Pd-catalyzed reaction of sterically hindered hydrazones with aryl halides: Synthesis of tetra-substituted olefins related to iso-combretastatin A4

Article abstract of DOI:10.1021/ol101639g

PdCl₂(MeCN)₂ in combination with dppp proved to be a powerful and efficient catalyst for the coupling of sterically hindered N-arylsulfonylhydrazones with aryl halides, thus providing a flexible and convergent access to tetrasubstituted olefins related to iso-combretastatin A4 in good yields. This new protocol has been applied successfully to the formal synthesis of biphenylisopropylidene 4-pyridine CYP17 inhibitor, 12b, of biological interest.

Full text of DOI:10.1021/ol101639g

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4042-4045
Pd-Catalyzed Reaction of Sterically
Hindered Hydrazones with Aryl Halides:
Synthesis of Tetra-Substituted Olefins
Related to iso-Combretastatin A4
Etienne Brachet, Abdallah Hamze,* Jean-Franc¸ois Peyrat, Jean-Daniel Brion, and
Mouad Alami*
UniVersity Paris-Sud 11, CNRS, BioCIS UMR 8076, Laboratoire de Chimie
The´rapeutique, Faculte´ de Pharmacie, 5 rue J.-B. Cle´ment, Chaˆtenay-Malabry
F-92296, France
mouad.alami@u-psud.fr; abdallah.hamze@u-psud.fr
Received July 15, 2010
ABSTRACT
PdCl2(MeCN)2 in combination with dppp proved to be a powerful and efficient catalyst for the coupling of sterically hindered
N-arylsulfonylhydrazones with aryl halides, thus providing a flexible and convergent access to tetrasubstituted olefins related to iso-combretastatin
A4 in good yields. This new protocol has been applied successfully to the formal synthesis of biphenylisopropylidene 4-pyridine CYP17
inhibitor, 12b, of biological interest.
Several colchicine site inhibitors (CSI) are undergoing
intensive investigation as vascular disrupting agents for
cancer therapy.1 Among them, the natural Z-stilbene com-
bretastatin A-42 (CA-4, 1) became one of the most interesting
antitubulin agents because it displays strong cell growth
inhibition even on multidrug-resistant cancer cell lines.3 In
addition, CA-4 induces rapid and reversible vascular shut-
down in established tumors in ViVo, consistent with an
antivascular mechanism of action.4 Currently, its water-
soluble prodrug CA-4P is undergoing several advanced
clinical trials for the treatment of anaplastic thyroid cancer.5
Despite its remarkable anticancer activity, the cis config-
uration of CA-4 is prone to isomerize to the thermodynami-
cally more stable trans form during storage and administra-
tion, producing a dramatic reduction in both antitubulin and
antiproliferative activities.6 Thus, to retain the cis-olefin
configuration of CA-4 required for bioactivity, extensive
studies have been conducted to prepare cis-restricted ana-
logues by incorporating the double bond in five-membered
aromatic heterocyclic rings.7
(1) Prinz, H. Exp. ReV. Anticancer Ther. 2002, 2, 695.
(2) (a) Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts, D. S.;
Garcia-Kendall, D. Experentia 1989, 45, 209. (b) Pettit, G. R.; Singh, S. B.;
Niven, M. L.; Hamel, E.; Schmidt, J. M. J. Nat. Prod. 1987, 50, 119. (c)
Hill, S. A.; Tozer, G. M.; Pettit, G. R.; Chaplin, D. J. Anticancer Res. 2002,
22, 1453. (d) Eloff, J. N.; Katerere, D. R.; McGaw, L. J. J. Ethnopharmacol.
2008, 119, 686.
Our interest in the 1,1-diarylethylene unit synthesis,8
combined with our efforts to discover novel potent tubulin
assembly inhibitors related to CA-4,9 led us to identify a
promising class of compounds (e.g., isoCA-4), with strong
(3) McGown, A. T.; Fox, B. W. Cancer Chemother. Pharmacol. 1990,
26, 79.
(5) Lippert, J. W. Bioorg. Med. Chem. 2007, 15, 605.
(6) Cushman, M.; Nagarathnam, D.; Gopal, D.; Chakraborti, A. K.; Lin,
C. M.; Hamel, E. J. Med. Chem. 1991, 34, 2579.
(4) Dark, G. G.; Hill, S. A.; Prise, V. E.; Tozer, G. M.; Pettit, G. R.;
Chaplin, D. J. Cancer Res. 1997, 57, 1829.
10.1021/ol101639g  2010 American Chemical Society
Published on Web 08/19/2010

