Efficient synthesis of 3-substituted 1,2,4-triazolo[4,3-a]pyridine by [bis(trifluroacetoxy)iodo]benzene-catalyzed oxidative intramolecular cyclization of heterocyclic hydrazones

Article abstract of DOI:10.1080/00397911003707162

A series of 1,2,4-triazolopyridines have been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with [bis(trifluroacetoxy) iodo]benzene. General applicability of this simple transformation was confirmed by synthesis of 1,2,4-triazolo[4,3-a]pyridine. The advantages of this protocol are the nontoxicity of catalyst and shorter reaction time to obtain good preparative yield.

Full text of DOI:10.1080/00397911003707162

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Efficient Synthesis of 3-Substituted
1,2,4-Triazolo[4,3-a]pyridine by
[Bis(Trifluroacetoxy)iodo]benzene-
Catalyzed Oxidative Intramolecular
Cyclization of Heterocyclic Hydrazones
Vikas S. Padalkar a , Vikas S. Patil a , Kiran R. Phatangare a , Prashant
G. Umape a & N. Sekar a
a Institute of Chemical Technology, Matunga, Mumbai, India
Published online: 25 Feb 2011.
To cite this article: Vikas S. Padalkar , Vikas S. Patil , Kiran R. Phatangare , Prashant G.
Umape & N. Sekar (2011) Efficient Synthesis of 3-Substituted 1,2,4-Triazolo[4,3-a]pyridine by
[Bis(Trifluroacetoxy)iodo]benzene-Catalyzed Oxidative Intramolecular Cyclization of Heterocyclic
Hydrazones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:6, 925-938
To link to this article: http://dx.doi.org/10.1080/00397911003707162
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Synthetic Communications1, 41: 925–938, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003707162
EFFICIENT SYNTHESIS OF 3-SUBSTITUTED
1,2,4-TRIAZOLO[4,3-a]PYRIDINE BY
[BIS(TRIFLUROACETOXY)IODO]BENZENE-CATALYZED
OXIDATIVE INTRAMOLECULAR CYCLIZATION OF
HETEROCYCLIC HYDRAZONES
Vikas S. Padalkar, Vikas S. Patil, Kiran R. Phatangare,
Prashant G. Umape, and N. Sekar
Institute of Chemical Technology, Matunga, Mumbai, India
GRAPHICAL ABSTRACT
Abstract A series of 1,2,4-triazolopyridines have been prepared by oxidative intramolecular
cyclization of heterocyclic hydrazones with [bis(trifluroacetoxy)iodo]benzene. General
applicability of this simple transformation was confirmed by synthesis of 1,2,4-triazolo
[4,3-a]pyridine. The advantages of this protocol are the nontoxicity of catalyst and shorter
reaction time to obtain good preparative yield.
Keywords [Bis(trifluroacetoxy)iodo]benzene; hydrazones; oxidation; 1,2,4-triazole
INTRODUCTION
Triazolopyridines represent an important class of heterocyclic compounds
having a wide range of pharmaceutical and biological activities including herbicidal,
antifungal, anticonvulsant, and anxiolytic activities.[1] A simple, versatile, and widely
applicable method for the synthesis of 1,2,4-triazolopyridine is therefore of consider-
able interest. The available methods for the preparation of triazolopyridine are based
on heterocyclic hydrazones or hydrazides as precursors. However, these methods
have some restrictions as regards to their applicability as they involve the use of toxic
reagents such as phosphorus oxychloride,[2] lead tetra-acetate,[2,3] bromine,[3,4] and
Received December 8, 2009.
Address correspondence to N. Sekar, Institute of Chemical Technology, Matunga, Mumbai 400
019, India. E-mail: sekarnm@rediffmail.com
925

926
V. S. PADALKAR ET AL.
Scheme 1. Synthesis of 3-substituted 1,2,4-triazolo[4,3-a]pyridine from 2-chloropyridine.
oxidation of 2-pyridylhydrazones with nitrobenzene at reflux temperature.[5]
Recently, synthetic methodologies have been developed using PS-PPh3=CCl3 under
microwave heating,[6] (diacetoxy) iodo benzene,[7] and oxidant chloroamine T,[8] as
well as electrochemical methods.[9] However, they also have some limitations such
as moisture sensitivity of the reagents, use of hazardous chemicals, and difficulty
in storage of reagents.
As a part of our ongoing research on 1,2,4-triazoles and to overcome the
limitations of the reported methods for the synthesis of 1,2,4-triazolopyridine, we
describe here in this letter a simple, efficient protocol for the synthesis of 1,2,4-triazo-
lopyridine by oxidative heterocyclization of hydrazones using [bis(trifluroacetoxy)
iodo]benzene.
Hypervalant iodine regents have found widespread applications in organic
synthesis because of their selectivity and simplicity in use.[10,11] [Bis(trifluroacetoxy)-
iodo]benzene is commercially available as a colorless crystalline solid. It is fairly
stable and can be kept without refrigeration for a long time with protection from
light. It is used for the synthesis of bridgehead heterocycles, synthesis of N-arylated
and N-alkylated heterocyclic fused aromatic compounds,[12] synthesis of pyrrolidi-
none and lactone skeletons,[13] oxidative deprotection of dithiane-containing
alkaloids,[14] direct a-hydroxylation of ketones,[15] and synthesis of azides.[16] In this
communication, we explore the applicability of [bis(trifluroacetoxy)iodo]benzene
(Scheme 1).
RESULTS AND DISCUSSION
Reaction of 2-chloropyridine (1) with hydrazine hydrate at a reflux tempera-
ture resulted in the formation of 2-hydrazinopyridine (2). Further condensation with
different aldehydes (3) in ethanol at a reflux temperature gave the corresponding
hydrazones (4) with high yield and purity. The hydrazones thus obtained were
oxidized by using [bis(trifluroacetoxy)iodo]benzene to give the corresponding 3-sub-
stituted 1,2,4-triazolo[4,3-a]pyridine (5).
Initially, the reaction of 2-hydrazinopyridine with benzaldehyde was carried
out in ethanol at reflux temperature as model reaction to explore the suitable
reaction condition for preparation of different hydrazones (Table 1, entry a).

OXIDATION OF 1,2,4-TRIAZOLE
927
Table 1. Synthesis of heterocyclic hydrazones from 2-hydrazinopyridine and different substituted
aldehydes
Entry
Aldehyde (3)
Product (4)
Yield (%) Mp (ꢀC)
a
92
148
b
c
i
98
189
98
195
98
215
(Continued )

928
V. S. PADALKAR ET AL.
Table 1. Continued
Product (4)
Entry
Aldehyde (3)
Yield (%)
Mp (ꢀC)
e
92
153
f
96
89
87
158
223
220
g
h
(Continued )

OXIDATION OF 1,2,4-TRIAZOLE
929
Table 1. Continued
Product (4)
Entry
Aldehyde (3)
Yield (%) Mp (ꢀC)
i
90
128
j
82
167
k
91
182
l
93
158
(Continued )

930
V. S. PADALKAR ET AL.
Table 1. Continued
Product (4)
Entry
Aldehyde (3)
Yield (%)
Mp (ꢀC)
m
89
189
n
92
175
o
p
94
92
185
164
aReagents and reaction conditions: 2-hydrazinopyridine (10 mmol), aldehydes (10 mmol); solvent:
ethanol; temperature: reflux temperature; time: 20 min.
bStarting compound 2-hydrazinopyridine prepared by the standard reported procedure.
cIsolated yield.
dCompounds were confirmed by physical constants.
Subsequently, the reaction was extended with different substituted aldehydes
carrying both electron-releasing as well as electron-withdrawing substituents.
Heterocyclization was carried out in dichloromethane at room temperature.
To identify an optimal reaction condition for oxidative heterocyclization to the
desired triazolopyridine 5, various solvents were studied (Table 2) at different
temperatures with heterocyclization of 2-[(2E)-2-benzylidenehydrazinyl] pyridine
as the model reaction (Table 3, entry a) in the presence of [bis (trifluroacetoxy)
iodo] benzene.

