Trichloroisocyanuric acid as an efficient homogeneous catalyst for the chemoselective synthesis of 2-substituted oxazolines, imidazolines and thiazolines under solvent-free condition

Article abstract of DOI:10.2298/JSC111031028H

Trichloroisocyanuric acid, as a commercially available and inexpensive catalyst, was used in a new, facile and efficient procedure for the synthesis of 2-oxazolines, 2-imidazolines and 2-thiazolines through the reaction of nitriles with 2-aminoethanol, ethylenediamine or 2-aminoethanethiol under solvent-free conditions.

Full text of DOI:10.2298/JSC111031028H

J. Serb. Chem. Soc. 77 (9) 1181–1189 (2012)
UDC 546.133.2’268.2:547.78:544.478:544.351
JSCS–4343
Original scientific paper
Trichloroisocyanuric acid as an efficient homogeneous catalyst
for the chemoselective synthesis of 2-substituted oxazolines,
imidazolines and thiazolines under solvent-free condition
SEYEDEH FATEMEH HOJATI* and SEYEDE ATEFE NEZHADHOSEINY
Department of Chemistry, Sabzevar Tarbiat Moallem University, Sabzevar 9617976487, Iran
(Received 31 October 2011, revised 21 March 2012)
Abstract: Trichloroisocyanuric acid, as a commercially available and inexpen-
sive catalyst, was used in a new, facile and efficient procedure for the synthesis
of 2-oxazolines, 2-imidazolines and 2-thiazolines through the reaction of
nitriles with 2-aminoethanol, ethylenediamine or 2-aminoethanеthiol under
solvent-free conditions.
Keywords: trichloroisocyanuric acid; oxazoline; imidazoline; thiazoline; sol-
vent-free condition.
INTRODUCTION
Developing new and efficient methods for the synthesis of heterocyclic bio-
logically active natural compounds has received considerable attention in organic
chemistry. This importance is due to their great applications in medicine. Oxazo-
lines, imidazolines and thiazolines are important substructures in a large number
1,2
of biologically active natural products. Many derivatives of these heterocycles
3,4
5
6
have shown antihypertensive, antidepressive, antihypercholesterolemic, anti-
7
8
9
diabetic, antitumor and anti-inflammatory properties. In addition to these se-
rious affairs, they are also known as valuable intermediates in organic transfor-
10,11
mations.
Furthermore, optically active mono- and bis-derivatives of these
heterocycles have been widely used as both auxiliaries and ligands in asymmetric
12–14
syntheses.
Numerous methods have been reported for the synthesis of 2-oxazolines,
15–25
2-imidazolines and 2-thiazolines from various precursors.
Although some of
these procedures have been successfully used for the synthesis of these hetero-
cycles, most of them suffer from disadvantages such as: strong acidic conditions,
long reaction times, low yields of products, use of complex and expensive re-
*Corresponding author. E-mail: sfhojati@sttu.ac.ir
doi: 10.2298/JSC111031028H
1181

1182
HOJATI and NEZHADHOSEINY
agents and toxic solvents. Therefore, the introduction of a new efficient method
for the synthesis of these useful moieties is still in demand.
Trichloroisocyanuric acid (1,3,5-trichloro-1,3,5-triazine-2,4,6(1H,3H,5H)-tri-
one or TCCA) is an N-halo compound which has been known since 1902 (Fig.
1). It has been used primarily as a disinfectant in swimming pools and water
26
treatment. Recently, TCCA has become attractive candidate as a homogeneous
27–35
catalyst in organic transformations
due to its lack of volatility, commercial
availability, low cost and ease of handling.
Fig. 1. Structure of trichloroisocyanuric acid.
Consequently, in continuation of our interest in the synthesis of 2-oxazoline,
36–38
2-imidazoline and 2-thiazoline derivatives,
this field was investigated (Scheme 1).
the catalytic activity of TCCA in
Scheme 1. Synthesis of 2-oxazoline, 2-imidazoline and 2-thiazoline derivatives
using TCCA as catalyst.
EXPERIMENTAL
General procedure for the conversion of nitriles to 2-oxazolines, 2-imidazolines and
2-thiazolines
A mixture of a nitrile (l mmol), 2-aminoethanol (6 mmol), ethylenediamine (4 mmol) or
2-aminoethanethiol (1.2 mmol) and TCCA (0.03 mmol for oxazoline, 0.1 mmol for imida-
zoline and 0.01 mmol for thiazoline synthesis) was stirred at 110 °C for an appropriate time,
according to Table I. The reaction was performed under solvent-free conditions. After com-
pletion of the reaction, monitored by TLC (eluent: n-hexane:EtOAc, 2:1 for oxazolines and
thiazolines, EtOAc:methanol, 10:1 for imidazolines), the reaction mixture was cooled to room
temperature and the crude product (1c–24c) was purified by column chromatography to afford
the pure products in high yields (Table I).

