Aminolysis of 2-aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b]1,3]thiazin- 7-ones

Article abstract of DOI:10.1007/s10593-005-0321-2

We have established that the products of aminolysis of 2-aryl-5-R-5,6- dihydro-7H-[1,2,4]triazolo-[5,1-b][1,3] thiazin-7-ones in boiling ethanol are 3-R-3-(5-aryl-4H-1,2,4-triazol-3-ylsulfanyl)-propanamides, and at 180°C-210°C (depending on the structure of the substituent R): 3-phenyl-4,5-dihydro-1H-1,2,4-triazoline-5-thione and 3-arylacrylamides or 3-(3-aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanamides. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0321-2

Chemistry of Heterocyclic Compounds, Vol. 41, No. 10, 2005
AMINOLYSIS OF 2-ARYL-5-R-5,6-DIHYDRO-
7
H-[1,2,4]TRIAZOLO[5,1-b]1,3]THIAZIN-7-ONES
V. N. Britsun, A. N. Esipenko, V. V. Pirozhenko, and M. O. Lozinskii
We have established that the products of aminolysis of 2-aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo-
[5,1-b][1,3]thiazin-7-ones in boiling ethanol are 3-R-3-(5-aryl-4H-1,2,4-triazol-3-ylsulfanyl)-
propanamides, and at 180°C-210°C (depending on the structure of the substituent R): 3-phenyl-4,5-
dihydro-1H-1,2,4-triazoline-5-thione and 3-arylacrylamides or 3-(3-aryl-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-1-yl)propanamides.
Keywords: 3-arylacrylamides, 3-aryl-4,5-dihydro-1H-1,2,4-triazoline-5-thiones, 2-aryl-5-R-5,6-
dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones,
3-(3-aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-
yl)propanamides, 3-R-3-(5-aryl-4H-1,2,4-triazol-3-ylsulfanyl)propanamides, aminolysis.
Earlier we proposed a novel method for synthesis of 2,5-diaryl-5,6-dihydro-7H-[1,2,4]triazolo[5,1-
b][1,3]thiazin-7-ones 1a-c including condensation of 3-aryl-4,5-dihydro-1H-1,2,4-triazoline-5-thiones with
3
1
-arylacryloyl chlorides [1, 2]. 2-Phenyl-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones 1 at
60°C-170°C react with ammonia and aromatic amines and are converted to 3-(5-aryl-4H-1,2,4-triazol-
ylsulfanyl)propanamides 2 [3]. We thought it would be of interest to study the reactions of 2,5-diaryl-substituted
compounds 1a-c with primary aliphatic and aromatic amines, and to compare them with analogous conversions
of 2-monoaryltriazolothiazinones 1d-f.
We have established that the direction of their reaction depends on the temperature conditions. Thus for
reaction of compounds 1a-c with aniline, benzylamine, and 3-aminomethylpyridine in boiling ethanol, the
reaction products are 3-propanamides 2a-e. At the same time, aminolysis of the same compounds in boiling
amine (180°C-184°C) leads to breakdown of the 1,3-thiazine ring and formation of 3-phenyl-4,5-dihydro-1H-
1
,2,4-triazoline-5-thione 3 and 3-arylacrylamides 4a-c (Tables 1, 2).
The same compounds are the result of thermal decomposition of propanamides 2a-3, which occurs when
their solutions in the corresponding amine or in 1,3-dichlorobenzene are boiled (180°C) for 30 min. At the same
time, compounds 2a-e are quite stable when briefly heated to 190°C; for example, amides 2b and 2d were
recrystallized from benzonitrile with no signs of decomposition.
1
In the H NMR spectra of compounds 2b-e, due to the presence of a chiral center (3-CH), the signals
from the protons of the 3-CH, 2-CH , and NHCH C H groups appear as multiplets. In the IR spectra of
2
2
6
5
-
1
compounds 2 (and also 4 and 5), we observe the characteristic absorption bands ν
region, νC=O in the 1670-1650 cm region, and ν in the 1610-1550 cm region.
in the 3300-3250 cm
N–H
-
1
-1
C=N
_
_________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1587-1592,
October, 2005. Original article submitted December 28, 2003.
1
334
0009-3122/05/4110-1334©2005 Springer Science+Business Media, Inc.

