Ligand-free palladium-catalyzed direct arylation of thiazoles at low catalyst loadings

Article abstract of DOI:10.1021/jo802360d

Ligand-free Pd(OAc)₂ was found to catalyze very efficiently the direct arylation of thiazole derivatives under very low catalyst concentration. By using activated aryl bromides, the reaction can be performed employing as little as 0.1-0.001 mol

Full text of DOI:10.1021/jo802360d

Ligand-Free Palladium-Catalyzed Direct Arylation of Thiazoles at
Low Catalyst Loadings
Julien Roger, Franc Pozˇgan, and Henri Doucet*
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-UniVersite´ de Rennes “Catalyse et
Organometalliques”, Campus de Beaulieu, 35042 Rennes, France
henri.doucet@uniV-rennes1.fr
ReceiVed October 21, 2008
Ligand-free Pd(OAc)2 was found to catalyze very efficiently the direct arylation of thiazole derivatives
under very low catalyst concentration. By using activated aryl bromides, the reaction can be performed
employing as little as 0.1-0.001 mol % catalyst. With such substrates, this procedure is economically
and environmentally attractive. On the other hand, in the presence of more challenging substrates, such
as some strongly deactivated or highly congested aryl bromides, in some cases, disappointing results
were obtained.
Introduction
reduced amount of waste, and the wider diversity of available
compounds. The major drawback of the reported procedures is
that they generally require 5-10 mol % of palladium catalyst
associated with 5-20 mol % of mono-8 or bidentate9 phosphine
ligands. Only a few examples of such reactions with low catalyst
loadings have been reported to date.10
The arylation of heteroaromatics, such as thiophenes, furans,
pyrroles, thiazoles, or oxazoles, is an important field for research
in organic synthesis due to the biological and physical properties
of such compounds.1 Palladium-catalyzed Suzuki,2 Stille,3 or
Negishi4 cross-couplings are among the most important methods
to perform such reactions. However, they require the preparation
of an organometallic derivative and provide an organometallic
salt (MX) as byproduct. Therefore, these reactions are not
economically and environmentally attractive. In 1990, Ohta et
al. reported the direct arylation of thiophenes, furans, or thiazoles
with aryl halides via a C-H bond activation in moderate to
good yields using 5 mol % of Pd(PPh3)4 as catalyst.5 Since these
exciting results, the palladium-catalyzed direct arylation of
heteroaryl derivatives with aryl halides or triflates has proved
to be a powerful method for the synthesis of arylated
heterocycles.6,7 This method provides a cost-effective and
environmentally attractive procedure for the preparation of
arylated heteroaromatics due to the reduced number of steps,
De Vries and co-workers have recently described extremely
promising results for the Heck and Suzuki reactions under low
(6) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (b)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (c) Satoh,
T.; Miura, M. Chem. Lett. 2007, 36, 200. (d) Doucet, H.; Hierso, J. C. Curr.
Opin. Drug DiscoVery DeV. 2007, 10, 672. (e) Campeau, L.-C.; Stuart, D. R.;
Fagnou, K. Aldrichim. Acta 2007, 40, 35.
(7) (a) Roger, J.; Doucet, H. Org. Biomol. Chem. 2008, 6, 169. (b) Derridj,
F.; Djebbar, S.; Benali-Baitich, O.; Doucet, H. J. Organomet. Chem. 2008, 693,
135. (c) Gottumukkala, A. L.; Derridj, F.; Djebbar, S.; Doucet, H. Tetrahedron
Lett. 2008, 49, 2926. (d) Ackermann, L.; Vincente, R.; Born, R. AdV. Synth.
Catal. 2008, 350, 741. (e) Besselie`vre, F.; Mahuteau-Betzer, F.; Grierson, D. S.;
Pigel, S. J. Org. Chem. 2008, 73, 3278. (f) Martin, T.; Verrier, C.; Hoarau, C.;
Marsais, F. Org. Lett. 2008, 10, 2909. (g) Gottumukkala, A. L.; Doucet, H. AdV.
Synth. Catal. 2008, 350, 2183.
