Derivatives of 4-amino-4H-1,2,4-triazole-3-thiols linked to the pyrrole cycle and some products of their S-alkylation

Article abstract of DOI:10.1007/s10593-007-0046-5

This study offers an access to 21 new heterocyclic compounds representing pyrrole derivatives of 4-amino-4H-1,2,4-triazole-3-thiols or 1,3,4-oxadiazole-2-thiols. The principal synthetic approach is based on the cyclization of substituted potassium 2-(pyrr

Full text of DOI:10.1007/s10593-007-0046-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
DERIVATIVES OF 4-AMINO-4H-1,2,4-TRIAZOLE-3-THIOLS
LINKED TO THE PYRROLE CYCLE AND SOME PRODUCTS
OF THEIR S-ALKYLATION
A. T. Bijev and P. Prodanova
This study offers an access to 21 new heterocyclic compounds representing pyrrole derivatives of
4-amino-4H-1,2,4-triazole-3-thiols or 1,3,4-oxadiazole-2-thiols. The principal synthetic approach is
based on the cyclization of substituted potassium 2-(pyrrolecarbonyl)hydrazine-1-carbodithionate with
hydrazine hydrate to 5-(substituted pyrrolyl)-4-amino-4H-1,2,4-triazole-3-thiols, followed by
S-alkylation with methyl iodide or benzyl chloride. Among the resulted thirteen S-alkyl derivatives, five
1,3,4-oxadiazole derivatives have been isolated as secondary products and their formation is explained
as being the result of S-alkylation of intermediate 1,3,4-oxa- diazole-2-thiols, generated in the alkaline
medium.
Keywords: pyrroles, 4H-1,2,4-triazole, alkylation, cyclization.
Due to their diverse biological activity, bis-heterocyclic systems containing the 1,2,4-triazole ring linked
to another aromatic or heteroaromatic ring are of interest in synthetic and pharmaceutical chemistry. Some
related structures published recently include 5-HT(1A) serotonin receptor ligands [1, 2], 1,2,4-triazole
derivatives for anti-HIV and antifungal evaluation [3, 4], anti-inflammatory [5] and antibacterial agents [6], as
well as benzodiazepine receptor agonists [7].
Despite the diverse pharmacological activities related to pyrrole compounds (such as anti-inflammatory
[8, 9], antitumor [10, 11], cytotoxic [12], anti-HIV-1 [13], sedative [14], etc.), no structural combinations
between heterocycles of 4H-1,2,4-triazole and 1H-pyrrole have been reported as yet. This fact motivated us to
synthesize 5-(substituted pyrrolyl)-4-amino-4H-1,2,4-triazole-3-thiols and their S-alkyl derivatives as
perspective candidates for pharmacological evaluations.
The synthetic approach was based on the cyclization of available substituted hydrazinecarbodithionic
acids of pyrrole [15] to 4-amino-4H-1,2,4-triazole-3-thiols followed by selective S-alkylation. The analogous
preparation of 5-(pyrazole-4-yl)-1,2,4-triazole-3-thiols was already reported [16].
4-Amino-5-(substituted pyrrolyl)-4H-1,2,4-triazole-3-thiols 1a–h were prepared by cyclization of
hydrazinecarbodithionic acids HetCONHNHCSSK (where Het is a pyrrole residue) after heating with hydrazine
hydrate.
The starting hydrazinecarbodithionic acids HetCONHNHCSSK (in the form of K-salts, known also as
dithiocarbazates) were synthesized earlier [15] from the relevant carboxylic acids of pyrrole via hydrazinolysis
of their esters and treatment of the resulted hydrazides with carbon disulfide in alkali media.
__________________________________________________________________________________________
University of Chemical Technology and Metallurgy Department of Organic Synthesis and Fuels, 1756
Sofia, Bulgaria; e-mail: a.bijev@uctm.edu, e-mail: pprodanova@abv.bg. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 3, pp. 383-391, March, 2007. Original article submitted April 12, 2006.
306
0009-3122/07/4303-0306©2007 Springer Science+Business Media, Inc.

