Thermoregulated copper-free Sonogashira coupling in water

Article abstract of DOI:10.1002/ejoc.201100367

The Sonogashira cross-coupling reaction between aryl halides and terminal alkynes was carried out smoothly in water over a thermoregulated ligand-palladium catalyst under copper-free conditions, resulting in good to excellent yields. The Sonogashira react

Full text of DOI:10.1002/ejoc.201100367

FULL PAPER
DOI: 10.1002/ejoc.201100367
Thermoregulated Copper-Free Sonogashira Coupling in Water
Ning Liu,[a] Chun Liu,*[a] Qiang Xu,[a] and Zilin Jin[a]
Keywords: Cross-coupling / Palladium / Green chemistry / Biphasic catalysis / Ligand effects
The Sonogashira cross-coupling reaction between aryl ha- those with an electron-donating group. Particularly, this pro-
lides and terminal alkynes was carried out smoothly in water
over a thermoregulated ligand–palladium catalyst under cop-
per-free conditions, resulting in good to excellent yields. The
Sonogashira reaction was sensitive to the electronic nature
of the substituents on the aryl halides. Aryl halides with an
electron-withdrawing group showed higher reactivity than
tocol could be applied to the synthesis of liquid crystals in-
volving trans-cyclohexyltolans. The products could be sepa-
rated from the reaction system easily by decanting, and the
catalyst was recovered in water and used directly for the next
run.
Introduction
we report efforts to carry out the Sonogashira cross-cou-
pling reaction successfully in the absence of both copper
and organic solvent.
The palladium-catalyzed Sonogashira cross-coupling re-
action is the most powerful method for sp2–sp carbon–
carbon bond formation between aryl or vinyl halides and
terminal alkynes.[1] Both aryl alkynes and conjugated en-
ynes find applications as pharmaceuticals, natural products,
and molecular organic materials.[2]
Thermomorphic systems offer an alternative approach
that facilitates catalyst recycling and thus has attracted con-
siderable attention.[16] Thermomorphic systems for the pal-
ladium-catalyzed Sonogashira reaction were reported by
the groups of Bergbreiter,[17] Chiba[18] and Lu.[19] However,
these methods require either copper co-catalyst or organic
co-solvent, and some suffer from limited substrate scope.
To the best of our knowledge, a thermoregulated ligand–
palladium catalyzed copper-free Sonogashira coupling of
aryl bromides in water has not been reported. Herein, we
report a thermoregulated Sonogashira coupling of aryl bro-
mides with terminal alkynes in the absence of both copper
and organic solvent.
Typical Sonogashira reactions are performed in the pres-
ence of a palladium/copper co-catalyst. The limitation of
this method is that copper acetylides generated in situ tend
to promote homocoupling of the terminal alkyne.[1d] There-
fore, a series of palladium/silver,[3] palladium/gold,[4] and
palladium-only[5] catalytic systems have been developed in
recent years. Another important area of the Sonogashira
reaction is the use of green solvents. In most cases, the Son-
ogashira reaction proceeds in organic solvents, however, de-
velopments in the use of environmentally benign solvents
for such a transformations have been reported in literature,
including the use of aqueous solvent,[6] solvent-free condi-
tions,[7] ionic liquid,[8] as well as supercritical carbon diox-
ide.[9] Among them, the use of water as a solvent has at-
tracted increasing attention due to cost, safety, and environ-
mental concerns. A number of palladium-catalyzed Sonoga-
shira reactions are performed in aqueous media with the
help of solubilizing additives[10] or organic co-solvents.[11]
In some cases, the aqueous protocols required more forcing
reaction conditions, such as microwave heating,[12] sub-su-
percritical water,[13] or photo-activation.[14] However, the
cross-coupling of aryl bromides with terminal alkynes using
water as sole medium is rarely reported.[10b,15] In this paper,
The key to the success of this approach is the use of a
polyethylene glycol modified phosphane ligand, which pos-
sesses a phase-transfer property due to the cloud point
(Cp), like a non-ionic surfactant. As shown in Figure 1, the
[a] State Key Laboratory of Fine Chemicals, Dalian University of
Technology,
Linggong Road 2, Dalian 116024, P. R. of China
Fax: +86-411-8899-3854
E-mail: chunliu70@yahoo.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100367.
