Synthesis of ethyl arylpropiolates through palladium-catalyzed cross-coupling reactions of aryl iodides with in situ generated lithium tetrakis(ethoxycarbonylethynyl)indates

Article abstract of DOI:10.1055/s-0033-1339110

An efficient synthetic method to access ethyl arylpropiolates has been developed; it involves a palladium-catalyzed cross-coupling reaction between a wide range of aryl iodides and lithium tetrakis(ethoxycarbonylethynyl)indates (0.35 equiv) generated in situ from indium trichloride and alkynides obtained from ethyl propiolate and n-butyllithium. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339110

SPECIAL TOPIC
▌2305
SSpyecnialtThopeicsis of Ethyl Arylpropiolates through Palladium-Catalyzed
Cross-Coupling Reactions of Aryl Iodides with In Situ Generated Lithium
Tetrakis(ethoxycarbonylethynyl)indates
Synthesis of Ethyl Arylpropiolates
Youngchul Park, Dongjin Kang, Woo Hyung Jeon, Taekyu Ryu, Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
Fax +82(33)2595667; E-mail: phlee@kangwon.ac.kr
Received: 21.02.2014; Accepted after revision: 13.04.2014
addition–
Abstract: An efficient synthetic method to access ethyl arylpropio-
lates has been developed; it involves a palladium-catalyzed cross-
coupling reaction between a wide range of aryl iodides and lithium
tetrakis(ethoxycarbonylethynyl)indates (0.35 equiv) generated in
situ from indium trichloride and alkynides obtained from ethyl
propiolate and n-butyllithium.
elimination
R1
LG CO2R2
R2 = alkyl
R1
CO2R2
Met
(1)
+
R1 = alkyl, aryl
cat.
Ar-X
+
CO2R
Ar
Ar
CO2R
(2)
(3)
Sonogashira reaction
Key words: cross-coupling,
palladium,
indium,
lithium
tetrakis(ethoxycarbonylethynyl)indate, propiolates, catalysis
cat.
Ar-I
R
+ ZnX
R
Negishi reaction
Alkynes are highly useful functional groups found in bio-
active compounds, synthetic intermediates, and electroor-
ganic materials.1 In particular, alkyl 3-arylpropiolates
have been receiving attention as important reagents due to
their usability in various organic reactions such as
Michael and Diels–Alder reactions.2 In general, synthetic
methods available to access alkyl 3-arylpropiolates may
be divided into several categories (Scheme 1), such as ad-
dition followed by elimination reaction of alkynides with
alkoxyformate derivatives (1)3 and palladium-catalyzed
cross-coupling reaction of electrophilic coupling partners
with alkoxypropiolates known as the Sonogashira reac-
tion (2).4 Although the Sonogashira reaction has been rec-
ognized as a highly practical method for the synthesis of
arylalkynes, the cross-coupling reaction of aryl halides
with alkoxypropiolates does not give good results for
alkynes bearing electron-withdrawing groups.5 To over-
come the limitation of the cross-coupling reactions, Neg-
ishi and co-workers developed an efficient palladium-
catalyzed cross-coupling reaction of aryl halides with
alkynylzinc derivatives generated in situ from electron-
deficient terminal alkynes (3).6 In addition, palladi-
um/copper-catalyzed arylation of electron-deficient
alkynes by using diaryliodonium salts has been reported
(4).7 Recently, copper- or palladium-catalyzed Sonogas-
hira-type coupling of arylboronic acids with terminal
alkynes proved to be an efficient synthetic method for eth-
yl arylpropiolates (5).8 Nevertheless, efficient synthetic
methods to prepare ethyl arylpropiolates are still required
to overcome shortcomings such as excessive use of re-
agents and narrow scope of aryl halides in the previously
reported results.
R = CO2Me, CO-n-C5H11, COCy, COPh
cat. Pd/Cu
Ph2IOTf
(4)
(5)
Ar
Ar
CO2R
CO2R
+
CO2R
cat. Cu or Pd
ArB(OH)2
+
CO2R
Scheme 1 Synthetic methods providing alkyl arylpropiolates
Recently, we developed a palladium-catalyzed decarbox-
ylative cross-coupling reaction9 and C–H alkynylation in-
volving propiolic acid10 and a multitude of palladium-
catalyzed cross-coupling reactions using organoindium
reagents.11 Stimulated by these results, we envisioned that
in situ generated lithium tetrakis(ethoxycarbonylethyn-
yl)indates could react with electrophiles through palladi-
um-catalyzed cross-coupling reactions to produce ethyl
arylpropiolates. Herein we report an atom-economical
synthetic method for accessing ethyl arylpropiolates
through palladium-catalyzed cross-coupling reactions of
aryl iodides with lithium tetrakis(ethoxycarbonyl-
ethynyl)indate (0.35 equiv) generated in situ from indium
trichloride and the alkynide obtained from ethyl propio-
late and n-butyllithium (Scheme 2).
cat. Pd
Ar
CO2Et
ArI
+
LiIn
CO2Et
4
Scheme 2 Cross-coupling reaction using lithium tetrakis(ethoxycar-
bonylethynyl)indate
First, on the basis of the reported synthetic methods for
the in situ generation of tri(organo)indiums12 and metal
tetra(organo)indates,13 lithium tetrakis(ethoxycarbonyl-
ethynyl)indate was efficiently generated in situ from the
reaction of indium trichloride with lithium ethoxycarbon-
SYNTHESIS 2014, 46, 2305–2311
Advanced online publication: 28.05.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339110; Art ID: SS-2014-C0123-ST
© Georg Thieme Verlag Stuttgart · New York

2306
Y. Park et al.
SPECIAL TOPIC
ylethynide, which was obtained from ethyl propiolate and fluoromethylphenyl)phosphine (16 mol%), tris(4-
n-butyllithium (Scheme 3).
