Synthesis of bis azole, diazole, and triazole derivatives from n-(4-chloro/iodophenyl)-n-carboxyethyl-β-alanine dihydrazides

Article abstract of DOI:10.1002/jhet.1070

A new potentially biologically active N-(4-chloro/iodophenyl)-N- carboxyethyl-β-alanine derivatives () and products of their cyclization were obtained and characterized by the methods of ¹H-NMR, ¹³C-NMR, IR, mass spectroscopy, and elemental analysis.

Full text of DOI:10.1002/jhet.1070

March 2013
Synthesis of Bis Azole, Diazole, and Triazole Derivatives from
309
N‐(4‐Chloro/Iodophenyl)‐N‐carboxyethyl‐β‐alanine Dihydrazides
a
a
a
*
Kazimieras Anusevicius, Rita Vaickelioniene, Vytautas Mickevicius,
and Gema Mikulskieneb
aDepartment of Organic Chemistry, Kaunas University of Technology,
LT‐50254 Kaunas, Lithuania
bDepartment of the Biochemistry of Xenobiotics, Vilnius University Institute of Biochemistry,
LT‐08662 Vilnius, Lithuania
E-mail: Vytautas.Mickevicius@ktu.lt
Received April 19, 2011
*
DOI 10.1002/jhet.1070
Published online 8 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
H
N
S
N
O
NH2
O
N
O
N
N
O
O
N
H
N
H
N
N
R
N
R
N
R
N
R
N
2a,b
3a, b
6a, b
4a, b
H
N
H
N
O
NH2
N
O
N
O
N
S
X
N
H
H
N
X
S
H
N
NH
N
O
O
N
N
N
H
N
H
NH2
R
N
R
N
R
N
.
7a, b
NH2
S
10, 11a, b
8, 9a, b
H
N
H
N
N
N
N
H
N
N
NH
N
H
X
X
A new potentially biologically active N‐(4‐chloro/iodophenyl)‐N‐carboxyethyl‐β‐alanine derivatives
(2−4, 8, 9a,b) and products of their cyclization (6, 7, 10, 11a,b) were obtained and characterized by the
1
methods of H‐NMR, 13C‐NMR, IR, mass spectroscopy, and elemental analysis.
J. Heterocyclic Chem., 50, 309 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Modification of β‐amino acids as potential sub-
stances for organic synthesis is presently a prevailing
method. Their fragments are structural parts of
peptides, coenzymes, alkaloids, and antibiotics.
Substituted β‐amino acids are excellent synthons for
the synthesis of azetidine [1–4], pyridine [5–8],
pyrimidine [9–11], quinoline [12,13], and other hetero-
cyclic systems [14,15] possessing valuable practical
properties. Carbohydrazides of N‐substituted β‐amino
acids can be used in the synthesis of important hetero-
cyclic compounds. Recently, the heterocyclicstructures
such as azole [16], oxadiazoles, and triazole
derivatives have appeared to be fast track because of
their diverse fungicidal [11,14,17], antiinflammatory
[15] antibacterial [11,17], antiviral [18], anticancer
[19], antihelminthic [20], crop‐protective (herbicidal,
fungicidal, and insecticidal) [20] biological activities.
Considering the aforementioned facts, this work re-
lates to the synthesis and structural studies of some
heterocyclic structures derived from N‐(4‐chloro/
iodophenyl)‐N‐carboxyethyl‐β‐alanines.
Azoles and their separate structural fragments are among
the most extensively studied compounds [22–28]. In
continuation of our interest in the chemistry of N‐
substituted β‐amino acids, N‐(4‐chloro/iodophenyl)‐N‐
carboxyethyl‐β‐alanine dihydrazides were selected for the
synthesis of bis azole, diazole, and triazole derivatives
(Scheme 1).
The structure of all the newly synthesized compounds
has been confirmed by elemental analysis, IR, mass, and
1H‐NMR and 13C‐NMR spectral data. The assignment of
resonances in the NMR spectra was based on the chemical
shift theory, multiplicities, intensity, and a comparison
with similar spectral characteristics of structurally related
compounds [29–41].
The starting compounds—carbohydrazides 2a,b—were
synthesized by the reaction of dicarboxylic acid esters
and hydrazine hydrate in boiling 2‐propanol with 78
−80% yields as illustrated in Scheme 1. Azole derivatives
can be obtained by the interaction of carbohydrazides and
diketones. Functionalized pyrrole derivatives 3a,b were
prepared by refluxing a mixture of the corresponding
© 2013 HeteroCorporation

310
K. Anusevicius, R. Vaickelioniene, V. Mickevicius, and G. Mikulskiene
Vol 50
Scheme 1. Synthesis of compounds 2−11a,b.
O
N
H
N
S
N
N
N
O
O
O
O
N
N
R
N
N
H
4a, b
N
R
N
N
R
N
6a, b
O
3a, b
H
N
S
N
H
O
O, H+
CH3COOH
, H+
O
O
S
H
O
NH2
O
N
O
O
-
+
+
N
H
N
S K
O
H
.
CS2, KOH
N2H4 H2O
R
N
R
N
R
N
2a, b
[5a, b]
1a, b
H
N
H
N
-
S K
O
O
NH2
O
N
H
S
C6H5NCX
.
