Synthesis of symmetrical and unsymmetrical diarylalkynes from propiolic acid using palladium-catalyzed decarboxylative coupling

Article abstract of DOI:10.1021/jo101398a

Figure presented. Symmetrical diarylalkynes were obtained from propiolic acid (or 2-butynedioic acid) and aryl halides in good yields. The optimized reaction conditions were 2.0 equiv of aryl halide, 1.0 equiv of propiolic acid, 5.0 mol % Pd(PPh₃

Full text of DOI:10.1021/jo101398a

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Synthesis of Symmetrical and Unsymmetrical Diarylalkynes from
Propiolic Acid Using Palladium-Catalyzed Decarboxylative Coupling
Kyungho Park,† Goun Bae,† Jeongju Moon,† Jaehoon Choe,‡ Kwang Ho Song,*,§ and
Sunwoo Lee*,†
†Department of Chemistry, Chonnam National University, 300 Yongbong-dong, Buk-gu,
Gwangju 500-757, Republic of Korea, ‡LG Chem Research Park, Daejeon 305-380, Republic of Korea, and
§Department of Chemical & Biological Engineering, Korea University, Seoul 136-713, Republic of Korea
khsong@korea.ac.kr; sunwoo@chonnam.ac.kr
Received July 16, 2010
Symmetrical diarylalkynes were obtained from propiolic acid (or 2-butynedioic acid) and aryl halides
in good yields. The optimized reaction conditions were 2.0 equiv of aryl halide, 1.0 equiv of propiolic
acid, 5.0 mol % Pd(PPh3)2Cl2, 10.0 mol % 1,4-bis(diphenylphosphino)butane (dppb), 2.0 equiv of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and dimethyl sulfoxide (DMSO) as the solvent. The
coupling reaction of 2-butynedioic acid with aryl halides required 110 °C. The coupling reaction
showed tolerance for functional groups such as ester, ketone, and aldehyde and exhibited chemo-
selectivity. In the coupling reaction of propiolic acid with aryl bromide, the diarylated product was
the major one at 80 °C, even though 1 equiv of aryl halides was employed. However, among the
monoarylated products that were formed predominantly at 25 and 50 °C in the coupling reaction with
aryl iodide, more Sonogashira coupling product was obtained than the decarboxylative coupling
product. Unsymmetrical diarylalkynes were also synthesized via this method, in which all reagents,
including propiolic acid, aryl iodide, and aryl bromides were added at the beginning of the reaction.
Introduction
inception, several new methodologies related to the Sonogashira
reaction have been developed and improved to overcome
several significant limitations, including the copper-free,3
ligand-free,4 microreactor,5 and aqueous condition6 reac-
tions. The structure of diarylalkyne was one of the impor-
tant starting materials for the synthesis of π-conjugated
compounds. For the synthesis of symmetrical diarylalkyne
derivatives, acetylene has been employed as an alkyne
source.7 However, it is disadvantaged by its cumbersome
handling in the gaseous state in the organic laboratory.
To overcome this problem, protected acetylenes such as
The Sonogashira coupling reaction of alkynes and aryl or
alkenyl halides is the most straightforward and powerful
method for the construction of sp carbon and sp2 carbon
bonds.1 The structure of arylalkynes and conjugated enynes
has received attention due to their important role in bioactive
compounds and conjugated functional materials.2 Since its
(1) For original work, see: (a) Sonogashira, K.; Tohda, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 16, 4467–4470. For reviews on the Sonogashira
reactions, see: (b) Tykwinski, R. P. Angew. Chem., Int. Ed. 2003, 42, 1566–
1568. (c) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979–2017.
(d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442–4489. (e) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133–173.
(f) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834–871.
(2) For bioactive compounds, see: (a) Boukouvalas, J.; Cote, S.; Ndzi, B.
Tetrahedron Lett. 2007, 48, 105–107. (b) Falcone, D.; Li, J.; Kale, A.; Jones,
G. B. Bioorg. Med. Chem. Lett. 2008, 18, 934–937. For conjugated functional
materials, see: (c) Moon, J. H.; McDaniel, W.; MacLean, P.; Hancock, L. F.
Angew. Chem., Int. Ed. 2007, 46, 8223–8225. (d) Liu, J.; Lam, J. W. Y.; Tang,
B. Z. Chem. Rev. 2009, 109, 5799–5867. (e) Heravi, M. M.; Sadjadi, S.
(3) (a) Kawanami, H.; Matsushima, K.; Sato, M.; Ikushima, Y. Angew.
Chem., Int. Ed. 2007, 46, 5129–5132. (b) Bakherad, M.; Keivanloo, A.;
Bahramian, B.; MIhanparast, S. Tetrahedron Lett. 2009, 50, 6418–6420.
(4) Biffis, A.; Scattolin, E.; Ravasio, N.; Zaccheria, F. Tetrahedron Lett.
2007, 48, 8761–8764.
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Published on Web 08/26/2010
DOI: 10.1021/jo101398a
r
2010 American Chemical Society

Park et al.
JOCArticle
trimethylsilylacetylene8 and 2-methylbut-3-yn-2-ol9 have com-
monly been employed. Nevertheless, further drawbacks include
the production of an equivalent of metal or organic waste,
with the former being expensive and the latter requiring a
strong base in the deprotection step. For example, Grieco and
co-workers employed trimethylsilylacetylene in the presence
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); however, their
method required a copper cocatalyst and 6 equiv of DBU.8b
Nishihara and co-workers used bis(trimethylsilyl)acetylene as
an alkyne source, but they also experienced some drawbacks.10
A large amount of copper cocatalyst (50 mol %) was required,
and they were only able to apply it to the aryl iodide substrates.
