Amidrazones in the synthesis of 1H-1,2,4-triazoles

Article abstract of DOI:10.1515/znb-2006-1009

The syntheses of various 2-(4-aryl-2,4-dihydro-3-phenyl-1,2,4-triazol-3- ylidene)indan-1,3-diones are reported. The key to their successful synthesis depends on the reaction of amidrazones 1a-f with 2-(1,3-dioxoindan-2-ylidene) malononitrile (2).

Full text of DOI:10.1515/znb-2006-1009

Amidrazones in the Synthesis of 1H-1,2,4-Triazoles
Ashraf A. Aly, Moshen A.-M. Gomaa, Ahmed M. NourEl-Din, and Magda S. Fahmi
Chemistry Department, Faculty of Science, El-Minia University, 61519-El-Minia, A. R. Egypt
Reprint requests to Prof. Dr. A. A. Aly. Tel(Fax): +20862346876.
E-mail: ashraf160@yahoo.com
Z. Naturforsch. 61b, 1239 – 1242 (2006); received January 30, 2006
Dedicated to Professor Henning Hopf on the occasion of his 65th birthday
The syntheses of various 2-(4-aryl-2,4-dihydro-3-phenyl-1,2,4-triazol-3-ylidene)indan-1,3-diones
are reported. The key to their successful synthesis depends on the reaction of amidrazones 1a – f with
2-(1,3-dioxoindan-2-ylidene)malononitrile (2).
Key words: Amidrazones, 2-(1,3-Dioxoindan-2-ylidene)malononitrile, 1H-1,2,4-Triazoles
Introduction
undertook to investigate, as the first example, the reac-
tions of amidrazones 1a – f with 2-(1,3-dioxoindan-2-
ylidene)malononitrile as electron π-deficient acceptor
aiming to obtain heterocyclic compounds, which might
have prospective biological activities.
The design and synthesis of 1,2,4-triazoles have at-
tracted much attention within the last decades due to
their wide applications and their therapeutic impor-
tance. For example, triazoles have been used as drugs
for certain antiasthmatic [1], antiviral (ribavirin) [2],
antifungal (fluconazole) [3], antibacterial [4], and hyp-
notic (triazolam) drugs [5]. Owing to the broad biolog-
ical activity of the 1,2,4-triazoles [6 – 12], the ring sys-
tem represents an attractive target for the elaboration of
solid-phase synthesis and the productionof combinato-
rial libraries. 1H-1,2,4-Triazoles are proved as electro-
chemically stable for fuel cell applications and effec-
tively promote proton conductivity of materials under
anhydrous conditions [13]. In general, 1H-1,2,4-tri-
azoles have wide applications as intermediates for phy-
tosanitary and pharmaceutical products. In addition,
some triazoles are used as pesticides, photoconductors,
and copying systems. Amidines are used very often
Results and Discussion
Herein, we report a general overall view of the re-
action between amidrazones 1a – f [24] with 2-(1,3-
dioxoindan-2-ylidene)malononitrile (2). Scheme 1
outlines the reaction of 1a – f with 2 in dry ethyl ac-
etate under N2 atmosphere. The reaction proceeded
in a few minutes to yield, after chromatographic pu-
rification and recrystallization, compounds 3a – f (62 –
85%). We chose amidrazones 1a – f having aryl groups
with electron donating and withdrawing substituents
on the benzene ring, in order to examine their reac-
tivity, which might affect the course of reaction.
The structures of 3a – f were established on the ba-
in pharmacological and medicinal applications [14– sis of mass, IR, H NMR and 13C NMR spectra as
1
18]. Amidrazone derivatives are considered as an im- well as elemental analyses. Compounds 3a – f show IR
−1
˜
portant class of amidines and they are used in hete- absorptions for NH groups at ν = 3280– 3200 cm
rocyclic syntheses [19]. We have recently reported on and broad bands at ν = 1685– 1680 cm−1 correspond-
˜
1
the synthesis of heterocyclces derived from [2.2]para- ing to the carbonyl groups. Surprisingly, the H NMR
cyclophanes (heterophanes) during the cycloadditions spectra of compounds 3a – f did not show any reso-
of alkenyl-[2.2]paracyclophanes with various selected nances due to the NH protons, which is explained by
dienophiles [20]. We have also investigated the reac- the presence of the triazole-H dione structure of 3a – f
tions of amidines and their analogues with π-acceptors in tautomerization with its ketohydroxy form (Fig. 1).
