Pd-EnCat TPP30 as a catalyst for the generation of highly functionalized aryl- and alkenyl-substituted acetylenes via microwave-assisted sonogashira type reactions

Article abstract of DOI:10.1002/ejoc.200900344

We report a rapid microwave-assisted Sonogashira crosscoupling of aryl iodides and bromides with terminal alkynes using Pd-EnCat TPP30. Both electron-rich and electrondeficient aryl halides reacted smoothly with a broad variety of terminal alkynes in MeCN

Full text of DOI:10.1002/ejoc.200900344

FULL PAPER
DOI: 10.1002/ejoc.200900344
Pd-EnCatTM TPP30 as a Catalyst for the Generation of Highly
Functionalized Aryl- and Alkenyl-Substituted Acetylenes via
Microwave-Assisted Sonogashira Type Reactions
Jörg Sedelmeier,[a] Steven V. Ley,*[a] Heiko Lange,[a] and Ian R. Baxendale[a]
Keywords: Cross-coupling / Heterogeneous catalysis / Reusable catalyst / Palladium / Microwave chemistry / Enynes
We report a rapid microwave-assisted Sonogashira cross-
coupling of aryl iodides and bromides with terminal alkynes
using Pd-EnCatTM TPP30. Both electron-rich and electron-
deficient aryl halides reacted smoothly with a broad variety
of terminal alkynes in MeCN at 100–120 °C. The coupling
products were obtained in good to excellent yields and in
high purity. This reaction can be performed under copper-
sphere. Furthermore, the encapsulated catalyst can be reco-
vered and recycled by a simple filtration of the reaction mix-
ture. It can be reused in further reactions with only minor
decrease in activity. Additionally, we were able to produce a
variety of enyne derivatives under modified conditions em-
ploying the same Pd-EnCatTM source.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
and DMF-free conditions and does not require an inert atmo- Germany, 2009)
tices. This type of heterogeneous catalyst was successfully
Introduction
applied in hydrogenation reactions as well as in various
C–C bond-forming reactions like Suzuki, Heck, and Stille
cross-couplings.[10a,10b,11] Very recently, the use of Pd-En-
CatTM was applied to Sonogashira coupling reactions
mainly with phenylacetylene reacting with aryl iodides.[12]
We were interested in extending these studies to include a
larger range of acetylenes and effect coupling with more
readily available aryl bromides to define a robust and easy
to operate process that would tolerate wide functionality.
As a consequence we report herein various copper-free
Sonogashira reactions between a broad variety of mainly
aryl bromides and some aryl iodides and various terminal
alkynes as well as some reactions of olefinic halides with
terminal alkynes catalyzed by Pd-EnCatTM TPP30 using
microwave activation.
The Sonogashira cross-coupling reaction is a powerful
method for C–C bond formation.[1] This reaction has found
a variety of applications ranging from the preparation of
fine chemicals to the synthesis of biologically active sub-
stances.[2] Traditionally, this transformation is carried out
in polar, high-boiling solvents such as DMF, NMP and
DMSO, with a complex palladium catalyst in conjunction
with a copper co-catalyst.[3] The difficult removal of the sol-
vent and the oxidative homo-coupling of acetylenes (Glaser
coupling)[4] in the presence of copper(I) salts renders these
protocols less than straightforward to employ. In addition,
the palladium complexes are often costly, not necessarily
readily available and their use in large-scale reactions can
be problematic. As a result of these problems, several modi-
fications to the Sonogashira coupling procedure have been
published, among them reactions in ionic liquids,[5] reac-
tions in water,[6] polymer- and zeolite-supported catalytic
reaction systems,[7] various copper-free conditions[8] and the
use of microwave irradiation.[9]
Results and Discussion
More recently, commercially available Pd-EnCatTM cata-
lysts have been described as an advanced palladium source
for cross-coupling reactions reducing palladium leaching
and being easier to handle, recover and reuse.[10] The pos-
sibility to recover and to reuse this catalyst system is highly
desirable as this leads to more sustainable chemical prac-
For the optimization of the reaction, different catalyst
forms and ratios, solvents, bases, and conditions for the mi-
crowave heating were examined. Because heterogeneous ca-
talysis often suffers from unfavourable kinetics compared to
the homogeneous processes, and because the encapsulated
catalyst itself often needs prior activation, we decided to
use microwave irradiation as a method of heating. In order
to avoid thermal decomposition using high power micro-
wave irradiation, the microwave vial was simultaneously
cooled by flowing a compressed air stream around the mi-
crowave cavity. This procedure repeatedly resulted in prod-
ucts with significantly higher purity.[10a,10b,13]
[a] Innovative Technology Centre, Department of Chemistry, Uni-
versity of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, United Kingdom
Fax: +44-1223-336-442
E-mail: svl1000@cam.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900344.