Figure 1. Thermoregulated ligand–palladium-catalyzed Sonoga-
shira reaction in water.
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Thermoregulated Copper-Free Sonogashira Coupling in Water
thermoregulated catalyst is able to transfer into the sub- such as morpholine, pyridine, and Et3N (Table 1, entries 1,
strate phase (organic phase) to catalyze the reaction at tem- 3, and 4) afforded better results than those with inorganic
peratures above its Cp, thus allowing the reaction to take bases (Table 1, entries 5–8). It is noteworthy that Et3N
place in the substrate phase. As soon as the system is cooled achieved the highest isolated yield (Table 1, entry 1). These
to a temperature below the Cp, the catalyst returns to the results indicate that the steric effect of Et3N might be the
water phase and can be reused for the next run.
main reason for the high activity. Thus, more hindered
(nPr)3N was further investigated (Table 1, entry 2). Unfor-
tunately, use of the latter base did not improve on the result
obtained with Et3N, which is consistent with reports by
Lipshutz and co-workers.[10b]
Results and Discussion
A thermoregulated ligand, Ph2P(CH2CH2O)nCH3 (n =
22) (L; Cp: 93 °C), was prepared according to a reported
method.[20] A water-soluble palladium complex, generated
in situ from L and PdCl2 in water at room temperature, was
applied to the copper-free Sonogashira reaction between
aryl halides and terminal alkynes.
Table 1. The effect of base on the Sonogashira reaction.[a]
It is known that control of the reaction temperature is
important for the efficiency of a reaction. To evaluate the
influence of reaction temperature on the Sonogashira reac-
tion, the cross-coupling of 4-bromo-1-nitrobenzene
(0.5 mmol) with phenylacetylene (0.75 mmol) using PdCl2
(0.3 mol-%) and L (0.6 mol-%) in water (1 mL), was chosen
as a model reaction. As shown in Figure 2, the reaction
temperature was found to play a crucial role in the Sonoga-
shira reaction. The cross-coupling was slow at temperatures
below 72 °C, and only 28% isolated yield was obtained. The
coupling reaction sharply accelerated when it was per-
formed 74 °C, affording the product in 68% yield. Upon
further increasing the reaction temperature to 78 °C, the
isolated yield increased to 82%. These results indicate that
the cloud point of the palladium catalyst is around 74 °C.
The catalyst stays in the water phase at lower temperatures
(below 74 °C) and transfers into the substrate phase at
higher temperatures (above 74 °C).
Entry
Base
Yield [%][b]
1
2
3
4
5
6
7
8
Et3N
92
64
34
28
(nPr)3N
morpholine
pyridine
NaOH
9
K3PO4·7H2O
K2CO3
Na2CO3
trace amount
trace amount
trace amount
[a] Reagents and conditions: 4-bromo-1-nitrobenzene (0.5 mmol),
phenylacetylene (0.75 mmol), base (1 mmol), PdCl2 (0.3 mol-%),
H2O (1 mL), L/Pd = 2:1 (molar ratio), 80 °C, 1 h. [b] Isolated yield.
Initially, we applied the optimized conditions for the
Sonogashira cross-coupling reaction of a range of aryl io-
dides with arylacetylene in the presence of 0.3 mol-% PdCl2
at 80 °C in 1 mL water. As illustrated in Table 2, the results
showed that the coupling of aryl iodides with arylacetylene
took place smoothly to give a near quantitative yield of
diarylacetylene (Table 2, entries 1–6). Since aryl bromides
are less expensive and more readily available than aryl io-
dides, we examined the coupling reaction of aryl bromides
under the optimized conditions and were pleased to find
that the present thermoregulated protocol can be applied
to the Sonogashira coupling of various alkynes with aryl
bromides, resulting in formation of the desired cross-cou-
pling products in good to excellent yields with a low catalyst
loading of 0.3 mol-%. As shown in Table 2, aryl bromides
containing an electron-withdrawing group such as 4-NO2
and 4-COCH3, reacted smoothly with electron-poor, elec-
tron-neutral, or electron-rich aryl alkynes to provide the
corresponding cross-coupling products in high yields
Figure 2. The effect of temperature on the Sonogashira reaction.
