Palladium-catalyzed coupling reaction of haloheteroaromatic compounds in water

Article abstract of DOI:10.3987/com-06-s(k)20

Palladium-catalyzed coupling reaction of π-deficient heteroaromatic halide in water was accomplished with excellent to good yields without any side reactions such as hydrolysis.

Full text of DOI:10.3987/com-06-s(k)20

HETEROCYCLES, Vol. 72, 2007
665
HETEROCYCLES, Vol. 72, 2007, pp. 665 - 671. © The Japan Institute of Heterocyclic Chemistry
Received, 17th November, 2006, Accepted, 1st February, 2007, Published online, 6th February, 2007. COM-06-S(K)20
PALLADIUM-CATALYZED COUPLING REACTION OF
HALOHETEROAROMATIC COMPOUNDS IN WATER
Naoki Inoue, Osamu Sugimoto,* and Ken-ichi Tanji*
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences
University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
osamu@smail.u-shizuoka-ken.ac.jp; tanji@smail.u-shizuoka-ken.ac.jp
Abstract - Palladium-catalyzed coupling reaction of π-deficient heteroaromatic
halide in water was accomplished with excellent to good yields without any side
reactions such as hydrolysis.
The use of water as a solvent in organic synthesis is helpful from the viewpoint of protection of the
environment and reduction of chemical resources; water is a non-toxic and cheap material. Recently,
organic reactions in aqueous media have been developed worldwide.1,2
The coupling reaction of aromatic compounds with alkenes or alkynes using a palladium complex as a
catalyst has been reported from the middle of the 1970s, and the reaction is well known as an important
method for introducing an alkenyl or alkynyl substituent into an aromatic moiety.3-5 Similarly,
ethynylheteroaromatics are prepared by the reaction of haloheteroaromatics with acetylene derivatives in
the presence of a palladium complex in organic solvent. For example, the coupling reaction of
bromopyridines with phenylacetylene proceed to give phenylethynylpyridines in toluene as a solvent.6
Although the palladium-catalyzed reaction of haloaromatics (halobenzenes and halonaphthalenes) in
water was already reported by Bhattacharya,7 the reaction of π-deficient haloheteroaromatics has not been
reported. It is well known that π-deficient nitrogen-containing heteroaromatics such as azines or diazines
are reactive with nucleophiles. For example, π-deficient nitrogen-containing heteroaromatic halides react
with carbanions, amines, or alkoxides to give the corresponding nucleophile-substituted π-deficient
nitrogen-containing heteroaromatics by an addition-elimination mechanism.8,9 Thus, in
palladium-catalyzed alkynylation of π-deficient nitrogen-containing heteroaromatic halides in water, an
undesired reaction such as hydrolysis may occur whereas the coupling reaction in organic solvents is
reported.10 In this paper we wish to report the palladium-catalyzed cross-coupling reaction of

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HETEROCYCLES, Vol. 72, 2007
iodoheteroaromatics in water.
At first, the reaction of 2-halopyridines with phenylacetylene in the presence of
tetrakis(triphenylphosphine)palladium, copper iodide, and diisopropylethylamine (DIEA) in water under
various conditions was carried out (Entries 1-5, Table 1). The desired product, 2-(phenylethynyl)pyridine,
was obtained using 2-bromopyridine (Entries 2-3), or 2-iodopyridine (Entries 4-5) as a substrate, whereas
the coupling reaction of 2-chloropyridine at 70 °C for 24 h afforded no product (Entry 1). The coupling
reaction proceeded smoothly using 2-iodopyridine as a substrate to give excellent yields of the product.
Some acetylene derivatives (1-hexyne, propargyl alcohol) were found to react to afford the corresponding
product, but reactivity of propargyl alcohol was lower than that of phenylacetylene or 1-hexyne (Entries
7-8). Cross-coupling reaction proceeded at a temperature between rt and 70 °C to afford the
corresponding 2-alkynylpyridines, and hydrolysis of 2-iodopyridine was not observed under these
conditions.
Table 1. Coupling reaction of 2-halopyridine with acetylene derivatives in water
N
N
Pd(PPh3)4, CuI
DIEA, H2O
R
R
+
X
Entry
X
R
Ph
Condition
70 °C, 24 h
rt, 72 h
Yield (%)
Recovery (%)
1
2
3
4
5
6
7
8
Cl
Br
Br
I
0
Ph
52
91
90
89
87
65
60
Ph
70 °C, 6 h
70 °C, 0.5 h
rt, 72 h
Ph
I
Ph
I
Bu
rt, 7 h
I
CH2OH
CH2OH
rt, 24 h
17
15
I
70 °C, 6 h
Next, the cross-coupling reaction using some haloheteroaromatics and alkynes was carried out. As shown
in Table 2, 3-iodopyridine (Entries 1-3), 4-iodopyridine (Entries 4-8), 5-bromopyrimidine (Entry 9),
2-iodoquinoline (Entries 10-12), 3-bromoquinoline (Entry 13), 4-iodoquinoline (Entries 14-16),
6-iodo-9-phenylpurine (Entries 17-19), and 2-iodoquinoxaline (Entries 20-22) were used as a substrate in
this coupling reaction. It was found that the use of iodoheteroaromatics as a substrate is a desirable
method for the coupling reaction in water since coupling reaction of bromoheteroaromatics
(5-bromopyrimidine and 3-bromoquinoline) with phenylacetylene in water did not proceed smoothly.

