Pd-catalyzed selective carbonylative and non-carbonylative couplings of propiolic acid: One-pot synthesis of diarylalkynones

Article abstract of DOI:10.1021/ol4004349

Diarylalkynones were synthesized from one-pot Pd-catalyzed carbonylative and noncarbonylative coupling reactions of propiolic acid with aryl iodides under a carbon monoxide atmosphere. Aryl iodide (2.0 equiv), propiolic acid (1.0 equiv), Pd(PPh₃)₂Cl₂ (5 mol %), CuCl (10 mol %), Et₃N (6.0 equiv), and CO (8 atm) were reacted under optimized conditions in CH₃CN at 80 °C for 1 h. This process afforded good yields and functional group tolerance.

Full text of DOI:10.1021/ol4004349

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed Selective Carbonylative and
Non-carbonylative Couplings of Propiolic
Acid: One-Pot Synthesis of
Diarylalkynones
Wonyoung Kim, Kyungho Park, Ahbyeol Park, Juseok Choe, and Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju, 500-757,
Republic of Korea
sunwoo@chonnam.ac.kr
Received February 15, 2013
ABSTRACT
Diarylalkynones were synthesized from one-pot Pd-catalyzed carbonylative and noncarbonylative coupling reactions of propiolic acid with aryl
iodides under a carbon monoxide atmosphere. Aryl iodide (2.0 equiv), propiolic acid (1.0 equiv), Pd(PPh3)2Cl2 (5 mol %), CuCl (10 mol %), Et3N
(6.0 equiv), and CO (8 atm) were reacted under optimized conditions in CH3CN at 80 °C for 1 h. This process afforded good yields and functional
group tolerance.
Many bioactive products as well as molecules of medical
and material importance are synthesized from ynones.1
Ynones are transformed into heterocylic compounds such
as pyrimidine,2 quinolone,3 furan,4 pyrazole,5 flavone,6
and oxime7 for numerous applications.
Several methods for the synthesis of arylynones have
been reported, most commonly using the coupling of acyl
halides and terminal alkynes8 (or alkynyl metal9) and the
Pd-catalyzed Sonogashira-typecarbonylation, which isthe
coupling reaction of aryl halides and terminal alkyne in the
presence of CO atmosphere.10
Although acyl halides showed good reactivity in this
transformation, they suffer some drawbacks in their
storage and limitation in commercial availability, which
necessitates a preparation process. As an aryl carbonyl
source, aryl ester11 and Weinreb amide,12 which are more
stable than acyl chloride, were used. However, they
showed low functional group tolerance because alkynyl-
lithium was used as the alkyne source. Very recently, the
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r
10.1021/ol4004349
XXXX American Chemical Society

