Pd-catalyzed decarboxylative arylation of thiazole benzoxazole, and polyfluorobenzene with substituted benzoic acids

Article abstract of DOI:10.1021/ol100296b

(Figure Represented) A Pd-catalyzed decarboxylative coupling of thiazoles and benzoxazole with various substituted benzoic acids Is developed. The reaction is compatible with both electron-rich and electron-poor benzoic acids. It can also be extended to the synthesis of polyfluoro-substituted biaryls using polyfluorobenzenes as the starting materials.

Full text of DOI:10.1021/ol100296b

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1564-1567
Pd-Catalyzed Decarboxylative Arylation
of Thiazole, Benzoxazole, and
Polyfluorobenzene with Substituted
Benzoic Acids
Kai Xie, Zhiyong Yang, Xingjian Zhou, Xiujian Li, Sizhuo Wang, Ze Tan,*
Xiangyu An, and Can-Cheng Guo
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan UniVersity, Changsha 410082, P. R. China
ztanze@gmail.com
Received February 4, 2010
ABSTRACT
A Pd-catalyzed decarboxylative coupling of thiazoles and benzoxazole with various substituted benzoic acids is developed. The reaction is
compatible with both electron-rich and electron-poor benzoic acids. It can also be extended to the synthesis of polyfluoro-substituted biaryls
using polyfluorobenzenes as the starting materials.
Over the past 30 years, Pd-catalyzed cross-coupling between
aryl halides and aryl metals has become one of the most
powerful methods for the syntheses of biaryls.1 However,
one fundamental drawback with these coupling reactions is
that they require the use of a stoichiometric amount of an
expensive organometallic reagent that often has to be
prepared either beforehand or in situ. In order to overcome
this problem, chemists have strived to develop couplings that
use other alternative reagents, and recently, benzoic acids
have emerged as viable coupling partners, largely through
the efforts of Goossen and others.2-6 What is interesting is
that benzoic acids can be used not only as the source of the
aryl electrophile but also as the aryl metal equivalent after
undergoing in situ decarboxylation to generate the aryl-Pd
species. For instance, Goossen,2 Larrosa,3 Becht,4 and others5
have all shown that benzoic acids, acting as organometallic
reagent equivalents, can be efficiently coupled with aryl
halides, diaryliodonium salts, and indoles. On the other hand,
Myers6a-c and others6d have shown that benzoic acids, acting
as organohalide equivalents, can efficiently undergo Pd-
catalyzed Heck coupling with various olefins. Detailed
(1) (a) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651. (b)
Hassan, J.; Sevignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359. (c) Anastasia, L.; Negishi, E. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New
York, 2002.
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Seddon, K. R. Org. Lett. 1999, 1, 997. (b) Stephan, M. S.; Teunissen,
A. J. J. M.; Verzijl, G. K. M.; de Vries, J. G. Angew. Chem., Int. Ed. 1998,
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(2) (a) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.;
Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (b) Goossen, L. J.; Deng,
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Chem. Soc. 2005, 127, 10323. (c) Tanaka, D.; Myers, A. G. Org. Lett. 2004,
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10.1021/ol100296b  2010 American Chemical Society
Published on Web 03/04/2010

