2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones

Article abstract of DOI:10.1023/B:COHC.0000046703.64531.64

A novel method for synthesis of 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4] triazolo[5,1-b][1,3]thiazin-7-ones by condensation of 3-R-4,5-dihydro-1H-1,2,4- triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl chlorides is proposed.

Full text of DOI:10.1023/B:COHC.0000046703.64531.64

Chemistry of Heterocyclic Compounds, Vol. 40, No. 8, 2004
2-R-5-AR(HET)-5,6-DIHYDRO-7H-[1,2,4]-
TRIAZOLO[5,1-b][1,3]-THIAZIN-7-ONES
V. N. Britsun and M. O. Lozinskii
A novel method for synthesis of 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones
by condensation of 3-R-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl
chlorides is proposed.
Keywords: 2-R-5-aryl(heteryl)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones, 3-aryl-(heteryl)-
2-propenoyl chlorides, 3-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thiones.
4,5-Dihydro-1H-1,2,4-triazole-5-thione is the starting reagent for synthesis of condensed heterocycles, in
particular derivatives of 4H-1,3-thiazin-4-one [1-3]. We know that 1,2,4-triazole-5-thiones are acylated by acid
chlorides only at the position 1 [4, 5], while compounds are readily added to the thione group (at 20°C) when
they contain an activated multiple bond, such as the methyl ester of propiolic acid [3], acrylic acid [6], or
acrylonitrile [7].
We established earlier [8] that when unsubstituted 1,2,4-triazole-5-thione 1a reacts with cinnamoyl
chloride (2a), it is not the corresponding 1-acyl-1,2,4-triazole-5-thione 3a that is formed but rather its cyclization
product: 5-phenyl-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one (4a). In this work, we have studied
such a reaction for novel examples with participation of 3-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thiones 1b-d and
3-aryl(heteryl)-2-propenoyl chlorides 2b-h, where (probably through intermediate acylation products of 3b-k
[9]) we obtain 2-R-5-R1-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]-thiazin-7-ones 4b-k.
H
Cl
N
N
Py
+
O
R1
– Py • HCl
R
S
N
H
2a–h
1a–d
O
O
N
N
N
N
R1
R
R1
R
N
S
N
SH
4a–k
3a–k
1a, 3, 4 a–h R = H; 1b, 3, 4 i R = Ph; 1c, 3, 4 j R = p-MeOC6H4;
1d, 3, 4 k R = p-NO2C6H4; 2–4 a, 3, 4 i–k R1= Ph; 2–4 b R1 = 3,4-(MeO)2C6H3,
c R1 = p-NO2C6H4, d R1 = p-ClC6H4, e R1 = p-FC6H4, f R1 = 1-naphthyl,
g R1 = 3,4-methylenedioxyphenyl, h R1 = 2-thienyl
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1256-1260,
August, 2004. Original article submitted February 4, 2002.
1092
0009-3122/04/4008-1092©2004 Springer Science+Business Media, Inc.

