Synthesis of mixed cyclotriveratrylenes

Article abstract of DOI:10.1016/j.tet.2011.12.080

Cyclotriveratrylenes containing one benzene ring and two indole rings linked through N1 and C2 can be prepared by acid-catalysed reactions of formaldehyde and aryl aldehydes with 1,2-di-(1-indolylmethyl)benzene compounds.

Full text of DOI:10.1016/j.tet.2011.12.080

Tetrahedron 68 (2012) 1862e1868
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of mixed cyclotriveratrylenes
Kittiya Somphol, Mardi Santoso, Mohan Bhadbhade, Christopher Gardner, Naresh Kumar,
*
David StC. Black
School of Chemistry, University of New South Wales, UNSW 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:
Cyclotriveratrylenes containing one benzene ring and two indole rings linked through N1 and C2 can be
prepared by acid-catalysed reactions of formaldehyde and aryl aldehydes with 1,2-di-(1-indolylmethyl)
benzene compounds.
Received 19 September 2011
Received in revised form 12 December 2011
Accepted 29 December 2011
Available online 3 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Acid-catalysts
Cyclotriveratrylenes
Benzylic alcohols
1. Introduction
2. Results and discussion
Cyclotriveratrylenes1 represent an important class of molecular
receptors, especially as their rigid crown conformation favours
spherical guests, such as fullerenes and carboranes.2e4 Their tri-
benzocyclononatriene core is most frequently constructed by the
reaction of activated 1,2-disubstituted benzenes with formalde-
hyde under acidic conditions,5e7 or the ‘trimerization’ of activated
3,4-disubstituted benzyl alcohols with acids.8,9 However, a step-
wise approach can be adopted, as shown by the acid-catalysed
condensation of 1,2-disubstituted benzenes with 3,30,4,40-tetra-
alkoxy-6,60-bis(chloromethyldiphenyl)-methanes.7,10
2.1. Synthetic strategy
In principle, there are two synthetic strategies that can be ap-
plied. The first starts with the acid-catalysed addition of indoles to
aldehydes to give diindolylmethanes, thus requiring the linker to be
inserted by the alkylation of the indole nitrogen atoms by a suitable
dihalide. The second strategy simply reverses these steps and re-
quires alkylation through the indole nitrogen atoms followed by
the acid-catalysed addition of an aryl aldehyde to afford the desired
cyclic compounds. The first strategy was quickly established to be
unsuccessful, as the reaction of several 2,20-diindolylmethanes
Pyrrolocyclotriveratrylenes11e14 (also called cyclononatripyrroles)
and indolocyclotriveratrylenes15e17 (also called cyclononatriindoles)
are cyclotriveratrylene derivatives in which the benzene rings have
been replaced by pyrrole and indole rings, respectively, and have been
synthesised by acid-catalysed cyclotrimerization reactions. A step-
wise approach to the synthesis of these systems has not been
reported.
with
a,a
0-dibromo-o-xylene gave complex mixtures including
polymers. On the other hand, the second reverse strategy was
found to be successful.
2.2. Reactions of N,N0-diindolyl-o-xylenes with aldehydes
When the diindolylxylene 2, prepared from skatole 1 and a, -
a0
In principle, a stepwise synthetic route would enable the
formation of mixed cyclotriveratrylenes, so it was decided to
investigate the possibility of generating compounds containing two
indole rings and one benzene ring. The indole rings would be linked
through N1 and C2.
dibromo-o-xylene, was reacted with excess formaldehyde in glacial
acetic acid at room temperature, the 2,20-linked cyclic diindolyl
compound 3 was obtained in 40% yield (Scheme 1). This nine-
membered ring compound is an analogue of cyclotriveratrylenes,
and the structure was confirmed by mass spectrometry, nuclear
magnetic resonance spectroscopy and X-ray crystallography.
Fig. 1 illustrates the X-ray crystal structure of the cyclic product
3, which can be seen to exist in a saddle conformation. The bond
* Corresponding author. Tel.: þ61 2 9385 4657; fax: þ61 2 9385 6141; e-mail
address: d.black@unsw.edu.au (D.StC. Black).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.080

K. Somphol et al. / Tetrahedron 68 (2012) 1862e1868
1863
Br
Br
Me
Me
Me
N
N
N
H
NaOH, DMSO
NaI
2
1
51%
HCHO
HOAc
40%
Me
Me
N
N
3
Scheme 1.
Scheme 2.
also has a saddle conformation (Fig. 2). The 1H NMR spectrum of
compound 6 showed an AB pattern for the N-methylene protons, as
a result of a more rigid structure than that of compound 3.
Fig. 1. ORTEP diagram of structure 3.18
lengths in the nine-membered ring of compound 3 show that the
ring is smaller than that of the indolocyclotriveratrylenes.17 This
situation, together with the presence of two alkyl groups adjacent
to the nine-membered ring, would cause considerable steric hin-
drance and be expected to destabilise the possible crown confor-
mation relative to the observed saddle conformation. The 1H NMR
spectrum of compound 3 showed three singlet resonances at 2.39,
4.67 and 5.02 ppm, respectively, for the C3 methyl protons, the
2,20-methylene protons and the N-methylene protons.
Fig. 2. ORTEP diagram of structure 6.18
Although the yield of compound 6 was higher than that of
Since one of the requirements for the formation of the nine-
membered ring is the nucleophilic reactivity at C2, the related
4,6-dimethoxyindole derivative 5 was investigated. Such 4,6-
dimethoxyindoles are known to have enhanced reactivity at C2,
as well as at C7.17,19,20 4,6-Dimethoxy-3-phenylindole 4 was reacted
compound 3,
methylindole analogue 8, prepared from 4,6-dimethoxy-3-
methylindole 7 and
0-dibromo-o-xylene, because of the possi-
a more general study was based on the 3-
a,a
bility of even greater reactivity at C2, as a consequence of the
electron donating 3-methyl group. When a mixture of diindolyl
compound 8 and aryl aldehydes were dissolved in anhydrous
chloroform and treated with phosphoryl chloride under stirring for
1e2 h, the reactions gave the 2,20-linked cyclic diindolyl com-
pounds 9aec in 71e99% yields. In contrast, only a 19% yield of the
cyclic product 9d could be obtained when the same diindolyl
compound 8 was reacted with p-nitrobenzaldehyde under the
same acidic conditions. However, when the acid catalyst was
changed to p-toluenesulfonic acid, compound 9d could be obtained
in 88% yield (Scheme 3). Clearly milder acidic conditions were more
appropriate for the more reactive aldehyde. Furthermore, the
with
a,a
0-dibromo-o-xylene and base to give the 1,10-linked bi-
indole 5 in 70% yield. When compound 5 was treated with form-
aldehyde in glacial acetic acid, only polymeric products were
obtained. No reaction occurred when compound 5 was treated with
p-chlorobenzaldehyde and hydrochloric acid in tetrahydrofuran.
However, compound
5
reacted smoothly with p-chlor-
obenzaldehyde and phosphoryl chloride in anhydrous chloroform
for 13 h at room temperature to give the 2,20-linked cyclic diindolyl
compound 6 in 68% yield (Scheme 2). There was no indication of
any reaction at C7 to give a possible eleven-membered ring com-
pound. X-ray crystallography showed that the cyclic compound 6

1864
K. Somphol et al. / Tetrahedron 68 (2012) 1862e1868
Scheme 3.
methyl group at C3 appears to have delivered both steric and
electronic benefits.
Treatment of compound 9c with hydrobromic acid in glacial acetic
acid, or aluminium chloride in benzene, or hydrogen or ammonium
formate with palladium on charcoal, all gave no reaction.
The 1H NMR data of the cyclic compounds 9 are similar to the 1H
NMR data of compound 6, especially the AB pattern of the two sets
of N-methylene protons. For instance, the N-methylene proton
resonances of the cyclic compound 9c appear at 4.58 and 4.94 ppm,
compared with signals at 4.80 and 5.14 ppm for compound 6.
Similarly, with respect to the 13C NMR data, the N-methylene car-
bon of compound 9c shows a signal at 48.18 ppm, compared with
that at 48.72 ppm for compound 6.
2.3. Reactions of N,N0-diindolylmethanes with aldehydes
The success of the synthesis of the nine-membered ring com-
pounds provided an incentive to synthesise the related six-
membered ring compounds by changing the N-linker. The acti-
vated N,N0-diindolylmethane 11 was obtained in moderate yield by
alkylation of 4,6-dimethoxy-3-methylindole 7 by diiodomethane.
When the diindolyl compound 11 was stirred with an excess of
formaldehyde in glacial acetic acid, paraformaldehyde or dime-
thoxymethane in dichloromethane catalysed by p-toluenesulfonic
acid, either polymeric materials or complex mixtures were formed.
However, the diindolylmethane 11 underwent cyclisation when it
was stirred at 0 ꢀC with aryl aldehydes to yield the six-membered
ring compounds 12 in 20e33% yields (Scheme 5). Compared with
A comparison of the NMR spectral data of the cyclic compounds 9c
and 6 shows similarities, so compounds 9 are also expected to exist in
the saddle conformation. A suitable single crystal for X-ray crystal-
lography could not be obtained. In an attempt to achieve a compound
with a crown conformation, the formylation of compound 9c was
investigated. Treatment of compound 9c with phosphoryl chloride
and dimethylformamide gave the dialdehyde 10 in 92% yield (Scheme
4). The 1H NMR spectrum confirmed the presence of the formylated
product 10 with the two aldehyde protons appearing as a singlet at
10.33 ppm, and the two sets of N-methyleneprotonsappearingastwo
doublets at 5.31 and 5.66 ppm. However, a single crystalof compound
10 could not be obtained, and its conformation was not able to be
predicted from the NMR spectra. This is due to the fact that the 1H
NMR spectrum of compound 10 is similar to the 1H NMR spectra of
both cyclotriveratrylenes, which exist in a crown conformation15e17
and the cyclic compound 6, which has a saddle conformation.
Me
Me
MeO
Me
MeO
MeO
OMe
CH2I2
N
N
N
MeO
H
NaOH
40%
OMe
7
11
RCHO, POCl3
CH2Cl2, 4 h
20-33%
12
____________
R
R
Me
Me
MeO
MeO
OMe
a
4-ClC6H4
Scheme 4.
N
N
b
c
4-NO2C6H4
4-MeOC6H4
The successful formylation of compound 9c is an indication of
the stability of the nine-membered ring. Indeed all attempts to carry
out hydrogenolysis of the xylyl group from compound 9c failed.
OMe
Scheme 5.

K. Somphol et al. / Tetrahedron 68 (2012) 1862e1868
1865
the formation of nine-membered ring compounds, the six-
membered ring compounds 12 could only be formed in low
yields, presumably because of the greater steric interference be-
tween the indole C3 substituents and the aryl group in a six-
membered ring compared to the nine-membered ring com-
pounds. The 1H NMR data of the cyclic compounds 12aec displayed
the methine bridge protons in the range 5.6e5.8 ppm, and the N-
methylene bridge protons as AB patterns at 5.65 and 6.59 (R¼Cl),
5.66 and 6.11 (R¼NO2) and 5.59 and 6.11 ppm (R¼OMe) while the
diindolylmethane starting material 11 showed the methylene
bridge protons as a singlet at 5.97 ppm. Additionally, the 13C NMR
spectrum showed the methine bridge carbons at 35.39, 36.01 and
35.06, and the methylene bridge carbons at 60.63, 54.63 and
53.82 ppm.
128.2 (ArCH), 111.2, 128.9, 135.0, 136.6 (ArC). Mass spectrum (EI): m/z
365(Mþ1,15%), 364(M, 55), 234(25),233(50),232(100), 219(25),218
(85), 217 (55), 130 (40), 104 (45).
4.1.2. 4,27-Dimethyl-11,20-diazaheptacyclo[18,7,0,01,20,03,11,05,10,013,18
21,26]heptadoaconta-1(27),3,5,7,9,13,15,17,21,23,25-undecaene (3). 1,2-
,
0
Di-(3-methylindol-1-ylmethyl)benzene 2 (0.19 g, 0.522 mmol) was
dissolved in glacial acetic acid (250 mL) and treated with excess 35%
aqueous formaldehyde (w10 mL) and stirred overnight at room
temperature. The yellow solution was diluted with water and
extracted with dichloromethane. The combined extracts were
washed with saturated sodium bicarbonate until the washings were
neutral, dried over magnesium sulfate and concentrated under re-
duced pressure. The crude product was purified using ‘dry-column’
flash chromatography with dichloromethane/light petroleum (1/1)
eluant to afford the title compound as a white solid (0.080 g, 40%); mp
320 ꢀC (dec); [Found: C, 82.3; H, 6.5; N, 7.0. C27H24N2$H2O requires C,
82.2; H, 6.6; N, 7.1%]; Rf (50% CH2Cl2/light petroleum) 0.43; nmax
(Nujol) 3020, 1460, 1415, 1360, 1340, 1310, 1280, 1210, 1170, 1020,
3. Conclusions
New examples of cyclotriveratrylenes containing one benzene
ring and two indole rings linked through N1 and C2 have been
prepared by acid-catalysed reactions of formaldehyde and aryl al-
dehydes with 1,2-di-(1-indolylmethyl)benzene compounds. Simi-
lar acid-catalysed cyclisation reactions of N,N0-diindolylmethanes
with aldehydes to form a new six-membered ring can also be
achieved, but in relatively lower yields than those for the nine-
membered ring formation.
1010, 845, 835, 750, 735, 660 cmꢁ1
60,500 cmꢁ1 Mꢁ1), 290sh (23,300), 296 (23,500). 1H NMR
(300 MHz, CDCl3): 2.39 (6H, s, Me), 4.67 (2H, s, CH2), 5.02 (4H, s, CH2
; lmax (CH2Cl2) 234 nm
(
3
d
benzyl), 7.01e7.07 (4H, m, ArH), 7.11e7.26 (2H, m, ArH), 7.18e7.21 (2H,
m, ArH), 7.34e7.36 (2H, m, ArH), 7.50e7.52 (2H, m, ArH). 13C NMR
(75 MHz, CDCl3): d 9.0 (Me), 23.0 (CH2), 47.5 (CH2 benzyl),110.1,118.1,
119.3, 121.3, 127.7, 131.4 (ArCH), 107.3, 128.9, 131.9, 136.3, 136.7 (ArC).
Mass spectrum (EI): m/z 377 (Mþ1, 5%), 376 (M, 20), 232 (100), 217
(15),188(10),144(10). CrystalsforasinglecrystalX-raydetermination
were obtained by recrystallization from chloroform.
4. Experimental
4.1. General
Melting points were measured using a Mel-Temp melting point
apparatus, and are uncorrected. Microanalyses were performed on
a Carlo Erba Elemental Analyser EA 1108 at the Campbell Micro-
4.1.3. 1,2-Di(4,6-dimethoxy-3-phenylindol-1-ylmethyl)benzene
(5). To
a stirred solution of 4,6-dimethoxy-3-phenylindole 4
(0.59 g, 2.33 mmol) in dichloromethane (40 mL) was added tetra-
butylammonium hydrogen sulfate (0.082 g, 0.241 mmol), followed
analytical Laboratory, University of Otago, New Zealand. 1H and 13
C
NMR spectra were obtained on a Bruker DPX300 (300 MHz) spec-
trometer. Mass spectra were recorded on either a Bruker FT-ICR MS
(EI) or a Micromass ZQ2000 (ESI) at UNSW, or a Shimadzu LCMS QP
8000 (ESI) at the University of Otago, New Zealand. Infrared spectra
were recorded with a Thermo Nicolet 370 FTIR spectrometer using
KBr discs. Ultraviolet-visible spectra were recorded using a Varian
Cary 100 Scan spectrometer. Column chromatography was carried
out using Merck 230e400 mesh ASTM silica gel, whilst preparative
thin layer chromatography was performed using Merck silica gel
7730 60GF254. Merck 60H silica gel was employed for ‘dry-column’
flash chromatography described by Harwood.21 Compounds were
detected by short and long wavelength ultraviolet light and with
iodine vapour.
by a,a
0-dibromo-o-xylene (0.32 g, 1.21 mmol) and 50% aqueous
sodium hydroxide (40 mL). After stirring for 36 h at room temper-
ature, the mixture was diluted with water and the two phases were
separated. The aqueous phase was extracted with dichloromethane
and the combined extracts were washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
crude product was purified using a plug of silica with dichloro-
methane/light petroleum (1/1) eluant to yield the title compound as
a white solid (0.50 g, 70%), mp 204e205 ꢀC; [Found: C, 78.7; H, 5.9;
N, 4.8. C40H36N2O4 requires C, 78.9; H, 6.0; N, 4.6%]; Rf (50% CH2Cl2/
light petroleum) 0.53; nmax (Nujol) 1600, 1580, 1500, 1460, 1380,
1340, 1320, 1280, 1230, 1210, 1180, 1060, 970, 940, 810, 790, 760,
740, 720, 700 cmꢁ1
;
lmax (CH2Cl2) 231 nm (
3
101,500 cmꢁ1 Mꢁ1),
288 (45,500); 1H NMR (300 MHz, CDCl3):
d
3.66 and 3.82 (12H, 2s,
4.1.1. 1,2-Di-(3-methylindol-1-ylmethyl)benzene (2). Freshlycrushed
potassium hydroxide (7.20 g,128 mmol)and3-methylindole1 (2.10 g,
0.016 mol) in dry dimethyl sulfoxide (40 mL) was stirred for 1 h at
OMe), 5.14 (4H, s, CH2), 6.19 (2H, d, J 1.8 Hz, H5), 6.27 (2H, d, J 1.8 Hz,
H7), 6.76 (2H, s, H2), 7.05e7.08 (2H, m, ArH); 7.21e7.36 (8H, m,
ArH), 7.57e7.60 (4H, m, ArH). 13C NMR (75 MHz, CDCl3):
d 47.8
room temperature.
a,a
0-Dibromo-o-xylene (2.11 g, 7.99 mmol) and
(CH2), 55.1 and 55.5 (OMe), 85.4 (C5), 92.3 (C7), 123.8, 125.7, 127.6,
128.6, 129.1, 129.4 (ArCH), 110.7, 118.6, 134.6, 135.8, 138.9 (ArC),
155.1 and 157.6 (CeOMe). Mass spectrum (MALDI): m/z 608, M.
sodium iodide (2.40 g, 16.0 mmol) were added and the mixture was
stirred for an additional 5 h. Water was added and the resulting pre-
cipitate was filtered off, washed with water and dried. The crude
product was purified using gravity column chromatography with
dichloromethane/light petroleum (1/1) as eluant and followed by re-
crystallization from methanol to afford the title compound as a white
solid (1.49 g, 51%); mp 142e143 ꢀC; [Found: C, 84.9; H, 6.9; N, 7.6.
C26H24N2$0.25H2O requires C, 84.6; H, 6.7; N, 7.6%]; Rf (50% CH2Cl2/
light petroleum) 0.63; nmax (Nujol) 3040, 1610,1580,1450,1375, 1315,
4.1.4. 2-(4-Chlorophenyl)-6,8,23,25-tetramethoxy-4,27-diphenyl-
11,20-diazaheptacyclo[18,7,0,01,20,03,11,05,10,013,18,021,26]heptadoa-
conta-1(27),3,5,7,9,13,15,17,21,23,25-undecaene (6). 1,2-Di(4,6-dime
thoxy-3-phenylindol-1-ylmethyl)benzene
5 (0.28 g, 0.461 mmol)
and p-chlorobenzaldehyde (0.065 g, 0.46 mmol) in anhydrous chlo-
roform were treated with a catalytic amount of phosphoryl chloride
and stirred for 13 h. The solution was basified with dilute aqueous
sodium hydroxide and extracted with dichloromethane. The com-
bined extracts were washed with saturated brine, dried over magne-
sium sulfate and concentrated under reduced pressure. The crude
product was purified using gravity column chromatography with
1240, 1185, 1120, 1010, 870, 850, 735 cmꢁ1
;
lmax (MeOH) 225 nm (
3
46,300 cmꢁ1 Mꢁ1), 290 (7300). 1H NMR (300 MHz, CDCl3):
d
2.43 (6H,
s, Me), 5.20 (4H, s, CH2), 6.79 (2H, s, H2), 6.94e6.97 (2H, m, ArH),
7.18e7.28 (8H, m, ArH), 7.67e7.71 (2H, m, ArH). 13C NMR (75 MHz,
CDCl3):
d 9.6 (Me), 47.2 (CH2), 109.3, 119.0, 119.1, 121.7, 125.3, 128.1,

1866
K. Somphol et al. / Tetrahedron 68 (2012) 1862e1868
dichloromethane/light petroleum (1/1) eluant to afford the title com-
pound as a white solid (0.23 g, 68%), mp 263e264 ꢀC; [Found: C, 76.9;
H, 5.4; N, 3.8. C47H39ClN2O4$0.25H2O requires C, 76.7; H, 5.4; N, 3.8%];
Rf (50% CH2Cl2/light petroleum) 0.48; nmax (Nujol) 3020, 1600, 1525,
purification, the title compound 9b (87 mg, 71%) was obtained as
a yellow solid, mp 278e279 ꢀC; [Found: C, 77.1; H, 6.7; N, 4.5.
C38H38N2O4$0.25H2O requires C, 77.2; H, 6.7; N, 4.7%]; nmax (KBr)
3436, 2980, 2921, 2834, 1735, 1618, 1612, 1592, 1496, 1461, 1450,
1443, 1323, 1312, 1248, 1210, 1153, 1127, 1102, 1065, 1041, 936,
1450,1340,1240,1205,1140,1080,1010, 925, 800, 760, 695 cmꢁ1
;
lmax
95,600 cmꢁ1 Mꢁ1), 288 (36,000); 1H NMR
3.67and3.78(12H, 2s,OMe), 4.80(2H, d,J15.4 Hz,
(CH2Cl2) 231 nm (
(300 MHz,CDCl3):
3
806 cmꢁ1
;
lmax (CH2Cl2) 231 nm
(
3
80,300 cmꢁ1 Mꢁ1), 287
2.38 (6H, s, Me
d
(31,900); 1H NMR spectrum (300 MHz, CDCl3):
d
CH2), 5.14 (2H, d, J 15.4 Hz, CH2), 6.23 (2H, d, J 2.0 Hz, H5), 6.41 (2H, d, J
2.0 Hz, H7), 6.51 (1H, s, CH bridging), 6.73 (2H, d, J 8.4 Hz, ClC6H4), 6.90
(2H, d, J 8.4 Hz, ClC6H4), 7.22e7.49 (14H, m, ArH). 13C NMR (75 MHz,
indolyl), 2.29 (3H, s, Me tolyl), 3.71 and 3.87 (12H, 2s, OMe), 4.58
and 5.00 (4H, 2d, J 15.8 Hz, CH2), 6.15 (2H, d, J 1.7 Hz, H5), 6.20 (1H,
s, CH bridging), 6.24 (2H, d, J 1.7 Hz, H7), 7.02 (4H, s, ArH tolyl),
7.21e7.24 (2H, m, ArH xylyl), 7.32e7.36 (2H, m, ArH xylyl); 13C NMR
CDCl3):d39.6(CHbridging), 48.7(CH2), 55.2and55.5(OMe), 86.9(C5),
92.4 (C7), 126.2, 127.3 (two overlapping), 127.7, 128.0, 129.5, 131.0
(ArCH), 111.8, 117.5, 130.9, 131.4, 132.6, 135.7, 136.6, 140.1 (ArC), 154.8
and 157.5 (CeOMe). Mass spectrum (ES): m/z 732 (M, 37Cl, 35%), 730
(M, 35Cl, 75), 729 (100). Crystals for a single crystal X-ray de-
termination were obtained by recrystallization from dichloro-
methane/methanol.
spectrum (75 MHz, CDCl3): d 12.0 (Me indolyl), 20.9 (Me tolyl), 39.0
(CH bridging), 48.2 (CH2), 55.1 and 55.4 (OMe), 86.7 (C5), 91.3 (C7),
127.4, 127.9, 129.0, 130.7 (ArCH), 109.4, 112.9, 132.1, 135.5, 137.0,
138.9, 139.5, 155.0, 156.8 (ArC). Mass spectrum (ESI): m/z 587 (Mþ1,
100%), 475 (50).
4.1.8. 2-(4-Chlorophenyl)-4,27-dimethyl-6,8,23,25-tetramethoxy-
11,20-diazahexacyclo[18,7,0,03,11,05,10,0 13,18,021,26]heptacosa-1(27),3,
5,7,9,13,15, 17,21,23,25-undecaene (9c). This compound was pre-
pared by the same method as compound 6, from the diindolylxy-
4.1.5. 1,2-Di(4,6-dimethoxy-3-methylindol-1-ylmethyl)benzene
(8). This compound was prepared by the same method as com-
pound 2, from 4,6-dimethoxy-3-methylindole
5.20 mmol), potassium hydroxide (0.29 g, 5.20 mmol), dry di-
methyl sulfoxide (20 mL) and
0-dibromo-o-xylene (0.86 g,
7
(1.00 g,
lene
8 (73 mg, 0.151 mmol), p-chlorobenzaldehyde (21 mg,
a,
a
0.150 mmol) and chloroform (5 mL). After stirring for 2 h and pu-
rification, the title compound 9c (90 mg, 99%) was obtained as
a white solid, mp 289e291 ꢀC; [Found: C, 73.1; H, 5.6; N, 4.5.
C37H35ClN2O4 requires C, 73.2; H, 5.8; N, 4.6%]; nmax (KBr) 3437,
2991, 2921, 2831, 2361, 2334, 2328, 1619, 1556, 1596, 1571, 1502,
2.60 mmol). After chromatography, it was recrystallised from
dichloromethane/light petroleum to yield the diindolylxylene 8
(0.56 g, 44%) as white crystals, mp 183e184 ꢀC; [Found: C, 74.5; H,
6.7; N, 5.7. C30H32N2O4 requires C, 74.4; H, 6.7; N, 5.8%]; Rf (50%
CH2Cl2/light petroleum) 0.67; nmax (KBr) 3417, 2922, 2840, 2355,
2336, 1614, 1556, 1502, 1470, 1453, 1433, 1325, 1272, 1222, 1204,
1452, 1485, 1431, 1316, 1293, 1209, 1142, 1123 cmꢁ1
231 nm (
(300 MHz, CDCl3):
;
lmax (CH2Cl2)
79,500 cmꢁ1 Mꢁ1), 284 (30,700); 1H NMR spectrum
2.37 (6H, s, Me), 3.71 and 3.86 (12H, 2s, OMe),
3
1161, 1144, 1100, 1046, 936, 818, 746 cmꢁ1
57,000 cmꢁ1 Mꢁ1), 279 (16,600); 1H NMR spectrum (300 MHz,
CDCl3): 2.40 (6H, d, J 1.1 Hz, Me), 3.69 and 3.87 (12H, 2s, OMe),
;
lmax (CH2Cl2) 231 nm (
3
d
4.58 and 4.94 (4H, 2d, J 16.0 Hz, CH2), 6.15 (2H, d, J 1.9 Hz, H5), 6.19
(1H, s, CH bridging), 6.24 (2H, d, J 1.9 Hz, H7), 7.07 (2H, d, J 8.3 Hz,
ArH), 7.16e7.26 (4H, m, ArH), 7.33e7.36 (2H, m, ArH); 13C NMR
d
5.01 (4H, s, CH2), 6.09 (2H, d, J 1.9 Hz, H5), 6.15 (2H, d, J 1.9 Hz, H7),
6.44 (2H, d, J 1.1 Hz, H2), 6.92e6.95 (2H, m, ArH xylyl), 7.22e7.26
spectrum (75 MHz, CDCl3):
d 12.0 (Me), 38.9 (CH bridging), 48.2
(2H, m, ArH xylyl). 13C NMR spectrum (75 MHz, CDCl3):
d
12.0 (Me),
(CH2) 55.1 and 55.4 (OMe), 86.6 (C5), 91.4 (C7), 127.5, 128.4, 129.4,
130.7 (ArCH),109.7,112.8,131.3,131.7,136.8, 139.5, 140.6,155.1,157.1
(ArC). Mass spectrum (ESI): m/z 607 (Mþ1, 35Cl, 100%).
47.3 (CH2) 55.1 and 55.4 (OMe), 85.2 (C5), 91.0 (C7), 122.5 (C2),
128.1, 128.5 (ArCH), 111.7, 113.0, 135.0, 138.4, 155.5, 157.3 (ArC). Mass
spectrum (ESI): m/z 485 (Mþ1, 100%), 378 (20).
4.1.9. 4,27-Dimethyl-2-(4-nitrophenyl)-6,8,23,25-tetramethoxy-
11,20-diazahexacyclo[18,7,0,03,11,05,10,013,18,021,26]heptacosa-
1(27),3,5,7,9,13, 15,17,21,23,25-undecaene (9d). Method A. This
compound was prepared by the same method as compound 6, from
the diindolylxylene 8 (100 mg, 0.207 mmol), p-nitrobenzaldehyde
(32 mg, 0.212 mmol) and chloroform (5 mL). After stirring for 2 h
and purification, the title compound 9d (25 mg, 19%) was obtained
as a brown solid.
4.1.6. 4,27-Dimethyl-2-phenyl-6,8,23,25-tetramethoxy-11,20-
diazahexacyclo[18,7,0,03,11,05,10,013,18,021,26]heptacosa-1(27),3,5,7,9,
13,15,17,21,23,25-undecaene (9a). This compound was prepared by
the same method as compound 6, from the diindolylxylene 8
(30 mg, 0.062 mmol), benzaldehyde (6.5 mg, 0.062 mmol) and
chloroform (5 mL). After stirring for 2 h and purification, the title
compound 9a (35 mg, 98%) was obtained as a yellow solid, mp
265e267 ꢀC; [Found: C, 75.5; H, 6.2; N, 4.7. C37H36N2O4$H2O re-
quires C, 75.2; H, 6.5; N, 4.7%]; nmax (KBr) 3428, 2917, 2835, 1614,
1595, 1500, 1465, 1450, 1311, 1246, 1208, 1153, 1126, 1101, 935, 808,
Method B.
A solution of the diindolylxylene 8 (50 mg,
0.103 mmol) and p-nitrobenzaldehyde (16 mg, 0.103 mmol) in dry
chloroform (5 mL) was treated with a catalytic amount of p-tolue-
nesulfonic acid monohydrate (several crystals). The reaction mix-
ture was stirred at room temperature for 2 h, and then the solution
was basified with dilute aqueous sodium hydroxide and extracted
with dichloromethane. The combined extracts were washed with
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The crude product was purified using flash col-
umn chromatography with dichloromethane eluant and followed
by recrystallization from dichloromethane/light petroleum to af-
ford the title compound 9d (58 mg, 88%) as brown crystals, mp
229e230 ꢀC; [Found: C, 70.0; H, 5.7; N, 6.6. C37H35N3O6$H2O re-
quires C, 69.9; H, 5.9; N, 6.6%]; Rf (50% CH2Cl2/light petroleum) 0.56;
nmax (KBr) 2937, 2839, 1620, 1593, 1521, 1500, 1453, 1345, 1317,
760 cmꢁ1
;
lmax (CH2Cl2) 230 nm
(
3
63,500 cmꢁ1 Mꢁ1), 234
2.39
(63,900), 287 (28,300); 1H NMR spectrum (300 MHz, CDCl3):
d
(6H, s, Me), 3.72 and 3.87 (12H, 2s, OMe), 4.60 and 5.01 (4H, 2d,
J 16.0 Hz, CH2), 6.16 (2H, d, J 1.3 Hz, H5), 6.26 (3H, br s, H7 and CH
bridging), 7.14e7.24 (7H, m, ArH), 7.34e7.37 (2H, m, ArH); 13C NMR
spectrum (75 MHz, CDCl3):
d 11.9 (Me), 39.4 (CH bridging), 48.2
(CH2), 55.1 and 55.4 (OMe), 86.7 (C5), 91.3 (C7), 126.0, 127.4,
128.1, 128.3, 130.7 (ArCH), 109.5, 112.9, 131.9, 136.9, 139.5, 142.0,
155.7, 156.9 (ArC). Mass spectrum (ESI): m/z 573 (Mþ1, 100%),
535 (35).
4.1.7. 4,27-Dimethyl-2-(4-methylphenyl)-6,8,23,25-tetramethoxy-
11,20-diazahexacyclo[18,7,0,03,11,05,10,013,18,021,26]heptacosa-
1(27),3,5,7,9,13,15, 17,21,23,25-undecaene (9b). This compound was
prepared by the same method as compound 6, from the diindo-
1247, 1206, 1152, 1127, 1105 cmꢁ1
45,300 cmꢁ1 Mꢁ1), 282 (21,300); 1H NMR spectrum (300 MHz,
CDCl3): 2.38 (6H, s, Me), 3.72 and 3.87 (12H, 2s, OMe), 4.62 and
; lmax (CH2Cl2) 226 nm
(
3
d
lylxylene
8
(100 mg, 0.207 mmol), p-tolualdehyde (25 mg,
4.93 (4H, 2d, J 16.0 Hz, CH2), 6.17 (2H, d, J 1.9 Hz, H5), 6.24 (2H, d, J
1.9 Hz, H7), 6.31 (1H, s, CH bridging), 7.24e7.27 (2H, m, ArH),
0.208 mmol) and chloroform (5 mL). After stirring for 1 h and

K. Somphol et al. / Tetrahedron 68 (2012) 1862e1868
1867
7.32e7.37 (4H, m, ArH), 8.09 (2H, d, J 9.0 Hz, ArH). 13C NMR spec-
trum (75 MHz, CDCl3): 12.1 (Me), 39.6 (CH bridging), 48.2 (CH2),
55.1 and 55.4 (OMe), 86.6 (C5), 91.6 (C7), 123.6, 127.7, 128.9, 130.7
(ArCH), 110.1, 112.8, 130.3, 136.5, 139.6, 146.3, 149.8, 155.2, 157.3
(ArC). Mass spectrum (ESI): m/z 617 (Mþ1, 100%).
nmax (KBr) 2925, 2842,1625,1597,1575,1504,1488, 1456, 1320,1296,
1212, 1167, 1128, 802 cmꢁ1
lmax (CH2Cl2) 231 nm
55,100 cmꢁ1 Mꢁ1), 282 (20,800); 1H NMR spectrum (300 MHz,
(CD3)2SO): 2.38 (6H, s, Me), 3.79 and 3.82 (12H, 2s, OMe), 5.65 and
d
;
(
3
d
6.59 (2H, 2d, J 11.3 Hz, CH2), 5.78 (1H, s, CH bridging), 6.19 (2H, d, J
1.5 Hz, H5), 6.84 (2H, d, J 1.5 Hz, H7), 7.09 and 7.29 (4H, 2d, J 8.5 Hz,
4.1.10. 2-(4-Chlorophenyl)-9,22-diformyl-4,27-dimethyl-6,8,23,25-
tetramethoxy-11,20-diazahexacyclo[18,7,0,03,11,05,10,013,18,021,26]hep-
tacosa-1(27),3,5,7,9,13,15,17,21,23,25-undecaene (10). To an ice cold
solution of phosphoryl chloride (0.18 mL, 0.20 mmol) in dry N,N0-
dimethylformamide (0.5 mL), a cold solution of compound 9c
(50 mg, 0.082 mmol) in dry N,N0-dimethylformamide (5 mL) was
added slowly. The reaction mixture was stirred in ice for 1 h, and
after dilution with water was basified with 10% sodium hydroxide
solution. The resulting precipitate was filtered off, washed with
water until the washings were neutral and dried to yield the title
compound 10 (50 mg, 92%) as a yellow solid, mp 275e276 ꢀC.
[Found: C, 70.3; H, 5.4; N, 4.3. C39H35ClN2O6 requires C, 70.6; H, 5.3;
N, 4.2%]; nmax (KBr) 2938, 2880, 2843, 1727, 1654, 1583, 1553, 1490,
ArH). 13C NMR spectrum (75 MHz, (CD3)2SO):
d 11.0 (Me), 35.4 (CH
bridging), 55.6 and 55.9 (OMe), 60.6 (CH2), 86.3 (C5), 92.1 (C7),129.0,
129.3 (ArCH), 72.6 (C5), 106.6 (C7), 112.4, 128.8, 135.9, 141.9, 155.0,
157.2 (ArC). Mass spectrum (ESI): m/z 519 (Mþ1, 37Cl, 55%), 517 (Mþ1,
35Cl, 70%).
4.1.13. 4,20-Dimethyl-6,8,16,18-2-(4-nitrophenyl)-tetramethoxy-11,13-
diazapentacyclo[11,7,0,03,11,05,10,014,19]icosa-1(20),3,5,7,9,14,16,18-
octaene (12b). This compound was prepared according to the
method described for preparation of compound 12a using the diin-
dolylmethane 11 (80 mg, 0.203 mmol), p-nitrobenzaldehyde (30 mg,
0.199 mmol) and dichloromethane (10 mL). After purification, the
title compound 12b (27 mg, 26%) was obtained as an orange solid, mp
253e254 ꢀC. [Found: C, 68.4; H, 5.6; N, 7.8. C30H29N3O6 requires C,
68.3; H, 5.5; N, 8.0%]; nmax (KBr) 2991, 2923, 2842, 1624, 1594, 1577,
1464, 1401, 1245, 1210, 1154, 1125, 1099, 1015, 797, 165 cmꢁ1
(CH2Cl2) 230 nm (
27,900 cmꢁ1 Mꢁ1), 263 (41,000), 328 (15,000);
1H NMR spectrum (300 MHz, CDCl3):
1.89 (6H, s, Me), 3.84 and
; lmax
3
d
1524, 1504, 1457, 1349, 1319, 1293, 1212, 1147, 1126, 805 cmꢁ1
(CH2Cl2) 231 nm (
60,200 cmꢁ1 Mꢁ1), 280 (37,100); 1H NMR spec-
trum (300 MHz, (CD3)2SO): 2.49 (6H, s, Me), 3.89 and 3.90 (12H, 2s,
; lmax
3.88 (12H, 2s, OMe), 5.31 and 5.66 (4H, 2d, J 16.0 Hz, CH2), 6.07 (2H,
s, H5), 6.26 (1H, s, CH bridging), 6.80e6.90 (4H, m, ArH), 7.13 and
7.25 (4H, 2d, J 8.3 Hz, ClArH), 10.33 (2H, s, CHO). 13C NMR spectrum
3
d
OMe), 5.66 and 6.11 (2H, 2d, J 10.0 Hz, CH2), 5.69 (1H, s, CH bridging),
6.24 (2H, d, J 1.9 Hz, H5), 6.41 (2H, d, J 1.9 Hz, H7), 7.28 and 8.06 (4H,
(75 MHz, CDCl3): d 11.0 (Me), 42.9 (CH bridging), 47.2 (CH2) 55.2 and
56.7 (OMe), 87.6 (C5), 126.6, 128.6, 130.7, 131.6 (ArCH), 107.3, 111.1,
115.2, 132.4, 136.3, 135.9, 136.4, 139.8, 161.1, 164.3 (ArC), 188.3 (CHO).
Mass spectrum (ESI): m/z 685 ([MþNa]þ, 100%), 633 (M, 70%).
2d, J 8.6 Hz, ArH).13C NMR spectrum (75 MHz, (CD3)2SO):
d 10.8 (Me),
36.0 (CH bridging), 54.2 (CH2), 55.2 and 55.8 (OMe), 84.6 (C5), 91.8
(C7), 123.8, 128.1 (ArCH), 108.2, 112.9, 127.3, 135.9, 146.6, 148.9, 154.5,
157.6 (ArC). Mass spectrum (ESI): m/z 528 (Mþ1, 100%), 204 (35).
4.1.11. Di(4,6-dimethoxy-3-methylindol-1-yl)methane (11). A mix-
ture of 4,6-dimethoxy-3-methylindole
7
(1.00 g, 5.23 mmol),
4.1.14. 4,20-Dimethyl-6,8,16,18-2-(4-methoxyphenyl)-tetramethoxy-
11,13-diazapentacyclo[11.7.0.03,11.05,10.014,19]icosa-
1(20),3,5,7,9,14,16,18- octaene (12c). This compound was prepared
according to the method described for preparation of compound 12a
using the diindolylmethane 11 (100 mg, 0.254 mmol), p-methox-
ybenzaldehyde (36 mg, 0.265 mmol) and dichloromethane (10 mL).
After purification the title compound 12c (26 mg, 20%) was obtained
as a white solid, mp 227e229 ꢀC. [Found: C, 70.4; H, 6.1; N, 5.2.
C31H32N2O5$0.25CH2Cl2 requires C, 70.3; H, 6.1; N, 5.3%]; nmax (KBr)
2991, 2923, 2842, 1624, 1594, 1577, 1524, 1504, 1457, 1349, 1319,
freshly crushed potassium hydroxide (0.29 g, 5.23 mmol) and dry
dimethyl sulfoxide (20 mL) was stirred at room temperature. After
1 h diiodomethane (0.72 g, 2.62 mmol) was added and the mixture
stirred for an additional 2 h. Water was added and the yellow
precipitate was collected, washed with water and dried. The crude
product was then purified by flash column chromatography
(dichloromethane/light petroleum, 1/1) to afford the diindolyl-
methane 11 (0.41 g, 40%) as a white solid, mp 192.5e195 ꢀC. [Found:
C, 69.8; H, 6.7; N, 7.0. C23H26N2O4 requires C, 70.0; H, 6.6; N, 7.1%]; Rf
(50% CH2Cl2/light petroleum) 0.68; nmax (KBr) 1620, 1593, 1563,
1499, 1452, 1293, 1463, 1210, 1182, 1148, 1105, 1055, 931, 796, 755,
1293, 1212, 1147, 1126, 805 cmꢁ1
58,500 cmꢁ1 Mꢁ1), 280 (36,100); 1H NMR spectrum (300 MHz,
CDCl3): 2.52 (6H, s, Me), 3.72 (3H, s, OMe), 3.90 (12H, s, OMe
;
lmax (CH2Cl2) 231 nm
(
3
739 cmꢁ1
;
lmax (CH2Cl2) 230 nm
(
3
65,500 cmꢁ1 Mꢁ1), 274
2.35 (6H, s, Me),
d
(22,600); 1H NMR spectrum (300 MHz, CDCl3):
d
indolyl), 5.59 and 6.11 (2H, 2d, J 9.0 Hz, CH2), 5.60 (1H, s, CH bridging),
6.23 (2H, d, J 1.9 Hz, H5), 6.41 (2H, d, J 1.9 Hz, H7), 6.73 and 7.02 (4H,
3.79 and 3.85 (12H, 2s, OMe), 5.97 (2H, s, CH2), 6.17 (2H, d, J 1.9 Hz,
H5), 6.44 (2H, d, J 1.9 Hz, H7), 6.61 (2H, br s, H2). 13C NMR spectrum
2d, J 8.7 Hz, ArH). 13C NMR spectrum (75 MHz, CDCl3):
d 10.7 (Me),
(75 MHz, CDCl3):
(C5), 91.4 (C7), 121.7 (ArCH), 112.8, 113.4, 137.9, 155.6, 157.7 (ArC).
Mass spectrum (ESI): m/z 395 (Mþ1, 2%), 204 (100).
d
11.9 (Me), 55.1 and 55.5 (OMe), 56.0 (CH2), 85.3
35.1 (CH bridging), 53.8 (CH2), 55.2, 55.6 and 55.8 (OMe), 84.6 (C5),
91.5 (C7), 113.9, 128.2 (ArCH), 107.2, 113.0, 129.4, 131.9, 133.4, 135.7,
155.4, 157.2 (ArC). Mass spectrum (ESI): m/z 511 (Mꢁ1, 20%), 503 (45),
429 (25), 338 (35), 324 (30), 310 (45), 288 (25), 208 (35).
4.1.12. 2-(4-Chlorophenyl)-4,20-dimethyl-6,8,16,18-tetramethoxy-
11,13-diazapentacyclo[11,7,0,03,11,05,10,014,19]icosa-1(20),3,5,7,9,14,16,18-
octaene (12a). A catalytic amount of p-toluenesulfonic acid mono-
hydrate (several crystals) was added to a mixture of diindolyl-
methane 11 (79 mg, 0.20 mmol), p-chlorobenzaldehyde (29 mg,
0.20 mmol) and dichloromethane (10 mL). The reaction mixture was
stirred in an ice bath for 4 h, and then water was added and the so-
lution extracted with dichloromethane. The combined extracts were
washed with saturated sodium bicarbonate and brine and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the crude product was purified using ‘dry-column’ flash
chromatography with dichloromethane/light petroleum eluant to
give the title compound 12a (34 mg, 33%) as a pale green solid, mp
259e260 ꢀC. [Found: C, 69.0; H, 5.7; N, 5.2. C30H29ClN2O4$0.75H2O
requires C, 69.1; H, 5.7; N, 5.4%]; Rf (50% CH2Cl2/lightpetroleum)0.51;
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged. M.S. acknowledges receipt of a post-
graduate scholarship from the Australian Government.
References and notes
1. Collet, A. In Comprehensive Supramolecular Chemistry; Atwood, J. L., Davies, J. E.
€
D., MacNicol, D. D., Vogtle, F., Lehn, J. M., Eds.; Pergamon: Oxford, 1996; Vol. 6,
pp 281e303.
2. Steed, J. W.; Junk, P. C.; Atwood, J. L.; Barnes, M. J.; Raston, C. L.; Burkhalter, R. S.
J. Am. Chem. Soc. 1994, 116, 10346e10347.
3. Hardie, M. J.; Godfrey, P. D.; Raston, C. L. Chem.dEur. J. 1999, 5, 1828e1833.
4. Hardie, M. J.; Raston, C. L. Cryst. Growth Des. 2001, 1, 53e58.

1868
K. Somphol et al. / Tetrahedron 68 (2012) 1862e1868
€
€
5. Robinson, G. M. J. Chem. Soc. 1915, 102, 267e276.
6. Erdtman, H.; Haglid, F.; Ryhage, R. Acta Chem. Scand. 1964, 1249e1254.
7. Lindsey, A. S. J. Chem. Soc. 1965, 1685e1692.
8. White, J. D.; Gesner, B. D. Tetrahedron Lett. 1968, 9, 1591e1594.
9. Collet, A. Tetrahedron 1987, 43, 5725e5759.
15. Bergman, J.; Hogberg, S.; Lindstrom, O. J. Tetrahedron 1970, 26, 3347e3352.
16. Bjeldanes, L. F.; Staub, R. E. J. Org. Chem. 2003, 68, 167e169.
17. Santoso, M.; Somphol, K.; Kumar, N.; Black, D. StC. Tetrahedron 2009, 65,
5977e5983.
18. Crystallographic data for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 835735 (3) and CCDC 835734 (6). X-ray crystal structures were obtained
by the Crystallography Laboratory, UNSW Analytical Centre, Sydney, Australia.
19. Black, D. StC.; Craig, D. C.; Kumar, N. Tetrahedron Lett. 1991, 32, 1587e1590.
20. Wood, K.; Black, D. StC.; Kumar, N. Tetrahedron Lett. 2009, 50, 574e576.
21. Harwood, L. M. Aldrichimica Acta 1985, 18, 25.
10. Lindsey, A. S. Chem. Ind. (London, U.K.) 1963, 823e824.
€
11. Treibs, A.; Kreuzer, F. H.; Haberle, N. Justus Liebigs Ann. Chem. 1970, 733, 37e43.
12. Fumoto, Y.; Uno, H.; Ito, S.; Tsugumi, Y.; Sasaki, M.; Kitawaki, Y.; Ono, N. J. Chem.
Soc., Perkin Trans. 1 2000, 2977e2981.
13. Uno, H.; Fumoto, Y.; Inoue, K.; Ono, N. Tetrahedron 2003, 59, 601e605.
14. Stepien, M.; Sessler, J. L. Org. Lett. 2007, 9, 4785e4787.