N2H4 H2O
X
H
N
X
S
H
N
2'3'
6'
NH
N
N
N
O
1'
N
N
N
N
H
4'
NH2
H
5'
2% NaOH
R
N
R
N
R
N
10, 11a, b
8, 9a, b
7a, b
NH2
S
H
N
H
N
N
N
O
N
H
N
NH
N
H
X
X
R = a) 4-Cl-C6H4; b) 4-I-C6H4; 8, 10 X = O; 9, 11 X = S
carbohydrazide 2, 2,5‐hexanedione, 2‐propanol, and the
catalytic amount of glacial acetic acid. The obtained prod-
ucts were identified from the characteristic resonances of
the four CH3 groups of the pyrrole ring varying in the
range 1.92−1.98 ppm with the intensity ratio of
0.1:0.8:0.1 and signals at 5.62 and 5.69 ppm, attributed
to the CH groups. Such dissolution of signals may be con-
ditioned by constrained rotation of pyrrole fragments of
symmetric molecules around the amide bond. The peaks
of the above‐mentioned appropriate groups in the usual re-
gion of the 13C‐NMR spectra confirmed the formation of
the pyrrole heterocycle.
In this work, bis 3,5‐dimethylpyrazole derivatives 4a,b
in a good yield were prepared by refluxing a mixture of
the corresponding carbohydrazide 2, 2,4‐pentanedione, 2‐
propanol, and a catalytic amount of hydrochloric acid.
The resonances at 2.15 and 2.45 ppm (CH3 groups), and
6.17 ppm (C═CH─C group) in the 1H‐NMR spectra
confirmed formation of pyrazole rings. The resonances at
∼ 13.38 ppm and ∼ 14.00 ppm of CH3 groups in the
13C‐NMR spectra of the 4a,b molecules and the signals
at ∼ 111.00 ppm, which were attributed to the CH, prove
the presence of the five‐membered heterocycle. The reso-
nances observed at about 143.00 ppm and at about 151.40
ppm were ascribed to the carbons of the N-C and N═C groups
of heterocycles, respectively.
One of the ways to obtain oxadiazole heterosystems is
their synthesis from dithiocarbazates. In this work, bis
1,3,4‐oxadiazoles 6a,b were prepared by refluxing respective
dihydrazides 2a,b, carbon disulfide, and potassium hydroxide
in 2‐propanol, followed by the dissolution of the resulting
potassium dithiocarbazates 5a,b in water and treatment of
the obtained solution with acetic acid to pH 6. The presence
of broad singlets at ∼ 14.35 ppm of NH protons in 1H‐NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis of Bis Azole, Diazole, and Triazole Derivatives from
311
N‐(4‐Chloro/Iodophenyl)‐N‐carboxyethyl‐β‐alanine Dihydrazides
spectra and two resonances at ∼ 162.30 ppm and ∼ 177.62
ppm, attributed to the N═C and C═S groups, respectively,
in 13C‐NMR spectra confirmed the formation of five‐mem-
bered oxadiazole rings in compound 6a,b.
additionally that the five‐membered heterocycle was
formed properly because the value of the β‐influence of
the NH2 substituent (7a,b) is similar to the Ph (11a,b)
one [29].
Dithiocarbazates 5a,b were also used for the synthesis of
triazoles. The bis 4‐amino‐1,2,4‐triazole derivatives 7a,b
were prepared by refluxing the aqueous solution of
dithiocarbazates 5a,b with hydrazine hydrate. The 1H‐
NMR and 13C‐NMR spectra showed the new signals
differing from the ones of 6a,b. The most important evi-
dence for the structure of 7a,b was the appearance of reso-
nances at ∼ 150.05 ppm (C═N) and ∼ 165.91 ppm (C═S)
in 13C‐NMR spectra. The NH group signals integrated for
one proton and the NH2 ones integrated for two protons,
which resonated at ∼ 13.50 ppm and at 5.60 ppm, respec-
EXPERIMENTAL
The 1H and 13C‐NMR spectra were recorded with a Varian
Unity Inova (300 MHz, 75 MHz) spectrometer operating in the
Fourier transform mode, using DMSO‐d6 and CDCl3 as solvents
and TMS as an internal reference (chemical shifts in δ, ppm). IR
spectra (ν, cm−1) were recorded on a Perkin‐Elmer Spectrum BX
FTIR spectrometer using KBr tablets. Mass spectra were obtained
with a Waters ZQ 2000 spectrometer using the atmospheric pres-
sure chemical ionization mode and operating at 25 V. Elemental
analyses were performed with a CE‐440 elemental analyzer.
Melting points were determined with an automatic APA1 melting
point apparatus and are uncorrected. TLC was performed with
Merck, Silica gel 60 F254 (Kieselgel 60 F254) silica gel plates.
General procedure for the synthesis of dihydrazides of N‐
(4‐halophenyl)‐N‐carboxyethyl‐β‐alanine 2a,b. To a solution
of the corresponding amino acid dimethyl ester 1 (13.74 g, 40
mmol) in 2‐propanol (50 mL) hydrazine hydrate (12 g, 240
mmol) was added, and the mixture was refluxed for 1 h. On
completing the reaction, the mixture was cooled to room
temperature, the precipitate was filtered off, washed with 2‐
propanol, and dried to give 2a and 2b in 9.57 g (80%) and
1
tively, in H‐NMR spectra also confirmed the products of
this cyclization.
