Synthesis of 16-E-([aryl]idene)-3-methoxy-estrones by a palladium catalysed Mizoroki-Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2017.06.002

16-E-Arylidene-3-methoxy-estrones were synthesized using a palladium catalysed Mizoroki-Heck reaction. This methodology tolerates various functional groups and gives the corresponding products in yields between 14 and 99%, which were strongly dependent on the electronic character of the aryl halides.

Full text of DOI:10.1016/j.tetlet.2017.06.002

Accepted Manuscript
Synthesis of 16-E-([aryl]idene)-3-methoxy-estrones by a Palladium catalysed
Mizoroki-Heck reaction
Steffen Riebe, Stefan Jopp, Peter Ehlers, Eva Frank, Gyula Schneider, János
Wölfling, Alexander Villinger, Peter Langer
PII:
S0040-4039(17)30712-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.002
TETL 48994
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 April 2017
30 May 2017
1 June 2017
Please cite this article as: Riebe, S., Jopp, S., Ehlers, P., Frank, E., Schneider, G., Wölfling, J., Villinger, A., Langer,
P., Synthesis of 16-E-([aryl]idene)-3-methoxy-estrones by a Palladium catalysed Mizoroki-Heck reaction,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.002
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2
Graphical Abstract
Synthesis of 16-E-([aryl]idene)-3-methoxy-estrones
Leave this area blank for abstract info.
by a Palladium catalysed Mizoroki-Heck reaction
Steffen Riebea, Stefan Joppa, Peter Ehlersa,b, Eva Frankc, Gyula Schneiderc, János Wölflingc,
Alexander Villingera, Peter Langer*a,b
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany;
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany;
c Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
Peter.langer@uni-rostock.de
O
O
Me
Me
Br
1.25 mol%
Pd(PPh3)4
H
H
+
DMF, 140 °C, 8 h
H
H
H
H
R
MeO
MeO
R
16 examples
14-99% yield

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of 16-E-([aryl]idene)-3-methoxy-estrones by a Palladium catalysed
Mizoroki-Heck reaction
Steffen Riebea, Stefan Joppa, Peter Ehlersa,b, Eva Frankc, Gyula Schneiderc, János Wölflingc, Alexander
Villingera, Peter Langer*a,b
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany;
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany;
c Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
peter.langer@uni-rostock.de; +49 (0)381/498-6410
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
16-E-Arylidene-3-methoxy-estrones were synthesized using a palladium catalysed Mizoroki-Heck
reaction. This methodology tolerates various functional groups and gives the corresponding products
in yields between 14 and 99%, which were strongly dependent on the electronic character of the aryl
halides.
Available online
Keywords:
Steroids
Palladium
Cross-Coupling
Heck-reaction
Estrogenic hormones have been recognized as important contributors of
estrogen dependent diseases.1 Thus, derivatisation of estrone derivatives at
various positions has been the focus of intensive research for potential
pharmaceutical applications.2 Functionalised estrones have been mainly
employed as inhibitors of estrogenic receptors or imaging agents in the
treatment of breast cancer.3 In particular, the majority of breast cancers are
primary initiated and stimulated by estrogenes. Especially, estradiol is known
to play a crucial role as a growth factor of such tumor cells.3,4
previously been studied by other groups and has been most famously applied
by Tietze and co-workers in the synthesis of enantiopure estrone.8
16-Methylene-3-methoxy-estrone
2 was synthesized from commercially
available 3-methoxyestrone by a literature procedure (Scheme 1).9 Next, the
Mizoroki-Heck reaction was tested using phenyl bromide under different
catalytic reaction conditions using DMF as solvent in the presence of NEt3 as
the base (Table 1). It became obvious that Pd(PPh3)4 was a suitable catalyst
for this reaction, while the more sterically encumbered and electron-rich
ligands PtBu3·HBF4 and XPhos gave lower yields. We were also able to
reduce the catalyst loading to 1.25 mol% which gave even higher yields than
the use of 5 mol%.
Several D-ring alkylated estrones display high affinity towards estrogenic
receptors and could block the biosynthesis of estrondiol and other estrogenes,
leading to
a depletion of the circulation and tissue concentration of
estrogenes.5 Recently, 16-arylidene estrones have been employed in the
synthesis of several bioactive compounds which show antiproliferative
activity against human cancer cells.6 Thus, the synthesis of new
antiestrogenes, which influence cell growth of estrogen receptor related
tumors, is of considerable current interest. As part of our ongoing interest in
the palladium catalysed functionalisation of estrone, we studied the synthesis
of 16-benzylidene-3-methoxy-estrones using the Mizoroki-Heck reaction.7
The Mizoroki-Heck reaction of non-steroid exo-methylene compounds has
O
O
Me
H
Me
H
O
Me
H
OH
H
H
i
H
ii
H
H
H
MeO
MeO
MeO
1
2
3
Scheme 1. Synthesis of starting material 3; i: 1, NaOMe (4 eq.), ethyl formate
(30 eq.), benzene, reflux, 4 h; ii: 2, formaldehyde (4 eq.), pyridine, r.t., 24 h

