Expeditious synthesis of 1,1-diarylethylenes related to isocombretastatin A-4 (isoCA-4) via palladium-catalyzed arylation of N-tosylhydrazones with aryl triflates

Article abstract of DOI:10.1016/j.tetlet.2009.09.046

A quick and efficient entry to 1,1-diarylethylenes via the reaction of polyoxygenated aryl N-tosylhydra-zones with aryl triflates is described. The reaction employs the catalytic system Pd(OAc)₂/XPhos, tBuOLi as the base and dioxane as the solv

Full text of DOI:10.1016/j.tetlet.2009.09.046

Tetrahedron Letters 50 (2009) 6549–6552
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Tetrahedron Letters
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Expeditious synthesis of 1,1-diarylethylenes related to isocombretastatin
A-4 (isoCA-4) via palladium-catalyzed arylation of N-tosylhydrazones
with aryl triflates
*
Bret Tréguier, Abdallah Hamze, Olivier Provot, Jean-Daniel Brion, Mouâd Alami
Univ Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-92296, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2009
Revised 4 September 2009
Accepted 9 September 2009
Available online 12 September 2009
A quick and efficient entry to 1,1-diarylethylenes via the reaction of polyoxygenated aryl N-tosylhydra-
zones with aryl triflates is described. The reaction employs the catalytic system Pd(OAc)2/XPhos, tBuOLi
as the base and dioxane as the solvent. A variety of substituents on both the coupling partners’ hydra-
zones and triflates are tolerated. This procedure provides a complementary route to the existing methods
for the access to 1,1-diarylethylenes of biological interest.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aryl triflates
Tosylhydrazones
Palladium
Xphos ligand
1,1-Diarylethylenes
Isocombretastatin A-4
Combretastatins CA-4 and CA-1 are a very interesting class of
cytotoxic agents of natural origin, which have received much
attention due to their simple structures, their high potency as cyto-
toxic and antimitotic agents as well as their ability to selectively
damage tumor neovasculature.1 Despite their remarkable antican-
cer activities, these Z-stilbene compounds are prone to double
bond isomerization during storage and administration.2 The E-iso-
mers display dramatically reduced inhibition of cancer cell growth
and tubulin assembly.3 A number of structure–activity relation-
ships (SARs) have been reported for the combretastatins.4 These
studies revealed that the 3,4,5-trimethoxyphenyl unit as well as
the cis orientation of the two aromatic rings are a prerequisite
for significant biological activities. Therefore, extensive studies
have been conducted to prepare various cis-restricted analogues
by inserting mainly the cis-olefin in a five-membered heterocyclic
ring (e.g., pyrazoles, thiazoles, triazoles, imidazoles, etc.).5
(isoCA), are easy to synthesize without the need to control the ole-
fin geometry and constitute the simplest isomers of isoCA. The
most active compound isoCA-4 appears to elicit its tumor cytotox-
icity in a fashion similar to CA-4, via inhibition of tubulin polymer-
ization, which then leads to cell cycle arrest in G2/M. As the
replacement of the 1,2-ethylene bridge by the 1,1-ethylene one re-
sulted in retention of biological activity, our finding encouraged us
to use this bioisostere10 in future structure–activity relationship
studies. To this end, a set of compounds derived from the general
structures 1 were considered (Fig. 1), and a versatile synthesis that
1
2
OH
OH
OMe
MeO
MeO
OH
OMe
MeO
MeO
Our interest in 1,1-diarylethylene unit synthesis,6,7 combined
with our efforts to discover novel potent tubulin assembly inhibi-
tors, related to CA-4,8 led us to identify a promising class of sub-
stances with strong anticancer activities, simply by switching the
trimethoxyphenyl nucleus from the C(1) to the C(2) position of
the ethylene bridge.9 In contrast to their natural parent combre-
tastatins A, these synthetic isomers, named isocombretastatins A
OMe
OMe
CA-1
CA-4
2
MeO
MeO
OH
OMe
MeO
MeO
1
R
OMe
OMe
iso CA-4
1
* Corresponding author. Tel.: +33 1 46 83 58 87; fax: +33 1 46 83 58 28.
E-mail address: mouad.alami@u-psud.fr (M. Alami).
Figure 1. Combretastatins A-1, A-4, synthetic tubulin polymerization inhibitor
isoCA-4 and target structure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.046

