A novel method for the synthesis of 3,5-disubstituted-(NH)-1,2,4-triazoles from 3,6-diaryl-1,2,4,5-tetrazines

Article abstract of DOI:10.1016/j.tetlet.2010.01.061

The reaction of 3,6-diaryl-1,2,4,5-tetrazines and 2-aryl substituted acetonitriles, under basic conditions, leads unexpectedly to 3,5-diaryl-(NH)-1,2,4-triazoles in moderate yields. A mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2010.01.061

Tetrahedron Letters 51 (2010) 1654–1656
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A novel method for the synthesis of 3,5-disubstituted-(NH)-1,2,4-triazoles
from 3,6-diaryl-1,2,4,5-tetrazines
*
Makhluf J. Haddadin , Ebrahim H. Ghazvini Zadeh
Department of Chemistry, American University of Beirut, Beirut, Lebanon
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 3,6-diaryl-1,2,4,5-tetrazines and 2-aryl substituted acetonitriles, under basic conditions,
leads unexpectedly to 3,5-diaryl-(NH)-1,2,4-triazoles in moderate yields. A mechanism is proposed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 28 October 2009
Revised 23 December 2009
Accepted 15 January 2010
Available online 22 January 2010
1. Introduction
unknown in the literature, and a base peak of m/z 134 (see Section
2 for HRMS details).
The synthesis of substituted 1,2,4-triazoles has received consid-
erable attention as these systems demonstrate a broad spectrum of
biological activities such as antifungal,1–3 anti-inflammatory,4–6
antibacterial,7–10 anticonvulsant,11,12 and anticancer behavior.13–
We next turned our attention to the synthesis of the known 3,5-
diphenyl-(NH)-1,2,4-triazole (3a) using benzyl cyanide (2a) as the
2-aryl substituted acetonitrile. Indeed, the reaction of 2a with 1a
using DBU as the base yielded the known triazole 3a19 as was indi-
16
Although several methods have been reported for the synthesis
of 3,5-diaryl-(NH)-1,2,4-triazoles 3 via the construction of five-
membered heterocycles,17 this work presents the reaction of 3,6-
R1
N
N
diaryl-1,2,4,5-tetrazines 1 and a-substituted acetonitriles 2 under
basic conditions as the first example of the transformation of a
1,2,4,5-tetrazine into a 1,2,4-triazole (Scheme 1).
H
R1
DBU
THF,
N
N
N
N
R2
CN
+
R2
N
Δ
R1
The formation of 3 was unexpected. In fact, it was envisaged
that, analogous to other protocols used by our group for synthesiz-
ing new derivatives of cinnoline,18 the reaction of 1,2,4,5-tetrazine
(1a) with o-nitrobenzyl cyanide (2b) in methanolic KOH solution
would afford 5-(2-nitrophenyl)-3,6-diphenylpyridazin-4-amine
(4), which upon ring closure should lead to the unknown pyridaz-
ino[4,5-c]cinnoline-5-oxide 5 (Scheme 1).1
1
2
3a-d
3a R1 = Ph; R2 = Ph
60%
51%
36%
43%
3b R1 = Ph; R2 = 2-NO2C6 H4
3c R1 = Ph; R2 = 5-Me-2-NO2C6H3
3d R1 = 4-BrC6H4; R2 = Ph
Evidence in support of structure 3b was provided by the 1H
NMR spectrum which showed nine aromatic protons instead of
the 14 expected for 4. In addition, the spectrum included a solvent
dependent one-proton broad signal, at 12.2–14.5 ppm. This broad
signal disappeared on the addition of deuterium oxide. Analysis
of the 13C NMR spectrum indicated that the product had only 14
carbon atoms. In essence, the structure of the product has two phe-
nyl groups, one of which must have come from o-nitrobenzyl cya-
nide (2b). This is supported by the IR spectrum which includes
strong sharp peaks at 1530 and 1350 cmÀ1, consistent with the
presence of a nitro group. The mass spectrum demonstrated two
major peaks: a molecular ion peak, m/z 266, which fits a molecular
formula of C14H10N4O2 and the possible structure 3b which is
Ph
Ph
Ph
N
N
N
N
NO2
NH2
N
N
O
Ph
a
1a
+
2b
4
5
N
N
H
N
H
O2N
3b
* Corresponding author.
E-mail address: haddadin@aub.edu.lb (M.J. Haddadin).
Scheme 1. Reagents and conditions: (a) KOH (5%), MeOH, reflux, 3 h.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.061