mechanistic investigations by Myers6a-c and Kozlowski7
have shed some light on the mechanism of these reactions.
Although some of the basic foundations have been laid,
compared with the well-established standard Pd-catalyzed
cross-coupling between organic halides and aryl metals, the
coupling with benzoic acids is much under-developed, and
thus there remains much to be explored. Herein we report
that benzoic acids can also efficiently couple with thiazoles,
benzoxazole, and polyfluorobenzenes via Pd-catalysis.
Coupling between heteroaromatic compounds and aryl
halides through various transition-metal-catalyzed processes
is well-documented (Scheme 1, eq 1).8 In sharp contrast,
matic nuclei in drugs and biologically active natural com-
pounds, we sought to extend this protocol to other hetero-
cycles as well (Scheme 1, eq 3).
When we treated benzothiazole (1a) with 2-nitrobenzoic
acid (2a, 1.5 equiv) in DMSO at 130 °C in the presence of
PdCl2 (20 mol %), PPh3 (40 mol %), and Ag2CO3 (3 equiv)
for 12 h (similar to Becht’s conditions), we were delighted
to see that the desired product 3a was formed in 68% yield
by GC analysis and that the decarboxylative coupling
occurred exclusively at the 2-position of the benzothiazole
(Table 1, entry 1). After column chromatography, 3a could
Table 1. Optimization of the Reaction Conditions for the
Pd-Catalyzed Decarboxylative Arylation of Benzothiazole with
2-Nitrobenzoic Acid
Scheme 1. Strategies for the Arylation of Heterocycles
the coupling of heteroaromatics with benzoic acids is rare.
As far as we know, only the Pd-catalyzed decarboxylative
coupling between indole and benzoic acids has been reported
(Scheme 1, eq 2).3 The coupling of other heterocycles such
as oxazoles and thiazoles with benzoic acids is totally
unknown. Because of the widespread presence of heteroaro-
a GC yields using decane as the internal standard. b Isolated yield in
parentheses.
be isolated in 60% yield. The yield dropped to 42% when
only 10 mol % of Pd-catalyst was used (Table 1, entry 2).
Replacing Ag2CO3 with Ag2O gave much lower yield, as
was the case when PdCl2 was substituted by Pd(OAc)2 (Table
1, entries 3 and 4). When Ag2CO3 was replaced with K2CO3,
very little 3a was formed (Table 1, entry 5). This observation
is consistent with the reported fact that the use of a silver
salt as the base was necessary for the coupling to occur.4
The use of other phosphine ligands such as dppe, dppp, and
dppb or no ligand did not improve the yield either; only
comparable or lower yields were obtained (Table 1, entries
6-9). Since the cost of these bidentate ligands is significantly
higher than PPh3, we opted to use the combination of PdCl2/
2PPh3/Ag2CO3 as our standard conditions.9 A control reaction
also indicated that no product could be formed in the absence
of Pd-catalyst (Table 1, entry 10).
(7) Dickstein, J. S; Mulrooney, C. A.; O’Brien, E. M.; Morgan, B. J.;
Kozlowski, M. C. Org. Lett. 2007, 9, 2441.
(8) For selected examples of Ru, Rh, Ni, Cu, and Pd catalysis, see: (a)
Lewis, J. C.; Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 2493. (b) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K.
J. Am. Chem. Soc. 2006, 128, 11748. (c) Wang, X.; Lane, B. S.; Sames, D.
J. Am. Chem. Soc. 2005, 127, 4996. (d) Deprez, N. R.; Kalyani, D.; Krause,
A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (e) Turner, G. L.;
Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996. (f)
Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148.
(g) Okazawa, T.; Satoh, M.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286. (h) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.;
Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835. (i) Martin,
T.; Verrier, C.; Hoarau, C.; Marsais, F. Org. Lett. 2008, 10, 2909. (j) Nakano,
M.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1851. (k) Wang,
J.-X.; McCubbin, J. A.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill,
M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923. (l) Stuart, D. R.; Fagnou, K.
Science 2007, 316, 1172. (m) Chiong, H. A.; Daugulis, O. Org. Lett. 2007,
9, 1449. (n) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem.,
Int. Ed. 2009, 48, 201. (o) Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.
Tetrahedron Lett. 2005, 46, 1349. (p) Gallagher, W. P.; Maleczka, R. E.,
Jr. J. Org. Chem. 2003, 68, 6775. (q) Yokooji, A.; Okazawa, T.; Satoh, T.;
Miura, M.; Nomura, M. Tetrahedron 2003, 59, 5685. (r) Pivsa-Art, S.; Satoh,
T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998,
71, 467. (s) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.;
You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (t) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 1128. (u) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404. (v) Do, H.-Q.; Khan, R. K. M.; Daugulis,
O. J. Am. Chem. Soc. 2008, 130, 15185. (w) Yoshizumi, T.; Tsurugi, H.;
Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598. (x) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
(9) Representative Procedure. To a flame-dried, three-neck, round-
bottom flask under nitrogen were added benzothiazole (68 mg, 0.5 mmol),
2-nitrobenzoic acid (126 mg, 0.75 mmol), Ag2CO3 (414 mg, 1.5 mmol),
PdCl2 (18 mg, 0.1 mmol), PPh3 (53 mg, 0.2 mmol), and DMSO (3 mL).
The reaction mixture was heated at 130 °C for 12 h. After cooling to rt, the
reaction mixture was diluted with ether and filtered through Celite. The
organic phase was washed with saturated NH4Cl, dried with MgSO4, filtered,
and concentrated via vacua. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate, 50/1) to afford
77 mg of the desired 2-(2-nitrophenyl)-benzothiazole in 60% yield.
Org. Lett., Vol. 12, No. 7, 2010
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With the standard protocol in hand, we next set out to
examine the scope and limitations of this coupling reaction
and, the results are shown in Table 2. We found that the
furnish any of the desired coupling product, it only produced
the N-methyl benzimidazole self-dimerization product (Table
2, entry 9).
Since polyfluorobenzenes are also known to participate
in the Cu-catalyzed coupling with aryl halides,8t we next
examined the possibility of coupling benzoic acids with
polyfluorobenzenes (Table 3). Much to our delight, treatment
Table 2. Pd-Catalyzed Decarboxylative Arylation of
Heteroaromatics with Benzoic Acids
Table 3. Pd-Catalyzed Decarboxylative Arylation of
Polyfluorobenzenes with Benzoic Acids
a All reactions were carried out using 20 mol % PdCl2, 3 equiv Ag2CO3,
a All reactions were carried out using 20 mol % PdCl2, 3 equiv Ag2CO3,
and 40 mol % PPh3 in DMSO at 130 °C for 12 h. b Isolated yields.
and 40 mol % PPh3 in DMSO at 130 °C for 12 h. b Isolated yields.
of 2-nitrobenzoic acid with pentafluorobenzene under our
standard conditions gave the desired coupled product 5a in
a satisfactory 58% yield (Table 3, entry 1). The decarboxy-
lative coupling took place only at the nonsubstituted position
of pentafluorobenzene. The couplings of pentafluorobenzene
with other nitrobenzoic acids all proceeded smoothly,
furnishing the desired coupled biaryls in yields between 49%
and 63% (Table 3, entries 3-5). It should be noted that a
chloride substituent can be tolerated in the reaction though
aryl chlorides are known to participate in the Pd-catalyzed
cross-couplings (Table 3, entry 3). Coupling using 2,6-
coupling was not limited to 2-nitrobenzoic acid. For example,
with thiazoles such as benzothiazole and 4,5-dimethylthiaz-
ole, other benzoic acids such as 2,6-dimethoxylbenzoic acid,
2,6-difluorobenzoic acid, and 2-fluoro-6-chloro-benzoic acid
as well as pentafluorobenzoic acid could also participate in
the coupling successfully, affording the desired products in
yields ranging from 42% to 63% (Table 2, entries 1-5, 7,
and 8). Benzoxazole can also be used (Table 2, entry 6).
Unfortunately, the use of N-methyl benzimidazole did not
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Org. Lett., Vol. 12, No. 7, 2010

