New reactivity patterns in activated indoles with 2-methyl substituents

Article abstract of DOI:10.1016/j.tet.2005.08.048

The synthesis and reactive properties of two new 3-aryl-2-methyl-4,6- dimethoxyindoles are reported. These compounds show typical electrophilic substitution and addition reactions at C7, but not oxidative dimerisation because of the reactivity of the 2-methyl group. This methyl group can be effectively oxidised to a carbaldehyde by selenium dioxide, but formation of 7,7′-diindolylselenides also occurs.

Full text of DOI:10.1016/j.tet.2005.08.048

Tetrahedron 61 (2005) 10490–10500
New reactivity patterns in activated indoles
with 2-methyl substituents
Ashley W. Jones, Tutik Dwi Wahyuningsih, Karin Pchalek, Naresh Kumar
*
and David StC. Black
School of Chemistry, University of New South Wales, UNSW Sydney NSW 2052, Australia
Received 30 May 2005; revised 25 July 2005; accepted 11 August 2005
Available online 12 September 2005
Abstract—The synthesis and reactive properties of two new 3-aryl-2-methyl-4,6-dimethoxyindoles are reported. These compounds show
typical electrophilic substitution and addition reactions at C7, but not oxidative dimerisation because of the reactivity of the 2-methyl group.
This methyl group can be effectively oxidised to a carbaldehyde by selenium dioxide, but formation of 7,70-diindolylselenides also occurs.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
intermediate amino ketone, and acid catalysed cyclisation to
give an indole.4 Replacement of the bromoacetophenone by
a bromopropiophenone leads in the same way to an
activated indole bearing a 2-methyl substituent. Thus,
a-bromopropiophenone and 4-bromo-a-bromopropiophe-
none, respectively, led to the aminoketones 1 and 2,
which were acetylated and cyclised to give the
N-acetylindoles 3 and 4, and after hydrolysis afforded the
indoles 5 and 6. Protection of the aminoketones requires
heating in acetic anhydride at 70 8C for 3 h, because of the
steric effect of the adjacent methyl group. Cyclisation is a
very clean process under mild conditions but hydrolysis of
the N-acetyl group requires longer reaction times than for
the 2-unsubstituted indoles, again because of the steric
influence of the 2-methyl group. The 1H NMR spectra
showed resonances for the 2-methyl protons at 2.3 ppm, and
the H5 and H7 protons from 6.2–6.4 ppm.
4,6-Dimethoxy-2,3-diphenylindole and related 2,3-disub-
stituted indoles have been shown to exhibit considerable
reactivity at C7.1–3 Typical reactions include Vilsmeier
formylation, Vilsmeier and Friedel-Crafts acylation, acid
catalysed addition of aldehydes, and oxidative dimerisation
to form 7,70-biindolyls. The related 3-substituted-4,6-
dimethoxyindoles show similar reactivity towards electro-
philes, but reaction can take place either at C7 or C2, or indeed
in some cases, at both. For a variety of purposes, we required
activated indoles, which were substituted at both C2 and C3,
and therefore, regioselectively reactive at C7, but in which the
resulting products could be transformed by manipulation of a
C2-substituent. We now report the synthesis and some
reactionsoftwo2-methylindoles.Whilemuchofthereactivity
is similar to that already described for 2,3-diaryl-4,6-
dimethoxyindoles, some important differences are evident
as a consequence of the 2-methyl group.
2.2. Formylation and acylation at C7
Treatment of the 2-methylindoles 5–6 with 1 equiv of the
Vilsmeier reagent at 0 8C gave the corresponding 7-carb-
aldehydes 7–8, respectively, in 94 and 95% yields.
Furthermore, these aldehydes could be reduced readily
with excess sodium borohydride in methanol to give the
alcohols 9–10, respectively. Vilsmeier acetylation was also
effected by treatment of the indoles 5–6 with N,N-
dimethylacetamide and phosphoryl chloride, to give the
7-acetylindoles 11–12, respectively, in high yield. The
synthetic utility of the Vilsmeier methodology was further
illustrated by the reaction of indole 5 with 4-chloro-N,N-
dimethylbenzamide and phosphoryl chloride, to give the
7-aroylindole 13 in 85% yield.
2. Results and discussion
2.1. Preparation of 3-aryl-2-methyl-4,6-dimethoxy-
indoles
The preparation is based on the process already established
for the synthesis of a range of 3-aryl-4,6-dimethoxyindoles,
by the combination of 3,5-dimethoxyaniline and a bromo-
acetophenone, followed by protection of the nitrogen of the
Keywords: Indoles; Oxidation; Selenium dioxide; Aldehydes.
*
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 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.048

A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
10491
their corresponding 7-methanols.2 The likely mechanism
for the coupling of the methanols is an acid-catalysed ipso-
substitution at the most nucleophilic 7-position, followed by
loss of a proton and formaldehyde to re-establish the
aromaticity of the benzene ring.
2.5. Oxidative dimerisation at C7
7,70-Biindolyls have been synthesised previously from 2,3-
diaryl-4,6-dimethoxyindoles by oxidation with benzo-
quinone, chloranil, dichlorodicyanoquinone, copper(II)
chloride and iodine monochloride.2,6 The 2-methyl-3-
phenylindole 5 was successfully oxidised to the 7,70-dimer
25 in 88% yield using benzoquinone. Reaction with
dichlorodicyanoquinone gave a lower yield, and the other
reagents caused general decomposition of the starting
material. It is likely that the 2-methyl group is a source of
some instability towards oxidation, as the following section
shows.
Direct reaction of indoles 5–6 with either trifluoroacetic
anhydride or trichloroacetyl chloride gave effectively
quantitative yields of the 7-substituted trifluoroacetyl-
indoles 14–15 or trichloroacetyl indoles 16–17. Reaction
of indole 6 with oxalyl chloride also gave the 7-chloro-
oxalyl derivative, which was easily converted into the ethyl
ester 18, dimethylamide 19 and hydroxamic acid 20. More
conventional Friedel–Crafts conditions were employed,
with aluminium chloride as catalyst, in the reaction of
indole 5 with pyridine-2,6-dicarbonyl chloride to give in
69% yield the product 21, which was required for a
particular project.
2.6. Oxidation of the C2-methyl group
One of the reasons for the interest in 2-methyl indoles
relates to the oxidation of the 2-methyl group, with the
possibility that further useful functionalisation might be
generated at C2, following prior substitution at C7.
2.3. Nitration at C7
It has been reported that 2,3-disubstituted indole derivatives
react easily with various oxidants.7 Oxidations of 2-methyl-
3-substituted indoles have been carried out using a wide
variety of oxidising reagents, for example, air,8,9 lead
tetraacetate,10 t-butylhypochlorite,10 activated manganese
dioxide,11 silver acetate,12 selenium dioxide,13 or periodic
acid.14 Most oxidising agents act as electrophiles and
initially attack the C-3 position of the indole ring, leading to
the formation of acyl indoles, oxindole derivatives,
dimerized products or products resulting from oxidative
cleavage of the C2–C3 double bond. Attempts to oxidise the
2-methylindoles 5–6 to the related 2-formyl indoles with
periodate, activated manganese dioxide, ceric ammonium
nitrate, or silver acetate proved to be unsuccessful.
However, selenium dioxide converted indoles 5–6 into the
2,20-diformyl-7,70-diindolylselenides 26–27 in 31 and 30%
yield, respectively. The less-activated N-acetylindole 3 also
gave the selenide 26 in 35% yield. Such selenium insertion
reactions have been observed previously for indole and
The controlled nitration of suitably activated indoles using
nitric acid adsorbed onto silica has been described recently.5
This reaction is very successful if the activated indole also
contains a modifying electron-withdrawing group. Conse-
quently, the N-acetylindole 3 was treated with nitric acid on
silica to give the corresponding 7-nitro compound, which
was rather labile under the reaction conditions, and
consequently converted directly into the 7-nitro-indole 22
in good yield.
2.4. Acid-catalysed addition of formaldehyde at C7
Reaction of the indoles 5–6 with formaldehyde in glacial
acetic acid gave the 7,70-diindolylmethanes 23–24 in 86 and
76% yield, respectively. The same compounds can also be
obtained by the treatment of the indole methanols 9–10 in
tetrahydrofuran with glacial acetic acid. This behaviour is
general for 2,3-disubstituted-4,6-dimethoxyindoles and

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A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
2-methylindole, with the linkage taking place at C3:
however, no 2-methyl oxidation occurred.15 Similar
reaction of simple 2,3-disubstituted indoles with selenium
dioxide gives no selenium compounds and the major
products are 2-acylindoles in yields of 22–44%.13 Although
indoles 5–6 are 2,3-disubstituted, they are also activated at
C7, allowing for selenium insertion to occur to form the
selenides 26–27.
The 7,70-diindolylmethane 23 also represents a suitably
7-protected indole, and it underwent reaction with selenium
dioxide to give the dialdehyde 36 in 43% yield: significantly
there was no oxidation of the methylene link.
3. Conclusions
In suitable examples, an indole 2-methyl group can be
oxidised to a formyl group, in a synthetically useful process
that delivers a variety of functionality to the indole ring. The
reaction probably proceeds by a mechanism similar to one
proposed by Sakai et al.13 involving direct oxidation at C2
(Scheme 1), rather than the more general initial oxidation at
C3 followed by intramolecular oxygen transfer within an
intermediate indoline system.
The ability of selenium dioxide to oxidise the 2-methyl
group of indoles 5–6 to a 2-formyl group raised the
possibility that similar oxidation might occur, but without
selenide formation, if C7 was substituted, preferably by an
electron-withdrawing group. Reaction of both the 7-tri-
fluoroacetyl indoles 14–15 and the 7-trichloroacetyl indoles
16–17 with approximately 4 equiv of selenium dioxide in
dioxan at reflux overnight, resulted in oxidation of the
methyl group to formyl, to give the aldehydes 28–29 and
30–31, respectively, in yields of 60–87%. On the other hand,
reaction of the 7-acetyl indole 11 gave a complex product
mixture. Treatment of the 7-trifluoroacetylindoles 28–29
with potassium hydroxide gave the corresponding 2-formyl-
7-carboxylic acids 32–33 in 95 and 82% yield, respectively.
