Synthesis of biaryls by Pd-catalyzed decarboxylative homo- and heterocoupling of substituted benzoic acids

Article abstract of DOI:10.1002/ejoc.201100913

By carefully choosing the right substrate ratio, catalyst combination, and base, symmetrical and unsymmetrical biaryls can be readily synthesized through the Pd-catalyzed decarboxylative homo- and heterocoupling of substituted benzoic acids. The reaction gave the desired products in 40-90% yield and is compatible with 2-nitro-, 2-methoxy-, 2-fluoro-, and 2-chloro-substituted benzoic acids. With the correct substrate ratio, catalyst combination, and base, symmetrical and unsymmetrical biaryls can be readily synthesized through the Pd-catalyzed decarboxylative homo- and heterocoupling of substituted benzoic acids.

Full text of DOI:10.1002/ejoc.201100913

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100913
Synthesis of Biaryls by Pd-Catalyzed Decarboxylative Homo- and
Heterocoupling of Substituted Benzoic Acids
Kai Xie,[a] Sizhuo Wang,[a] Zhiyong Yang,[a] Jidan Liu,[a] Anwei Wang,[a] Xiujian Li,[a]
Ze Tan,*[a] Can-Cheng Guo,[a] and Wei Deng*[a]
Keywords: Biaryls / Palladium / Decarboxylation / Cross-coupling / Carboxylic acids
By carefully choosing the right substrate ratio, catalyst com- zoic acids. The reaction gave the desired products in 40–90%
bination, and base, symmetrical and unsymmetrical biaryls
can be readily synthesized through the Pd-catalyzed de-
carboxylative homo- and heterocoupling of substituted ben-
yield and is compatible with 2-nitro-, 2-methoxy-, 2-fluoro-,
and 2-chloro-substituted benzoic acids.
under Pd catalysis, substituted benzoic acid derivatives can
undergo decarboxylative coupling with aryl halides and
iodonium salts to produce biphenyls. Even more impressive
is the development of a decarboxylative coupling between
substituted benzoic acids and unfunctionalized in-
doles.[5a,6c] This reaction does not require any prefunction-
alization of the indole substrate, thus making the reaction
very efficient. Along this line, we successfully developed an
efficient Pd-catalyzed decarboxylative coupling between
substituted benzoic acids and heteroaryls.[11] We also suc-
cessfully extended this protocol to the coupling between
substituted benzoic acids and polyfluorobenzenes.[11] Dur-
ing our investigation, we noticed that in some cases, one of
the main side products besides protodecarboxylation prod-
uct A is biphenyl product B derived from the decarbox-
ylative homocoupling of the substituted benzoic acids
[Equation (1)]. However, in other cases, for example, in the
case of coupling with 2,6-dimethoxybenzoic acid (C), de-
carboxylative homocoupling product E was not observed
[Equation (2)]. These observations made us wonder if un-
symmetrical biaryls can be synthesized from two different
benzoic acids. Through systematic investigations, we were
able to develop a protocol that can generate the desired un-
symmetrical biaryls from two different types of benzoic
acids in good yields.
Introduction
Among the various biaryl compounds, the syntheses of
2,2Ј-amine- or oxygen-substituted biaryls are particularly
important because once enantiomerically resolved, these
compounds can be further transformed into chiral phos-
phane, phosphate, phosphonite, and phosphoramidite li-
gands that can be used to catalyze a wide variety of asym-
metric reactions.[1] Prominent examples include BINAP,
BIPHEMP, and so on.[1] For their syntheses, copper-medi-
ated Ullmann coupling[2] and Pd-catalyzed cross-coupling[3]
between an aryl halide and an arylmetal species, such as
Suzuki and Negishi couplings, are the two most widely used
methods. However, Ullmann coupling is used mostly for the
homocoupling of aryl halides. As for the Pd-catalyzed cou-
plings, though extremely versatile, one of the fundamental
drawbacks associated with these couplings is that they re-
quire the preparation of organometallic reagents. In some
cases, these reagents may be difficult to prepare, and some
of them are quite sensitive to air and moisture. These
limitations continue to stimulate the development of new
procedures for the synthesis of biaryls, and herein we report
that substituted benzoic acids can also be used to synthesize
symmetrical and unsymmetrical 2,2Ј-substituted biaryls by
Pd-catalyzed decarboxylative coupling.[12]
Inspired by the recent work of Gooßen and others,[4–10]
we recently became interested in the development of Pd-
catalyzed coupling reactions using substituted benzoic acids
as reaction substrates. Gooßen and others have shown that
[a] State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan
University,
Changsha 410082, P. R. China
Fax: +86-731-88822484
E-mail: ztanze@gmail.com
weideng@hnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100913.
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Z. Tan, W. Deng et al.
SHORT COMMUNICATION
tives, the reactions of 5-chloro-2-nitrobenzoic acid are par-
ticularly favorable, generating the desired products in yields
above 70%, whereas other substrates gave lower yet still
synthetically useful yields. The reactions of 2,4-dimeth-
oxybenzoic acid gave much lower yields than those of 2,6-
dimethoxybenzoic acid, highlighting the importance of the
second chelating methoxy group (Table 2, Entries 4 & 5).
The reactions of pentafluorobenzoic acid and 2,6-difluo-
robenzoic acid also proceeded satisfactorily (Table 2, En-
