Copper-free sonogashira coupling reaction in phosphonium amino acid ionic liquids

Article abstract of DOI:10.1246/cl.2011.1027

Phosphonium amino acid ionic liquids were found to be useful for the copper-free and amine-free Sonogashira coupling reaction. A hydrophobic and lipophobic ionic liquid permitted easy separation of the product from ionic liquid and catalyst, and the recov

Full text of DOI:10.1246/cl.2011.1027

doi:10.1246/cl.2011.1027
Published on the web September 5, 2011
1027
Copper-free Sonogashira Coupling Reaction in Phosphonium Amino Acid Ionic Liquids
Takahide Fukuyama,* Md. Taifur Rahman, Shinji Maetani, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531
(
Received July 1, 2011; CL-110557; E-mail: ryu@c.s.osakafu-u.ac.jp)
Pd
Phosphonium amino acid ionic liquids were found to be
useful for the copper-free and amine-free Sonogashira coupling
reaction. A hydrophobic and lipophobic ionic liquid permitted
easy separation of the product from ionic liquid and catalyst,
and the recovered ionic liquid containing Pd catalyst could be
reused.
Ar
X
+
H
R
Ar
R
phosphonium-type
amino acid ILs
as a reaction
medium
acid-scavenging
functionality
R
Palladium­copper-catalyzed coupling reaction of aryl hal-
ides and terminal alkynes, namely the Sonogashira coupling
reaction, provides a powerful tool for access to a wide range of
O
R P
NH2
4
O
1
disubstituted alkynes. The origin of palladium-catalyzed reac-
tion for the same transformation is back in 1975, for which
Cassar and the Heck group independently reported the reaction
Scheme 1. Copper-free Sonogashira coupling reaction using
amino acid ionic liquid.
2
3
proceeded in the presence of strong base such as NaOCH or
3
amine as solvent. In 2002 we reported that the copper-free
Sonogashira coupling reaction (Cassar/Heck reaction) was
Table 1. Copper-free Sonogashira coupling reaction of 1a with
2a using tetrabutylphosphonium amino acid ionic liquidsa
Pd cat. 5 mol %
4
successfully carried out in ionic liquids, such as [bmim]PF6
Ph Br
+
H
Ph
Ph
Ph
to give good yields of disubstituted alkynes,5 and can create an
effective catalyst recycling system coupled with a microflow
technology. The Sonogashira coupling reactions, irrespective of
with or without copper, often employ a volatile and odorous
amine, as solvent and/or a base to scavenge the acid (HX) by-
product. We herein report an amine-free protocol in which
­7
[
TBP]AA, 90 °C
1a
2a
3a
b
Entry
AA
Pd cat.
Time/h
Yield /%
1
2
3
4
5
6
7
8
9
Gly
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl (PPh ) ]
2 3 2
7
3
5
3
4
5
6
3
3
39
18
37
68
79
88
84
68
99
L-Ala
L-Val
L-Met
L-Met
L-Phe
L-Phe
L-lle
8
phosphonium-based amino acid ionic liquids would serve as
[PdCl2(PPh3)2]
polar reaction media ensuring a copper-free system and an acid-
scavenger (Scheme 1).
[Pd(PPh ) ]
3
4
[PdCl2(PPh3)2]
[Pd(PPh3)4]
[PdCl2(PPh3)2]
[Pd(PPh3)4]
We investigated the reaction of bromobenzene (1a) with
phenylacetylene (2a) as a model of copper-free and amine-free
Sonogashira reaction using a variety of tetrabutylphosphonium
amino acid ionic liquids. Thus, when the reaction of 1a with 2a
was carried out in the presence of a catalytic amount of
L-lle
a
Conditions: 1a (0.25 mmol), 2a (1.2 equiv), Pd cat. (5 mol %),
b
[PdCl2(PPh3)2] (5 mol %) in [TBP][Gly] as a solvent at 90 °C for
ionic liquid (0.5 mL), 90 °C. NMR yield using 1,4-dimethoxy-
7
3
h, the coupling product, diphenylacetylene (3a), was formed in
9% yield (Table 1, Entry 1), after biphasic workup using
benzene as an internal standard.
hexane. [TBP][Ala] and [TBP][Val] gave similarly poor results.
