Pyrido- and Pyrazinosultones
RT. The solvent was evaporated and the residue was purified by
CCTLC (hexane/EtOAc, 1:1) to give 20a (75 mg, 80%) as a white
solid: mp (MeOH): 148–1498C; 1H NMR (300 MHz, (CD3)2CO): d=
0.77 (m, 3H), 2.15 (m, 1H), 2.33 (m, 1H), 3.44 (s, 2H), 7.18 (m, 5H),
8.66 (d, J=1.7 Hz, 1H), 9.48 (d, J=1.7 Hz, 1H); 13C NMR (75 MHz,
(CD3)2CO): d=8.3, 31.9, 45.3, 99.9, 128.3, 128.8, 129.2, 131.1, 132.2,
132.3, 135.3, 156.3, 162.5, 165.9; MS (ES+) m/z 333.1 [M+1]+, 355.1
[M+Na]+, 687.1 [2M+Na]+; Anal. calcd for C16H16N2O4S: C 57.82, H
4.85, N 8.43, found: C 57.65, H 4.71, N 8.32.
13C NMR (75 MHz, (CD3)2CO, 303K): d=12.1, 13.6, 32.3, 36.9, 42.9,
46.4, 44.3, 97.8, 127.9, 129.5, 130.0, 128.8, 131.8, 134.8, 153.6, 154.3;
IR (KBr): 1639 (CO), 1353, 1182 (SO2); MS (ES+) m/z 437.2 [M+1]+,
895.2 [2M+Na]+; Anal. calcd for C24H24N2O4S: C 66.03, H 5.54, N,
6.42, found: C 65.84, H 5.34, N 6.26.
(Æ)-3-Benzyl-3-ethyl-3H-[1,2]-oxathiole[4,3-b]pyrazine 1,1-diox-
ide (25a): A solution of 23a[8] (100 mg, 0.35 mmol) in DMF (4 mL)
was hydrogenated at 30 psi in the presence of 5% Pd/C (2 mg,
0.001 mmol) for 1 h at 308C. The catalyst was removed and glyoxal
(44 mL, 0.39 mmol) was added. The mixture was stirred for 4 h at
RT. The solvent was evaporated to dryness and the residue was pu-
rified by CCTLC (hexane/EtOAc, 2:1) to give 25a (50 mg, 37%) as a
white solid: mp (MeOH): 141–1428C; 1H NMR (300 MHz, CDCl3):
d=0.81 (m, 3H), 2.22 (m, 1H), 2.32 (m, 1H), 3.47 (s, 2H), 7.20 (m,
5H), 8.92 (d, J=2.4 Hz, 1H), 9.17 (d, J=2.4 Hz, 1H); MS (ES+) m/z
291.0 [M+1]+; Anal. calcd for C14H14 N2O3S: C 57.92, H 4.86, N 9.65,
found: C 57.70, H 4.61, N 9.42.
3,3-Dibenzyl-6-carbamoyl-3H-[1,2]-oxathiole[4,3-b]pyridine 1,1-
dioxide (20b): A solution of 15b (100 mg, 0.24 mmol) and MeOH
saturated with ammonia (6 mL) was stirred for 3 h at RT. The sol-
vent was evaporated and the residue was purified by CCTLC
(hexane/EtOAc, 1:1) to give 20b (41 mg, 43%) as a white solid: mp
(MeOH): 200–2018C; 1H NMR (400 MHz, (CD3)2CO): d=3.40 and
3.56 (AB system, J=À14.4 Hz, 4H), 7.18 (m, 10H), 7.88 (bs, 2H),
8.50 (d, J=1.8 Hz, 1H), 9.51 (d, J=1.8 Hz, 1H); 13C NMR (100 MHz,
(CD3)2CO): d=44.5, 98.2, 128.2, 129.1, 132.1, 128.5, 132.0, 130.7,
135.0, 156.0, 162.2, 166.6; IR (KBr): 1687 (CO), 1356, 1193 (SO2); MS
(ES+) m/z 395.1 [M+1]+, 811.2 [2M+Na]+; Anal. calcd for
C21H18N2O4S: C 63.94, H 4.60, N 7.10, found: C 63.67, H 4.29, N 6.90.
3,3-Dibenzyl-3H-[1,2]-oxathiole[4,3-b]pyrazine 1,1-dioxide (25b):
A solution of 23b[9] (100 mg, 0.29 mmol) in DMF (2 mL) was hydro-
genated as described for the preparation of 25a. The catalyst was
removed and glyoxal (38 mL, 0.33 mmol) was added. The mixture
was stirred for 4 h at RT. The solvent was evaporated to dryness
and the residue was purified by CCTLC (hexane/EtOAc, 2:1) to give
25b (41 mg, 40%) as a white solid: mp (MeOH): 147–1488C;
1H NMR (300 MHz, CDCl3): d=3.34 and 3.46 (AB system, J=
À14.4 Hz, 2H), 7.19, 7.24 (2 m, 10H), 8.62 (d, J=2.32 Hz, 1H), 8.86
(d, J=2.32 Hz, 1H); 13C NMR (175 MHz, CDCl3): d=43.8, 95.0,
127.6, 128.3, 130.9, 132.8, 145.9, 148.3, 153.9; MS (ES+) m/z 353.0
[M+1]+, 375.0 [M+Na]+, 727.1 [2M+Na]+; Anal. calcd for
C19H16N2O3S: C 64.76, H 4.58, N 7.95, found: C 64.63, H 4.33, N 7.69.
(Æ)-3-Benzyl-3-ethyl-6-methylcarbamoyl-3H-[1,2]-oxathiole[4,3-
b]pyridine 1,1-dioxide (21a):
A solution of 15a (100 mg,
0.29 mmol) and methylamine (8m solution in EtOH, 7 mL) was
stirred for 3 h at RT and the solvent was removed under reduced
pressure. The residue was purified by CCTLC (hexane/EtOAc, 1:1) to
give 21a (58 mg, 58%) as a white foam. 1H NMR (200 MHz,
(CD3)2CO): d=0.83 (m, 3H), 2.21 (m, 1H), 2.36 (m, 1H), 3.43 (s, 2H),
7.11 (m, 5H), 8.69 (d, J=1.8 Hz, 1H), 9.51 (d, J=1.8 Hz, 1H); MS
(ES+) m/z 347.3 [M+1]+; Anal. calcd for C17H18 N2O4S: C 58.94, H
5.24, N 8.09, found: C 58.75, H 5.31, N 8.15.
(Æ)-3-Benzyl-3-ethyl-5,6-dimethyl-3H-[1,2]-oxathiole[4,3-b]pyra-
zine 1,1-dioxide (26): A solution of 23a[9] (100 mg, 0.35 mmol) in
DMF (4 mL) was hydrogenated at 30 psi in the presence of 5% Pd/
C (2 mg, 0.001 mmol) for 30 min at 308C. The catalyst was re-
moved and butane-2,3-dione (68 mL, 0.77 mmol) was added. The
mixture was stirred in an Ace pressure tube for 14 h at 408C. The
solvent was evaporated to dryness and the residue was purified by
CCTLC (hexane/EtOAc, 2:1) to give 26 (31 mg, 28%) as a white
3,3-Dibenzyl-6-methylcarbamoyl-3H-[1,2]-oxathiole[4,3-b]pyri-
dine 1,1-dioxide (21b): A solution of 15b (100 mg, 0.24 mmol)
and methylamine (8m solution in EtOH, 7 mL) was stirred for
10 min at RT and the solvent was removed under reduced pres-
sure. The residue was purified by CCTLC (hexane/EtOAc, 1:1) to
give 21b (68 mg, 68%) as a white solid: mp (MeOH): 195–1988C;
1H NMR (300 MHz, (CD3)2CO, 303K): d=2.95, 2.94 (2 s, 3H), 3.42
and 3.57 (AB system, J=14.3 Hz, 4H), 7.16 (m, 10H), 8.14 (bs, 1H),
8.45 (d, J=1.8 Hz, 1H), 9.47 (d, J=1.8 Hz, 1H); 13C NMR (75 MHz,
(CD3)2CO, 303K): d=26.8, 44.2, 98.0, 128.0, 128.8, 132.1, 128.1,
131.8, 130.0, 135.7, 155.3, 161.6, 164.1; IR (KBr): 1671 (CO), 1341,
1194 (SO2); MS (ES+) m/z 409.0 [M+1]+, 431.0 [M+Na]+, 839.0
[2M+Na]+; Anal. calcd for C22H20N2O4S: C 64.69, H, 4.94; N 6.86,
found: C 64.83, H 4.72, N 6.65.
1
solid: mp (MeOH): 138–1398C; H NMR (500 MHz, CDCl3): d=0.80
(m, 3H), 2.12 (m, 1H), 2.18 (m, 1H), 2.68 (s, 3H), 2.73 (s, 3H), 3.32
and 3.37 (AB system, J=À14.4 Hz, 2H), 7.23 (m, 5H); 13C NMR
(125 MHz, CDCl3): d=7.7, 22.3, 23.0, 30.3, 44.4, 96.1, 127.4, 128.2,
130.9, 133.4, 142.6, 150.6, 155.7, 158.8; MS (ES+) m/z 319.0 [M+1]+,
341.0 [M+Na]+, 659.2 [2M+Na]+; Anal. calcd for C16H18N2O3S: C
60.36, H 5.70, N 8.80, found: C 60.19, H 5.49, N 8.63.
3,3-Dibenzyl-6-methylethylcarbamoyl-3H-[1,2]-oxathiole[4,3-
b]pyridine 1,1-dioxide (22): To
a
mixture of AlCl3 (42 mg,
5,5-Dibenzyl-4-[(Z)-2-methoxycarbonylethenylamine]-1,2-oxa-
thiole-2,2-dioxide (27) and 5,5-dibenzyl-4-[(E)-2-methoxycarbo-
nylethenylamine]-1,2-oxathiole-2,2-dioxide (28): A solution of
1b[9] (100 mg, 0.32 mmol) and methyl 3,3-dimethoxypropanoate
(152 mL, 1.07 mmol) in AcOH (0.5 mL) was stirred for 30 min at
110 8C. Then, the solvent was removed under reduced pressure
and the residue was purified by CCTLC (hexane/EtOAc, 3:1). The
fastest moving fractions afforded 27 (30 mg, 23%) as a white solid:
mp (toluene): 147–1488C; 1H NMR (200 MHz, (CD3)2CO): d=3.29
and 3.30 (AB system, J=À14.0 Hz, 4H), 3.78 (s, 3H), 5.23 (d, J=
8.4 Hz, 1H), 6.25 (s, 1H), 7.14 (dd, J=8.4, 11.5 Hz, 1H), 7.26 (m,
10H), 9.92 (bd, J=11.5 Hz, 1H); 13C NMR (125 MHz, (CD3)2CO): d=
43.3, 51.8, 92.0, 96.4, 97.0, 128.1, 129.0, 131.6, 134.4, 142.8, 151.2,
170.5; MS (ES+) m/z 400.6 [M+1]+, 422.5 [M+Na]+; Anal. calcd for
C22H23NO5S: C 63.90, H 5.61, N 3.39, found: C 63.75, H 5.52, N 3.31.
0.32 mmol) in dry 1,2-dicloroethane (4 mL) at 08C, a solution of
ethylmethylamine (51 mL, 0.60 mmol) in 1,2-dichloroethane (2 mL)
was slowly added. The reaction mixture was allowed to reach RT
and compound 15b (100 mg, 0.24 mmol) was added. The mixture
was stirred in an Ace pressure tube for 5 h at 808C. Then, the reac-
tion was quenched with H2O, and the mixture was stirred for
30 min at RT and filtered through a Celite pad. The organic layer
was washed with a saturated NaHCO3 (3 ꢄ 10 mL) and brine (3 ꢄ
10 mL), dried over Na2SO4, and evaporated to dryness. The final
residue was purified by CCTLC (hexane/EtOAc, 2:1) to give 22
(54 mg, 52%) as a white solid: mp (MeOH): 150–1528C; 1H NMR
(300 MHz, (CD3)2CO, 303K): d=1.10, 1.18 (2t, J=6.8 Hz, 3H), 2.92,
3.02 (2 s, 3H), 3.18, 3.54 (2q, J=6.8 Hz, 2H), 3.41 and 3.56 (AB
system, J=À14.4 Hz, 4H), 7.15 (m, 10H), 9.10 (s, 1H), 8.19 (s, 1H);
ChemMedChem 2011, 6, 686 – 697
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
695