The nitration of some 4,6-dimethoxyindoles

Article abstract of DOI:10.1016/j.tet.2004.08.086

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 adsorbed on silica, to give 7-nitro and 2-nitro-indoles, respectively. A 1-cyano-indole gives regioselectiv

Full text of DOI:10.1016/j.tet.2004.08.086

Tetrahedron 60 (2004) 10779–10786
The nitration of some 4,6-dimethoxyindoles
Ashley W. Jones, Bambang Purwono, Paul K. Bowyer, Peter S. R. Mitchell, Naresh Kumar,
*
Stephen J. Nugent, Katrina A. Jolliffe and David StC. Black
School of Chemistry, The University of New South Wales, UNSW Sydney NSW 2052, Australia
Received 14 May 2004; revised 15 July 2004; accepted 12 August 2004
Available online 30 September 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 adsorbed on silica, to give 7-nitro and 2-nitro-indoles, respectively. A 1-cyano-indole gives regioselectively the 2-nitro-
indole with loss of the cyano group.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
We were interested in the nitration of 4,6-dimethoxyindoles
for a variety of purposes, including their potential as a
source of amino indoles. Initial studies involved 4,6-
dimethoxy-2,3-diphenylindole 1a and the 40-bromophenyl
analog 1b. Investigated reaction conditions included a
mixture of concentrated nitric and sulfuric acids at 0 8C,
fuming nitric acid in tetrahydrofuran at K10 8C, copper(II)
nitrate and acetic anhydride in tetrahydrofuran at 0 8C,
concentrated nitric acid in acetic anhydride at K10 8C, and
concentrated nitric acid supported on silica gel at room
temperature: in all cases complex mixtures containing both
mono- and poly-nitrated products were obtained. Clearly
electron-withdrawing substituents were desirable and a
survey was carried out on a range of such indoles, using the
nitric acid on silica reagent. These reactions proceeded
extremely quickly, usually in less than 10 s, at room
temperature in dichloromethane, and gave good yields of
mononitrated compounds. Some of the precursor indoles
1a,13 1b,14,15 1c,13 1d,13 1g,16 1i,17 4b16 and 6b15 have been
reported previously, but details of the synthesis of 1e, 1f, 1g,
1h, 1j, 4a, 4b, 4c, 6a and 6c are provided here. Indoles 1e
and 1f were prepared using the N-phenacyl isatin ring-
opening and recyclisation strategy developed by Black and
Wong.18 The indole glyoxylic ester 1h was obtained by the
reaction of the new 3-(4-tert-butylphenyl)-4,6-dimethoxy-
indole with oxalyl chloride followed by methanol, and
indoles 1j and 4c by the reaction of 3-(4-chlorophenyl)-4,6-
dimethoxyindole with trichloroacetyl chloride. Indoles 6
were formed by phenylsulfonylation, acetylation and
cyanation, respectively, of the related indoles.
Indoles have long been known to be sensitive to acids and
therefore their nitration requires care in the design of
experimental conditions.1–3 While the 3-position is the
preferred site for electrophilic attack, in strong acid nitration
occurs on the 3H-indolium salt to give the 5-nitroindole
under the directing influence of the iminium moiety.
However, the 3,6-dinitroindole can be obtained via the
3-nitroindole under more neutral conditions. The nitration
of indoles containing hydrogen at C2 does not lead to well-
defined products but usually gives only polymeric material
presumably resulting from initial oxidative attack at C2 or at
the 2,3-double bond.4–7 While the nitration of 2-unsubsti-
tuted indoles in acidic conditions is unsuccessful, gramine
and tryptophan undergo nitration with concentrated nitric
acid in acetic acid.8,9 The success of these nitrations has
been attributed to protonation of the side chain amino group,
with the resulting positive charge preventing oxidative
attack through electrostatic repulsion. Indoles bearing a
3-aryl group can undergo nitration in that ring rather than
the indole ring.10 Also, ipso-nitration can occur at C3 with
the displacement of acyl and hydroxymethyl groups.11
Recently, nitric acid absorbed onto silica has been used to
mononitrate some activated indoles in reasonable chemical
yields and with moderate regioselectivity, provided they
also contained an electron-withdrawing group at N1 or
C2.12
Keywords: Indole; Nitration; Nitric acid.
Thus the indoles 1c–j with electron-withdrawing groups at
C2 (and sometimes also C3) gave the 7-nitro compounds
* Corresponding author. Tel.: C61-2-9385-4657; fax: C61-2-9385-6141;
e-mail: d.black@unsw.edu.au
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.086

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A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
clear regiochemical preference for formation of the 2-nitro-
indole 7c, possibly as the result of hydrogen bonding of the
cyano group on to free hydroxyl groups on the silica surface.
In an attempt to slow down the nitration reactions, a
nitrosation approach was investigated, as the nitrosonium
cation is less reactive than the nitronium cation: any nitroso
product could be subsequently oxidized to the related nitro
compound. The reactions of indoles with nitrous acid and
other nitrosating agents have been well studied.1,22,23
Preferred attack is at C3 and the 3-nitroso-indole is usually
isolated as its tautomeric isomer, the 3-oximino-3H-indole,
which can be oxidized to the related 3-nitro-indole. The
nitrosation of 3-aryl-4,6-dimethoxyindoles was examined
under both acidic (sodium nitrite in acetic acid) and basic
(iso-pentyl nitrate and potassium carbonate in dimethyl-
formamide) conditions. The reaction failed completely
under basic conditions, giving unchanged starting material.
However, the reaction using acidic conditions furnished a
complex mixture, which was suggested by 1H NMR
spectroscopy to contain 7-substituted products, and by
mass spectral analysis to contain both nitroso- and nitro-
indole derivatives.
Scheme 1.
2c–j, respectively, in yields of 60–96%. Reaction of the
2-formyl-3-methyl indole 1i produces not only the 7-nitro
derivative 2i in 68% yield, reaction for a longer time leads to
the 2,7-dinitro-derivative 3 in 45% yield, through an ipso-
substitution of the 2-formyl group (Scheme 1).
The presence of electron-withdrawing groups at C7, as in
indoles 4a–c, leads to formation of the 2-nitro-indoles 5a–c
respectively in 70–85%. Until recently 2-nitro-indoles were
relatively unknown and only the 3-methyl- and 3-phenyl-2-
nitro-indoles had been obtained in low yield and with
undesirable 3-substitution.19 2-Nitroindoles have been
synthesized directly through the thermolysis of b-substi-
tuted-o-azidostyrenes: 2-nitroindole itself was obtained in
three steps from 2-nitrobenzaldehyde in 40% overall
yield.20,21 The ability to nitrate specifically at the 2-position
is a new approach to 2-nitro-indoles that is extremely quick,
clean and high yielding (Scheme 2).
3. Conclusion
The use of nitric acid on silica is very effective for the
nitration of 4,6-dimethoxyindoles bearing an electron-
withdrawing group either at C2, C7 or N1. When such a
group is positioned at C7, an entry to the very rare 2-nitro-
indoles is provided.
4. Experimental
Scheme 2.
4.1. General information
Indoles 6a–c, substituted with electron-withdrawing groups
at N1, reacted extremely rapidly with nitric acid on silica to
give mixtures of mono- and dinitro-indoles, with conse-
quent reduced yields of isolated products. 1H NMR spectra
of the crude reaction mixtures indicated that partial
hydrolysis of the N-substituent had occurred, and therefore
complete removal of this substituent was effected by formal
hydrolysis. It was difficult to characterize all of these
products fully because of their variable stability. The
N-phenylsulfonylindole 6a gave a 75% yield of the rather
unstable 2,7-dinitro-indole 7a, while the N-acetylindole 6b
gave an approximately equal mixture of 2- and 7-nitro-
indoles 7b and 2b, respectively, the former being less stable
than the latter. Significantly, the N-cyanoindole 6c showed a
Melting points (uncorrected) were measured using a Mel-
Temp melting point apparatus. Microanalyses were per-
formed by the Microanalysis Unit of the Australian National
University, Canberra or the University of Otago, New
Zealand. Infrared spectra were recorded as Nujol mulls on a
Perkin–Elmer 298 or a Perkin–Elmer 580B spectrometer.
