A simple and efficient automatable one step synthesis of triazolopyridines from carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2007.02.004

Triazolopyridines can be rapidly and efficiently synthesized from a variety of carboxylic acids with 2-hydrazinopyridines in one simple step. The use of commercially available PS-PPh₃ resin combined with microwave heating delivered the product

Full text of DOI:10.1016/j.tetlet.2007.02.004

Tetrahedron Letters 48 (2007) 2237–2240
A simple and efficient automatable one step synthesis
of triazolopyridines from carboxylic acids
Ying Wang,* Kathy Sarris, Daryl R. Sauer and Stevan W. Djuric
High-Throughput Organic Synthesis Group, Medicinal Chemistry Technologies, Global Pharmaceutical Research and Development,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6113, United States
Received 15 December 2006; revised 1 February 2007; accepted 5 February 2007
Available online 7 February 2007
Abstract—Triazolopyridines can be rapidly and efficiently synthesized from a variety of carboxylic acids with 2-hydrazinopyridines
in one simple step. The use of commercially available PS-PPh3 resin combined with microwave heating delivered the product tri-
azolopyridines in good yields and purities.
Ó 2007 Elsevier Ltd. All rights reserved.
O
Lead optimization is one of the most critical phases
R'
within the drug discovery paradigm. Frequently, a criti-
R
R
N
H
cal part of the lead molecular skeleton has been studied
and shown to be crucial for a particular biological activ-
ity, while other parts of the molecular skeleton need
chemical modifications so as to achieve the desired prop-
erties of a development candidate.1 Thus, an ongoing
goal in the pharmaceutical industry has been to maxi-
mize the structural complexity and skeletal diversity of
lead compounds whilst still maintaining critical pharma-
cophores in order to increase the chance of finding an
optimal drug candidate.
O
N
O
N
N
R'
R
R
R
N
R'
3
1
O
R''(H)
N
OH
O
R'
R= Aryl, Alkyl
R
R'
N
N
2
4
R'
N
R
N
N
5
To this end, we have been actively involved in the prep-
aration of diverse biologically relevant heterocycles
from precursors containing common chemical function-
alities and readily available building blocks. In recent
Letters, we have reported general and efficient reaction
protocols for the preparation of 1,2,4-oxadiazoles 1,2
1,3,4-oxadiazoles 2,3 benzoxazoles 3 and benzimidazoles
4.4 Notably, all of these synthetic methods start from
readily accessible carboxylic acids as the common
precursor and utilize the same reagent combinations,
namely, PS-PPh3/CCl3CN under microwave heating
conditions.5 A key advantage of this approach is that
starting from a common carboxylic acid scaffold, by
simply using common reagents and a common opera-
tion, distinct structures can be easily accessed by utiliz-
ing a matrix of distinct building blocks (Fig. 1). In this
Figure 1. Syntheses of diverse structural motifs from carboxylic acid
with PS-PPh3/CCl3CN and microwave heating.
Letter, we report the further extension of our strategy
to synthesize triazolopyridines 5 from carboxylic acids
and 2-hydrazinopyridines.
Triazolopyridines are an important class of heterocyclic
compounds that have a wide range of pharmaceutical
and biological activities including herbicibal, antifungal,
anticonvulsant and anxiolytic activities.6 Although sev-
eral methods have been reported in the literature for the
synthesis of triazolopyridines, many either require harsh
reaction conditions or are multi-step in nature. Few very
reliable and operationally facile examples have been
reported for the efficient synthesis of triazolopyridines
from readily available carboxylic acids in one step.7
*
Corresponding author. Tel.: +1 847 935 3058; fax: +1 847 935 5212;
e-mail: wang.ying@abbott.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.004

2238
Y. Wang et al. / Tetrahedron Letters 48 (2007) 2237–2240
Table 1. Optimization of reaction conditions for the synthesis of representative triazolopyridines 8
NO2
N
O
N
HN
NH
O
OH
PS-PPh3
CCl3CN
N
O
+
O
+
+
NH2
N
N
N
N
N
N
H
H
Microwave
NO2
NO2
NO2
NO2
6
7
10
8
9
Entry
Solvent
Method8
Base
Product 8a
Product 9a
Product 10a
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
A
A
B
B
B
A
B
C
None
DIEA
DIEA
DIEA
DIEA
DIEA
None
None
Traceb
Traceb
30%
20%
95%
97%
15%
60%
14%
10%
40%
70%
None
None
30%
15%
35%
40%
10%
Traceb
Trace
Trace
Traceb
Traceb
a Conversion based on crude LC/MS analysis.
b Other unidentified peaks were also observed.
Table 2. Synthesis of triazolopyridines from carboxylic acids and 2-hydrazinopyridines with PS-PPh3/CCl3CN
2 equiv. CCl3CN
3 equiv. PS-PPh3
2 equiv. DIEA
R'
R'
O
N
R
+
NH2
R
OH
N
N
CH2Cl2, MW
150 °C, 15 mins
N
N
H
Entry
1
Acid
2-Hydrazinopyridine
Product
Isolated yield (%)
92
O
N
NH2
OH
N
N
H
N
N
NO2
O2N
2
3
4
61
85
75
NH2
N
N
N
H
N
N
CF3
CF3
N
NH2
N
N
H
N
N
Cl
NH2
N
Cl
N
N
H
N
N
N
5
6
7
80
65
68
NH2
N
N
N
H
N
O
N
NH2
OH
N
N
H
N
N
O
N
OH
N
N

Y. Wang et al. / Tetrahedron Letters 48 (2007) 2237–2240
2239
Table 2 (continued)
Entry
Acid
2-Hydrazinopyridine
Product
Isolated yield (%)
72
O
OH
8
9
N
N
N
N
N
O
67
N
N
OH
N
O
S
N
N
S
N
10
11
82
78
OH
N
N
O
O2N
N
N
O2N
OH
N
As mentioned previously, we have shown that the
reagent combination of PS-PPh3 and CCl3CN is partic-
ularly effective in enabling the transformation of
carboxylic acids into their heterocycle derivatives in a
facile manner. It was thought that triazolopyridines 5
could be synthesized from carboxylic acids using analo-
gous procedures. In practice, when 1 equiv of carboxylic
acid 6 and 1 equiv of 2-hydrazinopyridine 7 were heated
in the presence of 3 equiv PS-PPh3 and 2 equiv CCl3CN
in CH3CN under microwave conditions, bisacylated
product 10 was observed as the major product along
with acylated product 9 (Table 1, entries 1 and 2). Inter-
estingly, the desired product 8 was observed when the
reaction was carried out in a one-pot two step process
(method B) in CH3CN although side products 9 and
10 were also observed (Table 1, entry 3) in significant
amounts. In order to identify optimal conditions for
conversion to the desired triazolopyridine 8, various
solvents were studied using this one-pot two step process
(Table 1, entries 3–5) in the presence of DIEA as the
base. Encouragingly, we quickly discovered that when
CH2Cl2 was used as the solvent, 8 was obtained with
almost complete conversion as judged by crude LC/MS
analysis (Table 1, entry 5). Subsequently, we were
delighted to discover that near quantitative conversion
to 8 was observed when the reaction was carried out
in one step in CH2Cl2 (Table 1, entry 6).
appeared to play a dual role as the acylating reagent
and dehydrating reagent.
The conditions identified above were next used to study
the scope of the transformation.9 Gratifyingly, this
paradigm was found to be quite general and worked
well for both alkyl and aryl carboxylic acids to afford
the desired triazolopyridines in fair to excellent yields
(Table 2), although in some cases, small amounts of
acylated and bisacylated side products were also
observed. The reaction proved to be facile to workup
by simple filtration of the resin and evaporation of
the solvent.
In summary, we have developed an efficient and general
one step reaction protocol for the synthesis of triazolo-
pyridines starting from carboxylic acids. The use of
solid-phase reagents in combination with microwave
heating greatly simplified reaction optimization and
purification processes. The method we have developed
fits into our overall strategy where starting from a com-
mon precursor, in this case a carboxylic acid, using a
combination of the same reagents and a common oper-
ation, multiple heterocyclic scaffolds with distinct struc-
tural complexity and diversity can be easily accessed. We
believe that this approach provides the advantages for
both focused library synthesis and diversity-oriented
synthesis. Thus diverse structure skeletons can be
obtained within one library to greatly facilitate either
a hit to lead or the lead optimization process. Efforts
towards this goal are currently in process and will be
reported in due course.
Addition of DIEA as the base was found to be crucial
for the observed high conversion to 8 (Table 1, entry
7). However, when PS-DIEA was used as the base, 10
was the major product observed in the crude LC/MS
analysis. Also of note was the observation that 2 equiv
CCl3CN was necessary to achieve optimal conversion
to 8. With 1.2 equiv of CCl3CN, acylated product 9
was the major product along with small amount of tri-
azolopyridine 8 as observed by LC/MS analysis of the
crude reaction mixture (Table 1, entry 8). As observed
previously, the PS-PPh3/CCl3CN reagent combination
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.004.

2240
Y. Wang et al. / Tetrahedron Letters 48 (2007) 2237–2240
ielski, M.; Pufky, D.; Doring, M. Tetrahedron 2005, 61,
References and notes
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added to a microwave tube containing 0.3 mmol of PS-
PPh3 in 1 ml solvent. 0.2 mmol DIEA was also added for
entries 2 and 6. Finally 0.2 mmol CCl3CN was added. The
mixture was heated in microwave at 150 °C for 15 min;
Method B: 0.1 mmol of acid 6 was added to a microwave
tube containing 0.3 mmol of PS-PPh3 in 1 ml solvent
followed by 0.2 mmol CCl3CN. The mixture was heated
in microwave at 100 °C for 5 min. The microwave tube was
uncapped and 0.1 mmol 7 was added to the above mixture
followed by 0.2 mmol DIEA (entries 3–5). The mixture was
recapped and was heated again in microwave at 150 °C for
15 min; Method C: same as method B except 0.12 mmol of
CCl3CN was added.
9. General procedure: A Smith process vial (0.5–2 ml) was
charged with a stir bar. To the vessel were added 0.2 mmol
of the carboxylic acid and 0.2 mmol of the 2-hydrazino-
pyridine in 1.5 ml dry CH2Cl2. 0.6 mmol PS-PPh3 (3 mmol/
g) was added to the reaction mixture followed by 0.4 mmol
DIEA and 0.4 mmol CCl3CN. The reaction vessel was
sealed and heated in a microwave oven to 150 °C for
15 min. After cooling, the reaction vessel was uncapped and
the resin was filtered and washed by additional CH2Cl2 and
MeOH. The desired product triazolopyridine was isolated
by reverse-phase HPLC. All products thus obtained were
greater than 95% pure as determined by LC/MS and NMR
analysis.
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