Synthesis and fungicidal activity of 2-imino-3-(4-arylthiazol-2-yl)- thiazolidin-4-ones and their 5-arylidene derivatives

Article abstract of DOI:10.3390/50901055

Five derivatives of 2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones and a series of their 5-arylidene derivatives have been synthesized and tested for antifungal activity against seven agricultural fungi. 2-Imino-3-(2,4-dichloro-5- fluorophenylthiazol-2-yl)-4-thiazolidi-none and 2-imino-3-(2,4- dichlorophenylthiazol-2-yl)-4-thiazolidione, both of them new compounds, exhibited higher fungicidal effects than the other compounds prepared.

Full text of DOI:10.3390/50901055

Molecules 2000, 5, 1055-1061
molecules
ISSN 1420-3049
© 2000 by MDPI
http://www.mdpi.org
Synthesis and Fungicidal Activity of 2-Imino-3-(4-arylthiazol-2-
yl)-thiazolidin-4-ones and Their 5-Arylidene Derivatives
2,
Hui-Ling Liu1,2, Zongcheng Li1 and Thorleif Anthonsen *
1Pesticide Lab 3, Shenyang Research Institute of Chemical Industry, 110021 Shenyang, P.R. China
2Department of Chemistry, Norwegian University of Science and Technology, N-7491 Trondheim,
Norway
Tel.: +47 73596206, Fax: +47 73596255, E-mail: Thorleif.Anthonsen@chembio.ntnu.no
Received: 15 August 2000 / Accepted: 29 August 2000 / Published: 5 September 2000
Abstract: Five derivatives of 2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones and a series of their
5-arylidene derivatives have been synthesized and tested for antifungal activity against seven agri-
cultural fungi. 2-Imino-3-(2,4-dichloro-5-fluorophenylthiazol-2-yl)-4-thiazolidi-none and 2-imino-
3-(2,4-dichlorophenylthiazol-2-yl)-4-thiazolidione, both of them new compounds, exhibited higher
fungicidal effects than the other compounds prepared.
Keywords: 2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones, 5-arylidene derivatives, antifungal
activity.
Introduction
Thiazolidin-4-ones are important compounds due to their broad range of biological activities [1-7]. Over-
views of their synthesis, properties, reactions and applications have been published[8,9]. 2-Imino-thiazolidin-
4-ones have been found to have antifungal activity[10-12], and a convenient method for synthesis involves the
reaction of 2-haloacetamides with potassium thiocyanate to produce 2-imino-thiazolidin-4-ones. The R-N-
group at the 3-position of thiazolidin-4-ones may be varied to be alkyl, aryl, heterocyclic groups etc. It is also
well known that the thiazole moiety can be important for significant biological activity [13-16].

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Molecules 2000, 5
Results and Discussion
Syntheses
We have synthesized five thiazol-2-yl substituted 2-imino-thiazolidin-4-ones (1a-e) and a series of their 5-
arylidene derivatives (2a-l) via the key intermediates 3 (Scheme 1 and Table 1). The 2-amino-4-arylthiazoles
(3) were reacted with chloroacetyl chloride to produce the corresponding 2-chloro-acetamido-4-arylthiazoles
(4). The latter was treated with potassium thiocyanate in refluxing acetone to afford the related 2-imino-3-(4-
arylthiazol-2-yl)-thiazolidin-4-ones (1). No 2-(thiocyanato)-acetamido-4-arylthiazole intermediates were de-
tected. Condensation of 1 with different aromatic aldehydes gave the 5-arylidene-2-imino-3- (4-arylthiazol-2-
yl)-thiazolidin-4-ones (2).
Method 1
O
Method 2
O
S
S
+
+
Ar
CH 2X
H2N
NH2
Ar
CH 3
H2N
NH2
X = Cl, Br, I
1. I
2
2. NH3, H2O
Ar
Ar
O
N
N
O
Cl
KSCN
Cl
Cl
NH2
N
H
S
S
3
4
Ar
Ar
O
O
N
N
Ar´CHO
4
N 3
N
S
S
CHAr´
5
2 1S
S
HN
HN
1
2
Scheme 1. Synthesis of thiazol-2-yl substituted 2-imino-thiazolidin-4-ones (1a-e) and a series of their 5-
arylidene derivatives (2a-l). For substituents Ar and Ar´see Table 1.
The different 2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones (1a-e) were condensed with aromatic alde-
hydes to yield the related 5-arylidene derivatives (2a-l) (See Table 1 for structures). The reaction gave good
yields (50-75%) only when the aromatic part of the aldehyde was substituted with a nitro group. The yield of
the reaction of chloro-substituted aromatic aldehyde with 1 was low, and benzaldehyde reacted only with 1d
(27%). The condensation was carried out in acetic acid with anhydrous sodium acetate as catalyst. When
pyridine was used as catalyst, the yield of the reaction was low (< 20%).

