Palladium-Catalyzed Decarbonylative Heck Coupling of Aromatic Carboxylic Acids with Terminal Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c02462

A palladium-catalyzed decarbonylative alkenylation of aromatic carboxylic acids was developed. Under the reaction conditions, various benzoic acids including those bearing functional groups coupled to terminal alkenes, producing the corresponding internal alkenes in good to high yields. Cinnamic acids and bioactive benzoic acids such as 3-methylflavone-8-carboxylic acid, probenecid, adapalin, and febuxostat were also applicable to this reaction, demonstrating the potential synthetic value of this new reaction in organic synthesis.

Full text of DOI:10.1021/acs.orglett.0c02462

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Letter
Palladium-Catalyzed Decarbonylative Heck Coupling of Aromatic
Carboxylic Acids with Terminal Alkenes
Wenqing Yu, Long Liu, Tianzeng Huang, Xiangbing Zhou, and Tieqiao Chen*
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ABSTRACT: A palladium-catalyzed decarbonylative alkenylation of
aromatic carboxylic acids was developed. Under the reaction conditions,
various benzoic acids including those bearing functional groups coupled
to terminal alkenes, producing the corresponding internal alkenes in
good to high yields. Cinnamic acids and bioactive benzoic acids such as
3-methylflavone-8-carboxylic acid, probenecid, adapalin, and febuxostat
were also applicable to this reaction, demonstrating the potential
synthetic value of this new reaction in organic synthesis.
Scheme 1. Decarbonylative Heck Coupling of Carboxylic
Acids with Alkenes
eck coupling is one of the most powerful methods for
Hpreparing alkenes and has been widely used in the
synthesis of some natural products, synthetic drugs, and
functional material molecules.1 Usually, aryl halides,2 aryl
triflates,3 aryl diazonium salts,4 and so on5 are used as the aryl
source. For comparison, aromatic carboxylic acids are more
abundant and readily available. Their transformation for
constructing functional molecules has attracted chemists’
attention.6 Their utilization in Heck couplings as the aryl
source instead would greatly promote the synthesis of alkenes
with high synthetic efficiency. Chemists have converted
carboxylic acids into active derivatives such as aroyl chlorides,7
anhydrides,8 esters,9 and amides10 and then allowed these
derivatives to couple to alkenes. Despite the fact that the
corresponding internal alkenes could be produced by this
strategy, the prepreparation of these derivatives has decreased
their synthetic efficiency to some extent. The direct coupling of
aromatic carboxylic acids with alkenes through decarboxylation
has also been achieved; however, overstoichiometric oxidants
are required, which also lead to some oxidative side reactions
and the tolerance issue of functional groups prone to
oxidants.11 In 2002, Gooβen and coauthors reported a
palladium-catalyzed decarbonylation Heck reaction from
carboxylic acid using di-tert-butyl dicarbonate (Boc2O) as an
in situ activating reagent (Scheme 1A).12 This reaction avoided
the use of oxidants and the prepreparation of carboxylic
derivatives, well overcoming the issues described above.
However, because of the thermal instability, 3 equiv of
Boc2O was required. Moreover, most of the Boc2O (2.0 equiv)
should be slowly added via a syringe pump over several hours
for a better yield, limiting its practical application in organic
synthesis. In addition, only electron-rich benzoic acids and
three alkenes were demonstrated.
Herein we report a new palladium-catalyzed decarbonylative
Heck coupling reaction (Scheme 1B). This reaction used
Piv2O as the in situ activating reagent of carboxylic acids and
was conducted in one pot,13,14 well overcoming the
manipulation shortcoming of Gooβen’s work in which the
Received: July 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02462
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
activating reagent should be added slowly. This substrate scope
is also relatively general. Both electron-rich and electron-
deficient benzoic acids readily coupled with various aromatic
and electron-deficient aliphatic alkenes. This reaction was also
applicable to cinnamic acid and bioactive benzoic acids. These
results showed the potential application value of this new
reaction in organic synthesis.
Heating a mixture of Pd(TFA)2/dppb (5 mol %), 2-
naphthoic acid 1a, N,N-dimethylacrylamide 2a (2.0 equiv),
and Piv2O (1.5 equiv) in dioxane to 150 °C for 10 h, the
corresponding decarbonylative coupling product 3a was
produced in 60% yield (Table 1, entry 1). By the addition of
1, entries 11−16). Increasing the ratio of Pd/P to 1:4 led to a
slight decrease in yield, whereas no reaction was observed in
the absence of phosphine ligands (Table 1, entries 17 and 18).
This reaction also took place in THF, toluene, PhOMe, and
NMP but was sluggish in DMF and DCE (Table 1, entries
19−24). Elevating the reaction temperature could not enhance
the yield; whereas the reaction was conducted at 140 °C, only
a 58% yield of 3a was produced (Table 1, entries 25 and 26).
With the optimized reaction conditions in hand, the
substrate scope was subsequently investigated. As shown in
Table 2, this reaction was relatively general. Various carboxylic
acids coupled to terminal alkenes to produce the correspond-
ing products in good to high yields. In addition to 2-naphthoic
acid 1a, 1-naphthoic acid also worked well to give the product
3b in 97% yield. The π-extended anthracene-9-carboxylic acid
also proved to be a good substrate (3c). Under the reaction
conditions, both electron-rich and electron-deficient benzoic
acids were applicable, furnishing the expected coupling
products in good to high yields. The steric hindrance did
not seem to affect the reaction because benzoic acids bearing
4-Ph, 3-Ph, and 2-Ph were all decarbonylatively alkenylated,
and the coupling products 3g, 3h, and 3i were generated in 74,
89, and 86% yields, respectively. Halo groups (F and Cl) also
survived well. Heteroaromatic internal alkenes were also
efficiently prepared through a similar decarbonylative alkeny-
lation (3n−p). Notably, cinnamic acid was also workable,
providing an efficient method for the synthesis of dienes (3q
and 3r).
Other selected electron-deficient terminal alkenes such as
N,N-diethylacrylamide, 1-morpholinoprop-2-en-1-one, and
methyl acrylate were transformed into the corresponding
internal alkenes in the present catalytic system (3s−u).
However, only a trace amount of product was given with
acrylaldehyde (3v). The reaction also progressed sluggishly
with hept-1-ene (3w). To our delight, trimethyl(vinyl)silane
could couple to 1a to give 3x in 37% yield. Aromatic terminal
alkenes including those bearing functional groups also worked
well under the reaction conditions (3y−ac). The internal
alkenes exemplified by 2m were not applicable to this reaction.
Interestingly, this reaction was applicable to the modification
of bioactive carboxylic acids (Scheme 2). For example, 3-
methylflavone-8-carboxylic acid, a clinical drug for coronary
heart disease, was alkenylated to produce 3ae in 95% yield.
Probenecid is a clinical drug for hyperuricemia with chronic
gouty arthritis and gouty stones. It also reacted smoothly with
2a, producing the expected product 3af in 63% yield. The
clinic drugs adapalin and febuxostat were also proved to be the
right substrates, furnishing the coupling products in high
yields.
a
Table 1. Optimization of Reaction Conditions
b
entry
cat. Pd
additive
ligand
dppb
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
Pd(AcAc)2
PdCl2
-
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
60
90
89
22
58
40
41
19
75
N.D.
15
48
70
79
73
65
81
N.D.
61
39
22
12
trace
trace
58
NaCl
KCl
NaBr
NaF
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppp
dpppe
dppf
DPE-phos
PPh3
PPh2Cy
dppb
-
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
9
Pd2(dba)3
-
10
11
12
13
14
15
16
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
c
17
18
19
20
21
22
23
24
toluene
PhOMe
NMP
DMF
DCE
d
25
e
dioxane
dioxane
26
92
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), Piv2O (0.3 mmol),
catalyst (5 mol % Pd), ligand (Pd/P = 1:2), additive (50 mol %), N2,
150 °C, 10 h, solvent (2 mL). dppb (1,4-bis(diphenylphos
phanyl)butane); dppp (1,3-bis(diphosp-hino)propane); dpppe (1,5-
bis(diphenylphosphanyl)petane); dppf (1,1′-bis(diphenylphosphino)-
ferrocene); DPE-phos ((oxybis(2,1-phenylene))bis(diphenylphosph-
On the basis of previous literature,12,14 a plausible
mechanism was proposed. As shown in Scheme 3, the
carboxylic acid was first in situ activated by Piv2O to produce
a mixing anhydride A, followed by oxidative addition with the
active Pd(0) complex generated in situ to give an intermediate
B. The resulting B further underwent decarbonylation,17
transfer insertion, and β-elimination to yield the desired
product and complex E. Complex E was subsequently
transformed into the active Pd(0) catalyst to complete the
catalytic cycle.
b
c
ane)). GC yield using tridecane as an internal standard. dppb (10
d
e
mol %). 140 °C. 160 °C.
50 mol % NaCl, the yield of 3a increased to 90% (Table 1,
entry 2).15 A similar result was obtained with KCl (Table 1,
entry 3); however, NaBr and NaF could not enhance the
reaction (Table 1, entries 4 and 5). Other selected palladium
catalysts such as Pd(OAc)2 and Pd(AcAc)2 were tried, but
relatively low yields were given (Table 1, entries 6−9).16
Without the addition of palladium catalysts, no reaction took
place (Table 1, entry 10). The phosphine ligands were
subsequently screened, with dppb being the best choice (Table
In summary, we have developed a decarbonylative
alkenylation of carboxylic acids with terminal alkenes. This
reaction used Piv2O as the in situ activating reagent for
carboxylic acids, avoided the use of overstoichiometric
B
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a
Table 2. Scope of Decarbonylative Heck-Type Coupling of Carboxylic Acids with Alkenes
a
Conditions: carboxylic acid (0.2 mmol), alkene (0.4 mmol), Piv2O (1.5 equiv), NaCl (50 mol %), Pd(TFA)2 (5 mol %), dppb (5 mol %), N2, 150
b
°C, dioxane (2 mL), 10 h. GC yield using tridecane as the internal standard. The data in parentheses are isolated yields obtained by PTLC. For 3j
and 3ac, recrystallization was additionally performed. trans/cis was generally more than 30:1. Two isomers were detected by GC and GC-MS for
3q (trans/cis = 15/1) and 3r (trans/cis = 5:1). dppb (10 mol %). DPE-phos (10 mol %). THF. 12 h. 20 h NMR yield using tridecane as an
c
d
e
f
g
h
internal standard.
C
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Authors
Scheme 2. Modification of Bioactive Carboxylic Acids
through Decarbonylative Heck Coupling
a b
,
Wenqing Yu − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Long Liu − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China; orcid.org/0000-0002-6472-5057
Tianzeng Huang − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
a
Conditions: carboxylic acid (0.2 mmol), alkene (0.4 mmol), Piv2O
(1.5 equiv), NaCl (50 mol %), Pd(TFA)2 (5 mol %), dppb (5 mol
b
%), N2, 150 °C, 10 h, dioxane (2 mL). GC yield using tridecane as
an internal standard; The data in parentheses are isolated yields
obtained by PTLC. DPE-phos (10 mol %). THF. NMR yield using
tridecane as an internal standard.
c
d
e
Xiangbing Zhou − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Scheme 3. Proposed Mechanism for the Decarbonylative
Heck Coupling of Carboxylic Acids
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02462
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Partial financial support from the HNNSFC (no. 219MS005)
and the NSFC (No. 21871070) is gratefully acknowledged.
■
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02462.
General information, experimental procedures, charac-
terization data, and copies of 1H and 13C NMR
spectroscopies (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tieqiao Chen − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China; orcid.org/0000-0002-9787-9538;
Email: chentieqiao@hnu.edu.cn
D
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(15) The chloride might work through exchange with the
noncoordinating acidoligand. It was deduced that the chloride
could stabilize the palladium catalyst. Indeed, in the absence of
NaCl, a large amount of palladium black was generated in the
reaction. For similar reports, see refs 8a and 9c and references cited
therein. It was also reported that chloride could promote the β-H
elimination; see: (a) Han, X. L.; Liu, G. X.; Lu, X. Y. β-Hydride
Elimination in Palladium-Catalyzed Reactions. Chin. J. Org. Chem.
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Intramolecular Alkyne-α,β-Unsaturated Carbonyl Coupling. A Formal
Synthesis of (+)-Pilocarpine. Tetrahedron Lett. 1997, 38, 5213−5216.
(16) We noticed that a very low yield was given with PdCl2. The
result might be ascribed to the relative difficulty for the in situ
reduction of PdCl2 in comparison with Pd(OAc)2 under the reaction
conditions. First, the Pd(0) complex worked well (Table 1, entry 9).
Second, several control experiments with PdCl2 were conducted. By
the addition of 20% NaOAc, the yield was increased to 50%. It was
deduced that the phosphine ligand might act as the reductant of
PdCl2. With 7.5 mol % dppb, the yield was increased to 27%, whereas
the yield was increased to 46% with 10 mol % dppb.
(17) In this reaction, CO rather than CO2 was detected; see the SI.
F
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