(8) For direct 5-arylations of thiazoles with palladium associated to mono-
phosphine ligands see: (a) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.;
Tokunaga, K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.;
Honma, R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257. (b) Pivsa-Art, S.;
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998,
71, 467. (c) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada,
K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700. (d) Dahlgren,
A.; Kvarnstrom, I.; Vrang, L.; Hamelink, E.; Hallberg, A.; Rosenquist, A.;
Samuelsson, B. Bioorg. Med. Chem. 2003, 11, 827. (e) Yokooji, A.; Okazawa,
T.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2003, 59, 5685. (f) Oscarsson,
K.; Oscarson, S.; Vrang, L.; Hamelink, E.; Hallberg, A.; Samuelsson, B. Bioorg.
Med. Chem. 2003, 11, 1235. (g) Kobayashi, K.; Mohamed, A.; Mohamed, S.;
Mori, A. Tetrahedron 2006, 62, 9548. (h) Chiong, H. A.; Daugulis, O. Org.
Lett. 2006, 9, 1449. (i) Priego, J.; Gutierrez, S.; Ferritto, R.; Broughton, H. B.
Synlett 2007, 2957. (j) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.;
Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276.
* Corresponding author. Fax: +33 (0)2-23-23-69-39. Phone: +33 (0)2-23-
23-63-84.
(1) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon:
Amsterdam, The Netherlands, 2000.
(2) Stanetty, P.; Schnuerch, M.; Mihovilovic, M. D. J. Org. Chem. 2006,
71, 3754.
(3) (a) Guianvarc’h, D.; Fourrey, J.-L.; Maurisse, R.; Sun, J.-S.; Benhida,
R. Org. Lett. 2002, 4, 4209. (b) Haemmerle, J.; Schnuerch, M.; Stanetty, P.
Synlett 2007, 2975. (c) Zambon, A.; Borsato, G.; Brussolo, S.; Frascella, P.;
Lucchini, V. Tetrahedron Lett. 2008, 49, 66.
(4) Jensen, J.; Skjaerbaek, N.; Vedso, P. Synthesis 2001, 128.
(5) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951.
10.1021/jo802360d CCC: $40.75
Published on Web 01/09/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1179–1186 1179

Roger et al.
TABLE 1. Direct Arylation of 2-n-Propylthiazole with Para-Substituted Bromobenzenes (Scheme 1)b
a Reaction temp 120 °C. b Conditions: catalyst Pd(OAc)2, aryl bromide (1 mmol), 2-n-propylthiazole (2 mmol), KOAc (2 mmol), DMAc, 20 h, 150
°C, under argon, GC and NMR yields, yields in parentheses are isolated.
SCHEME 1. Direct Arylation of 2-n-Propylthiazole
arylation of heteroaromatics has been reported for the 2-arylation
of pyrroles or indoles. For these reactions, 1 mol % of catalyst
was employed.14 Therefore, the discovery of more effective
conditions, for the direct coupling of thiazole derivatives with
aryl bromides using a ligand-free catalyst, especially under low
catalyst loading conditions (less than 0.1 mol %), would be a
considerable advantage for industrial applications and also for
sustainable development. We have already reported preliminary
results for the 5-arylation of thiazole, furans, or thiophene
derivatives using ligand-free palladium catalyst.15 Here, we wish
to report on the reaction of a set of thiazoles using a very wide
variety of electronically and sterically diverse aryl or heteroaryl
bromides at low catalyst loadings.
catalyst loading (0.1-0.01 mol %) using ligand-free catalyst
Pd(OAc)2.11,12 They have demonstrated that, at elevated tem-
perature, when Pd(OAc)2 is employed as the catalyst precursor,
soluble palladium(0) colloids or nanoparticles are formed, and
that the Heck or Suzuki reaction takes place via the interaction
of the arylating agent with the palladium atoms in the outer
rim of the nanoparticles. This leads to the formation of the
monomeric or dimeric anionic palladium complexes that
undergo the usual steps of the Heck or Suzuki mechanisms.
