Crystal Growth & Design
Article
2Pyr Series. The synthesis of N-(pyridin-2-yl)picolinamides was
done according to an available literature procedure.34
of thionyl chloride was complete, the mixture was heated under reflux
for 3 h. The mixture was cooled to room temperature, and a solution of
2-aminopyridine (0.94 g, 10.0 mmol) and triethylamine (1.40 mL, 10.0
mmol) in 30 mL of acetonitrile was added in situ. The contents were
stirred overnight at room temperature. The organic layer was washed
with water and the solvent removed in vacuo. The product was purified
by column chromatography using hexane/ethyl acetate (90/10) as
eluent to isolate the pure product. Yield 28%. Mp: 137−139 °C (lit. mp
136−137 °C).36 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.13
(dd, J = 2.4, 0.9 Hz, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (ddd, J =
4.8, 2.0, 0.9 Hz, 1H), 8.37−8.30 (m, 1H), 8.19 (dt, J = 8.4, 1.0 Hz, 1H),
7.86 (ddd, J = 8.5, 7.4, 2.0 Hz, 1H), 7.54 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H),
7.19 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ
165.40, 153.00, 152.61, 149.68, 148.68, 138.91, 136.41, 130.55, 124.07,
120.75, 115.40.
Synthesis of N-(5-Chloropyridin-2-yl)nicotinamide. Nicotinic
acid (1.21 g, 9.83 mmol) and triethylamine (1.40 mL, 10.0 mmol) were
added to 30 mL of chloroform and cooled in an ice bath. Thionyl
chloride (0.73 mL, 10.0 mmol) was added dropwise under nitrogen.
After the addition of thionyl chloride was complete, the mixture was
heated under reflux for 3 h. The mixture was cooled to room
temperature, and a solution of 2-amino-5-chloropyridine (1.28 g, 10.0
mmol) and triethylamine (1.40 mL, 10.0 mmol) in 30 mL of
acetonitrile was added in situ. The contents were stirred overnight at
room temperature. The organic layer was washed with water and the
solvent removed in vacuo. The product was purified by column
chromatography using hexane/ethyl acetate (90/10) as eluent to
isolate the pure product. Yield: 28%, Mp: 193−195 °C. 1H NMR (400
MHz, DMSO-d6): δ 11.27 (s, 1H), 9.13 (d, J = 2.3 Hz, 1H), 8.76 (dd, J
= 4.9, 1.7 Hz, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.34 (dt, J = 8.0, 2.0 Hz,
1H), 8.24 (d, J = 8.9 Hz, 1H), 7.99 (dd, J = 8.9, 2.7 Hz, 1H), 7.59−7.51
(m, 1H). 13C NMR (101 MHz, DMSO-d6): δ 164.92, 152.51, 150.69,
149.09, 146.45, 138.03, 135.87, 129.73, 125.87, 123.47, 115.85.
Synthesis of N-(5-Bromopyridin-2-yl)nicotinamide. Nicotinic
acid (1.21 g, 9.83 mmol) and triethylamine (1.40 mL, 10.0 mmol) were
added to 30 mL of chloroform and cooled in an ice bath. Thionyl
chloride (0.73 mL, 10.0 mmol) was added dropwise under nitrogen.
After the addition of thionyl chloride was complete, the mixture was
heated under reflux for 3 h. The mixture was cooled to room
temperature, and a solution of 2-amino-5-bromopyridine (1.73 g, 10.0
mmol) and triethylamine (1.40 mL, 10.0 mmol) in 30 mL of
acetonitrile was added in situ. The contents were stirred overnight at
room temperature. The organic layer was washed with water and the
solvent removed in vacuo. The product was purified by column
chromatography using hexane/ethyl acetate (90/10) as eluent to
isolate the pure product. Yield: 28%. Mp: 190−192 °C. 1H NMR (400
MHz, DMSO-d6): δ 11.25 (s, 1H), 9.12 (dd, J = 2.4, 0.9 Hz, 1H), 8.75
(dd, J = 4.8, 1.7 Hz, 1H), 8.57−8.50 (m, 1H), 8.37−8.29 (m, 1H), 8.19
(dd, J = 8.9, 0.8 Hz, 1H), 8.09 (dd, J = 8.9, 2.5 Hz, 1H), 7.54 (ddd, J =
8.0, 4.8, 0.9 Hz, 1H), 2.08 (s, 2H). 13C NMR (101 MHz, DMSO-d6): δ
164.92, 152.51, 150.99, 149.09, 148.62, 140.75, 135.85, 129.72, 123.45,
116.34, 114.30, 30.73.
Synthesis of N-(Pyridin-2-yl)picolinamide. Picolinic acid (1.00
g, 8.13 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (4.00 g, 10.5 mmol), triethylamine (3.40 mL, 24.4
mmol), and 2-aminopyridine (0.836 g, 8.90 mmol) were dissolved in 60
mL of DMF. The reactants were stirred at room temperature for 14 h,
diluted with ethyl acetate, and washed with water. The organic layer was
dried with anhydrous magnesium sulfate and concentrated by rotary
evaporation to obtain the crude product, which was purified by column
chromatography using hexane/ethyl acetate (90/10) as eluent to
obtain the pure product. Yield 50%. Mp: 117−119 °C (lit. mp 107−108
°C).35 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.77 (ddd, J =
4.8, 1.7, 1.0 Hz, 1H), 8.44−8.37 (m, 1H), 8.29 (dt, J = 8.3, 1.0 Hz, 1H),
8.22 (dt, J = 7.8, 1.1 Hz, 1H), 8.12 (td, J = 7.7, 1.7 Hz, 1H), 7.91 (ddd, J
= 8.8, 7.3, 1.9 Hz, 1H), 7.74 (ddd, J = 7.6, 4.7, 1.3 Hz, 1H), 7.22 (ddd, J
= 7.4, 4.9, 1.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 161.55,
150.15, 148.35, 148.08, 138.28, 138.14, 127.20, 121.86, 119.88, 112.74.
Synthesis of N-(5-Chloropyridin-2-yl)picolinamide. Picolinic
acid (1.00 g, 8.13 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrame-
thyluronium hexafluorophosphate (4.00 g, 10.5 mmol), triethylamine
(3.40 mL, 24.4 mmol), and 2-amino-5-chloropyridine (1.14 g, 8.90
mmol) were dissolved in 60 mL of DMF. The reactants were stirred at
room temperature for 14 h, diluted with ethyl acetate, and washed with
water. The organic layer was dried with anhydrous magnesium sulfate
and concentrated by rotary evaporation to obtain the crude product,
which was purified by column chromatography using hexane/ethyl
acetate (90/10) as eluent to obtain the pure product. Yield 55%, Mp:
153−155 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.76
(ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.46 (dd, J = 2.6, 0.7 Hz, 1H), 8.31 (dd, J
= 8.9, 0.7 Hz, 1H), 8.22 (dt, J = 7.8, 1.1 Hz, 1H), 8.12 (td, J = 7.7, 1.7
Hz, 1H), 8.04 (dd, J = 8.9, 2.6 Hz, 1H), 7.74 (ddd, J = 7.6, 4.8, 1.3 Hz,
1H). 13C NMR (101 MHz, DMSO-d6): δ 162.76, 149.93, 149.45,
148.94, 147.51, 139.23, 139.06, 128.38, 126.66, 123.05, 115.00.
Synthesis of N-(5-Bromopyridin-2-yl)picolinamide. Picolinic
acid (1.00 g, 8.13 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrame-
thyluronium hexafluorophosphate (4.00 g, 10.5 mmol), triethylamine
(3.40 mL, 24.4 mmol), and 2-amino-5-bromopyridine (1.54 g, 8.90
mmol) were dissolved in 60 mL of DMF. The reactants were stirred at
room temperature for 14 h, diluted with ethyl acetate, and washed with
water. The organic layer was dried with anhydrous magnesium sulfate
and concentrated by rotary evaporation to obtain the crude product,
which was purified by column chromatography using hexane/ethyl
acetate (90/10) as eluent to obtain the pure product. Yield: 53%. Mp:
149−151 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.74
(d, J = 4.8 Hz, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.22 (dd, J = 17.5, 8.3 Hz,
2H), 8.16−8.06 (m, 2H), 7.73 (dd, J = 7.6, 4.8 Hz, 1H) 13C NMR (101
MHz, DMSO-d6): δ 162.76, 150.22, 149.68, 149.43, 148.93, 141.76,
139.21, 128.38, 123.04, 115.50, 115.05.
Synthesis of N-(5-Iodopyridin-2-yl)picolinamide. Picolinic
acid (1.00 g, 8.13 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrame-
thyluronium hexafluorophosphate (4.00 g, 10.5 mmol), triethylamine
(3.40 mL, 24.4 mmol), and 2-amino-5-iodopyridine (1.96 g, 8.90
mmol) were dissolved in 60 mL of DMF. The reactants were stirred at
room temperature for 14 h, diluted with ethyl acetate, and washed with
water. The organic layer was dried with anhydrous magnesium sulfate
and concentrated by rotary evaporation to obtain the crude product,
which was purified by column chromatography using hexane/ethyl
acetate (90/10) as eluent to obtain the pure product. Yield: 55%. Mp:
124−126 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.75
(ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.60 (dd, J = 2.2, 0.8 Hz, 1H), 8.27−8.17
(m, 2H), 8.12 (ddd, J = 15.6, 8.1, 1.3 Hz, 2H), 7.73 (ddd, J = 7.5, 4.8, 1.3
Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 162.56, 154.39, 150.23,
149.22, 148.76, 146.90, 139.00, 128.15, 122.81, 115.67, 87.70.
Synthesis of N-(5-Iodopyridin-2-yl)nicotinamide. Nicotinic
acid (1.21 g, 9.83 mmol) and triethylamine (1.40 mL, 10.0 mmol) were
added to 30 mL of chloroform and cooled in an ice bath. Thionyl
chloride (0.73 mL, 10.0 mmol) was added dropwise under nitrogen.
After the addition of thionyl chloride was complete, the mixture was
heated under reflux for 3 h. The mixture was cooled to room
temperature, and a solution of 2-amino-5-iodopyridine (2.20 g,10.0
mmol) and triethylamine (1.40 mL, 10.0 mmol) in 30 mL of
acetonitrile was added in situ. The contents were stirred overnight at
room temperature. The organic layer was washed with water and the
solvent removed in vacuo. The product was purified by column
chromatography using hexane/ethyl acetate (90/10) as eluent to
isolate the pure product. Yield: 25%. Mp: 192−194 °C. 1H NMR (400
MHz, DMSO-d6): δ 11.21 (s, 1H), 9.15−9.10 (m, 1H), 8.76 (dd, J =
4.8, 1.7 Hz, 1H), 8.65−8.60 (m, 1H), 8.34 (dt, J = 8.1, 2.0 Hz, 1H), 8.20
(dd, J = 8.8, 2.3 Hz, 1H), 8.12−8.05 (m, 1H), 7.55 (ddd, J = 8.0, 4.8, 0.9
Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 164.90, 153.53, 152.49,
151.24, 149.08, 146.09, 135.83, 129.75, 123.44, 116.72, 87.18.
3Pyr Series. The synthesis of N-(pyridin-2-yl)nicotinamides was
done according to an available literature procedure.36
Synthesis of N-(Pyridin-2-yl)nicotinamide. Nicotinic acid (1.21
g, 9.83 mmol) and triethylamine (1.40 mL, 10.0 mmol) were added to
30 mL of chloroform and cooled in an ice bath. Thionyl chloride (0.73
mL, 10.0 mmol) was added dropwise under nitrogen. After the addition
D
Cryst. Growth Des. XXXX, XXX, XXX−XXX