Palladium-Catalyzed Carboxylate-Assisted Ethoxycarboxylation of Aromatic Acids to Synthesize Monoethyl Phthalate Derivatives with Ethyl Bromodifluoroacetate

Article abstract of DOI:10.1021/acs.orglett.9b03196

A novel and efficient approach for direct carbonation of aromatic acids with ethyl bromodifluoroacetate as the carbonyl source is reported. A broad range of substrates bearing various functional groups were tolerated, leading to monoalkyl phthalate derivatives in moderate to good yields.

Full text of DOI:10.1021/acs.orglett.9b03196

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Carboxylate-Assisted Ethoxycarboxylation of
Aromatic Acids To Synthesize Monoethyl Phthalate Derivatives with
Ethyl Bromodifluoroacetate
Na Tao, Jie Wang, Chunchen Yuan, Runsheng Zeng,* and Ying-Sheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: A novel and efficient approach for direct
carbonation of aromatic acids with ethyl bromodifluoroacetate
as the carbonyl source is reported. A broad range of substrates
bearing various functional groups were tolerated, leading to
monoalkyl phthalate derivatives in moderate to good yields.
ransition-metal-catalyzed C−H functionalization reac-
expanded the scope of oxidative C−H carboxylation, the
Ttions have provided efficient approaches for the synthesis development of new carbonyl sources that can address new
challenging substrates is highly attractive.
of important chemical compound classes. For example,
oxidative C−H carbonylation represents a direct strategy in
the synthesis of the carbonyl-containing compounds. The
pioneering work in oxidative C−H functionalization/carbon-
ylation of arenes with CO was initially reported by Murahashi
in the 1950s.1 Later, Fujiwara and co-workers reported the
Pd(OAc)2-catalyzed direct carboxylation reaction of arenes
with CO to prepare aromatic acids.2 However, the lack of site
selectivity greatly limits its application in synthetic chemistry.
In 2008, the Yu group published the palladium-catalyzed
ortho-selective C−H ethoxycarbonylation of arenes with
diethyl azodicarboxylate as the carbonyl source.3 Since then,
various site-selective oxidative C−H carbonylation pathways
have been extensively explored, which afford a straightforward
way in synthesis of carbonyl compounds. Except for CO and
DEAD, carbonylation reagents CO2,4 carbamoyl chlorides,5
diaziridinone,6 diethyl azodicarboxylate,7 and glyoxylates8 all
can be applied to oxidative C−H carboxylation reactions
(Scheme 1b). Although these reports have significantly
Monoalkyl phthalate derivatives are important precursors for
synthesis of natural products, pharmaceuticals, and agro-
chemicals. Although several approaches to prepare phthalic
acids have been developed, a direct and efficient route to
prepare monoalkyl phthalate derivatives remains elusive and
limits the development and diversification of an important
class of molecules. The elegant palladium-catalyzed carbox-
ylation of benzoic acid derivatives to afford phthalic acids was
established by Yu in 2008 (Scheme 1a).9 Recently, Shi and co-
workers developed a palladium-catalyzed auxiliary assisted
alkoxycarbonylation of benzaimdes with chloroformates.10
However, it is challenge to transform phthalic acids or
benzamide to monoalkyl phthalates, which restricts further
application in synthetic chemistry. Herein, we report a
palladium-catalyzed ethoxycarboxylaion of aromatic acids
using ethyl bromodifluoroacetate as a new carbonyl source.
A wide variety of aromatic acids were well tolerated, leading to
the corresponding ethoxycarbonylation products in moderate
to good yields. A preliminary mechanistic study revealed the
reaction proceeds via a free-radical pathway.
Scheme 1. Direct C−H Carbonylation Reactions
Ethyl bromodifluoroacetate (BrCF2CO2Et) has been dem-
onstrated as a versatile fluorination reagent and normally
undergoes either single C−Br bond cleavage or double C−X
and C−R bond cleavage.11 Recently, our group successfully
introduced the difluoromethyl group to different sites of an
aromatic ring by employing ruthenium12 or palladium13
catalyst systems. To further explore the synthetic utility of
ethyl bromodifluoroacetate, we tried to install the difluoroalkyl
group on the aromatic ring of benzoic acids. With this goal in
mind, we initially treated benzoic acid 1a with ethyl
bromodifluoroacetate 2 in the presence of palladium acetate,
K2HPO4 (3 equiv), and benzoquinone (2 equiv) in
Received: September 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
hexafluoroisopropanol (HFIP) at 100 °C for 24 h (Table 1).
Interestingly, the important monoethyl phthalate 3a was
Scheme 2. Scope of Benzoic Acid and Its Derivatives
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
oxidant
base
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
BQ
Ag2CO3
K2S2O8
AgOAc
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2CO3
KOAc
DMAP
DBU
DABCO
DABCO
DABCO
31
none
16
24
56
none
19
47
35
37
Cu(OAc)2·H2O
NaIO4
Cu(OTf)2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
9
10
11
12
13
14
none
85/81
26
none
c
b
a
Reaction conditions: 1a (0.2 mmol), 2 (3 equiv), Pd(OAc)2 (10 mol
b
%), oxidant (2 equiv), base (3 equiv), solvent (1 mL), in air. 0.5
