Synthesis of Triazole Derivatives with Sterically Hindered Phenol Fragments

Full text of DOI:10.1080/00304948.2020.1823768

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Synthesis of Triazole Derivatives with Sterically
Hindered Phenol Fragments
Vladimir N. Koshelev , Olga V. Primerova , Ludmila V. Ivanova & Vladimir G.
Kutcherov
To cite this article: Vladimir N. Koshelev , Olga V. Primerova , Ludmila V. Ivanova & Vladimir G.
Kutcherov (2020): Synthesis of Triazole Derivatives with Sterically Hindered Phenol Fragments,
Organic Preparations and Procedures International, DOI: 10.1080/00304948.2020.1823768
To link to this article: https://doi.org/10.1080/00304948.2020.1823768
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1823768
EXPERIMENTAL PAPER
Synthesis of Triazole Derivatives with Sterically
Hindered Phenol Fragments
Vladimir N. Kosheleva, Olga V. Primerovaa , Ludmila V. Ivanovaa, and
Vladimir G. Kutcherovb,c
aDepartment of Organic and Petroleum Chemistry, Gubkin Russian State University of Oil and Gas
b
(National Research University), Moscow, Russia; Department of Physics, Gubkin Russian State University
c
of Oil and Gas (National Research University), Moscow, Russia; Department of Energy Technology, KTH
Royal Institute of Technology, Stockholm, Sweden
ARTICLE HISTORY Received 5 December 2019; Accepted 20 June 2020
In recent decades, the chemistry of functionally substituted 1,2,4-triazoles and the fused het-
erocyclic systems based on them have received significant attention due to their structural
and biological characteristics. The 1,2,4-triazole ring is a fragment of many fungicides such
as fluconazole, intraconazole, and voriconazole.1 3-R-4-Amino-1,2,4-triazole-5-thiones were
found to exhibit antimicrobial and anti-inflammatory activity.2–5 Fused heterocyclic triazoles
also possess important clinical applications; thus, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles were
reported as antiviral, antifungal, and antitumor agents.6–8 Anti-HIV activity was also found.9
Sterically hindered phenols were reported to possess anti-inflammatory and antimicrobial
properties,10,11 in addition to their well-known antioxidant activity.12
As a continuation of our studies on the synthesis of azoles containing a hindered phenol
moiety,13,14 in the present work we have synthesized a number of novel compounds: substi-
tuted arylideneamino-2,4-dihydro-3H-1,2,4-triazole-3-thiones, 1,2,4-triazolo[3,4-b][1,3,4]-
thiadiazoles and 6-aryl/alkyl-amino[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazoles, based on
3-(4-hydroxy-2,6-di-tert-butylphenyl) propanoic acid hydrazide, in search of new struc-
tures potentially exhibiting useful properties.
In this study two different approaches were used to prepare the starting 4-amino-3-[2-
(4-hydroxy-3,5-di-tert-butylphenyl)ethyl]-1,2,4-triazole-5-thione 3 (Scheme 1). In the first
case,15,16 the reaction of the hydrazide 1 with carbon disulfide and methyl iodide took place
in ethanol to give the methyl ester of dithiocarbazic acid 2 in two stages over 24 hours (see
Experimental section). Heterocyclization of the compound 2 with hydrazine hydrate lead
to the formation of 3-R-4-amino-1,2,4-triazol-5-thione 3 in 55% yield. In the second case
the 1,2,4-triazole 3 was obtained by the interaction of equimolar amounts of 3-(4-hydroxy-
3,5-di-tert-butylphenyl)propanoic acid 4 and thiocarbohydrazide. According to the pub-
lished data,17,18 this approach involves, in most cases, a short-term fusion of the initial
reagents, but, in our case, even short heating of the reaction mixture above the melting
point led to the destruction of the starting acid. So the reaction was carried out by refluxing
CONTACT Vladimir G. Kutcherov
vladimir.kutcherov@energy.kth.se
Department of Energy Technology, KTH Royal
Institute of Technology, Stockholm, Sweden.
ß 2020 The Author(s). Published with license by Taylor & Francis Group, LLC
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License
(http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,
provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

2
V. N. KOSHELEV ET AL.
Scheme 1. Preparation of key Triazolethione 3.
the starting reagents in pyridine for 12 hours, and the desired product was isolated in
35% yield.
3-R-4-Amino-1,2,4-triazole-5-thiones, as it was estimated, can exist both in thionic
1
and mercapto-forms.19 The H NMR spectrum of compound 3 contains a signal in the
9.5-10 ppm region corresponding to the proton in the triazole ring, with no peak at
6 ppm corresponding to the proton of the mercapto-group.20 In the IR spectrum there
are medium intensity bands at 1350-1330 and 1530-1520 cmꢀ1, corresponding to the
C ¼ S bond vibrations, and there are no bands in the 2610-2530 cmꢀ1 region character-
izing the vibrations of the C-SH unit.21 Thus, the spectral data suggest that compound
3 in the crystalline state, as well as in the DMSO solution, exists in a thionic form.
Compound 3 reacted further with a number of carboxylic acids, with aryl/alkyl iso-
thiocyanates and several aldehydes (Scheme 2).
According to the literature data, the reaction with acids is usually carried out by allowing
the starting materials to reflux in phosphorus oxychloride or thionyl chloride.22 In our case
the reaction of 4-amino-3-R-1,2,4-triazole-5-thione 3 with a series of carboxylic acids 5a-h
was carried out by the reflux of the starting reagents in POCl3 for 9 hours, and new 1,2,4-
triazolo [3,4-b][1,3,4]thiadiazoles 6a-h were obtained in yields of 35-81%.
In the IR spectra of the obtained compounds, there are no absorption bands at 3335
and 3269 cmꢀ1, indicating that there is no NH group, and no band in the region of
1530-1520 cmꢀ1 related to the C ¼ S bond, but there is a band at 750 cmꢀ1 correspond-
ing to the deformation vibrations of the C-S-C unit. There are no peaks at 9.5-10 ppm
1
in the H NMR spectra, indicating the absence of N-H protons.
One-pot reaction of the triazole 3 with aryl/alkyl isothiocyanates was carried out by
the reflux of the starting reagents in DMF during 24 hours and triazolothiadiazoles 8a,b
1
were obtained in yields of 35-41%. In the H NMR spectra of compounds 8a,b the sig-
nals of NH2 and NH (triazole) protons disappeared, but a singlet for the alkyl/aryl
amino proton appeared in the range of 5.47-5.57 ppm, confirming that the triazoles had
converted into triazolothiadiazoles.
Schiff bases 10a-c were obtained by the condensation of 1,2,4-triazole 3 with the
appropriate aldehydes in the presence of a catalytic amount of concentrated sulfuric
acid in refluxing i-PrOH in yields of 22-29%. The IR data for the compounds 10a-c
revealed bands at 1344 cmꢀ1 (C ¼ S stretching) and the absence of absorption in the
region of ꢁ2600-2550 cmꢀ1 cited for an SH group, indicating that these compounds are
1
in the thionic form. In the H-NMR spectra of the compounds 10a-c in DMSO-d6, the
N ¼ CH proton appeared near 8-10 ppm as a singlet.
In summary, 4-amino-1,2,4-triazol-5-thiones were used as convenient synthons for
the preparation of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles. It was established that the best

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Scheme 2. Reactions of Triazolethione 3.
yields (55%) of the 4-amino-3-R-1,2,4-triazol-5-thione 3 were achieved by heterocycliza-
tion of methylcarbodithionate 2. A number of novel condensed derivatives and Schiff
bases with hindered phenol fragments were obtained starting from the 4-amino-3-
R-1,2,4-triazole-5-thione. They were characterized using IR, 1H-NMR, 13C-NMR,
elemental analysis and mass spectroscopy methods. We hope that our study will
stimulate further research on these fascinating heterocyclic systems.
Experimental section
The IR spectra were obtained on an Agilent Cary 660 FTIR spectrometer using an ATR cell
with ZnSe crystal. 1H- and 13C-NMR spectra of solutions in DMSO-d6 were recorded on a
Bruker AM-300 spectrometer. All experiments were performed according to the standard
methods of Bruker. Chemical shifts were reported relative to Me4Si. The values of coupling
constants are given in Hz. The mass spectra were recorded on an MS-30 Kratos device (Eu,
70 eV). A peak of the molecular ion Mþ was observed for all synthesized compounds. The
melting points of the compounds obtained were determined in open capillary tubes.
Elemental analysis was carried out using a Vario Microcube analyzer. The course of reac-
tions and purity of the compounds obtained was monitored by TLC on silica gel plates in a
10:1 benzene-ethanol solvent system, unless otherwise noted.
Methyl 2-(3-(4-hydroxy-3,5-di-tert-butylphenyl)propanoyl)hydrazine-1-
carbodithionate (2)
A solution of 0.84 g (15 mmol) of KOH in 5 ml of water was added to a solution of 2.92 g
(10 mmol) of hydrazide 1 and 3.8 g (50 mmol) of carbon disulfide in ethanol at 0ꢂ C. The

4
V. N. KOSHELEV ET AL.
reaction mixture was stirred at 0ꢂ C for 4 hours, then an additional 24 hours at room tem-
perature. A solution of 2.84 g (20 mmol) of CH3I in 10 ml of ethanol was added, and the
mixture was stirred for 6 hours. The precipitate was filtered off and crystallized from a mix-
1
ture of benzene:hexane 5:1 to give 3.13 g, 82%, colorless crystals, m.p. 54-56ꢂ C. H NMR
(DMSO-d6): d 1.56 (18, s, t-Bu), 2.44 (2, t, J ¼ 6.6, ‘2-‘2), 3.67 (3, s, ‘3-S-),
7.02 s (2, s, ar), 7.28 (1, s, Ž), 8.11 (1, s, NH). MS: (Mþ), m/z 382.
Anal. Calcd for C19H30N2O2S2: C, 59.65; H, 7.90; N, 7.32; S, 16.76. Found: C, 59.78;
H, 7.99; N, 7.18; S, 16.67.
4-Amino-3-[2-(4-hydroxy-3,5-di-tert-butylphenyl)ethyl]-1,2,4-triazol-5-thione (3)
Method A. A mixture of 1.91 g (5 mmol) methyl 2-[3-(4-hydroxy-3,5-di-tert-butylphenyl)pro-
panoyl]hydrazine-1-carbodithionate 2 and 1.25 g (25 mmol) of hydrazine hydrate in 20 ml of
ethanol was refluxed for 5 hours. The reaction mixture was cooled to room temperature and
poured into water. Next, 10% HCl was added dropwise until the pH of the mixture reached 8,
and the precipitate formed was filtered off. The purification was carried out using a column of
silica gel, eluent benzene:ethanol 15:1, to give 0.96 g, 55%, colorless crystals, m.p. 155-156ꢂ C.
Method B. A mixture of 2.78 g (10 mmol) 3-(4-hydroxy-3,5-di-tert-butylphenyl)propa-
noic acid 4 and 1.06 g (10 mmol) of thiocarbodihydrazide in 15 ml of pyridine was
heated under stirring for 18 hours. After cooling, the reaction mixture was poured into
water and acidified with 10% HCl to a slightly acidic reaction, the solid filtered and
1
crystallized from ethanol to give 1.6 g, 46%, colorless crystals, m.p. 155-157ꢂ C. H
NMR (DMSO-d6): d 1.37 (18, s, t-Bu), 2.86 (4H, s, ‘2-‘2), 5.52 (2, s, NH2),
6.75 (1, s, Ž), 6.93 (2, s, ar), 13.46 (1, s, NH). 13C NMR (DMSO-d6): d 166.2,
152.0, 139.6, 131.66, 128.7, 124.9, 34.9, 32.0, 30.9, 27.1. MS: (Mþ), m/z 348.