HETEROCYCLES, Vol. 72, 2007
667
Table 2. Coupling reaction of haloheteroaromatics with acetylene derivatives in water
Pd(PPh3)4, CuI
Het
R
+
R
Het
X
DIEA, H2O
Entry
Het-I
R
Condition
Yield (%)
Recovery (%)
8
1
2
3
4
5
6
7
Ph
Bu
rt, 30 h
70 °C, 2 h
70 °C, 6 h
rt, 24 h
98
75
76
94
9
I
N
CH2OH
Ph
Bu
70 °C, 1 h
70 °C, 6 h
rt, 6 h
53
I
Bu
83
0
CH2OH
27
13
N
rt, 23 h, then
70 °C, 6 h
8
9
CH2OH
Ph
57
26
Br
N
70 °C, 18 h
25
N
10
11
12
Ph
Bu
rt, 24 h
92
91
89
70 °C, 6 h
70 °C, 24 h
N
I
CH2OH
Br
13
Ph
70 °C, 26 h
11
78
33
N
I
14
15
16
Ph
Bu
rt, 24 h
89
47
65
70 °C, 15 h
70 °C, 22 h
CH2OH
N
I
17
18
Ph
Bu
rt, 25 h
86
93
N
N
70 °C, 18 h
N
N
Me
19
20
21
22
Ph
CH2OH
Ph
70 °C, 23 h
rt, 22 h
0
76
17
88
88
57
N
Bu
70 °C, 6 h
70 °C, 15 h
N
I
CH2OH
In summary, the coupling reaction of π-deficient iodoheteroaromatics in aqueous media was
accomplished without any undesired side reactions such as hydrolysis.

