A convenient one-pot synthesis of N-fused 1,2,4-triazoles via oxidative cyclization using chromium (VI) oxide

Article abstract of DOI:10.1080/00397911.2018.1529795

A facile one-pot synthesis of N-fused 1,2,4-triazoles from heterocyclic hydrazines and aldehydes is reported. The reaction is efficiently promoted by chromium (VI) oxide to afford the desired products mostly in high yields and in relatively short time. The high yield of the products and short reaction time are notable advantages of the developed protocol. This protocol is effective toward various substrates having different functionalities.

Full text of DOI:10.1080/00397911.2018.1529795

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A convenient one-pot synthesis of N-fused 1,2,4-
triazoles via oxidative cyclization using chromium
(VI) oxide
Ashish Bhatt, Rajesh K. Singh & Ravi Kant
To cite this article: Ashish Bhatt, Rajesh K. Singh & Ravi Kant (2019) A convenient one-pot
synthesis of N-fused 1,2,4-triazoles via oxidative cyclization using chromium (VI) oxide, Synthetic
Communications, 49:1, 22-31, DOI: 10.1080/00397911.2018.1529795
To link to this article: https://doi.org/10.1080/00397911.2018.1529795
View supplementary material
Published online: 31 Jan 2019.
Submit your article to this journal
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
R
SYNTHETIC COMMUNICATIONSV
2019, VOL. 49, NO. 1, 22–31
https://doi.org/10.1080/00397911.2018.1529795
A convenient one-pot synthesis of N-fused
1,2,4-triazoles via oxidative cyclization
using chromium (VI) oxide
Ashish Bhatta , Rajesh K. Singhb, and Ravi Kanta
b
aDepartment of Chemistry, Mewar University, Chittorgarh, Rajasthan, India; Department of Pharmacy,
Mewar University, Chittorgarh, Rajasthan, India
ABSTRACT
ARTICLE HISTORY
Received 12 August 2018
A facile one-pot synthesis of N-fused 1,2,4-triazoles from heterocyclic
hydrazines and aldehydes is reported. The reaction is efficiently pro-
moted by chromium (VI) oxide to afford the desired products mostly
in high yields and in relatively short time. The high yield of the prod-
ucts and short reaction time are notable advantages of the devel-
oped protocol. This protocol is effective toward various substrates
having different functionalities.
KEYWORDS
Acetic acid; chromium (VI)
oxide; 1,2,4-triazoles;
[1,2,4]triazolo[4,3-a]pyri-
dines; [1,2,4]tria-
zolo[4,3-a]pyrazines
GRAPHICAL ABSTRACT
NH2
HN
X
Y
N
O
CrO3
N
+
X
N
Y
N
Het/Ar
H
Acetic acid, 110 °C
Ar/Het
3
2
1
X, Y = C or N
Ar = Ph, 2-Me Ph, 4-OMe Ph, 4-Cl Ph, 4-Br Ph, 4-CN Ph
Het = 2-furyl, 5-thiazolyl, 3-indolyl
Introduction
Fused aromatic heterocycles are among the most important compound classes in drug
discovery and also play a pivotal role in living organisms.[1,2] In particular, such scaf-
folds can be found as building blocks for DNA (guanine, adenine) but also in many
approved drugs including sildenafil, zolpidem, and trazodone, as well as in medicinal
chemistry studies[3–6] (i.e., tyrosine kinase c-Src inhibitors[7,8] or P38a inhibitors[8]
[Figure 1]).
CONTACT Ravi Kant
itsbhatt2007@yahoo.co.in
Department of Chemistry, Mewar University, NH-79, Gangrar,
Chittorgarh, Rajasthan 312901, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpom.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
R
SYNTHETIC COMMUNICATIONSV
23
O
N
NH
HN
F
N
N
F
N
N
O
N
N
N
N
O
N
N
H
N
sildenafil
P-38 a inhibitor
tyrosine kinase
c-Src inhibitor
N
N
N
N
N
N
N
O
O
N
Cl
trazodone
zolpidem
1,2,4-Triazoles have elicited considerable interest among medicinal chemists because
they are considered to be privileged structural constituents of many pharmaceutical
agents as well as natural products. In particular, compounds containing N-fused 1,2,4-
triazoles, such as triazolopyridine and triazolopyrazine substructures exhibit a wide
spectrum of biological activity including antifungal,[9] antimicrobial,[10] antiviral,[11]
