Palladium-Catalyzed Direct C-H Arylation of 3-Butenoic Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c03773

We report herein a direct method to synthesize 4-aryl-3-butenoic acid through a carboxylic-acid-directed oxidative Heck reaction. The various 4-aryl-3-butenoic acids are easily prepared in moderate to good yields. In view of the promising bioactivity of 4-phenyl-3-butenoic acid previously reported, its derivatives reported here may be bioactive.

Full text of DOI:10.1021/acs.orglett.0c03773

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Letter
Palladium-Catalyzed Direct C−H Arylation of 3‑Butenoic Acid
Derivatives
Shan Yang,§ Lingling Liu,§ Zheng Zhou, Zhibin Huang,* and Yingsheng Zhao*
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ABSTRACT: We report herein a direct method to synthesize 4-
aryl-3-butenoic acid through a carboxylic-acid-directed oxidative
Heck reaction. The various 4-aryl-3-butenoic acids are easily
prepared in moderate to good yields. In view of the promising
bioactivity of 4-phenyl-3-butenoic acid previously reported, its derivatives reported here may be bioactive.
Scheme 1. Functionalization of the 3-Butenoic Acid
Derivatives
fficient methods to build various important skeletons are
E
of current interest in organic synthetic chemistry.1 4-
Phenyl-3-butenoic acid has been found to be anti-inflammatory
and an inhibitor of histone deacetylase enzymes and
peptidylglycine α-hydroxylating monooxygenase (PHM).2
Such bioactivities have generated interest in 4-phenyl-3-
butenoic acid analogues. There are two main approaches to
synthesize the analogues.3 One is the condensation of aryl
acetaldehyde with malonic acid and another is through the
Wittig reaction of aryl acetaldehyde with 2-(carboxy-ethyl)-
triphenylphosphonium bromide as the coupling partner. The
research groups of Fu4 and Wu5 have transformed cinnamyl
alcohol into 4-phenyl-3-butenoic acid derivatives. These
methods greatly enrich the synthetic methodology of 4-
phenyl-3-butenoic acid derivatives, but the poor availability of
prefunctionalized starting material limits the scope of preparing
functional-group-substituted 4-aryl-3-butenoic acids. The
Mizoroki−Heck reaction is a straightforward way to prepare
substituted 4-aryl-3-butenoic acids; however, it usually
provides isomeric mixtures, limiting its applications.6 Recently,
Engle’s group7 has demonstrated that 3-butenoic acid is of
important synthetic utility and can provide various important
organic molecules. In 2018, Zhao’s group reported the
nickel(0)-catalyzed hydroarylation of unactivated alkenes and
styrenes with aryl boronic acids.8 Subsequently, the group of
Bi9 reported the copper-catalyzed aminoquinoline-assisted
Mizoroki−Heck reaction of 3-butenoic acids to form a
Csp3−Csp3 bond (Scheme1a). Inspired by these results, we
envisage that the 4-aryl-3-butnoic acids can be directly
synthesized through a palladium-catalyzed oxidative Mizor-
oki−Heck reaction assisted by a carboxylic acid group as a
weak coordination center. We report herein the synthesis of 4-
aryl-3-butenoic acids via carboxylic-acid-group -assisted direct
oxidative Heck coupling between 3-butenoic acid and
arylsulfonyl hydrazide. A variety of 4-aryl-3-butenoic acids
were obtained in moderate to good yields. Preliminary
mechanistic studies reveal that the carboxylic acid is very
important to realize this transformation in the presence of
copper(II) acetate, which plays an important role in activating
the arylsulfonylhydrazides to form the key palladium(II)
intermediate.
Arylsulfonyl hydrazide has emerged as a highly effective
arylation reagent in recent years,10 which does not require
harsh acidic or basic conditions to initiate the reaction. Several
protocols have been developed by using arylsulfonylhydrazides
as arylating agents. In 2017, Yin’s group reported a palladium-
catalyzed Sonogashira-type reaction of arylsulfonyl hydrazides
with terminal alkynes.11 However, the arylation of unactivated
olefins without a directing group has not been reported. With
this background, we first treated 3-butenoic acid with
benzenesulfonyl-hydrazide in the presence of Pd(PPh3)2Cl2
(2.5 mol %) in N,N-dimethylamide (DMF) at 100 °C for 10 h.
