Use of "homeopathic" ligand-free palladium as catalyst for aryl-aryl coupling reactions

Article abstract of DOI:10.1002/adsc.200404210

We have previously shown that the use of ligand-free palladium employing Pd(OAc)₂ as catalyst precursor in the Heck reaction of aryl bromides is possible if low catalyst loadings, typically between 0.01-0.1 mol % are used. We have now tested this phenomenon, which we have dubbed " homeopathic" palladium, in biaryl formation using the Suzuki, the Negishi and the Kumada cross-coupling reactions. The Suzuki reaction of aryl bromides, both activated and deactivated, is possible using 0.02-0.05 mol % of Pd(OAc)₂. In this reaction turnover frequencies up to 30,000 have been reached with activated substrates. Even aryl chlorides could be reacted if strongly electron-withdrawing substituents were present. The Negishi coupling with a variety of arylzinc halides was possible on aryl bromides containing electron-withdrawing substituents. The Kumada reaction only gave low yields of products under "homeopathic' conditions.

Full text of DOI:10.1002/adsc.200404210

FULL PAPERS
Use of “Homeopathic” Ligand-Free Palladium as Catalyst for
Aryl-Aryl Coupling Reactions
Asaf Alimardanov,a, b Lizette Schmieder-van de Vondervoort,a
a
a,
´
Andre H. M. de Vries, Johannes G. de Vries *
a
DSM Pharma Chemicals, Advanced Synthesis, Catalysis & Development, P. O. Box 18, 6160 MD Geleen,
The Netherlands
Fax: (þ31)-46-476-7604, e-mail: Hans-JG.Vries-de@dsm.com
b
Present address: Wyeth Research, 401 N. Middleton Road, Pearl River, NY 10965, USA
Received: July 4, 2004; Accepted: October 22, 2004
Abstract: We have previously shown that the use of li- up to 30,000 have been reached with activated sub-
gand-free palladium employing Pd(OAc)2 as catalyst strates. Even aryl chlorides could be reacted if strong-
precursor in the Heck reaction of aryl bromides is ly electron-withdrawing substituents were present.
possible if low catalyst loadings, typically between The Negishi coupling with a variety of arylzinc halides
0.01–0.1 mol % are used. We have now tested this was possible on aryl bromides containing electron-
phenomenon, which we have dubbed “homeopathic” withdrawing substituents. The Kumada reaction only
palladium, in biaryl formation using the Suzuki, the gave low yields of products under “homeopathicꢀ con-
Negishi and the Kumada cross-coupling reactions. ditions.
The Suzuki reaction of aryl bromides, both activated
and deactivated, is possible using 0.02–0.05 mol % Keywords: biaryls; cross-coupling; ligand-free palladi-
of Pd(OAc)2. In this reaction turnover frequencies um; nanoclusters; Negishi reaction; Suzuki reaction
Introduction
dium, once reduced to Pd(0), forms nanoclusters that
have a limited stability; eventually these clusters aggre-
Aromatic substitution reactions are among the most im- gate to form palladium black (Scheme 1).[7] By lowering
portant transition metal-catalysed reactions used for the the palladium concentration, the oxidative addition of
production of fine chemicals.[1] This steadily growing im- the aryl bromide can compete against the cluster forma-
portance is due to the mild conditions associated with tion. These results have recently been confirmed by
their use, making them compatible with a wide variety Schmidt[8] and by Yao.[9] We use the term “homeopathic
of functional groups.[2] Thus, these coupling reactions palladium”, originally coined by Beletskaya for these re-
can be used at an advanced stage in a total synthesis of actions where very low loadings of palladium can be
complex chemicals such as drugs, vitamins, flavours used.[10] Although these reactions are not homeopathic
and fragrances, agro-chemicals and performance mate- in palladium in the strictest sense, TEM analysis shows
rials.[3]
that the major part of the palladium is locked up in the
The use of 1–5 mol % of a catalyst constituted from a inside of the clusters during the reaction, implying that
palladium precursor and a phosphine ligand has domi- the real active palladium concentration probably is
nated the field for many years. However, the last 5 years two orders of magnitude smaller than the already low
has seen a tremendous advance in the development of range of 0.1–0.01 mol %.
new, more active catalyst systems. From the industrial
Interestingly, there is growing evidence that pallada-
viewpoint the high catalyst loadings and the use of phos- cycles and palladium pincer complexes also are rapidly
phines are detrimental due to the associated high cost converted to soluble palladium clusters in the Heck re-
and problems of purification. For this reason we have fo- action.[6,7] On the other hand, little is known about the
cussed on the use of ligand-free palladium.[4] Although fate of palladacycles in other C C bond forming reac-
À
the use of ligand-free palladium in the Heck reaction tions that often take place at much lower temperatures.
