Reaction of some 4,6-dimethoxyindoles with nitric acid: Nitration and oxidative dimerisation

Article abstract of DOI:10.1016/j.tet.2004.11.026

A range of 3-substituted-4,6-dimethoxyindoles bearing electron-withdrawing groups in either the 2- or 7-position, can be nitrated using nitric acid in acetonitrile, to give 7-nitro and 2-nitro-indoles, respectively. Those without electron-withdrawing groups undergo oxidative dimerisation at C7, if 2,3-disubstituted, and at C2, if N-methylated and unsubstituted at C2. Some 3-substituted-4,6-dimethoxyindoles can be nitrated using nitric acid in acetonitrile, to give 7-nitro and 2-nitro-indoles. Some undergo oxidative dimerisation at C7, if 2,3-disubstituted, and at C2, if N-methylated and unsubstituted at C2.

Full text of DOI:10.1016/j.tet.2004.11.026

Tetrahedron 61 (2005) 853–861
Reaction of some 4,6-dimethoxyindoles with nitric acid:
nitration and oxidative dimerisation
Tinnagon Keawin,a Shuleewan Rajviroongita and David StC. Blackb,
*
aDepartment of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
bSchool of Chemistry, The University of New South Wales, UNSW Sydney, NSW 2052, Australia
Received 30 August 2004; revised 25 October 2004; accepted 12 November 2004
Available online 10 December 2004
Abstract—A range of 3-substituted-4,6-dimethoxyindoles bearing electron-withdrawing groups in either the 2- or 7-position, can be nitrated
using nitric acid in acetonitrile, to give 7-nitro and 2-nitro-indoles, respectively. Those without electron-withdrawing groups undergo
oxidative dimerisation at C7, if 2,3-disubstituted, and at C2, if N-methylated and unsubstituted at C2.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
compounds 7–12 in yields of 63–85%. None of the indoles
1–6 have been reported previously, but are minor variants of
published compounds.6 All the nitro compounds 7–12 are
new, but the methyl ester analog of compound 9 has already
been reported.4 It is significant that 7-nitration still occurs in
high yield for the N-methylindole 6. The facility of this
reagent system is comparable to the use of nitric acid on
silica, being extremely simple: the only potential problem
lies in monitoring the progress of the reaction, so as not to
allow it to proceed for too long. In most cases, especially for
the faster reactions, there is a useful colour change from
yellow to green, as the conversion is completed.
The nitration of indoles has been the subject of investigation
for many years, and is difficult to achieve in a clean and
selective manner.1–3 We have recently reported that
selective nitration can be carried out in the case of
3-substituted-4,6-dimethoxyindoles, provided that an
electron-withdrawing substituent is also present.4 Thus, if
the electron-withdrawing substituent is at C2, nitration takes
place at C7, whereas if the electron-withdrawing substituent
is at C7, nitration occurs at C2. The very effective reagent
used in these experiments was concentrated nitric acid on
silica. Many years ago, we found that concentrated nitric
acid in acetonitrile was a highly successful reagent for the
oxidation of active methylene compounds,5 possibly via
intermediate nitro-aliphatic structures. We therefore
decided to investigate the use of this reagent on activated
4,6-dimethoxyindoles.
2. Results and discussion
2.1. Reaction of 4,6-dimethoxyindoles with C2 electron-
withdrawing substituents
The 3-aryl-4,6-dimethoxyindoles 1–6, each containing
carbonyl substituents at C2, underwent smooth reaction
with concentrated nitric acid in acetonitrile at room
temperature over 20–240 min to give the related 7-nitro
2.2. Reaction of 4,6-dimethoxyindoles with C7 electron-
withdrawing substituents
Keywords: Indoles; Nitric acid; Nitration; Oxidative dimerisation.
* Corresponding author. Tel.: C61 2 9385 4657; fax: C61 2 9385 6141;
e-mail: d.black@unsw.edu.au
The 3-aryl-4,6-dimethoxyindoles 13–18, each containing
carbonyl substituents at C7, underwent smooth reaction
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.026

854
T. Keawin et al. / Tetrahedron 61 (2005) 853–861
with concentrated nitric acid in acetonitrile at room
temperature over 20–240 min to give the related 2-nitro
compounds 19–24 in yields of 35–88%. Indoles 13 and 14
have been reported previously,7,8 while indoles 15–18 have
not, but are minor variants of published compounds.6
The nitro compound 19 has been reported,4 but compounds
20–24 are new, and expand the range of rare 2-nitro-indoles.
The unusually low yield of 35% occurs in the case of the
most highly activated 3-(4-methoxyphenyl)-substituted
indole 14. Again, it is significant that the N-methylindole
18 undergoes 2-nitration in high yield.
substituted by a methyl group. The new N-methylindoles
31–34 underwent reaction at 0 8C during 3–18 h to afford
the 2,20-biindolyls 35–38 in 25–72% yields. The structures
of the 2,20-biindolyls 35–38 were evident from their 1H and
13C NMR and mass spectra, and the compounds were fully
characterized. Although the yields of the 2,20-biindolyls are
only moderate good recovery of starting material can also be
achieved. Also the reactions are clean and the methodology
is very direct and compares favourably with the copper
coupling of 2-iodo-1-methylindole.11
2.3. Reaction of 4,6-dimethoxyindoles without electron-
withdrawing substituents
Nitration of activated indoles without the stabilizing
influence of electron-withdrawing substituents has been
found to be very difficult to control.4 Nevertheless, the
simple conditions of concentrated nitric acid in acetonitrile
warranted their investigation, in case clean and selective
reactions could be achieved. Thus the 2,3-disubstituted
indoles 25–27 were found to undergo smooth reaction over
3.5–4 h at 0 8C, to afford the 7,70-biindolyls 28–30 in high
yield. While the dimer 28 is a very well known compound,9
accessible by oxidative dimerisation from indole 25 using a
wide range of quinone and other oxidizing agents, dimers 29
and 30 are new. Indeed, attempts to generate them by
quinone oxidation of indoles 26 and 27 respectively, have
failed, presumably because of the susceptibility of the
2-methyl group to indiscriminate oxidation.10
Attempts to extend this methodology to non-activated
indoles were not successful. Treatment of 1-methylindole
and 1,3-dimethylindole with concentrated nitric acid in
acetonitrile rapidly switched from no reaction to the
formation of complex product mixtures. Thus it seems
that the methoxy groups play an important role in activating
both the 2- and 7-positions in the nitration and oxidative
coupling reactions. In the coupling reactions, the nitric acid
could be acting as an oxidizing agent to generate a radical
cation, which leads to dimerisation of radicals at C2 and C7.
It is also significant that dimerisation of N-methylindoles
31–33, which are potentially capable of dimerising at C2 or
C7, actually occurs selectively at C2. Presumably the
reaction is sterically controlled, as the N-methyl analog of
indole 25 cannot be oxidatively dimerised by reaction wit0h
quinones, even though the N-methyl analog of the 7,7 -
dimer 28 can be prepared as a stable compound by direct
methylation of compound 28.9
3. Conclusions
Concentrated nitric acid in acetonitrile offers simple and
effective conditions for the conversion of a range of
relatively activated indoles into related nitro compounds.
Some more highly activated indoles, provided that they are
substituted at nitrogen, undergo very useful oxidative
dimerisation processes at C7 or at C2. The nitration reaction
provides an effective route to relatively rare nitro-indoles,
while the oxidative coupling process has particular potential
for future development.
Reactions of 3-substituted-4,6-dimethoxyindoles with nitric
acid in acetonitrile were found to be indiscriminate and led
to complex product mixtures, unless the indole nitrogen was

T. Keawin et al. / Tetrahedron 61 (2005) 853–861
855
4. Experimental
0.742 mmol) at 0 8C for 20 min, followed by addition of
absolute ethanol (0.21 mL, 6.18 mmol) and heating to reflux
for 2 h. Chromatography and elution with 3:7 v/v ethyl
acetate/hexane and recrystallization afforded three products.
Melting points were determined by an Electrothermal
melting point apparatus and were uncorrected. The H and
1
13C NMR, and DEPT spectra were recorded on Bruker DPX
300 MHz spectrometer in CDCl3 using tetramethylsilane as
an internal standard. Infrared spectra were recorded on a
Spectrum GX FT-IR system 2000 (Perkin–Elmer) spec-
trometer. Elemental analyses were performed on a Perkin
Elmer Elemental Analyser 2400 CHN. Mass spectra were
recorded on a Finnigan MAT INCOS 50 mass spectrometer.