In addition, bis(tributylstannyl)acetylene has often been em-
ployed in symmetrical diarylalkynes as a functional mate-
rial, but it is very expensive and produces toxic organometal
waste.11 Recently, research has focused on expanding the pool
of viable aryl halide coupling partners by exploring new ligand
systems.12 However, the development of an alkyne source has
received less research attention.
SCHEME 1. Synthesis of Diarylalkyne from a Variety of
Alkyne Source
This method did not need copper as a cocatalyst and produced
CO2 as a byproduct. Despite its eco-friendliness, however, the
method suffered several drawbacks: 6 equiv of tetrabutylam-
monium fluoride (TBAF) was required for the synthesis of
unsymmetrical diarylalkynes from propiolic acid, high cata-
lytic loadings (5 mol % Pd2(dba)3 and 40 mol % PtBu3) were
required for the symmetrical diarylalkynes, both TBAF and
PtBu3 are expensive and sensitive to moisture, and, moreover,
the latter is unstable to air. Therefore, the requirement remains
for a general protocol that consists of an equal amount of
inexpensive base and a more stable ligand system (Scheme 1).
The decarboxylative coupling reaction has also been
investigated in a variety of coupling reactions.13 Most re-
cently, we first reported the use of propiolic acid as the alkyne
source in the palladium-catalyzed coupling reaction of aryl
halides and alkynes.14 We and another group15 reported the
decarboxylative coupling reaction of aryl or alkyl alkynyl
carboxylic acid with aryl halides using palladium catalyst.
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Results and Discussion
Synthesis of Symmetrical Diarylalkynes. First, we attem-
pted to find a less expensive base as a replacement for TBAF
and employed propiolic acid as the alkyne. To this end, we
screened a variety of bases in the reaction of propiolic acid
(1a) and phenyl bromide (2a) under the following conditions:
Pd(PPh3)2Cl2 as a palladium source and 1,4-bis(diphenyl-
phosphino)butane (dppb) as a ligand in DMSO solvent. The
results are summarized in Table 1.
The bases exerted a significant effect in the reaction. Com-
mon organic bases such as 4-N,N-dimethylaminopyridine
(DMAP), morpholine, 1,8-diaminonaphthalene, and pyridine
did not support the coupling reaction and showed no conver-
sion of phenyl bromide (Table 1, entries 1-4). Although Et3N
and DABCO resulted in 30% and 29% conversion, respec-
tively, the desired coupling product was not found in the reac-
tion mixture (entries 5 and 6). Among the organic bases, only
DBU and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) exhibited
good reactivity. Although all the inorganic bases showed some
reactivity, with Cs2CO3 affording the best result (entry 9), they
were all inferior to DBU. When TBAF was employed as a base,
the desired product was formed with 74% yield (entry 13).
Evaluation of the palladium sources revealed that Pd(PPh3)2-
Cl2 was superior to all other choices, with low to moderate
yields being attained, but not full conversion of phenyl bromide
(entries 14-16).
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Next, we screened a variety ligands and solvents for the
coupling reaction of propiolic acid and phenyl bromide
(Table 2). When the reaction was carried out with Pd(PPh3)2-
Cl2 in the absence of dppb as a ligand, the desired product
was obtained in 73% yield (entry 1). The yield was slightly
improved when the extra PPh3 ligand was added instead of
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TABLE 1. Screening of Bases and Palladium Sourcesa
SCHEME 2. Decarboxylative Coupling Reaction of 2-Butyne-
dioic Acid
entry
Pd source
base
DMAP
morpholine
1,8-di(NH2)Npc
pyridine
Et3N
DABCO
DBN
DBU
Cs2CO3
K2CO3
Na2CO3
K3PO4
TBAF
conv (%)b
yield (%)b
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
0
0
0
0
0
0
0
0
TABLE 3. Synthesis of Symmetrical Diarylalkynesa
0
30
29
64
100
76
53
37
54
82
70
58
90
0
61
99
64
42
34
30
74
68
52
85
9
10
11
12
13
14
15
16
DBU
DBU
DBU
Pd2(dba)3
Pd(PPh3)4
aReaction conditions: 2a (1.0 mmol), 1a (0.5 mmol), Pd (0.025 mmol),
dppb (0.05 mmol), base (1.0 mmol), and DMSO (3.0 mL) at 80 °C for 3 h.
bYield was determined by GC. c1,8-Diaminonaphthalene.
