The route of alkylation of 5-substituted 1,3,4-thiadiazoline-2-thiones

Article abstract of DOI:10.1023/A:1023776610073

The reaction of 5-anilino(toluidino-, morpholino)-1,3,4-thiadiazoline-2-thiones at 80°C with allyl bromide and benzyl chloride in alcohol, acetonitrile or DMF in the presence of KOH and also with phenoxymethyloxirane in alcohol in the absence of base gives the corresponding novel allyl-, benzyl-, and 2-hydroxy-3-phenoxypropyl products substituted at the exocyclic S atom. Alkylation of the indicated thiones with benzyl chloride at 150-153°C in DMF in the presence of KOH occurs similarly. Under these conditions, allyl bromide forms alkylation products at the endocyclic N₍₃₎ atom as a result of an S→N thio-Claisen rearrangement of the initially formed product which is allyl substituted at the exocyclic S atom.

Full text of DOI:10.1023/A:1023776610073

Chemistry of Heterocyclic Compounds, Vol. 39, No. 2, 2003
THE ROUTE OF ALKYLATION OF
5-SUBSTITUTED 1,3,4-THIADIAZOLINE-2-THIONES
Kh. Polvonov1, Q. Sabirov1, and Kh. M. Shakhidoyatov2
The reaction of 5-anilino(toluidino-, morpholino)-1,3,4-thiadiazoline-2-thiones at 80°C with allyl
bromide and benzyl chloride in alcohol, acetonitrile or DMF in the presence of KOH and also with
phenoxymethyloxirane in alcohol in the absence of base gives the corresponding novel allyl-, benzyl-,
and 2-hydroxy-3-phenoxypropyl products substituted at the exocyclic S atom. Alkylation of the indicated
thiones with benzyl chloride at 150-153°C in DMF in the presence of KOH occurs similarly. Under these
conditions, allyl bromide forms alkylation products at the endocyclic N(3) atom as a result of an S→N thio-
Claisen rearrangement of the initially formed product which is allyl substituted at the exocyclic S atom.
Keywords: allyl bromide, benzyl chloride, 5-substituted 1,3,4-thiadiazoline-2-thiones, phenoxy-2,3-
epoxypropane, S- and N-alkylation, S→N thio-Claisen rearrangement.
It is known that 1,3,4-thiadiazoline-2-thiones are categorized as heterocyclic compounds capable to
tautomeric conversion [1]. In alkylation reactions they can form products both at the exocyclic sulfur atom and
at the endocyclic N(3) atom. The methylation of 5-substituted 1,3,4-thiadiazoline-2-thiones by diazomethane in
ether gives a mixture of the isomeric alkylation products at the S and N atoms [2, 3] but the action of an
equimolar amount of methyl iodide in alcoholic base solution gives only S-methylated products [4]. It is
important to note that many S-substituted 1,3,4-thiadiazoline-2-thiones exhibit different kinds of biological
activity [5, 6].
In order to study the route of reaction for the alkylation of 5-substituted 1,3,4-thiadiazoline-2-thiones using
various alkylation agents and also the synthesis of novel, biologically active materials we have carried out, for the
first time, in this work the alkylation of the 5-anilino-(p-toluidino-, morpholino)-1,3,4-thiadiazoline-2-thiones
(1a-c) using allyl bromide (2a), benzyl chloride (2b), and phenoxymethyloxirane (3). The reaction of the thiones
1a-c with compounds 2a,b was carried out in the presence of potassium hydroxide at 78-80°C in alcohol,
acetonitrile, and DMF, and also in DMF at 150-153°C. The corresponding S-alkylated derivatives 4a-f were
obtained at 78-80°C over 5 h in all cases independently of the nature of the reagents and the solvent parameters.
H
N
N
N
N
KOH, EtOH, MeCN
R1CH2X
2a,b
+
R1
R
S
S CH2
R
S
S
4a–f
1a–c
1 a R = PhNH, b R = p-MeC6H4NH, c R = O(CH2CH2)2N; 2 a R1 = CH2=CH, X = Br,
b R1 = Ph, X = Cl; 4 a–c R1 = CH2=CH, d–f R1 = Ph, a, d R = PhNH,
b, e R = p-MeC6H4NH, c, f R = O(CH2CH2)2N
__________________________________________________________________________________________
1
Al-Khorezmi Urgench State University, Urgench 740000, Uzbekistan; e-mail: sadullaev@mail.ru,
a
hab@ursu.uzpac.uz. Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic
Uzbekistan, Tashkent 700170; e-mail: shakhi@icps.org.uz. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 2, pp. 258-262, February, 2003. Original article submitted June 23, 2000; revision submitted
March 15, 2001.
228
0009-3122/03/3902-0228$25.00©2003 Plenum Publishing Corporation

