A regioselective and convenient one-pot multicomponent synthesis of 9-amino-3,5-diaryl-4,9-dihydro-5H-[1,2,4]triazolo[5,1-c][1,2,4]triazepine-8-thiol

Article abstract of DOI:10.1080/00397911.2017.1314494

An efficient and environment-friendly procedure for the synthesis of a new series of nitrogen bridge-head [1,2,4]triazolo[5,1-c][1,2,4]triazepine derivatives through one-pot three-component reaction of polyfunctional triazole with aromatic aldehydes and acetophenone derivatives using alcoholic sodium hydroxide solution. The same new products were prepared in classical route through reaction of triazole with the corresponding chalcones under the same conditions.

Full text of DOI:10.1080/00397911.2017.1314494

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Regioselective and Convenient One-Pot
Multi-Component Synthesis of 9-Amino-3,5-
Diaryl-4,9-Dihydro-5H-[1,2,4]Triazolo[5,1-C]
[1,2,4]Triazepine-8-thiol
Amr Hassan Moustafa & Amer Anwar Amer
To cite this article: Amr Hassan Moustafa & Amer Anwar Amer (2017): A Regioselective
and Convenient One-Pot Multi-Component Synthesis of 9-Amino-3,5-Diaryl-4,9-
Dihydro-5H-[1,2,4]Triazolo[5,1-C] [1,2,4]Triazepine-8-thiol, Synthetic Communications, DOI:
10.1080/00397911.2017.1314494
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Date: 14 April 2017, At: 02:47

A Regioselective and Convenient One-Pot Multi-Component Synthesis of 9-Amino-
3,5-Diaryl-4,9-Dihydro-5H-[1,2,4]Triazolo[5,1-C] [1,2,4]Triazepine-8-Thiol
Amr Hassan Moustafa1, Amer Anwar Amer1
1Department of Chemistry, Faculty of Science, Sohag University, Sohag, Egypt
Address correspondence to Amr Hassan Moustafa, E-mail: amr_hassanegypt@ymail.com
Abstract
An efficient and environment-friendly procedure for the synthesis of a new series of
nitrogen bridge-head [1,2,4]triazolo[5,1-C][1,2,4]triazepine derivatives via one-pot three
component reaction of polyfunctional triazole with aromatic aldehydes and acetophenone
derivatives using alcoholic sodium hydroxide solution. The same new products were
prepared in classical route via reaction of triazole with the corresponding chalcones under
the same conditions.
GRAPHICAL ABSTRACT:
KEYWORDS: Triazole, Triazolotriazepine, Chalcone, Multi-component reaction,
Regioselectivity.
1

INTRODUCTION
Triazolethiones possess various biological activities including anticancer,[1,2] antiviral,[3,4]
anti-inflammatory,[5,6] antiproliferative,[7] antifungal,[8-10] antidepressant,[11]
antioxidant,[12,13] antiulicer,[12,14] and hypoglycaemic activities.[15] On the other hand,
compounds with triazepine skeletons have exhibited significant biological activities.[16,17]
The area of biological interest of this family of compounds have been extended to various
diseases such as cancer,[18] viral infections (HIV)[19] and cardiovascular disorders.[20,21]
1,2,4-Triazepines condensed with heterocycles were found to have salidiuretic and renal
vasodilator, antioxidant, and analgesic and immune modulating activities.[22–24]
Moreover, fused triazepine derivatives with a bridgehead nitrogen atom exhibit
interesting biological properties.[25] Therefore, the development of new methods for the
synthesis of these functionalized [1,2,4]triazolo[5,1-C][1,2,4]triazepine derivatives is an
important direction of synthetic chemistry. The use of multicomponent reactions as an
efficient method in the development and modification of various types of heterocyclic
systems, is a convenient approach to the preparation of a wide number of products with
certain substituents.[26,27] Hence, the discovery of novel protocols using multicomponent
strategy has become an increasingly active area of research for generating biologically
active polysubstituted nitrogen scaffolds for drug discovery program.
In view of the aforementioned facts, we have designed and developed a strategy to bring
together the [1,2,4]triazole and [1,2,4]triazepine moieties in a single fused structure by
2

one-pot multi-component reaction of polyfunctional triazole 1 with aromatic aldehydes
and acetophenone derivatives using sodium hydroxide as basic catalyst.
RESULTS AND DISCUSSION
In our previous work,[28] we have described the reaction of polyfunctional triazole 1[29]
with some enaminones in ortho-phosphoric acid to give pyrazolyltriazole derivatives I,
(Figure 1). In the present work, a facile method has been described for the synthesis of
title products II via an efficient one-pot synthesis of three-component reaction of triazole
1, aromatic aldehydes 2 and acetophenone derivatives 3 using an alcoholic solution of
sodium hydroxide as non-toxic and inexpensive catalyst, (Scheme 1). This protocol offers
flexibility in tuning the molecular complexity and diversity. The reactions proceeded to
completion in almost 8 hours and the products were obtained in good yield. From
previous work[28] and these results it’s clear that, the regioselective of the reaction of
triazole 1 with dienophiles is depends on the pH of the reaction medium.
As an introductory test, we run a model reaction in one pot by stirring at 0-5 oC of an
equimolecular amounts of benzaldehyde 2a and acetophenone 3a in aqueous ethanolic
sodium hydroxide for 1 hr. and then 4-amino-5-hydrazino-4H-[1,2,4]triazol-3-thiol 1 was
added. After addition, the reaction mixture was refluxed for 8 hours to produce the
desired product of 9-amino-3,5-diphenyl-4,9-dihydro-5H-[1,2,4]triazolo[5,1-
c][1,2,4]triazepine-8-thiol (4a) in 70 % yield. The scope of the method was investigated
with a series of aromatic aldehyde and acetophenone derivatives to afford the
corresponding product 4b-l. The same products 4a-l was also produced in the classical
3

method via reaction of 1 and chalcones 5a-l, respectively, under the same conditions,
(Scheme 1).
The plausible mechanism for the formation of product 4 was assumed to proceed via
production of chalcone 5 by reaction between aromatic aldehydes 2 and acetophenones 3,
then the condensation of 3-amino-[1,2,4]triazole (1) with chalcone 5 can proceed in two
possible ways, as shown in Scheme 1. In route 1, the NH group attacks the double bond
via a Michael addition reaction to give intermediate III, which cyclized by dehydration
through path A to give product 6 or through path B to give compound 7. On the other
hand, in route 2, the nucleophilic NH2 group of hydrazino group attacks the C=O group,
followed by elimination of H2O molecule to afford intermediate IV in tautomer with IV’.
Then, the endo-cyclic NH group of triazole ring in IV or the exo-cyclic NH of hydrazino
group in IV’ attacks the double bond via a Michael addition reaction giving product 4 or
6, respectively. The formation of product 4 and its regioselectivity has been substantiated
through NOESY spectral data.
The NOESY spectrum of compound 4j shows a correlation peak between the proton of H-
5 and two hydrogens of the exocyclic methylene group, also there is a correlation peak
between aryl protons and two hydrogens of the methylene group, in addition to a
correlation peak between the proton of the SH group and the protons of the NH2 group in
triazole ring. Also, there is no overlapping between the aromatic protons or H-5 with the
protons of the NH2 group, this results support the structure 4 and show that the structures
6 and 7 are incorrect.
4

The structures of the newly synthesized compounds 4a-l were confirmed by their spectral
(IR, 1H, 13C NMR, NOE) and elemental analyses. For example, the IR spectrum of
compound 4j shows seven absorption peaks at 1603 cm-1 for C=N, 2834, 2910, 2956 cm-1
for C-H aliphatic, 3062 cm-1 for C-H aromatic and 3160, 3268 cm-1 for NH2 group. Its
1HNMR spectrum shows the disappear of signals corresponding to hydrazino group, and
exhibits three singlet signals at δ 3.74, 5.73 and 13.15 characteristic of OCH3, NH2 and
SH groups, respectively, also it appears four doublet signals at δ 6.90, 7.34, 7.52 and 7.84
for aromatic protons, triplet signal at 5.50 with coupling constant (j) 10.6 Hz due to
CHtriazepine, and two doublet of doublets signals at δ 3.24 and 3.85 for CH2 group. The 13C
NMR spectrum of 4j shows two peaks at δ 42.3 and 64.9 which are assigned to CH2 and
CHtriazepine, respectively, one peak at δ 55.6 due to methoxy carbon, also there are three
peaks at δ 153.2, 159.4, 164.7 could be attributed for –C=N, while the other aromatic
carbon are characterized by peaks at δ 114.5, 128.6, 128.8, 129.2, 130.6, 132.2, 135.0 and
149.2.
We have then looked into possible replacing aromatic aldehydes by heterocyclic
aldehyde such as furfural; and acetophenones by 3-acetyl-, 4-acetylpyridine hoping to
obtain 9-amino-5-(furan-2-yl)-3-aryl-4,9-dihydro-5H-[1,2,4]triazolo[5,1-
c][1,2,4]triazepine-8-thiol 8a-d, 9-amino-5-aryl-3-(pyridin-3-yl)-4,9-dihydro-5H-
[1,2,4]triazolo[5,1-c][1,2,4]triazepine-8-thiol 9a-c and/or 9-amino-5-aryl-3-(pyridin-4-
yl)-4,9-dihydro-5H-[1,2,4]triazolo[5,1-c][1,2,4]triazepine-8-thiol 10a,b, respectively,
(Scheme 2). In each case the reaction underwent smoothly resulting in similar good
5