TABLE 2. Screening of Ligands and Solventsa
entry
ligand
solvent
DMSO
conv (%)b
yield (%)b
1
2
3
4
5
6
7
8
80
92
97
90
98
93
100
14
22
11
41
73
85
96
84
96
90
98
10
19
7
PPh3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO/H2Oc
toluene
digylme
p-xylene
NMP
PtBu3
PCy3
dppf
Xantphos
dppb
dppb
dppb
dppb
dppb
9
10
11
23
aReaction conditions: 2a (1.0 mmol), 1a (0.5 mmol), Pd(PPh3)2Cl2
(0.025mmol), ligand(0.05mmol), DBU(1.0mmol),andsolvent(3.0mL) at
80 °C for 3 h. bYield was determined by GC. cDMSO/H2O (v/v 4:1)
the dppb ligand (entry 2). Other monodentate and chelating
phosphine ligands resulted in good yields, but did not show
complete conversion (entries 3-6). Among the variety of
tested solvents, only DMSO exhibited the full conversion
and a high yield of the desired product. Moreover, the
desired product was obtained with high yield even in the
mixture of H2O and DMSO, which indicates the insensitivity
of this reaction system to moisture (entry 7). The product
yields were low in less polar solvents such as toluene,
diglyme, and p-xylene: 10%, 19%, and 7%, respectively
(entries 8-10). Interestingly, N-methylpyrrolidone (NMP),
which was the best solvent in the presence of TBAF, afforded
poor conversion and low yield (entry 11). On the basis
of these results, we optimized the reaction conditions as 2.0
equiv of aryl bromide, 1.0 equiv of propiolic acid, 5.0 mol %
Pd(PPh3)2Cl2, 10.0 mol % dppb, 2.0 equiv of DBU, and
aReaction conditions: Aryl halide (6.0 mmol), propiolic acid or
2-butynedioic acid (3.0 mmol), Pd(PPh3)2Cl2 (0.15 mmol), dppb (0.30
mmol), DBU (6.0 mmol), and DMSO (15.0 mL) bA: Yields from the
coupling reaction of propiolic acid at 80 °C for 3 h. cB: Yields from the
coupling reaction of 2-butynedioic acid at 110 °C for 3 h. dReaction time
was 1.5 h.
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TABLE 4. Coupling Reaction of Equimolecular Amounts of Propiolic Acid and Phenyl Halidea
yield (%)
entry
X
temp (°C)
time (h)
DBU (equiv)
conv (%)b
4c
5d
3e
f
f
1
2
3
4
5
6
I
I
I
Br
Br
Br
25
25
50
50
80
80
3
18
3
3
3
2
2
2
2
2
1
25
75
92
0
98
98
-
3
25
70
84
-
-
-
-
f
f
f
6
f
f
f
f
-
-
-
-
-
-
f
f
46(92g)
43(86g)
3
aReaction conditions: 1a (1.0 mmol), 2a or 2b (1.0 mmol), Pd (0.025 mmol), dppb (0.05 mmol), DBU (1.0 or 2.0 mmol), and DMSO (3.0 mL).
bConversion of PhX was determined by GC with internal standard 2-methoxynaphthalene. cYields were determined by NMR with internal standard
2-methoxynaphthalene after acidification of reaction mixture. dYields were determined after the conversion of 5 to methyl phenylpropiolate. eYields
f
g
were determined by GC and NMR with internal standard 2-methoxynaphthalene. Not detected. Yields were calculated on the basis of the molar
amount of phenyl halide.
DMSO as a solvent. We also applied the optimized condi-
tions to 2-butynedioic acid as an alkyne source for obtaining
symmetrical diarylalkyne. However, the desired coupled
product could be successfully obtained with high yield when
the reaction temperature was elevated to 110 °C (Scheme 2).
In an effort to explore the scope of the developed method,
we screened the coupling of a variety of aryl compounds and
propiolic acid and 2-butynedioic acid (Table 3). In general,
the product yield did not exhibit a strong dependence on
propiolic acid and 2-butynedioic acid, as shown by A and B
in Table 3. The yields were described on the basis of the
coupling reaction of propiolic acid (A yields in Table 3). First
the coupling of propiolic acid with phenyl bromide (2a),
iodide (2b), and triflate (2c) all gave the desired product,
diphenylacetylene (3a), with high yields of 98%, 95%, and
92% yields, respectively (entries 1-3). The ortho-substituted
aryl iodides and bromides resulted in good yields (entries
4-7), but 2-bromoanisole (2e) gave a slightly lower yield
than the others (entry 5). The para-substituted aryl bromides
all gave the corresponding products with good yields (entries
8-10). This system also proved to be tolerant of sterically
hindered aryl halides. Sterically demanding aryl halides such
as2k, 2l, and 2mwerecoupled withpropiolicacidtoafford the
desired products in good yields (entries 11-13). In addition,
2-bromobiphenyl (2n) also exhibited a good yield (entry 14).
Various heteroaromatic substrates such as 2-bromothiophene
(2o) and 3-bromopyridine (2p) also afforded the symmetrical
arylalkynes in 72% and 69% yield, respectively (entries 15
and 16). The aryl halides with electron-withdrawing groups
such as ester, ketone, and aldehyde were completely converted
to the desired product faster than the others (entries 17-19).
1-Bromonaphthalene (2t) afforded the symmetrical di-
naphthylacetylene 3t with 74% yield (entry 20). 1-Bromo-
chlorobenzene (2u) was coupled at the bromo-substituted
site, which demonstrated the catalytic system’s chemoselec-
tivity (entry 21). As shown in Table 3, all reaction yields
from the coupling reactions of 2-butynedioic acid were very
similar to those of propiolic acid (B in Table 3).
and decarboxylative (C-CO2H). To determine which reac-
tion site is more reactive under our optimized reaction
conditions, we investigated the relative amounts of two
reaction intermediates, phenylacetylene (4), which is pro-
duced from decarboxylative coupling, and phenylpropiolic
acid (5), which is produced from the Sonogashira coupling in
the reaction mixture. We carried out the coupling reaction of
equimolecular amounts of propiolic acid and phenyl halide
under a variety of reaction conditions.16 The results are
summarized in Table 4. With phenyl iodide, the coupling
reaction produced the monoarylated products at 25 and
50 °C, with no diarylated product being formed (entries
1-3). Among the monoarylated products, more Sonogashira
coupling product 5 was produced than the decarboxylative
coupling product 4. The Sonogashira coupling reaction was
faster than the decarboxylative coupling reaction at 25 and
50 °C. With phenyl bromide, no coupled product was found
at 50 °C (entry 4). As the reaction temperature was increased
to 80 °C, the conversion of phenyl bromide was increased
to 98%, but diphenylacetylene was formed as the major
product. We did not detect any monoarylated product in
GC and NMR investigations. Interestingly, the major pro-
duct was diphenylacetylene even though 1 equiv of base was
employed.
