PAPER
A New and Convenient Synthesis of 3-Aryl-3-hydroxyisoindol-1-ones
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Anal. Calcd for C16H14Cl2N2O2: C, 56.99; H, 4.18; N, 8.31. Found:
C, 57.04; H, 4.15; N, 8.32.
8a (Minor Isomer):
Pale yellow crystals; mp: 148-150 ºC (EtOAc/hexane).
IR (KBr): n = 3400, 1710, 1620, 1610 cm-1.
1H NMR (270 MHz, DMSO-d6): d = 2.71 (s, 6H, 2 ¥ CH3), 7.26 (s,
1H, OH), 7.31-7.42 (m, 5H, ArH), 7.72 (dd, 1H, J = 5.1, 1.1 Hz,
ArH), 8.47 (s, 1H, ArH), 8.80 (d, 1H, J = 5.1 Hz, ArH).
13C NMR (CDCl3/MeOH-d4, 30:1, v/v): d = 44.9, 90.1, 120.6,
126.3, 129.0, 129.6, 135.5, 137.7, 143.0, 145.7, 146.4, 161.0.
2-(Dimethylamino)pyrrolo[3,4-c]pyridine-1,3-dione (5); Typi-
cal Procedure
A
mixture of 3,4-pyridinedicarboxylic anhydride (1.00 g,
6.71 mmol) and 1,1-dimethylhydrazine (0.40 g, 6.71 mmol) in THF
(30 mL) was refluxed for 2 h. After removal of the solvent under re-
duced pressure, the residue was dissolved in Ac2O (20 mL) and
heated under refluxed for 2 h. HOAc was evaporated under reduced
pressure and the crude residue was dissolved in EtOAc (60 mL).
The organic layer was washed with 10% Na2CO3 (30 mL), brine
(30 mL), dried (Na2SO4), and concentrated. The crude product was
chromatographed on a silica gel column (EtOAc) to give 5 (0.84 g,
71%) as a pale yellow solid; mp: 141-142 ºC (EtOAc/hexane).
IR (KBr): n = 1790, 1740, 1710, 1610 cm-1.
1H NMR (270 MHz, CDCl3): d = 3.40 (s, 6H, 2 ¥ CH3), 7.74 (dd,
1H, J = 4.8, 1.1 Hz, ArH), 9.09 (d, 1H, J = 4.8 Hz, ArH), 9.14 (s,
1H, ArH).
MS (EI): m/z (%) = 269 (M+), 59 (100).
Anal. Calcd for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C,
66.81; H, 5.55; N, 15.52.
2-(Dimethylamino)-1-hydroxy-1-(4-methylphenyl)-1,2-dihy-
dropyrrolo[3,4-c]pyridin-3-one (7b) and 2-(Dimethylamino)-3-
hydroxy-3-(4-methylphenyl)-2,3-dihydropyrrolo[3,4-c]pyridin-
1-one (8b)
Compounds 7a and 7b were obtained by reaction of 5 with toluene
using the same procedure as above.
MS (EI): m/z (%) = 191 (M+), 149 (100).
7b (Major Isomer):
Yield: 61%; pale yellow crystals; mp: 163-165 ºC (EtOAc/hex-
Anal. Calcd for C9H9N3O2: C, 56.52; H, 4.73; N, 21.99. Found: C,
56.54; H, 4.74; N, 21.98.
ane).
IR (KBr): n = 3400, 1710, 1620, 1520 cm-1.
6-(Dimethylamino)pyrrolo[3,4-b]pyridine-5,7-dione (6)
Under the same condition used for 5, 2,3-pyridinedicarboxylic an-
hydride gave 6 (71%) as a pale yellow solid; mp: 140-142 ºC
(EtOAc/hexane).
IR (KBr): n = 1800, 1780, 1750, 1730 cm-1.
1H NMR (270 MHz, CDCl3): d = 3.06 (s, 6H, 2 ¥ CH3), 7.64 (dd,
1H, J = 4.8, 1.1 Hz, ArH), 8.16 (d, 1H, J = 4.8 Hz, ArH), 9.00 (s,
1H, ArH).
1H NMR (270 MHz, DMSO-d6): d = 2.28 (s, 3H, CH3), 2.72 (s, 6H,
2 ¥ CH3), 7.15 (d, 2H, J = 10.8 Hz, ArH), 7.19 (s, 1H, OH), 7.20-
7.28 (m, 3H, ArH), 8.74 (d, 1H, J = 4.9 Hz, ArH), 8.90 (d, 1H,
J = 0.8 Hz, ArH).
13C NMR (CDCl3/MeOH-d4, 30:1, v/v): d = 21.1, 45.2, 90.4, 117.8,
126.0, 126.1, 129.3, 134.5, 138.8, 144.4, 152.7, 155.5, 164.8.
MS (EI): m/z (%) = 283 (M+), 59 (100).
MS (EI): m/z (%) = 191 (M+), 149 (100).
Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C,
67.81; H, 6.08; N, 15.05.
Anal. Calcd for C9H9N3O2: C, 56.54; H, 4.74; N, 21.98. Found: C,
56.46; H, 4.78; N, 21.95.
8b (Minor Isomer):
Yield: 17%; pale yellow crystals; mp: 93-95 ºC (EtOAc/hexane).
IR (KBr): n = 3400, 1720, 1620, 1600 cm-1.
1H NMR (270 MHz, DMSO-d6): d = 2.29 (s, 3H, CH3), 2.71 (s, 6H,
2 ¥ CH3), 7.15 (d, 2H, J = 8.1 Hz, ArH), 7.18 (s, 1H, OH), 7.26 (d,
2H, J = 8.1 Hz, ArH), 7.70 (dd, 1H, J = 5.0, 1.1 Hz, ArH), 8.45 (d,
1H, J = 1.1 Hz, ArH), 8.78 (d, 1H, J = 5.0 Hz, ArH).
13C NMR (CDCl3/MeOH-d4, 30:1, v/v): d = 21.1, 44.9, 90.6, 117.6,
126.2, 129.3, 134.3, 138.9, 139.9, 142.8, 143.5, 149.0, 164.2.
MS (EI): m/z (%) = 283 (M+), 59 (100).
2-(Dimethylamino)-1-hydroxy-1-phenyl-1,2-dihydropyrro-
lo[3,4-c]pyridin-3-one (7a) and 2-(Dimethylamino)-3-hydroxy-
3-phenyl-2,3-dihydropyrrolo[3,4-c]pyridin-1-one (8a); Typical
Procedure
To a solution of 5 (0.20g, 1.05 mmol) in anhyd benzene (10 mL)
was added AlCl3 (0.70 g, 5.23 mmol) and the reaction mixture was
refluxed for 1 h. After addition of H2O (10 mL) to the mixture
with ice cooling, the aqueous layer was basified with 10% NaOH
(10 mL) and was extracted with EtOAc (2 ¥ 20 mL). The combined
organic extracts were washed with brine (20 mL), dried (Na2SO4),
and concentrated. The crude product was chromatographed on a
silica gel column (1,4-dioxane/benzene, 1:3) to give 7a (0.195 g,
77%) and 8a (0.034 g, 14%).
Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C,
67.70; H, 6.01; N, 14.74.
6-(Dimethylamino)-5-hydroxy-5-phenyl-5,6-dihydropyrro-
lo[3,4-b]pyridin-7-one (9a); Typical Procedure
7a (Major Isomer):
Pale yellow crystals; mp: 175-176 ºC (EtOAc/hexane).
To a solution of 6 (0.05 g, 0.26 mmol) in anhyd benzene (10 mL)
was added AlCl3 (0.18 g, 1.31 mmol) and the reaction mixture was
refluxed for 0.5 h. After addition of H2O (10 mL) to the mixture
with ice cooling, the aqueous layer was basified with 10% Na2CO3
(10 mL) and was extracted with EtOAc (2 ¥ 20 mL). The combined
organic extracts were washed with brine (20 mL), dried (Na2SO4),
and concentrated. The crude product was chromatographed on a
silica gel column (EtOAc) to give 9a (0.69 g, 98%) as a pale yellow
solid, mp: 142-143 ºC (EtOAc/hexane).
IR (KBr): n = 3400, 1700, 1620 cm-1.
1H NMR (270 MHz, DMSO-d6): d = 2.72 (s, 6H, 2 ¥ CH3), 7.24 (s,
1H, OH), 7.26 (dd, 1H, J = 1.6, 0.8 Hz, ArH), 7.06-7.08 (m, 5H,
ArH), 8.75 (d, 1H, J = 5.1 Hz, ArH), 8.92 (s, 1H, ArH).
13C NMR (CDCl3/MeOH-d4, 30:1, v/v): d = 45.0, 90.8, 118.7,
126.6, 126.8, 128.7 129.1, 137.3, 143.8, 152.5, 157.2, 165.0.
MS (EI): m/z (%) = 269 (M+), 59 (100).
IR (KBr): n = 3300, 1700, 1660, 1600, 1500 cm-1.
1H NMR (270 MHz, DMSO-d6): d = 2.73 (s, 6H, 2 ¥ CH3), 7.13 (s,
1H, OH), 7.30-7.41 (m, 5H, ArH), 7.54 (d, 1H, J = 8.1, 4.8 Hz,
Anal. Calcd for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C,
67.03; H, 5.63; N, 15.60.
Synthesis 2001, No. 2, 221–224 ISSN 0039-7881 © Thieme Stuttgart · New York