methoxyphenyl)phosphine (16 mol%), and 1,3-bis(diphe-
nylphosphino)propane (DPPP; 8 mol%), the desired cou-
pling product was not produced (entries 2–5). However,
when the tris(dibenzylideneacetone)dipalladium(0)–chlo-
roform complex (2 mol%) and (oxydi-2,1-phenyl-
ene)bis(diphenylphosphine) (DPEphos; 8 mol%) were
used, ethyl 3-(4-ethoxycarbonylphenyl)propiolate (5a)
was obtained in 26% yield (entry 6). The use of 4,5-bis(di-
phenylphosphino)-9,9-dimethylxanthene (Xantphos; 8
mol%) resulted in a slight increase in yield (30%; entry 7).
Treatment of ethyl 4-iodobenzoate (4b; 1 equiv) with
lithium tetrakis(ethoxycarbonylethynyl)indate (3; 0.35
equiv) gave the best result in the presence of the tris(di-
benzylideneacetone)dipalladium(0)–chloroform complex
(2 mol%) and Xantphos (8 mol%); 5a is produced in 88%
yield in tetrahydrofuran at 80 °C after three hours (entry
9). These results indicate that lithium tetrakis(ethoxycar-
bonylethynyl)indate (3) is more reactive than (ethoxycar-
bonylethynyl)zinc chloride and (ethoxycarbonylethyn-
yl)tributyltin chloride, because these reagents gave the
corresponding alkynes in 30% and 6% yields, respectively
(see the Supporting Information).4d,5b,6 When lithium tet-
rakis(ethoxycarbonylethynyl)indate (3; 0.30 equiv) was
used, the cross-coupling reaction was not completed, and
5a was produced in 75% yield together with 4b (17%)
(entry 10).
THF
n-BuLi
CO2Et
+
+
n-C4H10
Li
CO2Et
–78 °C
10 min
1
2
InCl3
1) –78 °C, 10 min
2) –78 to 25 °C
10 min
THF
LiCl
LiIn
CO2Et
4
+
3
Scheme 3 In situ generation of lithium tetrakis(ethoxycarbonyl-
ethynyl)indate
We initiated our studies with the reaction of ethyl 4-bro-
mobenzoate (4a) with in situ generated lithium tetra-
kis(ethoxycarbonylethynyl)indate (3) in the presence of a
palladium catalyst in tetrahydrofuran at 80 °C (Table 1).
First, the catalytic activity of a variety of palladium cata-
lysts was investigated. [1,1′-Bis(diphenylphosphino)fer-
rocene]dichloropalladium(II) [Pd(dppf)Cl2; 4 mol%] was
not effective (entry 1). Although the tris(dibenzylidene-
acetone)dipalladium(0)–chloroform complex (2 mol%) as
catalyst was used in the presence of a wide range of li-
gands such as triphenylphosphine (16 mol%), tris(4-tri-
Table 1 Optimization of Palladium-Catalyzed Cross-Coupling Reactions Using Lithium Tetrakis(ethoxycarbonylethynyl)indatea
CO2Et
X
cat.
+
LiIn
CO2Et
4
EtO2C
EtO2C
4a X = Br
4b X = I
3
5a
Entry
X
Cat. (mol%)
Ligand (mol%)
Time (h)
Yield (%)b
1
2
Br
Br
Br
Br
Br
Br
Br
I
Pd(dppf)Cl2 (4)
none
24
24
24
24
24
24
24
12
3
0
Pd2dba3·CHCl3 (2)
Pd2dba3·CHCl3 (2)
Pd2dba3·CHCl3 (2)
Pd2dba3·CHCl3(2)
Pd2dba3·CHCl3 (2)
Pd2dba3·CHCl3(2)
Pd(dppf)Cl2 (4)
Ph3P (16)
0
3
(4-F3CC6H4)3P (16)
(4-MeOC6H4)3P (16)
DPPP (8)c
0
4
0
5
0
6
DPEphos (8)d
Xantphos (8)e
none
26
7
30
8
60
9
I
Pd2dba3·CHCl3 (2)
Pd2dba3·CHCl3 (4)
Xantphos (8)e
Xantphos (8)e
88
10
I
4
75(17)f
a Reaction conditions: 4 (0.3 mmol), 3 (0.105 mmol, 0.35 equiv), THF, 80 °C (unless otherwise noted).
b Isolated yield.
c DPPP = 1,3-bis(diphenylphosphino)propane.
d DPEphos = (oxydi-2,1-phenylene)bis(diphenylphosphine).
e Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
f Reaction conditions: 4b (0.3 mmol), 3 (0.09 mmol, 0.30 equiv), THF, 80 °C. Number in parentheses indicates recovered yield of 4b.
Synthesis 2014, 46, 2305–2311
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Ethyl Arylpropiolates
2307
When lithium tetrakis(ethoxycarbonylethynyl)indate (3; 84% yield. The present method worked equally well with
0.35 equiv) reacted with phenyl iodide (Scheme 4), the 3,5-dimethyl-1-iodobenzene, resulting in the production
cross-coupling reaction was complete, producing ethyl of 5e in 85% yield. 1-Iodonaphthalene was treated with 3
phenylpropiolate (5b) in 83% yield, after three hours (1). to afford ethyl 3-(1-naphthyl)propiolate 5f in 82% yield.
