Synthesis of tethered indoles in the search for conformationally controlled calixindoles: An indole 3-substituent tether

Article abstract of DOI:10.1016/S0040-4020(01)00053-9

3-(2-Hydroxyphenyl)-4,6-dimethoxyindole 8 has been synthesised and linked to 1,3,5-tribromomethylbenzene and 1,2,4,5-tetrabromomethylbenzene to give the tri-indolyl and tetra-indolyl compounds 18 and 23, respectively. Attempts to generate capped calix[3]indoles and calix[4]indoles from these compounds were unsuccessful.

Full text of DOI:10.1016/S0040-4020(01)00053-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2203±2211
Synthesis of tethered indoles in the search for conformationally
controlled calixindoles: an indole 3-substituent tether
David StC. Black,p Naresh Kumar and Darryl B. McConnell
School of Chemistry, The University of New South Wales, UNSW Sydney, NSW 2052, Australia
Received 9 September 2000; revised 14 December 2000; accepted 4 January 2001
AbstractÐ3-(2-Hydroxyphenyl)-4,6-dimethoxyindole 8 has been synthesised and linked to 1,3,5-tribromomethylbenzene and 1,2,4,5-
tetrabromomethylbenzene to give the tri-indolyl and tetra-indolyl compounds 18 and 23, respectively. Attempts to generate capped calix[3]-
indoles and calix[4]indoles from these compounds were unsuccessful. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
4,6-dimethoxyindoles have been synthesised most effec-
tively by the acid-catalysed cyclisation of N-protected
anilino ketones followed by deprotection. N-protected
anilino ketones are required because of their lower reac-
tivity compared to the unprotected keto anilines,13±16
which undergo a Bischler rearrangement in the presence
of a small amount of aniline hydrobromide to give a 2-aryl-
indole. The tri¯uoroacetyl protecting group is effective for
the synthesis of 3-aryl-4,6-dimethoxyindoles12,17 because of
its ease of removal, although other protecting groups have
also been used.13±15
Calix[3]indoles and calix[4]indoles have been synthesised
by the reaction of speci®cally activated indoles with aryl
aldehydes, and also by the acid-catalysed cyclo-oligomeri-
sation of indolyl methanols.1±4 The use of alcohols derived
from indolylglyoxylamides has led to the formation of
minor amounts of the thermodynamically less stable cone
con®gurational isomers together with major amounts of the
thermodynamically more stable ¯attened partial cone
isomers.5 In an attempt to stabilise and maximise the cone
conformation it was proposed to synthesise calix[3]indoles,
which were capped either at the lower or upper rim through
the cyclo-oligomerisation of suitably tethered indoles.
Calixarenes have been capped via the upper rim using
polymethylene bridges.6±9 Calixresorcinarenes have been
successfully capped via the upper rim using methylene,
polymethylene, silyl and diazanaphthalene bridges.10±11 In
our case, the upper rim linkage strategy required an indole
that had suitable functionality at the upper rim enabling it to
be tied to a linker. This functionality was chosen to be a
hydroxyphenyl group positioned at the three position of the
indole ring. Molecular models indicated that a 2-hydroxy-
phenyl substituent would give rise to the least strained
capped calix[3]indole. The target indole was therefore
3-(2-hydroxyphenyl)-4,6-dimethoxyindole 8, the synthesis
and reactions of which are described in this paper.
2.1. Synthesis of 3-(2-hydroxyphenyl)-4,6-dimethoxy-
indole 8
2-Hydroxyacetophenone 1 was brominated using cupric
bromide
18±20
to give the 2-hydroxyphenacyl bromide 2 in
only moderate yield due to the presence of unreacted
starting material and dibrominated product. The phenacyl-
bromide 2 was then reacted with 3,5-dimethoxyaniline 3 in
re¯uxing ethanol and potassium hydrogen carbonate to
yield the anilino ketone 4 in 88% yield. This was stirred
at room temperature in acetic anhydride for 3 h to yield the
N-acetylanilino ketone 5 (Scheme 1). The complete hydro-
lysis of acetic anhydride and removal of the resulting acetic
acid is crucial as the presence of acetic acid in the subse-
quent cyclisation step reduces the potency of tri¯uoroacetic
acid such that cyclisation does not occur. This protection
method is simpler and cheaper than the use of tri¯uoroacetyl
protection, which also gave unreliable results and unwanted
by-products, and has now become general for the synthesis
of 3-aryl-4,6-dimethoxyindoles12. When anilino ketone 4
was added to the re¯uxing acetic anhydride the doubly
protected anilino ketone 6 resulted. Cyclisation of the
N-acetyl compound 5 was achieved with re¯uxing tri¯uoro-
acetic acid to yield the N-acetylindole 7 cleanly and repro-
ducibly. The N,O-diacetyl compound 6 gave the same
2. Results and discussion
General synthetic approaches to 3-aryl-4,6-dimethoxy-
indoles have been developed within our group.12 3-Aryl-
Keywords: capped calix[3]indole; 3-(2-hydroxyphenyl)-4,6-dimethoxy-
indole; tri-indolylphenoxymethylbenzene; tetra-indolylphenoxymethylbenzene.
Corresponding author. Tel.: 161-2-9385-4657; fax: 161-2-9385-6141;
e-mail: d.black@unsw.edu.au
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00053-9

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D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
Scheme 1.
product on treatment with re¯uxing tri¯uoroacetic acid. The
O-acetyl group was presumably cleaved by the strongly
acidic cyclisation conditions. Removal of the N-acetyl
protecting group was achieved by the use of potassium
hydroxide in methanol to yield the desired new indole
3-(2-hydroxyphenyl)-4,6-dimethoxyindole 8 reproducibly
in a yield of 78% from the anilino ketone 4 (Scheme 1).
The 3-arylindole 8 was shown to be different from the corre-
sponding 2-arylindole 9, which was synthesized by reacting
the anilino ketone 4 with aniline hydrobromide.16
10 as the major product (Scheme 1). The success of this
formylation method is attributed to protonation of the
phenolic oxygen and consequently its effective protection.
The 7-formylindole 10 could be reduced with sodium boro-
hydride in methanol to give the hydroxymethyl compound
11, although this was unstable and could not be charac-
terised. Instead the hydroxymethyl indole 11 was formed
in situ and then reacted with various acidic reagents which
resulted in only trace amounts of the desired calix[3]indole
accompanied by large amounts of polymeric material. The
presence of the free phenolic group appears to increase the
extent of polymerisation over macrocyclisation.
2.2. Reactions of 3-(2-hydroxyphenyl)-4,6-dimethoxy-
indole 8
The phenolic indole 8 was also reacted with 4-chloro-
benzaldehyde and phosphoryl chloride in an attempt to
form arylmethine bridged calix[3]indoles. These attempts
also resulted in only polymeric material.
To investigate the effect of a phenolic group on calixindole
formation, the syntheses of methylene bridged and aryl-
methine bridged calixindoles were attempted. When the
phenolic indole 8 was subjected to standard Vilsmeier
formylation conditions numerous products were obtained.
From this mixture small amounts of the 7-formyl and
2-formyl compounds were identi®ed but these products
were accompanied by a number of other unidenti®ed
products. Clearly, the phenolic hydroxyl group was
involved and it also possibly activated the 3-aryl ring to
substitution. Reaction of the indole 8 with triethylortho-
formate in tri¯uoroacetic acid21 gave the 7-formylindole
To form an upper rim capped calix[3] indole, it was initially
proposed to join three indole building blocks through the
upper rim to a linker to obtain the capped calix[3]indole
precursor. Macrocyclisation using the existing methodology
could then lead to an upper rim capped calix[3]indole.
1,3,5-Tris(bromomethyl)benzene 12 was chosen as the
linker because of its one-step synthesis from mesitylene

D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
2205
Scheme 2.
and the high reactivity of benzylic halides. Rather than
using the free indole 8 as the building block and risk benzyl-
ation of the indole nitrogen, it was proposed to use its direct
precursor, the N-acetyl indole 7. The linker 12 was synthe-
sized in low yield by reacting mesitylene with N-bromo-
succinimide in carbon tetrachloride under irradiation by
strong light.22 The crude material from this reaction required
repeated recrystallisations to afford the benzylbromide 12 in
suf®cient purity for subsequent steps.
success of the synthesis using acetophenone 1 rather than
indole 7 supported the hypothesis that 1,3,5-tris(bromo-
methyl)benzene 12 required a relatively small nucleophile
to affect tribenzylation. Bromination of compound 15 was
attempted using a wide variety of brominating conditions,
but gave mixtures of under- or over-brominated products
rather than the desired tribromo compound, so this approach
was abandoned.
2.3. Synthesis of 1,3,5-tris(indolyl)benzene
Prior to linking 3 equiv. of the indole 7 to the tris(benzyl)-
bromide 12, suitable conditions for the benzylation of indole
7 were sought. Reaction with benzyl bromide in re¯uxing
acetone and potassium carbonate gave the desired benzyl-
ated compound 13 in 89% (Scheme 2). When indole 7 was
reacted with the linker 12 in re¯uxing acetone and potas-
sium carbonate, only the mono-substituted product 14 was
observed and was identi®ed only by electrospray mass
spectroscopic analysis. The lack of reactivity could be
explained by insolubility of the reactants or by steric
hindrance. However, use of the more powerful solvent
dimethyl formamide at 1008C, with the addition of a
catalytic amount of potassium iodide, did not enable the
reaction to proceed.
It was thought that the N-protected anilino ketone 5 could
undergo reaction three times with the linker 12 as it would
avoid both the dif®cult synthetic steps and the steric
hindrance about the phenol. The reaction between 3 mol
of N-acetylanilino ketone 5 and 1 mol of 1,3,5-tris(bromo-
methyl)benzene 12 in re¯uxing acetone with potassium
carbonate for 24 h yielded the desired tri-substituted
compound 16 (Scheme 3). This reaction can be performed
on a 10 g scale in 99% yield. The compound displays a
three-fold axis of symmetry as shown by its 1H NMR spec-
trum and is a low melting, honeycomb-like solid that de®ed
recrystallization. The tris-aniline 16 was then re¯uxed in
tri¯uoroacetic acid in order to effect cyclisation to the tris-
N-acetylindole 17 but instead gave the N-acetylindole 7 as
the sole product. The strong acid presumably protonated the
phenolic oxygen and followed by cleaving the benzyloxy
bond. The reaction of compound 16 with tri¯uoroacetic acid
at room temperature gave the tris-N-acetylindole 17, with
less than 5% of the cleaved product as observed by 1H NMR
spectroscopy. The removal of the N-acetyl group proceeded
in re¯uxing methanolic potassium hydroxide to give the
An alternative strategy involved reaction of the indole
precursor 2-hydroxyacetophenone 1 with the linker 12 in
order to reduce the effect of steric hindrance in the phenol:
the indoles could subsequently be constructed while
attached to the linker. Three moles of 2-hydroxyaceto-
phenone 1 were reacted with tris(bromomethyl)benzene
12 in re¯uxing acetone and potassium carbonate to yield
the desired tri-substituted benzene 15 (Scheme 2). The
1
capped calix[3]indole precursor 18 (Scheme 3). The H

2206
D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
Scheme 3.
