N-methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT(1D) receptor agonist

Article abstract of DOI:10.1021/jm9805945

It has been observed that reported 5-HT(1D) receptor agonists have at least one heteroatom (N, O, or S) on the 5-substituent of the indole. This has led to the hypothesis that a 5-substituent capable of participating in hydrogen bonding is critical for conveying high affinity. This article describes the synthesis and biological evaluation of a new series of 5- alkyltryptamine analogues, which does not have a heteroatom in the 5- substituent group. In contrast to the hypothesis, 5-alkyltryptamines all exhibit high binding affinities for the human 5-HT(1D) receptor. The size of the lipophilic alkyl group at the 5-position of the indole has significant impact on the 5-HT(1D) binding affinity. Compounds with a tert-butyl group at the 5-position such as 9d, 10, and 11 were identified. These analogues display high binding affinity (K(i) < 1 nM) and moderate receptor selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan, rizatriptan, and VML-251.

Full text of DOI:10.1021/jm9805945

526
J . Med. Chem. 1999, 42, 526-531
Brief Articles
N-Meth yl-5-ter t-bu tyltr yp ta m in e: A Novel, High ly P oten t 5-HT1D Recep tor
Agon ist
Yao-Chang Xu,*,† J ohn M. Schaus,† Clint Walker,† J oe Krushinski,† Nika Adham,‡ J ohn M. Zgombick,‡
Sidney X. Liang,† Dan T. Kohlman,† and J ames E. Audia†
Discovery Chemistry Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, and
Synaptic Pharmaceutical Corporation, 215 College Road, Paramus, New J ersey 07652
Received October 20, 1998
It has been observed that reported 5-HT1D receptor agonists have at least one heteroatom (N,
O, or S) on the 5-substituent of the indole. This has led to the hypothesis that a 5-substituent
capable of participating in hydrogen bonding is critical for conveying high affinity. This article
describes the synthesis and biological evaluation of a new series of 5-alkyltryptamine analogues,
which does not have a heteroatom in the 5-substituent group. In contrast to the hypothesis,
5-alkyltryptamines all exhibit high binding affinities for the human 5-HT1D receptor. The size
of the lipophilic alkyl group at the 5-position of the indole has significant impact on the 5-HT1D
binding affinity. Compounds with a tert-butyl group at the 5-position such as 9d , 10, and 11
were identified. These analogues display high binding affinity (Ki < 1 nM) and moderate receptor
selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan,
rizatriptan, and VML-251.
Ch a r t 1
Serotonin (5-hydroxytryptamine, 5-HT) is a neuro-
transmitter widely distributed in the brain and periph-
eral tissues and is involved in the regulation of various
physiological functions such as mood, appetite, pain,
sexual behavior, body temperature, and blood pressure.1
Recent advances in the molecular cloning of seven
serotonin receptor families (5-HT1, 5-HT2, 5-HT3, 5-HT4,
5-HT5, 5-HT6, and 5-HT7) have provided a plethora of
medicinally important targets for drug discovery re-
search. Among the 5-HT receptor families, the 5-HT1
receptor family appears to be the most complex and has
been further subclassified into the 5-HT1A, 5-HT1B
,
5-HT1D, 5-HT1E, and 5-HT1F subtypes.2
Sumatriptan (1) is the first 5-HT1 receptor agonist
approved for the clinical treatment of migraine head-
aches.3 Although there is some debate surrounding its
exact mechanism of action,4 5-HT1D receptor activation
has been proposed to be involved in mediating its
therapeutic effects.5 Sumatriptan has high binding
affinity at the human 5-HT1D receptor (Ki ) 4.4 nM)
and varying selectivity relative to other 5-HT1 receptor
subtypes (Table 3). Further, some of the side effects for
sumatriptan have been postulated to be mediated by
activation of other 5-HT1 receptors including the 5-HT1A
and 5-HT1B subtypes.5,6
The clinical efficacy of sumatriptan in the treatment
of migraine,7 regardless of its specific mechanism of
action, has created tremendous interest among aca-
demic laboratories as well as pharmaceutical companies.
Second-generation 5-HT1D receptor agonists have been
developed in recent years,8 and many compounds in-
cluding naratriptan (2),9 rizatriptan (3),10,8c VML-251
(4)11 (Chart 1), and zolmitriptan12 have entered late-
stage clinical trials.