However, use of tris(ethoxycarbonylethynyl)indium (0.40
However, 1-naphthyl triflate was less reactive, producing
equiv) gave 5b in 80% yield after eight hours (2). These
5f in 42% yield after 24 hours (Scheme 5). Aryl iodides
results indicate that the type of indium reagent is different
bearing a strongly electron-donating methoxy group on
in these two reactions. Accordingly, in situ generation of
the phenyl ring turned out to be compatible with the reac-
lithium tetrakis(ethoxycarbonylethynyl)indate was as-
tion conditions. In particular, 2-iodoanisole was smoothly
converted into the desired propiolate 5g in 89% yield de-
spite steric repulsion. Also, 4-iodoanisole worked equally
well. The cross-coupling reaction between electron-defi-
sumed in the present reaction. In general, ate complexes
are more reactive than the corresponding neutral organo-
metallic reagents.13
cient aryl iodides and 3 proceeded efficiently, affording
the desired ethyl arylpropiolates. 1-Bromo-4-iodobenzene
cat. Pd2dba3·CHCl3
+
LiIn
CO2Et
4
PhI
Ph
Ph
CO2Et
(1)
(2)
Xantphos, THF
was selectively subjected to the coupling reaction to pro-
vide ethyl 3-(4-bromophenyl)propiolate (5j) in 82% yield.
The tolerance of the bromo group on the phenyl ring is es-
pecially important, as it potentially allows subsequent cat-
alytic cross-couplings. In addition, functional groups
commonly used in organic synthesis were tolerated. Sub-
strates possessing ketone and ester groups all smoothly re-
acted with 3 to afford ethyl arylpropiolates 5k, 5l, and 5m
in good yields. These results indicate that the present
cross-coupling reactions were not largely affected by ei-
ther electronic or steric effects on the aryl ring. We were
pleased to obtain the desired coupling products from sub-
strates containing heterocyclic moieties. For example, 2-
iodopyridine and 2-iodothiophene were treated with 3 to
produce ethyl 3-(2-pyridyl)propiolate (5n) and ethyl 3-(2-
thienyl)propiolate (5o) in 75% and 86% yields, respec-
tively. Encouraged by this result, we applied the present
3
5b 83%, 3 h
0.35 equiv
cat. Pd2dba3·CHCl3
Xantphos, THF
+
In
CO2Et
PhI
CO2Et
5b 80%, 8 h
3
0.40 equiv
Scheme 4
To establish the efficiency and scope of the present meth-
od, we applied this catalytic system to the reactions of a
number of aryl iodides with lithium tetrakis(ethoxycar-
bonylethynyl)indate (3) (Scheme 5). 2-Iodotoluene un-
derwent the palladium-catalyzed cross-coupling reaction
to give ethyl 3-(2-methylphenyl)propiolate (5c) in 90%
yield. The sterically hindered 2-iodo-m-xylene was not to-
tally ineffective. Subjecting 1-n-butyl-4-iodobenzene to
palladium catalysis provided the coupling product 5d in
cat. Pd2dba3·CHCl3
+
LiIn
CO2Et
4
ArI
Ar
CO2Et
Xantphos, THF
4
3
5
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
n-Bu
CO2Et
5b 83%, 3 h
5c 90%, 1.5 h
5d 84%, 1 h
5e 85%, 1.5 h
5f 82%, 4 h; 42%,a 24 h
OMe
MeO
O
CO2Et
CO2Et MeO
5h 82%, 2.5 h
CO2Et Br
5i 85%, 2.5 h
CO2Et
5j 82%, 2 h
5g 89%, 1.5 h
5k 80%, 4 h
CO2Et
EtO2C
CO2Et
5n 75%, 2 h
CO2Et
CO2Et EtO2C
5m 88%, 2 h
CO2Et
5a 88%, 3 h
CO2Et
5o 86%, 2 h
N
S
5l 80%, 4 h
EtO2C
CO2Et
5p 85%,b 1.5 h
Scheme 5 Palladium-catalyzed cross-coupling reactions of indate 3 with electrophiles. Reagents and conditions: 3 (0.35 equiv), Pd2dba3·CH-
Cl3 (2 mol%), Xantphos (8 mol%), THF, 80 °C. a 1-Naphthyl triflate was used. b Indate 3 (0.7 equiv) was used.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2305–2311

2308
Y. Park et al.
SPECIAL TOPIC
IR (film): 3054, 2987, 1711, 1422, 1271, 1195, 896, 716 cm–1.
method to dihalogenated aromatic compounds to obtain
disubstituted benzene. Gratifyingly, the reaction of 1,4-di-
iodobenzene with 0.70 equiv of lithium tetrakis(ethoxy-
carbonylethynyl)indate 3 produced 1,4-bis(ethoxycar-
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.3 Hz, 2 H), 7.65 (d,
J = 8.3 Hz, 2 H), 4.39 (q, J = 7.1 Hz, 2 H), 4.32 (q, J = 7.1 Hz, 2 H),
1.42–1.35 (m, 6 H).
bonylethynyl)benzene (5p) in 85% yield, indicating that 13C NMR (100 MHz, CDCl3): δ = 166.0, 154.1, 133.1, 132.4, 130.0,
124.4, 85.0, 83.0, 62.7, 61.8, 14.7, 14.5.
ethoxycarbonylethynyl group attached to indium was ef-
fectively transformed to electrophiles (Scheme 5).