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Microwave-Assisted Sonogashira Cross-Coupling Reactions
Optimization Studies
Table 2. Influence of the solvent on the Sonogashira coupling reac-
tion.[a]
We began by investigating the effect of different Pd-En-
CatTM species on the model reaction between 4-bromoace-
tophenone (1a) and phenylacetylene (2a) catalyzed by
3.5 mol-% of encapsulated palladium in the presence of tri-
ethylamine as base and THF as a solvent (Table 1). In this
initial coupling reaction the PPh3-containing Pd-EnCatTM
TPP30 proved to be superior to Pd-EnCatTM TOT30, Pd-
EnCatTM BINAP30, Pd-EnCatTM 30 and Pd-EnCatTM
40.[14] In the absence of any catalyst no coupling was ob-
served (Table 1, Entry 6).
Entry
Solvent
Conversion [%][b]
1
2
3
4
5
6
7
THF
62
58
70
73
22
44
35
1,4-dioxane
MeCN
DMF
toluene
iPrOH
EtOH
Table 1. Influence of the palladium source on the Sonogashira
coupling reaction.[a]
[a] Reactions were carried out using 0.5 mmol of aryl halide (1a),
1.0 mmol of phenylacetylene (2a), 1.0 mmol of NEt3 and 3.5 mol-
% of Pd under cooled microwave irradiation, in 0.8 mL of solvent
in a sealed tube at 100 °C for 20 min. [b] Conversions were deter-
1
mined by H NMR spectroscopy.
Table 3. Influence of the base on the Sonogashira coupling reac-
tion.[a]
Entry
Catalyst
Conversion [%][b]
1
2
3
4
5
6
Pd-EnCat 30
Pd-EnCat 40
Pd-EnCat TPP30
Pd-EnCat TOT30
Pd-EnCat BINAP30
no catalyst
12
55
62
49
31
0
[a] Reactions were carried out using 0.5 mmol of 4-bromoacetophe-
none (1a), 1.0 mmol of phenylacetylene (2a), 1.0 mmol of NEt3 and
3.5 mol-% of Pd under cooled microwave irradiation in THF
(0.8 mL) using a sealed tube at 100 °C for 20 min. [b] Conversions
Entry
Base
Conversion [%][b]
1
were determined by H NMR spectroscopy.
1
2
3
4
5
6
7
no base
NEt3
iPr2NEt
iPr2NH
pyrrolidine
morpholine
DBU
0
70
27
72
86
41
99
We then examined the influence of the solvent on the
coupling reaction. Protic solvents such as iPrOH and EtOH
led to only moderate formation of the desired coupling
product 3aa (Table 2, Entries 6 and 7). However, higher
yields were obtained in aprotic solvents, such as MeCN and
DMF (Table 2, Entries 3 and 4). MeCN was easier to re-
move and as it was preferred due to environmental reasons
this was used as the solvent of choice in all further experi-
ments.
[a] Reactions were carried out using 0.5 mmol of 4-bromoacetophe-
none (1a), 1.0 mmol of phenylacetylene (2a), 1.0 mmol of base and
3.5 mol-% of Pd under cooled microwave irradiation in MeCN
(0.8 mL) using a sealed tube at 100 °C for 20 min. [b] Conversions
1
were determined by H NMR spectroscopy.