All compounds in Chart 1 bind with high affinity (Ki
) 2.0-5.4 nM, Table 3) to the human 5-HT1D receptor.
A simple comparison of the 5-HT1D receptor agonists
1-4 would suggest that the key groups required for
binding and efficacy are a basic amine, an indole
nucleus, and a 5-substituent capable of participating in
hydrogen-bonding interactions as an acceptor and/or
donor. Among these key groups, the 5-substituent seems
to be the focus of the structure-activity relationship
(SAR) studies for improving affinity and selectivity at
the 5-HT1D receptor.8-12 It would appear that a 5-sub-
stituent capable of participating in hydrogen bonding
is critical for imparting high affinity. This apparent
† Lilly Corporate Center.
‡ Synaptic Pharmaceutical Corp.
10.1021/jm9805945 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/27/1999

Brief Articles
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 527
Sch em e 1
Sch em e 2
requirement has been supported by the fact that virtu-
ally all 5-HT1D receptor agonists reported in the litera-
ture have at least one heteroatom (N, O, or S) in the
5-substituent group.13 We now report on the binding
properties of compound 10 which has a non-heteroatom-
containing tert-butyl group on the 5-position of indole.
This compound possesses very high binding affinity for
the human 5-HT1D receptor and displays comparable
selectivity versus human 5-HT1A and 5-HT1B receptors
to those known clinical candidates 1-4. The chemical
synthesis, SAR studies, radioligand binding, and func-
tional data for this new class of compouunds are also
reported.
LiAlH4 reduction of the resulting tert-butyl carbamate.17
Di-N-alkylation of 9d with methyl methanesulfonate in
the presence of NaOH afforded N,N-dimethyl analogue
11. Direct N-alkylation of 9d with 1-iodopropane using
K2CO3 gave both monoalkylated and dialkylated ana-
logues 12 and 13, which were readily separated by silica
gel flash chromatography.
Due to the unavailability of 4-cyclopentylphenyl-
alanine, 5-cyclopentyltryptamine (17) was synthesized
using a different route shown in Scheme 2. Treatment
of 5-bromotryptamine (14) with benzyl bromide in the
presence of Na2CO3 in refluxing CH2Cl2 gave rise to
N,N-di-benzylated intermediate 15, which was con-
verted to the cyclopenten-1-yltryptamine derivative 16
following the chemistry developed by Rapoport et al.18
Debenzylation of 16 accompanied by hydrogenation of
the double bond for the cyclopentenyl ring was ac-
complished using catalytic transfer hydrogenation con-
ditions (Pd/C, HCO2NH4) in refluxing methanol19 to
afford analogue 17 in low overall yield.
Ch em istr y
Starting from the readily available 4-alkylanilines
5a -e, the preparation of 5-alkyltryptamine analogues
is presented in Scheme 1. Treatment of 5a -e with
NaNO2 in acid followed by reduction of the intermediate
diazonium salts with SnCl2‚2H2O gave the hydrazine
hydrochloride salts 6a -e.14 Fisher indolization of 6a -e
with 4-phthalimidobutanal diethyl acetal (7) in the
presence of a catalytic amount of concentrated HCl, in
refluxing EtOH, provided 5-alkyltryptamine derivatives
8a -e after purification by silica gel flash chromatog-
raphy.15 Removal of phthaloyl group from 8a -e by use
of hydrazine gave rise to the targeted 5-alkyltryptamine
analogues 9a -e.16
P h a r m a cology
The in vitro receptor affinities of compounds were
evaluated by radioligand binding assays using cell lines
expressing the human 5-HT1A, 5-HT1B, and 5-HT1D
receptors described previously.20 The binding data are
expressed in Ki values. The forskolin-stimulated aden-
ylate cyclase assays were performed with cell lines
expressing the human 5-HT1D receptor to evaluate the
agonist potency as previously reported.21
N-Methyl-5-tert-butyltryptamine (MBT, 10) was pre-
pared by introduction of a BOC group on the basic
nitrogen of 9d using (BOC)2O and NaOH, followed by

528 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Brief Articles
Ta ble 1. Binding of 5-Alkyltryptamines at the Cloned Human
