Synthesis of indolocyclotriveratrylenes

Article abstract of DOI:10.1016/j.tet.2009.05.092

Indolocyclotriveratrylenes linked through C2 and C3 can be prepared by acid-catalysed reactions of indole-2- or -3-methanols. The initial example, compound 1 has been confirmed, and an X-ray crystal structure is reported. Seven new examples of indolocyclo

Full text of DOI:10.1016/j.tet.2009.05.092

Tetrahedron 65 (2009) 5977–5983
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Synthesis of indolocyclotriveratrylenes
*
Mardi Santoso, Kittiya Somphol, 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:
Indolocyclotriveratrylenes linked through C2 and C3 can be prepared by acid-catalysed reactions of in-
dole-2- or -3-methanols. The initial example, compound 1 has been confirmed, and an X-ray crystal
structure is reported. Seven new examples of indolocyclotriveratrylenes, namely 7, 9, 11, 13, 17, 28 and 29
are described.
Received 4 March 2009
Received in revised form 12 May 2009
Accepted 28 May 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Acid-catalysts
Cyclotriveratrylenes
Benzylic alcohols
1. Introduction
a strong agonist of the oestrogen receptor.11,12 Further, in vitro treat-
ment of 3-hydroxymethylindole with aqueous hydrochloric acid gave
Cyclotriveratrylenes,1–6 cyclic oligomers based on the tribenzo-
cyclononatriene core, and their derivatives have been synthesised
by three methods: (i) the reaction of 1,2-disubstituted benzenes
with formaldehyde under acidic conditions,3,5 (ii) the treatment of
3,4-disubstituted benzyl alcohols with acids,7,8 and (iii) the acid-
catalysed condensation of 1,2-disubstituted benzenes with 3,30,4,40-
tetra-alkoxy-6,60-bis(chloromethyldiphenyl)methanes.4,5 They
have been shown to have a rigid crown conformation.
rise to the cyclic trimer 3 and its oligomers. However, this method
gave the indolocyclotriveratrylene only in low yields and required
HPLC purification.13 A trace (2%) of the cyclic trimer 3 was obtained
fromthepyrolysisof3-(diethylaminomethyl)-indolehydrochloride.14
R
Me
N
N
Indolocyclotriveratrylenes are cyclotriveratrylene derivatives in
which the benzene rings have been replaced by indole rings.
Therefore, the synthetic routes to cyclotriveratrylenes can also be
applied to indolocyclotriveratrylenes. The first preparation of
indolocyclotriveratrylenes was published in 1970 by Bergman and
co-workers,9 who reported that the reaction of 1-methylindole with
38% formaldehyde solution in the presence of sulfuric acid afforded
a trimeric compound with either a symmetrically linked structure 1
or an unsymmetrically linked structure 2 in 24% yield. Hiremath and
co-workers10 contemplated the preparation of a pyrano[3,4-b]in-
dole from the condensation of 2-hydroxymethyl-1-methylindole
R
N
R
N
Me
N
N
Me
1
R=Me
R=H
2
3
More recently, Bjeldanes and Staub15 showed that the reaction
of 3-(dimethylaminomethyl)-indole and dimethylsulfate in the
presence of sodium ethoxide afforded the trimer 3 in approxi-
mately 75% yield. However, the conformation of the indolocyclo-
triveratrylene was not reported.
and a-bromoacetone, but the liberated hydrobromic acid combined
with an intermediate to give the unexpected trimeric compound 1.
More recently it has been reported that the parent indolocyclo-
triveratrylene 3 produced under acidic conditions from the digestion
of indole-3-carbinol, which normally occurs in Brassica vegetables
such as cabbage, kale, cauliflower, Brussels sprouts and broccoli, is
2. Results and discussion
2.1. Preparation of cyclic trimer 1
It was of interest to carry out a systematic study on the syn-
thesis of indolocyclotriveratrylenes based on the acid-catalysed
* 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/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.092

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M. Santoso et al. / Tetrahedron 65 (2009) 5977–5983
reactions of indole-3-methanols and indole-2-methanols. This was
particularly relevant in view of earlier studies that revealed the
formation of calix-3- and calix-4-indoles by the acid-catalysed
reactions of 2- and 7-hydroxymethyl-4,6-dimethoxyindoles.16,17
Initially, the known18–20 3-hydroxymethyl-1-methylindole 4 was
treated with a catalytic amount of p-toluenesulfonic acid (ptsa) in
dichloromethane, and after 1 h at room temperature gave the
cyclic trimer 1 in 44% yield (Scheme 1). Formation of compound 1
could also be effected using other acid-catalysts such as tri-
fluoroacetic acid in chloroform, boron trifluoride diethyl etherate
in dichloromethane, K10 clay in dichloromethane, concentrated
hydrochloric acid in tetrahydrofuran and concentrated sulfuric
acid in glacial acetic acid. The spectroscopic properties of com-
hydride reduction of methyl 1-methylindole-2-carboxylate22 in
87% yield, and was treated with acid directly.
2.2. Preparation of related cyclic trimers with other
substituents on nitrogen
Some related indolocyclotriveratrylenes were then prepared in
order to establish the generality of the reaction. Thus, the 1-allyl-3-
hydroxymethylindole 6 was prepared by reduction of the related 3-
aldehyde23 with sodium borohydride and was treated directly with
ptsa in dichloromethane to give the cyclic trimer 7 in 44% yield
(Scheme 2).
pound 1 were consistent with those available in the literature.9
A
suitable crystal enabled an X-ray crystal structure determination
to be made, and this showed that the compound was in the saddle
or propeller conformation (Fig. 1).
A major steric factor is
presumably the close proximity of the N-methyl groups to the
nine-membered ring. The nine bond lengths involved in the nine-
membered ring are all slightly shorter than the corresponding
bond lengths in cyclotriveratrylene itself,21 and the nine bond
angles are considerably larger.
OH
Me
N
N
Me
ptsa / CH2Cl2
44%
4
Me
Scheme 2.
