Synthesis of 4,5-dihydro-1,3,4-thiadiazole-2-carboxamide and 2-carbamoyl-4,5-dihydro-1,3,4-thiadiazole 1-oxide derivatives based on hydrazones of oxamic acid thiohydrazides

Article abstract of DOI:10.1023/B:COHC.0000018342.57499.16

We have developed a method for obtaining derivatives of 4,5-dihydro-1,3,4-thiadiazole-2-carboxamide by acylation of hydrazones of oxamic acid thiohydrazides. Oxidation of the dihydrothiadiazole ring of the indicated products by hydrogen peroxide leads to formation of 2-carbamoyl-4,5-dihydro-1,3, 4-thiadiazole 1-oxides.

Full text of DOI:10.1023/B:COHC.0000018342.57499.16

Chemistry of Heterocyclic Compounds, Vol. 39, No. 12, 2003
SYNTHESIS OF 4,5-DIHYDRO-1,3,4-THIADIAZOLE-
2-CARBOXAMIDE AND 2-CARBAMOYL-4,5-DIHYDRO-
1,3,4-THIADIAZOLE 1-OXIDE DERIVATIVES BASED
ON HYDRAZONES OF OXAMIC ACID THIOHYDRAZIDES
V. N. Yarovenko, A. V. Shirokov, I. V. Zavarzin, O. N. Krupinova, A. V. Ignatenko,
and M. M. Krayushkin
We have developed a method for obtaining derivatives of 4,5-dihydro-1,3,4-thiadiazole-2-carboxamide
by acylation of hydrazones of oxamic acid thiohydrazides. Oxidation of the dihydrothiadiazole ring of
the indicated products by hydrogen peroxide leads to formation of 2-carbamoyl-4,5-dihydro-1,3,4-
thiadiazole 1-oxides.
Keywords: hydrazones, 1,3,4-dihydrothiadiazole, dihydro-1,3,4-thiadiazole 1-oxide, 1,3,4-thiadiazole,
oxamic acid thiohydrazides, thiophene.
We have developed previously a convenient general method for obtaining monothiooxamides by
reaction of accessible chloroacetamides with a pre-prepared solution of elemental sulfur in amine [1] and
showed that modification of the thioamide group in these monothiooxamides under treatment with
N-nucleophiles allows us to obtain a variety of hetarene carboxamides [2-4], while in the reaction with
hydrazines oxamic acid thiohydrazides of type 1 are formed (see Scheme 1) [5]. For the latter, we studied the
possibility of conversion to 1,3,4-dihydrothiadiazole derivatives, which are of interest for obtaining biologically
active compounds [6, 7].
Scheme 1
R3CHO
O
O
O
1
R1
R
R1
H
N
H
N
2a–e
S
R3
N
H
NH2
N
H
N
R3
N
H
2
R2
R
R2
S
S
N
NH
3a–h
A
B
1a–h
2 a R3 = Ph, b R3 = 2-thienyl, c R3 = 4-O2NC6H4, d R3 = 2-O2NC6H4,
e R3 = 5-methyl-2-thienyl; 1, 3 R1, R2, and R3 are given in Table 1.
_______
* Dedicated to J. P. Stradins on his 70th birthday.
__________________________________________________________________________________________
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991; e-mail:
yarov@mail.ioc.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1855-1860,
December, 2003. Original article submitted July 4, 2003.
0009-3122/03/3912-1633$25.00©2003 Plenum Publishing Corporation
1633