1
[21a] and various heterocycles such as dihydropy- The H NMR spectra indicated the presence of the
ridines [21b], acridinones [22, 23], pyrazolidines and hydroxyl proton for 3a – f, which is superimposed by
pyridazines [23], were obtained. In this publication we the aromatic protons and appeared between δ = 7.70 –
0932–0776 / 06 / 1000–1239 $ 06.00 © 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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A. A. Aly et al. · Amidrazones in the Synthesis of 1H,2,4-Triazoles
Scheme 1. Reaction of amid-
razones 1a – f with 2; synthesis of
1H-1,2,4-triazoles 3a – f.
Fig. 1. Tautomerism and some distinctive
δ values (1H and 13C NMR) for com-
pound 3c.
Fig. 2. Proposed mechanism for the for-
mation of 1H-1,2,4-triazoles 3a – f.
7.40 (see Experimental Section). The 13C NMR spec- the vinylic bond in 2-H2 accompanied by extrusion
tra of compounds 3a – f are in accordance with their of HCN from 2-H2 to form the intermediates 5a – f
1H NMR spectral data. For example, the 13C NMR (Fig. 2). A cyclization process then occurs followed
spectrum of compound 3c showed only one carbonyl by loss of another molecule of HCN; a [1,2]-H shift
signal which appears at δ = 185.0, whereas the C-OH finally affords the observed products 3a – f (Fig. 2).
resonates at δ = 165.2. Six distinguished carbon sig-
nals resonated in the 13C NMR spectrum of 3c at
δ = 55.9, 110.0, 136.8, 137.4, 150.5 and 162.5, corre-
sponding to OCH3, C-6, -8, -9, -3 and -5 (more NMR
data are shown in Fig. 1 and the Experimental Section).
In conclusion, we have now demonstrated a very
convenient procedure to synthesize 1,2,4-triazoles in
one step including a rapid reaction of amidrazones 1a –
f which behave hydrazoenamine-like. Amidrazones
1a – f react with the ylidene 2 via an initial addition of
It has been reported that the transformation of ar- the azoimine at the terminal hydrazino-nitrogen, fol-
ylamidrazones into 1,2,4-triazoles occurs via the ini- lowed by elimination of two molecules of HCN under
tial formation of azoimines [25]. On the other hand, it the reaction conditions to afford the title compounds.
is known that the acceptor 2 is considered as oxidiz- Additionally, the variation of the yields of the resulting
ing agent. Therefore, the proposed mechanism for the triazoles 3a – f depended on the type of substituents in
formation of triazoles 3a – f is thought to involve the the aromatic ring attached to the amino group in 1a– f,
initial abstraction of hydrogen atoms from the amidra- i. e. the presence of electron donating substituents such
zone moiety by the acceptor 2 to produce the oxidized as methyl and methoxy groups increased the yields
4a – f along with the dihydro-indandione 2-H2. Sub- of the obtained triazoles. However and in the case of
sequently, the hydrazoenamine-NH in 4a – f attacks electron withdrawing groups represented by a chlorine
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A. A. Aly et al. · Amidrazones in the Synthesis of 1H,2,4-Triazoles
1241
atom decreased the yield. Moreover, it was also noted – C23H15N3O2 (365.39): calcd. C 75.60, H 4.14, H 11.50;
found C 75.40, H 4.17, H 11.35.
that meta substitution with either an electron donating
or a withdrawing group decreases the yields of the cor-
responding products as in the case of 3e and 3f.
