5906 J . Org. Chem., Vol. 62, No. 17, 1997
Itoh et al.
several times): mp >300 °C; IR (KBr) 3280 (NH), 1636 and
1614 cm-1 (CdO); 1H NMR (DMSO-d6) δ 1.48 (3 H, s), 2.29 (3
H, s), 3.88 (3 H, s), 5.89 (1 H, s), 7.04 (1 H, t, J ) 7.4 Hz), 7.15
(1 H, t, J ) 7.4 Hz), 7.18 (1 H, s), 7.35 (1 H, d, J ) 8.1 Hz),
7.56 (1 H, d, J ) 8.1 Hz), 11.23 (1 H, br s); 13C NMR (DMSO-
d6) 9.2, 10.3, 36.4, 109.7, 111.4, 118.9, 119.2, 120.1, 122.6,
123.6, 127.1, 127.6, 128.2, 130.0, 135.2, 136.2, 143.9 (14 sp2
carbons), 167.7 (CdO), 182.3 (C)O) ppm; MS (EI) m/ z 304
(M+), 306 (M+ + 2, characteristic peak for o-quinone com-
pounds14). Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N,
9.20. Found: C, 74.68; H, 5.27; N, 9.08.
0.402 mmol) was treated in 1 N KOH aqueous CH3CN solution
(13 mL, 1:1, v/v) at 80 °C for 1 h. Acidification of the reaction
mixture to pH 3 with 1 N HCl gave a white precipitate that
was isolated by centrifugation and dried in vacuo (100%): mp
224-226 °C; IR (KBr) 3429 (NH), 2940 (-COOH), 1690 cm-1
1
(CdO); H NMR (CDCl3) δ 2.67 (3 H, d, J ) 1.1 Hz), 2.85 (3
H, s), 3.94 (3 H, s), 6.58 (1 H, d, J ) 7.6 Hz), 6.73 (1 H, dd, J
) 1.1 and 7.6 Hz), 8.88 (1 H, br s); MS (EI) m/ z 219 (M+).20
3,4-Dim eth yl-7-m eth oxyin d ole (18). A mixture of 17
(87.8 mg, 0.40 mmol) and 2CuO-Cr2O3 (18.4 mg, 0.059) in
quinoline (6 mL) was heated at 200 °C for 2 h. The mixture
was then extracted with ether and washed with 1 N HCl and
saturated NaHCO3(aq). The organic layer was further washed
2-Ca r b oxy-3-m et h yl-4-p h en yl-7-m et h oxyin d ole (13).
The starting indole derivative (12) was prepared from 4-meth-
oxy-3-biphenylamine and methyl R-ethylacetoacetate according
to the established procedure (combination of a J aap-Klinge-
mann reaction and a Fischer indolization).12,13 Compound 12
(65.5 mg, 0.222 mmol) was treated in 1 N KOH aqueous
CH3CN solution (7 mL, 1:1, v/v) at 80 °C for 1 h. Acidification
of the reaction mixture to pH 3 with 1 N HCl gave a white
precipitate that was isolated by centrifugation and dried in
vacuo (94%): mp >300 °C; IR (KBr) 3424 (NH), 1658 cm-1
with 1 N HCl several times and dried over MgSO4
.
After
removal of MgSO4 by filtration, evaporation of the solvent gave
a crude product from which 18 was isolated by flash column
chromatography (SiO2, CHCl3) in a 72% yield: mp 75-77 °C;
1
IR (KBr) 3440 cm-1
(NH); H NMR (CDCl3) δ 2.49 (3 H, d, J
) 0.8 Hz), 2.65 (3 H, s), 3.92 (3 H, s), 6.49 (1 H, d, J ) 7.8 Hz),
6.71 (1 H, dd, J ) 0.8 and 7.8 Hz), 6.89 (1 H, d, J ) 1.1 Hz),
8.06 (1 H, br s); MS (EI) m/ z 175 (M
+). Anal. Calcd for
1
(CdO); H NMR (CDCl3) δ 2.18 (3 H, s), 2.69 (1 H, br s), 4.01
C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.25; H,
7.39; N, 7.89.
(3 H, s), 6.76 (1 H, d, J ) 7.8 Hz), 6.89 (1 H, d, J ) 7.8 Hz),
7.39-7.47 (5 H, m), 9.04 (1 H, br s); HRMS (EI) m/ z 281.1064
(M+), calcd for C17H15O3N 281.1053.20
3,4-Dim eth yl-7-h yd r oxyin d ole (19). A CH3CN (8 mL)
solution of 18 (98.0 mg, 0.56 mmol) and trimethylsilyl iodide
(1.12 mg, 5.6 mmol) was stirred at the refluxing temperature
for 8 h. The reaction was quenched by adding Na2S2O3(aq)
and extracted with CH2Cl2 three times. The combined organic
layer was washed with aqueous Na2S2O3 and H2O and then
dried over MgSO4. After removal of MgSO4 by filtration,
evaporation of the solvent gave a crude product that was
purified by flash column chromatography (SiO2, CHCl3) (69%
yield): mp 120-123 °C; IR (KBr) 3448 (NH and OH); 1H NMR
(CDCl3) δ 2.49 (3 H, d, J ) 0.8 Hz), 2.64 (3 H, s), 4.68 (1 H, br
s), 6.43 (1 H, d, J ) 7.8 Hz), 6.61 (1 H, dd, J ) 0.8 and 7.8
Hz), 6.91 (1 H, d, J ) 1.1 Hz), 8.02 (1 H, br s); MS (EI) m/ z
161 (M+).20
3,4-Dim eth ylin d ole-6,7-d ion e (4). To a CH3CN solution
(24 mL) of 19 (62.0 mg, 0.385 mmol) was added Fremy’s salt
(418.3 mg, 1.56 mmol) in 0.062 M KH2PO4 aqueous solution
(24 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min
and at room temperature for 12 h. The final reaction mixture
was then extracted with CH2Cl2. After the extract was dried
over MgSO4, evaporation of the solvent gave a dark brown
residue from which quinone 4 was isolated in 80% yield by
flash column chromatography (SiO2, CHCl3, for the elemental
analysis, the sample was washed with ether several times):
mp >300 °C; IR (KBr) 3296 (NH), 1636 cm-1 (CdO); 1H NMR
(DMSO-d6) δ 2.18 (3 H, s), 2.26 (3 H, d, J ) 1.4 Hz), 5.73 (1 H,
d, J ) 1.4 Hz), 7.10 (1 H, d, J ) 2.4 Hz), 12.5 (1 H, br s); 13C
NMR (DMSO-d6) 11.9, 21.2, 120.6, 121.6, 128.0, 130.0, 152.3
(5 sp2 carbons), 167.4 (CdO), 183.1 (C)O) ppm; MS (EI) m/ z
177 (M+ + 2, characteristic peak for o-quinone compounds14),
175 (M+). Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N,
8.00. Found: C, 68.19; H, 5.03; N, 7.89.
2-Ca r boxy-3,7-d im eth yl-5-ben zyloxyin d ole (21). The
starting material 20 was prepared from 2-methyl-4-benzyl-
oxyaniline and methyl R-ethylacetoacetate according to the
established procedure (combination of a J aap-Klingemann
reaction and a Fischer indolization).12,13 2-Methyl-4-benzyl-
oxyaniline was prepared from 2-methyl-4-hydroxyaniline by
the standard procedures of amino acetylation with acetic
anhydride, benzylation of the hydroxy group with benzyl
chloride, and deprotection of the acetamide group with Na-
OH(aq).21 The indole derivative 20 (104 mg, 0.336 mmol) was
treated in 1 N KOH aqueous CH3OH solution (11 mL, 1:1, v/v)
at 80 °C for 1 h. Acidification of the reaction mixture to pH 3
with 1 N HCl gave a white precipitate that was isolated by
centrifugation and dried in vacuo (100%): mp 208-211 °C;
IR (KBr) 3484 (NH), 2924 (-COOH), 1660 cm-1 (CdO); 1H
NMR (CDCl3) δ 2.2 (1 H, br), 2.48 (3 H, s), 2.61 (3 H, s), 5.11
(2 H, s), 6.95 (1 H, s), 6.97 (1 H, s), 7.33-7.50 (5 H, m), 8.56 (1
H, br s); MS (EI) m/ z 295 (M+), 204 (M+-CH2Ph).20
3-Meth yl-4-p h en yl-7-m eth oxyin d ole (14). A mixture of
13 (390 mg, 1.39 mmol) and 2CuO-CrO2O3 (51.8 mg) in
quinoline (17 mL) was heated at 200 °C for 2 h. The mixture
was then extracted with ether and washed with 1 N HCl and
saturated NaHCO3(aq). The organic layer was further washed
with 1 N HCl several times and dried over MgSO4. After
removal of MgSO4 by filtration, evaporation of the solvent gave
white solids from which pure product 14 was obtained by
washing with ether in a 62% yield: mp 52-57 °C; IR (KBr)
1
3436 cm-1 (NH); H NMR (CDCl3) δ 1.87 (3 H, s), 3.99 (3 H,
s), 6.67 (1 H, d, J ) 7.8 Hz), 6.89 (1 H, d, J ) 7.8 Hz), 6.95 (1
H, s), 7.36-7.42 (5 H, m), 8.22 (1 H, br s); MS (EI) m/ z 237
(M+). Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90.
Found: C, 80.89; H, 6.35; N, 5.83.
3-Meth yl-4-p h en yl-7-h yd r oxyin d ole (15). A CH3CN (20
mL) solution of 14 (338 mg, 1.42 mmol) and trimethylsilyl
iodide (2.0 mL, 14.0 mmol) was stirred at the refluxing
temperature for 8 h. The reaction was quenched by adding
Na2S2O3(aq) and was extracted with CH2Cl2 three times. The
combined organic layer was washed with aqueous Na2S2O3 and
H2O and then dried over MgSO4. After removal of MgSO4 by
filtration, evaporation of the solvent gave a crude product that
was purified by flash column chromatography (SiO2, CHCl3)
(78% yield): oily material; IR (KBr) 3444 (NH), 3200-3500
1
cm-1 (OH); H NMR (CDCl3) δ 1.86 (3 H, s), 4.89 (1 H, br s),
6.58 (1 H, d, J ) 7.6 Hz), 6.79 (1 H, d, J ) 7.6 Hz), 6.96 (1 H,
s), 7.33-7.43 (5 H, m), 8.22 (1 H, br s); MS (EI) m/ z 223 (M+).20
3-Meth yl-4-p h en ylin d ole-6,7-d ion e (3). To a CH3CN
solution (70 mL) of 15 (246 mg, 1.10 mmol) was added Fremy’s
salt (1.18 g, 4.40 mmol) in 0.062 M KH2PO4 aqueous solution
(70 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min
and at room temperature for 3 h. The final reaction mixture
was then extracted with AcOEt. After the extract was dried
over MgSO4, evaporation of the solvent gave a dark brown
residue from which quinone 3 was isolated in 65% yield by
flash column chromatography (SiO2, CHCl3, for the elemental
analysis, the sample was washed with ether several times):
mp >300 °C; IR (KBr) 3288 (NH), 1638 cm-1 (CdO); 1H NMR
(DMSO-d6) δ 1.49 (3 H, s), 5.67 (1 H, s), 7.10 (1 H, s), 7.30-
7.50 (5 H, m), 12.69 (1 H, br s); 13C NMR (DMSO-d6) 11.6,
120.7, 122.4, 126.9, 128.2, 128.6, 129.1, 130.3, 130.5, 137.3,
153.4 (10 sp2 carbons), 167.0 (CdO), 183.1 (C)O) ppm; MS
(EI) m/ z 239 (M+ + 2, characteristic peak for o-quinone
compounds14), HRMS m/ z 237.0779, calcd for C15H11NO2
237.0790. Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67; N,
5.90. Found: C, 75.66; H, 4.58; N, 5.80.
2-Car boxy-3,4-dim eth yl-7-m eth oxyin dole (17). The start-
ing material 16 was prepared from 2-methoxy-5-methylaniline
and methyl R-ethylacetoacetate according to the established
procedure (combination of a J aap-Klingemann reaction and
a Fischer indolization).12,13 The indole derivative 16 (93.6 mg,
(21) Greene, T. W. Protective Groups in Organic Synthesis; J ohn
Wiley & Sons: New York, 1981.