Pd-catalyzed cross-coupling of carboxylic acids with nitroethane via combination of decarboxylation and dehydrogenation

Article abstract of DOI:10.1039/c0cc01029d

An unexpected coupling reaction of arene carboxylic acid with nitroethane via a combination of decarboxylation and dehydrogenation is described. The method provides exclusively (E)-β-nitrostyrenes. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0cc01029d

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Pd-catalyzed cross-coupling of carboxylic acids with nitroethane via
combination of decarboxylation and dehydrogenationw
Min Zhang, Jun Zhou, Jian Kan, Min Wang, Weiping Su* and Maochun Hong
Received 20th April 2010, Accepted 15th June 2010
First published as an Advance Article on the web 1st July 2010
DOI: 10.1039/c0cc01029d
An unexpected coupling reaction of arene carboxylic acid with
nitroethane via a combination of decarboxylation and dehydro-
genation is described. The method provides exclusively (E)-b-
nitrostyrenes.
that produce exclusively (E)-b-nitrostyrenes via a combination
of decarboxylation and dehydrogenation.
To achieve a decarboxylative a-arylation product of nitro-
ethane, we initially examined the reaction of 2,4-dimethoxy-
benzoic acid (1a) with 2.0 equiv. of nitroethane (2a) under
various conditions using bases such as Cs2CO3, K2CO3,
K3PO4 as additives, but did not obtain any product from this
reaction. Surprisingly, upon removal of base from the reaction
system, in presence of 10 mol% Pd(TFA)2 as catalyst,
2.5 equiv. of Ag2CO3 as oxidant in 5% DMSO–DMF, the
reaction gave an unexpected decarboxylative vinylation
product (3a) in 11% yield (entry 2, Table 1). We speculated
that introduction of additional acids to the reaction system
would increase the electrophilicity of the catalyst, thus
promoting decarboxylation of carboxylic acid. As expected,
addition of 1.0 equiv. of pivalic acid led to an increase in the
yield of 3a (entry 3). Replacing 5% DMSO–DMF with
10% DMSO–DME (DME = 1,2-dimethoxyethane) further
improved the yield. Screening analogs of pivalic acid as an
additive and their amounts revealed that 2.5 equiv. of pivalic
acid maximized the beneficial effect of the additional acid as an
The development of catalytic methods for decarboxylative
coupling of carboxylic acids has received much attention
recently since such transformations provide new opportunities
to use readily available carboxylic acids as starting materials
for organic synthesis.1–8 As a consequence, a series of efficient
catalyst systems have been established for the achievement of
decarboxylative cross-coupling of a wide range of carboxylic
acids with aryl halides, triflates2,3 and others.4 Advances have
also been reported in the development of Pd-catalyzed
decarboxylative Heck-type coupling of benzoic acids with
olefins.5 Very recently, the decarboxylative coupling reactions
of a-amino acids with an array of nucleophiles have
appeared.6 These studies demonstrated that depending on the
nature of the metal catalysts, the organometallic intermediates
generated from metal-promoted decarboxylation of carboxylic
acids served as either electrophiles or nucleophiles, which
indicates the potential of carboxylic acids as versatile coupling
components. Moreover, Pd-catalyzed carboxyl-directed ortho-
C–H functionalization,9 in conjunction with decarboxylative
cross-coupling, would offer a rapid entry into complex mole-
cules from readily available materials through concise steps.7
The development of the metal-catalyzed direct C–H func-
tionalization reactions provides the most atom-efficient syn-
thetic methods, and currently represents a very active area of
research.10,11 However, the reactions involving decarboxyla-
tive cross-coupling of benzoic acids with C–H bonds are still
scarce,6a,12 although this class of reactions combines the
advantages of the high efficiency of C–H functionalization
and the ready availability of carboxylic acids. The primary
obstacles to realize this process arise from the difference in
reaction rate between the two independent processes, decarboxyl-
ation and C–H cleavage, which often leads to homocoupling
or protodecarboxylation. Thus, the key to achieving this cross-
coupling is the identification of the critical factors whose
modification enables decarboxylation and C–H cleavage to
match each other. Herein, we report the first example of the
reactions of ortho-substituted benzoic acids with nitroethane
Table 1 Optimization of reaction conditionsa
Equiv. Additive
(equiv.)
Yield of
3a (%)b
Entry of 2a
Solvent
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
2
Cs2CO3 (1.0)
—
5% DMSO–DMF
5% DMSO–DMF
5% DMSO–DMF
10% DMSO–DME
10% DMSO–DME
10% DMSO–DME
10% DMSO–DME
10% DMSO–DME
10% DMSO–DME
0
11
19
28
44
33
21
22
38
PivOH (1.0)
PivOH (1.0)
PivOH (2.5)
PivOH (4.0)
AcOH (2.5)
EtCOOH (2.5)
1-AdCOOH
(2.5)
10
11
2
2
2
5
7
7
7
7
CF3COOH (2.5) 10% DMSO–DME
10
4
45
58
64
p-TsOH (2.5)
PivOH (2.5)
PivOH (2.5)
PivOH (2.5)
PivOH (2.5)
PivOH (2.5)
PivOH (2.5)
10% DMSO–DME
10% DMSO–DME
10% DMSO–DME
10% DMSO–DME
10% DMSO–dioxane 73
10% DMSO–dioxane 66
10% DMSO–dioxane 38
12c
13c
14c
15c
16c,d
17c,e
State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, Fujian 350002, China. E-mail: wpsu@fjirsm.ac.cn;
Fax: +86 591 8377 1575; Tel: +86 591 8377 1575
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. See DOI: 10.1039/c0cc01029d
