Regioselective synthesis of novel 4,4′-and 5,5′-bi-(1,2,4- triazole) derivatives

Article abstract of DOI:10.3184/030823407X237876

A regioselective synthesis is reported of a series of polysubstituted 1,2,4-triazoles and 4,4′- and 5,5′-bi-(1,2,4-triazoles) via 1,3-dipolar cycloaddition reactions of nitrilimines with some aza- and diaza-butadiene derivatives.

Full text of DOI:10.3184/030823407X237876

472 RESEARCH PAPER
AUGUST, 472–474
JOURNAL OF CHEMICAL RESEARCH 2007
Regioselective synthesis of novel 4,4'-and 5,5'-bi-(1,2,4-triazole) derivatives
Ahmad M. Farag*, Kamal M. Dawood and Nabila A. Khedr
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
A regioselective synthesis is reported of a series of polysubstituted 1,2,4-triazoles and 4,4'- and 5,5'-bi-(l,2,4-triazoles)
via 1,3-dipolar cycloaddition reactions of nitrilimines with some aza- and diaza-butadiene derivatives.
Keywords: 1,2,4-triazoles, 4,4'-bi-(l,2,4-triazoles), 5,5'-bi-(l,2,4-triazoles), nitrilimines, azabutadiene, diazabutadiene
The synthesis of 1,2,4-triazole derivatives has received a
R
C
N
NAr
CH
N
N CH Ph
Ph
considerable attention in view of their diverse pharmacological
activities.1-4 In addition, 3,3'-bis-1,2,4-triazoles have
proved to possess bactericidal, fungicidal, and anthelmintic
activities.3 As part of our ongoing research program dealing
with the synthesis of a variety of heterocyclic systems for
biological evaluation,5-14 and in continuation of our previous
studies concerned with the synthesis of 3,3'-bi-l,2,4-triazole
derivatives,15-17 the present work was undertaken to prepare
a series of novel 4,4'- and 5,5'-bi-(1,3,5-trisubstituted-
l,2,4-triazole) derivatives via 1,3-dipolar cycloaddition
reactions of nitrilimines to l,4-diphenyl-2,3-diaza-l,3-
butadiene (benzaldehyde azine, 3) (Scheme 1) and 1,4-di-
(4-methylphenyl)-l,4-diaza-l,3-butadiene (7) (Scheme 2),
respectively, with a view to investigating their potential
biological and pharmacological activity. The presence of
conjugated carbon–nitrogen double bonds in diazabutadienes
3 and 7 makes these readily accessible compounds potentially
useful for the synthesis of 4,4'- and 5,5'-bi-(1,2,4-triazole)
derivatives.
2
3
TEA
Ph
N
PhCH=N
R
X
N
N
R
C
Ar
NHAr
N
4a,b
1a,b
a: R = COPh, Ar = Ph
b: R = CO2Et, Ar = 4-MeC6H4
X = (a) Br, (b) Cl
N
R
Ar
N
R
N
N
N
N
Ph
Ph
H
Ph
H
Ph
N
N
Results and discussion
N
Ar
N
R
Ar
When an equimolar mixture of l,4-diphenyl-2,3-diaza-l,3-
butadiene (3) and the appropriate hydrazonoyl halide 1 was
refluxed in dry benzene in the presence of an equivalent
amount of triethylamine, it afforded, in each case, only 1:1
cycloadduct. In principle, two possible isomeric structures
4 and 5 can be written for the isolated products (Scheme 1).
Among these structures, the 4,5-dihydro-5-phenyl-4-
[(phenylmethylene)-amino]-1,3-disubstituted-1H-1,2,4-
triazole structure 4 was assigned to the isolated cycloadducts
6a,b
5a,b
Scheme 1
products. Mass spectrometry and 1H NMR spectra of the
isolated products showed that one of them is the starting
material 7 and the other is the 1:2 cycloadduct 8a but in a
fair yield. (Scheme 2) The latter cycloadduct was obtained
1
on the basis of their spectral data. The H NMR spectrum of
Cl
CH CH
N Ar'
4a revealed, in addition to an aromatic multiplet at d 7.1–7.8,
two singlet signals at d 6.65 and 8.30 corresponding to the
protons at C-5 of the triazoline ring moiety and the azomethine
group, respectively. Its mass spectrum showed, in addition to
a molecular ion peak at m/z 430, a fragment ion of m/z 326
corresponding to [M–PhCH=N]+. These findings exclude the
possible isomeric seven-membered structure 5 which may
arise from [4 + 3] type of cycloaddition.
