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S. Ferrer et al. / Tetrahedron 59 (2003) 3445–3454
5.1.1. Ethyl 1,2-dimethyl-5-methoxyindole-3-carboxyl-
ate 7. Ethyl 5-hydroxy-2-methylindole-3-carboxylate 6
(6.0 g, 27 mmol) in dry DMF (50 mL) was added under
N2 to a stirred suspension of KH (3.3 g, 82 mmol) in dry
DMF (200 mL) at 08C. The mixture was stirred for 45 min.
Iodomethane (11.7 g, 82 mmol) was added dropwise at 08C
and the mixture was warmed to 208C during 4 h. Saturated
aq. NH4Cl was added and the mixture was extracted thrice
with EtOAc. The combined extracts were washed with
water. Drying, evaporation and chromatography (EtOAc)
gave 7 (5.4 g, 81%) as a white solid: mp 119–1208C (lit.10
mp 119–1218C); NMR dH 1.45 (3H, t, J¼7.1 Hz, CH2CH3),
2.74 (3H, s, 2-Me), 3.66 (3H, s, NMe), 3.88 (3H, s, OMe),
4.39 (2H, q, J¼7.1 Hz, CH2), 6.87 (1H, dd, J¼8.8, 2.5 Hz,
6-H), 7.17 (1H, d, J¼8.8 Hz, 7-H), 7.66 (1H, d, J¼2.5 Hz,
4-H).
5.1.5. 1,2-Dimethyl-5-methoxyindole 13. 2-Methyl-5-
methoxyindole 12 (100 mg, 620 mmol) was added slowly
to a stirred suspension of NaH (27 mg, 60% in oil,
680 mmol) in dry DMF (15 mL) under Ar. The suspension
was heated at 458C for 10 min and cooled to 208C.
Iodomethane (750 mg, 5.3 mmol) was added during 5 min.
The mixture was heated at 608C for 1 h and poured onto cold
aq. NaHSO4 (10%). The mixture was extracted thrice with
EtOAc. Drying, evaporation and chromatography (EtOAc/
hexane 3:97) gave 13 (90 mg, 80%) as a pale buff solid:
mp 70–738C (lit.22 mp 73–748C); NMR dH 2.37 (3H, s,
2-Me), 3.59 (3H, s, NMe), 3.82 (3H, s, OMe), 6.16 (1H, s,
3-H), 6.73 (1H, dd, J¼2.4, 8.8 Hz, 6-H), 6.93 (1H, d, J¼
2.4 Hz, 4-H), 7.06 (1H, d, J¼8.8 Hz, 7-H).
5.1.6. 1,2-Dimethyl-5-methoxyindole-3-carboxaldehyde
14. POCl3 (169 mg, 1.1 mmol) was added dropwise to dry
DMF (80 mg, 1.1 mmol) and 13 (100 mg, 570 mmol) in
CH2Cl2 (3 mL) and the mixture was heated under reflux for
2 h. Aq. NaOAc (1.0 M, 10 mL) was added and the mixture
was stirred for 2.5 h before being extracted with EtOAc.
Drying, evaporation and chromatography (EtOAc/hexane
1:1) gave 14 (50 mg, 43%) as an off-white solid: mp 115–
1178C (lit.22 mp 108–1108C); NMR dH 2.62 (3H, s, 2-Me),
3.63 (3H, s, NMe), 3.89 (3H, s, OMe), 6.16 (1H, s, 3-H),
6.89 (1H, dd, J¼2.3, 8.9 Hz, 6-H), 7.17 (1H, d, J¼8.9 Hz,
7-H), 7.80 (1H, d, J¼2.3 Hz, 4-H), 10.10 (1H, s, CHO).
5.1.2. Ethyl 1,2-dimethyl-5-methoxy-4-nitroindole-3-
carboxylate 8 and ethyl 1,2-dimethyl-5-methoxy-6-
nitroindole-3-carboxylate 9. Conc. HNO3 (11 mL) in
AcOH (41 mL) was added to 7 (5.1 g, 21 mmol) in AcOH
(80 mL) at 2108C. The mixture was stirred for 2 h, while
warming to 208C. The suspension was poured onto ice/water
and, after 15 min, the solid was collected by filtration and
dried. Chromatography (EtOAc/hexane 1:1) yielded 9
(800 mg, 14%) as a pale yellow solid: mp 138–1398C
(lit.28 mp 139–1418C); NMR dH 1.46 (3H, t, J¼7.0 Hz,
CH2CH3), 2.79 (3H, s, 2-Me), 3.73 (3H, s, NMe), 4.02 (3H,
s, OMe), 4.40 (2H, q, J¼7.0 Hz, CH2), 7.79 (1H, s, 4-H),
7.96 (1H, s, 7-H). Further elution gave 8 (3.8 g, 63%) as a
pale yellow solid: mp 187–1888C (lit.10 mp 189–1928C);
NMR dH 1.36 (3H, t, J¼7.1 Hz, CH2CH3), 2.67 (3H, s,
2-Me), 3.66 (3H, s, NMe), 3.91 (3H, s, OMe), 4.29 (2H, q,
J¼7.1 Hz, CH2), 6.93 (1H, d, J¼9.1 Hz, 6-H), 7.30 (1H, d,
J¼9.1 Hz, 7-H).
5.1.7. 1,2-Dimethyl-5-methoxy-4-nitroindole-3-carbox-
aldehyde 15. Fuming HNO3 (90%, 2.0 mL) in AcOH
(8.2 mL) was added to 14 (700 mg, 3.4 mmol) in AcOH
(55 mL) at 58C during 5 min. The temperature was allowed
to rise to 208C during 3 h, the mixture was poured onto
ice and the precipitate was collected by filtration. Chroma-
tography (EtOAc/hexane 2:1) gave 15 (430 mg, 60%) as a
pale yellow solid: mp 235–2378C (lit.22 mp 236–2388C);
NMR dH ((CD3)2SO) 2.71 (3H, s, 2-Me), 3.76 (3H, s, NMe),
3.89 (3H, s, OMe), 7.25 (1H, d, J¼9.0 Hz, 6-H), 7.75 (1H, d,
J¼9.0 Hz, 7-H), 9.90 (1H, s, CHO).
5.1.3. Ethyl 4-amino-1,2-dimethyl-5-methoxyindole-3-
carboxylate 10. Compound 8 (2.18 g, 7.5 mmol) was
stirred under reflux with Sn powder (4.0 g, 34 mmol) in
EtOH (190 mL) and aq. HCl (9 M, 10 mL) for 30 min. The
cooled solution was decanted off and was neutralised with
aq. NaHCO3. The suspension was added to an equal volume
of water, was stirred overnight with CH2Cl2 (200 mL) and
was filtered (Celitew). The organic layer was dried.
Evaporation and chromatography (EtOAc) yielded 10
(1.56 g, 80%) as pale yellow crystals: mp 96–978C (lit.10
mp 96–988C); NMR dH 1.41 (3H, t, J¼7.0 Hz, CH2CH3),
2.64 (3H, s, 2-Me), 3.58 (3H, s, NMe), 3.87 (3H, s, OMe),
4.36 (2H, q, J¼7.0 Hz, CH2), 5.68 (2H, br s, NH2), 6.52
(1H, d, J¼8.7 Hz, 6-H), 6.88 (1H, d, J¼8.7 Hz, 7-H).
5.1.8. 4-Amino-1,2-dimethyl-5-methoxyindole-3-carbox-
aldehyde 16. Compound 15 (150 mg, 0.60 mmol) was
heated under reflux with Sn powder (350 mg, 2.9 mmol) in
EtOH (15 mL) and aq. HCl (3.0 M, 5 mL) for 1 h. The
solution was neutralised with aq. NaHCO3 and was
extracted thrice with CHCl3. Drying, evaporation and
chromatography (EtOAc/hexane 1:1) gave 16 (100 mg,
62%) as a pale yellow solid: mp 155–1578C (lit.22 mp 152–
1538C); NMR dH ((CD3)2SO) 2.61 (3H, s, 2-CH3), 3.59 (3H,
s, NCH3), 3.75 (3H, s, OCH3), 6.0 (2H, s, NH2), 6.56 (1H, d,
J¼9.0 Hz, 7-H), 6.85 (1H, d, J¼9.0 Hz, 6-H), 9.71 (1H, s,
CHO).
5.1.4. 1,2-Dimethyl-3-(hydroxymethyl)-5-methoxy-
indole-4,7-dione 11. NaBH4 (160 mg, 4.3 mmol) was
added to a suspension of 17 (100 mg, 0.43 mmol) in dry
MeOH (40 mL, degassed) under Ar. The mixture was stirred
for 1 h and aerated prior to the addition of water (20 mL).
The mixture was extracted thrice with CH2Cl2. Drying,
evaporation, chromatography (EtOAc) and recrystallisation
(EtOAc) afforded 11 (50 mg, 33%) as an orange-red solid:
mp 200–2018C (lit.30 mp 199–2008C); NMR dH 2.21 (3H,
s, 2-Me), 3.81 (3H, s, NMe), 3.88 (3H, s, OMe), 3.87 (1H, t,
J¼6.7 Hz, OH), 4.59 (2H, d, J¼7.0 Hz, CH2OH), 5.60 (1H,
s, 6-H).
5.1.9. 1,2-Dimethyl-3-formyl-5-methoxyindole-4,7-dione
17. Potassium nitrosodisulfonate (920 mg, 3.4 mmol) in aq.
NaH2PO4/Na2HPO4 buffer (30.5 mL, 0.3 M, pH 6.0) was
added to 16 (150 mg, 680 mmol) in acetone (30.5 mL) and
the mixture was stirred for 1 h. The acetone was evaporated.
The precipitate was washed with water and cold MeOH
and dried to give 17 (120 mg, 75%) as an orange solid: mp
240–2428C (lit.30 mp 246–2478C); NMR ((CD3)2SO) dH
2.50 (3H, s, 2-Me), 3.82 (3H, s, NMe), 3.88 (3H, s, OMe),
5.89 (1H, s, 6-H), 10.37 (1H, s, CHO).