Synthesis of azoles from 3,3'-[(4-alkoxyphenyl)imino]bis(propanoic acid hydrazides)

Article abstract of DOI:10.1007/s00706-009-0210-y

Reaction of 3,3'-[(4-alkoxyphenyl)imino]bis(propanoic acid hydrazides) with CS₂ in alkaline solution and subsequent acidification gave 5,5'-[[(4-alkoxyphenyl)imino]diethane-2,1-diyl]bis(1,3,4-oxadiazole-2(3H) -thiones). The same dihydrazides on

Full text of DOI:10.1007/s00706-009-0210-y

Monatsh Chem (2009) 140:1523–1528
DOI 10.1007/s00706-009-0210-y
ORIGINAL PAPER
Synthesis of azoles from 3,30-[(4-alkoxyphenyl)imino]bis
(propanoic acid hydrazides)
•
Ingrida Tumosiene Zigmuntas Jonas Beresnevicius
_
ˇ
Received: 11 July 2009 / Accepted: 12 October 2009 / Published online: 12 November 2009
Ó Springer-Verlag 2009
Abstract Reaction of 3,30-[(4-alkoxyphenyl)imino]bis
(propanoic acid hydrazides) with CS2 in alkaline solution
and subsequent acidification gave 5,50-[[(4-alkoxyphe-
nyl)imino]diethane-2,1-diyl]bis(1,3,4-oxadiazole-2(3H)-
thiones). The same dihydrazides on reaction with phenyl
isocyanates or phenyl isothiocyanates were converted to
bis[N0-(phenylaminocarbonyl)propanoic acid hydrazides]
and bis[N0-(phenylaminocarbonothioyl)propanoic acid
hydrazides], which underwent cyclization in alkaline
medium to produce 5,50-[[(4-alkoxyphenyl)imino]dieth-
ane-2,1-diyl]bis(4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-
ones) and their 3-thio analogues, whereas in sulfuric acid
or POCl3 5,50-[[(4-alkoxyphenyl)imino]diethane-2,1-diyl]
bis(N-phenyl-1,3,4-oxadiazol-2-amines) and 5,50-[[(4-alk-
oxyphenyl)imino]diethane-2,1-diyl]bis(N-phenyl-1,3,4-thi-
adiazol-2-amines) were obtained.
element of many drugs [5]. Cyclization of hydrazine
derivatives is a widely known method for synthesis of
diazoles.
N-Substituted 3-amino acids and their derivatives elicit a
broad spectrum of biological activity [6–8], therefore, in
this work 3,30-[(4-alkoxyphenyl)imino]bis(propanoic acid
hydrazides) were used for the synthesis of compounds
containing two oxadiazole, thiadiazole, or triazole rings in
their structure.
Results and discussion
Reaction of alkoxydithioformate with hydrazide [9] was
adopted for the synthesis of compounds 2 containing two
1,3,4-oxadiazol-2-thione fragments. 5,50-[[(4-Methoxyph-
enyl)imino]diethane-2,1-diyl]bis(1,3,4-oxadiazole-2(3H)-
thione) (2a) and its 4-ethoxy homologue 2b were prepared
[9] in 57–65% yield by heating under reflux the corre-
sponding hydrazides 1 with carbon disulfide in basic
medium and subsequent cyclization, in situ with hydro-
chloric acid, of the potassium salts of hydrazinocar-
bodithioates formed. Methanol and ethanol were tested as
solvents for this reaction. The better yields of 2 were
obtained in ethanol. The 13C NMR spectra of these com-
pounds exhibited carbon resonances at 162.79–162.82 ppm
confirming the presence of the C=N fragment of the oxadi-
azole ring (Scheme 1).
Keywords Dihydrazides ꢀ Hydrazinocarboxamides ꢀ
1,3,4-Oxadiazoles ꢀ 1,3,4-Thiadiazoles ꢀ 1,2,4-Triazoles
Introduction
Heterocyclic compounds are of particular importance
among pharmaceutically and biologically active com-
pounds. Five-membered heterocyclic compounds, triazoles,
oxazoles, and thiazoles, have a broad spectrum of biological
activity. 1,2,4-Triazoles and 1,3,4-oxadiazoles are known
for their anti-inflammatory [1], antibacterial [2, 3], and
antimicrobial [4] effect. The triazole system is a structural
Hydrazinocarboxamides undergo cyclization in phos-
phoryl chloride or sulfuric acid [9], forming 1,3,4-
oxadiazole derivatives. Reaction of dihydrazides 1 with
phenyl or 4-chlorophenyl isocyanates, or phenyl isothiocy-
anate in methanol gave hydrazinocarboxamides 3 and 4, and
hydrazinocarbothiamide derivatives 5, cyclization of which
in basic medium resulted in 5,50-[[(4-methoxyphenyl)
_
ˇ
I. Tumosiene ꢀ Z. J. Beresnevicius (&)
Department of Organic Chemistry, Kaunas University of
_
Technology, Radvilenu˛ pl. 19, 50254 Kaunas, Lithuania
e-mail: Zigmuntas.Beresnevicius@ktu.lt
123

_
ˇ
I. Tumosiene, Z. J. Beresnevicius
1524
Scheme 1
H
N
S
O
H
N
O
O10
H
X
N
N
9
12 13
9
9
3
2
CS2
N
NH2
ArNCX
MeOH,
10-20 min15
8
14 R'
R'
H10
8
N 11
N 7
N 7
8
1
4
7
O
O
N
O
KOH, EtOH
H
R
NH2
R
R
H
11,12
10
X
N
N
O
H
O
N
O
N
H
S
N
H
N
H
3a R = Me; R' = H; X = O
3b R = Et; R' = H; X = O
4a R = Me; R' = Cl; X = O
4b R = Et; R' = Cl; X = O
5a R = Me; R' = H; X = S
5b R = Et; R' = H; X = S
1a R = Me
1b R = Et
2a R = Me
2b R = Et
imino]diethane-2,1-diyl]bis(4-phenyl-2,4-dihydro-3H-1,2,4-
triazol-3-ones) 6a, 7a or their ethoxy derivatives 6b, 7b, and
the thio analogues 8. In the reaction of dihydrazides 3–5 with
phenyl isocyanate, crystals of the semicarbazides began to
appear after heating for 10 min, whereas for phenyl isothi-
ocyanate more prolonged heating was required (Scheme 2).
of the phenyl residue, whereas the signals of the primary
amino group present in the hydrazide 1 were absent. The
triazole ring proved to have a marked deshielding effect on
the hydrogen atoms of the neighboring methylene group, as
a result of which the signals in the 1H NMR spectra of 6–8
are found shifted down-field by 0.19 and 0.31 ppm in
comparison with the corresponding signals in the spectra of
the starting dihydrazides 1 [8].
1
The H NMR spectra of semicarbazides 3 and 4 and
thiosemicarbazide 5 showed a set of signals for the protons
Scheme 2
H
N
X
N
N
N
N
R'
R'
20% KOH, 1h, rf
N
O
R
3a, 3b, 4a, 4b, 5a, 5b
X
N
H
POCl3, 2h, rf or
H2SO4, 4h, rt
POCl3, 2h, rf or
H2SO4, rt
6a R = Me; R' = H; X = O
6b R = Et; R' = H; X = O
7a R = Me; R' = Cl; X = O
7b R = Et; R' = Cl; X = O
8a R = Me; R' = H; X = S
8b R = Et; R' = H; X = S
H
H
N
N
N
N
N
S
N
O
R'
R'
O
R
N
O
R
N
S
N
O
N
N
N
N
N
H
H
9a R = Me; R' = H
9b R = Et; R' = H
10a R = Me; R' = Cl
10b R = Et; R' = Cl
11a R = Me
11b R = Et
123

Synthesis of azoles from 3,30-[(4-alkoxyphenyl)imino]bis(propanoic acid hydrazides)
1525
Thus, 5,50-[[(4-methoxyphenyl)imino]diethane-2,1-diyl]
bis(N-phenyl-1,3,4-oxadiazol-2-amine) (9a), its ethoxy
analogue 9b, and chloro derivatives 10 were synthesized by
heating under reflux hydrazinocarboxamides 3 and 4 in
phosphoryl chloride or keeping them in sulfuric acid. Under
the same conditions, thiadiazole derivatives 11 were
J = 7.5 Hz; CH2C=N), 3.40 (t, 4H, J = 7.5 Hz, CH2N),
3.88 (q, 2H, J = 6.9 Hz, CH3CH2O), 6.59 (d, 2H,
J = 9.3 Hz, H(2,6)Ar), 6.75 (d, 2H, J = 9.3 Hz, H(3,5)Ar),
8.16 (br s, 2H, NH) ppm; 13C NMR: d = 174.90 (C-10),
162.82 (C-9), 149.54 (C-4), 142.06 (C-1), 115.41 (C-3, 5),
113.34 (C-2, 6), 63.22 (C-12), 47.63 (C-7), 34.13 (C-8),
14.83 (C-11) ppm; IR (KBr): ꢀm = 3,171 (NH), 1,507 (C=S)
cm-1; MS (15 eV): m/z (%) = 394 ([M ? H]?, 50).
1
obtained from hydrazinocarbothiamides 5. In the H NMR
spectra of 9–11 the proton signals of the CONHNH group
are absent in comparison with the spectra for 3–5. Mass
spectra of all synthesized compounds 2–11 showed molec-
ular ion peaks.
3,30-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
[N0-(phenylaminocarbonyl)propanoic acid hydrazide]
(3a, C27H31N7O5)
To a hot solution of 1.47 g 1a (5 mmol) in 50 cm3 MeOH
1.19 cm3 phenyl isocyanate (10 mmol) was added. The
mixture was heated under reflux until a precipitate appeared
(10 min) and cooled. The crystals were isolated by filtration,
washed with methanol, and recrystallized from DMF–H2O
Experimental
1H and 13C NMR spectra were recorded on a Varian Unity
Inova 300 spectrometer (300 and 75 MHz) using TMS as
an internal standard and DMSO-d6 as a solvent. IR spectra
were taken on a Perkin–Elmer Spectrum Bx FT-IR spec-
trometer. Mass spectra were recorded on a Waters
Micromass ZQ 2000 instrument using chemical ionization.
