.2
a Reagents and conditions: estrone–triflate (1 equiv), BnNH2
(1.1 equiv), Cs2CO3 (1 equiv), Pd(OAc)2 (10 mol %), X-Phos.
b LC yield.
L1
L2
L3
Ligands
L4
L5
As summarized in Table 2, it was found that toluene and
the mixture of toluene/tert-butyl alcohol (5:1) could be
used as appropriate solvent systems, whereas 1,4-diox-
ane gave mainly or exclusively estrone, which might
have been formed by hydrolysis of starting material,
without any traces of the desired product. It may be here
mentioned that similar results are reported for Buch-
wald couplings under microwave-reaction conditions.10
Figure 1. Ligand effect on palladium-catalyzed amination reaction of
estrone–triflate with benzylamine. Estrone–triflate (1 equiv), Cs2CO3
(1 equiv), BnNH2 (1.5 equiv), Pd(OAc)2 (10 mol %), ligand (5 mol %),
toluene, 120 °C, 15 h.
on X-Phos exhibits both dramatically increased activity
and stability relative to those based on simple biaryl
phosphine ligands.7 However, our best results were still
only 60% yield so we proceeded to further optimize the
reaction by varying other parameters, like palladium
source, solvent system, base and temperature.
In order to improve the yield of 6, either increasing
amounts of ligand, palladium or raising temperature
or a longer reaction time are considered. Thus, at first
to ensure higher conversion we repeated the amination
reaction by increasing the amount of X-Phos
(10 mol %, see Table 3) and observed better yields.
The reaction was scaled up to 20 g without yields getting
affected.
As the Pd source has been described to affect the amina-
tion step8 in a crucial way, reactions with two different
Pd sources were investigated and the results are com-
pared in Table 1.
Encouraged by our findings, subsequently, in order to
reduce the reaction time we decided to investigate other
solvents with higher boiling points by comparing ther-
mal heating with microwave-irradiation conditions.
Since the introduction of the high-speed microwave-
assisted synthesis, a lot of publications documented
the rate enhancement under microwave-irradiation
conditions.10 Besides, a better reproducibility often with
higher yields and less side reactions has been observed as
well. Though several reports of microwave-assisted Pd-
catalyzed aryl aminations have appeared in the litera-
ture,11 only recently first results with aryl triflates were
reported.12 In a first stage, we decided to investigate
the stability of estrone–triflate with and without the
presence of Cs2CO3 (see Table 4).
Reactions with both the catalysts successfully gave the
desired product in almost comparable yields (Table 1).
Due to a slightly higher yield and for economical rea-
sons, we decided to use the pre-catalyst Pd(OAc)2 for
further investigations.
We also wanted to explore the different solvent systems
(see Table 2). Toluene and 1,4-dioxane are often used
for aryl amination, while the mixture of toluene/tert-
butyl alcohol has been used for the amination of aryl
sulfonates.9
Table 1. Pd source effects on palladium-catalyzed amination reaction
a
of estrone–triflate with BnNH2
As given in Table 4, up to 160 °C estrone–triflate is sta-
ble within the solvents investigated. But, in the presence
of Cs2CO3 at temperatures higher than 100 °C, the
hydrolysis cannot be avoided. Finally, in DMF and
DMSO within 30 min at 160 °C estrone–triflate is com-
pletely hydrolyzed to estrone, whereas in NMP, 82%
of hydrolysis product formation is observed and 17%
of the starting material remain unreacted.
Entry
Pd source
Yieldb (%)
1
2
Pd2(dba)3
Pd(OAc)2
54.1
60.0
a Reagents: estrone–triflate (1 equiv), BnNH2 (1.1 equiv), Cs2CO3
(1 equiv), Pd(0) (10 mol %), ligand X-Phos (5 mol %), toluene at
120°C for 15 h in a sealed tube.
b Isolated yield.
a
Table 2. Solvent effect on palladium-catalyzed amination of estrone–triflate with BnNH2
Solvent
Productb 6 (%)
Triflateb 2 (%, recovered)
Estroneb (%)
Conditions (°C; h)
Toluene
Toluene/t-BuOH (5/1)
1,4-Dioxane
60
68.4
29.4
24.4
120; 15
120; 15
100; 6
3.4
100
a Reagents: estrone–triflate (1 equiv), BnNH2 (1.1 equiv), Cs2CO3 (1 equiv), Pd(OAc)2 (10 mol %), X-Phos (5 mol %).
b Isolated and LC data.

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U. Scho¨n et al. / Tetrahedron Letters 46 (2005) 7111–7115
Table 4. Aminoestrone synthesis: temperature and solvent effects
BnNH2 were varied to optimize the reaction conditions.
