Synthesis and utilisation of 2,7′-diindolylmethanes and a 2-(2-indolyl)pyrrolylmethane as macrocyclic precursors

Article abstract of DOI:10.1016/j.tet.2005.08.075

Treatment of 3-(4-chlorophenyl)-7-hydroxymethyl-4,6-dimethoxyindole with 3-(4-chlorophenyl)-4,6-dimethoxyindole results in the generation of two geometrically isomeric diindolylmethanes in addition to a novel triindolyl oligomer, which has been structurally characterised. The 2,7′- diindolylmethanes were found to be unstable under Vilsmeier formylation conditions, thus hampering macrocyle precursor construction. In an alternate approach, the 3-(4-chlorophenyl)-4,6-dimethoxyindole-7-carbaldehyde was converted into the indolyl-pyrrolyl macrocycle precursor 5-(3-(4-chlorophenyl)- 4,6-dimethoxyindole-2-ylmethyl)-4-ethyl-3-methylpyrrole-2,7-dicarbaldehyde, which was used to generate an unsymmetrical pentaaza macrocycle.

Full text of DOI:10.1016/j.tet.2005.08.075

Tetrahedron 61 (2005) 10781–10792
Synthesis and utilisation of 2,70-diindolylmethanes and a
2-(2-indolyl)pyrrolylmethane as macrocyclic precursors
b,
b
Paul K. Bowyer,a, David StC. Black and Donald C. Craig
*
*
aSchool of Agriculture and Wine, The University of Adelaide, Waite Campus, Glen Osmond SA 5064, Australia
bSchool of Chemistry, The University of New South Wales, UNSW Sydney NSW 2052, Australia
Received 9 February 2005; revised 1 August 2005; accepted 18 August 2005
Available online 19 September 2005
Abstract—Treatment of 3-(4-chlorophenyl)-7-hydroxymethyl-4,6-dimethoxyindole with 3-(4-chlorophenyl)-4,6-dimethoxyindole results
in the generation of two geometrically isomeric diindolylmethanes in addition to a novel triindolyl oligomer, which has been structurally
characterised. The 2,70-diindolylmethanes were found to be unstable under Vilsmeier formylation conditions, thus hampering macrocyle
precursor construction. In an alternate approach, the 3-(4-chlorophenyl)-4,6-dimethoxyindole-7-carbaldehyde was converted into the
indolyl-pyrrolyl macrocycle precursor 5-(3-(4-chlorophenyl)-4,6-dimethoxyindole-2-ylmethyl)-4-ethyl-3-methylpyrrole-2,7-dicarbalde-
hyde, which was used to generate an unsymmetrical pentaaza macrocycle.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
further allow the investigation of the chemical and physical
properties of metal complexes incorporating the indole unit.
We have been interested in the non-template synthesis of
indole-containing ligands for some time,1–4 and have
recently reported our latest results.5 We now report some
results relating to the generation of precursors of macro-
cyclic imines based on the 2,70-diindolylmethane and
2-(2-indolyl)pyrrole structures. Such diarylmethanes are
usually constructed by the reaction of electron-rich arenes
with formaldehyde, or by the acid-catalysed addition of an
arene to a benzylic alcohol, the latter being the initial
intermediate in the addition of an arene to formaldehyde.
The most effective route to the indolylmethanols proceeds
via the reduction of indole-carbaldehydes.
It has been shown previously7 that reduction of the
7-carbaldehyde functionality to the corresponding methyl
alcohol, followed by treatment with acid, promotes the
nucleophilic attack of existing unsubstituted indole sites on
the carbocation so generated. Such a procedure may also
give rise to trimeric cyclic and tetrameric oligomeric species
if self-condensation occurs.7
It has been observed that the nucleophilic attack of a 3-(4-
halophenyl)-4,6-dimethoxyindole on an indolyl-7-methanol
occurs primarily via position 2-to produce a 2,70-linked
diindolylmethane.7 A second isomer, the 7,70-linked
diindolylmethane, was also observed, although in much
lower yield. The latter would generate an eight-membered
bisanionic coordination sphere on coordination and was
thus, eliminated from this study.
2. Results and discussion
2.1. Diindolylmethane ligand systems
Treatment of the aldehyde 2, derived from highly
substituted indole 1,5 with an excess of sodium borohydride
in tetrahydrofuran affords the corresponding 7-methanol 3
(Scheme 1). This alcohol was found to be particularly
sensitive to acidic environments, presumably due to the
promotion of self-condensation reactions. Similarly, the
reaction of indole 1 with an excess of Vilsmeier reagent at
elevated temperature followed by basic work-up afforded a
good yield of the diformyl species 4, which can be
converted to 5 in the same manner (Scheme 1).
The first strategy has already been used to generate the
symmetrical 2,20-diiindolylmethane system.6 The construc-
tion of an unsymmetrical diindolylmethane would permit
the development of a series of macrocycles that would no
longer have a symmetrical coordination field. This would
Keywords: Indole; Diindolylmethane; Vilsmeier; Macrocycle.
*
Corresponding authors. Tel.: C61 8 83037239; fax: C61 8 83037116
(P.K.B.); tel.: C61 2 9385 4657; fax: C 61 2 9385 6141 (D.Stc.B);
e-mail addresses: paul.bowyer@adelaide.edu.au; d.black@unsw.edu.au
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.075

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P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
Scheme 1. Reagents and conditions: (i) POCl3, DMF, 0 8C; (ii) NaOH, H2O; (iii) NaBH4, THF, D; (iv) H2O; (v) POCl3, DMF, 50 8C.
Scheme 2. Reagents and conditions: (i) HOAc, D.
Reaction of 1 with 3 (Scheme 2) in boiling glacial acetic
acid gave three products: unsymmetrical 2,70-diindolyl-
methane 6 (separated from co-incident 1 after extensive
chromatography) and the 7,70-diindolylmethane 7. The third
product gave a mass spectral base peak that indicated the
The trimer (Fig. 1) crystallises in the monoclinic space group
P21/c and is a 2,7-disubstituted indole, where the substituent
indoles are pendant from the central indole via the two
methylene linkages. There are two distinct trimers (A and B)
within the unit cell with slightly differing structural parameters,
as indicated in Table 1. The tetrahedral nature of the linkages
enables the molecule to adopt a partial box configuration
(Fig. 2). An edge-to-face arene–arene interaction8 is apparent
within the lattice between the edge of a chlorophenyl moiety of
the central indole of one molecule and the face of a terminal 7,7-
linked indole of the adjacent molecule (median distance
1
presence of three chlorine atoms at m/z 885–891 and H
NMR data indicated a trimeric oligomer with two
inequivalent methylene groups, containing both 2,7- and
7,7-indolyl linkages. X-ray quality crystals of oligomer 8
were obtained such that an unambiguous structural assign-
ment could be made.

P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
10783
Figure 3. Partial unit cell diagram of 8, showing a tilted T-shaped edge-to-
face arene interaction. Hydrogen atoms have been removed and the
illustrated portions of different molecules have been shaded for clarity.
˚
HC29AKC4B/C5BZ2.800 A, Fig. 3). The centroid-to-cen-
˚
troid distance of 5.267 A is consistent with theoretical
calculations for such tilted T-shaped interactions.8 Selected
bond lengths and angles for 8 are given in Table 1;
crystallographic data are given in Table 2.
Figure 1. ORTEP view of trimer 8, showing atom-labelling scheme for
non-hydrogen atoms and the adopted partial box conformation. Thermal
ellipsoids enclose 10% probability levels.
Table 2. Crystallographic data for 8
Formula
C50H42Cl3N3O6
M
887.3
Monoclinic
P21/c
21.259(6)
19.554(3)
23.289(6)
90
116.75(1)
90
8645(4)
8
23.85
˚
Table 1. Selected bond lengths (A) and angles (8) for 8
Crystal system
Space group
a/A
b/A
˚
c/A
Trimer A
Trimer B
˚
˚
Pendant indole interplanar angle
2,7- Linkage angle
7,7-Linkage angle
O2-HN2
11.08
116.04
110.56
1.982
27.99
115.03
112.84
1.904
a/8
b/8
g/8
u/A
Z
O4-HN1
2.075
2.180
3
˚
mCu Ka/cmK1
T/K
294
No. of reflections
(total)
(unique)
Rint
R, Rw
8865
5021
0.014
0.064, 0.092
Two possible mechanisms exist for the formation of such an
oligomer, outlined in Scheme 3. Mechanism A is possible
but unlikely, as unsubstituted dimethoxyindoles have been
observed in previous studies to attack benzylic alcohols
preferentially via the C2 position.7 Mechanism B involves
the synthesis of the initial target 2,7-diindolylmethane
precursor 6, which then attacks another 7-hydroxymethyl-
indole to form 8. The slow addition of an excess of the
7-hydroxymethylindole 3 to the reaction mixture affords
initially the 2,7-diindolylmethane 6, but continued addition
results in its total consumption and almost total isolation of
the oligomer 8, suggesting that mechanism B is favoured.
Interestingly, the amount of 7,7-diindolylmethane 7 is also
observed to increase under these conditions, indicating that
it is the product of self-condensation of 7-hydroxymethyl-
indole 3.
Figure 2. Partial molecular structure of 8, showing the orientation of
pendant indole substituents in substructure B. Hydrogen atoms have been
removed for clarity.
It was envisaged that reaction of the trimeric oligomer 8
with 1 equiv of a 2,7-dihydroxymethylindole 5 could lead to

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P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
Scheme 5. Reagents and conditions: (i) 1.5 equiv POCl3, DMF, 20 8C;
(ii) NaOH, H2O.
products from 6. Procedural variations failed to yield further
10, as did alternative formylation reactions (data not
shown). Since a reliable method of securing macrocyclic
precursor 10 could not be found, a different approach to the
synthesis of unsymmetrical macrocycles was warranted.
A higher yield of an analogue of the unsymmetrical
macrocyclic precursor 6 was obtained by using the highly
activated indole 129 to produce 13 in addition to the two
other products 14 and 15 (Scheme 6) in addition to 7. The
observation of 7, 14 and 15 (trace amounts only; data not
shown) supports the hypotheses that 7,70-diindolylmethanes
form through self-condensation of hydroxymethyl species,
and that mechanism B (Scheme 3) is favoured for the
formation of indolyl trimers of this type. Formylation of 13
gave the monoformyl derivative 16 in good yield, but
consistently failed to produce the target diformyl species,
which parallels the synthetic difficulties associated with the
Scheme 3. Reagents and conditions: (i) as in Scheme 2.
the synthesis of a tetrameric box-type structure, however,
only polymeric material was obtained.
Vilsmeier formylation of 6 at K15 8C afforded mono- and
diformyl products: 9 was isolated in a yield of 75% whilst
the desired diformyl product 10 was obtained in a yield of
only 5% (Scheme 4).
1
synthesis of 10. The methylene resonance in the H NMR
spectrum of 16 (d 4.21) shows moderate deshielding
compared with the equivalent resonance in 9 (d 4.16),
indicating a difference in electron density about the
respective sp3 centres.
Clearly, electronic activity between the indole moieties of 6
and 13 prohibits diformylation under a range of conditions,
requiring an alternative method of generating unsym-
metrical ligand systems.
2.2. Indolylpyrrolylmethane ligand systems
It was initially envisaged that the employment of
established methods of annular linkage would permit the
synthesis of the desired 2- and 7-indolyl-pyrrole systems.
However, the product of condensation between 3 and
pyrrole was known to be highly unstable.10 Clearly, the
system required electronic deactivation and a simple way of
effecting this was to introduce an electron-withdrawing
formyl group to the already deactivated 3-halophenylindole
molecule. The poor availability of the 2-formyl analogue
of 26 reduced the possibility of synthesising the 7-(2-
pyrrolyl)indole structure in good yield. Further electronic
stability was obtained by using pyrrole carboxylic ester 17.
Scheme 4. Reagents and conditions: (i) POCl3, DMF, K15 8C; (ii) NaOH,
H2O.
Clearly the relative nucleophilicities of the 20- and
7-positions of 6 are very different, with 7-formylation
preceding 20-formylation as noted previously.5 The reaction
was investigated further, as 10 was not obtained quanti-
tatively. When 6 was reacted with a slight excess of the
Vilsmeier reagent at room temperature, work-up afforded
only a trace of 10 and a large amounts of dialdehyde 4 and
2,20-diindolylmethane-7,70-dicarbaldehyde6 11 (Scheme 5)
as identified by structural elucidation and comparison with
authentic samples. It is believed that 10 is produced initially
but rapidly decomposes into 4 and 11 via splitting of the
diindolyl bridge and subsequent reaction with breakdown
Thus, 2 and 1711 were combined to afford the indolyl-
pyrrole ester intermediate 18, which was treated with
trifluoroacetic acid followed by an excess of triethylortho-
formate12 to give 19 (Scheme 7).

P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
10785
Scheme 6. Reagents and conditions: (i) as in Scheme 2; (ii) POCl3, DMF, 0 8C; (iii) NaOH, H2O.
yield the highly insoluble orange-brown complex 22
(Scheme 8), which gave a molecular ion corresponding to
the NiL mass unit.
Scheme 7. Reagents and conditions: (i) K10 clay, N2, CH2Cl2; (ii) N2, TFA,
TEOF.
2.3. Formation of macrocycles and metal complexes
Dialdehyde 10 and 1,2-diaminobenzene could not be
condensed into a macrocycle using a standardised pro-
cedure,5 presumably due to spatial incompatibility, how-
ever, 10 reacted with 2,20-diaminodiphenylamine 2013 to
yield the unsymmetrical macrocycle 21 (Scheme 8). The
bridging NH resonance at d 7.94 (Fig. 4) is markedly
deshielded with respect to the field position of the bridging
NH proton in the corresponding symmetrical 2,20-linked
system6 (d 6.85), reflecting the vastly different electronic
environments in the geometric isomers. It is also an
indication that the 2,7-methylene linkage is likely to behave
significantly differently from the symmetrical 2,20-diindolyl
linkage during chemical manipulation, and supports the
synthetic difficulties experienced during formylation
reactions.
Scheme 8. Reagents and conditions: (i) C6H6, D, N2; (ii) Ni(OAc)2$4H2O,
CH3CN, Et3N, D.
Ligand 21 was reacted with nickel(II) acetate tetrahydrate to

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P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
Figure 4. 1H NMR spectrum (300 MHz; CDCl3) of 21, illustrating the unsymmetrical nature of the ligand.
Bisaldehyde 19 also failed to react with 1,2-diaminobenzene
yet reacted with 20 to produce macrocycle 23 (Scheme 9).
It is believed that the relatively low yield (42%) is a
consequence of some strain in this rather unusual ligand,
given that imine formation is an equilibrium process.
Ligand 23 was treated with nickel(II) acetate tetrahydrate to
afford red crystals of complex 24 (Scheme 9).
The presence of the nickel atom was confirmed by the mass
spectral molecular ion corresponding to the 35Cl MK1
isotopomer. The bridging amino group appears not to be
involved in metal chelation due to the presence of a strong
IR absorption at 3468 cmK1, as noted in previous studies.5
Both the colours of the complexes (for example, from
previous studies5 lmax(square-planar)Z517 nm with
moderately intense red-brown colouration; lmax(tetra-
hedral)Z398 nm with highly intense dark brown colour-
ation) and the 1H NMR spectrum of complex 24 (only in the
specific case of a square-planar Ni(II) complex is a
diamagnetic spectrum obtained; other geometries generate
paramagnetic spectra) indicate the presence of square-
planar nickel.5
The reaction of 10 and 19 with larger diamino spacers
resulted in the formation of polymeric materials only,
indicating that these diformyl species are subject to very
strict spatial compatibility limitations.
3. Conclusion
The acid-catalysed reaction of nucleophilic indoles with
Scheme 9. Reagents and conditions: (i) and (ii) as in Scheme 8.

P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
10787
hydroxymethylindoles leads to diindolylmethanes in a
rather unselective manner. Unfavourable electronic inter-
actions between indole groups in these unsymmetrical
species made formylation exceedingly difficult, resulting in
molecular decomposition. A viable alternative synthetic
route to an asymmetric pentaazamacrocycle was developed
via an indolylpyrrolylmethane. The macrocycles formed
from these precursors were found to coordinate nickel(II) to
yield square-planar neutral complexes.
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: C144 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
4.3. Preparation of diindolylmethanes
4.3.1.
3-(4-Chlorophenyl)-7-hydroxymethyl-4,6-
dimethoxyindole (3). The 7-formylindole 25 (1.00 g,
3.17 mmol) was dissolved in anhydrous THF with stirring,
sodium borohydride (excess) was added and the mixture
heated at reflux under a nitrogen atmosphere for 12 h. The
colourless mixture was cooled to room temperature and the
excess borohydride quenched by the slow addition of water
(10 mL). THF was then removed under reduced pressure
and the resulting solid filtered and washed with water
(100 mL) to afford title compound 3 (0.099 g, 98%) as white
microcrystals, mp 186–188 8C. (Found: C 64.6, H 5.4, N
4.1. C17H16ClNO3 requires C 64.3, H 5.1, N 4.4) nmax
(KBr)/cmK1 3437, 2994, 2951, 2836, 1622, 1599, 1566,
1553, 1518, 1498, 1464, 1451, 1429, 1397, 1346, 1331,
1310, 1275, 1252, 1206, 1173, 1144, 1109, 1092, 1017, 999,
936, 839, 816, 787, 749. lmax/nm (3/MK1 cmK1) 230
(28,600), 285 (13,500), 301 (12,000). dH(299.95 MHz;
(CD3)2CO; Me4Si) 3.85 and 3.90 (6H, s, OCH3), 5.04
(2H, d, JZ5.6 Hz, CH2), 6.31 (1H, s, indole H5), 7.06 (1H,
d, JZ2.6 Hz, indole H2), 7.31 and 7.51 (4H, dt, JZ8.2,
2.6 Hz, chlorophenyl), 8.91 (1H, s(br), NH); sample too
insoluble for dC; m/z (EI) 320 (MC1, 37Cl, 3%), 319 (M,
37Cl, 25), 318 (MC1, 35Cl, 10), 317 (M, 35Cl, 75), 299
(100).
4. Experimental
4.1. General information
Melting points are uncorrected. Microanalyses were
performed by Dr. Pham of The University of New South
Wales or the Microanalysis Unit of the Australian National
University, Canberra. 1H and 13C NMR spectra were
obtained in the designated solvents on a Bruker AC300F
(300 MHz) spectrometer. Chemical shifts are quoted as d
values in CDCl3 relative to internal Me4Si unless otherwise
stated; chemical shift measured in parts per million (ppm),
proton count, multiplicity, observed coupling constant (J) in
Hertz (Hz). Multiplicities are reported as singlet (s), broad
singlet (s(br)), doublet (d), triplet (t), quartet (q) and
multiplet (m). 13C NMR chemical shifts are reported in ppm
downfield from TMS (d) and identifiable carbons are given.
Infrared spectra were recorded as KBr discs on a Mattson
Sirius 100 FTIR spectrometer. Ultraviolet–visible spectra
were recorded in acetonitrile on a Hitachi UV-3200
spectrophotometer. EI mass spectra were recorded on an
AEI MS 12 mass spectrometer at 70 eV ionising potential
and 8000 V accelerating voltage with an ion source
temperature of 210 8C. MALDI-TOF mass spectra were
recorded on a Finnigan MAT Lasermat 2000. The principal
ion peaks m/z are reported together with their percentage
intensities relative to the base peak. Flash chromatography
4.3.2. 3-(4-Chlorophenyl)-4,6-dimethoxyindole-2,7-
dicarbaldehyde (4). To a stirred solution of 1 (3.00 g,
10.5 mmol) in anhydrous DMF at 0 8C was added dropwise
an ice-cold solution of phosphoryl chloride (excess) in DMF
(3 mL). The mixture was stirred at this temperature for 1 h,
then heated to 50 8C for 1 h. When no starting material
remained (TLC) water followed by 2 M NaOH was added
until a basic solution resulted. The solution was extracted
with chloroform (3!150 mL) and the combined extracts
washed with water until neutral rinsings were obtained. The
organic layer was collected, dried (MgSO4) and concen-
trated to afford title compound 4 (2.53 g, 70%) as yellow
needles, mp 250–252 8C. (Found: C 63.1, H 4.4, N 3.9.
C18H14ClNO4 requires C 62.9, H 4.1, N 4.1) nmax (KBr)/
cmK1 3420, 2971, 2851, 1645, 1591, 1566, 1534, 1515,
1478, 1452, 1431, 1400, 1377, 1353, 1335, 1235, 1219,
was carried out using Merck silica gel 7730 60GF254
.
Anhydrous tetrahydrofuran (THF) was distilled from
potassium and benzophenone; N,N-dimethylformamide
(DMF) was dried over calcium hydride then distilled
˚
under reduced pressure onto activated 4A molecular sieves;
chloroform (CHCl3) was distilled from phosphorus pent-
oxide; diethyl ether was distilled from sodium and
benzophenone. 3-(4-Chlorophenyl)-4,6-dimethoxyindole
1,9 3-(4-chlorophenyl)-4,6-dimethoxyindole-7-carbalde-
hyde 2,5 2,20-diaminodiphenylamine 20,13 and pyrrolylester
1711 were prepared according to the literature procedures, or
obtained from previous studies (116). 1,2-Diaminobenzene
was obtained commercially and purified before use. 14 and
15 were structurally confirmed by NMR and MS but not
otherwise characterised.
1161, 1121, 1092, 990, 862, 797, 735, 637, 610, 557. lmax
/
nm (3/MK1 cmK1) 226 (19,500), 254 (24,200), 306
(16,700), 349 (22,100), 366 (18,600). dH(299.95 MHz;
CDCl3; Me4Si) 3.87 and 4.02 (6H, s, OCH3), 6.17 (1H, s,
indole H5), 7.39 and 7.44 (4H, d, JZ8.7 Hz, chlorophenyl),
9.54 (1H, s, indole 2-CHO), 10.36 (1H, s, indole 7-CHO),
10.92 (1H, s(br), NH); dC(75.42 MHz; CDCl3) 55.68 and
56.47 (2C, OCH3), 87.57, 127.80 and 132.49 (5C, aryl CH),
104.03, 111.70, 128.31, 130.41, 132.15, 134.10, 138.09,
163.17 and 166.15 (9C, aryl C), 180.96 (1C, indole 2-CHO),
187.77 (1C, indole 7-CHO); m/z (EI) 346 (MC1, 35/37Cl,
5%), 345 (M, 35/37Cl, 35), 344 (MC1, 35/35Cl, 25), 343 (M,
35/35Cl, 100), 342 (MK1, 35/35Cl, 20).
4.2. Crystallography
The data were collected on a Nonius CAD-4 instrument.
Crystallographic data are summarised in Table 2. Crystallo-
graphic data (excluding structure factors) for the structure in
this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 181655. Copies of the data can be obtained,
4.3.3. 3-(4-Chlorophenyl)-2,7-dihydroxymethyl-4,6-
dimethoxyindole (5). The 2,7-diformylindole 4 (0.500 g,

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P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
1.45 mmol) was dissolved in anhydrous THF and reacted
with sodium borohydride according to the method of
preparation of compound 3 to afford title compound 5
(0.479 g, 95%) as white microcrystals, mp 208–210 8C.
(Found: C 60.9, H 5.1, N 3.6. C18H18ClNO4 requires C 60.6,
H 5.4, N 3.9) nmax (KBr)/cmK1 3362, 3229, 3003, 2959,
2938, 2907, 2841, 1624, 1601, 1568, 1551, 1524, 1495,
1466, 1451, 1433, 1397, 1368, 1346, 1289, 1263, 1215,
1181, 1157, 1123, 1105, 1092, 1057, 1024, 1009, 986, 909,
845, 822, 791, 766, 745, 716. lmax/nm (3/MK1 cmK1) 214
(26,700), 230 (36,200), 284 (14,200), 300 (12,100).
dH(299.95 MHz; CDCl3; Me4Si) 3.74 and 3.90, (6H, s,
OCH3), 4.72 and 5.02 (4H, s(br), CH2), 6.26 (1H, s, indole
H5), 7.34 (4H, s, chlorophenyl), 9.08 (1H, s(br), NH);
sample too insoluble for dC; m/z (EI) 350 (MC1, 37Cl, 8%),
349 (M, 37Cl, 35), 348 (MC1, 35Cl, 20), 347 (M, 35Cl, 100),
328 (50), 300 (45).
title compound 7 (0.017 g, 9%) as white plates, mp 219–
220 8C. (Found: C 67.3, H 5.0, N 4.6. C33H28Cl2N2O4
requires C 67.5, H 4.8, N 4.8) nmax (KBr)/cmK1 3345, 2996,
2957, 2938, 2837, 1622, 1595, 1564, 1537, 1520, 1487,
1462, 1451, 1431, 1408, 1396, 1364, 1333, 1295, 1217,
1202, 1157, 1123, 1111, 1090, 1040, 1012, 990, 947, 862,
835, 793, 729. lmax/nm (3/MK1 cmK1) 230 (67,300), 270
(25,200), 296 (33,000). dH(299.95 MHz; CDCl3; Me4Si)
3.79 and 4.18 (12H, s, OCH3), 4.30 (2H, s, CH2), 6.39 (2H,
d, JZ2.0 Hz, indole H2), 7.29 and 7.45 (8H, dt, JZ8.7,
2.6 Hz, chlorophenyl), 9.93 (2H, s(br), NH); dC(75.42 MHz;
CDCl3) 18.76 (1C, CH2), 55.39 and 59.02 (4C, OCH3),
90.30 (2C, indole C5), 105.10, 111.37, 117.58, 131.33,
134.79 and 138.12 (12C, aryl C), 122.01 (2C, indole C2),
127.63 and 130.65 (8C, chlorophenyl CH), 151.61 and
153.33 (4C, C-OCH3); m/z (EI) 591 (M, 37/37Cl, 1%), 590
(MC1, 35/37Cl, 2), 589 (M, 35/37Cl, 3), 588 (MC1, 35/35Cl,
15), 587 (M, 35/35Cl, 8), 586 (MK1, 35/35Cl, 18), 300 (75),
287 (100), 237 (65).
4.3.4. 3-(4-Chlorophenyl)-4,6-dimethoxy-2-(3-(4-chloro-
phenyl)-4,6-dimethoxyindol-7-ylmethyl)indole (6), 7,70-
di(3-(40-chlorophenyl)-4,6-dimethoxyindolyl)methane
(7) and 3-(4-chlorophenyl)-4,6-dimethoxy-2,7-di[3-(4-
chlorophenyl)-4,6-dimethoxyindol-7-ylmethyl]indole
(8). 3-(4-Chlorophenyl)-4,6-dimethoxyindole 1 (0.090 g,
0.32 mmol) was dissolved in the minimum amount of hot
glacial acetic acid and added rapidly to solid 3 (0.100 g,
0.315 mmol) under a nitrogen atmosphere and the reaction
monitored by TLC. After 10 min no further reaction was
observed and water (10 mL) was added. The mixture was
extracted with dichloromethane (3!50 mL), the organic
layer washed with water to neutrality, collected, dried
(MgSO4) and the solvent removed. Three products were
obtained using preparative TLC.
(iii) The second uppermost band (Rf 0.7 in 70:30
dichloromethane/n-hexane), colouring olive green on
exposure to iodine vapour, gave title compound 8
(0.003 g, 2%) as colourless needles, mp 159–161 8C.
(Found: C 66.2, H 5.1, N 4.5. C50H42Cl3N3O6 requires C
66.3, H 4.9, N 4.6) nmax (KBr)/cmK1 3434, 3372, 3308,
2996, 2938, 2837, 1622, 1597, 1562, 1514, 1522, 1489,
1464, 1427, 1398, 1335, 1273, 1215, 1155, 1109, 1013, 995,
945, 839, 791, 735. lmax/nm (3/MK1 cmK1) 233 (98300),
286 (46000), 302 (44300). dH(299.95 MHz; CDCl3; Me4Si)
3.55, 3.63, 3.71, 3.87 and 3.99 (15H, s, OCH3), 4.14 (5H, s,
OCH3 C2,7-CH2), 4.31 (2H, s, 7,7-CH2), 6.00, 6.35 and
6.44 (3H, s, indole H5), 6.61 and 7.03 (2H, d, JZ2.6,
2.1 Hz, indole H2), 7.36 (13H, m, chlorophenyl C NH),
9.74 and 9.87 (2H, s(br), NH); dC(75.42 MHz; CDCl3)
18.61 (1C, 7,7-CH2), 21.63 (1C, 2,2-CH2), 55.12, 57.61,
57.83 and 59.09 (4C, OCH3), 55.41 (2C, OCH3), 89.75 (2C,
indole C5), 90.45 (1C, indole C5), 101.89, 104.63, 105.19,
110.92, 112.70, 113.27, 117.07, 117.50, 131.29, 131.40,
131.80, 132.97, 134.39, 134.53, 134.82, 136.69 and 138.03
(19C, aryl C), 121.79 and 121.89 (2C, indole C2), 127.62
(6C, chlorophenyl CH), 130.55, 130.60 and 132.34 (6C,
chlorophenyl CH), 151.31, 151.51, 152.69, 153.05, 153.50
and 154.05 (6C, C-OCH3); m/z (EI) 891 (MC1, 35/37/37Cl,
1%), 890 (M, 35/37/37Cl, 2), 889 (MC1, 35/35/37Cl, 3), 888
(M, 35/35/37Cl, 4), 887 (MC1, 35/35/35Cl, 5), 886 (M,
35/35/35Cl, 4), 885 (MK1, 35/35/35Cl, 5), 300 (100), 84 (65),
44 (85).
(i) The third uppermost band (Rf 0.6 in 70:30 dichloro-
methane/n-hexane), colouring green on exposure to iodine
vapour, gave title compound 6 (0.061 g, 33%) as colourless
plates, mp 279–280 8C. (Found: C 67.6, H 5.1, N 4.6.
C33H28Cl2N2O4 requires C 67.5, H 4.8, N 4.8) nmax (KBr)/
cmK1 3428, 3349, 3003, 2932, 2839, 1624, 1595, 1564,
1549, 1514, 1489, 1464, 1451, 1337, 1308. 1211, 1163,
1144, 1128, 1117, 1090, 1051, 1013, 993, 966, 837, 824,
808, 789. lmax/nm (3/MK1 cmK1) 232 (59,600), 378
(27,500), 301 (24,800). dH(299.95 MHz; CDCl3; Me4Si)
3.73, 3.78, 3.84 and 4.05 (12H, s, OCH3), 4.21 (2H, s, CH2),
6.20 (1H, d, JZ2.0 Hz, indole H5), 6.37 (1H, d, JZ1.6 Hz,
indole H7), 6.39 (1H, s, indole H5), 6.72 (1H, d, JZ2.6 Hz,
indole H2), 7.19 (1H, br d, JZ2.0 Hz, NH), 7.29 and 7.44
(4H, dt, JZ8.7, 2.6 Hz, chlorophenyl), 7.48 and 7.50 (4H,
dt, JZ8.7, 2.0 Hz, chlorophenyl), 8.33 (1H, s(br), NH);
dC(75.42 MHz; CDCl3) 20.87 (1C, CH2), 55.03, 55.31,
55.57 and 57.36 (4C, OCH3), 86.70 and 89.30 (2C, indole
C5), 92.00 (1C, indole C7), 102.50, 110.69, 111.13, 112.32,
117.66, 131.46, 131.98, 132.54, 136.89 and 137.43 (12C,
aryl C), 121.56 (1C, indole C2), 127.59, 127.85, 130.57 and
132.39 (8C, chlorophenyl CH), 153.19, 153.39, 154.19 and
157.25 (4C, C-OCH3); m/z 591 (M, 37/37Cl, 2%), 590 (MC
1, 35/37Cl, 3), 589 (M, 35/37Cl, 4), 588 (MC1, 35/35Cl, 16),
587 (M, 35/35Cl, 8), 586 (MK1, 35/35Cl, 20), 585 (M-2,
35/35Cl, 2), 303 (6), 302 (33), 300 (100), 287 (50).
4.3.5. 3-(4-Chlorophenyl)-4,6-dimethoxy-2-(3-(4-chloro-
phenyl)-4,6-dimethoxy-indol-7-ylmethyl)indole-7-carb-
aldehyde (9) and 3-(4-chlorophenyl)-4,6-dimethoxy-2-(3-
(4-chlorophenyl)-4,6-dimethoxy-indol-7-ylmethyl)-
indole-2,7-dicarbaldehyde (10). To a stirred solution of 6
(0.030 g, 0.051 mmol) in anhydrous DMF at K15 8C was
added dropwise an ice cold solution of phosphoryl chloride
(1 mL) in DMF (3 mL) and the mixture stirred for 30 min,
then allowed to come to room temperature. Water (5 mL)
was added and the mixture stirred for 1 h, made alkaline
(pH 8) with 10% sodium hydroxide solution and stirred
overnight. The mixture was extracted with dichloromethane
(3!50 mL) and the organic layer washed to neutrality with
water. The organic layer was collected, dried (MgSO4), the
(ii) The highest-Rf band (Rf 0.8 in 70:30 dichloromethane/
n-hexane), colouring red on exposure to iodine vapour, gave

P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
10789
solvent removed and the crude product purified by
preparative TLC (3 exposures in 50:50 dichloromethane/
n-hexane eluent) to afford two bands.
hydroxide solution and stirred overnight. The mixture was
extracted with dichloromethane (3!50 mL) and the organic
layer washed to neutrality with water. The organic layer was
collected, dried (MgSO4), the solvent removed and the
crude mixture purified by preparative TLC (3 exposures in
50:50 dichloromethane/n-hexane eluent) to afford two
bands. The uppermost band (Rf 0.5 in dichloromethane)
was identified as 10, whilst the lower band (Rf 0.3)
colouring blue on exposure to iodine vapour was identified
as a mixture of coincident 4 (0.007 g, 39%) and the title
compound 11 (0.007 g, 22%), mp 299–301 8C. (Found: C
65.1, H 4.5, N 4.1. C35H28Cl2N2O6 requires C 65.3, H 4.4, N
4.4) nmax (KBr)/cmK1 3399, 3333, 2938, 2847, 1704, 1645,
1598, 1564, 1510, 1489, 1464, 1435, 1394, 1368, 1355,
1325, 1294, 1246, 1219, 1162, 1119, 1089, 1060, 1017,
988, 934, 850, 821, 795, 745, 720, 600, 566, 544. lmax/nm
(3/MK1 cmK1) 225 (41,100), 255 (54,000), 320 (24,500),
356 (19,000). dH(299.95 MHz; CDCl3; Me4Si) 3.77 and
3.90 (12H, s, OCH3), 4.06 (2H, s, CH2), 6.07 (2H, s, indole
H5), 7.29 (8H, s, chlorophenyl), 10.06 (2H, s(br), NH),
10.23 (2H, s, CHO); dC(75.42 MHz; CDCl3) 23.39 (1C,
CH2), 55.38 and 56.41 (4C, OCH3), 86.88, (2C, indole C5),
127.73 and 132.13 (8C, aryl CH), 104.28, 111.53, 114.05,
130.54, 132.26, 133.29 and 136.44 (18C, aryl C), 160.80
and 162.73 (4C, C-OCH3), 188.21 (2C, CHO); m/z 585
(MC1, 37Cl, 2%), 584 (M, 37Cl, 4), 583 (MC1, 35Cl, 4),
582 (M, 35Cl, 10), 283 (100).
(i) The higher Rf band gave title compound 9 (0.024 g, 75%)
as yellow plates, mp 228–230 8C. (Found: C 66.6, H 4.8, N
4.3. C34H28Cl2N2O5 requires C 66.4, H 4.6, N 4.6) nmax
(KBr)/cmK1 3414, 3351, 2994, 2959, 2932, 2839, 1632,
1593, 1564, 1547, 1537, 1520, 1489, 1464, 1451, 1433,
1397, 1368, 1352, 1339, 1325, 1309, 1252, 1211, 1190,
1157, 1121, 1092, 1013, 993, 937, 831, 822, 797, 735. lmax
/
nm (3/MK1 cmK1) 208 (39,600), 224 (36,400), 244
(30,700), 286 (15,200), 306 (15,600), 358 (6450).
dH(299.95 MHz; CDCl3; Me4Si) 3.79, 3.80, 3.93 and 4.17
(12H, s, OCH3), 4.16 (2H, s, CH2), 6.08 and 6.37 (2H, s, 2!
indole H5), 6.69 (1H, d, JZ2.6 Hz, indole H2), 6.94 (1H,
s(br), NH), 7.26 and 7.41 (4H, dt, JZ8.7, 2.6 Hz,
chlorophenyl), 7.42 and 7.48 (4H, d, JZ8.7 Hz, chloro-
phenyl), 10.34 (1H, s, CHO), 10.78 (1H, s(br), NH);
dC(75.42 MHz; CDCl3) 20.80 (1C, CH2), 55.34 (2C,
OCH3), 56.35 and 56.66 (2C, OCH3), 86.55 and 88.70
(2C, indole C5), 101.92, 104.34, 110.32, 111.04, 111.73,
117.86, 131.44, 134.40, 134.67, 136.30 and 137.29 (14C,
aryl C), 153.29 (1C, C-C]O), 121.22 (1C, indole C2),
127.59, 128.05, 130.56 and 132.40 (8C, chlorophenyl CH),
160.41 and 162.46 (2C, C-OCH3), 188.17 (1C, CHO); m/z
619 (M, 37/37Cl, 3%), 618 (MC1, 35/37Cl, 6), 617 (M,
35/37Cl, 10), 616 (MC1, 35/35Cl, 30), 615 (M, 35/35Cl, 20),
614 (MK1, 35/35Cl, 37), 300 (70), 299 (100).
4.3.7. 3-(4-Methoxyphenyl)-4,6-dimethoxy-2-(3-(4-chloro-
phenyl)-4,6-dimethoxyindol-7-ylmethyl)indole (13). The
reaction of 4,6-dimethoxy-3-(4-methoxyphenyl)indole 12
(0.256 g, 0.944 mmol) and 3-(4-chlorophenyl)-4,6-
dimethoxy-7-hydroxymethylindole 3 (0.200 g, 0.629 mmol),
as described for the reaction of compounds 1 and 3, gave
after thin-layer chromatography (Rf 0.4 in 70:30 dichloro-
methane/n-hexane), colouring dark green on exposure to
iodine vapour, a white solid, which was washed with glacial
acetic acid (5 mL), water (10 mL) then dried to afford
title compound 13 (0.250 g, 68%) as colourless micro-
crystals, mp 199–200 8C. (Found: C 68.0, H 5.7, N 4.4.
C34H31ClN2O5$H2O requires C 67.9, H 5.5, N 4.7) nmax
(KBr)/cmK1 3403, 2996, 2957, 2934, 2837, 1624, 1595,
1559, 1518, 1505, 1489, 1464, 1435, 1420, 1335, 1295,
1287, 1242, 1215, 1200, 1179, 1149, 1120, 1098, 1047,
(ii) The lower band colouring turquoise on exposure to
iodine vapour gave title compound 10 (0.002 g, 5%) as
yellow plates, mp 280–282 8C (dec). (Found: C 65.4, H 4.6,
N 4.2. C35H28Cl2N2O6 requires C 65.3, H 4.4, N 4.4) nmax
(KBr)/cmK1 3408, 3262, 2969, 2939, 2876, 2845, 1678,
1655, 1647, 1636, 1618, 1593, 1561, 1551, 1539, 1525,
1514, 1503, 1489, 1464, 1451, 1435, 1398, 1368, 1354,
1331, 1279, 1254, 1223, 1192, 1179, 1157, 1117, 1092,
1059, 999, 841, 822, 801. lmax/nm (3/MK1 cmK1) 262
(33,200), 325 (17,700), 361 (13,900). dH(299.95 MHz;
CDCl3; Me4Si) 3.74, 3.80, 3.94 and 4.17 (12H, s, OCH3),
4.14 (2H, s, CH2), 6.09 and 6.32 (2H, s, 2!indole H5), 7.35
and 7.36 (4H, s, chlorophenyl), 7.42 and 7.49 (4H, dt, JZ
8.7, 2.1 Hz, chlorophenyl), 8.03 (1H, s(br), NH), 9.38 (1H,
s, indole 2-CHO), 10.32 (1H, s, indole 7-CHO), 10.64 (1H,
s(br), NH); dC(75.42 MHz; CDCl3) 20.71 (1C, CH2), 55.23,
55.39, 56.38 and 56.61 (4C, OCH3), 86.61 and 88.99 (2C,
indole C5), 101.35, 104.28, 111.22, 112.30, 112.70, 128.75,
130.88, 131.50, 132.89, 133.54, 133.65, 133.68, 136.31 and
138.07 (14C, aryl C), 127.55, 127.82, 132.16 and 132.50
(8C, chlorophenyl CH), 155.91, 157.29, 160.72 and 162.62
(4C, C-OCH3), 180.72 (1C, 2-CHO), 188.24 (1C, 7-CHO);
m/z 645 (M, 35/37Cl, 1%), 644 (MC1, 35/37Cl, 4), 643 (M,
35/35Cl, 2), 642 (MK1, 35/35Cl, 5), 279 (100).
1032, 1015, 995, 949, 924, 835, 797. lmax/nm (3/MK1 cmK1
)
216 (56,300), 231 (66,200), 250 (27,000), 259 (23,000), 275
(27,600), 296 (25,000). dH(299.95 MHz; CDCl3; Me4Si)
3.71, 3.79, 3.83, 3.93, and 4.05 (15H, s, OCH3), 4.22 (2H, s,
CH2), 6.19 (1H, d, JZ2.0 Hz, indole H5), 6.37 (1H, s,
indole H5), 6.38 (1H, d, JZ2.1 Hz, indole H7), 6.89 (1H, d,
JZ2.6 Hz, indole H2), 7.09 and 7.53 (4H, d, JZ8.7 Hz,
methoxyphenyl), 7.20 (1H, s(br), NH), 7.29 and 7.44 (4H, d,
JZ8.7 Hz, chlorophenyl), 8.29 (1H, s(br), NH);
dC(75.42 MHz; CDCl3) 20.76 (1C, CH2), 55.17 (2C,
OCH3), 55.35, 55.60 and 57.40 (3C, OCH3), 86.70 and
89.29, 2 (2C, indole C5), 91.87 (1C, indole C7), 103.09,
110.65, 112.91, 117.47, 128.39, 131.39, 132.35, 134.47,
136.89 and 137.50 (11C, aryl C), 113.30 and 132.19 (4C,
methoxyphenyl CH), 121.62 (1C, indole C2), 127.58 and
130.56 (4C, chlorophenyl CH), 152.93, 153.24, 154.35,
157.07 and 158.14 (5C, C-OCH3); m/z 585 (MC1, 37Cl,
2%), 584 (M, 37Cl, 4), 583 (MC1, 35Cl, 4), 582 (M, 35Cl,
10), 283 (100).
4.3.6. 2,20-Di-3-(40-chlorophenyl)-4,6-dimethoxyindolyl-
methane-7,70-dicarbaldehyde (11). To a stirred solution of
6 (0.030 g, 0.051 mmol) in anhydrous DMF at K15 8C was
added dropwise an ice cold solution of phosphoryl chloride
(0.012 g, 0.077 mmol) in DMF (1 mL) and the mixture
stirred for 30 min, then allowed to come to room
temperature. Water (5 mL) was added and the mixture
stirred for 1 h, made alkaline (pH 8) with 10% sodium

10790
P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
4.3.8. 3-(4-Methoxyphenyl)-4,6-dimethoxy-2-(3-(4-chloro-
phenyl)-4,6-dimethoxy-indol-7-ylmethyl)indole-7-carb-
aldehyde (16). To a stirred solution of the diindolylmethane
13 (0.200 g, 0.343 mmol) in anhydrous DMF at K15 8C
was added dropwise an ice-cold solution of phosphoryl
chloride (0.105 g, 0.686 mmol) in DMF (1 mL) until no
starting material remained (TLC). Water (5 mL) was added
and the mixture stirred for 1 h, then made alkaline (pH 8)
with 10% sodium hydroxide solution. The mixture was
extracted with dichloromethane (3!50 mL) and the organic
layer washed to neutrality with water. The organic layer was
collected, dried (MgSO4), the solvent removed and the
crude product purified by preparative TLC (dichloro-
methane eluent). The yellow band (Rf 0.4) gave title
compound 16 (0.147 g, 70%) as yellow plates, mp 229–
230 8C. (Found: C 68.5, H 5.4, N 4.3. C35H31ClN2O6
requires C 68.8, H 5.1, N 4.6) nmax (KBr)/cmK1 3414, 2999,
2935, 2843, 1636, 1595, 1573, 1561, 1510, 1487, 1464,
1439, 1404, 1370, 1354, 1331, 1296, 1285, 1245, 1215,
1196, 1181, 1138, 1119, 1092, 1034, 1015, 995, 831, 797.
lmax/nm (3/MK1 cmK1) 226 (48,400), 254 (38,900), 306
(18,800), 362 (9400). dH(299.95 MHz; CDCl3; Me4Si) 3.71,
3.81, 3.82 and 3.97 (12H, s, OCH3), 4.21 (5H, s, OCH3C
CH2), 5.96 and 6.41 (2H, s, 2!indole H5), 6.73 (1H, s,
indole H2), 7.13, 7.32 and 7.49 (9H, m, aryl HCNH), 10.40
(1H, s, CHO), 10.79 (1H, s(br), NH); dC(75.42 MHz;
CDCl3) 20.50 (1C, CH2), 53.36, 55.06, 55.21, 55.85 and
56.47 (5C, OCH3), 86.07 and 88.46 (2C, indole C5), 102.26,
104.00, 110.06, 111.03, 112.22, 117.45, 127.83, 131.10,
134.09, 134.41, 136.05 and 137.30 (12C, aryl C), 113.24
and 132.02 (4C, methoxyphenyl CH), 121.22 (1C, indole
C2), 127.39 and 130.37 (4C, chlorophenyl CH), 153.01 (2C,
C-OCH3), 158.19, 160.39 and 162.11 (3C, C-OCH3),
187.81 (1C, CHO); m/z 614 (MC1, 37Cl, 3%), 613
(M, 37Cl, 5), 612 (MC1, 35Cl, 20), 611, (M, 35Cl, 20),
610 (MK1, 35Cl, 50), 324 (65), 311 (95), 299 (100).
10.33 (1H, s, CHO); dC(75.42 MHz; CDCl3) 10.50 (1C,
ethyl CH3), 15.50 (1C, CH3), 17.23 (1C, ethyl CH2), 23.19
(1C, CH2), 28.52 (3C, C(CH3)), 55.41 and 56.42 (2C,
OCH3), 80.28 (1C, CCH3), 86.92 (1C, indole C5), 127.75
and 132.00 (4C, chlorophenyl CH), 104.37, 111.43, 114.16,
119.24, 124.02, 125.92, 128.03, 130.56, 132.26, 133.37,
136.57, 160.80, 161.27 and 162.79 (14C, aryl C), 188.32
(1C, CHO); m/z 539 (MC1, 37Cl, 5%), 538 (M, 37Cl, 20),
537 (MC1, 35Cl, 15), 536 (M, 35Cl, 45), 165 (60), 57 (100).
4.4.2. 5-(3-(4-Chlorophenyl)-4,6-dimethoxyindole-2-
ylmethyl)-4-ethyl-3-methylpyrrole-2,7-dicarbaldehyde
(19). Under
a nitrogen atmosphere 18 (0.300 g,
0.559 mmol) and TFA (5 mL) were stirred together at
room temperature for 30 min, then triethylorthoformate
(2 mL) was added dropwise. The solution was stirred for a
further 45 min, water (20 mL) was added and the aqueous
solution extracted with dichloromethane (3!100 mL). The
organic layer was collected, dried (MgSO4) and the solvent
removed. The resulting solid was purified by preparative
thin-layer chromatography to afford title compound 19
(0.185 g, 71%) as colourless microcrystals, mp 217–218 8C.
(Found: C 65.6, H 5.5, N 5.8. C26H25ClN2O4$5 H2O
requires C 65.9, H 5.5, N 5.9) nmax (KBr)/cmK1 3351, 3248,
2967, 2920, 2851, 1628, 1607, 1597, 1566, 1510, 1491,
1464, 1449, 1395, 1366, 1329, 1300, 1275, 1250, 1213,
1200, 1165, 1119, 1090, 993, 874, 820, 795, 669. lmax/nm
(3/MK1 cmK1) 210 (34,000), 253 (37,700), 309 (36,000),
354 (13,300). dH(299.95 MHz; CDCl3; Me4Si) 1.00 (3H, t,
JZ7.7 Hz, CH3), 2.20 (3H, s, CH3), 2.29 (2H, q, JZ7.7 Hz,
CH2), 3.82 and 3.92 (6H, s, OCH3), 3.98 (2H, s, CH2), 6.07
(1H, s, H5), 7.31 (4H, s, chlorophenyl), 9.28 (1H, s, pyrrole
CHO), 9.79 (1H, s(br), pyrrole NH), 10.06 (1H, s, indole
CHO), 10.81 (1H, s(br), indole NH); dC(75.42 MHz;
CDCl3) 8.70 (1C, ethyl CH3), 14.96 (1C, CH3), 16.81,
(1C, ethyl CH2), 23.34 (1C, CH2), 55.32 and 56.26 (2C,
OCH3), 86.61 (1C, indole C5), 127.66 and 132.08 (2C,
chlorophenyl CH), 104.29, 111.49, 114.86, 124.51, 128.23,
129.62, 132.19, 133.52, 135.50, 136.40, 160.66 and 162.60
(12C, aryl C), 175.86 (1C, pyrrole CHO), 187.67 (1C, indole
CHO); m/z 467 (MC1, 37Cl, 5%), 466 (M, 37Cl, 30), 465
(MC1, 35Cl, 20), 464 (M, 35Cl, 85), 315 (55), 149 (100).
4.4. Preparation of indolyl-pyrrolyl systems
4.4.1.
7-Formyl-t-butyl-5-(3-(4-chlorophenyl)-4,6-
dimethoxyindol-2-ylmethyl)-4-ethyl-3-methylpyrrole-2-
carboxylate (18). Under a nitrogen atmosphere 2 (0.500 g,
1.58 mmol) and 17 were stirred rapidly together with K10
clay (1.5 g) in dichloromethane (100 mL). After approxi-
mately 5 min the product spot was observed (Rf 0.3,
CH2Cl2, colouring red in iodine vapour). The reaction was
left stirring overnight then the mixture was filtered, the
solvent removed and the residue purified chromato-
graphically (80:20 dichloromethane/n-hexane). The band
with Rf 0.2 gave title compound 18 (0.364 g, 43%) as yellow
crystals, mp 110–111 8C. (Found: C 66.9, H 6.4, N 5.1.
C30H33ClN2O5 requires C 67.1, H 6.2, N 5.2) nmax (KBr)/
cmK1 3451, 3410, 3368, 2967, 2928, 2868, 1678, 1643,
1595, 1566, 1555, 1510, 1491, 1464, 1452, 1435, 1395,
1368, 1356, 1326, 1276, 1254, 1215, 1198, 1161,
1121, 1095, 1061, 1018, 993, 822, 797, 774, 748. lmax/nm
(3/MK1 cmK1) 211 (34,600), 252 (41,200), 276 (36,800),
322 (15,400), 354 (12,300). dH(299.95 MHz; CDCl3;
Me4Si) 1.01 (3H, t, JZ7.5 Hz, CH3), 1.51 (9H, s, But),
2.23 (3H, s, CH3), 2.36 (2H, q, JZ7.5 Hz, ethyl CH2), 3.83
and 3.97 (6H, s, OCH3), 3.96 (2H, s, CH2), 6.15 (1H, s,
indole H5), 7.29 and 7.33 (4H, d, JZ8.7 Hz, chlorophenyl),
8.32 (1H, s(br), pyrrole NH), 10.25 (1H, s(br), indole NH),
4.5. Preparation of macrocycles and metal complexes
4.5.1. 4,28-Di-(4-chlorophenyl)-6,8,30,32-tetramethoxy-
11,18,25,34,35-pentaazaheptacyclo[25,5,2,2,3,90,5,360,
12,170,19,24029,33]hexatria-contane-1(32),3,5(36),6,8,10,12,
14,16,19,21,23,25,27,29(33),30-hexadecaene (21). The
bisaldehyde 10 (0.010 g, 0.016 mmol) and 2,20-diamino-
diphenylamine 20 (0.004 g, 0.02 mmol) were reacted
according to the general Schiff base procedure.5 The
solution was heated at reflux for 14 h, after which all
solvent was removed and the crude orange solid was
purified by preparative thin-layer chromatography (80:20
dichloromethane/n-hexane eluent) to afford title compound
21 (0.009 g, 72%) as orange crystals, mpO280 8C (dec).
(Found: C 69.7, H 4.6, N 8.6. C47H37Cl2N5O4 requires C
70.0, H 4.6, N 8.7) nmax (KBr)/cmK1 3435, 3370, 2955,
2929, 2843, 1620, 1591, 1568, 1555, 1512, 1495, 1464,
1452, 1433, 1414, 1381, 1360, 1346, 1325, 1271, 1254,
1211, 1171, 1144, 1099, 1011, 993, 831, 818, 795, 743.
lmax/nm (3/MK1 cmK1) 222 (40,200), 264 (38,700), 316

P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
10791
(20,700), 364 (18,600), 444 (11,800). dH(299.95 MHz;
CDCl3; Me4Si) 3.50, 3.66, 3.75 and 3.88 (12H, s, OCH3),
4.17 (2H, s(br), CH2), 6.01 and 6.14 (2H, s, 2!indole H5),
6.75 (1H, t, JZ6.7 Hz, aryl H), 6.98 and 7.19 (8H, m, aryl
HCchlorophenyl), 7.09 (1H, t, JZ8.2 Hz, aryl H), 7.37 and
7.41 (4H, d, JZ8.7 Hz, chlorophenyl), 7.51 (1H, d, JZ
7.2 Hz, aryl H), 7.56 (1H, d, JZ7.7 Hz, aryl H), 7.94 (1H, s,
bridging NH), 8.38 and 8.95 (2H, s, CH]N), 9.16 and 11.05
(2H, s(br), indole NH); dC(75.42 MHz; CDCl3) 21.56 (1C,
CH2), 55.16, 55.27, 55.58 and 56.63 (4C, OCH3), 86.82 and
87.66 (2C, indole C5), 110.51, 115.72, 119.04, 119.33,
122.39, 122.81, 123.30, 126.79, 127.57, 131.58, 132.26 and
132.5 (12C, aryl CH), 112.47, 112.90, 114.44, 116.98,
120.05, 121.21, 123.31, 125.20, 127.42, 131.37, 131.50,
132.31, 132.88, 135.08, 135.68, 138.49, 139.39, and 144.02
(18C, aryl C), 154.41, 154.91, 158.12 and 159.11 (4C,
C-OCH3), 159.00 and 159.48 (2C, CH]N); m/z (MALDI)
805 (MK1, 35/35Cl, 100%).
m, aryl H), 7.21 (1H, dd, JZ7.7, 1.3 Hz, aryl H), 7.32 and
7.37 (4H, d, JZ8.7 Hz, chlorophenyl), 7.53 (2H, t, JZ
9.0 Hz, aryl H), 7.88 (1H, s(br), pyrrole NH), 8.32 (1H, s,
pyrrole CH]N), 9.04 (1H, s, indole CH]N), 10.73 (1H,
s(br), indole NH); dC(299.95 MHz; CDCl3) 8.86 (1C, ethyl
CH3), 15.29 (1C, pyrrole CH3), 17.13 (1C, ethyl CH2),
22.79 (1C, bridging CH2), 55.33 and 56.77 (2C, OCH3),
87.97 (1C, indole C5), 102.48, 111.56, 114.53, 123.21,
125.02, 127.28, 129.95, 132.13, 133.74, 136.35, 136.57,
137.51, 138.44 and 143.97 (14C, aryl C), 111.61, 115.71,
116.49, 119.41, 120.11, 120.23, 125.72 and 125.81 (8C, aryl
CH), 127.53 and 132.30 (4C, chlorophenyl CH), 142.96
(1C, pyrrole CH]N), 158.23 and 159.67 (2C, C-OCH3),
158.78 (1C, indole CH]N); m/z (MALDI) 628 (M, 35Cl,
100%).
4.5.4. {29-(4-Chlorophenyl)-2-ethyl-25,27-dimethoxy-3-
methyl-8,15,22,30,32-pentaazacyclo[25,2,1,2,22,280,
7,12014,19]-dotriacontane-1,3,5,7,9,11,14,16,18,20,22,24,
26(32),27-tetradecaenato(2-)}nickel(II) (24). Macrocycle
23 (0.070 g, 0.11 mmol) was suspended in acetonitrile, the
mixture heated to 70 8C and triethylamine (3 drops) added.
Nickel(II) acetate tetrahydrate (0.0305 g, 0.123 mmol) was
added, resulting in an immediate colour change from yellow
to blood red. The mixture was heated for a further 1 h then
cooled to room temperature. The solution was filtered to
remove impurities, and the filtrate concentrated under
reduced pressure to afford title compound 24 (0.065 g,
85%) as red crystals, mp 300 8C (dec). (Found: C 66.6, H
4.8, N 10.0. C38H32ClN5NiO2 requires C 66.7, H 4.7, N
10.2) nmax (KBr)/cmK1 3468, 2967, 2932, 2843, 1572,
1528, 1503, 1470, 1400, 1383, 1364, 1344, 1263, 1235,
1179, 1135, 1088, 1011, 1003, 897, 847, 801, 750. lmax/nm
(3/MK1 cmK1) 228 (42,900), 276 (20,300), 296 (18,600),
316 (19,500), 461 (15,000), 562 (17,600). dH(299.95 MHz;
CDCl3; Me4Si) 1.05 (3H, t, JZ7.4 Hz, ethyl CH3), 2.23
(3H, s, CH3), 2.45 (2H, q, JZ7.4 Hz, ethyl CH2), 3.93 and
4.12 (6H, s, OCH3), 4.77 (2H, s, bridging CH2), 6.12 (1H, s,
indole H5), 6.86 and 7.13 (8H, m, aryl H), 7.28 and 7.47
(5H, m, chlorophenylCbridging NH), 8.18 (1H, s(br),
pyrrole CH]N), 8.96 (1H, s, indole CH]N); Sample too
insoluble for dC; m/z (MALDI) 683 (MK1, 35Cl, 90%).
4.5.2. {4,28-Di-(4-chlorophenyl)-6,8,30,32-tetramethoxy-
11,18,25,34,35-pentaazaheptacyclo[25,5,2,2,3,90,5,360,
12,170,19,24029,33]hexatria-contane-1(32),3,5(36),6,8,10,12,
14,16,19,21,23,25,27,29(33),30-hexadecaenato(2-)}nickel
(II) (22). The macrocycle 21 (0.005 g, 6.2!10K3 mmol)
was dissolved in the minimum amount of acetonitrile at
60 8C and triethylamine (2 drops) was added, followed by
nickel(II) acetate tetrahydrate (0.002 g, 6.8!10K3 mmol).
The orange solution was observed to darken on addition of
the salt, and was heated at 60 8C for a further 3 h. The
solution was filtered hot and the solvent removed to afford
title compound 22 (0.003 g, 50%) as orange-brown
microcrystals, mpO250 8C (dec). nmax (KBr)/cmK1 3444,
2955, 2929, 2843, 1590, 1575, 1554, 1509, 1492, 1453,
1449, 1432, 1413, 1376, 1362, 1346, 1324, 1269, 1254,
1210, 1172, 1146, 1097, 1010, 998, 836, 817, 794, 744.
lmax/nm (3/MK1 cmK1) 210 (sample too insoluble for the
calculation of extinction coefficients), 220, 261, 232, 359.
446. m/z (MALDI) 864 (MC1, 35/35Cl, 20%), 805 (M-Ni, 35/
35Cl, 70%).
4.5.3. 29-(4-Chlorophenyl)-2-ethyl-25,27-dimethoxy-3-
methyl-8,15,22,30,32-pentaazacyclo[25,2,1,2,22,280,
7,12014,19]-dotriacontane-1,3,5,7,9,11,14,16,18,20,22,24,
26(32),27-tetradecaene (23). The bisaldehyde 19 (0.030 g,
0.065 mmol) and 20 (0.012 g, 0.065 mmol) were reacted in
anhydrous benzene according to the general Schiff base
procedure.5 After 48 h no further reaction was observed, the
solution was allowed to cool to room temperature and all
solvent was removed. The residue was purified by
preparative thin-layer chromatography (70:30 CH2Cl2/
n-hexane eluent) and the uppermost band collected to
afford title compound 23 (0.017 g, 42%) as bright yellow
crystals, mp 280–282 8C. (Found: C 70.7, H 5.8, N 10.5.
C38H34ClN5O2$H2O requires C 70.6, H 5.6, N 10.8) nmax
(KBr)/cmK1 3457, 3366, 1605, 1580, 1562, 1507, 1479,
1464, 1412, 1383, 1362, 1327, 1294, 1271, 1213, 1171,
1121, 1094, 997, 895, 829, 795. lmax/nm (3/MK1 cmK1) 210
(sample too insoluble for the calculation of extinction
coefficients), 266, 324, 351, 397. dH(75.42 MHz; CDCl3;
Me4Si) 0.99 (3H, t, JZ7.4 Hz, ethyl CH3), 2.18 (3H, s,
CH3), 2.30 (2H, q, JZ7.4 Hz, ethyl CH2), 3.81 and 3.92
(6H, s, OCH3), 4.00 (2H, s, bridging CH2), 6.25 (1H, s,
indole H5), 6.88 (4H, m, aryl HCbridging NH), 7.11 (2H,
Acknowledgements
We are grateful to the Australian Research Council for
financial support including an Australian Postgraduate
Award to P. K. B.
References and notes
1. Black, D. Stc. ; Hartshorn, A. J.; Horner, M.; Hu¨nig, S. Aust.
J. Chem. 1977, 30, 2553.
2. Black, D. Stc. ; Hartshorn, A. J.; Horner, M.; Hu¨nig, S. Aust.
J. Chem. 1977, 30, 2493.
3. Black, D. Stc. ; Craig, D. C.; Kumar, N; Wong, L. C. H. Chem.
Commun. 1985, 1172.
4. Black, D. Stc. ; Brockway, D. J.; Moss, G. I. Aust. J. Chem.
1986, 39, 1231.

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P. K. Bowyer et al. / Tetrahedron 61 (2005) 10781–10792
5. Black, D. Stc. ; Bowyer, P. K.; Craig, D. C.; Rae, A. D.; Willis,
A. C. J. Chem. Soc., Dalton Trans. 2001, 1948–1958.
6. Bowyer, P. K. Honours Thesis, UNSW, 1991.
7. Black, D. Stc. ; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R.
Chem. Commun. 1993, 819.
M.; Kumar, N.; McConnell, D. B.; Popiolek, M. Aust. J. Chem.
1994, 47, 1741.
10. Bowyer, M. C. Ph.D. Thesis, UNSW, 1991.
11. Clezy, P. S.; Crowly, R. J.; Hai, T. T. Aust. J. Chem. 1982, 35,
411.
8. Jorgensen, W. L.; Severance, D. L. J. Am. Chem. Soc. 1990,
112, 4768–4774.
9. Black, D. Stc. ; Bowyer, M. C.; Bowyer, P. K.; Ivory, A.; Kim,
12. Clezy, P. S.; Fookes, J. R.; Liepa, A. J. Aust. J. Chem. 1972,
25, 1979.
13. Black, D. Stc. ; Rothnie, N. E. Aust. J. Chem. 1983, 36, 1141.