The starting compounds for the synthesis of phenyl‐
substituted triazoles—N‐phenylhydrazinecarboxamides 8a,b
and N‐phenylhydrazinecarbothioamides 9a,b— were
synthesized by refluxing the respective dihydrazides 2a,b with
phenyliso‐ and phenylisothiocyonates in methanol. Character-
istic resonances observed at 170.48 ppm (-CH2CONH-)
and at ∼ 155.30 ppm (-NHCONH-) in 13C‐NMR spectra
and resonances at 8.05 ppm (-CONHNHCO-), ∼ 8.73
ppm (-CONHPh), 9.77 ppm (-CONHNHCO-) in 1H‐
NMR spectra confirmed the formation of compounds 8a,b.
The intensity ratio of NH signals was found to be ∼ 1:1:1.
Resonances at 8.05 ppm and 9.77 ppm were observed as
doublets with a spin−spin coupling constant (J) of 1.5 Hz.
The 13C‐NMR spectra of the molecules 9a,b possessing
a -CONHNHCSNHPh fragment showed resonances at ∼
170.50 ppm and ∼ 181.00 ppm, which were attributed to
C═O and C═S groups, respectively. In the 1H‐NMR spec-
tra of compounds 9a,b, the broad singlets at ∼ 9.60 ppm
and 10.00 ppm were ascribed to the six NH groups. Their
intensity ratio was found to be 0.6:0.4. The low intensity
(0.08) traces of resonances observed in the spectral region
of NH protons should be a result of a competition between
the intermolecular and intramolecular hydrogen bonding.
The conversion of semicarbazides 8, 9a,b to bis triazoles
10, 11a,b was carried out by refluxing them in 2% aqueous
NaOH solution with the subsequent acidification of the
reaction mixture with acetic acid. The sharp singlets at
12.25 g (78%) yields, respectively.
3‐[4‐Chloro(3‐hydrazino‐3‐oxopropyl)anilino]propanohydrazide
(2a). This compound was obtained as a white powder (a mixture of 2‐
propanol and water), mp 148−149°C; IR: NH2 3273, NH 3229, C═O
1645, 1632 cm−1; 1H‐NMR: δ 2.24 (t, 4H, CH2CO, J = 7.2 Hz), 3.48
(t, 4H, CH2N, J = 7.2 Hz), 4.20 (s, 4H, CONHNH2), 6.68 (d, 2H, 2,6‐
Har, J = 9.1 Hz), 7.17 (d, 2H, 3,5‐Har, J = 9.1 Hz), 9.04 ppm (s, 2H,
CONHNH2); 13C‐NMR: δ 31.25 (CH2CO), 46.83 (CH2N), 113.18
(C‐2,6), 119.15 (C‐4), 128.69 (C‐3,5), 145.78 (C‐1), 169.74 ppm
(CONHNH2). Anal. Calcd. for C12H18IN5O2: C, 48.08; H, 6.05; N
23.36. Found: C, 48.26; H, 6.06; N 23.29.
3‐[(3‐Hydrazino‐3‐oxopropyl)‐4‐iodoanilino]propanohydrazide
(2b). This compound was obtained as a white powder (a mixture of
2‐propanol and water), mp 144−145°C; IR: NH2 3278, NH 3228,
1
C═O 1646, 1636 cm−1; H‐NMR: δ 2.24 (t, 4H, CH2CO, J = 7.0
Hz), 3.47 (t, 4H, CH2N, J = 7.0 Hz); 4.20 (s, 4H, CONHNH2),
6.53 (d, 2H, 2,6‐Har, J = 8.9 Hz), 7.41 (d, 2H, 3,5‐Har, J = 8.9 Hz);
9.04 ppm (s, 2H, CONHNH2); 13C‐NMR: δ 31.99 (CH2CO),
47.46 (CH2N), 76.47 (C‐4), 114.43 (C‐2,6), 129.88 (C‐3,5), 147.31
(C‐1), 170.51 ppm (CONHNH2); MS: m/z 391 (M+). Anal. Calcd.
for C12H18IN5O2: C, 36.84; H, 4.64; N, 17.90. Found: C 36.81; H
4.54; N 17.85.
General procedure for the synthesis of 3‐[(4‐halophenyl)
({2‐[(2,5‐dimethyl‐1H‐pyrrol‐1‐yl)carbamoyl]ethyl})amino]‐
N‐(2,5‐dimethyl‐1H‐pyrrol‐1‐yl)propanamides 3a,b. A mixture
of the corresponding carbohydrazide 2 (3 mmol), 2,5‐hexanedione
(1.14 g, 10 mmol), 2‐propanol (20 mL), and a catalytic amount
(1.0 mL) of glacial acetic acid was refluxed for 6 h, cooled to
room temperature, and diluted with water (20 mL). The formed
organic residue was filtered off, washed with 2‐propanol, and
dried to give 3a and 3b in 1.18 g (86%) and 1.32 g (80%) yields,
respectively.