H
N
N
R1
NHR2
O
Ph
+
N
H
S
3
4a–c
amine or 1,3-C H Cl
2
6
4
1
(
R = H)
1
2
boiling
(R = H)
R = NH
boiling
2
O
O
NHR2
R1
2
H
R = NH
2
N
N
N N
R1
Ar
C H OH
Ar
S
a–f
2
5
S
N
N
1
2a–i
2
R = NH
boiling
2
o
2
10 C or amine
1
(
R = H)
1
boiling (R = H)
NHR2
O
H
H
N
N
Ar
N
S
5
a–d
1
6 4 6 4
а–d, 2а–g, 3, 5 a, b Ar = Ph; 1e, 2h, 5c Ar = р-MeOC H ; 1f, 2i, 5d Ar = р-ClC H ;
1
1
1
1
а, 2a–c, 4a–c R = Ph; 1b, 2d R = р-MeOC H ; 1c, 2e R = m-NO C H ;
6 4 2 6 4
1
2
2
1
d–f, 2f–i, 5a–d R = H; 2a,f, 4a, 5a R = Ph; 2b,d,e,g–i, 4b, 5b–d R = PhCH ;
2
2
2
c, 4c R = (3-C H N)CH
5
4
2
Aminolysis of monoaryl triazolothiazinones 1d-f in boiling ethanol also leads to breaking of the
N(8)-C(7) bond and formation of amides 2f-i; and under harsh conditions (when solutions of compounds 1d-f
and 2f-i are boiled in aniline or benzylamine), the reaction products are 3-(3-aryl-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-1-yl)propanamides 5a-d. The same compounds are obtained when amides 2f-i are heated without solvents
at 210°C for 1 h, and also when their solutions are boiled in 1,3-dichlorobenzene or in N,N-dimethylaniline for 2
h.
1
In the H NMR spectra of compounds 1d-f and 2f-i, the signal from the SCH CH CO group appears at
2
2
3
4
.51-3.55 ppm, while the signal from the NCH CH CO group of the products 5a-d is observed downfield at
2 2
.34-4.42 ppm. In the IR spectra of compounds 5a-d, there is no absorption band for the S-H bond
-
1
-1
(
2280-2550 cm ) and we observe the absorption band for the ν
N–H
bond (1230-1240 cm [4]), indicating the
existence of 5a-d in the thione form, as is preferred for 1,2,4-triazole derivatives [5]. We have reason to believe
that the reaction occurs at N(1), since we know that alkylation of 5-alkylthio-3-aryl-1,2,4-triazoles occurs mainly
at the N(1) position while there is almost no formation of products of alkylation at N(4) [6, 7]. Apparently the
driving force for this isomerization is the thermodynamic factor. The C–N bond is energetically more favorable
than the C–S bond (for comparison: the strength of the Alk–SH and Ph–SH bonds are respectively 69 and 86
kcal/mole, while the strengths of the Alk–NH and Ph–NH bonds are respectively 87 and 104 kcal/mol [8]).
2
2
1
335

TABLE 1 Characteristics of Synthesized Compounds
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
mp, °С*
Yield, %
С
H
N
2
2
2
2
2
2
a
b
c
d
e
f
C23H20N4OS
69.27
5.31
5.03
5.48
5.35
5.23
5.09
5.68
5.44
4.39
4.61
5.13
4.97
13.70
13.99
13.35
13.52
16.62
16.85
12.49
12.60
15.50
15.24
17.41
17.27
179-181
205-206
168-170
201-204
180-182
149-151
73
84
77
75
79
67
6
8.98
C24H22N4OS
C23H21N5OS
C25H24N4O2S
C24H21N5O3S
C17H16N4OS
69.63
9.54
6
66.42
6.49
6
67.68
7.55
6
62.50
2.73
6
62.71
2.94
6
(147 [3])
2
2
2
3
g
h
i
C18H18N4OS
C19H20N4O2S
C18H17ClN4OS
C8H7N3S
63.70
3.88
5.19
5.36
5.31
5.47
4.86
4.60
3.73
3.98
16.39
16.56
15.49
15.21
15.19
15.03
23.50
23.71
133-135
69
72
75
69
6
61.73
1.94
137-140
145-148
258-260
6
57.76
7.98
5
54.01
4.22
5
(
256 [9])
148-150
151 [10])
107-110
104 [11])
81-83
4
4
a
C15H13NO
C16H15NO
80.89
0.69
5.66
5.87
6.36
6.27
62
70
8
(
(
b
80.74
0.98
6.51
6.37
5.74
5.90
8
4
5
5
5
5
c
C15H14N2O
75.70
5.61
6.01
5.92
4.73
4.97
5.07
5.36
5.66
5.47
11.58
11.76
17.05
17.27
16.69
16.56
15.43
15.21
60
59
61
55
58
7
a
b
c
C17H16N4OS
C18H18N4OS
C19H20N4O2S
C18H17ClN4OS
63.22
2.94
265-270
237-240
248-250
265-270
6
64.12
3.88
6
61.82
1.94
6
d
57.73
7.98
4.37
4.60
14.81
15.03
5
_
*
2
______
Compounds 2a,c,e-i, 3, 4a-c were recrystallized from ethanol;
b,d, 5a-d were recrystallized from benzonitrile.
Obviously, conversions of 2-aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones 1a-f to
form compounds 3, 4a-c, and 5a-d occur through a step including formation of 3-propanamides 2a-i, which
when treated with bases or at high temperature apparently eliminate a proton, in this case forming carbanion 6.
The latter probably is transformed to intermediate 7, and the subsequent direction of the reaction depends on
the presence or absence of a substituent in acrylamides 8. When R = Ar, the double bond of the 3-arylacrylamide is
1
part of a conjugated system and so is inactive even at high temperatures, and the process stops in the step
involving formation of triazolinethione 3 and 3-arylacrylamides 4. As we know, in unsubstituted (R = H)
1
acrylamides the double bond is quite reactive, and it readily reacts with anion 7 and is converted to the product 5.
1
336