In this work, from oxamic acid thiohydrazides 1a-h and aldehydes 2a-e, we have synthesized for the
first time the corresponding hydrazones 3a-h (Scheme 1), based on which we obtained the previously
undescribed 4,5-dihydro-1,3,4-thiadiazole-2-carboxamides 4a-g (Scheme 2) and 2-carbamoyl-4,5-dihydro-1,3,4-
thiadiazole 1-oxides 5a-c (Scheme 3).
Scheme 2
O
O
R4
R3
Cl
R4
N
N
H
N
R1
R2
5a–d
3a–c
S
O
4a–g
4 a R1 = R2 = H, R3 = Ph, R4 = Me; b R1 = 3-Cl, R2 = 4-Cl, R3 = Ph, R4 = Me;
c R1 = R2 = H, R3 = Ph, R4 = Et; d R1 = 3-Cl, R2 = 4-Cl, R3 = Ph, R4 = Et;
e R1 = R2 = H, R3 = R4 = Ph; f R1 = R2 = H, R3 = R4 = 2-thienyl; g R1 = R2 = H,
R3 = 2-thienyl, R4 = Ph; 5 a R4 = Me; b R4 = Et; c R4 = Ph; d R4 = 2-thienyl
1
Hydrazones 3a-h were obtained in 60% to 80% yields. According to the H NMR spectra for these
compounds, they are found in solution as two tautomeric forms: linear form A and cyclic form B.
So in the indicated spectra, we see a signal from the proton in the 5 position of the heterocycle of form
B in the 6.5-7.1 ppm region, and also a signal from the proton of the N=CH–R3 moiety of linear form A in the
8.7-9.1 ppm region. We determined the ratio of the tautomers 3A and 3B from the intensity ratio for the
indicated signals (see Table 1), and we established that the ratio is affected by the substituents both in the
"aldehyde" (R3) and the "thiohydrazide" (R1, R2) moieties of the molecule (Table 1).
So introducing an electron-acceptor substituent R3 shifts the equilibrium toward formation of the cyclic
product B (compounds 3a,d), while electron-acceptor substituents R1, R2 may have an opposite effect
(compound 3d,e).
Hydrazones 3a-h react smoothly with aliphatic, aromatic, and heteroaromatic acid chlorides, in this case
forming the corresponding 2-carbamoyl-4,5-dihydro-1,3,4-thiadiazoles 4a-g. During the reaction with acid
chlorides, probably the cyclic form B of hydrazone reacts.
The reaction can be conducted in a single flask by adding aldehyde 2 and acid chloride 5 sequentially to
the solution of thiohydrazide 1 in DMF.
TABLE 1. Substituent Dependence of the Ratio of Tautomeric Forms of
Hydrazones in Solutions, in DMSO-d6 at T = 297 K
Ratio, %
Compound*
R1
R2
R3
A
B
H
3-Cl
H
H
4-Cl
H
Ph
Ph
10
0
30
0
20
0
40
50
90
100
70
100
80
100
60
50
3a
3b
3с
3d
3e
3f
2-thienyl
4-O2NC6H4
4-O2NC6H4
2-O2NC6H4
5-methyl-2-thienyl
5-methyl-2-thienyl
H
H
3-Cl
3-Cl
2-Me
H
4-Cl
4-Cl
3-Me
3-Me
3g
3h
_______
* R1, R2, R3 are given for compounds 1 and 3.
1634

