5-aryl-1,3,4-oxadiazoline-2(3H)-thiones in reactions with alkyl haloacetates

Article abstract of DOI:10.1007/s10593-012-1020-4

The reaction of 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones with alkyl haloacetates has been studied. It was shown that the reaction proceeds to give S-substituted products. The effect of the nature of the substituents in the molecules of both the thiones and

Full text of DOI:10.1007/s10593-012-1020-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
5-ARYL-1,3,4-OXADIAZOLINE-2(3H)-THIONES
IN REACTIONS WITH ALKYL HALOACETATES
A. A. Ziyaev1*, I. F. Tozhiev1, and Kh. M. Shakhidoyatov1
The reaction of 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones with alkyl haloacetates has been studied. It
was shown that the reaction proceeds to give S-substituted products. The effect of the nature of the
substituents in the molecules of both the thiones and the haloacetates on the reaction route and yields
has been examined.
Keywords: alkylating agent, 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones, haloacetic acids, S- and
N-substituted products, alkylation, orientation.
The alkylation of 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones by alkylating agents of various types (alkyl-,
allyl-, and benzyl halides, -chloromethylalkyl esters etc.) has been studied previously [1-4]. Now we have
examined the reaction of 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones with alkyl haloacetates in order to establish
the factors influencing the reaction route and product yields.
Literature data regarding the reactions of alkyl -haloalkanoates with oxadiazoline thiones is very
contradictory. The reaction of 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones with chloroacetic acid in the presence of
NaOH (K2CO3) in DMF or alcohol [5, 6] and with its methyl and ethyl esters in the presence of KOH in
different solvents has been reported [7]. It was shown that the S-derivatives were formed exclusively. At the
same time, the authors of [8, 9] have studied the reactions of 5-(2,4-dichlorophenyl)-1,3,4-oxadiazoline-2-thione
with ethyl chloroacetate and have characterized the products obtained as N-alkyl derivatives.
The occurrence of this reaction at the N-center was taken without convincing evidence (more often from
IR spectroscopic data or simply by assigning this structure to the compound).
Scheme 1
H
N
N
R1
O
O
N
N
Na2CO3
Me2CO
+
S
X
R1
R
S
O
R
O
O
O
1–4
5a–f
6a–d, 7a,b, 8a–f, 9a–d
1, 6a–d R = Ph; 2, 7a,b R = 4-MeC6H4; 3, 8a–f R = 2-pyridyl; 4, 9a–d R = 2,4-Cl2C6H3;
5a, 6a, 7a, 8a, 9a R1 = Me; 5b, 6b, 7b, 8b, 9b R1 = Et; 5c, 8c R1 = Pr; 5d, 8d R1 = Bu;
5e, 6c, 8e, 9c R1 = i-Pr; 5f, 6d, 8f, 9d R1 = PhCH2; 5a–e X= Cl, f X = Br
_______
*To whom correspondence should be addressed, e-mail: ziyaev05@rambler.ru.
1S. Yu. Yunusov Institute for the Chemistry of Plant Substances, Uzbekistan Academy of Sciences, 77 Mirzo
Ulugbek Ave., Tashkent 100170, Uzbekistan.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 520-523, March 2012. Original
article submitted February 8, 2011. Revision submitted September 9, 2011.
488
0009-3122/12/4803-0488©2012 Springer Science+Business Media, Inc.

TABLE 1. Physicochemical Characteristics of Compounds 6-9
Com-
pound
Empirical
formula
Found N, %
Calculated N, %
——————
Mp, °С
Yield, %
6a
6b
6c
6d
7a
7b
8a
8b
8c
8d
8e
8f
С11H10N2O3S
10.41
11.19
10.38
10.60
10.34
10.06
8.82
8.58
10.39
10.60
10.26
10.06
17.03
16.72
16.21
15.84
14.78
15.04
13.98
14.32
15.28
15.04
13.17
12.84
8.98
8.78
8.12
8.41
7.76
8.07
7.34
7.09
83-84
82-83
76-77
93-94
77-79
68-70
78-80
37-39
38-40
Oil
97
91
92
88
96
92
88
81
79
80
82
90
94
84
86
92
C12H12N2O3S
C13H14N2O3S
C17H14N2O3S
C12H12N2O3S
C13H14N2O3S
C10H9N3O3S
C11H11N3O3S
C12H13N3O3S
C13H15N3O3S
C12H13N3O3S
C16H13N3O3S
C11H8Сl2N2O3S
C12H10Cl2N2O3S
C13H12Cl2N2O3S
C17H12Cl2N2O3S
66-68
82-84
85-86
66-67
96-98
106-107
9a
9b
9c
9d
We have thoroughly investigated the reaction of the 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones 1-4 (aryl =
phenyl, 2,4-dichlorophenyl, 4-methylphenyl, and -pyridyl) with the alkyl haloacetates 5a-f. The reaction
studied in most detail was that with C1 to C4 alkyl chloroacetates (Scheme 1).
The reactions were carried out by refluxing equimolar amounts of the thione, the haloacetate, and
potassium carbonate in acetone and the course of the reaction was monitored by TLC. The results obtained are
given in Tables 1 and 2.
Analysis of the products by 1H NMR and UV spectroscopy showed that the S-derivatives are formed in
all of the reactions (absorption bands at 270-286 nm in the UV spectra, absence of N–CH2 protons signals and
presence of S–CH2 protons signals in the 1H NMR spectra).
As is evident from Table 1, the reactions occur in good yields and the main part of the thione is
consumed over 7-10 h. Comparison of the results of the reaction of different thiones with the same ester has
shown that the thione aromatic ring substituents are not proven to have a marked effect on the yield of products.
Several reactions of the benzyl bromoacetate 5f with thiones 1, 3, 4 also yielded the S-derivatives with
comparable yields under the same conditions.
Hence the reaction of 5-aryl-1,3,4-oxadiazoline-2(3H)-thiones with alkyl haloacetates occurs with
exclusive formation of S-derivatives. The nature of the halogen in these reactions does not have a significant
effect on the product yields.
489