6550
B. Tréguier et al. / Tetrahedron Letters 50 (2009) 6549–6552
Table 1
would allow the incorporation of a variety of aryl substituents was
therefore needed.
Initial studies for Pd-catalyzed Barluenga coupling of N-tosylhydrazone 2a with 3a
Typically, the synthesis of the most active compound isoCA-4
was performed by the reaction of 3,4,5-trimethoxyacetophenone
N-tosylhydrazone11 2a with 2-tbutyldimethylsilyloxy-4-iodoani-
sole. Thus, when using Pd2(dba)3 (10 mol %) as a catalyst and
Xphos (20 mol %) as a ligand, the coupling reaction gave the de-
sired product isoCA-4 in a 75% yield.12 This synthetic approach
proved to be suitable for the synthesis of the others isocombretast-
atins A-1 to A-59a since no stoichiometric organometallic reagent
was employed and also, in view of the simple transformation of
the acetophenones into their corresponding N-tosylhydrazones.
Although this reaction has been investigated with aryl halides,9a,11
there is no report employing the use of aryl triflates. Extension of
this coupling reaction to include aryl triflates as electrophiles13 is
especially important since these substrates can be easily synthe-
sized from phenol sources and consequently can be revealed at a
late stage in a synthetic sequence. The commercial availability of
phenol derivatives will make this approach sufficiently diversity
oriented, thus fulfilling the recent demand for the generation of
large combinatorial chemical libraries. Herein we report our stud-
ies in the synthesis of 1,1-diarylethylenes 1 from the coupling of
polyoxygenated N-tosylhydrazone 2 with aryl triflates.
Initial studies were performed by coupling 3,4,5-trimethoxy-
acetophenone N-tosylhydrazone (2a) and aryl triflate 3a, as model
substrates using Pd2(dba)3 (5 mol %), Xphos (10 mol %) and tBuOLi
(2 equiv) in dioxane at 90 °C. Under these conditions (conventional
atmospheric pressure reaction), 1a was formed in a modest 54%
yield (entry 1). Fortunately, a much higher yield was obtained un-
der pressure by running the reaction in a sealed tube (84%, entry 2).
As summarized in Table 1, the nature of the base has an influence
on the outcome of the reaction. tBuOLi appeared the base of choice
to secure the 1,1-diarylethylene 1a formation since performing the
same reaction with tBuOK, Cs2CO3 or K3PO4 led to lower yields (en-
tries 3–6). The screening was continued with respects to palladium
source and ligands. We were pleased to find that the catalytic
activity of Pd(OAc)2 or PdCl2(MeCN)2 proved to be similar to
Pd2(dba)3 leading to 1a in excellent yields (89–91%, entries 9 and
NNHTs
+
LG
[Pd] (5 mol%)
Ligand (10 mol%)
MeO
MeO
MeO
MeO
base
1,4-dioxane
90 °C
OMe
OMe
OMe
OMe
2a
3
1a
sealed tube
3a: LG = OTf
3b: LG = Im (Im = Imidazolylsulfonate)
3c: LG = ONfF
3d: LG = OTs
PCy2
iPr
PtBu2
iPr
Pri
Pri
PCy2
PCy2
OMe
MeO
iPr
L3: XPhos
iPr
L4: tBuXPhos
L1: CyJohnPhos
L2: S-Phos
Entry
[Pd]/Ligand
LG
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd/C/L3
Pd(OH)2/C/L3
PdCl2(MeCN)2/L3
Pd(OAc)2/L3
Pd(OAc)2/L1
Pd(OAc)2/L2
Pd(OAc)2/L4
Pd(OAc)2/L3
Pd(OAc)2/L3
Pd(OAc)2/L3
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OSO2Im
ONfF
OTs
tBuOLi
tBuOLi
tBuOK
Cs2CO3
K3PO4
Li2CO3
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
54c
84
34
23
50
0
13
30
89
91
82
55
19
70
52
5
a
All reactions were heated in a sealed tube in dioxane using 2a (1 equiv), 3
(1 equiv), [Pd] (5 mol %), Ligand (10 mol %) and base (2 equiv) at 90 °C for 3 h.
b
Isolated yield of 1a.
Reaction was performed at 90 °C at atmospheric pressure.
c
Table 2
Synthesis of 1,1-diarylethylene 1a
Entry
Hydrazone 2
ArOTf 3
Product 1
MeO
Yieldb (%)
NNHTs
NNHTs
NNHTs
OTf
MeO
MeO
1
91
MeO
OMe
OMe
OMe
OMe
OMe
OMe
2a
3a
1a
1b
1c
OTf
MeO
MeO
MeO
MeO
2
90
OMe
2a
3e
OTf
MeO
MeO
MeO
MeO
3
75
OMe
OMe
OMe
2a
3f

