Copper-free, efficient, palladium (II)-catalyzed coupling of unactivated aryl iodides with terminal alkynes

Article abstract of DOI:10.1080/00397910701483449

Palladium(II)-catalyzed coupling of terminal alkynes with unactivated aryl iodides occurs at room temperature in good to excellent yields in the presence of tetrabutylammounium bromide as additive and piperidine as base in a tetrahydrofuran-water solution

Full text of DOI:10.1080/00397910701483449

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Copper‐Free, Efficient, Palladium
(II)‐Catalyzed Coupling of Unactivated Aryl
Iodides with Terminal Alkynes
a b
c d
c d
c d
Tianrui Ren
, Ye Zhang
, Weiwen Zhu
& Jiaju Zhou
a
Life and Environment Science College, Shanghai Normal University,
Shanghai, China
b
Institute of Process Engineering, Chinese Academy of Sciences, Beijing,
China
c
National Key Laboratory of Biochemical Engineering, Institute of Process
Engineering, Chinese Academy of Sciences, Beijing, China
d
Graduate University of Chinese Academy of Sciences, Beijing, China
Published online: 05 Oct 2007.
To cite this article: Tianrui Ren , Ye Zhang , Weiwen Zhu & Jiaju Zhou (2007) Copper‐Free, Efficient,
Palladium (II)‐Catalyzed Coupling of Unactivated Aryl Iodides with Terminal Alkynes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:19,
3279-3290, DOI: 10.1080/00397910701483449
To link to this article: http://dx.doi.org/10.1080/00397910701483449
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Synthetic Communications , 37: 3279–3290, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701483449
Copper-Free, Efficient, Palladium
II)-Catalyzed Coupling of Unactivated Aryl
Iodides with Terminal Alkynes
(
Tianrui Ren
Life and Environment Science College, Shanghai Normal University,
Shanghai, China and Institute of Process Engineering, Chinese Academy
of Sciences, Beijing, China
Ye Zhang, Weiwen Zhu, and Jiaju Zhou
National Key Laboratory of Biochemical Engineering, Institute of
Process Engineering, Chinese Academy of Sciences, Beijing, China and
Graduate University of Chinese Academy of Sciences, Beijing, China
Abstract: Palladium(II)-catalyzed coupling of terminal alkynes with unactivated aryl
iodides occurs at room temperature in good to excellent yields in the presence of tetra-
butylammounium bromide as additive and piperidine as base in a tetrahydrofuran–
water solution without addition of any cuprous salts.
Keywords: aryl iodide, catalysis, sonogashira reaction, terminal alkyne, unactivated
substrate
INTRODUCTION
[1]
Aryl alkynes are important intermediates in organic synthesis. Palladium-
catalyzed Sonogashira cross-coupling of terminal alkynes with aryl halides
[2]
has become a popular methodology for the synthesis of aryl alkynes. In
recent years, there have been some reports on the modification of Sonogashira
Received in Japan January 25, 2007
Address correspondence to Tianrui Ren, Life and Environment Science College,
Shanghai Normal University, Shanghai 200234 and Institute of Process Engineering-
Chinese Academy of Sciences, Beijing 100080, China. E-mail: trren@home.ipe.ac.cn
3
279

