Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors

Article abstract of DOI:10.1021/jm0503291

A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined

Full text of DOI:10.1021/jm0503291

J. Med. Chem. 2005, 48, 6023-6034
6023
Conformationally Restricted Homotryptamines. 2. Indole
Cyclopropylmethylamines as Selective Serotonin Reuptake Inhibitors
Ronald J. Mattson,* John D. Catt, Derek J. Denhart, Jeffrey A. Deskus, Jonathan L. Ditta, Mendi A. Higgins,
Lawrence R. Marcin, Charles P. Sloan, Brett R. Beno, Qi Gao, Melissa A. Cunningham, Gail K. Mattson,
Thaddeus F. Molski, Matthew T. Taber, and Nicholas J. Lodge
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492-7660
Received April 11, 2005
A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake
inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for
hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans.
The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis
stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl
groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-
bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound
(+)-12a demonstrated potent hSERT binding (Ki ) 0.18 nM) in vitro and was more than 1000-
fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-
dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin
reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine
but at an approximately 10-fold lower dose.
Introduction
serotonin (1) replaced the aminoethylene side chain with
a tetrahydropyridyl side chain to give 2 (RU 24969).8
The further extension of the side chain to aminocyclo-
hexenyl and aminocyclohexyl (3) gave compounds with
5-HT1A activity,9 SSRI activity,10 or both.11 Amino-
cyclopropane analogues (4) of serotonin also were in-
vestigated, with the conclusion that this was a good
strategy only for the tryptamines that exhibited 5-HT2C
binding rather than 5-HT1A or 5-HT2A activity.12
One key target for psychoactive drugs is the seroton-
ergic (5-HT) system, where the human serotonin trans-
porter (hSERT) is one of the major regulators of synaptic
5-HT levels. The selective serotonin reuptake inhibitors
(SSRIs) are effective antidepressants and are relatively
safe despite some recognized drawbacks.1 Although
SSRIs are prescribed most often for depressive dis-
orders, they are increasingly being used to treat a
variety of anxiety disorders, as well as being used as
off-label treatments for a broad list of other disorders.2
More recent SSRI research has focused on compounds
with additional properties that may result in a more
rapid onset of antidepressant action, e.g., SERT inhibi-
tion combined with 5-HT1A or 5-HT1B antagonism.3
Most binding studies of SERT inhibitors are consis-
tent with one hSERT binding site. A proposed 3D QSAR
model4 with a single binding site has been derived from
a diverse set of compounds including SSRIs, tricyclic
antidepressants, and other compounds such as ven-
lafaxine and trazodone. In contrast, site-directed mu-
tagenesis studies suggest multiple binding sites are
present on SERT. A 3D model5 of SERT based on
mutagenesis studies suggest there are at least three
ligand binding sites that bind imipramine, citalopram,
and paroxetine at different sites. Some SSRIs interact
with a low-affinity, allosteric binding site that modu-
lates the primary SERT binding site. The R-citalopram
and S-citalopram have different activities at the allo-
steric binding site,6 and this has been proposed as an
advantage for S-citalopram.7
We have previously reported a facile one-pot synthesis
of N,N-dimethylhomotryptamines13 (5) and their affin-
ity14 for hSERT. This initial pharmacological report
identified N,N-dimethylhomotryptamine as a basic scaf-
fold for potent SSRI activity. We now report a series of
conformationally restricted homotryptamines using the
cyclopropylmethylamine side chain (6) as new potent
SSRIs.
The conformational restriction of serotonergic ligands
is a well-precedented way to improve binding of these
agents. One of the earliest semirigid analogues of
Synthesis
The racemic trans-cyclopropanes were prepared from
the appropriately substituted indoles (7a-h, Scheme 1)
* To whom correspondence should be addressed. Phone: +1-203-
677-6355. Fax: +1-203-677-7702. E-mail: mattsonr@bms.com.
10.1021/jm0503291 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/20/2005

6024 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Mattson et al.
Scheme 1. Synthesis of Racemic trans- and
cis-Cyclopropanesa
Scheme 2. Enantioselective Synthesis of
trans-Cyclopropanes
Swern conditions to provide aldehydes 15a and 15e.
Reductive amination and hydrolysis of the indole N-1
tosyl group then provided the desired cis-cyclopropanes
16a and 16e.
The chiral trans-cyclopropanes were prepared by a
modification of published methods.12c,20 Horner-Wads-
worth-Emmons olefination of 8a and 8e using the
chiral phosphonate 1721 gave intermediates 18a and 18e
bearing the (+)-camphorsultam chiral auxiliary (Scheme
2). Intermediates 18a and 18e were cyclopropanated
with diazomethane and palladium acetate to stereose-
lectively produce the (1S,2S)-trans-cyclopropanes (19a
and 19e). Similar to the racemic synthesis, amides (19a
and 19e) were reduced to the corresponding alcohols and
then oxidized to the aldehydes (1S,2S)-11a and -11e,
which were then carried on to the trans-cyclopropanes,
[(+)-12a and -12e]. The (1R,2R)-trans-cyclopropanes
were prepared in a similar manner using the (-)-
camphorsultam chiral auxiliary. The (1S,2S)-stereo-
chemistry of 19a and (+)-12a were confirmed by X-ray
crystallography (Figures 1 and 2). To investigate the
effects of indole N-1 substituents on SERT inhibition,
(+)-12a was alkylated with dimethyl sulfate and diethyl
sulfate to give the indole N-1 methyl and ethyl deriva-
tives 20 and 21, respectively.
a (a) POCl3, DMF; (b) TsCl, NEt3; (c) NaH, (N-methoxy-N-
methylcarbamoylmethyl)phosphonate, THF; (d) CH2N2, Pd(OAc)2;
(e) LAH, THF; (f) Me2NH, NaBH(OAc)3; (g) NaOH, H2O/EtOH;
(h) NaH, (CF3CH2O)2P(O)CH2CO2Me, THF; (i) (COCl)2, DMSO,
CH2Cl2, then Et3N.
by modification of published methods.15 Indoles (7a-
h) that were not commercially available were prepared
by the published methods.16 Formylation17 of 7a-h
under Vilsmeier-Haack conditions with subsequent
tosylation of the indole N-1 position provided aldehydes
8a-h in good yields. Subsequent Horner-Wadsworth-
Emmons olefination of 8a-h with diethyl (N-methoxy-
N-methylcarbamoylmethyl)phosphonate18 gave the cor-
responding trans Weinreb amides 9a-h, which were
cyclopropanated with diazomethane and palladium
acetate to give the trans-cyclopropyl Weinreb amides
10a-h. Reduction of the Weinreb amides with LAH,
reductive amination of the resulting aldehydes 11a-h,
and hydrolysis of the N-tosyl group gave the racemic
trans-cyclopropanes 12a-h.
The racemic cis-cyclopropanes 16a and 16e were
prepared from 8a and 8e in a manner similar to the
procedure for trans-cyclopropanes. A cis-selective Still-
Gennari modified Horner-Wadsworth-Emmons olefi-
nation19 provided a 3:1 cis/trans mixture, from which
the cis olefins (13a and 13e) could be obtained pure by
silica gel chromatography. Cyclopropanation of 13a and
13e with diazomethane and palladium acetate regio-
selectively produced the cis-cyclopropanes (14a and
14e). Careful reduction of the ester with LAH gave the
corresponding alcohols, which were oxidized under
Figure 1. ORTEP drawing of 19a.

Indole Cyclopropylmethylamines as SSRIs
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6025
the enantiomers of 16a was assigned by analogy to those
of 16e based on the order of elution from the chiral
column and sign of optical rotation.
Results and Discussion
Our previous communication14 identified N,N-dim-
ethylhomotryptamines (5a and 5e, Table 1) as potent
serotonin reuptake inhibitors. In the current trans-
cyclopropylmethylamine series, the 5-cyano and 5-fluoro
compounds (12a and 12e) were more active at hSERT
than the prototypical homotryptamines (5a and 5e).
Moving a substituent around the indole ring showed
that the 7-cyano compound (12b) was equipotent with
the 5-cyano analogue (12a). However, the 7-fluoro
compound (12f) was less active than the 5-fluoro ana-
logue (12e). The 6-substituted compounds (12c and 12d)
and 4-substituted compounds (12g and 12h) were less
active than the 5-substituted analogues (12a and 12e).
The cis-cyclopropylmethylamines (16a and 16e) were
less active than either the trans-cyclopropanes (12a and
12e) or the homotryptamines (5a and 5e).
Figure 2. ORTEP drawing of (+)-(1S,2S)-12a‚HCl.
To define the stereochemical requirements for hSERT
inhibition, the binding of the enantiomers of the trans-
cyclopropanes (12a and 12e) and the cis-cyclopropanes
(16a and 16e) was investigated. In the trans-cyclopro-
panes, the (1S,2S)-enantiomers [(+)-12a and -12e] were
significantly (>50-fold) more active than the (1R,2R)-
enantiomers [(-)-12a and -12e]. In the cis-cyclopro-
panes, the (1R,2S)-enantiomers [(-)-16a and -16e] were
only slightly more active than the corresponding (1S,2R)-
enantiomers [(+)-16a and -16e]. Thus, the more active
enantiomers of the cis- and trans-cyclopropanes retained
the (S)-stereochemistry adjacent to the indole but differ
in the stereochemistry at the cyclopropane carbon that
bore the dimethylaminomethyl group.
Figure 3. ORTEP drawing of 22.
The enantiomers of both the trans- and cis-cyclopro-
panes (12a, 12e, 16a, and 16e) could also be separated
analytically and preparatively by chiral HPLC. The
enantiomers of 12a and 12e were separated on a
Chiralcel AD column HPLC using EtOH/hexane as the
eluent, with the (1R,2R)-enantiomer eluting before the
(1S,2S)-enantiomer. In both cases, the separated ma-
terials were identical to the corresponding material that
was stereoselectively synthesized. The cis-cyclopropanes
(16a and 16e) were similarly separated into their
enantiomers using the same column, with the (+)-
enantiomer eluting before the (-)-enantiomer. The
absolute stereochemistry of (-)-16e was determined to
be (1R,2S) by X-ray crystallography (Figure 3) of the
indole N-1 tosyl derivative (22). The stereochemistry of
The importance of the indole N-1 H to hSERT binding
was also investigated. The indole N-1 methyl and ethyl
analogues 20 and 21 demonstrated a 10- to 30-fold
decrease in affinity for hSERT relative to (+)-12a. Thus,
hydrogen bonding of hSERT to the indole N-1 hydrogen
Table 1. hSERT, hDAT, and hNET Binding of Indole Cyclopropylmethylamines
compd
R
R′
cis/trans
(
hSERT Ki (nM)
n
hDAT Ki (nM)
hNET Ki (nM)
fluoxetine
paroxetine
5a
0.72 ( 0.05
0.04 ( 0.003
2 ( 0.4
24
18
3
1900 (n ) 2)
440 (n ) 2)
400 (n ) 2)
90 (n ) 2)
5-CN
5-F
H
a
a
5e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
4 ( 0.3
3
a
a
12a
5-CN
7-CN
6-CN
4-CN
5-F
trans
trans
trans
trans
trans
trans
trans
trans
cis
(
(
(
(
(
(
(
(
(
(
1S,2S
1R,2R
1S,2S
1R,2R
1R,2S
1S,2R
1R,2S
1S,2R
1S,2S
1S,2S
0.56 ( 0.15
0.58 ( 0.11
7.4 ( 1.8
230, 420
2.1 ( 0.4
10 ( 2.4
38 ( 6.1
59 ( 17
7.1 ( 2.1
24 ( 5.9
0.18 ( 0.02
8.9 ( 1.7
0.68 ( 0.11
41 ( 2.7
5.7 ( 1.9
17 ( 2.6
14 ( 1.9
100 ( 1.4
6.5 ( 4.3
1.8 ( 1.1
13
3
a
a
12b
a
a
12c
3
a
a
12d
2
ntb
ntb
12e
7
a
a
12f
7-F
3
a
a
12g
6-F
3
a
a
12h
4-F
3
a
a
16a
5-CN
5-F
3
a
a
16e
cis
3
a
a
(+)-12a
(-)-12a
(+)-12e
(-)-12e
(-)-16a
(+)-16a
(-)-16e
(+)-16e
20
5-CN
5-CN
5-F
trans
trans
trans
trans
cis
12
5
2100 (n ) 2)
4600 (n ) 2)
a
a
11
4
a
a
5-F
a
a
5-CN
5-CN
5-F
3
a
a
cis
3
a
a
cis
4
a
a
5-F
5-CN
5-CN
cis
3
ntb
a
ntb
a
trans
trans
4
21
4
a
a
a Less than 50% inhibition at 1 µM. b nt: not tested.