TABLE 2. Spectroscopic Properties of Compounds 6-9
UV spectrum,
Com-
pound
1H NMR spectrum, , ppm (J, Hz)
λ
max, nm (log )
6a
6b
7.94 (2H, dt, J = 7.9, J = 1.4, H-2',6'); 7.40-7.50 (3H, m, H-3',4',5');
4.06 (2H, s, SCH2); 3.75 (3H, s, OCH3)
273 (4.00)
7.94 (2H, dt, J = 7.9, J = 1.4, H-2',6'); 7.40-7.50 (3H, m, H-3',4',5');
4.05 (2H, s, SCH2); 4.20 (2H, q, J = 7.0, СН2CH3);
1.24 (3H, t, J = 7.0, CH2CH3)
7.94 (2H, dt, J = 7.9, J = 1.4, H-2',6'); 7.40-7.50 (3H, m, H-3',4',5');
5.03 (1H, septet, J = 6.3, CH(CH3)2); 4.02 (2H, s, SCH2);
1.21 (6H, d, J = 6.3, CH(CH3)2)
278 (3.86)
276 (3.42)
6c
6d
7a
7.91 (2H, dt, J = 8.1, J = 1.6, H-2',6'); 7.40-7.48 (3H, m, H-3',4',5');
7.23-7.29 (5H, m, H Ph); 5.16 (2H, s, СН2Ph); 4.09 (2H, s, SCH2)
280 (3.88)
274 (3.94)
7.30 (2H, dt, J = 8.0, J = 2.0, H-2',6');
7.10 (2H, dt, J = 8.0, J = 2.0, H-3',5'); 4.10 (2H, s, SСН2);
3.74 (3H, s, COOCH3); 2.31 (3H, s, C6H4CH3)
7b
8a
8b
7.30 (2H, dt, J = 8.1, J = 2.1, H-2',6');
280 (3.86)
286 (3.70)
286 (3.84)
7.12 (2H, dt, J = 8.1, J = 2.1, H-3',5'); 4.16 (2H, q, J = 7.1, СН2CH3);
4.08 (2H, s, SCH2); 2.31 (3H, s, C6H4CH3);
1.21 (3H, t, J = 7.1, CH2CH3)
8.62 (1Н, ddd, J = 4.8, J = 1.8, J = 1.0, H-6');
8.13 (1Н, dt, J = 7.9, J = 1.0, H-3'); 7.78 (1Н, td, J = 7.9, J = 1.8, H-4');
7.33 (1Н, ddd, J = 7.9, J = 4.8, J = 1.0, H-5'); 4.07 (2H, s, SCH2);
3.741 (3H, s, COOCH3)
8.70 (1Н, ddd, J = 4.8, J = 1.9, J = 1.1, H-6');
8.13 (1Н, dt, J = 7.7, J = 1.1, H-3'); 7.82 (Н, td, J = 7.7, J = 1.9, H-4');
7.40 (1Н, ddd, J = 7.7, J = 4.8, J = 1.1, H-5');
4.20 (2H, q, J = 7.4, CH2CH3); 4.09 (2H, s, SCH2);
1.24 (3H, t, J = 7.4, CH2CH3)
8c
8.62 (1Н, ddd, J = 4.8, J = 1.8, J = 1.0, H-6');
8.13 (1Н, dt, J = 7.9, J = 1.0, H-3'); 7.78 (1Н, td, J = 7.9, J = 1.8, H-4');
7.33 (Н, ddd, J = 7.9, J = 4.8, J = 1.0, H-5');
4.08 (2H, t, J = 6.6, OCH2); 4.06 (2H, s, SCH2);
1.65 (2H, sextet, J = 7.3, CH2CH2CH3); 0.92 (3H, t, J = 7.3, CH2CH3)
286 (3.74)
286 (3.77)
8d
8.70 (1Н, ddd, J = 4.8, J = 1.9, J = 1.1, H-6');
8.13 (1Н, dt, J = 7.7, J = 1.1, H-3'); 7.83 (1Н, td, J = 7.7, J = 1.9, H-4');
7.40 (1Н, ddd, J = 7.7, J = 4.8, J = 1.1, H-5');
4.14 (2H, t, J = 6.6, COOCH2); 4.10 (2H, s, SCH2);
1.58 (2H, quin, J = 7.7, CH2CH2CH2);
1.31 (2H, sextet, J = 7.4, CH2CH2CH3); 0.85 (3H, t, J = 7.4, CH2CH3)
8e
8f
8.69 (1Н, ddd, J = 4.8, J = 1.7, J = 1.0, H-6');
8.12 (1Н, dt, J = 7.8, J = 1.0, H-3'); 7.80 (1Н, td, J = 7.8, J = 1.7, H-4');
7.38 (1Н, ddd, J = 7.7, J = 4.8, J = 1.0, H-5');
5.02 (1H, septet, J = 6.2, CH(CH3)2); 4.05 (2H, s, SCH2);
1.20 (6H, d, J = 6.2, CH(CH3)2)
286 (4.21)
286 (4.07)
8.70 (1Н, ddd, J = 4.8, J = 1.8, J = 1.1, H-6');
8.12 (1Н, dt, J = 7.7, J = 1.1, H-3'); 7.82 (1Н, td, J = 7.7, J = 1.8, H-4');
7.40 (1Н, ddd, J = 7.7, J = 4.8, J = 1.1, H-5');
7.22-7.32 (5H, m, CH2C6H5); 5.16 (2H, s, COOCH2); 4.13 (2H, s,
SCH2)
9a
9b
9c
7.83 (1H, d, J = 8.3, H-6'); 7.50 (1H, d, J = 2.0, H-3');
7.32 (1H, dd, J = 8.3, J = 2.0, H-5'); 4.05 (2H, s, SСH2);
3.74 (3H, s, COOCH3)
280 (3.64)
280 (3.48)
276 (3.53)
7.83 (1H, d, J = 8.3, H-6'); 7.50 (1H, d, J = 2.0, H-3');
7.32 (1H, dd, (J = 8.3, J = 2.0, H-5'); 4.20 (2H, q, J = 7.2, СН2CH3);
4.05 (2H, s, SCH2); 1.24 (3H, t, J = 7.2, CH2СН3)
7.84 (1H, d, J = 8.3, H-6'); 7.50 (1H, d, J = 2.0, H-3');
7.32 (1H, dd, J = 8.3, J = 2.0, H-5');
4.15-4.25 (1H, septet, J = 6.3, СН(СН3)2);
4.02 (2H, s, SCH2); 1.21 (6H, d, J = 6.3, CH(CH3)2)
9d
7.80 (1H, d, J = 8.6, H-6'); 7.50 (1H, d, J = 2.0, H-3');
7.31 (1H, dd, J = 8.6, J = 2.0, H-5'); 7.23-7.29 (5H, m, H Ph);
5.16 (2H, s, СН2Ph); 4.09 (2H, s, SCH2)
274 (3.84)
490