Synthesis of Unsymmetrical Diarylalkynes. The results
indicated that aryl iodide was coupled with propiolic acid
at room temperature and at 50 °C without any formation of
diarylacetylene. However, at least 80 °C was required for the
coupling reaction of aryl bromide with propiolic acid. To
investigate the reactivity of aryl iodide and bromide toward
propiolic acid in detail, a set of competition experiments were
conducted. In the model system, equimolecular amounts of
(16) We could not identify directly the intermediates 4 and 5 in the
reaction mixture by GC and NMR because the two intermediates have acidic
protons, which are difficult to detect in the basic conditions. Therefore, we
treated the reaction mixture of Table 4 with the following procedure. The
reaction mixture was reacted with MeI (1.0 mmol) and DBU (1.0 mmol) at
room temperature for 3 h for the conversion of phenylpropiolic acid to
methyl phenylpropiolate and treated with HCl etherate (1.0 mmol) for the
acidification of phenylacetylene. These two compounds were detected in GC
and NMR.
Reactivity of Propiolic Acid in the Coupling Reaction.
Propiolic acid has two coupling sites: Sonogashira (C-H)
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SCHEME 3. Comparison of the Reactivity of Aryl Iodide and Aryl Bromide in the Coupling of Propiolic Acid at 50 °C
TABLE 5. Synthesis of Unsymmetrical Diarylalkynesa
aReaction conditions: aryl iodide (3.0 mmol), aryl bromide (3.0 mmol), propiolic acid (3.0 mmol), Pd(PPh3)2Cl2 (0.15 mmol), dppb (0.30 mmol), DBU
(6.0 mmol), and DMSO (15.0 mL) at 50 °C for 5 h and then at 80 °C for 6 h. bYields of symmetrical diarylalkyne from aryl iodide.
phenyl iodide and 4-bromotoluene were allowed to react
with propiolic acid in the presence of 2.5 mol % of the
catalytic system for 5 h at 50 °C. Only phenyl iodide was
coupled with propiolic acid to produce phenylpropiolic acid
with 82% yield and phenyl acetylene with 4% yield, without
any conversion of 4-bromotoluene.16,17
These experimental results suggested that unsymmetrical
diarylalkyne could be obtained when all the reagents were
added at the beginning of the reaction. This reaction condi-
tion did not require the second addition of aryl bromide, as
had been the case in our previous report. As expected, the
reaction first proceeded at 50 °C for 5 h and then the reaction
temperature was raised to 80 °C. When aryl iodides and aryl
bromides were employed, the desired unsymmetrical dia-
rylalkyneswere obtained in goodyields. However, thesymme-
trical diarylalkyne was produced as a byproduct in 2-8%
yield. In the case of phenyl iodide, aryl bromides bearing both
an electron-donating group and an electron-withdrawing
group worked well (Table 5, entries 1-3). Heteroaromatic
bromides such as 2-bromothiophene, 2-bromopyridine, and
3-bromopyridine showed good yields with aryl iodides such as
phenyl iodide, 2-iodotoluene, and 4-iodotoluene (Table 5,
entries 4-8).
Conclusion
The simple synthesis method presented here offers advan-
tages in requiring neither a copper cocatalyst nor an excess of
(17) We found similar results when 4-iodotoluene and phenyl bromide
were employed as aryl halides instead of phenyl iodide and 4-bromotoluene.
6248 J. Org. Chem. Vol. 75, No. 18, 2010

Park et al.
JOCArticle
expensive TBAF reagents for the decarboxylation step. More-
over, expensive organometallic compounds such as silyl- or
tin-protected alkynes are not required and only benign CO2 is
produced as a waste. In summary, a palladium/DBU system
was successfully applied to the cross-coupling of aryl halides
(and aryl triflate) with propiolic acid and 2-butynedioic acid to
provide symmetrical diarylalkyne derivatives. 2-Butynedioic
acid required higher reaction temperature than propiolic acid.
To the best of our knowledge, 2-butynedioic acid has never
been employed as an alkyne source for the decarboxylative
coupling reaction, and this is the first example of double
decarboxylative coupling. In the coupling reaction of propiolic
acid with aryl halides, the diarylated product was the major
one at high temperature, whereas the monoarylated products
were formed predominantly at 25 and 50 °C when phenyl
iodide was employed. Among these monoarylated products,
more Sonogashira coupling product was obtained than the
decarboxylative coupling product. The competition experi-
mental data revealed the successful synthesis of unsymmetrical
diarylalkyne with this palladium/DBU system.
1,2-Di-p-tolylethyne (3h).20 4-Bromotoluene (2h) (1.02 g, 6.00
mmol) was coupled with 1a to give 551 mg (2.67 mmol, 89%) of
3h and coupled with 1b to give 569 mg (2.76 mmol, 92%) of 3h as
a white solid after chromatography: mp 138-140 °C; 1H NMR
(300 MHz, CDCl3) δ 7.41 (d, J = 7.8 Hz, 4H), 7.15 (d, J = 7.8
Hz, 4H), 2.36 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 138.1,
131.4, 129.1, 120.4, 88.9, 21.5; MS C16H14 206(100, [M]þ),
191(20), 102(10), 89(10).