Ar'
N
R
C
7
N
NHAr
TEA
1b,c
1b: R = CO2Et, Ar = 4-CH3C6H4
N
R
Ar
1c: R = COCH3,
Ar = 4-ClC6H4
N
Treatment of the isolated cycloadducts 4a,b with an
equivalent amount of the corresponding hydrazonoyl halides
1a,b in benzene, in the presence of triethylamine, afforded
the corresponding 4,4',5,5'-tetrahydro-5,5'-diphenyl-1,1',3,3'-
tetrasubstituted 4,4'-bi-1H-1,2,4-triazole derivatives 6a,b
in good yields similar to analogously reported bitriazole
derivatives.16 Their 1H NMR spectra revealed, in each case, the
lack of the characteristic singlet signal at d 8.3 corresponding
to the azomethine proton in 4 and showed a singlet signal in
the region d 6.6–6.9 due to the two protons at C-5 and C-5' of
the bi-1,2,4-triazole ring system.
N
Ar'
H
H
Ar'
N
7-10 a: R = CO2Et, Ar = Ar'
N
= 4-CH3C6H4
Ar
R
N
b: R = COCH3, Ar = 4-ClC6H4,
8a,b
Ar' = 4-CH3C6H4
Ar'
N
Ar
N
Ar'
Ar'N=CH
Ar
R
N
N
N
N
Next, the reaction of the 1,4-diazabutadiene derivative 7
with an equimolar amount of the hydrazonoyl chloride 1b,
under similar experimental conditions, furnished two isolable
R
R
N
N
Ar
Ar'
10a,b
9a,b
* Correspondent. E-mail: afarag49@yahoo.com
Scheme 2
PAPER: 07/4671

JOURNAL OF CHEMICAL RESEARCH 2007 473
solely by reaction of 7 with the hydrazonoyl chloride 1b in
1:2 molar ratio. This result reflects the higher reactivity of
the 1,4-diazabutadiene derivative 7 than its 2,3-isomer 3.
1H NMR spectrum of 8a was free of the azomethine proton
1,2,4-triazole derivatives 14, resulting from the addition of
nitrilimine dipoles 2 on the carbon-carbon double bond of the
styryl group in 12.
1
signal at d 8.38, shown in the H NMR spectrum of 7 and
Experimental
displayed a singlet signal at d 5.55 integrated for the two
chemically equivalent vicinal protons at C-5 and C-5' of
bi-triazoline ring system. The molecular ion peak was virtually
absent in the mass spectrum of the bi-triazoline derivative 8a:
however, it showed instead an abundant fragment ion peak at
m/z 322 corresponding to M+/2. This mode of fragmentation
excludes the fused bicyclic structure 9a formed by criss-
cross cycloaddition. Similar observations were recorded on
treatment of compound 7 with the hydrazonoyl chloride 1c in
1:2 molar ratio, where the bi-triazoline cycloadduct 8b was
exclusively obtained in a good yield. All attempts to isolate
the 1:1 cycloadducts 10a,b were unsuccessful.
The reaction of nitrilimines 1c,d,e with 1,4-diphenyl-1-aza-
1,3-butadiene (11) was also investigated. Thus, it has been
found that reaction of hydrazonoyl halides 1c,d,e with 11 in an
equimolar ratio, in benzene and in the presence of equivalent
amount of triethylamine, either at room temperature or at mild
reflux afforded, in each case, 1:1 cycloadducts identified as
4,5-dihydro-1,3,4-trisubstituted-5-styryl-1H-1,2,4-triazoles
12a–c (Scheme 3). The mass spectra of the formed products
exhibited in each case a peak corresponding to the molecular
ion (M+). 1H NMR spectrum of 12a, as an example, was free
of the characteristic azomethine N=CH proton signal that was
present in the starting cinnamaldehyde anil 11 at d 8.3 and
revealed a doublet at d 6.09 and a doublet of doublets at d 6.34
due to olefinic CH=CH protons in addition to a doublet at
d 6.71 due to the triazoline-5-CH proton. This finding excludes
the other possible isomeric structures 13 for the reaction
products. It is noteworthy that, treatment of compounds
12a–c with an excess of nitrilimines 2 gave no further
reaction and the starting materials 12a–c were recovered
unchanged. Moreover, the reaction of 11 with two equivalents
of hydrazonoyl halide 1, in the presence of triethylamine,
afforded the same 1:1 cycloadducts 12a–c and there was
no evidence for the formation of the 4,5-dihydropyrazolyl-
Melting points were measured with a Gallenkamp apparatus. The IR
spectra were recorded of samples in KBr on a Shimadzu FT-IR 8101
PC IR spectrophotometer. The H NMR spectra were determined in
CDCl3 at 300 MHz on a Varian Mercury VX 300 NMR spectrometer
using TMS as an internal standard. Mass spectra were measured on
a GCMS-QP1000 EX spectrometer at 70 eV. Elemental analyses
were carried out at the Microanalytical Centre of Cairo University.
