Heterocyclic synthesis using nitrile imines. 6. Synthesis of some new substituted 4,5-dihydro-1H-1,2,4-triazoles

Article abstract of DOI:10.1007/s10593-007-0047-4

A new series of substituted 1,2,4-triazoles was synthesized from the cycloaddition reaction of alkanal and cycloalkanal hydrazones containing electron-withdrawing groups (MeCO, PhCO, and MeOCO) with appropriate hydrazonoyl halides.

Full text of DOI:10.1007/s10593-007-0047-4

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
HETEROCYCLIC SYNTHESIS USING NITRILE IMINES.
6*. SYNTHESIS OF SOME NEW SUBSTITUTED
4,5-DIHYDRO-1H-1,2,4-TRIAZOLES
H. M. Dalloul, N. S. Al-Abadla, and Kh. A. El-Nwairy
A new series of substituted 1,2,4-triazoles was synthesized from the cycloaddition reaction of alkanal
and cycloalkanal hydrazones containing electron-withdrawing groups (MeCO, PhCO, and MeOCO)
with appropriate hydrazonoyl halides.
Keywords: hydrazonoyl halides, hydrazones, 1,2,4-triazoles, cycloaddition.
The synthesis of compounds incorporating 1,2,4-triazole rings has been attracting wide attention due to
their diverse pharmacological properties such as antimicrobial, anti-inflammatory, analgesic, and antitumor
activities [2-7]. It was reported that compounds having triazole moieties such as Vorozole, Letrozole, and
Anastrozole (Chart) appear to be very effective aromatase inhibitors, very useful for preventing breast cancer [8-
10]. Furthermore, some 1,2,4-triazol-5-one derivatives were found to possess antitumor activity [11-13].
Therefore, as a part of our continuing studies on triazole and their derivatives, we aimed to synthesize (Scheme)
a new series of substituted 1,2,4-triazoles 4a–o as possible biologically active compounds from the reaction of
different hydrazones 3 with N-aryl-substituted C-benzoyl-, C-(2-furoyl)-, C-(2-naphthoyl)-, and C-(2-
thenoyl)formonitrile imines 2.
N
N
N
N
N
N
CN
N
N
N
Me
N
Me
Me
N
N
NC
Cl
Cl
Me
CN
Me
Vorozole
Anastrozole
Letrozole
Nitrile imines 2 were generated in situ from the reaction of hydrazonoyl halides 1 with triethylamine.
The nitrile imines were not isolated but immediately reacted with the alkanal or cycloalkanal hydrazones 3
affording the corresponding 4,5-dihydro-1,2,4-triazoles 4a–o in moderate yields. No elimination of acetamide,
_______
* Part 5 [1].
__________________________________________________________________________________________
Department of Chemistry, Faculty of Applied Sciences, Al-Aqsa University of Gaza, P.O.Box 4051,
Gaza, Gaza Strip, PNA via Israel; e-mail: hanydallool@yahoo.com. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 3, pp. 392-398, March, 2007. Original article submitted December 20,
2006.
314
0009-3122/07/4303-0314©2007 Springer Science+Business Media, Inc.

benzamide, or methyl carbamate occurred to get the aromatic 1,2,4-triazoles 5. It is worth mentioning that the
reaction of nitrile imines with acetaldoxime was found to give directly aromatic 1,2,4-triazoles via elimination of
a water molecule [14]. The cyclocondensation adducts, 1,2,4,5-tetrazines 6a–o, were not observed, apparently
because of the low nucleophilicity of the nitrogen atom carrying the acetyl, benzoyl, and methoxycarbonyl
group.
Ar1
Ar
N
N
N
N
H
ArCO
R
ArCO
N
5a–o
Cl(Br)
1
NEt3, 0oC
Ar
N
N
H
H
R
R
H
THF / r.t.
–
+
ArCO
C
N
NAr1
ArCO
Ar1
N
N
N
+
HN
1 CO
R
COR1
2
3
4a–o
N
N
R
H
ArCO
N
N
1 CO
H
R
Ar1 =
X
6a–o
Entry
ArCO
R
R1
X
a
b
c
2-Naphthoyl
2-Naphthoyl
2-Naphthoyl
2-Naphthoyl
2-Naphthoyl
2-Naphthoyl
Benzoyl
Me
Et
Me
Ph
Ph
Ph
H
H
n-Hexyl
Cl
Cl
d
e
Cyclohexyl
Me
OMe
OMe
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
f
Et
g
h
i
Me
Benzoyl
Et
Cyclohexyl
Me
Ph
Benzoyl
Ph
j
2-Furoyl
Me
k
l
2-Furoyl
Et
Ph
2-Furoyl
Cyclohexyl
Me
OMe
Ph
m
n
o
2-Thenoyl
2-Thenoyl
2-Thenoyl
Et
OMe
Me
Cyclohexyl
The structures of the synthesized triazoles 4a–o have been confirmed by elemental analysis, and their
spectral data are depicted in the Experimental section. The IR spectra of the obtained compounds 4a-o showed a
strong absorption band in the region of 3350-3220 cm-1 that is assigned to NH and three groups of absorption
bands at 1690-1675, 1675-1660, and 1735-1725 cm-1 for the N-acetyl, N-benzoyl, and carbamate carbonyl groups,
respectively. The bands of NH and carbonyl of acetamide, benzamide, and carbamate groups characteristic of
compounds 5 were not observed. In the 1H NMR spectra, the signal of the proton at C-5 of the triazole ring was
recorded between 5.5-5.3 ppm and the amide proton at 8.9-8.2 for compounds 4a,g,j,o, 9.8-8.8 ppm for
compounds 4b-d,h,i,k,m, and 7.0-6.8 ppm for compounds 4e,f,l,n. The 13C NMR spectra showed the anticipated
resonance signals of the different carbons, especially the signal of the C-5 of triazole ring around 84 ppm and for
C=N carbon around 145 ppm.
315

TABLE 1. Physical Properties and Elemental Analysis Data of Compounds
4a-o
Found, %
Calculated, %
H
Com-
pound
Empirical
formula (mw)
mp, oC
Yield, %
C
N
4a
4b
4c
4d
4e
4f
C22H20N4O2
71.10
70.95
5.20
5.41
14.90
15.04
185-187
180-182
172-174
158-160
153-154
166-168
159-161
144-145
143-145
177-179
168-170
150-152
165-167
174-176
146-148
64
57
50
52
58
60
57
58
55
64
62
53
60
57
55
C28H24N4O2
75.20
74.98
71.50
71.30
71.40
71.57
68.80
68.64
68.90
69.21
65.10
64.95
66.80
66.59
68.90
69.06
55.20
55.42
62.20
62.49
58.70
58.54
59.50
59.36
52.20
51.97
58.30
58.53
5.20
5.39
6.00
5.80
5.60
5.44
5.40
5.51
6.00
5.81
4.50
4.71
5.10
4.89
5.70
5.59
4.50
4.36
4.70
4.53
5.20
5.38
3.90
4.03
4.20
4.36
5.50
5.38
12.60
12.49
10.20
10.39
10.30
10.43
14.10
13.92
13.60
13.45
13.90
13.77
12.80
12.94
11.30
11.50
16.00
16.16
13.10
13.25
12.90
13.00
13.30
13.19
14.10
14.26
12.80
13.00
C32H31ClN4O2
C32H29ClN4O2
C23H22N4O3
C24H24N4O3
4g
4h
4i
C22H19ClN4O2
C24H21ClN4O2
C28H27ClN4O2
C16H15ClN4O3
C22H19ClN4O3
C21H23ClN4O4
C21H17ClN4O2S
C17H17ClN4O3S
C21H23ClN4O2S
4j
4k
4l
4m
4n
4o
This assignment is in good agreement with literature data for the carbon flanked by two nitrogens and
the azomethine carbon in five-membered heterocycles [1, 15]. Again, if aromatic triazole 5 is formed, the C-5
would be observed over 150 ppm [14]. In conclusion, the results demonstrate that the reaction between nitrile
imines and alkanal or cycloalkanal hydrazones containing electron-withdrawing groups is a clear 1,3-dipolar
cycloaddition reaction.
EXPERIMENTAL
Melting points were determined in open capillaries on an Electrothermal Melting Temperature
Apparatus and are uncorrected. The IR spectra were obtained using a Satellite 3000 Mid IR spectrometer in KBr
1
pellets. The H and 13C NMR spectra were recorded on a Brucker AM 300 spectrometer (300 and 75 MHz
respectively) in CDCl3 using TMS as internal reference. All chemical shifts were reported from internal TMS.