Scheme 1
N
N
NH2NH2
Het
SH
N
Het–CO–NHNHCSSK
NH2
1a–h
Het
O
a
b
c
Me
Me
Me
O
Me
Me
Me
N
N
H
Me
N
H
H
d
e
f
O
O
O
Me
O
Me
O
Me
O
Me
Me
Me
Me
N
N
N
Cl
g
h
O
O
O
Me
O
Me
Me
Me
N
N
Me
O
Me
Scheme 2
O
O
SOCl2
EtOH
O
O
CS2
NH2NH2
Het
–EtOH
Het
NH
HN
K
NH
O
Het
OH
KOH
S
Het
NH2
S
Such types of aminosulfanyltriazoles as products 1a–h are recognized to exist both in thione and thiol
tautomeric forms [16-19]. Nevertheless, these structures have usually been presented as thiol compounds for
simplicity, including the cases where SH proton could not be located in the 1H NMR spectrum [19].
Scheme 3
H
N
N
N
N
S
Ar
SH
Ar
N
N
NH2
NH2
Ar = pyrazolyl, benzothiazolyl, 4-pyridyl, 2-thienyl
The synthesis of the targeted S-substituted derivatives was via S-alkylation of the thiol forms of 1a–h
with methyl iodide or benzyl chloride. In order to assure selectivity in the presence of the 4-NH2 group, the
alkylation was carried out in alkaline medium, affording the S−Na salts of 4-amino-5-sulfanyl-1,2,4-triazoles
307

1a–h. However, during the S-alkylation performed according to scheme 4 under thin layer chromatography
(TLC) control, we observed the formation of the secondary products and succeeded in separating and purifying
some of them by preparative TLC. Eventually, the S-methylation of 1a and the S-benzylation of 1d and 1f
yielded, parallel to the expected products 2 (2a1, 2d2, and 2f2, respectively), also the alternative products 3 (3a1,
3d2, and 3f2). These by-products whose 1H NMR spectra did not show signals for NH2 protons were identified as
derivatives of S-alkyl 1,3,4-oxadiazole-5-thiols. The new oxadiazoles 3c2 and 3h1, proved to be the only pure
products isolated from alkylation of 1c and 1h, respectively.
Scheme 4
N
N
N
N
R–X/NaOH
1a–h
+
Het
S
R
N
Het
S
R
O
NH2
2a,b,d–g
3a,c,d,f,h
2 a1,b1,e1, 3a1,h1 R = Me; 2 b2,d2,e2,f2,g2, 3 c2,d2,f2 R = PhCH2
Het are the same as in Scheme 1 (S-methyl products are denoted with subscript 1)
(S-benzyl derivatives have subscript 2)
The purity of the new compounds was proved in acceptable error range (within ±0.4%) by elemental
analyses, and their identities were confirmed by 1H NMR and IR spectra, interpreted in the Experimental section.
Adequate molecule ions for 1,3,4-oxadiazole derivatives 3 were registered by MS analysis.
The formation of the accompanying 1,3,4-oxadiazole derivatives was unexpected because no secondary
products were found in the synthesis (75% yield) of analogous pyrazole derivative 4-amino-5-{[3,5-dimethyl-
1-(4-nitrophenyl)pyrazol-4-yl]methyl}-4H-1,2,4-triazole-3-thiol [16].
A similar conversion of hydrazides to 1,3,4-oxadiazoles by treatment with carbon disulfide in alkaline
medium has been reported earlier [17, 20, 21].
Unlike the cases cited above, no oxadiazoles (as possible prerequisites for secondary reactions) were
found as by-products in the synthesis of 1a–h. Therefore the oxadiazole derivatives 3a1, 3c2, 3d2, 3h1, and 3f2
should appear in the next step during the S-alkylation of 1a–h, where in the alkaline solution 5-(substituted
pyrrolyl)-4-amino-4H-1,2,4-triazole-3-thiols 1a–h generate some amounts of intermediate 2-oxadiazolethiolates
capable of being S-alkylated.
Scheme 5
N
N
NaOH/H2O
–NH2NH2
R–X
1a–h
Het
S
Na
O
N
n
N
Het
S
R
O
3a1,h1,c2,d2,f2
This explanation complies with the reversibility of the opposite conversion of substituted 1,3,4-
oxadiazole-2-thiols to 4-amino-4H-1,2,4-triazole-3-thiols by refluxing with hydrazine [22].
1,3,4-Oxadiazole derivatives are also well known for a wide range of biological activities, including
anti-inflammatory [23, 24], antimicrobial [25], and antitumor effects [26], and the development of a parallel
access to such type of compounds may be a favorable supplement to the synthesis of the principal 1H-
1,2,4-triazoles. The pharmacological activity of the newly synthesized compounds is under evaluation.