Butadiene derivatives 3,18 719 and 1120 and hydrazonoyl halides
1a,21 1b,22 1d,23 1c,24 and 1e25 were prepared according to literature
procedures.
1
4,5-Dihydro-5-phenyl-4-N-[(phenylmethylene)amino]-1H-1,2,4-
triazoles 4a and 4b
Equimolar quantities of the 1,4-diphenyl-2,3-diaza-1,3-butadiene
(3) (0.416 g, 2 mmol) and the appropriate hydrazonoyl halide la,b
(2 mmol) were dissolved in dry benzene (20 ml). To the resulting
solution triethylamine (0.2 ml, 2 mmol) was added and the mixture
was refluxed for 3 h then left to cool. The solvent was evaporated
under reduced pressure and the oily residue was triturated with
methanol. The solid product so formed was collected by filtration
and recrystallised from the indicated solvent to afford 4a and 4b,
respectively.
3-Benzoyl-1,5-diphenyl compound (4a): Bright orange solid
(methanol) (0.75 g, 87%), m.p. 140–141°C. IR: nmax 1650 (C=O),
1600 cm-1 (C=N). 1H NMR: d 6.65 (s, 1H, triazoline-5-CH), 7.1–7.8
(m, 20H, ArH), 8.3 (s, 1H, N=CH); m/z 430 (M+). Found: C, 78.25; H,
4.90; N, 13.17. C28H22N4O requires C, 78.10; H, 5.15; N, 13.02%.
Ethyl 5-phenyl-1-p-tolyl-3-carboxylate (4b): Yellow crystals
(petroleum ether/benzene) (0.49 g, 60%), m.p 100–102°C.
IR: nmax 1730 (C=O), 1600 cm-1 (C=N). MS: m/z 412 (M+), 308
(M+- PhCH=N), 104 (PhCH=N). Found: C, 73.00; H, 5.84; N, 13.67.
C25H24N4O2 requires C, 72.79; H, 5.87; N, 13.58%.
4,4',5,5'-Tetrahydro-5,5'-diphenyl-1,1',3,3'-tetrasubstituted-[4,4'-bi-
1H-1,2,4-triazoles] 6a and 6b.
Equimolar (2 mmol) quantities of the appropriate 4(N-
phenylmethyleneamino)-1,2,4-triazole derivative 4a,b and the
corresponding hydrazonoyl halide 1a,b were dissolved in hot
benzene (15 ml). Triethylamine (0.2 ml, 2 mmol) was added and the
reaction mixture was refluxed for 3 h, then left to cool. The solvent
was distilled off under reduced pressure and the oily residue was
triturated with methanol. The solid product was collected by filtration
and recrystallised from ethanol to afford 6a and 6b, respectively.
3,3'-Dibenzoyl compound 6a: Orange-red solid (methanol)
(1.02g, 78%)m.p. 173–174°C. IR:nmax 1650(C=O), 1600cm-1 (C=N).
1H NMR: d 6.64 (s, 2H), 6.90–8.32 (m, 30H, Ar H). Found: C,
77.10; H, 4.90; N, 12.76. C42H32N6O2 requires C, 77.28; H, 4.94;
N, 12.88%.
X
Ph CH CH CH
N Ph
R
C
11
N
NHAr
1c-e
TEA
Ph
Diester 6b: Yellow crystals (pet. ether/benzene) (0.78 g, 63%),
1 c: X = Cl, R = COCH3,
1
m.p. 110–111°C. IR: nmax 1710 (C=O); 1610 cm-1 (C=N). H NMR:
Ar = 4-ClC6H4
Ph
H
CH=CH
d 1.5 (t, 6H), 2.4 (s, 6H) 4.5 (q, 4H), 6.9 (s, 2H, triazole-5-CH),
7.15–7.55 (m. 18H, ArH); m/z 308 (M+/2). Found: C, 69.97; H, 5.68;
N, 13.65. C36H36N6O4 requires C, 70.11; H, 5.88; N, 13.63%.