To our knowledge, so far, only one procedure using ligand-
free palladium catalyst for the 5-arylation of thiazoles via C-H
bond activation has been described.13 Fagnou and co-workers
have reported the 5-arylation of thiazole with 4-bromotoluene
in 71% yield in the presence of 10 mol % of Pd(OH)2/C as
catalyst.13 The use of ligand-free Pd(OAc)2 for the direct
Results and Discussion
First, we studied the coupling of 4-bromoacetophenone with
2-n-propylthiazole employing the “de Vries low catalyst loading
procedure”: elevated reaction temperature, polar solvent, acetate
as base, no ligand on palladium, and a low concentration of
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Arylation of Thiazoles at Low Catalyst Loadings
TABLE 2. Direct Arylation of 2-n-Propylthiazole with Meta-Substituted Bromobenzenes (Scheme 1)a
a Conditions: catalyst Pd(OAc)2, aryl bromide (1 mmol), 2-n-propylthiazole (2 mmol), KOAc (2 mmol), DMAc, 20 h, 150 °C, under argon, GC and
NMR yields, yields in parentheses are isolated.
Pd(OAc)2. We observed that using such conditions in the
presence of as little as 0.01 mol % of catalyst, the selective
formation of 1-[4-(2-propylthiazol-5-yl)phenyl]ethanone 1 was
observed with complete conversion of the aryl bromide and a
very high isolated yield (Scheme 1, Table 1, entry 1). No
formation of side products was detected during the course of
this reaction. With this procedure, the priority for the arylation
or 2-substituted thiazoles is clearly the 5-position. The 4-ary-
lation product, which was formed with another procedure,8e was
not detected. Moreover, the homocoupling product of 4-bro-
moacetophenone, which is often observed in palladium-catalyzed
reactions, was not observed.
Then, we examined the scope and limitations of this procedure
using para-, meta-, or ortho-substituted aryl bromides (Tables
1-3) and also heteroaryl bromides (Table 4). Electron-deficient
aryl bromides, 4-trifluoromethylbromobenzene and 4-bromoben-
zonitrile also gave selectively arylated products 6 and 7 in very
high yields of 93% and 89% and turnover numbers (TONs) of
14 000 and 54 000, respectively (Table 1, entries 11-14).
4-Bromopropiophenone, 4-bromobenzaldehyde, methyl 4-bro-
mobenzoate, or 4-bromobenzophenone were found to be slightly
less reactive and TONs of 800-6700 were obtained. With these
substrates, in all cases, good isolated yields of target compounds
2-5 were obtained employing only 0.1 mol % of catalyst (Table
1, entries 3-10). Using this substrate/catalyst ratio, 4-bromoni-
trobenzene gave 8 in moderate yield. This is probably due to
the partial poisoning of the catalyst in the presence of this
substrate (Table 1, entry 15). Activated aryl bromide, 4-fluo-
robromobenzene reacted with 2-n-propylthiazole gave the
expected product 9 in high TON of 9000 and in high yield (90%)
(Table 1, entry 16). Deactivated aryl bromides, 4-bromotoluene,
4-tert-butylbromobenzene, or 4-bromoanisole gave 10-12 in
89%, 71%, and 79% yields, respectively, using 0.1 mol % of
catalyst (Table 1, entries 17-20). On the other hand, using the
strongly deactivated aryl bromide, 4-bromo-N,N-dimethylaniline,
in the presence of 0.1 mol % of catalyst, 13 was obtained in
only 44% yield (Table 1, entry 23). For this reaction the
oxidative addition of aryl bromide to palladium appears to be
the rate-limiting step of the catalytic cycle. Interestingly, for
the reactions with 4-bromoanisole or 4-bromo-N,N-dimethyla-
niline, the yields of 12 and 13 were not improved by an increase
of the catalyst loading from 0.1 to 0.4 or 1 mol %, revealing
that the concentration of active Pd species is relatively similar
with these three different concentrations of Pd(OAc)2. For this
ligand-free procedure, under relatively high palladium concen-
trations, so-called “palladium black” forms more rapidly. This
“palladium black” is generally inactive for such catalyzed
reactions. Consequently the conversions of aryl bromides and
the yields of coupling products are not increased by a higher
catalyst loading.
