A general Pd-catalyzed decarboxylative cross-coupling reaction between aryl carboxylic acids: Synthesis of biaryl compounds

Article abstract of DOI:10.1002/anie.201200153

Acid to acid: A general method has been developed for the synthesis of biaryl compounds through a decarboxylative cross-coupling reaction between two different (hetero)aryl carboxylic acids (see scheme). The use of a Pd ^II/PCy₃ catalyst enables the cross-coupling reaction of electronically different or electronically similar aryl carboxylic acids. This method is compatible with substrates having nitro, cyano, fluoro, chloro, bromo, trifluoromethyl, and methoxy substituents. Copyright

Full text of DOI:10.1002/anie.201200153

Angewandte
Chemie
DOI: 10.1002/anie.201200153
Cross-Coupling
A General Pd-Catalyzed Decarboxylative Cross-Coupling Reaction
between Aryl Carboxylic Acids: Synthesis of Biaryl Compounds**
Peng Hu, Yaping Shang, and Weiping Su*
Biaryl compounds have fascinated chemists for over 100 years
because of their scientific and commercial value, and they are
still a focus of interest to synthetic chemists. Over the past
three decades, the persistent efforts of synthetic chemists to
develop efficient methods for transition-metal-catalyzed
cross-coupling reactions have revolutionized the synthesis of
biaryl compounds.[1,2] These methods, in particular palladium-
catalyzed cross-coupling reactions between aryl halides and
aryl organometallics, are widely used in modern academic and
industrial laboratories, but some limitations still remain.
Traditional cross-coupling methods require pre-activated
coupling partners, such as expensive and/or moisture-sensi-
tive organometallic reagents, and frequently produce
unwanted, often toxic, stoichiometric side-products.[1]
Demands for a sustainable development of society have
provided the impetus for chemists to develop more atom-
economical and greener reactions. In this context, significant
advances have recently been made in the development of
regioselectivity of the aryl–aryl coupling in a similar way to
the main group metal reagents in conventional cross-coupling
reactions. New catalytic methods for efficient decarboxylative
cross-coupling are highly desirable. Herein, we report a gen-
eral method for the Pd-catalyzed decarboxylative cross-
coupling of aryl carboxylic acids. This protocol not only
allows the cross-coupling of aryl carboxylic acids that are
electronically different but also those that are electronically
similar; the yields are generally good and a wide range of aryl
carboxylic acids serve as suitable substrates.
Our investigation on the decarboxylative cross-coupling
of aryl carboxylic acids stemmed from the mechanistic
hypothesis that is outlined in Scheme 1. This reaction may
occur through a sequence of steps consisting of an Ag-
À
catalytic methods for the direct arylation of aromatic C H
bonds, thus offering a very promising way to generate
valuable biaryl compounds from simple starting materials in
an atom- and step-economical fashion.[2i,3] Although many
elegant studies have demonstrated that high selectivity can be
achieved in such direct arylation reactions by tuning directing
groups, electronic effects, and steric factors, significant room
for improvement remains.[3]
Decarboxylative cross-coupling reactions of aryl carbox-
ylic acids have recently emerged as an attractive and
alternative approach to the synthesis of biaryl compounds
because a wide range of structurally diverse aryl carboxylic
acids are readily available.[4–9] Aryl carboxylic acids are
versatile arylating reagents that can be coupled with aryl
halides,[6] aryl organometallics,[8r] and even unfunctionalized
(hetero)arenes,[7] and release carbon dioxide as a side-prod-
uct. The aryl metal species generated in situ from the
decarboxylation of aryl carboxylic acids determine the
Scheme 1. Proposed mechanism for the decarboxylative cross-coupling
reaction of aryl carboxylic acids.