TABLE 2. Characteristics of Compounds 3, 4, 6
Found, %
——————
Com-
pound
Empirical
formula
Mass spectrum,
Calculated, %
mp, °C
9
1Н NMR spectrum, δ, ppm (J, Hz)
Yield, %
m/z
С
3
H
4
N
5
S
6
Cl
7
1
2
8
10
11
76
C15H13N3OS
63.54
63.58
4.67
4.62
14.85 11.30
14.83 11.32
—
283
153-155 6.60 (1H, s, S–CH– (B)); 7.00 (2H, m, C6H5); 7.40 (7H, m, C6H5);
7.90 (1H, d, J = 7.9, C6H5); 8.90 (s, N=CH (A)); 9.15 (s, NH(B));
10.00 (s, 2 NH (B)); 10.10 (s, NH (A)); 10.30 (s, NH (A))
3a
C15H11Cl2N3OS 51.19
51.15
3.11
3.15
11.90
11.93
9.12
9.10
20.15
20.13
352
289
328
165-167 6.65 (1H, s, S–CH– (B)); 7.40-7.60 (4H, m, C6H5 (B));
7.90 (1H, d, J = 7.92, C6H5 (B)); 8.10 (1H, s, C6H5 (B));
9.40 (1H, s, NH (B)); 10.50 (1H, s, NH (B))
153-156 6.60 (s, S–CH–(B)); 6.80-7.70 (8H, m, C6H5); 8.90 (s, N=CH (A));
9.15 (s, NH(B)); 10.00 (s, 2NH (B)); 10.10 (s, NH (A));
10.30 (s, NH (A))
202-204 6.75 (1H, s, S–CH– (B)); 7.10 (1H, t, J = 7.4, C6H5 (B));
7.30 (2H, t, J = 7.6, C6H5 (B)); 7.70 (4H, m, C6H5 (B));
8.30 (2H, d, J = 8.9, C6H5 (B)); 9.40 (1H, s, NH (B));
10.20 (1H, s, NH (B))
79
61
79
3b
3с
3d
C13H11N3OS2
C15H12N4O3S
54.00
53.96
3.85
3.83
14.50 22.17
14.52 22.16
—
—
54.91
54.87
3.64
3.68
17.09
17.06
9.74
9.77
C15H10Cl2N4O3S 45.36
45.35
2.57
2.54
14.07
14.10
8.12
8.07
17.81
17.85
396
396
331
203-206 6.80 (s, S–CH– (B)); 7.50 (d, J = 8.7, C6H5); 7.70 (3H, m, C6H5);
8.10 (2H, m, C6H5); 8.30 (3H, m, C6H5); 8.70 (s, СН=N (A));
9.50 (s, NH(B)); 10.50 (s, NH (B))
190-192 7.00 (1H, s, S–CH– (B)); 7.50-7.75 (4H, m, C6H5 (B));
7.90 (1H, m, C6H5 (B)); 8.10 (2H, m, C6H5 (B));
9.50 (1H, s, NH (B)); 10.50 (1H, s, NH (B))
134-136 2.10 (m, CH3); 2.20 (s, CH3); 2.30 (s, CH3); 2.40 (s, CH3);
6.60 (s, S–CH–(B)); 6.80-7.70 (5H, m, C6H5); 8.90 (s, N=CH (A));
9.15 (s, NH(B)); 9.60 (s, NH (B)); 10.10 (s, NH (A));
10.35 (s, NH (A))
85
81
56
3e
3f
C15H10Cl2N4O3S 45.32
45.35
2.51
2.54
14.14
14.10
8.05
8.07
17.87
17.85
C16H17N3OS2
57.92
57.98
5.23
5.17
12.73 19.30
12.68 19.35
—
3g

