Palladium-catalyzed chemoselective decarboxylative ortho acylation of benzoic acids with α-oxocarboxylic acids

Article abstract of DOI:10.1021/ol400919u

Palladium-catalyzed chemoselective decarboxylative cross coupling of benzoic acids with α-oxocarboxylic acids was realized via an arene sp ² C-H functionalization process. This work represents the first example of transition-metal-catalyzed cro

Full text of DOI:10.1021/ol400919u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Chemoselective
Decarboxylative Ortho Acylation of
Benzoic Acids with r‑Oxocarboxylic
Acids
Jinmin Miao and Haibo Ge*
Department of Chemistry and Chemical Biology, Indiana University Purdue University
Indianapolis, Indianapolis, Indiana 46202, United States
geh@iupui.edu
Received April 3, 2013
ABSTRACT
Palladium-catalyzed chemoselective decarboxylative cross coupling of benzoic acids with R-oxocarboxylic acids was realized via an arene sp2
CÀH functionalization process. This work represents the first example of transition-metal-catalyzed cross-coupling reactions with two acids
acting in different roles. The synthetic utility of this method was confirmed by the synthesis of pitofenone, an antispasmodic used in the combined
drug Spasmalgon.
2-Benzoylbenzoic acid derivatives are important inter-
mediates for the synthesis of various bioactive compounds1
and are often encountered as subunits of many biologically
active compounds,2 including natural products, pharma-
ceuticals, and agrochemical compounds. For example,
balanol, a fungal metabolite produced by the fungus
Verticillium balanoides and other fungi, is a potent inhibitor
of protein kinase C (PKC),1e,f narceine, an opium alkaloid
produced by the Papaver somniferum plant, is a bitter com-
pound with narcotic effects,1d and pitofenone, the key
ingredient in Spasmalgon (a combined drug), is an anti-
spasmodic (Figure 1).1c Additionally, 2-benzoylbenzoic
acids are often used as functional groups or substrates in
photochemistry,3 chromatography,4 and food chemistry.5
Despite the demonstrated biological importance of
2-acylbenzoic acids, synthetic methods for these species
are far from maturity. The most common routes start
from 1,3-isobenzofurandione derivatives and involve
either a nucleophilic addition/elimination process by orga-
nometallic reagents6 or a FriedelÀCrafts acylation process
(Scheme 1).7 In many cases, these reactions suffer severely
from poor regioselectivity on the benzofurandione, and
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r
10.1021/ol400919u
XXXX American Chemical Society

attracted considerable attention due to the low cost, ready
availability, and environmentally benign properties of
carboxylic acids.10 Along with the well-studied benzoic
acids, alkyl, alkenyl and alkynyl acids, R-oxocarboxylates,
and oxalates have also been demonstrated as effective
substrates, which enable the installation of a variety of
functional groups on aromatic rings. Furthermore, since
Crabtree first reported a direct decarboxylative cross cou-
pling of arenes with aromatic acids through a Pd(II)-
catalyzed CÀH functionalization process,11 the method
has attracted considerable attention because the prefunctio-
nalization of reaction substrates is avoided.12
As substrates, benzoic acids have been extensively stu-
died in decarboxylative cross-coupling reactions by both
Pd(0) and Pd(II) catalysis. It has been demonstrated that
either a silver or copper source could effectively mediate
the decarboxylation. On the other hand, from Yu’s studies,
benzoic acid derivatives were fairly stable at high tempera-
ture (130 °C) in the presence of a catalytic amount of
a Pd(II) source and an excess Ag(I) source.13 Moreover,
R-oxocarboxylic acids, utilized in Goossen’s laboratory in
Pd(0)-catalyzed decarboxylative cross couplings,14 have
also been demonstrated as effective coupling partners in
Pd(II) catalysis in our laboratory with either a silver or
persulfate source as an oxidant and the decarboxylation
reagent.8,15 It was also noted that, along with acteani-
lides and 2-phenylpyridines, cyclic enamides,16 O-methyl
oximes,17 phenylacetamides,18 O-phenyl carbamates,19
and 1-(pyrimidin-2-yl)-1H-indoles20 were also effective
Figure 1. Representative biologically active compounds con-
taining a 2-acylbenzoic acid/ester moiety.
thus substituted 2-acylbenzoic acids are difficult to
obtain in a satisfactory yield.6b,7c Therefore, the need for
complementary, concise, and effective approaches to ac-
cess these compounds is clear. On the basis of our success
on direct ortho acylation of 2-phenylpyridines and
acetanilides,8 we proposed that an efficient approach for
the synthesis of 2-acylbenzoic acids could be achieved
by decarboxylative cross coupling of benzoic acids with
R-oxocarboxylic acids by a Pd(II)-catalyzed CÀH functio-
nalization process (Scheme 1).
Scheme 1. Synthesis of 2-Acylbenzoic Acids
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Int. Ed. 2012, 51, 227.
Transition-metal-catalyzed cross coupling reactions re-
main one of the most powerful methods for carbonÀcarbon
(CÀC) bond formation.9 Among these methods, Pd(0)-
catalyzed decarboxylative cross coupling has recently
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McDonnell, J. M.; Newell, D. R.; Noble, M. E. M.; Revill, C. H.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