2-[2,4-Dihydro-4-(4-methylphenyl)-3-phenyl-1,2,4-triaz-
ol-5-ylidene]indane-1,3-dione (3b): Obtained as yellow
cryst◦als (0.61 g, 80%); Rf = 0.5 (CH2Cl2), m. p. 276 –
˜
278 C (EtOH). – IR (KBr): ν = 3200 (NH), 3050 – 2900
Experimental Section
(Ar-CH), 1682 (CO), 1600 (C=N) cm−1. – UV (CH3CN):
Melting points are uncorrected values. 1H NMR and
λ
max (log ε) = 430 (4.20). – 1H NMR (CDCl3): δ =
1
13C NMR spectra (Bruker AM 400, H: 400.13 MHz, 13C:
2.40 (s, 3 H, CH3), 7.60 – 7.30 (m, 14 H, Ar-H, OH). –
13C NMR (CDCl3): δ = 32.40 (CH3), 109.70 (C-6), 122.48
(Ar-CH-18), 125.20 (Ar-C), 126.92, 128.00 (2 Ar-CH),
128.24, 128.64, 128.72, 130.46 (Ar-CH, CH-11, -12, -13 and
-14), 130.80, 131.00 (2 Ar-CH), 136.50 (Ar-C-8), 136.68
(Ar-C-24), 137.40 (Ar-C-9), 138.60 (Ar-N-C-21), 150.30
(C-3), 162.30 (C-5), 165.10 (C-7-OH), 184.94 (C-10). – MS
(EI, 70 eV): m/z (%) = 380 [M+1] (20), 379 [M+] (14), 378
[M-1] (100), 364 (20), 350 (18), 306 (18), 288 (14), 223 (12),
209 (14), 120 (18), 104 (20). – C24H17N3O2 (379.42): calcd.
C 75.98, H 4.52, H 11.07; found C 75.80, H 4.46, H 11.05.
100.6 MHz) were obtained from CDCl3 solutions; the chem-
ical shifts are given relative to internal standard TMS. For
preparative thin layer chromatography (PLC), glass plates
(20 × 48 cm) were covered with a slurry of silica gel
Merck PF254 and air-dried using the solvents listed for devel-
opment. Zones are detected by quenching of indicator fluo-
rescence upon exposure to 254 nm UV light. Elemental anal-
yses were carried in Assiut Microanalysis Center of Assiut
University. Mass spectroscopy was performed with a Finni-
gan MAT 8430 spectrometer at 70 eV, Institute of Organic
Chemistry, TU-Braunschweig, Germany. IR spectra were run
on a Shimadzu 470 spectrometer using KBr pellets.
2-[2,4-Dihydro-4-(4-methoxyphenyl)-3-phenyl-1,2,4-tri-
azol-5-ylidene]indane-1,3-dione (3c): Obtained as yellow
cryst◦als (0.67 g, 85%); Rf = 0.6 (CH2Cl2), m. p. 290 –
Starting materials: Amidrazones 1a – f were pre-
pared according to reference [24]. 2-(1,3-Dioxoindan-
2-ylidene)malononitrile (2) was prepared following the
procedure mentioned in reference [26].
˜
292 C (EtOH). – IR (KBr): ν = 3260 (NH), 3030 – 2980
(Ar-CH), 1682 (CO), 1600 (C=N) cm−1. – UV (CH3CN):
λ
max (log ε) = 440 (4.5). – 1H NMR (CDCl3): δ = 3.88 (s,
3 H, OCH3), 7.70 (dd, 2 H, J = 7.8, 1.9 Hz, H-23,25), 7.60 –
7.58 (m, 2 H, H-17,19), 7.48 – 7.28 (m, 10 H, Ar-H, OH). –
13C NMR (CDCl3): δ = 55.90 (OCH3), 110.00 (C-6), 122.60
(Ar-CH-18), 125.20 (Ar-C), 127.00, 128.20 (2 Ar-CH),
128.30, 128.62, 128.80, 130.44 (Ar-CH, CH-11, -12, -13 and
-14), 130.80, 131.00 (2 Ar-CH), 136.80 (Ar-C-8), 137.40
(Ar-C-9), 139.00 (C-21), 150.50 (C-3), 160.20 (Ar-C-24),
162.50 (C-5), 165.20 (C-7), 185.00 (C-10). – MS (EI, 70 eV):
m/z (%) = 396 [M+1] (22), 395 [M+] (100), 394 [M-1]
(76), 366 (18), 352 (14), 336 (10), 290 (10), 223 (14), 209
(16), 192 (14), 121 (8), 104 (16). – C24H17N3O3(395.42):
calcd. C 72.90, H 4.33, H 10.63; found C 72.80, H 4.27,
H 10.65.