TABLE 2 (continued)
1
2
3
4
5
6
7
8
9
10
11
54
C15H15N3OS2
56.79
56.76
4.74
4.76
13.21 20.24
13.24 20.20
—
317
116-118 2.20 (3H, s, CH3); 2.55 (3H, s, CH3); 6.60 (s, S–CH–(B));
6.80-7.70 (7H, m, C6H5); 8.90 (s, N=CH (A)); 9.15 (s, NH(B));
10.00 (s, 2 NH (B)); 10.10 (s, NH (A)); 10.30 (s, NH (A))
3h
4a*
4b
C17H15N3O2S
62.71
62.75
4.68
4.65
12.88
12.91
9.89
9.85
—
325
393
339
144-147 2.40 (3H, s, CH3); 7.20 (2H, m, СН, C6H5); 7.40 (7H, m, C6H5);
87
80
82
7.75 (2H, d, J = 7.6, C6H5); 10.50 (1H, s, NH)
C17H13Cl2N3O2S 51.76
3.34
10.64
8.10
18.01
17.98
—
175-178 2.40 (3H, s, CH3); 7.20 (1H, s, СН); 7.40 (5H, m, C6H5);
51.79
63.66
63.70
3.32
10.66
8.13
7.70 (2H, m, C6H5); 8.10 (1H, s, C6H5); 10.65 (1H, s, NH)
C18H17N3O2S
5.02
5.05
12.41
12.38
9.42
9.45
152-161 1.00 (3Н, t, CH3); 2.85 (2H, m, J = 7, CH2);
7.20 (2H, m, СН, C6H5); 7.40 (7H, m, C6H5);
7.75 (2H, d, J = 7.92, C6H5); 10.50 (1H, s, NH)
4c
C18H15Cl2N3O2S 52.93
52.95
3.71
3.70
10.27
10.29
7.87
7.85
17.34
17.37
407
164-167 1.00 (3Н, t, CH3); 2.80 (2H, m, J = 7, CH2); 7.20 (1H, s, СН);
7.40 (5H, m, C6H5); 7.70 (3H, m, C6H5); 8.10 (2H, s, C6H5);
10.65 (1H, s, NH)
82
4d
C22H17N3O2S
C18H13N3O2S3
68.23
68.20
4.40
4.42
10.81
10.84
8.32
8.28
—
—
387
399
176-180 7.10 (1H, t, J = 7.4, СН, C6H5); 7.40-7.60 (13H, m, СН, C6H5);
74
70
4e
4f
8.00 (2H, d, J = 7.9, C6H5); 10.40 (1H, s, NH)
54.14
3.31
10.49 24.11
179-182 7.00 (1H, m, C6H5); 7.20 (4H, m, Het, CH, C6H5);
7.40 (2H, m, C6H5); 7.55 (1H, m, Het); 7.75 (2H, m, Het, C6H5);
8.00 (1H, m, C6H5); 8.25 (1H, d, J = 7.9, C6H5); 10.55 (1H, s, NH)
54.12
3.28
10.52 24.08
C20H15N3O2S2
C17H15N3O3S
61.09
61.05
3.83
3.84
10.72 16.33
10.68 16.30
—
—
393
341
409
403
189-192 7.00 (1H, t, J = 7.4, C6H5); 7.10 (1H, t, J = 7.4, C6H5);
67
71
65
46
4g
7.30-7.80 (10H, m); 8.00 (2H, d, J = 7.9, C6H5); 10.45 (1H, s, NH)
6a*2
6b
59.78
4.47
12.34
9.42
208-212 2.60 (3H, s, CH3); 7.00 (1H, s, CH); 7.20 (1H, t, J = 7.4, C6H5);
7.35 (7H, m, C6H5); 7.75 (2H, d, J = 7.9, C6H5); 10.75 (1H, s, NH)
237-240 2.60 (3H, s, CH3); 7.20 (1H, s, СН); 7.40 (5H, m, C6H5);
59.81
4.43
12.31
9.39
C17H13Cl2N3O3S 49.80
49.77
C22H17N3O3S
3.17
3.19
10.22
10.24
7.85
7.82
17.31
17.28
—
7.70 (2H, m, C6H5); 8.10 (1H, s, C6H5); 10.85 (1H, s, NH)
65.47
4.28
10.39
7.91
220-224 7.10 (1H, t, J = 7.37, C6H5); 7.40-7.60 (13H, m, СН, C6H5);
6c
65.49
4.25
10.41
7.95
8.00 (2H, d, J = 8.38, C6H5); 10.70 (1H, s, NH)
_______
13
δ
* С NMR spectrum, , ppm: 22.1, 69.6, 120.9, 124.7, 125.5, 128.6, 128.7, 128.75, 137.3, 140.9, 147.0, 156.8, 169.3.
2 13
δ
*
С NMR spectrum, , ppm: 21.8, 85.1, 120.8, 124.8, 126.3, 127.0, 128.0, 128.8, 129.3, 129.4, 132.05, 137.4, 147.8,
156.5, 169.6.