The ESITOf mass spectra were obtained from a Micromass
LCT mass spectrometer. Merck silica gel 60 PF254 was used
for preparative thin layer chromatography (PLC). Aceto-
nitrile and 65% nitric acid were commercial materials.
4.3.1. Ethyl 3-(4-bromophenyl)-4,6-dimethoxyindole-2-
carboxylate 2 (0.017 g, 7%). Pale yellow solid, mp 219–
221 8C. 1H NMR (300 MHz, CDCl3): d 8.86 (br s, 1H, NH),
7.39 and 7.25 (2d, 4H, 4-BrArH), 6.36 (d, 1H, H7, JZ
1.73 Hz), 6.07 (d, 1H, H5, JZ1.71 Hz), 4.12 (q, 2H,
OCH2CH3, JZ7.12 Hz), 3.77 and 3.57 (2s, 6H, 2!OMe),
1.09 (t, 3H, OCH2CH3, JZ7.12 Hz). 13C NMR (75 MHz,
CDCl3): d 160.7 (COOEt), 160.3 (COMe), 156.2 (COMe),
137.6 (Cq), 133.7 (Cq), 132.7 (2!CH), 129.6 (2!CH),
123.5 (Cq), 121.1 (Cq), 120.8 (Cq), 112.6 (Cq), 93.0 (C7),
85.8 (C5), 60.6 (OCH2CH3), 55.5 (OMe), 55.1 (OMe), 14.0
(OCH2CH3). IR (KBr): nmax 3337, 2925, 1662, 1587, 1344,
1262, 1218, 1151, 1095 cmK1. EIMS: m/z (relative
intensity) 405 ([MC2]C, 69), 403 (MC, 80), 359 (100),
357 (92), 278 (52), 250 (61). HRMS calcd for [C19H18-
BrNO4CH]C: 404.0497. Found: 404.0490.
4.1. Preparation of indole substrates
4.1.1. 2-Acetyl-3-(4-bromophenyl)-4,6-dimethoxyindole
1. To a solution of 3-(4-bromophenyl)-4,6-dimethoxyindole
(105.3 mg, 0.317 mmol) in dry dichloromethane (10 mL) at
0 8C was added SnCl4 (107.3 mg, 0.412 mmol) and the
mixture stirred at 0 8C for 45 min. To this solution was
added acetyl chloride (36.2 mg, 0.432 mmol) and the
mixture stirred at 0 8C for 2 h. After pouring into water,
the mixture was extracted with dichloromethane. The
organic layer was collected, washed with water, dried
over MgSO4 and evaporated under reduced pressure. The
crude product was purified by chromatography eluting with
7/3 v/v dichloromethane/hexane and recrystallization. Pale
yellow solid, mp 237–238 8C. 1H NMR (300 MHz, CDCl3):
d 9.05 (br s, 1H, NH), 7.44 and 7.22 (2d, 4H, 4-BrArH), 6.33
(d, 1H, H7, JZ1.59 Hz), 6.03 (d, 1H, H5, JZ1.65 Hz), 3.79
and 3.53 (2s, 6H, 2!OMe), 1.92 (s, 3H, COMe). IR (KBr):
nmax 3329, 2924, 1623, 1577, 1523, 1278, 1205, 1131,
817 cmK1. EIMS: m/z (relative intensity) 375 ([MC2]C,
70), 373 (MC, 69), 360 (11), 358 (10), 294 (18), 279 (100).
Anal. calcd for C18H16BrNO3: C, 57.77; H, 4.31; N, 3.74.
Found: C, 57.68; H, 4.55; N, 3.82.
4.3.2. Ethyl 3-(4-bromophenyl)-4,6-dimethoxyindole-2-
glyoxylate 3 (0.102 g, 35%). Pale yellow solid, mp 140–
141 8C. 1H NMR (300 MHz, CDCl3): d 9.48 (br s, 1H, NH),
7.41 and 7.22 (2d, 4H, 4-BrArH), 6.33 (d, 1H, H7, JZ
1.81 Hz), 6.03 (d, 1H, H5, JZ1.81 Hz), 3.70 (q, 2H,
OCH2CH3, JZ7.16 Hz), 3.78 and 3.56 (2s, 6H, 2!OMe),
1.09 (t, 3H, OCH2CH3, JZ7.16 Hz). 13C NMR (75 MHz,
CDCl3): d 164.0 (ArCOCOOEt), 162.4 (ArCOCOOEt and
COMe), 156.9 (COMe), 139.9 (Cq), 132.6 (2!CH), 132.4
(Cq), 130.1 (2!CH), 128.7 (Cq), 127.1 (Cq), 121.9 (Cq),
113.3 (Cq), 93.8 (C7), 85.6 (C5), 62.1 (OCH2CH3), 55.6
(OMe), 55.1 (OMe), 13.6 (OCH2CH3). IR (KBr): nmax 3326,
2929, 1742, 1603, 1571, 1523, 1207, 1155, 1133 cmK1
.
EIMS: m/z (relative intensity) 433 ([MC2]C, 25), 431
(MC, 28), 360 (55), 358 (58), 279 (100). Anal. calcd for
C20H18BrNO5: C, 55.57; H, 4.20; N, 3.24. Found: C, 55.78;
H, 4.27; N, 3.41.
4.2. General procedure for the reaction of 3-(4-bromo-
phenyl)-4,6-dimethoxyindole with oxalyl chloride
followed by alcohol or amine
4.3.3. Ethyl 3-(4-bromophenyl)-4,6-dimethoxyindole-7-
glyoxylate 15 (0.092 g, 31%). Pale yellow solid, mp 181–
1
182 8C. H NMR (300 MHz, CDCl3): d 10.59 (br s, 1H,
NH), 7.51 and 7.43 (2d, 4H, 4-BrArH), 7.11 (d, 1H, H2, JZ
2.13 Hz), 6.20 (s, 1H, H5), 4.33 (q, 2H, OCH2CH3, JZ
7.14 Hz), 3.96 and 3.95 (2s, 6H, 2!OMe), 1.44 (t, 3H,
OCH2CH3, JZ7.14 Hz). 13C NMR (75 MHz, CDCl3): d
185.1 (ArCOCOOEt), 166.0 (ArCOCOOEt), 162.2
(COMe), 162.1 (COMe), 138.5 (Cq), 134.2 (Cq), 131.0
(2!CH), 130.7 (2!CH), 122.0 (C2), 120.1 (Cq), 118.1
(Cq), 110.6 (Cq), 100.8 (Cq), 87.4 (C5), 61.5 (OCH2CH3),
56.9 (OCH3), 55.5 (OMe), 14.2 (OCH2CH3). IR (KBr): nmax
3428, 2977, 1729, 1616, 1583, 1536, 1309, 1212, 1180,
1083 cmK1. EIMS: m/z (relative intensity) 433 ([MC2]C,
37), 431 (MC, 34), 360 (97), 358 (100). Anal. calcd for
C20H18BrNO5: C, 55.57; H, 4.20; N, 3.24. Found: C, 55.97;
H, 4.49; N, 3.28.
3-(4-Bromophenyl)-4,6-dimethoxyindole (1.0 equiv) was
dissolved in anhydrous dichloromethane and the solution
was cooled at 0 8C in ice. Oxalyl chloride (1.2 equiv) was
added rapidly and the solution was allowed to stir at this
temperature. The alcohol or amine (10.0 equiv) was added
and the mixture warmed to room temperature or reflux.
Water was added when the reaction was completed and the
solution was extracted with CH2Cl2. The organic extract
was washed with water and saturated NaCl, dried over
MgSO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography
(ethyl acetate/hexane) and recrystallization (CH2Cl2/light
petroleum).
4.3. Compounds 2, 3, and 15
4.4. Compounds 4 and 16
According to the general procedure, 3-(4-bromophenyl)-
4,6-dimethoxyindole (0.205 g, 0.618 mmol) in dichloro-
methane (20 mL) was treated with oxalyl chloride (94.1 mg,
According to the general procedure, 3-(4-bromophenyl)-
4,6-dimethoxyindole (0.450 g, 1.35 mmol) in dichloro-
methane (20 mL) was treated with oxalyl chloride

856
T. Keawin et al. / Tetrahedron 61 (2005) 853–861
(206.4 mg, 1.63 mmol) at 0 8C for 30 min, followed by
addition of n-butylamine (1.35 mL, 13.5 mmol) and warm-
ing to room temperature for 2 h. Chromatography and
elution with 3:7 v/v ethyl acetate/hexane and recrystalliza-
tion afforded two products.