substrates for the direct decarboxylative acylation. These
results support the feasibility of chemoselective decarbox-
ylative cross coupling of benzoic acids with R-oxocar-
boxylic acids through Pd(II) catalysis under well-defined
reaction conditions. It is noteworthy that, although the
benzoic acid derivatives have been well studied as the
substrates in metal-catalyzed CÀH bond activation
reactions,9 direct ortho acylation of the benzoic acids
remains a challenge. Furthermore, transition-metal-cata-
lyzed cross coupling of two acids with different roles in the
reaction has never been reported. As part of our program
to develop novel transition-metal-catalyzed cross coupling
reactions with diverse substrates,8,15,21 we have developed
and report herein the synthesis of 2-acylbenzoic acid
derivatives through chemoselective decarboxylative cross
coupling of benzoic acids with R-oxocarboxylic acids via a
palladium-catalyzedCÀH bond functionalizationprocess.
(Table 1, entries 4 and 5). The following survey of catalysts
indicated that although PdCl2(MeCN)2 and Pd(OAc)2
could also catalyze this reaction, Pd(TFA)2 is more
effective (entries 7 and 8). Further screening of oxidants
showed that silver carbonate was the best choice. Due to
our success in the decarboxylation of R-oxocarboxylic
acids with a persulfate salt, replacement of Ag2CO3 with
K2S2O8, Na2S2O8, and (NH4)2S2O8 was also examined.
However, the addition of these persulfate salts led to the
decarboxylation of both acids while no desired product
was obtained (entry 11). Further optimization of reaction
conditions showed that although increasing the reaction
time had no apparent effect on this reaction, the yield was
significantly improved by increasing the amount of
Ag2CO3 and raising the reaction temperature (entries
12À14). It was also noted that the coupling product was
obtained either with less Pd catalyst or when dioxane was
usedasthe solvent, albeit in lower yields (entries 15 and 16).
Table 1. Optimization of Reaction Conditionsa
Scheme 2. Substrate Scope of Benzoic Acidsa,b
Pd source
oxidant
yield
(%)b
entry
(amt (mol %))
(amt (equiv))
solvent
1
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
DMF
THF
trace
trace
32
2
3
tBuOH
4
dioxane 55
5
DME
DME
DME
DME
DME
DME
58
trace
41
48
20
38
0
6
PdCl2(PhCN)2 (10) Ag2CO3 (2.0)
PdCl2(MeCN)2 (10) Ag2CO3 (2.0)
7
8
Pd(OAc)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (10)
Pd(TFA)2 (5)
Pd(TFA)2 (10)
Ag2CO3 (2.0)
Ag2O (2.0)
9
10
11
12c
13
14d
15
16d
AgOAc (2.0)
(NH4)2S2O8 (2.0) DME
Ag2CO3 (2.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
DME
DME
DME
DME
60
64
80
56
a Conditions: 1 (0.2 mmol), Pd(TFA)2 (0.02 mmol), 2a (0.6 mmol),
Ag2CO3 (0.6 mmol), 2 mL of DME, 150 °C, 24 h unless otherwise noted.
b Isolated yields. c 165 °C. d 130 °C. e 48 h.
dioxane 67
a Conditions: 1a (0.2 mmol), Pd source, oxidants, 2a (0.6 mmol),
2 mL of solvent, 120 °C, 24 h unless otherwise noted. b Isolated yields.
c 48 h. d 150 °C.
With the optimized reaction conditions in hand, we then
carried out the substrate scope study of substituted benzoic
acids. As shown in Scheme 2, this transformation is com-
patible with electron donating and electron withdrawing
group substituted benzoic acids (3aÀj), while substrates con-
taining electron-donating groups provided higher yields than
their electron-withdrawing counterparts, with the exception of
3e. As expected, halogens (F, Cl, and Br) were tolerated under
the current reaction system, allowing the further manipulation
of the initial products. Furthermore, good yields were also
observed with disubstituted benzoic acids (3k,l).
Next, a substrate scope study for the R-oxocarboxylic
acids was carried out. As shown in Scheme 3, electron-rich
groups (MeO and Me), and halogens (F, Cl, and Br) are
compatible with the current reaction conditions (3mÀv).
Considering that R-oxocarboxylic acid is a potential
