Synthesis of 4,7-indoloquinones from indole-7-carbaldehydes by Dakin oxidation

Article abstract of DOI:10.1016/j.tet.2008.05.107

Dakin oxidation of 4,6-dimethoxyindole-7-carbaldehydes, using hydrogen peroxide and hydrochloric acid, results in the synthesis of 6-methoxy-4,7-indoloquinones. The starting materials are readily available through the activation of the indole C7 position

Full text of DOI:10.1016/j.tet.2008.05.107

Tetrahedron 64 (2008) 7136–7142
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Synthesis of 4,7-indoloquinones from indole-7-carbaldehydes
by Dakin oxidation
*
Mahiuddin Alamgir, Peter S.R. Mitchell, Paul K. Bowyer, Naresh Kumar, David StC. Black
School of Chemistry, The University of New South Wales, UNSW, Sydney NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Dakin oxidation of 4,6-dimethoxyindole-7-carbaldehydes, using hydrogen peroxide and hydrochloric
acid, results in the synthesis of 6-methoxy-4,7-indoloquinones. The starting materials are readily
available through the activation of the indole C7 position by the presence of the methoxy groups.
Structural variation is possible through functionalities at C2 and C3. A 2,20-di-indolylmethane-7,70-di-
carbaldehyde can also be oxidized to a bisindoloquinone under these conditions. The related oxidation of
indole-7-carbaldehydes with m-chloroperbenzoic acid or preferably magnesium monoperphthalate in-
stead leads to oxidation at C2 to give indol-2-ones.
Received 14 March 2008
Received in revised form 8 May 2008
Accepted 22 May 2008
Available online 27 May 2008
Keywords:
Indole
Indoloquinones
4,7-Dione
Ó 2008 Elsevier Ltd. All rights reserved.
Dakin oxidation
1. Introduction
2. Results and discussion
Indoloquinones are an interesting and important class of bio-
reductive alkylating agents because of their vital role in some
biosynthetic routes.1 Moreover, these compounds are found as
structural units of natural products (e.g., murrayaquinone B),2 and
compounds having antifungal and cytotoxic activities (e.g., iso-
batzellin C),3 and antitumor activity (e.g., discorhabdin C, mito-
mycin C)4–6 (Fig. 1). As a consequence, the indoloquinones have
been subjected to intense analogue development, and a range of
4,7-indoloquinones have been synthesized as potential antitumor
agents.7–11 However, the procedures reported for the synthesis of
4,7-indoloquinones bear some limitations: they require several
steps9 or a nitration step,7 which sometimes lack selectivity. Thus,
an alternate general method for the preparation of 4,7-indoloqui-
nones is a desirable goal.
Dakin oxidation allows the preparation of phenols from aryl
aldehydes via oxidation with hydrogen peroxide. In initial experi-
ments, the oxidation of 4,6-dimethoxy-2,3-diphenylindole 1 using
sulfuric acid and hydrogen peroxide in a methanol and tetrahy-
drofuran mixture gave a number of products together with baseline
material. The main product from this reaction was identified as the
6-methoxy-4,7-indoloquinone 12. This synthesis was greatly im-
proved when the sulfuric acid was replaced by hydrochloric acid.
The indoloquinone 12 was obtained as a deep burgundy powder in
N
O
Cl
OMe
Me
N
Me
H2N
The readily available 4,6-dimethoxy activated indoles12–16 show
reactivity at C7. In particular, 3-substituted-4,6-dimethoxyindoles
can be selectively formylated at C7 in high yield using the Vilsmeier
reaction.17–19 The synthesis of a series of 6-methoxy-4,7-indolo-
quinones from 4,6-dimethoxyindole-7-carbaldehydes by Dakin
oxidation is reported herein.
N
H
O
Me
Me
O
Isobatzellin C
Murrayaquinone B
O
O
Br
Br
N
O
O
O
NH2
H2N
H3C
OMe
NH
N
N
H
N
H
O
Discorhabdin C
Mitomycin C
* Corresponding author. Tel.: þ61 2 9385 4657; fax: þ61 2 9385 6141.
E-mail address: d.black@unsw.edu.au (D.StC. Black).
Figure 1. Structures of some naturally occurring and bioactive indoloquinones.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.107

M. Alamgir et al. / Tetrahedron 64 (2008) 7136–7142
7137
55% yield after recrystallization from ethanol (Scheme 1). This
improved method was also applied to the other 3-aryl-4,6-dime-
thoxyindole-7-carbaldehydes 2–8 to give the 3-aryl-6-methoxy-
4,7-indoloquinones 13–19, respectively, in moderate to good yields
after recrystallization from ethanol. The reaction was also found to
be applicable to the 2,3-dimethyl- and 3-methyl-4,6-dimethoxy-
indole-7-carbaldehyde 9 and 10, and the desired compounds 20
and 21 were obtained, respectively, in 52 and 47% yields. Similarly,
the tetrahydrocarbazole-1-carbaldehyde 11, with hydrogen
peroxide in the presence of hydrochloric acid, in methanol and
tetrahydrofuran solution produced the 1,4-dione 22 in 50% yield
(Scheme 1).
bearing the methoxy group. The infrared bands at w1660 cmꢀ1and
w1633 cmꢀ1 represent the carbonyl group frequencies of the qui-
none functionality.
The mechanism for the formation of the indoloquinone could
involve a peroxy hemi-acetal intermediate,20 e.g., 25 produced in
the acidic environment containing methanol (Scheme 3). The in-
termediate 25 is then thought to be oxidized to the indolophenol 26
and further oxidation by the excess hydrogen peroxide leads to the
4,7-indoloquinone 14.
OMe
OMe
Ph
Ph
H2O2/HCl
MeOH/THF
N
N
MeO
MeO
aryl migration
R1
R1
MeO
O
H
H
+
H
H
OCH3
H
O
H2O2 / HCl
MeOH / THF
31-65%
OOH
R2
R2
OMe
Ph
3
25
N
N
MeO
MeO
H
H
O
H
O
N
MeO
Ph
H
OCH3
O
O
R1
12 Ph
13 Ph
14 Ph
R2
Ph
Me
H
R1
Ph
Ph
Ph
R2
Ph
Me
H
Yield %
55
1
2
3
4
5
6
7
8
9
59
O
OMe
Ph
60
hydrolysis
oxidation
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-tert-butylC6H4
4-PhC6H4
Me
H
15 4-ClC6H4
16 4-BrC6H4
17 4-MeOC6H4
18 4-tert-butylC6H4
19 4-PhC6H4
20 Me
H
52
H
H
53
N
H
N
MeO
MeO
H
H
59
H
O
H
H
50
OH
H
H
65
26
14
Me
H
Me
H
31
Scheme 3.
10 Me
11
21 Me
22
47
-(CH2)4-
-(CH2)4-
50
The related oxidation reaction of the indole-7-aldehyde 3 with
m-chloroperbenzoic acid (MCPBA) or preferably magnesium
monoperphthalate (MMPPA) did not yield the indoloquinone 14,
but gave the 7-formylindolone 27 in 72% yield (Scheme 4). Simi-
larly, 7-acetyl-4,6-dimethoxy-3-phenylindole 28 was converted
into 7-acetylindolone 29 in 66% yield. The more reactive 4,6-
dimethoxy-3-phenyl-7-trifluoroacetylindole 30 gave a complex
mixture of products reflecting the reactions occurring at C2.
Scheme 1.
The 2,20-di-indolylmethane-7,70-dicarbaldehyde 23 could also
be oxidized to give the bisindoloquinone 24. However, in this case
a longer time is required for the completion of the reaction (Scheme
2). Further oxidation of the indoloquinones was not observed in the
presence of excess hydrogen peroxide and the products were iso-
lated as stable solids.
OMe
OMe
Ph
Ph
OMe
OMe
R
R
MCPBA or
MMPPA
O
66-72%
N
N
MeO
MeO
N
N
OMe
H
H
MeO
H
H
R
O
R
O
O
H
O
H
23
R
H
R
H
3
28
30
27
29
Me
Me
H2O2 / HCl
MeOH / THF
R = 4-BrC6H4
57%
CF3
Scheme 4.
O
O
R
R
With the removal of a vulnerable C2, the related 2,3-diphenyl-7-
trifluoroacetylindole 31 underwent a Baeyer–Villiger oxidation to
give the 7-trifluoroacetoxy compound 32 in 65% yield (Scheme 5).
N
N
H
OMe
MeO
H
OMe
OMe
Ph
Ph
O
O
24
Scheme 2.
Ph
Ph
MCPBA
65%
N
N
MeO
F3C
MeO
H
H
O
The indoloquinones were mostly bright orange to red or deep
burgundy and showed high melting points. The structures were
identified particularly by the disappearance of the sharp methoxy
and aldehyde peaks in the 1H NMR spectra and the upfield shift of
the H5 protons to w5.7 ppm. In the 13C NMR spectra of the prod-
ucts it was significant to observe the presence of a single methoxy
carbon at w56 ppm. The carbonyl resonance at w183 ppm corre-
sponded to the C4 carbonyl and that of w171 ppm represented the
C7 carbonyl. The signal at w159 ppm represents the C6 carbon
COCF3
O
32
31
Scheme 5.
In general, the 3-substituted-4,6-dimethoxyindoles were found
to be too reactive and the presence of an electron-withdrawing
group seems essential to allow useful transformations to occur. In

7138
M. Alamgir et al. / Tetrahedron 64 (2008) 7136–7142
addition to the presence of such a group at C7, the N-acetyl- and N-
sulfonyl-indole 33 and 34, respectively, were converted to the
corresponding indolones 35 and 36, respectively (Scheme 6).
128.59, 128.97, and 130.73 (aryl CH), 122.87, 126.35, 128.05, 129.81,
130.50, 133.36, and 159.70 (aryl C), 171.25 and 183.28 (C]O). Mass
spectrum (þEI): m/z (%) 330 (Mþ1, 20), 329 (M, 100), 301 (10), 300
(28), 299 (11), 272 (10), 244 (11), 216 (12).
OMe
OMe
Ph
Ph
4.2.2. 6-Methoxy-2-methyl-3-phenylindole-4,7-dione (13)
MCPBA or
MMPPA
56-69%
According to the general procedure, treatment of 2-methyl-3-
phenylindole-7-carbaldehyde 215 (0.20 g, 0.67 mmol) in tetrahy-
drofuran/methanol (20 mL) with concentrated hydrochloric acid
(two drops) and 30% hydrogen peroxide solution (5 mL) afforded
the indoloquinone 13 as a red powder (0.10 g, 59%), mp 314 ꢁC
(dec). (Found: C, 71.13; H, 4.95; N, 5.33. C16H13NO3$0.1H2O requires:
C, 71.42; H, 4.94; N, 5.21%.) HRMS (þESI): C16H13NO3 [MþNa]þ re-
quires 290.0787, found 290.0785. nmax (KBr): 3410, 3190, 1665,
O
N
N
MeO
MeO
R
R
R
R
COMe
SO2Ph
33
34
COMe
SO2Ph
35
36
Scheme 6.
1635, 1598, 1492, 1454, 1338, 1253, 1117, 1033, 846, 703 cmꢀ1
(MeOH): 204 nm (
25,800 cmꢀ1 Mꢀ1), 225 (26,400), 285 (12,900),
364 (3900), 471 (2600). 1H NMR (300 MHz, DMSO-d6):
2.18 (3H, s,
Me), 3.73 (3H, s, OMe), 5.66 (1H, s, aryl H5), 7.34–7.35 (5H, m, aryl
H), 12.71 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6):
11.90 (Me),
. lmax
3
3. Conclusions
d
In summary, the synthesis of indoloquinones by Dakin oxidation
of indole-7-carbaldehydes was found to be general and can be
applied to a variety of functionalized indoles yielding products,
which are inaccessible by other methods.
d
56.74 (OMe), 108.00, 127.20, 128.02, and 130.22 (aryl CH), 122.52,
122.69, 128.52, 133.13, 136.66, and 159.46 (aryl C), 170.70 and
183.48 (C]O). Mass spectrum (þEI): m/z (%) 268 (Mþ1, 100), 267
(M, 18), 225 (37).
4. Experimental
4.1. General
4.2.3. 3-Phenyl-6-methoxyindole-4,7-dione (14)
According to the general procedure, treatment of 3-phenyl-
indole-7-carbaldehyde 319 (0.21 g, 0.74 mmol) in tetrahydrofuran/
methanol (30 mL) with concentrated hydrochloric acid (two drops)
and 30% hydrogen peroxide solution (4 mL) afforded the indolo-
quinone 14 as an orange powder (0.11 g, 60%), mp 320 ꢁC (dec).
(Found: C, 70.10; H, 4.34; N, 5.45. C15H11NO3$0.2H2O requires: C,
70.14; H, 4.47; N, 5.45%.) HRMS (þESI): C15H11NO3 [M] requires
253.0739, found 253.0726. nmax (KBr): 3110, 1660, 1620, 1600, 1540,
1400, 1330, 1300, 1250, 1140, 1080, 1010, 950, 840, 790, 760,
Melting points were measured using a Mel-Temp melting point
apparatus and are uncorrected. Microanalyses were performed on
Carlo Erba Elemental Analyser EA 1108 at the Campbell Microana-
lytical Laboratory, University of Otago, New Zealand. 1H and 13C
NMR spectra were obtained on a Bruker DPX300 (300 MHz) spec-
trometer. Mass spectra were recorded on either a Bruker Daltonics
Bio Apex II FTICR MS (HRMS-ESI) at School of Chemistry, University
of New South Wales, or a Shimadzu LCMS QP 8000 (EI) at the
University of Otago, New Zealand. Infrared spectra were recorded
with a Thermo Nicolet 370 FTIR spectrometer using KBr discs.
Ultraviolet–visible spectra were recorded using a Varian Cary
100 Scan Spectrometer.
690 cmꢀ1
371 (1400). 1H NMR (300 MHz, DMSO-d6):
(1H, s, aryl H5), 7.51 (1H, s, aryl H2), 7.25–7.39 (5H, m, aryl H), 10.64
(1H, br s, NH). 13C NMR (75 MHz, DMSO-d6):
57.13 (OMe), 109.16,
.
lmax (MeOH): 225 nm (
3
9200 cmꢀ1 Mꢀ1), 284 (6000),
d
3.77 (3H, s, OMe), 5.82
d
126.44, 128.99, 128.70, and 129.02 (aryl CH), 121.42, 127.27, 131.40,
133.28, and 159.57 (aryl C), 171.99 and 183.91 (C]O). Mass spec-
trum (þEI): m/z (%) 254 (Mþ1, 20), 253 (M, 100), 224 (30), 195 (80).
4.2. General procedure for the synthesis of 6-methoxy-
4,7-diones
4.2.4. 3-(40-Chlorophenyl)-6-methoxyindole-4,7-dione (15)
The indole-7-carbaldehyde was dissolved by warming in tetra-
hydrofuran/methanol (1:1). Concentrated hydrochloric acid (few
drops) was added to the solution and after 5 min stirring, excess
30% hydrogen peroxide solution was added slowly. The mixture
was stirred for another 2 h at room temperature before ice water
was added to quench the reaction. The resulting precipitate was
collected, washed with water, and recrystallized from ethanol to
afford the brightly colored indoloquinones.
According to the general procedure, treatment of 3-(40-chloro-
phenyl)indole-7-carbaldehyde 421 (0.30 g, 0.95 mmol) in tetra-
hydrofuran/methanol (30 mL) with concentrated hydrochloric acid
(two drops) and 30% hydrogen peroxide solution (6 mL) afforded
the indoloquinone 15 as a brick red powder (0.14 g, 52%), mp 320 ꢁC
(dec). (Found: C, 61.64; H, 3.65; N, 4.64. C15H10ClNO3$0.3H2O re-
quires: C, 61.47; H, 3.65; N, 4.78%.) HRMS (þESI): C15H10ClNO3
[MþNa]þ requires 310.0241, found 310.0237. nmax (KBr): 3392, 3134,
1663, 1624, 1602, 1547, 1401, 1331, 1254, 1090, 1025, 848, 801 cmꢀ1
.
4.2.1. 6-Methoxy-2,3-diphenylindole-4,7-dione (12)
lmax (MeOH): 203 nm (
(10,800), 283 (11,100), 365 (2700), 457 (2000). 1H NMR (300 MHz,
DMSO-d6): 3.75 (3H, s, OMe), 5.80 (1H, s, aryl H5), 7.54 (1H, s, aryl
H2), 7.39 (2H, d, J 8.6 Hz, aryl H), 7.76 (2H, d, J 8.6 Hz, aryl H), 13.01
(1H, br s, NH). 13C NMR (75 MHz, DMSO-d6):
56.85 (OMe), 108.89,
3
21,600 cmꢀ1 Mꢀ1), 228 (65,400), 252
According to the general procedure, treatment of 2,3-diphenyl-
indole-7-carbaldehyde 113 (0.75 g, 2.03 mmol) in tetrahydrofuran/
methanol (60 mL) with concentrated hydrochloric acid (two drops)
and 30% hydrogen peroxide solution (10 mL) afforded the indolo-
quinone 12 as a red powder (0.37 g, 55%), mp 329 ꢁC (dec). (Found:
C, 75.52; H, 4.77; N, 4.15. C21H15NO3$0.2H2O requires: C, 75.75; H,
4.66; N, 4.21%.) HRMS (þESI): C21H15NO3 [M] requires 329.1052,
found 329.1060. nmax (KBr): 3200, 1660, 1640, 1600, 1290, 1230,
d
d
127.98, 128.26, and 130.43 (aryl CH), 121.08, 124.63, 131.30, 132.00,
132.11, and 159.25 (aryl C), 171.66 and 183.52 (C]O). Mass spec-
trum (þEI): m/z (%) 289 (M, 37Cl, 4), 288 (Mꢀ1, 37Cl, 30), 287 (M,
35Cl, 32), 286 (Mꢀ1, 35Cl, 71), 245 (37Cl, 30), 243 (35Cl, 100).
1180, 1150, 1120, 1080, 1070, 1020, 920, 850, 770, 730, 690 cmꢀ1
lmax (MeOH): 238 nm (
6900 cmꢀ1 Mꢀ1), 280 (7800), 356 (1300).
1H NMR (300 MHz, DMSO-d6):
3.76 (3H, s, OMe), 5.74 (1H, s, aryl
H5), 7.17–7.25 (10H, m, aryl H), 13.07 (1H, br s, NH). 13C NMR
(75 MHz, DMSO-d6): 56.84 (OCH3), 108.29, 127.47, 127.67, 128.16,
.
3
4.2.5. 3-(40-Bromophenyl)-6-methoxyindole-4,7-dione (16)
d
According to the general procedure, treatment of 3-(40-bromo-
phenyl)indole-7-carbaldehyde 522 (0.50 g, 1.38 mmol) in tetrahy-
drofuran/methanol (50 mL) with concentrated hydrochloric acid
d

M. Alamgir et al. / Tetrahedron 64 (2008) 7136–7142
7139
(two drops) and 30% hydrogen peroxide solution (5 mL) afforded
the indoloquinone 16 as an orange powder (0.25 g, 53%), mp 326 ꢁC
(dec). (Found: C, 54.16; H, 3.21; N, 3.96. C15H10BrNO3 requires: C,
54.24; H, 3.03; N, 4.22%.) nmax (KBr): 3341, 3124, 1665, 1628, 1605,
1540, 1481, 1454, 1374, 1335, 1310, 1258, 1087, 1023, 1010, 852,
120 ꢁC. HRMS (þESI): C19H19NO3 [MþNa]þ requires 332.1257,
found 332.1262. nmax (KBr): 3257, 2960, 2868, 1662, 1604, 1462,
1393, 1363, 1269, 1079, 841 cmꢀ1
.
lmax (MeOH): 204 nm
25,900 cmꢀ1 Mꢀ1), 227 (20,500), 284 (7100), 359 (3400). 1H NMR
(300 MHz, DMSO-d6): 1.28 (9H, s, Me), 3.75 (3H, s, OMe), 5.79 (1H,
s, aryl H5), 7.56 (1H, s, aryl H2), 7.34–7.65 (4H, m, aryl H), 12.89 (1H,
br s, NH). 13C NMR (75 MHz, DMSO-d6):
31.46 (Me), 34.62 (ali-
(3
d
798 cmꢀ1
(29,300), 252 (19,800), 282 (17,600), 356 (5100), 458 (3100). 1H
NMR (300 MHz, DMSO-d6): 3.75 (3H, s, OMe), 5.80 (1H, s, aryl H5),
7.51 (1H, s, aryl H2), 7.54–7.71 (4H, m, aryl H), 13.01 (1H, br s, NH).
13C NMR (75 MHz, DMSO-d6):
56.85 (OMe), 108.92, 127.17, 130.76,
. lmax (MeOH): 204 nm (3
36,700 cmꢀ1 Mꢀ1), 226
d
d
phatic C), 56.79 (OMe), 108.90, 125.07, 128.45, and 128.53 (aryl CH),
126.10, 126.87, 130.19, 131.08, 150.07, and 159.27 (aryl C), 171.26 and
183.51 (C]O). Mass spectrum (þEI): m/z (%) 310 (Mþ1, 40), 308
(Mꢀ1, 34), 292 (66), 270 (66), 268 (54), 254 (100).
d
and 131.19 (aryl CH), 121.07, 124.65, 131.35, 131.39, 132.41, and
159.26 (aryl C), 171.66 and 183.50 (C]O). Mass spectrum (þEI): m/z
(%) 334 (Mþ2, 81Br, 65), 333 (Mþ1, 81Br, 20), 332 (Mþ2, 79Br, 100),
331 (Mþ1, 79Br, 68).
4.2.8. 3-(40-Biphenyl)-4,6-dimethoxyindole, 3-(40-biphenyl)-
4,6-dimethoxyindole-7-carbaldehyde (8) and 3-(40-biphenyl)-
6-methoxyindole-4,7-dione (19)
4.2.6. 3-(40-Methoxyphenyl)-6-methoxyindole-4,7-dione (17)
3-(40-Biphenyl)-4,6-dimethoxyindole was prepared by the
general method23 from 3,5-dimethoxyaniline (1.53 g, 100 mmol)
and 4-phenylphenacyl bromide (2.75 g, 100 mmol), via the in-
termediate anilino ketone, as a yellow solid (0.95 g, 29%), mp
181–183 ꢁC. (Found: C, 79.64; H, 5.80; N, 4.19. C22H19NO2$0.1H2O
requires: C, 79.78; H, 5.84; N, 4.23%.) nmax (KBr): 3420, 1629, 1580,
According to the general procedure, treatment of 3-(40-
methoxyphenyl)indole-7-carbaldehyde 622 (20 mg, 0.06 mmol) in
tetrahydrofuran/methanol (5 mL) with concentrated hydrochloric
acid (one drop) and 30% hydrogen peroxide solution (1 mL) affor-
ded the indoloquinone 17 as a red powder (10 mg, 59%), mp 320 ꢁC
(dec). (Found: C, 64.58; H, 4.80; N, 4.72. C16H13NO4$0.8H2O re-
quires: C, 64.55; H, 4.94; N, 4.71%.) HRMS (þESI): C16H13NO4
[MþNa]þ requires 306.0736, found 306.0725. nmax (KBr): 3419,
3124, 1665, 1634, 1602, 1547, 1489, 1403, 1336, 1254, 1090, 1021,
1558, 1468, 1335, 1216, 1190, 1167, 1135, 1098, 765 cmꢀ1
(MeOH): 209 nm (
21,500 cmꢀ1 Mꢀ1), 252 (12,100), 285 (8900). 1H
NMR (300 MHz, CDCl3): 3.83 and 3.86 (6H, 2s, OMe), 6.28 (1H, d,
. lmax
3
d
J 2.3 Hz, H5), 6.52 (1H, d, J 2.6 Hz, H7), 7.07 (1H, d, J 2.6 Hz, H2),
798 cmꢀ1
261 (15,500), 283 (18,600), 384 (3100), 479 (4500). 1H NMR
(300 MHz, DMSO-d6): 3.75 (3H, s, OMe), 5.78 (1H, s, aryl H5), 7.44
(1H, s, aryl H2), 6.90 (2H, d, J 8.6 Hz, aryl H), 7.69 (2H, d, J 8.6 Hz, aryl
H), 12.91 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6):
55.47, 56.79
.
lmax (MeOH): 205 nm (
3
36,400 cmꢀ1 Mꢀ1), 228 (30,100),
7.25–7.71 (9H, m, ArH), 8.12 (1H, br s, NH). 13C NMR (75 MHz,
CDCl3):
d 55.06 and 55.54 (OMe), 86.80, 92.24, 120.45, 126.28,
d
126.83, 126.91, 128.62, and 129.71 (ArCH), 110.26, 118.49, 135.07,
138.31, 138.36, 141.24, 154.86, and 157.61 (ArC). Mass spectrum
(þESI): m/z (%) 330 (Mþ1, 62), 329 (M, 75), 328 (100).
d
(OMe), 108.97, 113.74, 126.57, and 129.95 (aryl CH), 120.88, 125.47,
126.07, 131.02, 158.98, and 159.26 (aryl C), 171.49 and 183.51 (C]O).
Mass spectrum (þEI): m/z (%) 285 (Mþ2, 28), 284 (Mþ1, 100), 256
(12).
Phosphoryl chloride (0.2 mL, 2.17 mmol) was added dropwise to
ice cooled anhydrous N,N-dimethylformamide (2 mL), and the
mixture was added dropwise to a previously ice cooled stirred
solution
of
3-(40-biphenyl)-4,6-dimethoxyindole
(0.65 g,
1.97 mmol) in anhydrous N,N-dimethylformamide (10 mL) at 0 ꢁC.
The resulting reaction mixture was allowed to come to room
temperature and stirred for 2 h. The reaction was quenched with
ice water, basified with 20% sodium hydroxide solution, and stirred
vigorously for 2 h. The resulting precipitate was filtered, thoroughly
washed with water, and recrystallized (dichloromethane/light pe-
troleum) to afford the 7-formylindole 8 as yellow solid (0.65 g,
93%), mp 200–202 ꢁC. (Found: C, 77.26; H, 5.43; N, 3.93. C23H19NO3
requires: C, 77.29; H, 5.36; N, 3.92%.) nmax (KBr): 3403, 1640, 1593,
1557, 1466, 1389, 1357, 1346, 1322, 1268, 1252, 1211, 1176, 1085,
4.2.7. 3-(40-tert-Butylphenyl)-4,6-dimethoxyindole-7-carbaldehyde
(7) and 3-(40-tert-butylphenyl)-6-methoxyindole-4,7-dione (18)
A cooled solution of phosphoryl chloride (0.95 mL, 10.15 mmol)
in dry dimethylformamide (5.0 mL) was added dropwise to
a cooled solution of 3-(40-tert-butylphenyl)-4,6-dimethoxyindole23
(3.0 g, 9.70 mmol) in dry dimethylformamide (20 mL). The mixture
was stirred at 0 ꢁC for 15 min and then warmed at 80 ꢁC for another
30 min. Cold water (50 mL) was added, followed by excess 2 N
sodium hydroxide solution until the mixture was strongly basic.
The suspension was stirred at room temperature overnight, the
resulting precipitate was filtered, washed with water, and dried.
The resulting solid was flash chromatographed (eluent 70:30
dichloromethane/hexane) and yielded the formylindole 7 as yellow
crystals (2.63 g, 80%), mp 224 ꢁC. (Found: C, 74.6; H, 7.2; N, 4.3.
766 cmꢀ1
.
lmax (MeOH): 206 nm (
3
23,700 cmꢀ1 Mꢀ1), 250 (13,000),
3.96 and 4.01 (6H, 2s,
284 (10,000). 1H NMR (300 MHz, CDCl3):
d
OMe), 6.22 (1H, s, H5), 7.15 (1H, d, J 2.3 Hz, H2), 7.42–7.67 (9H, m,
ArH), 10.40 (1H, s, CHO), 10.56 (1H, br s, NH). 13C NMR (75 MHz,
CDCl3):
d 55.35 and 56.31 (OMe), 86.75, 121.81, 126.38, 126.91,
C
21H25NO3 requires: C, 74.3; H, 7.4; N, 4.1%.) lmax (MeOH): 228 nm
126.94, 128.65, and 129.66 (ArCH), 104.43, 118.38, 128.60, 134.40,
137.75, 138.70, 141.07, 161.33, and 163.01 (ArC), 188.27 (CO). Mass
spectrum (þESI): m/z (%) 359 (Mþ1, 72), 358 (100).
(3
21,400 cmꢀ1 Mꢀ1), 253 (27,000), 265 (20,400), 325 (11,500), 357
(10,000). nmax: 3380, 1645, 1610, 1595, 1580, 1260, 1220, 1180, 1125,
1095 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
1.38 (9H, s, CMe3), 3.95 and
According to the general procedure, treatment of 3-(40-phenyl-
phenyl)indole-7-carbaldehyde 8 (0.30 g, 0.84 mmol) in tetrahy-
drofuran/methanol (30 mL) with concentrated hydrochloric acid
(two drops) and 30% hydrogen peroxide solution (5 mL) afforded
the indoloquinone 19 as a brown powder (0.18 g, 65%), mp 304 ꢁC.
(Found: C, 74.34; H, 4.98; N, 3.90. C21H15NO3$0.6CH3OH requires: C,
74.43; H, 5.03; N, 4.02%.) HRMS (þESI): C21H15NO3 [MþNa]þ re-
quires 352.0944, found 352.0942. nmax (KBr): 3413, 3130, 1664,
3.99 (6H, 2s, OMe), 6.19 (1H, s, H5), 7.10 (1H, d, J 2.3 Hz, H2), 7.40
and 7.53 (4H, d, J 8.5 Hz, ArH), 10.40 (1H, s, CHO), 10.52 (1H, br s,
NH). 13C NMR (75 MHz, CDCl3):
d 31.46 (CMe3), 34.49 (CMe3), 55.42
and 56.38 (OMe), 86.70 (C5), 121.72 (C2), 123.72 and 129.00 (ArCH),
104.48, 110.24, 118.71, 132.41, 137.77, 148.83, 161.48, and 163.03
(ArC), 188.33 (CHO). Mass spectrum (þEI): m/z 339 (M, 5%), 338
(20), 337 (90), 322 (100), 161 (20), 97 (25), 83 (30), 69 (35), 57 (55),
55 (40).
According to the general procedure, treatment of 3-(40-tert-
butylphenyl)indole-7-carbaldehyde 7 (0.20 g, 0.59 mmol) in tetra-
hydrofuran/methanol (20 mL) with concentrated hydrochloric
acid (two drops) and 30% hydrogen peroxide solution (5 mL)
afforded the indoloquinone 18 as a red powder (0.09 g, 50%), mp
1631, 1605, 1482, 1337, 1311, 1255, 1091, 766 cmꢀ1
204 nm (
25,300 cmꢀ1 Mꢀ1), 262 (12,900). 1H NMR (300 MHz,
DMSO-d6): 3.77 (3H, s, OMe), 5.83 (1H, s, aryl H5), 7.58 (1H, s, aryl
H2), 7.32–7.86 (9H, m, aryl H), 13.02 (1H, br s, NH). 13C NMR
(75 MHz, DMSO-d6): 56.84 (OMe), 109.01, 126.54, 126.87, 127.17,
127.78, 129.24, and 129.32 (aryl CH), 125.62, 131.34, 132.33, 139.24,
. lmax (MeOH):
3
d
d

7140
M. Alamgir et al. / Tetrahedron 64 (2008) 7136–7142
140.19, and 159.27 (aryl C), 172.80 and 183.53 (C]O). Mass spec-
trum (þEI): m/z (%) 331 (Mþ2, 22), 330 (Mþ1, 100).
2940, 2847, 1665, 1637, 1593, 1562, 1452, 1394, 1241, 1216, 1119, 991,
817 cmꢀ1 33,000 cmꢀ1 Mꢀ1), 228 (26,800),
lmax (MeOH): 202 nm (
361 (4900). 1H NMR (300 MHz, DMSO-d6):
3.73 (6H, s, OMe), 3.93
.
3
d
4.2.9. 6-Methoxy-2,3-dimethylindole-4,7-dione (20)
(2H, s, CH2), 5.67 (2H, s, aryl H5), 7.26–7.33 (8H, m, aryl H), 12.66
(2H, br s, NH). Mass spectrum (þEI): m/z (%) 678 (M, 81Br, 15%), 676
(M, 79Br, 18), 589 (23), 579 (15), 578 (30), 574 (16), 374 (81Br, 100),
372 (79Br, 89), 346 (20), 344 (16), 293 (30).
According to the general procedure, treatment of 2,3-dimethyl-
indole-7-carbaldehyde 924,25 (0.20 g, 0.85 mmol) in tetrahydrofu-
ran/methanol (20 mL) with concentrated hydrochloric acid (two
drops) and 30% hydrogen peroxide solution (5 mL) afforded the
indoloquinone 20 as a dark brown powder (52 mg, 31%), mp 297 ꢁC
(dec). (Found: C, 63.07; H, 5.50; N, 6.52. C11H11NO3 0.3CH3OH re-
quires: C, 63.18; H, 5.72; N, 6.52%.) HRMS (þESI): C11H11NO3
[MþNa]þ requires 228.0631, found 228.0630. nmax (KBr): 3427,
3189, 2923, 1666, 1633, 1594, 1563, 1494, 1456, 1336, 1249, 1116,
4.3. 7-Formyl-4,6-dimethoxy-3-phenylindolin-2-one (27)
Method 1: 7-formylindole 319 (0.134 g, 0.48 mmol) was dis-
solved in a suspension of sodium hydrogen phosphate (0.2 g) in
dichloromethane (10 mL). m-Chloroperbenzoic acid (1.5 equiv, 50%,
0.25 g, 0.7 mmol) was added to this solution and the reaction
mixture allowed to stir at room temperature for 4 h. After this time,
the solution was filtered and the filtrate washed with aqueous so-
dium sulfate (2ꢂ10 mL). The dichloromethane layer was separated,
dried (MgSO4), and concentrated under reduced pressure. The re-
sultant residue was flash chromatographed (eluent 97:3 dichloro-
methane/methanol) and recrystallized (dichloromethane/light
petroleum) to give the 3-phenylindolinone 27 as a white crystalline
powder (0.093 g, 66%).
845 cmꢀ1
283 (12,800), 353 (4000), 467 (2100). 1H NMR (300 MHz, DMSO-
d6): 2.10 (3H, s, Me), 2.14 (3H, s, Me), 3.71 (3H, s, OMe), 5.63 (1H, s,
aryl H5), 12.35 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6):
9.71
. lmax (MeOH): 205 nm (3
12,200 cmꢀ1 Mꢀ1), 228 (14,900),
d
d
and 10.84 (Me), 56.70 (OCH3), 107.09 (aryl CH), 117.89, 124.12,
127.41, 136.86, and 160.19 (aryl C), 172.70 and 184.98 (C]O). Mass
spectrum (þEI): m/z (%) 207 (Mþ2, 14), 206 (Mþ1, 100).
4.2.10. 6-Methoxy-3-methylindole-4,7-dione (21)
According to the general procedure, treatment of 3-methyl-
indole-7-carbaldehyde 1024,25 (1 g, 4.55 mmol) in tetrahydrofuran/
methanol (40 mL) with concentrated hydrochloric acid (three
drops) and 30% hydrogen peroxide solution (10 mL) afforded the
indoloquinone 21 as a dark brown powder (0.41 g, 47%), mp 180–
182 ꢁC (lit.9 174–176 ꢁC). (Found: C, 62.75; H, 5.22; N, 6.90.
Method 2: 7-formylindole 319 (0.25 g, 0.89 mmol) was dissolved
in glacial acetic acid (20 mL). MMPPA (2.5 equiv, 80%, 1.38 g,
2.2 mmol) was added and the solution was stirred at room
temperature for 30 min. After extraction with dichloromethane
(2ꢂ50 mL), the extract was dried (MgSO4) and concentrated under
reduced pressure. The resultant residue was flash chromatographed
(eluent 97:3 dichloromethane/methanol) and recrystallized
(dichloromethane/light petroleum) to give the 3-phenylindolinone
27 as a white crystalline powder (0.19 g, 72%), mp 167–169 ꢁC.
(Found: C, 68.7; H, 5.0; N, 4.5. C17H15NO4 requires: C, 68.7; H, 5.1; N,
C
10H9NO3 0.2EtOH requires: C, 62.33; H, 5.13; N, 6.99%.) HRMS
(þESI): C10H9NO3 [MþNa]þ requires 214.0474, found 214.0475. nmax
(KBr): 3421, 2936, 1661, 1637, 1597, 1455, 1383, 1334, 1212, 1114,
1002, 791 cmꢀ1
.
lmax (MeOH): 206 nm (
(14,200), 282 (7600), 356 (2700), 481 (1300). 1H NMR (300 MHz,
DMSO-d6): 2.07 (3H, s, Me), 3.71 (3H, s, OMe), 5.67 (1H, s, aryl H5),
6.34 (1H, s, aryl H2), 12.23 (1H, br s, NH). 13C NMR (75 MHz, DMSO-
d6): 11.84 (Me), 56.40 (OMe), 106.42 and 110.17 (aryl CH), 122.95,
3
11,600 cmꢀ1 Mꢀ1), 228
4.7%.) nmax (KBr): 1720, 1660, 1600, 1270 cmꢀ1
246 nm (
7700 cmꢀ1 Mꢀ1), 291 (6000), 333 (1900). 1H NMR
(300 MHz, CDCl3): 3.78 and 3.96 (6H, 2s, OMe), 4.49 (1H, s, H3),
6.08 (1H, s, H5), 7.17–7.45 (5H, m, aryl H), 9.54 (1H, br s, NH), 10.26
(1H, s, CHO). 13C NMR (75 MHz, CDCl3):
49.06 (C3), 55.75
. lmax (MeOH):
d
3
d
d
125.61, 132.11, and 160.32 (aryl C), 172.70 and 184.91 (C]O). Mass
spectrum (þEI): m/z (%) 192 (Mþ1, 100).
d
and 55.99 (OMe), 88.39 (C5), 104.32 and 107.58 (C3a and C7),
127.45, 127.91, and 128.66 (aryl CH), 135.51 and 146.32 (C7a and
C10), 161.20 and 164.24 (C–OMe), 178.12 (NC]O), 188.69 (HC]O).
Mass spectrum (þEI): m/z (%) 298 (Mþ1, 20), 297 (M, 100), 282 (27),
266 (38), 149 (40).
4.2.11. 2-Methoxy-5,6,7,8-tetrahydrocarbazole-1,4-dione (22)
According to the general procedure, treatment of indole-
carbaldehyde 1125 (1.50 g, 5.79 mmol) in tetrahydrofuran/methanol
(70 mL) with concentrated hydrochloric acid (three drops) and 30%
hydrogen peroxide solution (30 mL) afforded the indoloquinone 22
as a dark brown powder (0.57 g, 50%), mp 179–180 ꢁC. HRMS
(þESI): C13H13NO3 [MþNa]þ requires 254.0787, found 254.0788.
nmax (KBr): 3411, 3205, 2935, 2842, 1661, 1628, 1594, 1456, 1313,
4.4. 7-Acetyl-4,6-dimethoxy-3-phenylindolin-2-one (29)
Method 1: following a similar procedure to that described for the
synthesis of indolinone 27, 7-acetylindole 2814 (0.29 g, 0.99 mmol)
was dissolved in a suspension of sodium hydrogen phosphate
(0.3 g) in dichloromethane (15 mL), using m-chloroperbenzoic acid
(1.0 equiv, 50%, 0.34 g, 0.99 mmol) and a reaction time of 3 h at
room temperature. Flash chromatography (eluent 97:3 dichloro-
methane/methanol) followed by recrystallization (dichloro-
methane/light petroleum) gave the 3-phenylindolone 29 as an
off-white crystalline powder (0.204 g, 66%).
1235, 1151, 1111, 1037 cmꢀ1
16,300 cmꢀ1 Mꢀ1), 227 (17,400), 283 (9400), 330 (3000), 469
(1100). 1H NMR (300 MHz, CDCl3):
1.74–1.79 (4H, m, CH2), 2.61
.
lmax (MeOH): 209 nm
(3
d
(2H, t, J 5.84 Hz, CH2), 2.74 (2H, t, J 5.8 Hz, CH2), 3.79 (3H, s, OMe),
5.62 (1H, s, aryl H5), 9.24 (1H, br s, NH). 13C NMR (75 MHz, DMSO-
d6):
d 22.17, 22.44, and 22.84 (CH2), 56.35 (OMe), 106.88 (aryl CH),
121.37, 123.93, 127.67, 138.46, and 159.97 (aryl C), 170.38 and 184.62
(C]O). Mass spectrum (þEI): m/z (%) 232 (Mþ1, 77), 231 (M, 18),
230 (Mꢀ1, 100).
Method 2: following a similar procedure to that described for the
synthesis of indolinone 27, 7-acetylindole 2814 (0.15 g, 0.51 mmol)
was dissolved in methanol (20 mL) with MMPPA (1.1 equiv, 80%,
0.35 g, 5.6 mmol) and the mixture was gently refluxed for 30 min.
Flash chromatography of the crude product (eluent 97:3 dichloro-
methane/methanol) gave the 3-phenylindolone 29 as an off-white
crystalline powder (0.1 g, 64%), mp 167–169 ꢁC. (Found: C, 68.6; H,
5.6; N, 4.3. C18H17NO4$0.25H2O requires: C, 68.5; H, 5.6; N, 4.4%.)
4.2.12. Bis[3-(40-bromophenyl)-6-methoxy-4,7-dione-indol-
2-yl]methane (24)
According to the general procedure, treatment of indole 2,20-di-
indolylmethane-7,70-dicarbaldehyde 2319 (25 mg, 0.034 mmol) in
tetrahydrofuran/methanol (10 mL) with concentrated hydrochloric
acid (one drop) and 30% hydrogen peroxide solution (2 mL) for 4 h
afforded the bisindolyl-4,7-quinone 24 asþan orange powder
(13 mg, 57%), mp 280–281 ꢁC (dec). HRMS ( ESI): C31H20Br2N2O6
[MþNa]þ requires 698.9573, found 698.9554. nmax (KBr): 3412,
nmax (KBr): 1710, 1640, 1600, 1220 cmꢀ1
8300 cmꢀ1 Mꢀ1), 283 (5700), 323 (1900). 1H NMR (300 MHz,
CDCl3): 2.62 (3H, s, Me), 3.75 and 3.96 (6H, 2s, OMe), 4.48 (1H, s,
H3), 6.11 (1H, s, H5), 7.16–7.32 (5H, m, aryl H), 9.94 (1H, br s, NH).
. lmax (MeOH): 246 nm (3
d

M. Alamgir et al. / Tetrahedron 64 (2008) 7136–7142
7141
13C NMR (75 MHz, CDCl3):
d
33.27 (Me), 49.30 (C3), 55.58 and 55.80
chromatography (eluent dichloromethane) yielded N-acetyl-2-
(4,6-dimethoxyphenylamino)-1-phenylethanone as an amber solid
(6.10 g, 94%), mp 75–77 ꢁC. (Found: C, 69.0; H, 6.3; N, 4.6.
(OMe), 88.87 (C5), 105.48 and 108.20 (C3a and C7), 127.31, 127.91,
and 128.61 (aryl CH), 135.83 and 147.47 (C7a and C10), 159.52 and
162.79 (C–OMe), 178.18 (NC]O), 198.64 (MeC]O). Mass spectrum
(þEI): m/z (%) 311 (M, 30), 296 (26), 137 (51), 121 (100).
C
18H19NO4 requires: C, 69.0; H, 6.1; N, 4.5%.) nmax (KBr): 1710, 1660,
1500, 1350, 1220, 1200, 1060 cmꢀ1
lmax (MeOH): 240 nm (
17,100 cmꢀ1 Mꢀ1), 278 (3300). 1H NMR (300 MHz, CDCl3):
1.99
.
3
d
4.5. 1-(40,60-Dimethoxy-30-phenylindol-7-yl)trifluoro-
ethanone (30)
(3H, s, Me), 3.73 (6H, s, OMe), 5.03 (2H, s, CH2), 6.39 (1H, dd, J 2.5,
2.3 Hz, H20), 6.55 (1H, d, J 4.1 Hz, H40), 7.42 (2H, dd, J 7.2, 7.7 Hz, aryl
H), 7.52 (1H, t, J 7.2 Hz, aryl H), 7.9 (2H, d, J 7.2 Hz, aryl H). 13C NMR
4,6-Dimethoxy-3-phenylindole12 (0.35 g, 1.38 mmol) was dis-
solved in dry tetrahydrofuran (10 mL) and the solution cooled in
ice. Trifluoroacetic anhydride (3.0 equiv, 0.6 mL, 4.14 mmol) was
slowly added and the reaction mixture was allowed to stir at room
temperature for 4 h. The reaction was quenched with ice water and
the precipitate filtered, dried (MgSO4), purified by column chro-
matography (eluent dichloromethane), and recrystallized
(dichloromethane/petroleum ether) to yield the 3-phenyl-7-tri-
fluoroacetylindole 30 as a bright yellow crystalline solid (0.28 g,
58%), mp 288–290 ꢁC (dec). (Found: C, 61.8; H, 4.5; N, 3.9.
(75 MHz, CDCl3): d 21.78 (Me), 55.31 (OMe), 55.88 (CH2), 99.95,
106.07, 127.75, 128.47, and 133.27 (aryl CH), 135.05 and 145.02 (aryl
C), 161.17 (C–OMe), 170.47 and 193.41 (C]O). Mass spectrum (þEI):
m/z (%) 313 (M, 7), 166 (100), 105 (20).
Trifluoroacetic acid (15 mL) was added to the above N-acetyl-
aminoketone (6.10 g, 19.49 mmol) and the mixture was stirred at
40 ꢁC under nitrogen for 8 h. The solution was then cooled and
poured into ice water. The resulting precipitate was filtered,
washed with water, and dried. Purification using a plug of silica
(eluent dichloromethane) and recrystallization (dichloromethane/
light petroleum) gave the N-acetylindole 33 as a light tan solid
(5.33 g, 93%), mp 146–147 ꢁC. (Found: C, 72.9; H, 6.0; N, 4.6.
C
18H14F3NO3 requires: C, 61.9; H, 4.0; N, 4.0%.) nmax (KBr): 1580,
1560, 1350, 1320, 1220, 1160, 1140, 1080 cmꢀ1
lmax (MeOH):
258 nm (
2000 cmꢀ1 Mꢀ1), 348 (1100), 375 (900). 1H NMR
(300 MHz, CDCl3): 3.94 and 4.01 (6H, 2s, OMe), 6.21 (1H, s, H5),
7.10 (1H, d, J 3.1 Hz, H2), 7.29–7.57 (5H, m, aryl H), 10.61 (1H, br s,
NH). 13C NMR (75 MHz, CDCl3):
55.50 and 56.55 (OMe), 87.55 (C5),
.
3
C
18H17NO3 requires: C, 73.2; H, 5.8; N, 4.7%.) nmax (KBr): 1700, 1590,
1550, 1300, 1280, 1260, 1200, 1150, 1100, 1030, 960 cmꢀ1
lmax
(MeOH): 238 nm (
20,000 cmꢀ1 Mꢀ1), 251 (23,100), 279 (6000),
317 (4900). 1H NMR (300 MHz, CDCl3):
2.62 (3H, s, Me), 3.74 and
d
.
3
d
d
121.68 (C2), 126.26, 127.72, and 129.50 (aryl CH), 110.73 (C7), 119.71
and 123.13 (C3 and C3a), 115.51 (CF3), 135.13 and 139.41 (C7a and
C10), 162.41 and 162.65 (C–OMe), 178.23 (C]O). Mass spectrum
(þEI): m/z (%) 349 (M, 87), 281 (21), 280 (100), 222 (21), 194 (21),
140 (60).
3.90 (6H, 2s, OMe), 6.41 (1H, d, J 1.9 Hz, H5), 7.25 (1H, d, J 1.0 Hz,
H2), 7.33–7.58 (5H, m, aryl H), 7.78 (1H, d, J 2.0 Hz, H7). 13C NMR
(75 MHz, CDCl3):
d 24.13 (Me), 55.13 and 55.72 (OMe), 92.86 (C7),
95.72 (C5), 120.71 (C2), 126.96, 127.58, and 129.41 (aryl CH), 112.38,
124.37, 134.32, and 138.15 (aryl C), 154.19 and 159.16 (C–OMe),
168.93 (C]O). Mass spectrum (þEI): m/z (%) 295 (M, 80), 253 (100),
252 (24), 238 (44).
4.6. 4,6-Dimethoxy-2,3-diphenylindol-7-yl
trifluoroacetate (32)
4.8. 1-Acetyl-4,6-dimethoxy-3-phenylindolin-2-one (35)
7-Trifluoroacetylindole 3113 (0.25 g, 0.59 mmol) was dissolved
in
a
suspension of sodium hydrogen phosphate (0.3 g) in
Method 1: N-acetylindole 33 (0.30 g, 1.02 mmol) was dissolved
dichloromethane (15 mL), and to this solution m-chloroperbenzoic
acid (50%, 0.22 g, 0.65 mmol) was added in small amounts. The
solution was allowed to stir at room temperature for 1 h before
being quenched with ice water. The solid precipitate was then
extracted with dichloromethane (2ꢂ50 mL). The dichloromethane
layer was dried (MgSO4) and the solvent removed under reduced
pressure. The crude product was purified by radial chromatography
(eluent dichloromethane) to yield the indolinone 32 as a white
powder (0.17 g, 65%), mp 288–290 ꢁC (dec). (Found: C, 63.0; H, 4.5;
N, 3.0. C24H18F3NO4$H2O requires: C, 62.8; H, 4.4; N, 3.1%.) nmax
in a suspension of sodium hydrogen phosphate (0.3 g) in
dichloromethane (10 mL). m-Chloroperbenzoic acid (1.5 equiv, 50%,
0.5 g, 1.5 mmol) was added to this solution and the reaction mix-
ture was allowed to stir at room temperature for 3 h. The solution
was filtered and the filtrate washed with aqueous sodium sulfate
(2ꢂ10 mL). The dichloromethane layer was separated, dried
(MgSO4), and concentrated under reduced pressure. The resultant
residue was flash chromatographed (eluent 97:3 dichloromethane/
methanol) and recrystallized (dichloromethane/light petroleum) to
give the indolinone 35 as an off-white crystalline powder (0.18 g,
56%).
Method 2: N-acetylindole 33 (0.30 g, 1.02 mmol) was dissolved
with warming in glacial acetic acid (20 mL). MMPPA (1.1 equiv, 80%,
0.69 g, 1.12 mmol) was added and the solution was brought to
a gentle reflux for 30 min. After this time, the reaction mixture was
cooled, poured into ice water, and extracted with dichloromethane
(2ꢂ50 mL). The combined dichloromethane layers were dried
(MgSO4) and concentrated under reduced pressure. The resulting
residue was flash chromatographed (eluent 97:3 dichloromethane/
methanol) and recrystallized (dichloromethane/light petroleum) to
give the indolinone 35 as an off-white crystalline powder (0.04 g,
13%), mp 167–169 ꢁC. (Found: C, 69.5; H, 5.4; N, 4.4. C18H17NO4
requires: C, 69.4; H, 5.5; N, 4.5%.) nmax (KBr): 1750, 1710, 1600, 1340,
(KBr): 1650, 1600, 1310, 1280, 1200, 1180, 1150, 1120 cmꢀ1
.
lmax
21,000 cmꢀ1 Mꢀ1), 311 (5600). 1H NMR
3.65 and 3.98 (6H, 2s, OMe), 6.39 (1H, s, H5),
(MeOH): 249 nm
(300 MHz, CDCl3):
(
d
3
7.38–7.80 (10H, m, aryl H), 10.65 (1H, br s, NH). 13C NMR (75 MHz,
CDCl3):
d 55.83 and 56.18 (OMe), 91.92 (C5), 112.38, 113.92, 114.05,
and 117.93 (C2, C3, C3a, and CF3), 127.42, 128.26, 128.74, 129.01,
132.51, and 133.03 (aryl CH), 132.84, 136.99, and 139.12 (C7a, C10,
and C100), 161.79 and 162.46 (C–OMe), 165.35 (C–O–C]O), 196.13
(C]O). Mass spectrum (þEI): m/z (%) 441 (M, 3), 388 (48), 352
(100).
4.7. 4,6-Dimethoxy-3-phenyl-1-acetylindole (33)
2-(3,5-Dimethoxyphenylamino)-1-phenylethanone12 (5.60 g,
20.66 mmol) was dissolved in acetic anhydride (20 mL), gently
warmed, and then left to stir at room temperature for 4 h. The
solution was quenched with water, gently warmed, and left to stir
for a further 2 h. The product was extracted with dichloromethane
(50 mL) and washed with water (4ꢂ50 mL), dried (MgSO4), and
concentrated under reduced pressure. Purification by column
1250, 1200, 1100, 1020 cmꢀ1
4700 cmꢀ1 Mꢀ1), 236 (4000), 280 (1100), 287 (1100). 1H NMR
(300 MHz, CDCl3): 2.61 (3H, s, Me), 3.66 and 3.87 (6H, 2s, OMe),
4.70 (1H, s, H3), 6.34 (1H, d, J 2.1 Hz, H5), 7.18–7.32 (5H, m, aryl H),
7.60 (1H, d, J 2.1 Hz, H7). 13C NMR (75 MHz, CDCl3):
26.69 (Me),
.
lmax (MeOH): 223 nm
(3
d
d
50.35 (Me), 55.45 and 55.75 (OMe), 94.80 (C5), 95.96 (C7), 106.50
(C3a), 127.64, 127.77, and 128.66 (aryl CH), 135.94 and 142.33 (C7a

7142
M. Alamgir et al. / Tetrahedron 64 (2008) 7136–7142
and C10), 156.18 and 161.63 (C–OMe), 171.22 (NC]O), 177.02
(MeC]O). Mass spectrum (þEI): m/z (%) 311 (M, 72), 270 (35), 269
(100), 254 (93), 240 (65), 238 (31).
receipt from the Australian Government of an Endeavour In-
ternational Postgraduate Research Scholarship and an Australian
Postgraduate Award, respectively.
4.9. 4,6-Dimethoxy-3-phenyl-1-phenylsulfonyl-indolin-
2-one (36)
References and notes
1. Iwasa, S.; Fakhruddin, A.; Widagdo, H. S.; Nishiyama, H. Adv. Synth. Catal. 2005,
347, 517–520.
2. Wu, T. S.; Ohta, T.; Furukawa, H.; Kuoh, C. S. Heterocycles 1983, 20, 1267–1269.
3. Sun, H. H.; Sakemi, S.; Burres, N.; McCarthy, P. J. Org. Chem. 1990, 55, 4964–
4966.
4. Tomasz, M.; Palom, Y. Pharmacol. Ther. 1997, 76, 73–87.
5. Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992,
114, 2175–2180.
6. Matsui, M.; Yamada, Y.; Uzu, K.; Hirata, T. J. Antibiot. 1968, 21, 189–198.
7. Skibo, E. B.; Xing, C. J. Med. Chem. 2001, 44, 3545–3562.
8. Maliepaard, M.; Wolfs, A.; Groot, S. E. Br. J. Cancer 1995, 71, 836–839.
9. Saa, J. M.; Marti, C.; Raso, A. G. J. Org. Chem. 1992, 589–594.
10. Hendricks, H. R.; Pizao, P. E.; Berger, D. P.; Kooistra, K. L.; Bibby, M. C.; Boven, E.;
Dreef-van, M. H. C.; Henrar, H. H.; Fiebig, H. H.; Double, J. A.; Hornstra, H. W.;
Pinedo, H. M.; Workman, P.; Schwartsman, G. Eur. J. Cancer 1993, 29A, 897–906.
11. Knoelker, H. J.; Hartman, K. Synlett 1993, 755–757.
12. Black, D. StC.; Gatehouse, B. M. K. C.; Theobald, F.; Wong, L. C. H. Aust. J. Chem.
1980, 33, 343–350.
13. Black, D. StC.; Bowyer, M. C.; Catalano, M. M.; Ivory, A. J.; Keller, P. A.; Kumar, N.;
Nugent, S. J. Tetrahedron 1994, 50, 10497–10508.
Method 1: following a similar procedure to that described for the
synthesis of indolinone 35, N-phenylsulfonylindole 3422 (0.28 g,
0.71 mmol) was dissolved in a suspension of sodium hydrogen
phosphate (0.15 g) in dichloromethane (20 mL), using m-chloro-
perbenzoic acid (1.1 equiv, 50%, 0.25 g, 0.7 mmol) and a reaction time
of 3 h at room temperature. Flash chromatography (eluent 97:3
dichloromethane/methanol) followed by recrystallization (dichloro-
methane/light petroleum) gave the 1-phenylsulfonylindolin-2-one
36 as a crystalline white powder (0.15 g, 52%).
Method 2: following a similar procedure to that described for the
synthesis of indolinone 35, N-phenylsulfonylindole 3421 (0.5 g,
1.3 mmol) was dissolved in glacial acetic acid (20 mL). MMPPA
(1.1 equiv, 80%, 0.87 g, 1.4 mmol) was added and the warmed so-
lution was stirred for 30 min. Flash chromatography of the crude
product (eluent 70:30 dichloromethane/methanol) gave the 1-
phenylsulfonylindolin-2-one 36 as a crystalline white powder
(0.36 g, 69%), mp 188–190 ꢁC. (Found: C, 64.4; H, 4.7; N, 3.2.
14. Black, D. StC.; Kumar, N.; Mitchell, P. S. R. J. Org. Chem. 2002, 67, 2464–2473.
15. Jones, A. W.; Wahyuningsih, T. D.; Pchalek, K.; Kumar, N.; Black, D. StC. Tetra-
hedron 2005, 61, 10490–10500.
C
22H18NO5S requires: C, 64.5; H, 4.7; N, 3.4%.) nmax (KBr): 1720,
1660, 1600, 1270, 1210, 1090, 980, 830 cmꢀ1 1H NMR (300 MHz,
CDCl3): 3.61 and 3.91 (6H, 2s, OMe), 4.53 (1H, s, H3), 6.28 (1H, d,
J 2.0 Hz, H5), 6.90–8.0 (10H, m, aryl H), 7.30 (1H, d, J 2.0 Hz, H7).
13C NMR (75 MHz, CDCl3):
50.09 (C3), 55.53 and 55.88 (OMe),
16. Pchalek, K.; Jones, A. W.; Wekking, M. M. T.; Black, D. StC. Tetrahedron 2005, 61,
77–82.
17. Black, D. StC.; Craig, D. C.; Kumar, N.; Wong, L. C. H. J. Chem. Soc., Chem. Commun.
1985, 1172–1173.
18. Black, D. StC.; Kumar, N.; Wong, L. C. H. J. Chem. Soc., Chem. Commun. 1985, 1174–
1175.
19. Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R. J. Chem. Soc., Chem.
Commun. 1993, 819–821.
20. Nikaido, M.; Aslanian, R.; Scavo, F.; Helquist, P.; Akermark, B.; Backvall, J. J. Org.
Chem. 1984, 49, 4740–4741.
21. Bowyer, P. K.; Black, D. StC.; Craig, D. C.; Rae, A. D.; Willis, A. C. J. Chem. Soc.,
Dalton Trans. 2001, 1948–1958.
.
d
d
92.57 (C7), 95.34 (C5), 106.69 (C3a), 127.61, 127.72, 127.91, 128.61,
129.15, and 134.37 (aryl CH), 135.48, 138.07, and 141.22 (C7a,
C10, and C100), 156.72 and 162.06 (C–OMe), 174.57 (C]O). Mass
spectrum (þEI): m/z (%) 409 (M, 7), 268 (28), 91 (100).
22. Jones, A. W.; Purwono, B.; Bowyer, P. K.; Mitchell, P. S. R.; Kumar, N.; Nugent,
S. J.; Jolliffe, K. A.; Black, D. StC. Tetrahedron 2004, 60, 10779–10786.
23. Black, D. StC.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.; Kim, M.; Kumar, N.;
McConnell, D. B.; Popiolek, M. Aust. J. Chem. 1994, 47, 1741–1750.
24. Black, D. StC.; Kumar, N.; Wong, L. C. H. Synthesis 1986, 474–476.
25. Black, D. StC.; Ivory, A. J.; Keller, A. A.; Kumar, N. Synthesis 1989, 322–323.
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged. M.A. and P.S.R.M. also acknowledge