(9) For direct 5-arylations of thiazoles with palladium associated to diphos-
phine ligands see: (a) Masui, K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita,
M.; Ikeda, T. Org. Lett. 2004, 6, 2011. (b) Hara, O.; Nakamura, T.; Sato, F.;
Makino, K.; Hamada, Y. Heterocycles 2006, 68, 1. (c) Turner, G. L.; Morris,
J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996. (d) Gottumukkala,
A. L.; Doucet, H. Eur. J. Inorg. Chem. 2007, 3626. (e) Derridj, F.; Gottumukkala,
A. L.; Djebbar, S.; Doucet, H. Eur. J. Inorg. Chem. 2008, 2550.
(10) (a) Battace, A.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M.
Organometallics 2007, 26, 472. (b) Battace, A.; Lemhadri, M.; Zair, T.; Doucet,
H.; Santelli, M. AdV. Synth. Catal. 2007, 349, 2507.
(11) (a) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285. (b) Reetz, M. T.;
de Vries, J. G. Chem. Commun. 2004, 1559. (c) de Vries, J. G. Dalton Trans.
2006, 421.
(12) Alimardanov, A.; Schmieder-van de Vondervoort, L.; de Vries, A. H. M.;
de Vries, J. G. AdV. Synth. Catal. 2004, 346, 1812.
(13) For direct 5-arylations of thiazoles with aryl halides, using ligand-less
palladium catalysts see: Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578.
(14) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476.
(15) Pozˇgan, F.; Roger, J.; Doucet, H. ChemSusChem 2008, 1, 404.
Next, we examined the reactivity of meta-substituted aryl
bromides with 2-n-propylthiazole (Table 2). As expected, the
electron-deficient aryl bromides, 3-bromoacetophenone, 3-bro-
mobenzaldehyde, 3-bromobenzonitrile, or 3-trifluoromethyl-
bromobenzene could be reacted by using similar substrate/
catalyst ratios as the para-substituted aryl bromides. In all cases,
using only 0.1-0.01 mol % of catalyst, the desired products
14-17 were obtained in good yields and TONs of 6500-10000.
Ortho substituents on the aryl bromides generally have a more
important effect on the reactions rates and yields of Heck
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Roger et al.
TABLE 3. Direct Arylation of 2-n-Propylthiazole with Ortho-Substituted Bromobenzenes (Scheme 1)a
a Conditions: catalyst Pd(OAc)2, aryl bromide (1 mmol), 2-n-propylthiazole (2 mmol), KOAc (2 mmol), DMAc, 20 h, 150 °C, under argon, GC and
NMR yields, yields in parenthesis are isolated.
reactions due to their steric or coordination properties. In some
cases, similar yields, as in the presence of the para-substituted
aryl bromides, were obtained (Table 3). We observed that the
coupling of 2-bromobenzonitrile or 1-bromonaphthalene with
2-n-propylthiazole proceeds nicely with only 0.01 mol % of
catalyst to give 21 and 24 in very high yields (Table 3, entries
4, 7, and 8). On the other hand, in the presence of 2-bromoben-
zaldehyde, 2-trifluoromethylbromobenzene, and 2-fluorobro-
mobenzene, 0.1 mol % of catalyst had to be employed, instead
of 0.01 mol % with the para-substituted aryl bromides, in order
to obtain high conversions of the starting material (Table 3,
entries 3, 5, and 6). 2-Bromoacetophenone was found to be
unreactive or gave unidentified products, even with 0.4 mol %
of catalyst (Table 3, entries 1 and 2). This is probably due to
the coordination of the acetyl function to palladium. The
reactivity of a few electron-rich ortho-substituted aryl bromides
has also been examined. 2-Bromotoluene gave 25 in good yield
with 0.1 mol % of catalyst (Table 3, entry 9), whereas
2-bromoanisole and 2-bromo-N,N-dimethylaniline were recov-
ered unreacted (Table 3, entries 10-13).