Reagents and conditions: 4-bromo-1-nitrobenzene (0.5 mmol),
phenylacetylene (0.75 mmol), Et3N (1 mmol), PdCl2 (0.3 mol-%),
H2O (1 mL), L/Pd = 2:1 (molar ratio), 1 h.
Generally, the nature of the base is an important factor (Table 2, entries 7–14). However, 4-bromobenzonitrile gave
that determines the efficiency of the Sonogashira cross-cou- a less satisfactory result (Table 2, entry 15). Aryl bromides
pling reaction.[7f,10b] Therefore, various bases were evalu- containing an electron-donating group were further investi-
ated for the coupling of 4-bromo-1-nitrobenzene with phen- gated. As illustrated in Table 2, 4-bromoanisole was less re-
ylacetylene in this thermoregulated system. The results are active in this system. Nonetheless, good yields were ob-
summarized in Table 1. Among the inorganic bases tested, tained by extending the reaction time to 6 h (Table 2, entries
stronger bases (Table 1, entry 5) gave better results than 16–18). For example, the coupling between 4-bromoanisole
weaker bases (Table 1, entries 6–8). Several organic amines, and phenylacetylene gave the desired product in 79% yield
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Table 2. Sonogashira reaction between aryl halides and terminal alkynes in water.[a]
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Thermoregulated Copper-Free Sonogashira Coupling in Water
Table 2. (Continued)
[a] Reagents and conditions: aryl bromide (0.5 mmol), terminal alkyne (0.75 mmol), Et3N (1 mmol), PdCl2 (0.3 mol-%), H2O (1 mL), L/
Pd = 2:1 (molar ratio), 80 °C. [b] 0.5 mol-% PdCl2. [c] Isolated yield.
(Table 2, entry 16). According to literature reports, the reac- chloro (Table 2, entries 20–21), were more reactive than 1-
tivity of alkylacetylenes is usually lower than those of aryl heptyne (Table 2, entry 19). However, efforts to activate aryl
alkynes.[21] To our delight, the catalytic system was also ef- chlorides in this thermoregulated system to reach a high
fective towards the couplings of alkylacetylenes bearing ali- yield were unsuccessful, even after prolonging the reaction
phatic substituents, giving the corresponding product in ex- time to 8 h and using a palladium loading of 0.5 mol-%
cellent yields (Table 2, entries 19–22). For example, 4- (Table 2, entry 23).
bromo-1-nitrobenzene underwent the Sonogashira coupling
Diarylacetylenes are of particular interest in the synthesis
with 1-heptyne to afford the desired product in 98% yield of liquid crystals due to their unique physical properties, [22]
(Table 2, entry 19). The results suggest that alkylacetylenes and the use of the Sonogashira cross-coupling reaction to
containing electron-withdrawing groups, such as cyano and access liquid crystals containing a diarylacetylene structural
Table 3. The synthesis of liquid crystals.[a]
[a] Reagents and conditions: aryl bromide (0.5 mmol), arylacetylene (0.75 mmol), Et3N (1 mmol), PdCl2 (1 mol-%), H2O (1 mL), L/Pd =
2:1 (molar ratio), 80 °C. [b] Isolated yield.
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C. Liu et al.
FULL PAPER
mercial sources and used without further purification. 1H NMR
spectra were recorded with a Bruker Advance II 400 spectrometer.
