Efficient copper-free Sonogashira coupling of aryl chlorides with palladium on charcoal

Article abstract of DOI:10.1039/b810928a

Palladium on charcoal serves as an efficient and reusable solid supported catalyst for the Sonogashira coupling of aryl chlorides with terminal acetylenes in the presence of a bulky, electron-rich biphenyl type ligand (XPhos), without copper co-catalyst. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810928a

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Efficient copper-free Sonogashira coupling of aryl chlorides
with palladium on charcoalw
´ ´ ´
Anna Komaromi and Zoltan Novak*
Received (in Cambridge, UK) 27th June 2008, Accepted 11th July 2008
First published as an Advance Article on the web 8th September 2008
DOI: 10.1039/b810928a
Palladium on charcoal serves as an efficient and reusable solid
supported catalyst for the Sonogashira coupling of aryl chlorides
with terminal acetylenes in the presence of a bulky, electron-rich
biphenyl type ligand (XPhos), without copper co-catalyst.
after 12 h. Among bidentate ligands dppf showed the highest
activity (37%), while biphenyl type ligands proved to be more
effective than the former. Almost complete conversions were
obtained with the application of triisopropyl substituted ortho-
biphenylphosphane ligand (XPhos).
After the ligand screening we chose XPhos as an excellent
candidate for further optimization. First, we studied the
applicability of different bases for the coupling, and we found
that organic bases such as amines (DIPA, MeNCy2) are not
effective at all. Although in the presence of strong inorganic
(KOH, NaOH) and organic bases (tBuOK, tBuONa and
MeONa) the conversion of chlorobenzene was almost com-
plete,7 we detected only a small amount of the desired product.
Among the carbonates, Li2CO3 was not effective, but in the
presence of Na2CO3 the conversion was 96% and K2CO3
resulted in full conversion in 12 h.
The palladium-catalyzed Sonogashira reaction is one of the
most frequently used synthetic tools for the construction of
new C(sp)–C(sp2) bonds in organic synthesis.1 While both aryl
iodides2 and bromides3 are excellent coupling partners of
terminal acetylenes, the achievement of cross couplings on
the more practical and accessible aryl chlorides4 is still chal-
lenging. Generally, the Sonogashira reaction required Cu(I)
co-catalyst for the achievement of efficient coupling, but the
presence of the copper salt can also facilitate the homo-
coupling of the terminal acetylene as a side reaction. There-
fore, considerable effort has been directed to the development
of effective copper-free processes.5 Additionally, the reduction
of the catalyst loading and the recycling of the palladium
metal are also quite important in this field of synthesis. For
these reasons, utilization of the most readily available palla-
dium on charcoal6 catalysts under copper-free conditions
would provide a good opportunity for recycling of the rela-
tively expensive transition metal and would also reduce the
metal and butadiyne contamination of the products.
After finding a suitable non-toxic base, we used K2CO3 for
further optimization studies concerning the effect of the
solvent, the amount of catalyst and the reaction temperature.
While in light of our earlier results,11b the choice of DMA as
solvent was obvious, we tested different solvents and we
optimized the reaction time. In DMA the reaction was com-
plete in 2 h at 110 1C with 5% Pd/C and 5% XPhos. DMF and
DMSO showed similar results to DMA, but slower reaction
was found in dioxane (90% conversion) and toluene (62%
conversion), and MeCN was not applicable at all.
Herein we report a straightforward procedure for the
Sonogashira coupling of aryl chlorides with acetylenes under
copper-free conditions in the presence of a palladium on
charcoal catalyst using a non-toxic carbonate base.
Our attempt to decrease both the reaction temperature and
the catalyst loading simultaneously caused significantly lower
conversions and the necessity of longer reaction times even in
the case of all three applicable polar solvents. In addition,
keeping the temperature at 110 1C we were able to reduce the
catalyst loading to 0.5 mol% without significant change in
reaction time (2 h) necessary for full conversion in DMA.
The palladium : ligand ratio is also important in solid-supported
coupling reactions. We have found that a 1 : 1 Pd : ligand ratio is
optimal from the point of view of efficiency and ligand saving. Our
final optimizations addressed the effect of copper. We have found
that the presence of CuI in the reaction mixture, even in a minimal
amount, caused significant disruption to the catalytic activity.
