A simple one-pot procedure for the synthesis of 1,2,4-triazolo[1,5-a ]pyrid-ines via pseudo five-component reactions catalyzed by molecular iodine

Article abstract of DOI:10.1055/s-0033-1339333

In this paper we report the synthesis of the 1,2,4-triazolo[1,5-a]pyridine ring system. The reaction between benzylidenehydrazines, dialkyl acetylenedicarboxylates, benzaldehydes, and malononitrile proceeds in EtOH at reflux in the presence of molecular iodine as catalyst in good to excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339333

LETTER
▌1825
lAetteSr imple One-Pot Procedure for the Synthesis of 1,2,4-Triazolo[1,5-a]pyrid-
ines via Pseudo Five-Component Reactions Catalyzed by Molecular Iodine
Synthesis of 1,2,4-Triazolo[1,5-a]pyridines
Abdolali Alizadeh,* Vahid Saberi, Javad Mokhtari
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received: 23.04.2013; Accepted after revision: 10.06.2013
preparation of biologically active compounds,8 we report
Abstract: In this paper we report the synthesis of the 1,2,4-triazo-
herein a single-step elaboration of 1,2,4-triazolo[1,5-
lo[1,5-a]pyridine ring system. The reaction between benzylidene-
a]pyridines using a conceptually distinct iodine-catalyzed
oxidative coupling approach.
hydrazines, dialkyl acetylenedicarboxylates, benzaldehydes, and
malononitrile proceeds in EtOH at reflux in the presence of molec-
ular iodine as catalyst in good to excellent yields.
On the basis of the known ability of molecular iodine to
activate imine bonds9 and the recently developed catalytic
construction of spiro nitrogen heterocycles,10 we envis-
aged a direct synthesis of 1,2,4-triazolo[1,5-a]pyridines
by reaction of hydrazones, dialkyl acetylenedicarboxyl-
ates, aldehydes, and malononitrile, leading initially to 1,4-
dihydropyridines and then molecular-iodine-catalyzed
C–N bond formation and synthesis of the 1,2,4-triazole nu-
cleus. To explore this approach, we selected benzylidene-
hydrazine (1a), dimethyl acetylenedicarboxylate (2a), 4-
chlorobenzaldehde (3a), and malononitrile for reaction
development and screened molecular iodine in a range of
solvents (Table 1). When 1a, 2a, 3a, and malononitrile
were reacted in the presence of 10 mol% molecular iodine
in ethanol at reflux under air, dimethyl 7-(4-chlorophe-
nyl)-8-cyano-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-
5,6-dicarboxylate (4a)11 was obtained in 75% yield (Table
1, entry 3).
Key words: benzylidenehydrazine, dialkyl acetylenedicarboxyl-
ate, benzaldehyde, malononitrile, 1,2,4-triazolo[1,5-a]pyridine, cat-
alyst, iodine, multicomponent reaction
The 1,2,4-triazole nucleus is an important structural motif
present in a large number of functionalized molecules
with a wide variety of uses, including applications in me-
dicinal chemistry, materials science, and organocatalysis.
As an example, 1,2,4-triazolo[1,5-a]pyridines1 provided
novel hinge binding motifs for the design of small-mole-
cule ATP-competitive JAK2 inhibitors (Figure 1).
N
N
HN
OMe
N
N
N
Me
N
N
NH
O
N
N
R
Table 1 Synthesis of 4a under Different Reaction Conditions
O
S
Me
Cl
O
O
Figure 1 Biologically active compounds having a 1,2,4-triazo-
lo[1,5-a]pyridine unit
CO2Me
CHO
+
MeO2C
MeO2C
CN
CN
CN
NH2
Ph
N
+
+
This class of heterocycles is of considerable interest due
to their use as antihypertensive, bronchodilatory, anti-in-
flammatory, analgesic, and positive inotropic agents.2–4
The importance of this heterocyclic moiety has prompted
the development of many practical synthetic routes to
1,2,4-triazole derivatives.5 The majority of these routes
rely on intramolecular condensation reactions of N-acyl-
amidrazones obtained from hydrazines and carboxylic
acid derivatives.6 A number of literature7 methods to pre-
pare the 1,2,4-triazolo[1,5-a]pyridine core were evaluated
and adapted to meet our design modifications. Although
the existing synthetic methods have provided a wide vari-
ety of 1,2,4-triazolo[1,5-a]pyridine, these typically in-
volve multistep reaction sequences. As part of our
continuing efforts into the design of new routes for the
Cl
N
N
CO2Me
N
Ph
1a
2a
3a
4a
Entry
Solvent
Catalyst (mol%) Time (h)
Yield (%)a
1
2
3
4
5
6
EtOH
EtOH
EtOH
MeCN
MeOH
EtOH
I2 (20)
I2 (15)
I2 (10)
I2 (20)
I2 (20)
–
5
5
74
73
75
56
61
0
5
12
12
24
a Benzylidenehydrazine (1 mmol), dimethyl acetylenedicarboxylate
(1 mmol), 4-chlorobenzaldehde (1 mmol), and malononitrile (1 mmol).