Finally, heating of triflate 5 at 160 °C for 10 min with
1.1 equiv of BnNH2, 5 mol % of X-Phos and 1 mol %
of Pd(OAc)2 are observed as optimized conditions. With
these data in hand, as mentioned above the Buchwald
reaction has been performed under thermal conditions
as well, yielding 78% of isolated amino benzyl estrone
6.14
under thermal conditionsa
Solvent Cs2CO3 Temp Time Triflate Estrone Impurity
(°C)
(h)
(%)
(%)
Toluene No
Toluene Yes
DMSO No
DMSO Yes
DMSO Yes
120
120
100
100
160
160
160
100
100
160
16
100
92.8
98
3.7
4.2
100
0
100
20.4
17.2
0
5.8
2
91.3
93.9
0
87.7
0
0
1.3
0
5
0.9
0
12.3
0
11.6
0.7
16
16
0.5
0.5
16
0.5
16
3
DMF
DMF
NMP
NMP
NMP
No
Yes
No
Yes
Yes
In addition, we explored the use of other bases under
microwave-irradiation conditions, such as K2CO3,
KO-t-Bu, Et3N and K3PO4. But, by using K2CO3 and
KO-t-Bu, we observed the formation of only traces of
product and by using Et3N estrone–triflate did not yield
formation of any product.
68
82.0
0.5
a Reactions performed in sealed tubes. LC–MS data.
To summarize, we have developed two different
approaches for the Pd(0)-catalyzed aminations of
estrone–triflate. The reaction can be carried out either
in toluene or toluene/tert-butanol (5:1) as a solvent
mixture at 120 °C for 15 h or the reaction time can be
reduced dramatically by using DMF as solvent at
160 °C for 10 min only.
Nevertheless, we replaced toluene by DMF in order to
investigate the Pd(0)-catalyzed amination in another sol-
vent at 160 °C. To our surprise, in contrast to the above
mentioned complete hydrolysis of estrone in DMF, we
observed the formation of benzylaminoestrone in good
yields. (Reaction conditions: estrone–triflate (1 equiv),
BnNH2 (1.1 equiv), Cs2CO3 (1 equiv), Pd(OAc)2
(1 mol %), X-Phos (5 mol %) at 160 °C in 10 min, yield
78%.) Obviously, the reactivity of benzylamine at
160 °C is higher than the rate of hydrolysis.
With these optimized conditions for the palladium-cata-
lyzed amination and subsequent hydrogenation, es-
trone–triflate 5 gives the desired 3-aminoestrone 6 with
an overall yield of about 55% (see Scheme 6).14,15
Encouraged by these results, we decided to optimize the
reaction conditions in DMF under microwave-irradia-
tion conditions too (Scheme 5).13 The results are sum-
marized in Table 5.
In conclusion, we have developed a convenient protocol
for the rapid and efficient preparation of 3-aminoestrone
via 3-benzylaminoestrone from estrone–triflate. We
developed a new methodology which is advantageous
over reported methods. Previously described processes
either needed long reaction hours or expensive reagents
By increasing the temperature to 160 °C within 30 min,
the reaction went to completion. Furthermore, the reac-
tion time and the equivalents of Pd(OAc)2, X-Phos and
O
O
H
Pd(OAc)2
microwave
H
H
H
N
H
H
H
H
H
+
N
O
X-Phos
Cs2CO3
O
S
O
CF3
solvent
120°C-160°C
5
6
Scheme 5. Microwave-assisted palladium-catalyzed amination.
Table 5. Optimization of palladium-catalyzed amination of estrone–triflate with BnNH2 under microwave-irradiation conditionsa
BnNH2 (equiv)
X-Phos (mol %)
Pd(OAc)2 (mol %)
Solvent
Temp (°C)
Time
6b (%)
1.5
1.5
1.5
1.5
1.5
1.1
10
10
10
10
10
5
10
10
10
2
10
1
Toluene
Toluene
DMF
DMF
DMF
120
120
160
160
160
160
15 h
74c
51d
97
94
93
0.5 h
0.5 h
0.5 h
5 min
10 min
DMF
93
a Reagents and conditions: estrone–triflate (1 equiv), BnNH2, Cs2CO3 (1 equiv), Pd(OAc)2, X-Phos.
b LC–MS yield.
c Conventional heating in sealed tubes; same conditions as mentioned before.
d Reaction incomplete, 49% starting material left.

U. Scho¨n et al. / Tetrahedron Letters 46 (2005) 7111–7115
7115
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O
O
7. Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 13978–13980.
8. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65,
1144–1157.
9. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653–
6655.
10. For reviews, see: (a) Kappe, C. O.; Stadler, A. Microwaves
in Organic and Medicinal Chemistry; Wiley-VCH, 2005; (b)
Microwave Assisted Organic Synthesis; Tierney, J. P.,
Lidstro¨m, P., Eds.; Blackwell, 2005; (c) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (d) Kappe,
C. O. Curr. Opin. Chem. Biol. 2002, 6, 314–320; (e)
Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH, 2002.