Finally, the comparison of the activity of the Pd/C8 to
several homogeneous palladium sources showed that the solid
supported catalyst has very high activity under the applied
conditions compared to the tested catalysts (Table 1).
At the begining of our examination we screened a variety of
ligands in the palladium on charcoal catalyzed Sonogashira
coupling (see ESIw). As a model reaction, coupling of chloro-
benzene and phenylacetylene was chosen to optimize reaction
conditions. The application of both electron-rich and electron-
deficient triarylphoshanes were not effective in the coupling.
Surprisingly, in the presence of bulky trialkyl phosphanes,
t
such as Bu3P, we did not observe detectable product forma-
tion. In contrast, application of Cy3P gave 20% conversion
Department of Organic Chemistry, Institute of Chemistry, Eotvos
¨
Lorand University, Pazmany Peter stny. 1/a, Budapest, Hungary.
¨
´
´
´
´
E-mail: novakz@elte.hu; Fax: +36-1-372-2909;
Tel: +36-1-209-0555 #1610
w Electronic supplementary information (ESI) available: Results of
the optimization studies, experimental procedures and characteriza-
tion data for the products (the identity and purity of the known
products was confirmed by 1H and 13C NMR spectroscopic analysis,
and the new products were fully characterized). See DOI: 10.1039/
b810928a
After the optimization studies, we applied our conditions in
the coupling of aryl chlorides and terminal acetylenes to assess
the scope of the reaction.z First, a wide range of aryl chlorides
bearing either electron-withdrawing or electron-donating
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Table 2 Sonogashira coupling of aryl chlorides with acetylenesa
Table 1 Comparison of palladium catalysts
Entry
Catalyst
Time (h)
Conv. (%)
1
2
3
4
5
6
7
8
Pd/C
PdCl2
1
1
1
1
1
1
1
1
65 (88)a
34
6
29
Pd(OAc)2
Pd(NO3)2
Pd(dba)2
Pd2(dba)3
(Allyl)2Pd2Cl2
PdCl2(PhCN)2
24
70 (85)a
21
12
a
Conversion after 1.5 h, determined by GC, in parentheses.
functional groups were coupled to phenylacetylene 2a (Table 2,
entries 1–11) with excellent yields in 2 h. Among the sub-
strates, sterically hindered ortho-chlorobenzene 1i and
2-chloro-1,3-dimethylbenzene were also successfully coupled
with phenylacetylene (entries 9 and 14). These results demon-
strate the high functional group tolerance of the catalyst
system and the applied conditions.
Besides aromatic systems we have also examined the beha-
vior of heterocyclic chlorides in the Sonogashira reaction.
Coupling of phenylacetylene with 2-chloropyridine 1l and
2-chlorothiophene 1m afforded the appropriate internal
acetylene with very good yields (entries 12, 13) in the same
reaction time. The coupling reactions of other aromatic
acetylenes such as 3-tolylacetylene 2b or 2-naphthylacetylene
2c and aryl chlorides having different electronic properties also
gave excellent isolated yields (entries 15–20). In contrast to the
straightforward coupling of arylacetylenes we have found that
the aliphatic alkynes showed lower reactivity toward the aryl
chlorides and gave slightly lower yields under our conditions.
Reaction of chlorobenzene with 1-octyne 2d required
prolonged reaction time to complete the reaction even in the
case of electron-deficient 4-cyanochlorobenzene (entry 22), but
after the appropriate reaction time we obtained all the internal
acetylenes in good isolated yields (entries 21–23). While our
attempts to couple trimethylsilylacetylene have been to date
unsuccessful due to its sensitivity, the TIPS protected acetylene
2e proved to be an excellent coupling partner (entries 24–26).
Besides the silyl-protected acetylenes, carbinol type acetylene
sources also play an important role for the introduction of
triple bonds into organic molecules.9 Therefore we examined
the possibility of coupling of 1-ethynyl-1-cyclohexanol10 2f
with different aryl chlorides for the construction of carbinol
protected internal acetylenes. These reactions also take place
in 8 h with full conversion obtaining the appropriate products
in good yields (entries 27–29).