Finally we tested different bases, as the presence of a
base is a fundamental requirement for the reaction (Table 3,
Entry 1). The most effective base was DBU (Table 3, Entry
7). Secondary amine bases like (iPr)2NH, pyrrolidine and
morpholine, which are commonly applied in Sonogashira
couplings,[1] were less effective when using encapsulated Pd-
species.
In addition, we investigated the influence of catalyst
loading on the Sonogashira reaction (Table 4). For the fava-
ourable substrate combination of 1j and 2b (formation of
3jb) the amount of palladium could be reduced to 0.5 mol-
% without significantly effecting the conversion. However,
in the case of the more challenging pairing of 1j and 2e
Further screening experiments with regard to the stoichi- using only 0.5 mol-% of palladium gave a poor conversion
ometry of the Sonogashira reaction revealed that a ratio of of only 9%. In order to create a generic protocol we decided
aryl halide/acetylene as low as 1:1.2:1.2 could be utilized. to apply 3.5 mol-% of palladium for all Sonogashira cou-
This constitutes a substantial decrease in the acetylene com- plings to ensure maximum conversions and fast reactions.
ponent and is an improvement when compared to other The reusable nature of the catalyst also renders this higher
protocols reported for the Sonogashira coupling.
loading of palladium of reduced significance.
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J. Sedelmeier, S. V. Ley, H. Lange, I. R. Baxendale
FULL PAPER
Table 4. Influence of the catalyst loading on the Sonogashira cou- Scope and Limitations
pling reaction.[a]
Under these optimized reaction conditions a variety of
mainly aryl bromides and some aryl iodides reacted well
with a broad range of terminal acetylenes affording the cor-
responding coupling products in good to excellent yields
(Table 5). This cross-coupling procedure tolerated ortho-
substitution in the aryl halides (Table 5, Entries 7–9, 16–17,
and 20–23). A high functional group compatibility (acetyl,
alcohol, ester, chloride, amide, nitrile and nitro) as well as
good yields and high-purity products were observed. Both
electron-deficient and electron-rich aryl halides were effec-
tive coupling partners for the Sonogashira coupling under
these new conditions. Regardless of their electronic proper-
ties, aryl-, heteroaryl- and alkyl-substituted terminal al-
kynes reacted smoothly with a variety of aryl halides to
produce the desired products. In addition, heterocyclic com-
pounds such as 2-bromopyridine and 3-bromochinoline
could be used as the halogen component to react with ter-
minal acetylenes yielding the corresponding disubstituted
Entry
Product
Catalyst loading [mol-%]
Conversion [%][b]
1
2
3
4
5
6
7
8
3jb
3jb
3jb
3jb
3je
3je
3je
3je
3.5
2
1
0.5
3.5
2
69
63
62
59
53
42
11
9
1
0.5
[a] Reactions were carried out under the corresponding reaction
conditions indicated in Table 5, Entries 31 and 32. [b] Conversions
were determined by H NMR spectroscopy.
1
Table 5. Sonogashira coupling reactions of aryl halides with terminal acetylenes.[a]
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Microwave-Assisted Sonogashira Cross-Coupling Reactions
Table 5. (continued)
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J. Sedelmeier, S. V. Ley, H. Lange, I. R. Baxendale
FULL PAPER
Table 5. (continued)
[a] Reactions were carried out using 0.3 mmol of aryl halide, 0.36 mmol of acetylene, 0.36 mmol of DBU and 3.5 mol-% of Pd under
cooled microwave irradiation in MeCN (0.8 mL) in a sealed tube. Compound purity determined by NMR and LCMS.
acetylenes in moderate to good yields (Table 5, Entries 31–
Indeed we were able to generate a number of function-
34). As expected, less activated aryl halides in combination alized enynes which can be further transformed to useful
with less reactive terminal alkynes gave slightly lower yields products. Using a cis/trans-mixture of β-bromostyrene (1l)
under the optimized standard conditions (Table 5, Entries as a vinyl bromide type substrate, the corresponding enynes
23, 29–30, and 32, 34). N-(4-Bromophenyl)acetamide 3ld and 3lf were isolated as mixtures of their geometric iso-
proved to be a difficult coupling partner (Table 5, Entries mers in good yields (Scheme 1). Additionally we showed
33 and 34). Unprotected 4-bromoaniline and aryl chlorides that the Sonogashira type coupling of both cis- and trans-
in general could not be coupled under the optimized reac- 1,2-dichloroethylene (Table 6, 1m, 1n, respectively) as halo-
tion conditions.