B. Tréguier et al. / Tetrahedron Letters 50 (2009) 6549–6552
6551
Table 2 (continued)
Entry
Hydrazone 2
ArOTf 3
Product 1
MeO
Yieldb (%)
NNHTs
NNHTs
OTf
MeO
MeO
4
5
6
69
94
97
MeO
Cl
OMe
OMe
Cl
2a
3g
1d
OTf
MeO
MeO
MeO
MeO
OTBDMS
OTBDMS
2b
3e
1e
NNHTs
OTf
OMe
OTBDMS
OTBDMS
OMe
2b
3a
1f
NNHTs
OTf
TBDMSO
TBDMSO
7
8
9
90
74
75
OTBDMS
OTBDMS
2c
3e
1g
NNHTs
OTf
TBDMSO
TBDMSO
OMe
OTBDMS
OTBDMS
OMe
2c
3a
1h
NNHTs
TfO
MeO
MeO
MeO
MeO
O
OMe
O
OMe
O
O
2a
3f
1i
NNHTs
TfO
MeO
MeO
MeO
MeO
O
O
10
66
O
OMe
OMe
O
2a
3g
1j
NNHTs
OTf
MeO
MeO
MeO
MeO
N
11
52c
N
OMe
OMe
2a
3e
1k
a
All reactions were heated in a sealed tube in dioxane using 2a (1 equiv), 3 (1 equiv), Pd(OAc)2 (5 mol %), XPhos (10 mol %) and tBuOLi (2 equiv) at 90 °C for 3 h.
b
c
Isolated yield of 1.
Not optimized.