N
N
Me
OH
1-Benzyl-3-hydroxymethylindole24,25
cyclic trimer in 45% yield. Reduction of 1-methoxy-
8 similarly gave the
N
Me
9
1
methylindole-3-carbaldehyde26 with sodium borohydride gave
the corresponding indole-3-methanol 10, which was directly
converted by treatment with ptsa in dichloromethane into the
cyclic trimer 11 in 47% yield. Treatment of the 1-tosylindole-3-
methanol27,28 12 with either ptsa or hydrochloric acid was in-
effective, but the use of boron trifluoride diethyl etherate gave
the cyclic trimer 13 in 11% yield (Scheme 2). All the indolocy-
clotriveratrylenes 1, 7, 9 and 11 show singlet resonances in the
range 4.00–4.16 ppm for the bridging methylene protons in their
1H NMR spectra, results which are consistent with saddle
conformations.
5
Scheme 1.
2.3. Preparation of related cyclic trimers from activated
indoles
Indoles incorporating methoxy or methylenedioxy sub-
stituents frequently show greater nucleophilic reactivity, so it was
of interest to investigate the application of such compounds to the
formation of indolocyclotriveratrylenes, especially because of the
rather moderate yields shown by the simple indole derivatives 4,
6, 8, 10 and 12. 4,6-Dimethoxyindole29 was initially N-methylated
to give compound 14, and the resulting product30,31 formylated at
C3 to give the 3-carbaldehyde32 15, which was reduced to the 3-
hydroxymethyl compound 16 (Scheme 3). Treatment of this
benzylic alcohol with ptsa in dichloromethane, as described for
the earlier examples, similarly gave the cyclic trimer 17 in 45%
yield. The same indolocyclotriveratrylene could also be formed in
46% yield by similar acid treatment of 2-hydroxymethyl-4,6-
dimethoxy-1-methylindole 20, derived from the lithium alumin-
ium hydride reduction of the corresponding 2-methylester
19. This latter compound was obtained by the methylation of 4,6-
dimethoxyindole-2-carboxylic acid33 18 and used directly
(Scheme 3).
Figure 1. ORTEP diagram derived from the single-crystal X-ray analysis of com-
pound 1.
The cyclic trimer 1 could also be synthesised in the same yield
by reaction of the 2-methanol 5 with ptsa in dichloromethane
(Scheme 1). The alcohol 5 was prepared by the lithium aluminium

M. Santoso et al. / Tetrahedron 65 (2009) 5977–5983
5979
MeO
MeO
O
O
O
O
CHO
RX
83-84%
POCl3 / DMF
83%
N
R
N
H
N
Me
N
Me
MeO
MeO
MeO
22 R = Me
21
14
15
23 R = CH2=CHCH2
94%
NaBH4
MeO
84-86%
POCl3 / DMF
OH
OH
CHO
O
O
O
NaBH4
86%
ptsa / CH2Cl2
45%
O
N
R
N
R
Me
MeO
N
Me
MeO
N
16
MeO
Me
24 R = Me
26 R = Me
OMe
25 R = CH2=CHCH2
27 R = CH2=CHCH2
N
Me
N
ptsa / CH2Cl2
MeO
ptsa / CH2Cl2
47-48%
OMe
OH
46%
MeO
N
Me
O
O
MeO
17
R
N
20
O
O
LiAlH4 88%
MeO
R
N
MeO
N
R
MeI
CO2H
CO2Me
92%
N
N
Me
MeO
MeO
H
O
O
18
19
Scheme 3.
28 R = Me
5,6-Methylenedioxyindole34 21 was N-methylated and N-ally-
lated to give indoles35,36 22 and 23, respectively (Scheme 4). These
in turn were formylated at C3 to give the two aldehydes 24 and 25,
which were each reduced with sodium borohydride to give the 3-
hydroxymethyl compounds 26 and 27, respectively. Treatment of
these benzylic alcohols with ptsa in dichloromethane, as described
above, generated a 48% yield of the cyclic trimer 28 and a 47% yield
of the cyclic trimer 29, respectively (Scheme 4).
The indolocyclotriveratrylenes 17, 28 and 29 showed singlet
resonances in their 1H NMR spectra at 4.20, 3.87 and 3.83 ppm,
respectively, all consistent with saddle conformations. In-
terestingly, there was effectively no increase in yields of indolocy-
clotriveratrylenes from the activated indole precursors.
29 R = CH2=CHCH2
Scheme 4.
OMe MeO
OH
MeO
MeO
OMe
H2O / reflux
90%
N
N
N
Me
MeO
Me
Me
30
16
Scheme 5.
4. Experimental
4.1. General
2.4. A note on reaction conditions
It should be noted that whilst the cyclotrimerisation reactions
reported above take place usually in dichloromethane with p-tol-
uenesulfonic acid as catalyst, it has long been known that
N-substituted-3-hydroxymethylindoles such as compound 4 are
smoothly converted by heating in water at reflux to the corre-
sponding 3,30-diindolylmethanes.19 Consequently, the 4,6-dime-
thoxy-1-methyl-3-hydroxymethylindole 16 was shown to undergo
a similar conversion to the 3.30-diindolylmethane 30, when heated
under reflux in water (Scheme 5).
Melting points were measured using a Mel-Temp melting point
apparatus, and are uncorrected. Microanalyses were performed by
the Microanalytical Unit, Research School of Chemistry, The Austra-
lian National University. 1H and 13C NMR spectra were obtained on
a Bruker AC300F (300 MHz) spectrometer. Mass spectra were
recorded on either an AEI MS 12 (EI) or a Finnegan MAT (MALDI)
spectrometer. Infrared spectra were recorded with a Perkin Elmer
298 IR spectrometer. Ultraviolet–visible spectra were recorded using
a Hitachi U-3200 spectrometer. Columnchromatography wascarried
out using Merck 70–230 mesh silica gel, whilst preparative thin layer
3. Conclusions
chromatography was performed using Merck silica gel 7730 60GF254.
Flashchromatography35,36 wascarriedoutusingMerck60Hsilicagel.
The formation of the nine-membered ring containing indolo-
cyclotriveratrylenes by the acid-catalysed reactions of 2-unsub-
stituted-3-hydroxymethyl indoles appears to be quite general.
Several examples have also indicated that the similar reactions of 3-
unsubstituted-2-hydroxymethylindoles are also probably general.
