New method for the general synthesis of [1,2,4]triazolo[1,5-a]pyridines

Article abstract of DOI:10.1002/ejoc.200500247

[1,2,4]Triazolo[1,5-a]pyridines without substituants on the 2-position have been prepared from 2-aminopyridines by cyclization of N-(pyrid-2-yl) formamidoximes with trifluoroacetic anhydride. Triazoles substituted at any position on the pyridine ring may be prepared in good yields and under mild reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500247

FULL PAPER
New Method for the General Synthesis of [1,2,4]Triazolo[1,5-a]pyridines
Elliott Huntsman[a] and Jaume Balsells*[a]
Keywords: Nitrogen heterocycles / Fused ring systems / Cyclization
[1,2,4]Triazolo[1,5-a]pyridines without substituents on the 2-
position have been prepared from 2-aminopyridines by cycli-
zation of N-(pyrid-2-yl)formamidoximes with trifluoroacetic
anhydride. Triazoles substituted at any position on the pyri-
dine ring may be prepared in good yields and under mild
reaction conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
substituent on the 6 position are especially challenging and
all the cyclization methods previously reported offer very
limited success to prepare these types of compounds.[7]
Introduction
6-Bromo[1,2,4]triazolo[1,5-a]pyridine (3) is a key compo-
nent of a larger molecule of pharmaceutical interest. The
synthesis of this type of heterocycles has been previously
reported in the literature by several synthetic methods such
as amination of 2-aminopyridine with hydroxylamine-O-
sulfonic acid (HSA), followed by cyclization with formic
Results and Discussion
The triazolo-pyridine 3 was successfully prepared by the
acid (18–27% overall yield);[1] reaction of 2-aminopyridines method of Lin[2] (Scheme 1). However, yields were consist-
with DMF–dimethyl acetal, (DMF–DMA) followed by cyc- ently lower than 50%.[8] While the formation of amidine
lization with HSA (26–87% yield);[2] cyclization of N-imi- intermediate 2 was nearly quantitative, subsequent cycliza-
nopyridine with HCN (2% yield);[3] isomerization of [1,2,4]- tion to 3 proceeded poorly. Additionally, a substantial
triazolo[4,3-a]pyridines in the presence of formic acid;[4] re- amount (10–30%) of N-hydroxy impurity 4[9] was produced
action of 2-aminopyridines with DMF–DMA and hydrox- in the cyclization reaction.
ylamine, followed by cyclization with polyphosphoric acid
The reaction is likely to proceed by replacing the dimeth-
(PPA) (54% overall yield);[5] and acetylation of formamid- ylamino moiety on 2 with HSA to form 5 (Scheme 2).[10]
oximes followed by heating in aqueous solution (2 steps, The sulfonyl moiety on intermediate 5 behaves as a leaving
25% overall yield).[6]
group, being displaced by the pyridine nitrogen during the
There are a number of significant disadvantages to these cyclization that produces 3.[2] However, if intermediate 5 is
methods, including low yields and scope limitation. In par- unstable to the reaction conditions, it could hydrolyze to
ticular, triazoles prepared from 2-aminopyridines bearing a produce 4. We thought that the reaction could be improved
Scheme 1. HSA synthesis of 3.
by replacing the sulfonyl group with a different chemical
entity that could stabilize intermediate 5 towards hydrolysis
and behave as a better leaving group towards the pyridine
nitrogen.
[a] Process Research Department, Merck Research Laboratories,
Merck & Co., Inc.,
P. O. Box 2000, Rahway, NJ 07065, USA
E-mail: Jaume_Balsells@merck.com
DOI: 10.1002/ejoc.200500247
Eur. J. Org. Chem. 2005, 3761–3765
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3761

E. Huntsman, J. Balsells
FULL PAPER
Scheme 2. Proposed mechanism in the HSA synthesis.
Intermediate 4 was easily prepared by treatment of amid-
ine 2 with hydroxylamine.[5] Several dehydrating agents were
screened as leaving groups to evaluate whether they could
promote the cyclization reaction more efficiently (Table 1).
PPA was quite efficient at promoting the cyclization to 3
at elevated temperatures.[11] Other sulfur and phosphorus
derived reagents afforded moderate yields of 3 at ambient
temperature. Trifluoroacetic anhydride (TFAA), afforded
the best results, cleanly promoting the desired reaction at
Scheme 3. The favorable effect of 3-substitution.
The TFAA-promoted synthesis of triazolo-pyridines is a
ambient temperature. The presence of the electron with- very general method which provides access to triazolo-pyri-
drawing trifluoromethyl moiety is key to the reaction, as dines substituted on any position of the pyridine ring. The
experiments conducted using acetyl chloride or acetic anhy- results obtained are summarized in Table 2. In most cases,
dride were unsuccessful. Under our optimized reaction con- both the intermediates 4a–i and the products 3a–i can be
ditions, the triazolo-pyridine 3 was obtained in 84% yield isolated by crystallization from the reaction mixture or
after crystallization.
workup solutions. No efforts were made to optimize yields
The scope of this chemical transformation was then ex- in the crystallization process and the crude workup solu-
plored for other, more challenging, substituted 2-aminopyr- tions were purified by chromatography in order to maxi-
idines. Typically, 3-substituted 2-aminopyridines are the mize the isolated yields.
best substrates for the cyclization because of the predomi-
As expected, the presence of a C-3 substituent on the
nance of the favorable geometrical isomer A over B pyridine ring afforded excellent yields of the desired tri-
(Scheme 3). While steric effects are minimal on 4 and 5- azolo-pyridines (Entries b and f). Yields for the cyclization
substituted 2-aminopyridines, the presence of a substituent reaction were also high for pyridines with substituents on
on the 6 position of the pyridine ring strongly hinders the C-4 and C-5. A small methyl group was well tolerated on
pyridine nitrogen making these types of substrates espe- C-6, as the reaction proceeded with high yield at ambient
cially difficult to prepare.
temperature. Not surprisingly however, when a much larger
Table 1. Screening of dehydrating reagents.
Dehydrating agent
Conversion (time/temp.)
Isolated yield
PPA
100% (1 h/reflux in THF)
11% (3 d/room temp.)
59% (3 d/room temp.)
95% (3 d/room temp.)
89% (3 d/room temp.)
46% (16 h/50 °C)
77%
15%
34%
44%
69%
31%
18%
84%
SOCl2
POCl3
MsCl
TsCl
Ac2O
AcCl
TFAA
36% (16 h/50 °C)
100% (1 h/room temp.)
3762
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3761–3765

New Method for the General Synthesis of [1,2,4]Triazolo[1,5-a]pyridines
FULL PAPER
Table 2. Synthesis of substituted triazoles.
1a–i
R
4a–i
isolated
3a–i
isolated
reaction temperature
a
b
c
d
e
f
g
h
i
H
63%
78%
76%
80%
81%
74%
92%
95%
80%
room temperature
room temperature
room temperature
room temperature
room temperature
room temperature
room temperature
reflux temperature
reflux temperature
77%
87%
68%
75%
91%
86%
84%
41%
45%
3-CH3
4-CH3
5-CH3
6-CH3
3-Br
5-Br
6-Br
5-COOMe
used without prior purification. Yields reported are for isolated
compounds judged pure by NMR or elemental analysis.
bromine group was present on C-6 the reaction did not oc-
cur at room temperature. Running the reaction at elevated
temperatures was necessary in order to promote the cycliza-
tion. Interestingly, the presence of a deactivating substituent
on C-5 (Entry i) also slowed down the cyclization reaction
and elevated temperatures were necessary to drive the reac-
tion to completion.
Compounds 3f–h are of particular interest as they can be
used as building blocks of larger molecules through metal
catalyzed cross-coupling reactions.[8]
N-(5-Bromopyrid-2-yl)formamidoxime (4g). General Procedure: 2-
Amino-5-bromopyridine (10.0 g, 58 mmol, 1.0 equiv.) was placed
in a round-bottom flask equipped with magnetic stirrer, condenser,
and nitrogen line, followed by 2-propanol (20 mL). To this mixture
at room temperature was added dimethylformamide dimethyl ace-
tal (8.95 g, 10.05 mL, 75 mmol, 1.3 equiv.). The reaction was heated
to reflux and aged 3 h. It was then cooled to 50 °C, and hydroxyl-
amine hydrochloride (5.21 g, 75 mmol, 1.3 equiv.) was added. The
reaction was aged at 50 °C overnight. The volatile components were
evaporated and the residue was purified by chromatography (silica
gel, packed in 50% ethyl acetate/hexane, eluted with 50% to 75%
ethyl acetate/hexane gradated elution) to obtain 11.51 g of 4g (92%
yield). M.p. 178–180 °C. LC-MS(ES+): m/z = 216 [M + H], 199
In summary, a new general synthetic method for the
preparation of [1,2,4]triazolo[1,5-a]pyridines has been de-
veloped, which requires inexpensive reagents and takes
place under mild reaction conditions.
1
[M – OH], 198 [M – H2O]. H NMR (DMSO): δ (ppm) = 10.18 (s,
1 H), 9.53 (d, J = 10, 1 H), 8.21 (d, J = 2.40, 1 H), 7.81–7.74 (m,
2 H), 7.03 (dd, J = 8.8, 0.8, 1 H). 13C NMR (DMSO): δ (ppm) =
Experimental Section
151.9, 148.1, 140.8, 135.6, 112.7, 110.7. IR: ν = 3324, 3059, 2780,
˜
1697, 1593, 1475, 1302, 1276, 940 cm–1. C6H6BrN3O (216.04):
calcd. C 33.36, H 2.80, N 19.45; found C 33.64, H 2.70, N 19.79.
General: 1Hand 13C NMR were recorded in [D6]DMSO with a
Bruker DPX400 spectrometer at a frequency of 400.13 MHz and
100.62 MHz, respectively. The chemical shifts (δ) are reported in
ppm relative to residual [D5]DMSO for proton (δ = 2.50 ppm) and
[D6]DMSO for carbon (δ = 39.5 ppm). Proton multiplicities are
abbreviated as follows: Singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m), and broad (b). All coupling constants (J) are
reported in Hertz (Hz). Infrared spectra were recorded with a Nico-
let 560 FT-IR spectrometer, using IR grade potassium bromide
(Sigma, EC no. 231–830–3) pellets as the measurement medium.
Peaks are reported in cm–1. HPLC analysis were carried out with
a Hewlett Packard 1100 system. Melting points were determined
with a Buchi B-545 apparatus and are uncorrected. Combustion
analysis was performed by Quantitative Technologies Inc., White-
house, NJ. Analytical thin-layer chromatography (TLC) was per-
formed on Merck silica gel 60 plates, 0.25 mm thick with F-254
indicator. Visualization was accomplished by UV light, 5% phos-
phomolybdic acid solution in ethanol. Flash column chromatog-
raphy was performed by the method of Still[12] with 32–63 µm silica
gel (Woelm). Solvents for extraction and chromatography were rea-
gent grade and used as received. All manipulations were carried
out under an inert atmosphere of nitrogen. Reagents were pur-
chased from Aldrich Chemical Co. unless otherwise noted and were
6-Bromo[1,2,4]triazolo[1,5-a]pyridine (3g). General Procedure: The
N-hydroxy intermediate (6.00 g, 27.8 mmol, 1.0 equiv.) was placed
in a round-bottom flask equipped with magnetic stirrer and nitro-
gen line, followed by addition of THF (60 mL). The resulting mix-
ture was cooled to 0 °C, and trifluoroacetic anhydride (6.41 g, 4.25
mL, 30.6 mmol, 1.1 equiv.) was added over 5–10 minutes, keeping
the internal temperature below 20 °C. After the addition was com-
plete, the reaction was warmed to room temperature and aged 3 h.
at room temperature. The reaction was quenched with saturate
aqueous NaHCO3 (125 mL), then extracted with MTBE three
times. The organic layers were combined, washed once with satu-
rated aqueous NaHCO3, dried with sodium sulfate, filtered, and
concentrated. The residue was purified by column chromatography
(silica gel, packed in 50% ethyl acetate/hexane, eluted with 50%
ethyl acetate/hexane) to obtain 4.63 g of 3g as an off-white solid
(84% yield). M.p. 115–118 °C. LC-MS(ES+): m/z = 198 (M), 200
[M + 2]. 1H NMR (DMSO): δ (ppm) = 9.37 (m, 1 H), 8.52 (s, 1
H), 7.84–7.78 (m, 2 H). 13C NMR (DMSO): δ (ppm) = 154.5,
149.1, 133.8, 130.0, 117.3, 108.2. IR: ν = 3125, 3065, 3019, 1496,
˜
1314, 1257, 1198, 1165, 809 cm–1. C6H4BrN3 (198.02): calcd. C
36.39, H 2.04, N 21.22; found C 36.27, H 1.79, N 20.86.
Eur. J. Org. Chem. 2005, 3761–3765
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3763

E. Huntsman, J. Balsells
FULL PAPER
N-(Pyrid-2-yl)formamidoxime (4a): Yield: 63%. M.p. 144–147 °C.
LC-MS(ES+): m/z = 138 [M + H]. H NMR (DMSO): δ (ppm) =
2957, 1519, 1441, 1324, 1258, 1186, 821 cm–1. C7H7N3 (133.15):
calcd. C 63.14, H 5.30, N 31.56; found C 62.89, H 5.04, N 31.54.
1
10.04 (s, 1 H), 9.30 (d, J = 10.0, 1 H), 8.12 (dq, J = 5.2, 0.7, 1 H),
7.85 (d, J = 10.0, 1 H), 7.61–7.55 (m, 1 H), 7.04 (dt, J = 8.4, 1.0,
1 H), 6.84–6.80 (m, 1 H). 13C NMR (DMSO): δ (ppm) = 152.9,
N-(6-Methylpyrid-2-yl)formamidoxime (4e): Yield: 81%. M.p. 185–
188 °C. LC-MS(ES+): m/z = 152 [M + H], 135 [M – OH], 134 [M –
H2O]. 1H NMR (DMSO): δ (ppm) = 9.99 (s, 1 H), 9.19 (d, J =
10.0, 1 H), 7.85 (d, J = 10.0, 1 H), 7.46 (t, J = 7.8, 1 H), 6.83 (d,
J = 8.4, 1 H), 6.68 (d, J = 7.2, 1 H), 2.33 (s, 3 H). 13C NMR
(DMSO): δ (ppm) = 156.3, 152.3, 138.7, 136.1, 115.6, 107.5, 24.4.
147.8, 138.4, 136.0, 116.6, 110.7. IR: ν = 3209, 2755, 1688, 1607,
˜
1580, 1442, 1213 cm–1. C6H7N3O (137.14): calcd. C 52.55, H 5.14,
N 30.64; found C 52.05, H 4.89, N 30.64.
IR: ν = 2848, 1683, 1604, 1467, 1317, 1220, 1166, 904 cm–1.
˜
[1,2,4]Triazolo[1,5-a]pyridine (3a): Yield: 77%. M.p. 110–112 °C.
1
C7H9N3O (151.17): calcd. C 55.62, H 6.00, N 27.80; found C 55.67,
H 5.85, N 27.40.
LC-MS(ES+): m/z = 120 [M + H]. H NMR (DMSO): δ (ppm) =
8.95 (dt, J = 6.8, 1.2, 1 H), 8.49 (s, 1 H), 7.85 (dt, J = 8.8, 1.2, 1
H), 7.66 (dq, J = 6.8, 1.2, 1 H), 7.2 (td, J = 6.8, 1.2, 1 H). 13C
NMR (DMSO), δ (ppm): 154.2, 150.3, 130.6, 129.5, 116.6, 114.7.
5-Methyl[1,2,4]triazolo[1,5-a]pyridine (3e): Yield: 91%. M.p. 54–
59 °C. LC-MS(ES+): m/z = 134 [M + H]. 1H NMR (DMSO): δ
(ppm) = 8.48 (s, 1 H), 7.69 (d, J = 9.0, 1 H), 7.57 (dd, J = 8.8, 7.2,
1 H), 7.05 (d, J = 7.2, 1 H), 2.71 (s, 3 H). 13C NMR (DMSO): δ
IR: ν = 3140, 3080, 3040, 1635, 1506, 1326, 1260, 1181, 770 cm–1.
˜
C6H5N3 (119.12): calcd. C 60.50, H 4.27, N 35.23; found C 60.22,
H 3.98, N 35.27.
(ppm) = 153.7, 150.4, 139.1, 130.2, 113.8, 113.5, 17.4. IR: ν = 3080,
˜
2985, 1638, 1556, 1515, 1307, 1197, 785 cm–1. C7H7N3 (133.15):
calcd. C 63.14, H 5.30, N 31.56; found C 62.80, H 5.23, N 31.17.
N-(3-Methylpyrid-2-yl)formamidoxime (4b): Yield: 78%. M.p. 110–
114 °C. LC-MS(ES+): m/z = 152 [M + H], 135 [M – OH], 134 [M –
1
H2O]. H NMR (DMSO): δ (ppm) = 10.03 (s, 1 H), 8.04 (dd, J =
N-(3-Bromopyrid-2-yl)formamidoxime (4f): Yield: 74%. M.p. 151–
155 °C. LC-MS(ES+): m/z = 216 [M + H], 199 [M – OH], 198 [M –
4.8, 1.2, 1 H), 7.96 (d, J = 9.6, 1 H), 7.73 (d, J = 9.6 Hz, 1 H), 7.50
(dd, J = 7.2, 0.8, 1 H), 6.85 (dd, J = 7.2, 4.8, 1 H), 2.19 (s, 3 H).
13C NMR (DMSO): δ (ppm) = 150.4, 145.5, 139.1, 136.4, 118.6,
1
H2O]. H NMR (DMSO): δ (ppm) = 10.68 (s, 1 H), 8.21 (dd, J =
4.8, 1.6, 1 H), 8.14 (bd, J = 9.6, 1 H), 8.02 (dd, J = 8.0, 1.6, 1 H),
7.92 (d, J = 9.6, 1 H), 6.91 (dd, J = 7.6, 4.8, 1 H). 13C NMR
117.3, 16.3. IR: ν = 3434, 3078, 2780, 1663, 1599, 1506, 1471, 1245,
˜
875 cm–1. C7H9N3O (151.17): calcd. C 55.62, H 6.00, N 27.80;
found C 55.36, H 5.80, N 27.69.
(DMSO): δ (ppm) = 148.3, 147.4, 141.8, 135.6, 118.7, 105.8. IR: ν =
˜
3414, 3075, 2912, 1666, 1591, 1453, 1265, 1016 cm–1. C6H6BrN3O
(216.04): calcd. C 33.36, H 2.80, N 19.45; found C 33.38, H 2.74,
N 18.99.
8-Methyl[1,2,4]triazolo[1,5-a]pyridine (3b): Yield: 87%. M.p. 56–
57 °C. LC-MS(ES+): m/z = 134 [M + H]. 1H NMR (DMSO): δ
(ppm) = 8.76 (d, J = 6.8, 1 H), 8.43 (s, 1 H), 7.44–7.40 (m, 1 H),
7.07 (t, J = 7.0, 1 H), 3.34 (s, 3 H). 13C NMR (DMSO), δ (ppm):
8-Bromo[1,2,4]triazolo[1,5-a]pyridine (3f): Yield: 86%. M.p. 150–
152 °C. LC-MS(ES+): m/z = 198 [M], 200 [M + 2]. 1H NMR
(DMSO): δ (ppm) = 9.00 (d, J = 6.8, 1 H), 8.57 (s, 1 H), 8.00 (d,
J = 8.0, 1 H), 7.14 (t, J = 7.2, 1 H). 13C NMR (DMSO): δ (ppm)
153.6, 150.7, 128.8, 127.0, 126.6, 114.4, 16.7. IR: ν = 3095, 3024,
˜
2917, 1630, 1505, 1346, 1260, 1194, 761 cm–1. C7H7N3 (133.15):
calcd. C 63.14, H 5.30, N 31.56; found C 62.73, H 4.97, N 31.29.
= 154.2, 149.2, 133.3, 129.3, 115.1, 109.1. IR: ν = 3101, 3080, 1628,
˜
1498, 1337, 1260, 1206, 752 cm–1. C6H4BrN3 (198.02): calcd. C
36.39, H 2.04, N 21.22; found C 36.37, H 1.87, N 21.11.
N-(4-Methylpyrid-2-yl)formamidoxime (4c): Yield: 76%. M.p. 137–
142 °C. LC-MS(ES+): m/z = 152 [M + H], 135 [M – OH], 134 [M –
1
H2O]. H NMR (DMSO): δ (ppm) = 10.00 (s, 1 H), 9.16 (d, J =
N-(6-Bromopyrid-2-yl)formamidoxime (4h): Yield: 95%. M.p. 172–
175 °C. LC-MS(ES+): m/z = 216 [M + H], 199 [M – OH], 198 [M –
10.0, 1 H), 7.98 (d, J = 5.2, 1 H), 7.82 (d, J = 10.0, 1 H), 6.86 (S,
1 H), 6.68 (d, J = 5.2, 1 H), 2.20 (s, 3 H). 13C NMR (DMSO): δ
1
H2O]. H NMR (DMSO): δ (ppm) = 10.25 (s, 1 H), 9.64 (d, J =
(ppm) = 153.1, 149.0, 147.5, 136.2, 118.0, 110.7, 21.0. IR: ν = 2847,
˜
9.6, 1 H), 7.67 (d, J = 9.6, 1 H), 7.52 (t, J = 7.8, 1 H), 7.04 (dd, J
1618, 1579, 1426, 1308, 1213, 904 cm–1. C7H9N3O (151.17): calcd.
C 55.62, H 6.00, N 27.80; found C 55.37, H 5.79, N 27.69.
= 7.8, 5.0, 2 H). 13C NMR (DMSO): δ (ppm) = 153.3, 141.3, 139.3,
135.2, 119.6, 109.6. IR: ν = 3427, 3279, 3080, 2783, 1683, 1598,
˜
1566, 1457, 1305, 780 cm–1. C6H6BrN3O (216.04): calcd. C 33.36,
H 2.80, N 19.45; found C 32.91, H 2.99, N 19.45.
7-Methyl[1,2,4]triazolo[1,5-a]pyridine (3c): Yield: 68%. M.p. 83–
85 °C. LC-MS(ES+): m/z = 134 [M + H]. 1H NMR (DMSO): δ
(ppm) = 8.80 (d, J = 6.8, 1 H), 8.39 (s, 1 H), 7.60 (br. s, 1 H), 7.02
(dd, J = 6.8, 1.6, 1 H), 2.42 (s, 3 H). 13C NMR (DMSO): δ (ppm)
5-Bromo[1,2,4]triazolo[1,5-a]pyridine (3h): Reaction was performed
at reflux temperature for 13 hours. Yield: 41%. M.p. 164–167 °C.
LC-MS(ES+): m/z = 198 [M], 200 [M + 2] peak. 1H NMR
(DMSO): δ (ppm) = 8.60 (s, 1 H), 7.89 (dd, J = 7.8, 2.2, 1 H),
7.64–7.57 (m, 2 H). 13C NMR (DMSO): δ (ppm) = 153.7, 151.1,
= 154.2, 150.5, 141.5, 128.4, 116.9, 114.9, 21.2. IR: ν = 3130, 3045,
˜
1642, 1501, 1344, 1260, 1210, 1192, 796 cm–1. C7H7N3 (133.15):
calcd. C 63.14, H 5.30, N 31.56; found C 62.89, H 5.11, N 31.51.
131.3, 118.8, 117.9, 115.7. IR: ν = 3084, 3029, 1624, 1491, 1297,
˜
N-(5-Methylpyrid-2-yl)formamidoxime (4d): Yield: 80%. M.p. 165–
169 °C. LC-MS(ES+): m/z = 152 [M + H], 135 [M – OH], 134 [M –
H2O]. 1H NMR (DMSO): δ (ppm) = 9.96 (s, 1 H), 9.16 (d, J =
10.0, 1 H), 7.95 (br. s, 1 H), 7.80 (d, J = 10.0, 1 H), 7.41 (dd, J =
8.4, 2.4, 1 H), 6.95 (d, J = 8.4, 1 H), 2.16 (s, 3 H). 13C NMR
(DMSO): δ (ppm) = 151.0, 147.3, 139.1, 136.3, 125.1, 110.3, 17.4.
1193, 784 cm–1. C6H4BrN3 (198.02): calcd. C 36.39, H 2.04, N
21.22; found C 36.28, H 1.80, N 20.97.
Methyl 6-{[(1Z)-(Hydroxyamino)methylene]amino}nicotinate (4i):
Yield: 80%. M.p. 193–196 °C. LC-MS(ES+): m/z = 196 [M + H],
179 [M – OH], 178 [M – H2O]. 1H NMR (DMSO): δ (ppm) =
10.37 (s, 1 H), 9.91 (d, J = 10.0, 1 H), 8.68 (d, J = 2.4, 1 H), 8.05
(dd, J = 8.8, 2.4, 1 H), 7.90 (d, J = 9.6, 1 H), 7.12 (d, J = 8.8, 1
H), 3.80 (s, 3 H). 13C NMR (DMSO): δ (ppm) = 165.6, 155.8,
IR: ν = 3370, 3013, 2771, 1680, 1613, 1496, 1283, 886 cm–1.
˜
C7H9N3O (151.17): calcd. C 55.62, H 6.00, N 27.80; found C 55.65,
H 5.76, N 27.38.
150.2, 139.0, 135.2, 118.3, 110.3, 52.2. IR: ν = 3322, 3079, 3023,
˜
6-Methyl[1,2,4]triazolo[1,5-a]pyridine (3d): Yield: 75%. M.p. 74–
77 °C. LC-MS(ES+): m/z = 134 [M + H]. 1H NMR (DMSO): δ
(ppm) = 8.76 (br. s, 1 H), 8.40 (s, 1 H), 7.73 (d, J = 9.2, 1 H), 7.50
1704, 1608, 1505, 1280, 1121, 880 cm–1. C8H9N3O3 (195.18): calcd.
C 49.23, H 4.65, N 21.53; found C 48.89, H 4.84, N 21.29.
(dd, J = 9.2, 1.6, 1 H), 2.35 (s, 3 H). 13C NMR (DMSO): δ (ppm) Methyl [1,2,4]Triazolo[1,5-a]pyridine-6-carboxylate (3i): Reaction
= 153.8, 149.0, 133.2, 127.2, 124.4, 115.7, 17.6. IR: ν = 3071, 3029,
was performed at reflux temperature for 20 h. Yield: 45%. M.p.
˜
3764
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3761–3765

New Method for the General Synthesis of [1,2,4]Triazolo[1,5-a]pyridines
FULL PAPER
166–170 °C. LC-MS(ES+): m/z = 178 [M + 1]. 1H NMR (DMSO):
δ (ppm) = 9.46 (s, 1 H), 8.67 (s, 1 H), 8.04 (d, J = 9.6, 1 H), 7.93
(d, J = 9.6, 1 H), 3.91 (s, 3 H). 13C NMR (DMSO): δ (ppm) =
[7] An alternative method to introduce substitution on this posi-
tion from the preformed [1,2,4]triazolo[1,5-a]pyridine was re-
ported: B. L. Finkelstein, J. Org. Chem. 1992, 57, 5538–5540.
[8] Similar results have been reported by other authors: a) L. M.
Gaster, J. D. Harling, J. P. Heer, T. D. Heightman, A. H. Payne,
PCT Int. Appl. 2003, WO2003042211A1; Chem. Abstr. 2003,
138, 401735; b) T. D. Heightman, A. H. Payne, PCT Int. Appl.
2003, WO2003042207A1; Chem. Abstr. 2003, 138, 401734; c)
L. M. Gaster, J. D. Harling, J. P. Heer, T. D. Heightman, A. H.
Payne, PCT Int. Appl. 2002, WO2002040476A1; Chem. Abstr.
2002, 136, 401764; d) L. M. Gaster, M. S. Hadley, J. D. Har-
ling, F. P. Harrington, J. P. Heer, T. D. Heightman, PCT Int.
Appl. 2001, WO2001062756A1; Chem. Abstr. 2001, 135,
195566.
164.6, 156.2, 151.6, 132.5, 129.7, 118.0, 116.4, 53.1. IR: ν = 3071,
˜
3034, 1725, 1635, 1443, 1312, 1165, 776 cm–1. C8H7N3O2 (177.16):
calcd. C 54.24, H 3.98, N 23.72; found C 53.84, H 3.71, N 23.33.
Acknowledgments
We thank Dr. Karl Hansen and Dr. Joseph D. Armstrong III for
their help in editing this manuscript and helpful discussion.
[9] Intermediates 4 have been shown to be formamide oximes: S.
Polanc, B. Vercek, B. Stanovnik, M. Tisler, J. Heterocycl.
Chem. 1974, 11, 103–104.
[10] HSA is also a known amination reagent for pyridines. An alter-
native plausible mechanism would involve the amination of the
pyridine ring on 2 followed by cyclization with displacement
of dimethylamine.
[1] K. T. Potts, H. R. Burton, J. Bhattacharyya, J. Org. Chem.
1966, 31, 260–265.
[2] Y.-I. Lin, S. A. Lang, J. Org. Chem. 1981, 46, 3123–3124.
[3] T. Okamoto, M. Hirobe, Y. Tamai, E. Yabe, Chem. Pharm.
Bull. 1966, 14, 506.
[4] K. T. Potts, C. R. Surapaneni, J. Heterocycl. Chem. 1970, 7,
[11] This method however, does not have general application as re-
1019.
ported by their authors; see ref.[5]
[5] S. Polanc, B. Vercek, B. Sek, B. Stanovnik, M. Tisler, J. Org.
Chem. 1974, 39, 2143–2147.
[6] B. Vercek, B. Stanovnik, M. Tisler, Z. Zrimsek, Org. Prep. Proc.
Int. 1978, 10, 293–295.
[12] W. C. Still, H. L. Ammon, P. Deshong, J. Am. Chem. Soc. 1995,
117, 5166–5167.
Received: April 6, 2005
Published Online: July 12, 2005
Eur. J. Org. Chem. 2005, 3761–3765
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3765