6026 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Mattson et al.
not bind significantly to the human dopamine trans-
porter (hDAT) or the human norepinephrine transporter
(hNET) (Ki ) 2.1 and 4.6 µM, respectively).23 Since (+)-
12a demonstrated greater than 1000-fold more potent
binding for hSERT than for hDAT, hNET, 5-HT1A, and
5-HT1B, it seems unlikely that these latter interactions
would exert significant pharmacological effects. Thus
(+)-12a demonstrated a high selectivity for hSERT.
Since these molecules bind with high affinity and
selectivity to hSERT in vitro, it was of interest to
determine if these compounds could produce functional
changes in serotonin levels in vivo. In microdialysis
studies in rats in vivo, (+)-12a produced robust, dose-
dependent increases in extracellular serotonin in the
frontal cortex (Figure 4). Doses of 1 and 0.3 mg/kg po
produced effects that were significantly greater than
vehicle, while the effects of 0.1 mg/kg were not statisti-
cally significant. The maximal effect of (+)-12a was
comparable to that of fluoxetine. However, the dose of
(+)-12a (1 mg/kg po) necessary to produce the maximal
response was approximately 10-fold lower than with
fluoxetine (10 mg/kg). Thus, (+)-12a produced potent
and robust effects on extracellular serotonin levels in
vivo, consistent with an earlier report.23
Compounds 12a,e and 16a,e share pharmacophoric
features (e.g., basic amine and substituted aromatic
ring) with other SSRIs such as sertraline and S-
citalopram. However, 12a,e and 16a,e lack the second
phenyl ring of the latter compounds and feature an
indole N-1 hydrogen as an additional site for a potential
hydrogen-bonding interaction. A computational study
of (+)-12a, (-)-16e, S-citalopram, and sertraline ((1S,4S)-
stereochemistry) was performed (Figure 5) to evaluate
the possibility that (+)-12a and (-)-16e might bind to
SERT in an analogous fashion to other known inhibi-
tors. The overall method used, including the use of an
Figure 4. Effects of (+)-12a on extracellular serotonin levels
in the frontal cortex of rats measured by microdialysis. Data
points represent mean ( SEM of five to six rats per group,
and the black arrow indicates the time of compound admin-
istration. Dosing was via oral gavage in a volume of 1 L/kg to
rats fasted overnight.
may play a role in the binding of these indole SSRIs, or
there may be limited steric tolerance in this region.
The selectivity of (+)-12a for hSERT versus other
receptors and transporters was also evaluated. Since it
is well established that the increase in synaptic 5-HT
caused by SSRIs is limited by feedback mechanisms
mediated by 5-HT1A and 5-HT1B autoreceptors,22 it was
of added importance to test (+)-12a for binding at a
variety of serotonergic receptors. Compound (+)-12a
demonstrated only modest binding at the 5-HT1A (Ki )
410 ( 10 nM) and at 5-HT6 (Ki ) 270 ( 40 nM)
receptors, while there was no significant binding (<32%
inhibition at 1 µM) at the 5-HT1B, 5-HT2A, 5-HT3,
5-HT5A, and 5-HT7 receptors. In addition, (+)-12a did
Figure 5. (a, b) Models showing overlays of low-energy conformations of sertraline ((1S,4S)-stereochemistry, orange carbon atoms),
S-citalopram (yellow carbon atoms), (-)-16e (gray carbon atoms, stick representation), and (+)-12a (gray carbon atoms, ball-
and-stick representation). Pink spheres are acceptor site points used in fitting procedure. Nonpolar hydrogen atoms are omitted
for clarity. The artwork was generated with DS ViewerPro 5.0 (Accelrys, Inc., San Diego, CA, 2002).

Indole Cyclopropylmethylamines as SSRIs
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6027
porter (hDAT), and the human norepinephrine transporter
(hNET) were determined using literature methods.14,23 Com-
pounds with significant hSERT binding (Ki < 100 nM) were
investigated for hDAT and hNET binding, and the results are
given as percent inhibition of radioligand binding at 1 µM.
Percent inhibition at both hNET and hDAT was found to be
<50% at 1 µM for all active compounds (hSERT Ki < 100 nM)
listed in Table 1. For (+)-12a, Ki values were determined for
hNET and hDAT inhibition.
acceptor site point located 2.8 Å from the basic nitrogen
atom in these compounds, is very similar to that
previously employed in a pharmacophore model for
SERT ligands.24 For each molecule, the conformers
shown in Figure 5 may or may not be representative of
its bioactive conformation. However, Figure 5 does show
good correspondence between the positions of the basic
nitrogen atoms, the substituted aromatic rings, the ring
substituents, and the acceptor site points for all four
compounds. Furthermore, the energies of the conformers
shown are all predicted to be relatively low using a high
level of DFT with an implicit solvation model. This
suggests that the four compounds have the ability to
interact with hSERT in a similar manner.
Binding studies for 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3,
5-HT5A, 5-HT6, and 5-HT7 serotonergic receptors were per-
formed on (+)-12a at Cerep, Celle L’Evescalult, France, with
the results expressed as percent inhibition of radioligand
binding at 1 µM. Further receptor binding studies for 5-HT1A
25
and 5-HT6 were performed on (+)-12a within our labs to
generate Ki values for these receptors. In vivo microdialysis
and 5-HT1A binding studies were performed by published
methodology.26
Conclusions
Computational Procedures. Initial conformational
searches were done for the N-protonated forms of (+)-12a, (-)-
16e, S-citalopram, and sertraline ((1S,4S)-stereochemistry)
using MacroModel 8.6 (Schro¨dinger, LLC, Portland, OR,
2004).27 Each search was carried out using the torsional
sampling (MCMM) option. Default settings were used except
for the number of steps, which was set to 2500. Conformers
were minimized using the Polak-Ribiere conjugate gradient
(PRCG) algorithm,28 OPLS2001 force field,29 and GB/SA water
solvation model,30 with the maximum number of steps set to
10 000. A gradient convergence criterion of 0.05 was employed.
For each molecule, all unique conformers were then subjected
to density functional theory (DFT) geometry optimization at
the RB3LYP/6-31+G* level including a self-consistent reaction
field (SCRF) water solvation model.31,32 DFT calculations were
performed with Jaguar 5.5 (Schro¨dinger, LLC, Portland, OR,
2003). Fine grid density and ultrafine accuracy level settings
were used. For the four molecules, each unique conformer
within 2.0 kcal/mol of the lowest energy conformer identified
was kept for further analysis. There were 18, 6, 10, and 9
conformers retained for (+)-12a, (-)-16e, citalopram, and
sertraline, respectively.
Pairwise rms fitting of each conformer of sertraline to all
conformers of (+)-12a, (-)-16e, and S-citalopram was per-
formed using SYBYL 6.9.2 (Tripos Inc., 1699 South Hanley
Road, St. Louis, MO, 63144) and a SYBYL Programming
Language (SPL) script written in-house that employs the “FIT”
function. Comparison of sertraline conformers to those of
S-citalopram was done using four points per molecule corre-
sponding to the centroids of both aromatic rings, the basic
nitrogen atom, and an acceptor site point located 2.8 Å from
the basic nitrogen atom along the N-H bond. The cyanophenyl
ring of S-citalopram was assumed to correspond to the di-
chlorophenyl ring in sertraline in the fitting procedure. Three
points per conformer were used in the fitting of sertraline to
(+)-12a and (-)-16e. These correspond to the centroids of the
substituted phenyl rings (the dichlorophenyl ring in sertraline),
the basic nitrogen atom, and an acceptor site point located 2.8
Å from the basic nitrogen atom along the N-H bond. Each
pairwise combination of a sertraline conformer with a con-
former of one of the other three compounds in which the rms
fit was less than or equal to 1.0 was retained for further
analysis. Models were generated from all remaining combina-
tions of sertraline/citalopram, sertraline/(+)-12a, and sertra-
line/(-)-16e conformers. Each model was scored on the basis
of the total relative energies of the conformers included in the
model. Figure 5 shows the first and second best scoring (lowest
overall energy) models. Only the conformation of sertraline
differs between the two models. The DFT energies of the
conformers of sertraline in Figure 5 are 1.3 and 1.4 kcal/mol
above the global minimum, respectively. The conformer of
S-citalopram shown in Figure 5 is 0.5 kcal/mol above the global
minimum. For both (+)-12a and (-)-16e, the conformers
shown are the lowest energy conformers found in the study.
The present work investigated a series of indole
cyclopropylmethylamines as conformationally restricted
homotryptamines with SSRI activity and determined
the preferred stereochemistry for binding of these
molecules to hSERT. Nitrile substituents at the 5 and
7 positions of the indole ring gave high affinity for
hSERT, and the preferred cyclopropane stereochemistry
was determined to be (1S,2S)-trans. The cis-cyclopro-
panes had 20- to 30-fold less affinity than the trans, and
the preferred cis-stereochemistry was (1R,2S)-cis. Sub-
stitution of the indole N-1 position with methyl or ethyl
groups gave a 10- to 30-fold decrease in affinity for
hSERT, suggesting either a hydrogen-bonding interac-
tion or limited steric tolerance in the region of the indole
nitrogen. Compound (+)-12a (BMS-505130) demon-
strated very potent hSERT binding (Ki ) 0.18 nM) in
vitro and was more than 1000-fold less potent at hDAT,
hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced
robust, dose-dependent increases in extracellular sero-
tonin in rat frontal cortex typical of an SSRI, and (+)-
12a was approximately 10-fold more potent than flu-
oxetine.
These conformationally restricted homotryptamines
are distinguished from other SSRIs, which have two
separated phenyl rings. In contrast, these homo-
tryptamines possess only one fused aromatic ring and
also feature an indole N-1 hydrogen that may provide
a site for an additional hydrogen-bonding interaction
with hSERT. The present studies add to the under-
standing of the SAR of the homotryptamine SSRIs and
the stereochemistry requirements of hSERT. Efforts
aimed at achieving even more potent homotryptamine
SSRIs will be reported in due course.
Experimental Section
Chemistry. NMRs were recorded on Bru¨ker Avance spec-
trometers. Elemental analyses were performed at Robertson
Microlit Laboratories, Madison, NJ, and were within (0.4 of
the calculated values. Exact mass determinations were made
using a Micromass LCT unit, and all samples were determined
using a TOF ESI (+) source. ORTEP drawings of the X-ray
crystal structures for 19a, (+)-12a‚HCl, and 22 are given in
Figures 1-3 with ellipsoids drawn at the 50% probability level
and H atoms arbitrarily scaled. Full crystallographic data for
these compounds have been deposited at the Cambridge
Crystallographic Data Center (CCDC reference numbers
268270, 268271, and 268272). Copies of the data can be
obtained free of charge via the Internet at http://www.
ccdc.cam.ac.uk.
Pharmacology. The binding affinities of these homo-
tryptamine analogues for hSERT, the human dopamine trans-
3-Formyl-1-(4-toluenesulfonyl)-1H-indole-5-carboni-
trile, 8a. POCl3 (10.9 mL, 117 mmol) was added dropwise over

6028 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Mattson et al.
30 min to anhydrous DMF (50 mL) that was maintained at
10-20 °C. The resulting mixture was stirred for 30 min and
then chilled to 0 °C. A solution of 5-cyanoindole (15 g, 106
mmol) in anhydrous DMF (30 mL) was added over 10 min.
The ice bath was removed, and the solution was warmed to
room temperature. After 2 h, a very thick paste resulted. The
off-white paste was carefully quenched with ice chips. An
aqueous solution of NaOH (2.12 g/100 mL H2O) was added.
After a mild exotherm, a clear yellow solution resulted. The
solution was poured into H2O (400 mL), and a fine solid was
immediately precipitated. The mixture was filtered through
a 600 mL glass fritted funnel of medium porosity. The yellow
filtrate was diluted with an equal volume of H2O and left to
stand for 16 h. The yellow precipitate was collected and dried
in vacuo to give (5-cyanoindol-3-yl)carboxaldehyde (13.6 g,
75%). 1H NMR (500 MHz, DMSO-d6) δ 12.58 (1H, br s), 10.00
(1H, s), 8.51 (1H, d, J ) 3.1 Hz), 8.46 (1H, d, J ) 0.6 Hz), 7.22
(1H, dd, J ) 8.6, 0.5 Hz), 7.64 (1H, dd, J ) 8.5, 1.6 Hz); MS
m/e 171 (M + H)+.
p-Tosyl chloride (15.2 g, 79.5 mmol) was added to a solution
of (5-cyanoindol-3-yl)carboxaldehyde (13.5 g, 79.5 mmol) and
triethylamine (12.2 mL, 87.5 mmol) in CH2Cl2 (250 mL). The
mixture was stirred for 24 h at room temperature. The solid
precipitate was collected, washed with EtOH, and dried in
vacuo to give 8a (16.85 g, 65%): mp 243 °C (dec); 1H NMR
(400 MHz, DMSO-d6) δ 10.09 (1H, s), 9.07 (1H, s), 8.49 (1H,
d, J ) 1.1 Hz), 8.16 (1H, dd, J ) 8.6, 0.3 Hz), 8.06 (2H, d, J )
8.5 Hz), 7.87 (1H, dd, J ) 8.7, 1.7), 7.48 (2H, d, J ) 8.1 Hz),
2.36 (3H, s); MS m/e 325 (M + H)+. Anal. (C17H12N2O3S) C, H,
N.
3-Formyl-1-(4-toluenesulfonyl)-1H-indole-7-carboni-
trile, 8b. 8b was prepared from 7-cyanoindole in a manner
similar to 8a (32%). 1H NMR (400 MHz, CDCl3) δ 10.15 (s,
1H), 8.61 (m, 1H), 8.53 (s, 1H), 7.99 (d, J ) 8.52 Hz, 2H), 7.73
(m, 1H), 7.45 (m, 1H), 7.37 (d, J ) 8.04 Hz, 1H), 2.43 (s, 3H);
MS (ESI) m/e 325.15 (M + H)+.
3-Formyl-1-(4-toluenesulfonyl)-1H-indole-6-carboni-
trile, 8c. 8c was prepared from (6-cyanoindol-3-yl)carboxal-
dehyde33 in a manner similar to 8a (88%). 1H NMR (400 MHz,
DMSO-d6) δ 10.1 (1H, s), 9.14 (1H, s), 8.46 (1H, s), 8.27 (1H,
d, J ) 8.2 Hz), 8.16 (2H, d, J ) 8.4 Hz), 7.81 (1H, dd, J ) 8.2,
1.3 Hz), 7.48 (2H, d, J ) 8.2 Hz), 2.36 (3H, s); MS m/e 323 (M
- H)-.
was warmed to room temperature and was stirred for 2 h.
After the mixture was cooled to 0 °C, 8a (16.8 g, 51.8 mmol)
was added. The resulting mixture was stirred at 0 °C for 1 h.
The reaction was quenched with aqueous HCl (0.1 N), and the
mixture was poured into H2O (250 mL). After it was made
acidic with HCl (1.0 N), the aqueous portion was extracted
with EtOAc (3 × 150 mL). The combined organic layers were
washed with brine (50 mL) and dried over anhydrous magne-
sium sulfate. The filtrate was concentrated in vacuo. The crude
product was purified by recrystallization from EtOAc to give
9a (19.1 g total; 12.5 g first crop, 6.58 g second crop; 91%) as
1
a white solid: mp 177-178 °C; H NMR (500 MHz, DMSO-
d6) δ 8.70 (1H, s), 8.47 (1H, s), 8.14 (1H, d, J ) 8.7 Hz), 7.98
(2H, d, J ) 8.4 Hz), 7.81 (1H, dd, J ) 8.7, 1.4 Hz), 7.72 (1H,
d, J ) 16.0 Hz), 7.44 (2H, d, J ) 8.2 Hz), 7.21 (1H, d, J ) 16.0
Hz), 3.77 (3H, s), 3.24 (3H, s), 2.34 (3H, s); MS m/e 410 (M +
H)+. Anal. (C21H19N3O4S) C, H, N.
trans-3-[7-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9b. 9b was prepared from
8b in a manner similar to 9a (88%). 1H NMR (400 MHz, CDCl3)
δ 8.18 (s, 1H), 8.06 (dd, J ) 1.16, 8.04 Hz, 1H), 7.95 (d, J )
8.48 Hz, 2H), 7.85 (dd, J ) 0.56, 16.00 Hz, 1H), 7.70 (dd, J )
1.00, 7.56 Hz, 1H), 7.39 (t, J ) 7.84 Hz, 1H), 7.34 (d, J ) 8.08
Hz, 2H), 7.12 (d, J ) 15.97 Hz, 1H), 3.82 (s, 3H), 3.34 (s, 3H),
2.41 (s, 3H); MS (ESI) m/e 410.13 (M + H)+.
trans-3-[6-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9c. 9c was prepared from
8c in a manner similar to 9a (77%). 1H NMR (300 MHz,
DMSO-d6) δ 8.77 (1H, s), 8.42 (1H, m), 8.07 (3H, dd, J ) 8.5,
2.4 Hz), 7.73 (2H, m), 7.45 (2H, d, J ) 8.2 Hz), 7.20 (1H, d, J
) 16 Hz), 3.77 (3H, s), 3.23 (3H, s), 2.34 (3H, s); MS m/e 408
(M - H)-. Anal. (C21H19N3O4S) C, H, N.
trans-3-[4-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9d. 9d was prepared from
8d in a manner similar to 9a (85%). 1H NMR (400 MHz,
CDCl3) δ 8.22-8.28 (m, 2H), 8.03 (s, 1H), 7.79 (dd, J ) 1.68,
6.76 Hz, 2H), 7.63 (dd, J ) 0.88, 7.56 Hz, 1H), 7.41 (dd, J )
7.72, 8.32 Hz, 1H), 7.29 (d, J ) 8.04 Hz, 2H), 7.07 (d, J ) 15.73
Hz, 1H), 3.80 (s, 3H), 3.32 (s, 3H), 2.38 (s, 3H); MS (ESI) m/e
410.14 (M + H)+.
trans-3-[5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9e. 9e was prepared from
8e in a manner similar to 9a (88%): mp 199-200 °C (dec); 1H
NMR (400 MHz, DMSO-d6) δ 8.56 (1H, s), 7.99 (1H, m), 7.93
(2H, d, J ) 8.4 Hz), 7.68 (2H, m), 7.42 (2H, d, J ) 8.1 Hz),
7.28 (1H, t, J ) 9.2 Hz), 7.12 (1H, d, J ) 16 Hz), 3.77 (3H, s),
3.22 (3H, s), 2.33 (3H, s); MS m/e 403 (M + H)+. Anal. (C20H19-
FN2O4S) C, H, N.
trans-3-[7-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9f. 9f was prepared from
8f in a manner similar to 9a (53%). 1H NMR (300 MHz, CDCl3)
δ 8.08 (1H, s), 7.84 (3H, m), 7.57 (1H, d, J ) 7.5 Hz), 7.29 (2H,
d, J ) 6.1 Hz), 7.23 (1H, m), 7.10 (1H, d, J ) 16.0 Hz), 7.02
(1H, m), 3.80 (3H, s), 3.33 (3H, s), 2.39 (3H, s); MS m/e 403.07
(M + H)+.
trans-3-[6-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9g. 9g was prepared from
8g in a manner similar to 9a (48%). 1H NMR (300 MHz, CDCl3)
δ 7.83-7.68 (6H, m), 7.28 (1H, s), 7.04 (2H), 3.79 (3H, s), 3.32
(3H, s), 2.37 (3H, s); MS m/e 403.09 (M + H)+.
trans-3-[4-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methylacrylamide, 9h. 9h was prepared
from 8h in a manner similar to 9a (59%). 1H NMR (300 MHz,
CDCl3) δ 7.84 (1H, s), 7.78 (2H, m), 7.28 (3H, m), 7.15 (1H, d,
J ) 15.9 Hz), 6.96 (1H, m), 3.78 (3H, s), 3.31 (3H, s), 2.36 (3H,
s); MS m/e 403.11 (M + H)+.
3-Formyl-1-(4-toluenesulfonyl)-1H-indole-4-carboni-
trile, 8d. 8d was prepared from 3-formyl-1H-indole-4-carbo-
nitrile34 in a manner similar to 8a (86%). 1H NMR (400 MHz,
CDCl3) δ 10.57 (s, 1H), 8.46 (s, 1H), 8.28 (dd, J ) 0.88, 8.52
Hz, 1H), 7.83-7.86 (m, 2H), 7.73 (dd, J ) 0.84, 7.60 Hz, 1H),
7.49 (dd, J ) 7.68, 8.44 Hz, 1H), 7.33 (d, J ) 8.04 Hz, 2H),
2.40 (s, 3H); MS (ESI) m/e 325.15 (M + H)+.
[7-Fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxalde-
hyde, 8f. 8f was prepared from 7-fluoroindole in a manner
1
similar to 8a (79%). H NMR (300 MHz, CDCl3) δ 10.13 (1H,
s), 8.43 (1H, s), 8.08 (1H, dd, J ) 0.6, 5.5 Hz), 7.89 (2H, dd, J
) 0.5 Hz, 5.7 Hz), 7.33 (2H, d, J ) 6.0 Hz), 7.27 (1H, m), 7.07
(1H, m), 2.42 (3H, s); MS m/e 318.20 (M + H)+.
[6-Fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxalde-
hyde, 8g. 8g was prepared from (6-fluoroindol-3-yl)carboxal-
dehyde35 in a manner similar to 8a (60%). 1H NMR (300 MHz,
CDCl3) δ 10.26 (1H, d, J ) 2.1 Hz), 8.20 (2H, m), 7.85 (2H, d,
8.4 Hz), 7.66 (1H, dd, J ) 7.1, 2.3 Hz), 7.34 (2H, d, J ) 8.20
Hz), 7.12 (1H, m), 2.40 (3H, s); MS m/e 318.20 (M + H)+.
[4-Fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxalde-
hyde, 8h. 8h was prepared from (4-fluoroindol-3-yl)carboxal-
dehyde36 in a manner similar to 8a (57%). 1H NMR (300 MHz,
CDCl3) δ 10.06 (1H, s), 8.29 (1H, s), 7.82 (3H, m), 7.33 (3H,
m), 7.07 (2H, dd, J ) 8.2, 1.9 Hz), 2.39 (3H, s); MS m/e 318.16
(M + H)+.
trans-3-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
N-methoxy-N-methyl-acrylamide, 9a. A solution of diethyl
(N-methoxy-N-methylcarbamoylmethyl)phosphonate (12.81 mL,
14.85 g, 62.1 mmol) in anhydrous THF (50 mL) was added to
a stirred suspension of oil-free NaH (1.49 g, 62.1 mmol) in
anhydrous THF (900 mL) maintained at 0 °C. The mixture
trans-2-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10a.
The following procedure was carried out behind a safety shield
using plastic-coated glassware free of scratches and ground
glass joints. 1-Methyl-3-nitro-1-nitrosoguanidine (14.4 g, 98
mmol) was carefully added portionwise over 30 min to an
Erlenmeyer flask containing a swirled mixture of aqueous
NaOH (100 mL, 5 N) and diethyl ether (250 mL) at 0°C. After