yields. The same products 8-10 were also produced in the classical route via reaction of 1
with corresponding chalcone. The chemical structure of the new products 8-10 could be
assigned to the reaction product based on IR, NMR and elemental analyses.
Reaction of triazole 1 with acetone and 4-chlorobenzaldehyde cannot proceed via one pot
multicomponent reaction, as a result of dimerization of acetone with two mole of
aldehydes in basic medium, but the reaction was optimized via two component reaction
of an equimolecular amounts of triazole 1 and 4-(4-chlorophenyl)but-3-en-2-one in an
aqueous ethanolic sodium hydroxide solution to afford the desired product 11, (Scheme
2). The structure of compound 11 was confirmed by IR, 1H, 13C NMR, NOE and
elemental analyses. Its IR spectrum shows seven absorption peaks at 3230, 3328 cm-1 due
to NH2 group, 3060 cm-1 for C-H aromatic, 2874, 2948, 2987 cm-1 for C-H aliphatic and
1636 cm-1 for C=N. Its 1HNMR spectrum shows the disappear of signals corresponding to
hydrazino group, and exhibits four singlet signals at δ 2.03, 5.59, 7.39 and 12.17 ppm
characteristic of CH3, NH2, 4CH aromatic and SH groups, respectively; triplet signal at δ
5.31 ppm with coupling constant (j) 10.6 Hz due to CHtriazepine, and two doublet of
doublets signals at δ 2.81 and 3.40 ppm for CH2 group with coupling constants (j) 11.0,
17.4. The 13C NMR spectrum of 11 shows seven peaks at δ 128.9, 129.1, 132.6, 139.8,
149.8, 156.5, 164.6 ppm, which are assigned to aromatic carbons, while there are three
peaks at δ 15.8, 46.3 and 64.0 ppm due to CH3, CH2, CHtriazepine, respectively. The
NOESY spectrum of product 11 shows across peak between CH3 (δ 2.03) and two protons
of CH2 (δ 2.82, 3.93), also there are correlation peaks between the protons of the CH
aromatic at δ 7.39 with CHtriazepine (δ 5.31) and one proton of CH2 (δ 2.82), while there is
6

no overlapping between the protons of NH2 group in triazole ring (δ 5.59) and the protons
of CH aromatic (δ 7.39).
CONCLUSIONS
In summary, we have developed a novel method for the synthesis of 9-amino-3,5-diaryl-
4,9-dihydro-5H-[1,2,4]triazolo[5,1-c] [1,2,4]triazepine-8-thiol via one-pot three
component reaction of triazole with aromatic aldehydes and acetophenone derivatives
using alcoholic sodium hydroxide solution. Also, the same products were prepared in
classical route via reaction of triazole with the corresponding chalcones under the same
conditions. Due to the availability of the starting materials, the simplicity of the
procedures, and the comparatively reasonable yields of the products, this synthetic
approach might be valuable for the synthesis of such ring systems.
EXPERIMENTAL
General Information
Melting points were detected with a Kofler melting points apparatus and uncorrected.
Infrared spectra were recorded with a FT-IR-ALPHBROKER-Platinum-ATR
spectrometer. 1H NMR and 13C NMR spectra for all compounds were recorded in
DMSO-d6 on a Bruker Bio Spin AG spectrometer at 400 MHz and 100 MHz,
respectively. Elemental analyses were obtained on a Perkin-Elmer CHN-analyzer model.
General Procedure For Synthesis of Compounds 4a-L, 8a-D, 9a-C And 10a,B:
Method A: General Procedure (Three-Component Reaction)
7

A mixture of aromatic aldehydes (0.01 mol) and acetophenone derivatives namely:
acetophenone, 4-chloro-, 4-methyl-, 4-methoxyacetophenone, 3-acetylpridine and/or 4-
acetylpyridine (0.01 mol) was stirred in an ice bath for 1 hr in 60 ml alcoholic sodium
hydroxide 0.5M (1.2 g NaOH in 40 ml ethanol and 20 ml water), then 4-amino-5-
hydrazino-4H-[1,2,4]triazol-3-thiol 1 (0.01 mol) was added to the reaction mixture. The
resulting mixture was heated for about 8 hrs. After completion of reaction (monitored
with TLC), the reaction mixture was cooled to RT, poured into ice-cold distilled water
and neutralized to pH ~ 6.5 with dilute hydrochloric acid. The crude precipitate which
formed was collected by filtration, washed several times with distilled water and dried.
For elemental analyses the products were recrystallized from ethanol.
Method B: General Procedure (Two-Component Reaction)
An equimolar amounts (0.01 mol) of chalcone and 4-amino-5-hydrazino-4H-
[1,2,4]triazol-3-thiol 1 was heated in 60 ml alcoholic sodium hydroxide 0.5M (1.2 g
NaOH in 40 ml ethanol and 20 ml water) for about 8 hrs. After completion of reaction
(monitored with TLC), the reaction mixture was cooled to RT, poured into ice-cold
distilled water and neutralized to pH ~ 6.5 with dilute hydrochloric acid. The crude
precipitate which formed was collected by filtration, washed several times with distilled
water and dried. For elemental analyses the products were recrystallized from ethanol.
9-Amino-3-(4-Chlorophenyl)- 5-(4-Methoxyphenyl)-4,9-Dihydro-5H-[1,2,4]-
Triazolo[5,1-C][1,2,4]-Triazepine-8-Thiol (4j)
8

Yield (Method A 75%, Method B 81 %); greenish yellow solid; m.p.: 218-219 °C. IR
cm-1. 1H NMR (400 MHz,
(ATR)
max 3268, 3160, 3062, 2956, 2910, 2834, 1603
DMSO-d6) 13.15 (s, 1H, SH), 7.84 (d, j = 8.4 Hz, 2H, CHarom.), 7.52 (d, j = 8.4 Hz,
2H, CHarom.), 7.34 (d, j = 8.6 Hz, 2H, CHarom.), 6.90 (d, j = 8.6 Hz, 2H, CHarom.), 5.73
(s, 2H, NH2), 5.50 (t, j = 10.6 Hz, 1H, CHtriazepine), 3.85 (dd, j = 17.3, 11.0 Hz, 1H, CH2),
3.74 (s, 3H, OCH3), 3.24 (dd, j = 17.3, 10.2 Hz, 1H, CH2). 13C NMR (100 MHz, DMSO-
d6) 164.7, 159.4, 153.2, 149.2, 135.0, 132.2, 130.6, 129.2, 128.8, 128.6, 114.5, 64.9,
55.6, 42.3. Anal. Calcd. for C18H17ClN6OS (400): C, 53.93; H,4.27; N, 20.96. Found: C,
54.01; H, 4.19; N,20.89.
9-Amino-5-(2-Furyl)-3-Phenyl-4,9-Dihydro-5H-[1,2,4]Triazolo[5,1-C][1,2,4]-
Triazepine-8-Thiol (8a)
Yield (Method A 64%, Method B 66 %); white solid; m.p.: 227-228 °C. IR (ATR)
max
cm-1. 1H NMR (400 MHz, DMSO-d6) 13.16 (s,
3295, 3200, 3082, 2963, 2933, 1618
1H, SH), 7.83 (s, 2H, CHphenyl), 7.59 (s, 1H, CHfuryl), 7.48 (s, 3H, CHphenyl), 6.48 (s, 1H,
CHfuryl), 6.40 (s, 1H, CHfuryl), 5.73(t, j = 9.1 Hz, 1H, CHtriazepine), 5.66 (s, 2H, NH2), 3.80
(dd, j = 16.6, 11.6 Hz, 1H, CH2), 3.51 (dd, j = 16.9, 8.6 Hz, 1H, CH2). 13C NMR (100
MHz, DMSO-d6) 165.2, 154.4, 151.7, 149.6, 143.6, 131.5, 130.5, 129.1, 127.1, 110.9,
109.2, 58.5, 38.5. Anal. Calcd. for C15H14N6OS (326): C, 55.20; H, 4.32; N, 25.75.
Found: C, 55.28; H, 4.22; N,25.71.
9-Amino-5-Phenyl-3-Pyridin-3-Yl-4,9-Dihydro-5H-[1,2,4]Triazolo[5,1-C]-[1,2,4]-
Triazepine-8-Thiol (9a)
9