The 4-phenyl-3-butenoic acid was obtained in 7% yield (Table
1, entry 1). When the oxidative silver acetate was added as an
oxidant, the conversion of 3-butenoic acid improved, and 3a
was obtained in 12% yield (Table 1, entry 2). Upon screening
the oxidants K2S2O8, Cu(OAc)2, Cu(acac)2, Cu(OTf)2, Cu2O,
and PhI(OAc)2, it was found that with copper acetate, the
Received: November 12, 2020
Published: December 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03773
© 2020 American Chemical Society
Org. Lett. 2021, 23, 296−299
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a
The para-substituted arylsulfonylhydrazides, including methyl,
tert-butyl, methoxy, fluorine, chlorine, and bromine (3b−3g),
resulted in the corresponding 4-aryl-3-butenoic acids in
moderate to good yields. It is worth mentioning here that
the sensitive functional group iodide (3h) also gave the
corresponding product in 80% yield. However, when there was
an electron-withdrawing group such as trifluoromethyl (3i) in
the para position, the yield was only slightly worse at 48%.
Further experiments revealed that the ortho- or meta-
substituted arylsulfonylhydrazides gave the corresponding
products in moderate to good yields. Gratifyingly, cyano
(3o) and carboxyl (3p) both performed well, yielding the 4-
aryl-3-butenoic acids in good yields. The biphenyl (3q),
naphthyl (3r), and dansylhydrazide (3s) (a naphthalene ring
structure with a Me2N substituent), were suitable for this
transformation, affording the corresponding products in good
yields.
Table 1. Optimization of Reaction Conditions
b
entry
oxidant
yield (%)
1
2
3
4
5
6
7
8
9
10
none
7
12
trace
83
71
34
52
69
47
AgOAc (75 mol %)
K2S2O8 (75 mol %)
Cu(OAc)2 (75 mol %)
Cu(OTf)2 (75 mol %)
Cu2O (75 mol %)
PhI(OAc)2 (75 mol %)
Cu(OAc)2 (50 mol %)
Cu(OAc)2 (30 mol %)
Cu(OAc)2 (10 mol %)
Cu(OAc)2 (75 mol %)
Cu(OAc)2 (75 mol %)
36
23
trace
c
11
d
12
Encouraged by these results, we investigated the applicability
of the standardized protocol to several α-substituted 3-
butenoic acids to understand the functional group tolerance
of the transformation (Scheme 3). The ethyl (4a), isopropyl
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Pd(PPh3)2Cl2
(2.5 mol %), oxidant (x mol %), DMF (1 mL), 100 °C 10 h. Isolated
yields are given. Under an O2 atmosphere. No Pd(PPh3)2Cl2.
b
c
d
a
Scheme 3. Effect of α-Substituted 3-Butenoic Acids
yield of 3a reached 83% (Table 1,entries 3−7). On reducing
the amount of copper acetate below the optimum level, the
yield of the product significantly decreased (Table 1, entries
8−10). When a catalytic amount of copper acetate and oxygen
was used, the yield of 3a decreased to 23% (Table 1, entry 11).
A control experiment was also performed, and its result
showed that the palladium catalyst was indispensable for this
transformation (Table 1, entry 12).
Using the optimal conditions, the applicability of arylsulfonyl
hydrazides (Scheme 2) to directly convert the readily available
3-butenoic acid to 4-aryl-3-butenoic acids was investigated.
a
Scheme 2. Effect of Benzenesulfonyl Hydrazides
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), Pd(PPh3)2Cl2
(2.5 mol %), Cu(OAc)2 (75 mol %), DMF (1 mL), 100 °C, 10 h;
Isolated yields are given.
(4b), isobutyl (4c), phenethyl (4i), and benzyl group (4h) as
α-substituents were well tolerated, giving the corresponding
product in good to excellent yields. These results suggest that
steric hindrance at the α-position has no effect on this
transformation. Delightfully, α-substituted 3-butenoic acids
containing a functional group at the end of the α-alkyl chain
gave a good yield of the desired product when the end group
was a methoxy (4d), chloride (4e), cyclopropyl (4f), or
cyclobutyl group (4g). This highlights the synthetic
importance of the present method.
To further test the value of the reaction, we carried out its
application on the gram scale for 24 h, and the 4-phenyl-3-
butenoic acid (3a) was obtained in 74% yield. 3a could be
easily converted into phenylbutyric acid, a bioactive compound
5, in 78% yield by treating it with palladium in a hydrogen
atmosphere (Scheme 4). Furthermore, the bioactive com-
pound Ravicti (6), used in the treatment of certain inborn urea
cycle disorders, could be easily obtained in 80% yield. These
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), Pd(PPh3)2Cl2
(2.5 mol %), Cu(OAc)2 (75 mol %), DMF (1 mL), 100 °C, 10 h.