gen partners were effective in Sonogashira couplings. Un-
fortunately, only traces of the desired enynes were observed
when employing the standard conditions; we recovered
mainly unreacted starting materials. Employing the corre-
Formation of Enynes
Enynes represent important building blocks in organic sponding 1,2-dibromoethylene also did not lead to a suc-
synthesis,[15] we were also interested in their preparation cessful reaction.[16] Finally it was determined that working
employing the new procedure.
under an inert atmosphere in dry toluene as solvent, using
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Microwave-Assisted Sonogashira Cross-Coupling Reactions
Table 6. Sonogashira-type coupling reactions of cis- and trans-1,2-dichloroethylene (1m, 1n).
[a] Concentration is given for the halogen component.
the Pd-EnCatTM TPP30 together with a catalytic amount none (1a) and phenylacetylene (2a) was chosen to examine
of copper(I) iodide the desired enynes could be generated the reusability of the encapsulated palladium species. After
in reasonable yields (Table 5, Entries 2–4).[17] Under these carrying out the transformation, the reaction mixture was
conditions the cis-1,2-dichloroethylene was more reactive filtered, and the residue was washed with diethyl ether and
than the trans-isomer.[18]
dichloromethane. The polymeric species was dried under
vacuum and subsequently reused without additional treat-
ment. No significant loss in the catalytic activity of the Pd-
EnCatTM TPP30 was observed up to the fifth use. However,
for the sixth run a slightly longer reaction time was neces-
sary to achieve the same result. These findings correspond
to the fact, that the encapsulated Pd-species used in the re-
actions are known to release metals only very slowly,[9]
which eventually lead to depletion of the metal reservoir of
the Pd-EnCatTM
.
We also wished to establish the mode of action of the
Pd-EnCatTM system by evaluating the level of active metal
leached into solution. In order to test the residual palla-
dium following a transformation substrates 1a and 2a were
coupled under the previously optimized reaction conditions
giving quantitative conversion to 3aa. The reaction mixture
was then immediately filtered to remove the heterogeneous
catalyst and a second substrate combination (1a and 2e)
was added to the solution. The homogeneous reaction mix-
ture was heated and the resulting solution analyzed. No
formation of the desired product 3ae was detected. It was
however apparent from visual inspection of the dark col-
oured reaction that small quantities of palladium are le-
ached under the standard reaction conditions albeit this
species is catalytically inactive and is presumably palladium
Scheme 1. Sonogashira reactions of β-bromostyrene. Reactions
were carried out using 0.3 mmol of aryl halide, 0.36 mmol of
acetylene, 0.36 mmol of DBU and 3.5 mol-% of Pd under cooled
microwave irradiation in MeCN (0.8 mL) in a sealed tube.
Recycling of the Catalyst
Reusability of the catalyst is an important consideration
pertaining to cost reduction and lowering the environmen-
tal impact, the recycle of the Pd-EnCatTM was investigated
(Table 7). The coupling reaction between 4-bromoacetophe-
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J. Sedelmeier, S. V. Ley, H. Lange, I. R. Baxendale
FULL PAPER
Table 7. Reusability of the Pd-EnCatTM TPP30.[a]
bromides as well as heteroaryl species underwent the cou-
pling reaction with differently substituted terminal alkynes
to afford the corresponding coupling products in moderate
to excellent yields. In addition, we were able to produce
enynes using the polymeric catalyst. Finally, we demon-
strated that the Pd-EnCatTM TPP30 can easily be recovered
and reused for at least five cycles without a significant loss
in catalytic activity.