5-HT1D Receptor
Ta ble 2. Binding of 5-tert-Butyltryptamines at the Cloned
Human 5-HT1D Receptor
compd
R
5-HT1D (Ki ( SEM, nM)
compd
R′
R′′
5-HT1D (Ki ( SEM, nM)
9a
9b
9c
9d
17
9e
5-HT
Me
Et
i-Pr
6.4 ( 1.8
3.7 ( 1.5
1.1 ( 0.2
0.6 ( 0.2
1.7 ( 0.5
3.4 ( 0.8
2.0 ( 0.2
9d
10
11
12
13
H
Me
Me
H
H
0.61 ( 0.15
0.45 ( 0.12
0.44 ( 0.05
6.2 ( 0.8
t-Bu
Me
H
n-propyl
c-pentyl
c-hexyl
OH
n-propyl
n-propyl
10.8 ( 0.9
Ta ble 3. Binding and Selectivity Comparison of MBT (10) with
Known Compounds
Resu lts a n d Discu ssion
Ki (nM)
As seen in Table 1, 5-alkyltryptamines all exhibit high
binding affinities for the human 5-HT1D receptor (Ki <
7 nM). However, the size of the lipophilic alkyl group
at the 5-position of the indole has significant impact on
the 5-HT1D binding affinity. Increasing the size of the
5-alkyl substituent resulted in an increased affinity for
the human 5-HT1D receptor. For example, compound 9a
with a small methyl substituent has the lowest affinity
for the 5-HT1D receptor (Ki ) 6.4 nM). The binding
affinity increased to Ki ) 1.1 and 0.6 nM when the
methyl group (9a ) was replaced by the isopropyl group
(9c) and tert-butyl group (9d ), respectively. This pre-
sents an increase of 6- and 11-fold for the 5-HT1D
binding affinity. Cycloalkyl groups, e.g., cyclopentyl (17)
and cyclohexyl (9e), can still be accommodated with
slight loss of the affinity (<6-fold).
It was very intriguing that the C-5 alkyl-substituent
analogues 9c, 9d , and 9e have higher binding affinity
for the 5-HT1D receptor than does serotonin (5-HT) itself.
This has led us to propose that the hydrogen-bonding
substituent at the indole C-5 position is not essential for
the high 5-HT1D binding affinity. Further, we believe
that the 5-HT1D receptor has a hydrophobic pocket in
the proximity of the 5-position of sertonin. The binding
affinity of the derivatives is dictated by the ability of
the C-5 alkyl group to fit into the hydrophobic pocket,
which is dependent on the size of alkyl group. It is
apparent from the SAR studies shown in Table 1 that
the tert-butyl group is the optimal substituent which is
among those examined at the indole C-5 position.
After identifying tert-butyl as an optimal group,
substitution of alkyl groups on the basic nitrogen was
explored. Introduction of a methyl group on the nitrogen
gives rise to a secondary amine analogue 10, which has
similar affinity as the parent compound (9d ). Introduc-
tion of an additional methyl group results in a similarly
potent tertiary amine analogue 11. Substitution of a
larger group such as propyl on the nitrogen (12, 13) is
detrimental to the 5-HT1D receptor binding affinity.
N-Methyl-5-tert-butyltryptamine (MBT) (10) was identi-
fied as a new lead compound in this series with a Ki )
0.45 nM, which is one of the highest affinity compounds
reported for the human 5-HT1D receptor.
5-HT1A
(5-HT1A/5-HT1D
5-HT1B
(5-HT1B/5-HT1D)
compd
5-HT1D
)
sumatriptan, 1 4.4 ( 0
naratriptan, 2 2.3 ( 0.2
rizatriptan, 3
VML-251, 4
MBT, 10
230 ( 1.0 (52)
45 ( 0.7 (20)
140 ( 8.0 (33)
62 ( 8.6 (14)
9.6 ( 0 (2)
3.3 ( 0.4 (1)
10.1 ( 0.7 (3)
10.3 ( 1.9 (2)
1.9 ( 0 (4)
4.3 ( 0.8
4.4 ( 0.4
0.45 ( 0.1
6.1 ( 0.7 (14)
Ta ble 4. 5-HT1D Receptor Intrinsic Activity Comparison
compd
EC50 (nM)
EMAX (% of 5-HT)
sumatripatan, 1
naratriptan, 2
rizatriptan, 3
MBT, 10
4.3 ( 0.1
1.6 ( 0.7
3.0 ( 0.5
0.22 ( 0.2
93
100
97
100
butyltryptamine (10) has highest binding affinity for the
5-HT1D receptor and is 5 times more potent than
naratriptan (2) which is the most potent among the
clinical candidates 1-4. As far as the selectivity against
the 5-HT1A receptor, compound 10 shows similar selec-
tivity as VML-251 (4) but has slightly lower selectivity
as compared to sumatriptan (1), naratriptan (2), and
rizatriptan (3). Although none of the 5-HT1D receptor
agonists in the current study demonstrate as good
selectivity versus the 5-HT1B receptor, the N-methyl-5-
tert-butyltryptamine (10) remains the most selective (4-
fold).
To determine the functional properties at the human
5-HT1D receptor, compound 10 and some known 5-HT1D
receptor agonists were evaluated for their ability to
inhibit forskolin-stimulated adenylate cyclase in a cell
line expressing the human 5-HT1D receptor.21 The
intrinsic activity including EC50 and EMAX of these
derivatives are provided in Table 4. MBT (10) did not
display any antagonist properties. Like these known
compounds such as sumatriptan, naratriptan, and riza-
triptan, MBT (10) was found to be a full 5-HT1D receptor
agonist (EMAX ) 100% of 5-HT). More importantly, 10
displays high agonist potency at the 5-HT1D receptor,
and the EC50 of 10 is about 7 times more potent than
that of naratriptan (2) as shown in Table 4.
In summary, we have identified a novel series of
5-HT1D receptor agonists, which have only lipophilic
alkyl groups at the indole C-5 position. This finding
indicates the hydrogen-bonding substituent at the C-5
position of the indole is not required for high-affinity
binding as previously suggested and further suggests
Table 3 compares the binding affinity for the 5-HT1D
receptor and selectivity versus the 5-HT1A and 5-HT1B
receptors of our lead compound 10 with the clinical
candidates 1-4. As shown in Table 3, N-methyl-5-tert-

Brief Articles
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 529
1.8 Hz, 1H), 7.06 (dd, J ) 9.0, 1.8 Hz, 1H), 7.30 (d, J ) 9.0 Hz,
the existence of a hydrophobic binding region near the
indole 5-position. This discovery should assist future
SAR studies in discovering more potent and selective
5-HT1D receptor agonists. The lead compound 10 gener-
ated from this limited SAR study displays one of the
highest binding affinities for the human 5-HT1D recep-
tor. It displays comparable selectivity versus 5-HT1A and
5-HT1B receptors with the known clinical candidates.
Functionally, 10 behaves as a potent agonist at the
human 5-HT1D receptor.
1H), 7.42 (s, 1H), 7.98 (br s, 1H). MS for HCl salt: 189 (M+
1). Anal. for oxalate salt: (C12H17N2Cl) C, H, N.
+
5-Isop r op yltr yp ta m in e (9c).22 Compound 9c was pre-
pared by the method described for 9b. Thus, a mixture of
4-isopropylphenylhydrazine hydrochloride (6c) (1.0 g, 5.37
mmol) and compound 7 (1.5 g, 5.11 mmol) in 50 mL of EtOH
was heated to 70 °C for 2 h in the presence of water (0.10 mL).
After addition of 0.5 mL of concentrated HCl solution, the
mixture was heated to reflux for 14 h. After the usual workup,
compound 8c was obtained as a crude mixture, which was used
for next step without further purification.