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Molecules 2000, 5
Table 1. Structure of compounds 1a-1e and 2a-2l, their melting points and yields of synthesis.
Substituent Ar
1a C6H5
Substituent Ar´
Mp,oC
240-242
290-291
187-190
173-175
232-234
256-260
288-290
278-280
238-240
286-287
282-286
>300
Yield,%
61
1b p-ClC6H4
81
1c p-O2NC6H4
1d 2,4-(Cl)2-5-FC6H2
1e 2,4-(Cl)2C6H3
2a C6H5
75
70
60
o-O2NC6H4
m-O2NC6H4
o-ClC6H4
52
2b C6H5
74
2c C6H5
21
2d p-ClC6H4
o-O2NC6H4
m-O2NC6H4
o-ClC6H4
58
2e p-ClC6H4
75
2f p-ClC6H4
25
2g p-O2NC6H4
2h p-O2NC6H4
2i p-O2NC6H4
2j 2,4-(Cl)2-5-FC6H2
2k 2,4-(Cl)2-5-FC6H2
2l 2,4-(Cl)2-5-FC6H2
o-O2NC6H4
m-O2NC6H4
o-ClC6H4
61
>300
75
>300
17
C6H5
258-260
289-292
270-274
27
o-O2NC6H4
m-O2NC6H4
53
70
The starting materials, the 2-amino-4-arylthiazoles (3), were synthesized by two different methods, either
starting with an arylketone (Method 1, Scheme 1)[17,18] or an a -halo arylketone (Method 2)[19]. Method
1, which involves the reaction of substituted acetophenone, thiourea and iodine, was a solid phase reaction.
The yield was low due to phase transfer limitations. Furthermore, iodine had to be recycled because of its high
price and the pollution problems. In order to overcome these drawbacks, the second method was employed.
When substituted a -halo-acetophenones, obtained by substitution of a -H of acetophenones by halogen, were
reacted with thiourea in 1-propanol (Method 2), the yield could be raised to about 90% and the reaction time
was decreased.
Fungicidal Activity
Compounds (1a-e and 2a-i) were tested for fungicidal activity against 7 agricultural fungi, Pleurotus os-
treatus (F1), Aspergillus niger (F2), Pythium aphanidermatum (F3), Gaeumannomyces graminis (F4), Fusar-
ium graminearium (F5), Pyricularia oryzae (F6) and Botrytis cinerea (F7). The results (Table 2) show that the
two new compounds (1d and 1e) have higher fungicidal activity than the others, the percentage inhibition of 1d
and 1e against Pythium aphanidermatum (F1) and of 1d against Gaeumannomyces graminis (F4) were higher
than 90. It may also be noticed that several of the compounds did not inhibit the growth of this fungus. Com-
pounds 1a, 1b, 1d and 1e were more fungicidal against Pythium aphanidermatum than against the other 6
fungi. Introduction of benzylidene group at C-5 decreased the fungicidal activity. The inhibition of all of the 5-
arylidene-4-thazolidinones was low.

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Molecules 2000, 5
Table 2. Percentage inhibition of compounds 1a-1e and 2a-2l against the fungi F1-F7*.
% Inhibition of 1a-1e and 2a-2l at 50 ppm against F1-F7
F1
82.6
72.4
12.4
95.0
97.2
84.1
5.9
F2
F3
8.8
3.8
8.8
12.5
0
F4
60.0
51.3
26.7
91.3
86.7
0
F5
F6
58.8
58.8
38.1
76.3
79.4
20.2
3.2
F7
3.5
0
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2f
54.3
52.3
56.2
58.8
62.8
54.3
49.7
23.6
60.8
58.8
40.8
62.8
52.3
42.7
47.7
49.7
69.3
21.1
29.7
2.2
0
38.8
48.6
61.9
20.6
37.4
58.8
61.9
31.8
24.7
51.6
28.0
38.1
48.5
45.4
38.2
0
3.8
25.0
17.2
12.5
16.3
46.2
16.3
0
64.7
0
0
0
0
0
27.5
66.7
71.3
0
84.8
84.1
0
0
14.8
26.5
0
0
0
2g
2h
2i
7.2
0
3.2
33.3
4.7
60.8
28.7
2.0
24.7
29.8
0
0
0
28.0
0
37.1
0
2.1
2j
11.5
15.2
32.6
4.1
2k
2l
0
0
50.4
11.7
33.8
0
Experimental
General
Melting points were recorded in open capillaries and are not corrected. IR spectra (KBr disks) were re-
1
corded using a Perkin-Elmer 237 spectrophotometer. H NMR spectra were recorded in CDCl solutions,
3
with Me Si as an internal reference. Chemical shifts are in ppm and coupling constants in Hz. Elemental analy-
4
ses (C, H and N) were carried out with a Coleman analyzer. The new compounds gave the following analyti-
cal results: 1d %C 39.79, %H 1.67, %N 11.60, calcd. for C H Cl FN OS : C 39.81, H 1.71, N 11.54
12 6
2
3
2
and 1e %C 46.68, %H 2.28, %N 13.61, calcd. for C H ClN OS : C 46.67, H 2.31, N 13.58. Com-
12 7
3
2
pounds 1a-1c, 2j and 2l all gave values in accordance with the calculated values based on the elemental com-
positions.
Test for Fungicidal Activity