coupling of aryl carboxylate salt and alkyne has been
reported; however, they still showed a narrow scope of
substrates.13
of aryl alkynyl carboxylic acid and aryl iodides in the
presence of CO.24
In terms of cost-effectiveness, nontoxicity of waste and
mild conditions in the coupling reaction, propiolic acid as
an alkyne source is an attractive alternative as it is easy to
handle and store because it is a stable liquid. Considering
its structural feature, it has two reactive sp carbon sites,
which showed different reactivity in the coupling reaction.
To expand our research of decarboxylative carbonyla-
tion, wefocused onthe carbonylationofpropiolic acid. We
envisioned that diaryl ynone would be obtained from the
one-pot reaction of aryl iodides and propiolic acid under
COatmosphereifnoncarbonylativecoupling occursatone
site of propiolic acid and carbonylative coupling at the
other site of propiolic acid. Herein, we report the one-pot
synthesis of diarylynone from the reaction of the aryl
iodides, propiolic acid, and carbon monoxide in the pres-
ence of palladium catalyst.
Since Kobayashi first reported palladium-catalyzed
Sonogashira-type carbonylation,10 more efficient and im-
proved methodologies have been developed and applied in
organic synthesis. As examples, recyclable catalytic
systems,14 reactionsinaqueous or ionic liquid,15 microflow
systems,16 the use of surrogate for carbon monoxide gas,17
palladium-free systems,18 and the expansion of substrates
have all been reported.19 However, they all used alkyl- or
arylalkynes as the coupling partner. When arylalkyne is
used as an alkyne source, it has to be prepared from aryl
halides and alkynes through a Sonogashira reaction.
As an alkyne source, acetylene is the simplest synthon
and is used in the Sonogashira coupling and Sonogashira-
type carbonylation. However, it cannot be easily handled
in the general laboratory as it is an explosive gas. To solve
these problems, trimethylsilylacetylene,20 2-methyl-but-3-
yn-2-ol,21 and bis(tributylstanyl)acetylene22 have been
used as a surrogate in the Sonogashira coupling and
carbonylation reactions. However, they have also some
drawbacks such as high cost, production of metallic waste,
and requirement for strong basic conditions. Recently, we
reported the synthesis of symmetric and unsymmetric
diaryl alkynes from the coupling reaction of aryl halides
with propiolic acid and the site-selective coupling reaction
of propiolic acid to produce aryl alkynyl carboxylic acid
and arylalkynes.23 In addition, we first reported the synthe-
sis of diarylynone from the decarboxylative carbonylation
To achieve our goal, we first screened a variety of
reaction parameters in the coupling reaction of iodoben-
zene and propiolic acid in the presence of carbon mon-
oxide. The results are summarized in Table 1.
The carbonylative reactions in DBU and DMSO, which
showed good yield in the synthesis of diarylalkynes,
afforded only noncarbonylative product even under 1
and 5 atm of CO (Table 1, entries 1 and 2). The use of
Et3N, which is a suitable base in the decarboxylative
carbonylation, showed unsatisfactory results in DMSO
and toluene (entries 3 and 4). The addition of 10 mol % of
CuI produced the desire product in 12% yield (entry 5).
DBU and toluene were not suitable as base and solvent,
respectively (entry 6). Among the solvents tested, CH3CN
showed 65% yield of 2a and 5% yield of 3a (entry 10).
Instead of CuI, CuBr and CuCl afforded the desired
product in 55% and 71% yield, respectively (entries 11
and 12). Keeping CuCl, Et3N, and CH3CN as the additive,
base, and solvent, respectively, a carbon monoxide atmo-
sphere of 8 bar showed a better result with a low amount of
3a (entry 13), compared to 10 bar. When the amount of
CuCl was decreased to 5 mol %, the product yield was
decreased to 54% (entry15). No product was formed when
the reaction was run at 50 °C (entry 16). These results
revealed optimized conditions in which aryl iodide
(2.0 equiv), propiolic acid (1.0 equiv), Pd(PPh3)2Cl2
(5 mol %), CuCl (10 mol %), Et3N (6.0 equiv), and CO
(8 atm) were reacted in CH3CN at 80 °C for 1 h.
Next, to evaluate the effectiveness of our new reaction
system, a range of aryl iodides was examined using the
preliminary optimized reaction conditions as shown in
Scheme 1. As expected, iodobenzene afforded 1,3-diphenyl-
prop-2-yn-1-one (2a) in 84% yield (entry 1). Alkyl-substituted
aryl iodides showed good yields (entries 2À4). 2-Iodo-
anisole provided the desired product in lower yield than
4-iodoanilsole, which may have been due to the steric
hindrance (entries 5 and 6). We found that the survival of
the halides, such as bromide, chloride and fluoride, pre-
sented an opportunity for further coupling with others
(entries 7À9). 4-Trifluoromethyl iodobenzene gave 69%
product yield (entry 10). Aryl iodides bearing ketone and
(13) Rad, M. N. S.; Behrouz, S. Synlett 2011, 2562.
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Yang, Z. J. Org. Chem. 2005, 70, 6097. (c) Sans, V.; Trzeciak, A. M.;
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A. T.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 18114.
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K. L.; Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4,
3199–3202. (c) Lo, P. K.; Li, K. F.; Wong, M. S.; Cheah, K. W. J. Org.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimized Conditions for the Synthesis of 2a from
Propiolic Acida
Scheme 1. Synthesis of Diarylalkynones from the Propiolic
Acida
yielde (%)
entry
additiveb
basec
solvent
atmd
2a
3a
96
1
DBU
DBU
Et3N
Et3N
Et3N
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMSO
DMSO
DMSO
toluene
toluene
toluene
diglyme
NMP
1
5
0
0
0
5
2
35
71
6
3
5
4
5
5
CuI
5
12
0
5
6
CuI
5
27
3
7
CuI
5
27
8
CuI
5
39
28
17
5
9
CuI
DMF
5
49
10
11
12
13
14
15
16g
CuI
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
65
CuBr
CuCl
CuCl
CuCl
CuClf
CuCl
5
55
18
3
5
71
8
86
trace
2
10
8
83
54
3
8
trace
a Reaction conditions: 1a (0.6 mmol), propiolic acid (0.3 mmol), and
Pd(PPh3)2Cl2 (0.015 mmol) were reacted in the presence of carbon
monoxide at 80 °C for 1 h. b 10 mol %. c 6 equiv was used. d Pressure
of carbon monoxide. e Determined by gas chromatography with internal
standard. f 5 mol % was used. g Reaction temperature was 50 °C.
a Reaction conditions: aryl iodide (6.0 mmol), propiolic acid (3.0 mmol),
Pd(PPh3)2Cl2 (0.15 mmol), CuCl (0.3 mmol), Et3N (18.0 mmol), and CO
(8 atm) were reacted in acetonitrile at 80 °C for 1 h. b β-Bromostyrene
was used.
ester groups also afforded the desired products (entries 11
and 12). 4-Iodobiphenyl and 1-iodonaphthalene showed
good yields (entries 13 and 14). Heteroaromatic iodides
such as 2-iodothiophene and 3-iodopyridine gave 2o and
2p in 67%, 42% yield, respectively (entries 15 and 16).
When we attempted to expand this method to aryl
bromides, only β-bromostyrene gave the desired product
2q in 72% yield (entry 17).
Table 2. Effect of Copper in the Carbonylative Coupling of
Phenylpropiolic Acid and Phenylacetylenea
To study the selective carbonylative and noncarbonyl-
ative coupling reaction toward propiolic acid, we investi-
gated the carbonylative reaction of phenyl propiolic acid
and phenyl acetylene in the presence or absence of CuCl, as
shown in Table 2.
Phenylpropiolic acid afforded the carbonylative product
as the major product both in the presence and absence of
CuCl (entries 1 and 2). In the case of phenylacetylene, the
reaction with CuCl afforded only noncarbonylative cou-
pling product (entry 3); however, carbonylative product
was formed in 68% with 29% yield of 3 in the absence of
CuCl. These results revealed that phenylpropiolic acid
preferred the carbonylative coupling, whereas phenylace-
tylene preferred the carbonylative coupling in the absence
of CuCl and noncarbonylative coupling in the presence of
CuCl.
yieldb (%)
entry
alkyne, Y =
additive
CuCl
2a
3
1
2
3
4
CO2H
CO2H
H
81
78
4
CuCl
99
29
H
68
a PhI (3.0 mmol), alkyne (3.0 mmol), Pd(PPh3)2Cl2 (0.15 mmol),
Et3N (18.0 mmol), and CO (8 atm) were reacted in the presence or
absence of CuCl (0.3 mmol) in acetonitrile at 80 °C for 1 h. b After
aqueous workup, the crude product was analyzed by gas chromatogra-
phy with internal standard and 1H and 13C NMR.
comparative experiments were conducted, as shown in
Table 3. An equal amount of iodobenzene, phenylpropio-
lic acid, and 4-tolylacetylene were reacted in one reaction
vessel. Both in the presence and absence of CuCl, terminal
alkyne II was more reactive than alkynyl carboxylic acid I.
To further study the different reactivity of alkynyl car-
boxylic acid and terminal alkyne toward carbonylation,
Org. Lett., Vol. XX, No. XX, XXXX
C