The crude mixture was then treated with hydrazine hydrate
(6 mL) in the presence of 80 mL of EtOH and 20 mL of H2O at
room temperature for 15 h. The volatiles were removed by
reduced pressure, and the residue was extracted with CH2Cl2
(80 mL × 3). The combined organic layers were washed with
H2O, dried, filtered, and then concentrated to a residue that
was purified by flash chromatography using 15% methanol,
1% NH4OH in CH2Cl2 to give 9c (310 mg, 1.30 mmol) in 25%
overall yield. HCl salt of 9c was prepared; mp 181-184 °C
Exp er im en ta l Section
Unless otherwise indicated all common reagents and an-
hydrous solvents were used as obtained from commerical
suppliers without further purification. 5-Methyltryptamine
(9a ) was obtained from Aldrich Chemical Company, Inc. Air-
sensitive reactions were run under a positive pressure of dry
nitrogen. Melting points were determined on a Hoover-Thomas
Uni-Melt capillary melting point apparatus and are uncor-
1
1
dec. H NMR (CDCl3) for free base: 1.30 (d, J ) 7.0 Hz, 6H),
rected. Routine H NMR spectra were recorded on a 300-MHz
1.45 (br s, 2H), 2.90 (t, J ) 7.1 Hz, 2H), 3.02 (m, 3H), 7.00 (s,
1H), 7.09 (d, J ) 8.0 Hz, 1H), 7.28 (d, J ) 8.0 Hz, 1H), 7.42 (s,
1H), 8.00 (br s, 1H). MS for HCl salt: 203 (M+ + 1). Anal. for
HCl salt: (C13H19N2Cl) C, H, N.
5-ter t-Bu tyltr yp ta m in e (9d ). Compound 9d was prepared
by the method described for 9b. Thus, a mixture of 4-tert-
butylphenylhydrazine hydrochloride (6d ) (2.97 g, 14.8 mmol)
and compound 7 (4.11 g, 14.1 mmol) in 110 mL of EtOH was
heated to 70 °C for 2 h in the presence of a small amount of
water (0.20 mL). After addition of 1 mL of concentrated HCl
solution, the mixture was heated to reflux for 14 h. After usual
workup, compound 8d was obtained in a crude mixture, which
was used for next step without further purification.
spectrometer. Chemical shifts are reported in parts per million
downfield (δ) from tetramethylsilane in the form: chemical
shift (multiplicity, coupling constant, number of protons). Mass
spectra were recorded using field desorption (FD) ionization
on a Varian MAT 731 mass spectrometer. Elemental analyses
were carried out by the Physical Chemistry Research depart-
ment of the Lilly Research Laboratories.
5-Eth yltr yp ta m in e (9b).13 To a stirred solution of 4-ethyl-
aniline (5b) (5.06 g, 41.7 mmol) in 40 mL of concentrated
hydrogen chloride solution at 0 °C was slowly added a solution
of NaNO2 (3.17 g, 45.9 mmol) in 30 mL of water. The mixture
was stirred for ca. 10 min upon completion of the addition.
The reaction mixture was transferred in dropwise fashion to
a solution of SnCl2‚H2O (29.20 g, 129.4 mmol) in 40 mL of
concentrated hydrogen chloride solution at room temperature.
A white paste was slowly formed upon stirring. After 1 h, the
white precipitate was collected by filtration and washed with
water. Upon drying, the crude 4-ethylphenylhydrazine hydro-
chloride (6b) (7.14 g, 41.3 mmol) was obtained in 99% yield.
Compound 7 was prepared by treating 4-aminobutyralde-
hyde diethyl acetal (8.33 g, 90% pure, 46.5 mmol) with
N-carbethoxyphthalmide (10.73 g, 48.95 mmol) in water (75
mL) in the presence of NaHCO3 (3.93 g, 46.82 mmol) for 2 h
at room temperature. The reaction mixture was extracted with
CH2Cl2 (100 mL × 3). The combined organic layers were
washed with 5% NaHCO3 solution, dried over K2CO3, filtered,
and concentrated to give relatively pure 7 (13.2 g, 45.3 mmol)
as a colorless oil in 97% yield.
A mixture of compound 6b (3.05 g, 17.7 mmol) and 7 (5.14
g, 17.64 mmol) in 140 mL of EtOH was heated to 60 °C for 1
h in the presence of a small amount of water (0.12 mL). After
addition of 1 mL of concentrated HCl solution, the mixture
was heated to reflux for 14 h. The volatiles were removed by
evaporation. The residue was redissolved in CH2Cl2 (150 mL)
and saturated Na2CO3 (100 mL). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried, filtered, and concen-
trated. The residue was purified by flash chromatography
using a 7:3 mixture of hexanes and ethyl acetate to give
compound 8b (2.70 g, 8.5 mmol) in 48% yield.