of aryl iodides has been known for years,[5] we have re-
The use of ligand-free palladium (0.5–2 mol %) in the
cently shown that use of ligand-free palladium in the Suzuki coupling of aryl bromides has been reported, but
Heck reaction of aryl bromides is possible only when Bu4NBr was needed for good yields.[11] We have publish-
the palladium-substrate ratio is kept low, typically ed preliminary high-throughput experimentation re-
from 0.01–0.1 mol %.[6] This is due to the fact that palla- sults showing that also in this case homeopathic palladi-
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DOI: 10.1002/adsc.200404210
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“Homeopathic” Ligand-Free Palladium as Catalyst
FULL PAPERS
À
Scheme 1. Nanoclusters as storage of palladium(0) in C C bond forming reactions.
Table 1. Homeopathic Suzuki reaction of aryl bromides [0.02 mol % Pd(OAc)2].
Entry
Aryl bromide
Boronic acid (ester)
GC yield
Isolated yield
1
2
3
4
5
6
7
8
4-bromoacetophenone
4-bromoacetophenone
4-bromoacetophenone
2-bromobenzonitrile
3-bromopyridine
2-bromoaniline
5-bromo-m-xylene
4-bromoacetophenone
phenylboronic acid
4-tolylboronic acid
2-indenylboronic acid
4-tolylboronic acid
phenylboronic acid
phenylboronic acid
phenylboronic acid
4-anilineboronic acid pinacol ester
95%
96%
100%
100%
100%
89%
85%
84%
76%
90%
95% (as HCl salt)
80% (as HCl salt)
34%
20%
[a]
Toluene as solvent.
um can be used even without tetraalkylammonium NMP/H2O (19:1) generally is the best solvent, although
salts.[12] Similar results were recently reported by Tao in some cases toluene could also be used. Out of a range
et al. who used PdCl2 in pyridine as solvent with of palladium precursors Pd(OAc)2 emerged as the best
K2CO3 as base.[13]
one, particularly when toluene was used as solvent. In
In this paper we report the synthetic details of the use NMP/H2O the choice of palladium precursor was less
of homeopathic palladium in the Suzuki reaction and critical and both Pd(II) as well as Pd(0) precursors could
the extension of its use to activated aryl chlorides. In ad- be used. Of a number of bases tested, K2CO3 gave the
dition we report our results on the use of homeopathic best results. Interestingly, in NMP/H2O 0.5 equivalent
palladium in the Negishi and the Kumada reactions.
of K2CO3 is sufficient, although in toluene 1.2 equiva-
lents were necessary. In Table 1 we list the results of a
number of 10-mmol scale experiments, which included
isolation, performed using 0.02 mol % of catalyst.
The reaction generally works well with aryl bromides
containing an electron-withdrawing group giving high
isolated yields. (Entries 1–4). Catalyst loadings can be
lowered even further. For example, 4-bromoacetophe-
none and phenylboronic acid are coupled almost quan-
Results and Discussion
Homeopathic Palladium in the Suzuki Reaction on
Aryl Bromides and Chlorides
Biaryl compounds are important intermediates for phar- titatively within an hour using 0.0025 mol % of
maceuticals and materials.[1b,2] The Suzuki reaction is Pd(OAc)2 (TOF>30,000 mol/mol·h). Unsubstituted
one of the methods used in their commercial produc- bromides gave excellent yields as well (not shown in
tion.[14] Its application in the production of o-tolylbenzo- this table; results obtained on 1-mmol scale).[12] Hetero-
nitrile, an intermediate for several members of the Sar- aromatic bromides can also be used. Good results were
tan family of blood-pressure lowering drugs, has been obtained with 3-bromopyridine (Entry 5). Using aryl
reported.[1b,15] We have used rapid screening in the bromides with electron-donating substituents resulted
Chemspeed ASW 2000 to establish the best conditions in mixed results; whereas 2-bromoaniline could be cou-
for the use of homeopathic palladium in the Suzuki reac- pled in high yield with phenylboronic acid (Entry 6), 5-
tion on bromobenzene.[12] Initially, we have focussed on bromo-m-xylene gave low yields of coupling products
aryl bromide conversion as a measure of the reaction under a variety of conditions (Entry 7). The reaction
rate. From these experiments we have established that also has a wide scope in boronic acids, although a poor
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Asaf Alimardanov et al.
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Scheme 2. Homeopathic Suzuki reaction on aryl chlorides.
yield was obtained in the reaction between 4-bromoace-
tophenone and 4-anilineboronic acid pinacol ester (En-
try 8).