However, good yields of the coupling product 3a was obtained
when [TBP][Met], [TBP][Phe], or [TBP][Ile] was used as a
solvent (Entries 4­9).
We then investigated the scope of the copper-free
Sonogashira coupling reaction using [TBP][Ile] as the solvent
and [Pd(PPh3)4] as the catalyst.9 The results are shown in
Table 2. The reaction of 1a with p-tolylacetylene (2b) gave 3b
in 88% yield (Entry 2). Under similar conditions, 4-bromoani-
sole (1b) also worked well to give the corresponding product
To recycle the Pd catalyst and the ionic liquid, removal of
HX from the solvent by aqueous inorganic base was carried out.
However, the water solubility of [TBP][Ile] made the separation
difficult. Therefore, modification of ionic liquid structure was
necessary to enhance the hydrophobic character of the ionic
liquid. For this purpose, we prepared several phosphonium
amino acid ionic liquids having longer alkyl chains on
phosphorus and nitrogen atoms and found that ionic liquid
prepared from tributyldecylphosphonium salt and N-heptylphen-
1
0
ylalanine was both hydrophobic and lipophobic for hexane.
Using the ionic liquid, catalyst recycling study was carried out
(Scheme 2). The first reaction of 1a with 2a gave the coupling
product 3a in 95% isolated yield. While [PdCl (PPh ) ] showed
3
c. The reaction of iodobenzenes 1c­1g with phenylacetylene
gave the corresponding disubstituted acetylenes in good yields
Entries 4­8). p-Chloroiodobenzene (1g) reacted with 2a to give
f, with the chloride functionality remaining intact (Entry 8).
(
3
2
3 2
a low solubility in the ionic liquid at the initial stage of the
reaction, a homogeneous solution was obtained after the
reaction. After extraction with hexane to separate the products
from the ionic liquid, HI was removed by biphasic treatment
Aliphatic acetylene, such as 1-octyne, could be employed as a
coupling partner to afford hexylphenylacetylene (3g) in 96%
yield.
Chem. Lett. 2011, 40, 1027­1029
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1
028
Table 2. Copper-free Sonogashira coupling reaction of aryl
halides with terminal alkynes using [TBP][Ile]a
[PdCl2(PPh3)2] (5 mol%)
1c
+
2a
90 °C, 3 h
[
Pd(PPh ) ] (5 mol %)
3 4
ionic liquid
1
.2 equiv
3a
Ar
X
+
H
R
Ar
R
[TBP][Ile], 90 °C
1
st use 95%
1
2
3
2nd use 89%
rd use 85%
2
2
2
a : R = Ph
b : R = p-Tol
c : R = n-Hex
+
3
[TBP][Ile] = Bu P
4
H N
COO
Ph
COO
hexane
K CO aq.
2
n-C10H21PBu3
n-C H15NH
Entry
1
1
2
Time/h
3
3
Yield/%b
7
2
3
Br 2a
Ph
3a 99c
1a
Scheme 2. Recycling study using a hydrophobic and lip-
ophobic ionic liquid.
2
3
1a
2b
8
p-Tol
Ph
3
b
88
We thank JSPS and MEXT, Japan for financial support of
this work. We also thank Katayama Seiyakusyo Co., Ltd. for the
generous gift of tetrabutylphosphonium amino acid ionic
liquids.
MeO
Br 2a
3
2
MeO
1
1
b
c
3c 84
3a 87
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
4
I
2a
Ph
References and Notes
1
a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
975, 16, 4467. For reviews, see: b) K. Sonogashira, in
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Fleming, Pergamon Press, New York, 1991, Vol. 3, pp. 521­
5
6
I
I
2a
2a
1
2
Ph
Ph
1
3
d 98
1
1
d
e
MeO
F
MeO
F
5
49. doi:10.1016/B978-0-08-052349-1.00071-8. c) K.
Sonogashira, in Metal-Catalyzed Cross-Coupling Reactions,
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7
8
9
I
I
2a
2a
2c
6
2
8
Ph
3e
67
1
f
2
3
L. Cassar, J. Organomet. Chem. 1975, 93, 253.
H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93,
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For recent reviews on ionic liquids, see: a) Ionic Liquids in
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Cl
Cl
Ph
4
3
3
f
96
96
1
g
1a
n-Hex
g
5
6
a) T. Fukuyama, M. Shinmen, S. Nishitani, M. Sato, I. Ryu,
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aConditions:
(
flash chromatography on SiO2. NMR yield.