4.1.1. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b]tri-1-
methylindole (1)
Method A: 3-Hydroxymethyl-1-methylindole20
4
(0.30 g,
1.86 mmol) in dichloromethane (70 mL) was treated with a catalytic

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M. Santoso et al. / Tetrahedron 65 (2009) 5977–5983
amountof p-toluenesulfonic acid monohydrate, and the mixture was
stirred for 1 h at room temperature. The solvent was removed under
reduced pressure and the crude product was purified using column
chromatography with dichloromethane/light petroleum (1/1) eluant
to afford the cyclic trimer 1 as a white solid (0.12 g, 44%), mp 278–
281 ꢀC (lit.9 275 ꢀC). nmax (Nujol) 3050, 1605, 1460, 1365, 1330, 1300,
dichloromethane/light petroleum (1/1) eluant to afford the trimer 9
as a white solid (0.33 g, 45%), mp 232–236 ꢀC. Found: C, 87.3; H, 6.1;
N, 6.3. C48H39N3 requires C, 87.6; H, 6.0; N, 6.4%. nmax (Nujol) 3020,
1610, 1450, 1360, 1300, 1260, 1170, 1070, 1030, 920, 800, 725,
700 cmꢁ1
296 (19,200). dH (300 MHz, CDCl3):
.
lmax (CH2Cl2) 232 nm (
3
64,100 cmꢁ1 Mꢁ1), 289 (19,700),
4.00 (6H, s, CH2 bridging), 5.39
d
1250, 1175, 1140, 1010, 880, 845, 790, 770, 730 cmꢁ1
234 nm (
135,300 cmꢁ1 Mꢁ1), 290 (38,700), 296 (37,900). dH
.
lmax (CH2Cl2)
(6H, s, CH2), 6.96–7.26 (27H, m, ArH). dC (75 MHz, CDCl3): 20.6 (CH2
bridging), 46.6 (CH2), 109.4, 117.5, 119.3, 121.2, 126.1, 127.3 and 128.8
(ArCH), 107.9, 127.7, 135.7, 136.4 and 138.0 (ArC). Mass spectrum
(EI): m/z 657 (M, 10%), 438 (20), 255 (30), 91(100).
3
(300 MHz, CDCl3): 3.74 (9H, s, Me), 4.05 (6H, s, CH2), 7.09 (3H, t, H5),
7.16 (3H, t, H6), 7.27 (3H, d, H7), 7.53 (3H, d, H4). dC (75 MHz, CDCl3):
20.4 (CH2), 29.7 (Me),108.9,117.2,118.9and120.7 (ArCH),107.0,127.5,
136.0 and 136.3 (ArC). Mass spectrum (EI): m/z 429 (M, 20), 286 (90),
285 (100), 270 (55), 255 (25),144 (50), 129 (20). Crystals for a single-
crystal X-ray determination were obtained by recrystallisation from
dichloromethane/light petroleum.
4.1.4. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b:]tri-1-
methoxymethylindole (11)
A mixture of 1-methoxymethylindole-3-carbaldehyde26 (0.34 g,
1.79 mmol) and sodium borohydride (0.34 g, 8.99 mmol) in abso-
lute ethanol (30 mL) was stirred for 1 h. The colourless solution was
evaporated almost to dryness and the white residue was suspended
in 10% aqueous sodium hydroxide and extracted several times with
dichloromethane. The combined extract was dried over sodium
sulfate and the solvent was removed under reduced pressure to
give the hydroxymethylindole 10 as a colourless oil (0.30 g, 88%). dH
(300 MHz, CDCl3): 3.20 (3H, s, OMe), 4.83 (2H, s, CH2OH), 5.34 (2H,
s, CH2), 7.08 (1H, s, H2), 7.21 (1H, t, H5), 7.30 (1H, t, H6), 7.48 (1H, d,
H7), 7.73 (1H, d, H4). dC (75 MHz, CDCl3): 55.7 (OMe), 56.7 (CH2OH),
77.0 (CH2), 109.9, 119.2, 120.2, 122.4 and 126.5 (ArCH), 116.1, 127.5
and 136.7 (ArC).
Method B: Methyl 1-methylindole-2-carboxylate22 (0.16 g,
0.85 mmol) in dry ether (45 mL) was added dropwise to lithium al-
uminium hydride (0.12 g, 3.16 mmol) in boiling dry ether (75 mL).
When the addition was complete, the solution was heated at reflux
for an additional 30 min. After cooling, ethyl acetate, cold water and
a small amount of dilute sodium hydroxide were added to de-
compose the excess of the reducing agent. The solvent was dried over
sodium sulfate and evaporated to give the hydroxymethylindole 5
(0.12 g, 86%) as a white solid. dH (300 MHz, CDCl3): 3.73 (3H, s, Me),
4.03 (2H, s, CH2), 7.03–7.17 (3H, m, ArH), 7.26 (1H, d, ArH), 7.51 (1H, d,
ArH). dC (75 MHz, CDCl3): 29.6 (Me), 57.1 (CH2OH), 101.1, 109.1, 119.4,
120.7 and 121.8 (ArCH), 127.1, 138.0 and 138.6 (ArC). 2-Hydrox-
ymethyl-1-methylindole (0.12 g, 0.75 mmol) was then treated
without further purification as 3-hydroxymethyl-1-methylindole in
Method A to give the trimer 1 as a white solid (0.05 g, 44%).
The hydroxymethylindole 10 (0.30 g, 1.57 mmol) in dichloro-
methane (70 mL) was treated with a catalytic amount of p-tolue-
nesulfonic acid and stirred at room temperature for 1 h. The solvent
was removed under reduced pressure and the crude product was
purified using column chromatography with dichloromethane/
light petroleum (3/1) eluant to afford the trimer 11 as a white solid
(0.13 g, 47%), mp 234–235 ꢀC. Found: C, 75.0; H, 6.4; N, 7.6.
C33H33N3O3$0.5H2O requires C, 75.0; H, 6.4; N, 7.9%. nmax (Nujol)
4.1.2. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b]tri-1-
allylindole (7)
A mixture of 1-allylindole-3-carbaldehyde (0.62 g, 3.35 mmol)
and sodium borohydride (0.50 g, 0.013 mol) in absolute ethanol
(30 mL) was heated at reflux for 30 min. After cooling, the solution
was evaporated almost to dryness and the white residue was sus-
pended in 5% aqueous sodium hydroxide. The precipitate was
filtered off, washed with water and dried to give 1-(prop-20-enyl)-
3-hydroxymethylindole 6 as a white solid (0.58 g, 95%). The crude
alcohol 6 (0.58 g, 3.10 mmol) in dichloromethane (70 mL) was
treated with a catalytic amount of p-toluenesulfonic acid mono-
hydrate, and stirred at room temperature for 1 h. The solvent was
removed under reduced pressure and the crude product was pu-
rified by column chromatography with dichloromethane/light pe-
troleum (1/3) eluant to afford the trimer 7 as a white solid (0.23 g,
44%), mp 297–299 ꢀC. Found: C, 82.8; H, 6.6; N, 7.6.
C36H33N3$0.75H2O requires C, 82.9; H, 6.6; N, 8.1%. nmax (Nujol)
3060, 1610, 1455, 1365, 1340, 1180, 1140, 1100, 905, 795, 740 cmꢁ1
.
lmax (CH2Cl2) 231 nm (
3
201,300 cmꢁ1 Mꢁ1), 286 (62,400), 294
(55,900). dH (300 MHz, CDCl3): 3.29 (9H, s, OMe), 4.16 (6H, s, CH2
bridging), 5.51 (6H, s, CH2), 7.12 (3H, t, H5), 7.20 (3H, t, H6), 7.41 (3H,
d, H7), 7.59 (3H, d, H4). dC (75 MHz, CDCl3): 29.7 (CH2 bridging),
55.8 (OMe), 77.2 (CH2), 109.8, 119.4, 119.7, 122.2 and 126.2 (ArCH),
115.4, 128.8 and 136.9 (ArC). Mass spectrum (EI): m/z 519 (M, 20%),
334 (100), 189 (40), 174 (70).
4.1.5. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b:]tri-1-
(4-toluenesulfonyl)indole (13)
1-(p-Toluenesulfonyl)-3-hydroxymethylindole27 12 (0.25 g,
0.83 mmol) in ethyl acetate (50 mL) was treated with a catalytic
amount of boron trifluoride diethyl etherate, and stirred for 2 h at
room temperature. The solvent was evaporated and the crude
product was submitted to preparative thin layer chromatography
with dichloromethane/light petroleum (2/1) eluant to afford the
trimer (0.026 g, 11%) as a white solid, mp 274–275 ꢀC. Found: C,
67.2; H, 4.8; N, 4.3. C48H39N3O6S3$0.5H2O requires C, 67.1; H, 4.7; N,
4.9%. nmax (Nujol) 3050, 1670, 1590, 1450, 1370, 1260, 1160, 805,
3050, 1620, 1450, 1370, 1300, 1260, 1170, 920, 740 cmꢁ1
. lmax
(MeOH) 231 nm (
3
125,700 cmꢁ1 Mꢁ1), 288 (31,700), 295 sh
(30,500), 338 (3700). dH (300 MHz, CDCl3): 4.12 (6H, s, CH2), 4.86
(6H, d, J 3.6 Hz, H10), 4.94 (3H, d, J 17.4 Hz, H30), 5.18 (3H, d, J 10.2 Hz,
H30), 5.92–6.04 (3H, m, H20), 7.15–7.34 (9H, m, ArH), 7.61 (3H, d, J
7.2 Hz, ArH). dC (75 MHz, CDCl3): 20.34 (CH2), 45.2 (C10), 116.2 (C30),
133.6 (C20), 109.3, 117.34, 119.1 and 120.9 (ArCH), 107.6, 127.7, 135.6
and 135.8 (ArC). Mass spectrum (EI): m/z 508 (Mþ1, 25%), 507 (M,
65), 338 (100), 297 (45), 295 (90), 256 (35), 255 (70), 170 (30), 156
(20).
740 cmꢁ1 98,600 cmꢁ1 Mꢁ1), 254 (41,500).
. lmax (CH2Cl2) 228 nm (3
dH (300 MHz, CDCl3): 2.36 (9H, s, Me), 4.11 (6H, s, CH2), 7.13 (6H, d, J
8.2 Hz, ArH), 7.22–7.33 (6H, m, H5 and H6), 7.42 (6H, d, J 8.2 Hz,
ArH), 7.52 (3H, d, J 6.7 Hz, H7), 8.15 (3H, d, J 7.7 Hz, H4). dC (75 MHz,
CDCl3): 21.6 (Me), 21.9 (CH2), 115.5, 118.92, 124.0, 124.9, 125.9 and
129.8 (ArCH), 120.0, 130.6, 133.6, 135.3, 136.8 and 144.9 (ArC). Mass
spectrum (ES): m/z 850 (M, 25%), 288 (100), 284 (45).
4.1.3. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b:]tri-1-
benzylindole (9)
1-Benzyl-3-hydroxymethylindole24 8 (0.79 g, 3.33 mmol) in
dichloromethane (70 mL) was treated with a small amount of p-
toluenesulfonic acid monohydrate, and stirred at room tempera-
ture for 1 h. The solvent was removed under reduced pressure and
the crude product was purified using column chromatography with
4.1.6. 4,6-Dimethoxy-1-methylindole-3-carbaldehyde (15)
4,6-Dimethoxy-1-methylindole 14 (2.30 g, 12.03 mmol) in dry
dimethylformamide (10 mL) was stirred in ice, and a cooled mix-
ture of phosphoryl chloride (1.20 mL, 12.87 mmol) in dry

M. Santoso et al. / Tetrahedron 65 (2009) 5977–5983
5981
dimethylformamide (2 mL) was added dropwise with ice cooling.