HRMS (EI): m/z [M + H]+ calcd for C14H14O4: 246.0892; found:
246.0894.
In conclusion, we have developed an efficient palladium-
catalyzed cross-coupling reactions of aryl iodides with
lithium tetrakis(ethoxycarbonylethynyl)indate (3; 0.35
equiv), generated in situ from indium trichloride and the
alkynide obtained from ethyl propiolate and n-butyllithi-
um, producing ethyl arylpropiolates in good to excellent
yields. These results indicate that the ethoxycarbonylethyn-
yl group attached to indium was effectively transformed
to an electrophile. Because alkynes with electron-with-
drawing groups are generally poor nucleophiles in the
Sonogashira reaction, these results afford good options
and tools for C–C bond-forming reactions.
Ethyl 3-Phenylpropiolate (5b)14
Yield: 83% (43.4 mg); colorless oil; Rf = 0.3 (EtOAc–hexane, 1:20).
IR (film): 3054, 2987, 2305, 2212, 1705, 1421, 1266, 896, 742 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.60–7.57 (m, 2 H), 7.47–7.42 (m,
1 H), 7.39–7.35 (m, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.5, 133.4, 131.0, 129.0, 120.0,
86.4, 81.1, 62.5, 14.5.
Ethyl 3-o-Tolylpropiolate (5c)
Yield: 90% (51.0 mg); colorless oil; Rf = 0.4 (EtOAc–hexane, 1:20).
IR (film) 3054, 2987, 2305, 1704, 1422, 1260, 896, 699 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 7.61 Hz, 1 H), 7.33
(td, J = 7.6, 1.2 Hz, 1 H), 7.23 (d, J = 7.7 Hz, 1 H), 7.18 (t, J = 7.6
Hz, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 2.49 (s, 3 H), 1.36 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 154.6, 142.6, 133.8, 131.0, 130.1,
126.2, 120.0, 85.5, 84.8, 62.4, 21.0, 14.5.
Reactions were carried out in flame-dried test tubes under a nitro-
gen atmosphere. Pd2dba3·CHCl3 and Xantphos were purchased and
were used as received. Commercially available reagents were used
without purification. THF was dried over Na and benzophenone.
All reaction mixtures were stirred magnetically and were monitored
by TLC (silica gel pre-coated glass plates, visualized with UV light
and then developed by using either I2 or a solution of anisaldehyde).
Flash column chromatography was carried out on silica gel (230–
400 mesh). 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded on a Bruker DPX FR (400 MHz) NMR spectrometer.
CDCl3 was used as the solvent, and chemical shift values (δ) are re-
ported relative to the residual signals of this solvent (δ = 7.26 for 1H
and δ = 77.2 for 13C). IR spectra were recorded on a Jasco FT/IR 460
Plus FT-IR spectrophotometer; samples were prepared as either a
thin film pressed between two NaCl plates or as a solid suspended
in a KBr disk. Mass spectra were obtained from the KBSI using a
VG Autospec Ultima high-resolution mass spectrometer. Melting
points were determined in open capillary tubes by using an Electro-
thermal 9100 apparatus.
HRMS (EI): m/z [M + H]+ calcd for C12H12O2: 188.0837; found:
188.0837
Ethyl 3-(4-Butylphenyl)propiolate (5d)
Yield: 84% (58.0 mg); colorless oil; Rf = 0.4 (EtOAc–hexane, 1:15).
IR (film): 3054, 2987, 1703, 1422, 1259, 1176, 721 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.2 Hz, 2 H), 7.18 (d,
J = 8.2 Hz, 2 H), 4.29 (q, J = 7.1 Hz, 2 H), 2.62 (t, J = 7.7 Hz, 2 H),
1.63–1.55 (m, 2 H), 1.37–1.31 (m, 5 H), 0.92 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.6, 146.6, 133.4, 129.1, 117.1,
87.1, 80.8, 62.4, 36.1, 33.6, 22.7, 14.5, 14.3.
HRMS (EI): m/z [M + H]+ calcd for C15H18O2: 230.1307; found:
230.1308.
Lithium Tetrakis(ethoxycarbonylethynyl)indate (3)
A solution of 1.6 M n-BuLi in hexane (0.42 mmol) was slowly add-
ed to a solution of ethyl propiolate (1; 0.42 mmol, 43 μL) in THF
(0.5 mL) at –78 °C under a N2 atmosphere. After being stirred for
10 min, this mixture was added to a solution of InCl3 (23.3 mg,
0.105 mmol) in THF (0.5 mL) at –78 °C. The mixture was stirred
for 10 min, and then the cooling bath was removed, and the reaction
mixture was warmed to r.t. over 10 min.
Ethyl 3-(3,5-Dimethylphenyl)propiolate (5e)
Yield: 85% (52.0 mg); colorless oil; Rf = 0.5 (EtOAc–hexane, 1:20).
IR (film): 3054, 2987, 1704, 1265, 1157, 855, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.21 (s, 2 H), 7.07 (s, 2 H), 4.29
(q, J = 7.1 Hz, 2 H), 2.30 (s, 6 H), 1.35 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.6, 138.6, 133.0, 131.1, 119.6,
87.1, 80.5, 62.4, 21.4, 14.5.
