Res Chem Intermed

DOI 10.1007/s11164-013-1259-0

Heterocyclization and functionalization of 1,2-bis-

(4-amino-5-mercapto-1,2,4-triazol-3-yl)benzene

Reda A. Haggam

Received: 26 February 2013 / Accepted: 4 May 2013

Ó Springer Science+Business Media Dordrecht 2013

Abstract 1,2-Bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)benzene (3) was synthe-

sized from the reaction of phthalic acid with thiocarbohydrazide. Reaction of 3 with
ethylbromoactate or ethylchloroacetate afforded compound 4. Heating of 3 with
chloroacetyl chloride or chloroacetic acid gave triazolothiadiazinone 5 and 8,
respectively. Refluxing of 3 with phenacyl bromide resulted in benzoyl-
methylthiotriazole 9. Treatment of 3 with chloroacetamide or benzyl chloride
yielded 11 and 13, respectively. Condensation of 3 with benzaldehyde or m-nitro-
benzaldehyde gave the products 14a and 14b in the ratio 1:2, and 15, respectively.

Keywords Phthalic acid
1,2,4-Triazole
Triazolothiadiazines

Triazolothiadiazoles
Alkylation
Schiff bases

Introduction

During the last few decades, the chemistry of 1,2,4-triazole and their fused
heterocyclic derivatives has received considerable attention due to their synthetic
and biological importance. The 1,2,4-triazole moieties have incorporated into
avariety of therapeutically interesting drug candidates involving antiviral (ribavarin)
and antimigraine (rizatriptan) [1–3]. Moreover, 4-amino-5-mercapto-1,2,4-triazole
derivatives possess comprehensive bioactivities such as antitumorial, antimicrobial,
anti-HIV and antibacterial activities [4–8]. 1,2,4-triazole-3-thiones and 2-amino-
1,3,4-thiadiazoles have been attracting considerable attention owing to their various
biological properties such as antioxidant [9, 10] and anticonvulsant [11–13]. The
synthetic nucleoside ribavirin, containing a 1,2,4-triazole ring, has become a unique
drug, when combined with the pegylated interferon-a, for the treatment of hepatitis

R. A. Haggam (&)
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
e-mail: rhaggam@yahoo.com

123
 R. A. Haggam

C virus infections [14]. Syntheses of the seco C-nucleosides 4-amino-3-(D-gluco- or

D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles and 4-amino-3-(D-glycero-D-
gluco-hexitol-1-yl)-5-mercapto-1,2,4-triazole [15–17] were undertaken with the
expectation that they would have improved biological activity over those without
the alditolyl residue. In view of these results, it has been planned to synthesize some
newer 1,2,4-triazoles linked to various alkyl chains and having mercapto and Schiff
bases substitution. Continuing our earlier studies [18, 19] regarding the chemistry of
1,2,4-triazoles, the synthesis of 1,2-bis(1,2,4-triazol-3-yl)benzene and their reactiv-
ities toward various alkylating and cyclizing agents have been reported.

Experimental

All experiments were carried out using drying solvents. Melting points were
determined on a Büchi melting point apparatus B-545 with open capillary tubes and
are uncorrected. Compounds were visualized with UV light (k = 254 nm). Products
were purified by recrystallization. IR spectra were measured on a Perkin-Elmer
Spectrum One (FT-IR-spectrometer). 1H, 13C NMR spectra were recorded on 300
(75) MHz on a Varian UnityInova spectrometer using DMSO as a solvent. The 1H
and 13C chemical shifts were referenced to residual solvent signals at dH/C 2.49/
39.50 (DMSO) relative to TMS as internal standards and coupling constant
(J) values are given in Hz. HSQC-, HMBC-, and COSY-spectra were recorded on a
Varian UnityInova at 300 MHz at HohenheimUniversity, Germany.

