was added dropwise to a suspension of anhydrous N,N-
dimethylformamide (2 mL) and sodium hydride (80% in paraffin,
92 mg, 2.5 mmol) under a nitrogen atmosphere. The mixture was
stirred for 1 h. A solution of 9 (1.7 mmol, 350 mg) in anhydrous
N,N-dimethylformamide (5 mL) was added, dropwise, and the
resulting mixture stirred at 100 ◦C for 20 h.
(cyclohexane–dichloromethane 4 : 6) to yield 110 mg (60%) of 13,
◦
1
mp 118–120 C; H NMR (CDCl3): d 7.80 (d, 1H, J = 7.2 Hz),
8.58 (d, 1H, J = 7.2 Hz); ms: m/e 185–183 (M+), 139–137, 125,
101. Anal. Calcd. for C6H2ClN3O2: C, 39.26; H, 1.10; N, 22.89.
Found C, 39.64; H, 1.32; N, 22.74%.
3-Nitro-6-oxazol-2-ylpyridine-2-carbonitrile (14). 2.5 M n-
butyl lithium in hexane (0.15 mL, 0.38 mmol) was added to
a deoxygenated, cooled (−70 ◦C) solution of oxazole (25 lL,
The solvent was removed under reduced pressure, and water
was added to the residue. The aqueous phase was extracted with
dichloromethane, and the collected organic layers were dried over
anhydrous sodium sulfate and evaporated under reduced pressure.
Based on HPLC analysis, the ratio between the two triazole
regioisomers was 30 : 70 (10–10ꢀ). The residue was purified by
flash chromatography on silica gel (ethyl acetate–methanol 95 :
5) (under these conditions, it was possible to obtain a fraction
enriched in the 2-triazole derivative). The fractions containing
the mixture of the two regioisomers were dissolved in chloroform
and then 6 drops of a solution of hydrobromic acid (48% w/w in
water) were added. The mixture was stirred at room temperature
for 5 min (under these conditions, the 1-triazole derivative yielded
degradation products). The solution was diluted with water and
rendered alkaline (pH 10) with 30% sodium hydroxide solution
at 0 ◦C. The aqueous phase was extracted with ethyl acetate, and
the organic layers were dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The residue was purified by
flash chromatography on silica gel (dichlor◦omethane–acetone 98 :
2) to give 83 mg (25%) of 10, mp 280–282 C; 1H NMR (CDCl3):
d 4.15 (s, 3H), 7.37 (d, 1H, J = 8.9 Hz), 7.87 (d, 1H, J = 8.9 Hz),
◦
0.38 mmol) in THF (2 mL). The mixture was stirred at −70 C
for 30 min and then 1 M zinc chloride in ether (1.14 mL,
1.14 mmol) was added. The reaction was warmed to 0 ◦C and
maintained at this temperature for 1 h. To this mixture was
added a solution of 13 (70 mg, 0.38 mmol) in deoxygenated THF
(2 mL) and tetrakis(triphenylposphine)palladium(0) [Pd(PPh3)4]
(44 mg, 0.038 mmol). The resulting mixture was refluxed for
4 h. The mixture was then cooled, diluted with ethyl acetate and
washed with water and brine. The organic phase was dried over
anhydrous sodium sulfate and evaporated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(cyclohexane–ethyl acetate 6 : 4) to give 16 mg (20%) of 14, mp
◦
1
116–118 C; H NMR (CDCl3) d 7.47 (s, 1H), 7.98 (s, 1H), 8.59
(d, 1H, J = 8.8 Hz), 8.74 (d, 1H, J = 8.8 Hz); ms: m/e 216 (M+),
186, 170. Anal. Calcd. for C9H4N4O3: C, 50.01; H, 1.87; N, 25.92.
Found C, 49.87; H, 2.03; N, 26.13%.
3-Amino-6-oxazol-2-ylpyridine-2-carbonitrile (15). Powdered
iron (1 mmol, 56 mg) was added to a solution of 14 (0.5 mmol,
108 mg) in methanol (2 mL) and hydrochloric acid (1 N solution,
9.8 mL). The mixture was stirred at 60 ◦C for 1 h and then basified
(pH 10) with 1 N sodium hydroxide solution and filtered through
a Celite cake, which was washed with several portions of ethyl
acetate and methanol. The layers were separated, and the aqueous
phase was extracted with additional ethyl acetate. The combined
organic phases were washed with brine, dried over anhydrous
sodium sulfate and evaporated under reduced pressure, to give
a residue that was used for the following reaction without further
purification, 1H NMR (CDCl3): d 4.74 (br, 2H), 7.23 (d, 1H, J =
8.6 Hz), 7.25 (s, 1H), 7.78 (s, 1H), 8.12 (d, 1H, J = 8.6 Hz); ms:
m/e 186 (M+), 158, 105.
1
8.03 (s, 2H), 8.10 (s, 1H); H NMR (DMSO-d6, 0.0042 M, 298
K): d 3.91 (s, 3H), 3.95 (s, 3H), 7.4–7.7 (m, 4H), 8.20 (s, 1H), 8.25
(s, 1H), 8.35 (s, 4H), 12.71 (br, 1H), 13.26 (br, 1H); ms: m/e 239
(M+), 184, 158.
Anal. Calcd. for C11H9N7: C, 55.22; H, 3.79; N, 40.98. Found
C, 54.89; H, 4.02; N, 41.17%.
6-Methoxy-3-nitropyridine-2-carbonitrile
(12). Copper(I)
cyanide (5.7 g, 63.49 mmol) was added to a solution of 2-
chloro-6-methoxy-3-nitropyridine (11) (4 g, 21.16 mmol) in
N,N-dimethylformamide (40 mL). The mixture was stirred at
90 ◦C for 5 h. The solution was poured into a water–ethyl acetate
(100 : 100) mixture and stirred for 5 min. The solution was filtered
over Celite. The layers were separated, the organic phase washed
with water and brine, dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The residue was purified by
flash chromatography on silica gel (cyclohexane–ethyl acetate 8 :
2) to yield 3.2 g (84%) of 12, mp 85–87 ◦C; 1H NMR (CDCl3): d
4.12 (s, 3H), 7.10 (d, 1H, J = 9.2 Hz), 8.45 (d, 1H, J = 9.2 Hz);
ms: m/e 179 (M+), 149, 133, 118. Anal. Calcd. for C7H5N3O3: C,
46.93; H, 2.81; N, 23.46. Found C, 47.07; H, 2.69; N, 23.07%.
5-Oxazol-2-yl-1H-pyrazolo[4,3-b]pyridin-3-ylamine (16).
A
mixture of 15, hydrochloric acid (12 N solution, 2 mL) and
water (1 mL) was stirred until a complete solution was obtained.
The solution was cooled to 0 ◦C and then a pre-chilled (0 ◦C)
solution of sodium nitrate (40 mg, 0.57 mmol) in water (1 mL)
was added dropwise. After 15 min, a pre-chilled solution of tin(II)
chloride dihydrate (283 mg, 1.25 mmol) in hydrochloric acid (12
N solution, 2 mL) was added dropwise. The resulting mixture was
stirred at room temperature for 1 h and then heated at 80 ◦C for
2 h. The mixture was cooled, basified with 30% sodium hydroxide
solution and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over anhydrous sodium
sulfate and evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel (ethyl acetate) to
yield 20 mg (26%) of 16, mp > 250 ◦C degradation (ethyl acetate);
1H NMR (CDCl3): d 4.69 (br, 2H), 6.99 (s, 1H), 7.33 (s, 1H), 7.76
(d, 1H, J = 8.9 Hz), 7.83 (s, 1H), 8.18 (d, 1H, J = 8.9 Hz); ms:
m/e 201 (M+), 172. Anal. Calcd. for C9H7N5O: C, 53.73; H, 3.51;
N, 34.81. Found C, 53.89; H, 3.64; N, 35.03%.
6-Chloro-3-nitropyridine-2-carbonitrile (13). Phosphoryl chlo-
ride (338 mg, 2.2 mmol) was added to a solution of 12 (179 mg,
1 mmol) in dry N,N-dimethylformamide (16 mL) at 0 ◦C. The
mixture was stirred at this temperature for 1 h and then heated
◦
at 95–99 C for 42 h; 1 mmol of phosphoryl chloride was added
every 14 h. The solution was cooled to 0 ◦C, quenched by adding
saturated sodium acetate solution and warmed in a water bath
for 3 min. After cooling, the mixture was extracted with ethyl
acetate and the organic phases were washed with water, dried over
anhydrous sodium sulfate and evaporated under reduced pressure.
The residue was purified by flash chromatography on silica gel
2570 | Org. Biomol. Chem., 2007, 5, 2567–2571
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The Royal Society of Chemistry 2007
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