The process occurs under mild conditions (boiling in pyridine for 1 h), and compounds 4 are formed in
good yields (50%-72%), where when R = H, R1 = Ar the yield is higher (4a-g, 60%-72%) than when R = Ar,
R1 = Ph (4i-k, 50%-55%); but when R = H, R1 = 2-thienyl, product 4h is obtained in 51% yield.
The composition and structure of the synthesized compounds 4 are confirmed by the elemental analysis
results and data from spectral investigation methods (Tables 1 and 2).
1
Meaningful proof for the formation of a heterocycle comes from the H NMR spectroscopy data. The
1
double bond of the starting 3-aryl-2-propenoyl chloride 2, the proton signals of which appear in the H NMR
spectra as two doublets in the 6.80 ppm and 7.50 ppm region, after heterocyclization is converted to the single
bond of compounds 4, with proton signals in the 3.30-5.50 ppm region (an ABX system). Analysis of the
lineshape in the 13C NMR spectrum for compound 4a, obtained without proton decoupling, also supports
formation of a six-membered thiazine ring, since the signal for the carbonyl carbon atom (δ 162.92 ppm) appears
3
as a doublet of triplets (2JCH = 7.1, JCH = 4.3 Hz) as a result of spin–spin coupling with the protons of the
CH2CH moiety. In the IR spectra of the products 4a-k, an absorption band for the C=O group is characteristic
(1730-1720 cm-1).
TABLE 1. Characteristics of Synthesized Compounds 4a-k, 5a-h
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
[М+]
С
H
N
4a
4b
C11H9N3OS
57.27
57.14
53.45
53.61
47.70
47.83
49.70
49.72
52.87
53.01
64.27
64.06
52.47
52.36
45.53
45.57
66.64
66.45
64.23
64.09
57.92
57.95
53.12
53.00
50.62
50.48
45.19
44.90
46.48
46.57
49.53
49.43
3.73
3.90
4.59
4.47
3.09
2.90
3.23
3.01
3.29
3.21
3.77
3.91
3.06
3.27
2.80
2.95
4.04
4.23
4.66
4.45
3.66
3.41
4.20
4.45
4.71
4.89
3.21
3.42
3.34
3.55
3.88
3.77
18.33
18.18
14.31
14.43
20.02
20.29
15.71
15.82
16.64
16.87
15.19
14.95
15.38
15.27
17.88
17.72
13.85
13.68
12.59
12.46
15.72
15.91
16.71
16.86
13.73
13.58
18.71
19.04
14.70
14.81
15.61
15.72
163-165
158-160
200-202
158-160
140-142
213-215
192-193
150-153
170-173
191-193
250-252
143-145
167-169
191-193
170-172
161-163
198-200
181-183
147-149
70
68
72
68
65
67
60
51
55
52
50
83
90
86
94
88
91
71
75
231
291
276
266
249
281
275
237
307
337
352
249
309
294
283
267
299
293
255
C13H13N3O3S
4c
4d
4e
4f
C11H8N4O3S
C11H8ClN3OS
C11H8FN3OS
C15H11N3OS
C12H9N3O3S
C9H7N3OS2
4g
4h
4i
C17H13N3OS
C18H15N3O2S
C17H12N4O3S
C11H11N3O2S
C13H15N3O4S
C11H10N4O4S
C11H10ClN3O2S
C11H10FN3O2S
C15H13N3O2S
C12H11N3O4S
C9H9N3O2S2
4j
4k
5a
5b
5c
5d
5e
5f
60.32
60.19
49.31
49.14
42.13
42.34
4.23
4.38
3.59
3.78
3.28
3.55
14.22
14.04
14.20
14.33
16.54
16.46
5g
5h
1093