catalyzed coupling of aryl halides with N-tosylhydrazones10
because these latter are readily available from the corre-
sponding ketones and the reaction did not require the use of
stoichiometric organometallic reagent. Although this proce-
dure, initially developed by Barluenga et al.,10 proved to be
successful for the preparation of iso-combretastatins A-1 to
A-5,9d to the best of our knowledge it was examined only
for the synthesis of di- and trisubstituted olefins.11 The
purpose of this work was to explore the reaction of sterically
hindered arylsulfonylhydrazones of ketones 7 with aryl
halides to provide targeted tetra-substituted olefins of type
5 and 6 related to isoCA-4.
The reaction of sterically hindered tosylhydrazone 7a with
4-iodoanisole was first examined under the conditions
described by Barluenga (Pd2dba3/Xphos, LiOtBu, dioxane,
90 °C).10a However, this transformation was inefficient and
resulted in concomitant formation of the desired compound
9a and byproduct trisubstituted olefin 10a in a 30/70 ratio
(Table 1, entry 1). After a tedious separation, 9a was isolated
in a low 15% yield. In this context, to circumvent the
formation of byproduct 10a, arising by thermal decomposi-
tion of 7a under alkaline media,12 we proceeded to optimize
the reaction.
The screening conditions revealed that the source of pal-
ladium13 used has an important influence on the reaction
selectivity (entries 1-5). We were delighted to find that the
use of PdCl2(MeCN)2 as the catalyst reversed the selectivity
obtained with Pd2dba3 (compare entries 1 and 5), providing thus
the desired compound 9a as the major product. The screening
reactions were continued with respect to the ligand, solvent,
and base. Evaluation of ligands revealed that dppp (L7) or dppb
(L8) in combination with PdCl2(MeCN)2 in dioxane at 90 °C
is superior to all other choices (entries 5-13). Use of other
diphenylphosphino-based ligands such as dppm (L5) or dppe
(L6) leads to a decrease in the formation of 9a (entries 10 and
11). With PdCl2(MeCN)2/dppp as the catalytic system, optimi-
zation with respect to the solvent showed that the reaction
proceeds more efficiently in a polar solvent such as dioxane,
dimethylacetamide or 1,2-dimethoxyethane (entries 13, 16, and
17) than in nonpolar solvent (entry 14). The influence of the
inorganic base was finally investigated. KOtBu and NaOtBu
afforded poor results in comparison to LiOtBu (entries 18, 19);
however, we were pleased to find that Cs2CO3 seems to be the
base of choice for this reaction and to exceed the threshold of
90% of the desired product 9a (entry 20, 9a/10a 91:9 ratio).
Under these conditions, pure compound 9a was obtained in an
Figure 1. Structure of CA4, isoCA-4, synthetic tubulin assembly
inhibitors 3, 4, and target structures 5, 6.
cytotoxic and antimitotic activities, simply by switching the
trimethoxyphenyl moiety from the C(1) to the C(2) position
of the ethylene bridge. In contrast to the parent natural
product 1, the double bond of isoCA-4 is not prone to
isomerization (Figure 1). Bioisosteric replacement was
successfully extended to compounds 3 and 4 having a tri-
or tetra-substituted double bond.9d In this article, we recon-
figured the substitution pattern around the double bond by
the preparation of 1,1-diarylethylene analogues of type 5 and
6, in which the double bond is tetra-substituted, including
those with a cycloalkylidene unit. In these two series of
designed analogues, we fixed one of the aryl groups as a
3,4,5-trimethoxyphenyl moiety, identical with the A-ring of
isoCA-4, and examined several substitutions on the B-ring.
Although the double bond in compounds 5 and 6 could
be generated by a Wittig reaction or by a two-step Grignard
addition/dehydration sequence,9b these two approaches are
not convergent and less suitable for the preparation of a
library of compounds with variation of substituents on the
B-ring. An alternative route consists of using the Pd-
(7) For a review, see: (a) Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.;
Dusacca, S.; Genazzani, A. A. J. Med. Chem. 2006, 49, 3033. (b) Bellina,
F.; Cauteruccio, S.; Monti, S.; Rossi, R. Bioorg. Med. Chem. Lett. 2000,
16, 5757. (c) Wu, M.; Li, W.; Yang, C.; Chen, D.; Ding, J.; Chen, Y.; Lin,
L.; Xie, Y. Bioorg. Med. Chem. Lett. 2007, 17, 869. For a recent clinical
study see: (d) Rustin, G. J.; Shreeves, G.; Nathan, P. D.; Gaya, A.; Ganesan,
T. S.; Wang, D.; Boxall, J.; Poupard, L.; Chaplin, D. J.; Stratford, M. R. L.;
Balkissoon, J.; Zweifel, M. Br. J. Cancer 2010, 102, 1355.
(10) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel, P.;
Amar, F.; Valdes, C. Chem.sEur. J. 2008, 14, 4792. (c) Barluenga, J.;
Escribano, M.; Moriel, P.; Aznar, F.; Valde´s, C. Chem.sEur. J. 2009, 15,
13291. (d) Treguier, B.; Hamze, A.; Provot, O.; Brion, J. D.; Alami, M.
Tetrahedron Lett. 2009, 50, 6549.
(8) Hamze, A.; Veau, D.; Provot, O.; Brion, J.-D.; Alami, M. J. Org.
Chem. 2009, 74, 1337.
(9) (a) Mousset, C.; Giraud, A.; Provot, O.; Hamze, A.; Bignon, J.; Liu,
J. M.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. Bioorg. Med. Chem.
Lett. 2008, 18, 3266. (b) Hamze, A.; Giraud, A.; Messaoudi, S.; Provot,
O.; Peyrat, J.-F.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.;
Dubois, J.; Brion, J.-D.; Alami, M. ChemMedChem 2009, 4, 1912. (c)
Giraud, A.; Provot, O.; Hamze, A.; Brion, J.-D.; Alami, M. Tetrahedron
Lett. 2008, 49, 1107. (d) Messaoudi, S.; Tre´guier, B.; Hamze, A.; Provot,
O.; Peyrat, J.-F.; Rodrigo De Losada, J. R.; Liu, J.-M.; Bignon, J.;
Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. J. Med.
Chem. 2009, 52, 4538.
(11) For the coupling of N-tosylhydrazone with arylboronic acids under
palladium catalysis, see: Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J.
Chem. Commun. 2010, 46, 1724. For the coupling of N-tosylhydrazones
with benzyl Halides, see: Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J.
Org. Lett. 2009, 11, 4732.
(12) When heating 7a in the presence of tBuOLi or Cs2CO3 (3 equiv)
in dioxane at 90 °C for 2 h, only byproduct 10a was formed; see: (a)
Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735. (b) Fulton, J. R.;
Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem. 2005, 1479.
(13) For more examples, please see Supporting Information.
Org. Lett., Vol. 12, No. 18, 2010
4043