4. Experimental
4.1. General
Mp were measured using a Mel-Temp melting point
apparatus, and are uncorrected. Microanalyses were
performed on a Carlo Erba Elemental Analyser EA 1108
at the Campbell Microanalytical Laboratory, University of
Otago, New Zealand. 1H and 13C NMR spectra were
obtained on a Bruker DPX300 (300 MHz) spectrometer.
Mass spectra were recorded on either a Bruker FT-ICR MS
(EI) or a Micromass ZQ2000 (ESI) at UNSW, or a
Shimadzu LCMS QP 8000 (ESI) at the University of
Otago, New Zealand. Infrared spectra were recorded with a
Thermo Nicolet 370 FTIR Spectrometer using KBr discs.
Ultraviolet–visible spectra were recorded using a Varian
Furthermore, reaction of the 7-nitro-indole 22 with selenium
dioxide proceeds smoothly to produce the 2-formyl-7-nitro-
indole 34 in 65% yield. In an alternative reaction, the
7-nitro-indole 22 was converted by sulfuryl chloride to the
related 2-chloromethyl compound, which was transformed
on chromatography in dichloromethane and methanol into
the 2-methoxymethylindole 35.
Scheme 1.

A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
10493
Cary 100 Scan Spectrometer. Column chromatography was
carried out using Merck 230–400 mesh ASTM silica gel,
whilst preparative thin layer chromatography was per-
stir for 2 h. The resulting precipitate was filtered off to yield
the indole 5 as a white solid (1.64 g, 95%), mp 130–131 8C
(ethanol). (Found: C, 76.4; H, 6.5; N, 5.3. C17H17NO2
requires C, 76.4; H, 6.4; N, 5.3%). nmax: 3380, 3360, 1610,
1595, 1580, 1550, 1500, 1435, 1405, 1330, 1245, 1205,
1185, 1145 cmK1. lmax: 236 nm (3 23,500 cmK1 MK1), 274
formed using Merck silica gel 7730 60GF254
.
4.2. Preparation of indoles
1
(16,600). H NMR spectrum (CDCl3): d 2.27 (3H, s, Me),
3.74 and 3.81 (6H, 2s, OMe), 6.31 (1H, d, JZ2.0 Hz, H5),
6.34 (1H, d, JZ2.0 Hz, H7), 7.31–7.37 (1H, m, ArH),
7.41–7.53 (4H, m, ArH), 7.75 (1H, s, NH). 13C NMR
spectrum (CDCl3): d 11.8 (Me), 55.0 and 55.4 (OMe), 86.8
(C5), 91.9 (C7), 125.4, 127.1, 130.9 (ArCH), 111.6, 113.8,
129.1, 136.7, 154.0, 156.6 (ArC). Mass spectrum (EI): m/z
267 (M, 100), 252 (65), 237 (25).
4.2.1. 2-(3,5-Dimethoxyphenylamino)-1-phenylpropan-
1-one (1). A mixture of 3,5-dimethoxyaniline (10.0 g,
65.3 mmol), 2-bromopropiophenone (14.1 g, 66.0 mmol),
and sodium hydrogen carbonate 11.0 g, 130.6 mmol in
absolute ethanol (100 mL) was heated under reflux for 3 h
with stirring. After cooling, the resulting white precipitate
was filtered off and washed with water to give the amino
ketone 1 (13.00 g, 70%) as a yellow solid, mp 118–119 8C
(ethanol). (Found: C, 71.7; H, 6.7; N, 5.0. C17H19NO3
requires C, 71.6; H, 6.7; N, 4.9%). nmax: 3360, 1670, 1600,
1520, 1220, 1200 cmK1. lmax: 218 nm (3 15,000 cmK1 MK1),
4.2.4. 1-(4-Bromophenyl)-2-[(3,5-dimethoxyphenyl)-
amino] propanone0 (2). 3,5-Dimethoxyaniline (5.00 g,
32.6 mmol),
2,4 -dibromopropiophenone
(9.56 g,
1
247 (12,200). H NMR spectrum (CDCl3): d 1.47 (3H, d,
32.7 mmol) and sodium hydrogen carbonate (2.72 g,
32.4 mmol) were added to absolute ethanol (100 mL) and
heated to reflux for 5 h. The mixture was allowed to cool to
room temperature and the resulting yellow precipitate was
filtered off, washed with water and dried to yield anilino
ketone 2 (10.10 g, 85%) as pale-yellow needles, mp 159–
160 8C (from ethyl acetate/light petroleum). (Found: C,
55.8; H, 5.2; N, 3.8. C17H18BrNO3 requires C, 56.0; H, 4.9;
N, 3.8%). nmax: 3402, 1687, 1619, 1583, 1479, 1199, 1168,
1070, 958 cmK1. lmax: 228 nm (3 17,350 cmK1 MK1), 263
JZ7.0 Hz, Me), 3.74 (6H, s, OMe), 4.77 (1H, br s, NH),
5.09 (1H, q, JZ7.0 Hz, CH), 5.86–5.90 (3H, m, H2, H4,
H6), 7.42–7.52 (4H, m, ArH), 7.58–7.63 (1H, m, ArH). 13C
NMR spectrum (CDCl3): d 19.49 (Me), 53.26 (CH), 55.08
(OMe), 90.07 (C4), 92.29 (C2, C6), 128.39, 128.81, 133.58
(ArCH), 134.58, 148.37, 161.77 (ArC), 200.39 (CO). Mass
spectrum (EI): m/z 285 (M, 10), 181 (20), 180 (100).
4.2.2. N-Acetyl-4,6-dimethoxy-2-methyl-3-phenylindole
(3). The anilino ketone 1 (5.00 g, 17.5 mmol) was partially
dissolved in acetic anhydride (20 mL) and heated at 70 8C
for 3 h. The solution was allowed to cool before water
(1 mL) was added and the solution was again warmed to
50–60 8C. Water was then added slowly so that the
temperature did not drop below 50 8C until the volume
was tripled. Stirring was continued until the solution
returned to room temperature. The solution was then
extracted with ethyl acetate. The organic phase was washed
with water until neutral, saturated sodium hydrogen
carbonate solution, brine and dried (sodium sulfate). The
solvent was removed under reduced pressure to yield an oil.
The crude protected anilino ketone was then dissolved in
trifluoroacetic acid (20 mL). The solution was allowed to
stir overnight after, which ice/water was added and the
resulting solid was filtered off. The precipitate was washed
with water until neutral and dried under vacuum. The
resulting crude product was purified by recrystallisation
from ethanol to yield the N-acetyl indole 3 as a white solid
(3.52 g, 65%), mp 146–148 8C (ethanol). (Found: C, 73.7;
H, 6.1; N, 4.5. C19H19NO3 requires C, 73.4; H, 6.2; N,
4.5%). nmax: 1695, 1590, 1565, 1410, 1360, 1280 cmK1. 1H
NMR spectrum (CDCl3): d 2.43 (3H, s, Me), 2.72 (3H, s,
COMe), 3.61 and 3.89 (6H, 2s, OMe), 6.36 (1H, d, JZ
2.0 Hz, H5), 7.33–7.42 (5H, m, ArH), 7.45 (1H, d, JZ
2.0 Hz, H7). 13C NMR spectrum (CDCl3): d 15.0 (Me), 27.4
(COMe), 55.2 and 55.7 (OMe), 92.7 (C5), 95.1 (C7), 126.5,
127.1, 130.9 (ArCH), 113.0, 122.0, 129.7, 135.1, 137.7,
153.5, 158.5 (ArC), 170.8 (CO). Mass spectrum (EI): m/z
309 (M, 60), 267 (100), 252 (60), 43 (100).
1
(16,950). H NMR spectrum (300 MHz, CDCl3): d 1.46
(3H, d, JZ7.2 Hz, Me), 3.73 (6H, s, OMe), 5.01 (1H, q, JZ
6.8 Hz, CHMe), 5.87, 5.90 (3H, 2d, JZ1.9 Hz, H2, H4,
H6), 7.64, 7.85 (4H, 2d, JZ8.7 Hz, ArH). 13C NMR
spectrum (75 MHz, CDCl3): d 19.2 (Me), 53.7 (CH), 55.1
(OMe), 90.7, 92.8, 129.8, 132.1 (ArCH), 128.8, 133.2,
147.6, 161.7 (ArC), 199.1 (CO). Mass spectrum (EI): m/z
366 (MC2, 81Br, 1%), 365 (2), 364 (M, 79Br, 1), 363 (2),
180 (100).
4.2.5. N-Acetyl-1-(4-bromophenyl)-2-[(3,5-dimethoxy-
phenyl)amido] propanone. The anilino ketone 2 (0.40 g,
1.10 mmol) was partially dissolved in acetic anhydride
(2 mL) and heated at 50 8C overnight. Water was then added
slowly so that the temperature did not drop below 50 8C
until the volume was tripled. Stirring was continued until the
solution returned to room temperature. The solution was
then extracted with ethyl acetate and the organic phase was
washed with saturated sodium hydrogen carbonate solution
and water until neutral, and then dried. The solvent was
evaporated off to give the title amido ketone (0.41 g, 92%)
as an off white solid, mp 140–14 8C. (Found: C, 56.3; H, 4.8;
N, 3.6. C19H20BrNO4 requires C, 56.2; H, 5.0; N, 3.5%).
nmax: 1689, 1654, 1592, 1324, 1203, 1162, 1071 cmK1
.
lmax: 228 nm (3 14,800 cmK1 MK1), 258 (20,900). 1H NMR
spectrum (300 MHz, CDCl3): d 1.23 (3H, d, JZ7.2 Hz,
Me), 1.85 (3H, s, COMe), 3.72 (6H, s, OMe), 6.06 (1H, q,
JZ7.2 Hz, CH), 6.26 (2H, d, JZ2.3 Hz, ArH), 6.43 (1H, t,
JZ2.3 Hz, ArH), 7.62, 7.89 (4H, 2d, JZ8.7 Hz, ArH). 13C
NMR spectrum (75 MHz, CDCl3): d 14.9, 22.5 (Me), 54.9
(CH), 55.4 (OMe), 100.4, 108.1, 129.9, 131.9 (ArCH),
128.2, 134.5, 140.6, 160.9 (ArC), 170.4, 198.0 (CO). Mass
spectrum (EI): m/z 408 (MC2, 81Br, 100%), 407 (86), 406
(M, 79Br, 92), 405 (51), 383 (40), 236 (47).
