Synthesis of cycloalkanoindoles by an unusual DAST-triggered rearrangement reaction

Article abstract of DOI:10.1002/ejoc.200300738

A series of 1,1-bis(indol-3-yl) and 1-(indol-2-yl)-1-(indol-3-yl)-ω- hydroxyalkanes, prepared from the corresponding indole derivatives and suitable hydroxyaldehydes via routine coupling reactions, were treated with DAST (diethylamino-sulfur trifluoride) under mild conditions, to generate a small library of cycloalkanoindoles. Irrespective of the substitution pattern, i.e. whether they are symmetrical or unsymmetrical derivatives, the same mixture of products is produced, in which the tetrahydro-1H-carbazole and hexahydrocyclo-hepta[b]indole scaffolds are substituted by a indol-3-yl nucleus on one of the two α-carbon atoms of the cycloalkane moieties. Thus, speculations on the reaction mechanism with the prediction of a common reaction intermediate are presented. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300738

FULL PAPER
Synthesis of Cycloalkanoindoles by an Unusual DAST-Triggered
Rearrangement Reaction
Giuseppe Giannini,*[a] Mauro Marzi,[a] Gian Piero Moretti,[a] Sergio Penco,[a]
Maria Ornella Tinti,[a] Silvia Pesci,[b] Francesco Lazzaro,[c] and Francesco De Angelis*[c]
Keywords: Cycloalkanoindole / Geminal bis(indolyl) compounds / Electrophilic substitution / Electrophilic annulation /
Rearrangement / Angiogenesis inhibitors
A series of 1,1-bis(indol-3-yl) and 1-(indol-2-yl)-1-(indol-3-
yl)-ω-hydroxyalkanes, prepared from the corresponding in-
dole derivatives and suitable hydroxyaldehydes via routine
coupling reactions, were treated with DAST (diethylamino-
sulfur trifluoride) under mild conditions, to generate a small
library of cycloalkanoindoles. Irrespective of the substitution
pattern, i.e. whether they are symmetrical or unsymmetrical
which the tetrahydro-1H-carbazole and hexahydrocyclo-
hepta[b]indole scaffolds are substituted by a indol-3-yl nuc-
leus on one of the two α-carbon atoms of the cycloalkane
moieties. Thus, speculations on the reaction mechanism with
the prediction of a common reaction intermediate are pre-
sented.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
derivatives, the same mixture of products is produced, in Germany, 2004)
Introduction
volved in the synthesis of substituted cycloalkanoindoles.
Several approaches are known for the synthesis of cycloalk-
anoindoles, for example, tetrahydrocarbazoles and hexa-
hydrocyclohept[b]indole derivatives, but most of them re-
quire multiple steps, and generally give low overall yields.
During our earlier research[12] aimed at the synthesis of 1,1-
bis(indol-3-yl)alkanes functionalized at the level of the alkyl
chain, we found that the 1,1-bis(indolyl)-ω-hydroxyalkyl de-
rivatives 1 and 2, when treated with DAST (diethylaminos-
ulfur trifluoride), afforded the indolyl-substituted cyloalk-
anoindole structural isomers 5 and 6 as the major products
(Figure 1 and Scheme 1).[13] It is worth noting that 5 and 6
are both formed, irrespective of which bis(indolyl)alkane
(i.e. the 3,3Ј-isomer 1 or the 2,3Ј-isomer 2) is used as the
starting material. This allows us to think of the reaction
mechanism as a DAST-mediated molecular rearrange-
ment.[14] The expected 1,1-bis(indolyl)-ω-fluoroalkyl deriva-
tives 3 and 4 were also formed, but in lower yields. In this
paper, we wish to present full details of the synthesis of
substituted cycloalkanoindoles starting from 1,1-bis(indol-
3-yl)alkanes, as well as their structural characterization;
also speculations on the reaction mechanism will be pro-
posed to a certain extent.
In the last few decades, compounds containing a perhyd-
rocycloalkano[b]indole structure have been synthesized and
studied with the aim of exploring their possible therapeutic
activity. Besides having the same 3-substituted indole nu-
cleus as such fundamental biomolecules as tryptophan and
melatonin, they also possess a molecular framework closely
related to that of many biologically active, naturally occur-
ring carbazole alkaloids. A series of aminotetrahydrocarb-
azole derivatives was found to act on the central nervous
system.[1] Cycloalkanoindoles have been studied for their
anti-inflammatory,[2] antidepressant[3] and analgesic
properties.[4Ϫ7] Antibacterial activity has been recognized in
a number of substituted tetrahydrocarbazoles,[8] while some
antitumor alkaloids, such as staurosporine, K-252a, and re-
beccamycin, possess a cycloalkanoindole structure.[9] Some
pyridiniotetrahydrocarbazoles and bis(indol-3-yl) deriva-
tives have been studied for their antiproliferative[10] and
cytodifferentiating properties, respectively.[11]
As a part of a medicinal chemistry program whose aim
is the design of angiogenesis inhibitors, we have been in-
[a]
Dept. of Chemistry, Sigma-Tau,
via Pontina km 30, 400, Pomezia (Rome), 00040 Italy
Fax: (internat.) ϩ 39-0691-393638
E-mail: giuseppe.giannini@sigma-tau.it
Results and Discussion
[b]
IRBM,
via Pontina Km 30, 600, Pomezia (Rome), 00040 Italy
The proposed starting materials for the synthesis of
indolyl(cycloalkanoindoles) were ω-functionalized 1,1-bis-
(indol-3-yl)- and 1-(indol-2-yl)-1-(indol-3-yl)alkanes; the
key step in the synthesis being an annulation reaction trig-
E-mail: silvia—pesci@merck.com
[c]
`
Dept. of Chemistry, Universita dell’Aquila,
Coppito, L’Aquila, 67010 Italy
Fax: (internat.) ϩ 39-0862-433753
E-mail: deangeli@univaq.it
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G. Giannini, F. De Angelis et al.
FULL PAPER
ence of Dy(OTf)3 (procedure B2), the 1,1-bis(indol-2-yl)hy-
droxyalkyl derivative is also formed (15Ϫ20%).
Scheme 2. Synthetic strategies for the preparation of geminal
bis(indolyl)hydroxyalkyl derivatives (only main products are re-
ported)
Figure 1. Bis(indolyl)alkanes and cycloalkanoindoles: reference
structures
Table 1. Bis(indolyl)hydroxyalkyl derivatives
Scheme 1. New DAST-triggered ring-closure reaction of bis-
(indolyl)alkanes; the 1,1-bis(indolyl)-ω-fluoroalkyl derivatives 3
and 4 are formed as by-products
gered by the creation of an electrophilic site at the carbon
of the alkyl chain. This reaction occurred as expected when
we treated the 1,1-bis(indolyl)-ω-hydroxyalkanes 1 and 2
with DAST.
With the aim of synthesizing a small library of bis(indol-
yl)alkane derivatives (Scheme 2; Table 1), with selected sub-
stituents on the indole nucleus and a hydroxy functionality
on the alkyl chain, we employed three different synthetic
procedures, all of them making use of masked hydroxyalde-
hydes as precursors of the electrophile. With poorly reactive
aldehydes like protected sugars (i.e. mannofuranose), the in-
dole derivative was activated as its magnesium salt; SnCl4
was used as the catalyst[15Ϫ18]. In this case, only the sym-
metrical 1,1-bis(indol-3-yl)hydroxyalkyl derivatives were
produced (procedure A). For unsubstituted linear hydroxy-
aldehydes, used in their furanose or pyranose forms, the re-
actions were catalyzed by dysprosium triflate [Dy(OTf)3][19]
or HCl (procedures Β1 and B3).[20,21] The catalyst used in-
fluences the ratio of symmetrical and unsymmetrical prod-
ucts, irrespective of the aldehyde substrate. In the presence
of HCl, the unsymmetrical product becomes predominant.
It should be considered that in the case of the 5,6-(methyl-
enedioxy)indole, when the condensation reaction with 2-
[a]
[b]
s.p.: substitution pattern of indoles.
ethoxytetrahydrofuran is carried out at 70 °C in the pres- 70 °C.
Reaction temperature
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Synthesis of Cycloalkanoindoles by an Unusual DAST-Triggered Rearrangement Reaction
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In a first attempt to explain the reaction mechanism, it
is conceivable that an initial electrophilic attack of the acti-
vated carbonylic carbon takes place at positions 3 (pre-
ferred) or 2 of the indole nucleus. The electrophilic attack,
promoted by the Lewis or protic acid, of the monoalkylin-
dolyl derivative at another indole molecule, is supposed also
to operate in the second step of the overall reaction, leading
to the bis(indolyl) derivative. However, in order to gain
further insight into the reaction mechanism, the symmetri-
cal bis(indolyl) derivative 12a was submitted to the reaction
conditions (HCl at 80 °C) that generally produce higher
yields of the unsymmetrical product in the condensation
reaction. Quite surprisingly, the substrate rearranged by for-
ming an almost equimolar mixture of the two regioisomers.
It should be concluded that, at least in some cases, a more
complicated reaction mechanism must be considered, in
which a common initially formed intermediate can lead, re-
versibly, to both reaction products. If this is the case, then
the 1-(indol-2-yl)-1-(indol-3-yl) derivatives, or even the 2,2Ј-
isomers, could be formed through a concomitant 1,2-hy-
dride shift from C-2 of the indole nucleus at the level of the
putative intermediate itself. It is also worth noting that the
2,3Ј-isomers are stable under reaction conditions that favor
isomerization; this is in agreement with the hypothesis that
they are the more stable regioisomers formed in the conden-
sation reactions.
Scheme 3. Cyclization reaction of bis(indolyl) derivatives
Table 2. 2,3,4,9-Tetrahydro-1H-carbazoles (n ϭ 0) and 5,6,7,8,9,10-
hexahydrocyclohepta[b]indoles (n ϭ 1)
In the literature, cases are described that support both
the possible reaction mechanisms, i.e. the direct electro-
philic attack at C-2 and the group rearrangement at C-2
after the initial attack at C-3. For the former case, it is re-
ported that strong electrophiles prefer to perform the sub-
stitution reaction at the 2-position on 3-alkylindoles.[22,23]
On the other hand, both the PictetϪSpengler type cycliza-
tion to form tetrahydro-β-carbolines[24] and the Plancher re-
arrangement of 3,3-dialkyl-3H-indolinium ions to give 2,3-
dialkylindoles are believed to occur through migration of
an alkyl moiety at the level of an indoline intermediate.[25,26]
Also, tetrahydrocarbazoles are reported to rearrange to 2,2-
spirocycloalkyl-3-oxoindole derivatives under photo-oxy-
genation conditions.[27]
All the 1,1-bis(indol-3-yl)- and the 1-(indol-2-yl)-1-(in-
dol-3-yl)hydroxyalkyl derivatives listed in Table 1 were
treated with DAST, in dichloromethane at room tempera-
ture. As observed above, besides the anticipated bis(indol-
yl)-fluorinated products 3 and 4, the indolyl-substituted
2,3,4,9-tetrahydro-1H-carbazoles 5a and 6a and the indolyl-
substituted 5,6,7,8,9,10-hexahydrocyclohepta[b]indole de-
rivatives 5b and 6b were unexpectedly formed from 1aϪ2a
and 1bϪ2b, respectively, in quite excellent yields (see Fig-
ure 1 and Scheme 1). A general scheme of the cyclization
reaction is shown in Scheme 3; a full list of the reaction
products and conditions is reported in Table 2. For the reac-
tion of 7, the 2,3,4,9-tetrahydro-1H-carbazole derivative 14
All the cycloalkanoindoles were characterized by 1H
was formed as the only product (Scheme 4). The protected NOESY and/or 1H,13C-HMBC. Diagnostic protonϪ
derivatives 14 and 17, were deprotected following standard carbon connectivities were detected between the proton on
procedures. Partial deprotection of 14 was also carried out the nitrogen and the nuclei α to C-2 of the indole ring. In
under mild conditions, giving rise to the monoacetonide de- particular, a strong NOE between N-5ϪH and the methyne
rivative 22.
proton was detected for 5b, while a strong NOE was ob-
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G. Giannini, F. De Angelis et al.
