Solvent-free reaction using phosphonium salts: Chlorination of hydroxyheteroaromatics and dehydration of primary amides

Article abstract of DOI:10.3987/COM-06-10820

Solvent-free chlorination of heteroaromatics using the phosphonium salt, prepared by reaction of triphenylphosphine with N-chlorosuccinimide, was accomplished by microwave-irradiation or heating to give the corresponding chloroheteroaromatics. Similarly, primary amides was converted into nitriles by this method.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10820

HETEROCYCLES, Vol. 68, No. 9, 2006
1973
HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1973 - 1979. © The Japan Institute of Heterocyclic Chemistry
Received, 20th June, 2006, Accepted, 21st July, 2006, Published online, 21st July, 2006. COM-06-10820
SOLVENT-FREE REACTION USING PHOSPHONIUM SALTS :
CHLORINATION
OF
HYDROXYHETEROAROMATICS
AND
DEHYDRATION OF PRIMARY AMIDES
Tatsuya Takahashi, Osamu Sugimoto,* Jiro Koshio, 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 - Solvent-free chlorination of heteroaromatics using the phosphonium
salt, prepared by reaction of triphenylphosphine with N-chlorosuccinimide, was
accomplished by microwave-irradiation or heating to give the corresponding
chloroheteroaromatics. Similarly, primary amides was converted into nitriles by
this method.
π-Deficient chloroheteroaromatics play a versatile role in organic synthesis. For example, they react with
1
nucleophiles to introduce nucleophilic substituents into the heteroaromatic ring. Introduction of
2
3
electrophilic substituents into the heteroaromatic ring can be accomplished by lithiation or magnesiation
of chloroheteroaromatics followed by reaction with electrophiles.
Figure 1. Structure of phosphonium salt (1)
+
Cl
N
Cl PPh3
-
N
dioxane, rt
O
O
O
O
PPh3
+
1
It is found that the chlorophosphonium salt (1, Figure 1), prepared by reaction of triphenylphosphine with
N-chlorosuccinimide, is useful for chlorination of nitrogen - containing heteroaromatics or dehydration of
4
primary amides. The phosphonium salts (1) show mild reactivity with water compared to the

1974
HETEROCYCLES, Vol. 68, No. 9, 2006
conventional chlorinating reagent such as phosphoryl chloride (phosphorus oxychloride, POCl
thionyl chloride, and addition of water to the reaction mixture at the work-up is not needed.
3
) and
In organic reactions, use of an organic solvent is a general method to mix a substrate with reagents.
However, from the viewpoint of protection of the environment and reduction of chemical resources,
development of solvent-free organic reactions would be helpful for us. Recently, microwave-irradiated
5
reaction of hydroxyheteroaromatics and primary amides using 1 without a solvent was preliminarily
6
reported by us. Here, we would like to report our further study using 1 under a solvent-free condition,
heating and microwave-irradiation.
At first, chlorination of 2(1H)-quinolinone using 1 was carried out under a variety of conditions in order
to optimize the condition as shown in Table 1. Microwave-irradiation was discontinued when the reaction
mixture melted and turned black. Both heating and microwave-irradiation gave the product,
2
-chloroquinoline, in good yields when excess amount of 1 (2 - 4 eq) was used. Under the heating
condition, the use of 1 (2 eq) was found to be the best condition (Table 1, Entry 5). Under
microwave-irradiating condition, on the contrary, at least 4 eq of 1 was required to afford the product in
good yield (Table 1, Entry 16). However, it is useful that the reaction of microwave-irradiated
chlorination requires shorter time than that of the heating condition.
Table 1. Optimization for solvent-free chlorination of 2(1H)-quinolinone using 1
1
No solvent
N
OPPh
Cl
3
N
H
O
N
Cl
O=PPh3
Heating
Microwave-irradiation
Entry
1 (eq)
Condition
Yield (%)
38
Entry
1 (eq)
Condition
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
2
2
3
4
80 ˚C, 2 h
105 ˚C, 2 h
130 ˚C, 2 h
150 ˚C, 2 h
130 ˚C, 2 h
130 ˚C, 4 h
9
1
1
1
1
1
2
3
4
150 W, 30 min
300 W, 11.5 min
600 W, 8 min
700 W, 3.5 min
1000 W, 5.5 min
300 W, 8 min
300 W, 7.5 min
300 W, 7 min
15
21
3
41
10
11
12
13
14
15
16
54
21
13
11
22
38
64
72
62
66
1
1
30 ˚C, 2 h
30 ˚C, 2 h
67
Table 2 shows the results of solvent-free chlorination of hydroxyheteroaromatics. The optimized
condition obtained in Table 1 was used (heating : 130 ˚C, 2 h with 2 eq of 1; microwave-irradiation : 300
W with 4 eq of 1). It was found that a variety of nitrogen-containing heteroaromatics can be applied to the
chlorination.