In DMF at the higher temperature (150-153°C) over 3 h the thiones 1a-c and benzyl chloride 2b also
gave the S-benzyl derivatives 4d-f. However, under the same conditions, the alkylation with allyl bromide 2a
gave as the basic product the N-allyl derivatives 5a-c with trace amounts of the corresponding S-derivatives
4a-c, as shown by TLC of the reaction mixtures.
N
N CH2CH=CH2
KOH, DMF
150–153 oC
1a–c
2a
+
R
S
S
5a–c
a R = PhNH, b R = p-MeC6H4NH, c R = O(CH2CH2)2N
The formation of compounds 5a-c is a result of a thio-Claisen rearrangement of the initially formed
S-allyl derivatives 4a-c. This was shown experimentally. Refluxing the individual compounds 4a-c in DMF for
3 h gave compounds 5a-c. A similar rearrangement has been observed in the case of the S-allyl derivatives of
thioquinolines [7].
When the thiones 1a-c are held with the oxirane 3 in ethanol for 5 h at 78°C the compounds 6a-c are
obtained in 68-76% yields (Table 1), and the structures are confirmed by their spectroscopic characteristics
(Table 2).
TABLE 1. Parameters for Compounds 4a-f, 5a-c, and 6a-c
Found, %
——————
Com-
pound
Empirical
formula
Rf (benzene–
Yield, %
mp*, °С
Calculated, %
ethanol, 10:1)
С
Н
N
C11H11N3S2
C12H13N3S2
C9H13N3OS2
C15H13N3S2
C16H15N3S2
C13H15N3OS2
C11H11N3S2
C12H13N3S2
C9H13N3OS2
53.28
53.54
0.52
0.44
17.01
16.87
96-98
101-103
42-43
0.47
0.53
0.72
0.64
0.52
0.66
0.71
0.45
0.41
0.35
0.66
0.26
72 (A), 64*2
68 (A), 62*2
60 (A), 59*2
65 (A), 81*2
61 (A), 79*2
54 (A), 52*2
78 (B)
4а
4b
4с
4d
4e
4f
54.89
5.11
15.80
54.75
4.94
15.96
44.66
44.44
5.42
5.35
17.39
17.28
60.36
4.47
14.32
120-121
126-127
108-109
142-143
149-150
71-72
60.20
4.35
14.05
61.47
61.34
4.96
4.79
13.31
13.42
53.39
0.66
14.48
53.24
0.51
14.33
53.23
53.01
0.60
0.44
17.10
16.87
5a
5b
5c
6a
6b
6c
54.91
5.14
16.14
73 (B)
54.75
4.94
15.96
44.60
44.44
5.46
5.35
17.48
17.28
70 (B)
C17H17N3O2S2 57.10
5.05
11.92
148-150
102-103
68-70
76 (C), 79*2
70 (C), 74*2
68 (C)
56.82
4.73
11.70
C18H19N3O2S2 58.18
57.91
C15H19N3O3S2 51.22
5.27
5.09
11.42
11.26
5.28
12.17
50.99
5.10
11.90
_______
* Solvent for crystallization: hexane–benzene, 10:1 (compound 4a), hexane
(4b,c,f, 5a,c, 6a-c), aqueous alcohol (4d,e), hexane–benzene, 2:1 (5b).
*2 Refluxing for 5 h in acetonitrile.
229

TABLE 2. Spectroscopic Characteristics for Compounds 4a-f, 5a-c and 6a-c
UV spectrum,
IR spectrum, ν, cm-1
Com-
1Н NMR spectrum, δ, ppm (J, Hz)
pound
λmax, nm
СН2=СН–
NH
OH
C–C arom.
1580, 1510
310
312
1630
3200
—
3.72 (2Н, d, J = 5, SCH2); 4.62 (2H, d, J = 5, CH=CH2); 5.12 (1H, m, J = 6, CH=CH2);
5.87 (1H, m, J = 8, NH); 7.00-7.70 (5H, m, J = 6, Н arom.)
4а
1635
3150
—
—
1590, 1520
2.25 (3H, s, J = 6.25, CH3–C6H4); 3.70 (2H, d, J = 6.25, SCH2); 4.65 (2H, d, J = 5, CH=CH2);
5.12 (1H, m, J = 5, CH=CH2); 5.85 (1H, m, J = 6.25, NH);
7.00-7.50 (5H, m, J = 7.5, Н arom.)
4b
305
1640
—
—
3.40 (4Н, m, J = 3.7, NCH2); 3.63 (6H, m, J = 5, 2OCH2, CH=CH2);
4с
4.10 (2H, d, J = 5, SCH2); 5.10 (1H, m, J = 3.75, CH=CH2)
313
312
—
—
3180
3170
—
—
1590, 1510
1585, 1520
4.10 (2H, d, J = 6.25, SCH2); 7.10-7.50 (11H, m, J = 5, NH, 10H arom.)
4d
4e
2.27 (3H, s, J = 6, CH3–C6H4); 4.05 (2H, d, J = 5.5, SCH2);
7.12-7.60 (10H, m, J = 7.6, NH, 9H arom.)
295
327
325
—
—
—
—
—
1580
3.38 (4H, m, J = 5, 2NCH2); 3.70 (4H, m, J = 5, 2OCH2); 4.30 (2H, s, J = 3.75, SCH2);
7.30 (5H, m, J = 5, Н arom.)
4f
1630
1630
3175
3200
1580, 1520
1590, 1510
4.24 (2H, s, J = 4, N3CH2); 4.85 (2H, d, J = 5.5, CH=CH2); 5.30 (1H, m, J = 7.5, CH=CH2);
5a
5b
5.85 (1H, m, NH); 7.10-7.50 (5H, m, Н arom.)
2.30 (3H, s, J = 6, CH3–C6H4); 4.25 (2H, s, J = 4, N3CH2); 4.80 (2H, d, J = 3.25, CH=CH2);
5.35 (1H, m, J = 7, CH=CH2); 5.80 (1H, m, J = 3.95, NH);
7.10-7.50 (5H, m, J = 7.3, Н arom.)
320
307
308
290
1640
—
—
3200
3170
—
—
—
3.90-4.20 (8Н, m, J = 3, NCH2, OCH2); 4.70 (2H, s, J = 3, N3–CH2, CH=CH2);
5c
6a
6b
6c
5.80 (1H, m, J = 4, CH=CH2)
3300
3350
3250
1600, 1500
1600, 1520
1575
3.30 (2H, m, J = 5, SCH2); 4.05 (2H, m, J = 3, 2OCH2); 4.75 (1H, m, J = 5, OСН);
6.78-7.40 (6H, m, J = 5, NH, 5Н arom.)
—
2.20 (3H, s, J = 6.1, CH3–C6H4); 3.32 (2H, m, J = 5, SCH2); 4.10 (2H, m, J = 5, OCH2);
4.70 (1H, m, J = 3.5, OСН); 6.78-7.40 (6H, m, J = 7.25, NH, 5H arom.)
—
3.35 (4Н, m, J = 3.75, 2NCH2); 3.75 (4H, m, J = 3.75, 2OCH2);
4.20 (5H, m, J = 2.5, SCH2, OCH and OCH2); 6.80-7.25 (5H, m, J = 5, H arom.)