Elemental analyses (C, H, N) were performed on an
Elemental Analyzer CE-440, and the results were found to
be in good agreement ( 0.2%) with the calculated values.
Melting points were determined on the Auto probe
analyzer APA 1. Monitoring of the reaction course and
purity of the compounds prepared was carried out using
TLC on Silufol 254 and Silufol UV-254 plates.
1
to afford 1.9 g (71%) 3a. M.p.: 200–201 °C; H NMR:
d = 2.40 (t, 4H, J = 7.2 Hz, CH2CO), 3.51 (t, 4H,
J = 7.2 Hz, CH2N), 3.69 (s, 3H, CH3O), 6.75 (d, 2H,
J = 7.2 Hz, H(2,6)Ar), 6.86 (d, 2H, J = 7.2 Hz, H(3,5)Ar),
7.24–7.46 (m, 10H, H–Ar0), 8.04, 8.71 (2s, 4H, NHNHCO),
9.73 (s, 2H, NHAr0) ppm; 13C NMR: d = 170.67 (C-9),
155.18 (C-10), 151.12 (C-4), 141.49 (C-1), 139.49 (C-11),
128.54 (C-13, 15), 121.78 (C-12, 16), 118.36 (C-14), 114.74
(C-3, 5), 114.36 (C-2, 6), 55.24 (C-17), 47.14 (C-7), 31.24
(C-8) ppm; IR (KBr): m = 1,660 (C=O) cm-1; MS (ESI,
ꢀ
20 eV): m/z (%) = 534 ([M ? H]?, 100).
3,30-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
[N0-(phenylaminocarbonyl)propanoic acid hydrazide]
(3b, C28H33N7O5)
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]-
bis(1,3,4-oxadiazole-2(3H)-thione) (2a, C15H17N5O3S2)
To a solution of 2.8 g KOH in 75 cm3 EtOH 4.5 cm3 CS2
(5.7 g, 75 mmol) was added drop-wise and stirred for
15 min at 20 °C. To this solution 7.37 g 1a (25 mmol) in
50 cm3 EtOH was added and the mixture was stirred at
reflux for 20 h. The liquid fraction was removed under
vacuo, the residue was dissolved in 75 cm3 H2O, HCl was
added to pH 3–4, and the slurry formed was separated,
washed with water and crystallized from methanol to give
Prepared similarly to 3a from 3.09 g 1b (10 mmol) and
2.38 cm3 phenyl isocyanate (20 mmol). Recrystallization
from DMF–H2O afforded 3.98 g (75%) 3b. M.p.: 201–
202 °C; 1H NMR: d = 1.27 (t, 3H, J = 6.9 Hz, CH3CH2O),
2.38 (t, 4H, J = 6.9 Hz, CH2CO), 3.40 (q, 2H, J = 6.9 Hz,
CH3CH2O), 3.55 (t, 4H, J = 7.2 Hz, CH2N), 6.77 (d, 2H,
J = 8.5 Hz, H(2,6)Ar), 7.00 (d, 2H, J = 8.5 Hz, H(3,5)Ar),
7.17–7.47 (m, 10H, H–Ar0), 7.99 (s, 2H, NHNHCO), 8.67
(s, 2H, NHNHCO), 9.70 (s, 2H, NHAr) ppm; 13C NMR:
d = 170.15 (C-9), 155.39 (C-10), 141.59 (C-1), 139.02
(C-11), 115.67 (C-3, 5), 128.11 (C-13), 151.14 (C-4),
129.21 (C-14), 115.89 (C-12), 114.32 (C-2, 6), 63.31
(C-17), 47.48 (C-7), 31.45 (C-8), 14.87 (C-18) ppm; IR
1
5.9 g (65%) 2a. M.p.: 108–109 °C; H NMR: d = 2.91
(t, 4H, J = 6.9 Hz, CH2C=N), 3.61 (t, 4H, J = 6.9 Hz,
CH2N), 3.69 (s, 3H, CH3O), 6.78–6.85 (m, 4H, HAr), 9.93,
10.08 (2 s, 2H, NH) ppm; 13C NMR: d = 177.74 (C-10),
162.79 (C-9), 141.74 (C-1), 115.41 (C-3, 5), 151.45 (C-4),
114.74 (C-2, 6), 55.22 (C-11), 47.24 (C-7), 32.49 (C-8)
(KBr): m = 1,676 (C=O) cm-1; MS (ESI, 20 eV): m/z
ppm; IR (KBr): m = 3,171 (NH), 1,512 (C=S) cm-1; MS
ꢀ
ꢀ
(%) = 548 ([M ? H]?, 80).
(20 eV): m/z (%) = 380 ([M ? H]?, 100).
3,30-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
[N0-[(4-chlorophenyl)aminocarbonyl]propanoic acid
hydrazide] (4a, C27H29Cl2N7O5)
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
(1,3,4-oxadiazole-2(3H)-thione) (2b, C16H19N5O3S2)
Prepared similarly to 2a from 3 cm3 (3.8 g, 50 mmol) CS2
and 7.73 g 1b (25 mmol). Crystallization from methanol
Prepared similarly to 3a from 2.95 g 1a (10 mmol) and
3.07 cm3 4-chlorophenyl isocyanate (20 mmol). Recrystalli-
zation from DMF–H2O afforded 5.9 g (98%) 4a. M.p.: 219–
1
afforded 6.83 g (57%) 2b. M.p.: 125–126 °C; H NMR:
d = 1.26 (t, 3H, J = 6.9 Hz, CH3CH2O), 2.26 (t, 4H,
123

_
ˇ
I. Tumosiene, Z. J. Beresnevicius
1526
1
220 °C; H NMR: d = 2.39 (t, 4H, J = 7.2 Hz, COCH2),
3.49 (t, 4H, J = 7.2 Hz, CH2N), 3.67 (s, 3H, CH3O), 6.73 (d,
2H, J = 9.3 Hz, H(2,6)Ar), 6.83 (d, 2H, J = 9.3 Hz, H(3,5)Ar),
7.29 (d, 4H, J = 6.9 Hz, H(3,5)Ar0), 7.47 (d, 4H, J = 6.9 Hz,
3,30-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
[N0-(phenylaminocarbonothioyl)propanoic acid hydrazide]
(5b, C28H33N7O3S2)
Prepared similarly to 5a from 3.1 g 1b (10 mmol) and
2.4 cm3 phenyl isothiocyanate (2.7 g, 20 mmol). Recrys-
tallization from DMF–H2O afforded 4.1 g (71%) 5b. M.p.:
133–134 °C; 1H NMR: d = 1.37 (t, 3H, J = 6.9 Hz,
CH3CH2O), 3.48 (t, 4H, J = 6.9 Hz, CH2O), 3.59 (t, 4H,
J = 6.9 Hz, CH2N), 3.99 (q, 2H, J = 6.9 Hz, CH3CH2O),
6.83 (d, 2H, J = 9.3 Hz, H(2,6)Ar), 6.91 (d, 2H, J = 9.3 Hz,
H
(2,6)Ar0), 8.12, 8.86 (2s, 4H, NHNHCO), 9.73, 9.80 (2s, 2H,
NHAr0) ppm; 13C NMR: d = 170.63 (C-9), 155.41 (C-10),
150.60 (C-4), 141.65 (C-1), 138.49 (C-11), 138.25 (C-14),
128.21 (C-13, 15), 125.41 (C-12, 16), 115.25 (C-3, 5), 113.73
(C-2, 6), 55.35 (C-17), 46.53 (C-7), 31.92 (C-8) ppm; IR
(KBr): m = 3,360, 3,341 (NH), 1,640 (C=O) cm-1; MS (ESI,
ꢀ
20 eV): m/z (%) = 603 ([M ? H]?, 60).
H
(3,5)Ar), 7.25 (t, 2H, J = 7.2 Hz, H(4)Ar0), 7.42 (t, 4H,
J = 7.2 Hz, H(3,5)Ar0), 7.49 (d, 4H, J = 7.2 Hz, H(2,6)Ar0),
9.67 (s, 4H, NHNHCO), 10.07 (br s, 2H, NHAr0) ppm; 13C
NMR: d = 181.08 (C-10), 170.59 (C-9), 150.45 (C-4),
141.50 (C-1), 139.01 (C-11), 129.45 (C-14), 128.00 (C-13,
15), 125.04 (C-12, 16), 115.45 (C-3, 5), 114.67 (C-2, 6),
63.24 (C-17), 46.95 (C-7), 31.28 (C-8), 14.76 (C-18) ppm;
3,30-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
[N0-[(4-chlorophenyl)aminocarbonyl]propanoic acid
hydrazide] (4b, C28H31Cl2N7O5)
Prepared similarly to 4a from 3.09 g 1b (10 mmol) and
3.07 cm3 4-chlorophenyl isocyanate (20 mmol). Recrystalli-
zation from DMF–H2O afforded 5.24 g (85%) 4b. M.p.: 201–
202 °C; 1H NMR: d = 1.29 (t, 3H, J = 6.9 Hz, CH3CH2O),
2.41 (t, 4H, J = 7.2 Hz, COCH2), 3.50 (t, 4H, J = 7.2 Hz,
CH2N), 3.99 (q, 2H, J = 6.9 Hz, CH3CH2O), 6.69 (d, 2H,
J = 9.3 Hz, H(2,6)Ar), 6.89 (d, 2H, J = 9.3 Hz, H(3,5)Ar),
7.35 (d, 4H, J = 6.9 Hz, H(3,5)Ar0), 7.52 (d, 4H, J = 6.9 Hz,
IR (KBr): m = 1,690 (C=O), 1,105 (C=S) cm-1; MS (ESI,
ꢀ
20 eV): m/z (%) = 580 ([M ? H]?, 100).
