Pd-Catalyzed decarboxylative alkynylation of alkynyl carboxylic acids with arylsulfonyl hydrazides via a desulfinative process

Article abstract of DOI:10.1039/C8NJ02964D

In the presence of a Pd(ii)/P-ligand catalytic system, decarboxylative alkynylation of alkynyl carboxylic acids and arylsulfonyl hydrazides by desulfinative coupling could provide aryl alkynes in satisfactory yields by either judiciously selecting palladium catalysts or modulating phosphine ligands under mild conditions. The reported coupling reactions are very practical as they do not require the protection of inert gas or oxygen and are tolerant to many functional groups.

Full text of DOI:10.1039/C8NJ02964D

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Pd-catalyzed decarboxylative alkynylation of alkynyl carboxylic
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acids with arylsulfonyl hydrazides via desulfinative process
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Sheng Changab, Ying Liua，Shu Zhu Yinc, Lin Lin Dongc, Jian Feng Wang d 
aCollege of Pharmacy, Jilin Medical University, Jilin, Jilin, 132013, China
bState Key Laboratory of Medicinal Chemical Biology, NanKai University, Tianjin,
300071, China
cCollege of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
dDepartment of Radiotherapy,China-Japan Union Hospital of Jilin University,
Changchun, Jilin, 130033, China
corresponding author. Tel.: +86 432 6456 0532.
E-mail address:jmu_changsheng@126.com, jfwang@jlu.edu.cn
Abstract
In the presence of Pd(II)/P-ligand catalytic system, decarboxylative alkynylation
of alkynyl carboxylic acids and arylsulfonyl hydrazides by desulfinative coupling
could present either aryl alkynes in satisfactory yields by judiciously selecting
palladium catalysts or modulating phosphine ligands under mild conditions. The
reported coupling reactions are very practical as they do not require the protection of
inert gas or oxygen and tolerant to many functional groups.
Keywords Pd-catalyzed, decarboxylative alkynylation, alkynyl carboxylic acids,
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arylsulfonyl hydrazides
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Introduction
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Functionalized aryl and heteroaryl alkynes are highly valuable classes of
compounds, which are not only important tools, structural elements in material
sciences and chemical biology, but also versatile building blocks in contemporary
organic synthesis.1 Such compounds are commonly formed by the coupling of aryl or
heteroaryl halides with terminal acetylenes catalyzed by palladium and other
transition metals, commonly termed as Sonogashira cross-coupling reaction. It is one
of the most important and widely used sp2–sp carbon–carbon bond formation
reactions in organic synthesis, frequently employed in the synthesis of natural
products, heterocycles, biologically active molecules, molecular electronics,
dendrimers and conjugated polymers or nanostructures.2
Recently, the direct alkynylation of (hetero)aromatic compounds has appeared as
an alternative to the Sonogashira reaction by using the alkynyl reagents prepared from
terminal alkynes, such as alkynyl halides,3 benziodoxolone-based hypervalent iodine
reagents,4 or arylsulfonylacetylenes.5 Alkynyl carboxylic acids are employed as
alkyne synthons yet demonstrate a sharp discrepancy in reactivity and selectivity
compared to terminal alkynes and related. It offers a novel method to obtain alkyne
products using aldehyde as precursor which are more accessible and cheaper than
alkyne related. One attractive alternative synthetic strategy to access internal alkynes
that has emerged recently is the transition-metal catalyzed decarboxylative
cross-coupling of aryl halides with alkynyl carboxylic acids catalyzed by palladium, 6
2

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nickel7 or copper.8 Recently, Lee et al. reported palladium-catalyzed decarboxylative
coupling of alkynyl carboxylic acids with aryl/alkenyl tosylates as pseudohalides for
the synthesis of aryl alkynes/enynones.9 Nagarkar et al. reported Pd-catalyzed
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decarboxylative Sonogashira reaction with arene diazonium tetrafluoroborate under
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ligand and co-catalyst free conditions.
Organometallic compounds such as
12
arylboronic acid,11 aryl silanes
and triarylbismuth reagents13 have also been
employed in the palladium or nickel-catalyzed decarboxylative Sonogashira coupling
reaction with alkynyl carboxylic acids. However, the use of boronic acids possess
some difficulty to purify and stoichiometry due to the formation of boroximes,
likewise the use of aryl silanes possess some difficulty in preparation and require the
introduce of fluoride or hydroxide ion to activate organosilanes.14 Although many
coupling methods have been described, however, the desulfinative & decarboxylative
coupling Sonogashira reaction was still obscured. In view of the recent progress in
desulfinative coupling, it is highly desirable to develop new strategies of
decarboxylative alkynylation for more convenient and efficient Csp−C bond
formations.
Commercial aryl sulfonyl/sulfinate compounds15 are recognized as the new aryl
sources that are universally utilized in desulfinative arylation reactions recently.16
Notably, owing to the features of good stability, versatile transformation models,
compatible with water and free of unpleasant odor, arylsulfonyl hydrazines are
regarded as particularly favorable aryl precursors in desulfination reactions by C−S
bond cleavage. Pd-catalyzed desulfinative cross-coupling of arylsulfonyl hydrazides
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have been well studied these years. Tian et al. first employed arylsulfonyl hydrazides
as aryl sources in Heck-type coupling reactions via desulfitation processes.17
Subsquently, arylsulfonyl hydrazides were employed as aryl sources in Hiyama18
coupling, Suzuki19 coupling, homocoupling,20 iodination21 and addition22. It is noted
that the groups of Dong and Zhou reported palladium-catalyzed desulfitative
Sonogashira coupling of arylsulfonyl hydrazides with terminal alkynes.23 However,
the development of new-type Pd-catalyzed decarboxylative & desulfinative
cross-coupling24 of arylsulfonyl hydrazides was still highly desirable. Herein we
reported the example of decarboxylative & desulfinative coupling of alkynyl
carboxylic acids with arylsulfonyl hydrazides with good to excellent efficiency.
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Pd
Ni Cu
Ar
X
R
Ar
R
COOH
X = Cl, Br, I
Pd
Ar OTs
Ar M
R
COOH
COOH
R
R
Ar
Ar
Pd
Ni
R
R
R
M = B(OH)2, Si(OR)3, Bi
Pd
COOH
COOH
Ar N2BF4
R
Ar
O
Pd
Ar S NHNH2
O
R
Ar
This work
Scheme 1 Transition-metal-catalyzed cross-coupling of alkynyl carboxylic acids to
afford aryl alkynes
Results and Discussion
With our continuous interest on the oxidative palladium-catalyzed cross-coupling,25
we initially tried to investigate the decarboxylative & desulfinative coupling of
corresponding alkynyl carboxylic acid derivatives with arylsulfonyl hydrazides (Table
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1). To our delight, when phenylpropiolic acids and phenylsulfonyl hydrazide was
stirred in DMA in the presence of Pd(OAc)2 and K2CO3 under air, the alkynylated
product was obtained although in low yield (Table 1, entry 1). It is noteworthy that
significant improvement was achieved when PPh3 was employed as ligand (Table 1,
entry 2). The screening of trialkyl phosphine ligands, such as PCy3, P(t-Bu)3 and
P(n-Bu)3, gave modest yields (Table 1, entries 3−5). We then screened the combination
of Pd(OAc)2 and some common triaryl phosphine ligands including P(o-tol)3 or P(p-tol)3,
no better results were obtained (Table 1, entries 6−7). To our delight, among the
triaryloxy phosphine ligands tested (P(OPh)3, P(OMe)3), P(OPh)3 was shown the best
efficiency (Table 1, entries 8−9). Interestingly, TFP (trifurylphosphine) could also be an
efficient ligand with a slightly low efficiency (Table 1, entry 10). We also tried to use
the Pd(OAc)2 with the nitrogen ligand, however, the use of 1,10-phenanthroline (phen)
did not work (Table 1, entry 11). Various palladium catalyzed systems were then
examined. Application of Pd(PPh3)4 as catalysts yielded traces of desired product
(Table 1, entry 12). It was observed that most of the Pd(II) catalysts could
successfully promote the reaction (Table 1, entries 13−17). Therefore, PdCl2 and
Pd(TFA)2 in combination with P(OPh)3 was applied with less effective affording
alkynylated product in yields varying between 66% and 73% (Table 1, entries 13−14).