308

EXPERIMENTAL
All commercial chemicals used in this study as starting materials and reagents were purchased from
''Merck'' (Darmstadt, Germany). The melting points were determined with a capillary digital melting point
apparatus IA 9200 Electrothermal, Southend-on-Sea, UK. The IR spectra were registered on a Specord IR-71
1
instrument, Carl Zeiss, Jena, Germany (KBr). The H NMR spectra (250 MHz, 20°C) were registered on a
Bruker Spectrospin WM250 spectrometer (Faenlanden, Switzerland), using TMS as internal standard. All NH
and SH protons were D2O exchangeable. Molecular ions of oxadiazole derivatives were registered on HP 6890
GC-HP 5973 MSD, Palo Alto, CA, USA, EI, 70 eV.
TLC characteristics of the products were measured on aluminum sheets of silica gel 60 F254, Merck
1.05554 at ambient temperature using a benzene–methanol mobile phase (the Rf value and the relevant C6H6–
MeOH ratio are given for each of the new compounds).
4-Amino-5-hetaryl-4H-1,2,4-triazole-3-thiols 1a-h (General procedure). To a solution of 20 mmol of
the relevant hydrazinecarbodithionic acid (K-salt) dissolved in 5 cm3 of H2O 40 mmol of hydrazine hydrate was
added. The mixture was refluxed for 1 h, cooled, diluted with water, and acidified with acetic acid. The residue
was filtered off, washed with cold water, and dried. Recrystallization from benzene/CCl4 afforded 1a-h in
80-85% yields.
4-Amino-5-(3,5-dimethylpyrrol-2-yl)-4H-1,2,4-triazole-3-thiol (1a). Mp 213-214°C, Rf 0.63 (5:1). IR
spectrum, ν, cm-1: 1370 (CH3), 2980 (CH3), 3280, 3100 (NH + NH2), 3420 (SH). 1H NMR (DMSO-d6), δ, ppm:
2.22, 2.40 (6H, 2s, 2CH3); 3.50 (2H, br. s, NH2); 5.5 (1H, s, SH); 5.75 (1H, s, H-4); 10.95 (1H, s, NH).
Found, %: C 45.58; H 5.05. C8H11N5S. Calculated, %: C 45.92; H 5.30.
Ethyl 5-(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)-2,4-dimethylpyrrole-3-carboxylate (1b). Mp 223-225°C,
Rf 0.41 (5:1). IR spectrum, ν, cm-1: 1430 (CH3 + CH2), 1700 (COOC2H5), 2980 (CH3 + CH2), 3150, 3330 (NH + NH2),
3420 (SH). 1H NMR (DMSO-d6), δ, ppm (J, Hz): 1.20 (3H, t, J = 7.0, CH3CH2); 2.22, 2.40 (6H, 2s, 2CH3); 3.50 (2H,
br. s, NH2); 4.05 (2H, q, J = 7.0, OCH2); 5.5 (1H, s, SH); 10.95 (1H, s, NH). Found, %: C 46.62; H 5.07. C11H15N5O2S.
Calculated, %: C 46.96; H 5.37.
4-Amino-5-(2,4-dimethylpyrrol-3-yl)-4H-1,2,4-triazole-3-thiol (1c). Mp 211–213°C, Rf 0.74 (10:3).
1
IR spectrum, ν, cm-1: 1370 (CH3), 2980 (CH3), 3100, 3270 (NH + NH2), 3410 (SH). H NMR (DMSO-d6), δ,
ppm: 2.20, 2.35 (6H, 2s, 2CH3); 3.65 (2H, br. s, NH2); 5.60 (1H, s, SH); 5.80 (1H, s, H-5); 10.95 (1H, s, NH).
Found, %: C 46.15; H 5.12. C8H11N5S. Calculated, %: C 45.92; H 5.30.
Ethyl 1-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2-methyl-5-phenylpyrrole-3-carboxy-
late (1d). Mp 234-236°C, Rf 0.41 (5:1). IR spectrum, ν, cm-1: 700, 745 (C6H5), 1480 (CH3 + CH2), 1680
(COOC2H5), 2940, 2955 (CH3 + CH2), 3100, 3180 (NH2), 3280 (SH). 1H NMR (acetone-d6), δ, ppm (J, Hz): 1.30
(3H, t, J = 7.1, CH3CH2); 2.45 (3H, s, CH3); 3.70 (1H, br. s, SH); 4.20 (4H, q, J = 7.1, OCH2); 4.80 (2H, s, NH2);
5.00 (2H, s, NCH2); 6.60 (1H, s, H-4); 6.95-7.50 (5H, m, C6H5). Found, %: C 56.84; H 5.26. C17H19N5O2S.
Calculated, %: C 57.13; H 5.36.
Ethyl 1-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2,4-dimethyl-5-phenylpyrrole-3-carboxy-
late (1e). Mp 246-248°C, Rf 0.54 (10:3). IR spectrum, ν, cm-1: 700, 755 (C6H5), 1495 (CH3 + CH2), 1680
1
(COOC2H5), 2960, 2995 (CH3 + CH2), 3200, 3400 (NH + NH2), 3460 (SH). H NMR (CDCl3), δ, ppm (J, Hz):
1.35 (3H, t, J = 7.1, CH3CH2); 2.05, 2.45 (6H, 2s, 2CH3); 3.00 (1H, br. s, SH); 4.15 (2H, q, J = 7.1, OCH2); 4.85
(2H, br. s, NH2); 4.95 (2H, s, NCH2); 6.95–7.50 (5H, m, C6H5). Found, %: C 58.54; H 5.78. C18H21N5O2S.
Calculated, %: C 58.20; H 5.70.
Ethyl
1-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-5-(4-chlorophenyl)-2-methylpyrrole-
3-carboxylate (1f). Mp 218-220°C, Rf 0.62 (10:3). IR spectrum, ν, cm-1: 820 (p-C6H4), 1470 (CH3 + CH2), 1690
(COOC2H5), 2900, 2955 (CH3 + CH2), 3190, 3240 (NH2), 3400 (SH). 1H NMR (acetone-d6), δ, ppm (J, Hz): 1.30
(3H, t, J = 7.1, CH3CH2); 2.45 (3H, s, CH3); 3.70 (2H, br. s, NH2); 4.20 (2H, q, J = 7.1, OCH2); 4.85 (1H, br. s,
SH); 5.10 (2H, s, NCH2); 6.60 (1H, s, H-4); 7.35 (4H, m, C6H4). Found, %: C 51.78; H 4.37. C17H18ClN5O2S.
Calculated, %: C 52.10; H 4.63.
309

Ethyl 1-[2-(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)ethyl]-5-(4-methoxyphenyl)-2-methyl-1H-3-pyrrole-
carboxylate (1g). Mp 185-187°C, Rf 0.44 (10:3). IR spectrum, ν, cm-1: 775 (C6H4), 1495 (CH3 + CH2), 1700
(COOC2H5), 2050 (SH), 2960, 2995 (CH3 + CH2), 3200, 3400 (NH + NH2), 3480 (SH). 1H NMR (CDCl3), δ, ppm (J,
Hz): 1.40 (3H, t, J = 7.0, CH3CH2); 1.60 (2H, br. s, NH2); 2.50 (3H, s, 2-CH3); 2.86 (2H, t, J = 6.8, CH2CH2N); 3.80
(3H, s, CH3O); 4.20-4.30 (4H, m, OCH2 + NCH2); 6.50 (1H, s, H-4); 6.90, 7.20 (4H, 2d, J = 8.5, C6H4). Found, %:
C 57.05; H 5.85. C19H23N5O3S. Calculated, %: C 56.84; H 5.77.
Ethyl
1-[2-(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)ethyl]-2-methyl-5-(4-methylphenyl)pyrrole-
3-carboxylate (1h). Mp 147–148°C, Rf 0.55 (5:1). IR spectrum, ν, cm-1: 820 (p-C6H4), 1490 (CH3 + CH2), 1690
1
(COOC2H5), 2960 (CH3 + CH2), 3190, 3240 (NH2), 3400 (SH). H NMR (CDCl3), δ, ppm (J, Hz): 1.30 (3H, t,
J = 7.2, CH3CH2); 2.40, 2.55 (6H, 2s, 2CH3); 2.95 (2H, t, J = 7.5, CH2CH2N); 4.27 (2H, q, J = 7.2, OCH2); 4.35
(2H, q, J = 7.5, NCH2); 5.75 (2H, br. s, NH2); 6.50 (1H, s, H-4); 7.18 (4H, br. s, C6H4); 12.50 (1H, s, SH).
Found, %: C 59.35; H 6.12. C19H23N5O2S. Calculated, %: C 59.20; H 6.01.
Ethyl 5-[4-amino-5-(methylsulfanyl)-4H-1,2,4-triazol-3-yl]-2,4-dimethylpyrrole-3-carboxylate (2b1)
and ethyl 1-{[4-amino-5-(methylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dimethyl-5-phenyl-pyrrole-3-
carboxy-late (2e1) (General procedure). To a stirred solution containing 3 mmol of 1b or 1e in 6 cm3 1M NaOH
1.11 g of MeI (7.8 mmol) was added dropwise at 10°C. The mixture was stirred at ambient temperature for 1.0-
1.5 h (TLC control), cooled, and filtered off. The precipitated product was washed with water and recrystallized
from ethanol/water to afford 2b1 or 2e1, respectively. Yields: 0.655 g, 74 % of 2b1 and 0.935 g, 81 % of 2e1.
Ethyl 5-[4-amino-5-(methylsulfanyl)-4H-1,2,4-triazol-3-yl]-2,4-dimethylpyrrole-3-carboxylate (2b1).
Mp 221-222°C, Rf 0.50 (5:1). IR spectrum, ν, cm-1: 1450, 1485 (CH3+CH2), 1695 (COOC2H5), 2850 (SCH3), 2960,
2995 (CH3 + CH2), 3150, 3330 (NH + NH2). 1H NMR (DMSO-d6), δ, ppm (J, Hz): 1.25 (3H, t, J = 7.0, CH3CH2);
2.25, 2.45 (6H, 2s, 2CH3); 2.55 (3H, s, CH3S); 4.10 (2H, q, J = 7.0, OCH2); 4.40 (2H, br. s, NH2); 11.00 (1H, s,
NH). Found, %: C 48.98; H 5.57. C12H17N5O2S. Calculated, %: C 48.80; H 5.80.
Ethyl
1-{[4-amino-5-(methylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dimethyl-5-phenylpyrrole-
3-carboxylate (2e1). Mp 126-128°C, Rf 0.69 (5:1). IR spectrum, ν, cm-1: 700, 760 (C6H5), 1465 (CH3 + CH2), 1690
(COOC2H5), 2900 (SCH3), 2940, 2965 (CH3 + CH2), 3050, 3285 (NH2). 1H NMR (CDCl3), δ, ppm (J, Hz): 1.35 (3H,
t, J = 7.1, CH3CH2); 2.05, 2.50 (6H, 2s, 2CH3); 2.60 (3H, s, CH3S); 4.15 (2H, q, J = 7.1, OCH2); 4.90 (2H, s, NCH2);
5.10 (2H, s, NH2); 7.00–7.30 (5H, m, C6H5). Found, %: C 58.93; H 6.26. C19H23N5O2S. Calculated, %: C 59.20;
H 6.01.
Ethyl 5-[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]-2,4-dimethylpyrrole-3-carboxylate (2b2),
ethyl 1-{[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dimethyl-5-phenylpyrrole-3-carboxy-
late (2e2) and ethyl 1-{2-[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]ethyl}-5-(4-methoxy-phenyl)-
2-methylpyrrole-3-carboxylate (2g2) (General procedure). To a stirred solution containing 1 mmol of 1b, 1e, or
1g in 2 cm3 1M NaOH 0.126 g PhCH2Cl (1 mmol) dissolved in 1 ml ethanol was slowly added dropwise at
10°C. The mixture was stirred at ambient temperature for 0.5-1.0 h (TLC control), cooled, and filtered off. The
precipitated product was washed with water and recrystallized from ethanol/water to afford 0.278 g, 75% of 2b2,
0.387 g, 84% of 2e2, and 0.378 g, 77% of 2g2, respectively.
Ethyl 5-[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]-2,4-dimethylpyrrole-3-carboxylate (2b2).
Mp 240-242°C, Rf 0.33 (5:1). IR spectrum, ν, cm-1: 710, 780 (C6H5), 1450, 1495 (CH3 + CH2), 1700 (COOC2H5),
2890 (SCH2), 2960, 2995 (CH3 + CH2), 3150, 3320 (NH + NH2). 1H NMR (DMSO-d6), δ, ppm (J, Hz): 1.25 (3H, t, J
= 7.1, CH3CH2); 2.25, 2.45 (6H, 2s, 2CH3); 4.10 (2H, q, J = 7.1, OCH2); 4.30 (2H, s, SCH2); 5.70 (2H, s, NH2);
6.95-7.40 (5H, m, C6H5). Found, %: C 57.86; H 5.95. C18H21N5O2S. Calculated, %: C 58.20; H 5.70.
Ethyl
1-{[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dimethyl-5-phenylpyrrole-
3-carboxylate (2e2). Mp 155-157°C, Rf 0.71 (5:1). IR spectrum (KBr), ν, cm-1: 700 + 760 (C6H5), 1485 (CH3 + CH2),
1
1685 (COOC2H5), 2900 + 2960 (SCH2 + CH3 + CH2), 3300 (NH2). H NMR (CDCl3), δ, ppm (J, Hz): 1.30 (3H, t,
J = 7.1, CH3CH2); 2.05 + 2.50 (6H, 2s, 2CH3); 3.50 (2H, s, NH2); 4.05 (2H, s, CH2S); 4.15 (2H, q, J = 7.1, OCH2); 4.90
(2H, s, NCH2); 6.90-7.30 (10H, m, 2C6H5). Found, %: C 64.75; H 5.97. C25H27N5O2S. Calculated, %: C 65.05; H 5.90.
310

Ethyl
1-{2-[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]ethyl}-5-(4-methoxyphenyl)-2-methyl-
pyrrole-3-carboxylate (2g2). Mp 117-119°C, Rf 0.56 (5:1). IR spectrum, ν, cm-1: 700, 770 (C6H5), 1490 (CH2),
1
1680 (COOC2H5), 2900 (SCH2 + CH3), 3050, 3100 (NH2). H NMR (CDCl3), δ, ppm (J, Hz): 1.40 (3H, t,
J = 7.0, CH3CH2); 2.50 (3H, s, 2-CH3); 2.85 (2H, t, J = 6.8, CH2CH2N); 3.50 (2H, s, CH2S); 3.80 (3H, s, CH3O);
4.20-4.40 (4H, m, OCH2 + NCH2); 4.73 (2H, br. s, NH2); 6.45 (1H, s, H-4); 6.86, 7.10 (4H, 2d, J = 8.5, C6H4);
7.15-7.40 (5H, m, C6H4 + C6H5). Found, %: C 63.76; H 6.05. C26H29N5O3S. Calculated, %: C 63.52; H 5.95.
3-(3,5-Dimethylpyrrol-2-yl)-5-(methylsulfanyl)-4H-1,2,4-triazol-4-amine (2a1) and 2-(3,5-dimethyl-
pyrrol-2-yl)-5-(methylsulfanyl)-1,3,4-oxadiazole (3a1). Triazole 1a (0.627 g, 3 mmol) was treated as described
in the procedure used for the preparation of 2b1 and 2e1. The TLC check proved that the resulting residue
consisted of two products with Rf values 0.60 and 0.77 (in benzene–ethanol, 5:1). They were separated on TLC
plates with silica gel 60 F254 for preparative layer chromatography (layer thickness 2 mm) using the same mobile
phases to yield: 0.207 g, 31 % of 2a1 as 4H-1,2,4-triazole derivative with Rf 0.60 and 0.150 g, 24 % of 3a1 as
1,3,4-oxadiazole derivative with Rf 0.77.
3-(3,5-Dimethylpyrrol-2-yl)-5-(methylsulfanyl)-4H-1,2,4-triazol-4-amine (2a1). Mp 192–194°C, Rf 0.60
1
(5:1). IR spectrum, ν, cm-1: 1450, 1485 (CH3), 2850 (SCH3), 2960, 2995 (CH3), 3150, 3330 (NH + NH2). H
NMR (DMSO-d6), δ, ppm: 2.30 (6H, s, 2CH3); 2.65 (3H, s, SCH3); 4.25 (2H, s, NH2); 5.65 (1H, s, H-4). Found, %:
C 48.75; H 6.03. C9H13N5S. Calculated, %: C 48.41; H 5.87.
2-(3,5-Dimethylpyrrol-2-yl)-5-(methylsulfanyl)-1,3,4-oxadiazole (3a1). Mp 162–164°C, Rf 0.77 (5:1).