EXPERIMENTAL
1
UV spectra were recorded on a Hitachi EPS-3T spectrometer using ethanol. H NMR spectra were
recorded on a Tesla BS-567 (100 MHz) (compounds 7a,b) or a Unity +400 instrument (400 MHz) (remaining
compounds) at 20-25ºC using CDCl3 with HMDS (δ 0.05 ppm) as internal standard. Monitoring of the reaction
course and the purity of the compounds synthesized was carried out by TLC on Silufol UV-254 plates in the
system CHCl3–EtOH (20:1) and revealed using iodine vapor.
Alkyl (5-aryl-1,3,4-oxadiazolylsulfanyl)acetates (6-9) (General Method). A mixture of 5-aryl-1,3,4-oxa-
diazoline-2(3H)-thione 1-4 (5 mmol), the alkyl haloacetate 5a-f (5 mmol), and potassium carbonate (5 mmol) in
dry acetone (20 ml) was refluxed for 7-10 h. After removal of the solvent, the residual crystals were washed
with NaOH solution to remove the unreacted thione and then with cold water to neutral reaction. In the case of
the oily products they were extracted with chloroform and also washed with alkali solution and water. The
crystalline compounds obtained were recrystallized from EtOH (compounds 6a-d, 7a,b), aqueous EtOH
(compounds 9a-d) or cyclohexane (compounds 8a-f).
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