Anal. Calcd for C18H28N4OS: C, 62.03; H, 8.10; N, 16.08; S, 9.20. Found: C, 62.21; H,
8.25; N, 16.01; S, 9.11.
General procedure for preparation of 3-[2-(4-hydroxy-3,5-di-tert-butylphenyl)
ethyl]-6-R-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (6a-h)
A mixture of 1.74 g (5 mmol) of 4-amino-1,2,4-triazole 3 and 5 mmol of the correspond-
ing carboxylic acid 5a-h were refluxed under stirring in 15 ml of POCl3 for 9 hours. The
reaction mixture was cooled, poured into ice water, a cooled 10% NaOH solution was
added until the pH of the mixture reached 6, the precipitate formed was filtered off and
purified using a silica gel column (toluene:ethanol 15:1).
3-[2-(4-Hydroxy-3,5-di-tert-butylphenyl)ethyl]-6-(4-pyridyl)-1,2,4-triazolo[3,4-b]
[1,3,4]thiadiazole (6a)
ꢀ1
ꢂ
Colorless crystals, yield: 0.84 g, 39%, m.p. 122-124 ‘ (dioxane:H2O 2:1). FT-IR cm
:
1
3624, 1596, 1474, 1434, 765. H NMR (DMSO-d6): d 1.31 (18, s, t-Bu), 3.05 (2H, t, J
¼ 6.6, ‘2-‘2), 3.34 (2, t, J ¼ 6.9, ‘2-‘2), 6.87 (2, s, ar), 6.91 (1, s, Ž),
7.84 (2, d, J ¼ 4.1, ar), 8.83 (2, d, J ¼ 3.9, ar). 13C NMR (DMSO-d6): d 164.20
(S-C ¼ N in triazole), 152.6, 151.4, 148.1, 139.43, 136.7, 131.2, 128.7, 124.8, 121.1, 34.8,
30.9, 30.8, (2(CH3)3), 27.2. MS: (Mþ), m/z 435.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
Anal. Calcd for C24H29N5OS: C, 66.18; H, 6.71; N, 16.08; S, 7.36. Found: C, 66.31; H,
6.90; N, 16.15; S, 7.42.
3-[2-(4-Hydroxy-3,5-di-tert-butylphenyl)ethyl]-6-(3-pyridyl)-1,2,4-triazolo[3,4-b]
[1,3,4]thiadiazole (6b)
ꢀ1
ꢂ
Colorless crystals, yield: 0.83 g, 38%, m.p. 160-162 ‘ (benzene:hexane 5:1). FT-IR cm
:
1
3624, 1602, 1474, 1435. 765. H NMR (DMSO-d6): d 1,28 (18, s, t-Bu), 3.00 (2H, t, J ¼
7.4, ‘2-‘2), 3.29 (2, t, J ¼ 9.0, ‘2-‘2), 6.70 (1, s, Ž), 6.81 (2, s, ar), 7.60-
7.65 (1H, m, Har), 8.25 (1, d, J ¼ 11.9, ar), 8.81 (1, d, J ¼ 6.2, ar), 9.06 (1H, s, Har).
13C NMR (DMSO-d6): d 163.7 (S-C ¼ N in triazole), 153.6, 152.6, 148.0, 139.4, 135.3,
131.2, 126.0, 124.9, 124.8, 34.8, 33.1, 30.8 (2(CH3)3), 27.2. MS: (Mþ), m/z 435.
Anal. Calcd for C24H29N5OS: C, 66.18; H, 6.71; N, 16.08; S, 7.36. Found: C, 66.02; H,
6.85; N, 16.24; S, 7.21.
3-[2-(4-Hydroxy-3,5-di-tert-butylphenyl)ethyl]-6-(4-nitrophenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole (6c)
ꢀ1
ꢂ
Yellow crystals, yield: 0.79 g, 33%, m.p. 124-126 ‘ (benzene: heptane 5:1). FT-IR cm
:
1
3627, 1602, 1525, 1347, 752. H NMR (DMSO-d6): d 1.32 (18, c, t-Bu), 3.05 (2H, t,
J ¼ 7.4, ‘2-‘2), 3.34 (2, t, J ¼ 7.1, ‘2-‘2), 6.72 (1, s, Ž), 6.87 (2, s,
ar), 8.15, (2, d, J ¼ 9.0, ar), 8.39 (2, d, J ¼ 9.0, ar). 13C NMR (DMSO-d6):
d 164.13 (S-C ¼ N in triazole), 152.6, 150.1, 148.1, 139.5, 135.1, 131.26, 129.0, 125.1,
124.8, 34.8, 30. 8, 33.0, 27.2. MS: (Mþ), m/z 479.
Anal. Calcd for C25H31N5O3S: C, 62.61: H, 6.09; N, 14.60; S, 6.69. Found: C, 62.78;
H, 6.22; N, 14.75; S, 6.51.
3-[2-(4-Hydroxy-3,5-di-tert-butylphenyl)ethyl]-6-(3-nitrophenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole (6d)
Yellow crystals, yield: 1.17 g, 49%, m.p. 116-118 ‘. FT-IR cmꢀ1: 3633, 1537, 1344, 771.
ꢂ
1H NMR (DMSO-d6): d 1.31 (18, s, t-Bu), 3.04 (2H, t, J ¼ 7.4, ‘2-‘2), 3.34 (2,
t, J ¼ 7.2, ‘2-‘2), 6.59 (1, s, Ž), 6.87 (2, s, ar), 7.88-7.94 (1, n, J ¼ 8.0,
ar), 8.33 (1, d, J ¼ 8.7, ar), 8.47 (1, d, J ¼ 14.88, ar), 8.63 (1, s, ar). 13C
NMR (DMSO-d6): d 164.1 (S-C ¼ N in triazole), 152.6, 148.82, 139.5, 133.8, 131.9,
131.3, 130.9, 127.4, 124.8, 121.8, 34.8, 33.0, 30.8, 27.1. MS: (Mþ), m/z 479.
Anal. Calcd for C25H31N5O3S: C, 62.61; H, 6.09; N, 14.60; S, 6.69. Found: C, 62.51;
H, 6.28; N, 14.69; S, 6.78.
3-[2-(4-Hydroxy-3,5-di-t-butylphenyl)ethyl]-6-[2-(4-hydroxy-3,5-di-tertbutylphenyl)
ethyl]-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6e)
ꢀ1
ꢂ
Colorless crystals, yield: 2.51 g, 85%, m.p. 118-120 ‘ (EtOH:H2O 5:1). FT-IR cm
:
1
3636, 1624, 1474, 1435, 768. H NMR (DMSO-d6): d 1,32 (18, s, t-Bu), 1,35 (18, s,
t-Bu), 2.85-2-96 (2H, m, ‘2-‘2), 3.16-3.25 (2, m, ‘2-‘2), 6.70 (1, s, Ž),

6
V. N. KOSHELEV ET AL.
6.80 (2, s, ar), 6.98, (2, s, ar). 13C NMR (DMSO-d6): d 170.0 (S-C ¼ N in tri-
azole), 152.8, 152.6, 147.2, 139.7, 139.5, 131.2, 130.5, 125.0, 124.7, 34.9 (CH2), 34.8, 34.1
(CH2), 30.9, 30.3, 27.1. MS: (Mþ), m/z 590.
Anal. Calcd for C35H50N4O2S: C, 71.15; H, 8.53; N, 9.48; S, 5.43. Found: C, 70.98; H,
8.71; N, 9.29; S, 5.35.
3-[2-(4-Hydroxy-3,5-di-t-butylphenyl)ethyl]-6-(1-naphthylmethyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole (6f)
ꢀ1
ꢂ
Colorless crystals, yield: 2.01 g, 81%, m.p. 220-222 ‘ (dioxane:H2O 4:1). FT-IR cm
:
1
3621, 1610, 1474, 1434, 752. H NMR (DMSO-d6): d 1,29 (18, s, t-Bu), 2.99 (2H, t, J
¼ 7.4, ‘2-‘2), 3.24 (2, t, J ¼ 7.2, ‘2-‘2), 4.49 (2H, s, CH2), 6.78 (1, s,
Ž), 6.87 (2, s, ar), 7.09 (1H, d, J ¼ 7.8, Har), 7.45-7.64 (1H, m, Har), 7.91-7.98
(1H, m, Har), 8.14 (1, d, J ¼ 6.1, ar). 13C NMR (DMSO-d6): d 170.1 (S-C ¼ N in
triazole), 153.1, 152.7, 147.2, 139.6, 134.1, 131.7, 131.3, 129.2, 129.1, 128.6, 127.8, 127.2,
126.6, 126.2, 124.7, 124.0, 35.8 (CH2), 34.8, 32.5, 30.827.2. MS: (Mþ), m/z 498.
Anal. Calcd for C30H34N4OS: C, 72.26; H, 6.88; N, 11.24; S, 6.43. Found: C, 72.15; H,
6.96; N, 11.17; S, 6.28.
3-[2-(4-Hydroxy-3,5-di-t-butylphenyl)ethyl]-6-coumaryl-1,2,4-triazolo[3,4-b][1,3,
4]thiadiazole (6g)
Yellow crystals, yield: 0.93 g, 37%, m.p. 154-156 ‘ (EtOH:H2O 2:1). FT-IR cmꢀ1: 3571,
ꢂ
1
1709, 1602, 1474, 1434, 762. H NMR (DMSO-d6): d 1.32 (18, c, t-Bu), 3.14 (2H, t, J
¼ 9.1, ‘2-‘2), 3.34 (2, t, J ¼ 7.5, ‘2-‘2), 6.60 (1, s, Ž), 6.85 (2, c,
ar), 7.34 (1H, s, Har), 7.46 (1H, t, Har), 7.55 (1H, d, J ¼ 8.1, Har), 7.77 (1H, t, Har),
8.01 (1H, d, J ¼ 7.9, Har) 9.03 (1H, s). 13C NMR (DMSO-d6): d 159.7 (S-C ¼ N in tri-
azole), 159.4 (C ¼ O), 154.1, 152.6, 143.7, 139.6, 135.2, 131.4, 131.0, 126.0, 124.7, 118.8,
117.0, 116.6, 34.8, 32.7, 30.9, 27.1. MS: (Mþ), m/z 502.
Anal. Calcd for C28H30N4O3S: C, 66.91; H, 6.02; N, 11.15; S, 6.38. Found: C, 67.02;
H, 6.20; N, 11.01; S, 6.26.
2,6-di-tert-Butyl-4-(2-(6-styryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)ethyl)
phenol (6h)
ꢂ
Colorless crystals, yield: 2.02g, 88%, m.p. 108-110 ‘ (EtOH:H2O 3:1). FT-IR cm-1: 3612,
1628, 1474, 1434, 751. 1H NMR (DMSO-d6): d 1.32 (18, c, t-Bu), 3.02 (2H, t, J ¼ 7.3, ‘2-
‘2), 3.17 (2, t, J ¼ 7.2, ‘2-‘2), 6.74 (1, s, Ž), 6.85 (2, s, ar), 7.44-7.47 (2H, m,
Har), 7.48 (2H, d, J ¼ 5.1, Har), 7.77 (1, d, J ¼ 1.7, -CH ¼ CH-), 7.79 (1, d, J ¼ 2.5,
-CH ¼ CH-). 13C NMR (DMSO-d6): d 170.8 (S-C¼ N in triazole), 157.4, 156.7, 152.5, 145.8,
144.3, 139.6, 136.0, 135.6, 134.2, 133.7, 129.5, 123.4, 39.6, 34.8, 31.9, 30.9. MS: (Mþ), m/z 460.
Anal. Calcd for C27H32N4OS: C, 70.40; H, 7.00; N, 12.16; S, 6.96; Found: C, 70.52; H,
7.19; N, 12.01; S, 7.25.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
7
General procedure for preparation of 6-aryl/alkylamino-3-substituted [1,2,4]
triazolo[3,4-b][1,3,4]- thiadiazoles (8a,b)
A mixture of 1.74 g (5 mmol) of 4-amino-1,2,4-triazole 3 and 5 mmol of the correspond-
ing isothiocyanate 7a,b was refluxed under stirring in 20 ml of DMF for 24 hours. The
reaction mixture was cooled, poured into ice water, the precipitate formed was filtered
off and purified using a silica gel column (CH2Cl2:EtOH 10:1).
2,6-di-tert-Butyl-4-(2-(6-((2-methoxyethyl)amino)-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazol-3-yl)ethyl)phenol (8a)
Yellow crystals, yield: 0.75 g, 35%, m.p. 111-113 ‘. FT-IR cmꢀ1: 3625, 3348, 1601,
ꢂ
1
1120, 752. H NMR (DMSO-d6): d 1.35 (18, s, t-Bu), 2.64 (1H, s), 2.73 (1H s), 3.32
(3H, s, O-CH3), 5.47 (1H, s, NH), 6.70 (1, s, Ž), 6.90 (2, s, ar). 13C NMR
(DMSO-d6): d 166.1 (S-C ¼ N in triazole), 165.2, 162.8, 152.6, 152.0, 139.6, 131.7, 131.0,
124.8, 34.9, 32.0, 30.9, 27.2. MS: (Mþ), m/z 431.
Anal. Calcd for C22H33N5O2S: C, 61.22; H, 7.71; N, 16.23; S, 6.91; Found: C, 61.36;
H, 7.90; N, 16.14; S, 6.75.
2,6-di-tert-Butyl-4-(2-(6-(p-tolylamino)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)
ethyl)phenol (8b)
Yellow crystals, yield: 0.95 g, 41%, m.p. 95-97 ‘. FT-IR cmꢀ1: 3631, 3422, 1602,
ꢂ
1
752. H NMR (DMSO-d6): d 1.35 (18, s, t-Bu), 2.24 (2H, s), 2.48-2.5 (1H, t), 2.72
(3H, s, -CH3), 5.47 (1H, s, NH), 6.70 (1, s, Ž), 6.90 (2, s, ar), 7.09 (2H, d, J ¼
8.1, Har), 7.44 (2H, d, J ¼ 8.3, Har). 13C NMR (DMSO-d6): d 166.1 (S-C ¼ N in tri-
azole), 162.8, 159.8, 152.6, 152.0, 139.6, 131.7, 130.2, 129.7, 124.8, 119.6, 36.2 (CH3),
34.9, 31.8, 30.9, 27.15. MS: (Mþ), m/z 463.
Anal. Calcd for C26H33N5OS: C, 67.35; H, 7.17; N, 15.11; S: 6.91. Found: C: 67.18; H:
7.32; N, 15.02; S, 6.75.
General procedure for preparation 5-substituted-4-arylidenylideneamino-)-2,4-
dihydro-3H-1,2,4-triazole-3-thiones (10a-c)
A mixture of 1.74g (5 mmol) of 4-amino-1,2,4-triazole 3 and 5 mmol of the corresponding
aldehyde 9a-c was refluxed under stirring in 20ml of i-PrOH and a few drops of H2SO4 for
10-12 hours. The reaction mixture was cooled, poured into ice water, the precipitate formed
was filtered off and dissolved in CHCl3. The solution was washed with NaHCO3 solution
and with water. The CHCl3 was evaporated under vacuum and the precipitate obtained was
purified using a silica gel column (benzene:EtOH 10:1 or toluene:EtOH 10:1).
5-(3,5-di-tert-Butyl-4-hydroxyphenethyl)-4-((4-(dimethylamino)benzylidene)amino)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (10a)
Orange crystals, yield: 0.62g, 26%, m.p. 220-222 ꢂ‘. FT-IR cmꢀ1: 3641, 1597, 750. 1H NMR
(DMSO-d6): d 1.35 (18, s, t-Bu), 2.25 (6H, s, N(CH3)2), 2.70-2.75 (2H, t, ‘2-‘2), 2.70-

8
V. N. KOSHELEV ET AL.
3.93 (2H, t, ‘2-‘2), 6.71 (1, s, Ž), 6.82 (2, s, ah), 7.83 (2H, d, J ¼ 7.9, Har), 8.1
(1H, s, CH¼), 8.27 (2H, d, J ¼ 8.3, Har), 12.23 (1H, s, NH). MS: (Mþ), m/z 479.
Anal. Calcd for C27H37N5OS: C, 67.61; H, 7.78; N, 14.60; S, 6.68. Found: C, 67.45; H,
7.68; N, 14.43; S, 6.55.
5-(3,5-di-tert-Butyl-4-hydroxyphenethyl)-4-((4-nitrobenzylidene)amino)-2,4-
dihydro-3H-1,2,4-triazole-3-thione (10b)
Yellow crystals, yield: 0.70 g, 29%, m.p. 199-201 ‘. FT-IR cmꢀ1: 3628, 1541, 1604, 755.
ꢂ
1H NMR (DMSO-d6): d 1.35 (18, s, t-Bu), 2.87 (2H, t, J ¼ 7.4, ‘2-‘2), 3.03 (2,
t, J ¼ 7.2, ‘2-‘2), 6.71 (1, s, Ž), 6.84 (2, s, ar), 8.10 (2H, d, J ¼ 8.6, Har),
8.34 (2H, d, J ¼ 8.9, Har), 10.25 (1H, s, CH¼), 13.93 (1H, s, NH). 13C NMR (DMSO-
d6): d 161.8 (C ¼ S), 158.9, 152.6, 151.7, 149.9, 138.3, 136.6. 131.2, 129.9, 124.9, 124.6,
34.8, 32.7, 30.7, 27.5. MS: (Mþ), m/z 481.
Anal. Calcd for C25H31N5O3S: C, 62.35; H, 6.49; N, 14.54; S, 6.66. Found: C, 62.47;
H, 6.67; N, 14.38; S, 6.51.
5-(3,5-di-tert-Butyl-4-hydroxyphenethyl)-4-((4-methoxybenzylidene)amino)-2,4-
dihydro-3H-1,2,4-triazole-3-thione (10c)
ꢀ1
ꢂ
Yellow crystals, yield: 0.51 g, 22%, m.p. 156-158 ‘. FT-IR cm 3635, 1601, 1242, 761.
1H NMR (DMSO-d6): d 1.35 (18, s, t-Bu), 2.87 (2H, t, J ¼ 7.4, ‘2-‘2), 2.96 (2,
t, J ¼ 7.2, ‘2-‘2), 3.87 (3H, s, O-CH3), 6.71 (1, s, Ž), 6.84 (2, s, ah), 7.06
(2H, d, J ¼ 8.9, Har), 7.79 (2H, d, J ¼ 8.9, Har), 9.57 (1H, s, CH¼), 13.74 (1H, s, NH).
13C NMR (DMSO-d6): d 168.30 (C ¼ S), 168.07, 166.52, 165.51, 157.36, 155.88, 144.24,
136.02, 135.61, 129.56, 119.88, 60.77, 39.55, 37.4, 35.56,32.3. MS: (Mþ), m/z 466.
Anal. Calcd for C26H34N4O2S: C, 66.92; H, 7.34; N, 12.01; S, 6.87. Found: C, 66.74;
H, 7.51; N, 11.86; S, 6.70.
ORCID
Olga V. Primerova
Vladimir G. Kutcherov
http://orcid.org/0000-0002-0162-2528
http://orcid.org/0000-0001-8199-5625
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