4.2.3. 4,6-Dimethoxy-2-methyl-3-phenylindole (5). The
N-acetyl indole 3 (2.00 g, 6.5 mmol) was partially dissolved
in ethanol (50 mL). An excess of crushed potassium
hydroxide was added to the above mixture and allowed to

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A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
4.2.6. 1-Acetyl-3-(4-bromophenyl)-4,6-dimethoxy-2-
methylindole (4). N-Acetyl-1-(4-bromophenyl)-2-[(3,5-
dimethoxyphenyl)amido]propanone (9.40 g, 23.1 mmol)
was dissolved in trifluoroacetic acid (32 mL). The solution
was stirred overnight after, which ice/water was added and
the mixture was extracted with dichloromethane. The
combined extract was washed with water until neutral and
dried. The solvent was evaporated under reduced pressure
and the residue was chromatographed (dichloromethane) to
afford the acetyl indole 4 (6.87 g, 77%) as a white solid, mp
172 8C. (Found: C, 58.4; H, 4.6; N, 3.6. C19H18BrNO3$0.1
H2O requires C, 58.5; H, 4.7; N, 3.6%). nmax: 1687, 1595,
(1H, s, H5), 7.36–7.39 (5H, m, ArH), 10.26 (1H, br, NH).
10.37 (1H, s, CHO). 13C NMR spectrum (75 MHz, CDCl3):
d 11.9 (Me), 55.2, 56.3 (OMe), 86.6 (C5), 125.7, 127.2,
130.8 (ArCH), 104.1, 111.6, 113.9, 130.7, 135.4, 136.2,
160.5, 162.2 (ArC), 188.3 (CO). Mass spectrum (EI): m/z
296 (MC1, 100%).
4.3.2. 3-(4-Bromophenyl)-4,6-dimethoxy-2-methylindole
7-carbaldehyde (8). This was prepared as described for the
7-carbaldehyde 7 from a solution of indole 6 (0.50 g,
1.4 mmol) in anhydrous dimethylformamide (w6 mL) and
a solution of phosphoryl chloride (0.15 mL, 1.59 mmol) in
anhydrous dimethylformamide (w0.4 mL). The resulting
precipitate was filtered off, washed with water until neutral
and dried to give the carbaldehyde 8 (0.51 g, 94%) as a
yellow solid, mp 255–256 8C. (Found: C, 58.1; H, 4.2; N,
1571, 1495, 1418, 1370, 1293, 1216, 1151 cmK1. lmax
:
208 nm (3 39,350 cmK1 MK1), 248 (23,600), 319 (4,950).
1H NMR spectrum (300 MHz, CDCl3): d 2.40 (3H, s, Me),
2.71 (3H, s, COMe), 3.62, 3.87 (6H, s, OMe), 6.34 (1H, d,
JZ2.3 Hz, H5), 7.38 (1H, d, JZ1.9 Hz, H7), 7.21, 7.50
(4H, 2d, JZ8.3 Hz, ArH). 13C NMR spectrum (75 MHz,
CDCl3): d 14.9, 27.4 (Me), 55.1, 55.7 (OMe), 92.6 (C5),
94.9 (C7), 130.3, 132.5 (ArCH), 112.6, 120.7, 120.8, 129.8,
134.0, 137.6, 153.4, 158.6 (ArC), 170.7 (CO). Mass
spectrum (EI): m/z 390 (MC2, 81Br, 100), 388 (M, 79Br,
100), 348 (56), 346 (60).
3.9. C18H16BrNO3 requires C, 57.8; H, 4.3; N, 3.7%). nmax
3314, 1637, 1590, 1451, 1390, 1245, 1162, 1118, 991, 813,
:
742 cmK1. lmax: 204 nm (3 40,100 cmK1 MK1), 229
(23,950), 253 (26,600), 326 (14,150). H NMR spectrum
1
(300 MHz, CDCl3): d 2.34 (3H, s, Me), 3.83, 3.97 (6H, 2s,
OMe), 6.13 (1H, s, H5), 7.25, 7.48 (4H, 2d, JZ8.3 Hz,
ArH), 10.27 (1H, br, NH). 10.36 (1H, s, CHO). 13C NMR
spectrum (75 MHz, CDCl3): d 11.9 (Me), 55.2, 56.3 (OMe),
86.6 (C5), 130.3, 132.3 (ArCH), 104.1, 111.3, 112.8, 119.7,
130.8, 134.4, 136.1, 160.4, 162.3 (ArC), 188.3 (CO). Mass
spectrum (EI): m/z 376 (MC2, 81Br, 19%), 375 (98), 374
(M, 79Br, 21), 373 (100), 360 (20), 358 (21), 279 (27).
4.2.7. 3-(4-Bromophenyl)-4,6-dimethoxy-2-methylindole
(6). The N-acetyl indole 4 (4.91 g, 12.65 mmol) was
partially dissolved in methanol (25 mL). An excess of
crushed potassium hydroxide was added and the mixture
was allowed to stir overnight. The resulting precipitate was
filtered off, washed and dried to yield the indole 6 as a white
solid (3.78 g, 86%), mp 162–163 8C. (Found: C, 58.7; H,
4.5; N, 4.1. C17H16BrNO2 requires C, 58.9; H, 4.7; N,
4.1%). nmax: 3338, 1620, 1561, 1487, 1340, 1319,
1217, 1199, 1151, 1129, 814 cmK1. lmax: 232 nm (3
22,950 cmK1 MK1). 1H NMR spectrum (300 MHz,
CDCl3): d 2.30 (3H, s, Me), 3.70, 3.82 (6H, 2s, OMe),
6.22 (1H, s, H5), 6.42 (1H, s, H7), 7.29, 7.48 (4H, 2d, JZ
8.2 Hz, ArH), 7.84 (1H, br, NH). 13C NMR spectrum
(75 MHz, CDCl3): d 11.9 (Me), 54.9, 55.6 (OMe), 86.6
(C5), 91.9 (C7), 130.1, 132.5 (ArCH), 111.4, 112.9, 119.4,
129.0, 134.9, 136.7, 154.0, 156.9 (ArC). Mass spectrum
(EI): m/z 348 (MC2, 81Br, 12%), 347 (100), 346 (M, 79Br,
12), 345 (98), 332 (29), 330 (29), 266 (8), 251 (86).
4.3.3. 7-Hydroxymethyl-4,6-dimethoxy-2-methyl-3-
phenylindole (9). Indole 7 (0.20 g, 0.68 mmol) was
dissolved in methanol (30 mL) to which excess sodium
borohydride was added. The mixture was then heated to
reflux under nitrogen for 1 h. Water was added and the
resulting precipitate was filtered, washed with water and
dried to yield the methanol 9 (0.19 g, 97%) as a white solid,
mp 268 8C (dec). (Found: C, 71.5; H 6.4; N, 4.7.
C18H19NO3$0.3 H2O requires C, 71.4; H, 6.5; N, 4.6%).
nmax: 3445, 3324, 1620, 1600, 1464, 1325, 1208, 1148,
1101, 997 cmK1. lmax: 203 nm (3 27,000 cmK1 MK1), 230
(38,550), 281 (14,000). 1H NMR spectrum (300 MHz,
d6-DMSO): d 2.28 (3H, s, Me), 3.64, 3.79 (6H, 2s, OMe),
4.53 (1H, t, JZ5.7 Hz, OH), 4.71 (2H, d, JZ5.7 Hz, CH2),
6.30 (1H, s, H5), 7.16–7.32 (5H, m, ArH), 10.64 (1H, s,
NH). 13C NMR spectrum (75 MHz, d6-DMSO): d 12.3
(Me), 54.1 (CH2), 55.4, 57.5 (OMe), 89.5 (C5), 125.3,
127.3, 130.9 (ArCH), 105.6, 111.9, 112.7, 130.8, 136.7,
153.0 (ArC). Mass spectrum (EI): m/z 296 (MK1, 25%),
280 (100).
4.3. Formylation and acylation of indoles
4.3.1. 4,6-Dimethoxy-2-methyl-3-phenylindole-7-carb-
aldehyde (7). A solution of phosphoryl chloride (0.04 mL,
0.41 mmol) in anhydrous dimethylformamide (w0.08 mL)
was added dropwise to a stirred solution of 3-phenyl indole
5 (0.10 g, 0.37 mmol) in anhydrous dimethylformamide
(w1.2 mL) at 0 8C. The mixture was stirred at this
temperature for 1 h, then allowed to come to room
temperature. Ice water was added and the mixture was
made strongly basic with 10% NaOH and stirred for another
15 min. The precipitate was filtered off, washed with water
until neutral and dried to give the carbaldehyde 7 (0.10 g,
95%) as a light brown solid, mp 254–256 8C. (Found: C,
72.2; H, 5.8; N, 4.7. C18H17NO3$0.2 H2O requires C, 72.3;
H, 5.9; N, 4.7%). nmax: 3314, 1635, 1597, 1449, 1361, 1245,
1161, 1120, 990 cmK1. lmax: 204 nm (3 30,300 cmK1 MK1),
4.3.4. 3-(4-Bromophenyl)-7-hydroxymethyl-4,6-di-
methoxy-2-methylindole (10). This was prepared as
described for the hydroxymethylindole 9 from indole 75
(0.30 g, 0.80 mmol) in methanol (60 mL) and excess
sodium borohydride to yield the methanol 10 (0.28 g,
93%) as a white solid, mp 240 8C (dec). (Found: C, 56.8; H
4.6; N, 3.7. C18H18BrNO3$0.2 H2O requires C, 56.9; H, 4.9;
N, 3.7%). nmax: 3580, 3312, 1619, 1595, 1488, 1343, 1150,
1
1104, 995 cmK1. lmax: 234 nm (3 27,300 cmK1 MK1). H
NMR spectrum (300 MHz, d6-DMSO): d 2.27 (3H, s, Me),
3.66, 3.79 (6H, 2s, OMe), 4.53 (1H, t, JZ5.7 Hz, OH), 4.69
(2H, d, JZ5.7 Hz, CH2), 6.31 (1H, s, H5), 7.25, 7.48 (4H,
2d, JZ8.7 Hz, ArH), 10.71 (1H, s, NH). 13C NMR spectrum
1
253 (23,050), 328 (10,600). H NMR spectrum (300 MHz,
CDCl3): d 2.36 (3H, s, Me), 3.82, 3.97 (6H, 2s, OMe), 6.13

A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
10495
(75 MHz, d6-DMSO): 12.2 (Me), 54.1 (CH2), 55.4, 57.5
(OMe), 89.5 (C5), 130.2, 132.9 (ArCH), 105.6, 111.4,
111.5, 118.4, 131.2, 136.0, 136.7, 152.9, 153.1 (ArC). Mass
spectrum (EI): m/z 378 (MC2, 81Br, 16%), 377 (93), 376
(M, 79Br, 13), 375 (100), 359 (88), 357 (85), 263 (27), 235
(25).
