6860
cmꢀ1
M. A. Chowdhury et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6855–6861
;
1H NMR (CDCl3) d 3.93 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 7.15 (d,
pyridone H-3), 7.12 (d, J = 1.8 Hz, 1H, phenyl H-3), 7.22 (dd, J = 7.9, 1.8 Hz, 1H,
phenyl H-5), 7.55 (d, J = 7.3 Hz, 1H, pyridone H-6), 7.73 (t, J = 60 Hz, 1H, CHF2),
7.89 (d, J = 7.9 Hz, 1H, phenyl H-6); 13C NMR (CDCl3) d 52.2, 56.2, 106.9, 107.4,
110.3, 118.3, 118.5, 121.5, 129.6, 132.4, 141.6, 152.3, 159.4, 161.0, 165.9.
J = 1.8 Hz, 1H, phenyl H-3), 7.22 (dd, J = 7.9, 1.8 Hz, 1H, phenyl H-5), 7.44 (dd,
J = 4.9, 1.2 Hz, 1H, pyridyl H-5), 7.56 (d, J = 1.2 Hz, 1H, pyridyl H-3), 7.92 (d,
J = 7.9 Hz, 1H, phenyl H-6), 8.48 (d, J = 4.9 Hz, 1H, pyridyl H-6); 13C NMR
(CDCl3) d 52.3, 56.3, 110.6, 118.9, 120.6, 121.1, 122.3, 132.6, 141.9, 150.1,
150.6, 152.3, 159.6, 166.0.
Methyl
(13b): This compound was obtained as a pale yellow solid in 61% yield; mp
125–127 °C; IR 1732, 1675 (CO) cmꢀ1 1H NMR (CDCl3) d 3.93 (s, 3H, OCH3),
5-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxybenzoate
Methyl 5-(2-chloropyridin-4-yl)-2-methoxybenzoate (12b): This compound was
;
obtained as a pale yellow solid in 85% yield; mp 93–95 °C; IR 1731 (CO) cmꢀ1
;
3.98 (s, 3H, OCH3), 6.59 (dd, J = 7.3, 1.2 Hz, 1H, pyridone H-5), 6.74 (d, J = 1.2 Hz,
1H, pyridone H-3), 7.09 (d, J = 9.2 Hz, 1H, phenyl H-3), 7.52 (d, J = 7.3 Hz, 1H,
pyridone H-6), 7.72 (t, J = 60 Hz, 1H, CHF2), 7.73 (dd, J = 9.2, 2.4 Hz, 1H, phenyl
H-4), 8.07 (d, J = 2.4 Hz, 1H, phenyl H-6); 13C NMR (CDCl3) d 52.3, 56.3, 106.5,
107.5, 112.7, 116.5, 120.6, 128.1, 129.3, 130.3, 131.7, 151.5, 160.6, 161.2, 165.8.
4-(N-Difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxycarbonylbenzenesul-
fonamide (20a): This compound was obtained as a pale yellow solid in 38%
1H NMR (CDCl3) d 3.94 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.11 (d, J = 9.2 Hz, 1H,
phenyl H-3), 7.44 (dd, J = 4.9, 1.2 Hz, 1H, pyridyl H-5), 7.54 (d, J = 1.2 Hz, 1H,
pyridyl H-3), 7.76 (dd, J = 9.2, 2.4 Hz, 1H, phenyl H-4), 8.10 (d, J = 2.4 Hz, 1H,
phenyl H-6), 8.43 (d, J = 4.9 Hz, 1H, pyridyl H-6); 13C NMR (CDCl3) d 52.3, 56.3,
112.8, 119.8, 120.8, 121.4, 128.5, 130.4, 131.8, 149.9, 150.0, 152.2, 160.2, 166.0.
5-(2-Chloropyridin-4-yl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (18a): This
compound was obtained as a white solid in 90% yield; mp 260–262 °C; IR
yield; mp 215–217 °C; IR 3338 (NH2), 1725, 1674 (CO) 1348, 1166 (SO2) cmꢀ1
;
3306 (NH), 1736 (CO), 1322, 1113 (SO2) cmꢀ1
;
1H NMR (CDCl3 + DMSO-d6) d
1H NMR (CDCl3 + DMSO-d6)
d
3.90 (s, 3H, OCH3), 6.67 (d, J = 7.4 Hz, 1H,
7.47 (dd, J = 4.9, 1.2 Hz, 1H, pyridyl H-5), 7.57 (d, J = 1.2 Hz, 1H, pyridyl H-3),
7.97 (d, J = 7.9 Hz, 1H, saccharinyl H-7), 8.05 (dd, J = 7.9, 1.8 Hz, 1H, saccharinyl
H-6), 8.14 (d, J = 1.8 Hz, 1H, saccharinyl H-4), 8.45 (d, J = 4.9 Hz, 1H, pyridyl H-
6); 13C NMR (CDCl3 + DMSO-d6) d 120.5, 121.4, 121.9, 126.8, 129.1, 133.2,
139.9, 142.0, 148.0, 150.0, 151.6, 160.1.
pyridone H-5), 6.76 (s, 1H, pyridone H-3), 7.11 (br s, 2H, SO2NH2 that
exchanges with D2O), 7.69 (d, J = 7.4 Hz, 1H, pyridone H-6), 7.70 (t, J = 60 Hz,
1H, CHF2), 7.89 (d, J = 8.5 Hz, 1H, phenyl H-5); 7.91 (s, 1H, phenyl H-3), 8.10 (d,
J = 8.5 Hz, 1H, phenyl H-6); 13C NMR (CDCl3 + DMSO-d6) d 52.9, 105.9, 107.5,
117.9, 127.7, 128.5, 129.3, 130.1, 130.8, 139.3, 142.6, 149.9, 160.0, 166.8.
5-(N-Difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxycarbonylbenzenesul-
fonamide (20b): This compound was obtained as a pale yellow solid in 35%
yield; mp 205–207 °C; IR 3371, 3262 (NH2), 1734, 1675 (CO) 1340, 1140 (SO2)
6-(2-Chloropyridin-4-yl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (18b): This
compound was obtained as a white solid in 65% yield; mp >360 °C; IR 1739
(CO) 1317, 1122 (SO2) cmꢀ1 1H NMR (CDCl3 + DMSO-d6) d 7.69 (dd, J = 4.9,
;
1.2 Hz, 1H, pyridyl H-5), 7.81 (d, J = 1.2 Hz, 1H, pyridyl H-3), 8.05 (d, J = 7.9 Hz,
1H, saccharinyl H-4), 8.17 (dd, J = 7.9, 1.8 Hz, 1H, saccharinyl H-5), 8.42 (d,
J = 1.8 Hz, 1H, saccharinyl H-7), 8.46 (d, J = 4.9 Hz, 1H, pyridyl H-6); 13C NMR
(CDCl3 + DMSO-d6) d 119.6, 120.6, 122.0, 125.2, 128.0, 132.7, 140.4, 142.8,
147.7, 150.0, 151.6, 159.7.
cmꢀ1 1H NMR (CDCl3 + DMSO-d6) d 3.90 (s, 3H, OCH3), 6.65 (d, J = 7.4 Hz, 1H,
;
pyridone H-5), 6.77 (s, 1H, pyridone H-3), 7.06 (br s, 2H, SO2NH2 that
exchanges with D2O), 7.67 (d, J = 7.4 Hz, 1H, pyridone H-6), 7.68 (t, J = 60 Hz,
1H, CHF2), 7.78 (d, J = 8.0 Hz, 1H, phenyl H-3); 7.85 (d, J = 8.0 Hz, 1H, phenyl H-
4), 8.25 (s, 1H, phenyl H-6); 13C NMR (CDCl3 + DMSO-d6) d 52.7, 105.6, 107.4,
117.7, 125.8, 129.5, 129.9, 131.1, 131.5, 138.5, 142.5, 149.9, 160.0, 166.8.
General procedure for the synthesis of 4- or 5-(N-difluoromethyl-1,2-dihydropyrid-
2-one-4-yl)salicylic acid (14a–b): A solution of BBr3 (5.24 mL of a 1 M solution
General procedure for the synthesis of 4- or 5-(2-chloropyridin-4-yl)-2-
methoxycarbonylbenzenesulfonamide (19a–b): Hydrogen chloride gas was
passed into a suspension of the saccharin derivative (18a or 18b) (1.16 g,
3.94 mmol) in MeOH (100 mL) at ꢀ5 °C for 1 h. The mixture was then heated at
reflux for 1 h, the mixture was cooled to 25 °C and the excess MeOH was
removed in vacuo. A saturated solution of aqueous NaHCO3 (25 mL) was added
to the residue and the mixture was extracted with EtOAc (3 ꢁ 50 mL). The
combined organic phases were successively washed with water (50 mL) and
brine, and the organic fraction was dried (MgSO4). Filtration and then removal
of the solvent from the organic fraction in vacuo afforded the crude product
which was purified by silica gel column chromatography using hexanes–ethyl
acetate (1:3, v/v) as eluent to furnish the respective title compound 19a or 19b.
Some physical and spectroscopic data for 19a–b are listed below.
in CH2Cl2, 5.24 mmol) was added to
difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxybenzoate
a
solution of
a
methyl 4- or 5-(N-
(13a–b)
(0.81 g, 2.62 mmol) in CH2Cl2 (15 mL) at ꢀ78 °C with stirring for 1 h under
argon. The mixture was then warmed to 25 °C, the mixture was stirred for
another 16 h, quenched with water (50 mL), and the mixture was extracted
with CH2Cl2 (3 ꢁ 25 mL). The combined CH2Cl2 extracts were successively
washed with water (50 mL) and brine, and the organic fraction was dried
(MgSO4). Filtration and then removal of the solvent from the organic fraction in
vacuo afforded the respective product 14a or 14b. The spectral and
microanalytical data for compounds 14a and 14b are listed below.
4-(2-Chloropyridin-4-yl)-2-methoxycarbonylbenzenesulfonamide (19a): This
compound was obtained as a white solid in 80% yield; mp 138–140 °C; IR
4-(N-Difluoromethyl-1,2-dihydropyrid-2-one-4-yl)salicylic acid (14a): This
compound was obtained as a white solid in 100% yield; mp 255–257 °C; IR
3359, 3273 (NH2), 1724 (CO), 1349, 1169 (SO2) cmꢀ1
;
1H NMR (CDCl3) d 4.06 (s,
1679 (CO) cmꢀ1 1H NMR (CDCl3 + DMSO-d6) d 6.54 (dd, J = 7.3, 1.8 Hz, 1H,
;
3H, OCH3), 5.81 (br s, 2H, SO2NH2 that exchanges with D2O), 7.47 (dd, J = 4.9,
1.2 Hz, 1H, pyridyl H-5), 7.59 (d, J = 1.2 Hz, 1H, pyridyl H-3), 7.89 (dd, J = 8.0,
1.9 Hz, 1H, phenyl H-5), 8.09 (d, J = 1.9 Hz, 1H, phenyl H-3), 8.30 (d, J = 8.0 Hz,
1H, phenyl H-6), 8.54 (d, J = 4.9 Hz, 1H, pyridyl H-6); 13C NMR (CDCl3) d 53.3,
120.1, 121.8, 129.0, 129.1, 129.9, 130.5, 140.5, 142.0, 148.1, 150.1, 152.2, 166.8.
4-(2-Chloropyridin-4-yl)-2-methoxycarbonylbenzenesulfonamide (19a): This
compound was obtained as a white solid in 80% yield; mp 138–140 °C; IR
pyridone H-5), 6.65 (d, J = 1.8 Hz, 1H, pyridone H-3), 7.01 (dd, J = 8.5, 1.8 Hz,
1H, phenyl H-5), 7.07 (d, J = 1.8 Hz, 1H, phenyl H-3), 7.52 (d, J = 7.3 Hz, 1H,
pyridone H-6), 7.63 (t, J = 60 Hz, 1H, CHF2), 7.87 (d, J = 8.5 Hz, 1H, phenyl H-6),
11.32 (br s, 1H, COOH that exchanges with D2O); 13C NMR (CDCl3) d 106.0,
106.8, 113.4, 114.6, 116.4, 117.3, 128.9, 130.5, 142.2, 151.2, 160.1, 161.2, 171.2.
Anal. Calcd for C13H9F2NO4: C, 55.52; H, 3.23; N, 4.98. Found: C, 55.83; H, 3.44;
N, 4.89.
3359, 3273 (NH2), 1724 (CO), 1349, 1169 (SO2) cmꢀ1
;
1H NMR (CDCl3) d 4.06 (s,
5-(N-Difluoromethyl-1,2-dihydropyrid-2-one-4-yl)salicylic acid (14b): This
compound was obtained as a white solid in 100% yield; mp 258–260 °C; IR
3H, OCH3), 5.81 (br s, 2H, SO2NH2 that exchanges with D2O), 7.47 (dd, J = 4.9,
1.2 Hz, 1H, pyridyl H-5), 7.59 (d, J = 1.2 Hz, 1H, pyridyl H-3), 7.89 (dd, J = 8.0,
1.9 Hz, 1H, phenyl H-5), 8.09 (d, J = 1.9 Hz, 1H, phenyl H-3), 8.30 (d, J = 8.0 Hz,
1H, phenyl H-6), 8.54 (d, J = 4.9 Hz, 1H, pyridyl H-6); 13C NMR (CDCl3) d 53.3,
120.1, 121.8, 129.0, 129.1, 129.9, 130.5, 140.5, 142.0, 148.1, 150.1, 152.2, 166.8.
5-(2-Chloropyridin-4-yl)-2-methoxycarbonylbenzenesulfonamide (19b): This
compound was obtained as a white solid in 81% yield; mp 180–182 °C; IR
1677 (CO) cmꢀ1 1H NMR (CDCl3 + DMSO-d6) d 6.55 (dd, J = 7.9, 1.8 Hz, 1H,
;
pyridone H-5), 6.61 (d, J = 1.8 Hz, 1H, pyridone H-3), 6.97 (d, J = 9.2 Hz, 1H,
phenyl H-3), 7.48 (d, J = 7.9 Hz, 1H, pyridone H-6), 7.63 (t, J = 60 Hz, 1H, CHF2),
7.64 (dd, J = 9.2, 2.4 Hz, 1H, phenyl H-4), 8.07 (d, J = 2.4 Hz, 1H, phenyl H-6),
11.50 (br s, 1H, COOH that exchanges with D2O); 13C NMR (CDCl3) d 104.9,
106.3, 112.1, 114.1, 116.9, 125.4, 127.6, 128.3, 132.1, 150.2, 159.4, 161.9, 170.5.
Anal. Calcd for C13H9F2NO4: C, 55.52; H, 3.23; N, 4.98. Found: C, 55.53; H, 3.34;
N, 4.87.
General procedure for the synthesis of N-acetyl-4- or 5-(N-difluoromethyl-1,2-
dihydropyrid-2-one-4-yl)-2-methoxycarbonylbenzenesulfonamide (21a–b): Acetyl
chloride (0.14 mL, 2 mmol), and then SiO2–OSO3H (8 mg), was added to a
solution of a 4- or 5-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-metho-
xycarbonylbenzenesulfonamide (20a or 20b, 0.36 g, 1 mmol) in CHCl3 (10 mL)
and CH3CN (3 mL). The reaction was allowed to proceed at reflux for 16 h under
argon. The mixture was filtered and the solvent was removed in vacuo. The
crude residue was purified by silica gel column chromatography using
hexanes–ethyl acetate (1:2, v/v), and then ethyl acetate, as eluent to furnish
the respective title product 21a or 21b. Some physical and spectroscopic data
for 21a–b are listed below.
1716 (CO), 1363, 1122 (SO2) cmꢀ1 1H NMR (CDCl3 + DMSO-d6) d 3.91 (s, 3H,
;
OCH3), 6.94 (br s, 2H, SO2NH2 that exchanges with D2O), 7.50 (dd, J = 5.5,
1.2 Hz, 1H, pyridyl H-5), 7.59 (d, J = 1.2 Hz, 1H, pyridyl H-3), 7.80–7.90 (m, 2H,
phenyl H-3, H-4), 8.28 (s, 1H, phenyl H-6), 8.43 (d, J = 5.5 Hz, 1H, pyridyl H-6);
13C NMR (CDCl3 + DMSO-d6) d 52.8, 120.3, 121.6, 126.2, 129.9, 130.0 130.8,
138.8, 142.6, 148.3, 150.1, 151.6, 167.0.
General procedure for the synthesis of methyl 4- or 5-(N-difluoromethyl-1,2-
dihydropyrid-2-one-4-yl)-2-methoxybenzoates (13a–b), or 4- or 5-(N-difluoro-
methyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxycarbonylbenzenesulfonamides
(20a–b): FSO2CF2CO2H (1.92 g, 10.84 mmol), and then NaHCO3 (0.30 g,
3.60 mmol), was added to a solution of a methyl 4- or 5-(2-chloropyridin-4-
yl)-2-methoxybenzoate (12a or 12b) (1.0 g, 3.60 mmol), or 4- or 5-(2-
chloropyridin-4-yl)-2-methoxycarbonylbenzenesulfonamide (19a or 19b)
(1.18 g, 3.60 mmol) in acetonitrile (25 mL). The mixture was then heated at
reflux under argon for 16 h, cooled to 25 °C, a saturated solution of aqueous
NaHCO3 (25 mL) was added, and the mixture was extracted with CHCl3
(3 ꢁ 30 mL). The combined organic extracts were successively washed with
10 N HCl (30 mL) to remove some unreacted starting material, water (50 mL)
and brine, and the organic fraction was dried (MgSO4). Filtration and then
removal of the solvent from the organic fraction in vacuo afforded the
respective title product (13a–b, 20a–b). Some physical and spectroscopic data
for 13a–b and 20a–b are listed below.
N-Acetyl-4-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxycarbonylben-
zenesulfonamide (21a): This compound was obtained as a pale yellow solid in
13% yield; mp 218–220 °C; IR 1715, 1670 (CO) 1362, 1166 (SO2) cmꢀ1 1H NMR
;
(CDCl3 + DMSO-d6) d 2.15 (s, 3H, COCH3), 4.00 (s, 3H, OCH3), 6.56 (dd, J = 7.3,
1.8 Hz, 1H, pyridone H-5), 6.82 (d, J = 1.8 Hz, 1H, pyridone H-3), 7.60 (d,
J = 7.3 Hz, 1H, pyridone H-6), 7.72 (t, J = 60 Hz, 1H, CHF2), 7.85 (dd, J = 8.6,
1.8 Hz, 1H, phenyl H-5); 7.98 (d, J = 1.8 Hz, 1H, phenyl H-3), 8.42 (d, J = 8.6 Hz,
1H, phenyl H-6), 9.00 (br s, 1H, NH that exchanges with D2O); 13C NMR (DMSO-
d6) d 23.2, 53.3, 105.8, 107.5, 117.8, 128.9, 129.8, 131.4, 132.1, 133.0, 137.0,
137.8, 149.8, 160.0, 166.3, 169.0.
Methyl
(13a): This compound was obtained as a pale yellow solid in 54% yield; mp
75–77 °C; IR 1729, 1678 (CO) cmꢀ1 1H NMR (CDCl3) d 3.92 (s, 3H, OCH3), 3.97
(s, 3H, OCH3), 6.57 (dd, J = 7.3, 1.2 Hz, 1H, pyridone H-5), 6.77 (d, J = 1.2 Hz, 1H,
4-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxybenzoate
N-Acetyl-5-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)-2-methoxycarbonyl
benzenesulfonamide (21b): This compound was obtained as a pale yellow solid
;
in 57% yield; mp 225–227 °C; IR 1715, 1670 (CO) 1362, 1166 (SO2) cmꢀ1 1H
;