Exploratory studies on the reaction between iodoarenes and acetylenes: One-pot, Pd-[Bmim][BF4] catalyzed preparation of trianisylethylene

Article abstract of DOI:10.1007/s10562-011-0549-7

The reaction between iodoarenes and acetylenes mediated by palladium was studied, showing selectivity changes based on the nature of the substituent. A new, phosphine-, copper-, and amine-free methodology was developed, in which the synthesis of trianisylethylene from 4-iodoanisole and trimethylsilylacetylene was promoted presumably by an N-heterocyclic-carbene derived from an ionic liquid and a palladium salt, using ethanol as the hydrogen source. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-011-0549-7

Catal Lett (2011) 141:549–553
DOI 10.1007/s10562-011-0549-7
Exploratory Studies on the Reaction Between Iodoarenes
and Acetylenes: One-pot, Pd-[Bmim][BF4] Catalyzed Preparation
of Trianisylethylene
•
Jose C. Barros Andrea L. F. Souza
•
´
Joaquim F. M. da Silva O. A. C. Antunes
•
Received: 9 April 2010 / Accepted: 8 January 2011 / Published online: 26 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The reaction between iodoarenes and acety-
lenes mediated by palladium was studied, showing selec-
tivity changes based on the nature of the substituent. A
new, phosphine-, copper-, and amine-free methodology
was developed, in which the synthesis of trianisylethylene
from 4-iodoanisole and trimethylsilylacetylene was pro-
moted presumably by an N-heterocyclic-carbene derived
from an ionic liquid and a palladium salt, using ethanol as
the hydrogen source.
breast cancer, infertility, osteoporosis, CNS, cardiovascular
or lipid malfunctions [5, 6].
Compounds of this class like tamoxifen, clomiphene and
broparoestrol (Fig. 1) are called Selective Estrogen
Receptor Modulators (SERMs). As they are neither estro-
gen nor hormones, they are considered to be potentially
safer than hormone replacement therapy [7], and are now a
strategy to prevent osteoporosis and reduce the risk of
breast cancer in postmenopausal women [8, 9].
Current approaches to these substituted ethylenes
include the hydroarylation reaction mediated by transition
metals like copper [10], cobalt [11], iron [12], gold
[13, 14], rhodium [15, 16], rhenium [17], platinum [18–20]
or palladium [20–27], and metal-free protocols [28].
Our group has been involved in the reaction between
haloarenes and acetylenes involving either Sonogashira
coupling [29, 30] or tandem Sonogashira coupling-hydro-
arylation [31] to furnish trisubstituted olefins, and in that
case, it was possible to direct the selectivity based on
catalyst nature, ligand and solvent properties, also the
phosphine-free and ionic liquid promoted reaction were
tested (Scheme 1).
Keywords Sonogashira reaction ꢀ Hydroarylation ꢀ
SERM
1 Introduction
Substituted olefins are valuable building blocks in organic
synthesis as they constitute the skeleton of oligoenes and
enynes present in natural products [1, 2], which show
interesting photochemical properties [3, 4]. In a medicinal
context, the triarylyethylene pharmacophore possess bio-
logical activities in estrogen-dependent disorders like
Here, we wish to disclose an expansion of our meth-
odology using different halides and acetylenes. For this we
have subjected alkynes and halides to our optimized con-
ditions [31] for a tandem reaction involving a Sonogashira
coupling followed by hydroarylation using Pd(OAc)2,
PPh3, K2CO3 and EtOH as a suitable solvent and hydrogen
transfer promoter [32].
This paper is dedicated to the memory of Professor Octavio Antunes
and his family.
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-011-0549-7) contains supplementary
material, which is available to authorized users.
J. C. Barros ꢀ A. L. F. Souza ꢀ J. F. M. da Silva (&) ꢀ
O. A. C. Antunes
2 Results and Discussion
´
Instituto de Quımica, Universidade Federal do Rio de Janeiro,
Av. Athos da Silveira Ramos 149, CT Bloco A, Cidade
First of all, we have evaluated the reaction between iodo-
benzene and several acetylenes (Scheme 2). The results are
´
Universitaria, Rio de Janeiro, RJ 21941-909, Brazil
e-mail: joaquim@iq.ufrj.br
123

550
J. C. Barros et al.
summarized in Table 1, where the three possible isomers of
the products are shown.
All experiments involving iodobenzene and alkynes
resulted in unreacted iodobenzene in the reaction mixtures.
As reactions were conducted in a stoichiometric fashion
(1 equivalent of alkynes and 2 equivalents of iodobenzene),
the presence of unreacted iodobenzene in reactions like
those in Table 1, entries 1, 6, and 7 indicates that conver-
sions were not completed, so disubstituted acetylenes were
found. But for the other reactions where no starting alkyne
nor disubstituted acetylenes were found, it could indicate
that some oligomerization of alkynes took place. Some
selectivities did not reach 100% and it was not possible to
identify all products formed in reaction mixtures.
Fig. 1 Structure of SERMs
As it can be drawn from Table 1, bulky alkynes resulted
in better selectivities toward the trisubstituted olefins
(entries 1,4,5 vs 2,3). The isomeric mixture of products
from the reaction involving but-3-yn-2-ol (entry 2) also
showed a fragment at m/z 222 revealing the presence of
oxidized byproduct (ketone), and this side reaction was
already reported elsewhere [33, 34]. But-3-yn-2-ol and
1-ethynylcyclohexanol have already been reported as
acetylene surrogates [35], but under our conditions,
diphenylacetylene was not detected in reaction mixtures.
The reaction involving propargyl alcohol (entry 3) showed
Scheme 1 Reaction between iodobenzene and phenylacetylene
Scheme 2 Reaction between haloarenes and acetylenes
Table 1 Selectivities in
Entry
Acetylene
Ligand
Selectivitya (%)
reaction between iodobenzene
and acetylenes
Trisubstituted
alkenes
Disubstituted
acetylene
1
2
PPh3
1/2/67b
16
PPh3
0/55/1c
–
3
4
5
6
PPh3
0/13/3
23/76/1
1/39/22
4/22/0
–
PPh3
–
PPh3
–
[Bmim][BF4]
41
a
Ratios of the three possible
isomers were determined by
GC/MS
b
Detection of [M-18] in GC/
MS analysis
7
[Bmim][BF4]
–
45
c
The other 45% represents the
oxidized product
123

One-pot, Pd-NHC Catalyzed Preparation of Trianisylethylene
551
only traces of coupled products together with homocou-
pling of the halide (1,10-biphenyl).
to afford substituted triphenyletylenes and the results are
showed in Table 2.
In the trisubstituted olefin series, the isomer ratio (i.e.: cis,
trans or gem in Tables 1 and 2) was assigned by NMR
analysis of crude mixture for entry 2 in Table 1, and the
assignment was based by comparison with literature data for
the synthesized compounds [36–40]. This analysis revealed
the trans-isomer (Z)-3,4-diphenylbut-3-en-2-ol as the major
one, followed by the oxidized byproduct of the reaction (4,4-
diphenylbut-3-en-2-one). The ratio trans:oxidized product
was 1:0.6, which ultimately agreed with the ratio obtained by
GC/MS analysis.
The reaction of 4-iodoaniline (entry 3) with phenyl-
acetylene resulted in an untreatable mixture of products.
2-Iodobenzoic acid as substate resulted in alkyne homo-
coupling (1,4-diphenylbuta-1,3-diyne) together with the
Sonogashira coupling product. As a general tendency,
electron withdrawing groups (EWG) in the haloarene
moiety (entries 2 and 6) favoured Sonogahira coupling
instead of hydroarylation. The reaction of 1-iodo-4-
nitrodobenzene resulted in 11% of 4-nitrostilbene as a
byproduct (entry 2).
The use of [Bmim][BF4] acting presumably as a N-het-
erocyclic carbene (NHC) precursor in place of triphenyl-
phosphine (entries 6 and 7) resulted mainly in Sonogashira
products. This corroborates our previous results of the role of
ligands (PPh3 vs NHC) in directing the selectivity to a
Sonogashira reaction or an hydroarylation [31].
The reactions employing [Bmim][BF4] as ligand follow
the same tendency described for PPh3, which is haloarenes
substituted with electron releasing groups (ERG) resulting
in hydroarylation (entry 7) while EWG-substituted halo-
arenes furnished Sonogashira product (entry 8). Besides the
fact that 4-iodoanisole and 1-iodo-4-nitrobenzene furnished
different structural patterns—a triphenylethylene and a
diphenylacetylene (Scheme 3)—it was worth to note that
In a second approach, several halides were reacted with
phenylacetylene under our optimized conditions (Scheme 2)
Table 2 Selectivities in
reaction between iodoarenes
and phenylacetylene
Entry
Halide
Ligand
Selectivitya (%)
Trisubstituted
alkenes
Disubstituted
acetylene
1
2
3
4
5
PPh3
PPh3
PPh3
PPh3
PPh3
16/20/47b
–
–
88c
d
–
–
d
–
–
–
25e
a
Ratios of the three possible
isomers were determined by
GC/MS
6
PPh3
\1
9
b
Plus 4% of
4-methoxybenzophenone
7
8
[Bmim][BF4]
[Bmim][BF4]
9/38/52
–
c
Plus 12% of 4-nitrostilbene
d
Products not detected
e
Plus 64% of alkyne
homocoupling
–
95f
f
Plus 3% of 4,40-
dinitrobiphenyl
123

