Synthesis of new di-(3-indolyl)arenes

Article abstract of DOI:10.1016/j.tet.2012.06.074

1,4-Di-(3-indolyl)benzene 6 and 2,8-di-(3-indolyl)dibenzofuran 12 were synthesized from 1,4-diacetylbenzene and 2,8-diacetyldibenzofuran, respectively, via indole synthetic strategies. Investigation into the acid-catalysed formation of macrocyclic systems

Full text of DOI:10.1016/j.tet.2012.06.074

Tetrahedron 68 (2012) 7429e7434
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Tetrahedron
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Synthesis of new di-(3-indolyl)arenes
Ibrahim F. Sengul, Kasey Wood, Paul K. Bowyer, Mohan Bhadbhade, Rui Chen, Naresh Kumar,
*
David StC. Black
School of Chemistry, The University of New South Wales, Sydney, NSW-2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
1,4-Di-(3-indolyl)benzene
6
and 2,8-di-(3-indolyl)dibenzofuran 12 were synthesized from
Received 28 March 2012
Received in revised form 30 May 2012
Accepted 18 June 2012
1,4-diacetylbenzene and 2,8-diacetyldibenzofuran, respectively, via indole synthetic strategies.
Investigation into the acid-catalysed formation of macrocyclic systems from these di-(3-indolyl)arenes
led to the development of the 18-membered macrocycle 14 from the diindolylbenzene 6, which was
capable of undergoing complexation with nickel(II) ions.
Available online 23 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Bis-indoles
3-Indolyls
Macrocycles
1. Introduction
earthworm Helicoverpa zea.8 Dissolution of 1,4-diacetylbenzene in
glacial acetic acid and dropwise addition of 2 equiv of bromine
Bisindole alkaloids are an important class of compounds of
particular interest in drug design due to their prevalent biological
activity.1 Of this class, the 3-substituted bisindoles are the most
common because the C3 position is the most reactive indole site.
Moreover, the incorporation of a five or six-membered aryl or
heteroaryl ring between the two indole units has been of consid-
erable interest to many researchers.2 Examples of such compounds
include the nortopsentins AeC, which exhibit in vitro cytotoxicity
against P388 cells,3 hamacanthin B, which shows cytotoxic activity
against a range of tumour cell lines,4 asterriquinone, which pos-
sesses antitumour activity5 and demethylasterriquinone B1, which
is a selective activator of the insulin receptor6 (Fig. 1).
As part of an on-going investigation into the chemistry of acti-
vated 3-substituted 4,6-dimethoxyindoles,7 we were interested in
the preparation of activated 3-substituted bisindoles linked by aryl
andheteroaryl rings. Such bisindoles wouldbecapable ofundergoing
electrophilic substitution at the typically unreactive C7 positions, in
addition to the N1 and C2 positions, enabling them to serve as po-
tential precursors for a diverse range of novel macrocyclic systems.
afforded the 1,4-di(bromoacetyl)benzene 2 in 60% yield.10 The re-
action of dibromo compound 2 at reflux for 2 h with 2 equiv of 3,5-
dimethoxyaniline and sodium bicarbonate generated the phenacyl
aniline 3 as an orange solid in 80% yield. The nitrogen atom of the
phenacyl aniline
3 was subsequently protected with a tri-
fluoroacetyl groupand the resulting N-protected intermediate 4 was
not isolated but cyclized directly to give the bisindole 5 in 80% yield
by stirring at room temperature for 3 days in trifluoroacetic acid
(Scheme 1).
H
R
O
N
R
N
Br
Br
N
N
H
NH
HN
HN
NH
nortopsentins A-C
hamacanthin B
N
H
O
O
N
O
O
2. Results and discussion
MeO
N
HO
The modified Bischler9 indole synthetic method was utilised for
the preparation of 1,4-di-(3-indolyl)benzene 6, which closely re-
sembles the ochrindole natural products, which are obtained from
Aspergillus ochraceus and show moderate activity against the corn
OMe
OH
HN
asterriquinone
Fig. 1. Representative 3-substituted bis-indoles.
demethylasterriquinone B1
* Corresponding author. Tel.: þ61 293854657; fax: þ61 293856141; e-mail ad-
dress: d.black@unsw.edu.au (D.StC. Black).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.074

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I.F. Sengul et al. / Tetrahedron 68 (2012) 7429e7434
Scheme 1. Reagents and conditions: (a) Br2, acetic acid, rt, 8 (54%); (b) 3,5-dimethoxyaniline, EtOH, NaHCO3, reflux, 3 (80%), 9 (90%); (c)TFAA, Et3N, THF, rt; (d) acetic anhydride, rt,
10 (83%); (e) TFA, 5 (80%), 11 (92%); (f) KOH, MeOH, rt, 6 (95%), 12 (69%).
Deprotection to afford the target diindolylbenzene 6 was carried
out using methanolic potassium hydroxide solution. The product
was isolated as a white solid in 95% yield and was found to be highly
insoluble. The 1H NMR spectrum of bisindole 6 showed singlets at
structural confirmation, and the crystal structure showed that the
two indole units were orientated in the same manner, with the NH
groups directed away from the dibenzofuran linker (Fig. 2).15
d
3.83 and
singlet at
and H2 protons appeared at
while the benzene aromatic protons appeared as a singlet at
d
3.86 corresponding to the methoxy groups and a broad
8.09 corresponding to the NH groups. The indole H5, H7
6.28, 6.53 and 7.08, respectively,
7.62.
d
d
d
d
d
The second linker of interest was dibenzofuran. Dibenzofuran
and its derivatives are associated with a range of biological activity,
such as antifungal, antibacterial, anti-inflammatory and antiallergic
activity.11 Moreover, while there are few examples of diaryl- and
heteroaryl-substituted dibenzofurans in the literature, such 3,6-
disubstituted dibenzofurans have been associated with antibacte-
rial and antifungal activity,12 and show potential as novel fluores-
cent probes and optoelectronic materials.13
Fig. 2. ORTEP diagram of compound 12.15
The modified Bischler indole synthetic strategy was again
employed14 for the preparation of 3,6-bis-(3-indolyl)dibenzofuran
12 (Scheme 1). Bromination of 3,6-diacetyldibenzofuran 7 was
performed using a variation of the procedure reported by Bruce
et al.,10 using 2 equiv of bromine in glacial acetic acid and generating
bromoketone 8 in 54% yield. Condensation of 2,8-di(bromoacetyl)
dibenzofuran 8 with 2 equivof 3,5-dimethoxyaniline at reflux for 6 h
in the presence of sodium bicarbonate afforded the corresponding
phenacyl aniline 9 as a yellow solid in 90% yield. Phenacyl aniline 9
was subsequently treated with acetic anhydride at room tempera-
ture for 12 h, giving rise to the protected anilino ketone 10 in 83%
yield. Formation of the indole ring systems was then achieved by
cyclisation of the N-protected anilino ketone 10 in the presence of
trifluoroacetic acid at 100 ꢀC for 3 h under an argon atmosphere.
Finally, deprotection of bisindole 11 was carried out at room tem-
perature for 3 h using potassium hydroxide in methanol, generating
the targeted 3,6-di-(3-indolyl)dibenzofuran 12 as a white solid in
69% yield after purification by column chromatography.
It was anticipated that each indole unit in di-(3-indolyl)arenes 6
and 12 would behave equivalently yet independently with respect
to functionalization and thus enable the subsequent development of
novel macrocyclic systems. We have previously demonstrated that
activated 3-substituted indoles can undergo acid-catalysed con-
densationwith aromatic aldehydes to afford 2,20-diindolylmethanes
or macrocyclic calix[3]indoles16 and therefore it was of interest to
extend this methodology to di-3-(indolyl)arenes 6 and 12.
In order to eliminate the possibility of C2eC7 reactions and
thereby reduce the number of potential products, initial C7-
formylation of the di-3-(indolyl)arenes was performed. Vilsmeier
formylation of compound 6 was performed at room temperature
over 20 min to give the 7,70-dicarbaldehyde 13 in 90% yield (Scheme
2). The 1H NMR spectrum indicated that the product was C2-sym-
metric, with the formyl signal appearing at
NH resonance accordingly deshielded with respect to the precursor
at 10.54. The H2 resonance appeared as a doublet at 7.16 due to
NH-induced splitting, while the H5 resonance appeared as a singlet
at 6.22, indicating that formylation occurred at C7.
With two major nucleophilic sites remaining on compound 13,
d 10.41 and the indole
d
d
The 1H NMR spectrum of 3-substituted-bisindole 12 showed
d
three doublets at
the indole H5, H7 and H2 protons, respectively. Two singlets at
3.73 and 3.76 corresponded to the methoxy groups and a third
singlet at 11.11 corresponded to the NH groups. The dibenzofuran
aromatic protons were present as multiplets at 7.63 and 7.71 and
doublet at 8.23. X-ray crystallography provided further
d 6.21, d 6.54 and d 7.25, which corresponded to
namely C2and C20, cyclisationwasthuslimitedtothesepositions. The
bisformyl benzenoid compound 13 was suspended in glacial acetic
acid and heated at reflux for 12 h in the presence of formaldehyde.
Surprisingly, the resulting precipitate was found to be a single
compound despite the potential to form polymeric or cyclic
d
d
d
d
d
a
d

I.F. Sengul et al. / Tetrahedron 68 (2012) 7429e7434
7431
Scheme 2. Reagents and conditions: (a) POCl3, DMF, 0 ꢀC to rt, 12 h., 90%; (b) HCHO, HOAc, reflux, 12 h., 10%; Ni(OAc)2, MeCN, 70 ꢀC, 12 h., 70%.
materials containing a number of benzenoid units. The 1H NMR
spectrum displayed a single set of indole resonances and a single
and phosphoryl chloride afforded only complex mixtures of poly-
meric materials. A similar result occurred in reactions with 40%
formaldehyde in methanolic hydrochloric acid.
broad methylene singlet at
d 4.27 in a ratio of two indole units for
one methylene group, signifying the formation of a macrocyclic
structure. Mass spectroscopic analysis indicated the formation of
the bisbenzenoid macrocycle 14, and no higher order macrocycles
were observed. This result suggests that the formation of larger
macrocycles is either geometrically or energetically disfavoured
and that compound 13 is predisposed to form system 14, with ring
closure of the intermediate mono-methylene compound being
reasonably rapid. However, macrocycle 14 was obtained only in
a low 10% yield.