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
(4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one)
(6a, C27H27N7O3)
H
(2,6)Ar0), 8.10, 8.75 (2s, 4H, NHNHCO), 9.74, 9.89 (2 s, 2H,
A solution of 0.53 g 3a (1 mmol) in 20 cm3 20% KOH
solution was heated under reflux for 1 h. The reaction
mixture was cooled, conc. HCl was added to pH 4, and the
precipitated crystals were isolated by filtration and washed
with water. Recrystallization from DMF–H2O afforded
NHAr0) ppm; 13C NMR: d = 171.02 (C-9), 156.11 (C-10),
150.63 (C-4), 141.69 (C-1), 138.53 (C-11), 138.28 (C-14),
128.37 (C-13, 15), 125.53 (C-12, 16), 115.41 (C-3, 5), 113.53
(C-2, 6), 55.34 (C-17), 46.53 (C-7), 24.82 (C-8), 17.08 (C-18)
-1
1
ꢀ
ppm; IR (KBr): m = 3,355, 3,324 (NH), 1,643 (C=O) cm
;
0.34 g (68%) 6a. M.p.: 190–191 °C; H NMR: d = 2.70
(t, 4H, J = 8.1 Hz, CH2C=N), 3.45 (t, 4H, J = 8.1 Hz,
CH2N), 3.78 (s, 3H, CH3O), 6.05 (d, 2H, J = 9 Hz,
MS (ESI, 20 eV): m/z (%) = 617 ([M ? H]?, 70).
3,30-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
[N0-(phenylaminocarbonothioyl)propanoic acid hydrazide]
H
(2,6)Ar), 6.55 (t, 2H, J = 9 Hz, H(3,5)Ar), 7.32–7.51 (m,
10H, H–Ar0), 11.74 (s, 2H, NH) ppm; 13C NMR: d = 154.21
(C-10), 150.79 (C-4), 145.01 (C-9), 140.44 (C-1), 132.72
(C-11), 129.41 (C-14), 128.62 (C-13, 15), 127.44 (C-12, 16),
114.61(C-3, 5), 113.11 (C-2, 6), 55.17 (C-17), 47.28 (C-7),
23.61 (C-8) ppm; MS (ESI, 20 eV): m/z (%) = 498
([M ? H]?, 45).
(5a, C27H31N7O3S2)
To a solution of 3 g 1a (10 mmol) in 80 cm3 MeOH was
added 2.4 cm3 (2.7 g, 20 mmol) phenyl isothiocyanate and
the reaction mixture was heated under reflux for 4 h. It was
cooled, Et2O was added, and the crystals were isolated by
filtration. Recrystallization from DMF–H2O afforded 3.9 g
1
(69%) 5a. M.p.: 110–111 °C; H NMR: d = 2.42 (t, 4H,
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
(4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one)
(6b, C28H29N7O3)
J = 7.2 Hz, CH2CO), 3.50 (t, 4H, J = 7.2 Hz, CH2N),
3.67 (s, 3H, CH3O), 6.75 (d, 2H, J = 9.3 Hz, H(2,6)Ar),
6.83 (d, 2H, J = 9.3 Hz, H(3,5)Ar), 7.16 (t, 2H, J = 7.2 Hz,
Prepared similarly to 6a from 1.37 g 3b (2.5 mmol).
Recrystallization from DMF–H2O afforded 1.06 g (74%)
6b. M.p.: 197–198 °C; 1H NMR: d = 1.27 (t, 3H,
J = 6.9 Hz, CH3CH2O), 2.50 (t, 4H, J = 8.1 Hz,
CH2C=N), 3.20 (t, 4H, J = 8.1 Hz, CH2N), 3.92 (q, 2H,
J = 6.9 Hz, CH3CH2O), 6.78 (d, 2H, J = 9 Hz, H(2,6)Ar),
6.99 (t, 2H, J = 9 Hz, H(3,5)Ar), 7.29–7.52 (m, 10H, H–Ar0),
11.79 (s, 2H, NH) ppm; MS (20 eV): m/z (%) = 512
([M ? H]?, 65).
H
(4)Ar0), 7.33 (t, 4H, J = 7.2 Hz, H(3,5)Ar0), 7.42 (d, 4H,
J = 7.2 Hz, H(2,6)Ar0), 9.55 (s, 4H, NHNHCO), 9.95 (s,
2H, NHAr0) ppm; 13C NMR: d = 180.97 (C-10), 170.57
(C-9), 151.27 (C-4), 141.55 (C-1), 139.01 (C-11), 128.90
(C-14), 128.00 (C-13, 15), 125.06 (C-12, 16), 114.73 (C-2,
6), 114.19 (C-3, 5), 55.25 (C-17), 46.94 (C-7), 31.26 (C-8)
ppm; IR (KBr): m = 1,701 (C=O), 1,110 (C=S) cm-1; MS
ꢀ
(ESI, 20 eV): m/z (%) = 566 ([M ? H]?, 100).
123

Synthesis of azoles from 3,30-[(4-alkoxyphenyl)imino]bis(propanoic acid hydrazides)
1527
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
[4-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one]
(7a, C27H25Cl2N7O3)
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
(4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-thione)
(8b, C28H29N7OS2)
Prepared similarly to 6a from 1.202 g 4a (2 mmol).