1,2-Bis(4-tert-butylphenyl)ethyne (3i).21 1-Bromo-4-tert-
butylbenzene (2i) (1.28 g, 6.00 mmol) was coupled with 1a to give
773 mg (2.58 mmol, 86%) of 3i and coupled with 1b to give 780 mg
(2.60 mmol, 89%) of 3i as a white solid after chromatography: mp
154 °C; 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 8.7 Hz, 4H),
7.35 (d, J = 8.7 Hz, 4H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 151.3, 131.2, 125.3, 120.4, 88.8, 34.8, 31.2; MS C22H26 290(47,
[M]þ), 275(100), 102(21).
1,2-Bis(4-methoxyphenyl)ethyne (3j).22 4-Bromoanisole (2j)
(1.12 g, 6.00 mmol) was coupled with 1a to give 636 mg (2.67
mmol, 89%) of 3j and coupled with 1b to give 651 mg (2.73
mmol, 91%) of 3j as a pale yellow solid after chromatography:
mp 147-148 °C; 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J = 9
Hz, 4H), 6.86 (d, J = 9 Hz, 4H), 3.82 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 159.4, 132.8, 115.7, 113.9, 87.9, 55.3; MS
C16H14O2 238(100, [M]þ), 223(70), 195(20), 152(20), 119(15).
1,2-Bis(2,5-dimethylphenyl)ethyne (3k).23 2-Bromo-p-xylene
(2k) (555 mg, 6.00 mmol) was coupled with 1a to give 598 mg
(2.55 mmol, 85%) of 3k and coupled with 1b to give 619 mg (2.64
mmol, 88%) of 3k as a white solid after chromatography: mp
111-113 °C; 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 2H), 7.11 (d,
J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 2.48 (s, 6H), 2.31(s,
6H); 13C NMR (75 MHz, CDCl3) δ 136.8, 135.0, 132.3, 129.3,
129.0, 123.2, 92.1, 20.7, 20.4; MS C18H18 234(100, [M]þ),
219(55), 204(55), 102(15).
Experimental Section
General Procedure for the Synthesis of Symmetrical Diary-
lalkynes Using Propiolic Acid or 2-Butynedioic Acid. Pd(PPh3)2-
Cl2 (105 mg, 0.15 mmol), 1,4-bis(diphenylphosphino)butane
(128 mg, 0.30 mmol), aryl halides (6.00 mmol), and propiolic
acid (1a) (212 mg, 3.0 mmol) or 2-butynedioic acid (1b) (342 mg,
3.0 mmol) were combined with DBU (913 mg, 6.0 mmol) in a
small round-bottomed flask. DMSO (15.0 mL) was added, and
the flask was sealed with a septum. The resulting mixture was
placed in an oil bath at 80 °C (for propiolic acid) or 110 °C (for
2-butynedioic acid) for 3 h (or 1.5 h). The reaction was poured
into 25 mL of saturated aqueous ammonium chloride and
extracted with Et2O (4 ꢀ 20 mL). The combined ether extracts
were washed with brine (90 mL), dried over MgSO4, and filtered.
The solvent was removed under vacuum, and the resulting crude
product was purified by flash chromatography on silica gel. The
product was eluted with 5% ethyl acetate in hexane.
1,2-Bis(2,6-dimethylphenyl)ethyne (3l).19 2-Bromo-m-xylene
(2l) (555 mg, 6.00 mmol) was coupled with 1a to give 605 mg
(2.58 mmol, 86%) of 3l and coupled with 1b to give 591 mg (2.52
mmol, 84%) of 3l as a yellow solid after chromatography: mp
115-116 °C; 1H NMR (300 MHz, CDCl3) δ 7.16-7.07 (m, 6H),
2.55 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 140.1, 127.6, 126.8,
123.6, 95.8, 21.6; MS C18H18 234(100, [M]þ), 219(60), 204(60),
105(25).
1, 2-Diphenylethyne (3a).8b Phenyl bromide (2a) (942 mg, 6.00
mmol) was coupled with 1a to give 524 mg (2.94 mmol, 98%) of
3a and coupled with 1b to give 519 mg (2.91 mmol, 97%) of 3a as
1,2-Dimesitylethyne (3m).19 Bromomesitylene (2m) (1.19 g,
6.00 mmol) was coupled with 1a to give 693 mg (2.64 mmol,
88%) of 3m and coupled with 1b to give 646 mg (2.46 mmol,
84%) of 3m as a white solid after chromatography: mp 125 °C;
1H NMR (300 MHz, CDCl3) δ 6.91 (s, 4H), 2.50 (s, 12H), 2.30 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 140.1, 137.7, 127.9, 121.1,
95.5, 21.8, 21.6; MS C20H22 262(100, [M]þ), 247(50), 232(70),
119(20).
1
a white solid after chromatography: mp 63-64 °C, H NMR
(300 MHz, CDCl3) δ 7.55-7.51 (m, 4H), 7.38-7.29 (m, 6H); 13
C
NMR (75 MHz, CDCl3) δ 131.6, 128.3, 128.2, 123.2, 89.3; MS
C14H10 178(100, [M]þ), 152(15), 89(10), 76(10).
