1000 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Zou et al.
7.68 (dd, J1=8.4 Hz, J2=7.4 Hz, 1H), 7.60 (brs, 1H), 4.18-4.12
(m, 1H), 4.04 (s, 3H), 1.43 (d, J = 6.9 Hz, 6H). 13C NMR (75.5
MHz, CDCl3): δ 168.9, 168.5, 167.3, 145.9, 134.9, 133.0, 129.9,
129.8, 128.8, 128.2, 127.5, 127.3, 127.0, 52.5, 28.5, 23.2. HRMS
(EI): calcd for C17H15NO4 (Mþ) 297.1001; found 297.1005. Mp:
302.5 °C.
Syntheses of Methyl 4-Isobutyl-1,3-dioxo-2,3-dihydro-1H-
benzo[e]isoindole-8-carboxylate (2g) and Methyl 4-Isobutyl-1,3-
dioxo-2,3-dihydro-1H-benzo[e]isoindole-6-carboxylate (2u). Com-
pounds 2g and 2u were made from 1g as a pair of regioisomers in
35% total yield by standard procedure and were purified by a
flash chromatography on silica gel (hexane/ethyl acetate = 20/1)
to give 2g (24 mg) as a solid in 17% yield and 2u (25 mg) as a solid
in 18% yield for three steps.
4.02 (s, 3H), 2.86 (s, 3H), 2.81 (s, 3H). 13C NMR (125 MHz,
THF): δ 170.8, 170.2, 166.9, 143.4, 135.6, 132.7, 132.5, 130.6,
129.8, 127.8, 127.5, 127.0, 126.4, 52.4, 15.0, 14.3. HRMS (EI):
calcd for C16H13NO4 (Mþ) 283.0845; found 283.0856. Mp:
297.0 °C.
Synthesis of Methyl 4-Isopropyl-1,3-dioxo-2,3-dihydro-1H-
benzo[e]isoindole-7-carboxylate (2j). Compound 2j was made
from 1j by the standard procedure and the crude product was
purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 15/1) to give 2j (59 mg) as a solid in 44% yield for three
steps. 1H NMR (500 MHz, DMSO): δ 11.33 (brs, 1H), 8.82 (d,
J=8.8 Hz, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 8.11 (d, J = 8.8 Hz,
1H), 4.07-4.02 (m, 1H), 3.94 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
13C NMR (75.5 MHz, DMSO): δ 170.0, 169.9, 165.9, 144.3,
135.7, 132.9, 130.9, 130.6, 129.0, 127.9, 127.8, 127.2, 124.5, 52.5,
27.5, 23.0. HRMS (EI): calcd for C17H15NO4 (Mþ) 297.1001;
found 297.1005. Mp: 289.2 °C.
Synthesis of Methyl 4-Isobutyl-1,3-dioxo-2,3-dihydro-1H-
benzo[e]isoindole-7-carboxylate (2k). Compound 2k was made
from 1k by the standard procedure and the crude product was
purified by a flash chromatography on silica gel (dichloro-
methane/THF =400/1) to give 2k (53 mg) as a solid in 38%
yield for three steps. 1H NMR (500 MHz, DMSO): δ 11.35 (brs,
1H), 8.86 (d, J=8.8 Hz, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 8.15 (dd,
J1 = 8.8 Hz, J2=1.6 Hz, 1H), 3.94 (s, 3H), 3.02 (d, J = 7.1 Hz,
2H), 2.03-1.97 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H). 13C NMR
(75.5 MHz, DMSO): δ 170.1, 169.9, 165.9, 137.2, 136.9, 135.2,
131.7, 130.7, 129.1, 128.1, 127.9, 127.3, 124.6, 52.6, 29.4, 22.2.
HRMS (EI): calcd for C18H17NO4 (Mþ) 311.1158; found
311.1165. Mp: 285.6 °C.
Synthesis of Methyl 4-(2-(Benzyloxy)ethyl)-1,3-dioxo-2,3-di-
hydro-1H-benzo[e]isoindole-7-carboxylate (2m). Compound 2m
was made from 1l by the standard procedure and the crude
product was purified by a flash chromatography on silica gel
(dichloromethane/THF = 400/1) to give 2m (54 mg) as a solid in
31% yield for three steps. 1H NMR (500 MHz, CDCl3): 8.95 (d,
J = 8.8 Hz, 1H), 8.61 (s, 1H), 8.22 (dd, J1 = 8.8 Hz, J2 = 1.5 Hz,
1H), 8.12 (s, 1H), 7.73 (brs, 1H), 7.26-7.21 (m, 5H), 4.53 (s, 2H),
4.02 (s, 3H), 3.87 (t, J = 6.2 Hz, 2H), 3.52 (t, J = 6.2 Hz, 2H).
13C NMR (125 MHz, CDCl3): δ 168.54, 168.48, 166.4, 138.2,
137.8, 135.9, 135.1, 131.3, 130.8, 130.3, 129.1, 128.32, 128.29,
128.1, 127.7, 127.6, 125.2, 72.9, 69.4, 52.5, 31.8. HRMS (EI):
calcd for C23H19NO5 (Mþ) 389.1263; found 389.1268. Mp:
197.3 °C.
Synthesis of Methyl 4-(2-(Benzyloxy)propyl)-1,3-dioxo-2,3-
dihydro-1H-benzo[e]isoindole-7-carboxylate (2n). Compound
2n was made from 1m by the standard procedure and the crude
product was purified by a flash chromatography on silica gel
(dichloromethane/THF = 400/1) to give 2n (60 mg) as a solid in
33% yield for three steps. 1H NMR (500 MHz, CDCl3): 8.96 (d,
J = 8.8 Hz, 1H), 8.61 (s, 1H), 8.25 (dd, J1=8.8 Hz, J2 = 1.5 Hz,
1H), 8.08 (s, 1H), 7.41 (brs, 1H), 7.13 (t, J = 7.3 Hz, 1H),
7.08-7.05 (m, 2H), 7.00 (d, J=7.3 Hz, 2H), 4.56 (d, J = 12.1 Hz,
1H), 4.33 (d, J = 12.1 Hz, 1H), 4.03 (s, 3H), 3.92-3.88 (m, 1H),
3.43-3.40 (m, 1H), 3.34-3.29 (m, 1H), 1.33 (d, J = 6.1 Hz, 3H).
13C NMR (75.5 MHz, DMSO): δ 170.0, 169.9, 165.8, 138.8,
137.9, 135.0, 134.4, 131.6, 130.6, 129.0, 128.2, 127.8, 127.7,
127.34, 127.30, 127.0, 124.5, 74.1, 69.4, 52.5, 37.9, 19.6. HRMS
(EI): calcd for C24H21NO5 (Mþ) 403.1420; found 403.1420. Mp:
233.9 °C.
Synthesis of Methyl 4-(2-Hydroxyethyl)-1,3-dioxo-2,3-dihy-
dro-1H-benzo[e]isoindole-7-carboxylate (2o). To a solution of
compound 2m (45.0 mg, 0.12 mmol) in methanol (0.5 mL) and
THF (0.5 mL) was added Pd/C (10% palladium on activated
carbon, 20.0 mg), and the mixture was stirred 25 °C under a
balloon pressure of H2 for 16 times. The mixture was filtered off
through a funnel and washed with methanol/THF (1/1, 30 mL).
The filtrate was concentrated under vacuum, and the residue
was purified by a flash chromatography on silica gel (dichloro-
methane/methanol = 80/1) to give 2o (30.5 mg) as a solid in 85%
Compound 2g. 1H NMR (500 MHz, CDCl3): δ 9.60 (s, 1H),
8.22 (d, J = 8.7 Hz, 1H), 7.94-7.92 (m, 2H), 7.59 (brs, 1H), 4.02
(s, 3H), 3.09 (d, J = 7.1 Hz, 2H), 2.09-2.03 (m, 1H), 0.99 (d, J =
6.3 Hz, 6H). 13C NMR (125 MHz, DMSO): δ 169.8, 169.6,
165.7, 138.3, 137.5, 135.1, 130.4, 129.1, 129.0, 128.7, 127.1,
126.2, 125.2, 52.3, 29.2, 22.0. HRMS (EI): calcd for C18H17-
NO4 (Mþ) 311.1158; found 311.1164. Mp: 200.0 °C.
Compound 2u. 1H NMR (500 MHz, CDCl3): δ 9.21 (d, J = 8.4
Hz, 1H), 9.10 (s, 1H), 8.33 (dd, J1 = 7.3 Hz, J2 = 1.2 Hz, 1H),
7.80 (brs, 1H), 7.68 (dd, J1 = 8.4 Hz, J2 = 7.3 Hz, 1H), 4.03 (s,
3H), 3.12 (d, J = 7.2 Hz, 2H), 2.09-2.02 (m, 1H), 0.99 (d, J =
6.7 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 169.0, 168.5, 167.2,
138.7, 134.4, 134.3, 132.9, 129.90, 129.86, 128.3, 127.7, 127.3,
127.1, 52.4, 40.7, 30.2, 22.3. HRMS (EI): calcd for C18H17NO4
(Mþ) 311.1158; found 311.1164. Mp: 204.1 °C.
Syntheses of Methyl 5-Ethyl-4-methyl-1,3-dioxo-2,3-dihydro-
1H-benzo[e]isoindole-8-carboxylate (2h) and Methyl 1,3-Dioxo-
4-propyl-2,3-dihydro-1H-benzo[e]isoindole-6-carboxylate (2s).
Compounds 2h and 2s were made from 1h as a pair of regioi-
somers in 39% total yield by the standard procedure and were
purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 20/1) to give 2h (21 mg) as a solid in 16% yield and 2s
(31 mg) as a solid in 23% yield for three steps.
1
Compound 2h. H NMR (500 MHz, DMSO): δ 11.27 (brs,
1H), 9.44 (d, J=1.7 Hz, 1H), 8.29 (d, J = 9.1 Hz, 1H), 8.10 (dd,
J1=9.1 Hz, J2=1.7 Hz, 1H), 3.95 (s, 3H), 3.18 (q, J=7.5 Hz,
2H), 2.76 (s, 3H), 1.20 (t, J = 7.5 Hz, 3H). 13C NMR (75.5 MHz,
DMSO): δ 170.5, 170.0, 165.8, 146.7, 135.7, 132.4, 130.3, 128.4,
127.2, 127.0, 126.6, 125.6, 125.4, 52.5, 21.3, 14.1, 13.3. HRMS
(EI): calcd for C17H15NO4 (Mþ) 297.1001; found 297.0996. Mp:
300.4 °C.
1
Compound 2s. H NMR (500 MHz, DMSO): δ 11.31 (brs,
1H), 9.04 (d, J = 8.3 Hz, 1H), 8.85 (s, 1H), 8.24 (d, J = 7.2 Hz,
1H), 7.78-7.75 (m, 1H), 3.96 (s, 3H), 3.09 (t, J = 7.4 Hz, 2H),
1.70-1.66 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H). 13C NMR (125
MHz, DMSO): δ 170.0, 169.5, 166.6, 138.1, 133.1, 131.9, 131.7,
129.4, 128.6, 128.2, 127.4, 127.0, 126.7, 52.4, 33.0, 23.4, 13.5.
HRMS (EI): calcd for C17H15NO4 (Mþ) 297.1001; found
297.1002. Mp: 219.0 °C.
Syntheses of Methyl 4-Ethyl-1,3-dioxo-2,3-dihydro-1H-benzo-
[e]isoindole-7-carboxylate (2i) and Methyl 4,5-Dimethyl-1,3-di-
oxo-2,3-dihydro-1H-benzo[e]isoindole-7-carboxylate (2l). Com-
pounds 2i and 2l were made from 1i as a pair of regioisomers in
58% total yield by the standard procedure and were purified by
a flash chromatography on silica gel (dichloromethane /THF =
400/1) to give 2i (48 mg) as a solid in 38% yield and 2l (25 mg) as
a solid in 20% yield.
1
Compound 2i. H NMR (500 MHz, DMSO): δ 11.35 (brs,
1H), 8.85 (d, J = 8.8 Hz, 1H), 8.72 (s, 1H), 8.38 (s, 1H), 8.15 (dd,
J1 = 8.8 Hz, J2=1.6 Hz, 1H), 3.95 (s, 3H), 3.16 (q, J=7.5 Hz,
2H), 1.30 (t, J=7.5 Hz, 3H). 13C NMR (125 MHz, DMSO): δ
169.9, 169.7, 165.7, 139.2, 135.4, 135.3, 131.1, 130.5, 129.0,
127.9, 127.8, 127.1, 124.4. 52.3, 23.8, 14.6. HRMS (EI): calcd
for C16H13NO4 (Mþ) 283.0845; found 283.0854. Mp: 194.2 °C.
Compound 2l. 1H NMR (500 MHz, CDCl3): δ 9.04 (d, J = 8.9
Hz, 1H), 8.91 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.44 (brs, 1H),