O
NHR2
H
–
N
N
Ar
R1
S
N
6
O
H
–
NHR2
N
N
+
Ar
S
N
R1
7
8
1
1
R = H
R = Ar
5
3
+ 4
1
TABLE 2. H NMR Spectra of Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (SSCC, J, Hz)
1
2
2
2
a
3.2 (2Н, m, Н-2); 5.2 (1Н, m, Н-3); 7.0 (1Н, m, Н arom.); 7.3-7.6 (12Н, m, Н arom.);
.0 (2Н, m, Н arom.); 10.0 (1Н, s, СОNH); 14.1 (1Н, br. s, NH triazole)
3.0 (2Н, m, Н-2); 4.1-4.2 (2Н, m, NHCН2); 5.2 (1Н, m, H-3); 6.9 (2Н, m, H arom.);
8
b
7
1
.2-7.7 (11Н, m, Н arom.); 8.0 (2Н, m, Н arom.); 8.5 (1Н, br. s, СОNН);
4.5 (1Н, br. s, NH triazole)
2
2
c
3.0 (2Н, m, Н-2); 4.1-4.3 (2Н, m, NHCН2); 5.2 (1Н, m, H-3); 7.1-7.6 (10Н, m, H arom.);
8
1
.0 (2Н, m, Н arom.); 8.3 (2Н, m, Н arom.); 8.5 (1Н, br. s, СОNН);
4.5 (1Н, br. s, NH triazole)
d
3.0 (2Н, m, Н-2); 3.7 (3Н, s, СН3О); 4.1-4.3 (2Н, m, NHCН2); 5.1 (1Н, m, H-3);
6
7
1
.9 (4Н, m, H arom.); 7.2 (3Н, m, Н arom.); 7.3 (2Н, d, J = 8.1, Н arom.);
.4-7.5 (3Н, m, Н arom.); 8.0 (2Н, m, Н arom.); 8.4 (1Н, br. s, СОNН);
4.4 (1Н, br. s, NH triazole)
2
e
3.1 (2Н, m, Н-2); 4.1-4.3 (2Н, m, NHCН2); 5.3 (1Н, m, H-3); 6.9 (2Н, m, H arom.);
7
8
1
.2 (3Н, m, Н arom.); 7.3-7.7 (4Н, m, Н arom.); 8.0 (3Н, m, Н arom.);
.1 (1Н, d, J = 7.9, Н arom.); 8.3 (1Н, m, Н arom.); 8.5 (1Н, br. s, СОNН);
4.3 (1Н, br. s, NH triazole)
2
2
2
4
g
h
i
2.7 (2Н, t, J = 6.4, Н-2); 3.5 (2Н, t, J = 6.4, Н-3); 4.3 (2Н, d, J = 6.1, NHСН2);
7
8
.3 (4Н, m, Н arom.); 7.5 (4Н, m, Н arom.); 8.0 (2Н, m, Н arom.);
.4 (1Н, t, J = 6.1, CONHСН ); 14.3 (1Н, br. s, NН triazole)
2
2.6 (2Н, t, J = 6.3, Н-2); 3.5 (2Н, t, J = 6.3, H-3); 3.8 (3Н, s, СН3О);
4
7
.3 (2Н, d, J = 6.2, NHСН ); 7.0 (2Н, d, J = 8.2, Н arom.); 7.3 (5Н, m, Н arom.);
2
.9 (2Н, d, J = 8.2, Н arom.); 8.4 (1Н, t, J = 6.2, CONHСН ); 14.2 (1Н, br. s, NН triazole)
2
2.7 (2Н, t, J = 6.4, H-2); 3.5 (2Н, t, J = 6.4, H-3); 4.3 (2Н, d, J = 6.1, NHСН2);
7
8
.2 (5Н, m, Н arom.); 7.6 (2Н, d, J = 7.9, Н arom.); 8.0 (2Н, d, J = 7.9, Н arom.);
.5 (1Н, t, J = 6.1, CONHСН ); 14.4 (1Н, br. s, NН triazole)
2
c
4.4 (2Н, d, J = 6.0, NHСН2); 6.7 (1Н, d, J = 12.5, Н-3); 7.4-7.8 (8Н, m, Ar);
.4 (1Н, d, J = 3.5, Н-6 pyridine); 8.5 (1Н, s, Н-2 pyridine); 8.7 (1Н, t, J = 6.0,
CONНСН2)
8
1
337