1,2-Bis(2-methoxyphenyl)ethyne (3d).18 2-Bromoanisole (2e)
(1.12 g, 6.00 mmol) was coupled with 1a to give 515 mg (2.16
mmol, 72%) of 3d and coupled with 1b to give 608 mg (2.55
mmol, 85%) of 3d as a yellow solid after chromatography: mp
123 °C; 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 9.6 Hz, 2H),
7.29 (t, J = 7.95 Hz, 2H), 6.96-6.88 (m, J = 7.65 Hz, 4H), 3.92
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 159.9, 133.5, 129.5, 120.4,
112.8, 110.7, 89.8, 55.9; MS C16H14O2 238(100, [M]þ), 223(25),
165(25), 152(20), 131(40).
1,2-Di(biphenyl-2-yl)ethyne (3n).24 2-Bromobiphenyl (2n) (1.40 g,
6.00 mmol) was coupled with 1a to give 773 mg (2.34 mmol, 78%)
of 3n and coupled with 1b to give 843 mg (2.55 mmol, 85%) of 3n as
an oil after chromatography: 1H NMR (300 MHz, CDCl3) δ 7.56
(m, 4H), 7.41-7.31(m, 10H), 7.23 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ143.5, 140.4, 133.0, 129.4, 129.3, 128.3, 127.9, 127.4, 126.9,
121.7, 91.8; MS C26H18 330(15, [M]þ), 165(100).
1,2-Di(thiophen-2-yl)ethyne (3o).25 2-Bromothiophene (3o)
(984 mg, 6.00 mmol) was coupled with 1a to give 411 mg (2.16
1,2-Di-o-tolylethyne(3f).19 2-Bromotoluene (2g) (1.02 g, 6.00
mmol) was coupled with 1a to give 588 mg (2.85 mmol, 95%) of 3f
and coupled with 1b to give 569 mg (2.76 mmol, 92%) of 3f as an oil
after chromatography: mp 28-30 °C; 1H NMR (300 MHz, CDCl3)
(20) Mino, T.; Shirae, Y.; Saito, T.; Sakamoto, M.; Fujita, T. J. Org.
Chem. 2006, 71, 9499–9502.
(21) Brizius, G.; Bunz, U. H. F. Org. Lett. 2002, 4, 2829–2831.
(22) Wan, S.; Wang, S. R.; Lu, W. J. J. Org. Chem. 2006, 71, 4349–4352.
(23) Rudenko, A. P.; Vasil’ev, A. V. Russ. J. Org. Chem. 1995, 31, 1360–
1379.
δ 7.50 (d, J = 7.8 Hz, 2H), 7.24-7.13 (m, 6H), 2.52 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 139.9, 131.8, 129.4, 128.2, 125.6, 123.3,
92.3, 20.9; MS C16H14 206(100, [M]þ), 191(25), 101(20), 89(20).
(18) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106, 4218–
4227.
(24) Li, C. W.; Wang, C. I.; Liao, H. Y.; Chaudhuri, R.; Liu, R. S. J. Org.
Chem. 2007, 72, 9203–9207.
(19) Zhang, W.; Wu, H.; Liu, Z.; Zhong, P.; Zhang, L.; Huang, X.;
Cheng, J. Chem. Commun. 2006, 46, 4826–4828.
(25) Yi, C.; Hua, R.; Zeng, H.; Huang, Q. Adv. Synth. Catal. 2007, 349,
1738–1742.
J. Org. Chem. Vol. 75, No. 18, 2010 6249

Park et al.
JOCArticle
mmol, 72%) of 3o and coupled with 1b to give 405 mg (2.13
mmol, 71%) of 3o as a yellow solid after chromatography: mp
99-100 °C; 1H NMR (300 MHz, CDCl3) δ 7.31-7.25 (m, 4H),
7.01 (dd, J = 3.6 Hz, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
132.1, 127.6, 127.1, 122.9, 86.2; MS C10H6S 190(100, [M]þ),
158(10), 145(15), 114(15)
washed with brine (90 mL), dried over MgSO4, and filtered.
The solvent was removed under vacuum, and the resulting crude
product was purified by flash chromatography on silica gel. The
product was eluted with 5% ethyl acetate in hexane.
1-(2-(4-Methylphenyl)ethynyl)benzene (7bh).26 Phenyl iodide
(2b) (612 mg, 3.00 mmol) and 4-bromotoluene (2h) (513 mg, 3.00
mmol) were coupled with 1a to give 438 mg (2.28 mmol, 76%) of
1,2-Di(pyridin-3-yl)ethyne (3p).9b 3-Bromopyridine (2p) (948
mg, 6.00 mmol) was coupled with 1a to give 373 mg (207 mmol,
69%) of 3p and coupled with 1b to give 422 mg (2.34 mmol, 78%)
1
7ah as a white solid after chromatography: mp 70-72 °C; H
NMR (300 MHz, CDCl3) δ 7.54-7.50 (m, 2H), 7.43 (d, J = 8.1
Hz, 2H), 7.37-7.30 (m, 3H), 7.13 (d, J = 7.8 Hz, 2H), 2.36 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 138.4, 131.5, 131.46, 129.1,
128.3, 128.0, 123.4, 120.1, 89.5, 88.7, 21.5; MS C15H13 192(100,
[M]þ), 165(15), 95(10).
1
of 3p as a white solid after chromatography: mp 59-60 °C; H
NMR (300 MHz, CDCl3) δ 8.79 (d, J = 3.2 Hz, 2H), 8.59 (d, J =
7.2 Hz, 2H), 7.83 (dt, J = 8.3 Hz, 1.8 Hz, 2H), 7.34-7.29 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 152.1, 148.9, 138.4, 122.9, 119.6,
89.0; MS C12H8N2 180(100, [M]þ), 153(10), 100(10), 74(15).