1
∼ 11.80 ppm were assigned to the NH group in H‐NMR
spectra and confirmed the formation of compounds 10a,
b. The extremely broad singlets at 13.77 (11a) and 13.26
1
(11b) ppm in the H‐NMR spectra of compounds 11a,b
may be ascribed to protons of the NH group. The reso-
nances at ∼ 150.10 ppm and ∼ 167.60 ppm were assigned
to C═N and C═S atoms, respectively, of the five‐
membered heterocycle moiety of compounds 11a,b in
13C‐NMR spectra. The chemical shifts of C═N and C═S
atoms of the 11a,b and 7a,b triazole heterocycles were
found to differ by a negligible margin. This implies
3‐[(4‐Chlorophenyl)({2‐[(2,5‐dimethyl‐1H‐pyrrol‐1‐yl)carbamoyl]
ethyl})amino]‐N‐(2,5‐dimethyl‐1H‐pyrrol‐1‐yl)propanamide (3a).
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K. Anusevicius, R. Vaickelioniene, V. Mickevicius, and G. Mikulskiene
Vol 50
This compound was obtained as a white powder (2‐propanol), mp
232−234°C; IR: NH 3260, C═O 1724, 1668 cm−1; NMR, a
General procedure for the synthesis of 1,3,4‐oxadiazole‐2
(3H)‐thiones 6a,b. A mixture of the corresponding dihydrazide
2 (5 mmol), potassium hydroxide (1.35 g, 20 mmol), carbon
disulfide (1.52 g, 20 mmol), and 2‐propanol (50 mL) was
refluxed for 24 h, and then the volatile fractions were separated
under reduced pressure. The obtained residue was dissolved in
water (30 mL), and the solution was acidified with acetic acid to
pH 6. The formed product was filtered off, washed with water,
and dried to give 6a and 6b in 1.42 g (74%) and 1.81 g (76%)
yields, respectively.
1
mixture of isomers: H‐NMR: δ 1.92, 1.94, 1.98 (3s, 0.1:0.8:0.1
(12H), CH3), 2.56 (t, 4H, CH2CO, J = 6.8 Hz), 3.67 (t, 4H,
NCH2, J = 6.8 Hz), 5.62, 5.69 (s, 0.8:0.2 (4H), CH), 6.60, 6.81
(d, 0.2:0.8 (2H), 2,6‐Har, J = 9.2 Hz), 7.14, 7.23 (d, 0.2:0.8 (2H),
3,5‐Har, J = 9.1 Hz), 10.63, 10.66 ppm (3s, 0.2:0.8 (2H), NH);
13C‐NMR: δ 10.84, 10.91 (CH3), 31.01 (CH2CO), 46.40 (CH2N),
102.85, 103.88 (CH), 113.34, 113.83 (C‐2,6), 119.76 (C‐4),
126.57 (C‐CH3), 128.82 (C‐3,5), 145.66 (C‐1), 170.04, ppm
(C═O); MS: m/z 456 (M+), 458 (M++2). Anal. Calcd. for
C24H30ClN5O2: C, 63.22; H, 6.63; N, 15.36. Found: 62.98; H
6.44; N 15.21.
3‐[(4‐Iodophenyl)({2‐[(2,5‐dimethyl‐1H‐pyrrol‐1‐yl)carbamoyl]
ethyl})amino]‐N‐(2,5‐dimethyl‐1H‐pyrrol‐1‐yl)propanamide (3b).
This compound was obtained as a white powder (2‐propanol), mp
199−201°C; IR: NH 3299, C═O 1682 cm−1; NMR, a mixture of
isomers: 1H‐NMR: δ 1.92, 1.93, 1.95, 1.98 (4s, 0.1:0.7:0.1:0.1
(12H), CH3), 2.54 (t, 4H, CH2CO, J = 6.6 Hz), 3.65 (t, 4H,
NCH2, J = 6.6 Hz), 5.62, 5.69 (s, 0.8:0.2 (4H), CH), 6.44, 6.66
(d, 0.2:0.8 (2H), 2,6‐Har, J = 9.0 Hz), 7.39, 7.48 (d, 0.2:0.8 (2H),
3,5‐Har, J = 8.9 Hz), 10.63, 10.67, 10.68 ppm (3s, 0.1:0.1:0.8
(2H), NH); 13C‐NMR: δ 10.88, 10.96 (CH3), 30.97, 31.19
(CH2CO), 46.26, 46.36 (CH2N), 77.28 (C‐4), 102.88, 103.91
(CH), 115.01, 115.07 (C‐2,6), 126.59, 127.06 (C‐CH3), 137.45
(C‐3,5), 146.38 (C‐1), 170.06, 170.20 ppm (C═O); MS: m/z 548
(M++1), 549 (M++2). Anal. Calcd. for C24H30IN5O2: C, 52.66; H,
5.52; N, 12.79. Found C 52.49; H 5.43; N 12.93.
General procedure for the synthesis of 3‐[(4‐halophenyl)[3‐
(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropyl]amino]‐1‐(3,5‐
dimethyl‐1H‐pyrazol‐1‐yl)propan‐1‐ones 4a,b. A mixture of
the corresponding carbohydrazide 2 (3 mmol), 2,4‐pentanedione
(1 g, 10 mmol), 2‐propanol (15 mL), and a catalytic amount
(0.5 mL) of hydrochloric acid was refluxed for 5 h, cooled to room
temperature, and diluted with water (20 mL). The formed organic
residue was filtered off, washed with 2‐propanol, and dried to give
4a and 4b in 1.07 g (83%) and 1.16 g (74%) yields, respectively.