NMR spectrum of the tris-indole compound shows only one
set of signals, re¯ecting the three-fold axis of symmetry.
gave a clean and selective result due to the very bulky
benzyl protecting group on the phenols. The resulting tris-
(formylindolyl)benzene 19 was reduced in situ to the tris-
alcohol using sodium borohydride in methanol but subse-
quent attempts to cyclise the alcohol with boron tri¯uoride
etherate in tetrahydrofuran, 4-toluenesulfonic acid in
dichloromethane or acetic acid failed to give anything
other than the polymer. The tris-indole 18 was also reacted
with formaldehyde in acetic acid in an attempt to form
methylene bridged calix[3]indoles but this reaction also
resulted in only polymeric material.
2.4. Attempted capped calix[3]indole formation
In an attempt to form capped C-arylcalix[3]indoles, the tris-
indole 18 was reacted with p-chlorobenzaldehyde and phos-
phoryl chloride in chloroform, but only polymeric material
was observed by 1H NMR spectroscopy.
To obtain a capped methylene bridged calix[3]indole the
tris-indole 18 was formylated using phosphoryl chloride
and dimethyl formamide to yield the tris(formylindolyl)-
benzene 19 which was not characterized (Scheme 3).
Although standard Vilsmeier conditions failed to give satis-
factory results with the parent indole 8, the tris-indole 18
Tris-indole 18 was reacted with oxalyl chloride in dichloro-
methane and then quenched with tertiary butylamine to give
a mixture of 2- and 7-substituted products. Owing to the
number of isomers, this mixture was not separated but

D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
2207
Scheme 4.
reduced to the corresponding hydroxyethanoates with
sodium borohydride in methanol and treated in situ with
concentrated hydrochloric acid. The result of this reaction
sequence was only the polymeric material.
Formaldehyde, in acetic acid was also reacted with the tetra-
indole 23 and only polymer was observed rather than the
desired methylene bridge capped calix[4]indole.
3. Conclusions
2.5. Attempted capped calix[4]indole formation
The failure of 3-phenolic indole 8 coupled to polybenzyl
linkers to form capped calixindoles of either three or four
indole units in size shows that this system is not suitable for
the capping of cone calixindoles. The use of aryl groups as
the major portion of the cap might be unsuitable due to the
size of the aryl rings. Alkyl chains might be more appro-
priate linkers as they would allow greater ¯exibility in the
cap portion of the molecule.
The strategy described above can also be applied to the
possible formation of capped a calix[4]indoles, with very
little synthetic variation, simply requiring a tetrabromide
instead of a tribromide. Consequently, 4 mol of the anilino
ketone 5 were reacted with 1,2,4,5-tetrabromomethyl-
benzene 20 to give the tetra-substituted benzene 21, which
was cyclized to tetra-N-acetylindole 22 in moderate yield
using tri¯uoroacetic acid at room temperature (Scheme 4).
The tetra-substituted compound 21 required a considerably
longer reaction time to effect complete cyclisation
compared with the tri-substituted compound 17. Depro-
tection of the tetra-N-acetylindole 22 was performed using
methanolic potassium hydroxide to give a low yield of the
desired tetra-indole 23, which could not be characterised
fully. When the crude tetra-indole 23 was reacted with
4-chlorobenzaldehyde and phosphoryl chloride in an
attempt to form arylmethine capped calix[4]indoles only
polymeric material was indicated by 1H NMR spectroscopy.
4. Experimental
4.1. General information
1H and 13C NMR spectrum were recorded at 300 MHz on a
Bruker AC300F spectrometer and at 500 MHz on a Bruker
AM500 spectrometer. Chemical shifts were measured on
the d scale internally referenced to the solvent peaks:

2208
D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
CDCl3 (7.30, 77.7 ppm) and d6-DMSO (2.30, 39.0 ppm). EI
mass spectral analyses were performed on a VG Quattro
mass spectrometer at 70 eV ionisation voltage and 2008C
ion source temperature. Microanalyses were performed by
Dr H. P. Pham of the UNSW Microanalytical Unit. Infrared
spectra were obtained on a Perkin±Elmer 298 IR spectro-
meter and a Mattson Sirius FTIR using KBr discs while
ultraviolet spectra were carried out on a Hitachi U-3200
and Carey 5 spectrophotometers.
1596m, 1200m, 1155m, 728m, 707m cm21; lmax 252 (e
12,400), 278 (3,700), 325 nm (3,400); dH (CDC3) 2.07
(3H, s, COMe), 3.82 (6H, s, OMe), 5.13 (2H, s, CH2),
6.47 (1H, t, Jˆ2.4 1 Hz, aryl), 6.57 (2H, d, Jˆ2.1 Hz,
aryl), 6.90 (1H, dt, Jˆ1.1, 7.6 Hz, aryl), 7.00 (IH, dd, Jˆ
8.0, 0.9 Hz, aryl), 7.49 (IH, dt, Jˆ1.5, 7.8 Hz, aryl), 7.72
(1H, dd, Jˆ8.0, 1.5 Hz, aryl), 11.89 (1H, s, OH); dC
(CDCl3) 22.6 (COMe), 56.0, 56.2 (OMe), 100.7, 106.9,
119.2, 119.7, 129.5, 137.3 (aryl CH), 118.6, 145.6, 162.1,
162.9 (aryl C), 171.5, 199.6 (carbonyl C); m/z 329 (M,
22%), 311 (10), 287 (10), 208 (10), 166 (100), 121 (20).
4.1.1. 2-Hydroxyphenacylbromide19 (2). Cupric bromide
(100.25 g, 0.449 mol) was partially dissolved in ethyl
acetate (400 ml) and brought to re¯ux. 2-Hydroxyaceto-
phenone 1 (27.1 ml, 0.225 mol) was dissolved in chloro-
form (200 ml) and added rapidly to the re¯uxing solution
and the mixture heated overnight. The solution was allowed
to cool and the cuprous bromide was ®ltered off and washed
with ethyl acetate. The combined organic phases were
washed with copious amounts of water until neutral, brine
and dried (MgSO4). The solvent was removed under
reduced pressure to yield 2 as golden oil (46.3 5 g, 96%),
which solidi®ed on standing at room temperature. This
material was used without further puri®cation.
Crude protected anilino ketone 5 was dissolved in tri¯uoro-
acetic acid (15 ml) and the solution was re¯uxed for 11 h.
After cooling to room temperature, ice/water (100 ml) was
added to the reaction mixture. The resulting solid was
®ltered and washed with water until washings were neutral.
The solid was dried under vacuum and a sample of the crude
product was puri®ed using a pad of silica gel with dichloro-
methane eluant to give the N-acetylindole 7 as colourless
needles, mp 1668C (from ethyl acetate/light petroleum)
(Found: C, 69.5; H, 5.5; N, 4.5. C18H17NO4 requires C,
69.4; H, 5.5; N, 4.5%); nmax 3518m, 1707s, 1597w,
1308m, 1211m, 826w cm21; lmax 244 (e 17,600), 275
(7,700), 316 nm (4,500); dH (CDCl3) 2.63 (3H, s, COMe),
3.77, 3.91 (6H, 2s, OMe), 5.77 (1H, br, OH), 6.44 (1H, d,
Jˆ2.0 Hz, H5), 6.98±7.07 (4H, m, aryl), 7.22 (1H, s, H2),
7.31 (1H, d, Jˆ8.2 Hz, aryl), 7.79 (1H, d, Jˆ2.0 Hz, NH);
dC (CDCl3) 24.0 (COMe), 55.4, 55.4 (OMe), 92.7 (C5), 95.3
(C7), 114.9 (C2), 118.0, 122.7, 128.2, 131.5 (aryl CH),
113.6, 118.6, 121.5, 136.8, 154.0, 155.6, 158.7 (aryl C),
169.7 (carbonyl C); m/z 311 (M, 70%), 269 (100), 254
(70), 238 (15), 226 (15), 211 (20).
4.1.2. 2-Hydroxy-(3,5-dimethoxyanilino)-acetophenone
(4). A mixture of 3,5-dimethoxyaniline 3 (2.65 g, 17.3
mmol), 2-hydroxyphenacylbromide 2 (5.66 g, 26.3 mmol)
and sodium bicarbonate (1.55 g) in anhydrous ethanol
(50 ml) was re¯uxed for 2.5 h. The mixture was allowed
to cool to room temperature and the resulting yellow pre-
cipitate was ®ltered off, washed with water (250 ml) and
dried to yield the anilino ketone 4 (4.37 g, 88%) as pale
cream needles, mp 158±1598C (from ethyl acetate/light
petroleum) (Found: C, 66.9; H, 6.2; N, 4.8. C16H17NO4
requires C, 66.9; H, 6.0; N, 4.9%); nmax, 3407w, 1644m,
1620m, 1583m, 1199m, 1156m, 756m cm21; lmax 251 (e
17,300), 327 nm (3,800); dH (d6-DMSO) 3.75 (6H, s, OMe),
4.74 (2H, s, CH2), 5.87 (1H, s, aryl), 5.97 (2H, d, Jˆ1.1 Hz,
aryl), 7.05, 7.60 (2H, 2t, Jˆ7.5 Hz, aryl), 7.11, 8.04 (2H, 2d,
Jˆ7.4 Hz, aryl); dC (d6-DMSO) 54.8 (CH2), 58.2 (OMe),
92.4, 94.8, 121.2, 122.5, 133.6, 139.2 (aryl CH), 123.8,
153.5, 163.7, 164.7 (aryl C), 204.5 (carbonyl C). m/z 287
(M, 10%), 167 (10), 166 (100).
Excess crushed potassium hydroxide was added to a
partially dissolved solution of crude N-acetylindole 7 in
methanol (70 ml). The mixture was stirred at room tempera-
ture for 2 h and the resulting precipitate was ®ltered off. The
®ltrate was concentrated to give more solid, and both solid
fractions were combined to yield indole 8 (1.71 g, 78% from
compound 4) as clear rhombs, mp 1128C (from ethyl
acetate/light petroleum) (Found: C, 71.6; H, 5.8; N, 5.2.
C16H15NO3 requires C, 71.4; H, 5.6; N, 5.2%); nmax
3310m, 1632w, 1543m, 1202m, 1144m, 1101m, 802m,
748m cm21; lmax 223 (e 37,500), 272 nm (12,500); dH
(CDCl3) 3.80, 3.90 (6H, 2s, OMe), 5.95 (1H, s, OH), 6.30
(1H, d, Jˆ1.9 Hz, H5), 6.57 (1H, d, Jˆ1.9 Hz, H7), 6.97±
7.07, 7.26±7.35 (4H, 2m, aryl), 8.28 (1H, br, NH); dH (d6-
DMSO) 3.72, 3.85 (6H, 2s, OMe), 6.24, 6.61 (2H, 2d,
Jˆ1.4 Hz, H5, H7), 6.84 (1H, t, Jˆ7.4 Hz, H50), 6.93
(1H, d, Jˆ7.9 Hz, H30), 7.10 (1H, t, Jˆ7.4 Hz, H40), 7.19
(1H, d, Jˆ1.4 Hz, H2), 7.33 (1H, d, Jˆ7.9 Hz, H60), 8.97
(1H, s, OH), 11.03 (1H, br, NH); dC (d6-DMSO) 55.3, 55.5
(OMe), 87.4 (Cs), 91.8 (C7), 115.3 (C2), 118.3, 122.7,
126.8, 132.8 (aryl CH), 111.4, 112.0, 123.7, 138.1, 154.5,
155.2, 156.7 (aryl C); m/z 269 (M, 100%), 254 (48), 237 (8),
226 (10), 211 (10).