HETEROCYCLES, Vol. 68, No. 9, 2006
1975
Table 2. Solvent-free chlorination of hydroxyheteroaromatics
1
Het OH
Het OPPh Cl
Het Cl
3
No solvent
O=PPh3
Amount of
Entry
Het-OH
Condition
Het-Cl
N
Yield (%)
1
(eq)
2
1
2
130 °C, 2 h
72
64
N
H
O
Cl
4
2
300 W, 7 min
O
Cl
3
4
130 °C, 2 h
83
61
4
300 W, 8.5 min
N
H
N
O
Cl
N
5
6
2
4
130 °C, 2 h
81
18
NH
N
300 W, 10.5 min
Me
N
N
Me
Me
N
Me
N
O
N
Cl
7
2
4
130 °C, 2 h
12
19
NH
N
N
N
8
9
300 W, 6 min
Ph
Ph
N
2
4
130 °C, 2 h
N
N
51
64
N
O
1
0
300 W, 5 min
Cl
N
H
O
Cl
11
2
4
2
130 °C, 2 h
300 W, 3 min
130 °C, 2 h
30
27
28
NH
1
1
2
3
N
N
OH
Cl
N
1
1
1
4
5
6
N
H
O
4
2
4
300 W, 5 min
130 °C, 2 h
42
20
10
Cl
H
N
O
O
N
N
Cl
Cl
N
H
300 W, 2.5 min
As an application, dehydration of primary amides using 1 was carried out under solvent-free condition as
shown in Table 3. In order to find the optimized condition, the reaction temperature was varied. It was
found that heating at 60-100 °C for 2 h was the best condition to give the product.

1976
HETEROCYCLES, Vol. 68, No. 9, 2006
Table 3. Solvent - free dehydration of primary amides
O
1
OPPh Cl
3
R
CN
R
NH2
No solvent
R
NH
O=PPh3
Amount
Entry
R-CONH2
Condition
R-CN
Yield (%)
of 1 (eq)
1
2
3
4
5
6
7
8
9
2
50 °C, 2 h
60 °C, 2 h
75
90
90
75
56
23
46
95
19
53
24
56
77
81
66
2
2
2
80 °C, 2 h
105 °C, 2 h
130 °C, 2 h
300 W, 6.5 min
300 W, 6.5 min
300 W, 5 min
60 °C, 2 h
MeO
CONH2
MeO
CN
2
1
2
4
2
2
1
0
105 °C, 2 h
130 °C, 2 h
300 W, 4.5 min
60 °C, 2 h
CONH2
CN
11
2
4
1
1
1
1
2
3
4
5
2
CH CONH2
105 °C, 2 h
300 W, 6 min
CH CN
2
2
2
4
In conclusion, solvent-free chlorination of hydroxyheteroaromatics and dehydration of primary amides
was accomplished. Although it is useful that microwave-irradiated reaction using 1 is complete in a few
minutes, the reaction sometimes results in a lowering of yields of the products. On the contrary, heatintg
reaction using 1 generally afforded the products in higher yields than microwave-irradiated reaction.
EXPERIMENTAL
1
Microwave-irradiation was carried out using a microwave oven (Matsushita NE-J720, Japan). H-NMR
spectra was measured with HITACHI R-90H spectrometer using tetramethylsilane as an internal standard.
Preparation of 1 : To a solution of triphenylphosphine (2623 mg, 10.0 mmol) in dioxane (100 ml),
N-chlorosuccinimide (1335 mg, 10.0 mmol) was added little by little and stirred for 30 min. The white
solid was filtered and dried under reduced pressure to give 1 in quantitative yield.
2
-Chloroquinoline : A mixture of 2(1H)-quinolinone (290 mg, 2.00 mmol) and 1 (1583 mg, 4.00 mmol)
was heated at 130 °C for 2 h. After the reaction mixture was dissolved in dichloromethane and basified

