Synthesis of substituted 1,2,4-triazoles and 1,3,4-thiadiazoles

Article abstract of DOI:10.1023/B:COHC.0000048294.27172.a3

The cyclization of 4-substituted 1-arylacetyl- and 1- aryloxyacetylthiosemicarbazides and also the potassium salt of (4-bromophenoxy)acetodithiocarbazinic acid in the presence of base gives the novel 3-arylmethyl- and 3-aryloxymethyl-5-mercapto-1,2,4-tria

Full text of DOI:10.1023/B:COHC.0000048294.27172.a3

Chemistry of Heterocyclic Compounds, Vol. 40, No. 9, 2004
SYNTHESIS OF SUBSTITUTED
1,2,4-TRIAZOLES AND 1,3,4-THIADIAZOLES
T. R. Hovsepian, E. R. Dilanian, A. P. Engoyan, and R. G. Melik-Ohanjanian
The cyclization of 4-substituted 1-arylacetyl- and 1-aryloxyacetylthiosemicarbazides and also the
potassium salt of (4-bromophenoxy)acetodithiocarbazinic acid in the presence of base gives the novel 3-
arylmethyl- and 3-aryloxymethyl-5-mercapto-1,2,4-triazoles and, in the presence of concentrated H2SO4,
the novel 5-substituted 2-arylmethyl- and 2-aryloxymethyl-1,3,4-thiadiazoles.
Keywords: thiadiazole, thiosemicarbazide, triazole, cyclization.
Certain substituted 1,2,4-triazoles show anti-inflammatory [1], vasodilatory [2], and psychotropic [3]
properties and derivatives of 5-amino-2-mercapto-1,3,4-thiadiazoles are active antimicrobial [4], hypoglycemic
[5, 6], or antitumor [7] agents. In a search for novel, active compounds within this group we have synthesized, in
this study, previously unrecorded 1,2,4-triazole and 1,3,4-thiadiazole derivatives having an arylmethyl or
aryloxymethyl substituent.
R1
R1
N
N
KOH
1
2
3
4
R2
R2
CNHNHCNHR
A
SH
A
N
R
(1a−e)
O
S
1a–i
2a–e
H2SO4
(1a–c, f–i)
1
R
N
N
N
2
R
NHR
A
S
3a–g
N
R3Cl
SR3
Br
2d
OCH2
N
Ph
4a,b
1a,b-3a,b R1 = Br, R2 = MeO, A = CH2, a R = Me, b R = Ph; 1c-f, 2c-e, 3c,d R1 = H,
R2 = Br, A = OCH2, 1c-3c R = PhCH2; 1d, 2d R = Ph, 1e, 2e R = All, 1f, 3d R = PhCO,
1g, 3e R1 = H, R2 = MeO, A = CH2, R = Me; 1h,i, 3f,g R1 = Br, A = CH2, R = Ph,
1h, 3f R2 = i-Pr, 1i, 3g R2 = Bu; 4a R3 = PhCH2, 4b R3 = NH2COCH2
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, Armenian Republic National Academy of Sciences,
Yerevan 375014; e-mail: melik@cornet.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9,
pp. 1377-1381, September, 2004. Original article submitted October 22, 2002; revision submitted March 1, 2004.
1194
0009-3122/04/4009-1194©2004 Springer Science+Business Media, Inc.

The starting 1,4-disubstituted thiosemicarbazides 1a-i were prepared by us by treatment of arylacetic and
aryloxyacetic acid hydrazides with different isothiocyanates [8, 9]. Compounds 1a-e were cyclized in basic
medium (4.5% aqueous KOH solution) with subsequent acidification of the reaction mixture using acetic acid to
give the 3,4-disubstituted 5-mercapto-1,2,4-triazoles 2a-e. Dehydrative cyclization of the thiosemicarbazides
1a-c,f-i in the presence of conc. H2SO4 led to the corresponding 2,5-disubstituted 1,3,4-thiadiazoles 3a-g which
occurred as white, crystalline materials, difficultly soluble in conventional organic solvents.
The reaction of 5-mercaptotriazole 2d with benzyl chloride or chloroacetamide in basic medium gave the
corresponding S-substituted triazoles 4a,b in close to quantitative yields.
The potassium salt of 4-amino-3-(4-bromophenoxy)acetodithiocarbazinic acid (6) was used for the
synthesis of 4-amino-3-(4-bromophenoxymethyl)-5-mercapto-1,2,4-triazole (2f) and 2-(4-bromophenoxy-
methyl)-5-mercapto-1,3,4-thiadiazole (5). The cyclization of 6 in hydrazine gave triazole 2f and in conc. H2SO4
the 1,3,4-thiadiazole 5.
N
N
NH2NH2
Br
Br
OCH2CNHNHCSK
OCH2
SH
N
O
S
6
NH2
2f
H2SO4
N
N
ClCH2COOMe
Br
SH
OCH2
S
5
N
N
SCH2COOMe
Br
OCH2
S
7
Thiadiazole 5 was treated with methyl chloroacetate to give the corresponding S-substituted derivative 7.
The composition and structure of the synthesized compounds 1-5, 7 were confirmed by the results of
elemental analysis (Table 1), 1H NMR spectroscopic data (Table 2), and mass spectrometry.
TABLE 1. Parameters for the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield,
%
mp, °С
Rf *
С
Н
N
5
S
6
1
2a
2b
2c
2
3
4
7
8
9
C11H12BrN3OS
С16H14BrN3OS
C16H14BrN3OS
C15H12BrN3OS
C12H12BrN3OS
42.28
42.05
51.24
51.07
51.23
51.07
49.61
49.79
3.67
3.85
13.56
13.37
9.88
10.20
8.67
8.52
8.63
8.52
8.57
8.85
9.64
9.83
224-226
203-205
193-195
211-213
132-133
0.59
0.71
0.61
0.57
0.47
85.3
90.4
79.8
75.6
76.9
3.76
3.75
11.08
11.17
3.61
3.75
11.02
11.17
2d
2e
3.28
3.34
11.73
11.60
44.48
44.18
3.62
3.71
12.70
12.88
1195