Ethyl 3-(4-Ethoxycarbonylphenyl)propiolate (5a); Typical Pro-
cedure
HRMS (EI): m/z [M + H]+ calcd for C13H14O2: 202.0994; found:
A mixture of Pd2dba3·CHCl3 (6.2 mg, 2 mol%), Xantphos (14.0 mg,
8 mol%), and ethyl 4-iodobenzoate (50.5 μL, 0.3 mmol) in THF (0.5
mL) was stirred for 10 min at r.t. This mixture was added to a 0.105
M solution of lithium tetrakis(ethoxycarbonylethynyl)indate in an-
hydrous THF (3; 0.105 mmol) under a N2 atmosphere. The reaction
mixture was heated at reflux for 3 h. After cooling to r.t., the reac-
tion mixture was quenched with sat. aq NH4Cl (20 mL). The aque-
ous layer was extracted with CH2Cl2 (3 × 20 mL), and the combined
organic phases were sequentially washed with brine (3 × 20 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:20) to give 5a.
202.0995.
Ethyl 3-(1-Naphthyl)propiolate (5f)1
Yield: 82% (55.2 mg); colorless oil; Rf = 0.4 (EtOAc–hexane, 1:15).
IR (film): 3054, 2987, 1704, 1265, 1207, 804, 742 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.4 Hz, 1 H), 7.94 (d,
J = 8.4 Hz, 1 H), 7.86 (t, J = 8.6 Hz, 2 H), 7.65–7.61 (m, 1 H), 7.56
(td, J = 8.1, 1.1 Hz, 1 H), 7.46 (dd, J = 8.1, 7.4 Hz, 1 H), 4.36 (q, J =
7.1 Hz, 2 H), 1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.6, 134.1, 133.4, 131.7, 128.9,
128.0, 127.3, 126.2, 125.5, 117.6, 85.8, 84.8, 62.6, 14.6.
Yield: 88% (65.0 mg); white solid; mp 38–40 °C; Rf = 0.3 (EtOAc–
hexane, 1:20).
Synthesis 2014, 46, 2305–2311
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Ethyl Arylpropiolates
2309
Ethyl 3-(2-Methoxyphenyl)propiolate (5g)14
Yield: 89% (54.5 mg); colorless oil; Rf = 0.2 (EtOAc–hexane, 1:15).
Ethyl 3-(3-Ethoxycarbonylphenyl)propiolate (5m)
Yield : 88% (65.0 mg); colorless oil; Rf = 0.3 (EtOAc–hexane,
1:20).
IR (film): 3054, 2986, 1703, 1492, 1421, 1259, 895, 698 cm–1.
IR (film): 3054, 2987, 1708, 1639, 1304, 1191, 896, 746 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 7.6, 1.71 Hz, 1 H),
7.43–7.38 (m, 1 H), 6.96–6.89 (m, 2 H), 4.30 (q, J = 7.1 Hz, 2 H),
3.90 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.0, 154.6, 135.3, 132.7, 120.9,
111.2, 109.2, 85.0, 83.5, 62.4, 56.2, 14.5.
1H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 8.12 (dt, J = 7.9, 1.3
Hz, 1 H), 7.75 (dt, J = 7.7, 1.2 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H),
4.39 (q, J = 7.1 Hz, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 1.43–1.35 (m, 6
H).
13C NMR (100 MHz, CDCl3): δ = 165.7, 154.2, 137.1, 134.4, 131.9,
131.5, 129.2, 120.4, 85.1, 81.6, 62.6, 61.8, 14.7, 14.5.
Ethyl 3-(3-Methoxyphenyl)propiolate (5h)15
Yield: 82% (50.2 mg); colorless oil; Rf = 0.2 (EtOAc–hexane, 1:20).
HRMS (EI): m/z [M + H]+ calcd for C14H14O4: 246.0892; found:
246.0894.
IR (film): 3054, 2987, 2305, 2221, 1705, 1422, 1265, 1234, 896,
741 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.27 (t, J = 7.9 Hz, 1 H), 7.18 (d,
J = 7.5 Hz, 1 H), 7.09 (dd, J = 2.5, 1.3 Hz, 1 H), 7.01–6.98 (m, 1 H),
4.30 (q, J = 7.1 Hz, 2 H), 3.80 (s, 3 H), 1.35 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 154.4, 130.1, 125.9, 121.0,
117.9, 117.8, 86.4, 80.8, 62.5, 55.7, 14.5.
Ethyl 3-(2-Pyridyl)propiolate (5n)18
Yield: 75% (40.0 mg); pale yellow oil; Rf = 0.3 (EtOAc–hexane,
1:5).
IR (film): 3054, 2987, 1710, 1422, 1257, 1206, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.66 (d, J = 5.1 Hz, 1 H), 7.73 (td,
J = 7.5, 1.6 Hz, 1 H), 7.60 (dd, J = 6.7, 0.9 Hz, 1 H), 7.38–7.34 (m,
1 H), 4.32 (q, J = 7.2 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 3 H)
13C NMR (100 MHz, CDCl3): δ = 153.9, 150.9, 141.0, 136.7, 128.9,
125.0, 84.1, 79.6, 62.7, 14.4.
Ethyl 3-(4-Methoxyphenyl)propiolate (5i)16
Yield: 85% (52.0 mg); colorless oil; Rf = 0.2 (EtOAc–hexane, 1:15).