The organic layer was washed with 2 M NaOH, water, dried
and concentrated. The residue was chromatographed
(dichloromethane) to give the ketone 13 (0.64 g, 85%) as
a yellow solid, mp 186–187 8C. (Found: C, 70.9; H, 5.0; N,
3.7. C24H20ClNO3 requires C, 71.0; H, 4.97; N, 3.5%). nmax
:
:
3386, 1589, 1546, 1356, 1287, 1196, 1149, 987 cmK1. lmax
242 nm (3 28,450 cmK1 MK1), 258 (28,050), 333 (11,450).
1H NMR spectrum (300 MHz, CDCl3): d 2.37 (3H, s, Me),
3.61, 3.81 (6H, 2s, OMe), 6.16 (1H, s, H5), 7.25–7.61 (9H,
m, ArH), 10.02 (1H, br, NH). 13C NMR spectrum (75 MHz,
CDCl3): d 11.9 (Me), 55.2, 56.1 (OMe), 87.8 (C5),
125.6, 127.2, 127.7, 129.6, 130.8 (ArCH), 103.5, 112.3,
114.1, 130.6, 135.5, 136.5, 137.6, 140.8, 158.9, 159.0,
173.3 (ArC), 194.5 (CO). Mass spectrum (EI): m/z 407
(MC2, 37Cl, 25%), 405 (M, 35Cl, 90), 355 (18), 267 (100),
252 (56).
4.3.5. 7-(4,6-Dimethoxy-2-methyl-3-phenylindolyl)-etha-
none (11). Indole 5 (1.0 g, 3.7 mmol) was added to a stirred
and ice cooled solution of N,N-dimethylacetamide (25 mL)
and excess phosphoryl chloride (1.2 g, 7.8 mmol). The
reaction mixture was stirred at room temperature for 0.5 h
and then warmed to 40–60 8C for 6 h. This mixture was then
poured into an ice cooled sodium hydroxide solution (10%,
100 mL). The resulting crude product was filtered off, and
recrystallised from methanol to afford the 7-acetyl indole 11
(0.94 g, 82%) as an off-white solid, mp 148 8C (from
methanol). (Found: C, 73.9; H, 6.1; N, 4.7. C19H19NO3
requires C, 73.8; H, 6.1; N, 4.5%). nmax: 3370, 1615, 1595,
4.3.8. 4,6-Dimethoxy-2-methyl-3-phenyl-7-trifluoro-
acetylindole (14). Indole 5 (1.0 g, 3.7 mmol) was dissolved
in dry dichloromethane (50 mL) and excess trifluoroacetic
anhydride (3.0 mL, 21.3 mmol) was added. The mixture
was stirred for 4 h at room temperature before water was
added and the organic layer extracted with dichloro-
methane. The organic layer was washed with water until
neutral then dried. The solvent was evaporated off and the
residue recrystallised from dichloromethane/light petroleum
to give compound 14 (1.1 g, 83%) as a yellow solid, mp
150–151 8C. (Found: C, 62.0; H, 4.5; N, 3.9.
C19H16NO3F3$0.25 H2O requires C, 62.0; H, 4.5; N,
3.8%). nmax: 3420, 1630, 1590, 1570, 1550, 1440, 1390,
1360, 1330, 1230, 1200, 1180 cmK1. lmax: 219 nm
(3 20,000 cmK1 MK1), 258 (20,400), 346 (11,000). 1H
NMR spectrum (CDCl3): d 2.36 (3H, s, Me), 3.84, 3.99 (6H,
2s, OMe), 6.16 (1H, s, H5), 7.28–7.41 (5H, m, ArH), 10.36
(1H, br s, NH). 13C NMR spectrum (CDCl3): d 11.8 (Me),
55.3, 56.4 (OMe), 87.4 (C5), 99.7 (CF3), 125.9, 127.3, 130.8
(ArCH), 112.1, 114.8, 115.5, 119.3, 135.1, 138.0, 161.5,
161.7 (ArC), 178.4 (CO). Mass spectrum (EI): m/z 364
(MC1, 15), 363 (M, 100), 294 (85), 147 (20).
1575, 1500, 1440, 1350, 1330, 1270, 1235, 1200, 1140 cmK1
.
lmax: 219 nm (3 15,500 cmK1 MK1), 251 (19,600), 324
(11,700). H NMR spectrum (CDCl3): d 2.37 (3H, s, Me),
1
2.69 (3H, s, COMe), 3.80, 3.98 (6H, 2s, OMe), 6.18 (1H, s,
H5), 7.24–7.43 (5H, m, ArH), 10.78 (1H, br s, NH). 13C
NMR spectrum (CDCl3): d 12.0 (Me), 33.1 (COMe), 55.1,
56.2 (OMe), 87.2 (C5) 125.5, 127.2, 130.9 (ArCH), 104.6,
111.9, 113.6, 130.5, 135.8, 137.5, 158.7, 160.2 (ArC), 198.7
(CO). Mass spectrum (EI): m/z 310 (MC1, 45), 309 (M,
100), 294 (55), 266 (75), 251 (20).
4.3.6. 7-(3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-
indolyl)-ethanone (12). To a stirred and ice cooled solution
of N,N-dimethylacetamide (2.4 mL) and excess phosphoryl
chloride (0.81 mL, 8.69 mmol) was added indole 6 (0.30 g,
0.87 mmol). The mixture was stirred at room temperature
for 30 min and then warmed to 40–60 8C overnight. The
mixture was then poured onto crushed ice containing 10%
NaOH. The resulting crude product was filtered off, washed
till neutral and dried. Column chromatography (dichloro-
methane) yielded the ketone 12 (0.30 g, 89%) as an off
white solid, mp 178–179 8C. (Found: C, 59.0; H, 4.7; N, 3.7.
C19H18BrNO3 requires C, 58.8; H, 4.7; N, 3.6%). nmax
:
4.3.9. 3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-7-tri-
fluoroacetylindole (15). Indole 6 (0.50 g, 1.4 mmol) was
dissolved in dry dichloromethane (25 mL) and excess
trifluoroacetic anhydride (1.22 mL, 8.7 mmol) was added.
The mixture was stirred for 4 h, water was then added and
the organic layer was extracted with dichloromethane. The
organic layer was washed with water until neutral then
dried. The solvent was evaporated off and the residue was
chromatographed (dichloromethane) to give compound 15
(0.63 g, 99%) as a yellow solid, mp 186–187 8C. (Found: C,
51.6; H 3.2; N, 3.3. C19H15BrF3NO3 requires C, 51.6; H,
3.4; N, 3.2%). nmax: 3371, 1632, 1587, 1327, 1222, 1155,
1128, 988 cmK1. lmax: 237 nm (3 25,350 cmK1 MK1), 344
3342, 1620, 1585, 1468, 1347, 1265, 1212, 1134, 1097,
992 cmK1. lmax: 230 nm (S 27,150 cmK1 MK1), 255
(26,900), 333 (14,200). 1H NMR spectrum (300 MHz,
CDCl3): d 2.34 (3H, s, Me), 2.68 (3H, s, COMe), 3.81, 3.98
(6H, 2s, OMe), 6.18 (1H, s, H5), 7.26, 7.48 (4H, 2d, JZ
8.3 Hz, ArH), 10.78 (1H, br, NH). 13C NMR spectrum
(75 MHz, CDCl3): d 11.9 (Me), 33.0 (COMe), 55.1, 56.1
(OMe), 87.2 (C5), 130.2, 132.4 (ArCH), 104.5, 111.5,
112.4, 119.5, 130.6, 134.7, 137.5, 158.5, 160.2 (ArC), 198.7
(CO). Mass spectrum (EI): m/z 390 (MC2, 81Br, 20%), 389
(96), 388 (M, 79Br, 20), 387 (100), 372 (20), 344 (30), 293
(42), 250 (20).
1
(13,600). H NMR spectrum (300 MHz, CDCl3): d 2.33
4.3.7. 7-(4-Chlorobenzoyl)-4,6-dimethoxy-2-methyl-3-
phenylindole (13). Phosphoryl chloride (0.2 mL,
2.2 mmol) was added to warm (60 8C) 4-chloro-N,N0-
dimethylbenzamide (0.7 g, 3.8 mmol). After stirring for
5 min, indole 5 (0.5 g, 1.9 mmol) was added and the mixture
was heated to 80 8C and stirred for 30 min. The reaction
mixture was allowed to cool, then 2 M NaOH (30 mL) was
added and the mixture was extracted with dichloromethane.
(3H, s, Me), 3.85, 3.98 (6H, 2 s, OMe), 6.14 (1H, s, H5),
7.24, 7.49 (4H, 2d, JZ8.7 Hz, ArH), 10.35 (1H, br, NH).
