3572 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 11
Kulkarni et al.
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IR (KBr) 3416, 3062, 1677, 1601, 1510 cm-1. GC-MS (EI) m/z
322 (M+). Anal. (C19H15ClN2O·HBr) C, H, N.
°C. H NMR (CDCl3) δ 2.45 (s, 3H), 3.83 (s, 3H), 6.92-6.94 (d,
J ) 7.6 Hz, 1H), 7.00-7.02 (d, J ) 8.4 Hz, 1H), 7.03-7.07 (td,
J ) 1.2, 7.2 Hz, 1H), 7.31-7.33 (dd, J ) 1.6, 7.6 Hz, 1H),
7.36-7.40 (m, 1H), 7.44-4.48 (m, 1H), 7.58-7.62 (m, 1H),
7.62-7.66 (t, J ) 8 Hz, 1H), 7.81-7.82 (t, J ) 1.6 Hz, 1H), 8.17-
8.19 (d, J ) 8.4 Hz, 1H), 8.56 (bs, 1H) ppm. 13C NMR (CDCl3) δ
24.2, 55.8, 111.2, 111.5, 113.1, 113.4, 119.9, 120.5, 120.7, 121.2,
124.0, 124.0, 128.4, 130.0, 130.9, 136.3, 136.4, 139.0, 141.6, 141.7,
150.8, 156.5, 157.2, 161.5, 164.0, 164.7, 164.8 ppm. IR (KBr) 3060,
1678, 1601, 1530, 1455 cm-1. GC-MS (EI) m/z 336 (M+). Anal.
(C20H17FN2O2 ·HBr) C, H, N.
3,5-Difluoro-N-(6-methylpyridin-2-yl)-benzamide (32). Pre-
pared as described in the general procedure D using 3,5-difluoro
benzoic acid (1.0 g, 5.66 mmol). Yield 1.0 g, 45%; mp 129-132
°C (white solid). 1H NMR (CDCl3) δ 2.45 (s, 3H), 6.95-7.03 (m,
2H), 7.41-7.46 (m, 2H), 7.64-7.68 (t, J ) 8.0 Hz, 1H), 8.12-8.14
(d, J ) 8.4 Hz, 1H), 8.56 (bs, 1H) ppm. 13CNMR (CDCl3) δ 24.2,
107.5, 107.8, 108.0, 110.6, 110.7, 110.8, 110.9, 111.3, 120.2, 137.9,
138.0, 139.1, 150.5, 157.3, 162.0, 162.1, 164.5, 164.6 ppm. IR
(KBr) 3338, 3074, 1696, 1599, 1580, 1561 cm-1. GC-MS (EI) m/z
248 (M+). Anal. (C13H10F2N2O) C, H, N.
5-Fluoro-2′-methyl-N-(6-methylpyridin-2-yl)biphenyl-3-car-
boxamide hydrobromide (39). Prepared from compound 36, as
described above for compound 38, using 2-methyl benzene boronic
acid (0.125 g, 0.9 mmol). Yield 0.14 g, 67%; HBr salt: white solid;
3,4-Difluoro-N-(6-methylpyridin-2-yl)-benzamide (33). Pre-
pared as described in the general procedure D using 3,4-difluoro
benzoic acid (1.0 g, 5.66 mmol). Yield 1.10 g, 45%; mp 88-91
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°C (white solid). H NMR (CDCl3) δ 2.45 (s, 3H), 6.94-6.96 (d,
mp 207-210 °C. H NMR (CDCl3) δ 2.28 (s, 3H), 2.46 (s, 3H),
J ) 7.2 Hz, 1H), 7.23-7.30 (m, 1H), 7.64-7.69 (m, 2H),
7.77-7.82 (m, 1H), 8.12-8.14 (d, J ) 8.0 Hz, 1H), 8.55 (bs, 1H)
ppm. 13C NMR (CDCl3) δ 24.0, 111.1, 117.1, 117.1, 117.3, 117.6,
117,8, 119.8, 123.5, 123.6, 123.6, 123.6, 131.5, 138.9, 149.1, 149.3,
150.4, 151.6, 151.6, 151.7, 151.8, 154.1, 154.2, 157.1, 163.4 ppm
IR (KBr) 3338, 3042, 1647, 1601, 1541 cm-1. GC-MS (EI) m/z
248 (M+). Anal. (C13H10F2N2O) C, H, N.
3-Cyano-5-fluoro-N-(6-methylpyridin-2-yl)-benzamide Hy-
drochloride (34). Prepared as described in the general procedure
D using 3-cyano-5-fluorobenzoic acid (900 mg, 5.46 mmol). Yield
407 mg, 100%; HBr salt: white solid; mp 245 -247 °C. 1H NMR
(CDCl3) δ 2.49 (s, 3H), 6.98-7.00 (m, 1H), 7.55-7.57 (m, 1H),
7.67-7.71 (m, 2H), 7.91-7.93 (m, 1H), 8.04 (s, 1H), 8.12-8.14
(s, 1H) ppm. 13C NMR (CDCl3) δ 24.2, 111.3, 120.0, 127.0, 139.3,
167.5 ppm. GC-MS (EI) m/z 255 (M+). Anal. (C14H10FN3O·HCl),
C, H, N.
6.94-6.96 (d, J ) 7.6 Hz, 1H), 7.21-7.34 (m, 5H), 7.61-7.62 (d,
J ) 2.0 Hz, 1H), 7.63-7.67 (t, J ) 7.6 Hz, 1H), 7.64-7.65 (m,
1H), 8.15-8.18 (d, J ) 8.4 Hz, 1H), 8.48 (bs, 1H) ppm. 13C NMR
(CDCl3) δ 20.3, 24.0, 111.0, 113.0, 113.2, 119.7, 119.8, 120.0,
123.4, 123.4, 126.1, 128.3, 129.5, 130.6, 135.2, 136.4, 136.4, 138.8,
139.5, 144.9, 145.0, 150.5, 157.0, 161.3, 163.8, 164.3 ppm. IR
(KBr) 3295, 3063, 1681, 1531, 1455 cm-1. GC-MS (EI) m/z 320
(M+). Anal. (C20H17FN2O·HBr) C, H, N.
3-Fluoro-N-(6-methylpyridin-2-yl)-4-(pyridine-3-yl)-benza-
mide hydrochloride (40). Prepared as described in the general
procedure E using pyridin-3-ylboronic acid (0.29 g, 2.41 mmol)
and compound 35 (0.62 g, 2.0 mmol). Yield 0.40 g, 65%; HCl
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salt: white solid; mp 280 °C (dec). H NMR (CDCl3) δ 2.50 (s,
3H), 6.96-6.98 (m, 1H), 7.41-7.44 (m, 1H), 7.57-7.94 (m, 5H),
8.18-8.20 (m, 1H), 8.67 (m, 1H), 8.84 (s, 1H) ppm. 13C NMR
(CDCl3) δ 24.3, 111.3, 115.9, 116.1, 120.0, 123.3, 123.4, 123.7,
131.1, 136.6, 139.1, 149.7, 157.3 ppm. GC-MS (EI) m/z 307 (M+).
Anal. (C18H14FN3O·2HCl·0.25H2O), C, H, N.
4-Bromo-3-fluoro-N-(6-methylpyridin-2-yl)-benzamide (35).
Prepared as described in the general procedure D using 4-bromo-
3-fluorobenzoic acid (0.87 g, 4.0 mmol) as a yellow solid. Yield
3-Chloro-N-(6-methylpyridin-2-yl)-4-(pyridine-3-yl)-benza-
mide Hydrochloride (41). Prepared as described in the general
procedure E using pyridin-3-ylboronic acid (431 mg, 3.53 mmol)
and 4-bromo-3-chloro-N-(6-methylpyridin-2-yl) benzamide (1.04
g, 3.21 mmol), which was prepared using the general procedure D
from 4-bromo-3-chlorobenzoic acid (942 mg, 4.0 mmol). Yield 775
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1.0 g, 81%. H NMR (CDCl3) δ 2.45-2.49 (s, 3H), 6.95-6.97
(m, 1H), 7.57-7.74 (m, 4H), 8.13-8.15 (m, 1H) ppm. GC-MS
(EI) m/z 310 (M+).
3-Bromo-5-fluoro-N-(6-methylpyridin-2-yl)-benzamide (36).
Prepared as described in the general procedure D using 3-bromo-
5-fluoro benzoic acid (2.0 g, 9.13 mmol) as a white solid. Yield
1
mg, 60%; HCl salt: white solid; mp 252-254 °C (dec). H NMR
1
2.36 g, 83%; mp 189-190 °C. H NMR (CDCl3) δ 2.58 (s, 3H),
(CDCl3) δ 2.50 (s, 3H), 6.97-6.99 (m, 1H), 7.41-7.50 (m, 2H),
7.66-7.70 (m, 1H), 7.82-7.92 (m, 2H), 8.11-8.20 (m, 2H),
8.70-8.72 (m, 2H) ppm. 13C NMR (CDCl3) δ 24.3, 111.2, 120.1,
125.9, 129.5, 131.9, 133.8, 135.7, 137.0, 139.2, 149.6, 150.0, 157.3,
167.4 ppm. GC-MS (EI) m/z 323 (M+). Anal. (C18H14ClN3O ·
2HCl·0.5H2O), C, H, N.
7.02-7.04 (d, J ) 8.0 Hz, 1H), 7.45-7.48 (m, 1H), 7.73-7.80
(m, 2H), 8.08-8.11 (dt, J ) 11.2, 1.2 Hz, 1H), 8.31-8.33 (d, J )
8.0 Hz, 1H) ppm. 13C NMR (CDCl3) δ 23.5, 112.2, 114.2, 114.4,
120.4, 122.8, 123.1, 126.8, 126.8, 139.9, 150.8, 156.8 164.1 ppm.
GC-MS (EI) m/z 309 (M+).
3-Fluoro-N-(6-methylpyridin-2-yl)-5-(pyridin-3-yl)-benza-
mide (37). Prepared as described in the general procedure E using
3-pyridyl boronic acid (0.18 g, 1.45 mmol) and compound 36 (0.30
g, 0.97 mmol). Yield 0.11 g, 37%; HBr salt: white solid; mp >275
5-Bromo-N-(6-methylpyridin-2-yl)nicotinamide (42). Prepared
as described in the general procedure D using 5-bromo nicotinic
acid (3.0 g, 14.8 mmol). Yield 4.43 g, 100%; mp 140-142 °C. 1H
NMR (CDCl3) δ 2.51 (s, 3H), 6.99-7.01 (m, 1H), 7.69-7.71 (m,
1H), 8.16-8.19 (m, 1H), 8.42-8.43 (m, 2H), 8.85-8.86 (m, 2H)
ppm. 13C NMR (CDCl3) δ 23.8, 111.9, 114.2, 120.4, 121.2, 131.6,
138.2, 139.7, 146.6, 154.2 ppm. Anal. (C20H18N2O2 ·HBr·H2O) C,
H, N.
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°C. H NMR (CDCl3) δ 2.47 (s, 3H), 6.96-6.98 (d, J ) 7.6 Hz,
1H), 7.40-7.44 (m, 1H), 7.46-7.50 (m, 1H), 7.65-7.69 (m, 2H),
7.89-7.91 (m, 2H), 8.17-8.19 (d, J ) 8.4 Hz, 1H), 8.67-8.68
(m, 1H), 8.69 (bs, 1H), 8.87-8.88 (m, 1H) ppm. 13C NMR (CDCl3)
δ 24.2, 111.3, 114.1, 114.4, 117.8, 118.0, 120.1, 121.9, 121.9, 124.0,
128.8, 132.3, 134.7, 137.7, 137.7, 139.1, 141.0, 141.1, 148.4, 149.9,
150.6, 157.3, 162.2, 164.2, 164.7 ppm. IR (KBr) 3382, 3063, 1686,
1597, 1554, 1461 cm-1. GC-MS (EI) m/z 307 (M+). Anal.
(C18H14FN3O.2HBr·1.5H2O) C, H, N.
6-bromo-N-(6-methylpyridin-2-yl)-nicotinamide (43). Prepared
as described in the general procedure D using 6-bromonicotinic
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acid (1.01 g, 5 mmol). Yield 1.24 g, 85%. H NMR (CDCl3) δ
2.47 (s, 3H), 6.97-6.99 (m, 1H), 7.46-7.48 (m, 1H), 7.67-7.69
(m, 1H), 8.11-8.13 (m, 1H), 8.19-8.20 (m, 1H), 8.94-8.95 (m,
1H) ppm.
5-Fluoro-2′-methoxy-N-(6-methylpyridin-2-yl)biphenyl-3-car-
boxamide Hydrobromide (38). To a clean and dry reaction tube,
compound 36 (0.20 g, 0.64 mmol), 2-dicyclohexylphosphino-2′,6′-
dimethoxy biphenyl (5 mg, 2 mol %), Pd(OAc)2 (1.5 mg, 1 mol
%), 2-methoxy benzene boronic acid (0.15 g, 0.9 mmol) powdered
potassium phosphate (0.27 g, 1.2 mmol), and degassed toluene/
EtOH (3 mL/0.5 mL) were added together and flushed with argon
and quickly sealed airtight. The reaction was heated to 100 °C for
2 h and filtered through celite and the filtrate was evaporated. The
crude product was passed through silica gel column eluting with
chloroform. Yield 0.13 g, 60%; HBr salt: white solid; mp 206-208
5-(3′-Pyridyl)-N-(6-methylpyridin-2-yl)-nicotinamide hydro-
bromide (44). Prepared using the general procedure E using
3-pyridyl boronic acid (0.19 g, 1.54 mmol) and compound 42 (0.30
g, 1.0 mmol). Yield 0.19 g, 64%; HBr salt: light-orange solid; mp
>275 °C. 1H NMR (CDCl3) δ 2.48 (s, 3H), 6.97-6.99 (d, J ) 7.6
Hz, 1H), 7.44-7.48 (m, 1H), 7.67-7.71 (t, J ) 7.6 Hz, 1H),
7.92-7.95 (m, 1H), 8.17-8.19 (d, J ) 8.0 Hz, 1H), 8.44-8.45 (t,
J ) 2.4 Hz, 1H), 8.71-8.73 (dd, J ) 1.6, 3.2 Hz, 1H), 8.83 (bs,
1H), 8.90-8.91 (dd, J ) 0.8, 1.6 Hz, 1H), 9.02-9.03 (d, J ) 2.0
Hz, 1H), 9.18-9.19 (d, J ) 2.0 Hz, 1H) ppm. 13CNMR (CDCl3) δ