TABLE 2. (continued)
1
2
5
5
5
a
c
2.9 (2Н, t, J = 6.3, Н-2); 4.4 (2Н, t, J = 6.3, Н-3); 7.0-7.3 (3Н, m, Н arom.);
7
1
.4-7.7 (5Н, m, Н arom.); 7.88 (2Н, m, Н arom.); 10.1 (1Н, s, СОNH);
4.0 (1Н, br. s, NН triazole)
2.7 (2Н, t, J = 6.3, Н-2); 3.8 (3Н, s, СН3О); 4.3 (2Н, d, J = 6.0, NHCH2C6H5);
4
7
.3 (2Н, t, J = 6.3, Н-3); 7.1 (2Н, d, J = 8.3, Н arom.); 7.2 (5Н, m, Н arom.);
.8 (2Н, d, J = 8.3, Н arom.); 8.5 (1Н, t, J = 6.0, СОNHСН ); 13.9 (1Н, br. s, NН triazole)
2
d
2.7 (2Н, t, J = 6.2, Н-2); 4.3 (2Н, d, J = 6.1, NHCH2C6H5); 4.3 (2Н, t, J = 6.2, H-3);
7
8
.1 (5Н, Н arom.); 7.6 (2Н, d, J = 7.9, Н arom.); 7.9 (2Н, d, J = 7.9, Н arom.);
.5 (1Н, t, J = 6.1, СОNHСН ); 14.0 (1Н, br. s, NН triazole)
2
EXPERIMENTAL
The 1H NMR spectra were recorded on a Varian 300 (300 MHz) in DMSO-d , internal standard TMS.
6
The IR spectra were taken on a UR-20 in KBr disks.
3
-R-3-(5-Aryl-4H-1,2,4-triazol-3-ylsulfanyl)propanamides 2a-i. A solution of 10 mmol of 2-aryl-5-R-
5
3
,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one 1a-f and 12 mmol amine in 10 ml ethanol was boiled for
0 min under reflux and then cooled. The precipitate of propanamide 2a-i was filtered out, washed with cold
ethanol, dried, and recrystallized from an appropriate solvent. The yields and melting points for propanamides
2
a-i are presented in Table 1.
Aminolysis of compounds 1a and 2a-c. A solution of 5 mmol triazolothiazine 1a or propanamide 2a-c
in 7 ml of the appropriate amine was boiled for 30 min under reflux and then the excess amine was driven off
under vacuum. The reaction mass was extracted with hot ethanol (2 × 5 ml) and then triazolinethione 3 was
filtered out. Then the filtrate was evaporated down to a volume of 3 ml and cooled. The precipitated
3-arylacrylamide 4a-c was filtered out and dried.
3
-(3-Aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanamides 5a-d. A solution of 5 mmol
triazolothiazinone 1d-f or propanamide 2f-i in 5 ml aniline (benzylamine) was boiled under reflux for 2 h. The
reaction mass was cooled and 10 ml ether was added. The precipitated propanamide 5a-d was filtered out and
dried.
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