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B. Tréguier et al. / Tetrahedron Letters 50 (2009) 6549–6552
see: (b) Ty, N.; Kaffy, J.; Arrault, A.; Thoret, S.; Pontikis, R.; Dubois, J.; Morin-
Allory, L.; Florent, J.-C. Bioorg. Med. Chem. Lett. 2009, 19, 1318–1322; (c) Ty, N.;
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10). Pd/C or Pd(OH)2 however, showed moderate catalytic activi-
ties (entries 7 and 8) since 1a was formed in lower yields than
those obtained with Pd(OAc)2 or PdCl2(MeCN)2. Evaluation of li-
gands revealed that Xphos (L3) and CyJohnPhos (L1) have a similar
efficiency and are superior to all other choices (entries 11–13). Fi-
nally we examined the effect of the leaving group (LG) of the elec-
trophilic coupling partner. A comparative study revealed that the
reactivity of triflate 3a is superior to that of imidazolylsulfonate
3b (entry 14) and nonaflate 3c (entry 15) whereas the coupling
failed when using tosylate 3d (entry 16). Considering its high cat-
alytic activity Pd(OAc)2 was our choice for further experimenta-
tion. In summary, the best conditions were found to require: 2a
(1 equiv), 3a (1 equiv), Pd(OAc)2 (5 mol %), Xphos (10 mol %), tBuO-
Li (2 equiv), dioxane in a sealed tube at 90 °C for 3 h.14 It should be
noted that microwave heating is also effective for this reaction.
However, if the reaction time is reduced (ꢀ0.5 h),15 a slightly lower
yield (78%) was obtained.
After these optimization studies, we applied this catalytic sys-
tem for the coupling of various aryl triflates and polyoxygenated
tosylhydrazones 2 to assess the scope of the developed reaction
conditions (Table 2). First, 3,4,5-trimethoxyacetophenone N-tos-
ylhydrazone 2a was reacted with various aryl triflates 3 to afford
the corresponding 1,1-diarylethylenes 1a–c (entries 1–3). Running
the reaction from aryl triflate 3g bearing a para sp2-carbon-chlo-
rine bond, the coupling reaction gave selectively 1d in a 69% yield
(entry 4). Among these substrates, the coupling reaction worked
efficiently even in the case of alkaline sensitive tosylhydrazones
2b and 2c bearing silyloxy groups in good to excellent yields (en-
tries 5–8). Heteroaromatic triflates 3f–e also were coupled success-
fully with hydrazone 2a and provided the desired coupling
products 1i–k in a satisfactory yield (entries 9–11), despite the fact
that the reaction conditions with these heterocyclic substrates had
never been optimized.
5. (a) Nam, N. H. Curr. Med. Chem. 2003, 10, 1697–1722; (b) Odlo, K.; Hentzen, J.;
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2008, 10, 3941–3944; (d) Yoshida, K.; Shishikura, Y.; Takahashi, H.; Imamoto, T.
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2008, 73, 7797–7799; (f) Li, J.-H.; Li, J.-L.; Xie, Y.-X. Synthesis 2007, 984–988; (g)
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2008, 18, 3266–3271; (c) Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J.-
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12. Only 50% of the desired product was obtained when running the coupling
reaction with Pd2(dba)3 (1 mol %) and Xphos (2 mol %).
In conclusion, we have described an efficient and general meth-
od for cross coupling of different aryl triflates with polyoxygenated
hydrazones catalyzed by the combination of Pd(OAc)2 or PdCl2(MeCN)2
and Xphos ligand in the presence of tBuOLi as the base in a sealed
tube. In our opinion, this approach seems to be a suitable method
for the synthesis of other isocombretastatin A analogues. The design
of antitumor agents based on the 1,1-diaryethylene scaffold in
future structure–activity relationship studies is currently under-
way; the results of synthetic and biological studies will be reported
in due course.
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3077–3119.
14. General procedure for the synthesis of 1. To a dioxane (6 mL) solution of N-
tosylhydrazone 2 (0.5 mmol), tBuOLi (1 mmol), Pd(OAc)2 (0.025 mmol), and X-
Phos (0.05 mmol) was added the aryl triflate 3 (0.5 mmol) in dioxane (2 mL).
The reaction vessel was sealed, and then heated at 90 °C for 3 h. The resulting
suspension was cooled to room temperature and filtered through a pad of
Celite eluting with AcOEt, and the inorganic salts were removed. The filtrate
was concentrated and purification of the residue by silica gel column
chromatography gave the desired product.
Diarylethylene 1a: Yield: 91%. Rf (cyclohexane/EtOAc: 6/4) = 0.60. IR (cmÀ1):
1579, 1507, 1454, 1411, 1346, 1299, 1233, 1174, 1122, 1030, 1004. 1H NMR: (d
ppm, CD3COCD3, 300 MHz): 3.75 (s, 3H, OCH3), 3.78 (s, 6H, OCH3), 3.82 (s, 3H,
OCH3), 5.34 (m, 2H, CH2), 6.60 (s, 2H), 6.92 (d, 2H, J = 8.7 Hz), 7.29 (d, 2H,
J = 8.7 Hz). 13C NMR (d ppm, 75 MHz, CD3COCD3): 55.5, 56.4 (2), 60.5, 106.8 (2),
112.7, 114.4 (2), 130.1 (2), 134.4, 138.2 (2), 150.6, 154.1 (2), 160.5.
Diarylethylene 1d: Yield: 69%. Rf (cyclohexane/EtOAc: 9/1) = 0.58. IR (cmÀ1):
1579, 1504, 1462, 1410, 1344, 1235, 1125, 1007. 1H NMR: (d ppm, CDCl3,
300 MHz): 3.73 (s, 6H, OCH3), 3.80 (s, 3H, OCH3), 5.34 (d, 2H, J = 1.0 Hz, CH2),
6.44 (s, 2H, CH), 7.22 (s, 4H, CH). 13C NMR (d ppm, 75 MHz, CDCl3): 56.1 (2),
60.9, 105.5 (2), 114.3, 128.4 (2), 129.6 (2), 133.7, 136.8, 137.8, 139.7, 149.0,
153.0 (2).
Acknowledgments
We thank the CNRS for support of this research and the ICSN for
a doctoral fellowship to B.T.
References and notes
Diarylethylene 1i: Yield: 75%. Rf (cyclohexane/EtOAc: 7/3) = 0.28. Mp: 143–
145 °C. IR (cmÀ1): 1719, 1574, 1508, 1453, 1411, 1350, 1221, 1177, 1124, 996.
1H NMR: (d ppm, CDCl3, 300 MHz): 3.82 (s, 6H), 3.89 (s, 3H), 5.54 (s, 1H), 5.56
(s, 1H), 6.42 (d, 1H, J = 9.5 Hz), 6.51 (s, 2H), 7.27 (dd, 1H, J = 1.6 Hz, J = 8.0 Hz),
7.35 (d, 1H, J = 1.5 Hz), 7.44 (d, 1H, J = 8.0 Hz), 7.71 (d, 1H, J = 9.5 Hz).13C NMR
(d ppm, 75 MHz, CDCl3): 56.0 (2), 60.8, 105.6 (2), 116.1, 116.2, 116.4, 118.2,
124.3, 127.4, 136.0, 138.1, 142.9, 145.1, 148.6, 153.0 (2), 153.9, 160.6.
15. The reaction was conducted according to the general method described above.
The reaction vessel was sealed, then placed in the Emrys Optimizer and
exposed to microwave irradiation according to the following specifications:
temperature: 120 °C; time: 30 min; fixed hold time: on; sample absorption:
high; pre-stirring: 60 s.
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