dimethoxylbenzoic acid gave slightly lower yields (51%,
Table 3, entry 2). Replacing one of the fluorine atoms on
pentafluorobenzene with a methoxy group did not affect the
coupling either (Table 3, entries 6 and 7).
Though the exact mechanism of this coupling is still not
clear, on the basis of results reported by others,2-8 a plausible
mechanism is proposed and shown in Scheme 2 (using
molecule to generate the intermediate III. After ꢀ-hydride
elimination, a Pd-hydride species IV is produced besides the
desired coupling product. IV will react with the carbonate
base to give Pd(0) and the Pd(0) catalyst is reoxidized to
Pd(II) by the Ag(I) salts, thus closing the catalytic cycle.
Alternatively, a mechanism that is similar to what was
proposed by Larrosa3 could be operative here, too.
In summary, we have discovered that, using Pd as the
catalyst and Ag2CO3 as the base and the oxidant, substituted
benzoic acids can be used to arylate thiazoles, benzoxazole
and polyfluorobenzenes after in situ decarboxylation. The
reaction occurs with high chemo- and regioselectivity,
representing an excellent alternative to those Pd-, Ni-, or Cu-
catalyzed coupling with aryl halides and sulfonates. Efforts
are currently underway to extend this protocol to other types
of benzoic acids, and the results will be reported in due
course.
Scheme 2. Possible Mechanism for the Pd-Catalyzed
Decarboxylative Arylation of Benzothiazole with Substituted
Benzoic Acids
Acknowledgment. Support of this work by the Ministry
of Education (China) and a grant from the National Science
Foundation of China (No. 20702012) are gratefully acknowl-
edged.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
benzothiazole as the model). First, Pd(II) catalyst reacts with
the carboxylic acid to form a Pd(II)-carboxylate intermediate
I, which subsequently decarboxylates to form an aryl-Pd(II)
species II. This aryl-Pd(II) species will undergo carbopal-
ladation with the C-N double bond in the benzothiazole
OL100296B
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