Ultraviolet–visible spectra were recorded in methanol
(unless otherwise stated) on a Hitachi UV-3200 spectro-
meter. 1H and 13C NMR spectra were obtained in the
designated solvents on a Bruker AC300F (300 MHz)
spectrometer or at 500 MHz with a Bruker AM-500
spectrometer. 1H NMR data are reported as follow:
chemical shift measured in parts per million (ppm) down-
field from TMS (d), multiplicity, observed coupling

A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
10781
constant (J) in Hertz (Hz), proton count. Multiplicities are
reported as singlet (s), broad singlet (bs), doublet (d), triplet
(t), quartet (q), quintet (quin) and multiplet (m). 13C NMR
chemical shifts are reported in ppm downfield from TMS
and identifiable carbons are given. The EI and ES mass
spectra were recorded on an AEI MS 12 mass spectrometer
at 70 eV ionizing potential and 8000 V accelerating voltage
with an ion source temperature of 210 8C. MALDI (matrix
assisted laser desorption) mass spectra were recorded on a
Finnigan MAT Lasermat 2000 for high molecular weight
compounds. The principal ion peaks m/z are reported
together with their percentage intensities relative to the
base peak (where possible). Kieselgel 60H (Merck, Art
7736) was employed for flash chromatography and thin-
layer chromatography (TLC) was performed on DC
Aluminium Foil Kieselgel F254 (Merck, Art 5554). Pre-
parative thin layer chromatography was performed on 3 mm
plates using Merck silica gel 7730 60GF254. Solvents and
reagents were purified by literature methods. Petroleum
ether refers to the hydrocarbon fraction of boiling range
60–80 8C. Compounds were detected by short and long
ultraviolet light and with iodine vapor.
218 nm (3 16,000 cmK1 MK1), 256 (14,000), 351 (10,000).
1H NMR spectrum (CDCl3): d 3.38, 4.01 (6H, 2s, OMe),
6.37 (1H, d, JZ2.0 Hz, H5), 6.53 (1H, d, JZ2.0 Hz, H7),
7.35–7.53 (3H, m, aryl), 7.80–7.83 (2H, m, aryl), 10.08 (1H,
bs, NH). 13C NMR spectrum (CDCl3): d 55.73, 56.26
(OMe), 87.81 (C5), 95.19 (C7), 128.36, 129.20, 133.24 (aryl
CH), 110.85, 130.11, 137.07, 137.51, 137.89, 152.50,
159.62 (aryl C), 164.71, 190.40 (CO). Mass spectrum: m/z
325 (M, 10%), 307 (10), 281 (70), 266 (20), 105 (100).
4.2.3. Methyl2-benzoyl-4,6-dimethoxyindole-3-carboxyl-
ate (1e). 2-Benzoyl-4,6-dimethoxyindole-3-carboxylic acid
(2.0 g, 6.1 mmol) in diethyl ether (50 mL) was treated with
an excess of diazomethane solution by slow addition over
30 min. The resulting solution was evaporated and the
residue recrystallised from methanol to yield 1e as a light
yellow solid (2.1 g, 98%), mp 144–145 8C (from methanol).
(Found: C, 67.3; H, 5.0; N, 4.1. C19H17NO5 requires C, 67.3;
H, 5.0; N, 4.1%). nmax: 3300, 1720, 1620, 1600, 1575, 1565,
1520, 1500, 1425, 1400, 1355, 1330, 1275, 1210 cmK1
.
lmax: 219 nm (3 18,000 cmK1 MK1), 257 (17,500), 353
(12,500). H NMR spectrum (CDCl3): d 3.27, 3.79, 3.84
1
(9H, 3s, OMe), 6.20 (1H, d, JZ2.0 Hz, H5), 6.44 (1H, d,
JZ2.0 Hz, H7), 7.42–7.54 (3H, m, aryl), 7.76–7.79 (2H, m,
aryl), 9.92 (1H, bs, NH). 13C NMR spectrum (CDCl3): d
51.66, 55.48, 55.60 (OMe), 85.92 (C5), 94.25 (C7), 128.29,
128.45, 132.15 (aryl CH), 111.74, 115.51, 131.30, 138.25,
138.74, 155.33, 161.04 (aryl C), 165.88, 187.86 (CO). Mass
spectrum: m/z 340 (MC1, 10%), 339 (M, 45), 278 (30), 105
(80), 77 (100).
4.2. Preparation of indoles
4.2.1. 4,6-Dimethoxy-1-(2-oxo-2-phenylethyl)indole-2,3-
dione. 4,6-Dimethoxyisatin (5.0 g, 24.1 mmol) was added
to a solution of NaOH (1.0 g, 25 mmol) in methanol
(150 mL) and the mixture was refluxed for 1 h. The
methanol was evaporated and the reddish-purple residue
was suspended in dry DMF (50 mL). A solution of phenacyl
bromide (4.8 g, 24.1 mmol) in DMF (10 mL) was added and
the reaction mixture was heated at 100 8C for 16 h. On
cooling, the dark solution was poured onto a mixture of ice
and 10% HCl (50 mL). The yellow precipitate was
collected, dried and chromatographed with DCM. The title
1-phenacyl isatin was obtained as a yellow solid (3.9 g,
50%), mp 210–212 8C (from EtOH). (Found: C, 66.4; H,
4.6; N, 4.3. C18H15NO5 requires C, 66.5; H, 4.7; N, 4.3%).
nmax: 1745, 1715, 1700, 1635, 1600, 1440, 1390, 1215,
1170 cmK1. lmax: 215 nm (3 18,300 cmK1 MK1), 249
(25,200), 352 (13,300). 1H NMR spectrum (CDCl3): d
3.85, 3.96 (6H, 2s, OMe), 5.10 (2H, s, CH2), 5.82 (1H, d,
JZ2.0 Hz, H5), 6.02 (1H, d, JZ2.0 Hz, H7), 7.50–7.68
(3H, m, aryl), 7.99–8.02 (2H, m, aryl). 13C NMR spectrum
(CDCl3): d 46.31 (CH2), 56.08, 56.26 (OMe), 90.77 (C5),
91.96 (C7), 128.12, 128.98, 134.03 (aryl CH), 100.98,
134.03, 153.29, 160.17, 161.27 (aryl C), 170.03, 176.53,
191.22 (CO). Mass spectrum: m/z 325 (M, 10%), 192 (60),
105 (100), 77 (40).
4.2.4. 2-Benzoyl-4,6-dimethoxyindole (1f). 4,6-Dimeth-
oxy-1-(2-oxo-2-phenylethyl)indole-2,3-dione
(4.0 g,
12.3 mmol) was added to 20% aqueous NaOH (90 mL)
and the mixture refluxed for 12 h. On cooling, the alkaline
solution was diluted with water (300 mL) and extracted with
chloroform. The extract was dried and concentrated to yield
the pale yellow 2-benzoyl indole 1f (2.8 g, 80%), mp 173–
175 8C. (Found: C, 71.4; H, 5.6; N, 4.7. C17H15NO5. 0.25
H2O requires C, 71.4; H, 5.5; N, 4.9%). nmax: 3310, 1635,
1615, 1590, 1570, 1510, 1490, 1390, 1290, 1220, 1200,
1150 cmK1. lmax: 219 nm (3 13,500 cmK1 MK1), 254
(13,500), 356 (17,500). 1H NMR spectrum (CDCl3): d
3.85, 3.91 (6H, 2s, OMe), 6.18 (1H, d, JZ1.9 Hz, H5), 6.48
(1H, d, JZ0.8 Hz, H3), 7.20 (1H, d, JZ1.9 Hz, H7), 7.47–
7.58 (3H, m, aryl), 7.95–7.97 (2H, m, aryl), 9.51 (1H, bs,
NH). 13C NMR spectrum (CDCl3): d 55.31, 55.54 (OMe),
85.98 (C5), 92.86 (C7), 111.32 (C3), 128.29, 129.01, 131.88
(aryl CH), 114.40, 132.49, 138.18, 139.62, 155.51, 161.24
(aryl C), 186.06 (CO). Mass spectrum: m/z 282 (MC1,
10%), 281 (M, 70), 266 (20), 238 (20), 149 (45), 105 (85),
77 (100).