Next, we tried to evaluate the difference in the reactivity
between mono- and di-ortho-substituted aryl bromides, and we
observed that 2,6-difluorobromobenzene and even the highly
hindered aryl bromide (9-bromoanthracene) could be employed
1182 J. Org. Chem. Vol. 74, No. 3, 2009

Arylation of Thiazoles at Low Catalyst Loadings
TABLE 4. Direct Arylation of 2-n-Propylthiazole with Heteroaryl Bromides (Scheme 1)a
a Conditions: catalyst Pd(OAc)2, aryl bromide (1 mmol), 2-n-propylthiazole (2 mmol), KOAc (2 mmol), DMAc, 20 h, 150 °C, under argon, GC and
NMR yields, yields in parentheses are isolated.
successfully (Table 3, entries 14 and 18). By using these
substrates, the products 28 and 30 were isolated in 66% and
75% yields, respectively. On the other hand, in the presence of
sterically congested 2,6-dimethylbromobenzene, no coupling
product was obtained (Table 3, entries 15-17). With this
substrate, we have employed substrate/catalyst ratios of 100,
250, or 1000, but in all cases, the target product 29 was not
detected.
This ligand-free procedure is not limited to aryl bromides.
Heteroaryl bromides are also suitable reactants (Table 4).
Pyridines are π-electron deficient and therefore the oxidative
addition of bromopyridines to palladium is, in general, relatively
easy. With 3-bromopyridine, 3-bromoquinoline, or 4-bromoiso-
quinoline, 32-34 were obtained in high TONs of 830-85000
by using only 0.1-0.001 mol % of catalyst (Table 4, entries
3-7). A high yield was also obtained with 5-bromopyrimidine
(Table 4, entry 8). These reactions are extremely clean, and very
high isolated yields were obtained in most cases. On the other
hand, 2-bromopyridine gave no coupling product 31 (Table 4,
entries 1 and 2). This result seems to indicate that, with this
substrate, an interaction between the heteroelement and the
palladium complex has a poisoning effect. Furans and thiophenes
are π-electron excessive and their oxidative addition to pal-
ladium is generally slower than that with pyridines. However,
2-bromothiophene and 2-acetyl-5-bromothiophene gave 36 and
37 in 62% and 61% yields, respectively, using 0.4 and 0.1 mol
% of catalyst (Table 4, entries 9 and 10). The formation of
unidentified side products was also observed in the course of
these reactions. 5-Bromofuraldehyde gave 38 in a high yield
of 82% with a TON of 900 (Table 4, entry 12).
Sterically hindered 2-ethyl-4-methylthiazole has been em-
ployed to determine the influence of a 4-substitution on thiazole
on the reaction rates with this ligand-free procedure (Table 5).
In most cases, this substrate was found to be less reactive than
2-n-propylthiazole by a factor of 10. For example, using
electron-deficient aryl bromides such as 4-bromoacetophenone
or 4-bromobenzonitrile TONs of 6600 and 2600 were obtained
with 2-ethyl-4-methylthiazole, whereas with 2-n-propylthiazole,
TONs of 79 000 and 54 000 had been obtained (compare Table
5 entries 2 and 6 with Table 1 entries 2 and 14). A very similar
trend was observed with 4-fluorobromobenzene (TONs of 930
instead of 9500; compare Table 5 entry 7 and Table 1 entry
16) or 2-bromobenzonitrile (TONs of 1000 instead of 9700;
compare Table 5 entry 11 and Table 3 entry 4). However, in
most cases, high yields of target coupling products 39-48 were
obtained by using as little as 0.1 mol % of catalyst. Therefore,
with this substrate also, this ligand-free procedure is very
attractive in terms of catalyst cost.
This procedure also tolerates functionalized thiazole deriva-
tives. For example, ethyl 2-methylthiazole-4-carboxylate has
been coupled successfully with 4-bromoacetophenone, 4-bro-
mobenzonitrile, or 4-bromopyridine (Table 6). In the course of
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Roger et al.
TABLE 5. Direct Arylation of 2-Ethyl-4-Methylthiazole with Bromobenzene Derivatives (Scheme 2)b
a 4-Bromopyridine hydrochloride was used with 3 mmol of KOAc. b Conditions: catalyst Pd(OAc)2, aryl bromide (1 mmol), 2-ethyl-4-methylthiazole
(2 mmol), KOAc (2 mmol), DMAc, 20 h, 150 °C, under argon, GC and NMR yields, yields in parentheses are isolated.