M. J. Haddadin, E. H. Ghazvini Zadeh / Tetrahedron Letters 51 (2010) 1654–1656
1655
cated by 1H NMR, 13C NMR, and HRMS spectroscopy and the melt-
R1
a
ing point, all of which lent indirect support to the formation of
1,2,4-triazole 3b.
N
c
N
N
N
N
R1
N
N
N
N
N
N
d
+
N
R1
A postulated mechanism involves the attack of a nucleophile
generated from 2, on the carbon atom of the tetrazine ring of 1,
accompanied by ring opening and ring closure in what is known
as the ANRORC (addition of nucleophile, ring opening and ring clo-
sure) mechanism. This transformation is completed by the elimi-
nation of an aryl nitrile, as outlined in Scheme 2.
b
R1
1a
N
R1CN
2
+
+
N2
N
Support for the reaction mechanism was provided by GC–MS
studies on two separate reactions under the same conditions
(DBU/THF): one reaction mixture was between 1a and 2b, and the
second using 1a alone. Although benzonitrile was present in both
reaction mixtures, there was a substantial difference in the quanti-
ties of benzonitrile formed where 80% excess of benzonitrile was
generated in the reaction mixture of 1a and 2b, which is attributed
to the loss of benzonitrile from the bicyclic intermediate. Loss of a
nitrile moiety from a 1,2,4-triazepine ring leading to pyrazoles is
established in the literature.20 Although 1a is reported to give ben-
zonitrile upon heating in solution and without a solvent,21,22 we
know of no report which indicates the formation of benzonitrile
from 1a under basic conditions (THF–DBU), Scheme 3. The nucleo-
philicity of DBU has been demonstrated by Baidya and Mayr.23
Scheme 3. Postulated mechanism for the generation of benzonitrile.
10:1?5:1) were evaporated in vacuo to yield the title product as
a purple solid (2.00 g, 70%). Mp 196–198 °C (Lit. 196–198 °C).24
1H NMR (300 MHz, CDCl3): d 8.67–8.62 (m, 4H), 7.68–7.58 (m,
6H). 13C NMR (75 MHz, CDCl3): d 164.0, 132.7, 131.8, 129.3, 128.0.
2.2. Procedure for the synthesis of 3,6-diphenyl-(NH)-1,2,4-
triazole (3a)
3,6-Diphenyl-1,2,4,5-tetrazine 1a (1.00 g, 4.2 mmol) was added
to a solution of benzyl cyanide 2a (0.50 g, 4.2 mmol) in dry THF
(15 mL). Upon the addition of DBU (1 mL), the mixture was heated
at reflux for 3 h. The resulting solution was evaporated under re-
duced pressure, and was extracted using CH2Cl2 (3 Â 50 mL). The
organic layer was washed with water (3 Â 50 mL) and with dilute
HCl (5N, 3 Â 50 mL). The organic layer was dried over anhydrous
Na2SO4 and was evaporated in vacuo. The resulting crude solid
was purified by column chromatography and the fractions (hex-
anes/ethyl acetate, 5:1?3:1) were evaporated in vacuo to yield
the title product as a white solid (0.54 g, 60%). Mp 188–189 °C
(Lit. 188–190 °C).19 1H NMR (300 MHz, CDCl3): d 7.92–8.03 (m,
4H), 7.38–7.46 (m, 6H). 13C NMR (75 MHz, CDCl3): d 167.1, 130.0,
129.3, 128.2, 127.0. IR (KBr, cmÀ1): mmax 3400 (br, N–H). GC–MS:
m/z (calculated M+ 221, found M+ 221, tR = 22.87 min). HRMS: m/
z (C14H11N3) calculated M+ 221.09530, found M+ 221.10257.
These findings establish the reaction of a-substituted acetonitr-
iles 2 with 3,6-diaryl-1,2,4,5-tetrazines 1 under basic conditions as
the first example of the synthesis of 3,6-diaryl-(NH)-1,2,4-triazoles
3 via the addition of the nucleophile, ring opening, and ring closure
(ANRORC).
2. Experimental section
2.1. Procedure for the synthesis of 3,6-diphenyl-1,2,4,5-
tetrazine (1a)
The title product was prepared according to a literature proce-