An alternative method for the formation of calix[3]indoles is to
treat 7-hydroxymethyl-3-substituted-4,6-dimethoxyindoles with
acid.18 Therefore bisindole 12 was treated with 2 equiv of Vils-
meiereHaack reagent at 0 ꢀC for 6 h to generate the bisindole
dicarbaldehyde 16 in 77% yield (Scheme 3). Compound 16 was
subsequently reduced to the corresponding dihydroxymethyl com-
pound 17 in 77% yield through treatment with sodium borohydride
at room temperature in ethanol. Submission of compound 17 to
a wide variety of acidic conditions resulted in the formation of
complex polymeric mixtures, and again no calix[3]indoles could be
detected. We have previously demonstrated that unsymmetrically
linked calix[3]indoles can be produced through reaction of 7,70-
dihydroxymethyl-2,20-di-indolylmethanes and 3-substituted-4,6-
dimethoxyindoles in the presence of acetic acid.17 In an attempt to
form a macrocyclic system containing four indole rings and two di-
benzofuran rings, dihydroxymethyldibenzofuran 17 and diindo-
lyldibenzofuran 12 were combined in the presence of acetic acid or
p-toluensulfonic acid. However, only complex mixtures of polymeric
materials were obtained. The conversion of the dialdehyde 6 into the
macrocyclic compound 14 prompted the reaction of dialdehyde 16
with formaldehyde in glacial acetic acid, but again no macrocyclic
product could be identified in the resulting polymeric mixture. As
a result of these experiments, it seems that the size of the di-
benzofuran linker is not optimal for calixindole or macrocycle for-
mation, but rather predisposes this system towards polymerization.
Macrocycle 14 represents a relatively low molecular weight li-
gand bearing two potential exocyclic coordination fields. Thus the
metal-binding potential of this compound was briefly explored.
Macrocycle 14 was suspended in acetonitrile and heated at 70 ꢀC for
12 h in the presence of triethylamine and nickel(II) acetate tetra-
hydrate. The product, obtained in 70% yield, was found to be too
insoluble for NMR characterization, however, the IR spectrum
showed no absorption in the region of 3600e3200 cmꢁ1 and in-
dicated that no free indole NH bonds were present. MALDI mass
spectroscopic analysis gave a 50% relative intensity peak corre-
sponding to the Ni2L complex 15, confirming the presence of two
nickel atoms. Interestingly, a 35% relative intensity peak was ob-
served corresponding to Ni2LeO, where the ligand is presumed to
have fragmented with the release of one aldehyde oxygen, possibly
indicating significant torsional strain within the chelate rings. A
70% relative intensity peak was also observed corresponding to the
loss of one nickel atom from the complex. Further metal binding
studies were discontinued owing to the insolubility of complex 15.
3-Substituted-4,6-dimethoxyindoles have been shown to un-
dergo acid-catalysed reactions with aromatic aldehydes to form
macrocyclic triindolyltrimethanes, known as calix[3]indoles.17 An
ambitious aim with regard to 3,6-di-(3-indolyl)dibenzofuran 12
was to form a cylindrical structure with a calix[3]indole at each end.
However, treatment of bisindole 12 at reflux with benzaldehyde
3. Conclusions
In conclusion, two new di-(3-indolyl)arenes 6 and 12 were syn-
thesized from 1,4-diacetylbenzene and 3,6-diacetyldibenzofuran.
These systems are capable of undergoing further functionalization at
the N1, C2 and C7 positions and thus may serve as precursors for
other novel compounds.
Scheme 3. Reagents and conditions: (a) POCl3, DMF, 0 ꢀC to rt, 6 h., 77%; (b) NaBH4, EtOH, rt, 6 h., 77%.

7432
I.F. Sengul et al. / Tetrahedron 68 (2012) 7429e7434
4. Experimental
s, CH2), 5.02 (2H, bs, NH), 5.95 (6H, bs, aryl H), 7.73 (2H, d, J 8.6 Hz,
linker H), 8.23 (2H, d, J 6.7 Hz, linker H), 8.73 (2H, d, J 1.5 Hz, linker
H); 13C NMR (75 MHz, CDCl3):
50.3 (CH2), 55.1 (OMe), 90.0, 91.9,
4.1. General
d
112.4, 121.3, 128.1 (aryl CH), 124.1, 130.7, 148.8, 159.7, 161.7 (aryl C),
193.6 (C]O); HRMS (ESI): Found m/z 555.2126 [MþH]þ;
C32H31N2O7 requires 555.2131.