4.1.3. N-Acetyl-2-hydroxy-(3,5-dimethoxyanilino)-aceto-
phenone (5), 1-acetyl-3-(2-hydroxyphenyl)-4,6-dimethoxy-
indole (7) and 3-(2-hydroxyphenyl)-4,6-dimethoxyindole
(8). The anilino ketone 4 (2.02 g, 7.03 mmol) was partially
dissolved in acetic anhydride (10 ml) and stirred at room
temperature for 3 h. Water (2 ml) was added and the
solution was warmed to 50±608C. Water was then added
slowly so that the temperature did not drop below 508C until
the volume was tripled. Stirring was continued until the
solution cooled to room temperature (approx. 1 h.). The
solution was extracted with ethyl acetate, the organic
phase washed with water until neutral, saturated sodium
hydrogen carbonate solution, brine and dried (MgSO4).
The solvent was removed under reduced pressure to yield
golden oil that was used directly in the next step. Crystal-
lization of a sample from ethyl acetate/light petroleum gave
the protected anilino ketone 5 as light cream needles, mp
111±1128C (Found: C, 65.8; H, 6.0; N, 4.2. C18HI9NO5
requires C, 65.6; H, 5.8; N, 4.3%); nmax 3136w, 1662m,
4.1.4. N-Acetyl-2-acetoxy-(3,5-dimethoxyanilino)-aceto-
phenone (6). The anilino ketone 4 (0.50 g, 1.74 mmol)
was partially dissolved in acetic anhydride (15 ml). The
mixture was heated to re¯ux for 1.5 h and water was
added slowly at this temperature until the volume was

D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
2209
tripled. The solution was allowed to cool to room tempera-
ture and extracted with dichloromethane. The organic phase
was washed with water until neutral, saturated sodium
hydrogen carbonate brine and dried (MgSO4). The solvent
was removed under reduced pressure to yield the diacetyl
compound 6 (0.30 g, 46%) as colourless plates, mp 1238C
(from ethyl acetate/light petroleum) (Found: C, 64.8; H, 5.9;
N, 3.8. C20H21NO6 requires C, 64.7; H, 5.7; N, 3.8%); nmax
®ltered off and washed with carbon tetrachloride. The
®ltrate was washed with saturated sodium hydrogen carbo-
nate solution, water and dried (MgSO4). The volume was
reduced to approximately 100 ml and then light petroleum
(200 ml) was added. The solution was placed in the freezer
and the resulting oily solid was ®ltered off. This process was
repeated several times and the crops of oily solid were
combined. This material was then carefully recrystallized
a number of times from chloroform/light petroleum to yield
1,3,5-tris(bromomethyl)benzene 12 as colourless needles
(30.0 g, 43%), mp 87±898C (lit.22 948C); dH (CDCl3) 4.49
(2H, s, CH2), 7.39 (3H, s, aryl).
1759m, 1698s, 1659s, 1605s, 1186s, 1007w, 762m cm21
max 236 (e 13,600), 277 nm (4,400); dH (CDCl3) 2.04, 2.31
;
l
(6H, 2s, COMe), 3.81 (6H, s, OMe), 4.91 (2H, s, CH2), 6.45
(1H,t, Jˆ2.2 Hz, aryl), 7.16 (2H, 2dd, Jˆ8.2, 0.8 Hz, aryl),
7.33 (1H, td, Jˆ7.6, 0.9 Hz, aryl), 7.55 (1H, td, Jˆ7.7,
1.6 Hz, aryl), 7.82 (1H, dd, Jˆ7.8, 1.6 Hz, aryl); dC
(CDCl3) 21.7, 22.6 (COMe), 56.1, 58.7 (OMe), 100.8,
106.8, 124.2, 126.7, 130.2, 133.9 (aryl CH), 106.9, 145.8,
149.4, 162.0 (aryl C), 169.8, 171.2, 194.9 (carbonyl C); m/z
371 (M, 5%), 329 (5), 208 (10), 167 (10), 166 (100), 163
(10),121 (25).
4.1.8.
1-Acetyl-3-(2-benzyloxyphenyl)-4,6-dimethoxy-
indole (13). Acetylindole 7 (0.20 g, 0.64 mmol), benzyl-
bromide (83 ml, 0.70 mmol) and potassium carbonate
(0.27 g, 1.92 mmol) were added to acetone (30 ml). The
mixture was re¯uxed under an atmosphere of argon over-
night and then poured onto concentrated hydrochloric acid/
ice (100 ml) and extracted with ethyl acetate (3£20 ml). The
organic phase was washed with water, brine and dried
(MgSO4). The solvent was removed under reduced pressure
and the crude product was puri®ed by ¯ash chromatography
(dichloromethane/light petroleum 50:50) to yield the
benzyloxyindole 13 (0.22 g, 89%) as colourless needles,
mp 1248C (from ethyl acetate/light petroleum) (Found: C,
74.7; H, 5.9; N, 3.6. C25H23NO4 requires C, 74.8; H, 5.8; N,
4.1.5. 2-(2-Hydroxyphenyl)-4,6-dimethoxyindole (9).
Indole 9 was prepared according to the method of Black
et al.16 to yield a cream solid, mp 1208C (Found: C, 71.2;
H, 5.3; N, 5.0. C16H15NO3 requires C, 71.4; H, 5.6; N,
5.2%); nmax 3425w, 3320w, 785s, 755s cm21; dH (CDCl3)
3.85, 3.94 (6H, 2s, OMe), 6.24, 6.52 (2H, 2d, Jˆ2.0 Hz, H5,
H7), 6.87 (1H, s, H3), 6.89 (1H, d, Jˆ7.6 Hz, H30), 6.99
(1H, t, Jˆ8.1 Hz, H50), 7.15 (1H, td, Jˆ7.8, 1.7 Hz, H40),
7.65 (1H, dd, Jˆ7.8, 1.7 Hz, H60), 9.22 (1H, br, NH); m/z
270 (M11, 20%), 269 (M, 100), 255 (20), 254 (100), 226
(25), 211 (50).