Dimethyl 4,40-(Ethyne-1,2-diyl)dibenzoate (3q).8b Methyl-4-
bromobenzoate (2q) (1.29 g, 6.00 mmol) was coupled with 1a
to give 689 mg (2.34 mmol, 78%) of 3q and coupled with 1b to
give 645 mg (2.19 mmol, 73%) of 3q as a white solid after
chromatography: mp 219-220 °C; 1H NMR (300 MHz, CDCl3)
δ 8.03 (d, J = 8.7 Hz, 4H), 7.61 (d, J = 8.7 Hz, 4H), 3.94 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 166.4, 131.6, 129.9, 129.6, 127.3,
91.4, 52.3; MS C18H14O4 294(100, [M]þ), 263(100), 176(25),
116(25).
1-(4-Phenylethynylphenyl)ethanone (7br).27 Phenyl iodide (2b)
(612 mg, 3.00 mmol) and 4-bromoacetophenone (2r) (597 mg, 3.00
mmol) were coupled with 1a to give 449 mg (2.04 mmol, 68%) of
7ar as a pale yellow solid after chromatography: mp 95-96 °C; 1H
NMR (300 MHz, CDCl3) δ 7.94 (d, J = 8.7 Hz, 2H), 7.62 (d, J =
8.7 Hz, 2H), 7.57-7.54 (m, 2H), 7.40-7.35 (m, 3H), 2.62 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 197.3, 136.2, 131.73, 131.7, 128.8,
128.4, 128.3(2C), 122.6, 92.7, 88.6, 26.6; MS C16H12O 220(70,
[M]þ), 205(100), 176(50), 176(45), 151(20), 88(20).
1-(2-(3-Chlorophenyl)ethynyl)benzene (7bu).15a Phenyl iodide
(2b) (612 mg, 3.00 mmol) and 1-bromo-3-chlorobenzene (2u)
(574 mg, 3.00 mmol) were coupled with 1a to give 479 mg (2.25
mmol, 75%) of 7au as a colorless oil after chromatography: 1H
NMR (300 MHz, CDCl3) δ 7.55-7.49 (m, 3H), 7.40 (m, 1H),
7.36-7.31 (m, 3H), 7.29-7.23 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 134.1, 131.6, 131.4, 129.7, 129.5, 128.6, 128.5, 128.4,
125.0, 122.7, 90.5, 87.9; MS C14H9Cl 212(100, [M]þ), 176(26),
151(7), 106(9), 88(12).
1,10-(4,40-(Ethyne-1,2-diyl)bis(4,1-phenylene))diethanone (3r).8b
4-Bromoacetophenone (2r) (1.19 g, 6.00 mmol) was coupled with
1a to give 637 mg (2.43 mmol, 81%) of 3r and coupled with 1b to
give 598 mg (2.28 mmol, 76%) of 3r as a white solid after
chromatography: mp 198-200 °C; 1H NMR (300 MHz, CDCl3)
δ 7.96 (d, J = 8.7 Hz, 4H), 7.63 (d, J = 8.7 Hz, 4H), 2.63 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 197.2, 136.6, 131.8, 128.3,
127.5, 91.6, 26.6; MS C18H14O 262(100, [M]þ), 247(50), 232(70),
119(20).
2-Phenylethynylthiophene (7bo).28 Phenyl iodide (2b) (612 mg,
3.00 mmol) and 2-bromothiophene (2o) (489 mg, 3.00 mmol)
were coupled with 1a to give 404 mg (2.19 mmol, 73%) of 7ao as
a colorless oil after chromatography: 1H NMR (300 MHz,
CDCl3) δ 7.53-7.50 (m, 2H), 7.36-7.31 (m, 3H), 7.28-7.26
(m, 2H), 7.01-6.99 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
131.9, 131.4, 128.4, 128.3, 127.2, 127.1, 123.2, 122.9, 93.0, 82.6;
MS C12H8S 184(100, [M]þ), 152(20), 139(20), 92(10).
4,40-(Ethyne-1,2-diyl)dibenzaldehyde (3s).19 4-Bromoabenzal-
dehyde (2s) (1.11 g, 6.00 mmol) was coupled with 1a to give 682
mg (2.91 mmol, 97%) of 3s and coupled with 1b to give 583 mg
(2.49 mmol, 83%) of 3s as a white solid after chromatography:
mp 213-214 °C; 1H NMR (300 MHz, CDCl3) δ 10.0 (s, 2H), 7.90
(d, J = 8.1 Hz, 4H), 7.71 (d, J = 8.1 Hz, 4H); 13C NMR (75
MHz, CDCl3) δ 191.6, 136.1, 132.6, 129.9, 128.9, 92.4; MS
C16H10O 234(100, [M]þ), 205(15), 176(40), 151(15), 88(10).
1,2-Di(naphthalen-1-yl)ethyne (3t).19 1-Bromonaphthalene
(2t) (1.24 g, 6.00 mmol) was coupled with 1a to give 618 mg
(2.22 mmol, 74%) of 3t and coupled with 1b to give 676 mg (2.43
mmol, 81%) of 3t asa yellow solid after chromatography: mp
127-128 °C; 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 8.4 Hz,
2H), 7.91-7.87 (m, 6H), 7.66-7.48 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 133.3, 130.6, 128.9, 128.4, 126.9, 126.5, 126.3,
125.3, 121.1, 92.4; MS C22H14 278(100, [M]þ), 138(15).