Yield (Method A 69%, Method B 70 %); pale yellow solid; m.p.: 188-190 °C. IR (ATR)
cm-1. 1H NMR (400 MHz, DMSO-d6) 13.05
max 3321, 3220, 3055, 2943, 2909, 1602
(s, 1H, SH), 9.01 (s, 1H, CHpyridyl), 8.64 (d, j = 3.9 Hz, 1H, CHpyridyl), 8.21 (d, j = 8.0 Hz,
1H, CHpyridyl), 7.50 (dd, j = 7.9, 4.8 Hz, 1H, CHpyridyl), 7.43 (d, j = 7.2 Hz, 2H, CHphenyl),
7.36 (t, j = 7.2 Hz, 2H, CHphenyl), 7.3 (m, 1H, CHphenyl), 5.77 (s, 2H, NH2), 5.57 (t, j =
10.8 Hz, 1H, CHtriazepine), 3.96 (dd, j = 17.4, 11.2 Hz, 1H, CH2), 3.30 (dd, j = 17.0, 10.7
Hz, 1H, CH2). 13C NMR (100 MHz, DMSO-d6) 164.8, 152.2, 151.0, 149.2, 148.2,
140.4, 134.2, 129.1, 128.3, 127.6, 127.3, 124.1, 65.3, 42.3. Anal. Calcd. for C16H15N7S
(337): C, 56.96; H, 4.48; N, 29.06. Found: C, 56.99; H, 4.32; N,29.09.
Synthesis of 9-Amino-5-(4-Chlorophenyl)-3-Methyl-4,9-Dihydro-5H-[1,2,4]-
Triazolo[5,1-C][1,2,4]Triazepine-8-Thiol (11)
An equimolar amounts (0.01 mol) of 4-(4-chlorophenyl)but-3-en-2-one and 4-amino-5-
hydrazino-4H-[1,2,4]triazol-3-thiol was heated in 60 ml alcoholic sodium hydroxide
0.5M (1.2 g NaOH in 40 ml ethanol and 20 ml water) for 8 hrs (monitored with TLC).
After completion of reaction, the reaction mixture was cooled to RT, poured into ice-cold
distilled water and neutralized to pH ~ 6.5 with dilute hydrochloric acid. The crude
precipitate which formed was collected by filtration, washed several times with distilled
water and dried. For elemental analyses the crude was recrystallized from ethanol to give
11. Yield 81 %; white solid; m.p.: 252-253 °C. IR (ATR) ν
max 3328, 3230, 3060, 2987,
cm-1. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H, SH), 7.39 (s, 4H,
2948, 2874, 1636
CHarom.), 5.59 (s, 2H, NH2), 5.31 (t, j = 10.6 Hz, 1H, CHtriazepine), 3.40 (dd, j = 17.4, 11.0
13
Hz, 1H, CH2), 2.81 (dd, j = 17.4, 10.4 Hz, 1H, CH2), 2.03 (s, 3H, CH3). C NMR
10

(100 MHz, DMSO-d6) δ 164.6, 156.5, 149.8, 139.8, 132.6, 129.1, 128.9, 64.0,
46.3, 15.8. Anal. Calcd. for C12H13ClN6S (308): C, 46.68; H, 4.24; N, 27.22. Found: C,
46.71; H, 4.21; N,27.32.
SUPPORTING INFORMATION
Complete experimental procedures and characterization data of compounds 4 & 8-11
associated with this manuscript are found in the Supporting Information file.
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13

Scheme 1. Reaction mechanism and stereoselective synthesis of [1,2,4]triazolo[5,1-
c][1,2,4]triazepines 4a-l.
14

Scheme 2. Synthesis of [1,2,4]triazolo[5,1-c][1,2,4]triazepines 8-11.
15

Figure 1.
16