4.2.2. 2-Benzoyl-4,6-dimethoxyindole-3-carboxylic acid.
4,6-Dimethoxy-1-(2-oxo-2-phenylethyl)indole-2,3-dione
(4.0 g, 12.3 mmol) was added to 20% aqueous NaOH
(90 mL) and the mixture refluxed for 12 h. On cooling, the
alkaline solution was diluted with water (300 mL), cooled in
an ice bath and slowly acidified with conc. HCl. The
precipitate was collected and dried to yield the title
2-benzoyl indole (3.0 g, 76%) as a light yellow solid, mp
206–207 8C. (Found: C, 66.0; H, 4.6; N, 4.2. C18H15NO5
requires C, 66.4; H, 4.6; N, 4.3%). nmax: 3375, 3125, 1685,
1660, 1635, 1620, 1580, 1530, 1510, 1420, 1390, 1340,
4.2.5. 4,6-Dimethoxy-3-(4-methoxyphenyl)indole-7-carb-
aldehyde, 4,6-dimethoxy-3-(4-methoxyphenyl)indole-2-
carbaldehyde (1g) and 4,6-dimethoxy-3-(4-methoxy-
phenyl)indole-2,7-dicarbaldehyde. To a stirred solution
of 4,6-dimethoxy-3-(4-methoxyphenyl)indole (2.0 g,
7.1 mmol) in anhydrous chloroform (10 mL) at K50 8C
was added dropwise an ice-cold solution of phosphoryl
chloride (1.0 mL, 10.7 mmol) in DMF (2 mL). The mixture
was stirred at this temperature for 1 h, then allowed to come
to room temperature. Ice water (10 mL) was added and the
1280, 1260, 1240, 1215, 1200, 1175, 1140 cmK1. lmax
:

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A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
mixture stirred vigorously for 1 h, then made strongly
alkaline with 10% NaOH and stirred vigorously for a further
4 h. The mixture was extracted with DCM (3!100 mL), the
organic layer collected, dried (MgSO4) and the solvent
removed under reduced pressure. The crude mixture was
purified by column chromatography (DCM).
added to a solution of excess methanol in diethyl ether
(20 mL). The mixture was stirred for 1 h. Water was then
added and the mixture extracted with DCM. The organic
layer was washed until neutral, then dried (MgSO4). The
solvent was removed under reduced pressure to give ester
1h as a light yellow solid (45 mg, 35%), mp 177–178 8C
(from methanol). (Found: C, 70.0; H, 6.4; N, 3.3.
The first band gave 4,6-dimethoxy-3-(4-methoxyphenyl)-
indole-7-carbaldehyde (1.1 g, 50%) as yellow needles, mp
199–201 8C (from DCM/petroleum ether). (Found: C, 69.2;
H, 5.5; N, 4.5. C18H17NO4 requires C, 69.4; H, 5.5; N,
4.5%). nmax: 3408, 1635, 1599, 1550, 1509, 1361, 1321,
1245, 1213, 1177, 1084, 981, 836 cmK1. lmax: 232 nm (3
C23H25NO5 requires C, 69.9; H, 6.4; N, 3.5%). nmax
3320, 3260, 1755, 1630, 1600, 1570, 1520, 1490, 1340,
:
1310, 1280, 1240, 1210, 1200, 1160, 1130, 1070 cmK1
.
lmax: 214 nm (3 31,800 cmK1 MK1), 259 (22,500), 348
(24,000). H NMR spectrum (CDCl3): d 1.36 (9H, s, But),
1
3.21, 3.64, 3.85 (9H, 3s, OMe), 6.10 (1H, d, JZ1.9 Hz, H5),
6.41 (1H, d, JZ1.9 Hz, H7), 7.37, 7.40 (4H, 2dd, JZ14.0,
8.7 Hz, aryl), 9.47 (1H, bs, NH). 13C NMR spectrum
(CDCl3): d 31.24 (CH3-But), 34.55 (C-But), 51.85, 55.15,
55.54 (OMe), 85.58 (C5), 93.54 (C7), 123.93, 130.65 (aryl
CH), 113.37, 127.39, 130.21, 130.59, 140.09, 150.38,
157.20, 162.29 (aryl C), 164.43, 177.56 (CO). Mass
spectrum: m/z 396 (MC1, 30%), 395 (M, 90), 338 (20),
280 (100), 265 (25).
1
2800 cmK1 MK1), 258 (3500), 333 (1200), 368 (1000). H
NMR spectrum (CDCl3): d 3.88, 3.90, 3.99 (9H, 3s, OMe),
6.17 (1H, s, H5), 6.96 (2H, d, JZ8.8 Hz, aryl), 7.06 (1H, d,
JZ2.5 Hz, H2), 7.53 (2H, d, JZ8.8 Hz, aryl), 10.42 (1H, s,
CHO), 10.52 (1H, s, NH). 13C NMR spectrum (CDCl3):
55.27, 55.35, 56.32 (OMe), 86.62, 113.19, 121.21, 130.47
(aryl CH), 104.45, 110.29, 118.42, 127.94, 137.62, 158.18,
161.42, 163.00 (aryl C), 188.25 (CHO). Mass spectrum: m/z
312 (MC1, 20%), 311 (M, 100), 296 (50), 97 (20), 69 (25),
57 (35).
The filtrate containing 2-indol-7-ylglyoxyloyl chloride was
evaporated under pressure. The residue was re-dissolved in
diethyl ether (10 mL) and excess methanol was added. The
mixture was allowed to stir for 1 h. The resulting precipitate
was dissolved in DCM, washed with water until neutral, and
dried to yield the methyl-[3-(4-tert-butylphenyl)-4,6-
dimethoxyindol-7-yl]-glyoxylate as a yellow solid (38 mg,
30%), mp 196–197 8C (from methanol). (Found: C, 69.6; H,
6.2; N, 3.3. C23H25NO5 requires C, 69.9; H, 6.4; N, 3.5%).
nmax: 3390, 1725, 1620, 1590, 1570, 1550, 1540, 1500,
1430, 1350, 1320, 1310, 1260, 1210, 1170, 1150, 1120,
1085, 1060 cmK1. lmax: 211 nm (3 23,500 cmK1 MK1), 256
(24,000), 340 (12,300). 1H NMR spectrum (CDCl3): d 1.37
(9H, s, But), 3.94 (9H, s, OMe), 6.17 (1H, s, H5), 7.11 (1H,
d, JZ2.3 Hz, H2), 7.47, 7.64 (4H, 2dd, JZ33.5, 8.3 Hz,
aryl), 10.53 (1H, bs, NH). 13C NMR spectrum (CDCl3): d
31.34 (CH3-But), 34.39 (C-But), 52.13, 55.48, 57.09 (OMe),
87.22 (C5), 121.82 (C2), 124.85, 128.95 (aryl CH), 100.67,
110.80, 119.03, 132.05, 138.34, 148.90, 162.03, 162.35
(aryl C), 166.44, 184.62 (CO). Mass spectrum: m/z 396
(MC1, 10%), 395 (M, 50), 336 (100).