dure.24 Elemental sulfur (1.00 g, 31.3 mmol) was added to a solu-
tion of benzonitrile (5.00 g, 48.5 mmol) in ethanol (25 ml).
Hydrazine monohydrate (3.00 g, 97.0 mmol) was added to the
solution which was heated at reflux for 3 h. The resulting yellow
precipitate was washed with cold ethanol (3 Â 10 ml) to afford
the dihydro derivative as a yellow solid (2.90 g, 51%). Glacial acetic
acid (10 mL) and aqueous sodium nitrite (1.76 g, 145.5 mmol)
were added to the resulting solid dihydrotetrazine and the mixture
was stirred for 20 min after which time the yellowish color turned
purple. The solid was collected by filtration and was washed with
water and methanol. The resulting purple solid was purified using
column chromatography and the fractions (hexanes/ethyl acetate,
2.3. 3-(2-Nitrophenyl)-5-phenyl-(NH)-1,2,4-triazole (3b)
White solid (580 mg, 51%). Mp 183–185 °C. 1H NMR (300 MHz,
CDCl3): d 12.2 (br s, 1H), 8.0 (dd, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.96–
7.92 (m, 2H), 7.81 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.65 (dt,
J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.55 (dt, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H),
7.44–7.40 (m, 3H). 1H NMR (300 MHz, DMSO-d6): d 14.77 (br s,
1H), 8.05 (d, J = 7.2 Hz, 1H), 8.02–7.97 (m, 3H), 7.92 (d, J = 7.2 Hz,
1H), 7.81 (t, J = 6.6 Hz, 1H), 7.72 (t, J = 6.6 Hz, 1H), 7.56–7.47 (m,
3H). 13C NMR (75 MHz, DMSO-d6): 155.7, 148.7, 132.4, 130.6,
130.4, 130.2, 129.1, 128.8, 127.0, 126.1, 123.6, 123.3. IR (KBr, cm
À1): mmax 3233 (br, N–H), 1531, 1374 (s, NO2). GC–MS: m/z (calcu-
lated M+ 266, found M+ 266, tR = 22.87 min). HRMS: m/z
(C14H10N4O2) calculated M+ 266.08038, found M+ 266.07983.
R1
R1
R1
N
N
N
N
R2
CN
N
N
N
N
N
+
HN
R1
N
2.4. 3-(5-Methyl-2-nitrophenyl)-5-phenyl-(NH)-1,2,4-triazole (3c)
NH2
R2
CN
R2
R1
R1
White solid (115 mg, 36%). Mp 151–153 °C. 1H NMR (300 MHz,
CDCl3): d 12.20 (br s, 1H), 8.00–7.93 (m, 2H), 7.79–7.76 (m, 2H),
7.44–7.40 (m, 3H), 7.36–7.33 (m, 1H), 2.45 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 158.1, 157.2, 146.7, 143.8, 132.0, 130.8, 130.4,
129.0, 127.6, 126.5, 124.4, 124.0, 21.3. IR (KBr, cmÀ1): mmax 3389
(br, N–H), 1531, 1344 (s, NO2). HRMS: m/z (C15H12N4O2) calculated
M+ 280.09603, found M+ 280.09548.
H
NC
Base
1
R1
R1
H
N
H
N
R1
N
N
N
N
N
H
N
N
N
N
[R1CN]
- [HCN]
3
N
H
2.5. 3-(4-Bromophenyl)-5-phenyl-(NH)-1,2,4-triazole (3d)
R1
R2
R1
NC
R2
R2
R1
White solid (200 mg, 43%). Mp 249–251 °C. 1H NMR (300 MHz,
CDCl3): d 8.06 (dd, J1 = 8.4, J2 = 1.8 Hz, 2H), 8.02–7.99 (m, 2H), 7.84–
Scheme 2. Postulated mechanism for the formation of 3.

1656
M. J. Haddadin, E. H. Ghazvini Zadeh / Tetrahedron Letters 51 (2010) 1654–1656
7.68 (m, 3H), 7.55–7.50 (m, 2H). 13C NMR (75 MHz, CDCl3): d 165.2,
131.9, 131.6, 131.4, 129.9, 129.5, 129.0, 127.9, 126.0, 125.7. IR (KBr,
cmÀ1): mmax 3325 (br, N–H). GC–MS: m/z (C14H10N3Br) calculated
[M+H]+ 300/302, found [M+H]+ 300/302, tR = 25.62 min).
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Acknowledgments
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We thank Ms. Abeer Jaber, Dr. Jalal Zafra, and Professor Musa Z.
Nazer of the University of Jordan for the high resolution mass spec-
tral (HRMS) data.
Supplementary data
Supplementary data (copies of 1H NMR, 13C NMR, IR, GC–MS,
and HRMS for compounds 3a–d) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.01.061.
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