Convenient two-step preparation of [1,2,4]triazolo[4,3-a]pyridines from 2-hydrazinopyridine and carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2006.08.075

Triazolopyridines are an important class of biologically active heterocyclic compounds. In this letter, we describe a new method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines starting from 2-hydrazinopyridine and carboxylic acids. The resulting ace

Full text of DOI:10.1016/j.tetlet.2006.08.075

Tetrahedron Letters 47 (2006) 7591–7594
Convenient two-step preparation of
[1,2,4]triazolo[4,3-a]pyridines from 2-hydrazinopyridine
and carboxylic acids
Aline Moulin, Jean Martinez and Jean-Alain Fehrentz*
Laboratoire des Amino-Acides, Peptides et Prote´ines, UMR 5810, CNRS, Universite´s Montpellier I et II,
Faculte´ de Pharmacie, 5 avenue Charles Flahault, BP 1441, 34093 Montpellier Cedex 5, France
Received 29 June 2006; revised 4 August 2006; accepted 21 August 2006
Abstract—Triazolopyridines are an important class of biologically active heterocyclic compounds. In this letter, we describe a new
method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines starting from 2-hydrazinopyridine and carboxylic acids. The resulting
acetohydrazides are cyclized in a key step using the Lawesson’s reagent. The reaction conditions were explored, as well as the scope
of this reaction concerning the substituent in position 3 of the triazolopyridine ring. We also demonstrated that this heterocycliza-
tion is racemization free in the presence of a chiral carbon in position a to the heterocycle.
Ó 2006 Elsevier Ltd. All rights reserved.
Triazolopyridines are an important class of heterocyclic
compounds. They express bactericidal,1,2 anxiolitic,3
herbicidal4 or diuretic and renal vasodilating5 activities
and can act as inhibitors of mitogen-activated protein
(MAP) kinases6,7 or as growth hormone secretagogues.8
They also can be used for the treatment of gastrointesti-
nal disorders9 or as antithrombotic agents.10
2-hydrazinopyridine and carboxylic acids in good to
high yield.
The synthetic route to the targeted molecules is outlined
in Scheme 1. Carboxylic acid 1 is coupled with BOP re-
agent15 to commercially available 2-hydrazinopyridine
to give the corresponding acetohydrazide 2. By reaction
with Lawesson’s reagent,16 2 is converted into the corre-
sponding substituted [1,2,4]triazolo[4,3-a]pyridine 3 in
one pot. A possible mechanism for this reaction is the
formation of the thioacetohydrazide, which is not iso-
lated, immediately followed by the nucleophilic attack
of the nitrogen atom of the pyridyl moiety on the thio-
carbonyl function. A rearomatization in two steps, as
showed in Scheme 1, gives the final bicycle.
Therefore, versatile and widely applicable methods
for the synthesis of these heterocycles are of consider-
able interest. Most methods for the preparation of these
compounds are based on heterocyclic hydrazones or
hydrazides as precursors. However, these methods have
some restrictions concerning their applicability and
the use of toxic reagents like lead tetra acetate or phos-
phorus oxychloride.11 In order to overcome these
limitations, the oxidants chloramine T12 and (diacet-
oxy)iodobenzene2 as well as an electrochemical method13
or copper-mediated oxidative heterocyclization14 have
been introduced.
Various conditions were tested on a model compound to
explore the influence of solvent, reaction temperature,
reaction time and number of equivalents of Lawesson’s
reagent on the conversion rate of the acetohydrazide 2a
to the 3-phenethyl-[1,2,4]triazolo[4,3-a]pyridine 3a
(Scheme 2). The results are summarized in Table 1.
As part of our continuing effort to target new bioactive
heterocyclic scaffolds, we describe a new two-step
method leading to [1,2,4]triazolo[4,3-a]pyridines from
We can see in Table 1 that 0.5 equiv of Lawesson’s
reagent is sufficient. In some cases, more equivalents
do not improve the conversion rate and lead to degrada-
tion (see entries 5 and 6). Best conversion rates were
obtained with acetonitrile or toluene as a solvent per-
forming the reaction at 80 °C for 2 h (entry 3 or entry
Keywords: [1,2,4]Triazolo[4,3-a]pyridine; Acetohydrazide; Lawesson’s
reagent.
*
Corresponding author. Tel.: +33 4 67 54 86 51; fax: +33 4 67 54 86
54; e-mail: jean-alain.fehrentz@univ-montp1.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.075

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A. Moulin et al. / Tetrahedron Letters 47 (2006) 7591–7594
BOP
DIEA
DCM
O
N
N
O
Lawesson's reagent
solvent, heating
R
R
R
+ H2N
N
N
N
OH
HN NH
H
2
3
1
N
- H2S
R
N
R
N
N
S
HS
R
N
N
N
NH
HN
S
N
H
H
H
Scheme 1. General synthetic route to [1,2,4]triazolo[4,3-a]pyridines.
OH
OH
Boc NH
N
N
Lawesson's reagent
solvent, heating
O
Boc NH
O
1c
N
O
1b
HN NH
N
2a
3a
BOP
NMM
NH2
N
N
H
Scheme 2. Model compound used for the study of the reaction
conditions.
H
N
H
N
Boc NH
N
N
H
Boc NH
N
N
O
2c
H
9 with, respectively, 80% and 84%), or with ethylene gly-
col dimethyl ether at 60 °C for 2 h (entry 16 with 86%).
O
2b
1 eq. Lawesson's Reagent
DME
2h, 80˚C
We then attempted to introduce a chiral carbon atom in
a position to the triazolopyridine to explore epimeriza-
tion during the cyclization reaction.
N
N
Boc NH
Boc NH
For this purpose, we synthesized two diastereoisomers
following Scheme 3, starting from (L) and (D) alanine
to obtain the corresponding acetohydrazides 2b and
2c, respectively. After heterocyclization, the triazolo-
N
N
N
3c
N
3b
1. HCl / MeOH
2. BOP, NMM
OH
Boc NH
Table 1. Influence of the reaction conditions on the conversion rate
determined by RP-HPLC analysis at 214 nm
O
9
Entry Time Temperature Solvent Lawesson’s Conversion
6
5
(h)
(°C)
reagent
(equiv)
(%)
O
O
7
3
Boc NH
Boc NH
N
N
N
N
8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
0.5
1.0
2.0
0.5
2.0
2.0
0.5
1.0
2.0
0.5
0.5
0.5
1.0
0.5
0.5
2.0
2.0
80
80
80
80
80
80
80
80
80
80
80
80
80
60
60
60
60
CH3CN 0.5
64
73
80
72
62
54
85
81
84
73
74
55
68
53
62
86
52
H
N
H
N
N
1
N
CH3CN 0.5
CH3CN 0.5
CH3CN 1.0
CH3CN 1.0
CH3CN 2.0
2
4b
4c
Scheme 3. Synthesis of L,L- and L,D-triazolopyridine diastereoisomers.
PhMe
PhMe
PhMe
PhMe
DME
DME
DME
PhMe
DME
DME
DME
0.5
0.5
0.5
1.0
0.5
1.0
2.0
0.5
0.5
0.5
1.0
pyridines 3b and 3c were, respectively, Boc deprotected,
and Boc (L) valine was coupled to afford the correspond-
ing diastereoisomers 4b and 4c.
The optical purity of these two diastereoisomers was
checked by H NMR. For this purpose, three experi-
ments were achieved: compounds 4b, 4c and also a 50/
50 (w/w) mixture of compounds 4b and 4c were ana-
lyzed in DMSO-d6.
1

A. Moulin et al. / Tetrahedron Letters 47 (2006) 7591–7594
Table 2. Variation of the R substituent
7593
Compound
Formula
Yield (%)
2
3
O
1a
85
80
OH
O
OH
1b
1c
94
70
70
O
O
N
H
O
O
O
OH
94
76
N
H
NH
OH
1d
70
98
O
O
N
H
O
O
Cl
OH
1e
98
Cl
Figure 1. (a) 1H NMR spectral data for compound 4b; (b) 1H NMR
spectral data for compound 4c; (c) H NMR spectral data for a 50/50
O
1
1f
88
60
0
OH
(w/w) mixture of compounds 4b and 4c.
N
O
O
These experiments revealed a different chemical shift for
the two diastereoisomers in two distinct regions of the
spectrum (Fig. 1): in the region 7.76–7.86 ppm, corre-
sponding to the H8 proton of the triazolopyridine ring,
and also in the region 8.20–8.80 ppm, corresponding
to the NH of the Boc group and the H5 proton of the
triazolopyridine.
OH
1g
100
N
H
O
All synthesized products were fully characterized by
RP-HPLC, LC/MS spectrometry, 1H and 13C NMR
(see Supplementary data).
In both cases, compounds 4b and 4c revealed a single
signal, whereas the mixture of the two diastereoisomers
showed the superposition of two distinct signals, which
corresponded to compounds 4b and 4c (Fig. 1). We
can conclude that the heterocyclization to triazolopyri-
dine using the Lawesson’s reagent is racemization free
for the carbon in position a to the heterocycle, in the
Heterocyclization tolerates a wide range of functional-
ities: aromatic and alkyl groups, as well as heterocyclic
groups, allowing to form biaryl compounds in some
cases (compounds 3e and 3f in Table 2). Relatively
bulky groups are well accepted (compounds 3d and 3e
in Table 2) but in some cases, steric hindrance seems
to be prohibitive for the ring formation (compound 3g
was not detected).
1
limit of the detection by H NMR.
To further investigate the scope of this reaction, several
substituents were introduced at the R position (Scheme
4), as shown in Table 2.
In conclusion, we propose a new convenient two-step
synthesis of [1,2,4]triazolo[4,3-a]pyridines allowing the
BOP
DIEA
O
N
O
1 eq. Lawesson's reagent
DCM
R
R
R
N
N
OH
1a-g
DME, 2h, 80 ºC
HN NH
2a-g
3a-g
N
H2N
N
N
H
Scheme 4. Introduction of several substituents at the R-position.

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A. Moulin et al. / Tetrahedron Letters 47 (2006) 7591–7594
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1
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Supplementary data
1
Synthetic procedures for all intermediates, MS, H and
13C NMR and RP-HPLC. Supplementary data associ-
ated with this article can be found in the online version,
at doi:10.1016/j.tetlet.2006.08.075.
14. Ciesielski, M.; Pufky, D.; Doering, M. Tetrahedron 2005,
61, 5942–5947.
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