All reagents andsolventswere obtained from commercialsources
and appropriately purified, if necessary. Melting points were mea-
sured using a Mel-Temp melting point apparatus and are un-
corrected. Microanalyses were performed on a Carlo Erba Elemental
Analyser EA 1108 at the Campbell Microanalytical Laboratory, Uni-
versity of Otago, New Zealand. 1H and 13C NMR spectra were
obtained on Bruker DPX300 (300 MHz) and Bruker DPX600
(600 MHz) spectrometers. Mass spectra were recorded on either
a Bruker FT-ICR MS (EI) or a Micromass ZQ2000 (ESI). Infrared
spectra were recorded with a Thermo Nicolet 370 FTIR Spectrometer
using KBr discs. Column chromatography was carried out using
Merck 230e400 mesh ASTM silica gel, whilst preparative thin layer
4.1.4. N,N0-(2,20-(Dibenzo[b,d]furan-2,8-diyl)bis(2-oxoethane-2,1-
diyl))bis(N-(3,5-dimethoxyphenyl)acetamide) (10). A mixture of the
anilino ketone 9 (2.00 g, 3.12 mmol) and acetic anhydride (3.80 g,
37.4 mmol) was heated at 50 oC for 1 h. Water (50 mL) was added
and the mixture was stirred overnight at rt. The precipitated
product was filtered, washed with water and dried to yield the
compound 10 as a yellow solid (1.90 g, 83%), mp 140e142 ꢀC (from
dichloromethane/hexane); [Found C, 66.9; H, 5.2; N, 3.9.
C36H30N2O9.0.2CH2Cl2 requires C, 66.9; H, 5.4; N, 4.3%]; nmax (KBr)
3452, 3086, 2934, 2839, 1696, 1600, 1595, 1461, 1414, 1338, 1203,
chromatography was performed using Merck silica gel 7730 60GF254
.
1154, 1063, 1025, 828, 692 cmꢁ1
;
lmax (MeCN) 250 nm
(
3
4.1.1. 1,10-(Dibenzo[b,d]furan-2,8-diyl)bis(2-bromoethanone)
(8). Bromine (0.62 g, 3.90 mmol) in acetic acid (10 mL) was added
dropwise to a warm solution (40 ꢀC) of 3,6-diacetyldibenzofuran 7
(2.00 g, 7.90 mmol) in acetic acid (30 mL). After 4 h at room temper-
ature, the crude product was purified via flash chromatography
(eluted with 80% dichloromethane/hexane) to yield compound 8 as
a yellow solid (1.08 g, 54%); mp 192e194 ꢀC; [Found C, 47.1; H, 2.6.
C16H10Br2O3 requires C, 46.8; H, 2.6%]; nmax (KBr) 3070, 2933, 1674,
1630, 1591, 1430, 1413, 1270, 1204, 1168, 1126, 1004, 936, 827, 763,
89,500 cmꢁ1 ꢁ1), 204 (121,450); 1H NMR (300 MHz, CDCl3):
M
d 2.
06 (6H, s, COMe), 3.80 (12H, s, OMe), 5.18 (4H, s, CH2), 6.43 (2H, s,
aryl H), 6.59 (4H, s, aryl H), 7.64 (2H, d, J 8.6 Hz, linker H), 8.14 (2H,
d, J 6.7 Hz, linker H), 8.60 (2H, s, linker H); 13C NMR (75 MHz,
CDCl3):
d 21.9 (COMe), 55.4 (CH2), 56.0 (OMe), 100.1, 106.1, 112.1,
121.5, 128.3 (aryl CH), 123.9, 131.0, 145.0, 159.4, 161.3 (aryl C), 170.8,
192.4 (C]O); HRMS (ESI): Found m/z 639.2337 [MþH]þ,
C36H35N2O9 requires 639.2343.
588 cmꢁ1
212 (29,200); 1H NMR (300 MHz, CDCl3):
d, J 8.6 Hz, benzofuran H), 8.22 (2H, d, J 8.6 Hz, benzofuran H), 8.69 (2H,
d, J 1.5, benzofuran H); 13C NMR (75 MHz, CDCl3):
30.4 (CH2), 112.4,
;
lmax (MeCN) 280 nm (
3
20,800 cmꢁ1 Mꢁ1), 254 (50,700),
4.1.5. 1,4-Di-[(4,6-dimethoxy-N-trifluoroacetyl)-3,30-indolyl]benzene
(5). The di-anilinobenzene 3 (11.0 g, 23.7 mmol) was placed in an-
hydrous tetrahydrofuran (200 mL) and the mixture stirred and
cooled in an ice bath. Anhydrous triethylamine was added (15.4 mL,
4.60 equiv), followed by trifluoroacetic anhydride (13.4 mL,
4.00 equiv) via a dropping funnel and the solution allowed to come
rt and stirred overnight. The resulting orange solid was filtered,
washed with water and dried to afford the crude product. The
protected di-anilinobenzene was placed in trifluoroacetic acid
(40 mL) and stirred at rt under nitrogen for 3 days. A white pre-
cipitate was observed and the mixture was filtered and the solid
washed with water to neutrality. The crude product was recrystal-
lised from acetone to afford the title compound 5 as pale yellow
needles (11.8 g, 80%), mp 285e286 ꢀC; (Found C, 58.4; H, 3.8; N, 4.3.
C30H22F6N2O6 requires C, 58.1, H, 3.6; N, 4.5%). nmax (KBr) 3175, 3142,
3023, 2975, 2962, 2841, 1721, 1611, 1595, 1493, 1463, 1404, 1346,
d
4.57 (4H, s, CH2Br), 7.71 (2H,
d
122.6, 129.4 (aryl CH), 124.1, 129.8, 159.7 (aryl C), 190.3 (C]O); HRMS
(ESI): Found m/z 410.9045 [MþH]þ, C16H11Br2O3 requires 410.9054.
4.1.2. 1,4-Di
Dimethoxyaniline (9.57 g, 62.5 mmol),
(30,50-dimethoxyanilino)acetylbenzene
0-dibromo-1,4-
(3). 3,5-
a,a
diacetylbenzene 2 (10.0 g, 31.3 mmol) and sodium hydrogen car-
bonate (6.30 g, 75.0 mmol) were heated at reflux in absolute ethanol
(350 mL). After 2 h the reaction mixture was chilled in an ice bath
and filtered. The product was washed with water (500 mL), then
cold ethanol (50 mL) and dried to afford the title compound 3 as an
orange powder (11.6 g, 80%), mp 180e182 ꢀC; [Found C, 67.0; H, 6.4;
N, 6.0. C26H28N2O6 requires C, 67.2; H, 6.1; N, 6.0%]; IR (KBr): nmax
(KBr) 3386, 2997, 2938, 2841, 1706, 1690, 1626, 1601, 1528, 1514,
1503, 1483, 1462, 1452, 1412, 1317, 1252, 1206, 1181, 1001, 990, 819,
1325, 1287, 1262, 1069, 1049, 829, 810, 762 cmꢁ1
342 nm (
8500 cmꢁ1 Mꢁ1), 273 (36,600), 260 (39,100), 212 (67,500):
1H NMR (300 MHz, CDCl3):
3.81 (6H, s, OMe), 3.92 (6H, s, OMe),
6.52 (2H, d, J 2.1, H5), 7.29 (2H, d, J 2.3, H2), 7.62 (4H, s, phenyl H), 7.77
(2H, d, J 2.1, H7); 13C NMR (75 MHz, CDCl3):
55.4, 55.9 (OMe), 93.5,
; lmax (MeOH)
3
681 cmꢁ1
217 (60,300); 1H NMR (300 MHz, CDCl3):
(4H, s, CH2), 4.92 (2H, s, NH), 5.90 (4H, d, J 2.3, aryl H), 5.93 (2H, t, J
2.0, aryl H), 8.12 (4H, s, aryl H); 13C NMR (75 MHz, CDCl3):
50.7
;
lmax (MeOH) 360 nm (
3
7250 cmꢁ1 Mꢁ1), 257 (36,800),
d
d
3.78 (12H, s, OMe), 4.63
d
d
97.4, 118.9, 128.5 (aryl CH), 112.4, 113.7, 117.5, 127.4, 132.6, 138.8,
154.5, 160.6 (aryl C and COCF3); MS (þEI): m/z 621 (Mþ1, 35%), 620
(M,100), 523 (35), 446 (15), 319 (15), 310 (25), 262 (15), 213 (45) 192
(20), 157 (15), 149 (20), 97 (20), 86 (20), 84 (35), 69 (45).
(CH2), 55.2 (OMe), 90.2, 92.1,128.2 (aryl CH),138.5, 148.6,161.8 (aryl
C), 194.3 (C]O); MS (þEI): m/z 465(Mþ1, 5%), 464 (M, 10), 272 (10),
271 (50), 167 (15), 166 (100), 153 (35), 138 (10), 124 (20), 45 (15).
4 .1. 3 . 1,1 0- ( D i b e n z o [ b , d ] f u r a n - 2 , 8 - d i y l ) b i s ( 2 - ( 3 , 5 -
dimethoxyphenylamino)ethanone) (9). A mixture of 3,5 dimethox-
yaniline (0.73 g, 4.80 mmol), dibenzofuran bromoeketones 8
(1.00 g, 2.40 mmol), sodium bicarbonate (0.61 g, 7.22 mmol) and
absolute ethanol (20 mL) was refluxed for 5 h. The reaction mixture
was cooled to rt and stirred for 1 h. The product was filtered,
washed with water (100 mL) and cold ethanol and dried to afford
the title compound 9 as a yellow powder (1.22 g, 90%), mp
146e148 ꢀC (from dichloromethane/hexane); [Found C, 60.9; H,
4.7; N, 3.9. C32H30N2O7.1.2CH2Cl2 requires C, 60.6; H, 4.9; N, 4.2%];
nmax (KBr) 3389, 2933, 2838, 1686, 1615, 1595, 1482, 1460, 1203,
4.1.6. 1-(3-(8-(1-Acetyl-4,6-dimethoxy-1H-indol-3-yl)dibenzo[b,d]
furan-2-yl)-5,7-dimethoxy-1H-indol-1-yl)ethanone (11). A mixture
of ketone 10 (2.00 g, 3.30 mmol) and trifluoroacetic acid (5 mL) was
refluxed under argon atmosphere for 3 h. The reaction mixture was
cooled to rt and poured into ice-cold water (30 mL). The pre-
cipitated product was filtered, washed with cold water and dried to
yield compound 11 (1.70 g, 92%) as a yellow solid, mp 238e240 ꢀC;
nmax (KBr) 3403, 2935, 2837, 1698, 1594, 1495, 1464, 1420, 1335,
1266, 1207, 1024, 965, 813 cmꢁ1
42,500 cmꢁ1 ꢁ1), 197 (48,250); 1H NMR (300 MHz, DMSO-d6):
2.68 (6H, s, COMe), 3.74 (6H, s, OMe), 3.82 (6H, s, OMe), 6.53 (2H,
;
lmax (MeCN) 220 nm
(
3
M
d
1152, 810 cmꢁ1
(96,750); 1H NMR (300 MHz, CDCl3):
;
lmax (MeOH) 251 nm (
3
92,900 cmꢁ1
M
ꢁ1), 216
d, J 2.2 Hz, indole H), 7.70 (2H, d, J 2.2 Hz, indole H), 7.73 (6H, s,
d
3.80 (12H, s, OMe), 4.73 (4H,
linker and indole H), 8.31 (2H, s, linker H); 13C NMR (75 MHz,

I.F. Sengul et al. / Tetrahedron 68 (2012) 7429e7434
7433
DMSO-d6):
d
24.6 (COMe), 55.8 (OMe), 93.1, 95.6, 111.0, 121.8, 123.1,
added and the reaction mixture was heated for 12 h. The resultant
precipitate upon cooling was filtered and washed with water to
afford compound 14 as a yellow solid (10.0 mg, 10%), mp>300 ꢀC
(dec); [Found: C, 66.4; H, 5.1; N, 4.8. C58H48N4O12.2.5CH3CO2H re-
quires C, 66.2; H, 5.1; N, 4.9%]; nmax (KBr) 3403, 3381, 3351, 3331,
3003, 2938, 2849, 1705, 1640, 1589, 1564, 1510, 1464, 1433, 1397,
1368, 1364, 1331, 1246, 1215, 1163, 1121, 1059, 991, 837, 797, 739,
556 cmꢁ1 lmax (MeCN, sample sparingly soluble) 262 nm, 358. 1H
129.5 (aryl CH), 112.0, 123.5, 129.7, 137.7, 154.2, 155.3, 159.3 (aryl C),
170.2 (C]O); HRMS (ESI): Found m/z 603.2126 [MþH]þ;
C36H31N2O7 requires 603.2131.
4.1.7. 1,4-[Di(4,6-dimethoxy)-3,30-indolyl]benzene (6). Methanolic
potassium hydroxide solution was added dropwise to a solution of
di-indolyl benzene 5 (2.00 g, 3.22 mmol) in methanol (100 mL)
until the pH was >9. The mixture was stirred overnight and the
resulting precipitate filtered and washed with water, then anhy-
drous diethyl ether to afford compound 6 as a white solid (1.31 g,
95%), mp 269e270 ꢀC; [Found: C, 72.9; H, 5.9; N, 6.4. C26H24N2O4
requires: C, 72.9; H, 5.6; N, 6.5%]; nmax (KBr) 3407, 2996, 2935, 2836,
NMR (300 MHz, CDCl3):
d 3.86 (12H, s, OMe), 3.98 (12H, s, OMe),
4.27 (4H, bs, CH2), 6.15 (4H, s, H5), 7.18 (8H, s, phenyl), 10.45 (4H, s,
CHO), 11.08 (4H, bs, NH). Sample too insoluble for 13C NMR; HRMS
(ESI): Found m/z 1015.3155 [MþNa]þ; C58H48N4NaO12 requires
1015.3155.
1624, 1582, 1552, 1325, 1215, 1145, 1048, 799 cmꢁ1
309 nm (
20,700 cmꢁ1 ꢁ1), 278 (19,800), 229 (51,000); 1H NMR
(300 MHz, DMSO-d6): 3.80 (12H, s, OMe), 6.24 (2H, d, J 1.6 Hz, H5),
6.56 (2H, d, J 1.6 Hz, H7), 7.20 (2H, d, J 2.1 Hz, H2), 7.52 (4H, s,
phenyl), 11.09 (2H, bs, NH); 13C NMR (75 MHz, DMSO-d6):
55.3,
; lmax (MeOH)
3
M
4.1.11. Di-indole tetracarbaldehyde(4-)dinickel(II) (15). The ligand
14 (10.0 mg, 0.01 mmol) was suspended in acetonitrile (20 mL) and
heated at 70 ꢀC under a nitrogen atmosphere. Anhydrous triethyl-
amine (3 drops) was added followed by nickel (II) acetate tetra-
hydrate (5.20 mg, 0.02 mmol) and the mixture heated at reflux for
12 h. The mixture was allowed to cool to room temperature then
filtered, affording the title compound 15 as a brown powder
(7.80 mg, 70%), mp>300 ꢀC, with decomposition. nmax (KBr) 2998,
2938, 2876, 2839, 1642, 1495, 1431, 1395, 1377, 1356, 1309, 1173,
d
d
55.6 (OMe), 87.7, 92.0, 121.6, 128.5 (aryl CH), 110.1, 117.5, 133.5,
139.0, 154.6, 157.0 (aryl C); HRMS (ESI): Found m/z 429.1808
[MþH]þ; C26H25N2O4 requires 429.1814.
4.1.8. 2,8-Bis(4,6-dimethoxy-1H-indol-3-yl)dibenzo[b,d]furan
(12). To a suspension of protected indole 11 (1.00 g, 1.90 mmol) in
methanol (15 mL), was added potassium hydroxide (0.78 g,
14.1 mmol). The mixture was stirred at rt for 2 h and then poured
into ice water (50 mL). The precipitated product was filtered,
washed with water and dried to yield the title compound 12 as
a yellow solid (0.60 g, 69%), mp 238e240 ꢀC; nmax (KBr) 3409, 2932,
2836, 2105, 1687, 1622, 1590, 1546, 1463, 1330, 1197, 1158, 1118,
1161, 1080, 997, 899, 839, 739 cmꢁ1
; lmax (MeCN, sample sparingly
soluble) 252 nm, 277, 403, 515; Sample too insoluble for 1H and 13
C
NMR; HRMS (ESI): Found m/z 1105.1721 [MþH]þ; C58H45N4Ni2O12
requires 1105.1741.
4.1.12. 3,30-(Dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-in-
dole-7-carbaldehyde) (16). Dimethylformamide (5 mL) was cooled
in an iced water bath, treated with phosphoryl chloride (0.07 mL,
0.80 mmol) and stirred for 20 min. This solution was then added
dropwise over 8 min to a solution of the 3-indolyl dibenzofuran 12
(0.20 g, 0.40 mmol) in dimethylformamide (5 mL) with stirring. The
resulting solution was stirred overnight at ambient temperature.
Ice cold water (5 mL) was added and the mixture was basified to pH
12 with 5 M sodium hydroxide. The mixture was then stirred at
ambient temperature for 30 min. The resulting precipitate was
filtered, washed with water and dried to give the desired formyl
indole 16 as a yellow solid, (0.17 g, 77%), mp 286e288 ꢀC; nmax (KBr)
3420, 1648, 1586, 1509, 1462, 1435, 1387, 1357, 1251, 1209,
810 cmꢁ1
;
lmax (MeCN) 232 nm (
3
97,250 cmꢁ1 Mꢁ1), 197 (91,150);
3.73 (6H, s, OMe), 3.76 (6H, s,
1H NMR (300 MHz, DMSO-d6):
d
OMe), 6.21 (2H, d, J 1.9 Hz, H5), 6.54 (2H, d, J 1.9 Hz, H7), 7.25 (2H, d,
J 2.3 Hz, H2), 7.63 and 7.71 (4H, m, linker H), 8.23 (d, 2H, J 1.2 Hz,
linker H), 11.11 (bs, 2H, indole NH); 13C NMR (75 MHz, DMSO-d6):
d
55.3, 55.5 (OMe), 87.6, 92.0, 110.7, 121.0, 121.9, 129.0 (aryl CH),
110.1, 117.0, 123.8, 131.8, 138.8, 1545.5, 156.9 (aryl C) HRMS (ESI);
Found m/z 519.1914 [MþH]þ; C32H27N2O5 required 519.1920.
4.1.9. 1,4-Di-[(4,6-dimethoxy)-3,30-indolyl]benzene-7,70-dicarbalde-
hyde (13). To a stirred solution of the di-indolyl benzene 6 (1.00 g,
2.33 mmol) in anhydrous dimethylformamide (5 mL) at 0 ꢀC was
added dropwise an ice cold phosphoryl chloride (1.07 g, 0.65 mL,
7.00 mmol) in dimethylformamide (2 mL). The mixture was stirred
at 0 ꢀC for 20 min, after which a slight excess of reagent was added.
The resulting solution was stirred overnight at ambient tempera-
ture. Ice cold water (5 mL) was added and the mixture was basified
to high pH 10 with 5 M sodium hydroxide. The mixture was then
stirred at ambient temperature for 30 min. The resulting precipitate
was filtered, washed with water and dried to give the title com-
pound 13 as a yellow powder (1.02 g, 90%), mp 310e312 ꢀC; [Found
C, 69.2; H, 5.2; N, 5.5. C28H24N2O6 requires C, 69.4; H, 5.0; N, 5.8%];
nmax (KBr) 3408, 3121, 2998, 2963, 2936, 2837, 1624, 1582, 1512,
1110 cmꢁ1
;
lmax (MeCN) 321 nm (
3
24,100 cmꢁ1 Mꢁ1), 251 (57,650),
3.92 (6H, s, OMe), 3.99
(65,900); 1H NMR (300 MHz, DMSO-d6):
d
(6H, s, OMe), 6.47 (2H, s, H5), 7.23 (2H, d, J 1.1 Hz, linker H), 7.64 (4H,
d, J 1.1 Hz, linker H), 8.32 (2H, s, H2), 10.36 (2H, s, CHO), 11.46 (2H,
bs, indole NH); 13C NMR (75 MHz, DMSO-d6):
d 56.1, 57.0 (Me), 88.1,
110.9, 121.4, 123.8, 129.2 (aryl CH), 104.3, 110.9, 117.3, 130.8, 136.2,
154.8, 161.3, 163.8 (aryl C), 186.8 (C]O); HRMS (ESI): Found m/z
575.1813 [MþH]þ; C34H27N2O7 required 575.1819.
