Efficient synthesis of polysubstituted olefins using stable palladium nanocatalyst: Applications in synthesis of tamoxifen and isocombretastatin A4

Article abstract of DOI:10.1021/ol5017367

A phosphine-free stable palladium nanocatalyst was used for an efficient synthesis of polysubstituted olefins from N-tosylhydrazones and aryl iodides. This methodology was successfully utilized in the synthesis of biologically important tamoxifen and isocombretastatin A4. The nanocatalyst was easily recovered and reused without any apparent loss in size and catalytic activity.

Full text of DOI:10.1021/ol5017367

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of Polysubstituted Olefins Using Stable Palladium
Nanocatalyst: Applications in Synthesis of Tamoxifen and
Isocombretastatin A4
Dhandapani Ganapathy and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India
S
* Supporting Information
ABSTRACT: A phosphine-free stable palladium nanocatalyst was used for
an efficient synthesis of polysubstituted olefins from N-tosylhydrazones and
aryl iodides. This methodology was successfully utilized in the synthesis of
biologically important tamoxifen and isocombretastatin A4. The nanocatalyst
was easily recovered and reused without any apparent loss in size and
catalytic activity.
lefins are one of the versatile functional groups and
in some cases external co-oxidants are used.6 From the
Ointermediates in organic synthesis because of their industrial and economical points of view, large-scale production
unique reaction properties.1 In addition, olefins are present in
faces a major challenge in purification of product from
expensive catalyst.
many natural products, biologically active molecules, and fine
chemicals. In particular, polysubstituted olefins have widespread
applications in natural products, pharmaceuticals, and func-
tional materials synthesis (Figure 1).2
In the last few decades, C−C bond-forming cross-coupling
reactions catalyzed by transition-metal nanoparticles have
emerged as an efficient tool in organic synthesis.7 In particular,
palladium nanoparticles (Pd NP) are one of the most
prominent metal nanocatalysts in several C−C bond-forming
cross-coupling reactions.8 The advantages of using Pd NP as
catalysts are low catalyst loading, good selectivity, and enhanced
reactivity because of their large surface area. In addition, the
semi-heterogeneous nature of nanoparticles offers ease of
separation and reusability of the catalyst. However, preparation
of metal nanoparticles often requires stabilizing agent to
prevent agglomerization and precipitation into bulk materials,
which are inactive to catalyze the reaction. In the literature, a
number of stabilizers such as thiols, phosphines, dendrimers,
and polymers are used for the synthesis of nanoparticles.9 Very
recently, we have reported synthesis and application of new
type of easily recoverable and reusable stable palladium
nanoparticles stabilized by a metal−carbon covalent bond.10
In this paper, for the first time, we report an efficient
phosphine-free synthesis of polysubstituted olefins 3 from N-
Figure 1. Biologically important polysubstituted olefins.
tosylhydrazone 1 and aryl iodides 2 using the stable Pd−C(sp2)
-
Although numerous methods exist for the synthesis of simple
olefins, synthesis of polysubstituted olefins is a challenging task
in synthetic organic chemistry. Among various methods
available for the synthesis of polysubstituted olefins, the
transition-metal-catalyzed C−C bond-forming cross-coupling
reaction is a powerful method.3 Recently, Barluenga et al.
reported a palladium-catalyzed cross-coupling reaction between
N-tosylhydrazone and aryl halides for the preparation of
polysubstituted olefins.4 Wang et al. and others utilized
arylboronic acids as coupling partners for polyolefin synthesis.5
These methods are highly efficient and use bulky and electron-
rich phosphine ligands, which are costly and sensitive to air, and
stabilized nanoparticle as easily recoverable and reusable
catalyst and application of this methodology as key step in
the synthesis of biologically important molecules (Scheme 1).
Our preliminary investigation for the synthesis of poly-
substituted olefin started with coupling of N-tosylhydrazone 1a
with 4-iodotoluene 2a in the presence of Pd NP 4a (1.0 mol %)
and LiO-t-Bu base in dioxane at 100 °C. The reaction afforded
75% of 1-methyl-4-(1-phenylvinyl)benzene 3a in 24 h. It is very
Received: February 24, 2014
Published: July 18, 2014
© 2014 American Chemical Society
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Scheme 1. Stable Pd NP-Catalyzed Polysubstituted Olefin
Synthesis
Scheme 2. Pd−C(binaphthyl) NP 4a Catalyzed Synthesis of
a
Polysubstituted Olefins
important to mention that this method involves a ligand free
protocol for the synthesis of polysubstituted olefins. Encour-
aged by this initial result, we were curious to investigate the
catalytic effect of other aryl derivatives stabilized Pd NP for this
polysubstituted olefin synthesis. Thus, simple phenyl 4b, p-
decylphenyl 4c, and p-decyloxyphenyl 4d stabilized Pd NPs
were synthesized, characterized (Figure 2), and used as catalyst
Figure 2. Aryl derivative stabilized Pd NPs.
for the above-mentioned reaction, and the results are
summarized in Table 1. The Pd NP 4b afforded poor yield
(30% of 3a), where 4c and 4d gave 62% and 60% yields,
respectively (Table 1, entries 1−4).