source of benzoic acid through decarboxylation and oxi-
dation, o-methylbenzoic acid was chosen as the substrate
for the decarboxylative cross-coupling reaction with
R-oxocarboxylic acid in the presence of a catalytic amount
of Pd(TFA)2 and an excess of Ag2CO3 as the oxidant and
the decarboxylation reagent on the basis of our previous
reports.8,21 After an extensive solvent screening, DME
and dioxane were shown to be optimal solvents for this
coupling, providing the desired product in moderate yields
(21) Li, M.-Z.; Wang, C.; Fang, P.; Ge, H.-B. Chem. Commun. 2011,
47, 6587.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Substrate Scope of R-Oxocarboxylic Acidsa,b
Scheme 4. Proposed Reaction Mechanism
Scheme 5. Synthesis of Pitofenone
a Conditions: 1a (0.2 mmol), Pd(TFA)2 (0.02 mmol), 2 (0.6 mmol),
Ag2CO3 (0.6 mmol), 2 mL of DME, 150 °C, 24 h unless otherwise noted.
b Isolated yields. c 165 °C. d 130 °C. e 48 h. f Ag2CO3 (0.5 mmol).
Unfortunately, strong electron-withdrawing groups are
not well tolerated in the current reaction system. As
observed in our previous studies,8 there is not an apparent
steric effect on these substrates (3n,o). In contrast, there is a
clear electronic effect. Furthermore, the sterically hindered
substrate 2,4,6-trimethylbenzoylformic acid also provided
the desired product 3x in high yield.
On the basis of the reports from Yu and our
laboratory,8,13,22 a decarboxylative cross-coupling reac-
tion mechanism is proposed (Scheme 4). It is believed that
this transformation starts with the palladation of silver
benzoate A into the Pd(II) intermediate B, which then
undergoesa transmetalationstepwiththeacylsilverspecies
C formed by the silver-mediated decarboxylation of 2, to
generate the Pd(II) intermediate D. Reductive elimination
of D provides the silver salt E and Pd(0), which will be
reoxidized into Pd(II) by Ag2CO3. Protonation of inter-
mediate E provides the desired product 3.
substitution of 3t by 1-(2-hydroxyethyl)piperidine, followed
by methylation, produced pitofenone in 91% yield over
two steps. It is noteworthy that this route also allows
the installation of extra substituents on the phenyl rings,
which facilitates the medicinal chemistry study of this
compound.
In summary, an efficient decarboxylative cross-coupling
reaction of benzoic acids with R-oxocarboxylic acids has
been developed via a palladium-catalyzed CÀH bond func-
tionalization process. This transformation is the first exam-
ple of direct ortho acylation of benzoic acids. The method
provides an efficient access to 2-acylbenzoic acid derivatives.
Furthermore, the synthesis of pitofenone was also achieved
by employing this transformation as a key step. In compar-
ison with the two reported syntheses,23 this route provides a
more efficient approach to access this compound.
Acknowledgment. We gratefully acknowledge Indiana
University Purdue University Indianapolis for financial
support. The Bruker 500 MHz NMR was purchased using
funds from an NSF-MRI award (CHE-0619254). We also
thank Dr. Cong Wang (Indina University Purdue Uni-
versity Indianapolis) for initial optimization of reaction
conditions.
To demonstrate the synthetic utility of this method, it was
applied to the synthesis of pitofenone (Scheme 5). Pd(II)-
catalyzed direct decarboxylative ortho acylation of benzoic
acid with (4-fluorobenzoyl)formic acid provided 2-(4-
fluorobenzoyl)benzoic acid (3t) in 62% yield. Nucleophilic
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14654. (c) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 460. (d) Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. J. Am. Chem. Soc. 2010, 132, 14137. (e) Engle, K. M.; Thuy-Boun,
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107390, 2004.
Supporting Information Available. Text and figures
giving experimental details and characterization data
for synthesized compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX