A facile synthesis of amide derivatives of [1,2,4]triazolo[4,3-a]pyridine

Article abstract of DOI:10.14233/ajchem.2017.20624

A facile synthesis for preparation of amide derivatives of [1,2,4]triazolo[4,3-a]pyridine can be achieved by the nucleophilic displacement of chloromethyl derivative with methyl amine followed by the reaction with acid analogues in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Reaction of 2-chloropyridine with hydrazine hydrate (99 %) gave 2-hydrazinopyridine (2). Compound 3 was obtained in good yields by treating 2-hydrazinopyridine with chloroacetyl chloride. Further 3-chloromethyl-[1,2,4]triazolo[4,3-a]pyridine (4) is obtained by treatment of compound 3 with POCl₃. Nucleophilic displacement of compound 4 with methyl amine gave methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (5). Finally protecting and deprotecting of compound 5 with Boc anhydride and HCl in dioxane gives hydrochloride salt of compound 5 i.e. (6) The reaction of hydrochloride salt of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine with 10 different acids yields amide analogues.

Full text of DOI:10.14233/ajchem.2017.20624

Asian Journal of Chemistry; Vol. 29, No. 9 (2017), 1920-1924
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20624
A Facile Synthesis of Amide Derivatives of [1,2,4]Triazolo[4,3-a]pyridine
1
1
2
N. MURTHY GANDIKOTA , R. SEKHAR BOLLA , I.V. KASI VISWANATH1,* and SRIDHARREDDY BETHI
1Department of Chemistry, K.L. University, Green Fields, Vaddeswaram, Guntur-522 502, India
2G.V.K. Bio Sciences, Hyderabad, India
*Corresponding author: E-mail: viswanath_fed@kluniversity.in
Received: 4 March 2017;
Accepted: 12 May 2017;
Published online: 15 July 2017;
AJC-18466
A facile synthesis for preparation of amide derivatives of [1,2,4]triazolo[4,3-a]pyridine can be achieved by the nucleophilic displacement
of chloromethyl derivative with methyl amine followed by the reaction with acid analogues in the presence of 1-[bis(dimethylamino)methylene]-
1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Reaction of 2-chloropyridine with hydrazine hydrate (99 %)
gave 2-hydrazinopyridine (2). Compound 3 was obtained in good yields by treating 2-hydrazinopyridine with chloroacetyl chloride.
Further 3-chloromethyl-[1,2,4]triazolo[4,3-a]pyridine (4) is obtained by treatment of compound 3 with POCl3. Nucleophilic displacement
of compound 4 with methyl amine gave methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (5). Finally protecting and deprotecting
of compound 5 with Boc anhydride and HCl in dioxane gives hydrochloride salt of compound 5 i.e. (6) The reaction of hydrochloride salt
of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine with 10 different acids yields amide analogues.
Keywords: s-Triazolo pyridines, Pyridine derivatives, 1,2,4-Triazolo[4,3-a]pyridine, Triazolo derivatives.
MAP kinase inhibitors [10-12] and secretagogues, which is a
INTRODUCTION
growth hormone. There are reports on some classes of 1,2,4-
Pyrolo, imidazo- and triazolo pyridines belonging to class
of N-bridge head 5,6-bicyclic heterocycles are important motifs
in bio-medicinal chemistry due to their good SAR (structure-
activity relationship). Among them s-triazolo(4,3-a)pyridine
ring system (I) that has been known since several years but to
which meager attention has been paid. An effort was initiated
to develop the synthesis amido aminomethyl fused triazoles
(II) that would be compatible with amino acid substrates and
polar functional groups.
A wide range of research was going on these derivatives
because of their interesting biological activities like anti-
microbial [1], antiviral [1], anticonvulsant [1], antifungal [1],
anticancer [1], antiallergic [2], herbicide activity [3], anti-
oxidants [1]. These fused triazoles with general formula I are
specially shows gastrointestinal [4] and chemotherapeutic
activity [4-6] due to their outstanding effectiveness against a
wide range of micro-organisms, such as, Staphylococcus aureus,
Escherichia coil, Proteus mirabilis, Pseudomonas aeruginosa
and Streptococcus pyogenes. These derivatives are used in the
treatment of schistosomiasis [7] a typical disease found in
Egypt. These 1,2,4-triazolo[4,3-a]pyridine derivatives have a
considerable effect on glutamate [8,9]. This helps us to cure
neurological and psychiatric disorders, which are associated
with glutamate dysfunction. Triazolopyridines are found in
triazolo[4,3-a]pyridine derivatives can be used as p38α inhibitors
[10-13]. They are useful in the treatment of inflammation, osteo-
arthritis, rheumatoid arthritis, cancer, reperfusion or ischemia
in stroke or heart attack, autoimmune diseases and other disorders.
Some biologically active molecules containing [1,2,4]triazolo-
[4,3-a]pyridine as a core moiety are represented in Fig. 1.
There are several methods for the preparation of amino
methyl derivatives. Decarboxylation of α-heteroaryl glycines,
reduction of methyl azides, nitriles and aldoximes are some
of them. To the best of our knowledge there are few reports
available for the synthesis of amino methyl substituted 1,2,4-
triazolo[4,3-a]pyridine, especially on our target molecule
methyl[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (V).
Several synthetic approaches were known for the synthesis
of 3-chloromethyl-[1,2,4]triazolo[4,3-a]pyridine (III) [4] and
[1,2,4]triazolo[4,3-a]pyridin-3-yl-ethylamine (IV) [14] and
fewer number of synthetic approaches are known for methyl-
[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (V) and ours
is a novel approach. But amide derivatives of V were not
reported yet. Intermediate 5 may be prepared by Mitsunobu
reaction [15]. This reaction can be carried out in the presence
of triphenyl phospine, diethyl azodicarboxylate (DEAD) and
TMS cyanide as an additive. But this procedure is complicated
and involves hazardous regent TMS cyanide. We synthesized

Vol. 29, No. 9 (2017)
N N
A Facile Synthesis of Amide Derivatives of [1,2,4]Triazolo[4,3-a]pyridine 1921
pyridine (4) [4,17]. Further, compound 4 is converted to methyl-
[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (5) by treating
N
N
O
with 2 M methyl-amine in methanol.As compound 5 was unable
to purify at that stage hence it was protected with (Boc)2O to
O
N
N
HN
give methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-carbamic
acid tert-butyl ester (6). Finally, compound 6 was deprotected
with HCl/dioxane to afford hydrochloride salt of methyl-
[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (7).
b
a
N
N
N
N
N
N
Fig. 3 illustrates the synthesis of amide derivative of methyl-
O
N
CN
O
[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (7). In this
reaction we used 1-[bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU)
as a peptide coupling reagent and N,N-diisopropylethylamine
(DIPEA) as a base in DMF solvent.A series of amide derivatives
were prepared by using above condition with good yields and
purity.
Cl
d
c
N
F
N
N
N
N
O
OH
F
O
N
N
N
N
e
f
.HCl
N
O
N
N
vii
Fig. 1. Biologically active molecules containing [1,2,4]triazolo[4,3-
a]pyridine as a core moiety
R
CH3
N
N
H
CH3
7
8a-8j
methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine (V) in
a economical way by using 2 M methyl amine/THF. After
preparing compound 7 we planned a methodology, which
involves acid amine coupling. In this methodology we will
get compounds with chemical formula II.
Bearing these results in mind, we have designed and synthe-
sized a new variety of amide derivatives of [1,2,4]triazolo[4,3-
a]pyridine.
Due to their high structure activity relationship values
N-(heteroarylmethyl)aromatic amides were falls under important
class of bioactive compounds [16] i.e. amino methyl derivatives
containing pyridine, thiophene, pyrazene and other hetero-
cyclic systems possess high potency of biological activity.
Fig. 3. Synthesis of N-(heteroarylmethyl)aromatic amide
All reagents were purchased from commercial sources
and were used as received. 1H NMR spectra were obtained on
a AGILENT 300 spectrometer at 300 MHz or AGILENT 400
spectrometer at 400 MHz with tetramethylsilane used as
an internal reference. Thin-layer chromatography (TLC) was
performed using Whatman No. 4500-101 (Diamond No.
MK6F silica-gel 60 Å) plates. Visualization of TLC plates was
performed using UV light (254 nm). LCMS was obtained on
the Column: X Bridge C18 (100 mm × 4.6 mm) 3.5 µm.
Synthesis of pyridin-2-yl-hydrazine (2): To a stirred
solution of 1 (20 g, 0.176 mol, 1 equiv) in hydrazine hydrate
(200 mL, 10 vol) was stirred at 100 °C for 48 h. When TLC
(8:2 EtOAc and methanol) showed complete consumption of
the starting material, the reaction mixture was diluted with
water (200 mL) and extracted with ethyl acetate (5 × 500 mL),
dried over Na2SO4 evaporated to dryness under reduced pressure
EXPERIMENTAL
Fig. 2 depicts the synthetic route for the preparation
hydrochloride salt of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-
ylmethyl-amine (7). 2-Chloro pyridine was treated with hydrazine
hydrate (99 %) at 100 °C for 48 h to yield hydrazine derivative
of pyridine (2) [2,5,7,9,17,18]. Compound 2 was selectively
mono acylated with chloroacetyl chloride to afford amide
derivative (3) of compound 2 [2,9,17,18]. Further, compound
3 was cyclized with POCl3 with the elimination of water
molecule to afford 3-chloromethyl-[1,2,4]triazolo[4,3-a]-
1
to afford 2 (15.0 g, 78 %) as a red oil; H NMR (300 MHz,
CDCl3): δ 8.14 (1H, d, J = 3 Hz, Ar-H), 7.51-7.45 (1H, m, Ar-
H), 6.71-6.66 (2H, m, Ar-H), 5.78 (1H, brs, -NH), 3.81 (2H,
brs, -NH2); LCMS calculated for C5H7N3: 109.13; Found 110.1,
[M+H]+
H
N
N
NH
NH
2
N
NH
Cl
i
ii
iii
N
Cl
N
N
Cl
N
O
1
2
3
4
N
N
N
N
N
N .HCl
CH3
iv
v
N
N
N
vi
CH3
CH3
N
N
N
H
H
Boc
5
7
6
Fig. 2. Synthesis of hydrochloride salt of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine

1922 Gandikota et al.
Asian J. Chem.
Synthesis of chloro-acetic acid N’-pyridin-2-yl-hydrazide
(3): To a stirred solution of compound 2 (5 g, 1 equiv) in dichloro-
methane (100 mL) was added chloroacetyl chloride (4.19 mL,
1.1 equiv) drop wise at 0 °C with vigorous stirring.After comple-
tion of addition formation of white precipitate was observed,
this was stirred at ambient temperature for 12 h. When TLC
(9:1 EtOAc and methanol) showed complete consumption of
the starting material, the reaction mixture was filtered and the
obtained solids were washed with dichloromethane (30 mL),
solids were dissolved in water (50 mL) and basified (pH 8.0)
with sat. NaHCO3 and extracted with dichloromethane (3 ×
100 mL), dried over Na2SO4, evaporated under reduced pressure
to afford compound 3 (5.00 g, 58 %) as a white solid; 1H NMR
(300 MHz, DMSO-d6): δ 10.87 (1H, brs, -NH), 10.59 (1H,
brs, -NH), 8.07-8.00 (2H, m, Ar-H), 7.13-7.03 (2H, m, Ar-H),
4.3 (2H, s, -CH2Cl); LCMS calculated for C7H8N3OCl: 185.61;
Found 186 [M+H]+.
Synthesis of 3-chloromethyl-[1,2,4]triazolo[4,3-a]-
pyridine (4): Under inert atmosphere POCl3 (25 mL, 5 vol)
was slowly added to compound 3 (5 g, 0.027 mol) at ambient
temperature, the resulting reaction mixture was stirred at 120 °C
for 12 h. Reaction was monitored byTLC (9:1 EtOAc/methanol),
which showed complete consumption of the starting material,
POCl3 was evaporated completely, the crude was basified with
sat. NaHCO3. The aqueous layer was extracted with dichloro-
methane (3 × 100 mL). The combined organic layers were
dried over Na2SO4, evaporated under reduced pressure to afford
crude product. The crude was triturated with ether to afford
compound 4 (2.5 g, 55.55 %) as a brown solid. 1H NMR (400
MHz, CDCl3): δ 8.19 (1H, d, J = 8 Hz,Ar-H), 7.84 (1H, d, J =
8 Hz, Ar-H), 7.39-7.34 (1H, m, Ar-H), 7.00-6.97 (1H, m, Ar-
H), 5.18 (2H, s, -CH2Cl). LCMS calculated for C7H6N3Cl:
167.60; Found 168.08, 170.08, [M], [M+2]+.
Synthesis of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-
ylmethyl-amine (5): To a stirred solution of compound 4 (2.50
g, 1.0 equiv) in MeOH (20 mL), was added 2 M solution of
methyl amine in methanol (3 mL) at ambient temperature.
The reaction mixture was stirred at the same temperature for
12 h. Reaction was monitored byTLC (9:1 EtOAc and methanol)
which showed complete consumption of the starting material,
the reaction mixture was evaporated under reduced pressure,
dried completely to give crude compound 5 (2.3 g) as a red liquid.
Synthesis of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-
ylmethyl-carbamic acid tert-butyl ester (6): To a stirred
solution of compound 5 (2.30 g, 1.0 equiv) in THF (20 mL)
was added Boc anhydride (3.85 mL, 1.1 equiv) at ambient tempe-
rature. The reaction mixture was stirred at the same temperature
for 12 h. Reaction was monitored by TLC (8:2 EtOAc and
methanol) which showed complete consumption of the starting
material, the reaction mixture was evaporated, obtained crude
was dissolved in water (20 mL). The aqueous layer was initially
extracted with pet. Ether (2 × 20 mL) to remove excess Boc
anhydride. Further the aqueous layer was extracted with
dichloromethane (3 × 20 mL). The combined organic layers
were dried over Na2SO4, evaporated under reduced pressure
to afford crude product. The crude was triturated with ether to
afford 6 (2.0 g, 54.0 %) as a brown solid. 1H NMR (400 MHz,
CDCl3): δ 8.54 (1H, brs, -NH-Boc), 7.77 (1H, d, J = 12 Hz,
Ar-H), 7.29 (1H, d, J = 8 Hz, Ar-H), 6.86 (1H, t, J = 6 Hz, Ar-
H), 5.02 (2H, s, -NCH2), 2.65 (3H, -s, -NCH3), 1.49 (9H, s, t-
Bu) MS, LCMS calculated for C13H18N4O2: 262.31; Found
263.19 [M + H]+.
Synthesis of hydrochloride salt of methyl-[1,2,4]triazolo-
[4,3-a]pyridin-3-ylmethylamine (7): To a stirred solution of
compound 6 (2 g, 1 equiv) in dioxane (10 mL) was added 2 M
HCl in dioxne (10 mL) at ambient temperature. The reaction
mixture was stirred at the same temperature for 12 h. Reaction
was monitored by TLC (8:2 EtOAc and methanol) which showed
complete consumption of the starting material, the reaction
mixture was evaporated under reduced pressure to dryness
and the obtained crude was triturated with ether to afford
compound 7 (1.3 g, 86 %) as brown solid. 1H NMR (300 MHz,
DMSO-d6): δ 9.61 (2H, brs, -NHHCl), 8.80 (1H, d, J = 6.4,
Ar-H), 7.89 (1H, d, J = 9.2, Ar-H), 7.56-7.53 (1H, t, J = 6.8,
Ar-H), 7.18-7.15 (1H, t, J = 6.4, Ar-H), 4.79 (2H, s, -NCH2),
2.70 (3H, s, -NCH3); LCMS calculated for C8H11N4Cl: 162.14;
Found 163.21 [M + H]+.
General synthetic procedure for synthesis of amide
derivatives of methyl-[1,2,4]triazolo[4,3-a]pyridin-3-
ylmethylamine (8a-8k): To a stirred solution of compound 7
(100 mg, 1.0 equiv) in DMF (3 mL) was added 4-bromo-2-
methyl-benzoic acid (241.32 mg, 1.1 equiv). To this mixture
DIPEA (0.526 mL, 3.0 equiv) followed by HATU (387.84 mg,
1.0 equiv) were added at ambient temperature. The reaction
mixture was stirred at the same temperature for 2 h. Reaction
was monitored by TLC (8:2 EtOAc and methanol), which
showed complete consumption of the starting material. The
reaction mixture was basified with sat. NaHCO3. The aqueous
layer was extracted with dichloromethane (3 × 100 mL). The
combined organic layers were washed with brine, dried over
Na2SO4 and evaporated under reduced pressure to afford crude
product. The crude was purified by silica-gel (100-200) column
chromatography using 5 % methanol/ethylacetate as an elluent
to afford 4-bromo-2,N-dimethyl-N-[1,2,4]triazolo[4,3-a]-
pyridin-3-ylmethyl benzamide (8a) (30 mg, 70 %) as a off-
white solid. Same procedure was adopted for the synthesis of
remaining compounds 8b-8k.