promoted decarboxylation of both carboxylic acid substrates
to generate the respective aryl–AgI species (F and G),
transmetalation of the respective aryl groups from AgI to
PdII to generate a Pd complex bearing two different aryl
fragments (I), and reductive elimination to give the product
E.[2k–m] In principle, this mechanism is plausible because each
step in the catalytic cycle is known.[7d,h,i] However, the
successful development of such a decarboxylative cross-
coupling reaction is a great challenge because aryl–AgI
species (F and G) tend to undergo protodecarboxylation[9]
or decarboxylative homocoupling.[8l] These side reactions
become prevalent when the transmetalation of the aryl group
from Ag to Pd to generate the Pd complex I and the product-
generating reductive elimination step are not sufficiently fast,
or when one of the two decarboxylation steps is much faster
than the other. The optimal reaction conditions should fulfill
the following requirements: 1) preferential formation of the
Pd complex I; 2) fast transmetalation of the aryl groups from
[*] Dr. P. Hu, Y. Shang, Prof. Dr. W. Su
State Key Laboratory of Structural Chemistry
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
Yangqiao west road 155#, Fuzhou
Fujian 350002 (China)
E-mail: wpsu@fjirsm.ac.cn
[**] Financial support from the 973 Program (2011CB932404 and
2011CBA00501), the NSFC (20821061 and 20925102), the Key
Project from CAS and NSF of Fujian Province (2009HZ0005) is
greatly appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200153.
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Ag to Pd; 3) fast reductive elimination of the cross-coupling
product from the Pd complex I; 4) achieving a balance in the
rates of the two decarboxylation steps. One of our strategies
was to identify a suitable ligand to modify the electron density
and steric environment on palladium, so that the formation of
the Pd intermediate bearing two different aryl groups would
be favored,[10] and both the transmetalation from Ag to Pd
and the reductive elimination of the cross-coupling product
would be accelerated.[11] The other strategy was to control the
factors affecting the rate of decarboxylation to establish
reductive elimination steps.[10,11] Initially, we observed that
polar solvents such as NMP and DMSO/DMF (1:20), which
are usually used for decarboxylative cross-coupling reactions,
gave only a trace amount of the desired product 3a together
with significant amounts of side-products derived from
protodecarboxylation (entries 1 and 2).[13] The addition of
the phosphine ligand PCy3 (15 mol%) to the reaction system
resulted in an increase of the yield of product 3a to 30%
(entry 3), thus illustrating the beneficial effect of the phos-
phine ligand. When DMSO/dioxane (1:20) was used as
a solvent in place of DMSO/DMF (1:20), a higher yield was
obtained (entry 4). Additionally, it was observed that varying
the ratio of DMSO to dioxane also had an effect on the yield
of 3a (entries 4–6). Further optimization of the solvent
revealed that DMSO/DME (3:17) was the best solvent
system (entry 8). The identity of the phosphine ligand used
also had an effect on the yield of 3a (entries 8 and 10–17).
Among the ligands tested, PCy3 afforded the best result
(entry 8). While varying the phosphine it was found that in the
cases in which a poor yield of 3a was obtained, the yields of
side-products arising from protodecarboxylation and/or
homocoupling increased significantly (entries 10–12, 14–17);
it was further noted that whereas electron-deficient aryl
carboxylic acid 2a underwent both homocoupling and proto-
decarboxylation side reactions, the electron-rich substrate 1a
underwent predominant protodecarboxylation. In the case
where iPr3P was used, the low yield of 3a was associated with
incomplete conversion of the aryl carboxylic acids rather than
the above side reactions (entry 13).[13] Other palladium
sources were also tested (entries 8 and 18–21) and [PdCl2-
(MeCN)2] was shown to be nearly as efficient as Pd(TFA)2
(entry 20), whereas the others were found to be inferior
(entries 18, 19, and 21).
With the optimized reaction conditions established, we
next evaluated the substrate scope of the cross-coupling
reaction between electronically different aryl carboxylic
acids. As shown in Scheme 2, reactions using a variety of
combinations of electron-deficient aryl carboxylic acids with
electron-rich aryl carboxylic acids having an array of sub-
stituents such as nitro, methoxy, trifluoromethyl, fluoro,
chloro, and even bromo, afforded the corresponding cross-
coupling products in good yields. Heteroaryl carboxylic acids
proved to be good substrates for this reaction and the
particular substitution pattern of the phenyl ring of such
carboxylic acids did not affect the yield (3g versus 3h, 3i
versus 3j, and 3k versus 3l).