1 (0.25 mmol), 2 (1.2 equiv), [Pd(PPh3)4]
5 mol %), [TBP][Ile] (0.5 mL), 90 °C. bIsolated yield after
c
For copper-free Sonogashira coupling reaction using an
ionic liquid, see: a) R. R. Deshmukh, R. Rajagopal, K. V.
Srinivasan, Chem. Commun. 2001, 1544. b) S. B. Park, H.
Alper, Chem. Commun. 2004, 1306. c) A. R. Gholap, K.
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with aqueous saturated K CO . The recovered ionic liquid
containing the Pd catalyst was able to be reused successfully
with only a slight loss in its activity.
2
3
In conclusion, phosphonium amino acid ionic liquids
were found to be useful for the copper-free and amine-free
Sonogashira coupling reaction. Among them, a hydrophobic and
lipophobic ionic liquid permitted easy separation of the product
from ionic liquid and catalyst, and the recovered ionic liquid
containing Pd catalyst could be reused. Detailed study on the
present copper- and amine-free Sonogashira coupling reaction
and other applications using amino acid ionic liquids are
currently underway in this laboratory.
7
For recent examples for copper-free Sonogashira reactions,
see: a) K. Prabakaran, F. N. Khan, J. S. Jin, Tetrahedron Lett.
2011, 52, 2566. b) B. de Carné-Carnavalet, A. Archambeau,
Chem. Lett. 2011, 40, 1027­1029
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1
029
C. Meyer, J. Cossy, B. Folléas, J.-L. Brayer, J.-P. Demoute,
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layer was evaporated and the residue was purified by column
chromatography on silica gel (hexane) to give 3a (42.3 mg,
95%). Ionic liquid solution was washed with a saturated
K CO aqueous solution (3 © 2 mL). The ionic liquid layer
2
3
was dried under reduced pressure and used for the next
cycle.
1
10 Yellow oil; H NMR (500 MHz, CDCl ): ¤ 7.33 (d, J =
3
8
9
a) J. Kagimoto, K. Fukumoto, H. Ohno, Chem. Commun.
7.8 Hz, 2H), 7.19 (t, J = 7.3 Hz, 2H), 7.10 (t, J = 7.3 Hz,
1H), 3.27 (t, J = 6.7 Hz, 1H), 3.09 (dd, J = 13.8, 5.5 Hz,
1H), 2.83 (dd, J = 13.8, 7.8 Hz, 1H), 2.65­2.59 (m, 1H),
2.44­2.35 (m, 10H), 1.51­1.41 (m, 18H), 1.29­1.19 (m,
2
006, 2254. b) J. Zhang, S. Zhang, K. Dong, Y. Zhang, Y.
Shen, X. Lv, Chem.®Eur. J. 2006, 12, 4021.
To a 10 mL flask was added tributyldecylphosphonium
N-heptyl-L-phenylalanine salt (540.5 mg), [PdCl2(PPh3)2]
1
3
20H), 0.97­0.83 (m, 15H). C NMR (100 MHz, CDCl3): ¤
177.7, 140.9, 129.0, 127.0, 124.5, 65.8, 48.3, 40.4, 31.2,
30.3, 29.9, 28.7, 28.4, 26.9, 23.3, 22.0, 21.3, 18.2, 17.8,
(
(
9.2 mg, 0.013 mmol), 1c (52.0 mg, 0.25 mmol), and 2a
31.2 mg, 0.31 mmol). The flask was evacuated and sub-
¹
1
sequently flushed with argon, and the reaction mixture was
stirred at 90 °C for 3 h. After the reaction, the product was
extracted with hexane (5 © 3 mL). The combined hexane
13.5, 12.9. IR (neat): 3313.1, 1575.6 cm
MS: FAB
+
(+) m/z = 343, [C22H48P] , FAB (¹): m/z 262,
¹
[C H NO ] .
1
6
24
2
Chem. Lett. 2011, 40, 1027­1029
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/