IR (film): 3054, 2986, 1701, 1421, 1266, 1168, 739 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54 (dt, J = 9.5, 2.3 Hz, 2 H), 6.88
(dt, J = 9.3, 2.3 Hz, 2 H), 4.29 (q, J = 7.1 Hz, 2 H), 3.83 (s, 3 H),
1.35 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.9, 154.7, 135.3, 114.7, 111.8,
87.3, 80.5, 62.3, 55.8, 14.5.
Ethyl 3-(2-Thienyl)propiolate (5o)19
Yield: 86% (46.5 mg); pale yellow oil; Rf = 0.4 (EtOAc–hexane,
1:10).
IR (film): 3054, 2986, 2212, 1701, 1421, 1174, 896, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.49 (dd, J = 3.6, 0.9 Hz, 1 H),
7.46 (dd, J = 5.0, 0.9 Hz, 1 H), 7.05 (dd, J = 5.1, 3.7 Hz, 1 H), 4.30
(q, J = 7.1 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H)
13C NMR (100 MHz, CDCl3): δ = 154.3, 136.9, 131.5, 127.9, 119.8,
85.3, 80.4, 62.5, 14.5.
Ethyl 3-(4-Bromophenyl)propiolate (5j)
Yield: 82% (62.3 mg); yellow oil; Rf = 0.4 (EtOAc–hexane, 1:20).
IR (film): 3054, 2986, 1707, 1422, 1272, 1072, 1012, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.5 Hz, 2 H), 7.44 (d,
J = 8.5 Hz, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.2, 134.7, 132.4, 125.8, 119.0,
85.1, 82.0, 62.6, 14.5.
HRMS (EI): m/z [M + H]+ calcd for C11H9BrO2: 251.9786; found:
1,4-Bis(ethoxycarbonylethynyl)benzene (5p)17
A solution of 1.6 M n-BuLi in hexane (0.84 mmol) was slowly add-
ed to a solution of ethyl propiolate (1; 0.84 mmol, 85 μL) in THF
(0.5 mL) at –78 °C under a N2 atmosphere. After being stirred for
10 min, this mixture was added to a solution of InCl3 (46.5 mg, 0.21
mmol) in THF (0.5 mL) at –78 °C. The mixture was stirred for 10
min, and then the cooling bath was removed, and the reaction mix-
ture was warmed to r.t. over 10 min. A mixture of Pd2dba3·CHCl3
(6.2 mg, 2 mol%), Xantphos (14.0 mg, 8 mol%) and 1,4-diiodoben-
zene (99.0 mg, 0.3 mmol) in THF (0.5 mL) was stirred for 10 min
at r.t. This mixture was added to a 0.21 M solution of lithium tetra-
kis(ethoxycarbonylethynyl)indate in anhydrous THF (3; 0.21
mmol) under a N2 atmosphere. The reaction mixture was heated at
reflux for 1.5 h. After cooling to r.t., the reaction mixture was
quenched with sat. aq NH4Cl (20 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 20 mL), and the combined organic phases
were sequentially washed with brine (3 × 20 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, EtOAc–hexane,
1:20) to give 5p.
251.9785.
Ethyl 3-(4-Acetylphenyl)propiolate (5k)17
Yield: 80% (52.0 mg); pale yellow solid; mp 82–83.5 °C; Rf = 0.3
(EtOAc–hexane, 1:10).
IR (film): 3054, 2986, 2305, 1707, 1688, 1422, 1265, 739 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.3 Hz, 2 H), 7.68 (d,
J = 8.3 Hz, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 2.62 (s, 3 H), 1.37 (t, J =
7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 197.4, 154.1, 138.4, 133.4, 128.7,
124.7, 84.8, 83.3, 62.8, 27.1, 14.5.
Ethyl 3-(2-Ethoxycarbonylphenyl)propiolate (5l)
Yield: 80% (59.0 mg); colorless oil; Rf = 0.2 (EtOAc–hexane, 1:20).
IR (film): 3054, 2987, 2305, 1706, 1422, 1264, 1195, 743 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.05–8.02 (m, 1 H), 7.70–7.67 (m,
1 H), 7.56–7.49 (m, 2 H), 4.43 (q, J = 7.1 Hz, 2 H), 4.31 (q, J = 7.1
Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H).
Yield: 85% (69.0 mg); pale yellow solid; mp 90–92 °C; Rf = 0.2
(EtOAc–hexane, 1:30).
IR (film): 3054, 2987, 1706, 1257, 1196, 895, 755 cm–1.
13C NMR (100 MHz, CDCl3): δ = 165.9, 154.4, 135.5, 133.7, 132,2
131.2, 130.5, 120.5, 85.1, 84.9, 62.5, 62.1, 14.5.
HRMS (EI): m/z [M + H]+ calcd for C14H14O4: 246.0892; found:
1H NMR (400 MHz, CDCl3): δ = 7.58 (s, 4 H), 4.31 (q, J = 7.1 Hz,
4 H), 1.36 (t, J = 7.1 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 154.1, 133.3, 122.2, 84.8, 83.3,
62.7, 14.5.
246.0894.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2305–2311

2310
Y. Park et al.
SPECIAL TOPIC
(8) (a) Zou, G.; Zhu, J.; Tang, J. Tetrahedron Lett. 2003, 44,
8709. (b) Pan, C.; Luo, F.; Wang, W.; Ye, Z.; Cheng, J.
Tetrahedron Lett. 2009, 50, 5044. (c) Zhou, M.-B.; Wei, W.-
T.; Xie, Y.-X.; Lei, Y.; Li, J.-H. J. Org. Chem. 2010, 75,
5635.