Pleasingly, the decarboxylative cross-coupling reaction
between electronically similar aryl carboxylic acids was
possible using the optimized reaction conditions (Scheme 3).
Both electron-deficient and electron-rich aryl carboxylic acids
underwent a cross-coupling reaction with electronically
similar partners to give the products in synthetically useful
yields. Notably, the biaryl products arising from the decar-
boxylative cross-coupling reaction of electron-deficient aryl
carboxylic acids were isolated in good yield (4a–4h); these
products are not readily accessible using conventional cross-
coupling methods because the required organometallic
reagents are difficult to synthesize or are of low reactivity.
Electron-rich heteroaryl and electron-rich aryl carboxylic
a
balance between two different decarboxylation
steps.[7d,h,i,9b,c]
Guided by the above requirements, we screened solvents,
phosphine ligands, and palladium sources for the reaction of
2,4-dimethoxybenzoic acid (1a) with 2-nitrobenzoic acid (2a)
(Table 1). The choice of solvent is known to control the
decarboxylation rate,[7d,h,i,9b,c] and the choice of phosphine
ligand is known to have a profound effect on the formation of
the key Pd intermediate, as well as on the transmetalation and
Table 1: A selection of results from the optimization studies on the
decarboxylative cross-coupling reaction of 2-nitrobenzoic acid with 2,4-
dimethoxybenzoic acid.[a]
Entry
Ligand
Solvent(v:v)
Yield [%][b]
1
2
3
4
5
6
7
8
–
–
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
NMP
trace
trace
30
39
46
33
48
60
52
trace
trace
24
36
8
8
7
5
54
DMSO/DMF(1:20)
DMSO/DMF(1:20)
DMSO/dioxane(1:20)
DMSO/dioxane(3:17)
DMSO/dioxane(4:16)
DMSO/DME(2:18)
DMSO/DME(3:17)
DMSO/DME(4:16)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
DMSO/DME(3:17)
9
PCy3
PPh3
10
11
12
13
14
15
16
17
18[c]
19[d]
20[e]
21[f]
tBu3P·HBF4
PCp3·HBF4
iPr3P·HBF4
S-Phos
DavePhos
tert-Butyl XPhos
XPhos
PCy3
PCy3
PCy3
PCy3
35
57
50
[a] Reaction conditions: 5 mol% of Pd(TFA)2, 15 mol% of phosphine
ligand, 0.2 mmol of 1a, 1.2 equiv of 2a, 3 equiv of Ag2CO3, 2 mL solvent,
1208C, 24 h. [b] Yield of isolated product. [c] PdCl2 was used in place of
Pd(TFA)2. [d] PdBr2 was used in place of Pd(TFA)2. [e] [PdCl2(MeCN)2]
was used in place of Pd(TFA)2. [f] [PdCl2(PhCN)2] was used in place of
Pd(TFA)2. Cy=cyclohexyl, DavePhos=2-dicyclohexylphosphino-2’-(N,N-
dimethylamino)biphenyl, DMF=dimethylformamide, DME=1,2-dime-
thoxylethane, DMSO=dimethylsulfoxide, NMP=N-methylpyrrolidone,
PCp3·HBF4 =tricyclopentylphosphine tetrafluoroborate, TFA=trifluor-
oacetate, S-Phos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl,
tert-Butyl XPhos=2-di-tert-butylphosphino-2’,4’,6’-triisoproylbiphenyl,
XPhos=2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.
2
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Scheme 3. The decarboxylative cross-coupling reaction between elec-
tronically similar aryl carboxylic acids. Reaction conditions: 5 mol% of
Pd(TFA)2 or [PdCl2(MeCN)2], 15 mol% of PCy3, 1–2 equiv of aryl
carboxylic acid, 3 equiv of Ag2CO3, 2 mL DMSO/DME (3:17), 1208C,
24 h.