d
: X = Cl, R = CO2Et,
N
Ar = 4-O2NC6H4
: X = Br, R = Ph,
Ar = 4-O2NC6H4
e
N
Ar
R
N
4,4',5,5'-Tetrahydro-4,4'-di-(4-tolyl-1,1',3,3'-tetrasubstituted-[5,5'-
bi-1H-1,2,4-triazoles] 8a and 8b
Equimolar quantities of the 1,4-di-(p-tolyl)-1,4-diaza-l,3-butadiene
(7) (0.472 g, 2 mmol) and the appropriate hydrazonoyl halide lb,c
(2 mmol) were dissolved in dry benzene (15 ml). To the resulting
solution triethylamine (0.2 ml, 2 mmol) was added. The reaction
mixture was refluxed for 3 h and the solvent was removed under
reduced pressure. The oily residue was triturated with methanol and
the solid product was collected by filtration and crystallised from
ethanol.
12–14 a: R = COCH3, Ar = 4-ClC6H4
12a–c
b
: R =CO2Et, Ar = 4-O2NC6H4
: R = Ph, Ar = 4-O2NC6H4
c
N
R
Ar
N
Ph
Ph
N=CH
Ar
H
Ph
H
Diester 8a: Yellow needles (methanol) (0.54 g, 42%), m.p. 197–
1
198°C. IR: nmax 1730 (C=O), 1600 cm-1 (C=N). H NMR: d 1.26 (t,
H
Ph
N
6H, 2 × ester CH3) 2.27 (s, 6H), 2.29 (s, 6H), 4.30 (q, 4H, 2 × ester
CH2), 5.55 (s, 2H, bitriazoline-5,5'-CH), 7.04–7.17 (m, 16H, Ar H),
m/z 322 (M+/2). Found: C, 70.60; H, 6.10; N, 13.23. C38H40N6O4
requires C, 70.78; H, 6.25; N, 13.03%.
N
N
R
Ar
R
N
N
Diketone 8b: Pale yellow crystals (methanol) (0.41 g, 33%),
m.p. 180–181°C. IR: nmax 1670 (C=O), 1603 cm-1 (C=N).
1H NMR: d 2.30 (s, 6H, p-CH3), 2.43 (s, 6H, CH3CO) 5.85 (s, 2H,
13a–c
14a–c
Scheme 3
PAPER: 07/4671

474 JOURNAL OF CHEMICAL RESEARCH 2007
2
K. Okonogi and A. Tasaka, Can. Pat. Appl. CA 2 132 791 (Chem. Abstr.,
1996, 124, 8821t).
S.M. Kudari, S.M. Beede and W. Munera, Asian J. Chem., 1997, 9, 20.
T. Denzel and H. Hoehn, U. S. Patent 1976, 3 971 801 (Chem. Abstr.,
1977, 86, P16675k).
M.R. Shaaban, T.S. Saleh, F.H. Osman and A.M. Farag, J. Heterocyclic
Chem., 2007, 44, 177.
K.M. Dawood, A.M. Farag and H.A. Abdel-Aziz, Heteroatom Chem.,
2007, 18, 294.
R.M. Shaaban, T.S. Saleh and A.M. Farag, Heterocycles, 2007, 71, 1765.
Y.M. Elkholy, K.A. Ali and A.M. Farag, Lett. Org. Chem., 2006, 3, 195.
K.M. Dawood, A.M. Farag and H.A. Abdel-Aziz, J. Chin. Chem. Soc.,
2006, 53, 873.
bitriazoline-5,5'-CH), 6.89–7.23 (m,16H, Ar H). MS: m/z 314 (37),
312 (100%) (M+/2). Found: C, 65.34; H, 4.71; N, 13.62; C1, 11.42.
C34H30C12N6O2 requires C, 65.27; H, 4.83; N, 13.43; Cl, 11.36%.
3
4
4,5-Dihydro-1,3,4-trisubstituted-5-styryl-1H-1,2,4-triazoles l2a–c
Equimolar quantities of 1,4-diphenyl-l-aza-l,3-butadiene (11)
(0.414 g, 2 mmol) and the appropriate hydrazonoyl halide 1c-e
(2 mmol) were dissolved in dry benzene (15 ml). To the resulting
solution triethylamine (0.2 ml, 2 mmol) was added, the reaction
mixture was refluxed for 3 h then left to cool. The solvent was
distilled off under reduced pressure and the residual oil was triturated
with methanol. The solid product was collected by filtration and
crystallised from the appropriate solvent to afford l2a–c.