equiv of Cu(OAc)2·H2O, O2 (1 atm). Yield of isolated product. Key:
c
benzoquinone (BQ), N,N-4-dimethylaminopyridine (DMAP), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane
(DABCO), hexafluoroisopropanol (HFIP).
obtained in 31% yield, in addition to recovering 1a. Although
a clear reason is unknown, we speculate the difluoromethyl
radical was not trapped by the deactivated phenyl ring and
results in its decomposition to the ethoxyacyl radical, which
reacts with palladium to afford the ethoxycarbonylation
product 3a. Encouraged by this result, several oxidants such
as Ag2CO3, K2S2O8, AgOAc, Cu(OAc)2·H2O, and NaIO4 were
further screened to improve the efficiency of this new protocol.
Using Cu(OAc)2·H2O as the oxidant resulted in 3a in 56%
yield. Several other bases including K2CO3, KOAc, DMAP,
DABCO, and DBU were further tested. Gratifyingly, 3a was
obtained in 81% yield when DABCO was used as the base.
Unfortunately, when catalytic amounts of Cu(OAc)2·H2O and
oxygen were both used as oxidants, a rather low yield of 3a was
observed. The control experiment showed palladium was
essential for this transformation, along with the recovered
starting material. It is worth noting that no other
ethoxycarbonylation products were obtained.
After the reaction conditions were optimized, several
aromatic acids were explored to test the functional group
tolerance of this protocol with the results summarized in
Scheme 2. The ortho- and meta-substituted benzoic acids were
well tolerated, yielding the corresponding products in
moderate to good yields (3b−e). The para-substituted benzoic
acids all afforded ethoxycarboxylated products in good yields.
Functional groups Me, Et, PhO, BnO, and n-PrO were all well
tolerated. The electron-withdrawing functional groups such as
Cl and CO2Me were tolerated as well but resulted in lower
yields. Interestingly, all disubstituted aromatic compounds
provided the ethoxycarbonylation products in good yields.
Dimethyl- or methoxy-substituted benzoic acids afforded the
corresponding products in good yield (3k−3m). Other
a
Reaction conditions: 1a (0.2 mmol), 2 (3 equiv), Pd(OAc)2 (10 mol
%), Cu(OAc)2·H2O (2 equiv), DABCO (3 equiv), HFIP (1 mL), in
air.
disubstituted benzoic acids were compatible in this trans-
formation, leading to the corresponding products in moderate
to good yields (3n−3w). Impressively, the 3,4,5-trimethox-
ybenzoic acid performed well, yielding 3x in 67% yield.
Interestingly, the benzoic acid 3y,14 a key precursor for anti-
infective agents, yielded 3y in 65% yield, highlighting the
importance of this new protocol.
To further demonstrate the synthetic utility of this
palladium-catalyzed ethoxycarbonylation of benzoic acid
derivatives, the gram-scale reaction with benzoic acid and
piperonylic acid was performed using 10 mmol, which yielded
the corresponding product in good yield (Scheme 3a). We
next showed the synthetic superiority of the monoalkyl
phthalate (Scheme 3b). The product 3a was easily transformed
into benzoyl chloride, which further reacted with 2,3,4,5,6-
pentafluoroaniline to generate 5, which is a well-known
substrate in C−H activation reactions. Notably, the product
3a can be directly reacted with isobutyl alcohol to give product
5 in good yield, highlighting the synthetic application of this
method.
Several reactions were performed to probe the mechanism of
this reaction pathway and are summarized in Scheme 4. First,
when 3 equiv of TEMPO was added under the standard
reaction conditions, 3a was not obtained. Second, we used 1,1-
B
DOI: 10.1021/acs.orglett.9b03196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3a. It should be mentioned that another catalytic route
involving the Pd(I)/Pd(III) pathway could not be ruled out.
In conclusion, we have developed an efficient palladium-
catalyzed oxycarboxylaion of aromatic acids with ethyl
bromodifluoroacetate as a new carbonyl source. A wide variety
of aromatic acids were well tolerated, leading to the
corresponding ethoxycarbonylation products in moderate to
good yields. A preliminary mechanistic study revealed the
reaction proceeded via a free-radical pathway.
Scheme 3. Gram-Scale Reaction and Synthetic Applications
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03196.
Scheme 4. Mechanistic Investigation
1
Experimental procedures, and H and 13C NMR spectra
for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yszhao@suda.edu.cn.
*E-mail:zengrunsheng@suda.edu.cn.
ORCID
Ying-Sheng Zhao: 0000-0002-6142-7839
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (Nos. 21772139, 21572149), the Jiangsu Province
Natural Science Found for Distinguished Young Scholars
(BK20180041), Project of Scientific and Technologic Infra-
structure of Suzhou (SZS20170), and the PAPD Project.
diphenylethylene to trap the ethoxyacyl radical potentially
generated during the reaction. To our delight, 6a was formed
1
in the reaction and confirmed by H NMR. These results
strongly suggest that this reaction proceeds via a free-radical
pathway. Finally, the isotopic experiments were performed, and
a kinetic isotopic effect of 2.0 was obtained, indicating the rate-
limiting step was C−H activation.
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