However, in the presence of CuCl, iodobenzene selectively
reacted with 4-tolylacetylene which has a terminal alkyne
to give noncarbonylative product 5 in 97% yield (entry 1).
In the absence of CuCl, terminal alkyne II afforded
carbonylative product 4 as the major product (entry 2).
When the amount of iodobenzene increased to 2 equiva-
lent, phenyl propiolic acid (I) gave the carbonylative
product 2a in 45% yield and 4-tolylacetylene gave the
noncarbonylative product 5 in 49% yield in the presence of
CuCl (entry 3). However, in the absence of CuCl, both I
and II afforded the corresponding carbonylative product
2a and 4, respectively (entry 4).
Finally, the reductive elimination of E gave the desired
product.
Scheme 2. Proposed Mechanism
Table 3. Comparative Experiments with Phenylpropiolic Acid
and p-Tolylacetylenea
In summary, we developed the one-pot synthesis of
diarylalkynone from the palladium-catalyzed noncarbon-
ylative Sonogashira coupling and decarboxylative carbon-
ylative coupling reaction of propiolic acid with aryl
iodide. This method showed good yields and functional
group tolerance. We report the following findings. (1)
Alkynyl carboxylic acid prefers decarboxylative carbonyl-
ation to noncarbonylative coupling under carbon mon-
oxide atmosphere. (2) Terminal alkyne provides carbonyl-
ative product in the presence of CuCl and noncarbonylative
product in the absence of CuCl. (3) The reactivity of
terminal alkyne and noncarbonylation is better than that
of alkynyl carboxylic acid and carbonylation, which provide
the selective carbonylative coupling products.
yield (%)b
product from I product from II
entry ratio of 1a:I:II additive
2a
3
4
5
1
2
3
4
1:1:1
1:1:1
2:1:1
2:1:1
CuCl
CuCl
2
7
97
15
49
4
74
48
45
35
2
a PhI (3.0 mmol), I (1.5 or 3.0 mmol), II (1.5 or 3.0 mmol), Pd(PPh3)2-
Cl2 (0.15 mmol), Et3N (18.0 mmol), and CO (8 atm) were reacted in the
presence or absence of CuCl (0.3 mmol) in acetonitrile at 80 °C for 1 h.
b After aqueous workup, the crude product was analyzed by gas chro-
matography with internal standard and 1H and 13C NMR.
From these results, we proposed the mechanism pre-
sented in Scheme 2. First, palladium complex A, produced
by the oxidative addition of aryl iodide to palladium, was
reacted withalkynylcoppercomplex thatwasformedinthe
presence of CuCl and base to afford palladium complex B.
Reductive elimination of B afforded the aryl alkynyl
carboxylic acid salt C. This is the catalytic cycle for
noncarbonylative coupling, with another catalytic cycle
for carbonylative coupling. The oxidative palladium com-
plex A reacted with carbon monoxide to produce complex
D and then afforded the palladium complex E through the
decarboxylative coupling of aryl alkynyl carboxylic acidC.
Acknowledgment. This research was supported by the
Nano•Material Technology Development Program
through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (Grant No. 2012M3A7B4049655).
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX