Formation of C-amido-calix[3]indoles from 2'- and 7'-indolylglyoxylamides

Article abstract of DOI:10.1016/S0040-4020(00)00774-2

A range of 2'- and 7'-indolylglyoxylic amides 1 and 2, derived from 3-(4'-chlorophenyl)-4,6-dimethoxyindole, have been reduced to the corresponding alcohols 3 and 4 respectively. On treatment with acid, these alcohols underwent trimerisation to give the calix[3]indoles 8. The major conformer was generally the flattened partial cone, but in certain cases the cone conformers could be detected and even isolated. The related 2'-indolylglyoxylic amides 13, derived from 4,6-dimethoxy-3-methylindole, were also converted into calix[3]indoles 15. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00774-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8513±8524
Formation of C-Amido-calix[3]indoles from 20- and
70-Indolylglyoxylamides
*
David StC. Black, Naresh Kumar and Darryl B. McConnell
School of Chemistry, The University of New South Wales, Sydney 2052, Australia
Received 15 March 2000; revised 9 August 2000; accepted 23 August 2000
AbstractÐA range of 20- and 70-indolylglyoxylic amides 1 and 2, derived from 3-(40-chlorophenyl)-4,6-dimethoxyindole, have been
reduced to the corresponding alcohols 3 and 4 respectively. On treatment with acid, these alcohols underwent trimerisation to give the
calix[3]indoles 8. The major conformer was generally the ¯attened partial cone, but in certain cases the cone conformers could be detected
and even isolated. The related 20-indolylglyoxylic amides 13, derived from 4,6-dimethoxy-3-methylindole, were also converted into
calix[3]indoles 15. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
Formation of alcohol precursors
Calix[3]indoles are macrocyclic compounds which consist
of three substituted indole units linked together by single
carbon bridges. Those described so far have been linked
through the 2- and 7-positions of the indoles.1±3 These
macrocyclic trimers can be linked symmetrically (i.e. 2,7;
2,7; 2,7) or unsymmetrically (i.e. 2,2; 7,2; 7,7). The sym-
metrically oriented calixindoles can be prepared either by
the reaction of 3-substituted-4,6-dimethoxyindoles with aryl
aldehydes in the presence of phosphoryl chloride1,3 or by the
acidic treatment of indolyl-2- or 7-methanols.2 Two
different conformations of calix[3]indoles are possible,
namely the ¯attened partial cone and the cone conforma-
tions. So far, all examples of the calix[3]indoles appear to be
in the ¯attened partial cone conformation, and routes to the
cone conformers are being pursued. In the case of calix[4]-
arenes, the cone conformation is stabilised by a cyclic
network of hydrogen bonds between the four phenolic
hydroxyl groups.4,5 It was hoped that a similar application
of hydrogen bonding phenomena might enable the forma-
tion of stable cone conformers of the calix[3]indoles. Thus
the oxygen atom of a carbonyl substituent on the linking
carbon atom might hydrogen bond with the adjacent indole
NH, and thereby stabilise the cone conformer. To this end,
C-amido-calix[3]indoles were sought by the acid-catalysed
trimerisation of appropriate indolyl methanol derivatives.
Some preliminary results of these studies have been
reported.6
The reaction of oxalyl chloride with 3-aryl-4,6-dimethoxy-
indoles has been shown to generate mixtures of 20- and 70-
glyoxylic acid chlorides, which could be converted into a
wide range of glyoxylic esters and amides, and these could
be separated readily and made available for further trans-
formations.7 The 20- and 70-indolylglyoxylic amides 1 and 2
respectively were reduced in high yield to the related 20- and
70-indolylmethanols 3 and 4 respectively, with sodium
borohydride in methanol (Scheme 1).
Unlike the glyoxylamides 1 and 2, the hydroxyethanamides
3 and 4 showed no sign of crystallinity and no signi®cant
hydrogen bonding. The indole NH protons for the alcohols 3
and 4 were observed around 8.5 and 9.3 ppm respectively in
1
the H NMR spectra in chloroform, compared with values
around 11.5 and 10.5 respectively for ketones 1 and 2.
However, the absence of hydrogen bonding in these pre-
cursors of calixindoles cast some doubt about their ability
to in¯uence the formation of cone conformers. Most
attempts to reduce the 20- and 70-indolylglyoxylic esters, 5
Keywords: calixarenes; indoles; keto acids and derivatives; hydroxy acids
and derivatives.
* Corresponding author. Tel.:1612-9385-4657; fax: 1612-9385-6141;
e-mail: d.black@unsw.edu.au
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00774-2

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D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
Scheme 1.
the H20 doublet in the case of the 70-hydroxyethanamides 4
was used to identify substitution at the 2- or 7-position of the
indole ring respectively. Accompanying this was the
appearance of the bridging methine proton as a singlet reso-
nance. The indole NH peaks were invaluable in identifying
products from complex mixtures because of their separation
down®eld from other resonances.
Calixindoles from 3-(4-chlorophenyl)-4,6-dimethoxy-
indole
Secondary C-amidocalixindoles. C-Methylamidocalixin-
doles. The secondary C-methylamidocalix[3]indole 8a
was used initially to investigate thoroughly the reaction
conditions and their effects on the products formed. This
calixindole 8a was formed when the 20-alcohol 3a was
treated with concentrated hydrochloric acid in tetrahydro-
and 6 respectively, gave unsatisfactory yields, impure
products and inconsistent results. However, when the
70-glyoxylic ester 6 was treated with an excess of lithium
aluminium hydride in tetrahydrofuran, the ethanediol 7 was
obtained as a stable, crystalline, white solid.
1
furan. The H NMR spectrum showed three sets of peaks
and consequently indicated the ¯attened partial cone
isomer. This compound will be referred to as calixindole
8a(fpcone). Formed together with this isomer was a trace of
the isomer 8a(cone). Use of carbon tetrachloride as solvent
led to a heterogeneous reaction and formation of a 65:35
mixture of isomer 8a(fpcone) and isomer 8a(cone), the
Formation of calixindoles
A variety of acid-catalysed reactions were used for the
formation of three new types of C-amidocalixindoles,
namely primary, secondary and tertiary amidomethine
bridged calixindoles. An attempt was made to ascertain
the major factors which control these reactions, by variation
of the type of amide, the temperature, the solvent and the
substrate regioisomer (i.e. 20- or 70-hydroxyethanamide). To
obtain ratios of the products formed, the indole NH peaks
were integrated. These peaks were chosen as they were clear
of any overlapping from other peaks and should all have
approximately the same T1 relaxation times so that the inte-
gration values should be relatively accurate. The primary
diagnostic tool used to determine whether calixindoles had
been formed was 1H NMR spectroscopy. The disappearance
of the two meta coupled doublets corresponding to H50 and
H70 of the 20-hydroxyethanamides 3 or the disappearance of
1
latter showing a very deshielded H NMR resonance at
11.8 ppm for the indole NH. The reaction of the 20-alcohol
3a with concentrated hydrochloric acid was also performed
in toluene and gave rise to three products in the ratio
55:20:25 as shown by 1H NMR spectroscopy. Two of
these compounds corresponded to calix[3]indoles
8a(fpcone) and 8a(cone), and the third was assigned the
calix[4]indole8 structure 9 on the basis of a MALDI mass
spectrum which showed a small peak at 1368 (M256),
consistent with a fragment ion for a tetramer which has
lost one methylamide group. This new compound also
showed a peak at 9.1 ppm in the 1H NMR spectrum assigned
to be the indole NH. The use of cyclohexane as solvent led

D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
8515
Table 1. Effect of solvent, catalyst and temperature on calixindole formation from alcohol 3a
Solvent
Catalyst
Temperature (8C)
% Yield of 8a(fpcone)
% Yield of 8a(cone)
% Yield of 9
THF
CCl4
CCl4
CCl4
Toluene
Cyclohexane
MeOH
THF
HCl (conc)
20
20
25
77
20
20
20
20
20
20
20
20
20
20
20
20
20
20
100
65
60
70
55
65
85
85
0
60
90
80
75
65
45
100
95
70
0
0
0
0
HCl (conc)
HCl (conc)
HCl (conc)
HCl (conc)
HCl (conc)
HCl (conc)/Ni(OAc)2
BF3´Et2O
BF3´Et2O
BF3´Et2O
BF3´Et2O
BF3´Et2O
p-TsOH/AcOH
p-TsOH
p-TsOH
K10 clay
POCl3
SnCl2´2H2O
35
40
30
20
20
15
15
0
0
25
15
0
0
0
10
10
0
0
5
CCl4
Toluene
CH2Cl2
Et2O
THF
CCl4
Toluene
CH2Cl2
THF
30
0
20
25
30
20
0
35
0
0
30
5
0
Et2O
to the formation of all three products. The change in solvent
could affect the reactivity of the intermediate carbocation
and also the degree of hydrogen bonding between the indole
NH and amide carbonyl oxygen atom.
precipitate was obtained from the reaction and identi®ed
as isomer 8a(cone). The 1H NMR spectrum showed a
broad peak at 2.95 ppm corresponding to the amido methyl
groups. Two singlet resonances corresponding to the two
non-equivalent methoxy groups occurred at 3.34 and
3.54 ppm, and a further two singlets at 5.88 and 6.02 ppm
were assigned to the bridging methine proton and the indole
H5 respectively. Two broad peaks from 6.70 to 7.50 ppm
corresponded to the p-chlorophenyl protons. The amide NH
was seen as a broad peak at 8.50 ppm and the typically
deshielded indole NH occurred at 11.75 ppm. The signi®-
cant broadening in the spectrum of the p-chlorophenyl ring,
amide NH and the amide methyl groups was resolved on
heating. Presumably, restricted rotation caused by crowding
is responsible for the broadening of these signals. Two
peaks were observed in the MALDI mass spectrum. The
higher mass peak at 1068 corresponded to the molecular
weight of a protonated trimer, while the second peak at
1010 mass units corresponded to loss of one methyl amide
group. All attempts to isolate and fully characterise isomer
8a(cone) failed because of its poor solubility, and
incompatibility with chromatography media.
A symmetrical calix[3]indole which cannot undergo
inversion must exist in the cone conformation. The presence
of three chiral centres in the molecule leads to two possible
isomeric forms that would display the symmetry exhibited
by isomer 8a(cone), namely a `tri-axial' isomer and a `tri-
equatorial' isomer (see Fig. 1). The `tri-axial' calixindole is
preferred as the most likely structure because the three
amide groups would be in less sterically demanding posi-
tions and also capable of hydrogen bonding to the indole NH
protons, thus explaining the deshielded NH peak. Molecular
modelling of a related series of C-amidocalix[3]indoles
which have no substituents on the indole ring also suggested
that the `tri-axial` diastereoisomer is the more energetically
favourable.
Various acid catalysts and solvents were investigated for
their effect on the reaction with alcohol 3a, and the results
are shown in Table 1.
When the 70-alcohol 4a was reacted with concentrated
hydrochloric acid in tetrahydrofuran, the two products
8a(fpcone) and 8a(cone) were obtained in a ratio of
65:35. Extended reaction and extraction with ethyl acetate
gave a product mixture corresponding to a trimer, a tetramer
A one pot synthesis was developed for C-amidocalixin-
doles: the 20-glyoxylamide 1a was reduced with sodium
borohydride in methanol and then acidi®ed directly using
concentrated hydrochloric acid. A small amount of white

8516
D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
Figure 1. `Tri-axial' and `tri-equatorial' cone conformers of calix[3]indole 8a.
and a pentamer, according to the MALDI mass spectrum.
The H NMR spectrum contained a broad peak at 8.8 ppm
a-cyano-4-hydroxycinnamic acid as the matrix gave rise to
peaks at 1195, corresponding to the protonated molecular
ion, and at 1095, corresponding to the removal of one
t-butylamide group. The spectrum using sinapinic acid as
the matrix showed essentially one peak corresponding to the
protonated molecular ion.
1
corresponding to the calix[5]indole NH. The larger size of
the lower rim (25-membered ring) could allow the amide
groups to pass through the annulus and invert, hence causing
the broadening of the indole NH peak. The variation in
product formation from the 20-alcohol 3a and the 70-alcohol
4a is likely to be caused by the different reactivities of the
two resulting carbocations and the different nucleophilic
strengths of the indole C2 and C7 sites. Experience indicates
that C2 is generally a more powerful nucleophilic site than
C7 and this would be consistent with the formation of more
of the less thermodynamically stable cone conformer from
alcohol 4a than from 3a.
The 1H NMR spectrum of isomer 8c(cone) shows one indole
NH occurring signi®cantly down®eld at 11.38 ppm. This
chemical shift in deuterated chloroform suggests a strongly
hydrogen bonded indole NH as originally planned. Singlet
resonances at 5.71, 5.77 and 6.03 ppm were assigned to the
amide NH, the methine proton and H5 respectively. The
only broadening in the spectrum occurs for the p-chloro-
phenyl ring protons occurring between 7.00 and 7.40 ppm.
Each p-chlorophenyl ring is ¯anked by two methoxy groups
at the upper rim, one at the 4-position of the indole contain-
ing the aryl ring and the other at the 7-position of the neigh-
bouring indole. CPK models of a cone shaped calix[3]indole
consistent with the structural features of isomer 8c(cone)
show that the 3-aryl moiety cannot rotate fully, mainly
because of the 4-methoxy group. A MALDI mass spectrum
of calixindole 8c(cone) using a-cyano-4-hydroxycinnamic
acid as the matrix showed only one peak at approximately
1096, corresponding to the M2100 peak. The spectrum
using the matrix sinapinic acid gave a protonated molecular
ion peak at 1195, and a peak at 1095 corresponding to
M2100. X-Ray quality crystals of the isomer 8c(cone)
were obtained by recrystallization from absolute ethanol,
and the subsequent crystal structure determination, details
of which have been deposited,6 proved the cone shape with a
`tri-axial' arrangement of substituents (Fig. 2). An exciting
feature of the crystal structure is that the calix[3]indole
8c(cone) contained an ethanol molecule inside the cup,
with the alkyl portion deep within the cavity. There is
presumably an interaction between the very electron rich
cup and the relatively electron poor alkyl portion of ethanol
which holds the ethanol molecule within the cup. The
ethanol molecule also interacts with the side of another
calix[3]indole molecule. The oxygen of the ethanol
molecule hydrogen bonds to an amide NH and the alcoholic
proton hydrogen bonds to a methoxy oxygen atom. The
hydrogen bonding of the amide carbonyls to the indole
NHs is not quite as expected. Instead of all three amide
carbonyls pointing into the annulus of the macrocycle and
C-n-Butylamidocalixindoles. As isomer 8a(cone) was a
minor product and could not be isolated, the amide groups
were varied with the hope that a symmetrical cone con-
former could be maximised and isolated. The use of long
alkyl chains has been shown to favour the cone conforma-
tion in calix[4]resorcinarenes.9±11 A similar approach was
adopted by increasing the chain length of the amide so that
aggregation of these alkyl chains might favour the cone
conformation in calixindoles. The 20-n-butylglyoxylamide
1b was reduced to the corresponding alcohol, which without
isolation was treated with concentrated hydrochloric acid in
a number of solvents. Although the cone isomer 8b(cone)
was observed, this product could not be isolated.
C-t-Butylamidocalixindoles. After a series of preliminary
experiments, it was found that reaction of alcohol 3c with
concentrated hydrochloric acid in re¯uxing chloroform gave
the two calix[3]indoles 8c(fpcone) and 8c(cone), which
1
could be separated by thin layer chromatography. The H
NMR spectrum of isomer 8c(fpcone) displays three sets of
peaks. The three indole NHs show chemical shifts of 11.30,
10.03 and 8.84 ppm in deuterated chloroform. The three
p-chlorophenyl rings can be clearly seen in the range of
7.04±7.61 ppm with one aryl ring showing considerably
broadened signals. The methine protons occur over a wide
range at 5.29, 5.48 and 6.10 ppm, while the H5 protons
occur over a narrower range at 6.14, 6.17 and 6.42 ppm.
The amide NHs are also in this area and can be differentiated
because of broadened signals at 5.26, 5.77 and 6.12 ppm.
The MALDI mass spectrum of the isomer 8c(fpcone) using

D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
8517
Figure 2. X-Ray crystal structure for calix[3]indole 8c(cone).
forming a hydrogen bonded network around the base of the
calix, only two carbonyls are in positions capable of hydro-
gen bonding to the indole NHs. However, all three indole
molecules are hydrogen bonded in some way. One amide
carbonyl oxygen atom is in a position capable of hydrogen
NHs in the 1H NMR spectrum which involves the hydrogen
bonding shown in the X-ray crystal structure. The bulky
t-butylamide groups do not allow all three amide carbonyls
to point simultaneously into the centre of the annulus. Only
two carbonyls can point in at any one time and the amides
rotate rapidly on the NMR time scale. The lesser degree of
hydrogen bonding is seen in the indole NH chemical shift
and the increased solubility is a consequence of the greater
¯exibility of the system provided by the t-butyl groups. All
three t-butyl groups are in an axial arrangement seemingly
aggregating at the base of the cone. The X-ray crystal
structure shows that the t-butyl groups are in such close
proximity that the base of the cone is almost completely
covered. The orientation of the p-chlorophenyl rings is
also interesting. The rings have all rotated to a position
where they are as far away as possible from the ¯anking
methoxy groups. Again the crystal structure shows the high
degree of steric hindrance around the p-chlorophenyl rings,
which show a consequent degree of distortion.
Ê
bonding to one indole via a 6-membered ring (2.723 A) and
Ê
another indole via a 7-membered ring (2.746 A). The
second carbonyl oxygen atom is only capable of hydrogen
Ê
bonding to one indole via a 6-membered ring (2.653 A), and
the third amide has the carbonyl oxygen atom pointing away
from the centre of the annulus and thus is not capable of
hydrogen bonding to an indole NH. The unsymmetrical
nature of the three amide groups in the X-ray crystal struc-
ture is not re¯ected in the 1H NMR spectrum. In solution the
amide groups could be in a ¯uxional equilibrium with only
two amides in hydrogen bonding positions at any one time,
as is the case in the X-ray structure, or all three amide car-
bonyl oxygen atoms could be hydrogen bonding in solution
but in the solid state one amide is forced to rotate out of the
hydrogen bonded position.
When the calixindole 8c(cone) was treated with methoxide
ion an irreversible isomerisation to the conformer
8c(fpcone) occurred. When this reaction was performed in
deuterated methanol/deuterated methoxide, the indole NHs,
amide NHs and the methine protons were all replaced by
deuterium. The reaction presumably proceeds via a planar
carbanion intermediate from the deprotonation of the
methine group rather than a ring opening process from
which polymeric material would be expected. The irre-
versible conversion shows that the isomer 8c(fpcone) is
indeed the thermodynamically more stable product. All
attempts to form metal complexes of the calixindole
8c(cone) failed, possibly because of prior interconversion
The indole NH 1H NMR chemical shift of calixindole
8a(cone) is observed at 11.75 ppm (in both d6-DMSO and
CDCl3), while that of calixindole 8c(cone) is seen at
11.38 ppm (also in both d6-DMSO and CDCl3) showing
that a greater degree of hydrogen bonding exists in the
former. It is proposed that calixindole 8a(cone) shows a
hydrogen bonded network involving all indole NHs in solu-
tion as originally suggested. The broadening of the amide
signals in the 1H NMR spectrum of this compound would be
caused by restricted rotation as the amides are ®xed by the
strong hydrogen bonded network. Calixindole 8c(cone) is
proposed to exhibit a time averaged signal for the indole

8518
D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
to isomer 8c(fpcone), or because the bulky t-butyl groups at
the base of the cone stop the metal ion from reaching the
indole binding sites.
interaction between the indole NHs in the calix[3]indole
structure it was proposed to replace the indole NH with a
larger group to encourage the system to form larger macro-
cycles. The glyoxylamide 1e was treated with an excess of
potassium hydroxide in dimethyl sulfoxide followed by
methyl iodide to obtain the N-methyl-dimethylglyoxyl-
amide 10, which was then reduced to the corresponding
alcohol 11 using sodium borohydride in methanol. When
the N-methyl alcohol 11 was reacted with concentrated
hydrochloric acid in tetrahydrofuran at room temperature
no reaction occurred.
When the 70-t-butylamidoalcohol 4c was reacted with
concentrated hydrochloric acid in dichloromethane the
calix[3]indole 8c(fpcone) was the major product and only
a slight trace of the conformer 8c(cone) was observed.
This result was in contrast to that observed for the acid
catalysis of the methylamides 3a and 4a. An additional
minor product corresponded to an unsymmetrical tetramer.
The crude reaction mixture showed a MALDI mass peak at
1593 consistent with the protonated molecular ion of a tetra-
1
mer and the H NMR spectrum showed four indole NH
signals.
Primary C-amidocalixindoles. A number of problems
were encountered with the isolation and characterisation
of primary C-amidocalixindoles. The products from these
macrocyclisation reactions were insoluble and very dif®cult
to purify. Because of these undesirable qualities only a
preliminary investigation was made. When the 70-alcohol
4d was reacted with concentrated hydrochloric acid in tetra-
hydrofuran the major product was an unsymmetrical
calix[3]indole 8d(fpcone), together with two symmetrical
products, which decomposed on attempted puri®cation.
Calixindoles from 4,6-dimethoxy-3-methylindole
Tertiary C-amidocalixindoles. C-Dimethylamidocalixin-
doles. The tertiary amidoalcohols were generally less
reactive than the corresponding primary and secondary
amidoalcohols, probably because of the increased steric
hindrance around the carbocation centre. The reactions of
the 20-dimethylamidoalcohol 3e and 70-dimethylamido-
alcohol 4e generally gave polymers and a 42% yield of an
unsymmetrical calixindole 8e(fpcone). Traces of two
symmetrical isomers showing strongly hydrogen bonded
NH resonances at 12.0 and 11.1 ppm were observed in
reactions of alcohols 3e and 4e respectively.
It was considered that the steric hindrance around the 3-aryl
rings of the 3-arylcalix[3]indole 8c(cone) was a signi®cant
factor inhibiting its formation. The synthesis of 3-methyl-
calix[3]indoles was undertaken to discover whether the
smaller methyl group at the upper rim would lead to an
increase in the cone conformer. CPK models of cone
calix[3]indoles showed that a 3-methyl group could rotate
freely.
C-Pyrrolididocalixindoles. 3-Methylindole 12 was
converted regiospeci®cally into the 20-indolylglyoxylpyrro-
lidide 13a, presumably as the result of the electron donating
in¯uence of the 3-methyl group. Consequently, reactions of
the 70-indolyl series could not be investigated. The 20-
indolylglyoxylamide 13a was reduced to the corresponding
alcohol 14a which was treated with concentrated hydro-
chloric acid to yield two macrocyclic products, which
were shown to be the unsymmetrical calixindole
15a(fpcone) and the symmetrical isomer 15a(cone) in the
ratio of 55:45. This latter product was again characterised by
the signi®cantly down®eld indole NH resonance
(11.57 ppm) in the 1H NMR spectrum. The H5 and methine
proton resonances occurred at 6.25 and 6.19 ppm but were
not differentiated. The two methoxy group resonances
occurred at 3.95 and 3.83 ppm while that for the 3-methyl
group was seen at 2.42 ppm. A MALDI mass spectrum
using a-cyano-4-hydroxycinnamic acid as the matrix
showed a large cluster of peaks centred about 933 mass
units. When the one pot synthesis using the
3-methylglyoxylamide 13a is compared with that of the
3-arylglyoxylamide 1f a great difference in products is
observed. Only a trace of symmetrical 3-arylcalixindole
was observed but the symmetrical 3-methylcalixindole
was almost the major product. The 3-aryl series also yielded
a minor amount of an unsymmetrical tetramer and no related
product was formed from the 3-methyl precursor.
C-Pyrrolididocalixindoles. When the 20-pyrrolididoalcohol
3f was treated with concentrated hydrochloric acid in
dichloromethane the sole product was the calixindole
8f(fpcone). The 1H NMR spectrum showed the three indole
NH resonances at 9.09, 10.07 and 11.12 ppm as well as the
six singlets occurring between 5.50 and 6.43 ppm arising
from the methine and H5 protons. When the 70-pyrrolidido-
alcohol 4f was treated with concentrated hydrochloric acid
in dichloromethane, calixindole 8f(fpcone) remained the
major product but was accompanied by a minor amount of
a tetrameric compound which gave rise to four sets of peaks
1
in the H NMR spectrum. When the one pot synthesis was
applied to this system considerably different results were
obtained. Three products were obtained from the 20-
glyoxylpyrrolidide 1f. The major product was the calixin-
dole 8f(fpcone) but it was accompanied by a signi®cant
amount of an unsymmetrical tetramer and a small amount
of the calix[3]indole 8f(cone).
Attempted synthesis of C-amido-N-methylcalixindoles
The appearance of tetrameric calixindoles in trace amounts
in some of these reactions prompted an attempt to promote
their formation. As there seemed to be a high level of steric

D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
8519
with the 3-methyl group providing less steric inhibition. The
3-methyl series also appears to be affected by solvent
changes to a greater extent than the 3-aryl series. So far
no substrates or reaction conditions have been found to
afford the cone isomers speci®cally.
Conclusion
The following general conclusions about C-amidocalix[3]-
indoles can be made. It seems that a carbonyl function is
required at the lower rim to allow the cone conformer to be
formed. However, this factor cannot be isolated from the
reactivity of the alcohols. All the cone calix[3]indoles
observed except the t-butylamide macrocycle 8c(cone)
exhibit a cyclic array of hydrogen bonds at the base of the
cone. This results in very rigid and insoluble molecules.
Generally the 20-alcohols 3 give only trimeric compounds
while the 70-alcohols 4 give rise to traces of tetramers and
pentamers as well. The size of the group at the 3-position of
the indole ring appears to affect the formation of the cone
conformation. The larger aryl ring could give rise to
unfavourable interactions with the neighbouring methoxy
groups and hence reduce the formation of this conformer.
The 3-methyl group on the other hand is smaller and would
interact to a lesser extent with the ¯anking methoxy groups
and thus allow the cone conformation to form more readily.
Reactions of the 3-methyl alcohols 14 appear to be affected
by solvent to a greater extent than the 3-aryl alcohols 3.
Experimental
C-t-Butylamidocalix[3]indoles. On the basis of previous
experiments it was decided to target calixindoles from the
t-butylglyoxylamide 13b, which could provide the best
chance of obtaining cone conformers. The t-butylglyoxyl-
amide 13b was reduced with sodium borohydride in metha-
nol, and the alcohol 14b was extracted into dichloromethane
and treated with concentrated hydrochloric acid. The only
product observed was the unsymmetrical calixindole
15b(fpcone). On the other hand, when the glyoxylamide
13b was reduced with sodium borohydride in methanol,
extracted into dichloromethane and treated with concen-
trated hydrochloric acid, a 50:50 mixture of calixindoles
General information
1H and 13C NMR spectra 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:
CDCl3 (7.30 ppm, 77.7 ppm) and d6-DMSO (2.30 ppm,
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 spectrometer and a Mattson Sirius FTIR using KBr discs
while ultraviolet spectra were carried out on a Hitachi
U-3200 and Carey 5 spectrophotometers. Electrospray
(ES) mass spectra were recorded on a VG Quattro mass
spectrometer at 4000 V probe voltage, 1000 V counter elec-
trode, 65 V cone voltage using a mixture of acetonitrile and
water (1.10 containing 1% acetic acid as the solvent and at
5 ml/min ¯ow rate). High molecular weight compounds
were measured using a matrix assisted laser desorption
(MALDI) mass spectrometer Finnigan MAT or Lasermat
2000.
1
15b(fpcone) and 15b(cone) was observed in the H NMR
spectrum. This striking difference in product distribution
brought about by a change in solvent was much larger
than experienced in the 3-aryl series and represents the high-
est proportion of calix[3]indole cone conformer achieved.
1
The H NMR spectrum of 15b(fpcone) showed methine
proton resonances at 5.35, 5.55 and 5.60 ppm and H5
resonances at 6.25, 6.30 and 6.35 ppm. The indole NH reso-
nances occurred at 8.2, 8.7 and 10.4 ppm. The spectrum of
the cone conformer 15b(cone) displayed the indole NH
resonance at 11.0 ppm, showing less deshielding relative
to the pyrrolididocalix[3]indole 13f(cone), and again
suggesting that the t-butyl groups do not allow maximum
hydrogen bonding. The methine and H5 resonances
appeared at 5.8 and 6.2 ppm, respectively, and the amide
protons showed a broad singlet resonance at 5.75 ppm.
N-Methyl-2-(30-(400-chlorophenyl)-40,60-dimethoxyindol-
20-yl)-2-hydroxyethanamide (3a). The 20-indolylglyoxyl-
amide7 1a (1.66 g, 4.45 mmol) was partially dissolved in
methanol (40 ml) and excess sodium borohydride was
added. The solution was stirred under nitrogen for 20 min.
Water was then added dropwise until the solution just began
Clearly the size of the group at the 3-position of the indole
ring considerably affects the formation of the cone isomer,

8520
D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
to turn cloudy. The volume was then immediately reduced
to approximately one third under reduced pressure until a
white precipitate formed. The resulting precipitate was
®ltered off, washed with water, dried and column chromato-
graphed (5% methanol/chloroform) to yield the 20-hydroxy-
ethanamide 3a (1.44 g, 86%) as a white solid, mp 1128C;
[Found: C, 60.7; H, 5.4; N, 7.0. C19H19ClN2O4 requires C,
60.9; H, 5.1; N, 7.5%]; nmax 3300br, 1625s, 1595s, 1550s,
1150s, 1045m, 810w cm21; lmax 223 (e 30,800), 275 nm
(15,000); dH (d6-DMSO) 2.76 (3H, d, Jˆ4.0 Hz, NMe),
3.74, 3.85 (6H, 2s, OMe), 5.0 (1H s, CHOH), 6.25, 6.61
(2H, 2s, H50, H70), 6.46 (1H, br, CHOH), 7.48, 7.67 (4H,
2d, Jˆ8.2 Hz, aryl), 7.67 (1H, d, Jˆ8.1 Hz, CONH), 11.10
(1H, br, NH); dC (d6-DMSO) 25.6 (NMe), 54.9, 55.2 (OM),
66.1 (CHO), 87.2 (C50), 91.5 (C70), 126.8, 132.5 (aryl CH),
110.1, 113.5, 130.3, 132.4, 134.2, 137.3, 154.0, 156.8 (aryl
C), 171.5 (carbonyl C); m/z 376 (M37Cl, 5%), 374 (M35Cl,
20%), 318 (30), 316 (100).
(d6-DMSO) 3.58±3.71 (2H, m, CH2OH), 3.88, 3.93 (6H,
2s, OMe), 4.82 (1H, t, Jˆ5.3 Hz, CH2OH), 5.27±5.30
(1H, m, CHOH), 5.53 (1H, d, Jˆ3.1 Hz, CHOH), 6.49
(1H, s, H50), 7.24 (1H, d, Jˆ1.8 Hz, H20), 7.45, 7.61 (4H,
2d, Jˆ8.5 Hz, aryl), 10.62 (1H, br, NH); dC (d6-DMSO)
55.1, 57.0 (OMe), 65.3 (alkyl CH2), 68.6 (alkyl CH), 89.3
(C50), 122.8 (C20), 127.3, 130.4 (aryl CH), 106.0, 110.4,
114.6, 129.5, 135.4, 136.8, 152.0, 152.8 (aryl C); m/z 349
(M37Cl, 10%), 347 (M35Cl, 35%), 329 (24), 318 (30), 316
(100), 300 (50).
N-t-Butyl-2-(30-(400-chlorophenyl)-40,60-dimethoxyindol-
20-yl)-2-hydroxyethanamide (3c). The hydroxyethana-
mide 3c was synthesised according to the method for
compound 3a using the following quantities: glyoxylamide
1c (2.18 g, 5.25 mmol), methanol (15 ml) and excess
sodium borohydride. This yielded a cream solid, which
after gravity column chromatography (2.5% methanol/
chloroform) gave the hydroxyethanamide 3c (2.16 g, 99%)
as a white solid, mp 109±1108C; [Found: C, 63.3; H, 6.3; N,
6.5. C22H25ClN2O4 requires C, 63.4; H, 6.0; N, 6.7%]; nmax
3350br, 1655m, 1625m, 1210m, 1150m cm21; lmax 224 (e
28,200), 242 (19,200), 275 (11,400), 300 nm (7,600); dH
(CDCl3) 1.22 (9H, s, CMe3), 3.74, 3.87 (6H, 2s, OMe),
4.18 (1H, br, OH), 5.17 (1H, s, CH), 5.39 (1H, br,
CONH), 6.25, 6.50 (2H, 2d, Jˆ1.6 Hz, H50, H70), 7.42,
7.51 (4H, 2d, Jˆ8.4 Hz, aryl), 8.55 (1H, br, NH); dC
(CDCl3) 29.1 (CMe3), 52.6 (CMe3), 55.7, 56.2 (OMe),
67.1 (CH), 87.4 (C50), 93.0 (C70), 128.8, 132.8 (aryl CH),
112.1, 115.5, 130.1, 133.2, 134.0, 137.9, 155.4, 158.7 (aryl
C), 170.9 (carbonyl C); m/z 418 (M37Cl, 5%), 416 (M35Cl,
10%), 318 (30), 316 (100).
N-Methyl-2-(30-(400-chlorophenyl)-40,60-dimethoxyindol-
70-yl)-2-hydroxyethanamide (4a). The 70-indolylglyoxyl-
amide7 2a (1.34 g, 3.59 mmol) was partially dissolved in
methanol (20 ml) and excess sodium borohydride was
added. The solution was stirred under nitrogen for 20 min.
Water was then added dropwise until the solution just began
to turn cloudy. The volume was then immediately reduced
to approximately one third under reduced pressure until a
white precipitate was formed. The resulting precipitate was
®ltered off, washed with water, dried and column
chromatographed (5% methanol/chloroform) to yield the
70-hydroxyethanamide 4a (1.28 g, 95%) as a white solid,
mp 221±2228C; [Found: C, 59.1; H, 5.4; N, 7.1.
C19H19ClN2O4´0.5H20 requires C, 59.5; H, 5.0; N, 7.3%)];
n
max 3420m, 3390s, 3230br, 1645s, 1615m, 1600m, 1540m,
N-t-Butyl-2-(30-(400-chlorophenyl)-40,60-dimethoxyindol-
70-yl)-2-hydroxyethanamide (4c). The hydroxyethana-
mide 4c was synthesised according to the method for
compound 3a using the following quantities: glyoxylamide
2c (0.15 g, 0.36 mmol), methanol (15 ml) and excess
sodium borohydride. After column chromatography (2.5%
methanol/chloroform) this yielded the hydroxyethanamide
4c (0.12 g, 80 %) as a white solid, mp 1868C; [Found: C,
61.5; H, 6.4; N, 6.3. C22H25ClN2O4´0.5H2O requires C, 62.0;
H, 6.2; N, 6.6%)]; nmax 3530br, 3400br, 3180br, 1660m,
1620m, 1525m, 1210m cm21; lmax 230 (e 28,000), 285
(13,200), 302 nm (11,500);: dH (CDCl3) 1.35 (9H, s,
CMe3), 3.88, 4.02 (6H, 2s, OMe), 5.65 (1H, s, CH), 6.37
(1H, s, H50), 6.39 (1H, br, CONH), 7.06 (1H, d, Jˆ2.6 Hz,
H20), 7.35, 7.54 (4H, 2d, Jˆ8.7 Hz, aryl), 9.37 (1H, br, NH);
dC (CDCl3) 29.3 (CMe3), 52.17 (CMe3), 55.9, 57.9 (OMe),
68.4 (CH), 89.3 (C50), 122.7 (C20), 128.3, 131.4 (aryl CH),
103.7, 112.4, 117.4, 132.1, 135.2, 137.2, 153.6, 155.1 (aryl
C), 173.2 (carbonyl C); m/z 418 (M37Cl, 5%), 416 (M35Cl,
20%), 318 (70), 316 (100), 251 (50), 121 (70).
1210m, 1130s, 1020s, 790s cm21; lmax 230 (e 27,700), 280
(16,100), 300 nm (12,400); dH (CDCl3) 2.84 (3H, d, Jˆ
5.1 Hz, Nme), 3.87, 4.02 (6H, 2s, OMe), 4.41 (1H, s,
OH), 5.77 (1H, s, CH), 6.31 (1H, br, CONH), 6.38 (1H, s,
H50), 7.05 (1H, s, H20), 7.34, 7.52 (4H, 2d, Jˆ8.2 Hz, aryl),
9.34 (1H, br, NH); dC (d6-DMSO) 25.8 (NMe), 55.4, 57.9
(OMe), 66.7 (alkyl CH), 90.2 (C50), 123.1 (C20), 127.7,
130.9 (aryl CH), 106.0, 110.6, 115.5, 130.0, 135.5, 136.7,
153.7, 153.7 (aryl C), 172.8 (carbonyl C); m/z 376 (M37Cl,
5%), 374 (M35Cl, 20%); 318 (30), 316 (100).
1-(30-(400-Chlorophenyl)-40,60-dimethoxyindol-70-yl)-1,2-
ethanediol (7). Lithium aluminium hydride (0.04 g,
1.1 mmol) was dissolved in anhydrous tetrahydrofuran
(30 ml) and cooled to 08C with an ice bath. A solution of
70-indolylglyoxylic ester7
6 (0.20 g, 0.54 mmol) in
anhydrous tetrahydofuran (10 ml) was added in portions,
and the solution was allowed to warm to room temperature
and stirred for a further 30 min. Water was added slowly
until all the lithium aluminium hydride was destroyed and
the resulting mixture was ®ltered through a pad of celite.
The resulting solution was extracted with dichloromethane,
washed with water, saturated brine solution and dried
(MgSO4). The solvent was removed under reduced pressure
to yield the diol 7 (0.12 g, 62%) as colourless rods, mp
1988C (from dichloromethane); [Found: C, 62.1; H, 5.4;
N, 4.0. C18H18ClNO4 requires C, 62.2; H, 5.2; N, 4.0%];
nmax 3437m, 3341br, 1599w, 1331w, 1211w, 1086w,
812w cm21; lmax 226 (e 27,300), 278 nm (17,700); dH
2-(30-(400-Chlorophenyl)-40,60-dimethoxyindol-20-yl)-2-
hydroxyethanamide (3d). The hydroxyethanamide 3d was
synthesised according to the method for compound 3a using
glyoxylamide 1d (0.58 g, 1.62 mmol), methanol (25 ml) and
excess sodium borohydride. After column chromatography
(5% methanol/chloroform) this yielded the hydroxyethana-
mide 3d (0.47 g, 80%) as a white solid, mp 118±1208C;
[Found: C, 59.9; H, 5.2; N, 7.3. C18H17ClN2O4 requires C,
59.9; H, 4.8; N, 7.8%]; nmax 3441w, 3341w, 1694m, 1215w,

D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
8521
1154m, 1047w cm21; lmax 223 (e 28,300), 273 (17,500),
364 nm (750); dH (d6-DMSO) 3.75, 3.86 (6H, 2s, OMe),
4.95 (1H, s, CHOH), 6.26, 6.62 (2H, 2d, Jˆ2.0 Hz, H50,
H70), 6.35, 7.47, 7.62 (3H, 3br, CONH2, OH), 7.49, 7.68
(4H, 2d, Jˆ8.2 Hz, aryl), 11.14 (1H, br, NH); dC (d6-
DMSO) 54.4, 54.7 (OMe), 65.8 (alkyl CH), 86.8 (C50),
91.0 (C70), 126.3, 132.0 (aryl CH), 109.6, 112.9, 129.8,
130.1, 133.8, 137.0, 153.5, 156.3 (aryl C), 173.3 (carbonyl
C); m/z 360 (M, 10%), 316 (10), 236 (20).
OMe), 4.61 (1H, br, OH), 5.12 (1H, br, CH), 6.23, 6.46 (2H,
2d, Jˆ1.7 Hz, H50, H70), 7.41, 7.53 (4H, 2d, Jˆ8.4 Hz,
aryl), 8.54 (1H, br, NH); dC (CDCl3) 23.7, 25.7 (CH2),
45.3, 46.6 (NCH2), 55.0, 55.5 (OMe), 64.7 (alkyl CH),
86.7 (C50), 92.3 (C70), 127.7, 132.2 (aryl CH), 110.6,
116.7, 128.6, 130.7, 133.4, 137.8, 154.9, 158.1 (aryl C),
170.0 (carbonyl C); m/z 416 (M37Cl, 10%), 414 (M35Cl,
35%), 318 (80), 316 (100), 301 (20), 281 (30).
N,N-Dimethyl-2-(30-(400-chlorophenyl)-40,60-dimethoxy-
indol-70-yl)-2-hydroxyethanamide (4e). The hydroxy-
ethanamide 4e was synthesised according to the method
for compound 3a using the following quantities: glyoxyl-
amide 2e (1.21 g, 3.13 mmol), methanol (25 ml) and excess
sodium borohydride. After column chromatography (2.5%
methanol/chloroform) this yielded the hydroxyethanamide
4e (1.06 g, 87%) as a white solid, mp 213±2148C, which
could not be obtained analytically pure; nmax 3440br,
3370br, 1635, 1590s, 1100m, 840m, 800m cm21; lmax 231
(e 24,500), 284 (13,300), 302 nm (11,100); dH (CDCl3)
2.93, 3.03 (6H, 2s, NMe), 3.86, 4.00 (6H, 2s, OMe), 4.40
(1H, d, Jˆ5.1 Hz, OH), 6.10 (1H, d, Jˆ5.1 Hz, CH), 6.34
(1H, s, H50), 7.02 (1H, d, Jˆ2.0 Hz, H20), 7.34, 7.52 (4H,
2d, Jˆ8.2 Hz, aryl), 9.21 (1H, br, NH); dC (CDCl3) 36.6,
37.0 (NMe), 55.8, 58.1 (OMe), 64.0 (alkyl CH), 89.1 (C50),
122.6 (C20), 128.3, 131.3 (aryl CH), 102.5, 112.1, 117.7,
132.1, 135.2, 137.3, 154.3, 155.8 (aryl C), 174.9 (carbonyl
C); m/z 390 (M37Cl, 5%), 388 (M35Cl, 10%), 318 (40), 316
(100), 251 (30); HRMS (ES): (M1Na)1, found 411.1063.
C20H21ClN2O41Na requires 411.1087.
2-(30-(400-Chlorophenyl)-40,60-dimethoxyindol-70-yl)-2-
hydroxyethanamide (4d). The hydroxyethanamide 4d was
synthesised according to the method for compound 3a using
glyoxylamide 2d (0.46 g, 1.28 mmol), methanol (20 ml) and
excess sodium borohydride. After column chromatography
(5% methanol/chloroform) this yielded the hydroxyethana-
mide 4d (0.38 g, 82%) as a white solid, mp 2318C; [Found:
C, 59.6; H, 4.9; N, 7.5. C18H17ClN2O4 requires C, 59.9; H,
4.8; N, 7.8%)]; nmax 3430m, 3200br, 1670s, 1620m, 1075m,
790m cm21; lmax 230 (e26,100), 278 nm (18,100); dH
(CDCl3) 3.87, 4.05 (6H, 2s, OMe), 4.21 (1H, d, Jˆ2.0 Hz,
OH), 5.44, 6.42 (2H, 2br, CONH2), 5.84 (1H, d, Jˆ2.0 Hz,
CH), 6.38 (1H, s, H50), 7.07 (1H, d, Jˆ2.6 Hz, H20), 7.35,
7.53 (2H, 2d, Jˆ5.1 Hz, aryl), 9.32 (1H, br, NH); dC (d6-
DMSO) 54.7, 57.1 (OMe), 65.9 (alkyl CH), 89.4 (C50),
122.3 (C20), 126.9, 130.1 (aryl CH), 105.2, 109.9, 114.7,
129.2, 134.8, 135.9, 152.9, 152.9 (aryl C), 174.1 (carbonyl
C); m/z 362 (M37Cl, 5%), 360 (M35Cl, 20%), 318 (15), 316
(40), 251 (25), 178 (25).
N,N-Dimethyl-2-(30-(400-chlorophenyl)-40,60-dimethoxy-
indol-20-yl)-2-hydroxyethanamide (3e). The hydroxy-
ethanamide 3e was synthesised according to the method
for compound 3a using the following quantities: glyoxyl-
amide 1e (0.60 g, 1.55 mmol), methanol (20 ml) and excess
sodium borohydride. After column chromatography (2.5%
methanol/chloroform) this yielded the hydroxyethanamide
3e (0.53 g, 88%) as colourless crystals, mp 210±2128C;
[Found: C, 61.8; H, 5.7; N, 6.7. C20H21ClN2O4 requires C,
61.8; H, 5.4; N, 7.2%]; nmax 3432br, 3191br, 1645s, 1206m,
1154m, 1071m, 835w cm21; dH (d6-DMSO) 2.57, 2.87 (6H,
2s, NMe), 3.73, 3.84 (6H, 2s, OMe), 5.25 (1H, s, CHOH),
5.5 (1H, br, OH), 6.25, 6.66 (2H, 2d, Jˆ1.9 Hz, H50, H70),
7.53±7.46 (4H, m, aryl), 10.8 (1H, br, NH); dC (d6-DMSO)
35.5 (NMe), 54.9, 55.2 (OMe), 63.2 (CH), 87.4 (C50), 91.7
(C70), 127.1, 132.2 (aryl CH), 110.0, 113.3, 130.5, 130.8,
134.0, 137.6, 154.1, 156.9 (aryl C), 170.3 (carbonyl C); m/z
390 (M37Cl, 5%) 388 (M35Cl, 15%), 318 (30), 316 (100),
281 (15).
2-(30-(400-chlorophenyl)-40,60-dimethoxyindol-70-yl)-2-
hydroxyethano-1-pyrrolidide (4f). The hydroxyethana-
mide 4f was synthesised according to the method for
compound 3a using the following quantities: glyoxylamide
2f (0.77 g, 1.86 mmol), methanol (20 ml) and excess
sodium borohydride. After column chromatography (2.5%
methanol/chloroform) this yielded the hydroxyethanamide
4f (0.66 g, 85%) as a white solid, mp 201±2028C, which
could not be obtained analytically pure; nmax 3430m,
3270br, 1740w, 1635s, 1600s, 1150m, 990m cm21; lmax
228 (e 78,900), 280 nm (45,100); dH (CDCl3) 1.64±1.70,
2.95±3.16, 3.42±3.65 (8H, 3m, CH2), 3.91, 4.04 (6H, 2s,
OMe), 4.91 (1H, d, Jˆ6.2 Hz, CHOH), 5.99 (1H, d,
Jˆ4.6 Hz, CHOH), 6.34 (1H, s, H50), 7.02 (1H, d,
Jˆ2.0 Hz, H20), 7.32±7.42 (4H, m, aryl), 9.36 (1H, br,
N); m/z 416 (M37Cl, 5%); 414 (M35Cl, 15%), 318 (40),
316 (100); HRMS (ES): (M1Na)1, found 437.1220.
C22H23ClN2O41Na requires 437.1238.
2-(30-(400-Chlorophenyl)-40,60-dimethoxyindol-20-yl)-2-
hydroxyethano-1-pyrrolidide (3f). The hydroxyethana-
mide 3f was synthesised according to the method for
compound 3a using the following quantities: glyoxylamide
1f (0.64 g, 1.55 mmol), methanol (15 ml) and excess
sodium borohydride. After column chromatography (2.5%
methanol/chloroform) this yielded the hydroxyethanamide
3f (0.59 g, 91%) as a white solid, mp 198±1998C; [Found:
C, 63.3; H, 5.9; N, 6.4. C22H23ClN2O4 requires C, 63.7; H,
3-(40-Chlorophenyl)-C-methylcarboxamidocalix[3]indole
[8a(fpcone)]. The 20-indolylalcohol 3a (1.44 g, 3.84 mmol)
was dissolved in tetrahydrofuran (70 ml) and concentrated
hydrochloric acid (approximately 1 ml) was added drop-
wise. The solution was allowed to stir for 1.5 h at room
temperature. Water was added and the mixture was
extracted with ethyl acetate. The organic layer was washed
with water, saturated brine solution and dried (MgSO4). The
solvent was removed under reduced pressure and the result-
ing solid was puri®ed using gravity column chromatography
(2.5% methanol/dichloromethane) to yield the calix[3]-
indole 8a(fpcone) (0.62 g, 45%) as colourless crystals, mp
2458C (from acetone); [Found: C, 64.1; H, 5.1; N, 7.5.
5.6; N, 6.8%]; nmax 3280br, 1630s, 1590m, 1150m cm21
;
lmax 223 (e 27,100), 241 (19,500), 276 (11,700), 300 nm
(7,800); dH (CDCl3) 1.72±1.82, 2.68±2.73, 2.85±2.92,
3.38±3.45, 3.50±3.58 (8H, 5m, CH2), 3.75, 3.85 (6H, 2s,

8522
D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
C57H51Cl3N6O9 requires C, 63.8; H, 4.8; N, 7.8%]; nmax
3420w, 3287w, 1657m, 1597m, 1215w, 1092w cm21
[8c(fpcone)] and C-t-butylcarboxamido-3-(40-chloro-
phenyl)calix[3]indole [8c(cone)]. The 20-t-butylhydroxy-
ethanamide 3c (1.86 g, 4.46 mmol) was dissolved in
chloroform (100 ml) and brought to re¯ux. Concentrated
hydrochloric acid (1 ml) was added rapidly to the re¯uxing
solution. The solution was immediately cooled and water
was added and the mixture was extracted with dichloro-
methane. The organic layer was washed with water and
dried (MgSO4). The solvent was removed under reduced
pressure. The resulting solid was puri®ed using gravity
column chromatography (40% ethyl acetate/n-hexane) to
give an overall yield of macrocyclic compounds of 71%.
The second band obtained from the column yielded calix[3]-
indole 8c(fpcone) (0.80 g, 45%) (which contained an
approximately 8% contamination of tetrameric macrocycle)
as a white solid, mp 220±2218C; [Found: C, 66.3; H, 6.1; N,
6.8. C66H69Cl3N6O9 requires C, 66.3; H, 5.8; N, 7.0%)]; nmax
3400br, 1670m, 1590m, 1205m, 1145m cm21; lmax 228 (e
90,000), 289 nm (33,600); dH (CDCl3) 0.99, 1.07, 1.23 (9H,
3s, Me), 3.50, 3.67, 3.70, 3.71, 3.77, 3.89 (18H, 6s, OMe),
5.29, 5.48, 6.10 (3H, 3s, CH), 5.26, 5.77, 6.12 (3H, 3s,
CONH), 6.14, 6.17, 6.42 (3H, 3s, H5), 7.04±7.61 (12H,
m, aryl), 8.84, 10.03, 11.30 (3H, 3s, NH); dC (CDCl3)
28.6, 28.8, 29.4 (CMe3), 40.2, 42.9, 43.2 (CMe3), 51.8,
52.1, 52.1, 55.9, 55.9, 55.9, 56.9, 57.2, 58.5 (OMe), 89.1,
89.1, 90.9 (C5), 127.4, 127.8, 128.4, 132.5, 132.8, 132.8
(aryl CH), 101.7, 101.9, 104.3, 113.2, 113.5, 113.8, 114.6,
115.3, 116.7, 131.4, 131.5, 131.8, 133.2, 133.2, 135.2,
135.5, 135.7, 136.0, 136.3, 137.1, 153.2, 153.5, 154.2,
154.3, 155.0, 155.2 (aryl C), 169.9, 171.5, 171.8 (carbonyl
C); m/z 1195 (M11, 80%).
;
lmax 228 (e 88,600), 282 nm (39,800); dH (d6-DMSO)
2.40, 2.45, 2.64 (9H, 3d, Jˆ4.1 Hz, NMe), 3.43, 3.69,
3.73, 3.84, 3.86, 3.95 (18H, 6s, OMe), 5.31, 5.65, 5.82
(3H, 3s, CH), 6.31, 6.49, 6.68 (3H, 3s, H5), 7.14±7.55
(12H, m, aryl), 7.93, 8.13, 8.45 (3H, 3d, Jˆ4.4 Hz,
CONH), 8.99, 10.61, 11.09 (3H, 3br, NH); dH (CDCl3)
2.41, 2.57, 2.73 (9H, 3d, Jˆ4.7 Hz, NMe), 3.43, 3.67,
3.68, 3.75, 3.78, 3.90 (18H, 6s, OMe), 5.35, 5.57, 5.90
(3H, 3s, CH), 5.52, 5.88, 6.06 (3H, 3d, Jˆ4.7 Hz;
CONH), 6.12, 6.21, 6.42 (3H, 3s, H5), 7.02±7.51 (12H,
m, aryl), 8.93, 9.64, 11.07 (3H, 3br, NH); dC (d6-DMSO)
25.1, 25.3, 25.5 (NMe), 37.5, 40.4, 41.2 (alkyl CH), 54.6,
54.6, 55.0, 55.6, 56.4, 57.1 (OMe), 88.4, 89.0, 90.3 (C5),
99.7, 100.8, 103.5 (C7), 126.2, 126.3, 126.3, 131.5, 131.9,
132.2br (aryl CH), 110.9, 111.3, 111.7, 112.6, 112.7, 113.5,
129.7, 129.8, 129.8, 130.3, 130.5, 130.8, 133.7, 133.7,
134.2, 134.3, 134.9, 135.9, 151.5, 151.5, 152.2, 152.3,
153.4, 153.5 (aryl C), 170.3, 171.0, 171.2 (carbonyl C);
m/z 1069 (M1H 35Cl, 55%), 1011 (50).
3-(40-Chlorophenyl)-C-methylcarboxamidocalix[3]indole
[8a(cone)]. The 20-glyoxylamide 1a (0.14 g, 0.38 mmol)
was dissolved in methanol and excess sodium borohydride
was added and the mixture allowed to stir for 30 min.
Concentrated hydrochloric acid was added cautiously until
hydrogen evolution ceased and then excess hydrochloric
acid was added (approx. 1 ml) and the solution was allowed
to stir for 1 h. The resulting precipitate was ®ltered off and
water was added to the ®ltrate, which was extracted with
dichloromethane. The organic layer was washed with water
and dried (MgSO4). The solvent was removed under
reduced pressure to yield a precipitate, which was dried
and partially characterised as the calix[3]indole 8a(cone)
(0.03 g, 22%) as a cream solid, mp.2858C; dH (CDCl3)
2.95 (9H, br, NMe), 3.34, 3.54 (18H, 2s, OMe), 5.88 (3H,
s, CH), 6.02 (3H, s, H5), 6.70±7.50 (12H, br, aryl), 8.50
(3H, bs, CONH), 11.75 (3H, s, NH); m/z 1091 (M1Na,
60%), 1069 (M1H,), 1012 (55); HRMS (ES): (M1K)1,
The ®rst band obtained from the column of the above reac-
tion product yielded calix[3]indole 8c(cone) (0.30 g, 17%)
as a white solid, mp 2158C; [Found: C, 66.1; H, 6.0; N, 6.8.
C66H69Cl3N6O9 requires C, 66.3; H, 5.8; N, 7.0%]; nmax
3420br, 3320br, 1670m, 1615m, 1595m, 1510m,
1210m cm21; lmax 229 (e 99,500), 277 (44,400), 309 nm
(28,300); dH (CDCl3) 1.14 (9H, s, Me), 3.35, 3.56 (18H, 2s,
OMe), 5.71 (3H, s, CONH), 5.77 (3H, s, CH), 6.03 (3H, s,
H5), 7.00±7.40 (12H, br, aryl), 11.38 (3H, s, NH); dC
(CDCl3) 29.4 (CMe3), 40.2 (alkyl CH), 52.5 (CMe3), 56.0,
56.4 (OMe), 88.5 (C5), 127.6, 133.2 (aryl CH), 103.5,
114.1, 114.8, 132.0, 132.8, 136.0, 136.7, 152.7, 153.9
(aryl C), 172.0 (carbonyl C); m/z 1195 (M11, 70%), 1126
(30), 1095 (40).
found
1107.2404.
C57H51Cl3N6O91K
requires
1107.2414;); HRMS (ES): (M1K)1, found 1107.2404.
C57H51Cl3N6O91K requires 1107.2414.
C-n-Butylcarboxamido-3-(40-chlorophenyl)calix[3]indole
[8b(fpcone)]. The 20-glyoxylamide 1b (0.20 g, 0.48 mmol)
was dissolved in methanol and excess sodium borohydride
was added and the mixture allowed to stir for 30 min.
Concentrated hydrochloric acid was added cautiously until
hydrogen evolution ceased and then excess hydrochloric
acid was added (approx. 1 ml) and the solution was allowed
to stir for 1 h. Water was then added and the mixture was
extracted with ethyl acetate. The organic layer was washed
with water, saturated brine solution and dried (MgSO4). The
solvent was removed under reduced pressure to yield crude
calix[3]indole 8b(fpcone) (0.18 g, 33%) as a green solid; dH
(CDCl3) 0.72±1.35 (21H, m, CH2, Me), 2.72±3.27 (6H, m,
CH2), 3.50, 3.68, 3.68, 3.72, 3.79, 3.91 (18H, 6s, OMe),
5.36, 5.55, 5.94 (3H, 3s, CH), 5.42, 5.79, 6.04 (3H, 3t,
Jˆ5.04 Hz, CONH), 6.13, 6.18, 6.40 (3H, 3s, H5), 7.04±
7.55 (12H, m, aryl), 8.94, 9.70, 11.06 (3H, 3s, NH).
Conversion of the calix[3]indole 8c(cone) to the calix[3]-
indole [8c(fpcone)]. The calix[3]indole 8c(cone) (0.20 g,
0.17 mmol) (90) was dissolved in a mixture of methanol
and sodium methoxide. The solution was brought to re¯ux
and allowed to stir for 1 h. Water was then added and the
resulting mixture was extracted with ethyl acetate. The
organic phase was washed with water, saturated brine solu-
tion and dried (MgSO4). The solvent was removed under
reduced pressure to yield calix[3]indole 8c(fpcone) (0.17 g,
86%).
3-(40-Chlorophenyl)-C-carboxamidocalix[3]indole [8d-
(fpcone)]. The 70-hydroxyethanamide 4d (0.34 g,
0.95 mmol) was partially dissolved in tetrahydrofuran and
concentrated hydrochloric acid (6 drops) was added. The
solution was allowed to stir at room temperature for 1 h.
C-t-Butylcarboxamido-3-(40-chlorophenyl)calix[3]indole

D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
8523
Water was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and dried
(MgSO4). The solvent was removed under reduced pressure
to yield calix[3]indole 8d(fpcone) (0.05 g, 16%); dH (d6-
DMSO) 3.38, 3.69, 3.74, 3.84, 3.86, 3.99 (18H, 6s, OMe),
5.32, 5.65, 5.94 (3H, 3s, CH), 6.31, 6.48, 6.64 (3H, 3s, H5),
6.86, 6.97, 7.97 (3H, 3br, CONH), 7.09, 7.12, 8.41 (3H, 3s,
CONH), 9.09, 10.80, 11.10 (3H, 3s, NH).
hydroxide was added until a strong red colour was evident.
Iodomethane (0.20 ml, 2.96 mmol) was added and the
mixture was stirred for 1 h. Water was then added and the
resulting precipitate ®ltered, washed with water and dried
under reduced pressure to yield the glyoxylamide 10
(0.40 g, 75%), as a yellow solid, mp 1938C, which could
not be obtained analytically pure; dH (CDCl3) 2.43, 2.75
(6H, 2s, CONMe), 3.60 (3H, s, NMe), 3.95, 4.10 (6H, 2s,
OMe), 6.13, 6.37 (2H, 2d, Jˆ1.8 Hz, H50, H70), 7.34 (4H, s,
aryl); dC (d6-DMSO) 32.1, 32.2 (CONMe), 36.0 (NMe),
54.8, 55.1 (OMe), 84.3 (C50), 93.0 (C70), 125.7, 132.0
(aryl CH), 110.8, 126.8, 127.1, 131.6, 131.6, 141.1, 155.7,
160.8 (aryl C), 164.9, 183.2 (carbonyl C); m/z 402 (M37Cl,
5%), 400 (M35Cl, 20%), 330 (10), 328 (40), 293 (60););
3-(40-Chlorophenyl)-C-dimethylcarboxamidocalix[3]in-
dole [8e(fpcone)]. The 20-indolyldimethylhydroxyethana-
mide 3e (0.50 g, 1.29 mmol) was partially dissolved in
methanol and concentrated hydrochloric acid (6 drops)
was added. The solution was allowed to stir at room
temperature for 1 h. The precipitate was ®ltered off and
water was added to the ®ltrate and the mixture was extracted
with dichloromethane. The organic layer was washed with
water and dried (MgSO4). The solvent was removed under
reduced pressure to yield calix[3]indole 8e(fpcone) (0.20 g,
42%) as colourless needles, mp 2488C (from ethanol/light
petroleum); [Found: C, 63.9; H, 5.4; N, 7.0.
C60H57Cl3N6O9´H2O requires C, 63.8; H, 5.3; N, 7.4%];
nmax 3420br, 3200br, 1630m, 1610m, 1590m, 1205m,
990w cm21; lmax 227 (e 108,900), 291 nm (38,600); dH
(CDCl3) 2.62, 2.71, 2.75, 2.78, 2.85 (18H, 6s, NMe), 3.37,
3.64, 3.67, 3.73, 3.77, 3.90 (18H, 6s, OMe), 5.69, 6.06, 6.08
(3H, 3s, CH), 6.19, 6.27, 6.45 (3H, 3s, H5), 7.10±7.45 (12H,
m, aryl), 9.10, 9.90, 10.94 (3H, 3br, NH); m/z 1111 (M11,
45%), 1040 (M, 100).
HRMS
C21H21ClN2O41Na requires 423.1082.
(ES):
(M1Na)1,
found
423.1031.
N,N-Dimethyl-2-(30-(400-chlorophenyl)-40,60-dimethoxy-
10-methylndol-20-yl)-2-hydroxyethanamide (11). The
hydroxyethanamide 11 was synthesised according to the
method for compound 3a using the following quantities:
glyoxylamide 10 (0.30 g, 0.75 mmol), methanol (20 ml)
and excess sodium borohydride. After column chromato-
graphy (5% methanol/chloroform) this yielded the hydro-
xyethanamide 11 (0.21 g, 70%) as a white solid, which
could not be obtained analytically pure; dH (CDCl3) 2.44,
2.93 (6H, 2s, CONMe), 3.68, 3.73 (6H, 2s, OMe), 3.92 (3H,
s, NMe), 4.85 (1H, d, Jˆ3.1 Hz, OH), 5.19 (1H, d,
Jˆ3.6 Hz, CH), 6.25, 6.41 (2H, 2d, Jˆ2.1 Hz, H50, H70),
7.40, 7.47 (4H, 2d, Jˆ8.7 Hz, aryl); m/z 404 (M37Cl, 5%),
402 (M35Cl, 15%), 332 (30), 330 (100), 295 (20);); HRMS
(ES): (M1Na)1, found 425.1211. C21H23ClN2O41Na
requires 425.1238.
C-Carboxypyrrolidido-3-(40-chlorophenyl)calix[3]indole
[8f(fpcone)]. The 20-indolylhydroxypyrrolidide 3f (1.05 g,
2.54 mmol) was dissolved in dichloromethane (30 ml) and
concentrated hydrochloric acid (1 ml) was added dropwise
and stirred at room temperature for 15 min. Water was
added and the mixture was extracted with dichloromethane.
The organic layer was washed with water and dried
(MgSO4). The solvent was removed under reduced pressure
and the crude product was puri®ed using a plug of silica gel
and eluting with chloroform to yield calix[3]indole
8f(fpcone) (0.59 g, 58 %) as a cream solid, mp.2908C;
[Found: C, 65.7; H, 5.6; N, 6.8. C66H63Cl3N6O9´H2O
requires C, 65.6; H, 5.4; N, 7.0%]; nmax 3420br, 3250br,
1645m, 1595m, 1340m, 1210m, 1150m cm21; lmax 228 (e
83,200), 286 nm (34,300); dH (CDCl3) 1.65±1.80 (12H, m,
CH2), 2.92±3.47 (12H, m, CH2), 3.32, 3.59, 3.61, 3.67, 3.73,
3.86 (18H, 6s, OMe), 5.50, 5.89, 6.02 (3H, 3s, CH), 6.08,
6.15, 6.43 (3H, 3s, H5), 7.09, 7.37 (12H, 2dd, Jˆ8.2 Hz,
aryl), 9.09, 10.07, 11.12 (3H, 3s, NH); dC (CDCl3) 24.8,
24.8, 25.0, 26.5, 26.6, 26.7 (CH2), 37.0, 39.4, 41.6 (alkyl
CH), 46.3, 46.7, 46.9, 46.9, 47.0, 47.4 (NCH2), 56.0, 56.1,
56.7, 57.1, 57.8, 58.4 (OMe), 89.3, 89.8, 91.2 (C5), 127.5,
127.7, 132.8, 133.1 (aryl CH), 99.8, 100.9, 105.2, 112.6,
113.5, 113.7, 114.9, 115.2, 116.3, 131.1, 131.9, 132.0,
132.2, 132.5, 132.8, 134.7, 135.6, 136.3, 136.4, 136.9,
138.1, 152.9, 153.2, 154.0, 154.7, 155.3 (aryl C), 170.4,
170.6, 171.2 (carbonyl C); m/z 1189 (M1H, 80%), 1122
(30), 1092 (45).
C-Carboxypyrrolidido-3-methylcalix[3]indole [15a(cone)].
The glyoxylpyrrolidide 13a (40 mg, 0.13 mmol) was
partially dissolved in methanol (15 ml) and excess sodium
borohydride was added. The solution was allowed to stir at
room temperature for 30 min. Concentrated hydrochloric
acid was then added until hydrogen evolution ceased and
additional acid (5 drops) was added. The solution was then
allowed to stir for an additional 30 min. Water was added
and the solution was extracted with ethyl acetate. The
organic layer was washed with water, saturated brine solu-
tion and dried (MgSO4). The resulting crude solid was puri-
®ed using radial chromatography (chloroform, then 0.5%
methanol/chloroform). The ®rst band yielded the calix[3]-
indole 15a(cone) (12 mg, 10%) which could not be obtained
analytically pure; dH (CDCl3) 1.70±2.00 (12H, m, CH2),
2.42, (9H s, Me), 3.40±3.90 (12H, m, CH2), 3.83, 3.95
(18H, 2s, OMe), 6.19 (3H, s, CH), 6.25 (3H, s, H5), 11.57
(3H, s, NH); m/z 934 (M11, 70%).
C-t-Butylcarboxamido-3-methylcalix[3]indole [15b(cone)]
and C-t-butylcarboxamido-3-methylcalix[3]indole [15b-
(fpcone)]. The t-butylglyoxylamide 13b (0.50 g, 1.57
mmol) was partially dissolved in methanol and excess
sodium borohydride was added and the mixture was stirred
at room temperature for 15 min. Concentrated hydrochloric
acid was added until hydrogen evolution ceased and then
a slight excess of acid was added (4 drops). The solution
was allowed to stir at room temperature for 30 min. Water
was then added and the mixture was extracted with
N,N-Dimethyl-2-(30-(400-chlorophenyl)-40,60-dimethoxy-
10-methylindol-20-yl)glyoxylamide (10). The 20-indolyl-
glyoxylamide 1e (0.50 g, 1.34 mmol) was dissolved in
dimethylsulfoxide (20 ml) and excess crushed potassium

8524
D. StC. Black et al. / Tetrahedron 56 (2000) 8513±8524
dichloromethane. The organic layer was washed with water
and dried (MgSO4). The crude material was puri®ed using
gravity column chromatography (40% ethyl acetate/light
petroleum). The faster moving band yielded the calix[3]-
indole 15b(cone) (0.34 g, 24%) as a white solid, mp
1988C; [Found: C, 66.8; H, 7.6; N, 8.7. C51H66N6O9´H2O
requires C, 66.2; H, 7.2; N, 9.1%]; dH (CDCl3) 1.42 (27H,
s, CMe3), 3.83, 3.96 (18H, 2s, OMe), 5.74 (3H, br, CONH),
5.80 (3H, s, CH), 6.19 (3H, s, H5), 10.94 (3H, br, NH); dC
(CDCl3) 11.2 (Me), 29.3 (CMe3), 40.4 (CMe3), 52.1 (alkyl
CH), 6.1, 57.9 (OMe), 88.7 (C5), 108.9, 131.7, 136.6, 152.3,
154.5 (aryl C), 172.1 (carbonyl C); m/z 908 (M11, 65%),
838 (60), 808 (100).
References
1. Black, D. StC.; Craig, D. C.; Kumar, N. J. Chem. Soc., Chem.
Commun. 1989, 425±426.
2. Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R.
J. Chem. Soc., Chem. Commun. 1993, 819±821.
3. Black, D. StC.; Craig, D. C.; Kumar, N. Aust. J. Chem. 1996,
49, 311±318.
4. Gutsche, C. D. Calixarenes, The Royal Society of Chemistry:
Cambridge, 1989.
5. Andreetti, G. D.; Ungaro, R.; Pochini, A. J. Chem. Soc., Chem.
Commun. 1979, 1005±1007.
6. Black, D. StC.; Craig, D. C.; Kumar, N.; McConnell, D. B.
Tetrahedron Lett. 1996, 37, 241±244.
The second band from the column yielded the calix[3]indole
15b(fpcone) (0.35 g, 25%) as a white solid, mp 176±1778C;
[Found: C, 67.2; H, 7.5; N, 8.9. C51H66N6O9 requires C,
67.5; H, 7.3; N, 9.3%]; dH (CDCl3) 0.95, 1.14, 1.40 (27H,
3s, CMe3), 3.85, 3.86, 3.88, 3.90, 3.93, 4.00 (18H, 6s, OMe),
5.17, 6.11, 6.25 (3H, 3br, CONH), 5.51, 5.56, 5.70 (3H, 3s,
CH), 6.22, 6.27, 6.35 (3H, 3s, H5; 8.18, 8.66, 10.37 (3H, 3s,
NH); m/z 906 (M11, 95%), 807 (100).
7. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron
1996, 52, 8925±8936.
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36, 8075±8078.
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J. A.; Sherman, J. C.; Helgeson, R. C.; Knobler, C. B.; Cram, D. J.
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Soc. 1988, 110, 634±635.
11. Tanaka, Y.; Kato, Y.; Aoyama, Y. J. Am. Chem. Soc. 1990,
112, 2807±2808.
Acknowledgements
We thank the Australian Research Council for ®nancial
support.