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Scheme 4. Cyclization reaction of mannofuranose derivatives
served between N-5ϪH and the methylene protons at C-6
in 6b. The structural assignment was also confirmed for 5b
1
using H 13C-HMBC; the diagnostic protonϪcarbon con-
nectivity between N-5ϪH and C-6 was detected (see head-
ing of Table 2 for sites numbering).
As already observed, the indolyl-substituted cyclized
products are formed as a mixture of two components, with
the indol-3-yl substituent at C-1 or C-4 (C-6 or C-10) of
the tetrahydrocyclohexane (hexahydrocycloheptane) ring
cumulated to the indole nucleus (it is important to note that
the indol-2-yl moiety, when present in the starting material,
is not conserved in the end products). These two product
types are formed in the same amounts, irrespective of which
compound, be it the symmetrical 1,1-bis(indol-3-yl)- or un-
Scheme 5. Hypothetical mechanism for the ring-closure reaction.
The direct electrophilic attack at C-2 (a*) and C-3 (b*) are also
symmetrical 1-(indol-2-yl)-1-(indol-3-yl) derivative, is used conceivable processes, leading to their respective products
as the starting material. Generally, the predominant isomer
is the one carrying the indol-3-yl substituent at C-1 (tetra- C-2 and C-3 of the indole nuclei. It should be emphasized
hydro-1H-carbazoles) or C-6 (hexahydrocyclohepta[b]in- that in both cases, pathway ‘‘b’’ appears to be preferred,
doles).
as seen in the predominance of the products arising from
These results indicate that the two reaction pathways, this route.
starting from the two different bis(indolyl) regioisomers,
must share common intermediates, which lead to the final
mixture of products. It is worth mentioning that a DAST-
mediated rearrangement reaction of the indole nucleus that
goes via a spiro intermediate was recently thoroughly inves-
tigated by D. J. Hallett, U. Gerhard and co-workers,[14]
while our chemical and pharmaceutical studies were already
in progress.[12,13] It is conceivable that also in our case, the
key step is the formation of a reactive electrophilic site on
the alkyl chain, and that this intramolecularly attacks one
of the two indole nuclei. A possible reaction mechanism,
which can account for the observed results, is shown in
Scheme 5 (the indol-3-yl moiety is represented by ‘‘R’’ in
the starting materials in the cases where it does not directly
participate in the reaction). The reaction of the hydroxy
group in the substrates with DAST creates a good leaving
group (LG), thus commencing the reaction sequence of
electrophilic annulation, with the formation of spiro-inter-
mediates on C-3 or C-2 from symmetrical and unsymmetri-
cal bis(indolyl) derivatives, respectively. Both the spiro-in-
termediates then undergo ring-enlargement through bond
Conclusions
In summary, we have developed a two-step, high-yielding
synthetic strategy for the preparation of indolyl(cycloalk-
anoindoles), such as tetrahydro-1H-carbazole and hexa-
hydrocyclohept[b]indole derivatives, containing a second
aromatic base (the indole itself or one of its derivatives) as a
substituent on one of the two α-positions of the cycloalkane
moiety. These cycloalkanoindole derivatives represent very
interesting molecular scaffolds in medicinal chemistry, be-
cause of the antiangiogenic and antitumour properties of
some members of the series. It is also worth noting that
ours is the second example of indole-substituted carbazole
derivatives present in the literature, the first very old one
appeared in the mid-seventies, and describes an indolyl-
tetrahydrocarbazolecarboxylic acid, produced by pyrolysis
from a sponge tryptophan metabolite (hypaphorine).[28]
Biology
Both geminal bis(indolyl) and cycloalkanoindole com-
shifts, either via pathway ‘‘a’’ or ‘‘b’’, giving rise to the inter- pounds were tested for enhancement of the cytodifferen-
mediate structures reported at the third level of Scheme 5. tiating properties of retinoid in myeloid leukemia cells. 1a
These cations are finally stabilized by loss of a proton from and 1b showed interesting cytotoxic and cell growth inhi-
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Synthesis of Cycloalkanoindoles by an Unusual DAST-Triggered Rearrangement Reaction
FULL PAPER
bition properties.[11] Most cycloalkanoindole derivatives
also behave as antiangiogenic and cytotoxic agents[13] (cell
cycle, apoptosis analysis on tumor cell lines and activity
data on tumor-resistant cell lines are also reported). In par-
ticular, with reference to the antiangiogenic activity, the
chemotactic assay with the Boyden chamber was performed
using both bovine aortal endothelial cell (BAEC) cultures
and bovine medullary endothelial cell (BMEC) cultures.
The most active compound was 5b, with about 60% of inhi-
bition of migration across a porous filter, in response to a
chemotactic stimulus. For the cytotoxic activity, prolifer-
ation screening tests were used, with different tumor lines
such as MCF-7 (human mammary carcinoma), LoVo (hu-
man colon carcinoma), MES-SA (human uterine sarcoma)
and K-562 (human chronic myeloid leukemia). For all the
compounds, the range of activity lies between 10Ϫ50 µ,
with the exception of 18, which showed sub-micromolar ac-
tivity in different cell lines.
Procedure B1: A different synthetic method (Scheme 2) was used
for simple hydroxyaldehydes: the indole or its derivative (2 mmol)
was dissolved, along with the aldehyde (5-hydroxypentanal or 2-
ethoxytetrahydrofuran, 1 mmol), in 15 mL of MeOH/H2O (2:1).
Then Dy(OTf)3 (0.4 mmol) was added, and the mixture was reacted
at 20Ϫ50 °C for 5Ϫ10 h. The reaction was quenched with 10%
aqueous NaHCO3, and extracted with CH2Cl2. The organic phase
was dried with anhydrous Na2SO4, and the solvents were evapo-
rated. The crude residue was purified by preparative-HPLC and
the two regioisomers were isolated.
Procedure B2: (Same experimental conditions as B1, but at higher
temperature, T ϭ 70 °C): at this temperature, the unusual 2,2Ј-
regioisomer 13 was isolated in a low yield (15Ϫ20%), using the 5,6-
(methylenedioxy)indole as starting material.
Procedure B3: The following modified procedure (Scheme 2) was
applied to increase the yield of the unsymmetrical 2,3Ј-regioisomer:
the indole or its derivative (2.4 mmol) was dissolved in a mixture
of CH3OH (10 mL) and HCl (1 , 5 mL). The hydroxyaldehyde
derivative (1 mmol) was added and the resulting solution was
warmed at 80 °C for 12Ϫ24 h. After this time, the methanol was
removed under vacuum and the residue was extracted with CH2Cl2.
The organic phase was washed with water, dried with anhydrous
Na2SO4, filtered and concentrated to dryness. The crude residue
was purified by flash chromatography, using a hexane/diethyl ether
gradient, ranging from 9:1 to 7:3, as the eluent. The unsymmetrical
2,3Ј-regioisomers were isolated with high yields.
Experimental Section
General Remarks: All commercially available chemicals were used
without further purification unless otherwise noted. Analytical thin
layer chromatography (TLC) was performed using Merck silica gel
60F254 glass sheets, and spots were visualized using a UV lamp
(254 nm), iodine and/or a phosphomolybdic acid solution (5% in
ethanol). Flash column chromatography was performed using
Merck silica Gel 60 (0.040Ϫ0.063 mm). High Pressure Liquid
Chromatographic (HPLC) was performed using a JASCO Detector
MD-910 and a JASCO Pump PU-980, with different columns as
indicated in detail for each compound. Melting points were deter-
mined in open capillaries using a Buchi 530 apparatus and are un-
corrected, or with a Mettler DSC-30/Mettler TG-50 apparatus.
NMR spectra were recorded with Varian VXR-300s or Bruker Av-
ance spectrometers at different frequencies (600 MHz, 500 MHz,
400 MHz or 300 MHz). Chemical shifts are given in ppm and are
referenced to residual protonated solvent signals as internal stand-
ard. Coupling constants J are given in Hz and the following ab-
breviations are used: s: singlet, d: doublet, dd: doublet of doublet,
t: triplet, m: multiplet. Mass spectra were obtained with Platform
LC micromass spectrometer. Elemental analysis were determined
with a Thermofinnigan EA1110 CHNS-O machine.
General Procedure for Synthesis of Cycloalkanoindole Derivatives
Procedure C: The symmetrical or unsymmetrical bis(indolyl) de-
rivative (1 mmol) (Scheme 3) was dissolved in CH2Cl2 (80 mL), and
diethylaminosulfur trifluoride (DAST) (400 µL, 3 mmol) was ad-
ded (T ϭ 0 °C Ϫ room temp.). The reaction was fast (after
15Ϫ20 min, almost complete conversion of the starting material
was observed). After 30Ϫ60 min, a 10% aqueous solution of
NaHCO3 was added, and the reaction mixture was extracted with
CH2Cl2. The organic phase was dried with anhydrous Na2SO4, and
the solvents were evaporated. The products were isolated by pre-
parative TLC or by preparative HPLC RP-18. The formation of
both derivatives (Scheme 3) was observed, starting from both the
symmetrical and the unsymmetrical bis(indolyl) derivatives (5a, 5b:
yield 55Ϫ70%; 6a, 6b: yield 5Ϫ7%).
Other General Procedures
General Procedures for the Synthesis of Bis(indole) Derivatives
Procedure D: The benzyloxy-substituted derivative 17 (1 mmol) was
dissolved in CH3OH (50 mL). After addition of the catalyst (10%
Pd/C, 30 mg), the solution was left under hydrogen (60 psi) at room
temperature. After 16 h, quantitative conversion of the starting ma-
terial was observed, and the catalyst was filtered off. The organic
phase was evaporated, and the deprotected product 20 was purified
by flash chromatography (yield 85%).
Procedure A: This methodology (Scheme 2) required the prep-
aration of the indolylmagnesium bromide by the following pro-
cedure: Indole (2 mmol) or its derivative was added to an anhy-
drous diethyl ether solution of alkylmagnesium bromide (2 mmol)
(prepared from the corresponding alkyl bromide (2 mmol) and
magnesium (2 mmol) in an anhydrous solvent, i.e. diethyl ether or
tetrahydrofuran), whilst stirring at room temperature. The solvent
was removed under vacuum, and the crude residue was dissolved
in an inert organic solvent, such as CH2Cl2 or CHCl2CHCl2. Next,
the Lewis acid (i.e. SnCl4, 2 mmol) and the aldehyde (i.e. 2,3,5,6-
di-O-isopropylidene--mannofuranose, 1 mmol) were added. After
stirring for 12Ϫ24 h at ϩ50 °C to ϩ80 °C, the reaction was
quenched by addition of a saturated aqueous solution of NaHCO3/
10%NH4Cl. The organic phase was washed with a small volume of
water, dried with anhydrous MgSO4, filtered and concentrated to
dryness. The desired product was purified by flash chromatography
(hexane/acetone).
Procedure E: The protected starting material 14 (1 mmol) was dis-
solved in tetrahydrofuran (50 mL) and HCl (1 ) was added. The
reaction mixture was reacted for 1 h at room temperature. After
addition of a saturated aqueous solution of NaHCO3, the THF
was evaporated, and the product was extracted with EtOAc. The
organic phase was evaporated, and the deprotected product was
purified by flash chromatography. 21 was isolated in quantitative
yield.
To obtain a selective deprotection of the starting material, the
acidic hydrolysis was performed at a lower temperature (e.g. HCl
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1  at 0 °C, for 30Ϫ60 min), obtaining 22 as the main product
(yield: 30%).
Compound 4b: Yield 11%, 35 mg. Starting materials: indole and 5-
hydroxypentanal; Procedure B1. TLC (hexane/iPrOH, 85:15; Rf ϭ
0.44); HPLC RP-18 (Tracer, 250 ϫ 4.6, 5 µm; H2O/CH3CN, 40:60;
flow: 1 mL/min; room temp. 14.2 min). Racemic mixture. 1H NMR
(600 MHz, [D6]DMSO): δ ϭ 10.87 (br. s, 1 H, H-1Ј), 10.72 (br. s,
1 H, H-1ЈЈ), 7.47 (d, J ϭ 8.1 Hz, 1 H, H-4Ј), 7.38 (d, J ϭ 8.1 Hz,
1 H, H-4ЈЈ), 7.32 (d, J ϭ 8.1 Hz, 1 H, H-7Ј), 7.25Ϫ7.22 (m, 2 H,
H-2Ј,7ЈЈ), 7.01 (t, J ϭ 8.1 Hz, 1 H, H-6Ј), 6.94 (t, J ϭ 8.1 Hz, 1 H,
H-6ЈЈ), 6.88 (t, J ϭ 8.1 Hz, 2 H, H-5Ј,5ЈЈ), 6.25 (d, J ϭ 1.6 Hz, 1
H, H-3ЈЈ), 4.39 (ddd, J1 ϭ 47.4, J2 ϭ J3 ϭ 6.0 Hz, 2 H, H-5), 4.32
(t, J ϭ 7.7 Hz, 1 H, H-1), 2.25Ϫ2.13 (m, 2 H, H-2), 1.77Ϫ1.60 (m,
2 H, H-4), 1.41Ϫ1.32 (m, 2 H, H-3) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ ϭ 143.4 (C-2ЈЈ), 136.3 (C-7Јa), 136.0 (C-7ЈЈa), 128.0
(4ЈЈa), 126.4 (C-4Јa), 122.2 (C-2Ј), 120.8 (C-6Ј), 119.8 (C-6ЈЈ), 119.1
(C-4ЈЈ), 118.7 (C-4Ј), 118.4 (C-5ЈЈ), 118.1 (C-5Ј), 116.7 (C-3Ј), 111.3
(C-7Ј), 110.7 (C-7ЈЈ), 97.9 (C-3ЈЈ), 83.8 (d, J ϭ 162 Hz, C-5), 35.8
(C-1), 34.0 (C-2), 29.7 (d, J ϭ 19 Hz, C-4), 23.4 (d, J ϭ 5 Hz, C-
3) ppm. 19F NMR (470 MHz, [D6]DMSO): δ ϭ Ϫ217.40 ppm. MS
(IS): m/z ϭ 319 [M Ϫ H]Ϫ. C21H21FN2 (320.20): calcd. C 78.72, H
6.61, N 8.74; found C 77.65, H 6.60, N 8.23. M.p. 77Ϫ81 °C (hygro-
scopic).
Compound 1a: Yield 42%, 128 mg. Starting materials: indole and 2-
methoxytetrahydrofuran; Procedure B1. TLC (hexane/EtOAc, 1:1;
Rf ϭ 0.26); HPLC RP-18 (Waters 300 ϫ 3.9, 5 µm; H2O/CH3CN,
50:50, flow: 1 mL/min; room temp. 8.30 min). 1H NMR (600 MHz,
[D3]CD3CN): δ ϭ 9.02 (br. s, 2 H, H-1Ј), 7.50 (d, J ϭ 8.1 Hz, 2 H,
H-4Ј), 7.35 (d, J ϭ 8.1 Hz, 2 H, H-7Ј), 7.15 (d, J ϭ 2.4 Hz, 2 H,
H-2Ј), 7.05 (t, J ϭ 8.1 Hz, 2 H, H-6Ј), 6.92 (t, J ϭ 8.1 Hz, 2 H, H-
5Ј), 4.45 (t, J ϭ 7.7 Hz, 1 H, H-1), 3.54 (t, J ϭ 6.5 Hz, 2 H, H-4),
2.50 (br. s, 1 H, 4-OH), 2.29Ϫ2.23 (m, 2 H, H-2), 1.59Ϫ1.52 (m, 2
H, H-3) ppm. 13C NMR (75 MHz, [D3]CD3CN): δ ϭ 137.9 (C-
7Јa), 128.1 (C-4Јa), 122.8 (C-2Ј), 122.3 (C-6Ј), 120.7 (C-3Ј), 120.3
(C-4Ј), 119.5 (C-5Ј), 112.3 (C-7Ј), 62.8 (C-4), 34.7 (C-1), 35.6 (C-
3), 32.5 (C-2) ppm. MS (IS): m/z ϭ 303 [M Ϫ H]Ϫ. C20H20N2O
(304.39): calcd. C 78.92, H 6.62, N 9.20; found C 78.88, H 6.70, N
9.10. M.p. 110Ϫ115 °C.
Compound 1b: Yield 40%, 127 mg. Starting materials: indole and 5-
hydroxypentanal; Procedure B1. TLC (hexane/EtOAc, 70:30; Rf ϭ
0.27); HPLC RP-18 (Waters 250 ϫ 4.6, 5 µm; H2O/CH3CN, 40:60;
flow:1 mL/min; room temp. 5.36 min). 1H NMR (600 MHz,
[D3]CD3CN): δ ϭ 9.00 (br. s, 2 H, H-1Ј), 7.49 (d, J ϭ 8.1 Hz, 2 H,
1,1-Bis(indol-3Ј-yl)-2,3;5,6-di-O-isopropylidene-1-deoxy-D-mannitol
H-4Ј), 7.34 (d, J ϭ 8.1 Hz, 2 H, H-7Ј), 7.15 (d, J ϭ 2.3 Hz, 2 H, (7):[15] Yield 55%, 262 mg. 1H NMR (500 MHz, [D3]CD3CN): δ ϭ
H-2Ј), 7.05 (t, J ϭ 8.1 Hz, 2 H, H-6Ј), 6.91 (t, J ϭ 8.1 Hz, 2 H, H- 9.18 (br. s, 1 H, H-1Ј), 8.99 (br. s, 1 H, H-1ЈЈ), 7.73 (d, J ϭ 7.9 Hz,
5Ј), 4.44 (t, J ϭ 7.7 Hz, 1 H, H-1), 3.45 (t, J ϭ 6.6 Hz, 2 H, H-5), 1 H, H-4Ј), 7.51 (d, J ϭ 7.9 Hz, 1 H, H-4ЈЈ), 7.41 (d, J ϭ 2.4 Hz,
2.39 (br. s, 1 H, 5-OH), 2.26Ϫ2.20 (m, 2 H, H-2), 1.58Ϫ1.51 (m,
1 H, H-2ЈЈ), 7.34 (d, J ϭ 7.9 Hz, 1 H, H-7ЈЈ), 7.31 (d, J ϭ 7.9 Hz,
1 H, H-7Ј), 7.09Ϫ7.02 (m, 3 H, H-2Ј,6Ј,6ЈЈ), 6.99Ϫ6.92 (m, 2 H,
2 H, H-4), 1.43Ϫ1.35 (m, 2 H, H-3) ppm. 13C NMR (75 MHz,
[D3]CD3CN): δ ϭ 137.9 (C-7Јa), 128.1 (C-4Јa), 122.8 (C-2Ј), 122.2 H-5Ј,5ЈЈ), 5.32 (dd, J1 ϭ 11.0, J2 ϭ 6.7 Hz, 1 H, H-2), 5.06 (d, J ϭ
(C-6Ј), 120.8 (C-3Ј), 120.2 (C-4Ј), 119.4 (C-5Ј), 112.3 (C-7Ј), 62.7 11.0 Hz, 1 H, H-1), 4.40 (d, J ϭ 6.7 Hz, 1 H, H-3), 3.90Ϫ3.80 (m,
(C-5), 36.1 (C-1), 34.9 (C-4), 33.7 (C-2), 25.5 (C-3) ppm. MS (IS):
m/z ϭ 317 [M Ϫ H]Ϫ. C21H22N2O (318.42). calcd. C 79.21, H 6.96,
N 8.79; found C 79.10, H 6.95, N 8.76. M.p. 190 °C (dec.).
2 H, H-5,6a), 3.71 (dd, J1 ϭ 8.2, J2 ϭ 4.3 Hz, 1 H, 1 H, H-6b),
3.33 (t, J ϭ 8.2 Hz, 1 H, H-4), 2.69 (d, J ϭ 8.2 Hz, 1 H, 4-OH),
1.44 (s, 3 H, H-4ЈЈЈa), 1.35 (s, 3 H, H-4ЈЈЈb), 1.15 (s, 3 H, H-4ЈЈЈЈa),
0.80 (s, 3 H, H-4ЈЈЈЈb) ppm. 13C NMR (75 MHz, [D3]CD3CN): δ ϭ
137.4 (C-7Јa), 137.2 (C-7ЈЈa), 128.1 (C-4Јa), 127.7 (C-4ЈЈa), 123.5
(C-2Ј), 122.6 (C-6ЈЈ), 122.5 (C-2ЈЈ), 122.1 (C-6Ј), 120.6 (C-4Ј), 119.8
(C-5ЈЈ), 119.7 (C-4ЈЈ), 119.5 (C-5Ј), 119.1 (C-3Ј), 116.7 (C-3ЈЈ),
112.2 (C-7ЈЈ), 112.1 (C-7Ј), 109.4 (C-2ЈЈЈЈ), 108.6 (C-2ЈЈЈ), 80.5 (C-
2), 77.1 (C-3), 77.0 (C-5), 70.5 (C-4), 67.2 (C-6), 34.7 (C-1), 26.8
(C-4ЈЈЈa), 26.6 (C-4ЈЈЈb), 25.6 (C-4ЈЈЈЈa), 24.9 (C-4ЈЈЈЈb) ppm.