Oxidation of compounds 4a,b,e, having different substituents on the 4 and 5 positions of the
heterocycle, by hydrogen peroxide in acetic acid leads to 2-carbamoyl-4,5-dihydro-1,3,4-thiadiazole 1-oxides
6a-c in good yields.
Scheme 3
O
R4
N
N
H
N
R1
H2O2
R3
4a b e
, ,
S
O
R2
O
6a–c
6 a R1 = R2 = H, R3 = Ph, R4 = Me; b R1 = 3-Cl, R2 = 4-Cl, R3 = Ph, R4 = Me;
1
2
3
4
c
R = R = H, R = R = Ph
Thus upon acylation of accessible hydrazones of oxamic acid thiohydrazides, 2-carbamoyl-4,5-dihydro-
1,3,4-thiadiazoles are formed, the oxidation of which leads to 2-carbamoyl-4,5-dihydro-1,3,4-thiadiazole
1-oxides containing different substituents on the ring.
EXPERIMENTAL
1
The H NMR spectra were recorded on Bruker WM-200 (200 MHz) and WM-250 (250 MHz)
spectrometers in DMSO-d6; the 13C NMR spectra were recorded on a Bruker AC-200 (50 MHz) apparatus in
DMSO-d6. The mass spectra were recorded on a Varian MAT CH-6 mass-spectrometer with direct injection of
the sample into the emission source, ionization energy was 70 eV, and operating voltage 1.75 kV. The IR
spectra were taken on a Specord M-80 for KBr disks. The melting points were measured on a Boetius hot stage
and were uncorrected. For analysis of all the reaction masses and monitoring the purity of the isolated products,
we used TLC on Silufol UV-254 plates in the solvent systems ethyl acetate–hexane, 1:2 (3a-h, 5a-g) and 1:1
(6a-c).
The characteristics of compounds 3, 4, and 6 are given in Table 2.
Oxamic Acid Thiohydrazides 1a-h were obtained by the procedure in [5].
N-Aryl-2-arylidene(hetarylidene)hydrazino-2-thiooxacetamides (Hydrazones of Oxamic Acid
Thiohydrazides) (3a-h). (General Procedure). Aldehyde 2 (1.1 mmol) was added to oxamic acid
thiohydrazide 1 (1 mmol) in ethyl alcohol (5 ml). The reaction mixture was boiled for 20 min, then cooled down
to room temperature; the precipitate of product 3 was filtered off and washed with hot ethanol.
N-Aryl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamides (4a-g). (General Procedure). A.
Acid chloride 5a-d (1.5 mmol) was added to thiohydrazone 3a-c (1 mmol) dissolved in DMF (3 ml) at room
temperature. The reaction mixture was stirred for 2 h, then poured into water; the precipitate of product 4 was
filtered off and recrystallized from ethanol.
B. Aldehyde 2a (1.1 mmol) was added to oxamic acid thiohydrazide 1a,b (1 mmol) in DMF (3 ml). The
reaction mixture was held for 10 min at 50°C, then cooled down to room temperature, and then acid chloride 5a
(1.5 mmol) was added. The reaction mass was stirred for 2 h and poured into water; the precipitate of products
4a,b was filtered off and recrystallized from ethanol. The yield of compound 4a and 4b was respectively 52%
1
and 47%. The products were identical to samples obtained by procedure A (mp, H NMR spectra and mass
spectra).
1637

N-Aryl-4-acetyl-2-carbamoyl-N-4,5-dihydro-1,3,4-thiadiazole 1-Oxides (6a-c). (General Procedure).
15% H2O2 (2 ml) was added to dihydrothiadiazole 3 (0.5 mmol) in acetic acid (8 ml). The reaction mixture was
boiled for 15 min, then cooled down to room temperature and poured into water. The precipitate was filtered
off, and oxides 6a-c were isolated from the precipitate using TLC (hexane–ethyl acetate, 1:1). IR spectrum,
ν, cm-1: 6a – 1040 (S=O), 6b – 1032 (S=O), 6c – 1028 (S=O).
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1638