3‐[(4‐Chlorophenyl)[3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐
oxopropyl]amino]‐1‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)propan‐1‐one
(4a). This compound was obtained as a white powder (2‐
propanol), mp 109−110°C; IR: C═O 1724, C═N 1600,
1580 cm−1; 1H‐NMR: δ 2.15 (s, 6H, 5′‐CH3), 2.45 (s, 6H, 3′‐
CH3), 3.26 (t, 4H, CH2 CO, J = 6.9 Hz), 3.72 (t, 4H, NCH2,
J = 7.1 Hz), 6.17 (s, 2H, CH), 6.83 (d, 2H, 2,6‐Har, J = 9.2
Hz), 7.18 ppm (d, 2H, 3,5‐Har, J = 9.1 Hz); 13C‐NMR: δ
13.36 (5′‐CH3), 13.98 (3′‐CH3), 32.96 (CH2CO), 46.10
(CH2N), 111.11 (CH), 113.55 (C‐2,6), 119.57 (C‐4), 128.73
(C‐3,5), 143.07 (N‐C‐CH3), 151.40 (N═C‐CH3), 154.66 (C‐1),
171.84 ppm (C═O). Anal. Calcd. for C22H26ClN5O2: C, 61.75;
H, 6.12; N, 16.37. Found: 61.57; H 6.13; N 16.32.
5‐(2‐{4‐Chloro[2‐(5‐thioxo‐4,5‐dihydro‐1,3,4‐oxadiazol‐2‐yl)
ethyl]anilino}ethyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (6a). This
compound was obtained as a yellow powder (2‐propanol), mp
159−160°C; IR: NH 3133, C═N 1617, 1597, C═S 1256, C-O-
1
C 1156 cm−1; H‐NMR: δ 2.99 (t, 4H, CH2C═N, J = 7.0 Hz),
3.68 (t, 4H, CH2N, J = 7.0 Hz), 6.74 (d, 2H, 2,6‐Har, J = 9.1
Hz), 7.19 (d, 2H, 3,5‐Har, J = 9.1 Hz), 14.38 ppm (br. s, 2H,
NH); 13C‐NMR: δ 23.17 (CH2C═N), 46.34 (CH2N), 113.74 (C‐
2,6), 120.35 (C‐4), 128.99 (C‐3,5), 145.17 (C‐1), 162.31
(C═N), 177.65 ppm (C═S). Anal. Calcd. for C14H14ClN5O2S2:
C, 43.80; H, 3.68; N, 18.24. Found: C, 43.75; H, 3.57; N, 18.20.
5‐(2‐{4‐Iodo[2‐(5‐thioxo‐4,5‐dihydro‐1,3,4‐oxadiazol‐2‐yl)
ethyl]anilino}ethyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (6b). This
compound was obtained as a yellow powder (2‐propanol), mp
152−153°C; IR: NH 3131, C═N 1616, 1587, C═S 1257, C-
O-C 1157 cm−1 1H‐NMR: δ 2.94 (t, 4H, CH2C═N, J = 6.9
;
Hz), 3.67 (t, 4H, CH2N, J = 6.9 Hz), 6.59 (d, 2H, 2,6‐Har, J =
9.0 Hz), 7.43 (d, 2H, 3,5‐Har, J = 8.8 Hz), 14.36 ppm (br. s,
2H, NH); 13C‐NMR: δ 23.12 (CH2C═N), 46.18 (CH2N),
78.04 (C‐4), 114.81 (C‐2,6), 137.57 (C‐3,5), 145.93 (C‐1),
162.26 (C═N), 177.63 ppm (C═S). Anal. Calcd. for
C14H14IN5O2S2: C, 35.38; H, 2.97; N, 14.73. Found: C,
35.47; H, 2.83; N, 14.64.
General procedure for the synthesis of 1,2,4‐triazole‐3‐
thiones 7a,b. A mixture of the corresponding dihydrazide 2 (5
mmol), potassium hydroxide (1.35 g, 20 mmol), carbon
disulfide (1.52 g, 20 mmol), and 2‐propanol (50 mL) was
refluxed for 24 h, and then the volatile fractions were separated
under reduced pressure. The obtained residue was dissolved in
water (5 mL), and hydrazine hydrate (1.5 g, 30 mmol) was
added. The mixture was refluxed for 20 h, diluted with water
(10 mL), cooled down, and acidified with acetic acid to pH 6.
The formed product was filtered off, washed with water, 2‐
propanol, and dried to give 7a and 7b in 1.48 g (72%) and 1.81
g (72%) yields, respectively.