(9) Kim, H.; Lee, P. H. Adv. Synth. Catal. 2009, 351, 2827.
(10) Kim, J.; Kang, D.; Yoo, E. J.; Lee, P. H. Eur. J. Org. Chem.
2013, 7902.
Acknowledgment
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIP) (No.
2014001403). This research was supported by Basic Science
Research Program through the National Research Foundation of
Korea (NRF) funded by the Ministry of Education
(2013R1A6A3A01058945).
(11) (a) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201.
(b) Lee, P. H.; Sung, S.-Y.; Lee, K.; Chang, S. Synlett 2002,
146. (c) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67,
8265. (d) Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem.
Int. Ed. 2002, 41, 3901. (e) Lee, P. H.; Seomoon, D.; Lee,
K.; Kim, S.; Kim, H.; Kim, H.; Shim, E.; Lee, M.; Lee, S.;
Kim, M.; Sridhar, M. Adv. Synth. Catal. 2004, 346, 1641.
(f) Lee, P. H.; Kim, S.; Lee, K.; Seomoon, D.; Kim, H.; Lee,
S.; Kim, M.; Han, M.; Noh, K.; Livinghouse, T. Org. Lett.
2004, 6, 4825. (g) Lee, P. H.; Shim, E.; Lee, K.; Seomoon,
D.; Kim, S. Bull. Korean Chem. Soc. 2005, 26, 157. (h) Lee,
P. H.; Lee, K. Angew. Chem. Int. Ed. 2005, 44, 3253. (i) Lee,
P. H.; Seomoon, D.; Lee, K. Org. Lett. 2005, 7, 343. (j) Lee,
P. H.; Lee, K.; Kang, Y. J. Am. Chem. Soc. 2006, 128, 1139.
(k) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem. Eur. J.
2007, 13, 5197. (l) Lee, J.-Y.; Lee, P. H. Bull. Korean Chem.
Soc. 2007, 28, 1929. (m) Seomoon, D.; Lee, P. H. J. Org.
Chem. 2008, 73, 1165. (n) Lee, J.-Y.; Lee, P. H. J. Org.
Chem. 2008, 73, 7413. (o) Lee, W.; Kang, Y.; Lee, P. H.
J. Org. Chem. 2008, 73, 4326. (p) Lee, K.; Lee, P. H.
Tetrahedron Lett. 2008, 49, 4302. (q) Kim, S.; Seomoon, D.;
Lee, P. H. Chem. Commun. 2009, 45, 1873. (r) Kim, H.; Lee,
K.; Kim, S.; Lee, P. H. Chem. Commun. 2010, 46, 6341.
(s) Mo, J.; Kim, S. H.; Lee, P. H. Org. Lett. 2010, 12, 424.
(t) Lee, P. H.; Mo, J.; Kang, D.; Eom, D.; Park, C.; Lee, C.-
H.; Jung, Y. M.; Hwang, H. J. Org. Chem. 2011, 76, 312.
(u) Mo, J.; Hwang, H.; Lee, P. H. Bull. Korean Chem. Soc.
2011, 32, 2911. (v) Lee, K.; Kim, H.; Mo, J.; Lee, P. H.
Chem. Asian J. 2011, 6, 2147. (w) Lee, D.; Ryu, T.; Park, Y.;
Lee, P. H. Org. Lett. 2014, 16, 1144.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
o
o
nr
i
References
(1) (a) Bohlmann, F.; Burkhart, F. T.; Zero, C. Naturally
Occurring Acetylenes; Academic Press: London, 1973.
(b) Hunstman, V. D. In The Chemistry of the Carbon–
Carbon Triple Bond; Patai, S., Ed.; Wiley-Interscience:
London, 1978, 553. (c) Martin, R. E.; Diederich, F. Angew.
Chem. Int. Ed. 1999, 38, 1350. (d) Siemsen, P.; Livingston,
R. C.; Diederich, F. Angew. Chem. Int. Ed. 2000, 39, 2632.
(e) Bunz, U. H. F. Chem. Rev. 2000, 100, 1605. (f) Tour, J.
M. Acc. Chem. Res. 2000, 33, 791. (g) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44,
4442.
(2) (a) Shen, T. Y.; Whiting, M. C. J. Chem. Soc. 1950, 1772.
(b) Obrecht, D. Helv. Chim. Acta 1991, 74, 27. (c) Obrecht,
D.; Zumbrunn, C.; Müller, K. J. Org. Chem. 1999, 64, 6182.
(d) Thiemann, T.; Fujii, H.; Ohira, D.; Arima, K.; Li, Y.;
Mataka, S. New J. Chem. 2003, 27, 1377. (e) Khalaf, A.;
Grée, D.; Abdallah, H.; Jaber, N.; Hachem, A.; Grée, R.
Tetrahedron 2011, 67, 3881. (f) Punner, F.; Schieven, J.;
Hilt, G. Org. Lett. 2013, 15, 4888.
(3) (a) Hendrickson, J. B.; Hussoin, M. S. Synthesis 1989, 217.
(b) Bottcher, A.; Becker, H.; Brunner, M.; Preiss, T.;
Henkelmann, J.; De Bakker, C.; Gleiter, R. J. Chem. Soc.,
Perkin Trans. 1 1999, 3555. (c) Dieter, R. K.; Lu, K.; Velu,
S. E. J. Org. Chem. 2000, 65, 8715. (d) Sarhan, A. E. A. O.;
Murakami, M.; Izumi, T. J. Heterocycl. Chem. 2002, 39,
691. (e) Furst, M.; Ruck-Braun, K. Synlett 2002, 1991.
(f) Stefani, H. A.; Cella, R.; Doerr, F. A.; de Pereira, C. M.
P.; Gomes, F. P.; Zeni, G. Tetrahedron Lett. 2005, 46, 2001.
(g) Gao, H.; Zhang, J. Chem. Eur. J. 2012, 18, 2777.
(4) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Moore, J. S. Acc. Chem. Res. 1997, 30,
402. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653,
46. (d) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103,
1979. (e) Tykwinski, R. R. Angew. Chem. Int. Ed. 2003, 42,
1566. (f) Marsden, J. A.; Haley, M. M. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, 317–
394. (g) Doucet, H.; Hierso, J.-C. Angew. Chem. Int. Ed.
2007, 46, 834. (h) Yin, L.; Liebscher, J. Chem. Rev. 2007,
107, 133.
(12) (a) Pérez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999,
1, 1267. (b) Gelman, D.; Schumann, H.; Blum, J.
Tetrahedron Lett. 2000, 41, 7555. (c) Pérez, I.; Sestelo, J. P.;
Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123, 4155.
(d) Hirashita, T.; Yamamura, H.; Kawai, M.; Araki, S.
Chem. Commun. 2001, 387. (e) Takami, K.; Yorimitsu, H.;
Shnokubo, H.; Matsubara, S.; Oshima, K. Org. Lett. 2001, 3,
1997. (f) Pena, M. A.; Perez, I.; Sestelo, J. P.; Sarandeses, L.
A. Chem. Commun. 2002, 2246. (g) Lehmann, U.; Awasthi,
S.; Minehan, T. Org. Lett. 2003, 5, 2405. (h) Pena, M. A.;
Sestelo, J. P.; Sarandeses, L. A. Synthesis 2003, 780. (i) Lee,
P. H.; Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103. (j) Pena,
M. A.; Sestelo, J. P.; Sarandeses, L. A. Synthesis 2005, 485.
(k) Barbero, M.; Cadamuro, S.; Dughera, S.; Giaveno, C.
Eur. J. Org. Chem. 2006, 4884. (l) Croix, C.; Balland-
Longeau, A.; Duchene, A.; Thibonnet, J. Synth. Commun.
2006, 36, 3261. (m) Pena, M. A.; Sestelo, J. P.; Sarandeses,
L. A. J. Org. Chem. 2007, 72, 1271. (n) Caeiro, J.; Sestelo,
J. P.; Sarandeses, L. A. Chem. Eur. J. 2008, 14, 741.
(o) Riveiros, R.; Saya, L.; Sestelo, J. P.; Sarandeses, L. A.
Eur. J. Org. Chem. 2008, 1959. (p) Lee, P. H.; Park, Y.;
Park, S.; Lee, E.; Kim, S. J. Org. Chem. 2011, 76, 760.
(q) Mo, J.; Eom, D.; Kim, S. H.; Lee, P. H. Chem. Lett. 2011,
40, 980.
(5) (a) Yoneda, N.; Matsuoka, S.; Miyaura, N.; Fukuhara, T.;
Suzuki, A. Bull. Chem. Soc. Jpn. 1990, 63, 2124.
(b) Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.;
Kondo, Y.; Yamanaka, H. Synthesis 1992, 746. (c) Kundu,
N. G.; Dasgupta, S. K. J. Chem. Soc., Perkin Trans. 1 1993,
2657. (d) Eckert, T.; Ipaktschi, J. Synth. Commun. 1998, 28,
327.
(6) (a) Negishi, E.-i.; Qian, M.; Zeng, F.; Anastasia, L.;
Babinski, D. Org. Lett. 2003, 5, 1597. (b) Anastasia, L.;
Negishi, E.-i. Org. Lett. 2001, 3, 3111.
(13) (a) Lee, P. H.; Lee, S. W.; Seomoon, D. Org. Lett. 2003, 5,
4963. (b) Lee, S. W.; Lee, K.; Seomoon, D.; Kim, S.; Kim,
H.; Kim, H. J. Org. Chem. 2004, 69, 4852. (c) Rodriguez,
D.; Sestelo, J. P.; Sarandeses, L. A. J. Org. Chem. 2004, 69,
(7) Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001, 3, 859.
Synthesis 2014, 46, 2305–2311
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
8136. (d) Kang, D.; Eom, D.; Kim, D. H.; Lee, P. H. Eur. J.
Synthesis of Ethyl Arylpropiolates
2311
(17) Walspurger, S.; Vasil’ev, A. V.; Sommer, J.; Pale, P.;
Org. Chem. 2010, 2330.
Savechenkov, Y. P.; Rudenko, A. P. Russ. J. Org. Chem.
2005, 41, 1485.
(18) Beveridge, R. E.; Arndtsen, B. A. Synthesis 2010, 1000.
(19) Kang, S.-K.; Yoon, S.-K.; Kim, Y.-M. Org. Lett. 2011, 3,
2697.
(14) Hapke, M.; Kral, K.; Spannenberg, A. Synthesis 2011, 642.
(15) Nie X.: Liu, S.; Zong, Y.; Sun, P.; Bao, J. J. Organomet.
Chem. 2011, 696, 1570.
(16) Li, Y.; Hesse, M. Helv. Chim. Acta 2003, 86, 310.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2305–2311