The second band gave 4,6-dimethoxy-3-(4-methoxyphenyl)-
indole-2-carbaldehyde 1g (0.2 g, 10%) as yellow crystals,
mp 215–216 8C (from DCM/petroleum ether). (Found: C,
69.2; H, 5.6; N, 4.4. C18H17NO4 requires C, 69.4; H, 5.5; N,
4.5%). nmax: 3302, 1618, 1579, 1535, 1501, 1368, 1268,
1217, 1132, 802 cmK1. 1H NMR spectrum (CDCl3): d 3.74,
3.87, 3.88 (9H, 3s, OMe), 6.16 (1H, d, JZ2.0 Hz, H5), 6.42
(1H, d, JZ2.0 Hz, H7), 6.96 (2H, d, JZ8.7 Hz, aryl), 7.48
(2H, d, JZ8.7 Hz, aryl), 9.12 (1H, sb, NH), 9.50 (1H, s,
CHO). 13C NMR spectrum (DMSO-d6): 55.32, 55.37, 55.59
(OMe), 86.62, 93.24, 113.06, 132.73 (aryl CH), 111.62,
124.95, 129.42, 131.30, 140.29, 156.67, 158.99, 161.06
(aryl C), 180.96 (CHO). Mass spectrum: m/z 312 (MC1,
20%), 311 (M, 100), 296 (20).
The third band gave 4,6-dimethoxy-3-(4-methoxyphenyl)-
indole-2,7-dicarbaldehyde (0.5 g, 20%) as yellow crystals
(Found: C, 67.4; H, 5.2; N, 4.1. C19H17NO5 requires C, 67.3;
H, 5.1; N, 4.1%). nmax: 3419, 1649, 1592, 1544, 1241, 1217,
990, 799, 608 cmK1. lmax: 248 nm (3 3150 cmK1 MK1),
1
311 (1900), 348 (2250), 361 (2050), 373 (1850). H NMR
4.2.7. 3-(4-Chlorophenyl)-4,6-dimethoxy-7-trichloro-
acetylindole (4c) and 3-(4-chlorophenyl)-4,6-dimethoxy-
2-trichloroacetylindole (1j). Trichloroacetyl chloride
(2.0 mL, 17.9 mmol) was added dropwise to a solution of
3-(4-chlorophenyl)-4,6-dimethoxyindole (1.0 g, 3.5 mmol)
in chloroform (20 mL). After completion of the addition, the
solution was refluxed under N2 overnight. The mixture was
allowed to cool to room temperature, then water (20 mL)
was added. The organic layer was extracted with DCM (2!
20 mL) and the organic layer was dried (MgSO4), the
solvent evaporated off under reduced pressure. Column
chromatography of the residue (DCM/petroleum ether) gave
the orange 4c as the first fraction (1.0 g, 66%), mp 178 8C
(DCM/petroleum ether). (Found: C, 50.0; H, 3.0; N, 3.1.
spectrum (CDCl3): d 3.86, 3.87, 3.83 (9H, 3s, OMe), 6.13
(1H, s, H5), 6.95 (2H, d, JZ8.7 Hz, aryl), 7.42 (2H, d, JZ
8.7 Hz, aryl), 9.55 (1H, s, 2-CHO), 10.34 (1H, s, 7-CHO),
10.86 (1H, sb, NH). 13C NMR spectrum (DMSO-d6) 55.43,
56.59, 57.28 (OMe), 89.42, 113.38, 132.68 (aryl CH),
103.19, 111.19, 123.63, 129.12, 131.43, 137.68, 159.42,
163.76, 166.49 (aryl C), 181.24, 187.27 (CHO). Mass
spectrum: m/z 340 (MC1, 20%), 339 (M, 100), 32 (25), 28
(100).
4.2.6. Methyl [3-(4-tert-butylphenyl)-4,6-dimethoxyin-
dol-7-yl] glyoxylate and methyl [3-(4-tert-butylphenyl)-
4,6-dimethoxyindol-2-yl] glyoxylate (1h). 3-(4-tert-Butyl-
phenyl)-4,6-dimethoxyindole (1.0 g, 3.2 mmol) was dis-
solved in anhydrous diethyl ether (30 mL). Oxalyl chloride
(0.39 mL, 4.0 mmol) was added in one portion. The mixture
was stirred for 3 h at room temperature. The resulting
orange-red precipitate was filtered off. This solid was then
C18H13Cl4NO3 requires C, 49.9; H, 3.0; N 3.2%). nmax
:
.
3380, 1610, 1580, 1560, 1340, 1245, 1215, 1080 cmK1
lmax: 212 nm (3 14,000 cmK1 MK1), 256 (12,600), 343
(8000). 1H NMR spectrum (CDCl3): d 3.43, 3.99 (6H,
2s, OMe), 6.23 (1H, s, H5), 7.08 (1H, d, JZ2.0 Hz, H2),

A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
10783
7.35–7.48 (4H, m, aryl), 10.29 (1H, sb, NH). 13C NMR
spectrum (CDCl3): d 55.45, 55.62 (OMe), 87.69 (C5),
121.84 (C2), 127.79, 130.74, (aryl CH), 98.65 (CCl3),
110.80, 118.53, 132.05, 133.81, 139.78, 160.38, 161.39
added HNO3 supported on silica gel (0.50 g). The mixture
was quickly shaken for 10 seconds and immediately filtered.
The solvent was removed and the residue recrystallised
from methanol.
(arylC), 182.36(CO). Massspectrum:m/z435(MC2,Cl37/37
,
7%), 433 (M, Cl35/35, 15), 316 (33), 314 (100).
4.4.1. Dimethyl-4,6-dimethoxy-7-nitroindole-2,3-dicarb-
oxylate (2c). Indole 1c (100 mg, 0.34 mmol) gave the
yellow nitrated indole 2c (110 mg, 96%), mp 267–268 8C
(from methanol). (Found: C, 49.6; H, 4.0; N, 8.1.
The second fraction produced the yellow 1j (0.30 g, 17%),
mp 214 8C (DCM/petroleum ether). (Found: C, 49.9; H, 2.9;
N, 3.3. C18H13Cl4NO3 requires C, 49.9; H, 3.0; N, 3.2%).
nmax: 3400, 1670, 1615, 1570, 1380, 1350, 1250, 1210,
1150 cmK1. lmax: 210 nm (3 21,200 cmK1 MK1), 281
C14H14N2O8 requires C, 49.7; H, 4.2; N, 8.3%). nmax
3460, 1740, 1710, 1630, 1590, 1555, 1520, 1500, 1450,
1420, 1345, 1320, 1290, 1250, 1225, 1200, 1120 cmK1
:
.
1
lmax: 205 nm (3 18,700 cmK1 MK1), 229 (22,300), 295
(14,700), 356 (13,200). 1H NMR spectrum (CDCl3): d 3.94,
3.97, 4.03, 4.09 (12H, 4s, OMe), 6.27 (1H, s, H5), 10.52
(1H, sb, NH). 13C NMR spectrum (CDCl3): d 52.43, 52.71,
56.45, 57.31 (OMe), 88.99 (C5), 111.22, 115.35, 123.71,
124.92, 131.76, 159.16, 159.68 (aryl C), 160.03, 165.43
(CO). Mass spectrum: m/z 339 (MC1, 10%), 338 (M, 100),
306 (50), 275 (35), 248 (65), 215 (40), 202(40).
(14,300), 360 (9600). H NMR spectrum (CDCl3): d 3.63,
3.88 (6H, 2s, OMe), 6.13 (1H, d, JZ2.0 Hz, H5), 6.45 (1H,
d, JZ2.0 Hz, H7), 7.36 – 7.48 (4H, m, aryl), 8.95 (1H, sb,
NH). 13C NMR spectrum (CDCl3): d 55.26, 55.70 (OMe),
87.57 (C5), 93.96 (C7), 127.34, 131.63, (aryl CH), 113.20,
120.67, 132.41, 132.86, 133.31, 139.13, 156.62, 161.47
(aryl C), 96.25 (CCl3), 170.64 (CO). Mass spectrum: m/z
435 (MC2, 37/37Cl, 10%), 433 (M, 35/35Cl, 25), 314 (35),
279 (90), 264 (50), 150 (100).
4.4.2. Methyl-4,6-dimethoxy-7-nitroindole-2-carboxyl-
ate (2d). Indole 1d (100 mg, 0.43 mmol) gave the yellow
nitrated indole 2d (95 mg, 80%), mp 230–231 8C (from
methanol). (Found: C, 50.3; H, 4.3; N, 9.8.
C12H12N2O6$0.25H2O requires C, 50.6; H, 4.4; N, 9.8%).
nmax: 3485, 1710, 1620, 1580, 1535, 1510, 1310, 1300,
1250, 1220, 1170, 970 cmK1. lmax: 209 nm (3 12,000 cmK1
4.2.8. 3-(4-Bromophenyl)-4,6-dimethoxyindole-7-carb-
aldehyde (4b). To a stirred solution of 3-(4-bromophenyl)-
4,6-dimethoxyindole (1.50 g, 6.8 mmol) in anhydrous
chloroform (10 mL) at K15 8C was added dropwise an ice
cold solution of phosphoryl chloride (0.63 mL, 6.8 mmol) in
DMF (1.5 mL). The mixture was stirred at this temperature
for 1 h, then allowed to come to room temperature. Ice water
(10 mL) was added and the mixture stirred vigorously for
1 h, then made strongly alkaline with 10% NaOH and stirred
vigorously for a further 4 h. The mixture was extracted with
DCM (3!100 mL), the organic layer collected, dried
(MgSO4) and the solvent removed under reduced pressure.
The crude product was column chromatographed (DCM) to
give 4b as yellow crystals (1.14 g, 70%), mp 218–220 8C
(from DCM/petroleum ether). (Found: C, 57.0; H, 4.2; N,
1
MK1), 225 (13,700), 292 (13,000), 356 (9000). H NMR
spectrum (DMSO-d6): d 3.86, 4.06, 4.08 (9H, 3s, OMe),
6.59 (1H, s, H5), 7.19 (1H, d, JZ2.6 Hz, H3), 10.94 (1H, sb,
NH). 13C NMR spectrum (DMSO-d6): d 52.39, 57.12, 58.03
(OMe), 90.25 (C5), 107.17 (C3), 79.53, 113.45, 126.74,
132.64, 158.40, 160.09 (aryl C), 160.84 (CO). Mass
spectrum: m/z 281 (MC1, 10%), 280 (M, 100), 248 (55),
218 (40), 201 (15), 190 (25).
3.7. C17H14BrNO3 requires C, 56.7; H, 3.9; N, 3.9%). nmax
:
.
4.4.3. Methyl-2-benzoyl-4,6-dimethoxy-7-nitroindole-3-
carboxylate (2e). Indole 1e (100 mg, 0.29 mmol) gave the
yellow nitrated indole 2e (102 mg, 90%), mp 188–190 8C
(from methanol). (Found: C, 58.8; H, 4.1; N, 7.3.
C19H16N2O7. 0.25 H2O requires C, 58.7; H, 4.3; N, 7.2%).
nmax: 3430, 3410, 1730, 1635, 1620, 1590, 1575, 1540,
3400, 1640, 1590, 1350, 1330, 1210, 1090, 980, 800 cmK1
lmax: 233 nm (3 2250 cmK1 MK1), 252 (2250), 267 (1500),
332 (1250), 363 (1000). 1H NMR spectrum (CDCl3): d 3.93,
4.00 (6H, 2s, OMe), 6.20 (1H, s, H5); 7.09 (1H, d, JZ
2.2 Hz, H2); 7.44 (2H, d, JZ8.6 Hz, aryl); 7.49 (2H, d, JZ
8.6 Hz, aryl); 10.39 (1H, s, CHO); 10.54 (1H, sb, NH). 13C
NMR spectrum (CDCl3): 55.44, 56.40 (OMe), 86.82, 121.83,
130.76, 131.03 (aryl CH), 104.50, 109.96, 117.73, 120.03,
134.42, 137.77, 161.27, 163.13 (aryl C), 188.37 (CHO).
Mass spectrum: m/z 362 (MC1, 81Br, 20%), 361 (M, 81Br,
100), 360 (MC1, 79Br, 22), 359 (M, 79Br, 100), 265 (35).
1490, 1395, 1300, 1275, 1255, 1240, 1210, 1190, 1175 cmK1
.
lmax: 208 nm (3 31,500 cmK1 MK1), 245 (25,000), 337
(21,800). 1H NMR spectrum (DMSO-d6): d 3.36, 4.02, 4.07
(9H, 3s, OMe), 6.65 (1H, s, H5), 7.51–7.56 (2H, m, aryl),
7.64–7.73 (3H, m, aryl), 11.92 (1H, sb, NH). 13C NMR
spectrum (DMSO-d6): d 51.96, 57.26, 58.08 (OMe), 91.28
(C5), 129.04, 129.11, 133.64 (aryl CH), 79.53, 110.50,
113.24, 131.80, 135.61, 137.69, 157.93, 159.98 (aryl C),
164.19, 187.23 (CO). Mass spectrum: m/z 385 (MC1,
15%), 384 (M, 100), 352 (20), 385 (25), 323 (25).
4.3. Preparation of nitric acid on silica gel
Silica gel (60H, Merck, 60 g) was added to nitric acid (8 M,
140 mL) and the resulting suspension stirred at room
temperature for 2 h. The suspension was filtered and the
silica gel allowed to dry in air for one week, then stored in
an airtight container. The nitric acid content of the gel was
determined by titration to be approximately 20%.
4.4.4. (4,6-Dimethoxy-7-nitroindol-2-yl)-phenylmetha-
none (2f). Indole 1f (100 mg, 0.36 mmol) gave the yellow
nitrated indole 2f (87 mg, 75%), mp 239–240 8C (from
methanol). nmax: 3460, 1620, 1575, 1565, 1515, 1410, 1310,
1290, 1250, 1215, 1190, 1170, 1110 cmK1. lmax: 309 nm (3
22,500 cmK1 MK1), 230 (17,500), 241 (16,900), 336
4.4. General procedure for the nitration of C-substituted
indoles
1
(21,800). H NMR spectrum (CDCl3): d 4.08, 4.11 (6H,
2s, OMe), 6.26 (1H, s, H5), 7.22 (1H, d, JZ2.6 Hz, H3),
7.49–7.64 (3H, m, aryl), 7.93–7.96 (2H, m, aryl), 10.73 (1H,
To a solution of indole (100 mg) in DCM (20 mL) was

10784
A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
sb, NH). 13C NMR spectrum (CDCl3): d 56.18, 57.36
(OMe), 88.39 (C5), 110.68 (C3), 128.51, 129.05, 132.43
(aryl CH), 114.36, 133.76, 133.99, 137.64, 159.48, 159.48,
160.95 (aryl C), 185.60 (CO). Mass spectrum: m/z 327 (MC
1, 15%), 326 (M, 100), 250 (35), 207 (20).
1530, 1500, 1420, 1390, 1340, 1310, 1280, 1240, 1200 cmK1
.
lmax: 204 nm (3 9500 cmK1 MK1), 234 (7100), 363 (8500).
1H NMR spectrum (DMSO-d6): d 2.72 (3H, s, CH3), 4.06,
4.07 (6H, 2s, OMe), 6.54 (1H, s, H5), 11.41 (1H, sb, NH).
Mass spectrum: m/z 282 (MC1, 20%), 281 (M, 50), 263
(50), 251 (100), 234 (20).
4.4.5. 4,6-Dimethoxy-3-(4-methoxyphenyl)-7-nitro-
indole-2-carbaldehyde (2g). Indole 1g (100 mg,
0.32 mmol) gave the yellow nitrated indole 2g (103 mg,
90%), mp 272–274 8C (from methanol). (Found: C, 59.3; H,
4.6; N, 7.9. C18H16N2O6. 0.5 H2O requires C, 59.2; H, 4.7;
N, 7.7%). nmax: 3450, 1650, 1620, 1580, 1570, 1550, 1510,
4.4.9. 3-(4-Chlorophenyl)-4,6-dimethoxy-7-nitro-2-tri-
chloroacetylindole (2j). The title compound was prepared
from 2-trichloroacetylindole 1j (0.20 g, 0.46 mmol) and
conc. HNO3 supported on silica gel (0.80 g). The nitro
compound 2j (0.16 g, 72%) was obtained as a yellow solid,
mp 202 8C (DCM/petroleum ether). (Found: C, 44.7; H, 2.5;
N, 5.9. C18H12Cl4N2O5. 0.3 H2O requires C, 44.8; H, 2.6; N,
5.8%). nmax: 3410, 1700, 1620, 1560, 1530, 1350, 1290,
1220, 1200, 980, 845 cmK1. lmax: 242 nm (3 28,400 cmK1
1490, 1440, 1420, 1340, 1300, 1260, 1230, 1210, 1180 cmK1
.
lmax: 204 nm (3 15,900 cmK1 MK1), 249 (16,000), 325
(11,400), 377 (9500). H NMR spectrum (CDCl3): d 3.89,
1
4.10 (9H, 2s, OMe), 6.23 (1H, s, H5), 6.98, 7.42 (4H, 2dd,
JZ34.3, 8.7 Hz, aryl), 9.57 (1H, s, CHO), 10.65 (1H, sb,
NH). 13C NMR spectrum (CDCl3): d 55.34, 55.94, 57.33
(OMe), 88.54 (C5), 113.19, 132.39 (aryl CH), 112.44,
112.97, 118.63, 123.33, 130.26, 131.97, 134.11, 159.76,
162.42 (aryl C), 181.35 (CO). Mass spectrum: m/z 357 (MC
1, 20%), 356 (M, 100).
1
MK1), 202 (24,900), 294 (12,600), 369 (12,500). H NMR
spectrum (CDCl3): d 3.80, 4.11 (6H, 2s, OMe), 6.21 (1H, s,
H5), 7.31–7.40 (4H, m, aryl), 11.29 (1H, sb, NH). 13C NMR
spectrum (CDCl3): d 56.09, 57.46 (OMe), 88.91 (C5),
127.67, 131.41 (aryl CH), 95.49 (CCl3), 112.73, 118.22,
122.21, 127.58, 131.88, 133.45, 133.89, 160.52, 162.14
(arylC), 171.15(CO). Massspectrum:m/z480(MC2, 37/37Cl,
7%), 478 (M, 10), 375 (98), 361 (30), 359 (100).
4.4.6. Methyl [3-(4-tert-butylphenyl)-4,6-dimethoxy-7-
nitroindol-2-yl] glyoxylate (2h). Indole 1h (100 mg,
0.25 mmol) gave the yellow nitrated indole 2h (111 mg,
84%), mp 284–285 8C (from methanol). (Found: C, 62.7; H,
5.4; N, 6.3. C23H24N2O7 requires C, 62.7; H, 5.5; N, 6.4%).
nmax: 3450, 1740, 1630, 1580, 1560, 1520, 1510, 1490,
4.4.10. Methyl 3-(4-chlorophenyl)-4,6-dimethoxy-7-
nitroindole-2-carboxylate (2k). The mixture of indole 2j
(670 mg, 1.40 mmol) in methanol (20 mL) was treated with
triethylamine (4 drops), then heated under reflux for 1 h.
The mixture was allowed to cool to room temperature and
the resulting precipitate was filtered, washed with methanol
and dried to give the ester 2k (430 mg, 78%) as a yellow
solid, mp 240 8C (methanol/DCM). (Found: C, 55.4; H, 3.9;
N, 7.0. C18H15ClN2O6 requires C, 55.3; H, 3.9; N, 7.2%).
nmax: 3460, 1700, 1680, 1580, 1325, 1285, 1225, 1200, 980,
800 cmK1. lmax: 242 nm (3 62,800 cmK1 MK1), 203
1440, 1420, 1340, 1320, 1290, 1230, 1210, 1150 cmK1
.
lmax: 206 nm (3 8000 cmK1 MK1), 245 (5900), 339 (6000).
1H NMR spectrum (CDCl3): d 1.29 (9H, s, But), 3.74, 3.85,
4.04 (9H, 3s, OMe), 6.23 (1H, s, H5), 7.20, 7.35 (4H, 2dd,
JZ48.7, 8.7 Hz, aryl), 9.08 (1H, sb, NH). 13C NMR
spectrum (CDCl3): d 31.21 (CH3-But), 34.61 (C-But), 52.05,
55.94, 57.26 (OMe), 88.52 (C5), 124.17, 130.48 (aryl CH),
113.04, 118.33, 128.29, 128.89, 129.96, 134.11, 151.10,
160.12, 162.53 (aryl C), 163.54, 177.43 (CO). Mass
spectrum: m/z 441 (MC1, 15%), 440 (M, 85), 343 (25),
325 (100), 307 (25).
1
(61,600), 368 (28,000), 294 (27,000). H NMR spectrum
(CDCl3): d 3.79, 3.80, 4.09 (9H, 3s, OMe), 6.20 (1H, s, H5),
7.34 (4H, s, aryl), 10.64 (1H, sb, NH). 13C NMR spectrum
(CDCl3): d 51.97, 55.87, 57.33 (OMe), 88.55 (C5), 127.20,
132.05 (aryl CH), 112.84, 122.71, 124.50, 127.09, 131.75,
132.47, 133.39, 159.02, 160.77 (aryl C), 161.72 (CO). Mass
spectrum: m/z 392 (MC2, 37/37Cl, 7%), 390 (M, 35/35Cl, 21),
358 (20).
4.4.7. 4,6-Dimethoxy-3-methyl-7-nitroindole-2-carbalde-
hyde (2i). Indole 1i (100 mg, 0.46 mmol) gave the yellow
nitrated indole 2i (78 mg, 60%), mp 243–245 8C (from
methanol). nmax: 3440, 3370, 3320, 1650, 1640, 1615, 1570,
1550 1450, 1430, 1410, 1300, 1280, 1220, 1200, 970 cmK1
.
lmax: 207 nm (3 16,600 cmK1 MK1), 230 (17,000), 323
(18,900), 360 (16,400). H NMR spectrum (DMSO-d6): d
4.4.11. 1-[3-(4-Bromophenyl)-4,6-dimethoxy-2-nitro-
indol-7-yl]-2,2,2-trifluoroethanone (5a). Indole 4a
(100 mg, 0.23 mmol) gave the yellow nitrated indole 5a
(94 mg, 85%), mp 232–234 8C (from methanol). (Found: C,
45.8; H, 2.6; N, 5.6. C18H12N2O5BrF3 requires C, 45.7; H,
2.6; N, 5.9%). nmax: 3390, 1720, 1630, 1600, 1580, 1490,
1440, 1420, 1400, 1360, 1320, 1300, 1230, 1200, 1190,
1170, 1160, 1120 cmK1. lmax: 232 nm(3 23,800 cmK1 MK1),
351 (16,900). 1H NMR spectrum (CDCl3): d 3.82, 4.05 (6H,
2s, OMe), 6.20 (1H, s, H5), 7.47, 7.64 (4H, 2dd, JZ78.4,
8.2 Hz, aryl) 11.30 (1H, sb, NH). 13C NMR spectrum
(CDCl3): d 55.91, 56.67 (OMe), 88.99 (C5), 130.57,
131.84 (aryl CH), 99.26, 104.96, 111.74, 118.72, 119.00,
122.45, 127.14, 129.89, 131.56, 164.57 (aryl C), 165.73
(CO). Mass spectrum: m/z 475 (MC2, 10%), 474 (MC1,
95), 472 (85), 458 (20), 442 (20), 403 (100), 403 (90), 392
(35), 149 (75).
1
2.63 (3H, s, CH3), 4.04, 4.06 (6H, 2s, OMe), 6.47 (1H, s,
H5), 9.99 (1H, s, CHO), 11.13 (1H, sb, NH). 13C NMR
spectrum (DMSO-d6): d 10.93 (CH3), 57.18, 57.97 (OMe),
89.81 (C5), 113.57, 124.13, 131.85, 133.39, 159.45, 163.02
(aryl C), 182.45 (CHO). Mass spectrum: m/z 265 (MC1,
15%), 264 (M, 100), 246 (30), 188 (50), 173 (40).