After stirring for 1 h with ice cooling, the mixture was allowed to
come to room temperature and poured into ice/water. It was ba-
sified with 10% aqueous sodium hydroxide and the precipitate was
filtered off, washed with water, dried and purified by flash chro-
matography to afford the aldehyde 15 as a white solid (2.18 g, 83%),
mp 129–130 ꢀC. Found: C, 65.5; H, 6.1; N, 6.2. C12H13NO3 requires C,
65.7; H, 6.0; N, 6.4%. nmax (Nujol) 1655, 1615, 1580, 1500, 1450, 1375,
1355, 1305, 1260, 1210, 1170, 1150, 1100, 1070, 1025, 930, 815, 770,
(3
114,700 cmꢁ1 Mꢁ1), 247 (136,300), 311 (129,600). dH (300 MHz,
CDCl3): 3.86, 3.88, 3.90 and 4.00 (12H, 4s, Me and OMe), 6.19 (1H, d,
J 1.8 Hz, H5), 6.34 (1H, d, J 1.8 Hz, H7), 7.33 (1H, s, H3). dC (75 MHz,
CDCl3): 31.7 (Me), 51.2 (CO2Me), 55.2 and 55.5 (OMe), 84.5 (C5),
92.4 (C7), 108.3 (C3), 112.0,141.4, 154.9, 160.0, 162.4 and 196.8 (ArC).
Mass spectrum (EI): m/z 249 (M, 100%), 234 (50), 191 (30).
Methyl 4,6-dimethoxy-1-methyl-2-carboxylate 19 (0.27 g,
1.08 mmol) in dry ether (50 mL) was added dropwise to a boiling
solution of lithium aluminium hydride (0.16 g, 4.22 mmol) in dry
ether (100 mL). When the addition was complete, the solution was
heated at reflux for an additional 30 min. After cooling, ethyl ace-
tate, cold water and a small amount of dilute sodium hydroxide
were added and the solution was dried over sodium sulfate, and
evaporated to yield the hydroxymethylindole 20 as a white solid
(0.21 g, 88%). dH (300 MHz, CDCl3): 3.67 (3H, s, Me), 3.86 and 3.89
(6H, 2s, OMe), 4.67 (2H, s, CH2OH), 6.20 (1H, d, J 1.8 Hz, H5), 6.35
(1H, d, J 1.8 Hz, H7), 6.42 (1H, s, C3). dC (75 MHz, CDCl3): 30.0 (Me),
55.3 and 55.6 (OMe), 57.2 (CH2OH), 85.2 (C5), 91.4 (C7), 98.6 (C3),
112.0, 136.0 and 139.4 (ArC), 153.7 and 157.6 (C–OMe). The
hydroxymethylindole 20 (0.21 g, 2.95 mmol) was dissolved in
dichloromethane (50 mL) and treated with a catalytic amount of p-
toluenesulfonic acid monohydrate and stirred for 1 h. The solvent
was evaporated and the crude product was purified using gravity
column chromatography with dichloromethane eluant to yield the
trimer 17 as a white solid (0.09 g, 46%).
745, 720, 685, 670 cmꢁ1 46,000 cmꢁ1 Mꢁ1),
. lmax (MeOH) 249 nm (3
332 (15,300). dH (300 MHz, CDCl3): 3.77 (3H, s, Me), 3.88 and 3.95
(6H, 2s, OMe), 6.39 (1H, d, J 1.9 Hz, H5), 6.40 (1H, d, J 1.9 Hz, H7),
7.66 (1H, s, H2), 10.35 (1H, s, CHO). dC (75 MHz, CDCl3): 34.5 (Me),
56.0 and 56.4 (OMe), 86.5 (C5), 94.7 (C7), 111.7, 118.6 and 139.5
(ArC), 155.6 and 158.8 (C–OMe), 188.2 (CHO). Mass spectrum (EI):
m/z 219 (M, 100%), 204 (30), 173 (55), 133 (55), 105 (35).
4.1.7. 3-Hydroxymethyl-4,6-dimethoxy-1-methylindole (16)
A mixture of 4,6-dimethoxy-1-methylindole-3-carbaldehyde
15 (2.18 g, 9.94 mmol) and sodium borohydride (4.78 g, 0.13 mol)
in absolute ethanol (30 mL) was heated at reflux for 30 min. After
cooling, the solution was evaporated almost to dryness and the
white residue was suspended in 5% aqueous sodium hydroxide.
The precipitate was filtered off, washed with water and dried to
give the alcohol 16 as a yellowish solid (2.07 g, 94%), mp 115–
116 ꢀC. Found: C, 64.7; H, 7.0; N, 6.1. C12H15NO3 requires C, 65.1; H,
6.8; N, 6.3%. nmax (Nujol) 3300, 1620, 1580, 1550, 1495, 1455, 1375,
1320, 1290, 1260, 1205, 1140, 1100, 1065, 1030, 975, 930, 790, 750,
4.1.9. 1-Methyl-5,6-methylenedioxyindole (22)
5,6-Methylenedioxyindole 21 (0.77 g, 4.78 mmol) and potas-
sium hydroxide (1.07 g, 19.07 mmol) in dry dimethyl sulfoxide
(10 mL) was stirred for 1 h at room temperature. Iodomethane
(0.60 mL, 9.64 mmol) was added and after stirring at room
temperature for 1 h, water was added to the mixture. The
resulting precipitate was filtered off, washed with water, dried
and purified using flash chromatography with chloroform/light
petroleum (1/1) eluant to afford the product 22 as a white solid
(0.70 g, 83%), mp 65 ꢀC. Found: C, 68.5; H, 5.4; N, 7.6. C10H9NO2
requires C, 68.6; H, 5.2; N, 8.0%. nmax (Nujol) 1450, 1375, 1330,
1280, 1240, 1170, 1120, 1075, 1035, 945, 850, 830, 805, 750,
700 cmꢁ1 50,300 cmꢁ1 Mꢁ1), 273 (8400).
. lmax (MeOH) 226 nm (3
dH (300 MHz, CDCl3): 3.64 (3H, s, Me), 3.86 and 3.94 (6H, 2s,
OMe), 4.73 (2H, d, J 6.7 Hz, CH2OH), 6.24 (1H, d, J 1.8 Hz, H5), 6.36
(1H, d, J 1.8 Hz, H7), 6.75 (1H, s, H2). dC (75 MHz, CDCl3): 32.8
(Me), 55.7 and 58.0 (OMe), 58.0 (CH2OH), 85.7 (C5), 91.4 (C7),
124.3 (C2), 111.6, 115.2 and 139.1 (ArC), 153.6 and 157.7 (C–OMe).