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
2f
C9H9BrN4OS
C11H12BrN3OS
C16H14BrN3OS
C16H14BrN3OS
C16H12BrN3O2S
C11H13N3OS
34.25
34.08
42.30
42.05
50.93
51.07
51.36
51.07
49.51
49.24
56.05
56.15
53.64
53.47
54.77
54.55
58.64
58.40
48.49
48.70
35.41
35.65
38.22
38.41
2.70
2.86
3.68
3.85
3.57
3.75
3.59
3.75
3.31
3.10
5.71
5.57
4.36
4.49
5.04
4.82
4.32
4.01
3.72
3.61
2.47
2.33
2.71
2.95
17.32
17.67
13.11
13.37
11.24
11.17
11.32
11.17
10.61
10.77
18.06
17.86
10.11
10.39
10.31
10.04
9.11
9.29
13.61
13.36
9.51
9.24
7.19
7.47
10.01
10.11
10.46
10.20
8.29
8.52
8.40
8.52
8.53
8.27
13.38
13.63
8.23
7.93
7.85
7.66
7.25
7.09
7.32
7.65
21.32
21.15
17.43
17.09
186-187
220-222
180-182
157-159
210-212
195-197
161-163
165-167
109-110
146-147
139-140
111-113
0.52
0.49
0.85
0.62
0.70
0.80
0.78
0.80
0.57
0.60
0.63
0.47
83.3
20.0
85.1
74.5
84.6
47.7
85.0
95.7
97.3
96.2
86.1
76.3
3a
3b
3c
3d
3e
3f
3g
4a
4b
5
C18H18BrN3OS
C19H20BrN3OS
C22H18BrN3OS
C17H15BrN4O2S
C9H7BrN2OS2
C12H11BrN2O3S2
7
_______
* Solvent systems; methanol–ether, 1:1 (compounds 2a,b); dioxane–
benzene, 1:2 (compounds 2c-f, 3c,d 4a,b, 5, and 7); acetone–benzene, 1:1
(compounds 3a,b,e-g).
TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Compound
Chemical shifts, δ, ppm (SSCC, J, Hz)*
2a
3.37 (3H, s, NCH3); 3.88 (3H, s, OCH3); 4.03 (2H, s, CH2);
6.92-7.50 (3H, m, C6H3); 13.4 (1H, br. s, SH)
2b
2c
3.77 (2H, s, CH2); 3.85 (3H, s, OCH3); 6.80-7.55 (8H, m, C6H3, C6H5);
13.6 (1H, br. s, SH)
4.85 (2H, s, CH2); 5.25 (2H, s, OCH2); 6.62-7.42 (9H, m, C6H4, C6H5);
13.82 (1H, br. s, SH)
2d
2e
4.82 (2H, s, OCH2); 6.65-7.59 (9H, m, C6H4, C6H5); 13.82 (1H, br. s, SH)
4.70 (2H, d, J = 6.5, N–CH2); 5.08 (2H, s, OCH2); 5.09-5.20 (2H, m, CH=CH2);
5.90 (1H, m, CH=CH2); 6.90-7.42 (4H, m, C6H4); 13.72 (1H, br. s, SH)
3a
3b
3.35 (3H, s, N–CH3); 3.82 (3H, s, OCH3 ); 4.15 (2H, s, CH2);
6.82-7.35 (3H, m, C6H3); 10.10 (1H, br. s, NH)
3.86 (3H, s, OCH3); 4.17 (2H, s, CH2); 6.88-7.58 (8H, m, C6H3, C6H5);
10.00 (1H, br. s, NH)
3d
4a
4b
5.43 (2H, s, OCH2); 6.90-8.20 (9H, m, C6H4, C6H5); 12.90 (1H, br. s, NH)
4.40 (2H, s, SCH2); 5.04 (2H, s, OCH2); 6.81-7.57 (14H, m, C6H4, 2C6H5)
3.87 (2H, s, SCH2); 5.03 (2H, s, OCH2); 6.78-7.60 (9H, m, C6H4, C6H5);
6.96 and 7.50 (2Н, two br. s, NH2)
5
7
5.50 (2H, s, OCH2); 6.85-7.42 (4H, m, C6H4); 14.40 (1H, br. s, SH)
3.69 (3H, s, OCH3); 4.13 (2H, s, SCH2); 5.40 (2H, s, OCH2);
6.90-7.40 (4H, m, C6H4)
_______
* Spectra recorded in DMSO-d6 (2-5) and CD3OD (7).
1196