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), Pd(TFA)2 (10 mol%),
b
Ag2CO3 (2.5 equiv.), solvent (2.0 mL), 100 1C, 24 h. GC yield.
Ag2CO3 (2.0 equiv.). Under air. Pd(MeCN)2Cl2 (20 mol%).
c
d
e
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Table 2 Decarboxylative coupling of benzoic acids with nitroethanea
additive (entry 5 vs. entries 6–11). We also observed that
reducing the amount of Ag2CO3 to 2.0 equiv. gave the same
result as obtained using 2.5 equiv. of Ag2CO3 (entry 12).
Increasing the amount of 2a relative to 1a resulted in a
significant increase in yield as a result of suppressing proto-
decarboxylation of benzoic acid (entry 12 vs. entries 13 and
14). Gratifyingly, 73% yield was obtained when the reaction of
1a with 7.0 equiv. of 2a was conducted in 10% DMSO–dioxane
at 100 1C (entry 15). Interestingly, the reaction can be carried
out under air with yield slightly reduced (entry 16).
Entry
1
Substrate
Product
Yield (%)b
71% (70%)
70%
2
3
Notably, when the optimized procedure (entry 15, Table 1)
was applied to a range of benzoic acids, small adjustments
were required to the reaction conditions in some cases due to
the variations in reactivity towards decarboxylation of benzoic
acids (Table 2). Since DMSO functions as a ligand for the
catalyst, we speculated that the amount of DMSO must be an
important parameter that influences the rate of decarboxylation.
As expected, in the cases of electron-rich benzoic acids, more
DMSO was required to slow the decarboxylation of more
electron-rich ones compared with the standard conditions
whereas a decreasing amount of DMSO and increasing
temperature were required for less electron-rich ones (3c–3e).
In the reaction of electron-deficient benzoic acids, pivalic acid
led to protodecarboxylation, therefore was removed from the
reaction system, and Pd(MeCN)2Cl2 was observed to perform
better than Pd(TFA)2 (3m–3o). Thus, both electron-rich and
-deficient benzoic acids underwent smoothly the reaction with
nitroethane to produce exclusively (E)-b-nitrostyrenes. In
most cases, synthetically useful yields were obtained. The
reaction conditions are compatible with halide substituents
(3f, 3h, 3l), providing an opportunity for further elaboration of
products. The heterocyclic carboxylic acids also served as
suitable substrates to participate in this reaction (3i–3l), in
which substituents ortho to carboxyl were required to afford
good yields. Because of the difficulty in slowing the rate of
decarboxylation, 2,4,6-trimethoxybenzoic acid yielded the
desired product in poor yield (3d). Unfortunately, when
1-nitropropane 3 was induced to react with 2,4-dimethoxy-
benzoic acid (1a), the reaction provided a mixture of E/Z
isomers in the ratio of 3 : 2, and the yield is quite low
(Scheme 1). Further investigation indicated that although
nitroethane and 1-nitropropane worked under the established
reaction conditions, more sterically demanding nitro compounds
such as 2-nitropropane, nitrocyclohexane, a- and b-nitroethyl-
benzene were ineffective.
74%c
28%d
4
5
6
65%e
52%e,f
7
8
40%f,g
73%e
9
68%
25%
10
11
12
13
67%e
64%e,f
63%f,g
14
60%f,g
53%f,g
This method is not limited to the small-scale reaction as
described above (e.g., 0.2 mmol). The reaction of 2,4-
dimethoxybenzoic acid with nitroethane on a gram scale
provided 70% yield (entry 1 in Table 2).
15
The difference in reaction conditions between electron-rich
and -deficient benzoic acids led us to consider whether there
were two different reaction pathways in the decarboxylative
coupling of benzoic acids with nitroethane. We observed that
stoichiometric Pd(TFA)2 enabled the reaction of electron-rich
benzoic acids with nitroethane in the absence of Ag2CO3
whereas the use of Ag2CO3 alone, in the absence of Pd(TFA)2
under otherwise identical conditions, was ineffective for the
decarboxylation of electron-rich benzoic acids, clearly indicating
that decarboxylation of electron-rich benzoic acids resulted
a
Reactions were run under the conditions of entry 15 in Table 1. See
b
Supporting Information for details. Isolated yields (Value in
parentheses refers to the yield from reaction on a 10 mmol scale).
c
d
15% DMSO. 40% DMSO. 5% DMSO. In the absence of
e
f
g
PivOH. Pd(MeCN)2Cl2 (20 mol%), 2% DMSO.
from the contribution of Pd(TFA)2 rather than Ag2CO3. In
contrast, the reactions of electron-deficient benzoic acids were
observed to mainly arise from Ag-promoted decarboxylation.13
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Scheme 1 Reaction of 2,4-dimethoxybenzoic acid (1a) with 1-nitro-
propane 3.
On the other hand, the detailed reaction behavior of nitro-
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unclear; the formation of vinylation products from this system
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In summary, we have described the first metal-catalyzed
method for the cross-coupling of a broad range of benzoic
acids with nitroethane that produces (E)-b-nitrostyrenes with
high selectivity. Current efforts are directed towards the
detailed investigation on the mechanism of this process, and
the improvement of substrate scope.
Financial support from the 973 Program (2006CB932903,
2009CB939803), NSFC (20821061, 20925102), ‘‘The
Distinguished Overseas Scholar Project’’, ‘‘One Hundred
Talent Project’’, and Key Project from CAS is gratefully
acknowledged.
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Chem. Commun., 2010, 46, 5455–5457 | 5457