Efficient synthesis of unsymmetric diarylalkynes from decarboxylative coupling in a continuous flow reaction system

Article abstract of DOI:10.1016/j.tetlet.2011.07.091

Unsymmetric diaryl alkynes were synthesized from the palladium-catalyzed decarboxylative coupling of aryl halides and propiolic acid using a continuous flow reaction system. This flow chemistry system continuously gave the desired products in moderate to good yields, and produced less byproduct than was formed in the batch reaction.

Full text of DOI:10.1016/j.tetlet.2011.07.091

Tetrahedron Letters 52 (2011) 5064–5067
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Tetrahedron Letters
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Efficient synthesis of unsymmetric diarylalkynes from decarboxylative coupling
in a continuous flow reaction system
Hee Joon Lee a, Kyungho Park b, Goun Bae b, Jaehoon Choe c, Kwang Ho Song a, , Sunwoo Lee b,
⇑
⇑
a Department of Chemical & Biological Engineering, Korea University, Seoul 136-713, Republic of Korea
b Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
c LG Chem Research Park, Daejeon 305-380, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Unsymmetric diaryl alkynes were synthesized from the palladium-catalyzed decarboxylative coupling of
aryl halides and propiolic acid using a continuous flow reaction system. This flow chemistry system con-
tinuously gave the desired products in moderate to good yields, and produced less byproduct than was
formed in the batch reaction.
Received 9 June 2011
Revised 20 July 2011
Accepted 21 July 2011
Available online 27 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Flow chemistry
Micromixer
Palladium
Diaryl alkynes
Decarboxylative coupling
Aryl alkynes are some of the most important building blocks in
the pharmaceutical and electro-material industries.1 The Sono-
gashira coupling reaction, which is the coupling between an sp car-
bon and an sp2 carbon in the presence of a palladium catalyst and
copper co-catalyst, has been employed as the key reaction for the
synthesis of diaryl alkynes.2 This traditional method for the syn-
thesis of unsymmetrical diaryl alkynes uses protected alkynes,
such as trimethylsilylacetylene,3 and 2-methylbut-3-yn-ol4 that
are coupled with aryl halides, and then a second Sonogashira reac-
tion is employed after the deprotection step. These reactions have
some drawbacks in that they produce organometallic waste and
require a multi-step process. To solve these problems, we have
developed the decarboxylative coupling of alkynyl carboxylic acid
and aryl halides to afford bond formation between the aryl carbon
and alkynyl carbon, and CO2 is released as a byproduct.5 Since our
first report of this decarboxylative coupling reaction, several re-
search groups have developed very useful methodologies using
the decarboxylative coupling of alkynyl carboxylic acid.6
alkynes from propiolic acid, and showed the broad scope of
substrates.5c However, this method has some drawbacks, in that
symmetric diaryl alkynes were always formed as a byproduct.
Therefore, it requires higher selectivity and a more versatile
processing method for application in the fine chemical industry.
Miniaturized continuous flow reactor technology has been paid
much attention in the pharmaceutical and fine chemical industries
due to its heat and mass transfer rate enhancements, higher yields
and greater product selectivity.7 A variety of transition-metal cata-
lyzed transformations have been successfully applied in the contin-
uous flow system.8 Conducting organic reactions with microfluidics
has a variety of attractive attributes:9 microfluidic systems provide
a high surface area to volume ratio for micromixing, thus affording
efficient mass transfer; and the flow aspect allows control over the
reactant residence times at large surface areas for selective cataly-
sis. In addition, the heat dissipation properties of the microchannels
can be employed for the subdued management of exothermic reac-
tions and thus achieve high selectivity. When the optimized condi-
tions are set up for the continuous flow system, several flow
reactors are placed in parallel to produce the coupled product on
a large scale without any more scale up reactors being needed.10
Therefore, we envision that the continuous flow reaction system
could provide a more practical and efficient method for the synthe-
sis of unsymmetric diaryl alkynes without the formation of sym-
metric ones as the side product. Since Ryu’s group first reported
As an alkyne source, propiolic acid has two alkynyl carbons
which show different reactivities: one is the terminal alkynyl car-
bon that is used in the Sonogashira reaction and the other is the car-
bon-bearing carboxylic acid for decarboxylative coupling. We
previously reported the one-pot synthesis of unsymmetric diaryl
⇑
Corresponding authors. Tel.: +82 2 3290 3307 (K.H.S.); tel.: +82 62 530 3385
(S.L.).
the microflow chemistry of Sonogashira coupling reaction,11
a
number of the related works have been published.12 However, there
is no example of the microflow chemistry for the decarboxylative
E-mail addresses:
(S. Lee).
khsong@korea.ac.kr (K.H. Song),
sunwoo@chonnam.ac.kr
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.091