In conclusion, we have herein presented a new strategy,
involving a decarboxylative cross-coupling reaction of aryl
carboxylic acids, for the synthesis of asymmetrical biaryl
compounds. This protocol not only effects the decarboxyla-
tive cross-coupling reaction between electronically different
aryl carboxylic acids but also that of electronically similar aryl
carboxylic acids; these reactions proceed in good yields and
have a broad substrate scope. The choice of solvent and
phosphine ligand was found to be crucial for achieving
a selective cross-coupling reaction.
Scheme 2. The decarboxylative cross-coupling reaction between elec-
tronically different aryl carboxylic acids. Reaction conditions: 5 mol%
of Pd(TFA)2 or [PdCl2(MeCN)2], 15 mol% of PCy3, 1–2 equiv of aryl
carboxylic acid, 3 equiv of Ag2CO3, 2 mL DMSO/DME (3:17), 1208C,
24 h. [a] Yield of isolated product in reaction run on a 1 mmol scale.
Experimental Section
In a glove box, a 25 mL tube equipped with a stir bar was charged with
Pd(TFA)2 (0.01 mmol), PCy3 (0.03 mmol), 2,4-dimethoxybenzoic acid
(0.2 mmol), 2-nitrobenzoic acid (0.24 mmol), Ag2CO3 (0.6 mmol),
DMSO (0.3 mL), and DME (1.7 mL). The tube was fitted with
a Teflon screwcap and removed from the glove box. The reaction
mixture was stirred at 1208C for 24 h. After cooling to RT, the
reaction mixture was diluted with diethyl ether (10 mL) and filtered
through a pad of silica gel; the pad of silica gel was then washed with
diethyl ether (20–50 mL). The filtrate was washed with a saturated
aqueous solution of NaCl (30 mL). The organic phase was dried over
Na2SO4, filtered, and then concentrated under reduced pressure. The
residue was then purified by flash column chromatography on silica
gel (3% diethyl ether/petroleum ether as eluent) to provide the
corresponding product 3a in 60% yield.
acids, or combinations thereof, also underwent the expected
cross-coupling reaction (4i–4l), the conjugated products of
which are interesting because they are often bioactive[12a] and
can be used for the preparation of organic semiconducting
materials.[12b] The variety of aryl substituents tolerated in
these cross-coupling reactions, such as fluoro, chloro, bromo,
trifluoromethyl, methoxyl, cyano, and nitro, provide oppor-
tunities for further synthetic elaboration. For example, the
nitro-containing biaryl products can be easily converted,
through selective reduction, into amino-substituted biaryl
compounds, which are common substructures in bioactive
compounds.[12c]
Received: January 7, 2012
Published online: && &&, &&&&
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Keywords: biaryls · carboxylic acids · cross-coupling ·
decarboxylation · heterocycles
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[6] For recent examples of decarboxylative cross-coupling reactions
of carboxylic acids with aryl halides, triflates, and tosylates, see:
a) L. J. Gooßen, G. Deng, L. M. Levy, Science 2006, 313, 662 –
664; b) L. J. Goossen, N. Rodrꢂguez, B. Melzer, C. Linder, G.
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4
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Angewandte
Chemie
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[11] The transmetalation is proposed to involve a three-coordinate
intermediate. The bulky ligands tend to dissociate from the
metal complex and form the coordinatively unsaturated com-
plex, thereby promoting transmetalation. For examples of bulky
ligands that accelerate reductive elimination, see: a) V. Farina, B.
[13] See the Supporting Information for details.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Cross-Coupling
P. Hu, Y. Shang, W. Su*
&&&& — &&&&
A General Pd-Catalyzed Decarboxylative
Cross-Coupling Reaction between Aryl
Carboxylic Acids: Synthesis of Biaryl
Compounds
Acid to acid: A general method has been
developed for the synthesis of biaryl
compounds through a decarboxylative
cross-coupling reaction between two dif-
ferent (hetero)aryl carboxylic acids (see
scheme). The use of a PdII/PCy3 catalyst
enables the cross-coupling reaction of
electronically different or electronically
similar aryl carboxylic acids. This method
is compatible with substrates having
nitro, cyano, fluoro, chloro, bromo, tri-
fluoromethyl and methoxy substituents.
6
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!