3
280
T. Ren et al.
catalyst systems to extend the application generality and to simplify the
catalyst systems, including development of copper-free Sonogashira
reaction. However, in the reported copper-free palladium-catalyst systems,
in order to achieve the satisfactory yield, the aryl halides bearing electron-
withdrawing substituents (activated substrates) or catalysts with special
[
3]
ligands are employed. In this article, we report that in the absence of
Cu(I), using piperidine as base and Bu NBr as additive, the readily
4
available Pd(OAc)2 and PPh3 can efficiently catalyze the reaction of
terminal alkynes with aryl iodides containing electron-donating groups
(
shira reaction
such as -NH , and -OCH ), which are unactivated substrates in the Sonoga-
3
2
[
2b,4,6]
in a mixture solution of THF and H O (10:1) at room
2
temperature to afford the desired cross-coupling aryl alkynes in good to
excellent yields.
RESULTS AND DISCUSSION
Initially, 2-iodo-4-nitro-phenylamine 1e and alkyne 2b were selected as the
coupling partners to optimize the reaction conditions, and the results are
[5]
listed in Table 1. As reported in the literature, the Sonogashira coupling of
terminal alkynes with activated substrates is usually carried out in the
presence of catalytic amounts of PdCl (PPh ) (2 mol%) and CuI (4 mol%) in
2
3 2
THF as solvent. Moreover, the molar ratio of aryl halide to alkyne is 1:1.2.
[6]
However, in the case of 2-iodo-4-nitro-phenylamine 1e, more catalyst and
alkyne are needed. The increased catalyst loading of CuI (up to 8 mol%) and
a large excess of alkyne (1e:2b ¼ 1:2.5) resulted in the oxidative homocoupling
[
7]
(
Glaser coupling) of the alkyne to the corresponding symmetrical diyne, and
the separation of the diyne from the desired cross-coupling product was difficult
because of their similar polarity. As a result, the desired cross-coupling product
was obtained in only 30% yield (Table 1, entry 1).
To avoid the severe side reaction, the cross-coupling reaction of 1e with
[
8]
2b was carried out under Jeffery’s conditions using Pd(OAc) and PPh as
catalysts in the presence of a base and a phase-transfer reagent without any
2 3
added cuprous salts. The desired cross-coupling product 3e was obtained in
49% yield (Table 1, entry 2), and the homocoupling product was not
detected. Encouraged by this result, we examined the effects of the molar
ratio of substrates, additives, solvents, and bases in the coupling reaction of
2-iodo-4-nitro-phenylamine 1e with 1-but-2-ynyl-piperidine 2b in the
presense of Pd(OAc) (5 mol%) and PPh (10 mol%) to further screen the
2
3
best reaction conditions. As shown in Table 1, the yield of the cross-
coupling product 3e could be remarkablely improved from 49% to 62% by
increasing the molar ratio of 2-amino-4-nitro-phenylamine 1e to 1-but-2-
ynylpiperidine 2b used in the reaction (Table 1, entry 3). When the phase
transfer reagent Bu NHSO , was replaced by Bu NBr, used as an additive,
4
4
4
a slight improvement in the coupling yield resulted (from 62% to 65%,

Coupling of Aryl Iodides with Terminal Alkynes
3281
Table 1. Effect of reaction conditions on the cross-coupling of 2-iodo-4-nitro-pheny-
a
lamine 1e with alkyne 2b
Molar ratio
of 1e:2b
Time
(h)
Entry
Solvent
THF
Additive
—
Base
Yield (%)
b
1
2
1:2.5
1:2
Et N
3
4
4
30
49
c
CH
(
3
CN/H
10:1)
2
O
Bu
4
NHSO
4
Et
3
N
3
4
1:2.5
1:2.5
CH CN/H O Bu NHSO Et N
4
4
62
65
3
2
4
4
3
(
CH
(
10:1)
3
CN/H
10:1)
CN
2
O
Bu
4
NBr
Et
3
N
5
6
7
1:2.5
1:2.5
1:2.5
CH
3
Bu
Bu
4
NBr
NBr
Et
Et
3
N
N
10
10
3
No reaction
d
THF
THF/H O
4
3
N/A
Bu NBr
4
Et N
3
72
83
42
2
(
10:1)
THF/H
10:1)
THF/H O
8
9
1:2.5
1:2.5
2
O
Bu
4
NBr
Piperidine
K CO
3
3
(
Bu NBr
4
2
2
3
(
10:1)
a
Reactions were performed using 0.4 mmol of 1e, 1 mmol of 2b, 1.2 mmol of base,
, 10 mol% of PPh , and 1 mmol of additive in a solution at rt.
The reaction was carried out using 0.4 mmol of 1e, 1 mmol of 2b, 1.2 mmol of base,
ca. 5 mol% of PdCl (PPh , and 8 mol% of CuI in 5 ml of THF for 4 h.
The reaction was carried out under Jeffery’s condtions. [1e]:[2b]:[Pd(OAc)
PPh ]:[Et N]:[Bu NHSO CN-H O (10:1); rt.
] ¼ 10:20:1:2:25:10; CH
Only a trace amount of the product was detected, and its yield was not determined.
ca. 5 mol% of Pd(OAc)
2
3
b
2
3 2
)
c
2
]:
[
3
3
4
4
3
2
d
Table 1, entry 4). As a solvent system, the use of a mixed solution is an
important factor in this coupling reaction. In the absence of water, no
coupled product was detected in CH CN (Table 1, entry 5) and only a trace
3
amount of product was detected in THF (Table 1, entry 6). Our results
suggest a remarkable increase of the coupling product 3e yield, and the rate
of this reaction when the coupling is performed in THF/H O (10:1, 72%,
2
Table 1, entry 7) instead of CH CN/H O (10:1, 65%). A yield of 83% was
3
2
obtained when replacing triethylamine with piperidine as base (Table 1, entry
), whereas the yield was 42% when K CO was employed as base (Table 1,
8
2
3
entry 9). It should be noted that under the reaction conditions of entry 8 (the
best reaction conditions), other palladium catalysts, such as PdCl , Pd (PPh ) ,
2
3 4