Entry
Run
Temp. [°C]
Time [min]
Conversion [%][b]
1
2
3
4
5
6
1
2
3
4
5
6
120
120
120
120
120
120
10
10
10
10
10
15
98
98
92
94
90
92
Experimental Section
General Remarks: Acetonitrile was used as purchased without fur-
ther purification. Toluene was dried, freshly distilled, and degassed
before use. All reactions in toluene were performed under an atmo-
sphere of argon and carried out using oven-dried glassware. All
reactants and reagents were used as purchased without further pu-
rification. Copper(I) iodide was stored under an inert atmosphere.
All microwave heating was performed on an Emrys synthesizer
(Biotage AG, 1725 Discovery Drive, Charlottesville, Virginia 22911,
USA) Reaction temperatures were measured using the internal IR-
detector and are specified without reference to internal calibration
and may differ from the true value. Air cooling of the microwave
reactions is via a regulated 2 bar nitrogen pressure delivered at at-
mospheric temperature (20 °C). A constant microwave power input
of 70–85 W was required to maintain the specified temperature of
100 or 120 °C. Infrared spectra were recorded as neat samples on
a Perkin–Elmer Spectrum One FT-IR spectrometer fitted with an
ATR sampling accessory. 1H NMR spectra were recorded at 27 °C
on Bruker DPX-400. Residual protic solvent was used as the in-
ternal reference (CHCl3 δH = 7.27 ppm). 13C NMR spectra were
recorded at 100 MHz, 125 MHz and 150 MHz on Bruker DPX-
400. The resonance CDCl3 (δC = 77.0 ppm, t) was used as the in-
ternal reference. Mass spectra were recorded on Waters LCT Premier,
Bruker Daltronics Bioapex II or Kratos Concept spectrometers.
Accurate mass data were obtained on Micromass Q-TOF by elec-
trospray ionisation (ESI). Melting points were performed on a
Reichert hot-stage apparatus and are uncorrected. Flash column
chromatography was carried out using silica gel [Merck or Breck-
land (230–400 mesh)] under pressure with DE/PE mixtures (DE =
diethyl ether, PE = petroleum ether, boiling range 40–60 °C).
[a] Reactions were carried out using 0.3 mmol of a 4-bromoace-
tophenone (1a), 0.36 mmol of phenylacetylene (2a), 0.36 mmol of
DBU and 3.5 mol-% of Pd-EnCatTM TPP30 under cooled micro-
wave irradiation in 0.8 mL of MeCN in a sealed tube. [b] Conver-
1
sions were determined by H NMR spectroscopy.
black. In an extension of this investigation we added an
excess of a strong palladium scavenger resin, Quadrapure-
TU, to a new reaction mixture prior to heating (1a and 2a).
This reaction proceeded to completion in an analogous way
to the original reaction to furnish 3aa. In addition the reac-
tion mixture showed none of the previously observed dark
contamination (Figure 1). We believe that these results indi-
cate that catalysis predominantly occurs within the En-
CatTM matrix (in association with the phosphane back-
bone) and that a combination of the heterogeneous catalyst
and a scavenger resin is an ideal combination to preform
these reactions cleanly.
Representative Procedure for the Preparation of the Aryl Acetylenes
and the Enynes 3ld and 3lf by Sonogashira Type Cross-Coupling
Reactions Using Pd-EnCatTM TPP30: Preparation of 1-[4-(Phenyl-
ethynyl)phenyl]ethanone (3aa): Under aerobic conditions, a micro-
wave vial was charged with Pd-EnCatTM TPP30 (40 mg, containing
0.01 mmol of Pd), DBU (45 µL, 0.3 mmol), 4-bromoacetophenone
(1a) (49.8 mg, 0.25 mmol), phenylacetylene (2a) (30.6 mg,
0.3 mmol) and MeCN (0.8 mL). The vial was sealed and the reac-
tion mixture was then irradiated under simultaneous cooling with
streaming air for 10 min at 100 °C. After the reaction was cooled to
ambient temperature, the crude reaction mixture was diluted with
diethyl ether and then filtered through a short plug of silica gel.