Table 1. Initial Studies for Pd-Catalyzed Coupling of Sterically
Hindered N-Tosylhydrazones 7a with 4-Iodoanisolea
Table 2. Synthesis of 1,1-Diarylcycloalkylidenes by
Pd-Catalyzed Coupling of Sterically Hindered
N-Tosylhydrazones with Aryl Halides
ratio
entry
Pd (mol %)
L (mol %) solvent
base
9a/10ab
1
2
3
4
5
6
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Pd2dba3
Pd(OH)2
Pd(OAc)2
Pd(PPh3)4
L1
L1
L1
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
dioxane LiOtBu
toluene LiOtBu
30/70c
16/84
33/67d
34/66
64/36e
0/100
44/56
52/48
14/86
55/45
80/20
80/20
25/75
65/35
80/20
88/12
30/70
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
L1
L2
L3
L4
L5
L6
L7
L8
L7
L7
L7
L7
L7
L7
L7
L7
L7
THF
LiOtBu
LiOtBu
LiOtBu
KOtBu
DMA
DME
DME
DME
DME
DME
NaOtBu 58/42
Cs2CO3
Cs2CO3
91/9f
91/9g h
,
91/9g i
,
dioxane Cs2CO3
a The reactions were carried out with 7a (1.2 mmol), 8 (1 mmol), [Pd]
(10 mol %), ligand (20 mol %), and base (3 equiv) at 90 °C in 5.0 mL of
solvent. b Ratio was determined by 1H NMR in the crude reaction mixture.
c Reaction with aryl bromide under this conditions gave the same ratio of
9a/10a. d Reaction was heated in a sealed tube. e Performing the reaction
without ligand gave a mixture of 9a and 10a in 10:90 ratio. f Isolated yield
of 9a was 85%. g Reaction conducted in the presence of PdCl2(MeCN)2 (5
mol %) and L7 (10 mol %). h Isolated yield of 9a was 81%. i Isolated yield
of 9a was 82%.
85% isolated yield. It should be noted that decreasing the
amount of Pd/L from 10:20 to 5:10 mol % had no effect on
the yield and the selectivity when the reaction was conducted
in DME or dioxane (entries 21 and 22).
With these optimized conditions in hand, the scope of this
reaction was then studied by coupling a series of sterically
hindered polyoxygenated arylsulfonylhydrazones 7 with dif-
ferent aryl halides. As shown in Table 2, this new protocol
furnished the expected 1,1-diarylethylenes 9 in good to excellent
yields, whatever the nature of the arylsulfonylhydrazone 7 (n
) 1, 2, or 3).14 The reaction displays little dependence upon
electronic and steric nature of the aryl halide. Electron-rich and
electron-poor substrates as well as meta-, ortho-, and para-
a Isolated yield.
4044
Org. Lett., Vol. 12, No. 18, 2010