a
Table 2. Palladium-catalyzed cross-coupling of iodobenzenes with terminal alkynes
Mp (8C)
b
Entry
1
Aryl-I
Alkyne
Product
Yield (%)
93
Obtained
88–90
Lit.
[
6]
89–90
[
9]
2
3
2a
2a
81
oil
oil
c
96
[10]
68–70
72–74

[
6]
4
5
2a
92
83
94–96
94–95
80–82
6
1e
87
153–155
(
continued)

Table 2. Continued
Mp (8C)
b
Entry
7
Aryl-I
Alkyne
Product
Yield (%)
79
Obtained
162–164
Lit.
2b
8
1f
83
148–149
9
2d
86
95–97

10
1g
2c
89
125–127
11
1g
2b
86
65–67
a
Reactions were carried out using 0.4 mmol of aryl iodide, 1 mmol of alkynes, 1.2 mmol of piperidine, 5 mol% of Pd(OAc) , 10 mol% of PPh , and
2
3
1
1
mmol of Bu
b
4
NBr in 5.5 ml of THF/H
2
O (10/1) at rt for 2–4 h.
Yield based on the amount of aryl iodide used.
Reactions were performed using 0.4 mmol of aryl iodide, 0.8 mmol of alkynes, 1.2 mmol of piperidine, 3 mol% of Pd(OAc) , 6 mol% of PPh , and
c
2
3
4 2
mmol of Bu NBr in 5.5 ml of THF/H O (10/1) at rt for 2 h.

3
286
T. Ren et al.
and PdCl (PPh ) showed very low catalytic activity to afford 3e in 0%, 21%,
2
3 2
and 0% yields, respectively, whether they combined with PPh or not.
3
Table 2 shows the Pd(OAc) -and PPh -catalyzed cross-coupling reactions
2
3
of a variety of terminal alkynes (2a–d) with the unactivated substrates such
as 2-iodoaniline 1a, 2-methoxyiodo-benzene 1b, 4-methyl-iodobenzene
1c, ethyl 4-amino-3-iodobenzoate 1d, 4-nitro-2-iodophenyl amine 1e,
2-amino-3-iodo-5-nitrobenzonitrile 1f, and methyl 4-amino-2-chloro-5-iodo-
benzoate 1g to give the cross-coupling products 3a–3k under the optimized
conditions as shown in entry 8 of Table 1. It was evident that the unactivated
aryl iodides containing electron-donating groups (such as amino group,
alkoxyl group, etc.) were employed and reacted well to give the corresponding
cross-coupling products in high yields under the optimized conditions.
In conclusion, an efficient copper-free catalyst system was developed
with high yields for the unactivated substrates in the Sonogashira reaction.
In addition, the procedure has several advantages including short reaction
time, high yields, and simple workup.
EXPERIMENTAL
Commercially available reagents were purchased from Aldrich and used
without further purification. All melting points were recorded using a
capillary melting-point apparatus and are uncorrected. The IR spectra were
determined neat or as KBr pellets on a Shimadzu FTIR-8300 spectrometer.
1
H NMR spectra were acquired using a Bruker DPX300 spectrometer in
CDCl solution with TMS as the internal standard. The elemental analyses
3
were performed at the Institute of Chemistry, Chinese Academy of Sciences.
Analytical thin-layer chromatography (TLC) was carried out using MN
Kieselgel G/UV 254 (Art. 816320) glass-backed plates. Yields were not
[6,9,10]
optimized. Partial products are already reported in the literature.
General Procedure
A mixture of aryl iodide (0.4 mmol), alkyne (1 mmol), piperidine (1.2 mmol),
Pd(OAc) (5 mol%), PPh (10 mol%), and Bu NHBr (1 mmol) was suspended
in 5.5 ml of THF–H O (10:1) under nitrogen. Stirring was continued at room
2
3
4
2
temperature until the disappearance of the starting aryl iodide (monitored by
thin-layer chromatography, TLC). The mixture was then hydrolyzed by 10 ml
of H O and extracted with 10 Â 3 ml of diethyl ether. Removal of the solvent
2
in vacuo followed by column chromatography gave the expected product.