1,2-Bis-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)benzene (3)

A mixture of phthalic acid (1) (10 mmol) and thiocarbohydrazide (2) (20 mmol) in
dry pyridine (10 mL) was heated under reflux for 4 h. The reaction mixture was
cooled and poured into ice-cold water. The formed product was filtered off, washed
with water and crystallized from ethanol/acetic acid (1:3) to give compound 3 in
93 % yield as white powder. Mp. 342–343 °C, IR (ATR): 3,360 cm-1 (NH2),
1,631 cm-1 (C=N), 1,600, 1,575, 1,547 cm-1 (C=C arom.). 1H NMR (300 MHz,
DMSO-d6): d = 7.87 (t, 1H, 3J = 7.6 Hz, 4J = 1.0 Hz, H-4), 7.96 (t, 1H,
3
J = 7.6 Hz, 4J = 1.0 Hz, H-5), 8.12 (d, 1H, 3J = 7.6 Hz, H-3), 8.24 (d, 1H,
3
J = 7.6 Hz, H-6), 14.32 (s, 2H, 2SH). 13C NMR (75 MHz, DMSO-d6): d = 120.2
(C-2), 122.5 (C-6), 123.6 (C-1), 125.7 (C-3), 132.0 (C-4), 133.9 (C-5), 140.3
(2NCS), 158.4, 161.2 (2NCN). Anal. Calcd for C10H10N8S2 (306.05): C, 39.20; H,
3.29; N, 36.57. Found: C, 39.17; H, 3.28; N, 36.51.

1,2-Bis-[4-amino-5-carboethoxymethylthio-4H-(1,2,4-triazol-3-yl)]-benzene (4)

Method A

To a solution of 3 (10 mmol) and anhydrous sodium acetate (20 mmol) in dry
ethanol (10 mL), ethyl bromoacetate (20 mmol) was added. The reaction mixture

123
Heterocyclization and functionalization

was heated under reflux for 6 h and then cooled. The formed precipitate was filtered
off, washed with ethanol, and then crystallized from ethanol to give compound 4 in
90 % yield as a yellow powder.

Method B

A solution of ethyl chloroacetate (20 mmol) in dry ethanol (10 mL) was added
dropwise to a solution of 3 (10 mmol) and 3 drops of triethylamine in dry ethanol
(10 mL). The mixture was heated under reflux for 6 h and then cooled. The formed
precipitate was filtered off, washed with ethanol and then crystallized from ethanol
to afford compound 4 in 91 % yield as yellow crystals. Mp. 221–222 °C, IR (ATR):
3,360 cm-1 (NH2), 1,631 cm-1 (C=N), 1,600, 1,575, 1,547 cm-1 (C=C arom.). 1H
NMR (300 MHz, DMSO-d6): d = 1.15 (t, 6H, 3J = 7.2 Hz, 2CH3), 4.12 (q, 4H,
3
J = 7.2 Hz, 2OCH2), 4.21 (s, 4H, 2SCH2), 7.89 (t, 1H, 3J = 7.6 Hz, H-4), 8.03 (t,
1H, 3J = 7.6 Hz, H-5), 8.20 (d, 1H, 3J = 7.6 Hz, H-3) 8.41 (d, 1H, 3J = 7.6 Hz,
H-6). 13C NMR (75 MHz, DMSO-d6): d = 14.6 (2CH3), 33.9 (2SCH2), 61.9
(2OCH2), 119.5 (C-2), 122.9 (C-6), 124.7 (C-1), 126.6 (C-3), 131.7 (C-4), 134.8
(C-5), 144.2, 144.4 (2NCN), 159.5 (2NCS), 169.0 (2C=O, ester). Anal. Calcd for
C18H22N8O4S2 (478.12): C, 45.18; H, 4.63; N, 23.42. Found: C, 45.10; H, 4.53; N,
23.39.

1,2-Bis-[5-oxo-4H-1,2,4-triazolo[3,4-b] [1,3,4]thiadiazin-3-yl]-benzene (5)

To a solution of 3 (10 mmol) in pyridine (10 mL), chloroacetyl chloride (20 mmol)
was added. The reaction mixture was heated under reflux for 2 h in oil bath and then
cooled. The mixture was poured into ice-cold water/hydrochloric acid with stirring.
The formed product was filtered off, washed with water, and then crystallized from
ethanol/dimethylformamide (1:1) to give compound 5 in 83 % yield as a faint
brown powder. Mp. 213–214 °C, IR (ATR): 3,260 cm-1 (NH), 1,593 cm-1 (C=N),
1,661 cm-1 (C=O). 1H NMR (300 MHz, DMSO-d6): d = 4.14 (s, 4H, 2SCH2),
7.91 (t, 1H, 3J = 7.6 Hz, H-4), 8.02 (t, 1H, 3J = 7.6 Hz, H-5), 8.19 (d, 1H,
3
J = 7.6 Hz, H-3) 8.41 (d, 1H, 3J = 7.6 Hz, H-6), 13.45 (br, 2H, 2NH).13C NMR
(75 MHz, DMSO-d6): d = 35.5 (2SCH2), 118.9 (C-2), 122.1 (C-6), 123.8 (C-2),
125.9 (C-3), 131.3 (C-4), 134.2 (C-5), 144.1, 143.5 (2NCN), 159.4 (2NCS), 169.6
(2C=O, amide). Anal. Calcd for C14H10N8O2S2 (386.04): C, 43.52; H, 2.61; N,
29.00. Found: C, 43.48; H, 2.57; N, 28.88.

1,2-Bis-[4-amino-5-carboxymethylthio-4H-1,2,4-triazol-3-yl]-benzene (8)

Method A

A mixture of 3 (10 mmol), chloroacetic acid (20 mmol) and potassium hydroxide
(20 mmol) in water (25 mL) was refluxed for 6 h. The solution was cooled, filtered,
and acidified with diluted hydrochloric acid. The formed precipitate was filtered off
and crystallized from ethanol/acetic acid (3:1) to give compound 8 in 81 % yield as
brown crystals.

123
 R. A. Haggam

Method B

A mixture of 3 (10 mmol), chloroacetic acid (20 mmol) and 5 drops of

triethylamine in dry ethanol (10 mL) was refluxed for 6 h. The reaction mixture
was cooled, poured into water and diluted hydrochloric acid. The formed precipitate
was filtered off and crystallized from ethanol/acetic acid (3:1) to give compound 8
in 84 % yield as brown crystals. Mp. 275–276 °C, IR (ATR): 1,734 cm-1 (C=O),
1,598 cm-1 (C=N), 1,217 cm-1 (C–O). 1H NMR (300 MHz, DMSO-d6): d 4.17 (s,
4H, 2SCH2), 7.87 (t, 1H, 3J = 7.6 Hz, H-4), 8.01 (t, 1H, 3J = 7.6 Hz, H-5), 8.19 (d,
1H, 3J = 7.6 Hz, H-3) 8.32 (s, 4H, 2NH2), 8.40 (d, 1H, 3J = 7.6 Hz, H-6).
13
C NMR (75 MHz, DMSO-d6): d 33.4 (2SCH2), 118.8 (C-2), 122.1 (C-6), 123.9
(C-1), 125.8 (C-3), 130.9 (C-4), 134.0 (C-5), 143.4, 144.0 (2NCN), 158.7 (2NCS),
169.6 (2C=O, acid). Anal. Calcd for C14H14N8O4S2 (422.06): C, 39.80; H, 3.34; N,
26.53. Found: C, 39.73; H, 3.23; N, 26.44.

1,2-Bis[4-amino-5-bezoylmethylthio-4H-(1,2,4-triazol-3-yl)]-benzene (9)

Method A

To a solution of 3 (10 mmol) and anhydrous sodium acetate (2 mmol) in dry ethanol
(10 mL), phenacyl bromide (20 mmol) was added. The reaction mixture was heated
under reflux for 6 h and then cooled. The formed precipitate was filtered off, washed
with water and ethanol, and then crystallized from ethanol/acetic acid (1:2) to give
compound 9 in 83 % yield as a yellow powder.

Method B

A solution of phenacyl bromide (20 mmol) in dry ethanol (10 mL) was added
dropwise to a solution of 3 (10 mmol) and 5 drops of triethylamine in ethanol
(10 mL). The mixture was heated under reflux for 6 h and then cooled. The formed
precipitate was filtered off crystallized from ethanol/acetic acid (1:2) to afford
compound 9 in 88 % yield as yellow powder. Mp. 324–325 °C, IR (ATR):
1,676 cm-1 (C=O), 1,595 cm-1 (C=N). 1H NMR (300 MHz, DMSO-d6): d = 5.02
(s, 4H, 2SCH2), 7.52–7.57 (m, 6H, Ar–H), 7.66 (d, 4H, 3J = 7.2 Hz, Ar–H), 7.89
(t, 1H, 3J = 7.6 Hz, H-4), 8.01 (t, 1H, 3J = 7.6 Hz, H-5), 8.18 (d, 1H, 3J = 7.6 Hz,
H-3), 8.28 (s, 4H, NH2), 8.38 (d, 1H, 3J = 7.6 Hz, H-6). Anal. Calcd for
C26H22N8O2S2 (542.13): C, 57.55; H, 4.09; N, 20.65. Found: C, 57.51; H, 3.99; N,
20.53.

General procedure for synthesis of compounds (11 and 13)

A mixture of 3 (10 mmol), chloroacetamide (20 mmol) or benzyl chloride

(20 mmol) in the presence of 5 drops of triethylamine in dry ethanol (10 mL)
was heated under reflux for 1–3 h. The reaction mixture was cooled, poured into
water, and diluted with hydrochloric acid for acidification or neutralization. The
formed precipitate was filtered off, dried, and crystallized from ethanol to afford

123
Heterocyclization and functionalization

compound 11 in 87 % yield as a pale yellow powder and compound 13 in 97 %

yield as a yellow powder.

1,2-Bis[4-amino-5-aminocarbonylmethylthio-4H-(1,2,4-triazol-3-yl)]-benzene
(11)

Yield: 87 %, pale yellow powder; Mp. 253–254 °C, IR (ATR): 3,458, 3,372,
3,347 cm-1 (2NH2), 1,684 cm-1 (C=O, amide), 1,669 cm-1 (C=N). 1H NMR
(300 MHz, DMSO-d6): d = 3.99 (s, 4H, 2SCH2), 7.22 (br s, 4H, 2NH2-N), 7.65 (br
s, 4H, 2NH2-C), 7.88 (t, 1H, 3J = 7.6 Hz, H-4), 8.01 (t, 1H, 3J = 7.6 Hz, H-5), 8.17
(d, 1H, 3J = 7.6 Hz, H-3), 8.38 (d, 1H, 3J = 7.6 Hz, H-6). 13C NMR (75 MHz,
DMSO-d6): d = 35.9 (2SCH2), 119.7 (C-2), 122.8 (C-6), 124.7 (C-1), 126.6 (C-3),
131.6 (C-4), 134.7 (C-5), 144.1, 145.1 (2NCN), 159.5 (2NCS), 169.6 (2C=O,
amide). Anal. Calcd for C14H16N10O2S2 (420.09): C, 39.99; H, 3.84; N, 33.31.
Found: C, 39.94; H, 3.71; N, 33.18.

1,2-Bis[4-amino-5-benzylthio-4H-(1,2,4-triazol-3-yl)]-benzene (13)

Yield: 97 %, yellow powder, Mp. 225–226 °C, IR (ATR): 1,660 cm-1 (C=N). 1H
NMR (300 MHz, DMSO-d6): d 4.52 (s, 4H, 2SCH2), 7.21–7.29 (m, 6H, Ar–H),
7.35 (d, 4H, 3J = 7.2 Hz, Ar–H), 7.86 (t, 1H, 3J = 7.6 Hz, H-4), 7.97 (t, 1H,
3
J = 7.6 Hz, H-5), 8.16 (d, 1H, 3J = 7.6 Hz, H-3), 8.38 (d, 1H, 3J = 7.6 Hz, H-6).
13
C NMR (75 MHz, DMSO-d6): d 35.3 (2SCH2), 118.8 (C-2), 122.1 (C-6), 124.0
(C-1), 125.8 (C-3), 127.4, 128.4, 128.9, 137.4 (2Ph), 130.7 (C-4), 134.0 (C-5), 143.4
and 144.1 (2NCN), 158.7 (2NCS). Anal. Calcd for C24H22N8S2 (486.14): C, 59.24;
H, 4.56; N, 23.03. Found: C, 59.22; H, 4.49; N, 22.87.

General procedure for synthesis of compounds (14a, 14b and 15)

A mixture of 3 (10 mmol) and benzaldehyde (20 mmol) or m-nitrobenzaldehyde

(20 mmol) in ethanol/acetic acid (1:2, 20 mL) was refluxed for 3–4 h, cooled, and
then poured into ice-cold water. The formed yellow precipitate was crystallized
from ethanol/acetic acid (1:1) and ethanol to afford compound 14b and 14a in 86 %
yield as a yellow powder and compound 15 in 79 % yield as pale yellow crystals,
respectively.

(1,2-Bis-[4-benzylideneamino-5-mercapto-1,2,4-triazol-3-yl]-benzene) (14a)
and (1,2-Bis-[5,6-dihydrophenyl-1,2,4-triazolo[3,4-b] [1,3,4] thiadiazol-3-yl]-
benzene) (14b)

Yield: 86 % in ratio 1:2 %, pale yellow powder; Mp. 322–323 °C, IR (ATR):
1,644 cm-1 (C=N), 1,628, 1,598 and 1,547 cm-1 (C=C arom.). 1H NMR
(300 MHz, DMSO-d6): d = 5.49 (s, 2H, 2HCNS), 7.35–7.61 (m, 8H, Ar–H),
7.88 (t, 1H, 3J = 7.6 Hz, H-4), 7.95 (t, 1H, 3J = 7.6 Hz, H-5), 8.14 (d, 1H,
3
J = 7.6 Hz, H-3), 8.25 (d, 1H, 3J = 7.6 Hz, H-6), 8.70, 10.64 (2S, 2H, 2HC=N,
syn and anti), 12.94 (br s, 2H, 2NH), 14.33 (br s, 2H, 2SH). Anal. Calcd for

123
 R. A. Haggam

C24H18N8S2 (482.11): C, 59.73; H, 3.76; N, 23.22. Found: C, 59.67; H, 3.74; N,

23.18.

(1,2-Bis-[5,6-dihydro-m-nitrophenyl-1,2,4-triazolo[3,4-b] [1,3,4] thiadiazol-3-

yl]-benzene) (15)

Yield: 79 %, pale yellow crystals; Mp. 213–214 °C, IR (ATR): 3,362 cm-1 (NH),
1,628 cm-1 (C=N). 1H NMR (300 MHz, DMSO-d6): d = 5.65 (s, 2H, 2HCNS),
7.79–7.84 (m, 8H, Ar–H), 8.32 (t, 1H, 3J = 7.8 Hz, H-4), 8.37 (t, 1H, 3J = 7.8 Hz,
H-5), 8.70 (d, 1H, 3J = 7.8 Hz, H-3), 8.90 (d, 1H, 3J = 7.8 Hz, H-6), 10.43 (s, 2H,
2NH). Anal. Calcd for C24H16N10O4S2 (572.08): C, 50.34; H, 2.82; N, 24.46.
Found: C, 50.31; H, 2.80; N, 24.52.

Results and discussion

Here, we demonstrate that the synthesis of the aminomercaptotriazole 3. In addition,

the reactions of 3 with halomethylene reagents were reported. The synthesis of
compound 3 has been achieved by the dehydrative cyclisation of phthalic acid (1)
with thiocarbohydrazide (2) in dry pyridine (Scheme 1). The aminomercaptotriazole
3 was reacted with ethylbromoactate under basic conditions in anhydrous sodium
acetate in dry ethanol or ethylchloroacetate with triethylamine to give the
carboethoxymethylated product 4 in very good yield without detecting their
cyclized derivative triazolothiadiazines 5 or 6 [18].
The structural assignment of the aminomercaptotriazole 3 rests mainly on its IR,
1
H NMR, 13C NMR, HMBC, 1H,1H-COSY and HSQC spectra and its elemental
analysis (see ‘‘Experimental’’).

H H
4 5
H 6 H
3
H2N 2 1
NH2
N N
N N
HS N N SH

The IR spectrum of compound 4 shows absorption bands at 1,727 and

1,596 cm-1 which correspond to the ester C=O and C=N groups, respectively.
The 1H NMR and 1H, 1H-COSY (Fig. 1) spectra of 4 displayed signals at d 1.15,
4.12 ppm as triplet and doublet with coupling constant J = 7.2 Hz for 2CH3 and
2OCH2 of two ethyl groups. Moreover, there is a singlet at d 4.21 ppm for 2SCH2
groups confirming that the formation of a S-alkyl not N-alkyl product.
The HSQC spectrum of compound 4 (Fig. 2) could be used to identify the carbon
atoms that are attached to hydrogens. The carbons of 2CH3, 2OCH2, and 2SCH2

123
Heterocyclization and functionalization

COOH

COOH
1
+
S O H H O
N N
H2N NH2 N N
N N
H H N N
S N N S
2 5

pyridine
4 h, reflux
93%

O
H2N NH2
H2N NH2 X
O N N
N N O N N O
N N 6 h, reflux S S
HS N N
N N SH
O O
3 4
a: X = Br, NaOAc/EtOH, 90%
b: X = Cl, TEA/EtOH, 91%

O O
N N
N N
N N
S N N S
6

Scheme 1 Synthesis of the aminomercaptotriazole 3 and the carboethoxy methylated compound 4

appear at d = 14.6, 61.9, and 33.9 ppm, respectively (Fig. 2). Also, the HSQC
spectrum revealed the carbons C-6, C-3, C-4, and C-5 at d = 122.8, 126.6, 131.7,
and 134.8 ppm, respectively.
The HMBC spectrum of compound 4 is used to determine the correlation
between the carbons and hydrogen atoms (Fig. 3). From the 13C NMR and HMBC
(Fig. 3) spectra, the proton 4-H displayed strong 3JCH correlations with C-2 at
d = 119.5 ppm and C-6 at d = 122.7 ppm. The proton 3-H showed strong 3JCH
correlations with C-1 at d = 124.7 ppm and C-5 at d = 134.8 ppm. Its 13C NMR
spectrum showed a signal at d 169.0 ppm corresponding to 2C=O groups and two
signals at d 144.2, 144.4 ppm for unsymmetrical 2NCN, while one signal at d
159.5 ppm was for symmetrical 2NCS groups. The 1H NMR spectrum of 4
displayed only half of the expected number of signals for the two triazole rings, but
all the expected numbers of signals for the phenyl group, indicating that the triazole
substituents are symmetrical and that it is non-planer compound.
Heating of compound 3 with chloroacetyl chloride under reflux for 2 h in an oil
bath in the presence of pyridine afforded triazolothiadiazinone 5 in 83 % yield. On
the other hand, if the reaction was carried out in acetone at room temperature for
24 h, no reaction product was obtained, but starting materials were obtained.

123
 R. A. Haggam

Fig. 1 The proton proton-correlated spectroscopy spectrum of compound 4

Fig. 2 The heteronuclear single quantum spectroscopy spectrum of compound 4

Refluxing of the aminomercaptotriazole 3 with chloroacetic acid in dry ethanol and

triethylamine or aquous potassium hydroxide gave product 8 (Scheme 2).
The IR spectrum of compound 8 showed absorption bands at 1,734, 1,598, and
1,217 cm-1 which could be correlated to the C=O, C=N, and C–O groups,
respectively. The chemical structure of 8 was confirmed from the analysis of its 1H
NMR and the 1H, 1H–COSY spectra which exhibited the presence of 2SCH2 groups

123
Heterocyclization and functionalization

H H
4 5
H 6 H
3
H2N 2 1
NH2
N N
H3C O CH3
N N O
S N N S
O O
4

Fig. 3 The heteronuclear multiple-bond spectroscopy spectrum of compound 4

at d 4.17 ppm as singlet, indicating that S-alkylation took place. There is another
singlet at d 8.32 ppm characteristic for 2NH2 protons. We can deduce that both 3-H
and 4-H protons are beside each other and also 5-H and 6-H. The HSQC spectrum
(Fig. 4) revealed the carbon atoms C-6, C-3, C-4, C-5, and SCH2 at d = 122.1,
125.8, 130.9, 134.0, and 33.4 ppm, respectively.
The 13C NMR and HMBC spectra of compound 8 (Fig. 5) demonstrated that the
proton 6-H exhibited strong 3JCH correlations with C-2 at d = 118.8 ppm, C-4 at
d = 130.9 ppm, and NCN at d = 143.4 ppm. The proton 3-H showed strong 3JCH
correlations with C-1 at d = 123.9 ppm and C-5 at d = 134.0 ppm. Its 13C NMR
spectrum showed a characteristic signal at d 169.6 ppm corresponding to 2C=O
groups. Moreover, no signals corresponding to the NH groups were found in the
spectrum, confirming that the triazolothiadiazinone 5 was not formed. The
elemental analysis of compound 8 is in agreement with its structure.
The aminomercaptotriazole 3 was refluxed with phenacyl bromide under basic
conditions in dry ethanol and anhydrous sodium acetate or triethylamine to yield the
benzoylmethylthiotriazole derivative 9 in good yield, but not the triazolothiadiazine
10. On heating 9 with acetic acid, the reaction did not also form compound 10. The
structure of compound 9 was established by its analysis and spectral data. The IR
spectrum of 9 exhibited a band at 1,676 cm-1 for the C=O group, indicating that the
triazolothiadiazine 10 was not formed (Scheme 3).
Treatment of 3 with chloroacetamide or benzyl chloride in the presence of a few
drops of triethylamine in ethanol under reflux for 1–3 h afforded the compounds 11

123
 R. A. Haggam

O H H O
H2N NH2 N N
Cl N N N N
Cl
N N N N
S N N S S N N S
O O
7 5
O
Cl
Cl
pyridine
2 h, oil bath

O
H2N NH2 Cl H2N NH2
N N OH N N
HO N N OH
N N 6 h, reflux
HS N N SH S N N S
TEA/EtOH 84% O
KOH/H2O 81% O
3 8
O
Cl
Cl
acetone, r.t
stirring 24 h
No rea.

Scheme 2 Reaction of the aminomeraptotriazole 3 with both chloroacetyl chloride and chloro acetic acid

Fig. 4 The heteronuclear single quantum spectroscopy spectrum of compound 8

and 13 but not 12. In addition, refluxing compound 11 with acetic acid,
triazolothiadiazine 12 was not obtained (Scheme 4).
The IR spectrum of 13 displayed a band at 1,660 cm-1 for the C=N group. In the
13
C NMR and HMBC spectra of 13, the proton 4-H exhibited strong 3JCH
correlations with C-2 at d = 118.8 ppm and C-6 at d = 122.1 ppm. The proton 3-H
showed strong 3JCH correlations with C-1 at d = 124.0 ppm and C-5 at
d = 133.9 ppm.

123
Heterocyclization and functionalization

H H
4 5
H 6 H
3
H2N 2 1
NH2
N N
N N
S N N S

13

Condensation of the aminomercaptotriazole 3 with benzaldehyde in ethanol/

acetic acid furnished a product whose 1H NMR spectrum indicated that its solution
in DMSO-d6 showed the existence of the Schiff base 14a as the minor form in
addition to the cyclic structure dihydrothiadiazole 14b as a major one in a ratio 1:2.
Moreover, the spectrum showed two signals at d 8.70 and 10.64 ppm, indicating the
presence of two geometric isomers, syn and anti of the CH=N group (Scheme 5).

H H
4 5
H 6 H
3
H2N 2 1
NH2
N N
HO N N OH
S N N S
O O
8

Fig. 5 The heteronuclear multiple-bond spectroscopy spectrum of compound 8

123
 R. A. Haggam

H2N NH2
N N
Ph N N Ph
S N N S
O O
9
O
H2N NH2 Cl AcOH
N N Ph 4 h, reflux
N N EtOH, 6 h, reflux
HS N N SH
3 a: TEA 88%
b: NaOAc 83%

Ph Ph
N N
N N
N N
S N N S
10

Scheme 3 Reaction of the aminomercaptotriazole 3 with phenacyl chloride under different reaction
conditions

H2N NH2 H2N NH2

N N
N N N N
N N
S N N
N N S S S
N N
13 12

Cl

TEA, EtOH AcOH, 2 h, reflux

1 h, reflux

O
H2N NH2 Cl H2N NH2
N N NH2 N N
N N TEA, EtOH H2N N N NH2
HS N N SH 3 h, reflux S N N S
O O
3 11

Scheme 4 Synthesis of the S-alkylated aminomercaptotriazoles 11 and 13

While reaction of 3 with m-nitrobenzaldehyde gave a product, its 1H NMR spectrum

indicated that its solution in DMSO-d6 showed the existence of just the cyclic
structure dihydrothiadiazole 15. Moreover, the spectrum showed no signals
corresponding to the CH=N and SH groups indicating that the Schiff base was
not formed (Scheme 5).