Hee Joon Lee et al. / Tetrahedron Letters 52 (2011) 5064–5067
5065
Table 1
In order to apply the batch reaction methodology to flow chem-
istry, the most important thing is for all the reagents to be in the
solution state. Organic reactions which require insoluble reagents
cannot be applied in flow chemistry. In those cases, some reagents
are introduced as salts to the batch reaction, and some others are
precipitated in the reaction mixture. Therefore, we first investigated
the optimized conditions under which all reagents exist in the solu-
tion state at room temperature in the reservoir. As shown in Table 1,
Pd(PPh3)2Cl2, and 1,4-bis(diphenylphosphino)butane (dppb) did not
show good solubility in DMSO (entry 1). When DBU was added to the
mixture, all reagents were soluble in DMSO (entry 2). However,
when propiolic acid was added, the precipitate was formed even
though additional DMSO was added (entry 3). The mixture of palla-
dium, ligand and iodobenzene showed good solubility in DMSO,
even in the presence of the internal standard naphthalene (entry
4). We found that propiolic acid and DBU have to be stored in sepa-
rate reservoirs (entry 5). The mixture of iodobenzene and propiolic
acid showed good solubility in DMSO (entry 6).
The optimized condition for the solubility of all reagents in DMSOa
Entry
Pd(PPh3)2Cl2
dppb
DBU
PhI
Propiolic acid
Solubility
1
2
3
4
5
6
+
+
+
+
+
+
+
+
ꢀ
+
+
ꢀ
ꢀ
ꢀ
+
ꢀ
ꢀ
+
Lowb
Highc
Lowb
Highc
Lowb
Highc
ꢀ
ꢀ
ꢀ
ꢀ
+
ꢀ
+
ꢀ
ꢀ
ꢀ
+
+
a
All reagents are dissolved in DMSO (12.0 mL). Pd(PPh3)2Cl2 (140.4 mg,
0.2 mmol), dppb (170.6 mg, 0.4 mmol), DBU (1.22 g, 8.0 mmol), iodobenzene
(816 mg, 4.0 mmol) and propiolic acid (280.2 mg, 4 mmol) were used in the solu-
bility test. ‘+’ stands for ‘in the presence’; ‘ꢀ ‘ stands for ‘in the absence’.
b
Precipitated was found in the solution.
Precipitated was not found in the solution.
c
coupling of alkynyl and aryl groups. Here, we report a microfluidic
system for the synthesis of unsymmetric diaryl alkynes from the
coupling reaction of propiolic acid and aryl halides.
Scheme 1. The continuous flow system.
Table 2
Optimization of the flow chemistry for the synthesis of unsymmetric diaryl alkynesa
Br
Me
Pd(PPh3)2Cl2
I
Me
O
dppf
2a
3aa
4aa
+
OH
tube 2
1a
DBU
tube 1
Entry
Tube 1 condition
Time (h)
Tube 2 condition
Time (h)
Micromixer
Yieldb (%)
Temp (°C)
Flow rate (mL/h)
Temp (°C)
Flow rate (mL/h)
3aa
4aa
c
1
2
3
4
5
6
7
8
50
50
50
50
50
50
50
80
50
50
50
1
1
1
3
1
3
4
1
1
1
3
0.46
0.46
0.46
0.15
0.46
0.15
0.12
0.46
0.46
2.40
0.80
80
100
120
120
120
120
120
120
160
120
120
1
1
1
3
1
3
4
1
1
1
3
0.92
0.92
0.92
0.31
0.92
0.31
0.23
0.92
0.92
4.80
1.60
ꢀ
24
35
39
52
48
75
82
12
37
27
37
34
33
32
17
15
3
c
ꢀ
c
ꢀ
c
ꢀ
c
+
c
+
+
+
+
+
+
c
0
c
55
31
33
22
c
9
c
10d
11d
c
a
Reaction condition: Reservoir A: iodobenzene (816 mg, 4.0 mmol) and propiolic acid (280.2 mg, 4.0 mmol) were dissolved in 12 mL DMSO. Reservoir B: Pd(PPh3)2Cl2
(140.4 mg, 0.2 mmol), dppb (170.6 mg, 0.4 mmol) and DBU (1.22 g, 8.0 mmol) were dissolved in 12 mL DMSO. Reservoir C: bromobenzene (628 mg, 4.0 mmol) was dissolved
in 24 mL DMSO. The tube is Teflon tube (the inside diameter = 0.08 cm, the outside diameter = 0.16 cm). The length of tube 1 is 1.0 m, and the length of tube 2 is 2.0 m).
b
The yield was determined by gas chromatography.
C
‘+’ Stands for ‘in the presence’; ‘ꢀ’ stands for ‘in the absence’ which means the connector was employed instead of micromixer.15
d
The following tube is employed (Teflon tube, the inside diameter = 0.18 cm, the outside diameter = 0.32 cm).

5066
Hee Joon Lee et al. / Tetrahedron Letters 52 (2011) 5064–5067
Based on our optimized conditions, we set up a continuous flow
diphenylacetylene, was formed as a byproduct in 34% yield (entry
1). Increasing the reaction temperature of the second flow to 110
and 120 °C, the desired product was formed in 35% and 39% yields,
respectively, however, the yield of byproduct did not decrease (en-
tries 2 and 3). Increasing the retention time (or flow rate) of the
first and the second flows to 3 h, the yield of the desired product
increased to 52%, however, the byproduct was still formed (entry
4). The reasons behind the formation of the byproduct might come
from the uncompleted coupling reaction of aryl iodide in the first
flow channel. To solve this problem, we employed the micromixers
to the flow systems.13 The micormixers afforded a variety of
advantages:14 (1) fast heat and mass transfer due to the large sur-
face to volume ratio; (2) increased liquid mixing speed through
double-step mixing; (3) reduced reaction time and increased
system in which two reservoirs were connected to the first flow
channel, as shown in Scheme 1. One reservoir contained aryl iodide
and propiolic acid in DMSO (reservoir A), and the other reservoir
contained Pd(PPh3)2Cl2, dppf and DBU in DMSO (reservoir B). Res-
ervoir C containing aryl bromide was connected to the second flow
channel.
We studied the selectivity and reactivity by varying the flow
rate and the temperature. As model substrates, iodobenzene, and
4-bromotolune were employed in the synthesis of unsymmetric
diaryl alkynes. The results are summarized in Table 2. When the
first flow system was run for 1 h at 50 °C, and the second flow sys-
tem run for 1 h at 80 °C, the desired unsymmetric diaryl alkyne
was obtained in 24% yield and the symmetric diaryl alkyne,
Table 3
The synthesis of unsymmetric diarylalkynes using continuous flow chemistrya
Entry
1
Aryl iodides
Aryl bromides
Productsb
Yieldc (%)
82 (0d)
I
Br
Me
Me
O
I
I
I
O
2
3
65 (3d)
61 (2d)
Br
Br
Me
O
Me
O
OMe
OMe
Cl
Cl
4
77 (0d)
Br
Br
I
I
S
5
6
75 (0d)
68 (0d)
S
N
N
N
Br
Br
I
I
I
O
Me
Me
7
8
9
42 (12d)
56 (7d)
62 (2d)
Me
O
Me
O
N
Br
Br
Me
O
Me
O
S
S
Me
O
Me
I
I
I
O
O
67(1d)
70 (0d)
85 (0d)
Br
Br
Me
Me
10
11
12
OMe
OMe
Me
Me
Me
OMe
OMe
N
N
Br
Me
a
Reactions conditions: reservoir A: aryl iodides (8.0 mmol) and propiolic acid (8.0 mmol) were dissolved in DMSO (24.0 mL). Reservoir B: Pd(PPh3)2Cl2 (0.4 mmol), dppb
(0.8 mmol), and DBU (16 mmol) were dissolved in DMSO (24.0 mL). Reservoir C: aryl bromides (8.0 mmol) were dissolved in DMSO (48 mL).
b
All compounds were characterized by comparison of their 1H and 13C NMR spectra with authentic samples or literature data.
The yield was isolated after 40 h from the starting point of the reaction to the end.
Yields of symmetrical diarylalkyne from aryl iodide.
c
d

Hee Joon Lee et al. / Tetrahedron Letters 52 (2011) 5064–5067
5067
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selectivity. When the reaction was carried out in the presence of
micromixers, the yield of desired product was increased to 48%,
and that of the byproduct was decreased to 15% (entry 5). This
means that the reaction with the micromixer gave better results
than reaction without the micromixer. Increasing the reaction time
to 4 h in both flow systems, the desired product was obtained in
82% yield, and a trace amount of diphenyl acetylene was formed
as the byproduct (entry 7). This result means that the flow chem-
istry provides the desired product with high selectivity, consider-
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reaction.5c Increasing reaction temperature afforded low yields
and selectivities (entries 8 and 9). The yields were low when the
reaction time and the inside diameter were increased (entries 10
and 11).
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strates for the synthesis of unsymmetrical diaryl alkynes. All sub-
strates and catalyst in the reservoirs were continuously pumped
to the micromixer and the reaction proceeded in a thermostated
tube with a mean residence time for the mixture of 4 h. The final
product was corrected after 40 h from the starting point of the
reaction to the end, because the time to reach the steady-state
has to be considered. The results are summarized in Table 3.16
When iodobenzene was employed as an aryl iodide, most aryl
bromides, bearing electron-donating or electron-withdrawing
groups, produced the corresponding unsymmetric diarylalkynes
with moderate to good yields. 40-Bromoacetophenone and methyl
40-bromobenzoate produce the corresponding symmetric diary-
lalkynes in 3% and 2% yields, respectively (entries 2 and 3). 3-Chlo-
robromobenzene coupled selectively at the carbon-bearing
bromide rather than the carbon-bearing chloride (entry 4). In addi-
tion, bromo heteroaromatic compounds, such as 2-bromothio-
phene and 2-bromopyridine also showed good yields without the
formation of dipheylacetylene (entries 5 and 6). In the case of 4-
iodoacetophenone, which is an aryl iodide bearing an electron-
withdrawing group, the symmetric diaryl alkynes, which come
from the coupling of 4-iodoacetophenone and propiolic acid, were
formed in 2–12% yields. Electron-donating aryl bromides such as
4-bromotoluene afforded 12% yield of byproduct (entry 7). When
the aryl iodides with electron-donating groups were employed,
all produced the desired unsymmetric diaryl alkynes in moderate
to good yields (entries 10–12).
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In conclusion, we first developed the continuous flow reaction
for the synthesis of unsymmetric diarylalkynes from the coupling
reaction of propiolic acid and aryl halides. The flow reaction system
highly depends on the solubility of the reagents and the flow rate.
We found that the propiolic acid and DBU have to be separately
stored in the reservoir for flow chemistry. The best retention time
is 4 h for the first and second flows. This continuous flow reaction
system affords unsymmetric diaryl alkynes in high yields with a
trace amount of symmetric diaryl alkynes as byproducts, and
showed high selectivity compared to the batch reaction system.
13. Micromixer was purchased HPIMM from Institute fur Mikrotechnik Mainz
GambH (IMM). HPIMM (standard mixing channels (
14. Hessel, V.; Löwe, H.; Schönfeld, F. Chem. Eng. Sci. 2005, 60, 2479.
lm), 45 lm ꢁ 200 lm).
15. The connector was purchase from Swagelock (model No.: SS-100-3, 316
stainless steel, 1/16 inch).
Acknowledgment
16. The system of flow reaction: Aryl iodides (8.0 mmol) and propiolic acid
(8.0 mmol) were dissolved in DMSO (24.0 mL) and transferred to syringe
A(50 mL). Pd(PPh3)2Cl2 (0.4 mmol), dppb (0.4 mmol), and DBU (16 mmol) were
dissolved in DMSO (24.0 mL) and transferred to syringe B(50 mL). Each
syringes were placed in the syringe pump (Harvard apparatus, Model No. 70-
2209). Aryl bromides (8.0 mmol) was dissolved in DMSO (48 mL) and
transferred to syringe C(100 mL). Syringe A and B were connected to the first
micromixer through Teflon tube (the outside diameter = 0.16 cm, the inside
diameter = 0.06 cm), and tube 1 (the length = 1.0 m) was connected between
the first micromixer and the second micromixer. Syringe C was connected to
the second micromixer, and tube 2 (the length = 2.0 m) was connected to the
second micromixer. Tubes 1 and 2 were put into the oil bath for thermal
heating.
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, Basic Research
Promotion Fund) (KRF-2008-314-D00070).
References and notes
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