Scheme 3.
We have not made attempts to discover the exact when the reaction was performed at ambient tempera-
boundaries of the ligand-free palladium catalyst/sub- ture over 4 days.
strate ratio in the Suzuki reaction. It seems that in this
Low catalyst loading Suzuki coupling of 4-chloroben-
case the working range is less stringent than for the zaldehyde (3) in NMPat 130 8C yielded only 3% of 4-bi-
Heck reaction. This is exemplified by 1) the high turn- phenylcarboxaldehyde (4) (Scheme 3). Low product
over frequencies we have observed in the ligand-free Su- yields were also obtained when the reaction was per-
zuki couplings (up to 30,000 mol/mol·h), so very low formed in DMF or DMA. Significant amounts of by-
loadings, e.g., 0.0025 mol % of palladium still result in products resulting from the reaction with the solvent
high yields in acceptable reaction times and 2) by the re- (product of condensation with DMA, 5) or the product
sults reported by Deng et al. They obtained good yields of solvent decomposition (reaction with dimethylamine
of Suzuki coupling products working at 2 mol % of li- formed as a result of decomposition of DMF to produce
gand-free palladium only if Bu4NBr was added.[11a] Pre- amine 6) were detected in the latter two cases. Only
sumably the tetraalkylammonim bromide stabilises the trace amounts of product were formed when toluene
clusters and prevents the deposition of palladium was used as a solvent.
black.[7] Leadbeater obtained poor yields of Suzuki cou-
Suzuki coupling of 4-chlorobenzotrifluoride (1b) us-
pling products with 5 mol % of Pd(OAc)2 in water under ing 0.005% or 0.05% of Pd(OAc)2 in DMF at 1308C af-
microwave conditions.[16] Thus, a safe range would be forded the desired product 2b in only 7% yield
from 0.0025–0.5 mol %.
(Scheme 2). Non-activated aryl chlorides, such as 4-
We next tried to extend the reaction to aryl chlor- chlorotoluene, yielded only trace amounts of the cross-
ides.[17] Indeed, activated aryl chlorides can successfully coupling product under similar conditions [0.01%
undergo ligand-free Suzuki coupling using Pd(OAc)2 as Pd(OAc)2, DMF, H2O, K3PO4, n-Bu4NBr, 130–1508C].
catalyst precursor.[11b,18] Heterogeneous palladium cata-
Low-Pd loading Suzuki coupling of 4-chloroacetophe-
lysts have also been used successfully.[19] Cross-coupling none (1c) was found to be slow, resulting in only 42%
of 4-chloronitrobenzene (1a) with phenylboronic acid in conversion after 7 days at 1308C in DMA-H2O
the presence of 0.05% Pd(OAc)2, 20% n-Bu4NBr, and (Scheme 2). The reaction is lower-yielding in the ab-
´
K3PO4 in DMF-H2O at 1308C for 17 h afforded 4-nitro- sence of n-Bu4NBr or at higher temperatures. Najera
biphenyl (2a) in 94% GC yield (Scheme 2). The reaction et al. obtained a 67% yield of 2c using 0.1 mol % of
can be performed in the absence of n-Bu4NBr under oth- Pd(OAc)2.[18]
erwise similar conditions to produce the biaryl product
For Suzuki reactions of unactivated aryl chlorides the
in 82% yield, however, 7% of nitrobenzene was also palladium catalysts based on basic phosphines obviously
formed in this case. The presence of water (in stoichio- give the best results.[17a] Najera et al. compared the activ-
´
metric quantities) is essential, since the reaction is very ity of an oxime-derived palladacycle with that of palladi-
slow and often does not go to completion under strictly um acetate in Suzuki couplings of p-bromo- as well as p-
anhydrous conditions.[20] The Suzuki coupling of 4-chloro- chloroacetophenone. In the case of the bromide the
nitrobenzene (1a) can be performed with even lower rates were identical, which we interpret as a strong indi-
catalyst loading. Thus, cross-coupling in the presence cation of a mechanistic similarity based on palladium
of 0.005% of Pd(OAc)2 under otherwise identical condi- nanoparticles, but in the case of the chloride the pallada-
tions resulted in 83% yield of biaryl 2a, with 3% of un- cycle gave higher rates than Pd(OAc)2 suggesting mech-
reacted chloride 1a remaining. The reaction does not anistic differences.[22]
take place in the absence of the catalyst under thermal
or microwave irradiation conditions.[21]
The reaction is rather limited in the scope of aryl chlor- Homeopathic Palladium in the Negishi Coupling
ides. Cross-coupling of 4-chlorobenzonitrile under the
similar conditions yielded the corresponding amide as In the Negishi coupling the aryl-aryl bond is formed by a
the major product, resulting from the hydrolysis of the transition metal-catalysed coupling between ArZnX
nitrile. The amide was the only product observed even and an aryl halide.[23] It is also possible to make the reac-
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“Homeopathic” Ligand-Free Palladium as Catalyst
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tion catalytic in ZnCl2.[24] This so-called double metal- amount of this side product increases with increasing
catalysed Negishi coupling has been used to produce palladium concentration.
ton amounts of OTBN.[1b–d] Frequently used catalysts
We next examined the scope of the homeopathic Ne-
are palladium or nickel accompanied by phosphorus- gishi reaction (Table 2). The Negishi coupling proceed-
based ligands, such as phosphines, bisphosphines and ed well using aryl iodides (Entries 1 and 5) or activated
phosphites.
aryl bromides (Entries 2–4) as substrates. Results with
In initial screening experiments, using 0.02 mol % of bromobenzene under a variety of conditions (En-
Pd(OAc)2 without ligands we found that no reaction oc- tries 6–11) and with aromatic bromides containing elec-
curred between ethyl 4-bromobenzoate (7) and PhZnBr tron-donating groups (Entries 12–15) were less than
(8) at room temperature in THF. Raising the tempera- satisfactory.
ture to 508C and switching the solvent to DMF or
NMPeventually led to a 75% yield of the desired biaryl
compound (Scheme 4). Lower or substantially higher Homeopathic Palladium in the Kumada Coupling
catalyst loadings led to lower yields. Some homo-cou-
pling is observed in these reactions, both of the aryl bro- The coupling between an arylmagnesium halide and an
mide as well as of the zinc reagent. The homo-coupling aryl halide is termed Kumada coupling.[2,20a] In principle
of ArZnBr has been explained by Elsevier et al. as a re- this would be the preferred method for cross-coupling as
sult of fast exchange of the organo group of the arylZnBr and boronic acid derivatives are often pre-
L2Pd(Ar)Br via pentavalent complexes.[25] Here a differ- pared from the corresponding Grignard reagents. How-
ent mechanism might be operative. The homo-coupling ever, in view of the higher reactivity of the Grignard re-
of ArZnBr may be the result of the coupling taking place agents the other two methods may be preferred for rea-
via two adjacent palladium atoms on the clusters as the sons of selectivity.
Scheme 4.
À
Table 2. Scope of homeopathic ligand-free Negishi coupling (ArXþAr’ZnX ! Ar Ar’).
À
À
Entry
ArX
Ar’ZnX
Solvent
Temp. [8C]
Yield of
Unreacted
ArX [%]
Ar Ar
[%]
Ar’ Ar’
[%]
[a, b]
À
Ar Ar’ [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
EtO2CC6H4I
EtO2CC6H4Br
NCC6H4Br
F3CC6H4Br
PhI
PhBr
”
”
PhZnBr
PhZnBr
PhZnBr
PhZnBr
4-MeC6H4ZnI
4-MeC6H4ZnI
”
”
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMA
NMP50
NMP100
THF-DMF
DMF
50
50
50
50
50
50
100
50
100
48
81
75
65
76
74
10
16
34
34
37
50
15[c]
5
0
0
0
2
0
85
83
52
53
1
5
5
9
6
<1
<1
<1
<1
<1
<1
<1
0
11
18
20
15
9
4
7
6
6
6
5
4
5
5
3
”
”
”
”
”
”
41
CH3C6H4Br
”
”
PhZnBr
”
”
55
50
25
25
42
89
79
45
DMF
DMF
12[d]
2[d]
0
0
MeOC6H4Br
PhZnBr
[a]
The reactions were typically performed with 0.02 mol % Pd(OAc)2 for 16 h.
GC yields using experimentally determined or calculated response factors.
0.01 mol % Pd(OAc)2 used.
[b]
[c]
[d]
Reaction time: 3 days.
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Scheme 5.
tion had gone to completion the mixture was allowed to cool
to ambient temperature. When toluene was used as the solvent
only water was added. When NMP/water was used more water
and an organic solvent were added. These mixtures were fil-
tered using dicalite speed plus filter aid in order to remove
Pd black. The two layers that were obtained were separated
and the organic phase was washed with water, dried on
Na2SO4, and concentrated. The reaction products that contain
an amine function were purified as HCl salts. The other prod-
ucts were purified by recrystallisation from hot IPA. All prod-
Unlike the case of the arylzinc derivatives, the choice
of solvents suitable for Kumada coupling is limited due
to the higher reactivity of the Grignard reagents. Polar
aprotic solvents like DMF or NMPcannot be used in
this case. Cross-coupling of 4-bromobenzotrifluoride
(12) with phenylmagnesium chloride in THFin the pres-
ence of 0.02 mol % of Pd(OAc)2 at 508C for 16 h did re-
sult in the formation of the biaryl product 2b, but in only
27% yield, with 28% of unreacted 12 and 4% of 4,4’-bis-
(trifluoromethyl)biphenyl (14) present (Scheme 5). Sig- ucts were known compounds and had NMR and mass spectra
in agreement with their structures.
nificant amounts of the Grignard homo-coupling prod-
uct 11 (54%), and aryl bromide reduction product tri-
fluorotoluene (13) (27%) were formed. Lower reaction
temperatures resulted in much slower reaction (4%
cross-coupling product, 83% aryl bromide, 17% biphen-
yl, 4% trifluorotoluene). Very low conversion (1%) was
observed in the case of 4-bromotoluene, with significant
amounts of 11 formed.
4-Nitro-1,1’-biphenyl from 4-Chloronitrobenzene
4-Chloronitrobenzene (1 g, 6.28 mmol, 99% pure), phenylbor-
onic acid (1.16 g, 1.5 equivs., 9.42 mmol), K3PO4 (2.69 g, 2
equivs., 12.56 mmol), n-Bu4NBr (0.409 g, 0.2 equivs.,
1.26 mmol), DMF (15 mL), and H2O (0.23 mL, 2 equivs.,
12.56 mmol) were placed in a 50-mL Schlenk tube. Pd(OAc)2
[0.005 mol %; 0.0003 mmol; 0.14 mL of the solution of 10 mg
of Pd(OAc)2 in 20 mL of DMF] was added. The solution was
deoxygenated by purging with Ar for 5 min. The reaction mix-
ture was stirred in a sealed Schlenk tube at 1308C for 4 h. GC
analysis using tridecane as an internal standard indicated the
formation of 4-nitro-1,1’-biphenyl in 85% yield.
Conclusion
We have shown that use of low (“homeopathic”) load-
ings of Pd(OAc)2 can be used to advantage in the Suzuki
reaction of a variety of arylboronic acids (and esters) on
aryl bromides and highly activated aryl chlorides. Also
in the Negishi reaction on activated aryl bromides the
homeopathic palladium concept can be used. However,
the method failed in the Kumada reaction, where the de-
sired cross-coupling products could only be obtained in
low yields.
Negishi Coupling
Arylzinc halide (3 mmol, 6 mL of 0.5 M THF solution) was
placed in a 25-mL, round-bottom flask. The solvent was evac-
uated in vacuum at room temperature. Anhydrous DMF
(4 mL) was added, followed by aryl halide (1 mmol) and
Pd(OAc)2 [0.02 mol %, 0.1 mL of the solution of 9 mg of
Pd(OAc)2 in 20 mL of DMF]. The reaction mixture was stirred
at 508C for 16 h. The yield was determined by CG using tride-
cane as an internal standard.
Experimental Section
Suzuki Reaction on Aryl Bromides
The aryl halide (10 mmol), boronic acid or ester (12–13 mmol)
and K2CO3 (5–10 mmol) were put in a 100-mL, three-neck,
round-bottom flask equipped with an egg-shaped magnetic
stirring bar, a condenser with N2 inlet on top and a thermome-
ter. After the solvent (NMP/H2O, 19:1, 50 mL) was added and
the reaction mixture was heated at 908C the Pd(OAc)2 solution
(0.02 mol % in 0.5–1.0 mL of solvent) was added. The conver-
sion of the aryl halide was determined by GC analysis (CPsil
5CB or CPsil 8CB column; temperature gradient from 80–
3008C) using hexyl ether as internal standard. After the reac-
Acknowledgements
We thank Joe Miller for stimulating discussions. We thank the
Dutch Ministry of Economic affairs for a subsidy under the
EET Scheme (EETK99104).
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[11] a) Y. Deng, L. Gong, A. Mi, H. Liu, Y. Jiang, Synthesis
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[13] X. Tao, Y. Zhao, D. Sheng, Synlett 2004, 359.
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[15] H. Geissler, in: Transition Metals for Organic Synthesis;
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Angew. Chem. Int. Ed. 2002, 41, 4176; b) R. B. Bedford,
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´
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[20] The presence of large excess of water leads to the forma-
tion of unidentified high-boiling point impurities, espe-
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[21] For an example of microwave-assisted transition metal-
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