N
N
H2C CHCH2OPh
1a–c
+
O
3
R
S
CH2CHCH2OPh
OH
S
6a–c
6 a R = PhNH, b R = p-MeC6H4NH, c R = O(CH2CH2)2N
We have found that UV spectroscopic data can be used to identify the S- or N-derivatives of the
1
5-R-1,3,4-thiadiazoline-2-thiones even though many authors have used only IR and H NMR spectroscopy
[8, 9]. Thus the presence of absorption maxima at 290-313 nm in the UV spectra of compounds 4a-f and 6a-c
points to the formation of the S-alkylated derivatives. Absorption maxima at 320-327 nm in the spectra of
compounds 5a-c confirm their thione structures.
In the 1H NMR spectra of compounds 4a-f and 6a-c the signals for the S–CH2 group protons is observed
at 3.30-4.30 ppm. The signals for the N(3)–CH2 group protons occur at lower field than for the S–CH2 group and
this is typical for compounds of the type 5a-c.
Hence we have shown that the reaction of the thiones 1a-c with allyl bromide 2a and benzyl chloride 2b
occurs in the presence of an equimolar amount of potassium hydroxide at 80°C to give the corresponding
S-alkyl derivatives 4a-f. A similar reaction route is observed when treating the same thiones with
phenoxymethyloxirane 3 in ethanol at 78°C in the absence of base. In the case of allyl bromide 2a in refluxing
DMF the products of allylation at the endocyclic N(3) atom are obtained as a result of the rearrangement of the
initially formed S-allylation products.
EXPERIMENTAL
UV spectra were taken on a Hitachi EPS-3T spectrometer for solutions in ethanol. IR spectra were
1
recorded on a UR-20 instrument for KBr tablets. H NMR spectra were recorded on a Jeol C-60HL (60 MHz)
instrument using CDCl3 solvent and HMDS internal standard. The purity of the compounds prepared was
controlled using TLC on Silufol UV-254 plates using benzene–alcohol (10:1) as eluent.
5-R-1,3,4-Thiadiazoline-2-thiones 1-3 were synthesized by a known method [10].
Method for the Alkylation of 5-R-1,3,4-thiadazoline-2-thiones 1a-c. A. A solution of compound 2a,b
(20 mmol) in DMF (10 ml) was added dropwise with stirring at 40-50°C over 30 min to a solution of the thione
1a-c (5 mmol) and potassium hydroxide (5 mmol) in DMF (15 ml). The reaction mixture was stirred at 80°C
for 5 h, diluted with water (100 ml), extracted with chloroform (3 × 20 ml), and the extract dried over calcium
chloride, the solvent evaporated, and the residue recrystallized to give the products 4a-f.
B. A solution of compound 2a (20 mmol) in DMF (10 ml) was added dropwise with stirring at 40-50°C
over 30 min to a solution of the thione 1a-c (5 mmol) and potassium hydroxide (5 mmol) in DMF (15 ml) and
then refluxed for 3 h. Solvent was distilled off at reduced pressure and the product was recrystallized to give
compounds 5a-c.
C. A solution of the oxirane 3 (1 mmol) in ethanol (10 ml) was added with stirring over 30 min to a
solution of the thione 1a-c (5 mmol) in ethanol (15 ml). The reaction mixture was refluxed for 5 h, ethanol was
distilled off, and the residue was recrystallized to give compounds 6a-c.
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