Coupling of Aryl Iodides with Terminal Alkynes
Analytical Data for Selected Compounds
3287
21 1
-(Phenylethynyl)aniline (3a): IR (KBr): 3460, 2206, 1620, 1450 cm . H
2
NMR (300 MHz, CDCl ): 4.22 (br, s, 2H), 6.77–6.69 (m, 2H), 7.18–7.11
3
(m, 1H), 7.42–7.32 (m, 4H), 7.58–7.51 (m, 2H).
1
1
7
-Methoxy-2-(phenylethynyl)benzene (3b): IR (KBr): 2950, 2160, 1600,
1
480. H NMR (300 MHz, CDCl ): 3.92 (s, 3H), 6.88–6.96 (m, 2H), 7.28–
.35 (m, 4H), 7.48–7.52 (m, 1H), 7.53–7.56 (m, 2H).
3
1
1
7
-Methyl-4-(phenylethynyl)benzene (3c): IR (KBr): 3010, 2238, 1620,
1
480. H NMR (300 MHz, CDCl ): 2.38 (s, 3H), 7.16 (d, J ¼ 7.8 Hz, 2H),
3
.33–7.35 (m, 3H), 7.40–7.43 (m, 2H), 7.51–7.53 (m, 2H).
Ethyl 4-amino-3-(phenylethynyl)benzoate (3d): IR (KBr): 3459, 2982,
1
200, 1698, 1600. H NMR (300 MHz, CDCl ): 1.24–1.27 (t, 3H), 4.20–
2
4
7
3
.23 (m, 2H), 4.66 (br, s, 2H), 6.58 (d, J ¼ 8.0 Hz, 1H), 7.26–7.21 (m, 3H),
.44–7.39 (m, 2H), 7.74–7.70 (m, 1H), 7.98 (d, J ¼ 1.8 Hz, 1H).
4
3
1
-Nitro-2-(3-piperidin-1-yl-prop-1-ynyl)phenylamine (3e): IR (KBr):
1
500, 2230, 1450, 1280. H NMR (300 MHz, CDCl ): 1.48 (m, 2H), 1.63–
.69 (m, 4H), 2.53–2.59 (m, 4H), 3.56 (s, 2H), 4.91 (s, br, 2H), 6.64–6.67
3
(
d, J ¼ 3.0 Hz, 1H), 7.99–8.03 (m, 1H), 8.21–8.22 (d, J ¼ 3.0 Hz, 1H).
Anal. calcd. for C H N O : C, 64.85; H, 6.61; N, 16.20. Found: C, 64.76;
4 17 3 2
1
H, 6.63; N, 16.22.
2
3
3
1
-(3-Morpholin-4-yl-prop-1-ynyl)-4-nitro-phenylamine (3f): IR (KBr):
1
450, 2260, 1650, 1450. H NMR (300 MHz, CDCl ): 2.63–2.66 (m, 4H),
3
.59 (s, 2H), 3.75–3.79 (m, 4H), 4.90 (br, s, 2H), 6.65–6.68 (d, J ¼ 9.0 Hz,
H), 8.00–8.04 (m, 1H), 8.21–8.22 (d, J ¼ 3.0 Hz, 1H). Anal. calcd. for
C H N O : C, 59.76; H, 5.79; N, 16.08. Found: C, 59.75; H, 5.82; N, 16.22.
13 15 3 3
2
(
-Amino-5-nitro-3-(3-piperidin-1-yl-prop-1-ynyl)-benzonitrile (3g): IR
1
KBr): 3350, 2260, 1600, 1480. H NMR (300 MHz, CDCl ): 1.58–1.62
3
(m, 2H), 1.64–1.67 (m, 4H), 2.54–2.56 (m, 4H), 3.57 (s, 2H), 5.64 (br, s,
2
calcd. for C H N O : C, 63.37; H, 5.67; N, 19.71. Found: C, 63.30; H,
H), 8.29–8.30 (d, J ¼ 3.0 Hz, 1H), 8.32–8.33 (d, J ¼ 3.0 Hz, 1H). Anal.
1
5 16 4 2
5
.73; N, 19.80.
2
-Amino-5-nitro-3-(3-pyrrolidin-1-yl-prop-1-ynyl)-benzonitrile (3h): IR
1
KBr): 3500, 2250, 1585, 1480. H NMR (300 MHz, CDCl ): 1.84–1.88
(
(
(
3
m, 4H), 2.67–2.71 (m, 4H), 3.72 (s, 2H), 5.64 (br, s, 2H), 8.29–8.30
d, J ¼ 3.0 Hz, 1H), 8.32–8.33 (d, J ¼ 3.0 Hz, 1H). Anal. calcd. for
C H N O : C, 62.21; H, 5.22; N, 20.73. Found: C, 62.16; H, 5.32; N, 20.66.
14 14 4 2

