Palladium-catalyzed decarbonylative sonogashira coupling of terminal alkynes with carboxylic acids

Article abstract of DOI:10.1021/acs.orglett.1c00768

A direct decarbonylative Sonogashira coupling of terminal alkynes with carboxylic acids was achieved through palladium catalysis. This reaction did not use overstoichiometric oxidants, thus overcoming the homocoupling issue of terminal alkynes. Under the reaction conditions, a wide range of carboxylic acids including those bioactive ones could couple readily with various terminal alkynes, thus providing a relative general method for preparing internal alkynes.

Full text of DOI:10.1021/acs.orglett.1c00768

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Letter
Palladium-Catalyzed Decarbonylative Sonogashira Coupling of
Terminal Alkynes with Carboxylic Acids
Xinyi Li, Long Liu, Tianzeng Huang, Zhi Tang, Chunya Li, Wenhui Li, Tao Zhang, Zhaohui Li,
and Tieqiao Chen*
Cite This: Org. Lett. 2021, 23, 3304−3309
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ABSTRACT: A direct decarbonylative Sonogashira coupling of
terminal alkynes with carboxylic acids was achieved through
palladium catalysis. This reaction did not use overstoichiometric
oxidants, thus overcoming the homocoupling issue of terminal
alkynes. Under the reaction conditions, a wide range of carboxylic
acids including those bioactive ones could couple readily with
various terminal alkynes, thus providing a relative general method
for preparing internal alkynes.
organohalides/pseudohalides. The requirement for presynthe-
arbon−carbon triple bonds (alkynes) are important
Cstructural unit of many natural products, pharmaceut- sizing those starting materials also greatly decreases the step
icals, and material functional molecules.1 They are also
efficiency and the total atom utilization. Recently, the oxidative
C−H alkynylation with terminal alkynes emerges as an
alternative method (Scheme 1B).6 However, besides the
relatively narrow substrate scope, the oxidative conditions
usually lead to the severe homocoupling issues of terminal
alkynes.
important building blocks in organic synthesis due to the
diverse reactivity.2 Therefore, their efficient synthesis always is
the key point of chemists’ attention.3−5 Among the established
synthetic methods, Sonogashira coupling can efficiently
produce alkynes (Scheme 1A).4 The C−H alkynylation of
active hydrocarbons or those bearing directing groups with the
preactivated alkynylating reagents such as alkynyl halides or
hypervalent iodine reagents is also extensively used for the
synthesis of alkynes (Scheme 1B).5 Despite the high efficiency,
those reactions highly depend on the transformation of
Carboxylic acids are naturally abundant. They are also
readily available in the synthetic world. Direct utilization of
carboxylic acids for constructing functional molecules in
organic synthesis attracts much attention from chemists.7
During the past decades, great progress has been made. As for
the synthesis of internal alkynes, decarboxylative coupling has
been achieved by Su,8 Tan,9 and Jana10 dependently (Scheme
1C); however, the three reactions were conducted under the
oxidative conditions with the use of NBS, dioxygen and
Ag2CO3/CuI as the oxidant, which also lead to the production
of byproduct 1,3-diynes through homocoupling of terminal
alkynes. In addition, steric and (or) electron-deficient
carboxylic acids were required in order to facilitate the
decarboxylation. Herein, we reported a redox-neutral reaction
of carboxylic acids with terminal alkynes through decarbon-
ylative coupling.11 This reaction overcame those issues such as
the use of overstoichiometric oxidants, homocouplings of
terminal alkynes, and the narrow substrate scope of carboxylic
acids encountered in the oxidative decarboxylative cou-
Scheme 1. Transition Metal Catalyzed Cross Couplings
Forming Internal Alkynes
Received: March 5, 2021
Published: April 20, 2021
https://doi.org/10.1021/acs.orglett.1c00768
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3304−3309
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Letter
plings.8−10 High tolerance of functional groups was also
demonstrated, i.e., alkyl, MeO, CF3O, TMS, F, Cl, CF3, CN,
carbonyl, sulfonamide, and heterocycles all survived well under
the reaction conditions. These advantages are also the
embodiment of sustainable chemical principles.12
A mixture of 1-naphthyl acid 1a and phenyl acetylene 2a
dissolved in DME was allowed to react at 130 °C for 12 h in
the presence of 2.5 mol % Pd2(dba)3, 10 mol % Xantphos
(bis(diphenylphosphino)-9,9-dimethylxanthene), and 1.5
equiv of Ac2O, producing decarbonylative coupling product
3a in 85% yield (Table 1, entry 1). The palladium catalyst was
essential to this reaction; no reaction was observed in its
absence (Table 1, entry 2). Pd(dba)2, Pd(OAc)2, Pd(TFA)2,
and PdCl2 could also efficiently mediate the reaction, though
the yields decreased to some extent (Table 1, entries 3−6).
The phosphine ligand was also pivotal.13 Without any
phosphine ligand, no 3a was detected (Table 1, entry 7).
When dppm (bis(diphenylphosphino)methane), dppe (1,2-
bis(diphenylphosph-ino)ethane), dpph (1,6-bis-
(diphenylphosphino)hexane), and monodentate phosphine
ligands such as PPh3, TFP (tri(2-furyl)phosphine), PPh2Cy,
and PCy3 were used, the reaction progressed sluggishly; the
yield was also low with dppp (1,3-bis(diphenylphosphino)-
propane), dppb (1,4-bis(diphenylphosphino)butane), and
DPE-phos ((oxidi-2,1-phenylene)bis(diphenylphosphine))
(Table 1, entries 8−17). As for the solvents, the reaction
also proceeded in cyclohexane, toluene, dioxane, ECS,
PhOMe, NMP, and DMF (Table 1, entries 18−24). In the
absence of Ac2O, the reaction did not take place (Table 1,
entry 25). Piv2O and Boc2O could also act as the in situ
activator for carboxylic acids, furnishing 3a in 54 and 60%
yield, respectively (Table 1, entries 26 and 27). Finally, the
reaction temperature was investigated. When the reaction was
conducted at 120 °C, the yield of 3a decreased quickly, while
the reaction efficiency was almost not enhanced by further
elevating the reaction temperature to 140 °C (Table 1, entries
28 and 29). Finally, reducing the loading of palladium catalyst
to 2 mol % (1 mol % Pd2(dba)3) led to a slight decrease of the
yield (Table 1, entry 30).
Table 1. Palladium-Catalyzed Decarbonylative Coupling of
a
1-Naphthyl Acids with Phenyl Acetylene
With the optimized reaction conditions at hand, the
substrate scope was subsequently investigated. This palla-
dium-catalyzed decarbonylative coupling is a rather general
reaction. A variety of internal alkynes including those with
functional groups were produced in good to high yields under
the reaction conditions. Thus, derivatives of phenyl acetylenes
bearing 2-methyl, 3-methyl, 4-methyl, 4-tertiary-butyl, 4-
methoxy, and 4-phenyl groups produced the coupling products
in high yields (Table 2, 3a−3g). Fluoride and chloride survived
well in the current catalytic system (Table 2, 3h−3k).
Substrates with electron-withdrawing groups such as CF3 and
CN also gave the expected alkynes in good yields (Table 2, 3l
and 3m). Exemplified by 3-ethynylpridine, 3-ethynylthiophene,
and 2-ethynylthiophene, heterocyclic aromatic alkynes also
worked, furnishing the corresponding internal alkynes 3n, 3o,
and 3p in 44, 89, and 54% yields, respectively. In addition to
aromatic terminal alkynes, conjugated enyne and aliphatic
alkynes were also decarbonylatively arylated with the strategy
(Table 2, 3q−3s). Notably, by slightly tuning the reaction
conditions, silyl terminal alkynes were also applicable to this
reaction, giving the expected products in moderate yields
(Table 2, 3t and 3u). Also worth noting is that those silyl
alkynes could be easily transformed into other internal alkynes
via protodesilylation and subsequent Sonogashira couplings or
sila-Sonogashira couplings.4b,14 However, when buta-1,3-
diynylbenzene was used, only a trace amount of coupling
product was detected under the reaction conditions (Table 2,
3v).
Notably, compared with the oxidative decarboxylative
alkynylation,8−10 the scope of carboxylic acids was also rather
general. Both electron-rich and electron-deficient benzoic acids
underwent decarbonylative coupling with terminal alkynes
under the similar reaction conditions. Thus, 2-naphthyl acid
coupled with 4-methoxyphenyl acetylene readily to produce
3w in 72% yield. Benzoic acid and its derivatives with valuable
functional groups such as methyl, acetoxy, trifuloromethoxy,
phenyl, fluoride, chloride, benzoyl, acetyl, and nitrile groups
also proved to be the right substrate and coupled smoothly
with terminal alkynes to give the decarbonylatively coupling
products in moderate to high yields (Table 2, 3x−3ai).
Heteroaromatic carboxylic acids and cinnamic acid also
b
entry
cat. Pd
P ligand
solvent
DME
yields (%)
1
2
3
4
5
6
7
8
Pd2(dba)3
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
85
N.D.
78
66
65
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
dioxane
ECS
PhOMe
cyclohexane
toluene
NMP
DMF
DME
DME
DME
DME
DME
DME
Pd(dba)2
Pd(OAc)2
Pd(TFA)2
PdCl2
30
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
N.D.
trace
16
60
46
dppm
dppe
dppp
dppb
dpph
DPE-phos
PPh3
TFP
PPh2Cy
PCy3
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
16
34
trace
trace
trace
trace
63
61
55
77
64
44
29
N.D.
54
60
44
89
76
c
25
26
27
28
29
30
d
e
f
g
h
a
Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv), Pd catalysts (5
mol % Pd), phosphine ligand (Pd/P = 1:4), anhydride (1.5 equiv),
solvent (2 mL), 130 °C, 12 h, N2 atmosphere. DME: 1,2-
dimethoxyethane. ECS: ethylene glycol diethyl ether. GC yields
using tridecane as an internal standard. Without Ac2O. Using Piv2O
instead of Ac2O. Using Boc2O instead of Ac2O. At 120 °C. At 140
b
c
d
e
f
g
h
°C. Using 2 mol % Pd.
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Letter
a
Table 2. Palladium-Catalyzed Decarbonylative Coupling of Aryl Acids with Terminal Alkynes
a
Reaction conditions: carboxylic acid 1 (0.2 mmol), alkyne 2 (1.5 equiv), Pd2(dba)3 (2.5 mol %), Xantphos (10 mol %), Ac2O (1.5 equiv), DME
(2 mL), 130 °C, 12 h, N2 atmosphere. GC yields were reported using tridecane as the internal standard. The data in parentheses are the isolated
b
c
yields. Alkyne 2 (2 equiv), Pd(dba)2 (5 mol %), Piv2O (1.5 equiv), dioxane, 150 °C. Pd(dppp)Cl2 (5 mol %), dppb (10 mol %), CuI (10 mol %),
d
Et3N (1 equiv), Boc2O (1.5 equiv), dioxane: Cy = 3:1, 120 °C. Acid 1 (0.15 mmol), alkyne 2 (2 equiv), PdCl2 (5 mol %), dppp (10 mol %),
Piv2O (1.5 equiv), dioxane, 150 °C, 16 h.
worked well in the current catalytic system, and the expected
coupling products were obtained in moderate yields (Table 2,
3aj−3al).
Practically, this reaction was applicable to the modification
of bioactive carboxylic acids. For example, eudesmic acid and
piperonylic acid were transformed into the expected internal
alkynes by the strategy (Table 2, 3am and 3an). Adapalene, a
clinic drug for the skin treatment of acne vulgaris with acne,
papule, and pustule, was decarbonylatively alkylated readily in
the current catalytic system (Table 2, 3ao). Probenecid shows
positive effect for chronic gout in clinic. It also coupled with
phenyl acetylene readily to produce the corresponding internal
alkynes (Table 2, 3ap). 3-Methylflavone-8-carboxylic acid also
served well to produce the coupling product in 84% yield
under the present reaction conditions (Table 2, 3aq).
The reaction mechanism is not fully understood at present.
We proposed that this palladium-catalyzed decarbonylative
coupling might take place as shown in Scheme 2.11 Carboxylic
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https://doi.org/10.1021/acs.orglett.1c00768
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Letter
Long Liu − Key Laboratory of Ministry of Education for
Scheme 2. Proposed Mechanism for the Palladium-
Catalyzed Decarbonylative Coupling
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
Zhi Tang − 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
Chunya Li − 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
Wenhui Li − 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
Tao Zhang − 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
Zhaohui Li − 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
acid was first activated in situ by acetic anhydride to produce
an asymmetric anhydride,15 followed by oxidative addition
with Pd(0) complex and decarbonylation to generate species
C. The resulting complex, C, underwent further ligand
exchange with terminal alkynes to give intermediate D. Finally,
reductive elimination of C afforded coupling product 3 and
regenerated the active Pd(0) catalyst.16
In conclusion, we have disclosed an efficient palladium-
catalyzed decarbonylative Sonogashira coupling. This is a
redox neutral reaction, thus avoided the production of
byproduct 1,3-diynes encountered under the oxidative reaction
conditions.6,8−10 The substrate scope was also general, i.e., a
variety of carboxylic acids and terminal alkynes can be used in
this reaction. We believe this reaction is a new relatively
general method for preparing internal alkynes from the readily
available and environment friendly chemicals. Along this line,
works including scope, limitations, and mechanistic studies are
underway in our lab.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00768
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* Supporting Information
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■
Notes
sı
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
General information, experimental procedures, charac-
Partial financial support from the Key R&D project of Hainan
province (No. ZDYF2020168) and National Natural Science
Foundation of China (No. 21871070) is gratefully acknowl-
edged. The authors thank Mr. Bin Song for repeating the
synthesis of 3h, 3x, and 3aa.
1
terized data, copies of H and 13C NMR spectroscopies
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
REFERENCES
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
■
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