4.4.8. 4,6-Dimethoxy-3-methyl-2,7-dinitroindole (3). To a
solution of indole 1i (100 mg, 0.46 mmol) in DCM (20 mL)
was added HNO3 supported on silica gel (0.50 g). The
mixture was stirred for 10 min and then filtered. The solvent
was removed and the residue triturated in methanol to give
the yellow dinitrated indole 3 (58 mg, 45%), mp 274–
276 8C. (Found: C, 47.3; H, 4.0; N, 14.7. C11H11N3O6
requires C, 47.0; H, 3.9; N, 14.9%). nmax: 3400, 1620, 1580,

A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
10785
4.4.12. 3-(4-Bromophenyl)-4,6-dimethoxy-2-nitroindole-
7-carbaldehyde (5b). Indole 4b (100 mg, 0.28 mmol) gave
the yellow nitrated indole 5b (90 mg, 80%), mp 288–290 8C
(from methanol). (Found: C, 50.4; H, 3.3; N, 3.9.
(C4, C6). Mass spectrum: m/z 394 (MC1, 4%), 393 (M, 15),
253 (20), 252 (100).
4.5.2. 3-(4-Chlorophenyl)-4,6-dimethoxy-indole-1-carbo-
nitrile (6c). The 3-(4-chlorophenyl)-4,6-dimethoxyindole
(1.0 g, 3.5 mmol) was added to a suspension of sodium
hydride (1.1 equiv) in DMF (10 mL) at room temperature
under N2. p-Nitrophenylisocyanate (0.69 g, 4.2 mmol) was
added slowly to the sodium salt of the indole and the
mixture was further stirred at room temperature for 1 h.
Water was added and extraction with ethyl acetate, followed
by drying and evaporation of the solvent yielded the cyano-
indole 6c (0.93 g, 85%) as white crystals, mp 214–215 8C
(from methanol). (Found: C, 65.1; H, 4.1; N, 8.9.
C17H13N2O5Br requires C, 50.4; H, 3.2; N, 6.9%). nmax
:
3400, 3355, 1650, 1600, 1575, 1530, 1510, 1485, 1450,
1400, 1360, 1290, 1230, 1220 cmK1. lmax: 205 nm (3
16,100 cmK1 MK1), 240 (19,900). 1H NMR spectrum
(CDCl3): d 3.80, 4.04 (6H, 2s, OMe), 6.18 (1H, s, H5),
7.47, 7.64 (4H, 2dd, JZ70.8, 8.2 Hz, aryl), 10.35 (1H, s,
CHO), 11.21 (1H, sb, NH). 13C NMR spectrum (CDCl3): d
55.70, 56.41 (OMe), 88.32 (C5), 130.48, 131.97 (aryl CH),
103.53, 118.66, 122.28, 126.46, 130.21, 132.25, 134.26,
163.47, 166.41 (aryl C), 187.56 (CHO). Mass spectrum: m/z
407 (MC2, 15%), 406 (MC1, 100), 404 (100), 376 (20),
374 (25), 368 (20).
C17H13N2O2Cl requires C, 65.3; H, 4.2; N, 9.0%). nmax
3130, 2215, 1615, 1590, 1560, 1550, 1500, 1450, 1430,
:
1300, 1260, 1240, 1200 cmK1. lmax: 210 nm (3 21,800 cmK1
1
4.4.13. 3-(4-Chlorophenyl)-4,6-dimethoxy-2-nitro-7-tri-
chloroacetylindole (5c). To a solution of 7-trichloroacetyl-
indole 4c (0.13 g, 0.3 mmol) in DCM (10 mL) was added
conc. HNO3 supported on silica gel (0.50 g). The mixture
was stirred for 10 min. After completion of the reaction, the
silica was filtered off. The filtrate was concentrated and the
residue chromatographed (DCM/petroleum ether) to give
compound 5c (0.10 g, 70%) as a yellow solid, mp 243 8C
(from DCM/petroleum ether). (Found: C, 45.2; H, 2.3; N,
5.1. C18H12Cl4N2O5. 0.1H2O requires C, 45.1; H, 2.6; N,
5.8%). nmax: 3400, 1650, 1580, 1485, 1290, 1235, 1220,
1160, 980, 840, 800, 720 cmK1. lmax: 227 nm (3
20,900 cmK1 MK1), 203 (16,400). 1H NMR spectrum
(CDCl3): d 3.80, 4.04 (6H, 2s, OMe), 6.21 (1H, s, H5),
7.36 – 7.41 (4H, m, aryl), 11.03 (1H, sb, NH). 13C NMR
spectrum (CDCl3): d 55.90 (OMe), 89.25 (C5), 127.73,
131.72 (aryl CH), 97.78, 98.23, 112.20, 119.20, 129.71,
134.23, 135.51, 136.68, 163.67, 163.90 (aryl C), 165.49
(CO). Mass spectrum: m/z 478 (M, 3%), 361 (30), 359
(100).
MK1), 245 (27,000). H NMR spectrum (CDCl3): d 3.77,
3.89 (6H, 2s, OMe), 6.38 (1H, d, JZ2.1 Hz, H5), 6.70 (1H,
d, JZ2.1 Hz, H7), 6.98 (1H, s, H2), 7.35, 7.46 (4H, dd, JZ
33.3, 8.2 Hz, aryl). 13C NMR spectrum (CDCl3): d 55.34,
55.88 (OMe), 87.28 (C5), 95.90 (C7), 107.47 (CN), 120.43
(C2), 127.94, 130.70 (aryl CH), 110.12, 123.96, 131.39,
133.46, 139.65, 155.15, 160.15 (aryl C). Mass spectrum: m/z
314 (MC2, 35%), 312 (M, 100), 262 (30).
4.6. General procedure for the nitration of N-substituted
indoles
To a solution of indole (100 mg) in dichloromethane
(20 mL) was added HNO3 supported on silica gel (0.50 g).
The mixture was quickly shaken for 10 s and immediately
filtered. The solvent was removed and the residue was run
on preparative TLC plates with DCM to separate out the
different bands. The crude nitrated indole fractions were
then hydrolysed in methanol with excess NaOH. Each
fraction was again run on a preparative TLC plate with
DCM to yield the deprotected nitrated indole products.
4.5. Preparation of N-substituted indoles
4.6.1. 4,6-Dimethoxy-2,7-dinitro-3-phenylindole (7a).
Indole 6a (100 mg, 0.25 mmol) gave the yellow nitrated
indole 7a (65 mg, 75%), mp 221–223 8C. nmax: 3420, 1620,
1605, 1570, 1555, 1515, 1490, 1430, 1410, 1355, 1330,
1310, 1280, 1270, 1220, 1195, 1170 cmK1. lmax: 207 nm (3
4.5.1. 4,6-Dimethoxy-3-phenyl-1-phenylsulfonylindole
(6a). 4,6-Dimethoxy-3-phenylindole (5.84 g, 23 mmol) in
anhydrous THF (100 mL) and the solution cooled in an ice-
ethanol bath. n-Butyllithium (1.6 M, 15.9 mL, 24.4 mmol)
was added dropwise over 5 min and the solution stirred
under N2 for 1 h. Phenylsulfonyl chloride (4.10 g, 23 mmol)
was added slowly over 5 min and the mixture stirred at room
temperature for 2 h. The reaction mixture was poured into
ice water (200 mL) and extracted with diethyl ether (3!
100 mL). The organic extract was dried (MgSO4), concen-
trated and the residue purified by column chromatography
(DCM/hexane) to give 6a as a white powder (6.85 g, 76%),
mp 157–159 8C. (Found: C, 67.1; H, 5.0; N, 3.5.
1
16,000 cmK1 MK1), 242 (11,800), 357 (11,300). H NMR
spectrum (CDCl3): d 3.78, 4.11 (6H, 2s, OMe), 6.24 (1H, s,
H5), 7.42 (5H, s, aryl) 10.97 (1H, sb, NH). 13C NMR
spectrum (CDCl3): d 55.97, 57.29 (OMe), 89.28 (C5),
127.39, 128.22, 130.02 (aryl CH), 111.76, 130.21, 130.54,
144.21, 149.70, 153.13, 160.20, 162.69 (aryl C). Mass
spectrum: m/z 344 (MC1, 15%), 343 (100), 313 (25), 267
(20), 105 (85), 77 (90).