13C NMR spectra were recorded at 100 MHz using TMS as in-
ternal standard. Mass spectroscopy data of the products were col-
lected with a MS-EI instrument. All products were isolated by
short chromatography on a silica gel (200–300 mesh) using petro-
leum ether (60–90 °C), unless otherwise noted. Compounds de-
scribed in the literature were characterized by 1H NMR spec-
troscopy and compared to the reported data.
unit has gained much attention. Present methods require
either copper co-catalyst or organic co-solvent, and suffer
from limited substrate scope.[23] To the best of our knowl-
edge, there is no report on the synthesis of liquid crystals
containing a diarylacetylene unit through a copper-free
Sonogashira coupling in water. Thus, we applied this
thermoregulated Sonogashira reaction system to the syn-
thesis of trans-cyclohexyltolan-type liquid crystals. In
Table 3, results of the Sonogashira coupling of aryl alkynes
with 1-bromo-4-(trans-4-propylcyclohexyl)benzene are re-
ported. Aryl alkynes bearing electron-poor, electron-neu-
tral, and electron-rich groups proceeded smoothly, afford-
Synthesis of Ph2P(CH2CH2O)nCH3 (n = 22) (L): The ligand
Ph2P(CH2CH2O)nCH3 (n = 22) (L, Cp: 93 °C) was prepared from
CH3(OCH2CH2)nOSO2CH3 (n = 22) and LiPPh2 according to the
reported method.[20] 1H NMR (400 MHz, D2O): δ = 2.39 (t, J =
ing the corresponding product in good yields at a palladium 7.6 Hz, 2 H), 3.37 (s, 3 H), 3.55–3.65 (m, 95 H), 7.31–7.50 (m, 10
H) ppm. 13C NMR (100 MHz, D2O): δ = 28.64 (d), 58.75 (s), 68.16
loading of 1 mol-% (Table 3, entries 1–4). 1-Bromo-4-(trans-
(d), 69.88–71.70 (m), 128.17 (s), 128.30 (d), 132.40 (d), 138.08
4-pentylcyclohexyl)benzene was also successfully coupled
(d) ppm. 31P NMR (400 MHz, D2O): δ = –22.70 ppm.
with 4-methoxyphenylacetylene to give the desired product
General Procedure for the Sonogashira Reaction of Aryl Halides
with Terminal Alkynes: A solution of PdCl2 (0.27 mg, 0.0015 mmol)
and ligand L (3.6 mg, 0.003 mmol) in deoxygenated H2O (1 mL)
was stirred at room temperature for 30 min under nitrogen. Et3N
(1 mmol, 101 mg), aryl halide (0.5 mmol), and terminal alkyne
(0.75 mmol) were then successively added. The reaction mixture
was heated in an oil bath under nitrogen with magnetic stirring.
After cooling to room temperature, the reaction mixture was added
to brine (15 mL) and extracted three times with diethyl ether
(3ϫ15 mL). The solvent was concentrated under vacuum and the
in 71% yield (Table 3, entry 5).
To evaluate the reusability of the thermoregulated li-
gand–palladium catalyst, recycling studies were carried out
for the cross-coupling of 4-bromo-1-nitrobenzene with
phenylacetylene in water (1 mL) at 80 °C for 1.5 h using a
palladium loading of 0.3 mol-% (Scheme 1). After the reac-
tion was complete and cooled to room temperature, the
product was extracted with ethyl ether and the water phase
containing the catalyst was loaded with the reactants and
bases for the next run. As shown in Scheme 1, the catalyst product was isolated by short column chromatography on a silica
gel (200–300 mesh).
can be recycled three times. However, a clear loss of cata-
lytic activity was observed in the fourth run. The cause of
the decrease in catalytic activity is under investigation.
Catalyst Recycling for the Sonogashira Reaction: When the reaction
was completed, the reaction mixture was cooled to room tempera-
ture and extracted with ethyl ether (2 mL). Et3N (1 mmol, 101 mg),
4-bromo-1-nitrobenzene
(0.5 mmol)
and
phenylacetylene
(0.75 mmol) were added to the aqueous phase that was separated
from the previous catalytic run under nitrogen, and reacted at
80 °C.