Recrystallization from DMF–H2O afforded 0.5 g (44%)
7a. M.p.: 251–252 °C; 1H NMR: d = 2.23 (t, 4H,
J = 7.2 Hz, CH2C=N), 3.23 (t, 4H, J = 7.2 Hz, CH2N),
3.63 (s, 3H, CH3O), 6.02 (d, 2H, J = 9.2 Hz, H(2,6)Ar), 6.57
(d, 2H, J = 9.2 Hz, H(3,5)Ar), 7.39 (d, 4H, J = 6.9 Hz,
Prepared similarly to 8a from 1.37 g 5b (2.5 mmol).
Recrystallization from DMF–H2O afforded 1.06 g (78%)
8b. M.p.: 236–237 °C; 1H NMR: d = 1.25 (t, 3H,
J = 6.9 Hz, CH3CH2O), 2.53 (t, 4H, J = 6.9 Hz,
CH2C=N), 3.24 (t, 4H, J = 6.9 Hz, CH2N), 3.85 (q, 2H,
J = 6.9 Hz, CH3CH2O), 5.97 (d, 2H, J = 9 Hz, H(2,6)Ar),
6.52 (d, 2H, J = 9 Hz, H(3,5)Ar), 7.36–7.56 (m, 10H,
H–Ar0), 13.79 (s, 2H, NH) ppm; 13C NMR: d = 167.51
(C-10), 150.26 (C-4), 150.09 (C-9), 141.73 (C-1), 140.09
(C-11), 133.51 (C-14), 129.44 (C-13, 15), 128.30 (C-12,
16), 115.29 (C-3, 5), 113.13 (C-2, 6), 63.14 (C-17), 47.51
(C-7), 23.20 (C-8), 14.74 (C-18) ppm; IR (KBr):
H
(3,5)Ar0), 7.57 (d, 4H, J = 6.9 Hz, H(2,6)Ar0), 11.78 (s, 2H,
NH) ppm; 13C NMR: d = 154.98 (C-10), 150.62 (C-4),
145.35 (C-9), 141.67 (C-1), 138.50 (C-11), 138.39 (C-14),
128.80 (C-13, 15), 125.56 (C-12, 16), 115.26 (C-3, 5),
113.89 (C-2, 6), 55.37 (C-17), 46.54 (C-7), 31.95 (C-8) ppm;
MS (20 eV): m/z (%) = 567 ([M ? H]?, 70).
m = 3,190 (NH) cm-1; MS (70 eV): m/z (%) = 544
ꢀ
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
[4-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one]
(7b, C28H27Cl2N7O3)
([M ? H]?, 90).
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
(N-phenyl-1,3,4-oxadiazol-2-amine) (9a, C27H27N7O3)
A mixture of 0.53 g 3a (1 mmol) in 10 cm3 POCl3 was
heated under reflux for 2 h, cooled and added drop-wise to
ice. The precipitate was isolated by filtration and washed
with water. Recrystallization from DMF–H2O afforded
Prepared similarly to 7a from 1.23 g 4b (2 mmol). Recrys-
tallization from DMF–H2O afforded 0.64 g (55%) 7b. M.p.:
229–230 °C; 1H NMR: d = 1.28 (t, 3H, J = 7.2 Hz,
CH3CH2O), 2.53 (t, 4H, J = 7.2 Hz, CH2C=N), 3.24
(t, 4H, J = 7.2 Hz, CH2N), 3.89 (q, 2H, J = 7.2 Hz,
CH3CH2O), 6.04 (d, 2H, J = 9.0 Hz, H(2,6)Ar), 6.58 (d, 2H,
J = 9.0 Hz, H(3,5)Ar), 7.41 (d, 4H, J = 8.7 Hz, H(3,5)Ar0),
7.58 (d, 4H, J = 8.7 Hz, H(2,6)Ar0), 11.78 (s, 2H, NH) ppm;
13C NMR: d = 154.02 (C-10), 150.00 (C-4), 144.90 (C-9),
140.21 (C-1), 133.19 (C-11), 131.62 (C-12, 16), 129.39
(C-14), 129.24 (C-13, 15), 115.16 (C-3, 5), 113.09 (C-2, 6),
63.11 (C-17), 47.41 (C-7), 23.54 (C-8), 14.72 (C-18) ppm;
MS (20 eV): m/z (%) = 581 ([M ? H]?, 100).
1
0.39 g (79%) 9a. M.p.: 179–180 °C; H NMR: d = 2.70
(t, 4H, J = 8.1 Hz, CH2C=N), 3.45 (t, 4H, J = 8.1 Hz,
CH2N), 3.79 (s, 3H, CH3O), 6.93 (d, 2H, J = 7.2 Hz,
(2,6)Ar), 7.06 (t, 2H, J = 7.2 Hz, H(3,5)Ar), 7.23–7.58
H
(m, 10H, H–Ar0), 9.77, 9.92 (2s, 2H, NH) ppm; IR (KBr):
m = 3,202 (NH), 1,628 (C=N) cm-1; MS (70 eV): m/z
ꢀ
(%) = 498 ([M ? H]?, 60).