Reaction of 1a – f with 2-(1,3-dioxoindan-2-ylidene)malono-
nitrile (2)
General procedure: A 250 ml two-necked round bottom
flask was flame-dried under N2 atmosphere and then cooled
to r. t. To this flask, absolute ethyl acetate (100 ml), a mixture
of 1a – f (2 mmol) and 2 (0.41 g, 2 mmol) was added. The
mixture was stirred for 10 – 20 min (the reaction was fol-
lowed by TLC analysis). The solvent was removed in vac.
and the residue was separated by preparative plates chro-
matography (silica gel, toluene : ethyl acetate 5 : 2). The ob-
tained products 3a – f were recrystallized from the stated sol-
vents.
2-(2,4-Dihydro-3,4-diphenyl-1,2,4-triazol-5-ylidene)ind-
2-[4-(4-Chlorophenyl)-2,4-dihydro-3-phenyl-1,2,4-triaz-
ane-1,3-dione (3a): Obtained as yellow needles (0.55 g, ol-5-ylidene]indane-1,3-dione (3d): Obtained as pale yel-
75%); Rf = 0.4 (CH2Cl2), m. p. 280 ◦C (acetone). – IR low crystals (0.54 g, 68%); Rf = 0.3 (CH2Cl2), m. p. 287 –
◦
˜
˜
(KBr): ν = 3280 (NH), 3010 – 2970 (Ar-CH), 1680 (CO), 289 C (MeOH). – IR (KBr): ν = 3220 (NH), 3020 – 2970
1590 (C=N) cm−1. – UV (CH3CN): λmax (log ε) = 410 (Ar-CH), 1685 (CO), 1590 (C=N) cm−1. – UV (CH3CN):
(4.10). – 1H NMR (CDCl3): δ = 7.50 – 7.38 (m, 13 H,
λ
max (log ε) = 420 (3.90). – 1H NMR (CDCl3): δ = 7.54 –
Ar-H, OH), 7.10 (dd, 2 H, J = 8.0, 2.0 Hz). – 13C NMR 7.34 (m, 12 H, Ar-H, OH), 7.00 (dd, 2 H, J = 7.8, 2.0 Hz,
(CDCl3): δ = 109.80 (C-6), 122.40 (Ar-CH-18), 125.00 H-23,25). – 13C NMR (CDCl3): δ = 108.60 (C-6), 121.00
(Ar-C), 126.90, 128.00 (2 Ar-CH), 128.20, 128.60, 128.80, (Ar-C-24), 122.60 (Ar-C-18), 123.90, 124.00 (2 Ar-CH),
130.20 (Ar-CH, CH-11,-12,-13 and -14), 130.60, 130.80 (2 125.30 (Ar-C), 126.70, 127.00 (2 Ar-CH), 128.16, 128.20,
Ar-CH), 132.40 (Ar-CH), 136.40 (Ar-C-8), 137.00 (Ar-C-9), 128.40, 130.23 (Ar-CH, CH-11, -12, -13 and -14), 136.40
138.20 (Ar-N-C-21), 150.00 (C-3), 162.00 (C-5), 165.00 (C-8), 136.80 (C-9), 138.20 (Ar-C-21), 150.00 (C-3), 159.80
(C-7-OH), 184.90 (C-10). – MS (EI, 70 eV): m/z (%) = (C-5), 165.00 (C-7), 184.20 (C-10). – MS (EI, 70 eV):
366 [M+1] (20), 365 [M+] (100), 364 [M-1] (60), 352 (14), m/z (%) = 401 [M+2] (18), 400 [M+2] (36), 399 [M+]
307 (12), 288 (14), 223 (12), 209 (14), 120 (18), 104 (20). (100), 364 [M-1] (34), 370 (16), 370 (18), 363 (20), 336
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A. A. Aly et al. · Amidrazones in the Synthesis of 1H,2,4-Triazoles
(12), 308 (14), 239 (14), 228 (14), 192 (16), 177 (18), 125 – C24H17N3O2 (379.42): calcd. C 75.98, H 4.52, H 11.07;
(20), 110 (14). – C23H14ClN3O2 (399.84): calcd. C 69.09, found C 75.86, H 4.52, H 11.00.