Mass spectrum (EI): m/z 221 (M, 100%), 204 (65), 146 (45), 134
(20), 118 (20).
4.1.8. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b:]tri-4,6-
dimethoxy-1-methylindole (17)
720 cmꢁ1 18,600 cmꢁ1 Mꢁ1), 280 (5300),
. lmax (MeOH) 222 nm (3
Method A: 3-Hydroxymethyl-4,6-dimethoxy-1-methylindole 16
(0.34 g, 1.54 mmol) in dichloromethane (70 mL) was treated with
a catalytic amount of p-toluenesulfonic acid monohydrate, and
stirred at room temperature for 1 h. The solvent was removed
under reduced pressure and the crude product was purified using
gravity column chromatography with dichloromethane eluant to
afford the trimer 17 (0.14 g, 45%) as a white solid, mp 241–243 ꢀC.
Found: C, 69.2; H, 6.4; N, 6.7. C36H39N3O6.H2O requires C, 68.9; H,
6.6; N, 6.7%. nmax (Nujol) 1620, 1580, 1450, 1370, 1350, 1330, 1285,
306 (8300), 310 (8400). dH (300 MHz, CDCl3): 3.72 (3H, s, Me),
5.93 (2H, s, CH2), 6.35 (1H, d, J 3.1 Hz, H3), 6.92 (1H, d, J 3.1 Hz,
H2), 6.79 and 7.00 (2H, 2s, H7 and H4). dC (75 MHz, CDCl3): 33.0
(Me), 100.5 (CH2), 90.2, 99.3, 101.0 and 127.3 (ArCH), 122.2, 132.0,
142.7 and 144.8 (ArC). Mass spectrum (EI): m/z 175 (M, 100%),
174 (30).
4.1.10. 5,6-Methylenedioxy-1-methylindole-3-carbaldehyde (24)
1-Methyl-5,6-methylenedioxyindole 22 (0.97 g, 5.54 mmol)
in dry dimethylformamide (5 mL) was stirred in ice, and
a cooled mixture of phosphoryl chloride (1.0 mL, 10.73 mmol) in
dry dimethylformamide (2 mL) was added dropwise with ice
cooling. After stirring for 1 h, the mixture was allowed to come
to room temperature and poured into ice/water. It was basified
with 10% aqueous sodium hydroxide and the crude product was
filtered off, washed with water, dried and recrystallised from
dichloromethane/light petroleum to afford the aldehyde 24 as
a white solid (0.98 g, 86%), mp 133–134 ꢀC. Found: C, 64.8; H,
4.2; N, 7.0. C11H9NO3 requires C, 65.0; H, 4.5; N, 6.9%. nmax
(Nujol) 1650, 1450, 1410, 1360, 1335, 1310, 1235, 1175, 1100,
1250, 1205, 1140, 1080, 1050, 1030, 935, 790, 775, 740 cmꢁ1
. lmax
(CH2Cl2) 234 nm (
3
193,100 cmꢁ1 Mꢁ1), 282 (52,800). dH (300 MHz,
CDCl3): 3.62 (9H, s, Me), 3.81 and 3.84 (18H, 2s, OMe), 4.20 (6H, s,
CH2), 6.13 (3H, d, J 1.9 Hz, H5), 6.32 (3H, d, J 1.9 Hz, H7). dC (75 MHz,
CDCl3): 21.6 (CH2), 29.7 (Me), 55.1 and 55.7 (OMe), 85.4 (C5), 90.9
(C7), 107.0, 111.6, 137.7 and 134.4 (ArC), 154.4 and 156.1 (C–OMe).
Mass spectrum (EI): m/z 610 (Mþ1, 30%), 609 (M, 80), 594 (20), 406
(30), 405 (100), 390 (30), 375 (25), 374 (20), 204 (30).
Method B: 4,6-Dimethoxyindole-2-carboxylic acid32 18 (1.21 g,
5.47 mmol) and freshly crushed potassium hydroxide (1.85 g,
0.033 mol) in dry dimethyl sulfoxide (20 mL) was stirred for 1 h at
room temperature. Iodomethane (1.40 mL, 0.022 mol) was added
and after stirring at room temperature overnight, water was added
to the mixture. The resulting precipitate was filtered off, washed
with water, dried and purified using flash chromatography to afford
the ester 19 (1.25 g, 92%), mp >340 ꢀC. nmax (Nujol) 1700, 1630,
1605, 1580, 1500, 1460, 1380, 1350, 1305, 1240, 1210, 1180, 1160,
1060, 1020, 955, 805, 770, 735, 715 cmꢁ1
. lmax (MeOH) 254 nm
(
3
14,800 cmꢁ1 Mꢁ1), 386 (22,900). dH (300 MHz, CDCl3): 3.75
(3H, s, Me), 6.00 (2H, s, CH2), 6.74, 7.47 and 7.67 (3H, 3s, H2 and
ArH), 9.84 (1H, s, CHO). dC (75 MHz, CDCl3): 33.9 (Me), 101.2
(CH2), 90.8, 100.8 and 137.6 (ArCH), 118.3, 119.4, 133.1, 145.3 and
146.2 (ArC), 184.2 (CHO). Mass spectrum (EI): m/z 203 (M,
100%), 202 (95).
1100, 990, 960, 940, 810, 760, 730, 680 cmꢁ1
. lmax (MeOH) 228 nm

5982
M. Santoso et al. / Tetrahedron 65 (2009) 5977–5983
4.1.11. 1-Allyl-5,6-methylenedioxyindole-3-carbaldehyde (25)
chromatography with dichloromethane/light petroleum (2/1) elu-
ant, followed by recrystallisation from dichloromethane/light pe-
troleum to afford the trimer 28 (0.048 g, 48%) as white needles,
mp>310 ꢀC. Found: C, 70.3; H, 4.9; N, 7.5. C33H27N3O6 requires C,
70.6; H, 4.8; N, 7.5%. nmax (Nujol) 1460, 1380, 1340, 1310, 1230, 1130,
5,6-Methylenedioxyindole 21 (1.80 g, 11.17 mmol) and freshly
crushed potassium hydroxide (2.51 g, 44.73 mmol) in dry dimethyl
sulfoxide (30 mL) was stirred for 1 h at room temperature. Allyl
chloride (1.80 mL, 22.11 mmol) and sodium iodide (3.30 g,
22.02 mmol)were added andafterstirringforanadditional1 h, water
was added to the mixture. The product was extracted several times
with dichloromethane. The organic layer was washed with brine,
dried over magnesium sulfate and evaporated under reduced pres-
sure. The crude product was purified using flash chromatography
with dichloromethane eluant to afford the title compound 23 as an oil
(1.90 g, 84%), which could not be obtained analytically pure. dH
(300 MHz, CDCl3):4.61(2H, s,H10), 5.06(1H, d,J17.1 Hz, H30),5.18(1H,
d, J 10.5 Hz, H30), 5.89–6.01 (1H, m, H20), 5.91 (2H, s, CH2), 6.37 (1H, d, J
3.2 Hz,H3), 6.94(1H, d,J3.2 Hz,H2), 6.76and6.99(2H, 2s, H7and H4).
dC (75 MHz,CDCl3):49.2(C10),117.2(C30),133.4 (C20),100.5 (CH2), 90.7,
99.4, 101.5 and 126.4 (ArCH), 122.4, 131.3, 142.8 and 144.7 (ArC).
The crude 1-allyl-5,6-methylenedioxyindole 23 (1.90 g, 9.44 mmol)
in dry dimethylformamide (10 mL) was stirred in ice, and a cooled
mixture of phosphoryl chloride (0.90 mL, 9.66 mmol) in dime-
thylformamide (1 mL) was added dropwise with ice cooling. After
stirring for 1 h, the mixture was allowed to come to room tem-
perature and poured into ice/water. It was basified with 10%
aqueous sodium hydroxide, the precipitate was filtered off, washed
with water, and dried. The crude product was purified by flash
chromatography with dichloromethane eluant, followed by
recrystallisation from dichloromethane/light petroleum to afford
the aldehyde 25 as light brown needles (1.82 g, 84%), mp 81–82 ꢀC.
Found: C, 68.0; H, 4.9; N, 6.2. C13H11NO3 requires C, 68.1; H, 4.8; N,
6.1%. nmax (Nujol) 1640, 1520, 1450, 1375, 1335, 1260, 1175, 1120,
1040, 940, 885, 860, 830, 810, 735 cmꢁ1
. lmax (CH2Cl2) 232 nm (3
78,600 cmꢁ1 Mꢁ1), 320 (43,100). dH (300 MHz, CDCl3): 3.63 (9H, s,
Me), 3.87 (6H, s, CH2), 5.89 (6H, s, OCH2O), 6.73 and 6.89 (6H, 2s, H7
and H4). dC (75 MHz, CDCl3): 20.7 (CH2), 30.0 (Me), 100.4 (OCH2O),
90.4 and 96.4 (C7 and C4), 107.5, 121.4, 131.4, 134.4, 142.4 and 144.1
(ArC). Mass spectrum (MALDI): m/z 560.56 (Mꢁ1).
4.1.14. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b:]tri-1-allyl-5,6-
methylenedioxyindole (29)
A mixture of 1-allyl-5,6-methylenedioxyindole-3-carbaldehyde
25 (0.20 g, 0.87 mmol) and sodium borohydride (0.42 g, 0.011 mol)
in absolute ethanol (30 mL) was heated under reflux for 30 min.
After cooling, the solution was evaporated almost to dryness and
the white residue was suspended in 5% aqueous sodium hydroxide.
The precipitate was filtered off, washed with water and dried to
give 1-allyl-3-hydroxymethyl-5,6-methylenenedioxyindole 27 as
a white solid (0.18 g, 90%). The crude alcohol 27 (0.18 g, 0.78 mmol)
in dichloromethane (40 mL) was treated with a small amount of p-
toluenesulfonic acid, and stirred at room temperature for 1 h. The
solvent was removed under reduced pressure and the crude
product was purified using column chromatography with chloro-
form eluant to afford the trimer 29 as a white solid (0.08 g, 47%),
mp>350 ꢀC. Found: C, 72.4; H, 5.2; N, 6.4. C39H33N3O6$0.5H2O re-
quires C, 72.2; H, 5.3; N, 6.5%. nmax (Nujol) 1460, 1350, 1280, 1240,
1170, 1140, 990, 940, 860, 830, 830, 800, 735 cmꢁ1
231 nm (
97,600 cmꢁ1 Mꢁ1), 320 (56,000). dH (300 MHz, CDCl3):
. lmax (CH2Cl2)
1080, 1030, 995, 930, 855, 820, 695 cmꢁ1
.
lmax (MeOH) 254 nm (
3
3
10,300 cmꢁ1 Mꢁ1), 286 (17,600). dH (300 MHz, CDCl3): 4.62 (2H, d, J
5.6 Hz, H10), 5.11 (1H, d, J 16.9 Hz, H30), 5.26 (1H, d, J 10.2 Hz, H30),
5.87–5.99 (1H, m, H20), 5.91 (2H, s, CH2), 6.72, 7.51 and 7.65 (3H, 3s,
ArH), 9.82 (1H, s, CHO). dC (75 MHz, CDCl3): 49.6 (C10), 118.7 (C30),
136.7 (C20),100.0 (OCH2O), 91.2,100.6 and 131.5 (ArCH),118.3,119.2,
132.2, 145.1 and 146.0 (ArC), 184.3 (CHO). Mass spectrum (EI): m/z
230 (Mþ1, 25%), 229 (100), 228 (40), 200 (35), 187 (25), 160 (55).
3.83 (6H, s, CH2 bridging), 4.64 (6H, s, H10), 4.82 (3H, d, J 17.2 Hz,
H30), 5.08 (3H, d, J 10.2 Hz, H30), 5.78–5.87 (3H, m, H20), 5.87 (6H,
s, CH2), 6.69 and 6.86 (6H, 2s, H7 and H4). dC (75 MHz, CDCl3):
20.5 (CH2 bridging), 45.5 (C10), 116.3 (C30), 133.4 (C20), 100.4 (CH2),
90.8 and 96.5 (C7 and C4), 108.0, 121.5, 130.8, 142.5, 144.1and
134.0 (ArC). Mass spectrum (EI): m/z 640 (Mþ1, 40%), 639 (M,
100), 598 (25), 426 (20), 425 (50), 383 (50), 343 (30), 214 (70),
173 (40).