TRICHLOROISOCYANURIC ACID AS HOMOGENEOUS CATALYST
1183
TABLE I. Synthesis of 2-oxazolines, 2-imidazolines and 2-thiazolines from nitriles catalyzed
by TCCA
Product (c)a
O
Yieldb, %
95
No.
Nitrile (a)
Time, min
60
1c
CN
N
O
2c
30
90
CN
N
O
Cl
Cl
Cl
3c
4c
120
60
98
90
O
N
Cl
CN
CN
CN
N
O
N
N
5c
6c
20
94
93
N
N
N
O
140
CN
CN
S
N
S
7c
8c
240
120
90
85
H
N
N
H
N
CN
N
Cl
Cl
9c
H
N
180
150
93
93
Cl
CN
Cl
N
10c
H
N
Br
CN
Br
N

1184
HOJATI and NEZHADHOSEINY
TABLE I. Continued
Product (c)a
Yieldb, %
98
Entry
Nitrile (a)
Time, min
8
11c
H
N
CN
CN
CN
N
N
N
12c
13c
14c
15c
H
N
150
15
95
94
90
95
N
N
N
H
N
N
N
N
120
2
H
N
CN
S
N
S
S
CN
N
16c
17c
1
5
96
97
S
F
CN
F
N
S
Cl
CN
Cl
N
18c
19c
2
2
80
98
S
Br
CN
Br
N
S
CN
N
O2N
HO
O2N
20c
21c
3
2
60
50
S
HO
CN
N
S
MeO
MeO
CN
N

TRICHLOROISOCYANURIC ACID AS HOMOGENEOUS CATALYST
1185
TABLE I. Continued
Product (c)a
S
Yieldb, %
Entry
Nitrile (a)
Time, min
1
22c
98
CN
N
N
N
S
23c
3
2
97
98
CN
CN
N
N
N
S
24c
S
S
N
a
The products were identified by comparison of their physical and spectral data with those of authentic samples;
isolated yield
b
General method for the conversion of dinitriles to mono- and bis-oxazolines,
mono-imidazolines and bis-thiazolines
To a mixture of a dinitrile (1 mmol) and 2-aminoethanol (10 mmol), ethylenediamine (8
mmol) or 2-aminoethanethiol (2.5 mmol), TCCA (0.06 mmol for oxazoline, 0.15 mmol for
imidazoline and 0.02 mmol for thiazoline synthesis) was added. The reaction mixture was
stirred at 110 °C without solvent. The progress of the reaction was followed by TLC (eluent:
n-hexane:EtOAc, 2:1 for mono- and bis-oxazolines and bis-thiazolines, EtOAc:methanol, 10:1
for mono-imidazolines). After the appropriate time according to Table II, the pure products
(1f–8f) were gained by column chromatography.
RESULTS AND DISCUSSION
In continuation of our work to recommend new catalysts for organic
36–42
syntheses,
now TCCA as a highly efficient homogeneous catalyst for the
preparation of 2-oxazolines, 2-imidazolines and 2-thiazolines from nitriles is pre-
sented (Scheme 1).
In order to find the optimum reaction conditions, benzonitrile was reacted
with 2-aminoethanol in the presence of TCCA. The model reaction was per-
formed using different molar ratios of substrates and catalyst, at various tempe-
ratures and in different polar and non-polar solvents. With the goal of performing
the synthesis in the absence of solvent as a special advantage of the method, the
model reaction was also investigated under solvent-free conditions. The best re-
sult was obtained in the reaction of benzonitrile (1 mmol), 2-aminoethanol (6
mmol) and TCCA (0.03 mmol) at 110 °C under solvent-free conditions (Table I,
entry 1). Using these optimized conditions, a variety of aromatic and heteroaro-
matic nitriles were reacted with 2-aminoethanol and corresponding 2-oxazolines
were generated in high yields (Table I, entries 1–6).
Similarly, the model reaction of benzonitrile with ethylenediamine was per-
formed in the presence of TCCA for optimization of 2-phenylimidazoline syn-