3-[(4-Nitrophenyl)ethynyl]aniline: 115.5 mg (97% yield); yellow so-
lid (m.p. 180–181 °C). 1H NMR (400 MHz, CDCl3, TMS): δ =
8.20–8.23 (m, 2 H, Ar-H), 7.63–7.66 (m, 2 H, Ar-H), 7.17 (t, J =
8.0 Hz, 1 H, Ar-H), 6.87–6.97 (m, 2 H, Ar-H), 6.70–6.73 (m, 1 H,
Ar-H), 3.74 (s, 2 H, NH2) ppm. 13C NMR: δ = 146.92 (Car), 146.45
(Car), 132.25 (2ϫCar), 130.42 (Car), 129.49 (Car), 123.62 (2ϫCar),
122.77 (Car), 122.25 (Car), 117.83 (Car), 116.28 (Car), 95.10 (CϵC),
86.97 (CϵC) ppm. MS (EI): m/z (%) = 238 (100) [M+], 238, 208,
180, 141, 104, 90, 76.
Scheme 1. Recycling experiments.
1-(Heptynyl)-4-nitrobenzene: 106.5 mg (98% yield); yellow liquid.
1H NMR (400 MHz, CDCl3, TMS): δ = 8.15 (d, J = 8.0 Hz, 2 H,
Ar-H), 7.51 (d, J = 8.0 Hz, 2 H, Ar-H), 2.44 (t, J = 7.2 Hz, 2 H,
CH2), 1.60–1.67 (m, 2 H, CH2), 1.34–1.47 (m, 4 H, CH2), 0.93 (t,
J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR: δ = 146.76 (Car), 132.42
(2ϫCar), 131.41 (Car), 123.66 (2ϫCar), 97.00 (CϵC), 79.48 (CϵC),
31.30 (CH2), 28.29 (CH2), 22.37 (CH2), 19.72 (CH2), 14.14
(CH3) ppm. MS (EI): m/z (%) = 217 (100) [M+], 217, 187, 158, 144,
130, 115, 77.
Conclusions
We have demonstrated that the thermoregulated ligand–
palladium-catalyst system gives good activity for the Sono-
gashira coupling with a wide range of substrates using
water as sole medium. Further work to develop more ef-
ficient thermoregulated ligands is underway in our labora-
tory.
6-(4-Nitrophenyl)hex-5-ynenitrile: 103.1 mg (96% yield); yellow li-
1
quid. H NMR (400 MHz, CDCl3, TMS): δ = 8.16 (d, J = 8.8 Hz,
2 H, Ar-H), 7.54 (d, J = 8.8 Hz, 2 H, Ar-H), 2.67 (t, J = 6.8 Hz, 2
H, CH2), 2.58 (t, J = 7.2 Hz, 2 H, CH2), 1.97–2.04 (m, 2 H,
CH2) ppm. 13C NMR: δ = 146.97 (Car), 132.43 (2ϫCar), 130.29
(Car), 123.60 (2ϫCar), 119.05 (CN), 93.09 (CϵC), 80.88 (CϵC),
24.33 (CH2), 18.74 (CH2), 16.39 (CH2) ppm. MS (EI): m/z (%) =
214 (100) [M+], 214, 184, 167, 149, 130, 77, 63, 51, 39.