H 3.53, Cl 8.87, H 10.51; found C 69.20, H 3.47, Cl 8.78,
H 10.50.
2-[2,4-Dihydro-4-(3-methylphenyl)-3-phenyl-1,2,4-triaz-
ol-5-ylidene]indane-1,3-dione (3e): Obtained as pale yel-
2-[4-(3-Chlorophenyl)-2,4-dihydro-3-phenyl-1,2,4-triaz-
ol-5-ylidene]indane-1,3-dione (3f): Obtained as pale yel-
low crystals (0.45 g, 62%); Rf = 0.2 (CH2Cl2), m. p. 246 –
◦
˜
248 C (EtOH). – IR (KBr): ν = 3200 (NH), 3025 – 2965
(Ar-CH), 1685 (CO), 1592 (C=N) cm−1. – UV (CH3CN):
low crystals (0.56 g, 74%); Rf = 0.4 (CH2Cl2), m. p.
λ
max (log ε) = 410 (3.80). – 1H NMR (CDCl3): δ = 7.60 –
◦
˜
268 C (EtOH). – IR (KBr): ν = 3240 (NH), 3030 – 2940
(Ar-CH), 1680 (CO), 1594 (C=N) cm−1. – UV (CH3CN):
7.38 (m, 13 H, Ar-H, OH), 7.50 (dd, 1 H, J = 1.8 Hz, H-22).
max (log ε) = 435 (4.25). – 1H NMR (CDCl3): δ = 2.36
–
13C NMR (CDCl3): δ = 108.90 (C-6), 122.00 (Ar-CH-22),
λ
124.00, 124.20 (2 Ar-CH), 125.00 (Ar-C), 126.00 (Ar-C-23),
126.30, 126.38, 127.00, 127.40, (Ar-CH), 128.00, 128.40,
128.60, 130.40 (Ar-CH, CH-11, -12, -13 and -14), 136.20
(C-8), 136.44 (C-9), 137.00 (Ar-C-21), 148.90 (C-3), 158.60
(C-5), 165.10 (C-7), 184.40 (C-10). – MS (EI, 70 eV): m/z
(%) = 401 [M+2] (20), 400 [M+2] (38), 399 [M+] (100), 364
[M-1] (36), 371 (14), 370 (16), 364 (12), 336 (8), 308 (8),
239 (12), 228 (14), 192 (14), 177 (14), 125 (16), 111 (18).
– C23H14ClN3O2 (399.84): calcd. C 69.09, H 3.53, Cl 8.87,
H 10.51; found C 69.00, H 3.50, Cl 8.78, H 10.45.
(s, 3 H, CH3), 7.62 (dd, 1 H, J = 1.8 Hz, H-22), 7.54 –
7.28 (m, 13 H, Ar-H, OH). – 13C NMR (CDCl3): δ =
32.60 (CH3), 109.72 (C-6), 122.50 (Ar-CH), 125.10 (Ar-C),
126.92, 127.20, 128.00, 128.20 (Ar-CH), 128.28, 128.62,
128.80, 132.00 (Ar-CH, CH-11, -12, -13 and -14), 130.84,
131.20 (Ar-CH), 136.54 (C-8), 136.62 (C-23), 137.20 (C-9),
138.10 (Ar-N-C-21), 150.10 (C-3), 162.20 (C-5), 165.00
(C-7), 184.80 (C-10). – MS (EI, 70 eV): m/z (%) = 380 [M+1]
(18), 379 [M+] (16), 378 [M-1] (100), 364 (18), 350 (22),
306 (24), 288 (16), 222 (16), 208 (12), 120 (16), 104 (18).
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