4‐Amino‐5‐(2‐{[2‐(4‐amino‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐
triazol‐3‐yl)ethyl]‐4‐chloroanilino}ethyl)‐2,4‐dihydro‐3H‐
1,2,4‐triazole‐3‐thione (7a). This compound was obtained
as a white powder (methanol), mp 269−270°C; IR: NH2
3258, NH 3118, C═N 1630, 1596, C═S 1297, 1284 cm−1
;
3‐[(4‐Iodophenyl)[3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropyl]
amino]‐1‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)propan‐1‐one (4b). This
compound was obtained as a white powder (2‐propanol), mp 128
−129°C; IR: C═O 1723, C═N 1590 cm−1; 1H‐NMR: δ 2.15 (s, 6H,
5′‐CH3), 2.45 (s, 6H, 3′‐CH3), 3.26 (t, 4H, CH2CO, J = 7.0 Hz),
3.70 (t, 4H, NCH2, J = 7.1 Hz), 6.17 (s, 2H, CH), 6.68 (d, 2H, 2,6‐
Har, J = 9.1 Hz), 7.44 ppm (d, 2H, 3,5‐Har, J = 8.9 Hz); 13C‐NMR:
δ 13.39 (5′‐CH3), 14.02 (3′‐CH3), 32.92 (CH2CO), 45.94 (CH2N),
77.06 (C‐4), 111.14 (CH), 114.76 (C‐2,6), 137.34 (C‐3,5), 143.10
(N‐C‐CH3), 151.44 (N═C‐CH3), 146.43 (C‐1), 171.84 ppm (C═O).
Anal. Calcd. for C22H26IN5O2: C, 50.88; H, 5.05; N, 13.48. Found:
C 50.98; H 5.18; N 13.55.
1H‐NMR: δ 2.88 (t, 4H, CH2C═N, J = 7.0 Hz), 3.68 (t,
4H, CH2N, J = 7.0 Hz), 5.60 (s, 4H, NH2), 6.82 (d, 2H,
2,6‐Har, J = 9.0 Hz), 7.18 (d, 2H, 3,5‐Har, J = 9.0 Hz),
13.50 ppm (s, 2H, NH); 13C‐NMR: δ 22.39 (CH2C═N),
46.89 (CH2N), 113.33 (C‐2,6), 119.63 (C‐4), 128.80 (C‐
3,5), 145.40 (C‐1), 150.07 (C═N), 165.92 ppm (C═S);
MS: m/z 412 (M+), 414 (M++2). Anal. Calcd. for
C14H18ClN9S2: C, 40.82; H, 4.40; N, 30.60. Found: C,
40.96; H, 4.25; N, 30.51.
4‐Amino‐5‐(2‐{[2‐(4‐amino‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐
triazol‐3‐yl)‐ethyl]‐4‐iodoanilino}ethyl)‐2,4‐dihydro‐3H‐1,2,4‐
triazole‐3‐thione (7b). This compound was obtained as a yellow
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis of Bis Azole, Diazole, and Triazole Derivatives from
313
N‐(4‐Chloro/Iodophenyl)‐N‐carboxyethyl‐β‐alanine Dihydrazides
powder (methanol), mp 194−196°C; IR: NH2 3256, NH 3120,
3182, C═O 1681, C═S 1182, 1161 cm−1
;
1H‐NMR: δ 2.46
1
C═N 1626, 1588, C═S 1296, 1284 cm−1; H‐NMR: δ 2.86 (t,
(t, 4H, CH2CO, J = 7.0 Hz), 3.5−3.6 (m, 4H, CH2N), 6.6
−7.5 (m, 14H, Har), 9.59, 10.00 ppm (2s, 6H, all NH); 13C‐
NMR: δ 31.11 (CH2CO), 46.07 (CH2N), 76.78 (C‐4), 114.64
(C‐2,6), 125.24 (C‐4′), 126.23 (C‐2′,6′), 128.13 (C‐3′,5′),
137.45 (C‐3,5), 139.09 (C‐1′), 146.59 (C‐1), 170.61 (C═O),
181.02 ppm (C═S). Anal. Calcd. for C26H28IN7O2S2: C,
47.20; H, 4.27; N, 14.82. Found: C, 47.05; H, 4.16; N, 14.65.
General procedure for the synthesis of 1,2,4‐triazol‐3‐ones
10a,b. A mixture of the corresponding semicarbazide 6 (1 mmol)
and 2% aqueous sodium hydroxide solution (20 mL) was refluxed
for 3 h, cooled to room temperature, and acidified with acetic acid
to pH 6. The formed organic residue was filtered off, washed with
water, and dried to give 10a and 10b in 0.33 g (65%) and 0.39 g
(65%) yields, respectively.
4H, CH2C═N, J = 6.4 Hz,), 3.61 (m, 4H, CH2N, J = 6.4 Hz),
5.60 (s, 4H, NH2), 6.68 (d, 2H, 2,6‐Har, J = 8.5 Hz), 7.42 (d,
2H, 3,5‐Har, J = 8.5 Hz), 13.49 ppm (s, 2H, NH); 13C‐NMR: δ
22.35 (CH2C═N), 46.73 (CH2N), 77.14 (C‐4), 114.53 (C‐2,6),
137.37 (C‐3,5), 146.16 (C‐1), 150.04 (C═N), 165.90 ppm
(C═S). Anal. Calcd. for C14H18IN9S2: C, 33.40; H, 3.60; N,
25.04. Found: C, 33.51; H, 3.61; N, 25.12.
General procedure for the synthesis of semicarbazides 8a,
b. A mixture of the corresponding dihydrazide 2 (10 mmol),
phenyl isocyanate (3.57 g, 30 mmol), and methanol (50 mL)
was refluxed for 2 h, then cooled to room temperature, the
formed precipitate was filtered off, washed with methanol, and
dried to give 8a and 8b in 4.95 g (92%) and 5.67 g (90%)
yields, respectively.
5‐(2‐{4‐Chloro[2‐(5‐oxo‐4‐phenyl‐4,5‐dihydro‐1H‐1,2,4‐triazol‐
3‐yl)ethyl]anilino}‐ethyl)‐4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐
one (10a). This compound was obtained as a white powder (2‐
propanol), mp 218−220°C; IR: NH 3190, C═O 1707, C═N 1594,
3,3′‐[(4‐Chlorophenyl)imino]bis[N′‐(phenylcarbamoyl)
propanohydrazide] (8a). This compound was obtained as a white
powder (methanol), mp 209−210°C; IR: NH 3304, C═O 1656,
1
1
1604 cm−1; H‐NMR: δ 2.42 (t, 4H, CH2CO, J = 6.9 Hz), 3.50
1579 cm−1; H‐NMR: δ 2.53 (t, 4H, CH2C═N, J = 7.8 Hz), 3.24
(t, 4H, CH2N, J = 6.9 Hz) 6.7−7.5 (m, 14H, Har), 8.05 (s, 2H,
CONHNHCO, J = 1.5 Hz), 8.73 (s, 2H, CONHPh), 9.77 ppm
(s, 2H, CONHNHCO, J = 1.5 Hz); 13C‐NMR: δ 31.16 (CH2CO),
46.56 (CH2N), 113.39 (C‐2,6), 118.50 (C‐2’,6′), 119.41 (C‐4),
121.92 (C‐4′), 128.68 (C‐3′,5′), 128.88 (C‐3,5), 139.59 (C‐1′),
145.80 (C‐1), 155.29 (NHCONH), 170.48 ppm (CH2CONH).
Anal. Calcd. for C26H28CIN7O4: C, 58.04; H, 5.25; N, 18.22.
Found: C, 58.20; H, 5.15; N, 18.12.
(t, 4H, CH2N, J = 7.8 Hz), 6.00 (d, 2H, 2,6‐Har, J = 9.0 Hz), 6.91
(d, 2H, 3,5‐Har, J = 9.0 Hz), 7.3−7.6 (m, 10H, Har), 11.82 ppm
(s, 2H, NH); 13C‐NMR: δ 23.43 (CH2C═N), 48.72 (CH2N),
112.48 (C‐2,6), 119.39 (C‐4), 127.51 (C‐3′,5′), 128.71 (C‐3,5 + C‐
4′), 129.50 (C‐2′,6′), 132.74 (C‐1′), 144.86 (C═N), 144.90 (C‐1),
154.28 ppm (C═O). MS: m/z 502 (M+), 504 (M++2). Anal. Calcd.
for C26H24ClN7O2: C, 62.21; H, 4.82; N, 19.53. Found: C, 62.03;
H, 4.74; N, 19.44.
3,3′‐[(4‐Iodophenyl)imino]bis[N′‐(phenylcarbamoyl)
propanohydrazide] (8b). This compound was obtained as a white
powder (methanol), mp 191−193°C; IR: NH 3287, C═O 1656,
5‐(2‐{4‐Iodo[2‐(5‐oxo‐4‐phenyl‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐
yl)ethyl]anilino}ethyl)‐4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one
(10b). This compound was obtained as a yellow powder (2‐propanol),
1
1621, 1601 cm−1; H‐NMR: δ 2.42 (t, 4H, CH2CO, J = 7.0 Hz),
mp 157−159°C; IR: NH 3188, C═O 1706, C═N 1582 cm−1
;
3.56 (t, 4H, CH2N, J = 7.0 Hz), 6.5−7.5 (m, 14H, Har), 8.05 (s, 2H,
CONHNHCO, J = 1.5 Hz), 8.74 (s, 2H, CONHPh), 9.77 ppm (s,
2H, CONHNHCO, J = 1.5 Hz); 13C‐NMR: δ 31.31 (CH2CO),
46.41 (CH2N), 76.78 (C‐4), 114.60 (C‐2,5), 118.51 (C‐2′,6′),
121.94 (C‐4′), 128.69 (C‐3′,5′), 137.47 (C‐3,5), 139.59 (C‐1′),
146.55 (C‐1), 155.31 (NHCONH), 170.48 ppm (CH2CONH). Anal.
Calcd. for C26H28IN7O4: C, 49.61; H, 4.48; N, 15.58. Found: C,
49.86; H, 4.32; N, 15.43.
General procedure for the synthesis of thiosemicarbazides
9a,b. A mixture of the corresponding dihydrazide 2 (10 mmol),
phenyl isothiocyanate (4.05 g, 30 mmol), and methanol (50 mL)
was refluxed for 2 h, and then cooled to room temperature; the
formed precipitate was filtered off, washed with methanol, and
dried to give 9a and 9b in 5.47 g (96%) and 6,29 g (95%)
yields, respectively.