Elemental analysis was performed at Cairo University, A.R.E. The hydrazonoyl halides 1 [17-20] and
alkanalhydrazones 3 [21, 22]were prepared according to the known literature procedures.
Synthesis of compounds 4a-o (General procedure). Triethylamine (0.03 mol) in dioxane (5 ml) was
added dropwise to a stirred solution of the appropriate hydrazonoyl halide 1 (0.005 mol) and the respective
alkanal or cycloalkanal hydrazone 3 (0.01 mol) in dioxane (70 ml) at room temperature. Stirring was continued
overnight, and the solvent was then evaporated under reduced pressure. The residue was washed several times
with water to get rid of the triethylamine salt. The resulting crude solid was collected and recrystallized from
ethanol or methanol to afford the desired products 4a-o.
316

4-Acetylamino-5-methyl-3-(2-naphthoyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazole (4a). IR spectrum,
1
ν, cm-1: 3260 (NH); 1690 (N−C=O); 1654 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz): 8.50-7.02 (4H, m,
13
arom. protons); 8.80 (1H, s, NH); 5.43 (1H, q, J = 9, CH); 2.0 (3H, s, CH3CO); 1.58 (3H, d, J = 9, CH3). C
NMR spectrum, δ, ppm: 184.3 (Ar−C=O); 177.5 (N−C=O); 145.35 (C=N); 141.34-115.51 (arom. carbons); 80.5
(C-5); 20.30 (CH3); 20.00 (CH3).
4-Benzoylamino-5-ethyl-3-(2-naphthoyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazole (4b). IR spectrum,
1
ν, cm-1: 3240 (NH); 1670 (N−C=O); 1640 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz): 8.55-7.01 (4H, m,
arom. protons); 9.20 (1H, s, NH); 5.42 (1H, t, J = 9, CH); 1.86 (2H, m, CH2); 0.95 (3H, t, J = 7, CH3). 13C NMR
spectrum, δ, ppm: 184.10 (Ar−C=O); 168.8 (N−C=O); 145.40 (C=N); 141.34–115.51 (arom. carbons); 84.10 (C-
5); 26.15 (CH2); 6.60 (CH3).
4-Benzoyl-1-(4-chlorophenyl)-5-n-hexyl-3-(2-naphthoyl)-4,5-dihydro-1H-1,2,4-triazole (4c). IR
1
spectrum, ν, cm-1: 3320 (NH); 1675 (N−C=O); 1645 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz): 8.50-7.04
13
(4H, m, arom. protons); 9.20 (1H, s, NH); 5.40 (1H, t, J = 9, CH); 1.82-0.60 (13H, m, n-hexyl protons). C
NMR spectrum, δ, ppm: 184.10 (Ar−C=O); 168.8 (N−C=O); 145.40 (C=N); 141.34-115.51 (arom. carbons);
84.50 (C-5); 26.65-4.60 (n-hexyl carbons).
4-Benzoylamino-1-(4-chlorophenyl)-5-cyclohexyl-3-(2-naphthoyl)-4,5-dihydro-1H-1,2,4-triazole (4d).
IR spectrum, ν, cm-1: 3230 (NH); 1660 (N−C=O); 1640 (Ar−C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.50-7.05
(4H, m, arom. protons); 9.30 (1H, s, NH); 5.41 (1H, d, J = 9, CH); 1.90–1.20 (11H, m, cyclohexyl protons). 13C
NMR spectrum, δ, ppm: 183.70 (Ar−C=O); 168.9 (N−C=O); 145.70 (C=N); 141.34–115.51 (arom. carbons);
87.50 (C-5); 40.30–24.20 (cyclohexyl carbons).
4-Methoxycarbonylamino-5-methyl-1-(4-methylphenyl)-3-(2-naphthoyl)-4,5-dihydro-1H-1,2,4-triazole
(4e). IR spectrum, ν, cm-1: 3280 (NH); 1730 (N−C=O); 1645 (Ar−C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.40-
7.15 (4H, m, arom. protons); 6.90 (1H, s, NH); 5.45 (1H, q, J = 9, CH); 3.70 (3H, s, CH3O); 2.30 (3H, s, CH3); 1.59
13
(3H, d, J = 9, CH3). C NMR spectrum, δ, ppm: 183.5 (Ar−C=O); 156.50 (N−C=O); 145.10 (C=N); 141.34-
115.51 (arom. carbons); 81.00 (C-5); 52.80 (O−CH3); 20.70 (CH3); 20.25 (CH3).
5-Ethyl-4-methoxycarbonylamino-1-(4-methylphenyl)-3-(2-naphthoyl)-4,5-dihydro-1H-1,2,4-triazole
1
(4f). IR spectrum, ν, cm-1: 3280 (NH); 1735 (N−C=O); 1645 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz): 8.40-
7.12 (4H, m, arom. protons); 6.90 (1H, s, NH); 5.43 (1H, t, J = 9, CH); 3.70 (3H, s, CH3O); 2.30 (3H, s, CH3);
13
1.85 (2H, m, CH2); 0.93 (3H, t, J = 7, CH3). C NMR spectrum, δ, ppm: 183.20 (Ar−C=O); 156.50 (N−C=O);
145.20 (C=N); 141.34-115.51 (arom. carbons); 84.20 (C-5); 52.80 (O−CH3); 26.15 (CH2); 20.65 (CH3);
6.60 (CH3).
4-Acetylamino-3-benzoyl-1-(4-chlorophenyl)-5-methyl-4,5-dihydro-1H-1,2,4-triazole (4g). IR spectrum,
ν, cm-1: 3350 (NH); 1690 (N−C=O); 1640 (Ar−C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.10-7.15 (4H, m, arom.
13
protons); 8.20 (1H, s, NH); 5.44 (1H, q, J = 9, CH); 1.98 (3H, s, CH3CO); 1.56 (3H, d, J = 9, CH3). C NMR
spectrum, δ, ppm: 183.8 (Ar−C=O); 168.8 (N−C=O); 145.40 (C=N); 141.34–115.51 (arom. carbons); 80.60
(C-5); 20.25 (CH3); 19.80 (CH3).
3-Benzoyl-4-benzoylamino-1-(4-chlorophenyl)-5-ethyl-4,5-dihydro-1H-1,2,4-triazole (4h). IR spectrum,
ν, cm-1: 3270 (NH); 1665 (N−C=O); 1640 (Ar−C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.15-7.15 (4H, m, arom.
protons); 9.20 (1H, s, NH); 5.42 (1H, t, J = 9, CH); 1.87 (2H, m, CH2); 0.94 (3H, t, J = 7, CH3). 13C NMR
spectrum, δ, ppm: 183.80 (Ar−C=O); 168.9 (N−C=O); 145.40 (C=N); 141.34–115.51 (arom. carbons); 84.20 (C-
5); 26.20 (CH2); 6.60 (CH3).
3-Benzoyl-4-benzoylamino-1-(4-chlorophenyl)-5-cyclohexyl-4,5-dihydro-1H-1,2,4-triazole (4i). IR
1
spectrum, ν, cm-1: 3245 (NH); 1665 (N–C=O); 1635 (Ar–C=O). H NMR spectrum, δ, ppm (J, Hz): 8.20-7.20
(4H, m, arom. protons); 9.80 (1H, s, NH); 5.40 (1H, q, J = 9, CH); 1.84-1.10 (11H, m, cyclohexyl protons). 13C
NMR spectrum, δ, ppm: 184.00 (Ar−C=O); 169.10 (N−C=O); 145.40 (C=N); 141.34-115.51 (arom. carbons);
87.40 (C-5); 40.20-24.20 (cyclohexyl carbons).
317

4-Acetylamino-1-(4-chlorophenyl)-3-(2-furoyl)-5-methyl-4,5-dihydro-1H-1,2,4-triazole
(4j).
IR
spectrum, ν, cm-1: 3290 (NH); 1680 (N−C=O); 1660 (Ar−C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.20-7.18 (4H,
m, arom. protons); 8.80 (1H, s, NH); 5.46 (1H, q, J = 9, CH); 1.98 (3H, s, CH3CO); 1.57 (3H, d, J = 9, CH3). 13C
NMR spectrum, δ, ppm: 178.10 (N−C=O); 173.30 (Ar−C=O); 145.50 (C=N); 141.34-115.51 (arom. carbons);
80.50 (C-5); 20.35 (CH3); 20.10 (CH3).