1,2-Bis(3-chlorophenyl)ethyne (3u).8b 1-Bromo-3-chloroben-
zene (2u) (1.15 g, 6.00 mmol) was coupled with 1a to give 675 mg
(2.73 mmol, 91%) of 3u and coupled with 1b to give 660 mg (2.67
mmol, 89%) of 3u as a white solid after chromatography: mp
81-82 °C; 1H NMR (300 MHz, CDCl3) δ 7.51 (m, 2H), 7.40 (m,
2H), 7.34-7.25 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 134.3,
131.5, 129.8, 129.6, 128.8, 124.5, 89.0; MS C14H8Cl XXXX(100,
[M]þ), 176(50), 150(10), 123(10), 88(10).
General Procedure for the Synthesis of Unsymmetrical Diary-
lalkynes Using Propiolic Acid. Pd(PPh3)2Cl2 (105 mg, 0.15
mmol), 1,4-bis(diphenylphosphino)butane (128 mg, 0.30 mmol),
aryl iodide (2b) (3.0 mmol), aryl bromide (3.0 mmol), and
propiolic acid (1a) (212 mg, 3.0 mmol) were combined with
DBU (913 mg, 6.0 mmol) in a small, round-bottomed flask.
DMSO (15.0 mL) was added, and the flask was sealed with a
septum. The resulting mixture was placed in an oil bath at 50 °C
for 5 h. Then the reaction temperature was increased to 80 °C,
and the mixture was stirred for 6 h. The reaction was poured into
25 mL of saturated aqueous ammonium chloride and extracted
with Et2O (4 ꢀ 20 mL). The combined ether extracts were
3-Phenylethynylpyridine (7bp).29 Phenyl iodide (2b) (612 mg,
3.00 mmol) and 3-bromopyridine (2p) (474 mg, 3.00 mmol) were
coupled with 1a to give 350 mg (1.95 mmol, 65%) of 7ap as a
yellow oil after chromatography: 1H NMR (300 MHz, CDCl3) δ
8.77 (d, J = 2.1 Hz, 1H), 8.54 (dd, J = 1.8 Hz, 3 Hz, 1H), 7.80
(dt, J = 8.1 Hz, 1.8 Hz, 1H), 7.57-7.52 (m, 2H), 7.38-7.34 (m,
3H), 7.27 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 152.2, 148.5,
138.4, 131.7, 128.8, 128.4, 123.0, 122.5, 120.4, 92.6, 85.9; MS
C13H8N 179(100, [M]þ), 151(15), 126(15), 76(15).
2-( p-Tolylethynyl)pyridine (7vw).30 4-Iodotoluene (2v) (654
mg, 3.00 mmol) and 2-bromopyridine (2w) (474 mg, 3.00 mmol)
were coupled with 1a to give 516 mg (2.67 mmol, 89%) of 7vw as
a yellow solid after chromatography: mp 63.6 °C; 1H NMR (300
MHz, CDCl3) δ 8.59-8.62 (m, 1H), 7.65 (td, J = 7.8, 1.8 Hz,
1H), 7.48-7.52 (m, 3H), 7.15-7.23 (m, 3H), 2.37 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 150.26, 143.89, 139.48, 136.35,
132.19, 129.41, 127.28, 122.81, 119.42, 89.78, 88.35, 21.82; MS
C14H11N 193(100, [M]þ), 165(10), 115(10).
3-( p-Tolylethynyl)pyridine (7vp).31 4-Iodotoluene (2v) (654
mg, 3.00 mmol) and 3-bromopyridine (2p) (474 mg, 3.00 mmol)
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6250 J. Org. Chem. Vol. 75, No. 18, 2010

Park et al.
JOCArticle
were coupled with 1a to give 470 mg (2.43 mmol, 81%) of 7vp as
a colorless oil after chromatography: 1H NMR (300 MHz,
CDCl3) δ 8.75 (d, J = 1.8 Hz, 1H), 8.52 (dd, J = 4.8, 1.5 Hz,
1H), 7.79 (dt, J = 8.1, 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.26
(dd, J = 8.1, 5.1 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H), 2.37 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 152.15, 148.31, 138.97, 138.26,
131.52, 129.15, 122.93, 120.61, 119.38, 92.82, 85.28, 21.49; MS
C14H11N 193(100, [M]þ), 165(15), 139(10).
J = 1.5 Hz, 1H), 8.56 (dd, J = 4.8, 1.5 Hz, 1H), 7.82 (m, J = 8.1,
1.8 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.71-7.30 (m, 4H), 2.54 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 151.99, 148.17, 140.17, 138.13,
131.84, 129.45, 128.73, 125.56, 122.90, 122.15, 120.58, 91.51, 89.69,
20.61; MS C14H11N 193(100, [M]þ), 165(15), 139(10).
Acknowledgment. This work was supported by the Korea
Research Foundation Grant funded by the Korean Government
(MOEHRD, Basic Research Promotion Fund) (KRF-2008-
314-D00070).
3-(o-Tolylethynyl)pyridine (7fp).32 2-Iodotoluene (2f) (654 mg,
3.00 mmol) and 3-bromopyridine (2p) (474 mg, 3.00 mmol) were
coupled with 1a to give 429 mg (2.22 mmol, 74%) of 7fp as a yellow
oil after chromatography: 1H NMR (300 MHz, CDCl3) δ 8.80 (d,
Supporting Information Available: Copies of spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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