HETEROCYCLES, Vol. 68, No. 9, 2006
1977
with triethylamine, dichloromethane and triethylamine was removed under reduced pressure. The residue
was treated with silica gel column chromatography (eluted with hexane-ethyl acetate (5:1)) to give
1
3
2
3
-chloroquinoline (236 mg, 72%). H-NMR (CDCl ) ppm : 7.37 (1H, d, J=8.7 Hz, C -H), 7.43-7.68 (1H,
6
5
7
8
4
m, C -H), 7.68-7.89 (2H, m, C and C -H), 8.03 (1H, d, J=8.1 Hz, C -H), 8.08 (1H, d, J=8.7 Hz, C -H).
-Chloroquinoline : A mixture of 4(1H)-quinolinone (290 mg, 2.00 mmol) and 1 (1583 mg, 4.00 mmol)
4
was heated at 130 °C for 2 h. After the reaction mixture was dissolved in dichloromethane and basified
with triethylamine, dichloromethane and triethylamine was removed under reduced pressure. The residue
was treated with silica gel column chromatography (eluted with hexane-ethyl acetate (5:1)) to give
1
3
4
-chloroquinoline (272 mg, 83%). H-NMR (CDCl ) ppm : 7.49 (1H, d, J=4.7 Hz, C -H), 7.57-7.90 (2H,
3
6
7
5
8
2
m, C and C -H), 8.00-8.33 (2H, m, C and C -H), 8.78 (1H, d, J=4.7 Hz, C -H).
-Chloro-2,6-dimethylpyrimidine : A mixture of 2,6-dimethyl-4(3H)-pyrimidinone (248 mg, 2.00 mmol)
4
and 1 (1583 mg, 4.00 mmol) was heated at 130 °C for 2 h. After the reaction mixture was dissolved in
dichloromethane and basified with triethylamine, dichloromethane and triethylamine was removed under
reduced pressure. The residue was treated with silica gel column chromatography (eluted with
1
hexane-ethyl acetate (3:2)) to give 4-chloro-2,6-dimethylpyrimidine (228 mg, 81%). H-NMR (CDCl
3
)
5
ppm : 2.48 (3H, s, CH
3
), 2.67 (3H, s, CH
3
), 7.03 (1H, s, C -H).
4
4
3
-Chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine : A mixture of 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-
(5H)-one (424 mg, 2.00 mmol) and 1 (3167 mg, 8.00 mmol) was treated with microwave-irradiation at
00 W for 6 min. After the reaction mixture was dissolved in dichloromethane and basified with
triethylamine, dichloromethane and triethylamine was removed under reduced pressure. The residue was
treated with silica gel column chromatography (eluted with hexane-ethyl acetate (5:1)) to give
1
4
-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (44 mg, 19%). H-NMR (CDCl
3
) ppm : 7.30-7.70 (3H,
3
6
m, phenyl-H), 8.06-8.28 (2H, m, phenyl-H), 8.34 (1H, s, C -H), 8.87 (1H, s, C -H).
-Chloroquinoxaline : A mixture of 2(1H)-quinoxalinone (292 mg, 2.00 mmol) and 1 (3167 mg, 8.00
2
mmol) was treated with microwave-irradiation at 300 W for 5 min. After the reaction mixture was
dissolved in dichloromethane and basified with triethylamine, dichloromethane and triethylamine was
removed under reduced pressure. The residue was treated with silica gel column chromatography (eluted
1
with hexane-ethyl acetate (4:1)) to give 2-chloroquinoxaline (211 mg, 64%). H-NMR (CDCl
3
) ppm :
6
7
5
8
3
7
.65-7.91 (2H, m, C and C -H), 7.91-8.24 (2H, m, C and C -H), 8.78 (1H, s, C -H).
-Chloroquinazoline : A mixture of 4(3H)-quinazolinone (292 mg, 2.00 mmol) and 1 (1583 mg, 4.00
4
mmol) was heated at 130 °C for 2 h. After the reaction mixture was dissolved in dichloromethane and
basified with triethylamine, dichloromethane and triethylamine was removed under reduced pressure. The
residue was treated with silica gel column chromatography (eluted with hexane-ethyl acetate (2:1)) to
1
give 4-chloroquinazoline (99 mg, 30%). H-NMR (CDCl
3
) ppm : 7.72 (1H, ddd, J=8.7 Hz, 6.4 Hz, 1.7 Hz,

1978
HETEROCYCLES, Vol. 68, No. 9, 2006
6
7
8
5
2
C -H), 7.82-8.17 (2H, m, C and C -H), 8.27 (1H, dd, J=8.1 Hz, 0.8 Hz, C -H), 9.05 (1H, s, C -H).
2
8
,4-Dichloroquinoline : A mixture of 4-hydroxy-2(1H)-quinolinone (322 mg, 2.00 mmol) and 1 (3167 mg,
.00 mmol) was treated with microwave-irradiation at 300 W for 5 min. After the reaction mixture was
dissolved in dichloromethane and basified with triethylamine, dichloromethane and triethylamine was
removed under reduced pressure. The residue was treated with silica gel column chromatography (eluted
1
with hexane-ethyl acetate (10:1)) to give 2,4-dichloroquinoline (165 mg, 42%). H-NMR (CDCl
3
) ppm :
3
6
7
8
7
.51 (1H, s, C -H), 7.51-7.91 (2H, m, C and C -H), 8.04 (1H, d, J=7.7 Hz, C -H), 8.21 (1H, d, J=7.5 Hz,
5
C -H).
2,3-Dichloroquinoxaline : A mixture of 2,3(1H,4H)-quinoxalinedione (324 mg, 2.00 mmol) and 1 (1583
mg, 4.00 mmol) was heated at 130 °C for 2 h. After the reaction mixture was dissolved in
dichloromethane and basified with triethylamine, dichloromethane and triethylamine was removed under
reduced pressure. The residue was treated with silica gel column chromatography (eluted with
1
hexane-ethyl acetate (10:1)) to give 2,3-dichloroquinoxaline (80 mg, 20%). H-NMR (CDCl
3
) ppm :
6
7
5
8
7
.65-7.90 (2H, m, C and C -H), 7.90-8.16 (2H, m, C and C -H).
-Methoxybenzonitrile : A mixture of 4-methoxybenzamide (302 mg, 2.00 mmol) and 1 (3167 mg, 8.00
4
mmol) was treated with microwave-irradiation at 300 W for 5 min. After the reaction mixture was
dissolved in dichloromethane and basified with triethylamine, dichloromethane and triethylamine was
removed under reduced pressure. The residue was treated with silica gel column chromatography (eluted
1
with hexane-ethyl acetate (2:1)) to give 4-methoxybenzonitrile (253 mg, 95%). H-NMR (CDCl
3
) ppm :
3
5
2
6
3
3
.85 (3H, s, OCH ), 6.94 (2H, d, J=9.0 Hz, C and C -H), 7.59 (2H, d, J=9.0 Hz, C and C -H).
Benzonitrile : A mixture of benzamide (242 mg, 2.00 mmol) and 1 (3167 mg, 8.00 mmol) was treated
with microwave-irradiation at 300 W for 4.5 min. After the reaction mixture was dissolved in
dichloromethane and basified with triethylamine, dichloromethane and triethylamine was removed under
reduced pressure. The residue was treated with silica gel column chromatography (eluted with
1
hexane-ethyl acetate (10:1)) to give benzonitrile (115 mg, 56%). H-NMR (CDCl
3
) ppm : 7.40-7.75 (5H,
m, phenyl-H).
Phenylacetonitrile : A mixture of phenylacetamide (270 mg, 2.00 mmol) and 1 (1583 mg, 4.00 mmol) was
heated at 105 °C for 2 h. After the reaction mixture was dissolved in dichloromethane and basified with
triethylamine, dichloromethane and triethylamine was removed under reduced pressure. The residue was
treated with silica gel column chromatography (eluted with hexane-ethyl acetate (5:1)) to give
1
phenylacetonitrile (190 mg, 81%). H-NMR (CDCl
3
) ppm : 3.73 (2H, s, CH
2
), 7.34 (5H, s, phenyl-H).

HETEROCYCLES, Vol. 68, No. 9, 2006
1979
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