123
Heterocyclization and functionalization

O2N NO2

H H H H
N N H H H H
N N N N
N N
S N N
S S N N
N N S
N N
15 14b
CHO

EtOH/AcOH
2 4 h reflux
NO2

CHO
H2N NH2 N N
N N EtOH/AcOH
3 h reflux N N
N N + 2 N N
HS N N SH HS N SH
N
3 14a

Scheme 5 Condensation of the aminomeraptotriazole 3 with aromatic aldehydes

Conclusion

In summary, we report on the synthesis of 1,2-bis(4-amino-5-mercapto-4H-1,2,4-

triazol-3-yl)benzene via the reaction of phthalic acid with thiocarbohydrazide.
Reactions of this starting material with several halomethylene reagents like
ethylhaloactates or chloroacetyl chloride to synthesize some novel cyclic and open
S-alkyltriazole derivatives with high yields were studied. The S-alkylation in all
cases is preferred to the N-alkylation owing to the high nucleophilicity of the sulfur
atom. Some of thiadiazoles and the Schiff bases were obtained via condensation of
the aminomercaptotriazole with aromatic aldehydes. The structures of the prepared
compounds have been elucidated unambiguously by analytical and spectroscopic
methods including 1H, 13C NMR spectroscopy, IR spectroscopy, and elemental
analysis.

Acknowledgments I am indebted to the Bioorganic Chemistry Institute, Hohenheim University,

Stuttgart, Germany for providing me with laboratory facilities for recording the analysis and correlations
spectra described in this research.

References

1. B.S. Holla, B. Veerendra, M.K. Shivananda, B. Poojary, Eur. J. Med. Chem. 759, 38 (2003)
2. J. Wu, X. Liu, X. Cheng, Y. Cao, D. Wang, Z. Li, Molecules 2003, 12 (2007)
3. S. Jubie, P. Sikdar, S. Antony, R. Kalirajan, B. Gowramma, S. Gomathy, K. Elango, Pak. J. Pharm.
Sci. 109, 24 (2011)
4. N. Demirbas, U.A. Demirbas, Bioorg. Med. Chem. 3717, 10 (2002)
5. N.N. Gulerman, H.N. Dogan, S. Rollas, C. Johansson, C.C. Elik, Farmaco 953, 56 (2001)
6. A.R. Farghaly, E. Declerk, H. Elkashef, Arkivoc 137, x, (2006)
7. S. Kiran, B.M. Singh, T. Parikshit, Eur. J. Med. Chem. 147, 41 (2006)
8. L.G. Almajan, I. Saramet, S.F. Barbuceanu, C. Draghici, G. Bancescu, Rev. Chem. (Bucharest) 896,
60 (2009)

123
 R. A. Haggam

9. I. Khan, S. Ali, S. Hameed, N.H. Rama, M.T. Hussain, A. Wadood, R. Uddin, Z. Ul-Haq, A. Khan,
S. Ali, M.I. Choudhary, Eur. J. Med. Chem. 5200, 45 (2010)
10. G. Ayhankilcigil, C. Kus, T. Çoban, B. Caneke, M. Iscan, J. Enz, Inhib. Med. Chem. 129, 19 (2004)
11. H.N. Dogan, A. Duran, S. Rollas, G. Sener, M.K. Uysal, D. Gülen, Bioorg. Med. Chem. 2893, 10
(2002)
12. R. Sharma, G.P. Misra, J. Sainy, S.C. Chaturvedi, Med. Chem. Res. 245, 20 (2011)
13. S.F. Barbuceanu, G. Saramet, G.L. Almajan, C. Draghici, F. Barbuceanu, G. Bancescu, Eur. J. Med.
Chem. 417, 49 (2012)
14. B.W. Dymock, P.S. Jones, F.X. Wilson, Antivir. Chem. Chemother. 79, 11 (2000)
15. L.F. Awad, E.S.H. El Ashry, Carbohydr. Res. 9, 312 (1998)
16. E.S.H. El Ashry, L.F. Awad, Nucleosides Nucleotides Nucleic Acids 901, 20 (2001)
17. E.S.H. El Ashry, L.F. Awad, Nucleosides Nucleotides Nucleic Acids 103, 20 (2001)
18. A.H. Moustafa, R.A. Haggam, M.E. Younes, E.S.H. El Ashry, Nucleosides Nucleotides Nucleic
Acids 1885, 24 (2005)
19. A.H. Moustafa, R.A. Haggam, M.E. Younes, E.S.H. El Ashry, Phosphorus Sulfur Silicon 2361, 181
(2006)

123