4.1.12. 3-Hydroxymethyl-1-methyl-5,6-methylenedioxyindole (26)
A mixture of 1-methyl-5,6-methylenedioxyindole-3-carbalde-
hyde 24 (0.39 g, 1.70 mmol) and sodium borohydride (0.73 g,
0.019 mol) in absolute ethanol (30 mL) was heated at reflux for
30 min. After cooling, the solution was evaporated almost to dry-
ness and the white residue was suspended in 5% aqueous sodium
hydroxide. The product was extracted several times with
dichloromethane, and the combined extracts were dried over so-
dium sulfate, concentrated under reduced pressure and recrystal-
lised from dichloromethane/light petroleum to afford the alcohol
26 (0.30 g, 86%), mp 120 ꢀC. Found: C, 65.0; H, 5.2; N, 7.0. C11H11NO3
requires C, 64.4; H, 5.4; N, 6.8%. nmax (Nujol) 3280, 1550, 1460, 1400,
1370, 1330, 1230, 1185, 1100, 1050, 1030, 1000, 930, 850, 835, 805,
4.1.15. 3,30-Di-(4,6-dimethoxy-1-methylindolyl)methane (30)
3-Hydroxymethyl-4,6-dimethoxy-1-methylindole 16 (0.44 g,
1.99 mmol) was heated under reflux overnight in water (50 mL).
After cooling, the crude product was filtered off, washed with
water, dried and purified using flash chromatography with
dichloromethane/light petroleum eluant to yield the product 30
(0.35 g, 90%) as a white solid, mp 177 ꢀC. Found: C, 69.7; H, 6.6; N,
7.0. C23H26N2O4 requires C, 70.0; H, 6.6; N, 7.1%. nmax (Nujol) 1620,
1580, 1500, 1450, 1370, 1320, 1260, 1210, 1170, 1145, 1090, 1045, 930,
805, 760, 735, 710 cmꢁ1 102,600 cmꢁ1 Mꢁ1),
. lmax (CH2Cl2) 232 nm (3
279 (25,000). dH (300 MHz, CDCl3): 3.55 (6H, s, Me), 3.83 and 3.84
(12H, 2s, OMe), 4.43 (2H, s, CH2), 6.17 (2H, d, J 1.9 Hz, H5), 6.30 (2H,
d, J 1.9 Hz, H7), 6.49 (2H, s, H2). dC (75 MHz, CDCl3): 23.3 (CH2), 32.7
(Me), 55.2 and 55.6 (OMe), 85.0 (C5), 90.8 (C7), 124.5 (C2), 112.4,
116.5 and 138.5 (ArC), 155.5 and 157.0 (C–OMe). Mass spectrum
(EI): m/z 395 (Mþ1, 35%), 394 (M, 100), 393 (45), 221 (80), 204
(100), 190 (40), 174 (25).
775 cmꢁ1 5400 cmꢁ1 Mꢁ1), 312 (8800). dH
. lmax (MeOH) 287 nm (3
(300 MHz, CDCl3): 3.67 (3H, s, Me), 4.76 (2H, s, CH2OH), 5.93 (2H, s,
OCH2O), 6.76, 6.92 and 7.09 (3H, 3s, H7, H4, H2). dC (75 MHz, CDCl3):
33.0 (Me), 57.2 (CH2OH), 100.7 (OCH2O), 90.4, 97.8 and 126.2
(ArCH), 115.0, 120.9, 132.5, 143.0 and 145.2 (ArC). Mass spectrum
(EI): m/z 205 (M, 85%), 188 (100).
4.2. Crystallographic study on compound 1
4.1.13. 1,4,7-Trihydrocyclononano[2,3-b:5,6-b:8,9-b:]tri-1-methyl-
5,6-methylenedioxyindole (28)
4.2.1. Crystal data
3-Hydroxymethyl-1-methyl-5,6-methylenedioxyindole 26 (0.11 g,
0.54 mmol) in dichloromethane was treated with a catalytic
amount of p-toluenesulfonic acid monohydrate, and stirred for 1 h
at room temperature. The solvent was removed under reduced
pressure and the crude product was purified using column
C30H27N3, M 429.6, monoclinic, space group P21, a 5.5045(8),
b
14.473(2),
1.27 g cmꢁ3, Z 2, mCu 5.41 cmꢁ1. Crystal size 0.06 by 0.07 by 0.27 mm,
qmax 120ꢀ, minimum and maximum transmission factors 0.93 and
0.97. The number of reflections was 1487 considered observed out
c 14.299(3) Å, b V
99.699(6)ꢀ, 1122.9(3) Å3, Dc
2

M. Santoso et al. / Tetrahedron 65 (2009) 5977–5983
5983
of 1781 unique data, with Rmerge 0.026 for equivalent reflections.
References and notes
Final residuals R, Rw were 0.037, 0.048 for the observed data.
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using the analytical method of de Meulenaer and Tompa.37 Re-
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q q scan mode using graphite monochromatized
/2
l
1.54184 Å). Data were corrected for absorption
s
determined by direct phasing and Fourier methods. Hydrogen
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from
Rw¼(
s
(Io)¼[
s
2(Io)þ(0.04Io)2]1/2. The weighted residual is defined as
S
w
D2 wF20)1/2. Atomic scattering factors and anomalous
/S
dispersion parameters were from International Tables for X-ray
Crystallography.38 Structure solutions were by SIR9239 and re-
finement used RAELS.40 ORTEP-II41 running on Power MacIntosh
was used for the structural diagrams, and a DEC Alpha-AXP
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Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC 719323). These data can be obtained free-of-
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Rd, Cambridge CB2 1EZ, UK;
fax: þ44 1223 336033.
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged. M.S. acknowledges receipt of a post-
graduate scholarship from the Australian Government.
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.05.092.