We note that 2-Ar-triazolo[5,1-b][1,3]thiazin-7-ones 4i-k are quite stable compounds, while their
analogs 4a-h which are unsubstituted at the 2 position slowly undergo hydrolysis due to moisture in the air when
stored under normal conditions, forming 3-aryl-3-(1H-1,2,4-triazole-5-thio)propanoic acids 5a-h:
O
N
N
OH
R1
H
H2O
4a–h
N
S
5a–h
5 a R1= Ph, b R1 = 3,4-(MeO)2C6H3, c R1 = p-O2NC6H4, d R1 = p-ClC6H4, e R1 = p-FC6H4,
f R1 = 1-naphthyl, g R1 = 3,4-methylenedioxyphenyl, h R1 = 2-thienyl
We may assume that the 2-aryl-substituted triazolothiazinones 4i-k are stable compounds because of
conjugation of the triazole ring with the aromatic ring at the 2 position. When compounds 4a-h are
recrystallized from aqueous acetic acid or when they are heated with hot water, the hydrolysis rate increases
considerably.
The composition and structure of acids 5 are supported by the results of elemental analysis (Table 1) and
1
data from spectral investigation methods. In the H NMR spectra of compounds 5, broadened singlets from
protons of the COOH (12.37-12.55 ppm) and NH (14.12-14.23 ppm) groups are characteristic, and in the IR
spectra there is a characteristic absorption band for C=O (1680-1720 cm-1).
Thus the reaction of 3-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl
chlorides is of a general nature, and is a novel and convenient one-step method for synthesis of substituted
5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones, allowing us to vary the substituents (Ar, Het) at the
positions 2 and 5.
TABLE 2. Spectral Characteristics of Compounds 4a-k, 5a-h
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
1
2
3
4a*
3100, 1730 (C=O),
1510, 1450, 1410, 1320
3.42 (1Н, m, Н-6); 3.90 (1Н, m, Н-6); 5.45 (1Н, m, Н-5);
7.42-7.51 (5Н, m, C6H5); 8.31 (1Н, s, Н-2)
4b
3100, 1730 (C=O),
1600, 1500, 1400, 1310
3.36 (1Н, m, Н-6); 3.77 (6Н, s, 2СН3О); 3.89 (1Н, m, Н-6);
5.40 (1Н, m, Н-5); 6.99 (2Н, m, о-, m-HAr);
7.10 (1Н, s, o-HAr); 8.28 (1Н, s, Н-2)
4c
3100, 1730 (C=O),
3.53 (1Н, m, Н-6); 3.94 (1Н, m, Н-6); 5.64 (1Н, m, Н-5);
1540 (N=O), 1500, 1400 7.80 (2Н, d, J = 9.3, o-HAr); 8.28 (2Н, d, J = 9.3, m-HAr);
8.32 (1Н, s, Н-2)
4d
4e
3100, 1720 (C=O),
1590, 1490, 1410, 1360
3.42 (1Н, m, Н-6); 3.85 (1Н, m, Н-6); 5.48 (1Н, m, Н-5);
7.52 (4Н, m, o-, m-HAr); 8.30 (1Н, s, Н-2)
3100, 1730 (C=O),
1590, 1510, 1400, 1310
3.50 (1Н, m, Н-6); 3.85 (1Н, m, Н-6); 5.43 (1Н, m, Н-5);
7.25 (2Н, t, J = 8.1, о-HAr); 7.67 (2Н, m, m-HAr);
8.30 (1Н, s, Н-2)
4f
3000, 1730 (C=O),
1590, 1500, 1390, 1320
3.50 (1Н, m, Н-6); 4.12 (1Н, m, Н-6); 6.39 (1Н, m, Н-5);
7.60-8.01 (6Н, m, C10H7); 8.25 (1Н, m, C10H7);
8.32 (1Н, s, Н-2)
4g
3000, 1720 (C=O),
1590, 1510, 1440,
1400, 1310
3.28 (1Н, m, Н-6); 3.88 (1Н, m, Н-6); 5.38 (1Н, m, Н-5);
6.06 (2Н, s, ОСН2О), 6.95 (2Н, m, о- и m-НAr);
7.11 (1Н, s, o-HAr); 8.29 (1Н, s, Н-2)
1094