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Molecules 2000, 5
Compounds (1a-e and 2a-i) were tested for fungicidal activity against 7 agricultural fungi, Pleurotus os-
treatus, Aspergillus niger, Pythium aphanidermatum, Gaeumannomyces graminis, Fusarium graminearium, Py-
ricularia oryzae and Botrytis cinerea, by the agar growth medium poison technique [12]. The concentration of
the test compounds was 50 ppm. After 48 h treatment, the growth diameter of the fungus on the agar was
measured and the percentage inhibition of growth by an inhibitor was calculated by comparison with the
growth in controls, i.e. untreated petri-dishes. The experiments were performed in triplicate. The results are
shown in Table 2.
2-Amino-4-phenylthiazole (3a). Method 1
Thiourea (30.4 g, 0.4 mole) and I (50.8 g, 0.2 mole) were triturated and mixed with acetophenone (24.0
2
g, 0.2 mole). The mixture was heated on a water bath with occasional stirring for 8 h. The obtained solid was
triturated with Et O to remove unreacted acetophenone, washed with aqueous sodium thiosulfate to remove
2
excess iodine and then with water. The crude product was dissolved in hot water, filtered to remove the sul-
phone, and 2-amino-4-phenylthiazole (3a) was precipitated by addition of NH ´ H O. Crystallization from
3
2
EtOH gave white crystals, yield 22.2 g (0.13 mole, 65%) m.p. 146-148oC, IR 3420, 3240, 1600, 1520,
-1 1
770, 710 cm , H NMR d 7.87 (2H, m, aromatic), 7.54 (3H, m, aromatic), 7.47 (1H, s, thiazole-H5).
2-Amino-4-(2,4-dichlorophenyl)thiazole (3e). Method 2
A solution of 2-chloro-1-(2,4-dichlorophenyl) ethanone (12.2 g, 0.05 mole) and thiourea (4.2 g, 0.05
mole) in 1-propanol (40 mL) was refluxed for 2 h. After addition of pyridine (5 mL) and continued reflux for 5
h, the solvent was removed in vacuo. The crude product was dried and crystallized from EtOH to give yellow
-1 1
crystals, yield 11.0 g (0.045 mole, 90.4%), mp 138-140oC, IR 3450, 3260, 1610, 1570, 1500 cm , H
NMR d 9.85, 8.10 (3H, m, aromatic), 7.85 (1H, s, thiazole).
2-Chloroacetamido-4-(4-chlorophenyl)thiazole (4b)
A solution of 2-amino-4-(4-chlorophenyl)thiazole (3.7 g, 0.02 mole) in dry benzene (60 mL) was cooled
to 0-5oC. Chloroacetyl chloride (5 mL, 0.04 mole) dissolved in dry benzene (20 mL ) was slowly added to
the solution with vigorous stirring. When the addition was complete, the reaction mixture was refluxed for 3 h.
Benzene was removed in vacuo. The residue was washed with 5% NaHCO , and subsequently with water.
3
The crude product was dried and crystallized from EtOH to give colorless crystals, yield 3.70 g (0.013 mole,
1
-1
64.4%), m.p 160-164oC, IR 3360, 3100, 1690, 1540, 840, 510 cm , H NMR d 7.87 (2H, m, aromatic),
7.39 (2H, m, aromatic), 6.93 (1H, s, thiazole), 4.09 (2H, m, -CH -). Other 2-chloroacetamido-4-
2
arylthiazoles were prepared by the same method.
2-Imino-3-[4-(2,4-dichloro-5-fluorophenyl)thiazol-2-yl]-thiazolidin-4-one (1d)
A mixture of 2-chloroacetamido-4-(2,4-dichloro-5-fluorophenyl)thiazole (10.0 g, 0.03 mole), KSCN (6.0
g, 0.06 mole) and dry acetone (100 mL) was refluxed for 3 h. Excess acetone was removed in vacuo and the
residue was stirred with water (50 mL). The solid product was filtered, washed with water, and dried. The
thiazolidinone 1d was obtained by crystallization from EtOH: yield 7.61g, (0.021 mole, 70%), m.p. 173-175°

1060
C, IR 3180, 3080, 1710, 1650, 1570, 1350, 730 cm , H NMR d 7.97 (1H, s, aromatic), 7.81 (1H, s,
Molecules 2000, 5
-1 1
aromatic), 7.26 (1H, s, thiazole), 4.20 (2H, s, -CH -). Similarly, other 2-imino-3-arylthiazol-2-yl-thiazolidin-
2
4-ones (1a-c, 1e) were also synthesized. No intermediates, 2-(thiocyanato)acetoamido-4-arylthiazoles, were
isolated in the procedure.
5-(3-Nitrobenzylidene)-2-imino-3-(4-phenylthiazol-2-yl)-thiazolidin-4-one (2b)
2-Imino-3-(4-phenylthiazol-2-yl)-thiazolidin-4-one (2.0 g, 0.01 mole) and 3-nitrobenzaldehyde ( 3.0 g,
0.02 mole) were added to a solution of anhydrous NaOAc (2.0 g, 0.02 mole) in AcOH (30 mL). The mixture
was refluxed for 5 h at 120oC and cooled to room temp. The solid product was filtered from the mixture,
washed with water, dried and crystallized from EtOH to form yellow crystals, yield 3.0 g (7.34 mmole,
-1 1
73.4%), m.p. 290-294oC, IR 3400, 1710, 1590, 1520, 1340, 1170, 770, 710 cm , H NMR d 7.34 (3H,
m, Ar), 7.93 (2H, m, Ar), 7.61 (1H, s, thiazole-5), 7.95 (1H, s, =CH), 7.96 (1H, s, Ar'-5), 8.38 (1H, s, Ar'-
6), 8.60 (1H, s, Ar'-4), 8.75 (1H, s, Ar'-2).
Acknowledgments: We are grateful to Pesticide Lab 5 of Research Institute of Chemical Industry, Shenyang,
P.R. China for antifungal screening; and the Physical Chemistry Lab, for spectroscopy and elemental analyses.
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Molecules 2000, 5
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