EXPERIMENTAL
1H NMR spectra were recorded on a Mercury-300 (300 MHz) instrument and mass spectra on an
MX-1320 spectrometer with direct introduction of the sample into the ion source. TLC was performed using
Silufol UV-254 plates and revealed using iodine vapor.
3-(3-Bromo-4-methoxybenzyl)-4-R-5-mercapto-1,2,4-triazoles (2a,b) and 3-(4-Bromophenoxy-
methyl)-4-R-5-mercapto-1,2,4-triazoles (2c-e) (General Method). A solution of KOH (40 mmol) in water
(30 ml) was added to a solution of the thiosemicarbazide 1a-e (25 mmol) and the mixture was refluxed for 2 h.
The cooled solution was acidified with glacial acetic acid and the precipitated product 2a-e was filtered off and
recrystallized from methanol. Mass spectrum of compound 2b, m/z (Irel, %): 375/377 [M]+ (96/100), 360/362
(29/29), 199/201 (14/15), 77 (50).
2-(3-R1-4-R2-Phenylmethyl)-5-NHR-1,3,4-thiadiazoles (3a,b,e-g) and 2-(3-R1-4-R2-Phenoxy-
methyl)-5-NHR-1,3,4-thiadiazoles (3c,d) (General Method). The thiosemicarbazide 1a-c, f-i (25 mmol) was
dissolved portionwise in conc. H2SO4 (d = 1.836, 35 ml). The solution was poured into iced water (250 ml). The
precipitated, white crystalline products 3a-g were filtered off, washed on the filter to neutral reaction of the
water washes, and recrystallized from ethanol. Mass spectrum of compound 3b, m/z (Irel, %): 375/377 [M]+
(72/68), 257/259 (24/27), 199/201 (40/32), 77 (86).
5-Benzylthio- and 5-Acetamidothio-3-(4-bromophenoxymethyl)-4-phenyl-1,2,4-triazole (4a and 4b)
(General Method). The triazole 2d (5 mmol) was dissolved in 15 ml of a solution of KOH (5 mmol) in
methanol at 40°C. Benzyl chloride or chloroacetamide (5 mmol) was added to the solution obtained and the
mixture was refluxed for 1 h. After cooling, the precipitated product 4a,b was filtered off and recrystallized from
methanol.
4-Amino-3-(4-bromophenoxymethyl)-5-mercapto-1,2,4-triazole (2f). A mixture of the salt 6
(10 mmol), hydrazine (95%, 20 mmol), and water (1 ml) was refluxed with stirring to the evolution of hydrogen
sulfide. Iced water (50 ml) was added to the reaction mass and the mixture was acidified using conc. HCl. The
precipitated product 2f was filtered off, washed on the filter with water, dried, and recrystallized from ethanol.
Mass spectrum, m/z (Irel, %): 300/302 [M]+ (40/32), 172/174 (100/94), 129 (87), 75 (23).
2-(4-Bromophenoxymethyl)-5-mercapto-1,3,4-thiadiazole (5). The salt 6 (5 mmol) was added in small
portions with stirring to H2SO4 (d = 1.836, 7 ml) at 0°C. After complete addition of the salt the stirring was
continued for a further 15 min and the solution was poured into ice (100 g). The precipitated crystalline product
5 was filtered off, washed with water, dried, and recrystallized from ethanol.
2-(4-Bromophenoxymethyl)-5-carboxymethylmethylthio-1,3,4-thiadiazole (7). Prepared from the
thiadiazole 5 (5 mmol) and methyl chloroacetate (5 mmol) as in the method for the synthesis of the products
4a,b (see above).
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