TABLE 2 (continued)
1
2
3
4h
3200, 1720 (C=O),
1580, 1500, 1400, 1310
3.61 (1Н, m, Н-6); 3.78 (1Н, m, Н-6); 5.68 (1Н, m, Н-5);
7.03 (1Н, d. d, J1 = 5.1, J2 = 3.0, HHet-4); 7.18 (1Н, d, J = 3.0,
HHet-3); 7.54 (1Н, d, J = 5.1, HHet-5); 8.27 (1Н, s, Н-2)
4i
4j
3200-3000, 1720 (C=O), 3.47 (1Н, m, Н-6); 3.88 (1Н, m, Н-6); 5.49 (1Н, m, Н-5);
1600, 1480, 1430 7.46-8.10 (10Н, m, 2C6H5)
3100-3000, 1720 (C=O), 3.38 (1Н, m, Н-6); 3.83 (3Н, s, СН3О); 3.90 (1Н, m, Н-6);
1600, 1480, 1460, 1410
5.48 (1Н, m, Н-5); 7.07 (2Н, d, J = 8.1, m-НAr);
7.41-7.54 (5Н, m, C6H5); 8.03 (2Н, d, J = 8.1, o-НAr)
4k
5a
5b
3100-3000, 1720 (C=O), 3.44 (1Н, m, Н-6); 3.95 (1Н, m, Н-6); 5.56 (1Н, m, Н-5);
1590, 1530 (N=O),
7.41-7.56 (5Н, m, С6Н5); 8.32 (2Н, d, J = 9.1, о-HAr);
1480, 1400
8.39 (2Н, d, J = 9.1, m-HAr)
3300-2800, 1700 (C=O), 3.14 (2Н, m, CН2CO); 5.01 (1Н, m, SCН); 7.40 (5Н, m, С6Н5);
1450, 1410, 1360
8.54 (1Н, br. s, Н-3); 12.44 (1Н, br. s, СООН);
14.13 (1Н, br. s, NH)
3300, 2900, 2550,
1700 (C=O), 1610,
1520, 1480
3.09 (2Н, m, CН2CO); 3.66 (6Н, s, 2 OСН3);
4.97 (1Н, m, SCН); 6.83 (2Н, d, J = 5.1, o-, m-HAr);
7.12 (1Н, s, o-HAr); 8.58 (1Н, br. s, Н-3);
12.38 (1Н, br. s, СООН); 14.15 (1Н, br. s, NH)
5c
5d
5e
3250, 2900, 2600,
1690 (C=O), 1520,
1500, 1410
3.05 (2Н, m, CН2CO); 5.13 (1Н, m, SCН);
7.11 (2Н, d, J = 9.1, o-HAr); 8.34 (2Н, d, J = 9.1, m-HAr);
8.48 (1Н, br. s, Н-3); 12.41 (1Н, br. s, СООН);
14.17 (1Н, br. s, NH)
3200, 2950, 2500,
1680 (C=O), 1490,
1430, 1370
3.04 (2Н, m, CН2CO); 4.98 (1Н, m, SCН);
7.36 (2Н, d, J = 9.2, о-НAr); 7.42 (2Н, d, J = 9.2, m-НAr);
8.47 (1Н, br. s, Н-3); 12.50 (1Н, br. s, СООН);
14.20 (1Н, br. s, NH)
3200, 2950, 2600,
1700 (C=O), 1660,
1490, 1370
3.09 (2Н, m, CН2CO); 4.99 (1Н, m, SCН);
7.15 (2Н, t, J = 7.7, o-НAr); 7.46 (2Н, t, J = 7.7, m-НAr);
8.49 (1Н, br. s, Н-3); 12.55 (1Н, br. s, СООН);
14.17 (1Н, br. s, NH)
5f
3100-2600, 1720 (C=O), 3.36 (2Н, m, CН2CO); 5.84 (1Н, m, SCН);
1500, 1400, 1310
7.57-8.33 (7Н, m, C10H7); 8.53 (1Н, br. s, Н-3);
12.40 (1Н, br. s, СООН); 14.23 (1Н, br. s, NH)
5g
5h
3100-2600, 1700 (C=O), 3.02 (2Н, m, CН2CO); 4.95 (1Н, m, SCН); 6.02 (2Н, s, ОСН2О),
1600, 1500, 1430, 1350
6.82 (2Н, m, o- и m-НAr); 7.01 (1Н, s, o-HAr); 8.48 (1Н, br. s, Н-3);
12.37 (1Н, br. s, СООН); 14.23 (1Н, br. s, NH)
3200, 2900, 2550,
1710 (C=O), 1530,
1480, 1320
3.07 (2Н, m, CН2CO); 4.94 (1Н, m, SCН);
6.92 (1Н, d. d, J1 = 5.4, J2 = 3.2, HHet-4); 7.13 (1Н, d, J = 3.2,
HHet-3); 7.58 (1Н, d, J = 5.4, HHet-5); 8.44 (1Н, br. s, Н-3);
12.41 (1Н, br. s, СООН); 14.15 (1Н, br. s, NH)
_______
13C spectrum, δ, ppm: 40.47 (C-6), 42.64 (C-5), 127.52 (C6H5),
*
128.80 (C6H5), 129.10 (C6H5), 136.66 (C6H5), 153.16 (C-2), 156.06 (C-3a),
162.93 (C-7).
EXPERIMENTAL
The NMR spectra were recorded on a Varian-300 (300 MHz (1H), 75 MHz (13C)) in DMSO-d6, internal
standard TMS. The mass spectra were taken on an MKh-1303; the IR spectra were taken on a UR-20 in KBr
disks.
2-R-5-Ar(Het)-5,6-Dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones (4a-k) (General Procedure).
Acid chloride 2 (10 mmol) in benzene (4 ml) was added to a solution of compound 1 (10 mmol) in pyridine
(4 ml) at 20°C. The solution was boiled for 1 h under reflux and then cooled, and then water was added. The
precipitated product 4 was filtered out, recrystallized from acetic acid, and dried.
1095

3-Ar(Het)-3-(1H-1,2,4-Triazole-5-thio)propanoic Acids (5a-h) (General Procedure). A mixture of
water (5 ml) and compound 4a-h (5 mmol) was held for 24 h at 95°C and then cooled. Product 5 was filtered
out, recrystallized from acetic acid, and dried.
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