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
(4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-thione)
(N-phenyl-1,3,4-oxadiazol-2-amine) (9b, C28H29N7O3)
A mixture of 1.36 g 3b (2.5 mmol) and 5 cm3 H2SO4 was
stirred at room temperature for 4 h. The reaction mixture
was cooled and added drop-wise to ice. The precipitate was
isolated by filtration and washed with water. Recrystalli-
zation from DMF–H2O afforded 1.03 g (81%) 9b. M.p.:
202–203 °C; 1H NMR: d = 1.34 (t, 3H, J = 6.9 Hz,
CH3CH2O), 2.35 (t, 4H, J = 6.9 Hz, CH2CO), 3.87
(t, 4H, J = 6.9 Hz, CH2N), 4.08 (q, 2H, J = 6.9 Hz,
CH3CH2O), 6.95 (d, 2H, J = 9.2 Hz, H(2,6)Ar), 7.13
(d, 2H, J = 9.2 Hz, H(3,5)Ar), 7.29 (t, 2H, J = 7.2 Hz,
(8a, C27H27N7OS2)
Compound 5a (0.28 g, 0.5 mmol) was dissolved in 20 cm3
20% KOH solution and heated under reflux for 1 h. After
cooling the reaction mixture to room temperature acetic
acid was added to pH 4, the precipitated crystals were
isolated by filtration and washed with water. Recrystalli-
zation from methanol afforded 0.21 g (81%) 8a. M.p.:
245–246 °C; 1H NMR: d = 2.24 (t, 4H, J = 7.05 Hz,
CH2C=N), 3.63 (t, 4H, J = 7.05 Hz, CH2N), 3.67 (s, 3H,
CH3O), 6.05 (d, 2H, J = 7.2 Hz, H(2,6)Ar), 6.69 (d, 2H,
J = 7.2 Hz, H(3,5)Ar), 7.46–7.61 (m, 10H, H–Ar0), 13.79
(s, 2H, NH) ppm; 13C NMR: d = 180.97 (C-10), 170.57
(C-9), 151.27 (C-4), 141.55 (C-1), 139.00 (C-11), 128.90
(C-14), 128.00 (C-13, 15), 125.06 (C-12, 16), 114.73 (C-3,
H
(4)Ar0), 7.37 (t, 4H, J = 7.2 Hz, H(3,5)Ar0), 7.50 (d, 4H,
J = 7.2 Hz,
(2,6)Ar0), 9.78 (s, 2H, NHAr0) ppm;
H
13C NMR: d = 168.65 (C-10), 155.09 (C-4), 154.93
(C-9), 141.54 (C-1), 139.96 (C-11), 126.08 (C-13, 15),
123.84 (C-14), 117.48 (C-12, 16), 117.33 (C-2, 6), 115.89
(C-3, 5), 63.66 (C-17), 47.75 (C-7), 28.53 (C-8), 14.47
5), 114.19 (C-2, 6), 55.25 (C-17), 46.94 (C-7), 31.26 (C-8)
-1
ꢀ
ꢀ
ppm; IR (KBr): m = 3,310 (NH), 1,520, 1,460 (CS) cm
;
(C-18) ppm; IR (KBr): m = 3,289 (NH), 1,707 (C=N)
MS (70 eV): m/z (%) = 530 ([M ? H]?, 80).
cm-1; MS (20 eV): m/z (%) = 512 ([M ? H]?, 100).
123

_
ˇ
I. Tumosiene, Z. J. Beresnevicius
1528
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
[N-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine]
(10a, C27H25Cl2N7O3)
(d, 2H, J = 9 Hz, H(3,5)Ar), 7.32 (m, 6H, H(3,4,5)Ar0), 7.58
(d, 4H, J = 7.5 Hz, H(2,6)Ar0), 10.32 (br s, 2H, NH) ppm;
13C NMR: d = 164.58 (C-10), 162.31 (C-9), 155.93 (C-4),
140.56 (C-1), 127.77 (C-11), 129.04 (C-14), 124.05 (C-13,
15), 121.78 (C-2, 6), 117.28 (C-12, 16), 115.11 (C-3, 5),
55.51 (C-17), 53.03 (C-7), 26.33 (C-8) ppm; IR (KBr):
ꢀm = 3,289 (NH), 1,431 (C=N) cm-1; MS (20 eV): m/z
(%) = 530 ([M ? H]?, 70).
Prepared similarly to 9b from 1.202 g 4a (2 mmol).