IR spectrum, ν, cm-1: 1375, 1490 (CH3), 2900 (SCH3), 2960, 2995 (CH3). 1H NMR (CDCl3), δ, ppm: 2.35 (6H, s,
2CH3); 2.70 (3H, s, SCH3); 5.70 (1H, s, H-4); 9.90 (1H, s, NH). Mass spectrum, m/z: 209 [М]+. Found, %:
C 51.26; H 5.37. C9H11N3OS. Calculated, %: C 51.66; H 5.30.
Ethyl
2-methyl-5-(4-methylphenyl)-1-{2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]ethyl}pyrrole-
3-carboxylate (3h1). Triazole 1h (1.155, 3 mmol) was treated as described in the procedure used for the
preparation of 2b1 and 2e1. The product obtained was recrystallized from ethanol/water to yield 0.750 g (65%) of
3h1.
Ethyl
2-methyl-5-(4-methylphenyl)-1-{2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]ethyl}pyrrole-
3-carboxylate (3h1). Mp 96-97°C, Rf 0.79 (5:1). IR spectrum, ν, cm-1: 780 (C6H4), 1480 (CH3 + CH2), 1685
(COOC2H5), 2900 (SCH3), 2960 (CH3 + CH2). 1H NMR (CDCl3), δ, ppm (J, Hz): 1.34 (3H, t, J = 7.2, CH3CH2);
2.39, 2.60, 2.65 (9H, 3s, 3CH3); 2.95 (2H, t, J = 7.5, CH2CH2N); 4.20-4.40 (4H, m, OCH2 + NCH2); 6.52 1(H, s,
H-4); 7.20 (4H, br. s, C6H4). Mass spectrum, m/z: 385 [М]+. Found, %: C 61.95; H 6.21. C20H23N3O3S.
Calculated, %: C 62.32; H 6.01.
Ethyl 1-{[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-2-methyl-5-phenylpyrrole-3-carboxy-
late (2d2) and ethyl 1-{[5-(benzylsulfanyl)-1,3,4-oxadiazol-2-yl]methyl}-2-methyl-5-phenylpyrrole-
3-carboxylate (3d2) (General procedure). Triazole 1d (0.357 g, 1 mmol) was treated as described in the
procedure for the preparation of 2b2, 2e2, and 2g2. The resulting precipitate was filtered off after 2 h-stirring, and
the TLC check indicated a mixture of two products with Rf values 0.45 and 0.88 (in benzene–methanol, 5:1).
They were separated on TLC plates with silica gel 60 F254 for preparative layer chromatography (layer thickness
2 mm) using the same mobile phase as follows: 0.160 g, 36 % of 2d2 as 4H-1,2,4-triazole derivative with Rf 0.45
and 0.120 g, 28 % of 3d2 as 1,3,4-oxadiazole derivative with Rf 0.88.
Ethyl 1-{[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-2-methyl-5-phenylpyrrole-3-carboxy-
late (2d2). Mp 128-133°C, Rf 0.45 (5:1). IR spectrum, ν, cm-1: 700, 760 (C6H5), 1460 (CH3 + CH2), 1700
1
(COOC2H5), 2900, 2960 (SCH2 + CH3 + CH2), 3300 (NH2). H NMR (CDCl3), δ, ppm (J, Hz): 1.35 (3H, t,
J = 7.1, CH3CH2); 2.50 (3H, s, CH3); 3.50 (2H, s, NH2); 4.15 (2H, q, J = 7.1, OCH2); 4.35 (2H, s, CH2S); 5.15
(2H, s, NCH2); 6.50 (1H, s, H-4); 6.90-7.30 (10H, m, 2C6H5). Found, %: C 64.06; H 5.73. C24H25N5O2S.
Calculated, %: C 64.41; H 5.63.
311

Ethyl 1-{[5-(benzylsulfanyl)-1,3,4-oxadiazol-2-yl]methyl}-2-methyl-5-phenylpyrrole-3-carboxylate
(3d2). Mp 78-80°C, Rf 0.88 (5:1). IR spectrum, ν, cm-1: 700, 760 (C6H5), 1460 (CH3 + CH2), 1700 (COOC2H5),
2900, 2960 (SCH2 + CH3 + CH2). 1H NMR (CDCl3), δ, ppm (J, Hz): 1.40 (3H, t, J = 7.1, CH3CH2); 2.60 (3H, s,
CH3); 4.00-4.40 (4H, m, OCH2 + SCH2); 5.15 (2H, s, NCH2); 6.50 (1H, s, H-4); 7.10–7.40 (10H, m, 2C6H5).
