Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT 6 receptor ligands

Article abstract of DOI:10.1039/b808641a

A series of novel indene derivatives designed by a scaffold selection gave access to several examples of (Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT₆ receptor ligands. Different synthetic multistep routes could be applied to these target compounds, each with their own complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence employing a modified Horner-Wadsworth-Emmons reaction, but better results were obtained with a procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed immediately by dehydration with acid and hydrolysis/ isomerization under basic catalysis. (3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively reduced to indenylsulfonamides 13-17 using an optimized procedure with AlH ₃-NMe₂Et. The binding at the 5-HT₆ receptor was with moderate affinity (K_i = 216.5 nM) for the (Z)- benzylideneindenylsulfonamide 12 and enhanced affinity for the simple indenylsulfonamide counterpart 13 (K_i = 50.6 nM). Selected indenylsulfonamides 14-17 were then tested, showing K_i values as low as 20.2 nM. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b808641a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6
receptor ligands†
Ermitas Alcalde,*a Neus Mesquida,*a Jordi Frigola,b Sara Lo´pez-Pe´reza and Ramon Merce`b
Received 21st May 2008, Accepted 11th July 2008
First published as an Advance Article on the web 11th August 2008
DOI: 10.1039/b808641a
A series of novel indene derivatives designed by a scaffold selection gave access to several examples of
(Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT6 receptor ligands.
Different synthetic multistep routes could be applied to these target compounds, each with their own
complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key
intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence
employing a modified Horner–Wadsworth–Emmons reaction, but better results were obtained with a
procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed
immediately by dehydration with acid and hydrolysis/isomerization under basic catalysis.
(3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively
reduced to indenylsulfonamides 13–17 using an optimized procedure with AlH3–NMe2Et. The
binding at the 5-HT6 receptor was with moderate affinity (Ki = 216.5 nM) for the
(Z)-benzylideneindenylsulfonamide 12 and enhanced affinity for the simple indenylsulfonamide
counterpart 13 (Ki = 50.6 nM). Selected indenylsulfonamides 14–17 were then tested, showing Ki
values as low as 20.2 nM.
Introduction
A survey of biologically active (Z)-stilbenes shows that (Z)-
aryl(heteroaryl)methylideneindenes 1 form an ensemble of com-
pounds with a variety of pharmacological profiles.1 Relevant
examples are the nonsteroidal anti-inflammatory drug (NSAID)
sulindac 2 together with sulindac sulfone 3 and sulindac-derived
compounds 4 (Fig. 1).2 Exisulind 3 is a new class of targeted
and pro-apoptopic drug, being the lead compound in a series
of selective apoptotic antineoplasic drugs. A library of sulindac
analogs 4 have led to new inhibitors of the tumor-relevant Ras
signal transduction pathway, underlining the advantage of using
biologically prevalidated compound classes in chemical biology
research.3,4 In an interesting study carried out concurrently with
our own, Glennon and co-workers have examined the binding
of several isotriptamines and indenes at the h5-HT6 serotonin
receptor, such as (E)-benzylideneindene 5 (Ki = 57 nM), (ben-
zylindenyl)ethanamine 6 (Ki = 3 nM) and isotryptamine analog
7 (Ki = 32 nM), revealing that the indolic nitrogen atom is not
essential for binding.5
As part of a project aimed at the study of (Z)-stilbenes
with potential biological effects on the central nervous system
(CNS), we focused our attention on an indene core of general
type 1, since indenes constitute a source of pharmacologically
active molecules, and their synthesis and pharmacology have
Fig. 1
not yet been extensively explored. We thus hoped to max-
imise the likelihood of discovering compounds with biological
properties. On the basis of these premises, the first series of
indene compounds was based on the cis-indene structure 1 in
which the (Z)-stilbene moiety was embedded and the traditional
N,N-dimethylaminoethyl CNS functionality was incorporated at
the 3-position. (Z)-Aryl(heteroaryl)methylideneindenes 8–11 were
synthesized and compounds 10 and 11 were profiled against a
panel of 64 radioligand binding assays along with the 5-HT6
aLaboratori de Qu´ımica Orga`nica, Departament de Farmacologia i Qu´ımica
Terape`utica, Facultat de Farma`cia, Universitat de Barcelona, Av. Joan XXIII
s/n, E-08028, Barcelona, Spain. E-mail: ealcalde@ub.edu
bESTEVE, Av. Mare de De´u de Montserrat, 221, E-08041, Barcelona, Spain
† Electronic supplementary information (ESI) available: 1H NMR and 13
C
NMR assignments, NMR spectra of targeted compounds, assays related
to the preparation of compounds 12–17, 19, 22 and 25, and 5-HT6 binding
affinity and functionality (Table S1). See DOI: 10.1039/b808641a
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3795
©

View Article Online
serotonin receptor, but none of them showed significant binding
affinities (Scheme 1).
a methyl group at the 2-position of the core ring should favor
the formation of both the (Z)-diastereoisomers of 8–12 and the
desired endo-olefin of the key indenylacetic acids in the preparation
of indenylsulfonamides 13–14 and 16–17.
The subsequent design step was namely the incorporation of
a sulfonamide group at the 5-position of the indene ring, since
studies of 5-HT6 serotonin receptor ligands have highlighted the
importance of the sulfonyl moiety (e.g. sulfonamides, sulfones)
for binding,6 such as the series of indole-based sulfonamides
developed by Esteve Laboratories, e.g. the indolylsulfonamide E-
6837.7–9 Accordingly, (Z)-benzylideneindenylsulfonamide 12 and
the simple indenylsulfonamide counterpart 13 were prepared, and
the binding was with moderate affinity (Ki = 216.5 nM) for 12
and significant affinity for 13 (Ki = 50.6 nM). Selected reduced
indenylsulfonamides 14–17 were then synthesized and exhibited
binding affinity with Ki values ≥20.2 nM.
A relevant parameter playing a crucial role in a scaffold
selection process concerns the scaffold synthetic accessibility and
the ease with which its derivatives can be prepared. Despite
the utility of indenes in drug discovery and development, along
with metallocene-based catalysis, e.g. olefin polymerization, their
complexity means that synthetic approaches have been far less
investigated than in the case of heteroaromatic compounds such
as indoles.10 Reasonable retrosynthetic routes to target indene
models 8–17 are shown in Scheme 1, proceeding from either 2-
methylindan-1-one or indan-1-one sulfonamides. The presence of
Results and discussion
Chemistry
According to the retrosynthetic analysis of Scheme 1, the two
types of target indene derivatives, (Z)-aryl(heteroaryl)methyl-
ideneindenes 8–12 and indenylsulfonamides 13–17, could be
prepared using multistep routes starting from substituted in-
danones. Thus, methylindanone was transformed to both in-
denylethanamine or indenylpyridine intermediates and a sub-
sequent reaction with an aromatic/heteroaromatic aldehyde,
using a Knoevenagel condensation, afforded the (Z)-arylmethyl-
ideneindenes 8–11, whereas multistep routes were required for
indenylsulfonamides 12–17. Two alternatives were examined for
the synthesis of the key (3-indenyl)acetic acids: the first protocol
was a two-step sequence involving the Horner–Wadsworth–
Emmons reaction (HWE) but better results were obtained with
an efficient procedure based on the condensation of indanones
with the lithium salt of ethyl acetate.
Scheme 1 Retrosynthetic pathways to the target (Z)-aryl(heteroaryl)methylideneindenes 8–12 and indenylsulfonamides 13–17.
3796 | Org. Biomol. Chem., 2008, 6, 3795–3810 This journal is The Royal Society of Chemistry 2008
©

View Article Online
Preparation of substituted indan-1-ones started with a malonic-
ester acid synthesis that gave the propanoic acid 18, which was
converted to the corresponding acid chloride and cyclized to 2-
methylindan-1-one 19 under Friedel–Crafts reaction conditions
(see ESI†). Nitration of 19 gave a mixture of nitroindan-1-one
isomers 20 and 21 in 46% and 8% yield, respectively (Scheme 2).
Catalytic hydrogenation of nitroindanones 20 and 21 gave the
corresponding aminoindanones 22 and 23 in 72% and 40% yield,
but when the reduction was scaled up to 35 mmol the yield
decreased. After trying different reducing agents and reaction
conditions, the best result for the reduction of 20 was achieved by
treatment with iron in aqueous acetic acid. The amino derivative
22 was afforded in good yield (85%), and could be scaled up to
40 mmol (see ESI).
Scheme 3 Synthesis of (Z)-aryl(heteroaryl)methylideneindenes. Reagents
and conditions: (i) (a) NaBH4, THF–MeOH, rt, (b) TsOH·H2O, toluene,
reflux, (ii) (a) n-BuLi, THF, -5 ◦C, (b) Me2N(CH2)2Cl·HCl, rt; (iii) (a)
NaOMe, MeOH, 0 ◦C, (b) HetCHO, MeOH, reflux; (iv) HCl, Et2O; (v)
(a) 2-bromopyridine, n-BuLi, Et2O, -60 ◦C, (b) 95–97% H2SO4, 0 ◦C.
As a starting point, the Horner–Wadsworth–Emmons reaction
was used to transform 28 into ethyl (Z)-indanylacetate 32, and
after examining various conditions, the reaction was improved by
increasing the amounts of sodium hydride to 11.5 equivalents and
triethyl phosphonoacetate to 10 equivalents, which led to olefin
32 in 73% yield (Scheme 4). Hydrolysis and isomerization of 32
under basic catalysis afforded the key (3-indenyl)acetic acid 33 in
94% yield. The optimized Horner–Wadsworth–Emmons protocol
was then employed to indanone sulfonamide 29 to give a mixture
of ethyl acetates 34a and 34b in very low yield (19%), showing that
the HWE reaction was clearly less efficient. Changing the basic
conditions,11a,b the isomeric acetates 34a and 34b were not formed
and the N-ethyl-N-indan-1-one sulfonamide 35 was produced
instead, probably due to the presence of LiBr and LiOH·H2O,11c
respectively (Scheme 4).
In consequence, an alternative method appeared to be the
addition of organometallic compounds to indanones. We first tried
the Reformatsky reaction between indanone sulfonamide 29 and
an ester-stabilized organozinc reagent (BrZnCH2CO2Et) but this
proved to be ineffective (see ESI). We then examined an aldol-type
condensation with indanone sulfonamide 29 using the lithium
salt of ethyl acetate, immediately followed by dehydration with
trifluoroacetic acid and hydrolysis/isomerization with NaOMe
in methanol, (3-indenyl)acetic acid 36 being obtained in an
acceptable yield of 56% (see Scheme 4 and ESI). Applying the
same experimental procedure, indanone sulfonamides 30 and 31
Scheme 2 Synthesis of aminoindan-1-ones. Reagents and conditions: (i)
(a) Na, EtOH, rt, (b) PhCH2Br, reflux, (c) KOH, H2O, reflux, (d) 170 ◦C;
(ii) (a) SOCl2, reflux, (b) AlCl3, toluene, reflux; (iii) KNO3, H2SO4, -5 ◦C;
(iv) Fe, AcOH–H2O, 90 ◦C; (v) H2, 10% Pd/C, EtOH, rt.
Compounds 8–10 were prepared from indanone 19 following
the three-step sequence shown in Scheme 3. The crucial step was
the conversion of indene 24 into (3-indenyl)ethanamine 25, which
was transformed to the (Z)-indenes 8–10 using a Knoevenagel
condensation with various aromatic/heteroaromatic aldehydes,
overall average yield being 12% (see ESI). A similar procedure was
then applied to the synthesis of indene 11, which began with the
addition of 2-lithiopyridine to 19, followed by dehydration with
sulfuric acid to give indenylpyridine 26. This was condensed with
2-thiophenecarboxaldehyde in the presence of NaOMe to afford
(Z)-thienylmethylideneindene hydrochloride 11·HCl in 1% overall
yield. The purity of (Z)-aryl(heteroaryl)methylideneindenes 8–11
was variable due to their troublesome isolation and purification,
chromatographic separations being necessary in all cases.
Although different multi-step synthetic routes could be applied
to the target indenylsulfonamides 12–17, a reasonable pathway ap-
peared to involve (3-indenyl)acetic acids as the key intermediates
(Scheme 1). Accordingly, preparation of the acetic acid derivatives
started with the reaction of aminoindanones 22, 27 and 23 with
the corresponding aryl(heteroaryl)sulfonyl chlorides, giving the
corresponding indanone sulfonamides 28–31 (Scheme 4).
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3797
©

View Article Online
Scheme 4 Synthesis of (3-indenyl)acetic acids 33, 36, 37 and 38. Reagents and conditions: (i) RSO2Cl, pyridine, CH2Cl2, rt; (ii) 10 equiv
(EtO)2P(O)CH2CO2Et, 11.5 equiv NaH, THF or DME, 0 ◦C → reflux; (iii) NaOMe, MeOH, reflux; (iv) 10 equiv (EtO)2P(O)CH2CO2Et, 12 equiv
˚
LiBr, 11.5 equiv Et3N, DME, reflux; (v) 10 equiv (EtO)2P(O)CH2CO2Et, 4 A MS, 11.5 equiv LiOH·H2O, THF, reflux; (vi) (a) EtOAc, LHMDS, THF,
-78 ◦C, (b) TFA, CH2Cl2, -5 ◦C, (c) NaOMe, MeOH, reflux.
were transformed to the corresponding (3-indenyl)acetic acids 37
and 38 in good yields.
Following a similar stepwise synthetic route, indenylsulfon-
amides 14–17 were obtained from the corresponding (3-indenyl)-
acetic acids 33 and 36–38 as shown in Scheme 6. Thus, compounds
33 and 36–38 were transformed to the corresponding amides 42–
45, which were effectively reduced to the target indenes 14–17 with
AlH3–NMe2Et, overall yields ranging from 13% to 40%.
Depending on the difficulties encountered in the isolation and
purification, the purity of the indenylsulfonamides 13–17 was
variable but sufficient for the preliminary testing of their affinity
for the 5-HT6 serotonin receptor. Among them, compound 16,
which had a good affinity for the 5-HT6 receptor, showed a purity
of 99.6% by HPLC.
Knoevenagel condensation between (3-indenyl)acetic acid
33 and benzaldehyde in the presence of NaH yielded (Z)-
benzylideneindene acetic acid 39 along with by-products from the
Cannizzaro reaction (see ESI). Compound 39 was transformed
to the corresponding indenylacetamide 40 and the amide group
was reduced with LiAlH4 in THF to give the target (Z)-
benzylideneindenylsulfonamide 12 in a very low overall yield of 7%
(Scheme 5). In a similar manner, the simpler indenylsulfonamide
counterpart 13 was prepared starting from indenylacetic acid 33,
which was transformed to indenylacetamide 41. After changing
the reducing agent to AlH3–NMe2Et in THF, acetamide 41 was
transformed to 13 in acceptable 33% overall yield.
Finally, incorporation of a sulfonamide moiety into the above-
mentioned (benzylindenyl)ethanamine 6, with a high affinity
3798 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Scheme 5 Reagents and conditions: (i) (a) NaH, THF, rt, (b) PhCHO, reflux; (ii) (a) 1,1¢-carbonyldiimidazole, THF, rt, (b) Me2NH, THF, rt; (iii) LiAlH4,
THF, rt → reflux; (iv) AlH3–NMe2Et, THF, 0 ◦C.
Scheme 6 Reagents and conditions: (i) (a) 1,1¢-carbonyldiimidazole, THF, rt, (b) pyrrolidine, THF, rt; (ii) AlH3–NMe2Et, THF, 0 ◦C or rt; (iii) (a) SOCl2,
CH2Cl2, reflux, (b) C4H8NH, CH2Cl2, rt.
to the 5-HT6 receptor,5 led to (benzylindenyl)sulfonamide 46,
a structurally similar model that could allow us to examine
the contribution of a sulfonamide moiety. Attempts were made
to prepare sulfonamide 46 either from (Z)-benzylideneindene
acetic acid 39 or from indanone sulfonamide 28, but the results
were unsuccessful (Scheme 7). Catalytic hydrogenation of (Z)-
benzylideneindene 39 gave products of decomposition, and treat-
ment of indanone sulfonamide 28 in a manner similar to that
reported by Trost and Latimer11d did not provide 3-benzylindan-
1-one 48, but benzylindanones 49 and 50, and these were not
further investigated.
by NOE studies. For example, irradiation of the methyl protons
of the indene core and the methyl protons of the imidazole ring
in compound 10 gave an NOE for the olefinic proton, confirming
the (Z)-configuration (Fig. 2).
Biological results
(Z)-Aryl(heteroaryl)methylideneindenes 10 and 11·HCl were pro-
filed against a panel of 64 radioligand binding assays, at a
compound concentration of 10 mM,12 and the binding affinities
were found not to meet criteria significant for the context of the
present study. At a micromolar level, the human 5-HT6 serotonin
binding affinity of (Z)-aryl(heteroaryl)methylideneindenes 8–11
The structures of the new compounds were confirmed by
spectroscopic methods (see Experimental and ESI). The (Z)-
configurations of the target indenylidenes 8–12 was confirmed
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3799
©

View Article Online
Scheme 7 Reagents and conditions: (i) H2, 10% Pd/C, EtOH; (ii) (a) LDA, THF, -78 ◦C → rt, (b) BnBr, THF, rt.
Fig. 2
was below 22% whereas (Z)-benzylideneindenylsulfonamide 12
showed an inhibition of 91.8% (see Table S1†).
The subsequent design step was an indole–indene scaffold
switch based on the highly potent agonist E-6837.7–9 Thus,
indenylsulfonamides 13–17 were only tested on the 5-HT6 receptor.
Accordingly, incorporation of the sulfonamide moiety at the
indene 5-position gave rise to an enhanced affinity for the 5-
HT6 serotonin receptor, as shown by the compound pairs 12
(Ki = 216.5 nM) and the more simple indenylsulfonamide 13
(Ki = 50.6 nM). Changing the dimethylamino group in 13 for
a pyrrolidine, compound pairs 14 (Ki = 62.9 nM) and 15 (Ki =
46.3 nM) showed similar binding affinities (Fig. 3). Comparing
the affinities of the isomer pairs inden-5-ylsulfonamide 14 (Ki =
62.9 nM) andinden-7-ylsulfonamide 17 (Ki = 157.5nM) permitted
us to rule out additional studies with compounds containing a
sulfonamide moiety in the 7-position of the indene core. Yet when
the sulfonamide substitution of a 2-naphthyl group in 14 was
replaced by an heteroaryl group in 16, the Ki decreased to 20.2 nM
(see Table S1†), a remarkable directing effect modulated by the
nature of the aryl(heteroaryl) ring in the sulfonamide moiety.
An array of highly potent and selective 5-HT6 ligands has
been reported in the last few years, but the majority have been
identified as antagonists. A major drawback to exploring agonists
is their moderate selectivity, especially against different subtypes of
Fig. 3 Indole–indene core change: an approach toward high affinity and
selective serotonin 5-HT6 receptor ligands.
5-HT serotonin receptors.9 When indenylsulfonamides 12 and 13
were tested in the cAMP assay, their functionality was found to
be that of 5-HT6 receptor agonists. Notably, indenylsulfonamide
13 proved to be a full agonist, and this series presents good
3800 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
potential for further development due to the utility of 5-HT6
receptor agonists in the investigation of the functional role of
5-HT6 receptors.
ammonium bicarbonate. Gradient conditions: 0–12 min: 5%
ACN to 95% ACN;◦12–17 min: isocratic 95% ACN. Flow rate:
1 mL min-1. T = 35 C; l = 210 nm; tR = 5.4 min.
Materials
Conclusions
2-Methyl-3-phenylpropanoic acid 18 and 2-methylindan-1-one
19 are currently commercially available. 2-Methyl-1H-indene
2413 and 6-aminoindan-1-one 2714 were prepared as previously
described and are currently commercially available. Diethyl
methylmalonate, (2-chloroethyl)dimethylamine hydrochloride, 2-
bromopyridine, 2-furaldehyde, 2-thiophenecarboxaldehyde, 3-
fluorobenzaldehyde, 2-naphthalenesulfonyl chloride and 5-chloro-
3-methyl-1-benzothiophene-2-sulfonyl chloride are commercial.
1-Methyl-1H-imidazole-2-carbaldehyde15 was prepared as previ-
ously described.
A scaffold selection from several (Z)-arylmethylideneindenes 8–12
involving an indole–indene core change led to the identification
of simple indenylsulfonamides 13–17 with good affinities at
the serotonin 5-HT6 receptors, showing Ki values as low as
20.2 nM. We determined a convenient synthetic pathway to the
target indenylsulfonamides using (3-indenyl)acetic acids as the
key intermediates, and several routes were then examined. The
best option to prepare the advanced intermediates was based
on an aldol-type condensation between indanone sulfonamides
and the lithium salt of ethyl acetate, immediately followed by de-
hydration with trifluoroacetic acid and hydrolysis/isomerization
with NaOMe in methanol. The structural changes responsible
for enhancing the 5-HT6 receptor binding profile are governed
by the chemical tractability of the indene-based scaffolds, and
additional studies are needed for general synthetic approaches
to the designed indene-based scaffold ligands. On the whole,
indenylsulfonamides 13–17 appeared to be interesting for further
development due to the utility of 5-HT6 receptor agonists in the
investigation of the functional role of 5-HT6 receptors. Efforts
are currently being directed towards the design and synthesis
of structural analogues both closely and distantly related to the
reported indenylsulfonamides in the quest for potent and selective
indene-based sulfonamide ligands for 5-HT6 serotonin receptors.
2-Methylindan-1-one 19
To 2.6 g (11.30 mmol) of sodium in 50 mL of dry ethanol was added
diethyl methylmalonate (20.0 g, 11.50 mmol) followed by addition
of benzyl bromide (20.2 g, 11.80 mmol) under argon atmosphere.
The resulting suspension was refluxed for 4 h. Water (60 mL)
and potassium hydroxide (16.8 g, 29.0 mmol) were added and the
mixture was refluxed for 4 h. After cooling to room temperature,
the solvents were removed in vacuum and the residue was dissolved
in 60 mL of water and acidified with concentrated HCl to pH = 1.
The precipitate was filtered and dried to give the diacid, which was
heated for decarboxylation for 2 h at 170 ◦C to yield 2-methyl-3-
phenylpropanoic acid 18 (16.5 g, 88%) as a colorless oil. IR (thin
-1
1
=
film): n(COO–H) 3028, n(C O) 1708 cm . H NMR (300 MHz,
CDCl3): d 1.39 (d, J = 7.2 Hz, 3H), 2.85–3.04 (m, 2H), 3.33
(dd, J = 6.0, 12.0 Hz, 1H), 7.39–7.53 (m, 5H), 11.84 (br s, 1H)
ppm. 13C NMR (CDCl3, 75.4 Hz): d 16.9 (CH3), 39.7 (CH2), 41.7
Experimental
General methods
=
(CH), 126.8 (CH), 128.8 (CH), 129.4 (CH), 139.4 (C), 183.2 (C O)
ppm. EI-MS m/z: 164 (M+, 10%), 91 (100). Propanoic acid 18
(4.0 g, 24.51 mmol) was reacted at 100 C for 1.5 h with thionyl
Melting point: Gallenkamp Melting Point Apparatus MPD350.
BM2.5 with digital thermometer; uncorrected. IR (KBr disks or
thin film): Nicolet 205 FT or Perkin Elmer 1430 spectrophotome-
◦
chloride (5.35 mL, 73.53 mmol). The excess of thionyl chloride was
removed in vacuum. The acid chloride was dissolved in dry toluene
(15 mL) and added to a suspension of AlCl3 (9.58 g, 73.53 mmol)
in dry toluene (40 mL). The mixture was heated at reflux for
1.5 h and then cooled and poured into ice. After acidification
with concentrated HCl to pH = 1, the mixture was extracted with
CH2Cl2 (2 ¥ 50 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and evaporated to dryness. The
resulting residue was distilled at 80–85 ◦C at 0.5 mmHg to give
2-methylindan-1-one 19 (2.64 g, 74%) as a yellow oil (lit.,16 an oil).
1
ters. H NMR: Varian Gemini 200 (200 MHz), Varian Gemini
300 (300 MHz) and Mercury 400 (400 MHz) spectrometers at
298 K. Chemical shifts referenced and expressed in ppm (d)
relative to the central peak of DMSO-d6 (2.49 ppm) and TMS
for chloroform-d. 13C NMR: Varian Gemini 200 (50.3 MHz),
Varian Gemini 300 (75.4 MHz) and Mercury 400 (100.6 MHz)
spectrometers at 298 K. Chemical shifts were referenced and
expressed in ppm (d) relative to the central peak of DMSO-d6
(39.7 ppm) and chloroform-d (77.0 ppm). (Z)-Configurations were
determined by NOE difference experiments (see Fig. 2 and ESI†).
MS: Hewlett-Packard spectrometer (HP-5989A model) using
EI at 70 eV. ESI-HRMS: Agilent LC/MSD-TOF spectrometer.
Microanalysis: Carlo Erba 1106 analyzer. TLC: Merck precoated
silica gel 60 F254 plates using UV light (254 nm) as a visualizing
agent or 3% aq. H2PtCl2 –10% aq. KI (1 : 1) or KMnO4 ethanolic
solution. Column chromatography: silica gel 60 ACC 35–70 mm
Chromagel (SDS) or neutral alumina 90 activity II-III (Merck).
For the target compounds, the chemical purity was determined
by HPLC using the following conditions. Waters Alliance 2690
and 2695 (software Millenium 3.20) and Agilent 1100 (software
Chemstation A.06.03) equipment with XBridge C18 (3.5 m,
0.46 ¥ 10 cm column). Mobile phase: acetonitrile (ACN)/10 mM
-1
1
=
IR (thin film): n(C O) 1710 cm . H NMR (200 MHz, CDCl3):
d 1.32 (d, J = 7.4 Hz, 3H), 2.68–2.80 (m, 2H), 3.38–3.49 (m, 1H),
7.36–7.47 (m, 2H), 7.57–7.63 (m, 1H), 7.76 (d, J = 7.4 Hz, 1H)
ppm. 13C NMR (CDCl3, 50.3 Hz): d 16.3 (CH3), 35.0 (CH2), 42.0
(CH), 123.9 (CH), 126.5 (CH), 127.3 (CH), 134.6 (CH), 136.3 (C),
+
=
153.4 (C), 209.4 (C O) ppm. EI-MS m/z: 146 (M , 70%), 131
(100).
2-Methyl-6-nitroindan-1-one 20 and 2-methyl-4-nitroindan-1-one
21
2-Methylindan-1-one 19 (20 g, 0.14 mol) was added in one portion
to 95–97% H2SO4 (40 mL) at 0 ◦C. A solution of KNO3 (15.2 g,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3801
©

View Article Online
0.15 mol) in 95–97% H2SO4 (120 mL) was added dropwise. The
mixture was stirred for 1 h at -5 ◦C and then poured over 2 L
of ice. The mixture was stirred at room temperature for 18 h and
extracted with CH2Cl2 (3 ¥ 400 mL). The combined organic layers
were washed with saturated Na2CO3 aqueous solution (400 mL)
and water (2 ¥ 400 mL), dried over anhydrous Na2SO4, filtered
and evaporated to dryness. The resulting residue was purified by
column chromatography on silica gel (hexanes–EtOAc mixtures
of increasing polarity as eluent) to afford 2-methyl-6-nitroindan-
1-one 20 (12 g, 46%), and 2-methyl-4-nitroindan-1-one 21 (2 g,
8%) as yellow solids.
concentrated in vacuum. The residue was taken up in 1 N HCl
(50 mL) and washed with EtOAc (3 ¥ 50 mL). The aqueous
phase was basified with 10% NaOH aqueous solution (80 mL).
The resulting solid was filtered and dried to give 4-amino-2-
methylindan-1-one 23 (1.01 g, 40%) as a yellow oil.
-1
IR (thin film): n(NH2) 3367; n(C O) 1694 cm . 1H NMR
=
(200 MHz, CDCl3): d 1.33 (d, J = 7.4 Hz, 3H), 2.47 (dd, J =
3.6, 16.6 Hz, 1H), 2.67–2.80 (m, 1H), 3.17 (dd, J = 7.6, 16.5 Hz,
1H), 3.78 (br s, 2H), 6.86–6.90 (m, 1H), 7.20–7.26 (m, 2H) ppm. 13C
NMR (CDCl3, 100.6 Hz): d 16.5 (CH3), 31.6 (CH2), 41.8 (CH),
113.8 (CH), 119.1 (CH), 128.7 (CH), 137.1, 138.5, 143.7, 209.6
+
=
(C O) ppm. ESI-HRMS calcd for C10H12NO [M + H] 162.0919;
◦
=
20. Mp 70–72 C. IR (thin film): n(C O) 1717; n(NO2) 1529,
found 162.0913.
1348 cm-1. H NMR (400 MHz, CDCl3): d 1.37 (d, J = 7.2 Hz,
1
3H), 2.84–2.88 (m, 2H), 3.51 (d, J = 8.8 Hz, 1H), 3.55 (d, J =
8.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 8.45 (dd, J = 2.4, 8.4 Hz,
1H), 8.56 (d, J = 2.0 Hz, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d
N,N-Dimethyl-2-(2-methyl-1H-inden-3-yl)ethanamine 25
To a stirred solution of 2-methyl-1H◦-indene 24 (0.75 g, 5.77 mmol)
in dry THF (15 mL) cooled to -5 C was added n-BuLi (1.6 M
in hexanes, 3.6 mL, 5.77 mmol) under argon atmosphere. After
stirring for 3 h at room temperature, (2-chloroethyl)dimethylamine
hydrochloride (0.42 g, 2.88 mmol) was added as a solid. The solu-
tion was allowed to stir overnight and was hydrolyzed with water
(25 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (2 ¥ 10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated to dryness.
The resulting residue was purified by column chromatography
on alumina (hexanes–EtOAc mixtures of increasing polarity as
eluent) to afford the amine derivative 25 (0.36 mg, 60%) as an oil
(lit.,17 colorless oil).
1H NMR (200 MHz, CDCl3): d 2.08 (s, 3H), 2.36 (s, 6H), 2.40–
2.50 (m, 2H), 2.63–2.80 (m, 2H), 3.27 (s, 2H), 7.01–7.40 (m, 4H)
ppm. 13C NMR (CDCl3, 50.3 Hz): d 14.0 (CH3), 23.8 (CH2), 42.6
(CH2), 45.3 (CH3), 58.3 (CH2), 117.9 (CH), 123.2 (CH), 123.6
(CH), 126.0 (CH), 134.6, 139.4, 142.5, 146.3 ppm. EI-MS m/z:
201 (M+, 2%), 58 (100).
16.1 (CH3), 35.1 (CH2), 42.8 (CH), 119.3 (CH), 127.5 (CH), 128.8
+
=
(CH), 137.3, 147.8, 159.1, 206.9 (C O) ppm. EI-MS m/z: 191 (M ,
18%), 176 (36), 151 (100). Found: C 62.00, H 4.71, N 7.34. Calcd
for C10H9NO3·0.1H2O: C 62.24, H 4.80, N 7.26%.
◦
=
21. Mp 74–76 C. IR (KBr): n(C O) 1720; n(NO2) 1523,
1353 cm-1. H NMR (400 MHz, CDCl3): d 1.38 (d, J = 7.2 Hz,
1
3H); 2.78–2.86 (m, 1H); 3.21(dd, J = 4.4, 20.0 Hz, 1H); 3.93 (dd,
J = 8.0, 16.0 Hz, 1H); 7.62 (dd, J = 7.2, 8.0 Hz, 1H); 8.09 (d, J =
7.2 Hz, 1H); 8.47 (dd, J = 0.8, 8.0 Hz, 1H) ppm. 13C NMR (CDCl3,
50.3 Hz): d 16.1 (CH3), 35.7 (CH2), 41.6 (CH), 128.7 (CH), 129.8
=
(CH), 129.9 (CH), 134.0, 139.3, 148.1, 207.0 (C O) ppm. EI-MS
m/z: 191 (M+, 98%), 151 (100). Found: C 61.07, H 4.84, N 7.15.
Calcd for C10H9NO3·0.33H2O: C 60.93, H 4.94, N 7.11%.
6-Amino-2-methylindan-1-one 22
To a stirred solution of 2-methyl-6-nitroindan-1-one 20 (3.5 g,
18.31 mmol) in a 1 : 1 glacial acetic acid–water solution (70 mL) at
90 ◦C was added iron (8.2 g, 0.15 mol) in portions. The resulting
suspension was stirred at the same temperature for 45 min. The
2-(2-Methyl-1H-inden-3-yl)pyridine 26
R
reaction mixture was filtered through Celiteꢀ and evaporated.
To a stirred solution of 2-bromopyridine (1.3 mL, 13.68 mmol)
in dry diethyl ether (10 mL) cooled to -60 ◦C was added n-BuLi
(1.6 M in hexanes, 9.0 mL, 13.68 mmol) under argon atmosphere.
The resulting mixture reaction was stirred for 20 min at this
temperature. Thereafter, a solution of 2-methylindan-2-one 19
(2.0 g, 13.68 mmol) in dry ethyl ether (12 mL) was added. After
a reaction time of 2 h at -50 ◦C, the reaction was hydrolyzed
with saturated aqueous NH4Cl solution (20 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 ¥
10 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated to dryness to afford a brown oil. The
obtained compound was treated at 0 ◦C with 96% H2SO4. The
solution was stirred for 2 h at this temperature and then poured
into ice (200 g). The resulting reaction mixture was neutralized
with solid NaOH and extracted with EtOAc (3 ¥ 100 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated to dryness. The resulting residue was purified by
column chromatography on silica (hexanes–EtOAc mixtures of
increasing polarity as eluent) to give the pyridine derivative 26 as
a yellow oil, yield 10%.
The resultant residue was dissolved in CH2Cl2 and washed with
saturated NaHCO3 aqueous solution (3 ¥ 100 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and evaporated
to dryness to afford 6-amino-2-methylindan-1-one 22 (2.5 g, 85%)
as a yellow solid. The product was used directly in the next step
without further p◦urification.
=
Mp 144–146 C. IR (KBr): n(NH2) 3461, 3358; n(C O)
1688 cm-1. 1H NMR (200 MHz, DMSO-d6): d 1.14 (d, J =
7.4 Hz, 3H), 2.40–2.60 (m, 2H), 3.10–3.25 (m, 1H), 5.28 (br s,
2H), 6.75 (d, J = 1.8 Hz, 1H), 6.91 (dd, J = 2.6, 10.0 Hz, 1H),
7.18 (d, J = 8.0 Hz, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d
16.3 (CH3), 33.7 (CH2), 42.0 (CH), 105.7 (CH), 122.4 (CH), 126.8
+
=
(CH), 136.7, 141.1, 148.4, 208.8 (C O) ppm. EI-MS m/z: 161 (M ,
99%), 146 (100), 132 (51). Found: C 67.68, H 6.71, N 7.90. Calcd
for C10H11NO·0.25CH2Cl2: C 67.48, H 6.35, N 7.68%.
4-Amino-2-methylindan-1-one 23
10% Pd/C (0.3 g) was added to a solution of 2-methyl-4-
nitroindan-1-one 21 (3.0 g, 15.7 mmol) in absolute ethanol
(250 mL) and the mixture was hydrogenated under atmospheric
pressure. After 18 h, the catalyst was filtered and the filtrate was
1H NMR (200 MHz, CDCl3): d 2.25 (s, 3H), 3.50 (s, 2H), 7.10–
7.28 (m, 4H), 7.42–7.46 (m, 2H), 7.74–7.82 (m, 1H), 8.74–8.76
3802 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
(m, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 15.2 (CH3), 43.6
(CH2), 119.7 (CH), 121.6 (CH), 123.2 (CH), 124.0 (CH), 124.1
(CH), 126.1 (CH), 132.2, 136.1 (CH), 142.1, 143.8, 145.2, 149.6
(CH), 154.8 ppm.
(247 mg, 2.25 mmol). Compound 10 was obtained as an orange
oil, yield 29%.
1H NMR (200 MHz, CDCl3): d 2.12 (s, 3H), 2.33 (s, 6H), 2.40–
2.52 (m, 2H), 2.68–2.80 (m, 2H), 3.66 (s, 3H), 6.65 (s, 1H), 6.94 (s,
1H), 7.01–7.19 (m, 3H), 7.25 (s, 1H), 8.51 (d, J = 8 Hz, 1H) ppm.
13C NMR (CDCl3, 50.3 Hz): d 10.2 (CH3), 24.3 (CH2), 33.4
(CH3), 45.4 (CH3), 58.1 (CH2), 112.2 (CH), 117.4 (CH), 121.8
(CH), 125.0 (CH), 125.3 (CH), 128.2 (CH), 129.2 (CH), 133.4,
134.1, 138.9, 144.2 ppm. ESI-HRMS calcd for C19H24N3 [M + H]+
294.1965; found 294.1960.
Synthesis of (Z)-heteroarylmethylideneindenes 8–11:
General procedure
To ◦a stirred solution of amine 25 or 26 (1 equiv) in dry MeOH at
-5 C was added sodium (2.5 equiv) in dry MeOH under argon
atmosphere. The mixture was warmed to room temperature and
stirred for 20 min. To this mixture was added the corresponding
aldehyde (1.05 equiv) and the reaction mixture was heated at reflux
for 12 h. After dilution with EtOH, the solvent was removed in
vacuum. The indene derivatives 8–11 were isolated from the crude
reaction mixture by column chromatography on alumina using
hexanes–EtOAc mixtures of increasing polarity as the eluent.
2-[(1Z)-2-Methyl-1-(2-thienylmethylidene)-1H-inden-3-yl]pyridine
11·HCl
The above procedure was followed using amine 26 (270 mg,
1.30 mmol) in dry MeOH (10 mL), sodium (75 mg, 3.25 mmol)
in dry MeOH (10 mL) and 2-thiophenecarboxaldehyde (0.13 mL,
1.37 mmol). To a solution of the resultant crude product in dry
MeOH (2 mL) was added HCl (2.0 M in diethyl ether, 5 mL) and
CH2Cl2 (2 mL). The red solid obtained was filtered and dried to
afford the hydrochloride 11·HCl (45 mg, 10%).
2-[(1Z)-1-(3-Furylmethylidene)-2-methyl-1H-inden-3-yl]-N,N-
dimethylethanamine hydrochloride 8·HCl
The above procedure was followed using amine 25 (170 mg,
0.84 mmol) in dry MeOH (5 mL), sodium (50 mg, 2.1 mmol)
in dry MeOH (5 mL) and 2-furaldehyde (0.08 mL, 0.88 mmol).
To a solution of the resultant crude product in dry acetone (1 mL)
was added HCl (2.0 M in diethyl ether, 1 mL). The yellow solid
obtained was filtered and dried to afford the hydrochloride 8·HCl,
yield 30%.
Mp 203–205 ◦C. 1H NMR (200 MHz, CDCl3): d 2.54 (s, 3H),
7.13–7.22 (m, 3H), 7.55–7.60 (m, 3H), 7.86 (dd, J = 6.2 and 6.4 Hz,
1H), 8.00 (d, J = 8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.46 (dd,
J = 7.6 and 7.5 Hz, 1H), 9.08 (d, J = 8 Hz, 1H) ppm. 13C NMR
(CDCl3, 50.3 Hz): d 14.5 (CH3), 123.3 (CH), 125.9 (CH), 127.7
(CH), 128.0 (CH), 128.7 (CH), 129.6 (CH), 131.8 (CH), 133.5
(CH), 138.2, 139.6, 141.1, 143.6, 144.9, 147.3, 149.9 ppm. ESI-
HRMS calcd for C20H16NS [M + H]+ 302.1000; found 302.0995.
Mp 170–171 ◦C. 1H NMR (200 MHz, CDCl3): d 2.20 (s, 3H),
2.90 (s, 6H), 3.12–3.19 (m, 4H), 6.67 (s, 1H), 6.92 (s, 1H), 7.00–
7.08 (m, 1H), 7.20–7.32 (m, 2H), 7.52 (s, 1H), 7.68 (s, 1H), 7.81 (d,
J = 8.0 Hz, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 10.5 (CH3),
21.1 (CH2), 42.9 (CH3), 56.3 (CH2), 111.5 (CH), 117.5 (CH), 120.5
(CH), 121.4, 122.9 (CH), 124.9 (CH), 128.0 (CH), 132.1, 134.1,
136.1, 141.0, 142.8 (CH), 143.3 (CH) ppm. ESI-HRMS calcd for
C19H22NO [M + H]+ 280.1696; found 280.1692.
Synthesis of indanones sulfonamides 28–31: General procedure
To a stirred solution of aminoindanones 22, 23 or 27 (1 equiv)
and pyridine in dry CH2Cl2 was added a solution of a convenient
substituted aromatic sulfonyl chloride (1.3 equiv) in dry CH2Cl2
under argon atmosphere. After stirring at room temperature for
18 h, the reaction mixture was washed with 2.5 N HCl, dried over
anhydrous Na2SO4, filtered and evaporated to dryness.
N,N-Dimethyl-2-[(1Z)-2-methyl-1-(2-thienylmethylidene)-1H-
inden-3-yl]ethanamine 9
The above procedure was followed using amine 25 (368 mg,
1.83 mmol) in dry MeOH (10 mL), sodium (105 mg, 4.58 mmol)
in dry MeOH (10 mL) and 2-thiophenecarboxaldehyde (0.18 mL,
1.92 mmol). Compound 9 was obtained as an orange oil, yield
28%.
1H NMR (200 MHz, CDCl3): d 2.13 (s, 3H), 2.34 (s, 6H), 2.42–
2.52 (m, 2H), 2.72–2.82 (m, 2H), 6.89–7.01 (m, 1H), 7.05 (s, 1H),
7.06–7.12 (m, 1H), 7.17–7.20 (m, 2H), 7.34–7.43 (m, 2H), 7.87 (d,
J = 8 Hz, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 10.3 (CH3),
24.1 (CH2), 45.3 (CH3), 58.1 (CH2), 117.7 (CH), 120.7 (CH), 122.7
(CH), 124.4 (CH), 127.2 (CH), 127.4 (CH), 127.9 (CH), 129.2
(CH), 134.0, 134.1, 137.4, 139.2, 141.8, 144.2 ppm. ESI-HRMS
calcd for C19H22NS [M + H]+ 296.1468; found 296.1467.
N-(2-Methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)naphthalene-2-
sulfonamide 28
The above procedure was followed using aminoindanone 22 (2.5 g,
15.51 mmol), dry pyridine (3 mL) in dry CH2Cl2 (65 mL) and 2-
naphthalenesulfonyl chloride (3.5 g, 20.16 mmol) in dry CH2Cl2
(20 mL). Indanone sulfonamide 28 (3.7 g, 68%) was obtained as
an off-white solid. The product was used directly in the next step
without further◦purification.
=
Mp 174–176 C. IR (KBr): n(NH) 3177; n(C O) 1693; n(SO2)
1
1341, 1158 cm-1. H NMR (200 MHz, CDCl3): d 1.24 (d, J =
7.2 Hz, 3H), 2.50–2.80 (m, 2H), 3.20–3.39 (m, 1H), 7.31 (d, J =
10.0 Hz, 1H), 7.43–7.44 (m, 1H), 7.49–7.62 (m, 4H), 7.79–7.90 (m,
4H), 8.39 (s, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 16.1 (CH3),
34.4 (CH2), 42.5 (CH), 116.0 (CH), 122.0 (CH), 127.4 (CH), 127.5
(CH), 127.8 (CH), 128.3 (CH), 128.8 (CH), 128.9 (CH), 129.2
N,N-Dimethyl-2-{(1Z)-2-methyl-1-[(1-methyl-1H-imidazol-2-
yl)methylidene]-1H-inden-3-yl}ethanamine 10
(CH), 129.5 (CH), 131.9, 134.8, 135.6, 136.2, 137.2, 150.2, 208.7
+
=
The above procedure was followed using amine 25 (430 mg,
2.14 mmol) in dry MeOH (12 mL), sodium (123 mg, 5.35 mmol) in
dry MeOH (12 mL) and 1-methyl-1H-imidazole-2-carbaldehyde
(C O) ppm. EI-MS m/z: 351 (M , 40%), 127 (100). Found: C
67.58, H 5.12, N 3.95. Calcd for C20H17NO3S·0.33EtOH: C 67.68,
H 5.22, N 3.82%.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3803
©

View Article Online
+
=
N-(3-Oxo-2,3-dihydro-1H-inden-5-yl)naphthalene-2-sulfonamide
29
(C O) ppm. ESI-HRMS calcd for [M + H] 352.1001; found
352.0997.
The above procedure was followed using aminoindanone 27 (3.0 g,
20.40 mmol), dry pyridine (4 mL) in dry CH2Cl2 (100 mL)
and 2-naphthalenesulfonyl chloride (6.0 g, 26.49 mmol) in dry
CH2Cl2 (25 mL). The resulting residue was purified by column
chromatography on silica (CH2Cl2–MeOH mixtures of increasing
polarity as eluent) to give indanone sulfonamide 29 (3.55 g, 53%)
Ethyl (2Z)-{2-methyl-6-[(2-naphthylsulfonyl)amino]-2,3-dihydro-
1H-inden-1-ylidene}acetate 32
To a stirred suspension of 55–65% NaH (0.95 g, 39.04 mmol)
in dry THF (200 mL) cooled to 0 ◦C was added dropwise triethyl
phosphonoacetate (6.9 mL, 34.10 mmol) under argon atmosphere.
After stirring for 1 h at the same temperature, a solution of
indanone sulfonamide 28 (1.2 g, 3.41 mmol) in dry THF (35 mL)
was slowly added. The resultant yellow solution was stirred at
room temperature for 1.5 h and at reflux for 24 h. The reaction
mixture was quenched by addition of water (150 mL) and extracted
with EtOAc (3 ¥ 200 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and evaporated to dryness. The
resulting residue was purified by column chromatography on silica
gel (hexanes–EtOAc mixtures of increasing polarity as eluent) to
afford the ethyl (Z)-indanylacetate 32 (1.06 g, 73%) as a yellow
as an off-white solid.
◦
=
Mp 211–212 C. IR (KBr): n(NH) 3200; n(C O) 1693; n(SO2)
1334, 1154 cm-1. H NMR (200 MHz, CDCl3): d 2.60–2.67 (m,
1
2H), 3.01–3.05 (m, 2H), 6.93 (s, 1H), 7.35–7.39 (m, 2H), 7.45–7.78
(m, 4H), 7.82–7.92 (m, 4H), 8.39 (s, 1H) ppm. 13C NMR (CDCl3,
50.3 Hz): d 25.5 (CH2), 36.8 (CH2), 116.1 (CH), 122.1 (CH), 127.8
(CH), 128.0 (CH), 128.6 (CH), 129.1 (CH), 129.2 (CH), 129.4
(CH), 129.7 (CH), 132.1, 135.1, 135.7, 136.1, 138.1, 152.2, 206.1
+
=
(C O) ppm. EI-MS m/z: 337 (M , 26%), 146 (100). Found: C
65.09, H 4.47, N 4.02. Calcd for C19H15NO3S·0.7H2O: C 65.20, H
4.72, N 4.00%.
solid.
◦
=
=
Mp 118–120 C. IR (KBr): n(NH) 3183; n(C O) 1682; n(C C)
1628; n(SO2) 1332, 1160 cm-1. H NMR (200 MHz, CDCl3): d
1
5-Chloro-3-methyl-N-(2-methyl-3-oxo-2,3-dihydro-1H-inden-5-
yl)-1-benzothiophene-2-sulfonamide 30
1.17–1.30 (m, 9H), 2.45–2.55 (m, 1H), 2.98–3.15 (m, 2H), 4.11
(q, J = 6.8 Hz, 2H), 5.78 (d, J = 1.4 Hz, 1H), 6.61 (s, 1H), 7.16
(d, J = 8.6 Hz, 1H), 7.26–7.34 (m, 1H), 7.54–7.62 (m, 2H), 7.74–
7.96 (m, 4H), 8.40 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 1.8 Hz,
1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 14.3 (CH3), 20.9 (CH3),
38.0 (CH2), 41.8 (CH), 60.0 (CH2), 111.7 (CH), 121.5 (CH), 122.4
(CH), 124.1 (CH), 125.5 (CH), 127.2 (CH), 127.7 (CH), 128.6
The above procedure was followed using aminoindanone 22 (1.0 g,
6.20 mmol) in dry pyiridine (40 mL) and 5-chloro-3-methyl-1-
benzothiophene-2-sulfonyl chloride (1.83 g, 6.51 mmol) in dry
pyridine (9 mL). The resulting residue was purified by column
chromatography on silica (CH2Cl2–MeOH mixtures of increasing
polarity as eluent) to give indanone sulfonamide 30 (1.2 g, 48%)
as a salmon-pin◦k solid.
(CH), 129.0 (CH), 129.2 (CH), 129.3 (CH), 131.8, 135.2, 136.0,
+
=
137.8, 145.7, 163.8, 166.2 (C O) ppm. EI-MS m/z: 421 (M , 64%),
375 (94), 184 (100). Found: C 64.70, H 5.59, N 3.18. Calcd for
C24H23NO4S·0.4CH2Cl2: C 64.34, H 5.27, N 3.08%.
=
Mp 245–246 C. IR (KBr): n(NH) 3120; n(C O) 1691; n(SO2)
1342, 1158 cm-1. 1H NMR (300 MHz, DMSO-d6): d 1.28 (d, J =
7.2 Hz, 3H), 2.62–2.90 (m, 6H), 3.36–3.52 (m, 4H), 7.54 (s, 1H),
7.59 (s, 2H), 7.72 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 8.39 (s, J =
8.0 Hz, 1H) ppm. 13C NMR (CDCl3, 75.4 Hz): d 12.5 (CH3), 16.1
(CH3), 34.3 (CH2), 42.4 (CH), 114.2 (CH), 124.0 (CH), 125.2 (CH),
{2-Methyl-5-[(2-naphthylsulfonyl)amino]-1H-inden-3-yl}acetic
acid 33
To a stirred suspension of ester derivative 32 (2.15 g, 5.10 mmol)
in dry MeOH (25 mL) at room temperature was slowly added
sodium (0.47 g, 20.40 mmol) in dry MeOH (25 mL) under argon
atmosphere. The resulting solution was refluxed for 18 h. The
reaction mixture was quenched by addition of water (150 mL) and
acidified with 5 N HCl. The resultant solid was filtered to give
127.7 (CH), 128.2 (CH), 128.3 (CH), 131.1, 136.9, 137.0, 137.1,
+
=
137.6, 140.9, 150.1, 208.5 (C O) ppm. EI-MS m/z: 405 (M , 9%),
146 (91), 181 (100). Found: C 55.13, H 3.90, N 3.53, S 14.95. Calcd
for C20H17NO3S·0.15CH2Cl2: C 54.94, H 3.92, N 3.35, S 15.32%.
acetic acid derivative 33 (1.89 g, 94%) as a light orange solid.
N-(2-Methyl-3-oxo-2,3-dihydro-1H-inden-7-yl)naphthalene-2-
sulfonamide 31
◦
=
Mp 176–178 C. IR (KBr): n(COO–H, NH) 3242; n(C O) 1705;
1
n(SO2) 1329, 1155 cm-1. H NMR (200 MHz, CDCl3): d 2.07 (s,
The above procedure was followed using aminoindanone 23
(0.72 g, 4.47 mmol), dry pyridine (1.5 mL) in dry CH2Cl2 (30 mL)
and 2-naphthalenesulfonyl chloride (1.3 g, 5.81 mmol) in dry
CH2Cl2 (10 mL). Indanone sulfonamide 31 (1.35 g, 83%) was
obtained as an off-white foamy solid. The product was used
directly in the◦next step without further purification.
3H), 3.20 (s, 2H), 3.48 (s, 2H), 6.85–6.95 (m, 1H), 7.08–7.18 (m,
2H), 7.40–7.95 (m, 7H), 8.31 (s, 1H) ppm. 13C NMR (CDCl3,
50.3 Hz): d 14.2 (CH3), 31.2 (CH2), 42.2 (CH2), 112.4 (CH),
117.3 (CH), 122.2 (CH), 123.5 (CH), 127.2 (CH), 127.7 (CH),
128.6 (CH), 128.8 (CH), 129.1 (CH), 131.8, 134.7, 134.9, 135.8,
+
=
139.0, 144.2, 146.7, 175.3 (C O) ppm. EI-MS m/z: 393 (M , 36%),
=
Mp 85–86 C. IR (KBr): n(NH) 3241; n(C O) 1697; n(SO2)
202 (100). Found: C 66.03, H 5.10, N 3.39, S 7.04. Calcd for
C22H19NO4S·0.5EtOAc: C 65.89, H 5.30, N 3.20, S 7.33%.
1
1338, 1159 cm-1. H NMR (200 MHz, CDCl3): d 1.06 (d, J =
7.2 Hz, 3H), 2.19–2.29 (m, 1H), 2.42–2.62 (m, 1H), 3.00–3.13 (m,
1H), 6.78 (s, 1H), 7.29 (m, 1H), 7.54–7.95 (m, 8H), 8.33 (d, J =
1.8 Hz, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 16.1 (CH3),
32.0 (CH2), 41.7 (CH), 121.4 (CH), 121.9 (CH), 127.8 (CH), 127.9
(CH), 128.4 (CH), 128.7 (CH), 128.8 (CH), 128.9 (CH), 129.2
(CH), 129.6 (CH), 131.8, 134.1, 134.9, 135.9, 137.5, 146.2, 208.4
Synthesis of ethyl acetates 34a and 34b
To a stirred suspension of 55–65% NaH (0.82 g, 34.19 mmol)
in dry DME (75 mL) cooled to 0 ◦C was added dropwise triethyl
phosphonoacetate (5.9 mL, 29.60 mmol) under argon atmosphere.
3804 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
After stirring for 1 h at the same temperature, a solution of
indanone 29 (1.0 g, 2.96 mmol) in dry DME (25 mL) was slowly
added. The resultant solution was stirred at reflux for 24 h.
The reaction mixture was quenched by addition of water and
extracted with EtOAc. The combined organic layers were dried
over anhydrous Na2SO4, filtered and evaporated to dryness. The
resulting residue was purified by column chromatography on silica
gel (hexanes–EtOAc mixtures of increasing polarity as eluent). The
mixture of isomeric esters 34a and 34b (230 mg, 19%) was obtained
as a yellow solid.
sulfonamides 29, 30 or 31 (1 equiv) in dry THF was added dropwise
and the mixture was stirred for 1 h at the same temperature. The
reaction mixture was quenched by addition of 1 N HCl and was
warmed to ambient temperature. The aqueous layer was separated
and extracted with EtOAc. The combined organic layers were
evaporated to dryness. Trifluoroacetic acid (7 equiv) was added
dropwise to a stirred solution of the resulting residue in dry CH2Cl2
at -5 ◦C. After 35 min, the mixture was concentrated in vacuum.
To a stirred solution of the resultant foamy solid in dry MeOH
at room temperature was added sodium (4 equiv) in dry MeOH
under argon atmosphere. The resulting mixture was refluxed for
24 h. To cooled reaction mixture EtOH was added dropwise, and
the mixture then evaporated. To the residue was added 5% aqueous
Na2CO3solution and washed with EtOAc. The aqueous layer was
acidified with 5 N HCl and extracted with EtOAc. The combined
organic layers were dried over anhydrous Na2SO4, filtered and
evaporated to dryness.
EI-MS m/z (%): 407 (M+, 60), 361 (56), 216 (54), 188 (60), 170
(85), 127 (100), 115 (90).
N-Ethyl-N-(3-oxo-2,3-dihydro-1H-inden-5-yl)naphthalene-2-
sulfonamide 35
Experiment 1. To a solution of anhydrous LiBr (6.18 g,
71.16 mmol) in dry DME was added triethyl phosphonoacetate
(11.9 mL, 59.30 mmol) and the mixture was stirred 5 min under
argon atmosphere. Dry triethylamine (9.5 mL, 68.49 mmol) was
added and the white suspension stirred for an additional 10 min.
A solution of indanone 29 (2.0 g, 5.93 mmol) in dry DME
(60 mL) was then added dropwise, and the reaction mixture was
stirred at reflux for 24 h. After being quenched with 1 N HCl,
the reaction mixture was extracted with CH2Cl2 (3 ¥ 50 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered and evaporated to dryness. The resulting residue was
purified by column chromatography on silica gel (hexanes–EtOAc
mixtures of increasing polarity as eluent). N-Ethyl-N-indan-1-one
sulfonamide 35 (680 mg, 31%) was obtained as an off-white solid.
{5-[(2-Naphthylsulfonyl)amino]-1H-inden-3-yl}acetic acid 36
The above procedure was followed using dry EtOAc (0.47 mL,
4.67 mmol), LHMDS (1.0 M in THF, 9.3 mL, 9.3 mmol), indanone
sulfonamide 29 (1.5 g, 4.45 mmol) in dry THF (35 mL); TFA
(2.1 mL, 27.66 mmol) in dry CH2Cl2 (20 mL) and sodium (0.4 g,
17.28 mmol) in dry MeOH (40 mL). (3-Indenyl)acetic acid 36
(0.95 g, 56%) w◦as obtained as a foamy yellow solid.
=
Mp 135–136 C. IR (KBr): n(COO–H, NH) 3276; n(C O) 1702;
1
n(SO2) 1325, 1156 cm-1. H NMR (200 MHz, CDCl3): d 3.15 (s,
2H), 3.49 (s, 2H), 6.37 (s, 1H), 6.90–7.96 (m, 10H), 8.32 (s, 1H)
ppm. 13C NMR (CDCl3, 50.3 Hz): d 33.7 (CH2), 37.5 (CH2), 113.3
(CH), 118.6 (CH), 122.2 (CH), 124.1 (CH), 127.2 (CH), 127.6
(CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 129.2 (CH), 131.8,
Experiment 2. To a solution of indanone sulfonamide 29
(1.0 g, 2.96 mmol) in dry THF (100 mL) was added triethyl
=
133.8 (CH), 134.7, 134.9, 135.7, 141.0, 145.3, 175.8 (C O) ppm.
˚
phosphonoacetate (5.9 mL, 29.60 mmol) and activated 4 A
EI-MS m/z: 379 (M+, 11%), 127 (100).
molecular sieves (5 g) under argon atmosphere, and the mixture
heated at reflux. LiOH·H2O (1.43 g, 34.19 mmol) previously
submitted to heating at 120 ◦C for 2 h was added, in three
portions, during the course of the reaction (24 h). After being
quenched with 1 N HCl, the reaction mixture was extracted with
EtOAc (3 ¥ 100 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and evaporated to dryness. The
resulting residue was purified by column chromatography on silica
gel (hexanes–EtOAc mixtures of increasing polarity as eluent). N-
Ethyl-N-indan-1-one sulfonamide 35 (100 mg, 9%) was obtained
as an off-white so◦lid.
1162 cm-1. 1H NMR (300 MHz, CDCl3): d 1.07 (t, J = 7.2 Hz, 3H),
2.70–2.74 (m, 2H), 3.14–3.18 (m, 2H), 3.66 (q, J = 7.2 Hz, 2H),
7.30 (s, 1H), 7.49–7.68 (m, 5H), 7.87–7.91 (m, 3H), 8.22 (s, 1H)
ppm. 13C NMR (CDCl3, 75.4 Hz): d 13.9 (CH3), 25.6 (CH2), 36.6
(CH2), 45.6 (CH2), 122.6 (CH), 122.7 (CH), 127.3 (CH), 127.4
(CH), 127.5 (CH), 127.9 (CH), 128.8 (CH), 129.1 (CH), 129.2
(5-{[(5-Chloro-3-methyl-1-benzothiophen-2-yl)sulfonyl]amino}-2-
methyl-1H-inden-3-yl)acetic acid 37
The above procedure was followed using dry EtOAc (0.23 mL,
2.33 mmol), LHMDS (1.0 M in THF, 4.7 mL, 4.7 mmol), indanone
sulfonamide 30 (0.9 g, 2.22 mmol) in dry THF (22 mL); TFA
(1.1 mL, 14.41 mmol) in dry CH2Cl2 (15 mL) and sodium (0.22 g,
9.61 mmol) in dry MeOH (25 mL). (3-Indenyl)acetic acid 37
(0.58 g, 54%) w◦as obtained as a foamy white solid.
=
Mp 197–198 C. IR (KBr): n(COO–H, NH) 3266; n(C O) 1710;
1
n(SO2) 1342, 1155 cm-1. H NMR (200 MHz, CDCl3): d 2.10 (s,
=
Mp 111–112 C. IR (KBr): n(C O) 1700; n(SO2) 1342,
2H), 2.32 (s, 3H), 3.28 (s, 2H), 3.48 (s, 2H), 6.86–6.95 (m, 1H),
7.02–7.06 (m, 2H), 7.19–7.33 (m, 2H), 7.58–7.61 (m, 2H) ppm. 13
C
NMR (CDCl3, 50.3 Hz): d 12.6 (CH3), 14.6 (CH3), 31.8 (CH2),
42.1 (CH2), 112.2 (CH), 117.2 (CH), 124.0 (CH), 125.2 (CH), 128.0
(CH), 130.2, 131.2, 135.8, 137.2, 137.8, 138.1, 139.0, 140.8, 144.0,
+
=
147.8, 172.3 (C O) ppm. EI-MS m/z: 447 (M , 13%), 202 (89),
(CH), 132.0, 134.8, 135.0, 136.3 (CH), 137.8, 138.4, 154.6, 205.9
156 (100).
+
=
(C O) ppm. EI-MS m/z: 393 (M , 16%), 127 (100).
{2-Methyl-7-[(2-naphthylsulfonyl)amino]-1H-inden-3-yl}acetic
Synthesis of (3-indenyl)acetic acids 36–38: General procedure
acid 38
Dry ethyl acetate (1.05 equiv) was added dropwise to a stirred
solution of lithium bis(trimethylsilyl)amide (1.0 M in THF,
2.1 equiv) at -78 ◦C. After 15 min, a solution of indanone
The above procedure was followed using dry EtOAc (0.17 mL,
1.79 mmol), LHMDS (1.0 M in THF, 3.6 mL, 3.6 mmol), indanone
sulfonamide 31 (0.6 g, 1.71 mmol) in dry THF (12 mL); TFA
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3805
©

View Article Online
(0.7 mL, 8.76 mmol) in dry CH2Cl2 (9 mL) and sodium (0.11 g,
4.74 mmol) in dry MeOH (11 mL). (3-Indenyl)acetic acid 38
(0.46 g, 68%)◦was obtained as a foamy light brown solid.
7.83 (m, 14H), 8.32–8.36 (m, 1H) ppm. EI-MS m/z: 508 (M+,
17%), 72 (100).
=
Mp 91–92 C. IR (KBr): n(COO–H, NH) 3251; n(C O) 1703;
N-{(1Z)-1-Benzylidene-3-[2-(dimethylamino)ethyl]-2-methyl-1H-
inden-5-yl}naphthalene-2-sulfonamide 12
1
n(SO2) 1328, 1158 cm-1. H NMR (200 MHz, CDCl3): d 2.04
(s, 3H), 3.15 (s, 2H), 3.45 (s, 2H), 6.82–7.80 (m, 10H), 8.31 (s,
1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 14.2 (CH3), 31.5 (CH2),
42.1 (CH2), 112.4 (CH), 117.5 (CH), 122.2 (CH), 123.5 (CH),
127.2 (CH), 127.6 (CH), 128.5 (CH), 128.8 (CH), 129.1 (CH),
To a stirred suspension of LiAlH4 (35 mg, 0.88 mmol) in dry THF
(20 mL) was added dropwise a solution of acetamide derivative
40 (110 mg, 0.22 mmol) in dry THF (10 mL). The resulting
mixture was heated at reflux for 2 h. The reaction mixture was
quenched by addition of water (20 mL) and 10% H2SO4 aqueous
solution (20 mL), stirred for 30 min and extracted with CH2Cl2 (3 ¥
25 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered and evaporated to dryness. The resulting residue
was purified by column chromatography on silica gel (CH2Cl2–
MeOH–NH4OH mixtures of increasing polarity as eluent) to
afford the indene derivative (Z)-12 (10 mg, 9%) as a yellow foamy
solid. Chemical purity by HPLC: 83.1%.
129.2 (CH), 131.8, 134.6, 134.9, 135.8, 139.0, 144.2, 147.4, 176.0
+
=
(C O) ppm. EI-MS m/z: 393 (M , 21%), 202 (59), 156 (100),
127 (91). Found: C 65.51, H 5.21, N 3.40, S 7.06. Calcd for
C22H19NO4S·0.5EtOAc: C 65.89, H 5.30, N 3.20, S 7.33%.
{(1Z)-1-Benzylidene-2-methyl-5-[(2-naphthylsulfonyl)amino]-1H-
inden-3-yl}acetic acid 39
To a stirred suspension of 55–65% NaH (0.55 g, 22.86 mmol)
in dry THF (75 mL) cooled to 0 ◦C was added dropwise a
solution of (3-indenyl)acetic acid 33 (1.5 g, 3.81 mmol) in dry THF
(40 mL). After stirring at room temperature for 1 h, a solution
of benzaldehyde (2 mL, 19.05 mmol) in dry THF (10 mL) was
slowly added. The resulting mixture was heated to reflux for 5 h.
The reaction mixture was quenched with ethanol (50 mL) and
evaporated. The resultant residue was dissolved in brine (200 mL)
and washed with CH2Cl2 (2 ¥ 150 mL). The aqueous layer was
acidified with 5 N HCl and extracted with CH2Cl2 (3 ¥ 100 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered and evaporated to dryness. The resulting residue was
purified by column chromatography on silica gel (hexanes–EtOAc
mixtures of increasing polarity as eluent) to afford the acetic acid
derivative (Z)-39◦(0.7 g, 38%) as a yellow solid.
1H NMR (200 MHz, CDCl3): d 2.10 (s, 3H), 2.28 (s, 6H), 2.28–
2.40 (m, 2H), 2.60–2.72 (m, 2H), 6.58–6.64 (m, 1H), 6.88–6.92 (m,
1H), 7.09–7.17 (m, 2H), 7.32–7.86 (m, 13H), 8.38 (s, 1H) ppm.
N,N-Dimethyl-2-{2-methyl-5-[(2-naphthylsulfonyl)amino]-1H-
inden-3-yl}acetamide 41
To a stirred solution of the (3-indenyl)acetic acid 33 (0.4 g,
1.02 mmol) in dry THF (50 mL) was added in portions 1,1¢-
carbonyldiimidazole (140 mg, 0.84 mmol) under argon atmo-
sphere. The resulting mixture was stirred at room temperature for
2 h and then dimethylamine (2M in THF, 1.02 mL, 2.04 mmol) was
added. After stirring for 18 h, the reaction mixture was evaporated,
dissolved in EtOAc (100 mL) and washed with water (3 ¥ 50 mL).
The organic layer was dried with anhydrous Na2SO4, filtered and
evaporated to dryness to give the acetamide derivative 41 (0.3 g,
71%) as a yellow solid. The product was used directly in the next
=
Mp 110–112 C. IR (KBr): n(COO–H, NH) 3245; n(C O)
-1
1
=
1705; n(C C) 1607; n(SO2) 1330, 1154 cm . H NMR (200 MHz,
CDCl3): d 2.18 (s, 3H), 3.58 (s, 2H), 7.00 (s, 1H), 7.14–7.17 (m,
2H), 7.33–7.80 (m, 12H), 8.32 (s, 1H) ppm. 13C NMR (CDCl3,
50.3 Hz): d 10.5 (CH3), 30.9 (CH2), 111.2 (CH), 116.2 (CH), 122.1
(CH), 123.2 (CH), 126.6 (CH), 128.0 (CH), 128.3 (CH), 128.6
(CH), 128.8 (CH), 129.1 (CH), 129.2 (CH), 130.7, 131.8, 135.4,
step without further purification.
◦
=
Mp 114–116 C. IR (thin film): n(NH) 3250; n(C O) 1610;
n(SO2) 1333, 1159 cm-1. H NMR (200 MHz, CDCl3): d 2.05 (s,
1
3H), 2.86 (s, 3H), 2.96 (s, 3H), 3.23 (s, 2H), 3.45 (s, 2H), 6.78–7.18
(m, 4H), 7.54–7.94 (m, 5H), 8.38 (s, 1H) ppm. 13C NMR (CDCl3,
50.3 Hz): d 14.3 (CH3), 31.6 (CH2), 35.8 (CH3), 37.5 (CH3), 42.3
(CH2), 113.0 (CH), 117.8 (CH), 122.5 (CH), 123.3 (CH), 127.1
(CH), 127.7 (CH), 128.5 (CH), 128.6 (CH), 129.0 (CH), 129.2
=
135.8, 136.3, 136.4, 138.0, 140.3, 145.2, 175.4 (C O) ppm. EI-MS
m/z: 481 (M+, 2%), 202 (100).
=
(CH), 131.9, 134.6, 134.9, 136.2, 139.2, 142.5, 147.0, 170.4 (C O)
N,N-Dimethyl-2-{(1Z)-1-benzylidene-2-methyl-5-[(2-
naphthylsulfonyl)amino]-1H-inden-3-yl}acetamide 40
ppm. EI-MS m/z: 420 (M+, 15%), 72 (100).
To a stirred solution of the acetic acid derivative 39 (0.2 g,
0.42 mmol) in dry THF (30 mL) was added in portions 1,1¢-
carbonyldiimidazole (140 mg, 0.84 mmol) under an argon atmo-
sphere. The resulting mixture was stirred at room temperature for
2 h., and then dimethylamine (2 M in THF, 0.42 mL, 0.84 mmol)
was added. After stirring for 18 h, the reaction mixture was
evaporated, dissolved in EtOAc (100 mL) and washed with water
(3 ¥ 50 mL). The organic layer was dried with anhydrous Na2SO4,
filtered and evaporated to dryness to give the acetamide derivative
40 (0.16 g, 75%) as a yellow oil. The product was used directly in
the next step without further purification.
N-{3-[2-(Dimethylamino)ethyl]-2-methyl-1H-inden-5-
yl}naphthalene-2-sulfonamide 13
To a stirred solution of AlH3–NMe2Et (0.5 M in toluene, 1.4 mL,
0.68 mmol) in dry THF (10 mL) cooled to 0 ◦C was added
via a hypodermic syringe a solution of acetamide derivative 41
(70 mg, 0.17 mmol) in dry THF (10 mL) previously cooled to
0 ◦C, under argon atmosphere. After stirring at 0 ◦C for 30 min,
the reaction mixture was hydrolyzed with water (5 mL) and 10%
H2SO4 aqueous solution (5 mL), stirred at room temperature
and basified with 20% aqueous ammonia. The layers were
separated and the aqueous layer was extracted with EtOAc (2 ¥
10 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered and evaporated to dryness. The resulting residue
=
IR (thin film): n(NH) 3247; n(C O) 1606; n(SO2) 1334,
1
1159 cm-1. H NMR (200 MHz, CDCl3): d 2.14–2.18 (m, 3H),
2.85–2.98 (m, 6H), 3.49–3.57 (m, 2H), 6.61–6.73 (m, 1H), 7.04–
3806 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
was purified by column chromatography on silica gel (CH2Cl2–
MeOH–NH3 mixtures of increasing polarity as eluent) to afford
the indene derivative 13 (32 mg, 46%) as a yellow oil.
(CH), 118.9 (CH), 122.5 (CH), 123.9 (CH), 127.1 (CH), 127.7
(CH), 128.5 (CH), 128.6 (CH), 129.0 (CH), 129.2 (CH), 132.2
=
(CH), 132.1, 134.4, 135.0, 136.0, 137.0, 141.4, 143.8, 168.8 (C O)
IR (thin film): n(NH) 3252; n(SO2) 1329, 1158 cm-1. 1H NMR
(200 MHz, CDCl3): d 1.99 (s, 3H), 2.23 (s, 6H), 2.23–2.30 (m,
2H), 2.48–2.59 (m, 2H), 3.15 (s, 2H), 6.90–6.93 (m, 2H), 7.14–
7.18 (m, 1H), 7.48–7.60 (m, 2H), 7.76–7.86 (m, 4H), 8.35 (s, 1H)
ppm. 13C NMR (CDCl3, 50.3 Hz): d 14.0 (CH3), 23.4 (CH2), 42.1
(CH2), 45.1 (CH3), 57.8 (CH2), 112.8 (CH), 118.3 (CH), 122.5
(CH), 123.5 (CH), 127.2 (CH), 127.7 (CH), 128.6 (CH), 128.7
(CH), 129.0 (CH), 129.2 (CH), 132.0, 134.0, 134.8, 135.0, 136.1,
139.8, 141.4, 147.6 ppm. Found: C 60.12, H 5.32, N 5.26. Calcd
for C24H26N2O2S·1.1CH2Cl2: C 60.30, H 5.68, N 5.60%.
ppm. EI-MS m/z: 432 (M+, 29%), 98 (100).
5-Chloro-3-methyl-N-[2-methyl-3-(2-oxo-2-pyrrolidin-1-ylethyl)-
1H-inden-5-yl]-1-benzothiophene-2-sulfonamide 44
The above procedure was followed using the acetic acid deriva-
tive 37 (0.22 g, 0.49 mmol), 1,1¢-carbonyldiimidazole (0.16 g,
0.98 mmol) and pyrrolidine (0.08 mL, 0.98 mmol) in dry THF
(24 mL). The amide derivative 44 (0.1 g, 41%) was obtained as a
brown oil.
=
IR (thin film): n(NH) 3079; n(C O) 1613; n(SO2) 1335,
1
1157 cm-1. H NMR (200 MHz, CDCl3): d 1.78–1.98 (m, 4H),
Synthesis of amide derivatives 42–44: General procedure
2.07 (s, 3H), 2.36 (s, 3H), 3.22 (s, 2H), 3.36–3.44 (m, 6H), 6.82–
6.88 (m, 1H), 7.08–7.14 (m, 2H), 7.32–7.38 (m, 1H), 7.60–7.64 (m,
2H), 7.82 (s, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 12.2 (CH3),
14.4 (CH3), 24.2 (CH2), 26.1 (CH2), 32.4 (CH2), 42.3 (CH2), 46.4
(CH2), 47.0 (CH2), 113.3 (CH), 118.1 (CH), 123.1 (CH), 123.2
(CH), 123.5 (CH), 127.3 (CH), 129.6, 131.0, 134.5, 136.4, 136.6,
To a stirred solution of (3-indenyl)acetic acids 33, 36 or 37 (1
equiv) in dry THF was added in portions 1,1¢-carbonyldiimidazole
(2 equiv) under argon atmosphere. The resulting mixture was
stirred at room temperature for 2 h and then a solution of pyrro-
lidine (2 equiv) in dry THF was added. After stirring for 18 h,
the reaction mixture was evaporated, dissolved in EtOAc and
washed with 1 N HCl. The organic layer was dried with anhydrous
Na2SO4, filtered and evaporated to dryness. The resulting residue
was purified by column chromatography on silica gel (CH2Cl2–
MeOH mixtures of increasing polarity as eluent).
=
137.6, 139.4, 140.5, 143.0, 147.0, 169.2 (C O) ppm. EI-MS m/z:
501 (M+, 7%), 70 (100).
N-[2-Methyl-3-(2-oxo-2-pyrrolidin-1-ylethyl)-1H-inden-7-
yl]naphthalene-2-sulfonamide 45
N-[2-Methyl-3-(2-oxo-2-pyrrolidin-1-ylethyl)1H-inden-5-
yl]naphthalene-2-sulfonamide 42
A mixture of SOCl2 (2 mL) and the acetic acid derivative 38 (0.15 g,
0.38 mmol) in dry CH2Cl2 (2 mL) was stirred at reflux for 2 h. The
reaction mixture was concentrated under reduced pressure. The
resulting brown solid was dissolved in dry CH2Cl2 (2.5 mL) and
a solution of pyrrolidine (0.11 mL, 1.33 mmol) in dry CH2Cl2
(24 mL) was added. After stirring for 18 h, the reaction mixture
was acidified with 1 N HCl and extracted with EtOAc (3 ¥ 25 mL).
The combined organic layers were dried with anhydrous Na2SO4,
filtered and evaporated to dryness to afford the amide derivative
45 (80 mg, 47%) as a yellow oil. The product was used directly in
the next step without further purification.
The above procedure was followed using the acetic acid deriva-
tive 33 (0.5 g, 1.27 mmol), 1,1¢-carbonyldiimidazole (0.42 g,
2.54 mmol) and pyrrolidine (0.21 mL, 2.54 mmol) in dry THF
(60 mL). The amide derivative 42 (0.2 g, 35%) was obtained as a
yellow oil.
=
IR (thin film): n(NH) 3063; n(C O) 1613; n(SO2) 1323,
1
1156 cm-1. H NMR (200 MHz, CDCl3): d 1.65–1.84 (m, 4H),
2.02 (s, 3H), 3.12 (s, 2H), 3.32–3.43 (m, 6H), 6.84–6.89 (m, 1H),
7.01–7.05 (m, 1H), 7.13 (s, 1H), 7.39–7.52 (m, 3H), 7.68–7.79 (m,
4H), 8.33 (s, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 14.4 (CH3),
24.2 (CH2), 26.2 (CH2), 32.7 (CH2), 42.2 (CH2), 46.1 (CH2), 46.8
(CH2), 112.8 (CH), 117.6 (CH), 122.6 (CH), 123.2 (CH), 127.0
(CH), 127.6 (CH), 128.3 (CH), 128.5 (CH), 128.9 (CH), 129.2
=
IR (thin film): n(NH) 3107; n(C O) 1620; n(SO2) 1336,
1
1162 cm-1. H NMR (200 MHz, CDCl3): d 1.82–1.98 (m, 7H),
2.97 (s, 2H), 3.40–3.60 (m, 6H), 6.58 (s, 1H), 7.54–7.62 (m, 4H),
7.85–7.98 (m, 4H), 8.32 (s, 1H) ppm. EI-MS m/z: 446 (M+, 3%),
127 (42), 70 (100).
(CH), 129.9, 131.9, 134.6, 135.2, 136.4, 138.9, 142.8, 147.1, 169.0
+
=
(C O) ppm EI-MS m/z: 446 (M , 22%), 70 (100).
Synthesis of amines derivatives 14–17: General procedure
N-[3-(2-Oxo-2-pyrrolidin-1-ylethyl)-1H-inden-5-yl]naphthalene-2-
sulfonamide 43
To a stirred solution of AlH3–NMe2Et (0.5 M in toluene, 2–
4 equiv) in dry THF cooled to 0 ◦C was added via a hypodermic
syringe a solution amide derivatives 42, 43, 44 or 45 (1 equiv) in dry
The above procedure was followed using the acetic acid deriva-
tive 36 (0.46 g, 1.21 mmol), 1,1¢-carbonyldiimidazole (0.40 g,
2.42 mmol) and pyrrolidine (0.19 mL, 2.42 mmol) in dry THF
(60 mL). The amide derivative 43 (0.37 g, 71%) was obtained as a
◦
THF previously cooled to 0 C, under argon atmosphere. After
stirring at 0 ◦C or room temperature for 30 min, the reaction
mixture was hydrolyzed with water and 10% H2SO4 aqueous
solution, stirred at room temperature and basified with 20%
aqueous ammonia. The layers were separated and the aqueous
layer was extracted with EtOAc. The combined organic layers were
dried over anhydrous Na2SO4, filtered and evaporated to dryness.
The resulting residue was purified by column chromatography on
silica gel (CH2Cl2–MeOH–NH3 mixtures of increasing polarity as
eluent).
yellow foamy solid.
◦
=
Mp 126–127 C. IR (thin film): n(NH) 3245; n(C O) 1615;
n(SO2) 1326, 1156 cm-1. 1H NMR (200 MHz, CDCl3): d 1.80–2.00
(m, 4H), 3.18 (s, 2H), 3.30–3.50 (m, 4H), 6.30 (s, 1H), 6.95–6.99
(m, 1H), 7.05–7.09 (m, 2H), 7.40–7.58 (m, 2H), 7.64–7.86 (m,
4H), 8.38 (s, 1H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 24.4 (CH2),
26.1 (CH2), 35.0 (CH2), 37.4 (CH2), 46.0 (CH2), 47.0 (CH2), 113.6
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3807
©

View Article Online
N-[2-Methyl-3-(2-pyrrolidin-1-ylethyl)-1H-inden-5-
N-[2-Methyl-3-(2-pyrrolidin-1-ylethyl)-1H-inden-7-
yl]naphthalene-2-sulfonamide 14
yl]naphthalene-2-sulfonamide 17
The above procedure was followed using the amide derivative 42
(200 mg, 0.45 mmol) in dry THF (12 mL) and AlH3–NMe2Et
(0.5 M in toluene, 3.6 mL, 1.8 mmol) in dry THF (10 mL). The
indene derivative 14 (70 mg, 36%) was obtained as a brown oil.
IR (thin film): n(NH) 3250; n(SO2) 1330, 1158 cm-1. 1H
NMR (200 MHz, CDCl3): d 1.70–1.80 (m, 4H), 1.98 (s, 3H),
2.35–2.64 (m, 8H), 3.13 (s, 2H), 6.92–6.97 (m, 2H), 7.13–7.17
(m, 1H), 7.49–7.59 (m, 2H), 7.78–7.85 (m, 4H), 8.36 (s, 1H)
ppm. 13C NMR (CDCl3, 50.3 Hz): d 14.0 (CH3), 23.4 (CH2),
24.8 (CH2), 42.1 (CH2), 54.0 (CH2), 54.7 (CH2), 112.8 (CH),
118.3 (CH), 122.6 (CH), 123.5 (CH), 127.2 (CH), 127.7 (CH),
128.5 (CH), 128.6 (CH), 129.0 (CH), 129 (CH), 131.9, 134.2,
134.6, 135.0, 136.4, 139.7, 141.0, 147.4 ppm. EI-MS m/z: 432
(M+, 2%), 84 (100). Found: C 64.98, H 6.32, N 6.00, S 6.31.
Calcd for C26H28N2O2S·0.75CH2Cl2: C 64.74, H 5.99, N 5.64,
S 6.46%.
The above procedure was followed using the amide derivative 45
(130 mg, 0.29 mmol) in dry THF (5 mL) and AlH3–NMe2Et (0.5 M
in toluene, 1.16 mL, 0.58 mmol) in dry THF (5 mL). The indene
derivative 17 (7 mg, 6%) was obtained as a yellow oil. Chemical
purity by HPLC: 89.0%
IR (thin film): n(NH) 3261; n(SO2) 1335, 1160 cm-1. 1H NMR
(400 MHz, CDCl3): d 1.90 (m, 4H), 1.99 (s, 3H), 2.64–2.76 (m,
8H), 3.08 (s, 2H), 6.97- 6.99 (m, 1H), 7.05–7.16 (m, 2H), 7.55–
7.65 (m, 2H), 7.77–7.80 (m, 1H), 7.85–7.90 (m, 3H), 8.35 (d, J =
1.6 Hz, 1H) ppm. 13C NMR (CDCl3, 100.6 Hz): d 14.1 (CH3),
23.7 (CH2), 40.5 (CH2), 54.2 (CH2), 54.9 (CH2), 116.4 (CH), 118.8
(CH), 122.5 (CH), 127.7 (CH), 128.0 (CH), 128.1 (CH), 129.0
(CH), 129.1 (CH), 129.5 (CH), 129.6 (CH), 131.6, 132.2, 135.1,
135.5, 136.7 ppm.
Attempted preparation of sulfonamide 46
Experiment 1. Pd/C (10 wt.%, 25 mg) was added to a solution
of acetic acid derivative 39 (220 mg, 0.46 mmol) in absolute
EtOH (15 mL). The resulting suspension was hydrogenated at
atmospheric pressure and room temperature for 4 h. The reaction
N-[3-(2-Pyrrolidin-1-ylethyl)-1H-inden-5-yl]naphthalene-2-
sulfonamide 15
The above procedure was followed using the amide derivative 43
(180 mg, 0.42 mmol) in dry THF (7 mL) and AlH3–NMe2Et
(0.5 M in toluene, 1.7 mL, 0.85mmol) in dry THF (7 mL). The
indene derivative 15 (100 mg, 57%) was obtained as a yellow
solid.
R
mixture was filtered trough Celiteꢀ and evaporated to dryness to
obtain decomposition products.
Experiment 2: N-(2-benzyl-2-methyl-3-oxo-2,3-dihydro-1H-
inden-5-yl)naphthalene-2-sulfonamide 49 and N-benzyl-N-(2-methyl-
Mp 119–120 ◦C. IR (thin film): n(NH) 3056; n(SO2) 1327,
3-oxo-2,3-dihydro-1H-inden-5-yl)naphthalene-2-sulfonamide
50.
1
1157 cm-1. H NMR (200 MHz, CDCl3): d 1.70–1.80 (m, 4H),
To a stirred solution of indanone sulfonamide 28 (1.0 g,
2.85 mmol) in dry THF (15 mL) cooled to -78 ◦C was added via a
hypodermic syringe LDA mono-THF complex solution (1.5 M in
cyclohexane, 6.7 mL, 9.98 mmol) under argon atmosphere. After
stirring at -78 ◦C for 1 h, the slurry was allowed to warm to room
temperature for 4 h. The resulting dark red solution was cooled
to -40 ◦C and a solution of benzyl bromide (0.85 mL, 7.13 mmol)
in dry THF (10 mL) was added. The resultant mixture was
stirred at room temperature for 18 h. The reaction mixture was
quenched by addition of brine (20 mL) and 2.5 N HCl (20 mL).
The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 ¥ 50 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and evaporated to dryness.
The resulting residue was purified by column chromatography
on silica gel (hexanes–EtOAc mixtures of increasing polarity as
eluent) to afford the benzylindanone derivatives 49 (660 mg, 52%)
2.46–2.76 (m, 8H), 3.16 (s, 2H), 6.15 (s, 1H), 7.00–7.06 (m, 2H),
7.20–7.52 (m, 3H), 7.69–7.78 (m, 5H), 8.35 (s, 1H) ppm. 13C NMR
(CDCl3, 50.3 Hz): d 23.4 (CH2), 27.1 (CH2), 37.8 (CH2), 54.0
(CH2), 54.6 (CH2), 113.8 (CH), 119.6 (CH), 122.5 (CH), 124.0
(CH), 127.1 (CH), 127.7 (CH), 128.4 (CH), 128.5 (CH), 129.0
(CH), 129.1 (CH), 129.6 (CH), 131.9, 134.2, 135.4, 136.6, 141.2,
141.8, 146.2 ppm. EI-MS m/z: 418 (M+, 1%), 84 (100). Found:
C 66.36, H 6.29, N 6.49, S 7.23. Calcd for C25H26N2O2S·2H2O: C
66.06, H 6.65, N 6.16, S 7.05%.
5-Chloro-3-methyl-N-[2-methyl-3-(2-pyrrolidin-1-ylethyl)-1H-
inden-5-yl]-1-benzothiophene-2-sulfonamide 16
The above procedure was followed using the amide derivative 44
(160 mg, 0.32 mmol) in dry THF (5 mL) and AlH3–NMe2Et
(0.5 M in toluene, 1.6 mL, 0.8 mmol) in dry THF (5 mL). The
indene derivative 16 (82 mg, 53%) was obtained as a brown solid.
Chemical purity◦by HPLC: 99.6%
and 50 (160 mg, 11%) as off-white solids.
◦
=
49: Mp 145–146 C. IR (KBr): n(NH) 3243; n(C O) 1709;
1
n(SO2) 1334, 1157 cm-1. H NMR (300 MHz, CDCl3): d 1.17
1
Mp 187–188 C. IR (thin film): n(SO2) 1333, 1157 cm-1. H
(s, 3H), 2.63 (d, J = 17.1 Hz, 1H), 2.73 (d, J = 13.5, 1H), 2.94 (d,
J = 13.5 Hz), 3.12 (d, J = 17.4 Hz, 1H), 7.02–7.11 (m, 5H), 7.18–
7.22 (m, 2H), 7.37–7.44 (m, 2H), 7.54–7.65 (m, 2H), 7.72–7.76 (m,
1H), 7.85–7.89 (m, 3H), 8. 37 (d, J = 1.8 Hz, 1H) ppm. 13C NMR
(CDCl3, 75.4 Hz): d 24.8 (CH3), 38.8 (CH2), 43.7 (CH2), 51.3, 116.7
(CH), 122.4 (CH), 126.7 (CH), 127.8 (CH), 127.9 (CH), 128.2
(CH), 128.3 (CH), 128.9 (CH), 129.3 (CH), 129.4 (CH), 129.7
(CH), 129.9 (CH), 130.4 (CH), 132.3, 135.3, 136.0, 136.4, 137.1,
NMR (200 MHz, CDCl3): d 1.80–1.86 (m, 4H), 2.02 (s, 3H), 2.38
(s, 3H), 2.39–2.62 (m, 6H), 3.18 (s, 2H), 6.86 (s, 1H), 7.02–7.10
(m, 1H), 7.15–7.12 (m, 1H), 7.20–7.38 (m, 2H), 7.63–7.67 (m,
2H) ppm. 13C NMR (CDCl3, 50.3 Hz): d 12.0 (CH3), 13.9 (CH3),
23.2 (CH2), 24.4 (CH2), 42.1 (CH2), 53.8 (CH2), 54.4 (CH2), 112.1
(CH), 117.9 (CH), 123.1 (CH), 123.5 (CH), 127.3 (CH), 131.2,
133.8, 134.6, 136.0, 137.0, 137.8, 139.5, 140.5, 141.1, 147.7 ppm.
ESI-HRMS calcd for C25H28N2O2S2Cl [M + H]+: 487.1275; found:
487.1274.
=
137.8, 149.7, 210.4 (C O) ppm. ESI-HRMS calcd for C27H24NO3S
[M + H]+ 442.1471; found 442.1479.
3808 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
◦
=
50: Mp 119–120 C. IR (KBr): n(NH) 3031; n(C O) 1707;
Fundacio´ Bosch i Gimpera-Universitat de Barcelona, Spain. N.M.
and S.L.-P. are grateful to ESTEVE for post-doctoral and graduate
fellowships, respectively. Thanks are also due to the AGAUR, Grup
de Recerca Consolidat 2005SGR00158.
n(SO2) 1352, 1164 cm-1. H NMR (300 MHz, CDCl3): d 1.19
1
(s, 3H), 2.67 (d, J = 17.4 Hz, 1H), 2.73 (d, J = 13.5 Hz, 1H),
2.95 (d, J = 13.5 Hz, 1H), 3.15 (d, J = 17.7 Hz, 1H), 4.76 (s,
2H), 7.03–7.06 (m, 3H), 7.12–7.20 (m, 5H), 7.23–7.29 (m, 3H),
7.53–7.70 (m 4H), 7.87–7.95 (m, 4H), 8.24 (d, J = 1.8 Hz, 1H)
ppm. 13C NMR (CDCl3, 75.4 Hz): d 24.7 (CH3), 39.1 (CH2), 44.0
(CH2), 51.3, 55.1 (CH2), 123.1 (CH), 123.4 (CH), 126.8 (CH),
127.3 (CH), 128.0 (CH), 128.1 (CH), 128.4 (CH), 128.8 (CH),
129.3 (CH), 129.6 (CH), 129.7 (CH), 130.4 (CH), 132.5, 135.3,
References
1 (a) M. Sharma and S. M. Ray, Bioorg. Med. Chem. Lett., 2007,
17, 6790–6796; (b) J. W. Huffman and L. W. Padgett, Curr. Med.
Chem., 2005, 12, 1395–1411; (c) J. W. Huffman, R. Mabon, M. -J.
Wu, J. Lu, R. Hart, D. P. Hurst, P. H. Reggio, J. L. Wiley and B. R.
Martin, Bioorg. Med. Chem., 2003, 11, 539–549; (d) T. M. Bo¨hme, C.
Keim, K. Kreutzmann, M. Linder, T. Dingermann, G. Dannhardt,
E. Mutschler and G. Lambrecht, J. Med. Chem., 2003, 46, 856–867;
(e) E. T. Goluboff, Expert Opin. Investig. Drugs, 2001, 10, 1875–1882;
(f) P. H. Reggio, S. Basu-Dutt, J. Barnett-Norris, M. T. Castro, D. P.
Hurst, H. H. Seltzman, M. J. Roche, A. F. Gilliam, B. F. Thomas, L. A.
Stevenson, R. G. Pertwee and M. E. Abood, J. Med. Chem., 1998, 41,
5177–5187; (g) E. M. Coyanis, J.-L. Panayides, M. A. Fernandes, C. B.
de Koning and W. A. L. van Otterlo, J. Organomet. Chem., 2006, 69,
5222–5239.
2 Adis International Limited, Drugs R&D, 2004, 5, 220–226.
3 I.-M. Karaguni, K.-H. Glu¨senkamp, A. Langerak, C. Geisen, V.
Ullrich, G. Winde, T. Mo¨ro¨y and O. Mu¨ller, Bioorg. Med. Chem. Lett.,
2002, 12, 709–713.
4 (a) O. Mu¨ller, E. Gourzoulidou, M. Carpintero, I. -M. Karaguni, A.
Langerak, C. Herrmann, T. Mo¨ro¨y, L. Klein-Hitpaß and H. Wald-
mann, Angew. Chem., Int. Ed., 2004, 43, 450–454; (b) H. Waldmann,
I. -M. Karaguni, M. Carpintero, E. Gourzoulidou, C. Herrmann, C.
Brockmann, H. Oschkinat and O. Mu¨ller, Angew. Chem., Int. Ed., 2004,
43, 454–458.
5 R. Kolanos, U. Siripurapu, M. Pullagurla, M. Riaz, V. Setola, B. L.
Roth, M. Dukata and R. A. Glennon, Bioorg. Med. Chem. Lett., 2005,
15, 1987–1991.
6 D. Sikazwe, M. L. Bondarev, M. Dukat, J. B. Rangisetty, B. L. Roth
and R. A. Glennon, J. Med. Chem., 2006, 49, 5217–5225.
7 R. Merce`, B. Andaluz and J. Frigola, World Pat. WO 03/042175 A1,
2003.
8 (a) J. Holenz, R. Merce`, J. L. D´ıaz, X. Guitart, X. Codony, A.
Dordal, G. Romero, A. Torrens, J. Mas, B. Andaluz, S. Herna´ndez,
X. Monroy, E. Sa´nchez, E. Herna´ndez, R. Pe´rez, R. Cub´ı, O. Sanfeliu
and H. Buschmann, J. Med. Chem., 2005, 48, 1781–1795; (b) K. Alex,
N. Schwarz, V. Khedkar, I. A. Sayyed, A. Tillack, D. Michalik, J.
Holenz, J. L. D´ıaz and M. Beller, Org. Biomol. Chem., 2008, 6, 1802–
1807.
9 (a) J. Holenz, P. J. Pauwels, J. L. D´ıaz, R. Merce`, X. Codony and H.
Buschmann, Drug Discovery Today, 2006, 11, 283–299; (b) D. J. Heal,
S. L. Smith, A. Fisas, X. Codony and H. Buschmann, Pharmacol. Ther.,
2008, 117, 207–231.
=
135.6, 135.7, 136.8, 136.9, 137.7 (CH), 138.9, 152.3, 210.1 (C O)
ppm. ESI-HRMS calcd for C34H30NO3S [M + H]+ 532.1940; found
532.1949.
5-HT6 binding assay
Membranes of HEK-293 cells expressing the 5HT6 human
recombinant receptor were supplied by Receptor Biology. In
these membranes the receptor concentration was 2.18 pmol mg-1
protein and the protein concentration was 9.17 mg mL-1. The
experimental protocol followed the method of B. L. Roth et al.
with slight modifications.18 The commercial membrane was diluted
(dilution 1 : 40) with the binding buffer: 50 mM Tris-HCl,
10 mM MgCl2, 0.5 mM EDTA (pH 7.4). The radioligand
used was [3H]-LSD at a concentration of 2.7 nM with a final
volume of 200 ml. Incubation was initiated by adding 100 ml
of the membrane suspension (ª22.9 mg membrane protein), and
continued for 60 min at a temperature of 37 ◦C. Incubation
was terminated by fast filtration through glass fibre filters in a
Harvester Brandel Cell manufactured by Schleicher & Schuell
GF 3362 pre-treated with a 0.5% polyethylenimine solution. The
filters were washed three times with 3 mL of Tris-HCl 50 mM
pH 7.4 buffer. The filters were transferred to phials and to each
phial 5 mL of liquid scintillation cocktail Ecoscint H was added.
The phials were allowed to reach equilibrium for several hours
before being counted in a Wallac Winspectral 1414 scintillation
counter. Non-specific binding was determined in the presence
of 100 mM serotonin. The tests of preferred compounds were
performed in triplicate. The inhibition constants (Ki, nM) were
calculated by non-linear regression analysis using the program
EBDA/LIGAND.19 A linear regression line of data points was
plotted, from which the concentration of competing ligand which
displaces 50% of the specific binding of the radioligand (IC50
value) was determined, and the Ki value was determined based
upon the Cheng–Prusof equation: Ki = IC50/(1 + L/KD) were
L is the concentration of free radioligand used in the assay
and KD is the dissociation constant of the radioligand for the
receptor.
10 (a) H. Tsukamoto, T. Ueno and Y. Kondo, Org. Lett., 2007, 9, 3033–
3036 and references therein; (b) P. V. Ivchenko, I. E. Nifant’ev, Y. N.
Luzikov and S. G. Mkoyan, Synthesis, 2007, 1038–1046.
11 (a) M. W. Rathke and M. Nowak, J. Org. Chem., 1985, 50,
2624–2626; (b) F. Bonadies, A. Cardilli, A. Lattanzi, L. R. Orelli
and A. Scettri, Tetrahedron Lett., 1994, 35, 3383–3386; (c) R. A.
Moss and P. K. Gong, Tetrahedron Lett., 2003, 44, 7845–7848;
(d) B. M. Trost and L. H. Latimer, J. Org. Chem., 1977, 42, 3212–
3214.
12 (a) MDS Pharma Services-Discovery. See the following website:
http://www.mdsps.com; (b) Assay Package – LeadProfilingScreenꢀR :
http://discovery.mdsps.com/Catalog/Discovery/AssayPackage.aspx?
id=68.
Adenylyl cyclase activity assay
Functional effects of the compounds were evaluated by cAMP
measurements on HEK-293F cells stably expressing the human
5-HT6 receptor using a HTRF assay format.20
13 M. Adamczyk and D. S. Watt, J. Org. Chem., 1984, 49, 4226–
4237.
14 D. L. Musso, F. R. Cochran, J. L. Kelley, E. W. McLean, J. L. Selph,
G. C. Rigdon, G. F. Orr, R. G. Davis, B. R. Cooper, V. L. Styles,
J. B. Thompson and W. R. Hall, J. Med. Chem., 2003, 46, 399–
408.
Acknowledgements
15 E. Alcalde, M. Alemany and M. Gisbert, Tetrahedron, 1996, 52, 15171–
15188.
This research was supported by ESTEVE, Barcelona, Spain,
through projects FBG-301362, FBG-302131 and FBG-302663
16 I. Smonou and M. Orfanopoulos, Synth. Commun., 1990, 20, 1387–
1397.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3795–3810 | 3809
©

View Article Online
17 P. M. G. Bavin, C. R. Ganellin, J. L. Loynes and R. G. W. Spickett,
J. Med. Chem., 1969, 12, 513–516.
18 B. L. Roth, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma,
Jr., Y. Shen, H. Y. Meltzer and D. R. Sibley, J. Pharmacol. Exp. Ther.,
1994, 268, 1403–1410.
20 (a) A. Fisas, X. Codony, G. Romero, A. Dordal, J. Giraldo, R. Merce`,
J. Holenz, D. Heal, H. Buschmann and P. J. Pauwels, Br. J. Pharmacol.,
2006, 148, 973–983; (b) G. Romero, E. Sanchez, M. Pujol, P. Perez, X.
Codony, J. Holenz, H. Buschmann and P. J. Pauwels, Br. J. Pharmacol.,
2006, 148, 1133–1143; (c) G. Romero, M. Pujol, P. Perez, H. Buschmann
and P. J. Pauwels, J. Pharmacol. Toxicol. Methods, 2007, 55, 144–
150.
19 P. J. Munson and D. Rodbard, Anal. Biochem., 1980, 107, 220–
239.
3810 | Org. Biomol. Chem., 2008, 6, 3795–3810
This journal is
The Royal Society of Chemistry 2008
©