2
O
O
Me
H
Me
H
H
H
CF3
H
H
CF3
Table 1. Optimisation of the Mizoroki-Heck reactiona
MeO
MeO
MeO
MeO
4c (15%)
mp 150-151°C
4d (38%)
mp 81-82°C
O
O
Me
Me
H
O
O
Me
Me
H
Br
H
H
i
H
H
H
H
H
+
Me
H
H
H
MeO
MeO
MeO
OMe
OMe
4e (99%)
mp 97-98°C
4f (17%)
mp 101-102°C
3
4a
O
O
Me
H
Me
Entry
Catalyst [mol%]
Pd(OAc)2 [5]
Ligand [mol%]
Yielda (%)
H
1
2
3
4
5
6
XPhos [10]
74
70
90
90
96
88
72
H
H
H
H
OMe
MeO
Pd(OAc)2 [5]
PtBu3·HBF4 [10]
4g (70%)
mp 138-139°C
4h (24%)
mp 127-128°C
Pd(PPh3)4 [5]
-
-
-
-
-
O
O
Pd(PPh3)4 [2.5]
Pd(PPh3)4 [1.25]
Pd(PPh3)4 [0.63]
Pd(PPh3)4 [0.31]
Me
Me
H
H
H
H
H
H
MeO
MeO
NO2
4j (58%)b
4i (86%)
mp 124-125°C
7
a
O
O
Isolated yield; Reagents and conditions i: catalyst, ligand, DMF (4 mL),
Me
Me
H
H
NEt3 (0.5 mL), 3 (0.5 mmol), PhBr (0.75 mmol), 140 °C, 8 h
H
H
H
H
MeO
MeO
NMe2
CN
With our optimized conditions in hand, we started to examine the scope of the
reaction.10 Several aryl bromides could be successfully employed to give the
desired products 4a-p in 14-96% yield (Table 2). In all cases, the E-isomers
were formed selectively. It should be noted that, while compounds 4a, 4j, 4k
and 4l have previously been synthesized via aldol condensation, these
reactions usually require highly alkaline conditions and thus result in low E-
selectivity.11 A broad range of functional groups were tolerated, including
nitro, cyano, and acetyl groups, as well as heterocyclic starting materials. The
yields were found to be strongly dependent on the substitution patterns. In
general, electron poor aryl bromides gave higher yields than electron rich
substrates. Aryl halides containing electron donating groups in the ortho or
para positions (e.g. methoxy) resulted in a decreased yield. The presence of
such a group in the meta position was no problem and resulted in a good yield
(70%). Interesting, sterically hindered 1-bromonaphthalene gave an excellent
86% yield. Practical aspects, such as isolation of the product from by-
products by column chromatography, also played an important role. In some
cases, the separation from by-products was difficult and resulted in a loss of
material. The use of aryl iodides or triflates did not result in an improvement
of the yield.
4k (33%)b
Me
4l (14%)b
Me
O
O
H
H
H
H
H
H
MeO
MeO
Me
F
4m (51%)
mp 127-128°C
4n (39%)
mp 172-173°C
O
O
O
Me
Me
H
H
S
H
H
H
H
MeO
MeO
N
4p (27%)
mp 167-168°C
4o (72%)
mp 203-204°C
a
Reagents and conditions i: Pd(PPh3)4 (1.25 mol%), 3 (0.5 mmol) ArBr (1.5
b
eq.), DMF (4 mL), NEt3 (0.5 mL), 140 °C, 8 h; Isolated yield; Known
compound.11a,11b
The structures of compounds 4a, 4n and 4p were independently confirmed by
single crystal X-ray structural analyses (Fig. 1-3).12 The structures clearly
show the E-configuration of the exocyclic double bond in all cases, using
electronically different substituents (phenyl, 4-fluorophenyl, 2-thienyl).
Table 2. Mizoroki-Heck reaction of 3a
O
O
Me
H
Me
H
H
i
H
Ar Br
+
Ar
H
H
MeO
MeO
3
4a-p
O
O
Me
H
Me
H
H
Figure 1. ORTEP plot of compound 4a.
H
H
H
MeO
MeO
CF3
4a (96%)b
4b (40%)
mp 89-90°C