TABLE 6. Direct Arylation of Ethyl 2-Methylthiazole-4-carboxylate with Bromobenzene Derivatives (Scheme 3)b
a 4-Bromopyridine hydrochloride was used with 3 mmol of KOAc. b Conditions: catalyst Pd(OAc)2 (0.004 mmol), aryl bromide (1 mmol), ethyl
2-methylthiazole-4-carboxylate (2 mmol), KOAc (2 mmol), DMAc, 3 h, 150 °C, under argon, GC and NMR yields, yields in parentheses are isolated.
1184 J. Org. Chem. Vol. 74, No. 3, 2009

Arylation of Thiazoles at Low Catalyst Loadings
TABLE 7. Direct Arylation of Thiazole or 4-Methylthiazole with Bromobenzene Derivatives (Scheme 4)a
a Conditions: catalyst Pd(OAc)2, aryl bromide (1 mmol), thiazole or 4-methylthiazole (2 mmol), KOAc (2 mmol), DMAc, 20 h, 130 °C for the
reactions with thiazole, 150 °C for the reactions with 4-methylthiazole, under argon, GC and NMR yields, yields in parentheses are isolated.
SCHEME 2. Direct Arylation of 2-Ethyl-4-methylthiazole
Conclusion
In summary, we have demonstrated that the “de Vries ligand-
free palladium procedure” is not limited to Heck or Suzuki
reactions. By using as little as 0.4-0.001 mol % of Pd(OAc)2
as catalyst precursor, the direct 5-arylation via C-H bond
activation of thiazole derivatives proceeds in moderate to very
high yields. With this ligand-free procedure, an increase of the
catalyst loading to 1 mol % generally led more rapidly to
aggregation of palladium to form so-called “palladium black”
and no improvement in the yield of coupling products was
observed. Therefore, this procedure is limited to activated and
some deactivated aryl bromides. However, it should be noted
that a wide range of functions such as acetyl, benzoyl, formyl,
nitro, nitrile, fluoro, methoxy, or trifluoromethyl on the aryl
bromide are tolerated. Satisfactory results were also obtained
with use of some sterically congested aryl bromides and
heteroaryl bromides. This low catalyst loading procedure is
economically and environmentally attractive. The only byprod-
ucts are AcOH/KBr instead of metallic salts with classical
coupling procedures such as Suzuki, Stille, or Negishi reactions.
Moreover, no preparation of an organometallic derivative is
required, reducing the number of steps and consequently the
amount of waste to prepare these compounds.
SCHEME 3. Direct Arylation of Ethyl
2-Methylthiazole-4-carboxylate
SCHEME 4. Direct Arylation of Thiazole or
4-Methylthiazole
this reaction, some decarboxylation of thiazole was observed
when long reaction times were employed. However, the
reactions are quite clean when they are stopped after 3 h, and
relatively high yields of products 49-51 were isolated. These
reactions were performed with only 0.4 mol % of catalyst.
Finally, we studied this reaction using thiazole or 4-meth-
ylthiazole (Scheme 4, Table 7). With these two substrates, we
could have observed the 2- or the 5-arylation products. However,
in all cases, only the 5-arylation products were formed. The
2-arylated or 2,5-diarylated thiazoles were not detected. Such
regioselective 5-arylation of thiazole had already been reported
by Fagnou and co-workers.13 Using the “Pd(OAc)2 ligand-free
procedure”, the reactions with thiazole and 4-bromoacetophe-
none or 4-bromobenzonitrile at 130 °C allow the formation of
products 52 and 53 in 90% and 88% yields, respectively (Table
7, entries 1-4). With this reactant substrate/catalyst ratios of
250 or 1000 were employed. Coupling reactions using 4-me-
thylthiazole with 4-bromoacetophenone, 4-bromobenzonitrile,
or 3-bromopyridine were performed at 150 °C in the presence
of only 0.1-0.01 mol % of catalyst (Table 7, entries 5-10).
Again, only the 5-arylation products were formed, and com-
pounds 54-56 were obtained in 86-90% yields.