Spectral data
4-Bromo-N-dimethyl-N-[1,2,4]triazolo[4,3-a]pyridin-3-
ylmethyl-benzamide (8a): Yield 38 %, Off-white solid. 1H
NMR (400 MHz, CDCl3, ppm): δ 8.74 (1H, d, J = 8 Hz, Ar-
H), 7.82 (1H, d, J = 6 Hz, Ar-H), 7.39-7.36 (3H, m, Ar-H),
7.19 (1H, d, J = 6 Hz, Ar-H), 6.94 (1H, t, J = 8 Hz, Ar-H),
5.31 (2H, s, N-CH2), 2.88 (3H, s, N-CH3), 2.13 (3H, s, Ar-
CH3); LCMS calculated for C16H15N4OBr: 359.22; Found
361.08 [M + 2]+.
4-Methoxy-N-methyl-N-[1,2,4]triazolo[4,3-a]pyridin-
3-ylmethyl-benzamide (8b): Yield 33 %, Off-brown solid.
1H NMR ((300 MHz, CDCl3, ppm): δ8.76 (1H, d, J = 6 Hz,
Ar-H), 7.79 (1H, d, J = 9 Hz, Ar-H), 7.29-7.25 (3H, m, Ar-H),
693-6.91 (3H, m, Ar-H), 5.30 (2H, s, N-CH2), 3.82 (3H, s, O-
CH3), 3.05 (3H, s, N-CH3); LCMS calculated for C16H16N4O2:
296.32; Found 297.21 [M + 1]+.
4-N-Dimethyl-N-[1,2,4]triazolo[4,3-a]pyridin-3-yl-
methyl-benzamide (8c): Yield 34 %, red gummy solid. 1H

Vol. 29, No. 9 (2017)
A Facile Synthesis of Amide Derivatives of [1,2,4]Triazolo[4,3-a]pyridine 1923
NMR ((300 MHz, CDCl3, ppm): δ8.76 (1H, d, J = 6, Ar-H),
7.79 (1H, d, J = 9.3, Ar-H), 7.33-7.31 (3H, m, Ar-H), 7.21-
7.18 (2H, m, Ar-H), 6.91-6.87 (1H, t, J = 6.6, Ar-H), 5.30
(2H, s, N-CH2), 3.05 (3H, s, N-CH3), 2.37 (3H, s, Ar-CH3);
LCMS calculated for C16H16N4O: 280.32; Found 281.18 [M +
1]+.
(400 MHz, DMSO-d6, ppm): δ168.54 (-NC=O), 149.68 (Ar-
C), 142.87 (Ar-C), 137.44 (Ar-C), 132.53 (Ar-C), 130.85 (Ar-
C), 127.95 (Ar-C), 124.48 (Ar-C), 117.96 (Ar-C), 115.21, Ar-
C), 113.56 (Ar-C), 40.12 (-NCH2), 35.45 (-NCH3); LCMS
calculated for C15H13N4OBr: 345.19; Found 344.99,346.88,
[M], [M + 2]+.
3-Mercapto-N-methyl-N-[1,2,4]triazolo[4,3-a]pyridin-
3-ylmethyl benzamide (8d): Yield 30 %, brown gummy
liquid. 1H NMR (400 MHz, DMSO-d6, ppm): δ8.51 (1H, s,
Ar-H), 7.92 (1H, d, J = 12 Hz, Ar-H), 7.56-7.35 (6H, m, Ar-
H), 7.04 (1H, s, Ar-H), 5.17 (2H, s, N-CH2), 2.84 (4H, s, N-
CH3, SH); LCMS calculated for C15H14N4OS: 298.09; Found
298.22 [M]+.
4-Bromo-3-fluoro-N-methyl-N-[1,2,4]triazolo[4,3-
a]pyridin-3-ylmethyl benzamide (8k): Yield 43 %, Off-white
solid. 1H NMR (300 MHz, CDCl3): δ8.69 (d, 1H, J = 6 Hz,
Ar-H), 7.80 (d, 1H, J = 9 Hz, Ar-H), 7.63-7.58 (m, 1H, Ar-H),
7.35-7.29 (1H, m, Ar-H), 7.20 (1H, d, J = 9 Hz, Ar-H), 7.09
(1H, d, J = 8.1 Hz, Ar-H), 6.93-6.89 (1H, m, Ar-H), 5.27 (2H,
s, -NCH2), 3.08 (3H, s, -NCH3); 13C NMR (400 MHz, DMSO-
d6, ppm): δ169.49 (-NC=O), 159.11 (Ar-C), 156.66 (Ar-C),
149.51 (Ar-C), 142.96 (Ar-C), 133.76 (Ar-C), 128.02 (Ar-C),
124.73 (Ar-C), 115.69 (Ar-C), 113.76 (Ar-C), 109.77 (Ar-C), 40.10
4-Bromo-2-fluoro-N-methyl-N-[1,2,4]triazolo[4,3-
a]pyridin-3-ylmethyl benzamide (8e): Yield 22 %, white
solid. 1H NMR (300 MHz, CDCl3): δ 8.61 (1H, d, J = 6 Hz,
Ar-H), 7.80 (1H, d, J = 9 Hz, Ar-H), 7.39-7.29 (3H, m, Ar-H),
7.28-7.21 (1H, m, Ar-H), 6.09 (1H, t, J = 9, Ar-H), 5.32 (2H,
s, N-CH2), 2.95 (3H, s, N-CH3); LCMS calculated for
C15H12N4OBrF: 363.18; Found 363.22, 365.20, [M], [M + 2]+.
2,N-Dimethyl-N-[1,2,4]triazolo[4,3-a]pyridin-3-yl-
methyl isonicotinamide (8f): Yield 28 %, Off-white solid.1H
NMR (300 MHz, CDCl3): δ 8.69 (1H, d, J = 6 Hz,Ar-H), 8.58
(1H, d, J = 6 Hz, Ar-H) 7.81 (1H, d, J = 9 Hz, Ar-H), 7.36-
7.30 (1H, m, Ar-H), 7.12 (1H, s, Ar-H), 7.06 (1H, d, J = 4.2
Hz, Ar-H), 6.95-6.91 (1H, t, J = 6 Hz, Ar-H), 5.29 (2H, s, N-
CH2), 3.03 (3H, s, N-CH3), 2.58 (3H, s, Ar-CH3); LCMS
calculated for C15H15N5O: 281.31; Found 282.20 [M + H]+.
4-Formyl-3-hydroxy-N-methyl-N-[1,2,4]triazolo[4,3-
a]pyridin-3-ylmethyl benzamide (8g): Yield 38 %, Brown
solid.1H NMR (400 MHz, CDCl3, ppm): δ 10.87 (1H, s, -CHO),
10.29 (1H, s, -OH), 8.55 (1H, d, J = 4 Hz, Ar-H), 7.81-7.70
(2H, dd, J 1 = 8 Hz, J 2 = 8 Hz, Ar-H), 7.42 (1H, d, J = 8 Hz,
Ar-H), 7.08-6.95 (3H, m, Ar-H), 5.21 (2H, s, -N-CH2), 2.92
(3H, s, -NCH3); LCMS calculated for C16H14N4O3: 310.31;
Found 311.15 [M + H]+.
TABLE-1
PHYSICAL DATA OF COMPOUNDS 8a-8k
Time
(h)
Compd.
Acid
Product
H3C
N
H3C
HOOC
N
O
N
N
N
Br
8a
2
Br
CH3
N
O
N
OCH3
N
HOOC
OCH3
8b
8c
8d
2
2
2
CH3
N
N
O
N
N
CH3
HOOC
CH3
CH3
SH
N
SH
N
O
N
HOOC
N
CH3
F
N
F
O
N
Br
N
8e
8f
2
2
2
HOOC
HOOC
HOOC
Br
N
3-Chloro-N-methyl-2-nitro-N-[1,2,4]triazolo[4,3-
a]pyridin-3-ylmethyl benzamide (8h): Yield 40 %, White
solid.1H NMR (400 MHz, CDCl3, ppm): δ8.63 (1H, d, J = 7.2
Hz,Ar-H), 8.17 (1H, d, J = 8.8 Hz,Ar-H), 7.80 (1H, d, J = 9.2
Hz, Ar-H), 7.57-7.54 (1H, dd, J1 = 4 Hz, J2 = 8 Hz, Ar-H),
7.40 (1H, d, J = 4 Hz, Ar-H), 7.36-7.34 (1H, m, Ar-H), 6.94-
6.91 (1H, t, J = 4 Hz, Ar-H), 5.39 (2H, s, -NCH2), 2.82 (3H, s,
-NCH3).
CH3
CH3
N
CH3
N
N
O
N
N
N
CH3
OH
N
OH
N
O
N
N
CHO
8g
CHO
CH3
4-Fluoro-3,N-dimethyl-N-[1,2,4]triazolo[4,3-a]pyridin-
3-ylmethyl benzamide (8i): Yield 53 %, Off-white solid. 1H
NMR (300 MHz, CDCl3, ppm): δ8.76 (1H, d, J = 6.4 Hz, Ar-
H), 7.79 (1H, d, J = 8.0 Hz, Ar-H), 7.36-7.33 (3H, m, Ar-H)
7.02 (1H, d, J = 9 Hz, Ar-H), 6.95 (1H, d, J = 7.2 Hz, Ar-H),
5.30 (2H, s, -NCH2), 3.05 (3H, s, -NCH3), 2.25 (3H, s, Ar-
CH-3), LCMS calculated for C16H15N4OF: 298.31; Found
299.24 [M + H]+.
2-Bromo-N-methyl-N-[1,2,4]triazolo[4,3-a]pyridin-3-
ylmethyl benzamide (8j): Yield 40 %, Off-white solid. 1H
NMR (300 MHz, CDCl3, ppm): δ8.74 (1H, d, J = 9 Hz, Ar-
H), 7.79 (1H, d, J = 9 Hz, Ar-H), 7.56-7.53 (1H, dd, J1 = 1.2
Hz, J2 = 6 Hz, Ar-H), 7.40-7.24 (4H, m, Ar-H), 6.58 (1H, brs,
-NCH), 5.10 (1H, brs, -NCH), 2.79 (3H, s, -NCH3);13C NMR
O2N
Cl
N
O2N
Cl
N
O
N
N
8h
8i
2
2
2
HOOC
CH3
N
O
N
HOOC
F
F
N
N
CH3
CH3
CH3
Br
N
Br
N
O
N
N
8j
HOOC
HOOC
N
CH3
F
F
N
O
N
Br
N
8k
2
Br
CH3

1924 Gandikota et al.
Asian J. Chem.
(-NCH2), 36.90 (-NCH3); LCMS calculated for C15H12N4OBrF:
363.18 Found 363.22,365.20, [M], [M + 2]+.
REFERENCES
1. R. Singh and A. Chouhan, World J. Pharm. Pharm. Sci., 3, 874 (2014).
2. T.L. Wright, 5-Chloro-s-triazolo[4,3-a]pyridin-7-carboxylic acids, E.P.
EP 0210648 B1 (1986).
RESULTS AND DISCUSSION
3. P. Bourgeois, R. Cantegril, A. Chìne, J. Gelin, J. Mortier and J. Moyroud,
Synth. Commun., 23, 3195 (1993);
https://doi.org/10.1080/00397919308011179.
4. J.A. Bristol and R.G. Lovey, [1,2,4]Triazolo[4,3-a]pyridines, U.S.Patent
4,358,453 (1982).
5. P.J. Nelson and K.T. Potts, J. Org. Chem., 27, 3243 (1962);
https://doi.org/10.1021/jo01056a061.
6. K. Stach, M. Thiel, W. Voemel and F. Wiedemann, 5-Nitrofuryl-2-s-
Triazolo-(4,3-a)pyridine Derivatives, U.S. Patent 3597423 (1971).
7. M.E.A. Zaki, O.A. Fathalla, S.A. Swelam and H.F. Aly, Acta Pol.
Pharm., 61, 55 (2004).
8. J.M. Cic-Nunez, A.I. De Lucas Olivares, A.A. Trabanco-Suarez and G.J.
MacDonald, 1,2,4-Triazolo[4,3-a]pyridine Derivatives and Their Use
as Positive Allosteric Modulators of MGLUR2 Receptors, U.S. Patent
20120184527A1 (2012).
9. J.M. Cid-Nunez, D. Oehlrich, A.A. Trabanco-Suarez, G.J. Tresadern,
J.A.V. Ramiro and G.J. MacDonald, 1,2,3-Triazolo[4,3-a]pyridine
Derivatives and Thier use for the Treatment of Prevention of Neurological
and Psychiatric Disorders, U.S. Patent 0184525A1 (2012).
10. J.F. Braganza, M.A. Letavic and K.F. Mcclure, Triazolo-pyridines as
Antiinflammatory Compounds, WO 2004072072 A1 (2004).
11. M.A. Dombroski, M.A. Letavic and K.F. Mcclure, Di andTrifluoro-Triazolo-
PyridinesAnti-inflammatory Compounds, WO 2004020440A1 (2004).
12. M.A. Letavic, M.A. Dombroski, K.F. McClure and E.R. Laird, Novel Benzo-
triazoles Antiinflammatory Compounds, U.S. Patent 2003/0078432 A1
(2003).
13. J.Aiguadé, C. Balagué, I. Carranco, F. Caturla, M. Domínguez, P. Eastwood,
C. Esteve, J. González, W. Lumeras, A. Orellana, S. Preciado, R. Roca,
L. Vidal and B. Vidal, Bioorg. Med. Chem. Lett., 22, 3431 (2012);
https://doi.org/10.1016/j.bmcl.2012.03.099.
14. J.J. Li, J.J. Li, J. Li, A.K. Trehan, H.S. Wong, S. Krishnananthan, L.J.
Kennedy, Q. Gao,A. Ng, J.A. Robl, B. Balasubramanian and B.-C. Chen,
Org. Lett., 10, 2897 (2008);
The key step in present research is the replacement of
chloro with methyl amine. It was assumed to be nucleophilic
substitution of order 2.The methyl amine replaces the chloro
in a concerted mechanism i.e. while the methyl amine attacks
the electron deficient carbon, at the same time chloro leaves
the carbon. Because of the high polarity and solubility issues
obtained amine was protected with Boc anhydride to purify,
later de protected to get hydrochloride salt of that amine.
Hydrochloride salt of methyl-[1,2,4]triazolo[4,3-a]pyridin-
3-ylmethyl-amine (7) was treated with various acid derivatives
in the presence of DIPEA and HATU in DMF at ambient
temperature to afford the amide derivatives 8a-8k. This method
has the advantages of easier work-up, mild reaction conditions.
The amidic products were confirmed by NMR, mass and
13C NMR spectral techniques. In the 300 MHz 1H NMR spectra
of derivatives 8j, 8k (in CDCl3), the following signals were
detected. Peaks at δ 8.74-6.89 for aromatic protons, singlet’s
at δ 6.58-5.24 corresponds to -NCH2 protons and a singlet at δ
2.78-3.08 represent -NCH3 protons. In 13C NMR (400 MHz,
DMSO-d6, ppm), the following signals were detected. A peak
at δ 168.54-168.49 corresponds to C=O of amide and a peak
at δ 36.90-35.45 corresponds to -NCH3 carbon. A peak at δ 40
corresponds to -NCH2 carbon. A series of peaks from δ 159.11-
109.56 represents aromatic carbons. Besides NMR studies,
mass spectra displayed the exact molecular ion peaks in positive
mode. The yields and physical data of the final compounds
are given in Table-1.
https://doi.org/10.1021/ol8011748.
15. J.Y. Roberge, G. Yu, A. Mikkilineni, X. Wu, Y. Zhu, R.M. Lawrence
and W.R. Ewing, ARKIVOC, 132 (2007);
Conclusion
https://doi.org/10.3998/ark.5550190.0008.c10.
16. I. Musie and B. Verèek, Synth. Commun., 31, 1511 (2001);
https://doi.org/10.1081/SCC-100104063.
17. A. Reichelt, J.R. Falsey, R.M. Rzasa, O.R. Thiel, M.M. Achmatowicz,
R.D. Larsen and D. Zhang, Org. Lett., 12, 792 (2010);
https://doi.org/10.1021/ol902868q.
18. T.L. Wright, (Tetrazolyl) Thienopyridinones, U.S. Patent 4593099 A
(1986).
The present study involves the synthesis of the novel series
of [1,2,4]triazolo[4,3-a]pyridine derivatives by adopting a simple
and versatile synthetic methodology. From the previous results,
we are expecting our newly designed molecules may be biolo-
gically active. Thus, this novel class of amide derivatives of
[1,2,4]triazolo[4,3-a]pyridine core represents the worthy hit
compounds, which can be a basis for further investigations
and development of novel potent agents.