Considering the mechanism of the reaction, it is important
to note that these kinds of solid supported systems are not
truly heterogeneous catalysts. It is well known, that palladium
on charcoal serves only as a heterogeneous source of cataly-
tically active palladium species for homogeneous coupling
involving leaching and redeposition steps.11 To prove this
presumption, we performed phase separation by hot filtration
a
Reaction conditions: 0.5 mmol aryl chloride, 0.75 mmol acetylene,
0.75 mmol K2CO3, 0.25 mL DMA, 1 mol% palladium using 10% w/w
Pd/C, and 1 mol% XPhos. bYields of isolated product after chroma-
c
tographic purification. 3 mol% Pd and ligand was used.
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products were purified by column chromatography using pure hexane or
hexane–ethyl acetate mixtures as eluent.
after 30 min. Examination of the filtered homogeneous reac-
tion mixture showed that the reaction took place after the
separation of the support, which is the sign of the presence of
leached palladium species.
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After the demonstration of applicability of palladium on
charcoal in Sonogashira coupling of aryl chlorides we ad-
dressed our next examination to the possibility of recycling
the palladium catalyst. Using the developed condition for the
coupling described above, we studied the activity of the
recycled catalyst in the coupling of chlorobenzene and phenyl-
acetylene. We found that the Pd/C catalyst can be reused after
filtration and subsequent treatments such as washing with
water, acetone and DCM, and drying. However, the activity
of the recycled catalyst decreased after each use, though
prolonged reaction time did result in full conversion in every
repeated run (12, 16, 18, 20 and 24 h, respectively). It is of note
that the addition of ligand to the reused catalysts was neces-
sary in every repeated run.
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In conclusion, we have successfully achieved the Sonogashira
reaction of aryl chlorides and terminal acetylenes without
copper co-catalyst in the presence of only 1 mol% palladium
on charcoal and 1 mol% of a bulky biaryl type phosphane
ligand. We established that the optimal choice of the
solvent, base and temperature are crucial for the completion
of the reactions. In addition, the conditions developed not
only provide one of the most efficient methodologies to date
for the coupling of aryl acetylenes with a wide variety
of structurally and electronically diverse aryl chlorides, but
also offers an alternative tool for the coupling of aliphatic
acetylenes, silyl or carbinol protected acetylenes. Besides
the synthetic value of the reaction conditions, the application
of Pd/C as the most readily available solid supported Pd
catalyst provides convenient and easy catalyst separation
and the possibility of reuse the catalyst after the reaction.
The authors thank Prof. K. Torkos, Dr Zs. Eke, Ms. D.
7 We have not been able to identify the side products of these
reactions yet, but significant decomposition of the aryl chloride
was observed under the applied reaction conditions.
8 All the coupling reactions were performed with Pd/C catalyst
containing 10% w/w palladium. The type of the applied catalyst
is very important for the successful coupling, therefore we also
tested several commercially available Pd/C catalysts. For the
results of such comparative studies see ESIw.
Benesoczki, Mr L. Tolgyesi and Prof. P. Kele for providing the
´
¨
necessary analytical background. The financial support of the
Hungarian Scientific Research Fund (OTKA D048657) is
gratefully acknowledged.
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z General procedure for the Pd/C-catalyzed Sonogashira coupling of aryl
chlorides: A dry 4 ml screw capped vial with septa was charged with 5 mg
of 10% Pd/C Selcat Q6 (0.005 mmol), 2.4 mg of XPhos (0.005 mmol) and
97 mg K2CO3 (0.75 mmol). The vial was purged with argon, then 0.25 mL
DMA was added followed by 0.5 mmol of the aryl chloride and 0.75
mmol of the acetylene. The reaction mixture was placed into a 110 1C oil-
bath and was stirred for the appropriate reaction time. After the mixture
was cooled to ambient temperature, the charcoal was filtered off and water
was added to the reaction mixture. The aqueous phase was extracted with
diethyl ether, and the combined organic phases were dried over magne-
sium sulfate. After the removal of the solvent in vacuum, the crude
´
kei, Z. Nova
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¨
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This journal is The Royal Society of Chemistry 2008
4970 | Chem. Commun., 2008, 4968–4970