Mass spectrum, m/z: 433 [М]+. Found, %: C 66.15; H 5.12. C24H23N3O3S. Calculated, %: C 66.49; H 5.35.
2-(Benzylsulfanyl)-5-(2,4-dimethylpyrrol-3-yl)-1,3,4-oxadiazole (3c2). Triazole 1c (0.627 g, 3 mmol) was
treated as described in the procedure for the preparation of 2b2, 2e2, and 2g2. After 2.5-h stirring, the product
obtained was recrystallized from ethanol/water to yield 0.384 g, 45 % of compound 3c2. Mp 107-110°C, Rf 0.83
(10:3). IR spectrum, ν, cm-1: 700, 745 (C6H5), 1485 (CH3 + CH2), 2900 (SCH2 + CH3 + CH2), 3200 (NH). 1H NMR
(DMSO-d6), δ, ppm: 2.25, 2.50 (6H, 2s, 2CH3); 4.50 (2H, s, SCH2); 6.50 (1H, s, H-5); 7.20-7.45 (5H, m, C6H5);
10.90 (1H, s, NH). Mass spectrum, m/z: 285 [М]+. Found, %: C 63.50; H 5.15. C15H15N3OS. Calculated, %:
C 63.13; H 5.30.
Ethyl 1-{[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-2-methyl-
pyrrole-3-carboxylate (2f2) and ethyl 1-{[5-(benzylsulfanyl)-1,3,4-oxadiazol-2-yl]methyl}-5-(4-chloro-
phenyl)-2-methylpyrrole-3-carboxylate (3f2) (General procedure). Triazole 1f (0.391 g, 1 mmol) was treated as
described in the procedure for the preparation of 2b2, 2e2, and 2g2. The resulting precipitate was filtered off after
2-h stirring, and the TLC check indicated a mixture of two products with Rf values of 0.45 and 0.60 (in
benzene/ethanol 10:1). They were separated on TLC plates with silica gel 60 F254 for preparative thin layer
chromatography (layer thickness 2 mm) using the same mobile phase as follows: 0.187 g, 39 % of 2f2 as 4H-
1,2,4-triazole derivative with Rf 0.45 and 0.135 g, 29 % of 3f2 as 1,3,4-oxadiazole derivative with Rf 0.60.
Ethyl 1-{[4-amino-5-(benzylsulfanyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-2-methylpyrrole-
3-carboxylate (2f2). Mp 116-118°C, Rf 0.45 (10:1). IR spectrum, ν, cm-1: 700, 775 (C6H5), 1480 (CH2), 1695
1
(COOC2H5), 2900 (SCH2 + CH2 + CH3), 3050-3100 (NH2). H NMR (CDCl3), δ, ppm (J, Hz): 1.35 (3H, t,
J = 7.1, CH3CH2); 2.55 (3H, s, 2-CH3); 4.30 (2H, q, J = 7.1, OCH2); 4.40 (2H, s, SCH2); 4.85 (2H, br. s, NH2);
5.15 (2H, s, NCH2); 6.45 (1H, s, H-4); 7.10-7.50 (9H, m, C6H4 + C6H5). Found, %: C 59.46; H 5.05.
C24H24ClN5O2S. Calculated, %: C 59.81; H 5.02.
Ethyl
1-{[5-(benzylsulfanyl)-1,3,4-oxadiazol-2-yl]methyl}-5-(4-chlorophenyl)-2-methylpyrrole-
3-carboxylate (3f2). Mp 107-109°C, Rf 0.60 (10:1). IR spectrum, ν, cm-1: 700, 770 (C6H5), 1475 (CH2), 1700
(COOC2H5), 2890 (SCH2), 2950 (CH2 + CH3). 1H NMR (CDCl3), δ, ppm (J, Hz): 1.30 (3H, t, J = 7.1, CH3CH2);
2.55 (3H, s, 2-CH3); 4.30 (2H, q, J = 7.1, OCH2); 4.40 (2H, s, SCH2); 5.15 (2H, s, NCH2); 6.55 (1H, s, H-4);
7.10-7.40 (9H, m, C6H4 + C6H5). Mass spectrum, m/z: 467 [М]+. Found, %: C 61.80; H 4.55. C24H22ClN3O3S.
Calculated, %: C 61.60; H 4.74
This study was supported by Johnson & Johnson Pharmaceutical Research & Development, a division of
Janssen Pharmaceutica N. V., Belgium, and is gratefully acknowledged.
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