Ketone 12a: Bright yellow crystals (ethanol) (0.60 g, 75%),
m.p. 160–161°C. IR: nmax 1680 (C=O), 1600 cm-1 (C=N). 1H NMR:
d 2.6 (s, 3H), 6.15 (d, 1 H, J = 7.6 Hz), 6.3 (dd, 1 H, J = 15.6, 7.8 Hz),
6.75 (d, 1 H, J = 15.6 Hz), 7.02–7.4 (m, 14H, Ar' H). MS: m/z 401
(M+). Found: C, 71.82; H, 5.16; N, 10.62; C1, 8.10. C24H20ClN3O
requires C, 71.72; H, 5.02; N, 10.46; Cl, 8.82%.
Ester 12b: Yellow crystals (ethanol) (0.65 g, 74%), m.p. 134–
135°C. IR: nmax 1732 (C=O), 1600 cm-1 (C=N). 1H NMR: d 1.18
(t, 3H), 4.26 (q, 2H), 6.49 (dd, l H, J = 15.4, 8.0 Hz), 6.82 (d, l H,
J = 8.0 Hz), 7.01 (d. 1H, J = 15.6 Hz), 7.20-8.19 (m, 14H, Ar'H).
MS: m/z 442 (M+). Found: C, 67.69; H, 4.90; N, 12.48. C25H22N4O4
requires C, 67.86; H, 5.01; N, 12.66%.
Styryltriaryl product 12c: Pale yellow crystals (ethanol/DMF)
(0.64 g, 72%), m.p. 285°C. IR: nmax 1615 cm-1 (C=N). 1H NMR:
d 6.55 (dd, 1H, J = 15.6, 7.6 Hz), 6.75 (d, 1 H J = 7.6 Hz), 7.0–8.2 (m,
20H, ArH and olefinic CH). MS: m/z 446 (M+). Found: C, 75.42; H,
5.05; N, 12.66. C28H22N4O2 requires C, 75.32; H, 4.97; N, 12.55%.
5
6
7
8
9
10 K.M. Dawood, A.M. Farag and H.A. Abdel-Aziz, Heteroatom Chem.,
2005, 17, 621.
11 K.M. Dawood, A.M. Farag and H.A. Abdel-Aziz, J. Chem. Res. (S),
2005, 378.
12 A.M. Farag, K.M. Dawood and H.A. Elmenoufy, Heteroatom Chem.,
2004, 15, 508.
13 K.M. Dawood, A.M. Farag and H.A. Abdel-Aziz, J. Chem. Res. (S),
2004, 808.
14 K.M. Dawood, E.A. Ragab and A.M. Farag, J. Chem. Res., (S), 2003,
685; (M), 2003, 1151.
15 K.M. Dawood, M.A. Raslan and A.M. Farag, Synth. Commun., 2003,
33, 4095.
16 A.M. Farag, A.S. Shawali, N.M. Abed and K.M. Dawood, Gazz. Chim.
Ital., 1993, 123, 467.
17 A.S. Shawali, A.M. Farag, H.A. Albar and K.M. Dawood, Tetrahedron,
1993, 49, 2761.
18 R. Huisgen, R. Grashey, E. Aufderhaar and R. Kunz, Chem. Ber., 1965,
98, 642.
19 H.H. Hatt, Org. Synth. Coll. 1943, 2, 395.
20 J.M. Kliegman and R.K. Barnes, J. Org. Chem., 1970, 35, 3140.
21 O. Doebner and W.V.Miller, Chem. Ber., 1883, 16, 1665.
22 A.S. Shawali and A.O. Abdelhamid, Bull. Chem. Soc. Jpn., 1976,
49, 321.
Received 29 May 2007; accepted 7 August 2007
Paper 07/4671 doi: 10.3184/030823407X237876
23 A.F. Hegarty, M.P. Cashman and F.L. Scott, Chem. Commun., 1971,
13, 884.
References
24 N.F. Eweiss and A.O. Abdelhamid,. J. Heterocycl. Chem., 1980, 17, 1713.
25 A.S. Shawali and H.M. Hassaneen, Tetrahedron Lett., 1972, 28, 2903.
1
Y. Naito, F. Akahoshi, S. Takeda, T. Okada, M. Kajii, H. Nishimura,
M. Sugiura, C. Fukaya and Y. Kagitani, J. Med. Chem., 1996, 39, 3019.
PAPER: 07/4671