1H‐NMR: δ 2.53 (t, 4H, CH2C═N, J = 7.6 Hz), 3.25 (t, 4H,
CH2N, J = 7.6 Hz), 5.88 (d, 2H, 2,6‐Har, J = 9.0 Hz), 7.17 (d,
2H, 3,5‐Har, J = 9.0 Hz), 7.3−7.5 (m, 10H, Har), 11.77 ppm
(s, 2H, NH); 13C‐NMR: δ 23.39 (CH2C═N), 46.52 (CH2N),
76.82 (C‐4), 113.69 (C‐2,6), 127.50 (C‐3′,5′), 128.71 (C‐4′),
129.51 (C‐2′,6′), 132.72 (C‐1′), 137.25 (C‐3,5), 144.85
(C═N), 145.79 (C‐1), 154.27 ppm (C═O). MS: m/z 594
(M++1), 595 (M++2). Anal. Calcd. for C26H24IN7O2: C,
52.62; H, 4.08; N, 16.52. Found: C, 52.72; H, 4.18; N, 16.44.
General procedure for the synthesis of 1,2,4‐triazole‐3‐thiones
11a,b. A mixture of the corresponding thiosemicarbazide 7 (1 mmol)
and 2% aqueous sodium hydroxide solution (20 mL) was refluxed for
3 h, cooled to room temperature, and acidified with acetic acid to pH
6. The formed organic residue was filtered off, washed with water,
and dried to give 11a and 11b in 0.40 g (74%) and 0.46 g (73%)
yields, respectively.
3,3′‐[(4‐Chlorophenyl)imino]bis[N′‐(phenylthiocarbamoyl)
propanehydrazide] (9a). This compound was obtained as a
white powder (methanol), mp 152−154°C; IR: NH 3212,
5‐(2‐{4‐Chloro[2‐(4‐phenyl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐
3‐yl)ethyl]anilino}‐ethyl)‐4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐
triazole‐3‐thione (11a). This compound was obtained as a
white powder (2‐propanol), mp 261−263°C; IR: NH 3402,
3192, C═O 1681, C═S 1184, 1163 cm−1 1H‐NMR: δ 2.46
;
(t, 4H, CH2CO, J = 7.0 Hz), 3.56 (t, 4H, CH2N, J = 7.0
Hz), 6.7−7.4 (m, 14H, Har), 9.60, 10.00 ppm (2s, 6H, all
NH); 13C‐NMR: δ 31.15 (CH2CO), 46.27 (CH2N), 113.39
(C‐2,6), 119.44 (C‐4), 125.28 (C‐4′), 126.26 (C‐2′,6′),
128.13 (C‐3′,5′), 128.88 (C‐3,5), 139.09 (C‐1′), 145.85 (C‐1),
170.42 (C═O), 180.94 ppm (C═S). Anal. Calcd. for
C26H28ClN7O2S2: C, 54.77; H, 4.95; N, 17.20. Found: C, 54.60;
H, 4.78; N, 17.04.
C═N 1598, 1571, C═S 1280 cm−1
;
1H‐NMR: δ 2.56
(t, 4H, CH2C═N, J = 7.2 Hz), 3.33 (t, 4H, CH2N, J = 7.0
Hz), 5.98 (d, 2H, 2,6‐Har, J = 9.0 Hz), 6.90 (d, 2H, 3,5‐Har,
J = 9.0 Hz), 7.4−7.6 (m, 10H, Har), 13.77 ppm (s, 2H NH);
13C‐NMR: δ 23.03 (CH2C═N), 46.92 (CH2N), 112.55 (C‐
2,6), 119.60 (C‐4), 128.38 (C‐3′,5′), 128.70 (C‐3,5),
129.54 (C‐2′,6′ + C‐4′), 133.54 (C‐1′), 144.78 (C‐1),
150.10 (C═N), 167.62 ppm (C═S); MS: m/z 534 (M+), 536
(M++2). Anal. Calcd. for C26H24ClN7S2: C, 58.47; H, 4.53;
N, 18.36. Found: C, 58.32; H, 4.37; N, 18.45.
3,3′‐[(4‐Iodophenyl)imino]bis[N′‐(phenylthiocarbamoyl)
propanohydrazide] (9b). This compound was obtained as a
white powder (methanol), mp 162−164°C; IR: NH 3211,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

314
K. Anusevicius, R. Vaickelioniene, V. Mickevicius, and G. Mikulskiene
Vol 50
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5‐(2‐{4‐Iodo[2‐(4‐phenyl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐
137.
3‐yl)ethyl]anilino}‐ethyl)‐4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazole‐
3‐thione (11b). This compound was obtained as a white powder
(2‐propanol), mp 149−151°C; IR: NH 3340, C═N 1588, 1572,
C═S 1285 cm−1; 1H‐NMR: δ 2.55 (t, 4H, CH2C═N, J = 7.3 Hz),
3.31 (t, 4H, CH2N, J = 7.3 Hz), 5.85 (d, 2H, 2,6‐Har, J = 9.0 Hz),
7.15 (d, 2H, 3,5‐Har, J = 9.0 Hz), 7.4−7.6 (m, 10H, Har), 13.26
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2′,6′ + C‐4′), 133.57 (C‐1′), 137.30 (C‐3,5), 145.59 (C‐1), 150.08
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C26H24IN7S2: C, 49.92; H, 3.87; N, 15.67. Found: C, 49.78; H,
3.69; N, 15.77.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet