Isomerization of 4-aminobenzofurans to 4-hydroxyindoles

Article abstract of DOI:10.1055/s-1998-2024

4-Amino-2-methylbenzofurans are quantitatively converted to 4-hydroxy- 2-methylindoles in acidic medium. The rearrangement mechanism involves the ring opening of the furan ring to produce an intermediate carbocation, which undergoes ring clo- sure to the

Full text of DOI:10.1055/s-1998-2024

March 1998
SYNTHESIS
309
Isomerization of 4-Aminobenzofurans to 4-Hydroxyindoles
A. Chilin,a P. Rodighiero,b A. Guiotto*a,b
a Dipartimento di Scienze Farmaceutiche, Università degli Studi di Padova, Via Marzolo 5, I-35131 Padova, Italy
b Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, associated to Istituto Nazionale
per la Chimica dei Sistemi Biologici, Via Marzolo 5, I-35131 Padova, Italy
Fax +39(49)8275366; E-mail: guiotto@pdfar3.dsfarm.unipd.it
Received 9 June 1997; revised 14 October 1997
Abstract: 4-Amino-2-methylbenzofurans are quantitatively con-
verted to 4-hydroxy-2-methylindoles in acidic medium. The rear-
rangement mechanism involves the ring opening of the furan ring
to produce an intermediate carbocation, which undergoes ring clo-
sure to the indole system. Isomerization takes place only in the
presence of a methyl substituent in 2 position.
Key words: aminobenzofurans, hydroxyindoles, synthesis, iso-
merization
In the last few years we have been interested in synthesiz-
ing some derivatives of 4H-furo[2,3-h]quinolin-4-one,1 to
find out whether they would show antiproliferative activ-
ity, similar to 2H-furo[2,3-h]quinolin-2-ones.2 During
these studies, we often used 4-aminobenzofurans as key
intermediates for the synthesis of furoquinolin-4-ones. It
immediately appeared that 4-aminobenzofurans are not
stable in acidic conditions and that they are easily inter-
converted to their structural isomers, 4-hydroxyindole de-
rivatives.
This finding must be taken into consideration when han-
dling aminobenzofurans, which are of great interest, both
as building blocks in organic and medicinal chemistry and
as true pharmacophores.3–5 In addition, it may be of some
importance in preparing hydroxyindole derivatives, since
they are very frequently used in the synthesis of several
compounds of biological interest.6–9
Our studies started from the observation that very differ-
R
R¢
R¢¢ R¢¢¢
R
R¢ R¢¢ R¢¢¢
ent products are formed during the reduction of 4-ni-
trobenzofurans under varying conditions. Whereas
catalytic hydrogenation of 2,7-dimethyl-4-nitrobenzofu-
ran (12) gives only 4-amino-2,7-dimethylbenzofuran (17)
in 87% yield, reduction of 12 with SnCl2 affords 4-hy-
droxy-2,5-dimethylindole (21) in 80% yield (Scheme 1).
1
2
3
4
5
6
7
8
9
Me
NH2
NHCO2Et –
OMe
Me
–
–
–
–
–
–
–
–
–
–
–
H
–
–
–
–
–
–
–
–
–
13 NHCO2Et
14 OMe
15 Me
16 Me
17 Me
18 NHCO2Et
19 OMe
20 Me
–
–
–
–
–
–
–
–
–
–
–
Me
Me
H
H
H
Me
–
Me Me
CH2COMe
CH(Me)COMe
CH2CºCH
Me
Me
Me
H
H
H
Me
Me
Careful investigation of the reaction progress showed that
compound 17 was initially formed, but was completely
converted into 21 during the subsequent workup of the re-
action mixture. Therefore, as soon as the starting compound
had disappeared, ethanol was evaporated from the reaction
mixture under reduced pressure and the semisolid residue
was further heated at 50°C for 15 minutes. In this way, the
initially formed aminobenzofuran remained in strong acidic
medium (concd HCl survives in the reaction mixture after
evaporation of EtOH) and isomerized to hydroxyindole.
Further confirmation of this finding was that compound17,
unequivocally prepared by catalytic reduction, was con-
verted to 21 in refluxing concentrated HCl, in 80% yield.
NHCO2Et CH2CºCH
OMe
Me Me
CH2CºCH
21 Me
Me
Me
Me
H
H
H
10 Me
11 Me
12 Me
–
–
–
Me 22 NHCO2Et
Me Me 23 OMe
Me
H
Scheme 1
according to Scheme 1, starting from 2-hydroxy-4-nitro-
toluene (1), 2-ethoxycarbonylamino-5-nitrophenol (3),
and 2-methoxy-5-nitrophenol (4), which were condensed
with the appropriate a-halo ketone or propargyl chloride1
to give ethers 5–9. These compounds were then cyclized
under appropriate conditions to 7-methyl- or 7-ethoxycar-
bonylamino- or 7-methoxy-4-nitrobenzofurans 10–14. 2-
Substituted nitrophenols were chosen so that only one
possibility of cyclization of the ethereal moiety in the
ortho position could occur. 2-Amino-5-nitrophenol (2)
Various methylated nitrobenzofurans were reacted under
the same conditions in order to define the role of methyl
substitution on the furan ring. Thus, nitrobenzofurans car-
rying a methyl group either in the 2 or 3 position or two
methyl groups in both the 2 and 3 positions were prepared,

310
Papers
SYNTHESIS
Intermediates 5, 7, 10, 12 were prepared according to literature meth-
ods,1 preparation of the other starting materials is not described in the
literature.
was previously protected as ethyl carbamate to avoid side
reactions on the amino group.
The nitrobenzofuran intermediates were then reduced un-
equivocally to the corresponding aminobenzofurans 15–
19 by catalytic hydrogenation and then submitted to
isomerization in various acidic media. Compounds 16, 17,
18 and 19, i.e. those carrying the methyl group in 2 posi-
tion, were quantitatively converted into the corresponding
5-substituted-4-hydroxyindoles 20, 21, 22 and 23 in all
2-Ethoxycarbonylamino-5-nitrophenol (3):
A suspension of 2 (12.5 g, 81.1 mmol) and ethyl chloroformate
(17.6 g, 15.5 mL, 162.2 mmol) in Et2O (800 mL) was stirred at r.t. un-
til 2 had disappeared (9 d, TLC). The solid was filtered and the solu-
tion concentrated under reduce pressure. The residue was crystallized
from EtOAc to give 3 (10.1 g, 55%); mp 179 °C.
IR (KBr): n = 3235, 2990, 1730, 1590, 1560, 1510, 1340, 1200, 1060,
acidic conditions tested, i.e. concd HCl, glacial AcOH, 740 cm–1.
1H NMR (CDCl3): d = 1.36 (t, J = 7.2 Hz, 3 H, CH2CH3), 4.30 (q, J
CF3CO2H (TFA) or HClO4 in AcOH. On the contrary,
compound 15 remained unchanged. Isomerization was
also performed in concd H2SO4 with the same results, but
degradation of reaction products occurred to various ex-
tents.
= 7.2 Hz, 2 H, CH2CH3), 7.75 (d, J = 8.9 Hz, 1 H, H-3), 7.78 (d, J =
2.3 Hz, 1 H, H-6), 7.84 (dd, J = 8.9 Hz, 2.3 Hz, 1 H, H-4).
Anal. Calcd (C9H10N2O5): C, 47.79; H, 4.46; N, 12.38. Found: C,
47.78; H, 4.55; N, 12.31.
1-Methyl-2-(1-methyl-2-oxoprop-1-yloxy)-4-nitrobenzene (6):
To a solution of 1 (7.5 g, 49.1 mmol) in acetone (150 mL) were added
2-chlorobutan-3-one (7.9 g, 74.3 mmol) and anhyd K2CO3 (15 g). The
mixture was refluxed until 1 had disappeared (10 h, TLC). After cool-
ing, the solid was filtered and washed with acetone. The solvent was
evaporated from the combined filtrate and washings and the residue
was crystallized from cyclohexane to give 6 (10.7 g, 98%); mp 86°C.
IR (KBr): n = 2985, 2925, 1710, 1510, 1345, 1245, 1095, 860, 800,
740 cm–1.
Reduction of nitro groups and concomitant isomerization
using SnCl2 and concd HCl was successful only for com-
pounds 12, 13 and 14. Compound 10 gave only the ami-
nobenzofuran 15, as expected, and compound 11 afforded
the hydroxyindole 20 only in low yield (8%).
These findings reveal that the conversion of the benzofu-
ran system to the indole system does not seem to be a hy-
drolysis of the system analogous to the one described for
the conversion of 4-alkylaminoindoles to 1-alkyl-4-ami-
noindoles,8 which requires the presence of water. Instead,
the isomerization reported by us here occurs only in the
presence of concentrated acids, as shown by the fact that
all the attempts to isomerize the aminobenzofurans in di-
lute acids, such as 6M HCl or 70% HClO4 failed. As
shown in Scheme 2, we suggest that the rearrangement
mechanism involves the opening of the furan ring to pro-
duce a tertiary carbocation intermediate, which undergoes
ring closure to the more stable indole system: in the ab-
sence of the methyl group in the 2 position, secondary car-
bocation cannot be generated, or does not survive long
enough to undergo isomerization.
1H NMR (CDCl3): d = 1.58 (d, J = 6.8 Hz, 3 H, CHCH3), 2.25 (s, 3 H,
COCH3), 2.38 (s, 3 H, Ar-CH3), 4.80 (q, J = 6.8 Hz, 1 H, CH), 7.32
(d, J = 8.2 Hz, 1 H, H-6), 7.49 (d, J = 2.1 Hz, 1 H, H-3), 7.80 (dd, J =
8.2 Hz, 2.1 Hz, 1 H, H-5).
Anal. Calcd (C11H13NO4): C, 59.19; H, 5.87; N, 6.27. Found: C,
59.28; H, 5.85; N, 6.21.
1-Carbethoxyamino-4-nitro-2-(prop-2-yn-1-yloxy)benzene (8):
To a solution of 3 (3.8 g, 16.8 mmol) in acetone (150 mL) were added
propargyl chloride (3.1 g, 3 mL, 41.7 mmol) and anhyd K2CO3 (15 g).
The mixture was refluxed until 3 had disappeared (10 h, TLC). After
cooling, the solid was filtered and washed with acetone. The solvent
was evaporated from the combined filtrate and washings and the res-
idue was crystallized from EtOAc/cyclohexane to give 8 (2.7 g,
60%); mp 135 °C.
IR (KBr): n = 3410, 3255, 2950, 1730, 1545, 1480, 1340, 1230, 1055,
810, 740 cm–1.
1H NMR (CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.63 (t, J =
2.4 Hz, 1 H, CºCH), 4.28 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.88 (d, J =
2.4 Hz, 2 H, CH2), 7.46 (br s, 1 H, NH), 7.88 (d, J = 2.4 Hz, 1 H, H-
3), 7.97 (dd, J = 9.0 Hz, 2.4 Hz, 1 H, H-5), 8.33 (d, J = 9.0 Hz, 1 H,
H-6).
Anal. Calcd (C12H12N2O5): C, 54.55; H, 4.58; N, 10.60. Found: C,
54.38; H, 4.55; N, 10.55.
1-Methoxy-4-nitro-2-(prop-2-yn-1-yloxy)benzene (9):
Compound 4 (5.0 g, 29.6 mmol) was reacted with propargyl chloride
(5.2 g, 5.0 mL, 69.1 mmol) in the presence of anhyd K2CO3 (15 g) as
described for compound 8. The residue was crystallized from EtOAc/
cyclohexane to give 9 (3.7 g, 60%); mp 140°C.
Scheme 2
IR (KBr): n = 3300, 1580, 1520, 1340, 1270, 1140, 1095, 1000, 815,
740 cm–1.
1H NMR (CDC13): d = 2.59 (t, J = 2.4 Hz, 1 H, CºCH), 3.99 (s, 3 H,
OCH3), 4.85 (d, J = 2.4 Hz, 2 H, CH2), 6.95 (d, J = 8.8 Hz, 1 H, H-6),
7.93 (d, J = 2.6 Hz, 1 H, H-3), 7.98 (dd, J = 8.8 Hz, 2.6 Hz, 1 H, H-5).
Anal. Calcd (C10H9NO4): C, 57.97; H, 4,38; N, 6.76. Found: C, 57.88;
H, 4.50; N, 6.65.
Analytical TLC was performed on precoated 60 F254 silica gel plates
(0.2 mm, Merck) with an EtOAc/cyclohexane mixture (3:7). Column
chromatography was performed using silica gel (0.063–0.100 mm,
Merck), eluting with CH2Cl2. Melting points were determined using
an open-capillary melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin Elmer 1600 FT-IR spectrometer.
1H NMR spectra were recorded on a Varian-Gemini 200 MHz spec-
trometer and refer to the deuterium lock signal from the sample
solvent. Microanalyses were performed by the Microanalytical Labo-
ratory of the Department of Pharmaceutical Sciences of University of
Padova. All reagents and solvents were of commercial quality and
were used without further purification.
4-Nitro-2,3,7-trimethylbenzofuran (11):
A solution of 6 (5.0 g, 22.3 mmol) in toluene (500 mL) was refluxed for
40 h, adding portions of MeSO3H (10.7 g, 111.3 mmol) during inter-
vals. After cooling, the solution was washed with H2O and the dried
(Na2SO4) organic phase concentrated under reduced pressure. Column
chromatography of the residue yielded 11 (2.7 g, 60%); mp 79 °C.

March 1998
SYNTHESIS
311
4-Amino-7-ethoxycarbonylamino-2-methylbenzofuran (18): yield
93% (4.3 g); gum.
IR (KBr): n = 2975, 2925, 1585, 1520, 1440, 1350, 1260, 1160, 1030,
800, 735 cm–1.
1H NMR (CDCl3): d = 2.30 (q, J = 0.7 Hz, 3 H, CH3 at 2 or 3), 2.46
(q, J = 0.7 Hz, 3 H, CH3 at 2 or 3), 2.55 (s, 3 H, 7-CH3), 7,05 (d, J =
8.2 Hz, 1 H, H-6), 7.86 (d, J = 8.2 Hz, 1 H, H-5).
Anal. Calcd (C11H11NO3): C, 64.38; H, 5.40; N, 6.83. Found: C,
64.40; H, 5.56; N, 6.92.
IR (neat): n = 3420 and 3355 (NH2), 2970, 1710, 1525, 1410, 1220,
1090, 795 cm–1.
1H NMR (DMSO-d6): d = 1.21 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.39 (d,
J = 0.9 Hz, 3 H, 2-CH3), 4.07 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.34 (br
s, 2 H, NH2), 6.25 (d, J = 8.2 Hz, 1 H, H-5 or H-6), 6.62 (q, J = 1.0
Hz, 1 H, H-3), 6.78 (d, J = 8.2 Hz, 1 H, H-5 or H-6), 8.72 (br s, 1 H,
NH).
7-Ethoxycarbonylamino-2-methyl-4-uitrobenzofuran (13):
A mixture of 8 (2.7 g, 10.2 mmol), CsF (1.0 g, 6.6 mmol) and N,N-
diethylaniline (15 mL) was heated at 210°C for 2 h. After cooling, the
mixture was diluted with EtOAc (100 mL), washed with 1 M HCl
(5 ´ 100 mL) and the dried (Na2SO4) organic phase concentrated un-
der reduced pressure. Column chromatography of the residue yielded
13 (1.9 g, 70%); mp 152°C.
Anal. Calcd (C12H14N2O3): C, 61.53; H, 6.02; N, 11.96. Found: C,
61.41; H, 6.00; N, 11.86.
4-Amino-7-methoxy-2-methylbenzofuran (19): yield 88% (3.1 g);
gum.
IR (neat): n = 3420 and 3355 (NH2), 2930, 1510, 1415, 1265, 1085,
970, 790 cm–1.
IR (KBr): n = 3380, 2970, 1730, 1590, 1530, 1495, 1310, 1230, 1195,
1H NMR (CDCl3): d = 2.47 (d, J = 1.0 Hz, 3 H, 2-CH3), 3.05 (br s,
2 H, NH2), 3.94 (s, 3 H, OCH3), 6.31 (q, J = 1.0 Hz, 1 H, H-3), 6.40
(d, J = 8.3 Hz, 1 H, H-5 or H-6), 6.58 (d, J = 8.3 Hz, 1 H, H-5 or H-6).
Anal. Calcd (C10H11NO2): C, 67.78; H, 6.26; N, 7.90. Found: C,
67.75; H, 6.20; N, 7.82.
1030, 810 cm–1.
1H NMR (CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.55 (d, J
= 0.9 Hz, 3 H, 2-CH3), 4.32 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.16 (q, J
= 0.9 Hz, 1 H, H-3), 7.35 (br s, 1 H, NH), 8.05 (d, J = 9.1 Hz, 1 H, H-
5 or 6), 8.17 (d, J = 9.1 Hz, 1 H, H-5 or 6).
Anal. Calcd (C12H12N2O5): C, 54.55; H, 4.58; N, 10.60. Found: C,
54.40; H, 4.56; N, 10.62.
Reduction of Nitrobenzofurans 10–14 with SnCl2; General Proce-
dure for One-Pot Reaction:
To a solution of nitrobenzofuran (10 mmol) in EtOH (100 mL) was
added a solution of SnCl2·2H2O (18.0 g, 80 mmol) in concd HCl
(50 mL) and the mixture was kept at r.t. with stirring until all the start-
ing material had disappeared (10 h). The mixture was concentrated
under reduced pressure at 50°C and kept under vacuum at this temper-
ature for another 15 min. The residue was diluted with 10% NaHCO3
(100 mL) and extracted with EtOAc (3 ´ 50 ml). The dried (Na2SO4)
organic phase was concentrated under reduced pressure and the resi-
due was purified by column chromatography.
7-Methoxy-2-methyl-4-nitrobenzofuran (14):
A mixture of 9 (2.4 g, 11.6 mmol), CsF (1.1 g, 7.2 mmol) and N,N-
diethylaniline (10 mL) was reacted as described for compound 13.
Column chromatography of the residue yielded 14 (1.7 g, 70%); mp
153°C.
IR (KBr): n = 2975, 1590, 1495, 1320, 1280, 1095, 960, 790, 730 cm–1.
1H NMR (CDCl3): d = 2.56 (d, J = 1.2 Hz, 3 H, 2-CH3), 4.11 (s, 3 H,
OCH3), 6.79 (d, J = 8.8 Hz, 1 H, H-6), 7.15 (q, J = 1.2 Hz, 1 H, H-3),
8.17 (d, J = 8.8 Hz, 1 H, H-5).
From 10: The workup gave only 15 (1.6 g, 98%).
From 11: The workup gave 16 (1.5 g, 88%) and 4-hydroxy-2,3,5-tri-
methylindole (20; 0.14 g, 8%); mp 174°C.
Anal. Calcd (C10H9NO4): C, 57.97; H, 4.38; N, 6.76. Found: C, 57.90;
H, 4.36; N, 6.70.
4-Aminobenzofurans 15–19; General Procedure:
Compound 20:
To a solution of nitrobenzofuran (20.0 mmol) in absolute EtOH
(100 mL) was added a catalytic amount of Pd/C and the mixture was
kept at r.t. under a low pressure of H2. After stirring for 10 h, the cat-
alyst was filtered and the mixture was concentrated under reduced
pressure. The residue was purified by column chromatography.
IR (KBr): n = 3415 (NH), 3320 (OH), 2920, 1570, 1490, 1455, 1325,
1235, 1070, 920, 780 cm–1.
1H NMR (CDCl3): d = 2.30 (q, J = 0.7 Hz, 3 H, 2- or 3-CH3), 2.31 (s,
3 H, 5-CH3), 2.45 (q, J = 0.7 Hz, 3 H, 2- or 3-CH3), 4.88 (br s, 1 H,
NH or OH), 6.75 (d, J = 8.2 Hz, 1 H, H-6 or H-7), 6.83 (d, J = 8.2 Hz,
1 H, H-6 or H-7), 7.53 (br s, 1 H, NH or OH).
Anal. Calcd (C11H13NO): C, 75.40; H, 7.48; N, 7.99. Found: C, 75.43;
H, 7.54; N, 7.90.
4-Amino-3, 7-dimethylbenzofuran (15): yield 95% (3.1 g); gum.
IR (neat): n = 3485, 3390 (NH2), 2930, 1630, 1510, 1440, 1230, 1120,
1080, 805, 780 cm–1.
From 12: The workup gave 4-hydroxy-2,5-dimethylindole (21; 1.3 g,
79%); mp 88 °C.
1H NMR (CDCl3): d = 2.38 (s, 3 H, 7-CH3), 2.43 (d, J = 1.3 Hz, 3 H,
3-CH3), 3.89 (br s, 2 H, NH2), 6.37 (d, J = 7.7 Hz, 1 H, H-5 or H-6),
6.84 (d, J = 7.7 Hz, 1 H, H-5 or H-6), 7.27 (q, J = 1.3 Hz, 1 H, H-2).
Anal. Calcd (C10H11NO): C, 74.51; H, 6.88; N, 8.69: Found: C, 74.63;
H, 6.61; N, 8.71.
Compound 21:
IR (KBr): n = 3385 (NH), 3235 (OH), 2925, 1600, 1510, 1325, 1240,
1080, 900, 785 cm–1.
1H NMR (CDCl3): d = 2.20 (s, 3 H, 5-CH3), 2.41 (d, J = 0.9 Hz, 3 H,
2-CH3), 4.92 (br s, 1 H, NH or OH), 6.19 (q, J = 0.9 Hz, 1 H, H-3),
6.82 (d, J = 8.2 Hz, 1 H, H-6 or H-7), 6.88 (d, J = 8.2 Hz, 1 H, H-6 or
H-7), 7.80 (br s, 1 H, NH or OH).
4-Amino-2,3, 7-trimethylbenzofuran (16): yield 90% (3.2 g); mp 53°C.
IR (KBr): n = 3415, 3315 (NH2), 2925, 1630, 1510, 1450, 1225, 1130,
1080, 810, 750 cm–1.
Anal. Calcd (C10
H11NO): C, 74.51; H, 6.88; N, 8.69. Found: C, 74.45;
1H NMR (CDCl3): d = 2.36 (s, 6 H, 2- and 3-CH3), 2.39 (d, J = 0.7
Hz, 3 H, Ar-CH3), 3.80 (br s, 2 H, NH2), 6.36 (d, J = 7.7 Hz, 1 H, H-
5), 6.79 (dq, J = 7.7 Hz, 0.7 Hz, 1 H, H-6).
H, 6.92; N, 8.61.
From 13: The workup gave 5-ethoxycarbonylamino-4-hydroxy-2-
methylindole (22; 1.9 g, 80%) as a gum.
Anal. Calcd (C11H13NO): C, 75.40; H, 7.48; N, 7.99. Found: C, 75.53 ;
H, 7.51; N, 7.91.
Compound 22:
IR (neat): n = 3410 (NH), 3295 (OH), 2975, 1730, 1560, 1510, 1260,
1090, 780 cm–1.
4-Amino-2, 7-dimethylbenzofuran (17): yield 87% (2.8 g); gum.
IR (neat): n = 3385 and 3275 (NH2), 2915, 1635, 1510, 1460, 1225,
1185, 1040, 800 cm–1.
1H NMR (CDCl3): d = 1.32 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.39 (d, J
= 1.0 Hz, 3 H, 2-CH3), 4.25 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.35 (q, J
= 1.0 Hz, 1 H, H-3), 6.73 (d, J = 8.4 Hz, 1 H, H-6 or H-7), 6.77 (d, J
= 8.4 Hz, 1 H, H-6 or H-7), 7.95 (br s, 1 H, NH or -OH).
Anal. Calcd (C12H14N2O3): C, 61.53; H, 6.02; N, 11.96. Found: C,
61.45; H, 6.10; N, 12.00.
1H NMR (CDCl3): d = 2.38 (d, J = 0.7 Hz, 3 H, 7-CH3), 2.45 (d, J =
1,1 Hz, 3 H, 2-CH3), 3.70 (br s, 2 H, NH2), 6.29 (q, J = 1.1 Hz, 1 H,
H-3), 6.41 (d, J = 7.8 Hz, 1 H, H-5), 6.80 (dq, J = 7.8 Hz, 0.7 Hz, 1 H,
H-6).
From 14: The workup gave 4-hydroxy-5-methoxy-2-methylindole
(23; 1.4 g, 80%) as a gum.
Anal. Calcd (C10H11NO): C, 74.51; H, 6.88; N, 8.69. Found: C, 74.41;
H, 6.90; N, 8.66.

312
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SYNTHESIS
Compound 23:
(1) Rao, V. S.; Rodighiero, P.; Chilin, A.; Castellin, A.; Manzini, P.;
Guiotto, A. Liebigs Ann. 1997, 419.
(2) Rodighiero, P.; Guiotto, A.; Chilin, A.; Bordin, F.; Baccichetti,
F.; Carlassare, F.; Vedaldi, D.; Caffieri, S.; Pozzan, A.;
Dall’Acqua, F. J. Med. Chem. 1996, 39, 1293.
(3) Mustafa, A. In The Chemistry of Heterocyclic Compounds;
Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1974;
Vol. 29, p 1.
IR (neat): n = 3470 (NH), 3390 (OH), 2930, 1510, 1450, 1235, 1090,
915, 770 cm–1.
1H NMR (CDCl3): d = 2.39 (br s, 3 H, 2-CH3), 3.89 (s, 3 H, OCH3),
6.30 (br s, 1 H, H-3), 6.76 (d, J = 8.6 Hz, 1 H, H-6 or H-7), 6.81 (d, J
= 8.6 Hz, 1 H, H-6 or H-7), 7.76 (br s, 1 H, NH or OH).
Anal. Calcd (C10H11NO2): C, 67.78; H, 6.26; N, 7.90. Found: C,
67.64; H, 6.22; N, 7.86.
(4) Cagniant, P.; Cagniant, D. In Advances in Heterocyclic Chemis-
try; Katritzky, A. R.; Boulton, A. J., Eds.; Academic: New York,
1975; Vol. 18, p 337.
(5) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Hetero-
cyclic Chemistry; Bird, C. W.; Cheeseman, G. W. H., Eds.; Per-
gamon: Oxford, 1984; Vol. 4, p 657.
(6) Sundberg, R. J. Indoles; Academic: New York, 1996.
(7) Spande, T. F.; Remers, W. A. In The Chemistry of Heterocyclic
Compounds; Weissberger, A.; Taylor, E. C., Eds.; Wiley: New
York, 1979; Vol. 25, Part I, p 1.
(8) Saxton, J. E. In The Chemistry of Heterocyclic Compounds;
Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1983;
Vol. 25, Part IV, p 1.
Methyl Substituted 4-Hydroxyindoles 20–23; General Procedure
for Stepwise Reaction:
A solution of 4-aminobenzofuran (2.0 mmol) in concd HCl (20 mL)
or glacial AcOH (10 mL) or TFA (2 mL) or HClO4 in AcOH (5 mL)
was refluxed under N2 for 4h. The mixture was neutralized with aq
10% NaHCO3 solution and extracted with EtOAc (3 ´ 50 mL). The
dried (Na2SO4) organic phase was concentrated under reduced pres-
sure and the residue was purified by column chromatography.
4-Hydroxy-2,3,7-trimethylindole (20): yield 80% (0.27 g); mp, IR and
1H NMR as above reported.
4-Hydroxy-2,5-dimethylindole (21): yield 80% (0.26 g); mp, IR and
1H NMR as above reported.
(9) Brown. T.; Joule, J. A.; Sammers, P. G. In Comprehensive Or-
ganic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon
Press: Oxford, 1979; Vol. 4, p 411.
5-Ethoxycarbonylamino-4-hydroxy-2-methylindole (22): yield 80%
(0.37 g); IR and 1H NMR as above reported.
4-Hydroxy-5-methoxy-2-methylindale (23): yield 80% (0.28 g); IR
(10) Ley, S. V.; Porter, R. A. J. Chem. Soc., Chem. Commun. 1982,
1356.
and 1H NMR as above reported.