Isolated yields are given.
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Scheme 4. Gram-Scale Reaction and Other Applications
Scheme 6. Plausible Catalytic Cycle
results indicate that this transformation may give various
phenylbutyric acid analogues having potential for applications
in drug discovery.
To understand the mechanism of the reaction, we carried
out a series of reactions (Scheme 5). On the basis of previous
Scheme 5. Preliminary Mechanistic Study
intermediate I, and it is transformed into II by treating with 1,
which concomitantly releases N2 and SO2. Thereafter, the
Heck reaction occurs to generate intermediate III, which forms
the key intermediate IV. Its β-H elimination, results in the
highly regioselective formation of product 3. Palladium(0)
further reacts with copper(II) acetate under an oxygen
atmosphere to give the palladium(II) complex for the next
cycle.
In conclusion, we have developed the palladium-catalyzed
direct arylation of 3-butenoic acid, which gives important 4-
aryl-3-butenoic acid analogues. A wide variety of functional-
group-substituted 4-phenyl-3-butnoic acids have been easily
prepared in moderate to good yield. This may result in the
discovery of new bioactive compounds. Preliminary mecha-
nistic studies reveal that the reaction follows an oxidative
Heck-reaction-type mechanism, assisted by carboxylic acid.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03773.
Detailed experimental procedures and characterization
data (PDF)
reports,9 control experiments were carried out. First, the
reaction was performed in the presence of a free-radical
scavenger, 2,6-di-tert-butyl-4-methylphenol (BHT). The re-
action proceeded efficiently, indicating that it probably did not
undergo a free-radical pathway. Subsequently, when the
substrate 7, which has a competitive reaction center, was
subjected to standardized reaction conditions, product 8 was
observed in 55% yield, whereas 9 was absent. On the basis of
the previous reports,6b it appeared that the complex A was
generated with the help of copper(II) acetate. It was easily
transformed into complex B, rather than complex C, due to the
ring strain. Interestingly, when 3-butenoic acid was treated
with iodobenzene for Heck coupling, the 4-phenylbutenoic
acid was obtained in 55% yield as a 9:1 (E/Z) mixture (3a′),
along with isomeric 3-phenyl-3-methylpropenoic acid (10) in
19% yield. These results are consistent with previous reports.6
On the basis of these results, we may speculate that the
complex II appears to be formed in the catalytic cycle, which
gives intermediate III. The β-H elimination in IV leads to a
high regioselective product.
AUTHOR INFORMATION
Corresponding Authors
■
Zhibin Huang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China; Email: zbhuang@suda.edu.cn
Yingsheng Zhao − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China; School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang 453000, P. R. China;
orcid.org/0000-0002-6142-7839; Email: yszhao@
suda.edu.cn
Authors
Shan Yang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
Lingling Liu − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
On the basis of the existing literature,10,12 and the above
experimental facts, a plausible reaction pathway is proposed in
Scheme 6. First, Pd(PPh3)2Cl2 and ArSO2NHNH2 generate
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G. M.; Yang, S. L.; He, M. Y.; Wang, F.; Marsters, R. P.; McAlpine, I.;
Engle, K. M. Palladium(II)-catalyzed γ-selective hydroarylation of
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Materials Science, Soochow University, Suzhou 215123, P. R.
China
Zheng Zhou − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03773
Author Contributions
§S.Y. and L.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (no. 21772139), The Jiangsu Province Natural Science
Fund for Distinguished Young Scholars (BK20180041), the
Prospective Study Program of Jiangsu (17KJA150006), and
the PAPD Project. The project was also supported by the
Open Research Fund of the School of Chemistry and
Chemical Engineering, Henan Normal University.
(8) Lv, H. G.; Xiao, L. J.; Zhao, D. B.; Zhou, Q. L. Nickel(0)-
catalyzed linear-selective hydroarylation of unactivated alkenes and
styrenes with aryl boronic acids. Chem. Sci. 2018, 9, 6839.
(9) Tang, C. L.; Zhang, R.; Zhu, B.; Fu, J. K.; Deng, Y.; Tian, L.;
Guan, W.; Bi, X. H. Directed Copper -Catalyzed Intermolecular
Heck-Type Reaction of Unactivated Olefins and Alkyl Halides. J. Am.
Chem. Soc. 2018, 140, 16929−16935.
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