13C NMR spectrum (75 MHz, CDCl3): d 11.8 (Me), 55.3,
56.5 (OMe), 87.4 (C5), 99.7 (CF3), 130.4, 132.3 (ArCH),
111.8, 113.6, 115.4, 119.2, 119.9, 130.6, 134.1, 137.9, 161.5
(ArC), 178.8 (CO). Mass spectrum (EI): m/z 444 (MC2,
81Br, 20%), 443 (MC1, 100), 442 (M, 79Br, 25), 374 (63),
372 (66).

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A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
4.3.10. 4,6-Dimethoxy-2-methyl-3-phenyl-7-trichloro-
acetylindole (16). Trichloroacetyl chloride (2.0 mL,
17.9 mmol) was added dropwise to a solution of the indole
5 (1.0 g, 3.7 mmol) in chloroform (20 mL). After com-
pletion of the addition, the solution was heated to reflux
under a nitrogen atmosphere overnight. The solution was
allowed to cool to room temperature, then water was added,
the organic layer extracted with dichloromethane, dried
and concentrated. The residue was recrystallised from
dichloromethane/light petroleum to give compound 16, as
an orange solid (1.0 g, 66%), mp 186–187 8C. (Found: C,
55.3; H, 3.9; N, 3.4. C19H16NO3Cl3 requires C, 55.3; H, 3.9;
N, 3.4%). nmax: 3445, 3410, 1640, 1590, 1570, 1560, 1490,
1450, 1410, 1390, 1355, 1320, 1250, 1220, 1200, 1170,
1140 cmK1. lmax: 226 nm (3 30,100 cmK1 MK1), 264
(26,200), 345 (12,700). 1H NMR spectrum (CDCl3): d
2.35 (3H, s, Me), 3.83, 3.96 (6H, 2s, OMe), 6.16 (1H, s, H5),
7.27–7.39 (5H, m, ArH), 10.05 (1H, br s, NH). 13C NMR
spectrum (CDCl3): d 11.9 (Me), 55.3, 55.5 (OMe), 87.3
(C5), 98.6 (CCl3), 125.8, 127.2, 130.8 (ArCH), 98.2, 112.2,
114.8, 130.4, 135.2, 138.3, 159.4, 160.7 (ArC), 182.3 (CO).
Mass spectrum (EI): m/z 415 (MC2, 5), 413 (M, 10), 411
(10), 294 (100).
3.82, 3.91 (6H, 2s, OMe), 4.40 (2H, q, JZ7.2 Hz, OCH2),
6.12 (1H, s, H5), 7.24, 7.48 (4H, 2d, JZ8.3 Hz, ArH), 10.29
(1H, br, NH). 13C NMR spectrum (75 MHz, CDCl3): d 11.9
(Me), 14.1 (Me), 55.3, 56.8 (OMe), 61.3 (OCH2), 87.3 (C5),
130.3, 132.3 (ArCH), 100.5, 111.9, 113.2, 119.8, 130.9,
134.2, 137.0, 161.1, 161.2 (ArC), 166.0, 185.1 (CO). Mass
spectrum (EI): m/z 448 (MC2, 81Br, 10%), 447 (43), 446
(M, 79Br, 10), 445 (41), 375 (20), 374 (96), 373 (34), 372
(100).
4.3.13. N,N-Dimethyl-2-(3-(4-bromophenyl)-4,6-di-
methoxy-2-methylindol-7-yl) glyoxylamide (19). Indole
6 (0.80 g, 2.31 mmol) was dissolved in anhydrous
dichloromethane (20 mL) and the solution cooled to 0 8C.
Oxalyl chloride (0.27 mL, 2.8 mmol) was then added
rapidly and the solution was allowed to stir for 15 min at
this temperature. The solution was then warmed to room
temperature and excess dimethylamine solution (40%) was
added. The mixture was stirred for another 1 h, water was
added and the mixture extracted with dichloromethane. The
organic layer was washed with water, dried and concen-
trated to afford the amide 19 (0.83 g, 81%) as a yellow solid,
mp 249 8C. (Found: C, 56.8; H, 4.7; N, 6.4. C21H21BrN2O4
requires C, 56.6; H, 4.8; N, 6.3%). nmax: 3354, 1649, 1580,
1451, 1357, 1284, 1228, 1128, 794 cmK1. lmax: 238 nm
4.3.11. 3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-7-
trichloroacetylindole (17). Trichloroacetyl chloride
(0.4 mL, 3.6 mmol) was added dropwise to a solution of
the indole 6 (0.25 g, 0.7 mmol) in chloroform (10 mL), then
the solution was heated to reflux under a nitrogen
atmosphere overnight, allowed to cool to room temperature,
then water was added, the organic layer was extracted with
dichloromethane, and concentrated. The residue was
chromatographed (dichloromethane) to give compound 17
(0.30 g, 85%) as an orange solid, mp 181–182 8C. (Found:
C, 46.7; H, 3.1; N, 2.9. C19H15BrCl3NO3 requires C, 46.4;
H, 3.1; N, 2.8%). nmax: 3407, 1629, 1585, 1560, 1468, 1355,
1247, 993 cmK1. lmax: 237 nm (3 28,900 cmK1 MK1), 347
(7,150). 1H NMR spectrum (300 MHz, CDCl3): d 2.33 (3H,
s, Me), 3.83, 3.96 (6H, s, OMe), 6.16 (1H, s, H5), 7.24, 7.49
(4H, 2d, JZ8.3 Hz, ArH), 10.04 (1H, br, NH). 13C NMR
spectrum (75 MHz, CDCl3): d 11.8 (Me), 55.2, 55.5 (OMe),
87.4 (C5), 98.5 (CCl3), 130.3, 132.3 (ArCH), 98.3, 111.9,
113.6, 119.8, 130.4, 134.2, 138.3, 159.5, 160.5 (ArC), 182.3
(CO). Mass spectrum (EI): m/z 493 (MC2, 28%), 491 (M,
41), 374 (100), 372 (95), 220 (24).
1
(S 27,700 cmK1 MK1), 348 (13,550). H NMR spectrum
(300 MHz, CDCl3): d 2.34 (3H, s, Me), 2.94, 3.07 (6H, 2s,
NMe2), 3.81, 3.91 (6H, 2s, OMe), 6.13 (1H, s, H5), 7.23,
7.48 (4H, 2d, JZ8.7 Hz, ArH), 10.45 (1H, br, NH). 13C
NMR spectrum (75 MHz, CDCl3): d 11.9 (Me), 33.7, 36.6
(NMe2), 55.3, 57.3 (OMe), 87.5 (C5), 130.3, 132.4 (ArCH),
101.5, 111.9, 113.0, 119.8, 132.4, 134.3, 137.0, 160.7, 161.1
(ArC), 169.2, 190.2 (CO). Mass spectrum (EI): m/z 447
(MC2, 81Br, 7%), 446 (34), 445 (M, 79Br, 6), 444 (34), 374
(93), 372 (100).
4.3.14. N-Hydroxy-N-methyl-[2-(3-(4-bromophenyl)-4,6-
dimethoxy-2-methylindol-7-yl)] glyoxylamide (20).
Indole 6 (0.25 g, 0.57 mmol) was dissolved in anhydrous
dichloromethane (10 mL) and the solution cooled to 0 8C
with an ice bath. Oxalyl chloride (0.06 mL, 0.60 mmol) was
then added rapidly and the solution was allowed to stir for
15 min. N-methylhydroxylamine hydrochloride (0.25 g,
2.99 mmol) was added, followed by triethylamine
(0.4 mL). The mixture was stirred at room temperature for
2 h, water was added and extracted with dichloromethane.
The organic layer was acidified with 2 M HCl, washed with
water, dried and concentrated to give the hydroxamic acid
20 (0.14 g, 55%) as a yellow solid, mp 242–243 8C (from
methanol). (Found: C, 51.9; H, 4.2; N, 6.0.
C20H19BrN2O5$0.9 H2O requires C, 51.8; H, 4.5; N,
6.0%). nmax: 3361, 3120, 1646, 1583, 1466, 1368, 1271,
1213, 1121, 985 cmK1. lmax: 234 nm (3 29,250 cmK1 MK1),
4.3.12. Ethyl 2-(3-(4-bromophenyl)-4,6-dimethoxy-2-
methylindol-7-yl)glyoxylate (18). Indole 6 (1.50 g,
4.33 mmol) was dissolved in anhydrous dichloromethane
(37.5 mL) and the solution cooled to 0 8C. Oxalyl chloride
(0.5 mL, 5.2 mmol) was then added rapidly and the solution
was allowed to stir for 15 min at this temperature. The
solution was then warmed to room temperature and excess
ethanol was added. The mixture was refluxed for 1 h, the
solvent was then evaporated off, water was added and
extracted with dichloromethane. The organic layer was
washed with water, dried and concentrated to afford the
ester 18 (1.72 g, 89%) as a yellow solid, mp 231–232 8C.
(Found: C, 56.7; H, 4.4; N, 3.2. C21H20BrNO5 requires C,
56.5; H, 4.5; N, 3.1%). nmax: 3338, 1735, 1583, 1468, 1210,
1131, 1072, 794 cmK1. lmax: 234 nm (3 27,350 cmK1 MK1),
1
348 (12,300). H NMR spectrum (300 MHz, d6-DMSO): d
2.29 (3H, s, Me), 3.18 (3H, s, NMe), 3.79, 3.88 (6H, 2s,
OMe), 6.37 (1H, s, H5), 7.25, 7.51 (4H, 2d, JZ8.3 Hz,
ArH), 9.94 (1H, s, OH), 11.22 (1H, br, NH). 13C NMR
spectrum (75 MHz, d6-DMSO): d 12.1 (Me), 35.9 (NMe),
55.9, 57.9 (OMe), 88.8 (C5), 130.4, 133.0 (ArCH), 101.7,
111.5, 112.2, 119.1, 132.4, 135.1, 135.9, 160.1, 161.0
(ArC), 169.3, 189.3 (CO). Mass spectrum (EI): m/z 449
(MC2, 81Br, 5%), 448 (24), 447 (M, 79Br, 5), 446 (24), 373
(29), 372 (100).