C22H19NO4S requires C, 67.2; H, 4.9; N, 3.6%). nmax
:
1590, 1340, 1200, 1180, 1170, 1140, 1100, 810, 800, 750,
4.6.2. 3-(4-Bromophenyl)-4,6-dimethoxy-2-nitroindole
(7b). Indole 6b (100 mg, 0.27 mmol) gave the yellow
nitrated indole 7b (35 mg, 35%), mp 211–213 8C nmax:
3390, 1620, 1570, 1520, 1490, 1420, 1340, 1290, 1250,
1210, 1180, 1150, 1120 cmK1. lmax: 215 nm (3 25,300 cmK1
MK1), 261 (13,500), 385 (10,800). 1H NMR spectrum
(CDCl3): d 3.64, 3.87 (6H, 2s, OMe), 6.17 (1H, d, JZ
2.1 Hz, H5), 6.38 (1H, d, JZ2.1 Hz, H7), 7.30, 7.52 (4H,
2dd, JZ57.9, 8.7 Hz, aryl) 9.25 (1H, sb, NH). 13C NMR
spectrum (CDCl3): d 55.16, 55.64 (OMe), 85.50 (C5), 94.48
720, 680 cmK1. lmax: 230 nm (3 15,900), 246 (14,300), 287
(3500), 304 (1900). H NMR spectrum (CDCl3): d 3.72,
1
3.90 (6H, 2s, OMe), 6.35 (1H, d, JZ2.1 Hz, H5), 7.22 (1H,
d, JZ2.1 Hz, H2), 7.23–7.56 (9H, m, H7 and aryl), 7.91–
7.94 (2H, m, aryl). 13C NMR spectrum (CDCl3): d 55.18,
55.83 (OMe), 89.87 (C5), 95.24 (C7), 121.54 (C2), 126.80,
127.07, 127.64, 129.31, 129.55, 133.86 (aryl CH), 113.03,
124.70, 133.86, 137.53, 138.09 (aryl C), 154.70, 159.25

10786
A. W. Jones et al. / Tetrahedron 60 (2004) 10779–10786
(C7), 130.27, 132.10 (aryl CH), 111.99, 119.81, 122.06,
130.69, 134.67, 135.81, 157.23, 162.69 (aryl C). Mass
spectrum: m/z 379 (MC2, 10%), 378 (MC1, 100), 376
(90), 346 (40), 315 (30), 253 (25).
References and notes
1. Indoles—Part Two; Houlihan, W. J., Ed.; Wiley: New York,
1972; pp 540–550.
2. Sundberg, R. J. The Chemistry of Indoles; Academic: New
York, 1970; pp 11–14.
4.6.3. 3-(4-Bromophenyl)-4,6-dimethoxy-7-nitroindole
(2b). Indole 6b (100 mg, 0.27 mmol) also gave the yellow
nitrated indole 2b (40 mg, 40%), mp 218–220 8C. (Found:
C, 50.2; H, 3.6; N, 7.2. C16H13N2O4Br. 0.25 H2O requires C,
50.3; H, 3.6; N, 7.4%). nmax: 3420, 1610, 1570, 1550, 1535,
1500, 1450, 1440, 1360, 1350, 1320, 1300, 1280, 1250,
1230, 1210 cmK1. lmax: 213 nm (3 23,000 cmK1 MK1), 263
3. Joule, J. A. Indole and its derivatives. Science of Synthesis
2001, 10, 361–652.
4. Noland, W. E.; Smith, L. R.; Johnson, D. C. J. Org. Chem.
1963, 28, 2262–2266.
5. Bauer, H.; Strauss, E. Chem. Ber. 1932, 65, 308–315.
6. Noland, W. E.; Robinson, D. N. Tetrahedron 1958, 3, 68–72.
7. Atkinson, C. M.; Kershaw, J. W.; Taylor, A. J. Chem. Soc.
1962, 4426–4429.
1
(14,800), 283 (7400). H NMR spectrum (CDCl3): d 3.93,
4.08 (6H, 2s, OMe), 6.26 (1H, s, H5), 7.13 (1H, d, JZ
2.6 Hz, H2), 7.38–7.51 (4H, m, aryl), 10.31 (1H, sb, NH).
13C NMR spectrum (CDCl3): d 55.59, 57.22 (OMe), 88.26
(C5), 121.80 (C2), 130.64, 131.04 (aryl CH), 118.98,
120.44, 130.64, 131.80, 133.34, 133.60, 156.84, 160.23
(aryl C). Mass spectrum: m/z 379 (MC2, 35%), 377 (M,
100), 347 (25).
8. Berti, G.; Da Settimo, A. Gazz. Chim. Ital. 1960, 90, 525–538.
9. DeFazi, R.; Berti, G.; Da Settimo, A. Gazz. Chim. Ital. 1959,
87, 2238–2257.
10. Noland, W. E.; Rush, K. R.; Smith, L. R. J. Org. Chem. 1966,
31, 65–69.
11. Colonna, M.; Greci, L.; Poloni, M. J. Chem. Soc., Perkin
Trans. 2 1981, 628–632.
12. Roue, N.; Delahaigne, T.; Barret, R. Heterocycles 1996, 43,
263–266.
4.6.4. 3-(4-Chlorophenyl)-4,6-dimethoxy-2-nitroindole
(7c). Indole 6c (100 mg, 0.32 mmol) gave the yellow
nitrated indole 7c (53 mg, 50%), mp 216–217 8C. (Found:
C, 57.2; H, 3.9; N, 8.3. C16H13N2O4Cl$0.25H2O requires C,
57.0; H, 4.0; N, 8.3%). nmax: 3370, 1620, 1590, 1580, 1570,
1535, 1520, 1490, 1455, 1440, 1385, 1335, 1280, 1270,
1240, 1200, 1170, 1140, 1120 cmK1. lmax: 220 nm (3
13. Black, D. StC.; Kumar, N.; Wong, L. C. H. Aust. J. Chem.
1986, 39, 15–20.
14. Black, D. StC.; Gatehouse, B. M. K. G.; Theobald, F.; Wong,
L. C. H. Aust. J. Chem. 1980, 33, 343–350.
15. 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.
1
15,700 cmK1 MK1), 260 (18,900), 385 (15,700). H NMR
spectrum (CDCl3): d 3.64, 3.87 (6H, 2s, OMe), 6.16 (1H, d,
JZ1.6 Hz, H5), 6.38 (1H, d, JZ1.6 Hz, H7), 7.35, 7.42
(4H, m, aryl), 9.26 (1H, sb, NH). 13C NMR spectrum
(CDCl3): d 55.15, 55.64 (OMe), 85.51 (C5), 94.48 (C7),
127.34, 131.82 (aryl CH), 112.06, 119.84, 130.19, 133.76,
135.82, 153.86, 157.23, 162.69 (aryl C). Mass spectrum: m/z
334 (MC1, 35%), 333 (M, 20), 332 (100), 302 (50), 271
(45).
16. Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R.
J. Chem. Soc., Chem. Commun. 1993, 819–821.
17. Black, D. StC.; Kumar, N.; Wong, L. C. H. Synthesis 1986, 6,
474–476.
18. Black, D. StC.; Wong, L. C. H. J. Chem. Soc., Chem. Commun.
1980, 200.
19. Tapia, R.; Torres, G.; Valderrama, J. A. Synth. Commun. 1986,
16, 682–687.
20. Berti, G.; Da Settimo, A.; Nannipieri, E. J. Chem. Soc. C 1968,
2145–2151.
21. Russell, G. A.; Yao, C. F.; Tashtoush, H. I.; Russell, J. E.;
Dedolph, D. F. J. Org. Chem. 1991, 56, 663–669.
22. Pelky, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38,
5603–5606.
Acknowledgements
We thank the Australian Research Council for financial
support.
23. Madelung, W. Justus Liebigs Ann. Chem. 1914, 405, 58–95.