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EXPERIMENTAL
1
All melting points were not corrected. H-NMR spectra was measured with Hitachi R-90H spectrometer
(90 MHz) and JEOL JNM-EX270 FT NMR system (270 MHz) using tetramethylsilane as an internal
standard. Iodoheteroaromatics except iodopyridines (commercially available), 2-iodoquinoline and
6-iodo-2-methyl-9-phenylpurine (prepared from 2-chloroquinoline and 6-chloro-2-methyl-9-phenylpurine,
respectively) were prepared from hydroxyheteroaromatics according to the procedure reported by us11
with minor modifications.
Preparation of 6-iodo-2-methyl-9-phenylpurine : A mixture of 6-chloro-2-methyl-9-phenylpurine (4894
mg, 20.0 mmol), sodium iodide (8993 mg, 60.0 mmol), 2-butanone (100 mL), and hydroiodic acid (1 mL)
was stirred at room temperature for 14 h and then heated to reflux for 5 h. After the reaction mixture was
basified with triethylamine, the insoluble solids was filtered off. The filtrate was treated with silica gel
column chromatography (eluted with hexane – EtOAc (3:2)) to give 6-iodo-2-methyl-9-phenylpurine.
Coupling reaction of iodoheteroaromatics with acetylene derivatives (general procedure) :
Iodoheteroaromatics (2.00 mmol), acetylene derivatives (3.00 mmol), diisopropylethylamine (3.00 mmol),
water (10 mL), copper iodide (0.02 mmol), and tetrakis(triphenylphosphine)palladium (0.01 mmol) was
added to a round-bottom flask and stirred at the condition shown in Table 1. The reaction mixture was
extracted with EtOAc and the organic layer was treated with silica gel column chromatography to give
the corresponding ethynylheteroaromatics.
1
2-(Phenylethynyl)pyridine12 : Pale yellow oil. MS 179 (M+). H-NMR (CDCl3) ppm : 7.18-7.28 (1H, m,
pyridine-H), 7.32-7.42 (3H, m, phenyl-H), 7.48-7.73 (4H, m, phenyl and pyridine-H), 8.63 (1H, d, J=4.6
Hz, pyridine-H).
1
2-(1-Hexynyl)pyridine13 : Yellow oil. MS 159 (M+). H-NMR (CDCl3) ppm : 0.94 (3H, t, J=7.3 Hz,
CH3CH2CH2CH2), 1.40-1.70 (4H, m, CH3CH2CH2CH2), 2.45 (2H, t, J=7.2 Hz, CH3CH2CH2CH2),
7.12-7.22 (1H, m, pyridine-H), 7.36 (1H, d, J=7.8 Hz, pyridine-H), 7.61 (1H, t, J=7.8 Hz, pyridine-H),
8.54 (1H, d, J=4.6 Hz, pyridine-H).
3-(2-Pyridinyl)-2-propyn-1-ol14 : Pale yellow solids. Mp 85 °C (lit.,13 81-83 °C). MS 133 (M+). 1H-NMR
(CDCl3) ppm : 2.58 (1H, brs, OH), 4.53 (2H, d, J=5.9 Hz, CH2), 7.20-7.30 (1H, m, pyridine-H), 7.44 (1H,
d, J=7.9 Hz, pyridine-H), 7.67 (1H, td, J=7.9 Hz, 2.0 Hz, pyridine-H), 8.57 (1H, d, J=2.0 Hz, pyridine-H).
1
3-(Phenylethynyl)pyridine15 : Pale brown solids. Mp 50 °C (lit.,14 50-51 °C). MS 179 (M+). H-NMR
(CDCl3) ppm : 7.29 (1H, dd, J=7.8 Hz, 4.4 Hz, pyridine-H), 7.32-7.42 (3H, m, phenyl-H), 7.50-7.60 (2H,
m, phenyl-H), 7.81 (1H, dt, J=7.8 Hz, 1.5 Hz, pyridine-H), 8.55 (1H, dd, J=4.4 Hz, 1.5 Hz, pyridine-H),

HETEROCYCLES, Vol. 72, 2007
669
8.77 (1H, d, J=1.5 Hz, pyridine-H).
1
3-(1-Hexynyl)pyridine16 : Yellow liquids. MS 159 (M+). H-NMR (CDCl3) ppm : 0.96 (3H, t, J=7.3 Hz,
CH3CH2CH2CH2), 1.40-1.55 (2H, m, CH3CH2CH2CH2), 1.55-1.65 (2H, m, CH3CH2CH2CH2), 2.43 (2H, t,
J=6.9 Hz, CH3CH2CH2CH2), 7.22 (1H, dd, J=8.0 Hz, 4.6 Hz, pyridine-H), 7.67 (1H, dt, J=8.0 Hz, 1.6 Hz,
pyridine-H), 8.48 (1H, dd, J=4.6 Hz, 1.6 Hz, pyridine-H), 8.62 (1H, d, J=1.6 Hz, pyridine-H).
3-(3-Pyridinyl)-2-propyn-1-ol17 : White solids. Mp 101-102 °C (lit.,16 99-100 °C). MS 133 (M+).
1H-NMR (CDCl3) ppm : 2.76 (1H, brs, OH), 4.52 (2H, d, J=4.6 Hz, CH2), 7.20-7.32 (1H, m, pyridine-H),
7.74 (1H, dt, J=8.1 Hz, 2.0 Hz, pyridine-H), 8.53 (1H, dd, J=4.6 Hz, 2.0 Hz, pyridine-H), 8.73 (1H, d,
J=2.0 Hz, pyridine-H).
4-(Phenylethynyl)pyridine18 : Pale brown solids. Mp 94-94.5 °C (lit.,17 91-93 °C). MS 179 (M+).
1H-NMR (CDCl3) ppm : 7.35-7.42 (5H, m, phenyl and pyridine-H), 7.53-7.59 (2H, m, phenyl-H), 8.61
(2H, d, J=5.9 Hz, pyridine-H).
1
4-(1-Hexynyl)pyridine19 : Yellow liquids. MS 159 (M+). H-NMR (CDCl3) ppm : 0.95 (3H, t, J=7.3 Hz,
CH3CH2CH2CH2), 1.40-1.70 (4H, m, CH3CH2CH2CH2), 2.43 (2H, t, J=6.9 Hz, CH3CH2CH2CH2), 7.24
(2H, d, J=6.3 Hz, pyridine-H), 8.52 (2H, d, J=6.3 Hz, pyridine-H).
1
3-(4-Pyridinyl)-2-propyn-1-ol20 : Milky white solids. Mp 119-120 °C. MS 133 (M+). H-NMR (CDCl3)
ppm : 2.31 (1H, t, J=5.2 Hz, OH), 4.52 (2H, d, J=5.2 Hz, CH2), 7.29 (2H, d, J=5.8 Hz, pyridine-H), 8.57
(2H, d, J=5.8 Hz, pyridine-H).
1
5-(Phenylethynyl)pyrimidine12 : Dark brown liquids. MS 180 (M+). H-NMR (CDCl3) ppm : 7.28-7.69
(5H, m, phenyl-H), 8.85 (1H, s, pyrimidine-H), 9.13 (1H, s, pyrimidine-H).
2-(Phenylethynyl)quinoline21 : Pale yellow solids. Mp 64-65 °C (lit.,20 66-67 °C). MS 229 (M+). 1H-NMR
(CDCl3) ppm : 7.35-7.43 (3H, m, phenyl-H), 7.56 (1H, td, J=7.8 Hz, 1.4 Hz, quinoline-H), 7.62 (1H, d,
J=8.4 Hz, quinoline-H), 7.64-7.70 (2H, m, phenyl-H), 7.74 (1H, td, J=7.8 Hz, 1.4 Hz, quinoline-H), 7.81
(1H, d, J=7.8 Hz, quinoline-H), 8.14 (1H, d, J=7.8 Hz, quinoline-H), 8.15 (1H, d, J=8.4 Hz, quinoline-H).
2-(1-Hexynyl)quinoline19,21 : Yellow liquids. MS 209 (M+). 1H-NMR (CDCl3) ppm : 0.96 (3H, t, J=7.3 Hz,
CH3), 1.43-1.60 (2H, m, CH2), 1.60-1.74 (2H, m, CH2), 2.51 (2H, t, J=7.3 Hz, CH2), 7.46 (1H, d, J=8.4
Hz, quinoline-H), 7.52 (1H, t, J=7.8 Hz, quinoline-H), 7.70 (1H, dd, J=8.4 Hz, 7.8 Hz, quinoline-H), 7.77
(1H, d, J=7.8 Hz, quinoline-H), 8.08 (2H, d, J=8.4 Hz, quinoline-H).
3-(2-Quinolinyl)-2-propyn-1-ol21 : Brown solids. Mp 82-84 °C (lit.,20 86-87 °C). MS 183 (M+). 1H-NMR
(CDCl3) ppm : 2.97 (1H, brs, OH), 4.61 (2H, s, CH2), 7.50 (1H, d, J=8.5 Hz, quinoline-H), 7.55 (1H, t,
J=8.4 Hz, quinoline-H), 7.73 (1H, t, J=8.4 Hz, quinoline-H), 7.80 (1H, d, J=8.4 Hz, quinoline-H), 8.09
(1H, d, J=8.4 Hz, quinoline-H), 8.13 (1H, d, J=8.5 Hz, quinoline-H).
3-(Phenylethynyl)quinoline12 : Pale brown liquids. MS 229 (M+). 1H-NMR (CDCl3) ppm : 7.27-7.90 (8H,
m, phenyl- and quinoline-H), 8.11 (1H, d, J=8.3 Hz, quinoline-H), 8.30 (1H, d, J=1.9 Hz, quinoline-H),