Compound 2b: Yield 45%, 143 mg. Starting materials: indole and
5-hydroxypentanal; Procedure B3. TLC (hexane/iPrOH, 97.5:2.5;
Rf ϭ 0.51); HPLC RP-18 (Waters 250 ϫ 4.6, 5 µm; H2O/CH3CN,
40:60; flow: 1 mL/min; room temp. 6.16 min). Racemic mixture. 1H
NMR (600 MHz, [D3]CD3CN): δ ϭ 9.14 (br. s, 1 H, H-1Ј), 8.97 (br.
s, 1 H, H-1ЈЈ), 7.48Ϫ7.44 (m, 2 H, H-4Ј,4ЈЈ), 7.39 (d, J ϭ 8.2 Hz, 1
H, H-7Ј), 7.23Ϫ7.19 (m, 2 H, H-7ЈЈ,2Ј), 7.08 (t, J ϭ 8.2 Hz, 1 H,
H-6Ј), 7.02Ϫ6.95 (m, 2 H, H-5ЈЈ,6ЈЈ), 6.94 (t, J ϭ 8.2 Hz, 1 H, H-
5Ј), 6.36 (m, 1 H, H-3ЈЈ), 4.38 (t, J ϭ 7.6 Hz, 1 H, H-1), 3.47 (t,
J ϭ 6.6 Hz, 2 H, H-5), 2.24Ϫ2.18 (m, 2 H, H-2), 1.59Ϫ1.52 (m,
2 H, H-4), 1.42Ϫ1.32 (m, 2 H, H-3) ppm. 13C NMR (100 MHz,
[D3]CD3CN): δ ϭ 144.7 (C-2ЈЈ), 137.9 (C-7Јa), 137.2 (C-7ЈЈa), 129.7
(C-4ЈЈa), 127.8 (C-4Јa), 123.3 (C-2Ј), 122.6 (C-6Ј), 121.5 (C-6ЈЈ),
120.5 (C-4ЈЈ), 120.1 (C-4Ј), 120.0 (C-5ЈЈ), 119.8 (C-5Ј), 118.3 (C-
3Ј), 112.4 (C-7Ј), 111.6 (C-7ЈЈ), 99.5 (C-3ЈЈ), 62.6 (C-5), 37.3 (C-1),
35.2 (C-4), 33.5 (C-2), 25.2 (C-3) ppm. . MS (IS): m/z ϭ 317 [M Ϫ
H]Ϫ. C21H22N2O (318.20): calcd. C 79.21, H 6.96, N 8.79; found
C 78.64, H 7.15, N 8.45. M.p. 200 °C (dec.).
1,1-Bis(7-azaindol-3-yl)-2,3;5,6-di-O-isopropylidene-1-deoxy-D-
mannitol (8): Yield 22%, 105 mg. Starting materials: 7-azaindole
and 2,3:5,6-di-O-isopropylidene--mannofuranose. Procedure A.
TLC (CH2Cl2/CH3COCH3, 1:1; Rf ϭ 0.17); HPLC RP-18 (Tracer,
250 ϫ 4.6, 5 µm; H2O/CH3CN, 60:30; flow: 1 mL/min; room temp.
9.73 min). 1H NMR (600 MHz, [D3]CD3CN): δ ϭ 9.61 (br. s, 1 H,
H-1Ј), 9.39 (br. s, 1 H, H-1ЈЈ), 8.19 (dd, J1 ϭ 4.7, J2 ϭ 1.3 Hz, 1
H, H-6Ј), 8.16 (dd, J1 ϭ 4.7, J2 ϭ 1.3 Hz, 1 H, H-6ЈЈ), 8.03 (dd,
J1 ϭ 7.7, J2 ϭ 1.3 Hz, 1 H, H-4ЈЈ) 7.85 (dd, J1 ϭ 7.7, J2 ϭ 1.3 Hz,
1 H, H-4Ј), 7.53 (d, J ϭ 2.3 Hz, 1 H, H-2Ј), 7.13 (d, J ϭ 2.3 Hz, 1
H, H-2ЈЈ), 6.98 (dd, J1 ϭ 7.7, J2 ϭ 4.7 Hz, 2 H, H-5Ј,5ЈЈ), 5.24 (dd,
J1 ϭ 10.9, J2 ϭ 6.8 Hz, 1 H, H-2), 5.04 (d, J ϭ 10.9 Hz, 1 H, H-
Compound 3b: Yield 12%, 38 mg. Starting materials: indole and 5-
hydroxypentanal; Procedure B1. TLC (hexane/iPrOH, 9:1; Rf ϭ 1), 4.40 (d, J ϭ 6.8 Hz, 1 H, H-3), 3.88 (dd, J1 ϭ 8.3, J2 ϭ 6.2 Hz,
0.64); HPLC RP-18 (Tracer, 250 ϫ 4.6, 5 µm; H2O/CH3CN, 40:60; 1 H, H-6a), 3.83 (m, 1 H, H-5), 3.72 (dd, J1 ϭ 8.3, J2 ϭ 4.3 Hz, 1
flow: 1 mL/min; room temp. 10.9 min). 1H NMR (300 MHz,
[D6]DMSO): δ ϭ 10.72 (br. s, 2 H, H-1Ј), 7.50 (d, J ϭ 8.1 Hz, 2
H, H-4Ј), 7.29 (d, J ϭ 8.1 Hz, 2 H, H-7Ј), 7.22 (d, J ϭ 2.0 Hz, 2
H, H-6b), 3.26 (t, J1 ϭ J2 ϭ 8.3 Hz, 1 H, H-4), 2.74 (d, J ϭ 8.3 Hz,
1 H, 4-OH), 1.45 (s, 3 H, H-4aЈЈЈ), 1.34 (s, 3 H, H-4bЈЈЈ), 1.15 (s,
3 H, H-4aЈЈЈЈ), 0.79 (s, 3 H, H-4bЈЈЈЈ) ppm. 13C NMR (100 MHz,
H, H-2Ј), 6.99 (t, J ϭ 8.1 Hz, 2 H, H-6Ј), 6.86 (t, J ϭ 8.1 Hz, 2 H, [D3]CD3CN): δ ϭ 149.8 (C-7Јa), 149.7 (C-7ЈЈa), 144.5 (C-6Ј), 143.9
H-5Ј), 4.39 (ddd, J1 ϭ 47.4, J2 ϭ J3 ϭ 5.9 Hz, 2 H, H-5), 4.38 (t, (C-6ЈЈ), 129.0 (C-4ЈЈ), 128.0 (C-4Ј), 123.9 (C-2ЈЈ), 123.3 (C-2Ј),
J ϭ 7.5 Hz, 1 H, H-1), 2.27Ϫ2.16 (m, 2 H, H-2), 1.80Ϫ1.58 (m, 2
120.4 (C-4aЈЈ), 119.9 (C-4Јa), 117.8 (C-3ЈЈ), 116.5 (C-5Ј), 116.2 (C-
H, H-4), 1.47Ϫ1.30 (m, 2 H, H-3) ppm. MS (IS): m/z ϭ 319 [M Ϫ 5ЈЈ), 115.2 (C-3Ј), 109.6 (C-2ЈЈЈЈ), 108.9 (C-2ЈЈЈ), 80.3 (C-2), 77.1
H]Ϫ. C21H21FN2 (320.20): calcd. C 78.72, H 6.61, N 8.74; found C (C-3), 77.0 (C-5), 70.8 (C-4), 67.4 (C-6), 35.2 (C-1), 26.9 (C-4aЈЈЈ),
78.64, H 6.55, N 8.65. Yellow oil (hygroscopic).
2416
26.8 (C-4bЈЈЈЈ), 25.7 (C-4aЈЈЈЈ), 25.0 (C-4bЈЈЈ) ppm. MS (IS): m/z ϭ
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 2411Ϫ2420

Synthesis of Cycloalkanoindoles by an Unusual DAST-Triggered Rearrangement Reaction
FULL PAPER
477 [M Ϫ H]Ϫ. C26H30N4O5 (478.21): calcd. C 65.26, H 6.32, N
11.70; found C 65.47, H 6.35, N 12.01. M.p. 210 °C (dec.).
TLC (hexane/iPrOH, 75:25; Rf ϭ 0.44); HPLC RP-18 (Waters 250
ϫ 4.6, 5 µm; H2O/CH3CN, 60:40; flow: 1 mL/min; room temp.
17.5 min). 1H NMR (600 MHz, [D3]CD3CN): δ ϭ 8.88 (br. s, 2 H,
H-1Ј), 7.04 (d, J ϭ 2.2 Hz, 2 H, H-2Ј), 6.83 (s, 4 H, H-4Ј,7Ј),
5.83Ϫ5.81 (m, 4 H, H-8Ј), 4.21 (t, J ϭ 7.5 Hz, 1 H, H-1), 3.54Ϫ3.50
(m, 2 H, H-4), 2.47 (br. t, J ϭ 5.0 Hz, 1 H, 4-OH), 2.20Ϫ2.13 (m,
2 H, H-2), 1.55Ϫ1.48 (m, 2 H, H-3) ppm. 13C NMR (75 MHz,
[D3]CD3CN): δ ϭ 145.3, 142.9 (C-5Ј, C-6Ј), 132.6 (C-7Јa), 121.8
(C-4Јa), 121.5 (C-2Ј), 120.6 (C-3Ј), 101.5 (C-8Ј), 98.7 (C-4Ј), 93.0
(C-7Ј), 62.6 (C-4), 34.8 (C-1), 35.3 (C-4), 31.9(C-2) ppm. MS (IS):
m/z ϭ 391 [M Ϫ H]Ϫ. C22H20N2O5 (392.41): calcd. C 67.34, H
5.14, N 7.14; found C 67.30, H 5.20, N 7.10. M.p. 240 °C (dec.)
Compound 9: Yield 40%, 212 mg. Starting materials: 5-benzyloxyin-
dole and 5-hydroxypentanal; Procedure B1. TLC (hexane/iPrOH,
75:25; Rf ϭ 0.24); HPLC RP-18 (Waters 250 ϫ 4.6, 5 µm; H2O/
CH3CN, 30:70; flow: 1 mL/min; room temp. 6.0 min). 1H NMR
(300 MHz, CDCl3): δ ϭ 7.90 (br. s, 2 H, H-1Ј), 7.40Ϫ6.90 (m, 18
H, H-10Ј, 11Ј, 12Ј, 4Ј, 6Ј, 7Ј, 2Ј), 5.05 (s, 4 H, H-8Ј), 4.35 (t, J ϭ
7.5 Hz, 1 H, H-1), 3.60 (br. t, J ϭ 6.5 Hz, 2 H, H-5), 2.25Ϫ2.15
(m, 2 H, H-2), 1.70Ϫ1.40 (m, 4 H, H-3,4) ppm. MS (IS): m/z ϭ
529 [M Ϫ H]Ϫ. C35H34N2O3 (530.67): calcd. C 79.22, H 6.46, N
5.28; found C 79.00, H 6.47, N 5.22. Yellow oil.