Indole Cyclopropylmethylamines as SSRIs
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6029
vigorous bubbling had ceased, the organic layer (containing
diazomethane) was decanted into a chilled (0 °C) Erlenmeyer
flask containing KOH chips (20 g). The mixture was swirled
for 10 min, and the yellow solution was decanted into a
dropping funnel. The solution of diazomethane was added over
30 min to an open flask containing a stirred mixture of 9a
(8.0 g, 19.6 mmol) and palladium acetate (132 mg, 0.58 mmol)
in CH2Cl2 (200 mL) maintained at 0 °C. After the mixture was
stirred for 1 h, a second batch of freshly prepared diaz-
omethane (98 mmol) in ∼250 mL of diethyl ether was added
over 30 min. After the mixture was stirred for 1 h, the reaction
was quenched with AcOH (4 mL) and the mixture was poured
into an aqueous saturated solution of NaHCO3 (250 mL). The
aqueous layer was extracted with EtOAc (3 × 100 mL). The
organic layers were washed with brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo. The crude
product was triturated with EtOAc (150 mL) and cooled with
vigorous stirring to 0 °C for 1 h. The product was collected by
vacuum filtration and rinsed with cold EtOAc (25 mL). The
white solid was dried under vacuum to afford 4.46 g (54%) of
10a. An analytical sample was obtained by recrystallization
from EtOAc/hexane: mp 174-175 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.23 (1H, d, J ) 1.1 Hz), 8.07 (1H, d, J ) 8.6 Hz),
7.91 (2H, d, J ) 8.4 Hz), 7.86 (1H, s), 7.75 (1H, dd, J ) 8.6,
1.5 Hz), 7.40 (2H, d, J ) 8.2 Hz), 3.64 (3H, s), 3.16 (3H, s),
2.43 (2H, m), 2.33 (3H, s), 1.43 (2H, m); MS m/e 424 (M + H)+.
Anal. (C22H21N3O4S) C, H, N.
trans-2-[7-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl)-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10b.
10b was prepared from 9b in a manner similar to 10a (71%).
1H NMR (400 MHz, CDCl3) δ 7.88-7.92 (m, 3H), 7.65 (dd, J
) 1.08, 7.56 Hz, 1H), 7.55 (d, J ) 0.96 Hz, 1H), 7.26-7.34 (m,
3H), 3.73 (s, 3H), 3.27 (s, 3H), 2.52 (m, 1H), 2.39 (s, 3H), 1.63-
1.66 (m, 2H), 1.2-1.33 (m, 1H); MS (ESI) m/e 424.15 (M +
H)+.
trans-2-[6-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10c.
10c was prepared from 9c in a manner similar to 10a (64%).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (1H, d, J ) 1.0 Hz), 7.98
(3H, m), 7.83 (1H, m), 7.67 (1H, dd, J ) 8.2, 1.3 Hz), 7.41 (2H,
d, J ) 8.1 Hz), 3.63 (3H, s), 3.15 (3H, s), 2.40 (2H, m), 2.33
(3H, s), 1.45 (2H, m); MS m/e 422 (M - H)-. Anal. (C22H21N3O4S)
C, H, N.
trans-2-[4-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10h.
10h was prepared from 9h in a manner similar to 10a (98%).
1H NMR (300 MHz, CDCl3) δ 7.74 (3H, m), 7.23 (4H, m), 6.89
(1H, dd, J ) 8.0, 10.0 Hz), 3.70 (3H, s), 3.26 (3H, s), 2.47 (2H,
m), 2.36 (3H, s), 1.60 (1H, m), 1.29 (1H, m); MS m/e 417.11 (M
+ H)+.
trans-2-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11a. Powdered LAH (1.79
g, 47.3 mmol) was carefully added portionwise to a stirred
solution of 10a (4.0 g, 9.45 mmol) in anhydrous THF (250 mL)
at -40 °C. The resulting mixture was stirred at -40 °C for 2
h. The reaction was quenched with EtOAc (25 mL), and the
mixture was warmed to room temperature. After 30 min, H2O
(1.79 mL) was added followed by a solution of aqueous NaOH
(15% w/v, 3.58 mL). After the mixture was stirred for 30 min
at room temperature, the aluminum salts were removed by
vacuum filtration. The salts were rinsed with EtOAc (100 mL),
and the combined filtrates were concentrated in vacuo. The
crude material was purified by silica gel chromatography using
hexane/EtOAc (4:1 to 3:1) as the eluent to give 11a (2.86 g,
74%) as a white solid. An analytical sample was obtained by
recrystallization from EtOAc/hexane: mp 165-167 °C; 1H
NMR (400 MHz, DMSO-d6) δ 9.08 (1H, d, J ) 5.5 Hz), 8.32
(1H, d, J ) 1.1 Hz), 8.06 (1H, d, J ) 8.6 Hz), 7.90 (2H, d, J )
8.6 Hz), 7.89 (1H, s), 7.75 (1H, dd, J ) 8.6, 1.5 Hz), 7.40 (2H,
d, J ) 8.2 Hz), 2.77 (1H, m), 2.33 (3H, s), 2.13 (1H, m), 1.74
(2H, m); MS m/e 363 (M - H)-. Anal. (C20H16N2O3S) C, H, N.
trans-2-[7-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11b. 11b was prepared from
10b in a manner similar to 11a (80%). 1H NMR (400 MHz,
CDCl3) δ 9.51 (d, J ) 4.12 Hz, 1H), 7.91 (d, J ) 8.44 Hz, 2H),
7.82 (dd, J ) 1.20, 7.92 Hz, 1H), 7.68 (dd, J ) 1.04, 7.60 Hz,
1H), 7.60 (d, J ) 1.04 Hz, 1H), 7.30-7.35 (m, 3H), 2.62 (m,
1H), 2.40 (s, 3H), 2.17-2.20 (m, 1H), 1.75-1.80 (m, 1H), 1.51-
1.55 (m, 1H).
trans-2-[6-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11c. 11c was prepared from
10c in a manner similar to 11a (37%). 1H NMR (400 MHz,
DMSO-d6) δ 9.11 (1H, d, J ) 5.5 Hz), 8.33 (1H, d, J ) 1.0 Hz),
7.99 (3H, m), 7.88 (1H, d, J ) 8.1 Hz), 7.69 (1H, dd, J ) 8.2,
1.4 Hz), 7.41 (2H, d, J ) 8.0 Hz), 2.76 (1H, m), 2.33 (3H, s),
2.14 (1H, m), 1.70 (2H, m); MS m/e 363 (M - H)-. Anal.
(C20H16N2O3S) C, H, N.
trans-2-[4-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11d. 11d was prepared from
10d in a manner similar to 11a (74%). 1H NMR (400 MHz,
CDCl3) δ 9.33 (d, J ) 4.92 Hz, 1H), 8.21 (dd, J ) 0.88, 8.48
Hz, 1H), 7.74 (dd, J ) 1.76, 6.68 Hz, 2H), 7.59 (dd, J ) 0.88,
7.56 Hz, 1H), 7.45 (d, J ) 1.20 Hz, 1H), 7.39 (dd, J ) 7.80,
8.32 Hz, 1H), 7.26-7.28 (m, 2H), 2.90-2.91 (m, 1H), 2.38 (s,
3H), 2.09-2.12 (m, 1H), 1.78-1.80 (m, 1H), 1.47-1.52 (m, 1H).
trans-2-[5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11e. 11e was prepared from
10e in a manner similar to 11a (76%). 1H NMR (400 MHz,
DMSO-d6) δ 9.08 (1H, d, J ) 5.6 Hz), 7.90 (1H, m), 7.84 (2H,
d, J ) 8.4 Hz), 7.75 (1H, s), 7.51 (1H, dd, J ) 9.1, 2.6 Hz),
7.38 (2H, d, J ) 8.1 Hz), 7.20 (1H, t, J ) 9.2 Hz), 2.69 (1H,
m), 2.32 (3H, s), 2.09 (1H, m), 1.68 (2H, m); MS m/e 358 (M +
H)+. Anal. (C19H16FNO3S) C, H, N.
trans-2-[4-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10d.
10d was prepared from 9d in a manner similar to 10a (78%).
1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J ) 0.40, 7.96 Hz, 1H),
7.76 (d, J ) 8.40 Hz, 2H), 7.57 (dd, J ) 0.44, 7.56 Hz, 1H),
7.44 (d, J ) 1.24 Hz, 1H), 7.37 (t, J ) 8.08 Hz, 1H), 3.73 (s,
3H), 3.27 (s, 3H), 2.72-2.74 (m, 1H), 2.36-2.38 (m, 4H), 1.68-
1.72 (m, 1H), 1.30-1.35 (m, 1H); MS (ESI) m/e 424.16 (M +
H)+.
trans-2-[5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10e.
10e was prepared from 9d in a manner similar to 10a (99%).
1H NMR (400 MHz, CDCl3) δ 7.89 (1H, m), 7.72 (2H, d, J )
8.4 Hz), 7.30 (1H, s), 7.23 (3H, m), 7.04 (1H, t, J ) 9.0 Hz),
3.71 (3H, s), 3.26 (3H, s), 2.40 (2H, m), 2.34 (3H, s), 1.59 (1H,
m), 1.25 (1H, m); MS m/e 417 (M + H)+.
trans-2-[7-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10f. 10f
trans-2-[7-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11f. 11f was prepared from
10f in a manner similar to 11a (52%). 1H NMR (300 MHz,
CDCl3) δ 9.48 (1H, d, J ) 4.3 Hz), 7.81 (2H, d, J ) 7.6 Hz),
7.51 (1H, d, J ) 0.9 Hz), 7.29 (4H, m), 7.16 (1H, m), 6.98 (1H,
dd, J ) 7.8, 12 Hz), 2.61 (1H, m), 2.37 (3H, s), 2.16 (1H, m),
1.76 (1H, m), 1.53 (1H, m); MS m/e 358.07 (M + H)+.
1
was prepared from 9d in a manner similar to 10a (87%). H
NMR (300 MHz, CDCl3) δ 7.81 (2H, d, J ) 7.7 Hz), 7.47 (1H,
d, J ) 0.9 Hz), 7.38 (1H, dd, J ) 7.9, 0.8 Hz), 7.27 (2H, m),
7.09 (1H, m), 6.89 (1H, m), 3.73 (3H, s), 3.27 (3H, s), 2.41 (2H,
m), 2.39 (3H, s), 1.60 (1H, m), 1.31 (1H, m); MS m/e 417.09 (M
+ H)+.
trans-2-[6-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10g.
10g was prepared from 9g in a manner similar to 10a (95%).
1H NMR (300 MHz, CDCl3) δ 7.83-7.66 (4H, m), 7.50 (1H,
dd, J ) 5.2, 8.6 Hz), 7.23 (2H, m), 6.99 (1H, m), 3.70 (3H, s),
3.25 (3H, s), 2.44 (2H, m), 2.35 (3H, s), 1.58 (m, 1H), 1.25 (1H,
m); MS m/e 417.09 (M + H)+.
trans-2-[6-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11g. 11g was prepared from
10g in a manner similar to 11a (59%). 1H NMR (300 MHz,
CDCl3) δ 9.43 (1H, d, J ) 4.4 Hz), 7.75 (2H, d, J ) 8.4 Hz),
7.69 (1H, dd, J ) 2.3, 9.7 Hz), 7.44 (1H, dd, J ) 8.7, 5.2 Hz),
7.27 (3H, m), 6.99 (1H, m), 2.56 (1H, m), 2.37 (3H, s), 2.13
(1H, m), 1.72 (1H, m), 1.48 (1H, m); MS m/e 358.08 (M + H)+.

6030 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Mattson et al.
trans-2-[4-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11h. 11h was prepared from
10h in a manner similar to 11a (59%). 1H NMR (300 MHz,
CDCl3) δ 9.34 (1H, d, J ) 4.7 Hz), 7.74 (3H, m), 7.24 (4H, m),
6.92 (1H, m), 2.78 (1H, m), 2.36 (3H, s), 2.10 (1H, m), 1.73
(1H, m), 1.47 (1H, m); MS m/e 358.10 (M + H)+.
CDCl3) δ 8.81 (brd s, 1H), 7.54 (dd, J ) 0.80, 8.20 Hz, 1H),
7.48 (dd, J ) 0.76, 7.36 Hz, 1H), 7.20 (t, J ) 7.84 Hz, 1H),
7.01 (dd, J ) 0.68, 2.32 Hz, 1H), 2.62 (m, 1H), 2.41 (m, 1H),
2.37 (s, 6H), 2.13 (m, 1H), 1.24 (m, 1H), 0.88 (m, 2H).
trans-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12e. 12e was prepared from
11e in a manner similar to 12a (68%). 1H NMR (400 MHz,
DMSO-d6) δ 10.8 (1H, br s), 7.29 (2H, m), 7.09 (1H, s), 6.90
(1H, t, J ) 9.2 Hz), 2.39 (1H, m), 2.19 (7 H, m), 1.69 (1H, m),
1.06 (1H, m), 0.85 (1H, m), 0.68 (1H, m).
trans-2-(7-Fluoro-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12f. 12f was prepared from 11f
in a manner similar to 12a (43%). 1H NMR (500 MHz, DMSO-
d6) δ 11.33 (s, 1H), 7.44 (d, J ) 7.5 Hz, 1H), 7.18 (d, J ) 2.5
Hz, 1H), 6.97 (m, 1H), 6.92 (m, 1H), 3.20 (br, 2H), 2.84 (s, 6H),
2.07 (m, 1H), 1.34 (m, 1H), 1.12 (m, 1H), and 0.99 (m, 1H).
trans-2-(6-Fluoro-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12g. 12g was prepared from
11g in a manner similar to 12a (33%). 1H NMR (500 MHz,
DMSO-d6) δ 10.94 (s, 1H), 7.61 (dd, J ) 12.5, 3.0 Hz, 1H), 7.10
(m, 1H), 7.07 (d, J ) 2.5 Hz, 1H), 6.88 (m, 1H), 3.05 (m, 2H),
3.00 (s, 6H), 2.02 (m, 1H), 1.20 (m, 1H), 1.02 (m, 1H), 0.95 (m,
1H).
trans-2-(4-Fluoro-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12h. 12h was prepared from
11h in a manner similar to 12a (67%). 1H NMR (500 MHz,
DMSO-d6) δ 11.16 (s, 1H), 7.16 (d, J ) 8.0 Hz, 1H), 7.12 (d, J
) 2.5 Hz, 1H), 7.03 (m, 1H), 6.73 (dd, J ) 19.0, 7.5 Hz, 1H),
3.17 (m, 1H), 3.12 (m, 1H), 2.81 (s, 6H), 2.14 (m, 1H), 1.32 (m,
1H), 1.04 (m, 1H), 0.99 (m, 1H).
trans-2-(5-Cyano-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12a. A mixture of 11a (2.0 g,
5.49 mmol), dimethylamine (8.2 mL, 16.5 mmol, 2.0 M/THF),
and anhydrous EtOH (70 mL) was heated to 80 °C with
stirring until all solids were dissolved (20 min). The reaction
vessel was removed from the heating source, and NaBH(OAc)3
was added. After the mixture was stirred for 30 min, the
reaction vessel was placed in an ice bath and the reaction was
quenched with aqueous HCl (40 mL, 1 N). The resulting
mixture was stirred for 20 min and then poured into a
saturated aqueous solution of NaHCO3 (100 mL) and brine
(50 mL). The aqueous layer was extracted with EtOAc (3 ×
100 mL). The combined organic extracts were washed with
brine (20 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The solid residue was dried
under vacuum for 24 h, and the crude product was taken on
without purification. A sample of trans-2-[5-cyano-1-(4-tolu-
enesulfonyl)-1H-indol-3-yl]-1-(N,N-dimethylaminomethyl)cy-
clopropane was purified by silica gel chromatography for
analytical purposes. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (1H,
d, J ) 1.0 Hz), 8.06 (1H, d, J ) 8.6 Hz), 7.89 (2H, d, J ) 8.4
Hz), 7.74 (1H, dd, J ) 8.6, 1.6 Hz), 7.67 (1H, s), 7.39 (2H, d, J
) 8.1 Hz), 2.32 (5 H, m), 2.21 (6 H, s), 1.83 (1H, m), 1.21 (1H,
m), 1.07 (1H, m), 0.80 (1H, m); MS m/e 394 (M + H)+.
Water (5 mL) and an aqueous solution of NaOH (2 mL, 10
N) were sequentially added to a flask charged with a solution
of the crude trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]-
1-(N,N-dimethylaminomethyl)cyclopropane dissolved in an-
hydrous EtOH (60 mL). The resulting mixture was heated at
70 °C for 45 min. After the mixture was cooled to room
temperature, the reaction was quenched with aqueous HCl (21
mL, 1 N) and the mixture was then poured into a mixture of
saturated aqueous NaHCO3 (100 mL) and brine (50 mL). The
aqueous layer was extracted with 10% MeOH/EtOAc (4 × 100
mL). The combined organic layers were washed with brine (25
mL), dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The crude material was purified by
chromatography using silica gel pretreated with 2% triethy-
lamine in chloroform/MeOH (9:1). The column was eluted
using a step gradient of a ternary solvent mixture (chloroform/
MeOH/NH4OH (2 M in MeOH); 90/10/0, 85/15/1, 80/20/1, 80/
20/2) to give 12a (1.2 g, 98%) as an off-white solid foam after
drying under vacuum. Recrystallization from EtOH/H2O pro-
vided 12a (934 mg total (583 mg first crop, 351 mg second
Methyl cis-3-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-
3-yl]acrylate, 13a. A solution of bis(2,2,2-trifluoroethyl)-
(methoxycarbonylmethyl)phosphonate (470 µL, 2.2 mmol) in
anhydrous THF (5 mL) was added to a stirred suspension of
oil-free sodium hydride (89 mg, 2.2 mmol) in anhydrous THF
(25 mL) maintained at 0 °C. The mixture was warmed to room
temperature and was stirred for 1.5 h. After the mixture was
cooled to 0 °C, 8a (600 mg, 1.85 mmol) was added. The
resulting mixture was stirred at room temperature for 5 h.
The solvent was evaporated, and the residue was taken up in
brine (20 mL) and extracted with EtOAc (3 × 10 mL). The
organic layers were dried with anhydrous magnesium sulfate,
and the solvent was removed in vacuo. The product was
purified by silica gel chromatography using EtOAc/hexane
1
(15%) as the eluent to give 13a (192 mg, 27%). H NMR (300
MHz, CDCl3) δ 9.08 (1H, s), 8.10 (1H, d, J ) 8.3 Hz), 7.92 (1H,
d, J ) 1.0 Hz), 7.86 (2H, d, J ) 8.4 Hz), 7.59 (1H, dd, J ) 8.6,
1.5 Hz), 7.29 (2H, d, J ) 8.1 Hz), 6.98 (1H, d, J ) 13.0 Hz),
6.08 (1H, d, J ) 12.6 Hz), 3.80 (3H, s), 2.37 (3H, s); MS m/e
395.1 (M + H)+.
1
crop), 77%): mp 120-121 °C; H NMR (400 MHz, DMSO-d6)
Methyl cis-3-(5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-
3-yl)acrylate, 13e. 13e was prepared from 8b in a manner
similar to 13a (30%). 1H NMR (400 MHz, CDCl3) δ 9.01 (s,
1H) 7.94 (dd, J ) 4.40, 9.04 Hz, 1H), 7.84 (dd, J ) 1.68, 6.68
Hz, 2H), 7.21-7.26 (m, 2H), 7.06 (dt, J ) 6.44, 9.00 Hz, 1H),
6.93 (dd, J ) 0.64, 12.60 Hz, 1H), 6.00 (d, J ) 12.60 Hz, 1H),
3.80 (s, 3H), 2.35 (s, 3H); MS (ESI) m/e 374.10 (M + H)+.
Methyl cis-2-(5-Cyano-1-(4-toluenesulfonyl)-1H-indol-
3-yl)cyclopropanecarboxylate, 14a. The following proce-
dure was carried out behind a safety shield using plastic-coated
glassware free of scratches and ground glass joints. 1-Methyl-
3-nitro-1-nitrosoguanidine (850 mg, 5.8 mmol) was carefully
added portionwise over 10 min to an Erlenmeyer flask
containing a swirled mixture of aqueous NaOH (100 mL, 5 N)
and diethyl ether (50 mL) at 0 °C. After vigorous bubbling had
ceased, the organic layer (containing diazomethane) was
decanted into a chilled (0 °C) Erlenmeyer flask containing
KOH chips (2 g). The mixture was swirled for 10 min, and the
yellow solution was decanted into a dropping funnel. The
solution of diazomethane was added over 10 min to an open
flask containing a stirred mixture of 13a (220 mg, 0.58 mmol)
and palladium acetate (7 mg, 0.029 mmol) in CH2Cl2 (50 mL)
maintained at 0 °C. After the mixture was stirred for 30 min,
the reaction was quenched with AcOH (2 mL) and poured into
δ 11.34 (1H, br s), 8.09 (1H, s), 7.47 (1H, d, J ) 8.4 Hz), 7.40
(1H, dd, J ) 8.4, 1.5 Hz), 7.23 (1H, d, J ) 2.0 Hz), 2.37 (2H,
m), 2.21 (6 H, s), 1.80 (1H, m), 1.09 (1H, m), 0.91 (1H, m),
0.73 (1H, m). Anal. (C15H17N3) C, H, N.
trans-2-(7-Cyano-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12b. 12b was prepared from
11b in a manner similar to 12a (56%) as a pale-yellow solid
that was recrystallized from ethyl/hexane as off-white
needles: mp 146 °C; 1H NMR (400 MHz, CDCl3) δ 8.76 (brd s,
1H), 7.92 (d, J ) 7.96 Hz, 1H), 7.50 (dd, J ) 0.84, 7.44 Hz,
1H), 7.15 (dd, J ) 7.56, 7.92 Hz, 1H), 6.99 (d, J ) 1.56 Hz,
1H), 2.51 (m, 1H), 2.35-2.40 (m, 7H), 1.78 (m, 1H), 1.26 (m,
1H), 0.90 (m, 1H), 0.84 (m, 1H).
trans-2-(6-Cyano-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12c. 12c was prepared from
11c in a manner similar to 12a (66%). 1H NMR (400 MHz,
DMSO-d6) δ 11.4 (1H, br s), 7.80 (1H, s), 7.74 (1H, d, J ) 8.5
Hz), 7.32 (2H, m), 2.39 (1H, m), 2.20 (7H, s), 1.76 (1H, m),
1.05 (1H, m), 0.90 (1H, m), 0.74 (1H, m). Anal. (C15H17N3‚
0.14H2O) C, H, N.
trans-2-(4-Cyano-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, 12d. 12d was prepared from
11d in a manner similar to 12a (65%). 1H NMR (400 MHz,

Indole Cyclopropylmethylamines as SSRIs
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6031
aqueous NaOH (0.5 N, 40 mL). The aqueous layer was
extracted with EtOAc (3 × 10 mL). The organic layers were
dried over anhydrous magnesium sulfate and concentrated in
vacuo. The product was purified by silica gel chromatography
using EtOAc/hexane (15%) as the eluent to give 14a (187 mg,
7.24 (dd, J ) 4.40, 8.84 Hz, 1H), 6.93 (m, 2H), 2.42 (m, 1H),
2.18 (s, 3H), 2.08 (m, 1H), 1.70 (dd, J ) 8.72, 12.56 Hz, 1H),
1.33 (m, 1H), 1.22 (m, 1H), 0.66 (m, 1H).
(+)-N-[(E)-3-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-
yl]-2-propenoyl]bornane-10,2-sultam, 18a. NaH (0.69 g of
60% in oil, 17.3 mmol) was washed with hexane (5 mL) and
then suspended in THF (500 mL) at 0 °C. (+)-Sultam, 17 (6.8
g, 17.3 mmol), in THF (50 mL) was then added over 10 min.
The mixture was stirred for 1 h at room temperature, then
cooled to 0 °C before adding 8a (4.67 mg, 14.4 mmol) in one
portion. The mixture was stirred for 24 h at room temperature,
and the solvent was removed in vacuo. The residue was
dissolved in H2O (100 mL) and was extracted with EtOAc (3
× 50 mL). The organic phase was dried over magnesium
sulfate for 16 h. The resulting crystals were collected by
filtration. The filtrate was evaporated, and the residue was
recrystallized from EtOAc/hexane to give a second crop of
crystals. (+)-18a (4.71 g, 58%) was collected as a white solid:
mp 203-205 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (1H, s),
8.09 (1H, d, J ) 8.8 Hz), 7.98 (1H, s), 7.81 (1H, d, J ) 15.7
Hz), 7.80 (2H, d, J ) 8.4 Hz), 7.62 (1H, dd, J ) 8.6, 1.4 Hz),
7.29 (2H, d, J ) 8.1 Hz), 7.25 (1H, d, J ) 15.6 Hz), 3.99 (1H,
dd, J ) 7.4, 5.2 Hz), 3.53 (2H, AB, ∆ν ) 32 Hz, J ) 13.8 Hz),
2.38 (3H, s), 2.25-2.12 (2H, m), 2.01-1.87 (3H, m), 1.48-1.32
(2H, m), 11.21 (3H, s), 1.00 (3H, s); MS m/e 564.3 (M + H)+.
(+)-N-[(E)-3-[5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-
3-yl]-2-propenoyl]bornane-10,2-sultam, 18e. 18e was pre-
pared from 8e in a manner similar to 18a (62%). 1H NMR (400
MHz, CDCl3) δ 7.94 (1H, dd, J ) 9.1, 4.4 Hz), 7.90 (1H,s), 7.85
(1H, d, J ) 15.6 Hz), 7.76 (2H, d, J ) 8.4 Hz), 7.50 (1H, dd, J
) 9.0, 2.4 Hz), 7.26 (2H, d, J ) 8.1 Hz), 7.21 (1H, d, J ) 15.6
Hz), 7.10 (1H, td, J ) 8.9, 2.4 Hz), 3.99 (1H, dd, J ) 7.5, 5.1
Hz), 3.51 (2H, AB, ∆ν ) 28 Hz, J ) 13.7 Hz), 2.36 (3H, s),
2.26-2.10 (2H, m), 1.97-1.87 (3 H, m), 1.49-1.32 (2H, m),
1.21 (3H, s), 1.00 (3H, s); MS m/e 557.3 (M + H)+.
N-[(1S,2S)-trans-2-[5-Cyano-1-(4-toluenesulfonyl)indol-
3-yl]cycloprop-1-yl]carbonylbornane-10,2-sultam, 19a.
The following reaction was performed behind a blast shield
using glassware without ground glass joints. A solution of
diazomethane in ether was prepared by slowly adding 1-meth-
yl-3-nitro-1-nitrosoguanidine (13.3 g, 90 mmol) to a mixture
of diethyl ether (200 mL) and 5 N NaOH (200 mL) at 0 °C
and then decanting the ether layer. The ether layer was dried
with KOH and transferred to a dropping funnel. This ethereal
diazomethane solution was then added dropwise over 30 min
to a solution of 18a (5.1 g, 9.0 mmol) and palladium(II) acetate
(100 mg, 0.45 mmol) in CH2Cl2 (200 mL) at a temperature of
-10 °C. The mixture was stirred a further 20 min with the
temperature maintained below -5 °C, and the reaction was
then quenched by the addition of AcOH (6 mL). To the mixture
1 N NaOH (10 mL) was added, and the layers were separated.
The aqueous layer was extracted with EtOAc (2 × 30 mL),
and the combined organic layers were dried with magnesium
sulfate and evaporated to dryness. The crude product was
purified by chromatography on silica gel using EtOAc/hexane
(20%) to give 19a (3.23 g, 62%) as a white solid. This material
was recrystallized from boiling EtOH (350 mL) to give white
crystals (1.18 g). The mother liquor was evaporated and
recrystallized from boiling EtOH (100 mL) to provide a second
crop of 19a (total amount 1.22 g, white solid, 46%): mp 188-
190 °C; 1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J ) 8.6 Hz),
7.99 (1H, d, J ) 1.0 Hz), 7.75 (2H, d, J ) 8.4 Hz), 7.57 (1H, d,
J ) 1.2 Hz), 7.54 (1H, dd, J ) 8.6, 1.5 Hz), 7.25 (2H, m), 3.96
(1H, dd, J ) 7.4, 5.1 Hz), 3.53 (2H, AB, ∆ν ) 18 Hz, J ) 13.8
Hz), 2.57 (1H, dt, J ) 7.7, 4.8 Hz), 2.45 (1H, m), 2.36 (3H, s),
2.16-2.04 (2H, m), 2.00-1.87 (3 H, m), 1.81 (1H, dt, J ) 9.1,
4.3 Hz), 1.55 (3H, s), 1.50-1.32 (2H, m), 1.29 (1H, m), 1.21
(3H, s), 1.00 (3H, s); MS m/e 578.2 (M + H)+. The crystals for
X-ray crystallography were developed by slow evaporation
from MeCN/i-PrOH/H2O and collected.
1
82%). H NMR (400 MHz, CDCl3) δ 7.98 (1H, d, J ) 8.7 Hz),
7.89 (1H, s), 7.73 (2H, d, J ) 6.7 Hz), 7.52 (2H, m), 7.24 (2H,
d, J ) 8.0 Hz), 3.34 (3H, s), 2.38 (1H, m), 2.34 (3H, s), 2.22
(1H, m), 1.61 (1H, m), 1.25 (1H, m); MS m/e 473.2 (M + H)+.
Methyl cis-2-(5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-
3-yl)cyclopropanecarboxylate, 14e. 14e was prepared from
13e in a manner similar to 14a (73%). 1H NMR (400 MHz,
CDCl3) δ 7.84 (dd, J ) 4.36, 9.04 Hz, 1H), 7.70 (dd, J ) 1.76,
6.64 Hz, 2H), 7.42 (d, J ) 1.04 Hz, 1H), 7.17-7.21 (m, 3H),
6.98 (dt, J ) 2.56, 9.04 Hz, 1H), 3.32 (s, 3H), 2.32-2.36 (m,
4H), 2.15-2.19 (m, 1H), 1.58-1.63 (m, 1H), 1.41-1.45 (m, 1H);
MS (ESI) m/e 410 (M + Na)+.
cis-2-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl)-
cyclopropanecarboxaldehyde, 15a. Powdered LAH (120
mg, 3.16 mmol) was carefully added to a stirred solution of
14a (185 mg, 0.47 mmol) in anhydrous THF (10 mL) at -30
°C. The resulting mixture was stirred at -20 °C for 1.5 h. The
reaction was quenched with EtOAc (5 mL), and the mixture
was warmed to room temperature. After 10 min, H2O (120 µL)
was added and after 5 min followed by a solution of aqueous
NaOH (1 N, 360 µL). After a further 5 min, H2O (120 µL) was
added and the solution was stirred 20 min. The aluminum
salts were removed by vacuum filtration. The salts were rinsed
with EtOAc (100 mL), and the combined filtrates were
concentrated in vacuo. The crude material was purified by
silica gel chromatography using EtOAc/hexane (45%) to give
cis-2-[5-cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]cyclo-
propanemethanol (131 mg, 76%) as a white solid. 1H NMR (400
MHz, CDCl3) δ 8.04 (1H, d, J ) 8.6 Hz), 7.99 (1H, d, J ) 1.0
Hz), 7.74 (2H, d, J ) 6.8 Hz), 7.57 (1H, dd, J ) 8.6, 1.6 Hz),
7.44 (1H, d, J ) 1.3 Hz), 7.26 (2H, d, J ) 8.2 Hz), 3.50 (1H,
m), 3.16 (1H, m), 2.36 (3H, s), 2.05 (1H, m), 1.60 (1H, m), 1.19
(1H, m), 0.99 (1H, t, J ) 5.5 Hz), 0.72 (1H, q, J ) 5.6 Hz); MS
m/e 349 (M - OH)+.
To a -78 °C solution of oxalyl chloride (52 µL, 0.60 mmol)
in CH2Cl2 (20 mL) was added DMSO (50 µL, 0.70 mmol)
dropwise. After the mixture was stirred for 10 min, a solution
of cis-2-[5-cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]cyclopro-
panemethanol (129 mg, 0.35 mmol) in CH2Cl2 (5 mL) was
added dropwise. After the mixture was stirred for 20 min at
-78 °C, triethylamine (294 µL, 2.10 mmol) was added drop-
wise. The mixture was stirred for 5 min at -78 °C and then
warmed to room temperature. The mixture was washed with
H2O (2 × 5 mL) and dried with anhydrous magnesium sulfate,
and the solvent was evaporated to give 15a, which was taken
on without purification.
cis-2-(5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl)-
cyclopropanecarboxaldehyde, 15e. 15e was prepared from
14b in a manner similar to 15a via the intermediate cis-(2-
(5-fluoro-1-tosyl-1H-indol-3-yl)cyclopropyl)methanol (64%). 1H
NMR (400 MHz, CDCl3) δ 7.90 (dd, J ) 4.36, 9.04 Hz, 1H),
7.70 (dd, J ) 1.68, 6.68 Hz, 2H), 7.32 (d, J ) 1.16 Hz, 1H),
7.21-7.28 (m, 3H), 7.04 (dt, J ) 2.52, 9.00 Hz, 1H), 3.45-
3.47 (m, 1H), 3.13 (t, J ) 9.80 Hz, 1H), 2.34 (s, 3H), 1.98-
2.05 (m, 1H), 1.54-1.60 (m, 1H), 1.11-1.16 (m, 1H), 0.92-
0.95 (m, 1H), 0.70 (dd, J ) 5.64, 11.00 Hz, 1H); MS (ESI) m/e
342.14 (M - OH)+. Subsequent Swern oxidation gave 15e,
which was taken on without purification.
cis-2-(5-Cyano-1H-indol-3-yl)-1-(N,N-dimethylamino-
methyl)cyclopropane, 16a. 16a was prepared from 15a in
a manner similar to 12a (75% over three steps). 1H NMR (400
MHz, CDCl3) δ 8.47 (1H, br s), 8.07 (1H, s), 7.41 (2H, apparent
q, J ) 8.0 Hz), 7.03 (1H, s), 2.37 (1H, dd, J ) 12.6, 4.7 Hz),
2.18 (6 H, s), 1.97 (1H, m), 1.69 (1H, dd, J ) 12.6, 8.6 Hz),
1.34 (1H, m), 1.22 (1H, m), 0.71 (1H, q, J ) 5.0 Hz).
cis-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-dimethylamino-
methyl)cyclopropane, 16e. 16e was prepared from 15e in
a manner similar to 12a (77% over three steps). 1H NMR (400
MHz, CDCl3) δ 8.31 (s, 1H), 7.34 (d J ) 2.52, 9.56 Hz, 1H),
N-[(1S,2S)-trans-2-[5-Fluoro-1-(4-toluenesulfonyl)indol-
3-yl]cycloprop-1-yl]carbonylbornane-10,2-sultam, 19e. 19e
was prepared from 18e in a manner similar to 19a (56%) as a
1
white solid. H NMR (400 MHz, CDCl3) δ 7.87 (dd, J ) 9.1,

6032 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Mattson et al.
4.4 Hz, 1H), 7.72 (d, J ) 8.3 Hz, 2H), 7.49 (s, 1H), 7.27 (m,
1H), 7.21 (d, J ) 8.2 Hz, 2H), 7.01 (td, J ) 9.0, 2.5 Hz, 1H),
3.94 (dd, J ) 7.6, 5.0 Hz, 1H), 3.51 (AB, ∆ν ) 21.6 Hz, J )
13.8 Hz, 2H), 2.57 (m, 1H), 2.43 (m, 1H), 2.34 (s, 3H), 1.82-
2.17 (m, 4H), 1.76 (p, J ) 4.5 Hz, 1H), 1.23-1.60 (m, 4H), 1.22
(s, 3H), 0.99 (s, 3H).
that solidified on standing (590 mg, 77% over three steps from
alcohol): [RD] +17.5° (c 2.92 mg/mL, EtOH); 1H NMR (400
MHz, CDCl3) δ 8.82 (1H, brs), 8.04 (1H, s), 7.38 (1H, dd, J )
7.2, 1.4 Hz), 7.34 (1H, dd, 7.2, 0.5 Hz), 6.96 (1H, d, J ) 1.6
Hz), 2.49 (1H, dd, J ) 12.4, 6.4 Hz), 2.37 (1H, dd, J ) 12.4,
7.0 Hz), 2.37 (6 H, s), 1.76 (1H, m), 1.23 (1H, m), 0.90 (1H, m),
0.84 (1H, m). The free base was converted to the HCl salt, and
crystals for X-ray were developed by slow evaporation from
EtOH/MIBK and collected.
(1S,2S)-trans-2-[5-Cyano-1-(4-toluenesulfonyl)-1H-in-
dol-3-yl]cyclopropanecarboxaldehyde, (1S,2S)-11a. A so-
lution of 19a (2.30 g, 3.98 mmol) in THF (100 mL) was cooled
to -40 °C (dry ice/MeCN). LAH (600 mg, 15.9 mmol) was
added, with a further addition (600 mg) after 1 h (reaction
temperature maintained at -40 °C throughout). After a total
reaction time of 1.5 h, EtOAc (50 mL) was added and the
mixture was warmed to room temperature. Water (1.2 mL)
was added, and after 10 min 1 N NaOH (3.6 mL) was added.
After another 5 min, more H2O (1.2 mL) was added, and the
mixture was stirred for a final 15 min. Magnesium sulfate was
added, and the mixture was filtered through Celite and sand
and rinsed with EtOAc. The filtrate was evaporated in vacuo.
The crude material was partially purified on a short pad of
silica by elution with EtOAc/hexane (50%) to give (1S,2S)-
trans-2-[5-cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]cyclopro-
panemethanol as a white solid (1.18 mg, 81%): mp 140-141
°C; 1H NMR (400 MHz, CDCl3) δ 8.03 (1H, dd, J ) 8.6, 0.6
Hz), 8.00 (1H, d, J ) 1.5 Hz), 7.74 (2H, d, J ) 8.6 Hz), 7.55
(1H, dd, J ) 8.6, 1.5 Hz), 7.33 (1H, d, J ) 1.0 Hz), 7.26 (2H,
d, J ) 8.5 Hz), 3.77 (1H, m), 3.60 (1H, m), 2.37 (3H, s), 1.77
(1H, m), 1.37 (1H, m), 0.95 (2H, t, J ) 7.0 Hz); MS m/e 349.1
(M - OH)+.
(1S,2S)-trans-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-di-
methylaminomethyl)cyclopropane, (+)-12e. 12e was pre-
pared from (1S,2S)-11e in a manner similar to (1S,2S)-12a
via the intermediate (1S,2S)-trans-1-(N,N-dimethylaminom-
ethyl)-2-[5-fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]cyclopro-
1
pane. H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J ) 9.0, 4.4
Hz), 7.73 (2H, d, J ) 8.4 Hz), 7.32-7.27 (2H, m), 7.23 (2H, d,
J ) 8.1 Hz), 7.06 (1H, td, J ) 9.1, 2.5 Hz), 3.16 (1H, dd, J )
11.1, 6.5 Hz), 2.96 (1H, dd, J ) 11.2, 7.3 Hz), 2.82 (3H, s),
2.08 (6 H, s), 2.03 (1H, m), 1.44 (1H, m), 1.18 (2H, t, J ) 7.2
Hz); MS m/e 387.4 (M + H)+. Subsequent hydrolysis of the
indole N-1 tosyl group gave (1S,2S)-12e as a clear oil that
solidified on standing (71% over four steps from the sultam):
mp 88-90 °C; [RD] +51.4° (c 2.45 mg/mL, EtOH); 1H NMR (400
MHz, CDCl3) δ 8.05 (1H, brs), 7.33 (1H, dd, J ) 9.6, 2.5 Hz),
7.24 (1H, dd, J ) 8.8, 4.4 Hz), 6.98-6.88 (2H, m), 2.45 (1H,
dd, J ) 11.0, 6.5 Hz), 2.37 (1H, dd, J ) 11.1, 6.8 Hz), 2.35 (6
H, s), 1.68 (1H, m), 1.21 (1H, m), 0.87 (1H, m), 0.76 (1H, m).
The crystals for X-ray crystallography were developed by slow
evaporation from EtOH/hexane and collected.
Oxalyl chloride (0.42 mL, 4.8 mmol) in CH2Cl2 (50 mL) at
-78 °C was treated with DMSO (0.39 mL, 5.4 mmol) dropwise.
After addition, the mixture was stirred for 15 min and a
solution of (1S,2S)-trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-
3-yl]cyclopropanemethanol (1.17 g, 3.2 mmol) in CH2Cl2 (10
mL) was added dropwise. After a further 15 min, triethylamine
(2.45 mL, 17.6 mmol) was added dropwise. The mixture was
stirred a further 5 min at -78 °C and was then warmed to
room temperature. The mixture was washed twice with H2O
(10 mL), dried with MgSO4, and evaporated to dryness to give
(1S,2S)-11a as a yellow oil that was taken on without purifica-
tion.
(1S,2S)-trans-2-[5-Fluoro-1-(4-toluenesulfonyl)-1H-in-
dol-3-yl]cyclopropanecarboxaldehyde, (1S,2S)-11e. 11e
was prepared from 18e in a manner similar to (1S,2S)-11a
via the intermediate (1S,2S)-trans-2-[5-fluoro-1-(p-toluene-
sulfonyl)indol-3-yl]cyclopropanemethanol (100%). 1H NMR
(400 MHz, CDCl3) δ 7.89 (1H, dd, J ) 9.0, 4.4 Hz), 7.70 (2H,
d, J ) 8.4 Hz), 7.30-7.20 (4H, m), 7.03 (1H, td, J ) 9.0, 2.6
Hz), 3.73 (1H, dd, J ) 11.2, 6.4 Hz), 3.59 (1H, dd, J ) 11.2,
7.2 Hz), 2.34 (3H, s), 1.72 (1H, dt, J ) 9.6, 5.3 Hz), 1.34 (1H,
m), 0.96-0.86 (2H, m); MS m/e 360.1 (M + H)+. Subsequent
Swern oxidation gave (1S,2S)-11e that was taken on without
purification.
(1S,2S)-trans-2-(5-Cyano-1H-indol-3-yl)-1-(N,N-dime-
thylaminomethyl)cyclopropane, (+)-12a. The crude (1S,2S)-
11a was dissolved in hot EtOH (50 mL) and treated with
dimethylamine (3.2 mL, 2 M solution in THF, 6.4 mmol). After
the mixture was stirred for 5 min, NaBH(OAc)3 (2.71 g, 12.8
mmol) was added in several portions over 10 min while the
mixture was cooled in a 10 °C H2O bath. After being stirred
for 45 min at room temperature, the mixture was concentrated
in vacuo, the residue was taken up in brine (10 mL), and 1 N
NaOH was added until a solution was achieved. The sample
was extracted with EtOAc (4 × 10 mL), and the organic layer
was dried with magnesium sulfate and evaporated to give (+)-
12a as a yellow oil. A solution of this material in EtOH (25
mL), H2O (4 mL), and NaOH (2 mL, 10 N, 20 mmol) was
heated to 70 °C for 1 h. The mixture was cooled to room
temperature, poured into brine (100 mL), and extracted twice
with EtOAc (50 mL) and three times with EtOAc/MeOH (9:1,
50 mL). The organic layer was dried with magnesium sulfate
and concentrated in vacuo. The residue was purified by silica
gel chromatography using chloroform/MeOH/NH4OH (2 M
MeOH) (90:10:1) as the eluent to give (+)-12a as a yellow oil
Preparative Chiral HPLC Resolution of trans-2-(5-
Cyano-1H-indol-3-yl)-1-(N,N-dimethylaminomethyl)cy-
clopropane, 12a. The enantiomers were separated on a
Chiralpak AD column, 50 mm × 500 mm with 20 µm packing,
using 5% EtOH/hexane (0.15% diethylamine added in hexane
as modifier) as the eluent, with a flow rate of 60 mL/min for
75 min and the UV detector at 280 nm.
(1R,2R)-trans-2-(5-Cyano-1H-indol-3-yl)-1-(N,N-dimeth-
ylaminomethyl)cyclopropane, (-)-12a, eluted at 29.9 min:
100% purity with >99% ee; [RD]22 -17.0° ( c 2.59 mg/mL,
EtOH). This material was converted to the maleate salt: >97%
purity (reverse-phase HPLC), >99.5% purity with >99% ee
(Chiralpak AD 4.6 mm × 250 mm, 10% MeOH, 90% hexane
(0.15% diethylamine), 1.0 mL/min, tR )7.30 min); [RD]22 +3.2°
(c 2.54 mg/mL, EtOH) and [RD]22 -9.9° (c 3.33 mg/mL, H2O).
Anal. Calcd for C15H17N3‚C4H4O4: C, 64.21; H, 5.96; N, 11.82.
Found: C, 63.31; H, 5.94; N, 11.34. 1H NMR (400 MHz, DMSO-
d6) δ 11.47 (s, 1H), 9.65 (br, 1H), 9.35 (br, 1H), 8.18 (d, 1H, J
) 0.6 Hz), 7.44 (dd, 2H, J ) 15.9, 8.4 Hz), 7.32 (d, 1H, J ) 0.6
Hz), 3.21 (dq, 2H, J ) 57.0, 7.1, 33.2, 7.1 Hz), 2.84 (s, 6 H),
2.10 (q, 1H, J ) 4.2 Hz), 1.18 (m, 1H), 1.15 (m, 1H), 1.02 (m,
1H).
(1S,2S)-trans-2-(5-Cyano-1H-indol-3-yl)-1-(N,N-dimethyl-
amino-methyl)cyclopropane, (+)-12a, eluted at 49.0 min and
was identical to material enantioselectively synthesized.
Preparative Chiral HPLC Resolution of trans-2-(5-
Fluoro-1H-indol-3-yl)-1-(N,N-dimethylaminomethyl)cy-
clopropane, 12e. The enantiomers were separated on a
Chiralpak AD column, 50 mm × 500 mm with 20 µm packing,
using 5% EtOH/hexane (0.15% diethylamine added in hexane
as modifier) as the eluent, with a flow rate of 60 mL/min for
75 min and the UV detector at 280 nm. The injection load was
80 mg in 6.5 mL of EtOH/hexane (4:5).
(1R,2R)-trans-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-dimeth-
ylaminomethyl)cyclopropane, (-)-12e, eluted at 47.6 min: 96%
purity with >99% ee (Chiralpak AD, 4.6 mm × 250 mm, 5%
MeOH, 95% hexane (0.15% diethylamine), 0.5 mL/min, tR
)
21.57 min). The compound was characterized as the maleate
salt: [RD]22 -51.1° (c 4.64 mg/mL, EtOH). 1H NMR (400 MHz,
DMSO-d6) δ 10.96 (1H, br s), 9.35 (1H, br s), 7.36 (1H, dd, J )
10.0, 2.4 Hz), 7.32 (1H, dd, J ) 8.8, 4.6 Hz), 7.19 (1H, d, J )
2.3 Hz), 6.92 (1H, td, Jt ) 9.3, Jd ) 2.5 Hz), 3.19 (m, 2H), 2.83
(s, 6H), 2.00 (m, 1H), 1.26 (m, 1H), 1.09 (m, 1H), 0.92 (m, 1H).
Anal. (C14H17FN2‚C4H4O4) C, H, N.

Indole Cyclopropylmethylamines as SSRIs
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6033
(1S,2S)-trans-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-dimeth-
ylaminomethyl)cyclopropane, (+)-12e, eluted at 60.8 min and
was identical to material that was enantioselectively synthe-
sized.
Preparative Chiral HPLC Resolution of cis-2-[5-
Cyano-1H-indol-3-yl]-1-(N,N-dimethylaminomethyl)-
cyclopropane, 16a. The enantiomers were separated on a
Chiralpak AD column, 21 mm × 250 mm with 20 µm packing,
using 10% EtOH/hexane (0.15% diethylamine added in hexane
as modifier) as the eluent, with a flow rate of 20 mL/min for
45 min and the UV detector at 241 nm. The injection load was
18 mg in 1 mL of 1:3 EtOH/hexane.
using CH2Cl2/MeOH (containing 2 M NH4OH) (4:96) as the
eluent to give 22 as a white solid (36 mg, 86%). 1H NMR (400
MHz, CDCl3) δ 7.90 (dd, J ) 8.6, 4.5 Hz, 1H), 7.68 (d, J ) 8.5,
2H), 7.18-7.25 (m, 4H), 7.02 (td, J ) 9.1, 2.8 Hz, 1H), 2.32 (s,
3H), 2.25 (m, 1H), 2.12 (s, 6H), 1.94 (q, J ) 7.2 Hz, 1H), 1.65
(m, 1H), 1.36 (m, 1H), 1.20 (m, 1H), 0.69 (m, 1H). The crystals
for X-ray crystallography were developed by slow evaporation
from EtOAc/hexane and collected.
Supporting Information Available: Results from HRMS,
HPLC, and elemental analysis. This material is available free
of charge via the Internet at http://pubs.acs.org.
(1S,2R)-cis-2-[5-Cyano-1H-indol-3-yl]-1-(N,N-dimethyl-
aminomethyl)cyclopropane, (+)-16a, eluted at 21.02 min with
>97% purity with >99% ee (Chiralpak AD 4.6 mm × 250 mm,
10% MeOH, 90% hexane (containing 0.15% diethylamine), 1.0
mL/min, tR ) 8.02 min, sign of rotation determined by laser
polarimetry).
(1R,2S)-cis-2-[5-Cyano-1H-indol-3-yl]-1-(N,N-dimethyl-
aminomethyl)cyclopropane, (-)-16a, eluted at 34.84 min with
>98% purity with >99% ee (Chiralpak AD 4.6 mm × 250 mm,
10% MeOH, 90% hexane (containing 0.15% diethylamine), 1.0
mL/min, tR ) 10.91 min, sign of rotation determined by laser
polarimetry).
Preparative Chiral HPLC Resolution of cis-2-(5-Fluoro-
1H-indol-3-yl)-1-(N,N-dimethylaminomethyl)cyclopro-
pane, 16e. The enantiomers were separated using the same
method as for 16a but using 5% EtOH/hexane as the eluent.
(1S,2R)-cis-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, (+)-16e, eluted at 23.47 min with
>94% purity with >99% ee (Chiralpak AD 4.6 mm × 250 mm,
5% MeOH, 95% hexane (0.15% diethylamine), 10.5 mL/min,
tR ) 20.18 min, sign of rotation determined by laser polarim-
etry).
References
(1) Ananth, J. Treatment-resistant depression. Psychother.
Psychosom. 1998, 67, 61-70.
(2) Lee, K. C.; Feldman, M. D.; Finley, P. R. Beyond depression:
evaluation of newer indications and off-label uses for SSRIs.
Formulary 2002, 37, 312-319.
(3) (a) Takeuchi, K.; Kohn, T. J.; Honigschmidt, N. A.; Rocco, V. P.;
Spinazze, P. G.; Koch, D. J.; Nelson, D. L.; Wainscott, D. B.;
Ahmad, L. J.; Shaw, J.; Threlkeld, P. G.; Wong, D. T. Advances
toward new antidepressants beyond SSRIs: 1-aryloxy-3-
piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/
SSRI activities. Part 1. Bioorg. Med. Chem. Lett. 2003, 13, 1903-
1905. (b) Takeuchi, K.; Kohn, T. J.; Honigschmidt, N. A.; Rocco,
V. P.; Spinazze, P. G.; Koch, D. J.; Atkinson, S. T.; Hertel, L.
W.; Nelson, D. L.; Wainscott, D. B.; Ahmad, L. J.; Shaw, J.;
Threlkeld, P. G.; Wong, D. T. Advances toward new antidepres-
sants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with
dual 5-HT1A receptor antagonism/SSRI activities. Part 2. Bioorg.
Med. Chem. Lett. 2003, 13, 2393-2397. (c) Takeuchi, K.; Kohn,
T. J.; Honigschmidt, N. A.; Rocco, V. P.; Spinazze, P. G.; Koch,
D. J.; Atkinson, S. T.; Hertel, L. W.; Nelson, D. L.; Wainscott,
D. B.; Ahmad, L. J.; Shaw, J.; Threlkeld, P. G.; Wong, D. T.
Advances toward new antidepressants beyond SSRIs: 1-aryloxy-
3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/
SSRI activities. Part 3. Bioorg. Med. Chem. Lett. 2003, 13, 3939-
3942. (d) Rocco, V. P.; Spinazze, P. G.; Kohn, T. J.; Honigschmidt,
N. A.; Nelson, D. L.; Wainscott, D. B.; Ahmad, L. J.; Shaw, J.;
Threlkeld, P. G.; Wong, D. T. Takeuchi, K. Advances toward new
antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-
2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part
4. Bioorg. Med. Chem. Lett. 2004, 14, 2653-2656. (e) Oficialde-
gui, A. M.; Martinez, J.; Perez, S.; Hears, B.; Irurzun, M.; Palop,
J. A.; Tordera, R.; Lasheras, B.; del Rio, J.; Monge, A. Design,
synthesis and biological evaluation of new 3-[(4-aryl)piperazin-
1-yl]-1-arylpropane derivatives as potential antidepressants with
a dual mode of action: serotonin reuptake inhibition and 5-HT1A
receptor antagonism. Farmaco 2000, 55, 345-353. (f) Evrard,
D. A.; Zhou, P.; Yi, S.; Zhow, D.; Smith, D.; Sullivan, K. M.;
Hornby, G. A.; Scheckter, L. E.; Andree, T. H.; Mewshaw, R. E.
Studies towards the next generation of antidepressants. Part 4:
Derivatives of 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine with
affinity for the serotonin transporter and the 5-HT1A receptor.
Bioorg. Med. Chem. Lett. 2005, 15, 911-914.
(4) Wellsow, J.; Machulla, H.-J.; Kovar, K.-A. 3D QSAR of serotonin
transporter ligands: CoMFA and CoMSIA studies. Quant.
Struct.-Act. Relat. 2002, 21, 577-589.
(5) (a) Ravna, A. W.; Edvardsen, O. J. A putative three-dimensional
arrangement of the human serotonin transporter transmem-
brane helices: a tool to aid experimental studies. J. Mol.
Graphics Modell. 2001, 20, 133-144. (b) Ravna, A. W.; Sylte,
I.; Dahl, S. Molecular mechanism of citalopram and cocaine
interactions with neurotransmitter transporters. J. Pharmacol.
Exp. Ther. 2003, 307, 34-41.
(6) Chen, F.; Larsen, M. B.; Sanchez, C.; Wiborg, O. The S-
enantiomer of R,S-citalopram increases inhibitor binding to the
human serotonin transporter by an allosteric mechanism.
Comparison with other serotonin transporter inhibitors. Eur.
Neuropsychopharmacol. 2005, 15, 193-198.
(7) Sanchez, C.; Bogeso, K. P.; Ebert, B.; Reines, E. H.; Braestrup,
C. Escitalopram versus citalopram: the surprising role of the
R-enantiomer. Psychopharmacology 2004, 174, 163-176.
(8) (a) Euvrard, C. R.; Boissier, J. R. Biochemical assessment of the
central 5-HT agonist activity of RU 24969 (a piperidinyl indole).
Eur. J. Pharmacol. 1980, 63, 65-72. (b) Guillaume, J.; Dumont,
C.; Laurent, J.; Nedelec, L. Synthesis of 3-(1,2,3,6-tetrahydro-
pyridin-4-yl)1H-indoles and study of their serotoninergic and
antidopaminergic properties. Eur. J. Med. Chem. 1987, 22, 33-
43.
(1R,2S)-cis-2-(5-Fluoro-1H-indol-3-yl)-1-(N,N-dimethyl-
aminomethyl)cyclopropane, (-)-16e, eluted at 39.08 min with
>96% purity with >99% ee (Chiralpak AD 4.6 mm × 250 mm,
5% MeOH, 95% hexane (0.15% diethylamine), 0.5 mL/min, tR
) 30.97 min, sign of rotation determined by laser polarimetry).
(1S,2S)-trans-2-[5-Cyano-1-methyl-1H-indol-3-yl]-1-(N,N-
dimethylaminomethyl)cyclopropane, 20. A solution of (+)-
12a (90 mg, 0.38 mmol) in THF (5 mL) was treated with
potassium tert-butoxide (46 mg, 0.41 mmol) and stirred for 1
h at room temperature. Dimethyl sulfate (52 mg, 0.41 mmol)
was added, and the mixture was stirred for 3 h. The THF was
removed in vacuo, and the remaining aqueous suspension was
extracted with EtOAc (4 × 5 mL). The organic layer was dried
with magnesium sulfate, and the solvent was removed in
vacuo. The residue was purified by silica gel chromatography
using chloroform/NH4OH (2 M in MeOH) (97:3) to give 20 (62
1
mg, 65%). H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J ) 1.2
Hz), 7.42 (1H, dd, J ) 8.8, 1.2 Hz), 7.28 (1H, d, J ) 8.4 Hz),
6.84 (1H, s), 3.73 (3H, s), 2.44 (1H, dd, J ) 13.2, 6.8 Hz), 2.34
(1H, dd, J ) 13.1, 6.8 Hz), 2.33 (6 H, s), 1.75 (1H, m), 1.21
(1H, m), 0.90 (1H, m), 0.84 (1H, m).
(1S,2S)-trans-2-[5-Cyano-1-ethyl-1H-indol-3-yl]-1-(N,N-
dimethylaminomethyl)cyclopropane, 21. 21 was prepared
from (+)-12a using diethyl sulfate in a manner similar to 20
(46%). 1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J ) 1.5 Hz),
7.40 (1H, dd, J ) 8.8, 1.6 Hz), 7.31 (1H, d, J ) 8.4 Hz), 6.90
(1H, s), 4.10 (2H, q, J ) 7.2 Hz), 2.44 (1H, dd, J ) 12.9, 6.5
Hz), 2.34 (1H, dd, J ) 13.0, 6.8 Hz), 2.33 (6 H, s), 1.74 (1H,
m), 1.23 (1H, m), 0.88 (1H, m), 0.81 (1H, m).
(1R,2S)-cis-2-(5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-
3-yl)-1-(N,N-dimethylaminomethyl)cyclopropane, 22. To
a solution of (-)-16e (25 mg, 0.11 mmol) in DMF (2 mL) at 0
°C was added dropwise a solution of sodium bis(trimethylsilyl)-
amide (0.20 mL, 0.6 M in toluene, 0.12 mmol). After the
mixture was stirred 15 min at 0 °C, p-tosyl chloride (31 mg,
0.16 mmol) was added and the mixture was stirred a further
30 min. The mixture was poured into brine (20 mL) and
extracted with EtOAc (4 × 5 mL). The combined organic
phases were dried with magnesium sulfate and evaporated to
dryness. The residue was purified by silica gel chromatography
(9) LeBoulleuc, K. L.; Mattson, R. J.; Mahle, C. D.; McGovern, R.
T.; Nowak, H. P.; Gentile, A. J. Bivalent indoles exhibiting
serotonergic binding affinity. Bioorg. Med. Chem. Lett. 1995, 5,
123-126.

6034 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Mattson et al.
(10) Cipollina, J. A.; Mattson, R. J.; Sloan, C. P. Antidepressant
3-(aminocycloalkenyl)indole-5-nitrile derivatives. U.S. Patent
5,468,767, 1995; CAN 124:175827.
(11) Meagher, K. L.; Mewshaw, R. E.; Evrard, D. A.; Zhou, P.; Smith,
D. L.; Scerni, R.; Spangler, T.; Abulhaw, S.; Shi, X.; Scheckter,
L. E.; Andree, T. H. Studies towards the next generation of
antidepressants. Part 1: indolylcyclohexylamines as potent
serotonin reuptake inhibitors. Bioorg. Med. Chem. Lett. 2001,
11, 1885-1888.
(22) Blier, P. Pharmacology of rapid-onset antidepressant treatment
strategies. J. Clin. Psychiatry 2001, 62 (Suppl. 15), 12-17.
(23) Taber, M. T.; Wright, R. N.; Molski, T. F.; Clarke, W. J.; Brassil,
P. J.; Denhart, D. J.; Mattson, R. J.; Lodge, N. J. Neurochemical,
pharmacokinetic, and behavioral effects of the novel selective
serotonin reuptake inhibitor BMS-505130. Pharmacol., Biochem.
Behav. 2005, 80, 521-528.
(24) Gundertofte, K.; Bøgesø, K. P.; Liljefors, T. A Stereoselective
Pharmacophoric Model of the Serotonin Re-uptake Site. In
Computer-Assisted Lead Finding and Optimization: Current
Tools for Medicinal Chemistry; van de Waterbeemd, H., Testa,
B., Folkers, G., Eds.; Verlag Helvetica Chimica Acta: Basel,
Switzerland, 1997; pp 443-459.
(25) Lindner, M. D.; Hodges, D. B., Jr.; Hogan, J. B.; Orie, A. F.;
Corsa, J. A.; Barten, D. M.; Polson, C.; Robertson, B. J.; Guss,
V. L.; Gillman, K. W.; Starrett, J. E., Jr.; Gribkoff, V. K. An
assessment of the effects of serotonin 6 (5-HT6) receptor antago-
nists in rodent models of learning. J. Pharmacol. Exp. Ther.
2003, 307 (2), 682-691.
(12) (a) Kaiser, C.; Zirkle, C. L. Cyclopropylamine derivatives and
processes for their preparation. U.S. Patent 3,010,971, 1960;
CAN 56:79376. (b) Vangveravong, S.; Nichols, D. L. Stereose-
lective synthesis of trans-2-(indol-3-yl)cyclopropylamines: rigid
tryptamine analogs. J. Org. Chem. 1995, 60, 3409-3416. (c)
Vangveravong, S.; Kanthasamy, A.; Lucaites, V. L.; Nelson, D.
L.; Nichols, D. E. Synthesis and serotonin receptor affinities of
a series of trans-2-(indol-3-yl)cyclopropylamine derivatives. J.
Med. Chem. 1998, 41, 4995-5001.
(13) Denhart, D. J.; Mattson, R. J.; Ditta, J. L.; Macor, J. E. One-pot
synthesis of homotryptamines from indoles. Tetrahedron Lett.
2004, 45, 3803-3805.
(26) Mattson, R. J.; Catt, J. D.; Sloan, C. P.; Gao, Q.; Carter, R. B.;
Gentile, A.; Mahle, C. D.; Matos, F. F.; McGovern, R.; Vander-
Maelen, C. P.; Yocca, F. D. Development of a presynaptic 5-HT1A
antagonist. Bioorg. Med. Chem. Lett. 2003, 13, 285-288.
(27) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W.
C. MacroModelsan integrated software system for modeling
organic and bioorganic molecules using molecular mechanics.
J. Comput. Chem. 1990, 11, 440-467.
(28) Polak, E.; Ribiere, G. Note sur la Convergence de Me´thodes de
Directions Conjugue´es (Note on the convergence of methods of
conjugates). Rev. Fr. Inf. Rech. Oper. 1969, 16, 35-43.
(29) Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. Development
and testing of the OPLS all-atom force field on conformational
energetics and properties of organic liquids. J. Am. Chem. Soc.
1996, 118, 11225-11236.
(30) Still, W. C.; Tempczyk, A.; Hawlely, R. C.; Hendrickson, T. A.
Semianalytical treatment of solvation for molecular mechanics
and dynamics. J. Am. Chem. Soc. 1990, 112, 6127-6129.
(31) For a description of the B3LYP hybrid functional used, see the
following. Jaguar 5.5 Operating Manual; Schro¨dinger, LLC:
Portland, OR, 2004, and references therein.
(32) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; John Wiley & Sons: New York, 1986;
Chapter 4.
(14) Schmitz, W. D.; Denhart, D. J.; Brenner, A. B.; Ditta, J. L.;
Mattson, R. J.; Mattson, G. K.; Molski, T. F.; Macor, J. E.
Homotryptamines as potent and selective serotonin reuptake
inhibitors (SSRIs). Bioorg. Med. Chem. Lett. 2005, 15, 1619-
1621.
(15) (a) Vangveravong, S.; Kanthasamy, A.; Lucaites, V. L.; Nelson,
D. L.; Nichols, D. E. Synthesis and serotonin receptor affinities
of a series of trans-2-(indol-3-yl)cyclopropylamine derivatives.
J. Med. Chem. 1998, 41, 4995-5001. (b) Appelberg, U.; Nohell,
N.; Hecksell, U. Derivatives of 2-arylcyclopropylamine: Synthe-
sis and interactions with 5-HT1A receptors. Bioorg. Med. Chem.
Lett. 1996, 6, 415-420.
(16) Indoles from 2-methylnitrobenzenes by condensation with
formamide acetals followed by reduction: (a) Batcho, A. D.;
Leimgruber, W. 4-benzyloxyindole (1H-indole, 4-(phenylmeth-
oxy)-). Org. Synth. 1985, 63, 214-225. (b) For 4-, 6-, and
7-cyanoindole: Clark, R. D.; Repke, D. B. Some observations on
the formation of 1-hydroxyindoles in the Leimgruber-Batcho
indole synthesis. J. Heterocycl. Chem. 1985, 22, 121-125. (c) For
5- and 6-(trifluoromethyl)indole: Bromidge, S. M. Preparation
of pyridinioarylcarbamoylindoline derivatives as serotonin re-
ceptor antagonists. WO 9737989, 1997.
(17) H-, 4-F-, 5-MeO-, and 5-BnO-indole-3-carboxaldehyde were
commercially available.
(18) Netz, D. F.; Seidel, J. L. Diethyl (N-methoxy-N-methylcarbam-
oylmethyl)phosphonate, a useful Emmons-Horner-Wittig re-
agent. Tetrahedron Lett. 1992, 33, 1957-1958.
(19) (a) Still, W. C.; Gennari, C. Direct synthesis of Z-unsaturated
esters. A useful modification of the Horner-Emmons olefination.
Tetrahedron Lett. 1983, 24, 4405-4408. (b) Beckmann, M.;
Hildebrandt, H.; Winterfeldt, E. Pure enantiomers from retro-
Diels-Alder processes. Tetrahedron: Asymmetry 1990, 1, 335-
345. (c) Carter, N. B.; Nadany, A. E.; Sweeneny, J. B. Recent
developments in the synthesis of furan-2(5H)-ones. J. Chem.
Soc., Perkin Trans. 1 2002, 2324-2342.
(20) An alternative enantioselective synthesis has been described
separately: Marcin, L. R.; Denhart, D. J.; Mattson, R. J.
Catalytic asymmetric diazoacetate cyclopropanation of 1-tosyl-
3-vinylindoles. A Route to conformationally restricted homot-
ryptamines. Org. Lett. 2005, 7, 2651-2654.
(21) Cecil, A. R. L.; Hu, Y.; Vicent, M. J.; Duncan, R.; Brown, R. C.
D. Total Synthesis and preliminary biological evaluation of cis-
solamin isomers. J. Org. Chem. 2004, 69, 3368-3374.
(33) Tidwell, R. R.; Geratz, J. D.; Dubovi, E. J. Aromatic amidines.
Comparison of their ability to block respiratory syncytial virus
induced cell fusion and to inhibit plasmin, urokinase, thrombin,
and trypsin. J. Med. Chem. 1983, 26, 294-298.
(34) Yamada, F.; Somei, M. The chemistry of indoles. Part XXXVIII.
A convenient synthetic approach to 4-substituted indoles. Het-
erocycles 1987, 26, 1173-1176.
(35) Pedras, M.; Soledade, C.; Ahiahonu, A.; Pearson, W. K. Probing
the phytopathogenic stem rot fungus with phytoalexins and
analogues: unprecedented glucosylation of camalexin and 6-meth-
oxycamalexin. Bioorg. Med. Chem. 2002, 10, 3307-3312.
(36) Kalir, A.; Balderman, D. Improved synthesis of some fluoroin-
doles. Isr. J. Chem. 1968, 6, 927-932.
JM0503291