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HETEROCYCLES, Vol. 72, 2007
9.00 (1H, d, J=1.9 Hz, quinoline-H).
1
4-(Phenylethynyl)quinoline21 : Yellow oil. MS 229 (M+). H-NMR (90 MHz, in CDCl3) ppm : 7.30-7.90
(8H, m, phenyl- and quinolinyl-H), 8.13 (1H, dd, J=7.3 Hz, 2.2 Hz, quinolinyl-H), 8.36 (1H, dd, J=7.3 Hz,
2.2 Hz, quinolinyl-H), 8.89 (1H, d, J=4.6 Hz, quinolinyl-H).
4-(1-Hexynyl)quinoline21 and 4-iodoquinoline (an inseparable mixture): Pale yellow solids with oil. MS
255 (M+) and 209 (M+). 1H-NMR (CDCl3) ppm : 1.00 (3H, t, J=7.3 Hz, CH3CH2CH2CH2), 1.48-1.78 (4H,
m, CH3CH2CH2CH2), 2.60 (2H, t, J=7.3 Hz, CH3CH2CH2CH2), 7.43 (1H, d, J=4.6 Hz, product-H),
7.55-7.80 (m, product and substrate-H), 7.98-8.13 (m, product and substrate-H), 8.27 (1H, d, J=7.3 Hz,
product-H), 8.46 (0.69H, d, J=4.6 Hz, substrate-H), 8.83 (1H, d, J=4.6 Hz, product-H).
3-(4-Quinolinyl)-2-propyn-1-ol21 : Pale orange solids. Mp 142-143 °C (dec.) (lit.,20 142-144 °C). MS 183
(M+). 1H-NMR (CDCl3) ppm : 2.66 (1H, brs, OH), 4.69 (2H, s, CH2), 7.46 (1H, d, J=4.6 Hz, quinoline-H),
7.59 (1H, t, J=8.1 Hz, quinoline-H), 7.74 (1H, t, J=8.1 Hz, quinoline-H), 8.13 (1H, d, J=8.1 Hz,
quinoline-H), 8.24 (1H, d, J=8.1 Hz, quinoline-H), 8.86 (1H, d, J=4.6 Hz, quinoline-H).
2-Methyl-9-phenyl-6-(phenylethynyl)purine : White needles (recryst. from benzene). Mp 207-208 °C. MS
1
310 (M+). H-NMR (CDCl3) ppm : 2.86 (3H, s, CH3), 7.36-7.46 (3H, m, phenyl-H), 7.48-7.54 (1H, m,
phenyl-H), 7.56-7.66 (2H, m, phenyl-H), 7.72-7.82 (4H, m, phenyl-H), 8.35 (1H, s, C8-H). Anal. Calcd
for C20H14N4: C, 77.40; H, 4.55; N, 18.05. Found: C, 77.23; H, 4.54; N, 18.03.
6-(1-Hexynyl)-2-methyl-9-phenylpurine : Pale brown needles (recryst. from petroleum benzin). Mp
1
107-108 °C. MS 290 (M+). H-NMR (CDCl3) ppm : 0.96 (3H, t, J=7.3 Hz, CH3CH2CH2CH2), 1.53 (2H,
sextet, J=7.3 Hz, CH3CH2CH2CH2), 1.73 (2H, quintet, J=7.3 Hz, CH3CH2CH2CH2), 2.62 (2H, t, J=7.3 Hz,
CH3CH2CH2CH2), 2.81 (3H, s, CH3), 7.48 (1H, t, J=7.8 Hz, phenyl-H), 7.59 (2H, t, J=7.8 Hz, phenyl-H),
7.73 (2H, d, J=7.8 Hz, phenyl-H), 8.30 (1H, s, purine-H). Anal. Calcd for C18H18N4: C, 74.46; H, 6.25; N,
19.30. Found: C, 74.40; H, 6.28; N, 19.17.
1
2-(Phenylethynyl)quinoxaline22 : Yellow solids. MS 230 (M+). Mp 65 °C (lit.,21 64-65 °C). H-NMR
(CDCl3) ppm : 7.32-7.48 (3H, m, phenyl-H), 7.63-7.73 (2H, m, phenyl-H), 7.73-7.85 (2H, m,
quinoxaline-H), 8.05-8.15 (2H, m, quinoxaline-H), 8.99 (1H, s, quinoxaline-H).
1
2-(1-Hexynyl)quinoxaline23 : Yellow oil. MS 210 (M+). H-NMR (CDCl3) ppm : 0.98 (3H, t, J=7.3 Hz,
CH3CH2CH2CH2), 1.45-1.60 (2H, m, CH3CH2CH2CH2), 1.60-1.76 (2H, m, CH3CH2CH2CH2), 2.55 (2H, t,
J=7.3 Hz, CH3CH2CH2CH2), 7.69-7.82 (2H, m, quinoxaline-H), 8.02-8.11 (2H, m, quinoxaline-H), 8.83
(1H, s, quinoxaline-H).
3-(2-Quinoxalinyl)-2-propyn-1-ol24 : Pale brown solids. Mp 142 °C (lit.,23 140-141 °C). MS 184 (M+).
1H-NMR (CDCl3) ppm : 2.34 (1H, q, J=6.1 Hz, OH), 4.63 (2H, d, J=6.1 Hz, CH2), 7.73-7.87 (2H, m,
quinoxaline-H), 8.02-8.17 (2H, m, quinoxaline-H), 8.90 (1H, s, quinoxaline-H).

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