The introduction of various palladium with phosphine ligands (Pd(dppe)Cl2,
Pd(PPh3)3Cl2 and Pd(dppp)Cl2) slightly increased the yields (Table 1, entries 15–17).
Among the Pd(II) catalysts tested, Pd(dppf)Cl2 was the most effective affording the
addition product in 88% yield (Table 1, entry 18). (Optimization table of bases and
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solvents was putted in SI section) Clearly, desired product was not generated in the
absence of a palladium catalyst or an base (Table 1, entries 19−20). We subsequently
explored the effect on the reaction yield of other variations such as temperature, solvents,
concertrtion, use of various bases, etc. The details were summarized in the Supporting
Information (Table SI).
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Table 1. Optimization of palladium-catalyzed coupling of phenylsulfonyl
hydrazide and phenylpropiolic acid a
catalyst
O
ligand
COOH
S
NHNH2
K2CO3, DMA
80oC, 12 h, air
O
entry
1
ligand
-
catalyst
yield (%) b
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
15
58
47
41
53
62
71
75
50
74
<5
2
PPh3
3
PCy3
4
P(t-Bu)3
P(n-Bu)3
P(o-tol)3
P(p-tol)3
P(OPh)3
P(OMe)3
TFP
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10
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-
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
Pd(PPh3)4
PdCl2
66
73
79
84
87
88
Pd(TFA)2
Pd(dppe)Cl2
Pd(PPh3)3Cl2
Pd(dppp)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
-
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c
-
-
a
Reaction conditions: phenylpropiolic acid (1.0 mmol), phenylsulfonyl
hydrazide (1.1 mmol), catalyst (0.05 mmol), ligand (0.1 mmol), K2CO3 (1.5
mmol), DMA (1 mL), 80 oC, 12 h, under air. b Isolated yields. c The reaction was
done without K2CO3.
With the establishment of these optimum conditions, the scope of
palladium-catalyzed desulfinative cross-coupling reaction was first evaluated (Table
2). First, 4-methoxy-phenylsulfonyl hydrazide was fixed as the substrate to test
various substituted propiolic acids derivatives. Generally, introduction of methoxy,
methyl, ethyl, n-butyl and nitro substituents into para positions of the benzene ring
was well tolerated, and the reaction efficiency was marginally affected by such
electronic perturbation (Table 2, 2a-2e). Furthermore, the reaction efficiency was
essentially not affected when a 3-methyl or 3-bromo group was introduced (Table 2,
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2f-2g). Halogen substituted phenyl propiolic acid was also reactive under thisDrOeIa: 1c0t.1i0o3n9/C8NJ02964D
condition without influence of C-Br bond (Table 2, 2g). Fused-ring substrate such as
naphthalen-2-yl propiolic acid was coupled with 4-methoxy-phenylsulfonyl hydrazide
smoothly (Table 2, 2h). The applicability of the method towards heteroaryl propiolic
acid derivatives was also tested with good efficiency (Table 2, 2i). The scope of the
alkylpropiolic acids substrate was then examined, indicating that the reaction’s broad
feasibility. In general, various n-alkyl-substituted propiolic acids all underwent
smooth coupling with 4-methoxy-phenylsulfonyl hydrazide under the standard
conditions to afford the alkyne products in 66%-75% yields (Table 2, 2j-2l).
Furthermore, t-butyl-substituted propiolic acids coupled with comparably efficiency
(Table 2, 2m).
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Table 2. Scope of Pd-catalyzed coupling of alkynyl carboxylic acids with
4-methoxy-phenylsulfonyl hydrazide a,b
Pd(dppf)Cl2
O
P(OPh)3
MeO
S
NHNH2
MeO
R
R
HOOC
K2CO3, DMA
80oC, 12 h
O
MeO
MeO
OMe
MeO
MeO
MeO
2b 89%
2a 82%
2d 78%
2c 81%
NO2
MeO
2e 72%
2f 86%
MeO
MeO
MeO
O
2h 83%
2i 70%
2g 80%
Br
MeO
MeO
MeO
MeO
2j 68%
2k 75%
2m 63%
2l 66%
a Reaction conditions: alkynyl carboxylic acids (1.0 mmol), 4-methoxy-phenylsulfonyl hydrazide
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(1.1 mmol), Pd(dppf)Cl2 (0.05 mmol), P(OPh)3 (0.1 mmol), K2CO3 (1.5 mmol), DMA (1 mL), 80
oC, 12 h, under air. b Isolated yields.
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We next examined the scope of the method with different arylsulfonyl hydrazide
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derivatives. As presented in Table 3, the desired products 3a-3b were obtained in
good yields with alkyl substituents like methyl, ethyl at 4-position of the phenyl ring.
Likewise, the reaction exhibited good reactivity with substrates having no substituent
(Table 3, 3c). Various functional groups commonly utilized in organic synthesis were
fully compatible with the simple cross-coupling method. Accordingly, substrates
bearing methoxy, nitro, chloro, trifluoro methyl, acetyl, and ester functionalities at
phenyl ring were all smoothly coupled in high yields (Table 3, 3d-3i). The reaction
delivered alkynylated aromatic compounds 3j-3k in good yields having
trifluoromethoxy or bromo substituent on the benzene moiety. Electron-rich substrates
bearing methoxy (3l) and methyl (3m) substituents on the phenyl ring and
arylsulfonyl hydrazide bearing electron deficient functional group such as
trifluoromethyl (3n) at meta-position underwent the decarboxylative cross-coupling in
good yields. As expected, the reaction furnished the desired product (3o) in good
yield with 3-iodophenyl sulfonyl hydrazide. Substrates having ortho-methoxy (3p),
ortho-methyl (3q), ortho-chloro (3r), or ortho-trifluoromethyl (3s) substituents at
phenyl moiety gave slightly lower reactivity, presumably due to steric reason. The
substrate scope of this transformation was further extended to the synthesis of fused
ring and heteroaryl derivatives (Table 3, 3t–3u), which were afforded in moderate
yields. For the substrates bearing two sulfonyl hydrazide, the desired douple
alkynylated products (3v) were obtained smoothly.
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Table 3. Scope of Pd-catalyzed coupling of phenylpropiolic acid with arylsulfonyl
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hydrazide a,b
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Pd(dppf)Cl2
O
P(OPh)3
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S
NHNH2
HOOC
K2CO3, DMA
80oC, 12 h
R
R
O
MeO
O
3a 90%
3e 81%
3c 88%
3b 85%
3d 86%
3h 84%
O2N
Cl
F3C
3f 83%
3g 76%
O
F3CO
Br
EtO
3i 73%
3j 76%
3k 82%
3l 89%
MeO
3n 82%
I
3m 86%
3o 85%
F3C
3q 79%
OMe
CF3
3s 66%
3p 75%
Cl 3r 70%
N
Ph
3p 78%c
Ph
3t 62%
3u 59%
a
Reaction conditions: phenylpropiolic acid (1.0 mmol), arylsulfonyl hydrazide (1.1 mmol),
o
Pd(dppf)Cl2 (0.05 mmol), P(OPh)3 (0.1 mmol), K2CO3 (1.5 mmol), DMA (1 mL), 80 C, 12 h,
under air. Isolated yields.c phenylpropiolic acid (2.0 mmol), benzene-1,3-disulfonyl hydrazide
b
(1.0 mmol).
Preliminary studies were performed to gain insight into the reaction mechanism
(Scheme 2). The cross-coupling reaction could not be terminated by radical scavenger
(such as TEMPO), and decent yield of desired products were detected under standard
conditions (Scheme 2, Eq 1). The radical pathway could be ruled out. Potassium
3-phenylpropiolate could coupled with phenylsulfonyl hydrazide under standard
condtions in the yield of 85%, which indicate that carboxylic acid anion might be
involved in this coupling process (Scheme 2, Eq 2). The replacement of
phenylsulfonyl hydrazide with phenyl sulfonamide could not afford alkynylated
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product, and the coupling of phenylsulfonyl hydrazide with phenylacetylene could not
been proceeded either (Scheme 2, Eq 3 and Eq 4). The controlled experiments
revealed that the cross-coupling transformation could be surpressed under the
protection of argon, and the yield of alkynylated product was not enhanced under
oxygen atmosphere, revealed that oxygen is indispensable for the reaction (Scheme 2,
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Eq 5 and Eq 6).
Pd(dppf)Cl2
O
P(OPh)3
72%
Eq 1
Eq 2
COOH
S
NHNH2
TEMPO
K2CO3, DMA
80 oC, 12 h
O
Pd(dppf)Cl2
P(OPh)3
O
K
COO
COOH
H
S
NHNH2
85%
trace
trace
K2CO3, DMA
80 oC, 12 h
O
Pd(dppf)Cl2
P(OPh)3
O
S
NH2
Eq 3
Eq 4
K2CO3, DMA
80 oC, 12 h
O
Pd(dppf)Cl2
P(OPh)3
O
S
NHNH2
K2CO3, DMA
80 oC, 12 h
O
Pd(dppf)Cl2
P(OPh)3
O
S
COOH
COOH
NHNH2
NHNH2
Eq 5
Eq 6
trace
89%
K2CO3, DMA
O
o
Ar
80 C, 12 h,
Pd(dppf)Cl2
P(OPh)3
O
S
K2CO3, DMA
O
o
O
80 C, 12 h,
2
Scheme 2. Control experiments for decarboxylative & desulfinative coupling.
According to the above result, a tentative mechanism for palladium-catalyzed
decarboxylative & desulfinative coupling was outlined in Scheme 3. The initial step
would be the reaction of the ligand coordinated Pd(II)-complex with arylsulfonyl
hydrazide gives an Pd(II) intermediate A by deprotonation, then (arylsulfonyl)diazene
was generated via β-hydride elimination. Pd(II)-complex B was formed by another
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deprotonation with (arylsulfonyl)diazene, and providing ArPd(II)Cl intermediate (C)
by liberation of N2 and SO2. Transmetallation of species C with the in situ generated
potassium 3-propiolate gives intermediate D, which then undergoes reductive
elimination to give the desired cross-coupling product with the release of CO2. The
Pd(II) species are then regenerated through the oxidation of the Pd(0) species with
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oxygen to complete the catalytic cycle.
O
HCl
O
base
Cl
S NHNH2
O
Pd(II)L2
H
L2Pd(II)Cl2
N
N
H
S
H
Pd(II)L2
O
Cl
O2
A
O
N
S
NH
L2Pd(II)Cl2
O
L2Pd(0)
R
Cl
HCl base
O
L2(II)Pd
N
Pd(II)L2
N
B
S
R
O
CO2
D
Pd(II)L2
Cl
N2
SO2
K2CO3
C
R
COOK
R
COOH
Scheme 3. Possible Mechanism for Decarboxylative & Desulfinative Coupling
Conclusion
In conclusion, we have reported the first decarboxylative & desulfinative coupling
with alkynyl carboxylic acids and arylsulfonyl hydrazides. This strategy provide new
methods for the decarboxylative alkynylation by exploiting a decarboxylative &
desulfinative process. We expect that these new synthetic methods will be of great
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interest in the synthesis of versatile aryl alkynes building blocks and may enable the
development of a broad range of Pd-catalyzed reactions through decarboxylative &
desulfinative pathway.
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Acknowledgements: This work was supported by The Science Fund for
Distinguished Youth of Jilin Science and Technology Bureau (201750237); The State
Key Laboratory of Medicinal Chemical Biology (NanKai University)(2017001) ；
National innovative undertaking plan of college students (201713743012); The
Science Fund for Distinguished Youth of Administration of traditional Chinese
Medicine of Jilin Province (2018105); National fund project of Education
Department of Jilin Province(2016242)
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Table of Contents Entry
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The decarboxylative alkynylation of alkynyl carboxylic acids and arylsulfonyl
hydrazides by desulfinative coupling could present either aryl alkynes in satisfactory
yields by judiciously selecting palladium catalysts or modulating phosphine ligands
under mild conditions.
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O
Pd-catalyzed
R
S NHNH2
O
HOOC
R
Ligand-promoted
Decarboxylative & Desulfinative Alkynylation