Compound 10: Yield 13%, 40 mg. Starting materials: 7-azaindole
and 2-methoxytetrahydrofuran; Procedure A. TLC (hexane/iPrOH,
75:25; Rf ϭ 0.18); HPLC RP-18 (Waters 250 ϫ 4.6, 5 µm; H2O/
CH3CN, 60:40; flow: 1 mL/min; room temp. 4.4 min). 1H NMR
(600 MHz, [D6]DMSO): δ ϭ 11.30 (br. s, 2 H, H-1Ј), 8.10 (dd, J1 ϭ
4.5, J2 ϭ 1.3 Hz, 2 H, H-6Ј), 7.83 (dd, J1 ϭ 7.7, J2 ϭ 1.3 Hz, 2 H,
Compound 12b: Yield 26%, 102 mg. Starting materials: 5,6-(methyl-
enedioxy)indole and 2-methoxytetrahydrofuran; Procedure B3.
TLC (hexane/iPrOH, 75:25; Rf ϭ 0.41); HPLC RP-18 (Waters 250
ϫ 4.6, 5 µm; H2O/CH3CN, 60:40; flow: 1 mL/min; room temp.
23.4 min). Racemic mixture. 1H NMR (600 MHz, [D3]CD3CN):
δ ϭ 8.98 (br. s, 1 H, H-1Ј), 8.79 (br. s, 1 H, H-1ЈЈ), 7.03 (d, J ϭ
2.4 Hz, 1 H, H-2Ј), 6.88 (s, 1 H, H-4ЈЈ), 6.86 (s, 1 H, H-7Ј), 6.80 (s,
1 H, H-4Ј), 6.72 (s, 1 H, H-7ЈЈ), 6.22 (d, J ϭ 2.1 Hz, 1 H, H-
3ЈЈ), 5.84Ϫ5.81 (m, 4 H, H-8Ј,8ЈЈ), 4.19 (t, J ϭ 7.7 Hz, 1 H, H-1),
3.54Ϫ3.49 (m, 2 H, H-4), 2.50 (br. t, J ϭ 4.9 Hz, 1 H, 4-OH),
2.14Ϫ2.10 (m, 2 H, H-2), 1.53Ϫ1.46 (m, 2 H, H-3) ppm. 13C NMR
(75 MHz, [D3]CD3CN): δ ϭ 145.6 (C-5Ј,6Ј), 144.7 (C-5ЈЈ,6ЈЈ), 143.4
(C-6Ј,5Ј), 143.3 (C-6ЈЈ,5ЈЈ), 143.0 (C-2ЈЈ), 132.7 (C-7Јa), 131.8 (C-
7ЈЈa), 123.3 (C-4ЈЈa), 121.8 (C-2Ј), 121.7 (C-4Јa), 118.7 (C-3Ј),
101.6, 101.4 (C-8Ј,8ЈЈ), 99.9 (C-3ЈЈ), 99.3 (C-4ЈЈ), 98.5 (C-4Ј), 93.1
(C-7Ј), 92.7 (C-7ЈЈ), 62.5 (C-4), 37.2 (C-1), 32.1 (C-3), 31.6 (C-2)
ppm. MS (IS): m/z ϭ 391 [M Ϫ H]Ϫ. C22H20N2O5 (392.41): calcd.
C 67.34, H 5.14, N 7.14; found C 67.14, H 5.36, N 7.10. M.p. 205
°C (dec.).
H-4Ј), 7.38 (d, J ϭ 2.3 Hz, 2 H, H-2Ј), 6.90 (dd, J1 ϭ 7.7, J2
ϭ
4.5 Hz, 2 H, H-5Ј), 4.37Ϫ4.31 (m, 2 H, H-1, H-4-OH), 3.45Ϫ3.40
(m, 2 H, H-4), 2.22Ϫ2.16 (m, 2 H, H-2), 1.47Ϫ1.41 (m, 2 H, H-3)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 148.7 (C-7Јa), 142.1
(C-6Ј), 126.9 (C-4Ј), 122.3 (C-2Ј), 118.7 (C-4Јa), 117.2 (C-3Ј), 114.5
(C-5Ј), 60.6 (C-4), 33.5 (C-1), 31.2 (C-3), 30.7 (C-2) ppm. MS (IS):
m/z ϭ 305 [M Ϫ H]Ϫ. C18H18N4O (306.37): calcd. C 70.57, H 5.92
N 18.29; found C 70.67, H 5.60 N 18.10. M.p. 221 °C (dec.).
Compound 11a: Yield 23%, 93 mg. Starting materials: 5,6-(methyl-
enedioxy)indole and 5-hydroxypentanal. Procedure B1. TLC (hex-
ane/iPrOH, 97.5:2.5; Rf ϭ 0.55); HPLC RP-18 (Waters 250 ϫ 4.6,
5 µm; H2O/CH3CN, 50:50; flow: 1 mL/min; room temp. 6.7 min).
1H NMR (600 MHz, [D3]CD3CN): δ ϭ 8.86 (br. s, 2 H, H-1Ј), 7.03
(d, J ϭ 2.3 Hz, 2 H, H-2Ј), 6.82 (s, 4 H, H-4Ј,7Ј), 5.82Ϫ5.80 (m, 4
H, H-8Ј), 4.19 (t, J ϭ 7.5 Hz, 1 H, H-1), 3.46Ϫ3.42 (m, 2 H, H-5),
2.39 (br. t, 1 H, 5-OH), 2.17Ϫ2.10 (m, 2 H, H-2), 1.55Ϫ1.48 (m,
2 H, H-4), 1.38Ϫ1.30 (m, 2 H, H-3) ppm. 13C NMR (75 MHz,
[D3]CD3CN): δ ϭ 145.7, 143.3 (C-5Ј, C-6Ј), 133.0 (C-7Јa), 122.2
(C-4Јa), 121.8 (C-2Ј), 121.0 (C-3Ј), 101.9 (C-8Ј), 99.1 (C-4Ј), 93.4
(C-7Ј), 63.1 (C-5), 35.9 (C-1), 35.4 (C-4), 34.0 (C-2), 25.8 (C-3)
ppm. MS (IS): m/z ϭ 407 [M ϩ H]ϩ. C23H22N2O5 (406.44): calcd.
C 67.97, H 5.46, N 6.89; found C 67.95, H 5.51, N 6.82. M.p. 200
°C (dec.).
Compound 13: Yield 15%, 59 mg. Starting materials: 5,6-
(methylenedioxy)indole and 2-methoxytetrahydrofuran; Procedure
B2. TLC (hexane/iPrOH, 75:25; Rf ϭ 0.60); HPLC RP-18 (Waters
250 ϫ 4.6, 5 µm; H2O/CH3CN, 60:40; flow: 1 mL/min; room temp.
19.9 min). 1H NMR (300 MHz, [D3]CD3CN): δ ϭ 9.10 (br. s, 2 H,
H-1Ј), 7.05 (s, 2 H, H-4Ј,7Ј), 6.90 (s, 2 H, H-7Ј,4Ј), 6.40 (s, 2 H, H-
3Ј), 6.00 (s, 4 H, H-8Ј), 4.25 (t, J ϭ 7.5 Hz, 1 H, H-1), 3.62 (t, J ϭ
6.7 Hz, 2 H, H-4), 2.30Ϫ2.20 (m, 2 H, H-2), 1.70Ϫ1.60 (m, 2 H,
H-3) ppm. 13C NMR (75 MHz, [D3]CD3CN): δ ϭ 145.1, 143.6 (C-
5Ј, C-6Ј), 140.9 (C-2Ј), 132.1 (C-7Јa), 123.0 (C-4Јa), 101.5 (C-8Ј),
100.5 (C-3Ј), 99.5 (C-4Ј), 92.9 (C-7Ј), 62.5 (C-4), 39.6 (C-1), 31.9
(C-3), 31.4 (C-2) ppm. MS (IS): m/z ϭ 391 [M Ϫ H]Ϫ. C22H20N2O5
(392.41): calcd. C 67.34, H 5.14, N 7.14; found C 67.26, H 5.35, N
7.10. M.p. 250 °C (dec.).
Compound 11b: Yield 24%, 97 mg. Starting materials: 5,6-(methyl-
enedioxy)indole and 5-hydroxypentanal; Procedure B3. TLC (hex-
ane/iPrOH, 97.5:2.5; Rf ϭ 0.63); HPLC RP-18 (Waters 250 ϫ 4.6,
5 µm; H2O/CH3CN, 50:50; flow 1 mL/min; room temp. 8.2 min).
Racemic mixture. 1H NMR (600 MHz, [D3]CD3CN): δ ϭ 8.97 (br.
s, 1 H, H-1Ј), 8.78 (br. s, 1 H, H-1ЈЈ), 7.03 (d, J ϭ 2.4 Hz, 1 H, H-
2Ј), 6.87 (s, 1 H, H-4ЈЈ), 6.86 (s, 1 H, H-7Ј), 6.80 (s, 1 H, H-4Ј),
6.72 (s, 1 H, H-7ЈЈ), 6.21 (d, J ϭ 2.1 Hz, 1 H, H-3ЈЈ), 5.85Ϫ5.80
(m, 4 H, H-8Ј, 8ЈЈ), 4.18 (t, J ϭ 7.6 Hz, 1 H, H-1), 3.45 (br. t, J ϭ
6.4 Hz, 2 H, H-5), 2.42 (br. s, 1 H, 5-OH), 2.13Ϫ2.08 (m, 2 H, H-
2), 1.55Ϫ1.49 (m, 2 H, H-4), 1.38Ϫ1.31 (m, 2 H, H-3) ppm. 13C
NMR (75 MHz, [D3]CD3CN): δ ϭ 145.6 (C-5Ј/6Ј), 144.7 (C-5ЈЈ/
6ЈЈ), 143.4 (C-6Ј/5Ј), 143.3 (C-6ЈЈ/5ЈЈ), 143.1 (C-2ЈЈ), 132.6 (C-7Јa),
131.8 (C-7ЈЈa), 123.3 (C-4ЈЈa), 121.8 (C-2Ј), 121.7 (C-4Јa), 118.7 (C-
3Ј), 101.6, 101.3 (C-8Ј, 8ЈЈ), 99.8 (C-3ЈЈ), 99.3 (C-4ЈЈ), 98.5 (C-4Ј),
93.1 (C-7Ј), 92.7 (C-7ЈЈ), 62.6 (C-5), 37.3 (C-1), 35.0 (C-4), 33.5 (C-
2), 25.2 (C-3) ppm. . MS (IS): m/z ϭ 407 [M ϩ H]ϩ. C23H22N2O5
(406.18): calcd. C 67.98, H 5.42, N 6.89; found C 67.75; H 5.38, N
6.75. M.p. 220 °C (dec.).
1-(1H-Indol-3-yl)-2,3,4,9-tetrahydro-1H-carbazole (5a): Yield 64%,
183 mg. Starting material: 1a; Procedure C. TLC (hexane/iPrOH,
9:1; Rf ϭ 0.66); HPLC RP-18 (Waters 250 ϫ 4.6, 5 µm; H2O/
CH3CN, 40:60; flow: 1 mL/min; room temp. 8.4 min). Racemic
1
mixture. H NMR (600 MHz, [D3]CD3CN): δ ϭ 9.10 (br. s, 1 H,
H-1Ј), 8.60 (s, 1 H, H-9), 7.46 (m, 1 H, H-5), 7.40 (ddd, J1 ϭ 8.2,
J2 ϭ J3 ϭ 0.9 Hz, 1 H, H-7Ј), 7.29 (ddd, J1 ϭ 8.1, J2 ϭ 1.8, J3 ϭ
0.8 Hz, 1 H, H-4Ј), 7.15 (m, 1 H, H-8), 7.09 (m, 1 H, H-6Ј),
7.03Ϫ6.97 (m, 2 H, H-6,7), 6.98 (d, J ϭ 2.4 Hz, 1 H, H-2Ј), 6.92
(m, 1 H, H-5Ј), 4.46 (m, 1 H, H-1), 2.83Ϫ2.79 (m, 2 H, H-4), 2.23
(m, 1 H, H-2a), 2.12Ϫ1.99 (m, 2 H, H-2b,3a), 1.86 (m, 1 H, H-3b)
ppm. 13C NMR (100 MHz, [D3]CD3CN): δ ϭ 137.9 (C-1a), 137.8
(C-7Јa), 137.0 (C-8a), 128.6 (C-5a), 127.5 (C-4Јa), 123.9 (C-2Ј),
122.4 (C-6Ј), 121.5 (C-7), 119.8 (C-4Ј), 119.7 (C-5Ј), 119.4 (C-6),
118.7 (C-3Ј), 118.6 (C-5), 112.4 (C-7Ј), 111.5 (C-8), 110.6 (C-4a),
Compound 12a: Yield 35%, 137 mg. Starting materials: 5,6-(methyl-
enedioxy)indole and 2-methoxytetrahydrofuran; Procedure B1. 33.2 (C-1), 33.1 (C-2), 23.1 (C-3), 21.8 (C-4) ppm. MS (IS): m/z ϭ
Eur. J. Org. Chem. 2004, 2411Ϫ2420
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2417

G. Giannini, F. De Angelis et al.
FULL PAPER
287 [M ϩ H]ϩ. C20H18N2 (286.20): calcd. C 83.30, H 6.99, N 9.71;
found C 83.21, H 6.91, N 9.53. M.p. 207 °C.
300 ϫ 3.3, 5 µm; H2O/CH3CN, 40:60, flow: 1 mL/min; room temp.
12.8 min). Only one diastereoisomer was isolated (configuration at
C1/C4: undetermined). 1H NMR (300 MHz, [D3]CD3CN): δ ϭ
9.23 (br. s, 1 H, H-1Ј), 8.91 (s, 1 H, H-9), 7.69 (m, 1 H, H-5), 7.51
(d, J ϭ 7.8 Hz, 1 H, H-4Ј), 7.48 (d, J ϭ 8.0 Hz, 1 H, H-7Ј),
7.30Ϫ7.15 (m, 2 H, H-8,6Ј), 7.13Ϫ7.02 (m, 3 H, H-7,6,5Ј), 6.94 (d,
J ϭ 2.4 Hz, 1 H, H-2Ј), 4.72Ϫ4.61 (m, 2 H, H-4ЈЈ,2), 4.53 (d, J ϭ
5.6 Hz, 1 H, H-3), 4.52 (d, J ϭ 5.5 Hz, 1 H, H-1), 3.97 (dd, J1 ϭ
8.4, J2 ϭ 6.4 Hz, 1 H, H-5ЈЈa), 3.73Ϫ3.65 (m, 2 H, H-5ЈЈb,4), 1.46
(s, 3 H, H-4ЈЈЈa), 1.43 (s, 3 H, H-6ЈЈa), 1.40 (s, 3 H, H-4ЈЈЈb), 1.34
(s, 3 H, H-6ЈЈb) ppm. 13C NMR (75 MHz, [D3]CD3CN): δ ϭ 137.9
(C-7Јa), 137.7 (C-8a), 135.7 (C-1a), 128.2 (C-5a), 127.5 (C-4Јa),
124.5 (C-2Ј), 122.7 (C-6Ј), 121.9 (C-7), 120.1 (C-5,5Ј), 119.9 (C-4Ј),
119.8 (C-6), 115.9 (C-3Ј), 112.5 (C-7Ј), 111.9 (C-8), 109.7 (C-2ЈЈ),
108.4 (C-2ЈЈЈ), 107.6 (C-4a), 80.8 (C-2), 78.0 (C-4ЈЈ), 75.9 (C-3),
68.3 (C-5ЈЈ), 40.8 (C-4), 38.1 (C-1), 28.3 (C-4ЈЈЈa), 26.8 (C-6ЈЈa),
25.9 (C-4ЈЈЈb), 25.5 (C-6ЈЈb) ppm. MS (IS): m/z ϭ 459 [M ϩ H]ϩ.
C28H30N2O4 (458.24): calcd. C 73.34, H 6.59, N 6.11; found C
73.11, H 6.63, N 5.55. M.p. 204Ϫ206 °C (dec.)
4-(1H-Indol-3-yl)-2,3,4,9-tetrahydro-1H-carbazole (6a): Yield 7%,
20 mg. Starting material: 1a; Procedure C. TLC (hexane/iPrOH,
9:1; Rf ϭ 0.55); HPLC RP-18 (Waters 250 ϫ 4.6, 5 µm; H2O/
CH3CN, 40:60; flow: 1 mL/min; room temp. 12.4 min). Racemic
1
mixture. H NMR (600 MHz, [D3]CD3CN): δ ϭ 8.96 (br. s, 1 H,
H-1Ј), 8.94 (s, 1 H, H-9), 7.44 (d, J ϭ 7.8 Hz, 1 H, H-4Ј), 7.36
(ddd, J1 ϭ 8.2, J2 ϭ J3 ϭ 0.9 Hz, 1 H, H-7Ј), 7.27 (ddd, J1 ϭ 8.1,
J2 ϭ J3 ϭ 0.9 Hz, 1 H, H-8), 7.07 (m, 1 H, H-6Ј), 6.96Ϫ6.90 (m,
2 H, H-7,5Ј), 6.84 (d, J ϭ 8.1 Hz, 1 H, H-5), 6.77 (d, J ϭ 2.4 Hz,
1 H, H-2Ј), 6.71 (m, 1 H, H-6), 4.50 (t, J ϭ 5.9 Hz, 1 H, H-4),
2.90Ϫ2.76 (m, 2 H, H-1), 2.17 (m, 1 H, H-3a), 2.05 (m, 1 H, H-
3b), 1.95 (m, 1 H, H-2a), 1.84 (m, 1 H, H-2b) ppm. 13C NMR
(100 MHz, [D3]CD3CN): δ ϭ 137.9 (C-7Јa), 137.1 (C-8a), 136.2 (C-
1a), 128.5 (C-5a), 127.7 (C-4Јa), 123.7 (C-2Ј), 122.1 (C-6Ј), 121.2
(C-7), 120.9 (C-3Ј), 119.9 (C-4Ј), 119.3 (C-5Ј), 119.2 (C-5), 119.1
(C-6), 112.5 (C-4a), 112.3 (C-7Ј), 111.3 (C-8), 32.9 (C-3), 31.2 (C-
4), 23.9 (C-1), 21.8 (C-2) ppm. . MS (IS): m/z ϭ 287 [M ϩ H]ϩ.
C20H18N2 (286.20): calcd. C 83.30, H 6.99, N 9.71; found C 82.95,
H 6.95, N 9.51. M.p. 182 °C.
Compound 15: Yield 55%, 214 mg. Starting materials: 11aϪ11b;
Procedure C. TLC (hexane/EtOAc, 8:2, Rf ϭ 0.23); HPLC RP-18
(Waters 300 ϫ 3.3, 5 µm; H2O/CH3CN, 40:60, flow 1 mL/min,
room temp. 15.4 min). M.p. 184 °C (dec.).Racemic mixture. 1H
NMR (500 MHz, [D3]CD3CN): δ ϭ 9.01 (br. s, 1 H, H-1Ј), 8.37 (s,
1 H, H-5), 6.94 (s, 1 H, H-7Ј), 6.91 (s, 1 H, H-4Ј), 6.83 (s, 1 H, H-
1), 6.80 (d, J ϭ 2.3 Hz, 1 H, H-2Ј), 6.67 (s, 1 H, H-4), 5.90 (s, 2 H,
H-8Ј), 5.85Ϫ5.83 (m, 2 H, H-11), 4.44 (dd, J1 ϭ 8.5, J2 ϭ 3.2 Hz,
1 H, H-6), 2.92Ϫ2.72 (m, 2 H, H-10), 2.27 (m, 1 H, H-7a), 2.05 (m,
1 H, H-7b), 1.89Ϫ1.73 (m, 4 H, H-8,9) ppm. 13C NMR (100 MHz,
[D3]CD3CN): δ ϭ 145.5 (C-5Ј), 144.4 (C-2), 143.3 (C-6Ј), 142.9 (C-
3), 139.3 (C-6a), 132.7 (C-7Јa), 129.8 (C-4a), 124.0 (C-1a), 122.7
(C-2Ј), 121.3 (C-4Јa), 118.2 (C-3Ј), 113.4 (C-10a), 101.5 (C-8Ј),
101.1 (C-11), 98.4 (C-1), 97.3 (C-4Ј), 93.0 (C-7Ј), 92.4 (C-4), 38.1
(C-6), 35.3 (C-7), 29.5 (C-8), 29.5 (C-9), 25.4 (C-10) ppm. MS (IS):
m/z ϭ 389 [M ϩ H]ϩ. C23H20N2O4 (388.19): calcd. C 71.12, H
5.19, N 7.21; found C 70.95, H 5.00, N 7.12.
6-(1H-Indol-3-yl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole
(5b):
Yield 65%, 195 mg. Starting materials: 2bϪ1b; Procedure C. TLC
(hexane/iPrOH, 95:5; Rf ϭ 0.22); HPLC RP-18 (Waters 300 ϫ 3.3,
5 µm; H2O/CH3CN, 40:60; flow: 1 mL/min; room temp. 22.1 min).
M.p. 206Ϫ208 °C. Racemic mixture. 1H NMR (500 MHz,
[D6]DMSO): δ ϭ 10.80 (br. s, 1 H, H-1Ј), 10.41 (s, 1 H, H-5), 7.49
(d, J ϭ 7.9 Hz, 1 H, H-4Ј), 7.44 (m, 1 H, H-1), 7.36 (d, J ϭ 8.0 Hz,
1 H, H-7Ј), 7.18 (m, 1 H, H-4), 7.07 (t, J ϭ 8.0 Hz, 1 H, H-6Ј),
6.99Ϫ6.91 (m, 3 H, H-5Ј,2,3), 6.68 (d, J ϭ 2.2 Hz, 1 H, H-2Ј), 4.64
(dd, J1 ϭ 5.9, J2 ϭ 3.1 Hz, 1 H, H-6), 2.97 (m, 1 H, H-10a), 2.75
(m, 1 H, H-10b), 2.36 (m, 1 H, H-7a), 1.98 (m, 1 H, H-7b), 1.88
(m, 1 H, H-9a), 1.76 (m, 1 H, H-8a), 1.71Ϫ1.53 (m, 2 H, H-8b,9b)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 139.7 (C-5a), 136.6
(C-7Јa), 134.2 (C-4a), 128.6 (C-1a), 126.0 (C-4Јa), 123.5 (C-2Ј),
120.7 (C-6Ј), 119.6 (C-3), 118.5 (C-4Ј), 118.2 (C-5Ј), 117.7 (C-2),
117.2 (C-1), 115.6 (C-3Ј), 111.4 (C-7Ј,10a), 110.5 (C-4), 36.3 (C-6),
33.2 (C-7), 28.6 (C-9), 26.5 (C-8), 24.0 (C-10) ppm. MS (IS): m/z ϭ
299 [M Ϫ H]Ϫ. C21H20N2 (300.20): calcd. C 83.96, H 6.71, N 9.33;
found C 81.19, H 6.50, N 9.03.
Compound 16: Yield 58%, 217 mg. Starting materials: 12aϪ12b;
Procedure C. TLC (hexane/iPrOH, 9:1, Rf ϭ 0.31); HPLC RP-18
(Waters 300 ϫ 3.3, 5 µm; H2O/CH3CN, 40:60, flow: 1 mL/min,
room temp. 11.5 min). Racemic mixture. 1H NMR (500 MHz,
[D3]CD3CN): δ ϭ 8.94 (br. s, 1 H, H-1Ј), 8.42 (s, 1 H, H-9), 6.88
(s, 2 H, H-7Ј,5), 6.85 (d, J ϭ 2.4 Hz, 1 H, H-2Ј), 6.69 (s, 1 H, H-
8), 6.61 (s, 1 H, H-4Ј), 5.87Ϫ5.81 (m, 4 H, H-10,8Ј), 4.30 (dd, J1 ϭ
7.8, J2 ϭ 6.6 Hz, 1 H, H-1), 2.77Ϫ2.66 (m, 2 H, H-4), 2.20 (m, 1
H, H-2a), 2.05Ϫ1.91 (m, 2 H, H-2b,3a), 1.81 (m, 1 H, H-3b) ppm.
13C NMR (100 MHz, [D3]CD3CN): δ ϭ 145.4 (C-5Ј), 144.6 (C-6),
143.2 (C-6Ј), 142.9 (C-7), 136.6 (C-1a), 132.6 (C-7Јa), 131.6 (C-8a),
122.4 (C-2Ј,5a), 121.4 (C-4Јa), 119.1 (C-3Ј), 110.8 (C-4a), 101.5 (C-
10), 101.2 (C-8Ј), 98.2 (C-4Ј), 97.6 (C-5), 93.1 (C-7Ј), 92.8 (C-8),
33.3 (C-1), 33.0 (C-2), 23.2 (C-3), 21.8 (C-4) ppm. MS (IS): m/z ϭ
375 [M ϩ H]ϩ. C22H18N2O4 (374.19): calcd. C 70.58, H 4.85, N
7.48; found C 70.15, H 4.75, N 7.25. M.p. 200 °C (dec.)
10-(1H-Indol-3-yl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (6b):
Yield 6%, 18 mg. Starting materials: 2bϪ1b; Procedure C. TLC
(hexane/iPrOH, 95:5; Rf ϭ 0.15); HPLC RP-18 (Waters 300 ϫ 3.3,
5 µm; H2O/CH3CN, 40:60, flow: 1 mL/min, room temp. 16.6 min).
Racemic mixture. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 10.68 (br.
s, 1 H, H-5), 10.61 (s, 1 H, H-1Ј), 7.62 (d, J ϭ 7.7 Hz, 1 H, H-4Ј),
7.31 (d, J ϭ 7.9 Hz, 1 H, H-7Ј), 7.24 (d, J ϭ 7.9 Hz, 1 H, H-4),
7.14 (d, J ϭ 7.9 Hz, 1 H, H-1), 7.05 (t, J ϭ 7.9 Hz, 1 H, H-6Ј),
6.97 (t, J ϭ 7.7 Hz, 1 H, H-5Ј), 6.93 (t, J ϭ 7.9 Hz, 1 H, H-3), 6.79
(t, J ϭ 7.9 Hz, 1 H, H-2), 6.48 (br. s, 1 H, H-2Ј), 4.79 (t, J ϭ
3.9 Hz, 1 H, H-10), 2.98Ϫ2.87 (m, 2 H, H-6), 2.45 (m, 1 H, H-9a),
2.01Ϫ1.81 (m, 2 H, H-9b,7a), 1.72 (m, 1 H, H-8a), 1.63Ϫ1.43 (m,
2 H, H-7b,8b) ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 137.4
(C-5a), 136.7 (C-7Јa), 134.3 (C-4a), 128.5 (C-1a), 126.2 (C-4Јa),
123.5 (C-2Ј), 120.5 (C-6Ј), 119.6 (C-3), 118.6 (C-4Ј), 118.0 (C-5Ј),
117.7 (C-2), 117.4 (C-3Ј), 117.1 (C-1), 114.5 (C-10a), 111.3 (C-7Ј),
110.2 (C-4), 33.7 (C-9), 31.8 (C-10), 28.3 (C-6), 27.3 (C-7), 25.2 (C-
8) ppm. MS (IS): m/z ϭ 299 [M Ϫ H]Ϫ. C21H20N2 (300.20): calcd.
C 83.96, H 6.71, N 9.33; found C 82.29, H 6.53, N 9.11. M.p.
170 °C.
2-Benzyloxy-6-[5-benzyloxy-1H-indol-3-yl]-5,6,7,8,9,10-hexahydro-
cyclohepta[b]indole (17): Yield 62%, 318 mg. Starting material: 9;
Procedure C. TLC (hexane/iPrOH, 9:1, Rf ϭ 0.62); HPLC RP-18
(Waters 300 ϫ 3.3, 5 µm; H2O/CH3CN, 40:60, flow: 1 mL/min,
room temp. 27.1 min). M.p. 286 °C (dec.). Racemic mixture. 1H
NMR (500 MHz, [D3]CD3CN): δ ϭ 9.04 (br. s, 1 H, H-1Ј), 8.43 (s,
1 H, H-5), 7.47 (d, J ϭ 7.6 Hz, 2 H, H-13), 7.39 (d, J ϭ 7.6 Hz, 2
H, H-10Ј), 7.38 (t, J ϭ 7.6 Hz, 2 H, H-14), 7.35Ϫ7.25 (m, 5 H, H-
11Ј,7Ј,15,12Ј), 7.05 (d, J ϭ 2.4 Hz, 1 H, H-1), 7.04 (d, J ϭ 8.7 Hz,
1 H, H-4), 6.93 (d, J ϭ 2.5 Hz, 1 H, H-4Ј), 6.90 (d, J ϭ 2.3 Hz, 1
Compound 14: Yield 70%, 321 mg. Starting material: 7 ؊ Procedure
C. TLC (hexane/acetone, 8:2, Rf ϭ 0.75); HPLC RP-18 (Waters
2418
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2411Ϫ2420

Synthesis of Cycloalkanoindoles by an Unusual DAST-Triggered Rearrangement Reaction
FULL PAPER
H, H-2Ј), 6.84 (dd, J1 ϭ 8.8, J2 ϭ 2.5 Hz, 1 H, H-6Ј), 6.71 (dd, H, H-4), 6.90 (d, J ϭ 2.5 Hz, 1 H, H-2Ј), 6.83 (d, J ϭ 2.2 Hz, 1 H,
J1 ϭ 8.7, J2 ϭ 2.4 Hz, 1 H, H-3), 5.10 (s, 2 H, H-11), 4.96 (s, 2 H, H-1), 6.82 (d, J ϭ 2.2 Hz, 1 H, H-4Ј), 6.70 (dd, J1 ϭ 8.6, J2
H-8Ј), 4.52 (dd, J1 ϭ 8.4, J2 ϭ 2.6 Hz, 1 H, H-6), 2.89Ϫ2.81 (m, 2 2.2 Hz, 1 H, H-6Ј), 6.53 (dd, J1 ϭ 8.4, J2 ϭ 2.2 Hz, 1 H, H-3), 6.34
ϭ
H, H-10), 2.29 (m, 1 H, H-7a), 2.05 (m, 1 H, H-7b), 1.88 (m, 1 H,
(br. s, 1 H, 5Ј-OH), 6.28 (br. s, 1 H, 2-OH), 4.48 (dd, J1 ϭ 8.6,
J2 ϭ 2.7 Hz, 1 H, H-6), 2.93Ϫ2.76 (m, 2 H, H-10), 2.28 (m, 1 H,
H-8a), 1.85Ϫ1.74 (m, 3 H, H-8b,9) ppm. 13C NMR (100 MHz,
[D3]CD3CN): δ ϭ 153.6 (C-5Ј,2), 141.7 (C-5a), 139.3 (C-12), 139.0 H-7a), 2.07 (m, 1 H, H-7b), 1.94 (m, 1 H, H-8a), 1.90Ϫ1.71 (m, 3
(C-9Ј), 133.2 (C-7Јa), 130.7 (C-4a), 130.5 (C-1a), 129.3 (C-14), H, H-8b,9) ppm. 13C NMR (100 MHz, [D3]CD3CN): δ ϭ 151.1
129.3 (C-11Ј), 128.6 (C-10Ј), 128.6 (C-13), 128.5 (C-15,12Ј), 127.9 (C-5Ј), 150.9 (C-2), 141.8 (C-6a), 132.8 (C-7Јa), 130.9 (C-1a), 130.2
(C-4Јa), 125.0 (C-2Ј), 117.4 (C-3Ј), 113.2 (C-6Ј), 113.2 (C-10a),
(C-4a), 128.2 (C-4Јa), 124.9 (C-2Ј), 117.0 (C-3Ј), 112.9 (C-7Ј), 112.6
113.1 (C-7Ј), 112.1 (C-4), 111.7 (C-3), 103.7 (C-4Ј), 102.5 (C-1), (C-10a), 112.4 (C-6Ј), 111.8 (C-4), 110.7 (C-3), 104.1 (C-4Ј), 102.7
71.4 (C-11), 71.3 (C-8Ј), 38.1 (C-6), 35.1 (C-7), 29.5 (C-8), 29.4 (C-
9), 25.3 (C-10) ppm. MS (IS): m/z ϭ 513 [M ϩ H]ϩ. C35H32N2O2
(C-1), 38.2 (C-6), 35.2 (C-7), 29.7 (C-8), 29.6 (C-9), 25.3 (C-10)
ppm. MS (IS): m/z ϭ 333 [M ϩ H] ϩ. C21H20N2O2 (332.19): calcd.
(512.33): calcd. C 82.00, H 6.29, N 5.46; found C 81.08, H 6.17, C 75.88, H 6.06, N 8.43; found C 75.00, H 5.96, N 8.03.
N 5.25.
2,3-Dihydroxy-4-(1,2-dihydroxyethyl)-1-(1H-indol-3-yl)-2,3,4,9-
6,7-Methylenedioxy-4-[(5,6-methylenedioxy)-1H-indol-3-yl)-2,3,4,9-
tetrahydro-1H-carbazole (18): Yield 5%, 19 mg. Starting materials:
12aϪ12b; Procedure C. TLC (hexane/iPrOH, 9:1, Rf ϭ 0.20);
HPLC RP-18 (Waters 300 ϫ 3.3, 5µm; H2O/CH3CN, 40:60, flow:
1 mL/min, room temp. 7.9 min). M.p. 228 °C (dec.). Racemic mix-
tetrahydro-1H-carbazole (21): Yield Ͼ 98%, 374 mg. Starting mate-
rials: 14Ϫ22; Procedure E. TLC (hexane/iPrOH, 75:25, Rf ϭ 0.15);
HPLC RP-18 (Waters 250 ϫ 4, 5 µm; H2O/CH3CN, 40:60, flow:
1 mL/min, room temp. 2.9 min). M.p. 195 °C (dec.). 1H NMR
(400 MHz, [D3]CD3CN): δ ϭ 9.31 (br. s, 1 H, H-1Ј), 8.76 (br. s, 1
H, H-9), 7.60 (m, 1 H, H-5), 7.42 (d, J ϭ 8.2 Hz, 1 H, H-7Ј), 7.40
(d, J ϭ 8.2 Hz, 1 H, H-4Ј), 7.18Ϫ7.08 (m, 3 H, H-8,2Ј,6Ј),
7.05Ϫ6.97 (m, 2 H, H-6,7), 6.92 (t, J ϭ 8.2 Hz, 1 H, H-5Ј), 4.39
(dd, J1 ϭ 8.0, J2 ϭ 2.2 Hz, 1 H, H-2), 4.33 (d, J ϭ 8.0 Hz, 1 H,
H-1), 4.28Ϫ4.22 (m, 2 H, H-3,2ЈЈ), 3.68 (dd, J1 ϭ 10.7, J2 ϭ 4.0 Hz,
1 H, H-3ЈЈa), 3.58 (dd, J1 ϭ 10.7, J2 ϭ 7.5 Hz, 1 H, H-3ЈЈb), 3.41
(t, J1 ϭ J2 ϭ 4.0 Hz, 1 H, H-4) ppm. 13C NMR (100 MHz,
[D3]CD3CN): δ ϭ 138.0 (C-7Јa, 8a), 137.3 (C-1a), 128.9 (C-5a),
127.7 (C-3Јa), 125.8 (C-2Ј), 122.4 (C-6Ј), 121.6 (C-7), 120.2 (C-4Ј),
120.2 (C-5), 119.7 (C-5Ј), 119.6 (C-6), 114.6 (C-3Ј), 112.4 (C-7Ј),
111.6 (C-8), 107.0 (C-4a), 75.3 (C-3), 73.7 (C-2), 73.2 (C-2ЈЈ), 65.5
(C-3ЈЈ), 43.8 (C-4), 38.3 (C-1) ppm. MS (IS): m/z ϭ 379 [M ϩ H]ϩ.
C22H22N2O4 (378.18): calcd. C 69.80, H 5.86, N 7.40; found C
69.70, H 5.85, N 7.35.
1
ture. H NMR (500 MHz, [D3]CD3CN): δ ϭ 8.85 (br. s, 1 H, H-
1Ј), 8.78 (s, 1 H, H-9), 6.88 (s, 1 H, H-7Ј), 6.81 (s, 1 H, H-8), 6.75
(d, J ϭ 2.3 Hz, 1 H, H-2Ј), 6.73 (s, 1 H, H-4Ј), 6.21 (s, 1 H, H-5),
5.87Ϫ5.83 (m, 2 H, H-8Ј), 5.78Ϫ5.74 (m, 2 H, H-10), 4.31 (dd,
J1 ϭ 6.9, J2 ϭ 5.8 Hz, 1 H, H-4), 2.88Ϫ2.70 (m, 2 H, H-1), 2.13
(m, 1 H, H-3a), 1.99 (m, 1 H, H-3b), 1.96 (m, 1 H, H-2a), 1.84 (m,
1 H, H-2b) ppm. 13C NMR (100 MHz, [D3]CD3CN): δ ϭ 145.2
(C-5Ј), 144.2 (C-6), 142.9 (C-6Ј), 142.4 (C-7), 134.7 (C-1a), 132.6
(C-7Јa), 131.6 (C-8a), 122.3 (C-2Ј,5a), 121.5 (C-4Јa), 120.9 (C-3Ј),
112.8 (C-4a), 101.4 (C-8Ј), 101.1 (C-10), 98.5 (C-4Ј), 98.3 (C-5),
93.0 (C-7Ј), 92.7 (C-8), 33.1 (C-3), 31.7 (C-4), 23.9 (C-1), 22.3 (C-
2) ppm. MS (IS): m/z ϭ 373 [M Ϫ H]Ϫ. C22H18N2O4 (374.19):
calcd. C 70.20, H 5.36, N 7.44; found C 70.28, H 5.37, N 7.40.
2-(Benzyloxy)-10-[5-benzyloxy-1H-indol-3-yl]-5,6,7,8,9,10-hexa-
hydrocyclohepta[b]indole (19): Yield 5%, 26 mg. Starting material:
9; Procedure C. TLC (hexane/iPrOH, 9:1, Rf ϭ 0.4); HPLC RP-18
(Waters 300 ϫ 3.3, 5 µm; H2O/CH3CN, 40:60, flow: 1 mL/min,
room temp. 18.1 min). M.p. 237 °C (dec.). Racemic mixture. 1H
NMR (500 MHz, [D3]CD3CN): δ ϭ 8.82Ϫ8.77 (br. s, 2 H, H-5,1Ј),
7.47 (d, J ϭ 7.6 Hz, 2 H, H-10Ј), 7.43Ϫ7.20 (m, 9 H, H-
11Ј,13,14,7Ј,15,12Ј), 7.17 (d, J ϭ 8.7 Hz, 1 H, H-4), 7.16 (d, J ϭ
2.5 Hz, 1 H, H-4Ј), 6.83 (dd, J1 ϭ 8.8, J2 ϭ 2.5 Hz, 1 H, H-6Ј),
6.75 (d, J ϭ 2.5 Hz, 1 H, H-1), 6.69 (dd, J1 ϭ 8.7, J2 ϭ 2.5 Hz, 1
H, H-3), 6.55 (d, J ϭ 2.2 Hz, 1 H, H-2Ј), 5.08 (s, 2 H, H-8Ј), 4.90
(m, 2 H, H-11), 4.71 (t, J ϭ 4.3 Hz, 1 H, H-10), 2.97Ϫ2.82 (m, 2
H, H-6), 2.48 (m, 1 H, H-9a), 1.96 (m, 1 H, H-9b), 1.76 (m, 1 H,
H-8a), 1.66Ϫ1.54 (m, 3 H, H-8b,7) ppm. 13C NMR (100 MHz,
[D3]CD3CN): δ ϭ 153.5 (C-2), 153.4 (C-5Ј), 139.7 (C-5a), 139.2 (C-
9Ј), 139.1 (C-12), 133.3 (C-7Јa), 131.0 (C-4a), 130.5 (C-1a), 129.3
(C-14), 129.2 (C-11Ј), 128.7 (C-10Ј), 128.6 (C-13), 128.6 (C-12Ј),
128.5 (C-15), 128.1 (C-4Јa), 125.3 (C-2Ј), 119.2 (C-3Ј), 116.1 (C-
10a), 112.9 (C-7Ј), 112.9 (C-4), 111.8 (C-6Ј), 111.6 (C-3), 104.0 (C-
4Ј), 102.5 (C-1), 71.4 (C-8Ј), 71.2 (C-11), 34.7 (C-9), 33.4 (C-10),
29.7 (C-6), 28.5 (C-7), 26.6 (C-8) ppm. MS (IS): m/z ϭ 511 [M Ϫ
H]Ϫ. C35H32N2O4 (512.33): calcd. C 82.00, H 6.29, N 5.46; found
C 81.20, H 6.08, N 5.25.
4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydroxy-1-(1H-indol-3-yl)-
2,3,4,9-tetrahydro-1H-carbazole (22): Yield 30%, 126 mg. Starting
material: 14; Procedure E. TLC (hexane/iPrOH, 75:25, Rf ϭ 0.31);
HPLC RP-18 (Waters 250 ϫ 4, 5 µm; H2O/CH3CN, 40:60, flow:
1 mL/min, room temp. 4.3 min). M.p. 166 °C (dec.). 1H NMR
(400 MHz, [D3]CD3CN): δ ϭ 9.17 (br. s, 1 H, H-1Ј), 8.60 (br. s, 1
H, H-9), 7.58 (m, 1 H, H-5), 7.36 (d, J ϭ 8.1 Hz, 1 H, H-7Ј), 7.21
(d, J ϭ 8.1 Hz, 1 H, H-4Ј), 7.10 (d, J ϭ 2.5 Hz, 1 H, H-2Ј),
7.07Ϫ6.99 (m, 2 H, H-8,6Ј), 6.95Ϫ6.87 (m, 2 H, H-7,6), 6.83 (t,
J ϭ 8.1 Hz, 1 H, H-5Ј), 4.45 (m, 1 H, H-4ЈЈ), 4.26Ϫ4.23 (m, 2 H,
H-1,2), 4.07 (dd, J1 ϭ 8.2, J2 ϭ 6.2 Hz, 1 H, H-5ЈЈa), 3.93 (d, J ϭ
3.0 Hz, 1 H, H-3), 3.78 (t, J ϭ 8.2 Hz, 1 H, H-5ЈЈb), 3.30 (dd, J1 ϭ
7.7, J2 ϭ 3.0 Hz, 1 H, H-4), 3.20 (br. s, 1 H, 3-OH), 2.98 (br. s, 1
H, 2-OH), 1.35 (s, 3 H, H-6ЈЈa), 1.24 (s, 3 H, H-6ЈЈb) ppm. 13C
NMR (100 MHz, [D3]CD3CN): δ ϭ 138.1 (C-7Јa), 137.9 (C-8a),
136.7 (C-1a), 129.0 (C-5a), 127.6 (C-4Јa), 125.8 (C-2Ј), 122.4 (C-
6Ј), 121.7 (C-7), 121.0 (C-5), 120.0 (C-4Ј), 119.8 (C-5Ј), 119.6 (C-
6), 114.3 (C-3Ј), 112.5 (C-7Ј), 111.4 (C-8), 109.6 (C-2ЈЈ), 108.2 (C-
4a), 79.8 (C-4ЈЈ), 73.3 (C-2), 72.6 (C-3), 69.0 (C-5ЈЈ), 44.5 (C-4),
38.3 (C-1), 26.9 (C-6ЈЈa), 25.8 (C-6ЈЈb) ppm. MS (IS): m/z ϭ 419
[M ϩ H]ϩ. C25H26N2O4 (418.21): calcd. C 71.75, H 6.26, N 6.69;
found C 71.76, H 6.27, N 6.60.
2-Hydroxy-6-(5-hydroxy-1H-indol-3-yl)-5,6,7,8,9,10-hexahydro-
cyclohepta[b]indole (20): Yield 85%, 282 mg. Starting material: 17;
Procedure C. TLC (hexane/iPrOH, 9:1, Rf ϭ 0.35); HPLC RP-18
(Waters 300 ϫ 3.3, 5 µm; H2O/CH3CN, 45:55, flow 1 mL/min,
room temp. 4.2 min). M.p. 248 °C (dec.). Racemic mixture. 1H
NMR (400 MHz, [D3]CD3CN): δ ϭ 8.93 (br. s, 1 H, H-1Ј), 8.30 (s,
1 H, H-5), 7.27 (d, J ϭ 8.6 Hz, 1 H, H-7Ј), 6.97 (d, J ϭ 8.4 Hz, 1
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2420
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