H
H
a
H
H
H
H
O
S
H
O
CF3
O
2
1
O
b or c
O
O
H
H
H
d
H
H
H
H
H
6
N
4
N
H
11. (a) Weigand, K.; Pelka, S. Mol. Divers. 2003, 7, 181–184;
(b) Maes, B. U. W.; Loones, K. T. J.; Lemiere, G. L. F.;
Dommisse, R. A. Synlett 2003, 1822–1825; (c) Wan, Y.;
Alterman, M.; Hallberg, A. Synthesis 2002, 1597–1600.
12. Jensen, T. A.; Liang, X.; Tanner, D.; Skjaerbaek, N.
J. Org. Chem. 2004, 69, 4938–4947.
Scheme 6. Improved synthesis of 3-aminoestrone. Reagents and
conditions: (a) Tf2O, Et3N, DCM, 0 °C (90–94% yield); (b) estrone–
triflate (1 equiv), BnNH2 (1.5 equiv), Pd(OAc)2 (10 mol %), X-Phos
(10 mol %), Cs2CO3 (1 equiv), toluene, 120 °C, 15 h (74% yield); or
estrone–triflate (1 equiv), BnNH2 (1.1 equiv), Cs2CO3 (1 equiv),
Pd(OAc)2 (1 mol %), X-Phos (5 mol %), DMF, 160 °C, 10 min (yield
78%); (c) BnNH2 (1.1 equiv), Pd(OAc)2 or Pd2(dba)3 (1 mol %), X-
Phos (5 mol %), Cs2CO3 (1 equiv) DMF under MW conditions, 160 °C
in 10 min (93%); (d) methanol:THF (1:1), acetic acid (1%), 10%
palladium over carbon (20% w/w), 55 psi, 30 °C, 6 h (76% yield).
13. EmrysTM Optimizer from Biotage (formerly Personal
Chemistry) was used for all experiments described here
(power 300 W).
14. Typical procedure for Pd(0)-catalyzed amination of
estrone–triflate 5: initially, pre-catalyst was prepared by
heating palladium acetate (55 mg, 10 mol %), cesium
carbonate (0.806 g, 2.4 mmol), X-Phos (118 mg,
10 mol %) and benzylamine (0.298 ml, 2.73 mmol) in
DMF (7.5 mL) in a sealed tube under nitrogen gas
atmosphere at 70 °C for 10 min and cooled to rt. Then,
the triflate 5 (1 g, 2.48 mmol) was dissolved in DMF
(2.5 mL) and charged into the tube, purged with nitrogen
and heated at 160 °C for 10 min. The reaction mixture was
cooled to rt, filtered through a pad of Celite, poured into
water (100 mL) and extracted with dichloromethane
(50 mL). Organic layer was washed with saturated brine
solution (30 mL) and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure
to get the crude product which was purified on column
chromatography using DCM/n-hexane (60:40) to yield the
desired product 6 as colourless solid (0.7 g, 78%), mp 136–
138 °C. Mass spectrum: m/e: 360.2 (MH+). 1H NMR
(200 MHz, CDCl3): d 7.35–6.39 (m, 8H, aromatic), 4.31 (s,
2H, benzylic), 3.00–1.26 (m, 15H, steroid envelope) and
0.91 (s, 3H, C18-CH3).
to prepare 3-aminoestrone, our method gives the product
in very short reaction times (10 min), in good yields. This
compound is not only prepared through conventional
heating conditions but also can be synthesized under
microwave-irradiation conditions in quantitative yield.
Acknowledgements
We thank Dr. Milind Joshi for analytical support, as
well as Manfred Buckendahl, Ute Kluge and Jurgen
¨
Fasterding for technical support.
References and notes
´
15. 3-Aminoestra-1,3,5(10)-trien-17-one 4: the benzylamino
derivative 6 (20 g, 55.7 mmol) was hydrogenated over 10%
palladium over carbon (4 g) in a methanol/tetrahydro-
furan mixture (100 mL each) containing 1% acetic acid for
6 h at 55 psi at ambient temperature in Parr hydrogenator.
The catalyst was filtered over Celite bed and the solvent
mixture was removed under reduced pressure. The prod-
uct was purified on silica gel (230–400 mesh) column
chromatography using ethyl acetate/n-hexane (5:95) as
eluent affording the product in tan crystals form in 11.4 g
(76%) quantity, mp 199–200 °C. The characteristics of 3-
aminoestrone are identical to those reported in the
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1
literature.16 Mass spectrum: m/e: 271 (MH2+). H NMR
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3.47–1.39 (m, 15H, steroid envelope) and 0.83 (s, 3H, C18–
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