Recrystallization from DMF–H2O afforded 0.56 g (50%)
10a. M.p.: 226–227 °C; 1H NMR: d = 2.36 (t, 4H,
J = 6.9 Hz, CH2CO), 3.65 (s, 3H, CH3O), 3.86 (t, 4H,
J = 6.9 Hz, CH2N), 7.15 (d, 2H, J = 9.2 Hz, H(2,6)Ar),
7.29 (d, 2H, J = 9.2 Hz, H(3,5)Ar), 7.45 (d, 4H, J = 7.2 Hz,
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
(N-phenyl-1,3,4-thiadiazol-2-amine)
(11b, C28H29N7OS2)
H
(3,5)Ar0), 7.61 (d, 4H, J = 7.2 Hz, H(2,6) Ar0), 9.76 (s, 2H,
NHAr0) ppm; 13C NMR: d = 168.85 (C-10), 160.00 (C-9),
155.06 (C-4), 154.05 (C-1), 138.69 (C-11), 138.22 (C-14),
128.72 (C-13, 15), 123.94 (C-2, 6), 119.77 (C-12, 16),
115.68 (C-3, 5), 55.78 (C-17), 51.85 (C-7), 28.49 (C-8) ppm;
MS (20 eV): m/z (%) = 567 ([M ? H]?, 100).
Prepared similarly to 11a from 1.45 g 5b (2.5 mmol).
Recrystallization from DMF–H2O afforded 0.88 g (65%)
11b. M.p.: 170–171 °C; 1H NMR: d = 1.24 (t, 3H,
J = 6.9 Hz, CH3CH2O), 2.47 (t, 4H, J = 7.2 Hz, CH2CS),
3.14 (t, 4H, J = 7.2 Hz, CH2N), 3.83 (q, 2H, J = 6.9 Hz,
CH3CH2O), 6.49 (d, 2H, J = 9.2 Hz, H(2,6)Ar), 7.15 (d,
2H, J = 9.2 Hz, H(3,5)Ar), 7.21 (t, 2H, J = 7.2 Hz,
5,50-[[(4-Ethoxyphenyl)imino]diethane-2,1-diyl]bis-
[N-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine]
(10b, C28H27Cl2N7O3)
Prepared similarly to 9b from 1.232 g 4b (2 mmol).
Recrystallization from DMF–H2O afforded 0.99 g (86%)
10b. M.p.: 221–222 °C; 1H NMR: d = 1.29 (t, 3H,
J = 6.9 Hz, CH3CH2O), 2.38 (t, 4H, J = 7.2 Hz,
CH2C=N), 3.67 (t, 4H, J = 6.9 Hz, CH2N), 3.93 (q, 2H,
J = 6.9 Hz, CH3CH2O), 7.27–7.34 (m, 4H, H–Ar), 7.48–
7.67 (m, 8H, H–Ar0), 8.84, 9.42 (2s, 2H, NH) ppm; 13C
NMR: d = 153.44 (C-10), 148.55 (C-4), 138.53 (C-9),
138.27 (C-1), 128.37 (C-11), 128.21 (C-14), 125.53 (C-13,
15), 119.89 (C-12, 16), 115.20 (C-2, 6), 114.48 (C-3, 5),
63.25 (C-17), 47.53 (C-7), 24.82 (C-8), 17.08 (C-18) ppm;
MS (20 eV): m/z (%) = 581 ([M ? H]?, 100).
H
(4)Ar0), 7.39–7.54 (m, 8H, H(2,3,5,6)Ar0), 8.66 (s, 2H,
0
ꢀ
NHAr ) ppm; IR (KBr): m = 3,290 (NH), 1,432 (C=N)
cm-1; MS (20 eV): m/z (%) = 544 ([M ? H]?, 80).
References
1. Shehata A (2003) Saudi Pharm J 11:87
2. Mekuskiene G, Tumkevicius S, Vainilavicius P (2002) J Chem Res
(S) 213
3. El-Massy AH, Fahmy HH, Abdelwahed SHA (2000) Molecules
5:1429
4. Tumosiene I, Kantminiene K, Pavilonis A, Mazeliene Z,
ˇ
_
ˇ
_
Beresnevicius ZJ (2009) Heterocycles 78:59
ˇ
_
5,50-[[(4-Methoxyphenyl)imino]diethane-2,1-diyl]bis-
(N-phenyl-1,3,4-thiadiazol-2-amine)
(11a, C27H27N7OS2)
5. Wujec M, Pitucha M, Dobosz M, Kosikowska U, Malm A (2004)
Acta Pharm 54:251
ˇ
_
6. Beresnevicius ZJ, Viliu¯nas V, Kantminiene K (2000) Chem
Heterocycl Comp 36:504
7. Mickevicius M, Mickevicius V, Beresnevicius ZJ, Jakiene E
(2005) Chem Technol 3(37):50
Prepared similarly to 9a from 0.23 g 5a (0.4 mmol).
Recrystallization from DMF–H2O afforded 0.11 g (51%)
11a. M.p.: 114–115 °C; 1H NMR: d = 3.09 (t, 4H,
J = 6.9 Hz, CH2CO), 3.73 (s, 3H, CH3O), 3.86 (t, 4H,
J = 6.9 Hz, CH2N), 6.99 (d, 2H, J = 9 Hz, H(2,6)Ar), 7.24
_
ˇ
8. Tumosiene I, Jakiene E, Beresnevicius ZJ, Mikulskiene G (2006)
_
_
Chem Technol 3(41):58
9. Dawood KM, Farag AM, Abdel-Aziz HA (2005) Heteroat Chem
16(7):621
123