Dimeric ortho-palladated homoveratrylamine as an efficient homogeneous catalyst for copper-free Sonogashira cross-coupling reaction

Article abstract of DOI:10.1002/aoc.2920

The catalytic activity of ortho-palladated [Pd{C6H2(CH2CH2NH2)-(OMe)2,3,4} (m-Br)]2, a complex of homoveratrylamine in the copper-free Sonogashira coupling reaction has been investigated. This complex is a catalyst that is efficient, stable and non-sensitive to air and moisture in the Sonogashira reaction. In this homogeneous catalytic system, various aryl halides were efficiently coupled with phenylacetylene in mostly moderate to good yields in N-methylpyrrolidone at 100 °C under copper-free conditions. Copyright

Full text of DOI:10.1002/aoc.2920

Full Paper
Received: 30 April 2012
Revised: 30 July 2012
Accepted: 6 August 2012
Published online in Wiley Online Library: 3 October 2012
(wileyonlinelibrary.com) DOI 10.1002/aoc.2920
Dimeric ortho-palladated homoveratrylamine as
an efficient homogeneous catalyst for copper-
free Sonogashira cross-coupling reaction
a,b
a
a
Abdol R. Hajipour *, Hannaneh Rahimi and Fatemeh Rafiee
The catalytic activity of ortho-palladated [Pd{C6H2(CH2CH2NH2)-(OMe)2,3,4}(m-Br)]2, a complex of homoveratrylamine in
the copper-free Sonogashira coupling reaction has been investigated. This complex is a catalyst that is efficient, stable and
non-sensitive to air and moisture in the Sonogashira reaction. In this homogeneous catalytic system, various aryl halides were
ꢀ
efficiently coupled with phenylacetylene in mostly moderate to good yields in N-methylpyrrolidone at 100 C under copper-
free conditions. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: Sonogashira reaction; catalyst; ortho-palladated complex; internal alkynes
as thermally stable and oxygen insensitive catalysts for the
Sonogashira cross coupling reaction.
Palladium-catalyzed transformations are among the most potent
Introduction
and convenient tools of modern organic synthesis for C-C bond
[1,2]
Results and Discussion
formation.
There are various cross-coupling reactions, and
among them Sonogashira coupling reactions of acetylenes with
aryl or alkenyl halides or triflates have been developed in organic
chemistry and material science for the production of internal
The ortho-palladated complex [Pd{C H (CH CH NH )–(OMe) ,3,4}
6
2
2
2
2
2
[
32]
(
m-Br)]2 was prepared according to our previous work.
[3–6]
The acetate-bridged ortho-palladated complex was obtained
alkyne and enynes.
Alkynes are the building blocks of a wide
from homoveratrylamine by addition of Pd(OAc) in acetonitrile
2
range of pharmaceuticals, natural products, biologically active
molecules, conducting polymers, nonlinear, optical and liquid-
as a binuclear complex. The halogen-bridged ortho-palladated
complex was prepared by the addition of NaBr to a solution of
the acetate-bridged complex in acetone.
[7–12]
crystal materials.
The Sonogashira cross-coupling reactions
are usually mediated by phosphane-based palladium complexes.
Generally, sterically hindered phosphine ligands showed high
activities in cross-coupling reactions such as Sonogashira
A suitable chemical production process via palladium catalysis
requires high catalyst productivity and activity. Furthermore, the
availability and cost of catalysts and the price of the organic
starting materials are of great importance for industrial processes.
Homoveratrylamine is an available and inexpensive amine. The
ortho-palladation reaction of this substrate is simple and leads
to an efficient catalyst for coupling reactions even with unreac-
tive aryl chlorides, which are readily available and inexpensive
substrates. Herein, the efficiency of this catalyst is evaluated in
the Sonogashira reaction of various types of aryl halides with
phenylacetylene (Scheme 1).
In order to optimize the reaction conditions, we first carried
out the cross-coupling reaction between 4-bromobenzonitrile
with phenylacetylene as a model reaction. We examined the
effect of various reaction parameters such as solvent, base
and temperature on yields of the coupling products as shown
in Table 1. The data showed that the best results were obtained
[13–15]
couplings.
Most research has developed to obtain high
catalytic activity with efficient catalytic systems. Moreover, a
number of important studies have focused on the development
[16–18]
of phosphine-free ligands such as N-heterocyclic carbenes.
Phosphine ligands suffer some drawbacks such as sensitivity to air
or moisture and the requirement for an inert environment and
large amounts of palladium source for carrying out the reaction.
Although carbene-type ligands are more stable than alkyl
phosphines, they must be synthesized through multiple steps.
Among the advanced catalysts, the palladacycles are the most
important class of organometallic catalyst precursors and are used
for highly efficient catalysis at very low concentration for C-C bond
formation in organic synthesis, material science, biologically active
[
19–22]
[23]
compounds and macromolecular chemistry.
Oxime
and
[24]
ferrocenylimine palladacycles as effective catalysts were found
to promote the Sonogashira reaction. The high productivity of
palladacycle catalysts is due to the slow generation of paltry ligated
Pd(0) complexes from a stable palladium(II) pre-catalyst that
*
Correspondence to: Abdol R. Hajipour, Pharmaceutical Research Laboratory,
Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR
Iran. E-mail: haji@cc.iut.ac.ir
[
25]
undergoes an activation process.
In continuation of our recent investigations on the synthesis
and applications of the palladacycle catalysts in cross-coupling
a Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran
[26–33]
reactions,
Pd{C (CH
we now wish to report the extension of dimeric
NH )–(OMe) ,3,4}(m-Br)] homogeneous complex
b Department of Neuroscience, University of Wisconsin Medical School, Madison,
WI, 53706-1532, USA
[
H
6 2
CH
2 2
2
2
2
Appl. Organometal. Chem. 2012, 26, 727–730
Copyright © 2012 John Wiley & Sons, Ltd.

A. R. Hajipour et al.
OMe
when the cross-coupling reaction was carried out with 0.8 mol%
of dimeric complex (Table 2, entry 5).
The optimized reaction conditions were applied to the
Sonogashira cross-coupling reaction of various aryl halides
with phenylacetylene (Table 3).
OMe
Pd
Br
2
Ph
NH2
X
(
dimeric complex)
R
+
Ph
H
R
Piperidine, NMP
We examined the electronic and steric effects on the resulting
yields and conversion times of the reactions. Aryl halides substi-
tuted with electron-withdrawing groups in comparison to
electron-donating substituent gave better conversions in
shorter reaction times. The effects of steric hindrance and
chemo-selectivity of the procedure were examined using
2-, 3- and 4-chlorobromobenzene (Table 3, entries 12–14).
An increasing hindrance in the vicinity of the leaving group
results in a decrease in the conversion. In these reactions, Br acted
as a better leaving group. In some of these cross-coupling reactions
1,4-diphenylbuta-1,3-diyne was formed as a by-product (3–15%).
The Sonogashira reaction probably proceeds through oxidative
addition of the aryl halide to the Pd(0) catalytic species that
generates homogeneous Ar-Pd-X species. The coordination of the
alkyne to the metal center followed based-assisted H-X elimination
gave Ar-Pd-C&tbond;C-Ph, which by reductive elimination yielded
°
1
00 C
Scheme 1. The Sonogashira cross-coupling reaction of various aryl
halides by dimeric ortho-palladated complex.
Table 1. Optimization of reaction conditions for the Sonogashira
a
cross-coupling reaction
ꢀ
b
Entry
Solvent
Base
Temperature ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
NMP
NMP
NMP
NMP
NMP
NMP
—
NaOAc
100
100
100
100
100
100
100
100
80
45
50
55
70
75
90
60
88
75
75
65
0
NEt
Pyrrolidine
CO
Cs CO
3
K
2
3
2
3
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
[
34]
the coupling product and Pd(0).
DMAc
DMAc
DMF
A study on NC palladacycle catalyst cross-coupling showed
that palladacycles decompose to liberate catalytic Pd(0) species
[
35,36]
10
11
12
13
100
80
and show a positive Hg(0) test.
To evaluate the proposed
CH
3
CN
mechanism, the mercury drop test was utilized, since mercury
leads to amalgamation of the surface of a heterogeneous
catalyst. In contrast, Hg(0) is not expected to have a poisoning
EtOH
EtOH
r.t.
70
45
[
35,37]
a
effect on homogeneous palladium complexes.
When a drop
Reaction conditions: 4-bromobenzonitrile (0.5mmol), phenylacetylene
0.5mmol), base (1mmol), ortho-palladated catalyst (1 mol%), 2 h.
of Hg(0) was added to the reaction mixture of 4-bromobenzonitrile
and phenylacetylene under the mentioned optimized conditions
and heated using an oil bath, no catalytic activity was observed
for the catalyst. The data obtained confirmed the Pd(0):Pd(II) cycle.
(
b
GC yield.
using N-methylpyrrolidone (NMP) as solvent and piperidine as a
ꢀ
base at 100 C. Under these conditions 4-cyanodiphenylacetylene
was obtained as the desired product in 90% yield and 1,
Conclusion
4
-diphenylbuta-1,3-diyne was formed as a by-product in 3% yield
via the homo-coupling of phenylacetylene.
We employed dimeric ortho-palladated complex [Pd{C
6 2
H
Furthermore, we optimized the percentage of catalyst used,
employing various amounts of catalyst for this cross-coupling us-
ing piperidine as a base and NMP as solvent. The results are sum-
marized in Table 2. A low palladium concentration usually led to a
longer period of reaction, as increasing the amount of palladium
catalyst shortened the reaction time, but did not increase the
yield of cross-coupled product. The best result was obtained
(
CH CH NH )–(OMe) ,3,4}(m-Br)] as a catalyst that is highly efficient,
2
2
2
2
2
stable and non-sensitive to air and moisture in the Sonogashira
cross-coupling reaction. The catalytic amount of this catalyst led
to formation of substituted aromatic alkynes in good to excellent
yields under copper-free conditions.
Experimental
Table 2. Optimization of the catalyst concentration on the Sonogashira
cross-coupling reaction
a
Chemicals
b
Entry
Catalyst (mol%)
Time (h:min)
Conversion (%)
All melting points were taken on a Gallenkamp melting apparatus
and are uncorrected. H NMR spectra were recorded at 500MHz
in CDCl solution at room temperature (tetramethylsilane was used
3
as an internal standard) on a Bruker Avance 500 instrument
(Rheinstetten, Germany). FT-IR spectra were recorded on a spectro-
photometer (Jasco 680, Japan). Spectra of solids were carried out
using KBr pellets. Vibrational transition frequencies are reported
1
1
2
3
4
5
6
7
None
0.2
0.5
0.6
0.8
1
12
5
0
50
65
75
90
90
90
5
5
2:30
2:30
2
À1
2
as wave number (cm ). We used a Beifin 3420 gas chromatograph
equipped with a Varian CP SIL 5CB column (30 m, 0.32 mm,
a
Reactions conditions: 4-bromobenzonitrile (0.5mmol), phenylacetylene
0.5mmol), piperidine (1mmol), NMP (3 ml), ortho-palladated catalyst.
0.25 mm) for examination of reaction competition and yields.
(
b
Palladium acetate, aryl halides and all chemicals were purchased
from Merck and Aldrich and were used as received.
GC yield.
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 727–730

Sonogashira cross-coupling reaction
a
Table 3. Sonogashira reaction using dimeric ortho-palladated complex of homoveratrylamine
[ref.]
c
Entry
Ar–X
Product
Time (h)
Yield (%)
[
24]
1
2
3
4
5
6
7
8
9
Ph-I
Ph-C&tbond;C-Ph
p-O N-C -C&tbond;C-Ph
m-O N-C
p-MeO-C
Ph-C&tbond;C-Ph
p-MeO-C -C&tbond;C-Ph
p-NC-C
o-O N-C
p-OHC-C
p-MeOC-C
p-Cl-C -C&tbond;C-Ph
m-Cl-C
o-Cl-C
1-Ph-C&tbond;C-naphthalene
1
0.35
0.6
2.5
10
18
2.5
10
5
88
97
94
70
50
43
90
66
60
55
79
66
50
56
67
38
35
[
39]
p-O
2
N-C
N-C
6
H
4
-I
2
6 4
H
[40]
m-O
2
6
H
4
-I
-I
2
6 4
H -C&tbond;C-Ph
[38]
p-MeO-C
Ph-Br
6
H
4
6 4
H -C&tbond;C-Ph
[24]
[38]
p-MeO-C
6
H
4
-Br
6 4
H
[
24]
p-NC-C
o-O N-C
p-OHC-C
p-MeOC-C
p-Cl-C -Br
m-Cl-C
o-Cl-C
6
H
4
-Br
-Br
-Br
-Br
6 4
H -C&tbond;C-Ph
[24]
2
6
H
4
2
6 4
H -C&tbond;C-Ph
[
39]
6
H
4
6 4
H -C&tbond;C-Ph
[24]
10
11
12
13
14
15
16
17
6
H
4
6
H
4
-C&tbond;C-Ph
10
0.8
1
[
38]
6
H
4
6 4
H
[
41]
6
H
4
-Br
-Br
6 4
H -C&tbond;C-Ph
[
41]
6
H
4
6
H
4
-C&tbond;C-Ph
1.2
5
[
38]
1-Br-naphthalene
9-Br-phenanthrene
[42]
9-Ph-C&tbond;C-phenanthrene
;5
[24]
p-O
2
N-C
6
H
4
-Cl
p-O
2
N-C
6
H
4
-C&tbond;C-Ph
18
24
[
24]
2-Br-pyridine
2-Ph-C&tbond;C-pyridine
a
Reaction conditions: arylhalide (0.5 mmol), phenylacetylene (0.5 mmol), piperidine (1 mmol), NMP (3 ml), ortho-palladated catalyst (0.8 mol%).
b
Isolated yield.
General Procedure for the Synthesis of Dimeric ortho-Palladated
After the reaction was complete, the mixture was cooled to room
Complex
temperature and diluted with n-hexane and water. The organic
phase was dried over MgSO , filtered and concentrated under
reduced pressure using a rotary evaporator. The residue was
4
A 50 ml round-bottom flask was charged with homoveratrylamine
(1.1 mmol), Pd(OAc)2 (1.1mmol) and acetonitrile (20 ml) and
purified by silica gel column chromatography. The products were
refluxed for 4 h. The resulting suspension was filtered through a
1
13
characterized by comparing their m.p., IR and H, C NMR spectra
plug of MgSO , the solvent was removed under reduced pressure,
[24,38–42]
4
with those found in the literature.
and then CH Cl (2ml) and n-hexane (15 ml) or Et O (7ml) was
2
2
2
added to give acetate-bridged ortho-palladated complex as a yel-
low precipitate, which was filtered off, washed with water and air
dried. To a solution of this complex (0.2mmol) in acetone (25 ml)
was added NaBr (1.94mmol) and the suspension was stirred for
Acknowledgments
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran,
and Isfahan Science and Technology Town (ISTT), IR Iran. Further
financial support from the Center of Excellence in Sensor and
Green Chemistry Research (IUT) is gratefully acknowledged.
8
h; then acetone was evaporated, CH Cl (10 ml) was added and
2 2
the mixture was filtered through a plug of MgSO . The filtrate was
4
concentrated to 2 ml under reduced pressure using a rotary
evaporator and n-hexane (15 ml) or Et O (7ml) was added. The
2
produced suspension was filtered off and air dried to afford the
halogen-bridged ortho-palladated complex as an orange solid.
ꢀ
1
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Appl. Organometal. Chem. 2012, 26, 727–730