OXIDATION OF 1,2,4-TRIAZOLE
931
Table 2. Optimization of reaction condition for the synthesis
of triazolopyridine
Entry
Solvent
Yielda
Temp. (ꢀC)
1
2
3
4
5
CH3CN
THF
59
71
94
75
63
75
75
25
60
55
CH2Cl2
CCl4
MeOH
aIsolated yield after crystallization in benzene.
Note. Catalyst: [bis(trifluroacetoxy)iodo]benzene (11 mmol
equivalent); time: 10 min.
Encouragingly, we quickly noticed that when dichloromethane was used as a
solvent, compound 5 was obtained with complete conversion as confirmed by
thin-layer chromatography (TLC). Subsequently, we were delighted to discover that
nearly quantitative conversion to 5 was observed when the reaction is carried out in
dichloromethane at room temperature.
These conditions were used further to study the scope of the transformation.
Gratifyingly, this paradigm was found to be quite general and worked well for both
electron-donating and electron-withdrawing heterocyclic hydrazones to afford the
desired triazolopyridine in excellent yields (Table 3) in a short reaction time. The
reaction proved to have facile workup.
CONCLUSION
In conclusion, we have developed an efficient and simple protocol for the synthesis
of a wide variety of 1,2,4-triazolo compounds by oxidation of heterocyclic substituted
hydrazones using trivalent iodine regent [bis(trifluroacetoxy)iodo]benzene at room tem-
perature. The method developed is mild and gives good yield of 1,2,4-triazolo(4,3-
a)pyridine starting from 2-chloropyridine. We believe that this approach provides the
advantage for both focused library synthesis and diversity-oriented synthesis.
EXPERIMENTAL
All commercial reagents and solvents were procured from S. D. Fine chemicals
(India) and were used without further purification. The reaction was monitored by
TLC using 0.25-mm E-Merck silica-gel 60 F254 precoated plates, which were visua-
lized with ultraviolet light. Melting points were measured on a standard melting-point
1
apparatus from Sunder Industrial Product Mumbai and are uncorrected. H NMR
spectra were recorded on VXR 400-MHz instrument using tetramethylsilane
(TMS) as an internal standard.
Procedure for Preparation of 2-Hydrazine Pyridine (2)
2-Chloropyridine (20 mmol) was mixed with hydrazine hydrate (5 vol), and the
resultant mixture was heated under reflux in an oil bath for 6 h. The reaction was

932
V. S. PADALKAR ET AL.
Table 3. Synthesis of 1,2,4-triazolo[4,3-a]pyridine from heterocyclic hydrazones by using [bis-
(trifluroacetoxy)iodo]benzene
Entry
Hydrazones
Product
Yield (%)
a
94
b
c
d
91
94
89
(Continued )

OXIDATION OF 1,2,4-TRIAZOLE
933
Table 3. Continued
Entry
Hydrazones
Product
Yield (%)
e
91
f
87
93
95
g
h
i
88
(Continued )

934
V. S. PADALKAR ET AL.
Table 3. Continued
Entry
Hydrazones
Product
Yield (%)
j
85
k
91
l
90
m
84
(Continued )

OXIDATION OF 1,2,4-TRIAZOLE
935
Table 3. Continued
Entry
Hydrazones
Product
Yield (%)
n
88
o
94
p
96
aReagents and reaction conditions: Hydrazones (10 mmol), [bis-(trifluroacetoxy)iodo]benzene
(11 mmol); solvent: anhydrous dichloromethane; temperature: room temperature; time: 10 min.
bIsolated yield after crystallization and structure were confirmed by 1H NMR spectra and physical
constants.
monitored by TLC. After the completion of the reaction, the reaction mixture was
cooled and extracted with diethyl ether (2 ꢁ 20 mL). The organic layer was dried over
anhydrous sodium sulfate and kept in the freezer. A white crystalline powder of the
product was obtained. Yield 79%, mp 45 ꢀC (lit. 45–46 ꢀC).
General Procedure for Preparation of Heterocyclic Hydrazones (4a–p)
2-Hydrazinopyridine (2) (10 mmol) was dissolved in a boiling ethanol (10 mL),
and the different substituted aldehydes (3a–p) (10 mmol in 10 mL ethanol), were
added dropwise to the solution. After that, the solution was stirred and heated under
reflux for 20 min. The hydrazones (4a–p) formed were filtered from the cooled
solution and used in the next reaction without purification.

936
V. S. PADALKAR ET AL.
General Procedure for Preparation of 1,2,4-Triazolo[4,3-a]pyridines
(5a–p)
Hydrazones (4a–p) (10 mmol) was dissolved in dichloromethane (10 mL),
[bis(trifluroacetoxy)iodo]benzene (11 mmol) was added, and the reaction mixture
was stirred at room temperature for 10 min. After completion of the reaction,
the reaction mixture was diluted with dichloromethane (10 mL) and washed succes-
sively with 10% sodium bisulfate solution (2 ꢁ 20 mL), 10% sodium bicarbonate
solution (2 ꢁ 20 mL), and water (2 ꢁ 20 mL). The organic layer obtained was dried
over anhydrous sodium sulfate and concentrated under reduced pressure to give
the crude product, which was further crystallized from ethanol to afford the
product.
Representative Spectral Data
3-Phenyl-[1,2,4]triazolo[4,3-a]pyridine (Table 3, entry a). 1H NMR
(400 MHz) d 7.12 (t, 1H), 7.56–7.62 (m, 4H), 7.87–7.94 (m, 3H), 8.59 (m, 1H); mp
174 ꢀC; HPLC purity: 99.87%.
3-(4-Chlorophenyl)[1,2,4]triazolo[4,3-a]pyridine (Table 3, entry c). 1H
NMR (400 MHz) d 7.21 (d, 2H), (7.25–7.48, m, 4H), 7.84 (m, 1H), 7.52 (m,1H),
8.68 (d, 1H); mp 132 ꢀC; HPLC purity: 99.31%.
3-(4-Methylphenyl)[1,2,4]triazolo[4,3-a]pyridine (Table 3, entry e). 1H
NMR (400 MHz) d 2.43 (s, 3H), 7.23 (d, 2H), 7.41 (d, 2H), 8.65 (d, 2H), 7.83
(m, 1H), 7.43 (m, 2H); mp 152 ꢀC; HPLC purity: 98.89%.
3-(4-Methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine (Table 3, entry f). 1H
NMR (400 MHz) d 3.83 (3H, s), 6.92 (d, 2H), 7.43 (d, 2H), 8.61 (d, 1H), 7.81
(m, 1H), 7.45 (m, 2H); mp: 125 ꢀC; HPLC purity: 99.08%.
3-(3-Nitrophenyl)[1,2,4]triazolo[4,3-a]pyridine (Table 3, entry g). 1H
NMR (400 MHz) d 7.01 (m,1H), 7.37 (m, 1H), 7.87 (m, 2H), 8.32 (m, 2H), 8.58
(m, 2H); mp 290 ꢀC; HPLC purity: 99.45%.
N,N-Dimethyl-4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)aniline
(Table
3,
entry k). 1H NMR (400 MHz) d 2.96 (s, 6H), 6.87 (d, 2H), 7.19 (m,1H), 7.64 (m,
3H), 7.97 (d, 1H), 8.57 (d, 1H); mp 192 ꢀC; HPLC purity: 98.86%.
9-Ethyl-3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-9H-carbazole
(Table
3,
entry o). 1H NMR (400 MHz) d 1.63 (s, 3H), 3.94 (q, 2H), 7.43 (d, 1H), 7.13 (m,
1H), 7.02 (m, 1H), 7.62 (d, 2H), 7.30 (d, 2H), 7.43 (d, 1H), 8.64 (d, 1H), 7.43 (m,
2H); mp 167 ꢀC; HPLC purity: 99.23%.
1
3-[(E)-2-Phenylethenyl][1,2,4]triazolo[4,3-a]pyridine (Table 3, entry p). H
NMR (400 MHz) d 6.99 (d, 1H), 6.76 (d, 1H), 7.24–7.43 (m, 6H), 8.69 (d, 1H), 7.85
(d, 1H), 7.58 (m, 1H); mp 169–171 ꢀC; HPLC purity: 99.57%.

OXIDATION OF 1,2,4-TRIAZOLE
937
ACKNOWLEDGMENT
The author is thankful to Indian Institute of Technology Mumbai, for provid-
1
ing the H NMR facility.
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