Table 3. Synthesis of 1,1-Diarylethylenes by Pd-Catalyzed
Coupling of Unhindered Tosylhydrazone 7f with Aryl Halides
and Pseudohalides
Figure 2. Synthesis of isopropylidene CYP17 inhibitor.
illustrate the synthetic potential of our protocol, we decided to
perform the formal synthesis of compound 12b of biological
interest (Figure 2). Reaction of tosylhydrazone 7h with 4-io-
dopyridine under our optimized conditions gave the expected
coupling product 11 in 90% yield, clearly demonstrating its
effeciency with heteroaryl halides. Further Suzuki coupling of
the carbon-chlorine bond of 11 with 6-methoxynaphthyl-2-
boronic acid under Buchwald conditions16 resulted in the
formation of 12a in 85% yield, which can be converted to the
active product 12b by a known procedure.15
In conclusion, the combination of PdCl2(MeCN)2 and dppp
affords an efficient catalytic system for the coupling of
sterically hindered as well as unhindered tosylhydrazones
with aryl halides or pseudohalides. This new protocol is
chemoselective and general and provides an efficient syn-
thetic route to a wide range of tetrasubstituted olefins,
including those having a cycloalkylidene unit. The utility of
this method was demonstrated by the formal synthesis of
compound 13b of biological interest. The synthesis and
evaluation of a library of tetra-substituted olefins related to
isoCA-4 will be reported in due course.
a Isolated yield.
substituted aryl iodides (entries 1, 3, and 4) all reacted
completely and effectively within 3 h. Aryl bromides also can
be employed with similar results (entry 2 and 11). In addition,
this new protocol allows one to utilize aryl halides with strong
electron-withdrawing groups such as a cyano or a nitro function
(entries 5, 10, 18, and 20).
To extend the scope of this transformation, we then
examined under our optimized conditions the coupling of
unhindered arylsulfonylhydrazones. As summarized in Table
3, polyoxygenated hydrazone 7f undergoes the coupling
reaction efficiently with various aryl halides or pseudohalides
under the catalytic system PdCl2(MeCN)2/dppp. The repre-
sentative examples in Table 3 clearly demonstrated the
generality of this reaction. A comparative study with aryl
triflate (entry 3) or imidazolylsulfonate (entry 4) gave a slight
reduction in yield in comparaison to aryl iodide (entry 1).
Finally, the coupling with 4-iodo-2-methoxynitrobenzene
gave 9u, precursor of isoNH2CA-4 of biological interest.9b
Recently, introduction of isopropylidene substituents onto the
linker of 1,1-diarylethylenes resulted in several strong CYP17
inhibitors as a promising therapy for prostate cancer.15 To
Acknowledgment. The CNRS is gratefully acknowledged
for financial support of this research.
Supporting Information Available: Experimental pro-
cedures and characterization data, including copies of 1H and
13C NMR spectra, are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101639G
(14) Coupling of 4-iodoanisole with arylsulfonylhydrazone 7 having a
cyclopropyl moiety (n ) 0) under our optimized conditions failed and
provided a complex mixture.
(15) Hu, Q.; Yin, L.; Jagusch, C.; Hille, U. E.; Hartmann, R. W. J. Med.
Chem. 2010, 53, 5049.
(16) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
Org. Lett., Vol. 12, No. 18, 2010
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