1186
HOJATI and NEZHADHOSEINY
thesis. After several experiments, 1:4:0.1 molar ratio of benzonitrile: ethylene-
diamine: catalyst at 110 °C in the absence of solvent was selected as the best re-
action conditions (Table I, entry 7). Subsequently, heterocyclization of a great
variety of aromatic and heteroaromatic nitriles with ethylenediamine were per-
formed to prepare the corresponding 2-imidazoline products (Table I, entries 7–
–14).
Furthermore, cyclocondensation of benzonitrile with 2-aminoethanethiol was
performed in the presence of different amounts of TCCA. The effects of tem-
perature and solvent were also investigated. The best result was obtained with
1:1.2:0.01 molar ratios of benzonitrile:2-aminoethanethiol:TCCA at 110 °C under
solvent-free conditions. Various aromatic and heteroaromatic nitriles were re-
acted with 2-aminoethanethiol in the presence of TCCA under the optimum re-
action conditions. The corresponding 2-substituted thiazolines were generated in
good to excellent yields (Table I, entries 15–24).
Extensive applications of both chiral and achiral bis-oxazolines, bis-imi-
dazolines and bis-thiazolines as ligands in various complex structures promoted
the use of the present method for the synthesis of these useful ligands from di-
nitriles. Therefore, dicyanobenzene derivatives were reacted with 2-aminoetha-
nol, ethylenediamine or 2-aminoethanethiol in the presence of TCCA at 110 °C
under solvent-free conditions (Table II). As given in Table II, the conversion of
dinitriles to mono-oxazolines (10–20 min) and bis-oxazolines (300–390 min) is a
special time-dependent chemo-selective procedure. It is also important to note
that the synthesis of mono-imidazolines and bis-thiazolines is a chemo-selective,
but not a time-dependent reaction (Table II). Mono-imidazolines were satisfac-
torily produced after 20–30 min (Table II, 5f and 6f) and prolonging the reaction
time did not lead to the production of the corresponding bis-imidazolines.
Whereas, bis-thiazolines were exclusively obtained from the reactions of dinit-
riles with 2-aminoethanethiol after 7–10 min (Table II, 7f and 8f).
TABLE II. Synthesis of mono- and bis-derivatives of oxazolines, imidazolines and thiazolines
from dinitriles catalyzed by TCCA
Entry
Dinitrile (e)
Product (f)a
Time, min Yieldb, %
1f
10
95
O
CN
N
NC
NC
NC
NC
2f
20
92
O
N
CN

TRICHLOROISOCYANURIC ACID AS HOMOGENEOUS CATALYST
1187
TABLE II. Continued
Entry
3f
Dinitrile (e)
Product (f)a
Time, min Yieldb, %
O
N
300
80
CN
N
NC
O
4f
390
20
97
92
N
O
O
N
NC
CN
5f
H
N
CN
N
NC
NC
6f
30
7
95
95
H
N
NC
CN
NC
N
7f
CN
S
S
NC
N
N
S
8f
S
10
92
NC
CN
N
a
The products were identified by comparison of their physical and spectral data with those of authentic samples;
b
isolated yield
It is noteworthy that the method is selective for the reaction of aromatic
nitriles as aliphatic nitriles are unreactive under these conditions.
In order to show the superiority of TCCA over other catalysts, the results
obtained in the present study for the synthesis of 2-phenyloxazoline are com-
pared with some other results reported in the literature in Table III. It is note-
TABLE III. Comparison of some other procedures with the present method for the synthesis
of 2-phenyloxazoline (1c)
Entry Catalyst amount, mol %
Temperature, °C
Time, h
Yield, %
Ref.
1
2
3
4
5
TCCA (3)
Bi(OTf)3 (5)
ZrOCl2.8H2O (10)
H3PW12O40 (1)
ZnCl2 (1.25)
110
100
100
1
3.5
5
3.5
12
95
88
90
85
74
–
31
33
–
100
130, under N2
34

1188
HOJATI and NEZHADHOSEINY
worthy that the catalytic activity of TCCA was greater than those of some active
Lewis acids or solid acids, as given in Table III.
CONCLUSIONS
In summary, TCCA was employed as a novel and highly efficient catalyst
for the synthesis of 2-oxazolines, 2-imidazolines and 2-thiazolines from nitriles
in high yields. This homogeneous catalyst is commercially available, inexpensive
and non-volatile and is a chemical commonly found in organic laboratories.
Furthermore, the efficiency and chemoselectivity of the protocol was also inves-
tigated in the selective preparation of aromatic and heteroaromatic mono- and
bis-oxazolines, mono-imidazolines and bis-thiazolines. In addition, the absence
of hazardous and non-green solvents, easy work-up and approximately short
reaction times are another noteworthy advantage of the reported protocols.
SUPPLEMENTRY MATERIAL
The physical and spectral data of the prepared compounds are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgments. The authors are grateful to the Research Council of Sabzevar Tarbiat
Moallem University, Iran, for the financial support of this work.
И З В О Д
ТРИХЛОРИЗОЦИЈАНУРНА КИСЕЛИНА КАО ЕФИКАСАН ХОМОГЕНИ КАТАЛИЗАТОР
У ХЕМOСЕЛЕКТИВНОЈ СИНТЕЗИ 2-СУПСТИТУИСАНИХ ОКСАЗОЛИНА,
ИМИДАЗОЛИНА И ТИАЗОЛИНА У РЕАКЦИЈАМА БЕЗ РАСТВАРАЧА
SEYEDEH FATEMEH HOJATI и SEYEDE ATEFE NEZHADHOSEINY
Department of Chemistry, Sabzevar Tarbiat Moallem University, Sabzevar 9617976487, Iran
Трихлоризоцијанурна киселина је комерцијално доступан и приступачан реагенс,
који је употребљен као катализатор у синтези 2-оксазолина, 2-имидазолина и 2-ти-
азолина, у реакцији 2-аминоетанола, етилендиамина или 2-аминоетантиола у одсуству
растварача.
(Примљено 31. октобра 2011, ревидирано 21. марта 2012)
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