Experimental Section
General Remarks: All the reactions were carried out under nitro-
gen. All aryl halides and terminal alkynes were purchased from
Alfa Aesar or Avocado. Other chemicals were purchased from com-
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Thermoregulated Copper-Free Sonogashira Coupling in Water
[3]
U. Létinois-Halbes, P. Pale, S. Berger, J. Org. Chem. 2005, 70,
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1-(5-Chloropentynyl)-4-nitrobenzene: 108.6 mg (97% yield); yellow
liquid. 1H NMR (400 MHz, CDCl3, TMS): δ = 8.16 (d, J = 8.4 Hz,
2 H, Ar-H), 7.52 (d, J = 8.8 Hz, 2 H, Ar-H), 3.71 (t, J = 6.4 Hz, 2
H, CH2), 2.67 (t, J = 6.8 Hz, 2 H, CH2), 2.06–2.12 (m, 2 H,
CH2) ppm. 13C NMR: δ = 146.89 (Car), 132.45 (2ϫCar), 130.73
(Car), 123.63 (2ϫCar), 94.40 (CϵC), 80.20 (CϵC), 43.70 (CH2),
31.19 (CH2), 17.12 (CH2) ppm. MS (EI): m/z (%) = 223 (100) [M+],
223, 193, 188, 157, 142, 102, 88, 77, 63, 51, 39.
[4]
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[6]
1-(Phenylethynyl)-4-(4-propylcyclohexyl)benzene: 112.4 mg (74%
yield); light-yellow solid (m.p. 87–88 °C). 1H NMR (400 MHz,
CDCl3, TMS): δ = 7.53–7.51 (m, 2 H, Ar-H), 7.45 (dd, J = 8.4,
1.6 Hz, 2 H, Ar-H), 7.35–7.31 (m, 3 H, Ar-H), 7.19 (d, J = 8.4 Hz,
2 H, Ar-H), 2.50–2.43 (m, 1 H, cHex-H), 1.90–1.85 (m, 4 H,
CH2CH2), 1.49–0.99 (m, 9 H, cHex-H), 0.90 (t, J = 8.0 Hz, 3 H,
CH3) ppm. 13C NMR: δ = 148.35 (Car), 131.58 (3ϫCar), 128.32
(2ϫCar), 128.06 (Car), 126.92 (2ϫCar), 123.55 (Car), 120.57 (Car),
89.65 (CϵC), 88.69 (CϵC), 44.60 (CcHex), 39.72 (CcHex), 37.01
(CH2), 34.17 (2ϫCcHex), 33.50 (2ϫCcHex), 20.06 (CH2), 14.45
(CH3) ppm. MS (EI): m/z (%) = 302 (100) [M+], 302, 217, 204, 191,
165, 115, 91, 55.
[7]
[8]
3-{[4-(4-Propylcyclohexyl)phenyl]ethynyl}aniline: 131.8 mg (83%
1
yield); brown solid (m.p. 95–96 °C). H NMR (400 MHz, CDCl3,
TMS): δ = 7.43 (d, J = 8.0 Hz, 2 H, Ar-H), 7.18 (d, J = 8.0 Hz, 2
H, Ar-H), 7.12 (t, J = 8.0 Hz, 1 H, Ar-H), 6.93 (d, J = 8.0 Hz, 1
H, Ar-H), 6.84 (s, 1 H, Ar-H), 6.66–6.63 (m, 1 H, Ar-H), 3.67 (s,
2 H, NH2), 2.47–2.43 (m, 1 H, cHex-H), 1.90–1.85 (m, 4 H,
CH2CH2), 1.49–0.99 (m, 9 H, cHex-H), 0.90 (t, J = 8.0 Hz, 3 H,
CH3) ppm. 13C NMR: δ = 148.24 (Car), 146.24 (Car), 131.56
(2ϫCar), 129.25 (Car), 126.88 (2ϫCar), 124.22 (Car), 122.07 (Car),
120.65 (Car), 117.82 (Car), 115.17 (Car), 89.04 (CϵC), 88.90 (CϵC),
44.59 (CcHex), 39.70 (CcHex), 37.00 (CH2), 34.15 (2ϫCcHex), 33.50
(2ϫCcHex), 20.04 (CH2), 14.42 (CH3) ppm. MS (EI): m/z (%) = 317 [9]
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The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 20976024, 20923006, 21076034),
Fundamental Research Funds for the Central Universities (grant
number DUT11LK15), Dalian University of Technology (grant
numbers DUTTX2009102, JG0916), and the Ministry of Educa-
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