1
259 (27,300), 336 (15,400). H NMR spectrum (300 MHz,
CDCl3): d 1.41 (3H, t, JZ7.2 Hz, Me), 2.33 (3H, s, Me),

A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
10497
4.3.15. 2,6-Di-(4,6-dimethoxy-2-methyl-3-phenylindole-
7-carbonyl)pyridine (21). To a suspension of aluminium
chloride (0.11 g, 0.82 mmol) in anhydrous and ethanol-free
chloroform (2 mL) was added pyridine-2,6-dicarbonyl
chloride (0.20 g, 0.37 mmol) under an argon atmosphere.
The pink mixture was stirred for 2 h, before indole 5 (0.20 g,
0.74 mmol) in chloroform (0.5 mL) was added, and the
mixture stirred for another 6 h. Both methanol (5 drops) and
water (3 mL) were added and stirring was continued for
30 min. The mixture was extracted with dichloromethane
(3!5 mL), dried with magnesium sulfate, and purified by
column chromatography on silica gel (dichloromethane/
methanol, 98:2) yielding compound 21 (0.34 g, 69%) as a
bright yellow powder, mp 260–300 8C (dec). Found: C,
69.8; H, 5.3; N, 5.8. C41H35N3O6$HCl requires C, 70.1; H,
5.2; N, 6.0%. nmax: 3383, 3354, 1613, 1586, 1552, 1452,
1368, 1274, 1214, 1160, 990, 702 cmK1. lmax: 232 nm (3
44,600), 336 (22,700). 1H NMR spectrum (300 MHz,
CDCl3): d 2.37 (6H, s, Me), 3.53 (6H, s, OMe), 3.77 (6H,
s, OMe), 6.07 (2H, m, H5 Ind), 7.33–7.41 (10H, m, Ph), 7.58
(2H, d, J 7.9 Hz, Py), 7.93 (1H, t, J 7.9 Hz, Py), 10.34 (2H,
br s, NH). The compound was too insoluble for measure-
ment of a 13C NMR spectrum. Mass spectrum (EI): m/z
1353.6 (100, [2MCNa]C), 666.6 (79, MHC).
glacial acetic acid (5 mL) was warmed at 60 8C and then
formaldehyde (40%, 1.5 mL) was added and the mixture
stirred overnight. The precipitate was filtered off, washed
and dried to give compound 23 (0.13 g, 76%) as a white
solid.
Method B. The 7-hydroxymethylindole
9 (0.05 g,
0.17 mmol) in glacial acetic acid (3 mL) and tetrahydro-
furan (2 mL) were stirred at room temperature for 30 min.
The precipitate was filtered off, washed and dried to produce
compound 23 (0.04 g, 79%) as a white solid.
Mp 310 8C (dec). (Found: C, 76.7; H, 6.2; N, 5.1.
C35H34N2O4 requires C, 76.9; H, 6.3; N, 5.1%). nmax
:
.
3338, 1599, 1519, 1435, 1341, 1151, 1115, 1002, 995 cmK1
lmax: 246 nm (S 52,250 cmK1 MK1), 310 (17,900). 1H
NMR spectrum (300 MHz, CDCl3): d 2.38 (6H, s, Me),
3.67, 4.16 (12H, 2s, OMe), 4.28 (2H, s, CH2), 6.34 (2H, s,
H5), 7.22–7.40 (10H, m, ArH), 9.72 (2H, br, NH). 13C NMR
spectrum (75 MHz, CDCl3): d 12.3 (Me), 18.7 (CH2), 55.6,
57.9 (OMe), 89.9 (C5), 125.1, 126.9, 130.8 (ArCH), 104.4,
112.9, 113.9, 130.2, 136.3, 136.6, 150.6, 152.6 (ArC). Mass
spectrum (EI): m/z 547 (M, 33%), 280 (72), 268 (100).
4.3.18. Di-[3-(4-bromophenyl)-4,6-dimethoxy-2-methyl-
indol-7-yl]methane (24). Method A. Indole 6 (0.20 g,
0.58 mmol) in glacial acetic acid (10 mL) was warmed at
60 8C and then formaldehyde (40%, 2 mL) was added and
the mixture stirred overnight. The precipitate was filtered
off, washed and dried to give compound 24 (0.17 g, 86%) as
a white solid.
4.3.16. 4,6-Dimethoxy-2-methyl-7-nitro-3-phenylindole
(22). To a solution of N-acetylindole 3 (2.0 g, 6.5 mmol)
in dichloromethane (100 mL) was added concd nitric acid
supported on silica gel (2.0 g). The mixture was quickly
shaken for 10 s and immediately filtered. The solvent was
removed and the residue recrystallised from ethanol to
afford 1-acetyl-4,6-dimethoxy-2-methyl-3-phenylindole
(0.46 g, 20%) as an orange solid, mp 192–193 8C (from
ethanol). nmax: 1720, 1610, 1600, 1585, 1575, 1510, 1435,
1410, 1320, 1260, 1220, 1200, 1180, 1140, 1120 cmK1. 1H
NMR spectrum (CDCl3): d 2.37 (3H, s, Me), 2.58 (3H, s,
COMe), 3.71, 3.98 (6H, 2s, OMe), 6.32 (1H, s, H5), 7.26–
7.36 (5H, m, ArH). 13C NMR spectrum (CDCl3): d 13.3
(Me), 26.7 (COMe), 55.6, 57.7 (OMe), 90.8 (C5) 126.9,
127.4, 130.8 (ArCH), 114.4, 119.1, 127.2, 129.2, 131.3,
134.0, 152.4, 156.7 (ArC), 172.1 (CO). Mass spectrum (EI):
m/z 354 (M, 10), 312 (100), 236 (20), 220 (25), 192 (20).
Method B. The 7-hydroxymethylindole 10 (0.05 g,
0.13 mmol) in glacial acetic acid (2 mL) and tetrahydro-
furan (2 mL) were stirred at room temperature for 30 min.
The precipitate was filtered off, washed and dried to produce
compound 24 (0.03 g, 73%) as a white solid.
Melting point 274 8C (dec). (Found: C, 59.4; H, 4.4; N, 4.0.
C35H32Br2N2O4 requires C, 59.7; H, 4.6; N, 3.9%). nmax
3339, 3307, 1625, 1598, 1488, 1460, 1340, 1155, 1119,
:
1
999 cmK1. lmax: 244 nm (S 52,700 cmK1 MK1). H NMR
spectrum (300 MHz, CDCl3): d 2.35 (6H, s, Me), 3.69, 4.16
(12H, 2s, OMe), 4.25 (2H, s, CH2), 6.33 (2H, s, H5), 7.23,
7.44 (8H, 2d, JZ8.3 Hz, ArH), 9.72 (2H, br, NH). 13C NMR
spectrum (75 MHz, CDCl3): d 12.2 (Me), 18.6 (CH2), 55.4,
57.9 (OMe), 89.7 (C5), 130.1, 132.4 (ArCH), 104.3, 112.6,
112.7, 119.1, 130.3, 135.2, 136.5, 150.7, 152.4 (ArC). Mass
spectrum (EI): m/z 706 (MC2, 81Br, 20%), 704 (M, 79Br,
35), 360 (88), 358 (100), 346 (60), 345 (68), 330 (23), 251
(59).
The unpurified N-acetylindole (0.40 g, 1.1 mmol) was
partially dissolved in ethanol (20 mL). An excess of crushed
potassium hydroxide was added to the above mixture, which
was allowed to stir for 2 h. The resulting precipitate was
filtered off to yield the nitro indole 22 (0.32 g, 90%) as a
orange solid, mp 229–231 8C (from ethanol). (Found: C,
61.1; H, 4.7; N, 8.3. C17H16N2O4$0.5 H2O requires C, 60.9;
H, 4.5; N, 8.3%). nmax: 3350, 1610, 1590, 1580, 1560, 1510,
1460, 1440, 1400, 1330, 1285, 1220, 1180, 1120, 980 cmK1
.
lmax: 220 nm (3 26,900 cmK1 MK1), 263 (20,000), 362
(8,700). H NMR spectrum (CDCl3): d 2.37 (3H, s, Me),
4.3.19. 4,6,40,60-Tetramethoxy-2,20-dimethyl-3,30-di-
phenyl-7,70-biindolyl (25). 1,4-Benzoquinone (81 mg,
0.75 mmol) was dissolved in tetrahydrofuran (20 mL), and
both concd hydrochloric acid (2 mL) and indole 5 (200 mg,
0.75 mmol) were added. The mixture was stirred vigorously
at room temperature for 1 h prior to the addition of water
(20 mL) and extraction with dichloromethane (3!20 mL).
The combined organic layers were dried with sodium
sulfate, the solvent evaporated under reduced pressure and
the crude brown residue recrystallised from dichloro-
methane/light petroleum to yield compound 25 (0.35 g,
1
3.82, 4.04 (6H, 2s, OMe), 6.19 (1H, s, H5), 7.32–7.39 (5H,
m, ArH), 10.05 (1H, br s, NH). 13C NMR spectrum (CDCl3):
d 11.9 (Me), 55.5, 57.2 (OMe), 88.2 (C5) 126.1, 127.3,
130.8 (ArCH), 112.5, 115.3, 118.7, 131.1, 132.0, 134.7,
155.9, 159.6 (ArC). Mass spectrum (EI): m/z 313 (MC1,
20), 312 (M, 100), 236 (20), 192 (20).
4.3.17. Di-[4,6-dimethoxy-2-methyl-3-phenylindol-7-yl]
methane (23). Method A. Indole 6 (0.17 g, 0.64 mmol) in

10498
A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
88%) as a pale grey powder, mp 220–222 8C. (Found: C,
75.5; H, 6.4; N, 5.2. C34H32N2O4. 0.5H2O requires: C, 75.4;
H, 6.1; N, 5.2%). nmax: 3450, 3167, 2837, 1600, 1511, 1466,
1328, 1212, 1197, 1134, 992, 761 cmK1. lmax: 237 nm
filtrate and the yellowish precipitate collected and dried.
Column chromatography (dichloromethane) yielded the
aldehyde 28 (0.36 g, 60%) as a yellow solid, mp 188–
190 8C (ethanol). (Found: C, 60.6; H, 3.8; N, 3.9.
1
(3 49,300), 290 (19,500). H NMR spectrum (300 MHz,
C19H14F3NO4 requires C, 60.5; H, 3.7; N, 3.7%). nmax:
d6-DMSO): d 2.15 (6H, s, Me), 3.65 (6H, s, OMe), 3.72 (6H,
s, OMe), 6.44 (2H, s, H5), 7.15–7.33 (10H, m, Ph), 9.99
(2H, s, NH). 13C NMR spectrum (75 MHz, d6-DMSO): d
12.2 (Me), 55.4 (OMe), 56.8 (OMe), 90.0 (C5), 99.4, 111.6,
112.6, 130.8, 137.0, 137.1, 152.9, 153.5 (ArC), 125.1,
127.3, 130.9 (ArCH). Mass spectrum (ES): m/z 533.2
(100%, MC).
3425, 1650, 1620, 1590, 1570, 1540, 1440, 1400, 1340,
1320, 1240, 1210, 1190, 1170, 1130 cmK1. lmax: 208 nm (3
19,100 cmK1 MK1), 249 (27,700), 320 (20,100), 359
1
(23,600). H NMR spectrum (CDCl3): d 3.87, 4.02 (6H,
2s, OMe), 6.17 (1H, s, H5), 7.40–7.49 (5H, m, ArH), 9.53
(1H, s, CHO), 10.93 (1H, br s, NH). 13C NMR spectrum
(CDCl3): d 55.8, 56.6 (OMe), 88.2 (C5), 99.6 (CF3), 27.5,
128.0, 131.1 (ArCH), 112.3, 115.2, 118.8, 130.1, 131.5,
131.8, 139.9, 164.4, 165.3 (ArC), 178.2, 181.2 (CO). Mass
spectrum (EI): m/z 378 (MC1, 45), 377 (M, 95), 308 (100),
250 (20), 222 (35).
4.3.20. 7-70-Seleno-bis-(4,6-dimethoxy-3-phenylindole)-
2,20-dicarbaldehyde (26). N-Acetyl-4,6-dimethoxy-2-
methyl-3-phenylindole 3 (1.0 g, 3.2 mmol) was dissolved
in dioxane (100 mL) to which selenium dioxide (1.4 g,
12.9 mmol) was added. The mixture was then heated to
reflux for 24 h, cooled and filtered. Water was then added to
the filtrate and the yellowish precipitate collected and dried.
Column chromatography (dichloromethane) yielded the
selenide 26 (0.36 g, 35%) as a yellow solid, mp 276–
278 8C. (Found: C, 64.2; H, 4.1; N, 4.6. C34H28N2O6Se
requires C, 63.9; H, 4.4; N, 4.4%). nmax: 3380, 3350, 1645,
1620, 1570, 1540, 1500, 1440, 1340, 1250, 1220, 1210,
1170, 1150 cmK1. lmax: 208 nm (3 34,400 cmK1 MK1), 262
(31,200), 327 (24,800). 1H NMR spectrum (CDCl3): d 3.74,
4.26 (12H, 2s, OMe), 6.26 (2H, s, H5), 7.37–7.49 (10H, m,
ArH), 9.54 (2H, s, CHO), 10.14 (1H, br s, NH). 13C NMR
spectrum (CDCl3): d 55.3, 57.2 (OMe), 88.4 (C5), 127.4,
127.5, 131.5 (ArCH), 90.9, 111.9, 130.7, 131.5, 132.4,
142.4, 158.6, 160.5 (ArC), 181.7 (CHO). Mass spectrum
(EI): m/z 641 (MC2, 15), 640 (MC1, 45), 638 (20), 360
(35), 280 (100). This was similarly prepared from the indole
5 in 30% yield.
4.3.23. 3-(4-Bromophenyl)-4,6-dimethoxy-7-trifluoro-
acetylindole-2-carbaldehyde (29). Trifluoroacetylindole
15 (0.15 g, 0.34 mmol) was dissolved in dioxane (15 mL)
to which selenium dioxide (0.18 g, 1.7 mmol) was added.
The mixture was then heated to reflux for 24 h, cooled and
filtered. Water was then added to the filtrate and the
precipitate collected and dried. Column chromatography
(dichloromethane) yielded the aldehyde 29 (0.13 g, 86%) as
a yellow solid, mp 270–271 8C. (Found: C, 49.9; H, 2.7; N,
3.2. C19H13BrF3NO4 requires C, 50.0; H, 2.9; N, 3.1%).
nmax: 3387, 1652, 1581, 1317, 1211, 1158, 1056, 981,
832 cmK1. lmax: 231 nm (3 22,850 cmK1 MK1), 254
(26,700), 348 (9,800), 368 (10,650). 1H NMR spectrum
(300 MHz, CDCl3): d 3.89, 4.04 (6H, 2s, OMe), 6.19 (1H, s,
H5), 7.36, 7.57 (4H, 2d, JZ8.3 Hz, ArH), 9.54 (1H, s,
CHO), 10.99 (1H, br, NH). 13C NMR spectrum (75 MHz,
CDCl3): d 55.7, 56.6 (OMe), 88.2 (C5), 99.6 (CF3), 130.7,
132.6 (ArCH), 112.0, 122.4, 128.5, 130.4, 131.7, 139.8,
164.1, 165.3 (ArC), 180.7 (CO). Mass spectrum (EI): m/z
458 (MC2, 81Br, 24%), 457 (90), 456 (M, 79Br, 21), 455
(89), 388 (97), 387 (20), 386 (100).
4.3.21.
7-70-Seleno-bis-[3-(4-bromophenyl)-4,6-di-
methoxyindole]-2,20-dicarbaldehyde (27). Indole 6
(0.80 g, 2.31 mmol) was dissolved in dioxane (35 mL) to
which selenium dioxide (0.66 g, 6.23 mmol) was added.
The mixture was then heated to reflux for 9 h and filtered.
The filtrate was concentrated and the residue was
chromatographed (dichloromethane) to give the selenide
27 (0.17 g, 31%) as a green solid, mp 294 8C (dec). (Found:
C, 50.1; H, 3.3; N, 3.3. C34H26Br2N2O6Se$0.9 H2O requires
C, 50.2; H, 3.4; N, 3.4%). nmax: 3416, 1639, 1613, 1566,
1527, 1333, 1226, 1215,1139 cmK1. lmax: 229 nm (3
4.3.24. 4,6-Dimethoxy-3-phenyl-7-trichloroacetylindole-
2-carbaldehyde (30). 2-Methyl-3-phenyl-4,6-dimethoxy-7-
trichloroacetylindole 16 (0.66 g, 1.6 mmol) was dissolved in
dioxane (50 mL) to which selenium dioxide (0.7 g,
6.5 mmol) was added. The mixture was then heated to
reflux for 24 h, cooled and filtered. Water was then added to
the filtrate and the yellowish precipitate collected and dried.
Column chromatography (dichloromethane) yielded the
aldehyde 30 (0.41 g, 60%) as a yellow-green solid, mp
200–202 8C. (Found: C, 53.6; H, 3.3; N, 3.5. C19H14Cl3NO4
requires C, 53.5; H, 3.3; N, 3.3%). nmax: 3440, 1640, 1630,
1
36,850 cmK1 MK1), 265 (55,250), 328 (29,850). H NMR
spectrum (300 MHz, CDCl3): d 3.75, 4.25 (12H, 2s, OMe),
6.26 (2H, s, H5), 7.32, 7.51 (8H, 2d, JZ8.4 Hz, ArH), 9.52
(2H, s, CHO), 10.13 (2H, br, NH). 13C NMR spectrum
(75 MHz, CDCl3): d 55.2, 57.1 (OMe), 88.4 (C5), 130.5,
132.7 (ArCH), 90.9, 111.7, 121.9, 129.1, 131.2, 131.3,
142.3, 158.4, 160.5 (ArC), 181.1 (CO). Mass spectrum (EI):
m/z 797 (M, 81Br, 10%), 795 (M, 79Br, 7), 438 (50), 362
(100).
1590, 1580, 1530, 1450, 1400, 1385, 1350, 1240, 1200 cmK1
.
lmax: 210 nm (3 24,100 cmK1 MK1), 251 (31,400), 334
(26,300). 1H NMR spectrum (CDCl3): d 3.87, 4.02 (6H, 2s,
OMe), 6.19 (1H, s, H5), 7.41–7.51 (5H, m, ArH), 9.55 (1H,
s, CHO), 10.63 (1H, br s, NH). 13C NMR spectrum (CDCl3):
d 55.6, 55.7 (OMe), 88.1 (C5), 98.5 (CCl3), 127.5, 127.8,
131.1 (ArCH), 112.5, 130.1, 131.6, 131.7, 140.2, 145.2,
163.2, 163.2 (ArC), 181.3, 182.0 (CO). Mass spectrum (EI):
m/z 427 (M, 10), 308 (100).
4.3.22. 4,6-Dimethoxy-3-phenyl-7-trifluoroacetylindole-
2-carbaldehyde (28). 2-Methyl-3-phenyl-4,6-dimethoxy-
7-trifluoroacetylindole 14 (0.58 g, 1.6 mmol) was dissolved
in dioxane (50 mL) to which selenium dioxide (0.7 g,
6.5 mmol) was added. The mixture was then heated to reflux
for 24 h, cooled and filtered. Water was then added to the
4.3.25. 3-(4-Bromophenyl)-4,6-dimethoxy-7-trichloro-
acetylindole-2-carbaldehyde (31). Trichloroacetylindole
17 (0.20 g, 0.41 mmol) was dissolved in dioxane (20 mL) to

A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
10499
which selenium dioxide (0.18 g, 1.7 mmol) was added. The
mixture was then heated to reflux for 24 h, cooled and
filtered. Water was then added to the filtrate and the
precipitate collected and dried. Column chromatography
(dichloromethane) yielded the aldehyde 31 (0.14 g, 67%) as
a pale-yellow solid, mp 234 8C (dec). (Found: C, 44.9; H,
2.2; N, 2.5. C19H13BrCl3NO4 requires C, 45.1; H, 2.6; N,
2.8%). nmax: 3399, 1652, 1579, 1354, 1238, 1207, 1165,
983 cmK1. lmax: 223 nm (3 19,600 cmK1 MK1), 255
(28,750), 321 (12,450). 1H NMR spectrum (300 MHz,
CDCl3): d 3.87, 4.02 (6H, 2s, OMe), 6.20 (1H, s, H5), 7.37,
7.57 (4H, 2d, JZ8.3 Hz, ArH), 9.54 (1H, s, CHO), 10.63
(1H, br, NH). 13C NMR spectrum (75 MHz, CDCl3): d 55.6,
55.7 (OMe), 88.3 (C5), 98.4 (CCl3), 130.7, 132.6 (ArCH),
97.8, 112.3, 122.3, 128.5, 130.6, 131.6, 140.1, 163.0, 163.2
(ArC), 180.7, 182.1 (CO). Mass spectrum (EI): m/z 507
(MC2, 81Br, 5%), 505 (M, 79Br, 7), 388 (100), 386 (100).
indole 22 (100 mg, 0.32 mmol) was dissolved in dioxane
(10 mL) to which selenium dioxide (140 mg, 1.3 mmol) was
added. The mixture was then heated to reflux for 24 h,
cooled and filtered. Water was then added to the filtrate and
the yellowish precipitate collected and dried. Column
chromatography (dichloromethane) yielded the aldehyde
34 (68 mg, 65%) as a yellow solid, mp 238–240 8C
(methanol). (Found: C, 62.3; H, 4.3; N, 8.5. C17H14N2O5
requires C, 62.6; H, 4.3; N, 8.6%). nmax: 3450, 1650, 1610,
1580, 1560, 1510, 1290, 1130, 1110, 1090 cmK1. lmax
:
207 nm (3 21,000 cmK1 MK1), 249 (26,600), 325 (19,500),
366 (16,400). 1H NMR spectrum (CDCl3): d 3.87, 4.10 (6H,
2s, OMe), 6.22 (1H, s, H5), 7.43–7.50 (5H, m, ArH), 9.56
(1H, s, CHO), 10.68 (1H, br s, NH). 13C NMR spectrum
(CDCl3): d 55.9, 57.3 (OMe), 88.5 (C5), 127.6, 128.1, 131.0
(ArCH), 112.2, 118.4, 130.3, 131.1, 131.9, 133.9, 159.8,
162.3 (ArC), 181.3 (CO). Mass spectrum (EI): m/z 327
(MC1, 20%), 326 (M, 100), 325 (25), 250 (25).
4.3.26. 2-Formyl-4,6-dimethoxy-3-phenylindole-7-carb-
oxylic acid (32). The mixture of 7-trifluoroacetylindole 28
(2.0 g, 5.3 mmol) and potassium hydroxide (7.5 g,
134 mmol) in ethanol–water (3/1, 400 mL) was heated to
reflux for 3 h. After cooling, the mixture was acidified with
concd hydrochloric acid to afford the carboxylic acid 32
(1.6 g, 95%) as a white solid, mp 225–226 8C (decarb-
oxylates). (Found: C, 66.3; H, 4.7; N, 4.3. C18H15NO5
requires C, 66.5; H, 4.6; N, 4.3%). nmax: 3450, 3270,
1700, 1650, 1610, 1590, 1570, 1540, 1520, 1440, 1420,
1340, 1250, 1225, 1200, 1180 cmK1. lmax: 216 nm (3
19,200 cmK1 MK1), 228 (18,800), 248 (20,100), 287
4.3.29. 4,6-Dimethoxy-2-methoxymethyl-7-nitro-3-
phenylindole (35). A solution containing the indole 22
(100 mg, 0.32 mmol) in dichloromethane (20 mL) was
chilled in an ice bath. To this was added a solution of
sulfuryl chloride (43 mg, 0.32 mmol) in dichloromethane
(5 mL) slowly over 30 min with stirring. The solvent was
then removed under reduced pressure and the residue
chromatographed (dichloromethane/methanol 95:5) to pro-
duce the methoxymethylindole 35 (46 mg, 42%) as a yellow
solid, mp 175–177 8C. (Found: C, 62.0; H, 5.2; N, 8.2.
C18H18N2O5$0.25 H2O requires C, 62.3; H, 5.4; N, 8.1%).
nmax: 3350, 1610, 1600, 1590, 1570, 1510, 1490, 1440,
1410, 1330, 1300, 1240, 1210, 1190 cmK1. lmax: 224 nm (3
1
(9,300), 334 (21,200). H NMR spectrum (d6-DMSO): d
3.80, 3.97 (6H, 2s, OMe), 6.45 (1H, s, H5), 7.39–7.53 (5H,
m, ArH), 9.44 (1H, s, CHO), 10.72 (1H, br s, NH). 13C NMR
spectrum (d6-DMSO): d 56.1, 57.3 (OMe), 90.3 (C5), 127.8,
131.2, 131.5 (ArCH), 94.8, 135.4, 111.5, 128.0, 129.1,
132.0, 139.9, 160.9, 163.6 (ArC), 167.7, 181.2 (CO). Mass
spectrum (EI): m/z 326 (MC1, 20%), 325 (M, 95), 307
(100), 306 (55).
1
21,700 cmK1 MK1), 257 (19,300), 370 (10,800). H NMR
spectrum (CDCl3): d 3.34, 3.82, 4.05 (9H, 3s, OMe), 4.48
(2H, s, CH2), 6.21 (1H, s, H5), 7.32–7.48 (5H, m, ArH),
10.30 (1H, br s, NH). 13C NMR (CDCl3): d 55.5, 57.2, 58.1
(OMe), 65.4 (CH2), 88.1 (C5) 126.5, 127.3, 130.6 (ArCH),
112.1, 117.4, 127.6, 131.1, 132.4, 133.8, 156.6, 160.2
(ArC). Mass spectrum (EI): m/z 343 (MC1, 20%), 342 (M,
100), 326 (40), 311 (50), 292 (25).
4.3.27. 3-(4-Bromophenyl)-2-formyl-4,6-dimethoxy-
indole-7-carboxylic acid (33). The mixture of indole 29
(0.17 g, 0.37 mmol) and potassium hydroxide (0.51 g,
9.31 mmol) in ethanol–water (3/1, 30 mL) was heated to
reflux for 3 h. After cooling, the mixture was acidified with
concd hydrochloric acid and the precipitate was filtered off
to give the carboxylic acid 33 (0.12 g, 82%) as a yellow
solid, mp 232 8C (dec). (Found: C, 53.8; H, 3.4; N, 3.5.
4.3.30. Di-(4,6-dimethoxy-3-phenylindol)-7-yl methane-
2,20-dicarbaldehyde (36). This was prepared as described
for indole 26 from indole 23 (0.15 g, 0.27 mmol) and
selenium dioxide (0.12 g, 1.10 mmol) in dioxane (7.5 mL)
under reflux for 4 h to give the dialdehyde 36 (67 mg, 43%)
as a white solid, mp 302–304 8C. (Found: C, 73.1; H, 5.3; N,
4.9. C35H30N2O6 requires C, 73.2; H, 5.3; N, 4.9%). nmax
:
C18H14BrNO5 requires C, 53.5; H, 3.5; N, 3.5%). nmax
3415, 3348, 1702, 1640, 1591, 1469, 1363, 1349, 1233,
:
3315, 1646, 1618, 1588, 1525, 1446, 1257, 1217,
1157,1120. 991 cmK1. lmax: 229 nm (3 26,700 cmK1 MK1),
266 (56,150), 327 (30,650), 359 (19,900). 1H NMR spectrum
(300 MHz, CDCl3): d 3.74, 4.34 (12H, 2s, OMe), 4.31 (2H,
s, CH2), 6.35 (2H, s, H5), 7.38–7.51 (10H, m, ArH), 9.55
(2H, s, CHO), 10.55 (2H, br s, NH). 13C NMR spectrum
(75 MHz, CDCl3): d 18.1 (CH2), 55.2, 56.9 (OMe), 88.6
(C5), 127.2, 127.3, 131.3 (ArCH), 102.8, 112.5, 130.1,
131.9, 132.6, 139.2, 155.3, 155.8 (ArC), 181.8 (CO). Mass
spectrum (EI): m/z 575 (M, 83%), 282 (100), 268 (25).
1209, 1170, 981 cmK1. lmax: 201 nm (3 32,000 cmK1 MK1),
262 (21,300), 335 (21,000). H NMR spectrum (300 MHz,
1
d6-DMSO): d 3.83, 3.97 (6H, 2s, OMe), 6.48 (1H, s, H5),
7.48, 7.61 (4H, 2d, JZ8.3 Hz, ArH), 9.47 (1H, s, CHO),
10.77 (1H, br, NH), 12.48 (1H, br, OH). 13C NMR spectrum
(75 MHz, d6-DMSO): d 56.3, 57.3 (OMe), 90.5 (C5), 130.8,
133.5 (ArCH), 94.9, 111.3, 121.7, 127.3, 131.2, 131.3,
139.8, 160.8, 163.6 (ArC), 167.6, 181.3 (CO). Mass
spectrum (EI): m/z 406 (MC2, 81Br, 7%), 405 (33), 404
(M, 79Br, 7), 403 (34), 387 (65), 386 (31), 361 (94), 359
(100), 265 (48).
Acknowledgements
4.3.28. 4,6-Dimethoxy-7-nitro-3-phenylindole-2-carb-
aldehyde (34). 4,6-Dimethoxy-2-methyl-7-nitro-3-phenyl-
Financial support from the Australian Research Council is

10500
A. W. Jones et al. / Tetrahedron 61 (2005) 10490–10500
Kumar, N.; Nugent, S. J.; Jolliffe, K. A.; Black, D. StC.
Tetrahedron 2004, 60, 10779–10786.
gratefully acknowledged. T.D.W. and K.P. acknowledge
receipt of an Indonesian Government Quality of Under-
graduate Education (QUE) Scholarship, and an Inter-
national Postgraduate Scholarship, respectively.
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