Experimental Section
General Procedure. As a typical experiment, the reaction of
4-bromoacetophenone (0.199 g, 1 mmol), 2-n-propylthiazole (0.254
g, 2 mmol), and KOAc (0.196 g, 2 mmol) at 150 °C during 20 h
in DMAc (3 mL) in the presence of Pd(OAc)2 (0.0224 mg, 0.0001
mmol) under argon affords the corresponding product 1-[4-(2-
propylthiazol-5-yl)phenyl]ethanone9d (1) after extraction with dichlo-
romethane, evaporation, and filtration on silica gel (pentane/ether)
1
in 94% (0.231 g) isolated yield. H NMR (200 MHz, CDCl3) δ
7.94 (d, J ) 8.5 Hz, 2H), 7.90 (s, 1H), 7.58 (d, J ) 8.5 Hz, 2H),
3.01 (t, J ) 7.4 Hz, 2H), 2.58 (s, 3H), 1.85 (sext., J ) 7.4 Hz,
2H), 1.02 (t, J ) 7.4 Hz, 3H).
1-[4-(2-Propylthiazol-5-yl)phenyl]propan-1-one (2) (Table 1,
entry 3). The reaction of 4-bromopropiophenone (0.213 g, 1 mmol),
2-n-propylthiazole (0.254 g, 2 mmol), and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (0.224 mg, 0.001 mmol) in DMAc at 150 °C affords
1
the corresponding product 2 in 89% (0.231 g) isolated yield. H
NMR (200 MHz, CDCl3) δ 7.88 (s, 1H), 7.84 (d, J ) 8.0 Hz, 2H),
J. Org. Chem. Vol. 74, No. 3, 2009 1185

Roger et al.
7.50 (d, J ) 8.0 Hz, 2H), 2.91 (m, 4H), 1.78 (sext., J ) 7.4 Hz,
2H), 1.15 (t, J ) 7.1 Hz, 3H), 0.96 (t, J ) 7.1 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 199.6, 171.9, 138.8, 137.1, 135.9, 128.7, 126.3,
35.6, 31.7, 23.2, 13.6, 8.2. Anal. Calcd for C15H17NOS (259.36):
C 69.46, H 6.61. Found: C 69.47, H 6.50.
DMAc at 150 °C affords the corresponding product 39 in 93%
(0.228 g) isolated yield. H NMR (200 MHz, CDCl3) δ 7.93 (d, J
) 7.1 Hz, 2H), 7.45 (d, J ) 7.1 Hz, 2H), 2.95 (q, J ) 7.1 Hz, 2H),
2.56 (s, 3H), 2.44 (s, 3H), 1.34 (t, J ) 7.1 Hz, 3H); 13C NMR (50
MHz, CDCl3) δ 197.1, 171.1, 148.1, 137.3, 135.7, 129.7, 128.9,
128.6, 26.9, 26.5, 16.4, 14.2. Anal. Calcd for C14H15NOS (245.34):
C 68.54, H 6.16. Found: C 68.64, H 6.10.
1
1-[3-(2-Propylthiazol-5-yl)phenyl]ethanone (14) (Table 2,
entry 1). The reaction of 3-bromoacetophenone (0.199 g, 1 mmol),
2-n-propylthiazole (0.254 g, 2 mmol), and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (0.0224 mg, 0.0001 mmol) in DMAc at 150 °C
affords the corresponding product 14 in 90% (0.221 g) isolated
Ethyl 5-(4-Acetylphenyl)-2-methylthiazole-4-carboxylate (49)
(Table 6, entry 1). The reaction of 4-bromoacetophenone (0.199
g, 1 mmol), ethyl 2-methylthiazole-4-carboxylate (0.342 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.896 mg, 0.004
mmol) in DMAc at 150 °C during 3 h affords the corresponding
1
yield. H NMR (200 MHz, CDCl3) δ 8.01 (s, 1H), 7.81 (s, 1H),
7.79 (d, J ) 8.0 Hz, 1H), 7.63 (d, J ) 8.0 Hz, 1H), 7.40 (t, J ) 8.0
Hz, 1H), 2.92 (t, J ) 7.6 Hz, 2H), 2.56 (s, 3H), 1.80 (sext., J )
7.6 Hz, 2H), 1.00 (t, J ) 7.6 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 197.4, 171.3, 138.2, 137.7, 137.2, 132.2, 130.8, 129.3, 127.7,
126.0, 35.5, 26.6, 23.3, 13.6. Anal. Calcd for C14H15NOS (245.34):
C 68.54, H 6.16. Found: C 68.57, H 6.19.
1
product 49 in 68% (0.197 g) isolated yield. H NMR (200 MHz,
CDCl3) δ 7.99 (d, J ) 8.2 Hz, 2H), 7.57 (d, J ) 8.2 Hz, 2H), 4.30
(q, J ) 7.1 Hz, 2H), 2.76 (s, 3H), 2.63 (s, 3H), 1.25 (t, J ) 7.1 Hz,
3H); 13C NMR (50 MHz, CDCl3) δ 197.4, 165.1, 161.8, 144.7,
140.5, 137.1, 135.4, 130.2, 128.0, 61.5, 26.7, 19.3, 14.1. Anal. Calcd
for C15H15NO3S (289.35): C 62.26, H 5.23. Found: C 62.40, H 5.31.
5-(4-Acetylphenyl)thiazole (52) (Table 7, entry 1).16 The
reaction of 4-bromoacetophenone (0.199 g, 1 mmol), thiazole (0.170
g, 2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.896
mg, 0.004 mmol) in DMAc at 130 °C during 20 h affords the
corresponding product 52 in 90% (0.183 g) isolated yield. 1H NMR
(200 MHz, CDCl3) δ 8.80 (s, 1H), 8.15 (s, 1H), 7.96 (d, J ) 8.3
Hz, 2H), 7.62 (d, J ) 8.3 Hz, 2H), 2.59 (s, 3H).
2-(2-Propylthiazol-5-yl)benzaldehyde (20) (Table 3, entry
3).9d The reaction of 2-bromobenzaldehyde (0.185 g, 1 mmol), 2-n-
propylthiazole (0.254 g, 2 mmol), and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (0.224 mg, 0.001 mmol) in DMAc at 150 °C affords
1
the corresponding product 20 in 90% (0.208 g) isolated yield. H
NMR (200 MHz, CDCl3) δ 10.12 (s, 1H), 7.94 (d, J ) 8.0 Hz,
1H), 7.55 (m, 2H), 7.44 (m, 2H), 2.98 (t, J ) 7.1 Hz, 2H), 1.82
(sext., J ) 7.1 Hz, 2H), 1.01 (t, J ) 7.1 Hz, 3H).
3-(2-Propylthiazol-5-yl)pyridine (32) (Table 4, entry 3). The
reaction of 3-bromopyridine (0.158 g, 1 mmol), 2-n-propylthiazole
(0.254 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(0.0224 mg, 0.0001 mmol) in DMAc at 150 °C affords the
corresponding product 32 in 96% (0.196 g) isolated yield. 1H NMR
(200 MHz, CDCl3) δ 8.79 (s, 1H), 8.54 (d, J ) 4.2 Hz, 1H), 7.87
(s, 1H), 7.84 (d, J ) 7.2 Hz, 1H), 7.33 (dd, J ) 7.2 and 4.2 Hz,
1H), 3.01 (t, J ) 7.5 Hz, 2H), 1.88 (sext., J ) 7.5 Hz, 2H), 1.05
(t, J ) 7.5 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 172.3, 149.4,
147.9, 139.1, 134.9, 134.0, 128.3, 124.1, 36.0, 23.7, 14.1;. Anal.
Calcd for C11H12N2S (204.29): C 64.67, H 5.92. Found: C 64.87,
H 5.90.
Acknowledgment. This research was supported by a Marie
Curie Intra-European Fellowships within the 6th European
Community Framework Programme. J.R. is grateful to “Min-
iste`re de la Recherche” for a grant. We thank the CNRS and
“Rennes Metropole” for providing financial support and P. H.
Dixneuf for useful discussions.
1
Supporting Information Available: Graphical H and 13C
NMR spectra of new compounds and 1H NMR of known
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1-[4-(2-Ethyl-4-methylthiazol-5-yl)phenyl]ethanone (39) (Table
5, entry 1). The reaction of 4-bromoacetophenone (0.199 g, 1
mmol), 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), and KOAc
(0.196 g, 2 mmol) with Pd(OAc)2 (0.224 mg, 0.001 mmol) in
JO802360D
(16) Jensen, J.; Skjaerbaek, N.; Vedso, P. Synthesis 2001, 128.
1186 J. Org. Chem. Vol. 74, No. 3, 2009