6.30 (s, 1H, H5), 3.79 and 3.54 (2s, 6H, 2!OMe), 3.00–
2.93 (m, 4H, N(CH2CH3)2), 1.02 and 0.78 (2t, 6H,
N(CH2CH3)2, JZ7.10 Hz). 13C NMR (75 MHz, CDCl3): d
182.4 (ArCOCONEt2), 165.9 (ArCOCONEt2), 162.0
(COMe), 157.0 (COMe), 139.4 (Cq), 132.7 (2!CH),
132.0 (Cq), 129.9 (2!CH), 127.7 (Cq), 126.8 (Cq), 121.9
(Cq), 113.6 (Cq), 93.6 (C7), 85.1 (C5), 55.6 (OMe), 55.2
(OMe), 42.5 (N(CH2CH3)2), 38.9 (N(CH2CH3)2), 13.9
(N(CH2CH3)2), 12.4 (N(CH2CH3)2). IR (KBr): nmax 3314,
2982, 2937, 1644, 1609, 1575, 1529, 1381, 1255, 1207,
1152, 1133, 810 cmK1. EIMS: m/z (relative intensity) 460
([MC2]C, 19), 458 (MC, 24), 360 (30), 358 (30), 279
(100). Anal. calcd for C22H23BrN2O4: C, 57.53; H, 5.05; N,
6.10. Found: C, 57.57; H, 5.26; N, 6.23.
4.4.1. N-n-Butyl 3-(4-bromophenyl)-4,6-dimethoxy-
indole-2-glyoxylamide 4 (0.143 g, 23%). Yellow solid,
mp 139–140 8C. 1H NMR (300 MHz, CDCl3): d 11.58 (br s,
1H, NH), 7.51 and 7.34 (2d, 4H, 4-BrArH), 6.40 (d, 1H, H7,
JZ1.66 Hz), 6.10 (d, 1H, H5, JZ1.66 Hz), 3.88 and 3.65
(2s, 6H, 2!OMe), 3.35 (q, 2H, NHCH2CH2CH2CH3, JZ
6.64 Hz), 1.53 and 1.38 (2m, 4H, NHCH2CH2CH2CH3),
0.94 (t, 3H, NHCH2CH2CH2CH3, JZ7.26 Hz). 13C NMR
(75 MHz, CDCl3): d 172.8 (ArCOCONHBun), 163.5
(COMe), 162.2 (COMe), 156.7 (ArCOCONHBun), 139.7
(Cq), 133.7 (Cq), 132.2 (2!CH), 130.0 (2!CH), 129.7
(Cq), 126.9 (Cq), 121.4 (Cq), 113.2 (Cq), 93.8 (C7), 85.7
(C5), 55.6 (OMe), 55.1 (OMe), 39.0 (NHCH2CH2CH2CH3),
31.1 (NHCH2CH2CH2CH3), 19.9 (NHCH2CH2CH2CH3),
13.6 (NHCH2CH2CH2CH3). IR (KBr): nmax 3328, 2958,
2930, 1619, 1513, 1480, 1317, 1212, 1158 cmK1. EIMS:
m/z (relative intensity) 460 ([MC2]C, 45), 458 (MC, 48),
360 (61), 358 (61), 279 (100). Anal. calcd for
C22H23BrN2O4: C, 57.53; H, 5.05; N, 6.10. Found: C,
57.90; H, 5.27; N, 6.51.
4.5.2. N,N-Dimethyl 3-(4-bromophenyl)-4,6-dimethoxy-
indole-7-glyoxylamide 17 (0.133 g, 49%). Yellow solid,
mp 234–235 8C. 1H NMR (300 MHz, CDCl3): d 10.69 (br s,
1H, NH), 7.41 and 7.35 (2d, 4H, 4-BrArH), 7.03 (d, 1H,
H2), 6.12 (s, 1H, H5), 3.86 and 3.85 (2s, 6H, 2!OMe), 3.45
(br s, 2H, N(CH2CH3)2), 3.20 (q, 2H, N(CH2CH3)2, JZ
6.98 Hz), 1.21 and 1.09 (2t, 6H, N(CH2CH3)2, JZ7.13,
7.08 Hz). 13C NMR (75 MHz, CDCl3):
d 190.0
(ArCOCONEt)2, 168.4 (ArCOCONEt)2, 161.9 (COMe),
161.5 (COMe), 138.7 (Cq), 134.3 (Cq), 131.0 (2!CH),
130.7 (2!CH), 121.9 (C7), 120.0 (Cq), 117.9 (Cq), 110.6
(Cq), 101.7 (Cq), 87.6 (C5), 56.7 (OMe), 55.5 (OMe), 41.7
(N(CH2CH3)2), 38.2 (N(CH2CH3)2), 13.4 (N(CH2CH3)2),
12.7 (N(CH2CH3)2). IR (KBr): nmax 3370, 2974, 2929, 1639,
1607, 1577, 1537, 1359, 1220, 1090 cmK1. EIMS: m/z
(relative intensity) 460 ([MC2]C, 33), 458 (MC, 35), 360
(87), 358 (100). Anal. calcd for C22H23BrN2O4: C, 57.53; H,
5.05; N, 6.10. Found: C, 57.44; H, 5.08; N, 6.24.
4.4.2. N-n-Butyl 3-(4-bromophenyl)-4,6-dimethoxy-
indole-7-glyoxylamide 16 (0.291 g, 40%). Yellow solid,
mp 219–220 8C. 1H NMR (300 MHz, CDCl3): d 10.44 (br s,
1H, NH), 7.50 and 7.42 (2d, 4H, 4-BrArH), 7.07 (d, 1H,
H2), 6.19 (s, 1H, H5), 5.95 (br t, 1H, NHBun), 3.95 and 3.92
(2s, 6H, 2!OMe), 3.45 (q, 2H, NHCH2CH2CH2CH3, JZ
6.72 Hz), 1.65 and 1.47 (2m, 4H, NHCH2CH2CH2CH3),
1.00 (t, 3H, NHCH2CH2CH2CH3, JZ7.28 Hz). 13C NMR
(75 MHz, CDCl3): d 190.0 (ArCOCONHBun), 167.8
(ArCOCONHBun), 162.2 (COMe), 161.6 (COMe), 138.7
(Cq), 134.2 (Cq), 131.0 (2!CH), 130.7 (2!CH), 121.7
(C2), 120.0 (Cq), 118.0 (Cq), 110.5 (Cq), 101.4 (Cq), 87.9
(C5), 57.1 (OMe), 55.4 (OMe), 39.0 (NHCH2CH2CH2CH3),
31.5 (NHCH2CH2CH2CH3), 20.0 (NH CH2CH2CH2CH3),
13.8 (NHCH2CH2CH2CH3). IR (KBr): nmax 3405, 3284,
2958, 1667, 1583, 1559, 1538, 1360, 1325, 1221, 1116,
802 cmK1. EIMS: m/z (relative intensity) 460 ([MC2]C,
42), 458 (MC, 45), 360 (99), 358 (100). Anal. calcd for
C22H23BrN2O4: C, 57.53; H, 5.05; N, 6.10. Found: C, 57.70;
H, 5.14; N, 6.16.
4.6. Compounds 6 and 18
According to the general procedure, 3-(4-bromophenyl)-
4,6-dimethoxy-1-methylindole (0.170 g, 0.491 mmol) in
dichloromethane (10 mL) was treated with oxalyl chloride
(74.8 mg, 0.590 mmol) at 0 8C for 30 min followed by
addition of ethanol (10 mL) and heating to reflux for 2 h.
Chromatography and elution with 1:1:3 v/v/v ethyl acetate/
dichloromethane/hexane and recrystallization afforded two
products.
4.6.1. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-1-methyl-
indole-2-glyoxylate 6 (0.074 g, 34%). Yellow solid, mp
1
138–139 8C. H NMR (300 MHz, CDCl3): d 7.40 and 7.18
4.5. Compounds 5 and 17
(2d, 4H, 4-BrArH), 6.26 (d, 1H, H7), 6.06 (d, 1H, H5), 3.95
and 3.84 (2s, 6H, 2!OMe), 3.56 (s, 3H, NMe), 3.54 (q, 2H,
OCH2CH3, JZ7.21 Hz), 1.05 (t, 3H, OCH2CH3, JZ
7.21 Hz). IR (KBr): nmax 2941, 1737, 1639, 1614, 1509,
1256, 1211, 1181, 1153 cmK1. EIMS: m/z (relative
intensity) 447 ([MC2]C, 17), 445 (MC, 17), 374 (28),
372 (28), 293 (100). Anal. calcd for C21H20BrNO5: C,
56.52; H, 4.52; N, 3.14. Found: C, 56.72; H, 4.57; N, 3.29.
According to the general procedure, 3-(4-bromophenyl)-
4,6-dimethoxyindole (0.200 g, 0.602 mmol) in dichloro-
methane (20 mL) was treated with oxalyl chloride (91.7 mg,
0.722 mmol) at 0 8C for 30 min followed by addition of
N,N-diethylamine (0.63 mL, 60.2 mmol) and warming to
room temperature for 2 h. Chromatography and elution with
6:4 v/v ethyl acetate/hexane and recrystallization afforded
two products.
4.6.2. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-1-methyl-
indole-7-glyoxylate 18 (0.112 g, 51%). Pale yellow solid,
1
mp 162–163 8C. H NMR (300 MHz, CDCl3): d 7.39 and
4.5.1. N,N-Dimethyl 3-(4-bromophenyl)-4,6-dimethoxy-
indole-2-glyoxylamide 5 (0.046 g, 17%). Yellow solid, mp
235–236 8C. 1H NMR (300 MHz, CDCl3): d 9.22 (br s, 1H,
NH), 7.39 and 7.21 (2d, 4H, 4-BrArH), 6.34 (s, 1H, H7),
7.28 (2d, 4H, 4-BrArH), 6.78 (s, 1H, H2), 6.15 (s, 1H, H5),
4.33 (q, 2H, OCH2CH3, JZ7.11 Hz), 3.82 and 3.78 (2s,
6H, 2!OMe), 3.58 (s, 3H, NMe), 1.34 (t, 3H, OCH2CH3,

T. Keawin et al. / Tetrahedron 61 (2005) 853–861
857
JZ7.12 Hz). 13C NMR (75 MHz, CDCl3): d 185.0 (ArCO-
COOEt), 165.1 (ArCOCOOEt), 160.9 (COMe), 159.6
(COMe), 136.7 (Cq), 134.3 (Cq), 131.2 (2!CH), 130.6
(2!CH), 129.2 (C2), 120.0 (Cq), 117.0 (Cq), 112.8 (Cq),
104.2 (Cq), 87.8 (C5), 61.8 (OCH2CH3), 57.2 (OMe), 55.3
(OMe), 38.1 (NMe), 14.2 (OCH2CH3). IR (KBr): nmax 2946,
4.7.3. 3-(4-Bromophenyl)-4,6-dimethoxy-1-methylindole
33. According to the general procedure, 3-(4-bromophenyl)-
4,6-dimethoxyindole (0.358 g, 1.08 mmol) in dimethyl-
sulfoxide (10 mL) was treated with sodium hydride
(31.3 mg, 1.30 mmol) for 1 h followed by addition of
methyl iodide (0.08 mL, 1.30 mmol). Chromatography and
elution with 1/2/6 v/v/v ethyl acetate/dichloromethane/
hexane and recrystallization afforded 33 (0.34 g, 81%).
1741, 1631, 1578, 1542, 1290, 1212, 1036, 815 cmK1
.
EIMS: m/z (relative intensity) 447 ([MC2]C, 37), 445
(MC, 37), 374 (98), 372 (100), 294 (26), 293 (88). Anal.
calcd for C21H20BrNO5: C, 56.52; H, 4.52; N, 3.14. Found:
C, 56.75; H, 4.59; N, 3.25.
1
Pale yellow solid, mp 144.5–146 8C. H NMR (300 MHz,
CDCl3): d 7.39 (s, 4H, 4-BrArH), 6.81 (s, 1H, H2), 6.32 (d,
1H, H7, JZ1.66 Hz), 6.19 (d, 1H, H5, JZ1.63 Hz), 3.82
and 3.73 (2s, 6H, 2!OMe), 3.66 (s, 3H, NMe). IR (KBr):
(
max 3001, 2934, 1617, 1582, 1541, 1214, 1153, 835 cmK1
.
4.7. General procedure for methylation of 4,6-
dimethoxyindoles
EIMS: m/z (relative intensity) 347 ([MC2]C, 77), 345
(MC, 77), 332 (17), 330 (19), 304 (12), 302 (13), 251 (100),
236 (25), 208 (16). Anal. calcd for C17H16BrNO2: C, 58.97;
H, 4.66; N, 4.05. Found: C, 59.38; H, 4.36; N, 3.71.
To a suspension of sodium hydride (1.2 equiv) in dry
dimethylsulfoxide under nitrogen was added a solution of
the indole (1.0 equiv) in dry dimethylsulfoxide and the
mixture stirred at room temperature for 1 h. Methyl iodide
(1.2 equiv) was added and the mixture stirred at room
temperature for 18 h. Water was added and the solution was
extracted with CH2Cl2. The organic layer was washed with
water and saturated NaCl, dried over MgSO4, and
concentrated under reduced pressure. The crude product
was purified by column chromatography (ethyl acetate/
dichloromethane/hexane) and recrystallization (CH2Cl2/
light petroleum).
4.7.4. 3-(4-Bromophenyl)-4,6-dimethoxy-1,7-dimethyl-
indole 34. To a solution of 3-(4-bromophenyl)-4,6-
dimethoxy-7-carboxaldehyde 13 (123.4 mg, 0.34 mmol) in
ethanol (10 mL) was added hydrazine 35% solution in water
(0.32 mL, 3.43 mmol) at reflux. After 3 h, to this solution
was added KOH (384.4 mg, 6.85 mmol) in ethylene glycol
(10 mL) and the mixture warmed to 150 8C for 18 h. After
cooling to room temperature, the reaction mixture was
neutralised with dilute hydrochloric acid and extracted
several times with CH2Cl2. The combined organic layer was
washed with H2O, saturated NaCl solution, then dried over
MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by chromatography and
elution with 1/1 v/v dichloromethane/hexane to give 3-(4-
bromophenyl)-4,6-dimethoxy-7-methylindole (93.6 mg,
79%).
4.7.1. 4,6-Dimethoxy-1,3-dimethylindole 31. According to
the general procedure, 4,6-dimethoxy-3-methylindole
(0.350 g, 1.83 mmol) in dimethylsulfoxide (30 mL) was
treated with sodium hydride (52.7 mg, 2.20 mmol) for 1 h
followed by addition of methyl iodide (0.14 mL,
2.20 mmol). Chromatography and elution with 7:3 v/v
dichloromethane/hexane and recrystallization afforded 31
(0.334 g, 89%). Colourless solid, mp 105–106 8C. 1H NMR
(300 MHz, CDCl3): d 6.47 (s, 1H, H2), 6.23 (s, 1H, H7),
6.08 (s, 1H, H5), 3.79 and 3.78 (2s, 6H, 2!OMe), 3.54 (s,
3H, NMe), 2.33 (s, 3H, 3-Me). IR (KBr): nmax 2965, 2931,
According to the general procedure, 3-(4-bromophenyl)-
4,6-dimethoxy-7-methylindole (0.053 g, 0.154 mmol) in
dimethylsulfoxide (5 mL) was treated with sodium hydride
(4.2 mg, 0.184 mmol) for 1 h followed by methyl iodide
(0.01 mL, 0.184 mmol). Chromatography and elution with
7/3 v/v dichloromethane/hexane and recrystallization
afforded 34 (0.053 g, 95%). Colourless solid, mp 194–
1619, 1589, 1459, 1315, 1265, 1214, 1146, 1105 cmK1
.
EIMS: m/z (relative intensity) 206 ([MC1]C, 17), 205
(MC, 100), 191 (18), 190 (61), 162 (33), 147 (22). Anal.
calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C,
70.56; H, 7.39; N, 7.04.
1
195 8C. H NMR (300 MHz, CDCl3): d 7.48 and 7.43 (2d,
4H, 4-BrArH), 6.80 (s, 2H, H2), 6.37 (s, 2H, H5), 4.01 and
3.90 (2s, 6H, 2!OMe), 3.80 (s, 3H, NMe), 2.61 (s, 3H,
ArMe). 13C NMR (75 MHz, CDCl3): d 154.1 (COMe),
152.3 (COMe), 137.9 (Cq), 135.1 (Cq), 131.1 (2!CH),
130.4 (2!CH), 128.4 (C2), 119.3 (Cq), 115.4 (Cq), 112.2
(Cq), 102.5 (Cq), 90.6 (C5), 57.9 (OMe), 55.2 (OMe), 37.1
(NMe), 10.2 (ArMe). IR (KBr): nmax 2996, 2935, 2840,
1613, 1587, 1545, 1512, 1467, 1333, 1210, 1121, 1088,
1040, 794 cmK1. EIMS: m/z (relative intensity) 361 ([MC
2]C, 96), 359 (MC, 100), 346 (42), 344 (35), 266 (54), 264
(58), 250 (27). Anal. calcd for C18H18BrNO2: C, 60.01; H,
5.04; N, 3.89. Found: C, 59.69; H, 4.93; N, 3.87.
4.7.2. 4,6-Dimethoxy-1-methyl-3-phenylindole 32.
According to the general procedure, 4,6-dimethoxy-3-
phenylindole (0.258 g, 1.01 mmol) in dimethylsulfoxide
(10 mL) was treated with sodium hydride (29.1 mg,
1.21 mmol) for 1 h followed by addition of methyl iodide
(0.07 mL, 1.21 mmol). Chromatography and elution with
6:3 v/v dichloromethane/hexane and recrystallization
afforded 32 (0.226 g, 83%). Colourless solid, mp 119–
1
120 8C. H NMR (300 MHz, CDCl3): d 7.53 (d, 2H, PhH,
JZ7.33 Hz), 7.28 (t, 2H, PhH, JZ7.48 Hz), 7.16 (t, 1H,
PhH, JZ7.23 Hz), 6.82 (s, 1H, H2), 6.23 (d, 1H, H7, JZ
1.47 Hz), 6.19 (d, 1H, H5, JZ1.36 Hz), 3.82 and 3.73 (2s,
6H, 2!OMe), 3.67 (s, 3H, NMe). IR (KBr): nmax 2961,
2934, 1623, 1599, 1585, 1541, 1505, 1333, 1210, 1151,
1048, 802, 767, 703 cmK1. EIMS: m/z (relative intensity)
269 ([MC1]C, 19), 268 (MC, 100), 252 (51), 237 (14), 224
(22), 221 (16). Anal. calcd for C17H17NO2: C, 76.38; H,
6.41; N, 5.24. Found: C, 76.70; H, 6.57; N, 5.33.
4.8. General procedure for nitration or oxidative
dimerisation
To a solution of the indole in acetonitrile was added 65%
nitric acid with stirring at 0 8C or room temperature. The
reaction was closely monitored by TLC. Water was added
when the reaction was completed and the solution was

858
T. Keawin et al. / Tetrahedron 61 (2005) 853–861
extracted with CH2Cl2. The organic layer was washed with
water and saturated NaCl solution, then dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
product was purified by chromatography and recrystalliza-
tion from dichloromethane/hexane.
4.8.4. N-n-Butyl 3-(4-bromophenyl)-4,6-dimethoxy-7-
nitroindole-2-glyoxylamide 10. Following the general
procedure, treatment of indole 4 (0.064 g, 0.139 mmol) in
acetonitrile (10 mL) with 65% nitric acid (0.08 mL) at room
temperature for 20 min afforded nitroindole 10 (0.051 g,
73%) purified by chromatography and elution with 7:3 v/v
ethyl acetate/hexane and recrystallization. Pale yellow
solid, mp 194–196 8C. 1H NMR (300 MHz, CDCl3): d
12.97 (br s, 1H, NH), 7.36 (br t, 1H, CONHBun), 7.53 and
7.28 (2d, 4H, 4-BrArH), 6.19 (s, 1H, H5), 4.11 and 3.82 (2s,
6H, 2!OMe), 3.37 (q, 2H, NHCH2CH2CH2CH3, JZ
6.66 Hz), 1.54 and 1.37 (2m, 2H, NHCH2CH2CH2CH3),
0.93 (t, 3H, NHCH2CH2CH2CH3, JZ7.18 Hz). 13C NMR
(75 MHz, CDCl3): d 174.3, 160.1, 162.3, 162.1, 133.6,
132.5, 131.9, 131.5, 130.4, 129.4, 128.0, 121.9, 118.6,
112.7, 88.6, 57.4, 55.9, 39.2, 31.1, 20.0, 13.6. IR (KBr): nmax
3390, 3357, 2959, 2934, 1651, 1619, 1570, 1517, 1322,
1290, 1228, 1200 cmK1. EIMS: m/z (relative intensity) 505
([MC2]C, 31), 503 (MC, 33), 405 (54), 403 (52), 324
(100). Anal. calcd for C22H22BrN3O6: C, 52.39; H, 4.40; N,
8.33. Found: C, 51.91; H, 4.46; N, 8.05. HRMS calcd for
[C22H22BrN3O6CH]C: 504.0770. Found: 504.0762.
4.8.1. 2-Acetyl-3-(4-bromophenyl)-4,6-dimethoxy-7-
nitroindole 7. Following the general procedure, treatment
of indole 1 (0.040 g, 0.107 mmol) in acetonitrile (10 mL)
with 65% nitric acid (0.08 mL) at room temperature for
120 min afforded nitroindole 7 (0.034 g, 75%) purified by
chromatography and elution with 4:1 v/v dichloromethane/
hexane and recrystallization. Pale green solid, mp 278–
1
279 8C. H NMR (300 MHz, CDCl3): d 10.72 (br s, 1H,
NH), 7.60 and 7.29 (2d, 4H, 4-BrArH), 6.19 (s, 1H, H5),
4.11 and 3.78 (2s, 6H, 2!OMe), 2.03 (s, 3H, COMe). 13C
NMR (75 MHz, CDCl3): d 189.5, 162.1, 153.6, 133.4,
132.5, 132.1, 131.9, 131.0, 123.4, 122.2, 118.4, 113.4, 88.4,
57.3, 55.9, 28.4. IR (KBr): nmax 3411, 2924, 1642, 1575,
1543, 1365, 1223 cmK1. EIMS: m/z (relative intensity) 420
([MC2]C, 100), 418 (MC, 89), 324 (84). HRMS calcd for
[C18H15BrN2O5CNa]C: 441.0062. Found: 441.0075.
4.8.5. N,N-Dimethyl 3-(4-bromophenyl)-4,6-dimethoxy-
7-nitroindole-2-glyoxylamide 11. Following the general
procedure, treatment of indole 5 (0.062 g, 0.133 mmol) in
acetonitrile (10 mL) with 65% nitric acid (0.16 mL) at room
temperature for 20 min afforded nitroindole 11 (0.042 g,
63%) purified by chromatography and elution with 1:1 v/v
ethyl acetate/hexane and recrystallization. Pale yellow
solid, mp 214–215 8C. 1H NMR (300 MHz, CDCl3): d
10.73 (br s, 1H, NH), 7.42 and 7.18 (2d, 4H, 4-BrArH), 6.11
(s, 1H, H5), 4.03 and 3.70 (2s, 6H, 2!OMe), 3.06–2.93 (m,
4H, N(CH2CH3)2), 1.06 and 0.78 (2t, 6H, N(CH2CH3)2, JZ
7.10 Hz). 13C NMR (75 MHz, CDCl3): d 182.2, 165.2,
162.3, 160.0, 133.7, 132.4, 130.9, 130.2, 128.9, 126.4,
122.4, 118.3, 113.3, 88.6, 57.4, 56.0, 42.5, 39.1, 13.9, 12.3.
IR (KBr): nmax 3414, 2924, 1648, 1619, 1569, 1542, 1366,
1302, 1274, 1224 cmK1. EIMS: m/z (relative intensity) 505
([MC2]C, 7), 503 (MC, 7), 405 (23), 403 (26), 324 (100).
Anal. calcd for C22H22BrN3O6: C, 52.39; H, 4.40; N, 8.33.
Found: C, 52.65; H, 4.40; N, 8.34.
4.8.2. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-7-nitro-
indole-2-carboxylate 8. Following the general procedure,
treatment of indole 2 (0.042 g, 0.105 mmol) in acetonitrile
(15 mL) with 65% nitric acid (0.12 mL) at room tempera-
ture for 30 min afforded nitroindole 8 (0.031 g, 66%)
purified by chromatography and elution with 4:1 v/v
dichloromethane/hexane and recrystallization. Pale yellow
solid, mp 227–228 8C. 1H NMR (300 MHz, CDCl3): d 10.66
(br s, 1H, NH), 7.28 and 7.51 (2d, 4H, 4-BrArH), 6.21 (s,
1H, H5), 4.26 (q, 2H, OCH2CH3, JZ7.12 Hz), 4.10 and
3.81 (2s, 6H, 2!OMe), 1.22 (t, 3H, OCH2CH3, JZ
7.11 Hz). 13C NMR (75 MHz, CDCl3): d 161.7, 160.4,
158.9, 132.4, 132.4, 130.0, 124.1, 123.0, 121.5, 118.5,
112.7, 88.4, 61.0, 57.3, 55.9, 14.1. IR (KBr): nmax 3456,
2924, 1715, 1623, 1578, 1469, 1288, 1225 cmK1. EIMS:
m/z (relative intensity) 450 ([MC2]C, 100), 448 (MC, 97),
422 (47), 420 (55), 374 (29), 372 (30), 323 (40). HRMS
calcd for [C19H17BrN2O6CNa]C: 471.0168. Found:
471.0152.
4.8.6. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-1-methyl-
7-nitroindole-2-glyoxylate 12. Following the general
procedure, treatment of indole 6 (0.025 g, 0.057 mmol) in
acetonitrile (10 mL) with 65% nitric acid (0.08 mL) at room
temperature for 60 min afforded nitroindole 12 (0.024 g,
85%) purified by chromatography and elution with 4:1 v/v
dichloromethane/hexane and recrystallization. Pale yellow
solid, mp 208–209 8C. 1H NMR (300 MHz, CDCl3): d 7.51
and 7.23 (2d, 4H, 4-BrArH), 6.22 (s, 1H, H5), 4.02 and 3.85
(2s, 6H, 2!OMe), 3.74 (s, 3H, NMe), 3.66 (q, 2H,
OCH2CH3, JZ7.14 Hz), 1.15 (t, 3H, OCH2CH3, JZ
7.14 Hz). 13C NMR (75 MHz, CDCl3): d 179.3 (ArCO-
COOEt), 163.2 (ArCOCOOEt), 158.6 (COMe), 154.4
(COMe), 133.0 (2!CH), 130.2 (2!CH), 132.9 (Cq),
131.4 (Cq), 130.4 (Cq), 128.7 (Cq), 122.4 (Cq), 121.5
(Cq), 112.5 (Cq), 88.1 (C5), 62.3 (OCH2CH3), 57.3 (OMe),
55.7 (OMe), 33.7 (NMe), 13.5 (OCH2CH3). IR (KBr): nmax
2992, 1737, 1646, 1621, 1569, 1524, 1323, 1223, 1206,
804 cmK1. EIMS: m/z (relative intensity) 492 ([MC2]C,
25), 490 (MC, 26), 419 (37), 417 (40), 339 (34), 338 (100).
4.8.3. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-7-nitro-
indole-2-glyoxylate 9. Following the general procedure,
treatment of indole 3 (0.067 g, 0.154 mmol) in acetonitrile
(10 mL) with 65% nitric acid (0.08 mL) at room tempera-
ture for 240 min afforded nitroindole 9 (0.051 g, 69%)
purified by chromatography and elution with 1:1:2 v/v/v
ethyl acetate/dichloromethane/hexane and recrystallization.
1
Pale yellow solid, mp 221–223 8C. H NMR (300 MHz,
CDCl3): d 11.09 (br s, 1H, NH), 7.54 and 7.29 (2d, 4H,
4-BrArH), 6.23 (s, 1H, H5), 3.89 (q, 2H, OCH2CH3, JZ
7.10 Hz), 4.13 and 3.84 (2s, 6H, 2!OMe), 1.20 (t, 3H,
OCH2CH3, JZ7.18 Hz). 13C NMR (75 MHz, CDCl3): d
176.5, 163.1, 162.3, 160.3, 134.0, 132.4, 131.2, 130.4,
128.2, 128.1, 122.5, 118.4, 112.9, 88.8, 62.5, 57.4, 56.0,
13.6. IR (KBr): nmax 3395, 2924, 1742, 1614, 1575, 1317,
1276, 1206 cmK1. EIMS: m/z (relative intensity) 478 ([MC
2]C, 17), 476 (MC, 15), 405 (34), 403 (34), 324 (100). Anal.
calcd for C20H17BrN2O7: C, 50.33; H, 3.59; N, 5.87. Found:
C, 50.26; H, 3.72; N, 5.74.

T. Keawin et al. / Tetrahedron 61 (2005) 853–861
859
HRMS calcd for [C21H19BrN2O7CNa]C: 513.0273. Found:
513.0273.
procedure, treatment of indole 16 (0.098 g, 0.212 mmol)
in acetonitrile (10 mL) with 65% nitric acid (0.08 mL) at
room temperature for 20 min afforded nitroindole 22
(0.0731 g, 68%) purified by chromatography and elution
with 7:3 v/v ethyl acetate/hexane and recrystallization.
Yellow solid, mp 245–246 8C. 1H NMR (300 MHz,
CDCl3): d 10.93 (br s, 1H, NH), 7.49 and 7.18 (2d, 4H,
4-BrArH), 6.45 (br t, 1H, NHBun), 6.13 (s, 1H, H5), 4.00
and 3.77 (2s, 6H, 2!OMe), 3.47 (q, 2H, NHCH2CH2CH2-
CH3, JZ6.63 Hz), 1.67 and 1.50 (2m, 4H, NHCH2CH2-
CH2CH3), 1.02 (t, 3H, NHCH2CH2CH2CH3, JZ7.28 Hz).
13C NMR (75 MHz, CDCl3): d 190.0, 166.8, 165.9, 163.7,
135.5, 135.3, 132.1, 130.5, 129.8, 122.5, 118.9, 111.5,
100.5, 89.2, 57.1, 55.9, 39.0, 31.5, 20.0, 13.8. IR (KBr): nmax
3412, 3271, 2933, 1652, 1626, 1578, 1497, 1371, 1298,
1230, 1164, 986 cmK1. EIMS: m/z (relative intensity) 505
([MC2]C, 3), 503 (MC, 33), 460 (26), 458 (29), 405 (20),
403 (18), 360 (93), 358 (100). Anal. calcd for
C22H22BrN3O6: C, 52.39; H, 4.40; N, 8.33. Found: C,
52.63; H, 4.29; N, 7.95. HRMS calcd for [C22H22N3O6BrC
H]C: 504.0770. Found: 504.0764.
4.8.7. 3-(4-Bromophenyl)-4,6-dimethoxy-2-nitroindole-
7-carboxaldehyde 19. Following the general procedure,
treatment of indole 13 (0.098 g, 0.273 mmol) in acetonitrile
(10 mL) with 65% nitric acid (0.08 mL) at room tempera-
ture for 60 min afforded nitroindole 19 (0.072 g, 65%)
purified by chromatography and elution with 4:1 v/v
dichloromethane/hexane and recrystallization. Pale yellow
solid, mp 284–286 8C. 1H NMR (300 MHz, CDCl3): d 11.21
(br s, 1H, NH), 10.36 (s, 1H, CHO), 7.54 and 7.30 (2d, 4H,
4-BrArH), 6.18 (s, 1H, H5), 4.04 and 3.80 (2s, 6H, 2!
OMe). 13C NMR (75 MHz, CDCl3): d 187.6, 166.4, 163.5,
135.7, 134.3, 132.0, 130.5, 130.2, 122.3, 118.6, 111.2,
103.6, 88.3, 56.4, 55.7. IR (KBr): nmax 3409, 2869, 1649,
1602, 1495, 1299, 1247, 1219, 1151 cmK1. EIMS: m/z
(relative intensity) 406 ([MC2]C, 64), 404 (MC, 78), 376
(30), 374 (32), 295 (68), 280 (100). Anal. calcd for
C17H13BrN2O5: C, 50.39; H, 3.23; N, 6.91. Found: C,
50.75; H, 3.42; N, 6.55.
4.8.8. 4,6-Dimethoxy-3-(4-methoxyphenyl)-2-nitro-
indole-7-carboxaldehyde 20. Following the general
procedure, treatment of indole 14 (0.102 g, 0.327 mmol)
in acetonitrile (10 mL) with 65% nitric acid (0.08 mL) at
room temperature for 120 min afforded nitroindole 20
(0.041 g, 35%) purified by chromatography and elution
with 1:1 v/v ethyl acetate/hexane and recrystallization. Pale
yellow solid, mp 241–242 8C. 1H NMR (300 MHz, CDCl3):
d 11.10 (br s, 1H, NH), 10.28 (s, 1H, –CHO), 7.31 and 6.88
(2d, 4H, 4-MeOArH), 6.09 (s, 1H, H5), 3.96, 3.81, and 3.73
(3s, 12H, 3!OMe). 13C NMR (75 MHz, CDCl3): d 187.7,
166.5, 163.8, 159.5, 135.8, 134.5, 131.9, 123.1, 120.3,
112.8, 111.6, 103.5, 88.1, 56.4, 55.8, 55.2. IR (KBr): nmax
3406, 2924, 2852, 1649, 1598, 1509, 1302, 1238, 1217,
1175 cmK1. EIMS: m/z (relative intensity) 357 ([MC1]C,
19), 356 (MC, 100), 326 (30), 295 (21), 280 (13). HRMS
calcd for [C18H16N2O6CNa]C: 379.0906. Found:
379.0909.
4.8.11. N,N-Dimethyl 3-(4-bromophenyl)-4,6-dimethoxy-
2-nitroindole-7-glyoxylamide 23. Following the general
procedure, treatment of indole 17 (0.050 g, 0.109 mmol) in
acetonitrile (15 mL) with 65% nitric acid (0.12 mL) at room
temperature for 20 min afforded nitroindole 23 (0.041 g,
74%) purified by chromatography and elution with 7:3 v/v
ethyl acetate/hexane and recrystallization. Yellow solid, mp
244–246 8C. 1H NMR (300 MHz, CDCl3): d 11.37 (br s, 1H,
NH), 7.48 and 7.23 (2d, 4H, 4-BrArH), 6.11 (s, 1H, H5),
3.90 and 3.73 (2s, 6H, 2!OMe), 3.45 (br q, 2H,
N(CH2CH3)2), 3.12 (q, 2H, N(CH2CH3)2, JZ7.03 Hz),
1.22 and 1.13 (2t, 6H, N(CH2CH3)2, JZ7.08 Hz). 13C NMR
(75 MHz, CDCl3): d 189.4, 167.6, 165.3, 163.7, 135.6,
135.4, 132.0, 130.5, 130.1, 122.3, 118.7, 111.8, 101.0, 88.9,
56.7, 55.8, 41.7, 38.3, 13.4, 12.6. IR (KBr): nmax 3404, 2927,
1646, 1631, 1596, 1578, 1466, 1299, 1241, 1165 cmK1
.
EIMS: m/z (relative intensity) 505 ([MC2]C, 9), 503 (MC,
10), 405 (100), 403 (90), 324 (24). Anal. calcd for
C22H22BrN3O6: C, 52.39; H, 4.40; N, 8.33. Found: C,
52.34; H, 4.56; N, 8.18. HRMS calcd for [C22H22BrN3O6C
Na]C: 526.0590. Found: 526.0597.
4.8.9. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-2-nitro-
indole-7-glyoxylate 21. Following the general procedure,
treatment of indole 15 (0.069 g, 0.158 mmol) in acetonitrile
(10 mL) with 65% nitric acid (0.08 mL) at room tempera-
ture for 240 min afforded nitroindole 21 (0.064 g, 85%)
purified by chromatography and elution with 1:1:2 v/v/v
ethyl acetate/dichloromethane/hexane and recrystallization.
Yellow solid, mp 209–210 8C. 1H NMR (300 MHz, CDCl3):
d 11.27 (br s, 1H, NH), 7.57 and 7.33 (2d, 4H, 4-BrArH),
6.19 (s, 1H, H5), 4.44 (q, 2H, COOCH2CH3, JZ7.15 Hz),
4.01 and 3.83 (2s, 6H, 2!OMe), 1.43 (t, 3H, OCH2CH3,
JZ7.10 Hz). 13C NMR (75 MHz, CDCl3): d 184.7, 165.5,
165.2, 164.3, 135.8, 135.2, 132.0, 130.6, 130.1, 122.5,
118.8, 111.9, 100.2, 88.9, 61.8, 57.0, 56.0, 14.2. IR (KBr):
nmax 3407, 2984, 1744, 1636, 1579, 1309, 1232, 1207, 1161,
817 cmK1. EIMS: m/z (relative intensity) 478 ([MC2]C,
17), 476 (MC, 18), 447 (31), 445 (31), 405 (84), 403 (83),
374 (73), 372 (72), 293 (100). HRMS calcd for [C20H17-
BrN2O7CNa]C: 499.0117. Found: 499.0118.
4.8.12. Ethyl 3-(4-bromophenyl)-4,6-dimethoxy-1-
methyl-2-nitroindole-7-glyoxylate 24. Following the
general procedure, treatment of indole 18 (0.050 g,
0.112 mmol) in acetonitrile (10 mL) with 65% nitric acid
(0.12 mL) at room temperature for 120 min afforded
nitroindole 24 (0.049 g, 88%) purified by chromatography
and elution with 1:1:1 v/v/v ethyl acetate/dichloromethane/
hexane and recrystallization. Yellow solid, mp 212.5–
1
213 8C. H NMR (300 MHz, CDCl3): d 7.54 and 7.26 (2d,
4H, 4-BrArH), 6.23 (s, 1H, H5), 4.45 (q, 2H, OCH2CH3, JZ
7.10 Hz), 3.96 and 3.75 (2s, 6H, 2!OMe), 3.68 (s, 3H,
NMe), 1.41 (t, 3H, OCH2CH3, JZ7.10 Hz). 13C NMR
(75 MHz, CDCl3): d 184.6 (ArCOCOOEt), 164.5 (ArCO-
COOEt), 164.5 (COMe), 162.0 (COMe), 137.8 (Cq), 131.9
(2!CH), 130.9 (Cq), 130.5 (2!CH), 122.1 (Cq), 120.1
(Cq), 111.4 (Cq), 103.5 (Cq), 88.9 (C5), 62.1 (OCH2CH3),
57.0 (OMe), 55.7 (OMe), 37.7 (NMe), 14.2 (OCH2CH3). IR
(KBr): nmax 2982, 1728, 1664, 1579, 1497, 1311, 1294,
1227, 1155, 1055, 800 cmK1. EIMS: m/z (relative intensity)
4.8.10. N-n-Butyl 3-(4-bromophenyl)-4,6-dimethoxy-2-
nitroindole-7-glyoxylamide 22. Following the general

860
T. Keawin et al. / Tetrahedron 61 (2005) 853–861
492 ([MC2]C, 13), 490 (MC, 14), 419 (99), 417 (100), 293
(27). HRMS calcd for [C21H19BrN2O7CNa]C: 513.0273.
Found: 513.0264.
2!NMe), 2.29 (s, 6H, 2!Me). 13C NMR (75 MHz,
CDCl3): d 157.5, 155.5, 138.9, 125.3, 113.0, 112.4, 91.0,
85.1, 55.7, 55.2, 30.4, 11.5. IR (KBr): nmax 2936, 1622,
1581, 1257, 1212, 1150, 803 cmK1. EIMS: m/z (relative
intensity) 409 ([MC1]C, 13), 408 (MC, 49), 393 (23), 174
(15), 105 (100), 77 (55). HRMS calcd for [C24H28N2O4C
H]C: 409.2127. Found: 409.2132.
4.8.13. 7,70-Bi(4,6-dimethoxy-2,3-diphenyl)indolyl 28.
According to the general procedure, treatment of indole
25 (0.150 g, 0.456 mmol) in acetonitrile (15 mL) with 65%
nitric acid (0.12 mL) at 0 8C for 4 h afforded dimer 28
(0.128 g, 86%) purified by chromatography and elution with
1:1 v/v dichloromethane/hexane and recrystallization.
4.8.17. 2,20-Bi(4,6-dimethoxy-1-methyl-3-phenyl)indolyl
36. According to the general procedure, treatment of indole
32 (0.081 g, 0.302 mmol) in acetonitrile (10 mL) with 65%
nitric acid (0.08 mL) at 0 8C for 18 h afforded dimer 36
(0.020 g, 25%) purified by chromatography and elution with
1:1 v/v dichloromethane/hexane and recrystallization.
Colourless solid, mpO320 8C. 1H NMR (300 MHz,
CDCl3): d 7.32–7.13 (m, 10H, PhH), 6.31 (s, 2H, H7),
6.21 (s, 2H, H5), 3.89 and 3.79 (2s, 12H, 4!OMe), 3.14 (s,
6H, 2!NMe). 13C NMR (75 MHz, CDCl3): d 157.5, 154.9,
139.0, 135.5, 130.3, 128.0, 127.1, 125.3, 118.1, 110.7, 92.0,
85.2, 55.6, 50.1, 30.4. IR (KBr): nmax 3449, 2931, 1617,
1583, 1323, 1257, 1214, 1150, 696 cmK1. EIMS: m/z
(relative intensity) 533 ([MC1]C, 6), 532 (MC, 17), 456
(7), 165 (100), 149 (25). HRMS calcd for [C34H32N2O4C
Na]C: 555.2260. Found: 555.2252.
1
Colourless solid, mp 295–296 8C (lit. 290 8C)9. H NMR
(300 MHz, CDCl3): d 8.01 (br s, 2H, NH), 7.46–7.15 (m,
20H, PhH), 6.49 (s, 2H, H5), 3.83 and 3.79 (2s, 12H, 4!
OMe). 13C NMR (75 MHz, CDCl3): 154.8, 154.1, 137.0,
136.0, 132.9, 132.8, 131.4, 128.2, 128.0, 127.2, 126.8,
125.8, 114.9, 113.5, 98.7, 90.7, 57.6, 55.4. IR (KBr): nmax
3456, 2995, 2931, 2836, 1599, 1425, 1330, 1137, 698 cmK1
.
EIMS: m/z (relative intensity) 657 ([MC1]C, 11), 656
(MC, 24), 419 (99), 417 (100), 293 (33).
4.8.14. 7,70-Bi(4,6-dimethoxy-2-methyl-3-phenyl)indolyl
29. According to the general procedure, treatment of indole
26 (0.200 g, 0.750 mmol) in acetonitrile (20 mL) with 65%
nitric acid (0.16 mL) at 0 8C for 3.5 h afforded dimer 29
(0.163 g, 82%) purified by chromatography and elution with
1:1 v/v dichloromethane/hexane and recrystallization. Pale
yellow solid, mp 291–293 8C. 1H NMR (300 MHz, CDCl3):
d 7.68 (br s, 2H, NH), 7.49–7.24 (m, 10H, PhH), 6.47 (s, 2H,
H5), 3.79 (2s, 12H, 4!OMe), 2.28 (s, 6H, Me). 13C NMR
(75 MHz, CDCl3): d 153.7, 153.5, 136.3, 136.1, 130.9,
130.0, 127.0, 125.3, 114.0, 112.3, 98.7, 90.7, 57.8, 55.3,
12.1. IR (KBr): nmax 3456, 2934, 1601, 1427, 1326, 1211,
1123 cmK1. EIMS: m/z (relative intensity) 533 ([MC1]C,
37), 532 (MC, 100), 486 (54), 267 (68), 252 (57) Anal. calcd
for C34H32N2O4: C, 76.67; H, 6.06; N, 5.26. Found: C,
76.31; H, 6.13; N, 5.23.
4.8.18. 2,20-Bi(3-(4-bromophenyl)-4,6-dimethoxy-1-
methyl)indolyl 37. According to the general procedure,
treatment of indole 33 (0.102 g, 0.296 mmol) in acetonitrile
(10 mL) with 65% nitric acid (0.08 mL) at 0 8C for 18 h
afforded dimer 37 (0.064 g, 63%) purified by chromato-
graphy and elution with 3:2 v/v dichloromethane/hexane
and recrystallization. Pale yellow solid, mp 259–261 8C. 1H
NMR (300 MHz, CDCl3): d 7.25 and 7.08 (2d, 8H,
4-BrArH), 6.38 (d, 2H, H7, JZ1.71 Hz), 6.31 (d, 2H, H5,
JZ1.71 Hz), 3.92 and 3.80 (2s, 12H, 4!OMe), 3.26 (s, 6H,
2!NCH3). 13C NMR (75 MHz, CDCl3): d 157.9, 154.8,
139.1, 134.3, 131.7, 130.2, 125.7, 119.4, 117.6, 110.4, 92.3,
85.2, 55.6, 55.1, 30.6. IR (KBr): nmax 3447, 2933, 1622,
1582, 1506, 1327, 1258, 1213, 1151, 1074 cmK1. EIMS:
m/z (relative intensity) 692 ([MC2]C, 33), 690 (MC, 56),
688 (30), 361 (99), 359 (100), 265 (91). Anal. calcd for
C34H30Br2N2O4: C, 59.15; H, 4.38; N, 4.06. Found: C,
59.29; H, 4.72; N, 4.27.
4.8.15. 7,70-Bi(4,6-dimethoxy-2-methyl-3-(4-bromo-
phenyl)indolyl 30. According to the general procedure,
treatment of indole 27 (0.100 g, 0.289 mmol) in acetonitrile
(10 mL) with 65% nitric acid (0.08 mL) at 0 8C for 4 h
afforded dimer 30 (0.082 g, 82%) purified by chromato-
graphy and elution with 1:1 v/v dichloromethane/hexane
and recrystallization. Pale yellow solid, mp 282–283 8C. 1H
NMR (300 MHz, CDCl3): d 7.68 (br s, 2H, NH), 7.49 and
7.33 (2d, 8H, 4-BrArH), 6.46 (s, 2H, H5), 3.81 and 3.78 (2s,
12H, 4!OMe), 2.25 (s, 6H, Me). 13C NMR (75 MHz,
CDCl3): d 153.6, 136.3, 135.0, 132.5, 130.1, 119.3, 112.9,
111.9, 98.6, 90.5, 57.7, 55.2, 12.1. IR (KBr): nmax 3458,
2936, 1591, 1428, 1327, 1212, 1135 cmK1. EIMS: m/z
(relative intensity) 692 ([MC2]C, 49), 690 (MC, 100), 688
(51), 644 (48), 345 (37). Anal. calcd for C34H30Br2N2O4: C,
59.15; H, 4.38; N, 4.06. Found: C, 59.00; H, 4.70; N, 3.95.
4.8.19. 2,20-Bi(3-(4-bromophenyl)-4,6-dimethoxy-1,7-
dimethyl)indolyl 38. According to the general procedure,
treatment of indole 34 (0.052 g, 0.0145 mmol) in aceto-
nitrile (10 mL) with 65% nitric acid (0.08 mL) at 0 8C for
10 h afforded dimer 38 (0.038 g, 72%) purified by
chromatography and elution with 1:1 v/v dichloromethane/
hexane and recrystallization. Colourless solid, mp 302–
1
303 8C. H NMR (300 MHz, CDCl3): d 7.18 and 6.78 (2d,
8H, 4-BrArH), 6.35 (s, 2H, H5), 3.92 (s, 6H, OMe), 3.72 (s,
12H, ArOMe and NMe), 2.62 (s, 6H, ArMe). 13C NMR
(75 MHz, CDCl3): d 154.7, 152.5, 138.5, 134.4, 131.7,
129.7, 128.2, 119.2, 117.7, 112.3, 102.2, 90.3, 57.7, 55.0,
34.0, 10.7. IR (KBr): nmax 3449, 2930, 1611, 1587, 1510,
1459, 1333, 1246, 1215, 1181, 1133, 1078 cmK1. EIMS:
m/z (relative intensity) 720 ([MC2]C, 53), 718 (MC, 100),
716 (53), 372 (53), 370 (53). Anal. calcd for
C36H34Br2N2O4: C, 60.18; H, 4.77; N, 3.90. Found: C,
59.79; H, 4.68; N, 3.80.
4.8.16. 2,20-Bi(4,6-dimethoxy-1,3-dimethyl)indolyl 35.
According to the general procedure, treatment of indole
31 (0.100 g, 0.488 mmol) in acetonitrile (10 mL) with 65%
nitric acid (0.08 mL) at 0 8C for 3 h afforded dimer 35
(0.034 g, 35%) purified by chromatography and elution with
1:1 v/v dichloromethane/hexane and recrystallization.
Colourless solid, mp 167–169 8C. 1H NMR (300 MHz,
CDCl3): d 6.41 (d, 2H, H7, JZ1.64 Hz), 6.25 (d, 2H, H5,
JZ1.64 Hz), 3.94 and 3.92 (2s, 12H, 4!OMe), 3.42 (s, 6H,

T. Keawin et al. / Tetrahedron 61 (2005) 853–861
861
Kumar, N.; Nugent, S. J.; Jolliffe, K. A.; Black, D. StC.
Tetrahedron 2004, in press.
Acknowledgements
We thank the Thailand Research Fund for the award of a
Royal Golden Jubilee Ph.D. scholarship to T. K., and the
Australian Research Council for financial support.
5. Black, D. StC.; Strauch, R. J. Aust. J. Chem. 1988, 41,
1613–1619.
6. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron
1996, 52, 8925–8936.
7. Black, D. StC.; Kumar, N.; Wong, L. C. H. Synthesis 1986,
474.
8. 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.
References and notes
1. Indoles-Part Two; Houlihan, W. J., Ed.; Wiley: New York,
1972; pp 540–550.
9. Black, D. StC.; Choy, A.; Craig, D. C.; Ivory, A. J.; Kumar, N.
J. Chem. Soc., Chem. Commun. 1989, 111–112.
10. Wahyuningsih, T. D. Ph.D. Thesis, The University of New
South Wales, 2004.
2. Sundberg, R. J. The Chemistry of Indoles; Academic: New
York, 1970; pp 11–14.
3. Joule, J. A. Indole and its Derivatives. In Science of Synthesis,
Thieme: Stuttgart, 2001; Vol. 10, pp 361–652.
4. Jones, A. W.; Purwono, B.; Bowyer, P. K.; Mitchell, P. S. R.;
11. Bergman, J.; Eklund, N. Tetrahedron 1980, 36, 1439–1443.