SYNLETT 2013, 24, 1825–1829
Advanced online publication: 01.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339333; Art ID: ST-2013-D0375-L
© Georg Thieme Verlag Stuttgart · New York

1826
A. Alizadeh et al.
LETTER
The reaction also proceeded in other solvents such as ace- amount of molecular iodine was increased to 15 mol% or
tonitrile and methanol, albeit in lower yield (Table 1, en- 20 mol% (74% and 73% yields, Table 1, entries 1 and 2).
tries 5 and 6). In another attempt, when the reaction was
With the optimum reaction conditions in hand, we next in-
carried out in the absence of molecular iodine, no product
vestigated the scope of the synthesis of 1,2,4-triazolo[1,5-
was formed after 24 hours at 25 °C (Table 1, entry 6). Un-
a]pyridine (Table 2). Benzaldehydes with electron-with-
drawing and electron-releasing groups gave the corre-
sponding 1,2,4-triazolo[1,5-a]pyridines 4a–h in good
der the same reaction conditions, it was expectable to ob-
serve that similar high yields were obtained when the
yield.
Table 2 Synthesis of 1,2,4-Triazolo[1,5-a]pyridine Derivatives
.
R3
CO2R2
NH2
CHO
R2O2C
R2O2C
CN
CN
CN
I2 (10 mol%)
EtOH, reflux
N
+
+
+
R1
R3
N
N
CO2R2
N
1
2
3
4
R1
Entry
1
2
3
Product 4
Yield (%)
MeO OMe
O
N
O
CO2Me
CO2Me
O
H
NH2
NH2
NH2
NH2
N
N
N
N
N
N
Cl
4a
75
Cl
N
MeO OMe
O
N
O
O
O
CO2Me
CO2Me
O
H
N
N
4b
4c
4d
70
72
76
N
EtO
N
OEt
Br
O
N
CO2Et
CO2Et
O
H
Br
N
N
EtO OEt
O
N
CO2Et
CO2Et
O
H
N
Cl
N
Cl
N
EtO
N
OEt
O
N
O
CO2Et
CO2Et
Cl
O
Cl
NH2
N
4e
69
H
Cl
N
Cl
N
Synlett 2013, 24, 1825–1829
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,2,4-Triazolo[1,5-a]pyridines
1827
Table 2 Synthesis of 1,2,4-Triazolo[1,5-a]pyridine Derivatives (continued)
.
R3
CO2R2
NH2
CHO
R2O2C
R2O2C
CN
CN
CN
I2 (10 mol%)
EtOH, reflux
N
+
+
+
R1
R3
N
N
CO2R2
N
1
2
3
4
R1
Entry
1
2
3
Product 4
Yield (%)
MeO OMe
O
N
O
CO2Me
CO2Me
O
H
NH2
N
N
N
Cl
4f
72
Cl
Cl
N
Cl
MeO OMe
O
N
O
Cl
CO2Me
CO2Me
Cl
O
NH2
N
N
H
4g
4h
68
75
Cl
Cl
N
Cl
N
Cl
OMe OMe
O
N
O
CO2Me
CO2Me
O
H
NH2
N
N
N
Cl
Cl
N
The structures of all products 4a–h were elucidated from yl acetylenedicarboxylate to yield enaminone 5a, then re-
their mass, IR, and 1H NMR and 13C NMR spectra as de- action of enaminone 5a with the product of Knoevenagel
scribed for 4a. The mass spectrum of 4a displayed the mo- condensation 6a, followed by loss of H2O to give interme-
lecular ion peak at m/z = 446, and the IR spectrum showed diate 7a. In the next step molecular iodine could coordi-
absorption bands due to the CN group at 2358 cm–1 and nate with the imine group with nucleophilic attack of the
the CO2Me groups at 1748 cm–1. The 1H NMR spectrum NH2 group and finally oxidation of intermediate 8a lead-
of 4a showed two sharp singlets for 2 CH3 groups (δ = ing to the product. Evidence supporting this proposed
3.65 and 4.17 ppm) and the aromatic protons gave rise to mechanism came from the observation that when the in-
1
multiplets in the region δ = 7.38–8.37 ppm. The H-de- termediate 7a was prepared in a separate exercise and sub-
coupled 13C NMR spectrum of 4a showed 19 distinct res- sequently reacted with molecular iodine under the same
onances.
conditions, the expected product 4a was obtained in a
yield similar to that obtained in the one-pot reaction
(Scheme 1).
Although the detailed mechanism of the above reaction
remains to be fully clarified, compound 4a could be
formed via attack of the benzylidenehydrazine on dimeth-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1825–1829

1828
A. Alizadeh et al.
LETTER
K.; Armstrong, J. D. III. Org. Lett. 2005, 7, 1039. (c) Stocks,
M. J.; Cheshire, D. R.; Reynold, R. Org. Lett. 2004, 6, 2969.
(7) (a) Potts, K. T.; Burton, H. R.; Bhattacharyya, J. J. Org.
Chem. 1966, 31, 260. (b) Potts, K. T.; Burton, H. R.; Roy, S.
K. J. Org. Chem. 1966, 31, 265. (c) Potts, K. T.; Surapaneni,
C. R. J. Heterocycl. Chem. 1970, 7, 1019. (d) Vercek, B.;
Ogorevc, B.; Stanovnik, B.; Tisler, M. Monatsh. Chem.
1983, 114, 789.
Ph
H
O
CO2Me
N
N
OMe
NH2
+
Ph
N
MeO2C
CO2Me
I2
1a
2a
5a
O
CN
CN
CN
(8) (a) Alizadeh, A.; Mokhtari, J. Synth. Commun. 2012, 42,
686. (b) Alizadeh, A.; Mokhtari, J.; Ahmadi, M.
H
+
CN
Cl
Cl
Tetrahedron 2012, 68, 319. (c) Alizadeh, A.; Rezvanian, A.;
Mokhtari, J. Synthesis 2011, 3491. (d) Alizadeh, A.;
Rezvanian, A.; Zhu, L. G. Tetrahedron 2010, 66, 6924.
(e) Alizadeh, A.; Rezvanian, A.; Zhu, L. G. J. Org. Chem.
2012, 77, 4385.
3a
6a
Cl
Cl
(9) (a) Jin, G.; Zhao, J.; Han, J.; Zhu, S.; Zhang, J. Tetrahedron
2010, 66, 913. (b) Kavala, V.; Lin, C.; Kuo, C.; Fang, H.;
Yao, C. Tetrahedron 2011, 68, 1321.
(10) Alizadeh, A.; Mokhtari, J. Tetrahedron 2013, 69, 6313.
(11) Typical Procedure for the Preparation of Dimethyl 7-(4-
Chlorophenyl)-8-cyano-2-phenyl-[1,2,4]triazolo[1,5-
a]pyridine-5,6-dicarboxylate (4a)
MeO2C
CN
MeO2C
MeO2C
CN
oxidation by I2
– 2 H2
4a
– I2
••
MeO2C
I–
N
+N
NH2
N
NH
Ph
HN
I
A solution of benzaldehyde (0.212 g, 2 mmol) and hydrazine
hydrate (0.16 g, 1 mmol) was magnetically stirred in EtOH
(5 mL) for 20 min. Then a solution of DMAD (0.142 g, 1
mmol) was added, and the mixture was stirred for 3 min. At
this point, the condensation product of 4-chlorobenz-
aldehyde (0.140 g, 1 mmol) and malononitrile (6a, 0.066 g,
1 mmol) was added, and the reaction mixture was stirred for
3 h under reflux and progress was followed by TLC. After
completion, the reaction mixture was cooled to r.t., I2 (0.1
mmol) was added, and the mixture was stirred for a further 2
h. The progress of the reaction was again followed by TLC
and, after completion, the solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (n-hexane–EtOAc, 5:1). All products gave
satisfactory spectroscopic data in accordance with the
assigned structures.
Ph
7a
8a
Scheme 1 Probing the mechanism for the formation of title com-
pounds
In conclusion we have developed a novel pseudo five-
component synthesis of 1,2,4-triazolo[1,5-a]pyridines
from benzylidenehydrazine, aromatic aldehydes, malono-
nitrile, and acetylenic esters. The high yields, mild reac-
tion conditions, ease of purification, and ready availability
of the starting materials make this a convenient procedure
for the synthesis of 1,2,4-triazolo[1,5-a]pyridines. This
protocol not only provides a novel and effective method-
ology for the preparation of functionalized 1,2,4-triazo-
lo[1,5-a]pyridines but also opens up the use of
benzylidenehydrazine intermediates to design other simi-
lar multicomponent reactions. Further expansion of the re-
action scope and synthetic applications of this
methodology are in progress in our laboratory.
Representative Spectroscopic Data
Dimethyl 7-(4-Chlorophenyl)-8-cyano-2-phenyl-
[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4a)
White powder; yield: 0.26 g (59%); mp 263–265 °C. IR
(KBr): 2358 (CN), 1748 (CO2Me), 1538 and 1443 (Ar),
1251 (C–O of ester) cm–1. 1H NMR (500.13 MHz, CDCl3):
δ = 3.65 (3 H, s, OCH3), 4.17 (3 H, s, OCH3), 7.38 (2 H, d,
3JHH = 8.0 Hz, 2 CH of Ar), 7.52–7.54 (5 H, m, 5 CH of Ar),
8.37 (2 H, d, 3JHH = 8.0 Hz, 2 CH of Ar) ppm. 13C NMR
(125.75 MHz, CDCl3): δ = 53.4 (OCH3), 54.3 (OCH3), 102.4
(C8), 112.6 (C5), 118.6 (CN), 128.3 (2 CHmeta of Ph), 128.8
(2 CH of Ar), 128.9 (C6), 129.2 (2 CH of Ar), 129.7 (2
CHortho of Ph), 131.5 (CHpara of Ph), 132.8 (Cipso of Ph),
135.3 (C–Cl), 136.5 (Cipso of Ar), 147.6 (C8a), 150.77 (C7),
159.9 (C2),163.6 (C=O), 167.8 (C=O) ppm. MS (EI, 70 eV):
m/z (%) = 446 (22) [M+], 367 (35), 298 (31), 224 (22), 190
(36), 167 (22), 149 (57), 111 (28), 97 (46), 81 (57), 69 (100),
57 (65). Anal. Calcd (%) for C23H15ClN4O4 (446.85): C,
61.82; H, 3.38; N, 12.54. Found: C, 61.79; H, 3.39; N, 12.55.
Dimethyl 2,7-Bis(4-chlorophenyl)-8-cyano-
[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4f)
White powder; yield: 0.24 g (51%); mp 281–283 °C. IR
(KBr): 2357 (CN), 1746 (CO2Me), 1440 (Ar), 1259 (C–O of
ester) cm–1. 1H NMR (400.13 MHz, CDCl3): δ = 3.66 (3 H,
OCH3), 4.17 (3 H, OCH3), 7.38 (2 H, d, 3JHH = 8.0 Hz, 2 CH
of Ar), 7.50 (2 H, d, 3JHH = 8.0 Hz, 2 CH of Ar), 7.54 (2 H,
d, 3JHH = 8.0 Hz, 2 CH of Ar), 8.32 (2 H, d, 3JHH = 8.0 Hz, 2
CH of Ar) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 53.4
(OCH3), 54.40 (OCH3), 102.4 (C8), 112.5 (C5), 118.8 (CN),
References and Notes
(1) (a) Nettekoven, M.; Pullmann, B.; Schmitt, S. Synthesis
2003, 1649. (b) Dugan, B. J.; Gingrich, D. E.; Mesaros, E.
F.; Milkiewicz, K. L.; Curry, M. A.; Zulli, A. L.;
Dobrzanski, P.; Serdikoff, C.; Jan, M.; Angeles, T. S.;
Albom, M. S.; Mason, J. L.; Aimone, L. D.; Meyer, S. L.;
Huang, Z.; Wells-Knecht, K. J.; Ator, M. A.; Ruggeri, B. A.;
Dorsey, B. D. J. Med. Chem. 2012, 55, 5243.
(2) Utsumi, Y. JP 81,100,783, 1981; Chem. Abstr. 1982, 96,
6735x.
(3) Kubo, K.; Ito, N.; Souzo, I.; Isomura, Y.; Homma, H.;
Murakai, M. GB 1588166, 1981; Chem. Abstr. 1982, 96,
68987q.
(4) Koeckritz, P.; Liebscher, J.; Huebler, D. Ger. (East)
DD280110, 1990; Chem. Abstr. 1991, 114, 81850z.
(5) (a) Huntsman, E.; Balsells, J. Eur. J. Org. Chem. 2005,
3761. (b) Al-Masoudi, I. A.; Al-Soud, Y. A.; Al-Salihi, N. J.;
Al-Masoudi, N. A. Chem. Heterocycl. Compd. (N.Y.) 2006,
42, 1377.
(6) (a) Larsen, S. D.; DiPaolo, B. A. Org. Lett. 2001, 3, 3341.
(b) Balsells, J.; DiMichele, L.; Liu, J.; Kubryk, M.; Hansen,
Synlett 2013, 24, 1825–1829
© Georg Thieme Verlag Stuttgart · New York

LETTER
127.3 (C6), 129.1 (2 CH of Ar), 129.2 (2 CH of Ar), 129.5 (2
Synthesis of 1,2,4-Triazolo[1,5-a]pyridines
1829
3JHH = 8.0 Hz, 2 CH of Ar), 7.38 (2 H, d, 3JHH = 8.0 Hz, 2 CH
of Ar), 7.54 (2 H, d, 3JHH = 8.0 Hz, 2 CH of Ar), 8.27 (2 H,
d, 3JHH = 8.0 Hz, 2 CH of Ar) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 29.7 (Me), 53.3 (OCH3), 54.3 (OCH3), 100.2
(C8), 112.7 (C5), 118.3 (CN), 126.0 (C6), 128.2 (2 CH of Ar),
129.2 (2 CH of Ar), 129.5 (2 CH of Ar), 129.6 (2 CH of Ar),
132.4 (Cipso of Ar), 135.6 (C–Cl), 136.5 (Cipso of Ar), 140.6
(C–Me), 142.0 (C8a), 151.8 (C7), 155.0 (C2), 164.6 (C=O),
166.0 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 460 (53) [M+],
422 (38), 391 (27), 364 (89), 199 (43), 163 (43), 138 (100),
111 (49), 75 (46), 59 (58) (32). Anal. Calcd (%) for
C24H17ClN4O4 (460.87): C, 62.55; H, 3.72; N, 12.16. Found:
C, 62.53; H, 3.73; N, 12.14.
CH of Ar), 129.6 (2 CH of Ar), 132.6 (Cipso of Ar), 135.2 (C–
Cl), 136.7 (Cipso of Ar), 137.7 (C–Cl) 147.7 (C8a), 150.7 (C7),
159.7 (C2), 163.5 (C=O), 166.7 (C=O) ppm. MS (EI, 70 eV):
m/z (%) = 481 (31) [M+], 480 (100) [M+ – 1], 449 (22), 364
(51), 190 (22), 163 (22), 138 (72), 102 (30), 75 (53), 59 (33).
Anal. Calcd (%) for C23H14Cl2N4O4 (481.30): C, 57.40; H,
2.93; N, 11.64. Found: C, 57.42; H, 2.92; N, 11.65.
Dimethyl 7-(3-Bromophenyl)-8-cyano-2-p-tolyl-
[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4h)
White powder; yield: 0.25 g (55%); mp 287–289 °C. IR
(KBr): 2359 (CN), 1742 (CO2Me), 1441 (Ar), 1264 (C–O of
ester) cm–1. 1H NMR (400.13 MHz, CDCl3): δ = 2.45 (3 H,
s, Me), 3.66 (3 H, OCH3), 4.17 (3 H, OCH3), 7.33 (2 H, d,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1825–1829