552
J. C. Barros et al.
Inspired by Wu’s results employing trimethylsilylacet-
ylene (TMSA) as an acetylene surrogate [41], we have
applied our catalytic system—Pd(OAc)2, K2CO3, EtOH
and stoichiometric halide—to this reaction in substitution
of Wu catalytic system—Pd(OAc)2 or Pd(PPh3)4 or
Pd2(dba)3, sodium methoxide, dry methanol and five
equivalents of halide. For the reaction between 4-iodoani-
sole and TMSA to furnish trianisylethylene, the conver-
sions and selectivities were evaluated and the results are
illustrated in Table 3.
Scheme 3 Reaction between phenylacetylene and ERG or EWG-
substituted iodobenzenes
Due to volatility of TMSA (b.p. 53 °C) the experiments
were conducted in a sealed tube under argon atmosphere.
Initially, we have screened the reaction in presence of tri-
phenylphosphine, showing that 3 days resulted in better
conversion than 1 day (entries 1 vs 2). However, as the
current synthetic methodologies developed in our labora-
tory avoid toxic, expensive and moisture sensitive phop-
shines, we have tried both a ligand-free and a system
containing [Bmim][BF4] as pre-ligand, and the latter
showed better conversion (entries 3 vs 4).
both methodologies under ionic liquid as ligand resulted in
cleaner reactions as revealed by GC analysis. The hydro-
arylation of some hydroxylated internal acetylenes was
already reported to proceed in presence of this ionic liquid,
but in a system comprising amine and formic acid [34].
The role of [Bmim][BF4] acting as a ligand in the
reaction of 4-iodoanisole prompted us to attempt a new
preparation of symmetrically trisubstituted ethylenes.
These compounds could be employed in the preparation of
chlorotrianisene (TACEÒ) and amotriphene (MyordilÒ)
following a general retrosynthetic path (Scheme 4).
Based on our proposed mechanism of a tandem Sono-
gashira coupling-hydroarylation reaction, which would
comprise at least three equivalents of added base, and
together with Wu uses of five equivalents of CH3ONa, we
have screened the reaction employing 6 equivalents of base
resulting in better conversions (entries 4 vs 5).
Lowering the Pd content from 5 to 1 mol% or the reaction
time from 3 to 1 day resulted in lower selectivities (entries 5
vs 6 and 5 vs 7) with traces of the intermediate 1,2-bis(4-
methoxyphenyl)ethyne (the Sonogashira product).
Attempts to use less expensives but-3-yn-2-ol or
1-ethynylcyclohexanol as acetylene surrogates [42] in
substitution of TMSA did not succeed, only starting
material being recovered, which was attributed to the lower
reactivity of these acetylenes compared to the silylated one.
A mechanistic pathway for this kind of reaction was
proposed by Wu [42] and by us [31] and comprised a
Scheme 4 Retrosynthetic analysis of amotriphene and chlorotriani-
sene
Table 3 Conversions and selectivities in reaction between 4-iodonisole and trimethylesilylacetylene
Entry
Ligand
Time
(days)
Amount
of base (eq.)
Amount of
Pd cat. (mol%)
Conversiona (%)
Selectivitya (%)
1
2
3
4
5
6
7
a
PPh3
1
3
3
3
3
3
1
2
2
2
2
6
6
6
5
5
5
5
5
1
5
89
[99
17
97
PPh3
[99
74
–
[Bmim][BF4]
[Bmim][BF4]
[Bmim][BF4]
[Bmim][BF4]
52
[99
[99
92b
98c
[99
[99
[99
Conversions and selectivities were determined by GC/MS
Plus 7% of Sonogashira product 1,2-bis(4-methoxyphenyl)ethyne
Plus 2% of Sonogashira product
b
c
123

One-pot, Pd-NHC Catalyzed Preparation of Trianisylethylene
553
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3 Conclusion
We were able to prepare trianisylethylene in a one step
procedure from 4-iodoanisole and trimethylsilylacetylene.
To the best of our knowledge, this is the first one-step,
copper-, phosphine- and amine-free, presumably NHC
promoted preparation of trianisylethylene allowing a for-
mal synthesis of chlorotrianisene and amotriphene. Also,
our methodology uses readily available ethanol as a source
of hydrogen for the hydroarylation, which is safer than the
recently presented TFA mediated protocols [28, 42]. The
functionalization of triarylethylenic core of antiestrogenic
compounds will be subject of a forthcoming manuscript.
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