4.1.13. (3,30-(Dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-in-
dole-7,3-diyl))dimethanol (17). To a solution of the formyl indole 16
(0.20 g, 0.30 mmol) in ethanol (20 mL) was added the excess so-
dium borohydride. The reaction mixture was stirred at room tem-
perature for 6 h. The excess borohydride was quenched with the
slow addition of distilled water (40 mL). The mixture was then
extracted several times with ethyl acetate. The combined extracts
were dried over anhydrous sodium sulfate, concentrated under
reduced pressure and recrystallized from dichloromethane/light
petroleum to afford the alcohol 17 as a white solid (0.13 g, 77%),
mp>300 ꢀC; nmax (KBr) 3411, 2934, 2836, 1621, 1596, 1517, 1462,
1468, 1441, 1425, 1393, 1375, 1289, 1125, 934, 754 cmꢁ1
(MeOH) 351 nm (
23,900 cmꢁ1
252 (39,800), 235 (31,900); 1H NMR (300 MHz, DMSO-d6):
;
lmax
3
M
ꢁ1), 328 (26,600), 272 (23,600),
d
3.99
(6H, s, OMe), 4.03 (6H, s, OMe), 6.50 (2H, s, H5), 7.19 (2H, d, J 2.4 Hz,
H2), 7.51 (4H, s, phenyl H), 10.34 (2H, s, CHO), 11.44 (2H, s, NH); 13C
NMR (75 MHz, DMSO-d6): d 56.1, 57.1 (OMe), 88.1, 123.6, 128.8 (aryl
CH), 104.4, 110.1, 117.8, 133.1, 136.4, 161.4, 163.1 (aryl C), 186.9 (CHO);
HRMS (ESI): Found m/z 485.1713[MþH]þ; C28H25N2O6 requires
485.1699.
1330, 1199, 1148, 1117, 1023, 999, 821 cmꢁ1
34,600 cmꢁ1 Mꢁ1), 230 (73,400), 198 (72,200); 1H NMR (300 MHz,
DMSO-d6): 3.86 (6H, s, OMe), 3.91 (6H, s, Me), 4.80 (4H, s, CH2),
;
lmax (MeCN) 277 nm (
3
4.1.10. Di-indole tetracarbaldehyde (14). Diformylbenzene 13
(100 mg, 0.21 mmol) was placed in glacial acetic acid (70 mL) and
heated to reflux. An excess of 40% formaldehyde solution was
d
6.43 (2H, s, OH), 6.64 (2H, s, H5), 7.33 (2H, d, J 2.6 Hz, linker H), 7.70
and 7.75 (4H, m, linker H), 8.27 (2H, s, H2), 10.97 (2H, bs, indole

7434
I.F. Sengul et al. / Tetrahedron 68 (2012) 7429e7434
6. Webster, N. J. G.; Park, K.; Pirrung, M. C. ChemBioChem. 2003, 4, 379e385.
NH); 13C NMR (75 MHz, DMSO-d6):
d
53.9 (CH2), 55.5, 57.5 (OMe),
7. (a) Brown, V. H.; Skinner, W. A.; DeGraw, J. I. J. Heterocycl. Chem. 1969, 6,
539e543; (b) Black, D. StC.; Bowyer, M. C.; Catalano, M. M.; Ivory, A. J.; Keller, P.
A.; Kumar, N.; Nugent, J. Tetrahedron 1994, 50, 10497e10508; (c) Keawin, T.;
Rajviroongit, S.; Black, D. StC. Tetrahedron 2005, 61, 853e861.
8. de Guzman, F. S.; Bruss, D. R.; Rippentrop, J. M.; Gloer, K. B.; Gloer, J. B. J. Nat.
Prod. 1994, 57, 634e639.
89.6, 110.7, 121.0, 129.0 (aryl CH), 79.6, 106.2, 116.8, 122.8, 138.3,
153.4, 153.7, 154.5 (aryl C); HRMS (ESI): Found m/z 601.1945
[MþNa]þ; C34H30N2NaO7 required 601.1951.
Acknowledgements
9. Nordlander, J. E.; Catalane, D. B.; Kotian, K. D.; Stevens, R. M.; Haky, J. E. J. Org.
Chem. 1981, 46, 778e782.
10. Bruce, M. J.; McLean, G. A.; Royles, B. J. L.; Smith, D. M.; Standring, P. N. J. Chem.
Soc., Perkin Trans. 1 1995, 1, 1789e1795.
11. (a) Qu, J.; Xie, C.; Guo, H.; Yu, W.; Lou, H. Phytochemistry 2007, 68, 1767e1774;
(b) Randhavane, P.; Karale, B. J. J. Heterocycl. Chem. 2009, 46, 732e736.
12. Roberts, C. D.; Keicher, J. D.; Gezginci, M. H.; Velligan, M. D. U.S. Patent
US6951880B2, 2005.
We thank the University of New South Wales and the Turkish
Government for their financial support.
References and notes
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€
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