3.5%); nmax 1707m, 1605w, 1310m, 1211m, 748m cm21
;
lmax 249 (e 24,200), 276 (12,200), 315 nm (5,700); dH
(CDCl3) 2.60 (3H, s, COMe), 3.70, 3.99 (6H, 2s, OMe),
5.14 (2H, s, CH2), 6.45 (1H, d, Jˆ2.1 Hz, H5), 7.08±7.53
(9H, m, aryl), 7.31 (1H, s, H2), 7.88 (1H, d, Jˆ2.1 Hz, H7);
dH (CDCl3) 24.7 (COMe), 55.8, 56.4 (OMe), 70.9 (CH2),
93.6 (C5), 96.4 (C7), 112.8 (C2), 120.9, 122.3, 127.4, 128.1,
128.9, 129.2, 132.4 (aryl CH), 114.6, 120.2, 124.7, 137.9,
138.2, 154.8, 157.6, 160.1 (aryl C), 169.7 (carbonyl C); m/z
401 (M, 60%),359 (20), 268 (100), 257 (50), 91 (50).
4.1.6. 3-(2-Hydroxyphenyl)-4,6-dimethoxyindole-7-carb-
aldehyde (10). Triethylorthoformate (3 ml) was added
dropwise to the indole 8 (1.07 g, 3.97 mmol) in tri¯uoro-
acetic acid (10 ml) and the mixture was stirred for 45 min at
room temperature. Water (50 ml) was added and stirring
was continued for 10 min. The solution was then extracted
with ethyl acetate and the organic phase was washed with
water until neutral, then brine and dried (MgSO4). The
solvent was removed under reduced pressure and the
crude, product was puri®ed by chromatography on a silica
gel column with dichloromethane as the eluant to yield the
formyl indole 10 (63 g, 53%) as yellow needles, mp 2238C
(from ethyl acetate/light petroleum) (Found: C, 68.7; H, 5.3;
N, 4.6. C17H15NO4 requires C, 68.7; H, 5.1; N, 4.7%); nmax
3440m, 1265w, 1210w, 1075w, 980w cm21; lmax 251 (e
24,500), 272 (16,200), 334 (11,800), 358 nm (9,800); dH
(CDCl3) 3.91, 4.04 (6H, 2s, OMe), 6.23 (1H, s, H5), 6.94
(1H, td, Jˆ7.4, 1.2 Hz, H40), 7.00 (1H, dd, Jˆ7.3, 1.2 Hz,
H60), 7.21±7.29 (2H, m, aryl), 10.42 (1H, s, CHO), 10.62
(1H, br, NH); dC (CDCl3) 56.4, 57.1 (OMe), 87.7 (C5),
115.9 (C2), 120.6, 123.5, 129.3, 132.3 (aryl CH), 105.3,
111.8, 112.1, 122.8, 138.2, 154.7, 161.7, 164.0 (aryl C),
188.8 (carbonyl C); m/z 298 (M11, 20%), 297 (M, 100),
282 (40), 254 (20), 211 (25).
4.1.9. 1,3,5-Tris(2-acetylphenoxymethyl)benzene (15).
2-Hydroxyacetophenone 1 (0.46 ml, 3.82 mmol), 1,3,5-
tris(bromomethyl)benzene 12 (0.44 g, 1.23 mmol) and
potassium carbonate (1.06 g, 7.64 mmol) were added to
acetone (50 ml) and the mixture was re¯uxed under an
atmosphere of argon overnight. The mixture was ®ltered
through a pad of celite and washed with acetone. The
solvent was removed under reduced pressure to yield the
tri-substituted compound 15 (0.56 g, 87%) as a white solid,
mp 958C (from ethyl acetate/light petroleum) (Found: C,
76.0; H, 5.9. C33H30O6 requires C, 75.9; H, 5.8%); nmax
1665br, 1599s, 1294s, 1235s, 750m cm21; lmax 246 (e
19,400); 303 nm (9,600); dH (CDCl3) 2.59 (3H, s, COMe),
5.25 (2H, s, CH2), 7.06 (1H, t, Jˆ7.7 Hz, aryl), 7.02 (1H, d,
Jˆ7.7 Hz, aryl), 7.47 (1H, td, Jˆ8.6, 1.8 Hz, aryl), 7.77
(1H, dd, Jˆ6.0, 1.7 Hz, aryl), 7.54 (1H, s, aryl); dC
(CDCl3) 32.5 (COMe, 70.9 (CH2), 113.5, 121.8, 126.9,
131.1, 134.2 (aryl CH), 129.4, 138.2, 158.2 (aryl C),
200.2 (carbonyl C); m/z 545 (M1Na, 90%).
4.1.7. 1,3,5-Tris(bromomethyl)benzene22 (12). Mesity-
lene (23.7 g, 0.20 mol), N-bromosuccinimide (112.47 g,
0.63 mol), and dibenzoylperoxide (approximately 50 mg)
were dissolved in carbon tetrachloride (500 ml) and re¯uxed
under irradiation by a 250 W lamp for 16 h. The solution
was then cooled in an ice bath and the succinimide was
4.1.10. 1,3,5-Tris-(2-(1-acetyl-3,5-dimethoxyphenylamino-
acetyl))phenoxymethylbenzene (16). 1,3,5-Tris(bromo-
methyl)benzene 12 (3.18 g, 8.91 mmol), anilino ketone 6
(9.11 g, 27.62 mmol) and potassium carbonate (5.53 g,
41.43 mmol) were added to acetone (150 ml) and the

2210
D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
mixture was re¯uxed under an atmosphere of argon for 24 h.
The mixture was ®ltered through a pad of celite and washed
with acetone. The solvent was removed under reduced
pressure to yield the tri-substituted compound 16 (9.73 g,
99%) as a honeycomb like solid, mp 778C; (Found: C, 68.3;
H, 6.0; N, 3.6. C63H63N3O15 requires C, 68.7; H, 5.8; N,
3.8%); nmax 1660s, 1600s, 750m, 700m cm21; lmax 244
(e26,000), 280 (13,000), 304 nm (8,500); dH (CDCl3) 1.99
(3H, s, COMe), 3.74 (6H, s, OMe), 5.01, 5.21 (4H, 2s, CH2),
6.39 (1H, t, Jˆ2.6 Hz, aryl), 6.52 (2H, d, Jˆ2.6 Hz, aryl),
7.01 (1H, d, Jˆ8.2 Hz, aryl), 7.06 (1H, t, Jˆ7.7 Hz, aryl),
7.47 (1H, t, Jˆ7.2 Hz, aryl), 7.50 (1H, s, aryl), 7.87 (1H, dd,
Jˆ7.7, 2.1 Hz, aryl); dC (CDCl3) 22.5 (COMe), 56.0 (OMe),
61.1, 70.7 (CH2), 100.2, 106.6, 113.5, 121.8, 131.4, 134.6,
161.7 (aryl CH), 126.3, 127.0, 138.0, 146.2, 158.3 (aryl C),
171.0, 195.7 (carbonyl C); m/z 1139 (40%, M1K), 1124
(40, M1Na).
aminoacetyl))phenoxymethylbenzene (21). N-Acetylanilino
ketone 5 (1.20 g, 3.65 mmol), 1,2,4,5-tetrakis(bromo-
methyl)benzene 20 (0.40 g, 0.88 mmol) and potassium
carbonate (0.54 g, 4.67 mmol) were added to acetone
(50 ml) and re¯uxed for 4.5 h. The mixture was then ®ltered
through a pad of celite and washed with acetone and the
solvent removed under reduced pressure to yield the tetra-
anilino ketone 21 (1.13 g, 88%) as cream needles, mp 185±
1878C (from ethyl acetate/light petroleum) (Found: C, 68.5;
H, 5.8; N, 3.7. C82H82N4O20 requires C, 68.2; H, 5.7; N,
3.9%); nmax 1685s, 1670s, 1650s, 1600s, 1210s, 1150s,
700m, 760m, 770m cm21; lmax 274 nm (e 14,800); dH
(CDCl3) 1.94 (6H, s, COMe), 3.69 (12H, s, OMe), 4.94,
5.25 (8H, 2s, CH2), 6.35 (2H, t, Jˆ2.2 Hz, aryl), 6.44 (4H,
d, Jˆ2.2 Hz, aryl), 7.00±7.07 (2H, m, aryl), 7.44 (2H, td,
Jˆ7.9, 1.6 Hz, aryl), 7.78 (2H, dd, Jˆ9.0, 1.7 Hz, aryl), 7.77
(1H, s, aryl); dC (CDCl3) 22.6 (COMe), 56.0 (OMe), 60.6,
69.0 (CH2), 100.4, 106.8, 113.7, 122.0, 131.3, 134.7, 130.4
(aryl CH), 127.3, 135.5, 146.1, 158.0, 161.8 (aryl C), 171.0,
196.1 (carbonyl C); m/z 1480 (M1K, 25%), 1465 (M1Na,
30%).
4.1.11. 1,3,5-Tris-(2-(1-acetyl-4,6-dimethoxyindol-3-yl))-
phenoxymethylbenzene (17). Tri-substituted compound 16
(2.30 g, 2.09 mmol) was dissolved in tri¯uoroacetic acid
(15 ml) and stirred at room temperature for 3 h. Ice/water
(100 ml) was then added, and the resulting solid was ®ltered
and washed with water until neutral. The solid was dried,
dissolved in dichloromethane and puri®ed using a pad of
silica gel to yield the tris(N-acetylindolyl)benzene 17
(1.54 g, 70%) as colourless needles, mp 234±2358C (from
ethyl acetate) (Found: C, 71.0; H, 5.8; N, 3.9.
C63H57N3O12´H2O requires C, 71.0; H, 5.6; N, 3.9%); nmax
1700s, 1600m, 1570m, 1205s, 825m, 765m cm21; lmax
271 nm (e 19,000); dH(CDCl3) 2.56 (3H, s, COMe),
3.49, 3.91 (6H, 2s, OMe), 4.62 (2H, s, CH2), 6.33,
7.82 (2H, 2d, Jˆ2.1 Hz, indole H5, H7), 6.62 (1H, s,
indole H2), 7.00 (1H, d, Jˆ7.7 Hz, aryl), 7.01 (1H, t,
Jˆ7.7 Hz, aryl), 7.15 (1H, s, aryl), 7.39±7.43 (2H, m,
aryl; m/z 1047 (M, 2%), 1005 (2), 738 (8), 696 (7), 654
(5), 268 (100).
4.1.14. 1,2,4,5-Tetrakis-(2-(1-acetyl-4,6-dimethoxyindol-
3-yl))phenoxymethylbenzene (22). Tetra-anilino ketone
21 (2.68 g, 1.86 mmol) was dissolved in tri¯uoroacetic
acid (15 ml) and stirred at room temperature for 6.5 h. Ice/
water (100 ml) was then added and the resulting solid was
®ltered and washed with water until neutral. The solid was
dried, dissolved in dichloromethane and puri®ed using a pad
of silica gel to yield the tetrakis-N-acetylindole 22 (2.01 g,
79%) as a cream solid, mp 218±2198C (from ethyl acetate)
(Found: C, 71.5; H, 5.8; N, 3.8. C82H74N4O16 requires C,
71.8; H, 5.4; N, 4.1%); dH (CDCl3) 2.39 (6H, s, COMe),
3.39, 3.83 (12H, 2s, OMe), 4.68 (4H, s, CH2) 6.25, 7.72 (4H,
2d, Jˆ2.0 Hz, indole H5, H7), 6.60 (2H, d, Jˆ8.1 Hz, aryl),
6.91 (1H, s, aryl), 7.00 (2H, t, Jˆ7.6 Hz, aryl), 7.08 (2H, s,
indole H2), 7.20 (2H, td, Jˆ7.9, 1.7 Hz, aryl), 7.35 (2H, dd,
Jˆ7.5, 1.6 Hz, aryl); dC (CDCl3) 24.5 (COMe), 55.6, 56.3
(OMe), 68.4 (CH2), 93.5 (indole C5), 96.4 (indole C7),
112.4 (indole C2), 120.9, 122.0, 128.3, 129.3, 132.2 (aryl
CH), 114.6, 120.4, 124.6, 135.0, 138.1, 154.9, 157.1, 160.1
(aryl C), 169.6 (carbonyl C); m/z 1390 (M1Na. 10%), 1327
(20).
4.1.12. 1,3,5-Tris-(2-(4,6-dimethoxyindol-3-yl))phenoxy-
methylbenzene (18). Excess crushed potassium hydroxide
was added to a partially dissolved solution of the tris-
(N-acetylindolyl)benzene 17 (0.54 g, 0.52 mmol) in
methanol. The mixture was re¯uxed for 2 h and after
cooling it room temperature the resulting precipitate was
®ltered. Water was added to the ®ltrate and the resulting
second crop was collected. The two crops were combined
to yield the tris(indolyl)benzene 18 (0.38 g, 80%) as colour-
less crystals, mp 164±1668C (from ethyl acetate) (Found: C,
74.1; H, 5.7; N, 4.3. C57H5IN3O9 requires C, 74.3; H, 5.6; N,
4.1.15.
1,2,4,5-Tetrakis-(2-(4,6-dimethoxyindol-3-yl)-
phenoxymethylbenzene (23). Excess crushed potassium
hydroxide was added to a partially dissolved solution of
the tetra-N-acetylindole 22 (1.40 g, 1.02 mmol) in
methanol. The mixture was brought to re¯ux for 6 h, and
after cooling to room temperature the resulting precipitate
was ®ltered. The solid was washed with water and dried
under vacuum to yield the tetrakis-indole 23 (0.47 g, 38%)
as a white solid, 233±2348C, which could not be obtained
analytically pure. nmax 3390br, 1620m, 1580s, 1540m,
1210s, 1140s, 805m, 755m, 740m cm21; lmax 221 (e
19,400), 274 nm (8,900); dH (CDCl3) 3.55, 3.71 (12H,
OMe), 4.73 (4H, s, CH2), 6.10, 6.13 (4H, 2s, indole H5,
H7), 6.66 (2H, d, Jˆ2.1 Hz, indole H2), 6.83 (2H, d,
Jˆ7.7 Hz, aryl), 7.03 (1H, s, aryl), 7.03 (2H, t, Jˆ6.7 Hz,
aryl), 7.19 (2H, t, Jˆ6.7 Hz, aryl), 7.49 (2H, dd, Jˆ7.7,
1.8 Hz, aryl), 7.69 (2H, br, NH); m/z 1200 (M1H, 55%);
HRMS (ES): (M1K)1, found 1241.4239. C74H66N4O121K
requires 1241.4308.
4.6%); nmax 3380br, 1635m, 1590m, 1550m, 800m cm21
;
lmax 221 (e 101,000), 274 nm (50,000); OH (CDCl3) 3.58,
3.67 (6H, 2s, OMe), 4.63 (2H, s, CH2), 6.14, 6.16 (2H, 2d,
Jˆ1.8 Hz, indole H5, H7), 6.62 (1H, d, Jˆ2.1 Hz, indole
H2), 6.74 (1H, s, aryl), 6.93(1H, d, Jˆ8.1 Hz, aryl), 7.04
(1H, t, Jˆ7.5 Hz, aryl), 7.27 (1H, td, Jˆ6.0 Hz, aryl), 7.46
(1H, dd, Jˆ6.9, 1.6 Hz, aryl), 7.63 (1H, d, Jˆ1.8 Hz, NH);
dC (CDCl3) 55.7, 56.1 (OMe), 70.7 (CH2), 87.4 (indole C5),
92.7 (indole C7), 113.1 (indole C2), 120.1, 122.5, 125.0,
128.0, 132.9 (aryl CH), 112.2, 113.4, 126.6, 138.2, 138.3,
155.5, 157.4, 157.9 (aryl C); m/z 921 (M, 5%), 654 (10), 269
(100), 237 (85).
4.1.13. 1,2,4,5-Tetrakis-(2-(N-acetyl-3,5-dimethoxyphenyl-

D. StC. Black et al. / Tetrahedron 57 (2001) 2203±2211
2211
10. Helgeson, R. C.; Mazaleyrat, J.-P.; Cram, D. J. J. Am. Chem.
Soc. 1981, 103, 3929±3931.
Acknowledgements
11. Cram, D. J.; Karbach, S.; Kim, H.-E.; Knobler, C. B.;
Maverick, E. F.; Erickson, J. L.; Helgeson, R. C. J. Am.
Chem. Soc. 1988, 110, 2229±2237.
We thank the Australian Research Council for ®nancial
support.
12. Black, D. StC.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.;
Kim, M.; Kilmar, N.; McConnell, D. B.; Popiolek, M. Aust. J.
Chem. 1994, 47, 1741±1750.
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