tries 6–12), thus providing a new synthetic route to poly-
fluoro-substituted biphenyls. One thing to note in these
coupling reactions is that the chloride substituent is well
tolerated.
We also investigated the decarboxylative homocoupling
of various substituted benzoic acids to form symmetrical
biaryls, and the results are summarized in Table 3. Under
the standard conditions, 2-nitrobenzoic acid derivatives, 3-
nitrobenzoic acid, and 2-fluorobenzoic acids all underwent
decarboxylative homocoupling smoothly to give the desired
products in satisfactory yields (Table 3). Compared to 3-
nitrobenzoic acid and 2-fluoro-substituted benzoic acids,
the reaction of 2-nitrobenzoic acid gave much higher yields
(up to 90%; Table 3, Entries 1, 3–7).
Results and Discussion
At the outset, we decided to study the heterocoupling
between 2,6-dimethoxybenzoic acid and 2-nitrobenzoic acid
as our model reaction, as product G is well functionalized
at the 2- and 2Ј-positions. These functional groups are con-
venient handles for further transformations. When C was
treated with 2-nitrobenzoic acid (1.5 equiv.) in the presence
of PdCl2 (10 mol-%) and Ag2CO3 (3 equiv.) in DMSO at
130 °C for 6 h, we were delighted to see that the desired
heterocoupling product G was produced in 19% yield
(Table 1, Entry 1). Addition of PPh3 (20 mol-%) as ligand
increased the yield to 70% (Table 1, Entry 2). However, the
use of dppe and dppp as ligands in place of PPh3 did not
improve the yield, only affording G in lower yields (50 and
57% yield, respectively; Table 1, Entries 3 & 4). Substituting
PdCl2 with Pd(OAc)2 had a detrimental effect on the reac-
tion (Table 1, Entry 5). When Ag2CO3 was replaced with
CuCO3Cu(OH)2, the yield dropped to 35% (Table 1, En-
try 6). Changing the ratio of C/F to 1:2 or 1.5:1 also gave
lower yields (Table 1, Entries 7 & 8). A control experiment
also showed that a Pd catalyst was necessary for the reac-
tion to proceed (Table 1, Entry 9). On the basis of these
results, we decided to use treat C with F (1.5 equiv.) in the
presence of PdCl2/PPh3/Ag2CO3 in DMSO at 130 °C and
use these conditions as our standard conditions.
Conclusions
Table 1. Optimization of the reaction conditions for the Pd-cata-
lyzed coupling between 2,6-dimethoxybenzoic acid (C) and 2-nitro-
benzoic acid (F).
In summary, we have demonstrated that not only sym-
metrical but also unsymmetrical biaryls can be efficiently
synthesized through the Pd-catalyzed decarboxylative
homo- or heterocoupling of substituted benzoic acids.
Compared to the traditional route of first converting the
acids into amines, followed by diazotization to form aryl
halides, which are then subjected to Ullmann coupling con-
ditions to produce the desired biaryls,[13] this method is
much more straightforward and simple to run, provided
that the needed benzoic acid is commercially available or
can be readily synthesized. Though narrower in substrate
scope, our method could potentially be useful in selected
cases and complementary to Pd-catalyzed cross-coupling
between aryl halides and organometallic reagents.
[a] Isolated yield. [b] The yield of 2,2Ј-dinitro-1,1Ј-biphenyl was
24% (based on F). [c] C/F = 1:2. [d] C/F = 2:1.
Experimental Section
General Procedure: In a 25-mL round-bottom flask equipped with
a reflux condenser under a N2 atmosphere was placed 2,6-dimeth-
oxybenzoic acid (67.6 mg, 0.5 mmol), 2-nitrobenzoic acid
(125.3 mg, 0.75 mmol), PdCl2 (9 mg, 0.05 mmol), PPh3 (26 mg,
0.1 mmol), Ag2CO3 (413.6 mg, 1.5 mmol), and DMSO (3 mL). The
mixture was heated to 130 °C for 6 h. After cooling to room tem-
perature, the reaction mixture was diluted with diethyl ether
(25 mL) and water (25 mL). The aqueous layer was extracted with
diethyl ether (3ϫ25 mL) and washed with brine. The organic layers
With the optimized conditions in hand, we next explored
the reaction scope. Using the standard conditions, a series
of 2-nitrobenzoic acids were treated with 2,6-dimeth-
oxybenzoic acid, 2,4-dimethoxybenzoic acid, pentafluo-
robenzoic acid, 2,6-difluorobenzoic acid, and 2-fluoro-6-
chlorobenzoic acid; the reaction proceeded smoothly to
produce the desired unsymmetrical biaryls in 40–79% yield
(Table 2). Among the various 2-nitrobenzoic acid deriva- were combined and dried with MgSO4, filtered, and concentrated
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Pd-Catalyzed Synthesis of Biaryls
Table 2. Synthesis of unsymmetrical biaryls through Pd-catalyzed decarboxylative coupling of different arenecarboxylic acids.
[a] Isolated yield based on acid A. [b] GLC yield based on acid A. [c] Isolated yield based on acid B.
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate) to af-
ford the desired product (91 mg) in 70% yield.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data;
1H and 13C NMR spectra for all new compounds.
Eur. J. Org. Chem. 2011, 5787–5790
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Z. Tan, W. Deng et al.
SHORT COMMUNICATION
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Acknowledgments
This work was supported by grants from the National Natural Sci-
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for New Century Excellent Talents in University (NCET-09-0334)
and the Fundamental Research Funds for Central Universities, Hu-
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Received: June 22, 2011
Published Online: September 9, 2011
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