Synthesis and biological activities of some novel triazolothiadiazines and schiff bases derived from 4-amino-3-(4-hydroxyphenyl)-1H-1,2,4-triazole-5(4H)- thione

Article abstract of DOI:10.1080/10426500902848393

A series of novel 4-(6-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazin-3-yl)phenols (5a-5n) and (E)-4-substituted-3-(4-hydroxyphenyl)-1H-1, 2,4-triazole-5(4H)-thiones (6a- 6h) has been synthesized in high yields. The structures of all the title compounds have been determined by elemental analysis, IR, MS, ¹H NMR, and ¹³C NMR, and the compound 5a was investigated with X-ray crystallography (CCDC No. 666889). Most of the title compounds possessed high plant growth-regulating activities. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902848393

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Synthesis and Biological Activities of
Some Novel Triazolothiadiazines and
Schiff Bases Derived from 4-Amino-3-(4-
hydroxyphenyl)-1H-1,2,4-triazole-5(4H)-
thione
Qichun Ding a , Lixue Zhang a & Haile Zhang b
a College of Chemistry and Materials Engineering, Wenzhou
University, Wenzhou, P.R. China
b Department of Molecular Biology & Chemistry, Scripps Research
Institute, San Diego, California, USA
Published online: 24 Feb 2010.
To cite this article: Qichun Ding , Lixue Zhang & Haile Zhang (2010): Synthesis and Biological
Activities of Some Novel Triazolothiadiazines and Schiff Bases Derived from 4-Amino-3-(4-
hydroxyphenyl)-1H-1,2,4-triazole-5(4H)-thione, Phosphorus, Sulfur, and Silicon and the Related
Elements, 185:3, 567-572
To link to this article: http://dx.doi.org/10.1080/10426500902848393
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Phosphorus, Sulfur, and Silicon, 185:567–572, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902848393
SYNTHESIS AND BIOLOGICAL ACTIVITIES OF SOME
NOVEL TRIAZOLOTHIADIAZINES AND SCHIFF BASES
DERIVED FROM 4-AMINO-3-(4-HYDROXYPHENYL)-1H-
1,2,4-TRIAZOLE-5(4H)-THIONE
Qichun Ding,1 Lixue Zhang,1 and Haile Zhang2
1College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
P.R. China
2Department of Molecular Biology & Chemistry, Scripps Research Institute,
San Diego, California, USA
A series of novel 4-(6-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)phenols
(5a–5n) and (E)-4-substituted-3-(4-hydroxyphenyl)-1H-1,2,4-triazole-5(4H)-thiones (6a–
6h) has been synthesized in high yields. The structures of all the title compounds have been
determined by elemental analysis, IR, MS, 1H NMR, and 13C NMR, and the compound
5a was investigated with X-ray crystallography (CCDC No. 666889). Most of the title
compounds possessed high plant growth–regulating activities.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Biological activities; hydroxyphenyl; Schiff base; synthesis; 1,2,4-triazoles; tria-
zolothiadiazines
INTRODUCTION
The broad biological and pharmacological activities of various thiadiazines fused with
an s-triazole ring have been extensively studied, and s-triazolo[3,4-b][1,3,4]thiadiazines
especially have been shown to possess a wide spectrum of bioactivities1 such as anal-
gesic,2 anthelmintic,3 antitubercular,4 plant-growth regulating,5 antiviral,6 antifungal,7 and
anticancer properties.8 In a previous article, we have reported the synthesis of some com-
pounds containing the thiadiazine ring, which possessed moderate regulating effects on the
growth of mung bean sprouts.9 Recently, progress has been made into combining the 1,2,4-
triazole nucleus with N-bridged heterocycles.10–13 As a continuation of our research on the
synthesis and biological properties of triazole derivatives, we have synthesized a series of
substituted fused triazole systems containing a 4-hydroxyphenyl group and determined the
plant growth–regulating effects of some title compounds.
Received 28 October 2008; accepted 25 February 2009.
Address correspondence to Lixue Zhang, College of Chemistry and Materials Engineering, Wenzhou
University, Wenzhou 325027, P.R. China. E-mail: zhanglixuelz@yahoo.com.cn
567

568
Q. DING ET AL.
RESULTS AND DISCUSSION
1
All the compounds have been characterized by elemental analysis, H NMR, and
1
13C NMR. The signals at δ 4.29–4.50 ppm in the H NMR and 20.29–25.77 in the 13C
NMR spectra that are attributed to SCH2 (SCH for 5n) clearly confirm that the thiadiazine
1
rings are all formed. In the H NMR and 13C NMR spectra, the peaks of the N CH
proton at 9.36–10.08 ppm and the corresponding carbon at about 150 ppm correspond to
1
the above-mentioned open chain structure. When looking at the H NMR and 13C NMR
spectra of the fluoro-substituted compounds 5a, 5f, 5m, 6b, and 6c, it should be noted that
the second-order pattern representative of a substituted phenyl ring is further complicated
due to the presence of the couplings with 19F.
The title compounds have been investigated for their biological activities in regulating
the growth of wheat and radishes using sterilized distilled water as a reference (see Table
S1, available online in the Supplemental Materials).
Ethyl 4-hydroxybenzoate 1 reacted with 85% hydrazine hydrate to give the corre-
sponding hydrazide 2, which was heated with carbon disulfide in the presence of absolute
ethanol and potassium hydroxide to afford the intermediate potassium acylhydrazine dithio-
formate 3 (Scheme 1). This salt underwent ring closure with an excess of 85% hydrazine
hydrate, and then 4-amino-3-(4-hydroxyphenyl)-1H-1,2,4-triazole-5(4H)-thione 4 was ob-
tained. The appropriate substituted ω-bromoacetophenones were added into a solution
of 4 in absolute ethanol and 4-(6-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-
yl)phenol 5a–5m were formed (Scheme 2). The reaction of the triazole 4 and the appropriate
benzaldehyde in refluxing absolute ethanol for about 4 h, while maintaining a pH value
at 5–6 during the reaction, afforded Schiff bases 6a–6h (Scheme 2). After concentration
under reduced pressure, the crude products were recrystallized from alcohol to afford the
pure Schiff bases.
NH2NH H2O 85%
CS2, KOH
HO
COOC2H5
CONHNH2
HO
EtOH
1
2
N
NH
H2O 85%
NH2NH2
HO
S
CONHNHCSS-K+
HO
N
NH2
4
3
Scheme 1 The synthesis of 4-amino-3-(4-hydroxyphenyl)-1H-1,2,4-triazole-5(4H)-thione 4.
Under the same conditions described for 5a–5m, 4-amino-3-(4-hydroxyphenyl)-1H-
1,2,4-triazole-5(4H)-thione 4 reacted with 2-bromocyclohexanone to yield compound 5n,
which contains four rings (Scheme 3).
The purified product 5a was dissolved in absolute acetic acid and kept at room
temperature for 20 days, and the single crystals were formed, but it is very interesting that
the crystals of 5a separated out in a form of an acetate coordinate (CCDC No. 666889).

SYNTHESIS AND BIOLOGICAL ACTIVITIES
569
N
N
R1COCH2X (X=Br, Cl)
HO
S
N
N
N
NH
5a-5m
R1
HO
S
N
NH2
N
NH
R2CHO
HO
S
4
N
N
6a-6h
R2
5a: R1=
CF3
5h: R1=
6b: R2=
6c: R2=
F
NO2
5b: R1=
5c: R1=
5d: R1=
OEt
5i: R1=
5j: R1=
5k; R1=
F
6d: R2=
Cl
OCH3
6e: R2=
6f : R2=
Cl
Br
OCH3
OCH3
Cl
5l: R1=
5m: R1=
6a: R2=
5e: R1=
NO2
Cl
6g: R2=
6h: R2=
5f : R1=
5g: R1=
F
F
F
O
NO2
Scheme 2 The synthesis of the title compounds.
O
Br
N
N
N
NH
HO
HO
S
S
N
N
N
NH2
4
5n
Scheme 3 The reaction of 4 and 2-bromocyclohexanone.
Unfortunately the low quality of the crystal led to an unacceptable R factor (>0.100), so it
is not appropriate to discuss the structure in detail or present a table of bond lengths/angles,
but we do present the result of the X-ray structure in Figure 1 to show the novel nature of
the compounds formed in this synthesis.

570
Q. DING ET AL.
Figure 1 ORTEP drawing of the compound 5a showing the atom numbering scheme.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Bruker Advance-300 NMR
spectrometer in DMSO-d6 solution using TMS as internal reference. Carbon, hydrogen,
and nitrogen analyses were determined on a Flash-1112 series elemental analyzer. IR
spectra were recorded on a Nicolet 670FT-IR using the smart OMNI-Sampler in the range
4000–400 cm−1. MS spectra were recorded on an Agilent 1100 LC/MS. Melting points
were determined on an XT-4 melting point apparatus and were uncorrected. Melting points
of these newly synthesized compounds are much higher than those congeneric ones which
have no hydrogen bonds. The crystal structure was determined on Bruker APEX area-
detector diffractometer. All chemicals and solvents used were of AR grade.
4-Amino-3-(4-hydroxyphenyl)-1H-1,2,4-triazole-5(4H)-thione, whose tautomer is
4-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)phenol, was prepared from ethyl 4-hydroxy-
benzoate 1 (Scheme 1), following the literature of Zhang et al.14.
Synthesis of 4-(6-Substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazin-3-yl)phenol (5a–5m)
The appropriate substituted ω-bromoacetophenone (0.02 mol) was added into a so-
lution of 4 (0.02 mol) in absolute ethanol (20 mL), and the mixture was refluxed on an
oil-bath for about 2 h. After concentration under reduced pressure, the crude products were
recrystallized from ethanol to afford the compounds 5a–5m. In the same conditions, 4 (0.02
mol) reacted with 2-bromocyclohexanone (0.02 mol) to give compound 5n. An example of

SYNTHESIS AND BIOLOGICAL ACTIVITIES
571
the characterization is provided for compound 5a; the complete characterization data can
be found in the Supplemental Materials (available online).
5a: 4-(6-(Trifluoromethyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)
phenol. Yield: 88.0%; Mp 258–260◦C; IR (cm−1): 3428 (OH), 3052 (ArH), 1523 (C N),
1
1470 (N C S), 1102 (C F), 687 (C S C); MS-ESI (m/z): 299.3 (M−1); H NMR
(300 MHz, DMSO-d6, 25◦C, TMS) δ (ppm) = 10.11 (s, 1H, OH), 7.74 (d, J = 8.6 Hz,
2H, ArH), 6.92 (d, J = 8.6 Hz, 2H, ArH), 4.29 (s, 2H, SCH2); 13C NMR (DMSO-d6) δ
(ppm) = 159.92 (1C, C OH), 152.16 (1C, CH2C N), 145.46 (1C, N C N), 141.24
(1C, S C N), 129.82 (2C, aromatic CH), 121.38 (q, J = 271.2 Hz, 1C, CF3), 117.31
(1C, aromatic quaternary C), 115.80 (2C, aromatic CH), 20.29 (1C, SCH2); Elemental
anal. calc. (%) for C11H7F3N4OS (300.26): C 44.00, H 2.35, N 18.66; Found: C 44.15, H
2.22, N 18.54.
Synthesis of (E)-3-(4-hydroxyphenyl)-4-arylideneamino-1H-1,2,4-
triazole-5(4H)-thiones (6a–6i)
To a solution of compound 4 (0.02 mol) dissolved in absolute alcohol (20 mL), the
appropriate benzaldehyde (0.02 mol) was added. The mixture was refluxed for 4 h with
stirring. The solid that was obtained upon cooling was filtered, washed with cold water,
dried, and recrystallized from alcohol to give the Schiff bases 6a–6h. An example of the
characterization is provided here for 6a; the complete characterization data can be found
in the Supplemental Materials (available online).
6a: (E)-4-(Benzylideneamino)-3-(4-hydroxyphenyl)-1H-1,2,4-triazole-5
(4H)-thione. Yield: 83.2%; Mp 247–249◦C; IR (cm−1): 3425 (OH), 3324 (NH), 3015
(ArH), 1536 (C N), 1478 (N–C S), 1276 (C S); MS-ESI (m/z): 295.3 (M−1); 1H NMR
(300 MHz, DMSO-d6, 25◦C, TMS) δ (ppm) = 14.09 (s, 1H, NH),10.09 (s, 1H, OH),
10.07 (s, 1H, CH), 8.02–7.97 (m, 2H, ArH), 7.71–7.66 (m, 2H, ArH), 7.43–7.35 (m, 3H,
ArH), 6.89–6.86 (m, 2H, ArH); 13C NMR (DMSO-d6) δ (ppm) = 163.56 (1C, CH N),
161.94 (1C, C S), 159.75 (1C, C-OH), 149.19 (1C, N C N), 135.14 (1C, aromatic
quaternary C), 130.25 (1C, aromatic CH), 127.64 (2C, aromatic CH), 125.51 (2C, aromatic
CH), 125.48 (2C, aromatic CH), 120.05 (2C, aromatic CH), 115.58 (2C, aromatic CH);
Elemental anal. calc. (%) for C15H12N4OS (296.35): C 60.79, H 4.08, N 18.91; Found: C
60.54, H 4.13, N 18.76.
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