anti-inflammatory,[12] antiasthmatic,[13] antiproliferative,[14] and hypotonic.[15] In add-
ition, they have often been used as bioisosteres of esters and amides, and as dipeptido-
mimetics in a number of pharmacologically important molecules.[16] On the other
hand, they also play important roles as ligands in organometallic compounds, as precur-
sors for N-heterocyclic carbenes, as ionic liquids and as corrosion inhibitors.[17]
Due to their importance, many efficient methods have been developed to access N-
fused 1,2,4-triazoles.[18] Among them, coupling of carboxylic acids or their derivatives
with amidrazones, followed by cyclodehydration is the most common explored strategy
(Scheme 1).[19] However, some of these protocols suffer from the limitations of harsh
conditions, tedious synthetic procedures, time taking reactions and unsatisfactory yields.
Hence, the development of milder and more general procedures to access N-fused 1,2,4-
triazoles with high yields in short reaction time remains desirable.
The described oxidative cyclization has previously been reported for the preparation
of triazoloquinoxalines.[20–26] Other methods reported in the literature for the
NH2
N
R
NH
N
HN
HN
N
O
Z
O
N
+
N
R
X
- H2O
Z
Z
R
X = Cl, OH
Scheme 1. General synthesis of N-fused 1,2,4-triazoles.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
24 A. BHATT ET AL.
Table 1. Optimization of the reaction conditions.
NH2
HN
O
N
CrO3
N
N
+
N
Ph
H
Solvent, 110 °C
Ph
2a
1a
3a
Entry
Solvent
CrO3 (eq.)
Time
Yield (%)
1
2
3
4
5
7
8
9
Formic acid
AcOH
DMF
DMSO
HMPT
AcOH
0.5
0.5
0.5
0.5
0.5
1
1 h
45 min
1.5 h
1.5 h
1 h
30 min
15 min
10 min
71
80
50
60
65
90
95
81
AcOH
AcOH
1.5
2
cyclization of the triazole ring usually require a combination of NBS and base,[27]
refluxing orthoesters,[28,29] acids,[29,30] desulfurization of thiosemicarbazides,[31] or cyc-
lization of hydrazides in polyphosphoric acid (PPA).[29] A couple of examples of oxida-
tive cyclizations using chloramine-T have previously been reported.[32]
Chromium trioxide (CrO3) is one of the most widely used of all oxidizing reagents in
organic synthesis because of its commercial availability at low cost. Our continued inter-
est in the development of useful synthetic methodologies prompted us to explore the
feasibility of chromium trioxide (CrO3) for the one-pot synthesis of N-fused 1,2,4-tria-
zoles with high yields. However, it has not been investigated as a catalyst in the synthe-
sis of 1,2,4-triazoles until now.
Result and discussion
Our preliminary investigation began with the reaction of 2-hydrazinopyridine (1a) and
benzaldehyde (2a) in the presence of CrO3 (0.5 eq.) in formic acid at 110 ꢀC tempera-
ture. We were delighted to observe the formation of the desired product (3a), albeit in
a low yield of 71% (Table 1, entry 1). Next, we optimized the reaction conditions in
order to increase the yield. Thus, different solvents were screened and the results are
summarized in Table 1. It was found that acetic acid was the most superior solvent in
terms of the reaction time and yield of the product (Table 1, entry 2). Once, we had
established a suitable solvent for the synthesis of N-fused 1,2,4-triazoles, we then
focused on the quantity of CrO3. An increase in the amount of CrO3 (from 0.5 eq. to
1.5 eq.) not only decreased the reaction time from 1 h to 15 min, but also increased the
product yield from 80% to 95% (Table 1, entry 8). Further increasing the quantity of
CrO3 (from 1.5 eq. to 2 eq.) led to a decrease in the yield to 81% (Table 1, entry 9).
Therefore, we decided to perform the subsequent reactions of the heterocyclic hydra-
zines with different aldehydes in the presence of CrO3 (1.5 eq.) in acetic acid at 110 ꢀC.
The effect of temperature on the reaction rate as well as on the yields of the products
was also investigated. Faster reactions occurred on increasing the temperature but the