3
288
T. Ren et al.
Methyl 4-amino-2-chloro-5-(3-pyrrolidin-1-yl-prop-1-ynyl)benzoate (3i):
1
IR (KBr): 3500, 2260, 1580, 1460. H NMR (300 MHz, CDCl ): 1.85–1.89
3
(
m, 4H), 2.66–2.74 (m, 4H), 3.69–3.71 (d, J ¼ 6.0 Hz, 2H), 3.83–3.87
(m, 3H), 4.62 (br, s, 2H), 6.72 (s, 1H), 7.92 (s, 1H). Anal. calcd. for
C H ClN O : C, 61.54; H, 5.85; N, 9.57. Found: C, 61.44; H, 5.83; N, 9.60.
1
5
17
2 2
Methyl 4-amino-2-chloro-5-(3-morpholin-4-yl-prop-1-ynyl)benzoate (3j):
1
IR (KBr): 3500, 2230, 1600, 1450. H NMR (300 MHz, CDCl ): 2.62–2.65
3
(
(
t, 4H), 3.54–3.56 (d, J ¼ 6.0 Hz, 2H), 3.75–3.79 (t, 4H), 3.87–3.88
d, J ¼ 3.0 Hz, 3H), 4.59 (br, s, 2H), 6.73 (s, 1H), 7.93 (s, 1H). Anal.
calcd. for C H ClN O : C, 58.35; H, 5.55; N, 9.07. Found: C, 58.30; H,
2 3
1
5
17
5
.53; N, 9.13.
Methyl 4-amino-2-chloro-5-(3-piperidin-1-yl-prop-1-ynyl)benzoate (3k):
1
IR (KBr): 3300, 2250, 1600, 1450. H NMR (300 MHz, CDCl ): 1.45–
3
1
3
.47(m, 2H), 1.62–1.66 (m, 4H), 2.54–2.57 (t, 4H), 3.53 (s, 2H), 3.83–
.87 (m, 3H), 4.60 (br, s, 2H), 6.72 (s, 1H), 7.93 (s, 1H). Anal. calcd. for
C H ClN O : C, 62.64; H, 6.24; N, 9.13. Found: C, 62.66; H, 6.38; N, 9.20.
19
1
6
2 2
ACKNOWLEDGMENTS
The present work was financially supported by the National 973 Program of
China (Contract No. 2003CB114400) and the National Natural Science Foun-
dation of China (No. 20672113).
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