4-Benzoylamino-1-(4-chlorophenyl)-5-ethyl-3-(2-furoyl)-4,5-dihydro-1H-1,2,4-triazole
(4k).
IR
1
spectrum, ν, cm-1: 3320 (NH); 1675 (N−C=O); 1660 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz): 8.20-7.20
(4H, m, arom. protons); 8.90 (1H, s, NH); 5.43 (1H, q, J = 9, CH); 1.84 (2H, m, CH2); 0.95 (3H, t, J = 9, CH3).
13C NMR spectrum, δ, ppm: 173.50 (Ar−C=O); 169.20 (N−C=O); 145.40 (C=N); 141.34-115.51 (arom.
carbons); 84.50 (C-5); 26.30 (CH2); 6.70 (CH3).
1-(4-Chlorophenyl)-5-cyclohexyl-3-(2-furoyl)-4-methoxycarbonylamino-4,5-dihydro-1H-1,2,4-triazole
1
(4l). IR spectrum, ν, cm-1: 3270 (NH); 1725 (N−C=O); 1650 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz):
8.25-7.15 (4H, m, arom. protons); 6.95 (1H, s, NH); 5.35 (1H, d, J = 9, CH); 1.80–1.10 (11H, m, cyclohexyl
protons). 13C NMR spectrum, δ, ppm: 173.60 (Ar−C=O); 156.6 (N−C=O); 145.75 (C=N); 141.34–115.51 (arom.
carbons); 87.80 (C-5); 52.80 (O−CH3); 40.90-24.20 (cyclohexyl carbons).
1
4-Benzoylamino-1-(4-chlorophenyl)-5-methyl-3-(2-thenoyl)-4,5-dihydro-1H-1,2,4-triazole (4m). IR
1
spectrum, ν, cm-1: 3270 (NH); 1665 (N−C=O); 1655 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz): 8.30-7.20
(4H, m, arom. protons); 8.80 (1H, s, NH); 5.48 (1H, q, J = 9, CH); 1.56 (3H, d, J = 9, CH3). 13C NMR spectrum,
δ, ppm: 174.20 (Ar−C=O); 169.20 (N−C=O); 145.45 (C=N); 141.34–115.51 (arom. carbons); 84.45 (C-5); 20.35
(CH3).
1-(4-Chlorophenyl)-5-ethyl-4-methoxycarbonylamino-3-(2-thenoyl)-4,5-dihydro-1H-1,2,4- triazole
1
(4n). IR spectrum, ν, cm-1: 3260 (NH); 1735 (N−C=O); 1660 (Ar−C=O). H NMR spectrum, δ, ppm (J, Hz):
8.25-7.16 (4H, m, arom. protons); 7.00 (1H, s, NH); 5.41 (1H, t, J = 9, CH); 3.67 (3H, s, CH3O); 1.85 (2H, m,
CH2); 0.96 (3H, t, J = 7, CH3). 13C NMR spectrum, δ, ppm: 174.20 (Ar−C=O); 156.50 (N−C=O); 145.50 (C=N);
141.34–115.51 (arom. carbons); 84.40 (C-5); 52.90 (O−CH3); 26.25 (CH2); 6.65 (CH3).
4-Acetylamino-1-(4-chlorophenyl)-5-cyclohexyl-3-(2-thenoyl)-4,5-dihydro-1H-1,2,4-triazole (4o). IR
1
spectrum, ν, cm-1: 3255 (NH); 1675 (N−C=O); 1655 (Ar−C=O) H NMR spectrum, δ, ppm (J, Hz): 8.30-7.20
(4H, m, arom. protons); 8.90 (1H, s, NH); 5.32 (1H, q, J = 9, CH); 1.96 (3H, s, CH3CO); 1.81-1.20 (11H, m,
cyclohexyl protons). 13C NMR, δ, ppm: 178.30 (N−C=O); 174.40 (Ar−C=O); 145.70 (C=N); 141.34-115.51
(arom. carbons); 87.60 (C-5); 40.90-24.20 (cyclohexyl carbons).
The authors wish to thank the Ministry of Higher Education for financial support.
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