The organic layer was concentrated to yield the coupling product
Figure 1. Comparision of the Pd-EnCatTM TPP30 (left vial) and
Pd-EnCatTM TPP30 with Quadrapure-TU scavenger resin (right
vial).
1
Conclusions
3aa in 98% yield. H NMR (400 MHz, CDCl3): δ = 7.95 (d, J =
8.3 Hz, 2 H, Ph/Ar), 7.62 (d, J = 8.3 Hz, 2 H, Ph/Ar), 7.60–7.54
(m, 2 H, Ph/Ar), 7.39–7.37 (m, 3 H, Ph/Ar), 2.62 (s, 3 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 197.3 (C=O), 136.1 (Ph/
Ar), 131.7 (Ph/Ar), 131.6 (Ph/Ar), 128.8 (Ph/Ar), 128.4 (Ph/Ar),
128.2 (Ph/Ar), 122.6 (Ph/Ar), 92.6 (CϵC), 88.5 (CϵC), 26.6 (CH3)
We have developed an efficient, rapid, easy to operate
catalytic procedure for the microwave-assisted Sonogashira
cross-coupling reaction by using an encapsulated palladium
species Pd-EnCatTM TPP30 as catalyst in MeCN under
copper-free reaction conditions. Various aryl iodides and ppm. The spectroscopic data correspond to the literature.[9b]
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Microwave-Assisted Sonogashira Cross-Coupling Reactions
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Representative Procedure for the Preparation of the Enynes 3mc,
2nb, and 3nc by Sonogashira Type Cross-Coupling Reactions Using
Pd-EnCatTM TPP30: Preparation of (Z)-1-Chloro-5,5-diethoxypent-
1-en-3-yne (3mc): Under inert conditions, a microwave vial was
charged with Pd-EnCatTM TPP30 (80 mg, containing 0.02 mmol of
Pd), CuI (9 mg, 0.06 mmol) and with dry and degassed toluene
(3 mL). Then cis-dichloroethylene (1m) (75 µL, 1.0 mmol), 3,3-di-
ethoxyprop-1-yne (2c) (72 µL, 0.5 mmol) and DBU (76 µL,
0.5 mmol) were added. The vial was sealed and the reaction mix-
ture was then irradiated for 10 min at 100 °C. After the reaction
was cooled to ambient temperature, the crude reaction mixture was
diluted with diethyl ether and then filtered through a short plug of
silica gel. The crude mixture was purified by column chromatog-
raphy to yield coupling product 3mc in 89% yield. 1H NMR
(400 MHz, CDCl3): δ = 6.44 (d, J = 7.6 Hz, 1 H, ClHC=CH), 5.91
(dd, J = 7.6, 1.2 Hz, 1 H, ClHC=CH), 5.43 [br. d, J = 1.2 Hz, 1
H, CH(OCH2CH3)2], 3.84–3.68 (m, 2 H, OCHA2CH3), 3.67–3.52
(m, 2 H, OCHB2CH3), 1.25 (t, J = 7.0 Hz, 6 H, OCH2CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 130.0 (ClHC=C), 111.3
(ClHC=C), 92.4 (CϵC), 91.2 (CϵC), 75.1 [CH(OCH2CH3)2], 61.3
(OCH2CH3), 15.0 (OCH2CH3) ppm. The spectroscopic data corre-
spond to the literature.[18]
[8]
[9]
[10]
[11]
Supporting Information (see also the footnote on the first page of
this article): Full experimental data and complete spectroscopic
data for every newly synthesized compound.
Acknowledgments
[12]
[13]
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The authors thank the German Academic Exchange Service
(DAAD) for a postdoctoral fellowship (J. S.), the Alexander von
Humboldt Foundation for a postdoctoral fellowship (H. L.), the
Engineering and Physical Sciences Research Council (EPSRC) for
funding (I. R. B., H. L.), and the BP 1702 professorship (S. V. L.).
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Eur. J. Org. Chem. 2009, 4412–4420
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Sedelmeier, S. V. Ley, H. Lange, I. R. Baxendale
FULL PAPER
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Received: March 30, 2009
Published Online: July 24, 2009
4420
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4412–4420