Table 1. Effect of Solvent and Bases for the Synthesis of
a
Polysubstitued Olefin
b
entry
Pd NP
solvent
base
time (h)
yield (%)
1
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4a
4a
4a
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
Cs2CO3
K2CO3
K3PO4
KOAc
18
24
24
24
18
24
18
24
24
24
24
30
24
75
30
62
60
82
69
93
10
2
3
4
5
6
7
8
c
9
K3PO4
45
10
11
12
13
toluene
EtOH
K3PO4
42
K3PO4
trace
38
DCE
K3PO4
DME
K3PO4
68
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), Pd NPs 4a (1
a
b
c
Reaction conditions: 1a−x(0.5 mmol), 2a−x (0.5 mmol), Pd NPs 4a
mol %), base (1.5 mmol), solvent (4 mL). Isolated yield. Pressure
tube was used.
b
(1 mol %), K3PO4 (1.5 mmol), in dioxane (4 mL). Mixture of
isomers from same starting material. All are isolated yields.
To improve the yield of this olefin synthesis, several bases
were screened and K3PO4 gave the best result with 93% of
isolated yield within 18 h (Table 1, entries 5−8). To increase
the efficiency of the reaction, the effect of solvents and
temperature were studied and in all the cases, the olefin 3a was
obtained comparatively in poor yield (Table 1, entries 9−13).
The optimization results are summarized in Table 1.
Having optimized reaction conditions in hand (Table 1,
entry 7), several polysubstituted olefins were synthesized to
show the substrate scope, and the results are summarized in
Scheme 2. The coupling of various substituted N-tosylhy-
drazone and aryl iodides smoothly proceeded with good to
excellent yield to produce polysubstituted olefins. Both
electron-withdrawing and electron-donating groups in the
coupling partners have efficiently worked in this synthesis. In
particular, N-tosylhydrazone substituted with three methoxy
groups coupled with 4-methoxybenzene efficiently to form
highly electron-rich olefin (3m). In addition, it is worthy to
note that even sterically hindered aryl iodides afforded good
yields (3k,l,o). 1,4-Diiodobenzene reacted with acetophenon-
derived hydrazone and gave iodoolefin (3p) with 68% yield.
The hydrazone derived from linear ketone such as
propiophenone reacted with 4-iodotoluene and gave a
1:1mixture of E/Z isomers. Similarly, the hydrazone derived
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from 4-phenylbutan-2-one gave a mixture of regioisomers 3qa
and 3qb. Interestingly, α-disubstituted hydrazones are
efficiently coupled with aryl iodides (Schemes 2, 3s−x). The
hydrazone derived from 2-methyl-1-phenylpropan-1-one gave
tetrasubstituted olefins 3t and 3v with 82 and 74% yield,
respectively. Heteroaromatic iodide also coupled, and the
reaction afforded 68% of 3x. When the reaction was carried out
with 4-bromotoluene in the presence 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl (Xphos) 12% of 3a was isolated.
However, the yield was not increased by changing the ligands
and the reaction conditions.
Scheme 3. Synthesis of Cytotoxic Agent Isocomberstatin A4
Then we investigated the recyclability nature of catalyst 4a,
and catalyst 4a was successfully recovered by centrifugation and
reused for four cycles without any appreciable loss in the
catalytic efficiency (Figure 3). This is in agreement with
HRTEM analysis as the 4a showed same particle size without
any obvious agglomerization before and after the catalytic
cycles (Figure 4).
positive breast cancer.12 This molecule was successfully
synthesized by coupling of iodobenzene 9 with the aryl
hydrazone 8 to afford the precursor of tamoxifen 10 as a
mixture of Z/E isomer (69:31 ratios) with 80% of isolated
yield.13 Later, the intermediate 10 was successfully converted to
tamoxifen in two steps (Scheme 4).
Scheme 4. Synthesis of Anticancer Agent Tamoxifen
Figure 3. Catalytic recycles for the synthesis of polysubstituted olefins.
We have developed an efficient methodology for the
synthesis of polysubstituted olefins using stable, easily
recoverable, and reusable Pd NP as catalyst from tosylhy-
drazone and aryl iodides. This methodology was successfully
utilized as a key step for the synthesis of very important
anticancer agents, isocombretastatins, and tamoxifen in good
yields. The application of this methodology in the synthesis of
other biologically important molecules and the mechanistic
studies are underway.
Figure 4. HRTEM images of Pd NPs 4a before catalytic (a) and after
the catalytic cycles (b).
ASSOCIATED CONTENT
* Supporting Information
■
S
To know the application of this methodology, it was used as
key step for the synthesis of biologically important molecules
such as isocombretastatin A4 and tamoxifen. The synthesis of
cytotoxic agent isocombretastatins11 7 was accomplished by the
coupling of N-tosylhydrazone 4 derived from 1-(3,4,5-
trimethoxyphenyl)ethanone with iodo derivative 5 in the
presence of 4a under optimized reaction conditions with 72%
yield. The hydrolysis of 6 afforded isocombretastatin A4 7 with
80% isolated yield (Scheme 3).
Experimental details and procedures, compound character-
ization data, and copies of 1H and 13C spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gsekar@iitm.ac.in.
Notes
Tamoxifen is currently used as a potential antagonistic
prodrug for the treatment of all stages of estrogen-receptor-
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank DST nanomission (SR/NM/NS-1034/2012(G)),
New Delhi, for financial support. D.G.P. thanks CSIR, India, for
senior research fellowship.
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