3
Org. Chem. 1981, 46, 3259-3262; (g) T. L. Fevig, J. A.
Katzenellenbogen J. Org. Chem. 1987, 52, 247-251.
4.
5.
P. Tapolcsányi, J. Wölfling, G. Falkay, Á. Márki, R. Minorics, G.
Schneider Steroids 2002, 67, 371-377.
(a) R. M. Mohareb, F. Al-Omran, R. A. Azzam Steroids 2014, 84,
46-56; (b) I. V. Zavarzin, Y. S. Antonov, E. I. Chernoburova, M. A.
Shchetinina, N. G. Kolotyrkina, A. S. Shashkov Russ. Chem. Bull.
Int. Ed. 2013, 62, 2603-2608; (c) G. M. Allan, H. R. Lawrence, J.
Cornet, C. Bubert, D. S. Fischer, N. Vicker, A. Smith, H. J. Tutill, A.
Purohit, J. M. Day, M. F: Mahon, M. J. Reed, B. V. L. Potter J. Med.
Chem. 2006, 49, 1325-1345.
Figure 2. ORTEP plot of compound 4n.
6.
(a) A-González, L. A. Mendez-Delgado, P. Merino-Montiel, J. M.
Padrón, S. Montiel-Smith, J. L. Vega-Báez, S. Meza-Reyes Steroids
2016, 116, 13-19; (b) R. Maltais, A. Trottier, A. Delhomme, X.
Barbeau, P. La güe, D. Poirier Eur. J. Med. Chem. 2015, 93, 470-
480; (c) R. Maltais, A. Trottier, X. Barbeau, P. Lagüem M. Perreault,
J.-F. Thériault, S.-X. Lin, D. Poirier J. Steroid Biochem. Mol. Biol.
2016, 161, 24-35; (d) Y. Laplante, C. Cadot, M.-A. Fournier, D.
Poirier Bioorg. Med. Chem. 2008, 16, 1849-1860.
7.
8.
(a) A. Ivanov, S. A. Ejaz, S. J. A. Shah, P. Ehlers, A. Villinger, E.
Frank, G. Schneider, J. Wölfling, J. Iqbal, P. Langer Bioorg. Med.
Chem. 2017, 25, 949-962; (b) A. Ivanov, S. Boldt, Z. un Nisa, S. J.
A.Shah, P. Ehlers, A. Villinger, G. Schneider, J. Wölfling, Q.
Raman, J. Iqbal, P. Langer RSC Adv. 2016, 6, 11118-11127.
(a) A. Arcadi, M. Chiarini, F. Marinelli, Z. Berente, L. Kollàr Org.
Lett. 2000, 2, 69-72; (b) A. Arcadi, M. Chiarini, F. Marinelli, Z.
Berente, L. Kollàr Eur. J. Org. Chem. 2001, 16, 3165-3173; (c) S. H.
Kim, K. H. Kim, H. J. Lee, J. N. Kim Tetrahedron Lett. 2013, 54,
329-334; (d) Y.-H. Ding, H.-X. Fan, J. Long, Q. Zhang, Y. Chen
Bioorg. Med. Chem. Lett. 2013, 23, 6087-6092; (e) B. Schmidt, F.
Wolf, C. Ehlert J. Org. Chem 2016, 81, 11235-11249; (f) L. F.
Tietze, T. Nöbel, M. Spescha J. Am. Chem. Soc. 1998, 120, 8971-
8977.
Figure 3. ORTEP plot of compound 4p.
In conclusion, we have developed a new method for the synthesis of 16-
benzylidene-3-methoxy-estrones using the Mizoroki-Heck reaction.
Advantageously, the reaction can be performed with relatively low catalyst
loading of Pd(PPh3)4, tolerates a wide range of functional groups and gives
exclusively the E-configured products.
Acknowledgment. Financial support from the State of Mecklenburg-
Vorpommern and from the Hungarian National Research, Development and
Innovation Office (K113150) and by the State of Mecklenburg-Vorpommern
is gratefully acknowledged.
9.
G. Schneider, I. Vincze, L. Hackler, G. Bombi Synthesis 1983, 665-
669.
10.
General synthetic procedure. 3-Methoxy-16-methylene-estra-
1,3,5(10)-triene-17-one 1 (1 equiv.) and Pd(PPh3)4 (1.25 mol%) were
dissolved in dry DMF (4 mL) and NEt3 (0.5 mL) in a glass tube,
followed by the aryl bromide (1.5 equiv.). The tube was sealed and
stirred at 140 °C for 8 h. Afterwards, water (5 mL) was added and
extracted using CH2Cl2 (3 x 5 mL). The combined organic layers
were dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The crude product was purified by column chromatography
using heptane/ethyl acetate.
References
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16-E-(Benzylidene)-3-methoxy-1,3,5 (10)-estratriene-17-one (4a):
colourless solid; (Hep/EA; 6/1), (180.2 mg, 96%); Rf (Hep/EA;
6/1) = 0.35. mp. 175-176 °C. 1H NMR (250 MHz, CDCl3) δ = 7.59
(a) O. A. Akanni, B. A. Marples Steroids 1993, 58, 234-238; (b) A.
Takadate, J. Fishman J. Org. Chem. 1979, 44, 67-71; c) E.R: Clark,
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(d, 4J = 1.4 Hz, 1H,
Ar), 7.56 (bs, 1H, C=C-H), 7.52–7.31 (m,
4H, Ar), 7.23 (d, 3J = 8.6 Hz, 1H, Ar), 6.74 (dd, 3J = 8.6 Hz,
4J = 2.6 Hz, 1H, Ar), 6.67 (bs, 1H, Ar), 3.79 (s, 3H, OMe), 3.10–
2.85 (m, 3H), 2.65–2.23 (m, 3H), 2.19–1.98 (m, 2H), 1.83–1.45 (m,
5H), 1.01 (s, 3H, CH3). 13C NMR (63 MHz, CDCl3) δ = 209.58
(C=O), 157.63 (C-OMe), 137.66 (C), 136.01 (C), 135.63 (C), 133.17
(CH), 132.06 (C), 130.31 (CH), 129.23 (CH), 128.68 (CH), 126.28
(CH), 113.91 (CH), 111.58 (CH), 55.20 (OMe), 48.58 (CH), 47.82
(C), 44.04 (CH), 37.98 (CH), 31.69 (CH2), 29.64 (CH2), 29.13
(CH2), 26.84 (CH2), 25.97 (CH2), 14.55 (CH3). IR (ATR, cm-1):
ṽ = 3061 (w), 3029 (w), 2976 (w), 2920 (m), 2897 (w), 2881 (w),
2858 (w), 2842 (m), 2817 (w), 1709 (s), 1682 (w), 1651 (w), 1624
(s), 1608 (s), 1583 (m) 1572 (m), 1557 (w), 1538 (w), 1502 (s), 1465
(a) F: B. González, G. Neef, U. Eder, R. Wiechert, E. Schillinger, Y.
Nishino Steroids 1982, 40, 171-187; (b) A. C. Stalford, J. L. Maggs,
T. L. Gilchrist, K. Park Steroids 1997, 62, 750-761; (c) S. D. Jonson,
D. A. d’Avignon, J. A. Katzenellenbogen, M. J. Welch Steroids
1998, 63, 470-478; (d) A. C. Stalford, J. L. Maggs, T. L. Gilchrist, B.
K. Park Steroids 1997, 62, 750-761; (e) V. Perron, D. Rabouin, E.
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4
(m), 1447 (s), 1377 (m), 1340 (m), 1334 (m), 1316 (m), 1296 (m),
1286 (m), 1246 (s), 1234 (s), 1186 (s), 1165 (m), 1116 (m), 1101
(m), 1088(s), 1074 (m), 1051 (m), 1033 (s), 1019 (m), 1001 (m), 992
(m), 970 (m), 943 (s), 924 (w), 906 (s), 864 (s), 844 (m), 822 (s), 788
(m), 772 (s), 745 (m), 686 (s), 630 (m), 614 (m), 588 (m), 566 (s),
540 (m). MS (EI, 70 eV): m/z (%) = 373 (29), 372 (M+, 100), 228
(20), 227 (84), 186 (16), 174 (22), 160 (20), 116 (88), 115 (55), 91
(30). HRMS (EI): calculated C26H28O2 ([M]+) 372.208, found
372.208.
12.
CCDC-1550963, 1550964 and 1550965 contain supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
11.
(a) J. C. Touchstone, W. H. Elliot, S. A. Thayer, E. A. Doisy J. Am.
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Leclercq Indian J. Chem., Sect. B 2003, 42, 166-172.

5
-
-
First Pd catalyzed Heck reactions of steroids
Synthesis of various 16-E-Arylidene-3-
methoxy-estrones
-
High E-selectivity