The above crude residue was then treated with hydrazine
hydrate (12 mL) in the presence of 160 mL of EtOH and 40
mL of H2O at room temperature for 14 h. After workup, the
residue was purified by flash chromatography using 10%
methanol, 1% NH4OH in CH2Cl2 to give 9d (1.59 g, 7.3 mmol)
in 52% overall yield. Hydrochloride salt of 9d was prepared;
1
mp 246-248 °C. H NMR (CDCl3) for free base: 1.20 (s, 9H),
2.92 (q, J ) 7.0 Hz, 2H), 3.05 (t, J ) 7.0 Hz, 2H), 7.02 (s, 1H),
7.30 (s, 2H), 7.58 (s, 1H), 7.97 (br s, 1H). MS for hydrochloride
salt: 217 (M+ + 1). Anal. for oxalate salt: (C14H21N2Cl) C, H,
N.
5-Cyclop h en yltr yp ta m in e (17). To a stirred solution of
5-bromotryptamine (14) (2.68 g, 11.2 mmol) in 20 mL of CH2Cl2
were added Na2CO3 (3.00 g, 28.3 mmol), H2O (10 mL), and
benzyl bromide (3.99 g, 23.3 mmol). The mixture was heated
to reflux for 3 h. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (30 mL × 3). The
combined organic layers were washed with water, dried,
filtered, and concentrated to a residue that was purified by
flash chromatography using a 4:1 mixture of hexanes and ethyl
acetate to give N,N-dibenzyl-5-bromotryptamine (15) (3.36 g,
8.0 mmol) in 71% yield.
Compound 15 (1.72 g, 4.1 mmol) in 10 mL of THF was then
added to a suspension of KH (1.00 g, 20%, 5.0 mmol) in 10
mL of THF at 0 °C. After stirred at 0 °C for 15 min, the mixture
was cooled to -78 °C. t-BuLi (1.7 M, 6.2 mL, 10.54 mmol) was
then added dropwise. After 20 min of stirring, cyclopentanone
(1.14 g, 13.57 mmol) was introduced via syringe. The reaction
mixture was slowly warmed to room temperature. Cold H3PO4
solution (1M, 15 mL) was added. The organic layer was
separated, and the aqueous layer was extracted wiith diethyl
ether. The combined organic layers were washed with water,
dried, filtered, and concentrated. The residue was then redis-
solved in CH2Cl2 (25 mL). After addition of 1 mL of trifluoro-
acetic acid, the mixture was stirred at 0 °C for 3 h. Dichloro-
methane (20 mL) and 1 N NaOH solution (20 mL) were added.
The organic layer was separated, washed with water, dried
over Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography using a 5:1 mixture of
Compound 8b (2.70 g, 8.5 mmol) was then treated with
hydrazine hydrate (8 mL) in the presence of 80 mL of EtOH
and 20 mL of H2O at room temperature for 15 h. The volatiles
were removed by reduced pressure, and the residue was
extracted with CH2Cl2 (80 mL × 3). The combined organic
layers were washed with H2O, dried, filtered, and then
concentrated to a residue that was purified by flash chroma-
tography using 15% methanol, 1% NH4OH in CH2Cl2 to give
9b (1.50 g, 8.0 mmol) in 94% yield. HCl salt of 9b was
prepared; mp 252 °C dec. 1H NMR (CDCl3) for free base: 1.30
(t, J ) 7.5 Hz, 3H), 1.49 (br s, 2H), 2.76 (q, J ) 7.5 Hz, 2H),
2.90 (t, J ) 7.4 Hz, 2H), 3.03 (t, J ) 7.4 Hz, 2H), 7.02 (d, J )

530 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Brief Articles
hexanes and ethyl acetate to give the tryptamine analogue 16
(129 mg, 0.32 mmol) in 8% overall yield from 15.
tryptamine (11) (45 mg, 0.18 mmol) in 10% yield. Hydro-
bromide salt of 11 was prepared; mp 184-186 °C. 1H NMR
(CDCl3) for free base: 1.40 (s, 9H), 2.38 (s, 6H), 2.65 (m, 2H),
2.97 (m, 2H), 6.98 (br s, 1H), 7.28 (m, 2H), 7.59 (s, 1H), 8.07
(br s, 1H). MS for free base: 244 (M+). HRMS for hydro-
bromide: calcd for C16H25N2, 245.2018; found, 245.2030.
N-n -P r op yl-5-ter t-bu tyltr yp ta m in e (12) a n d N,N-Di-n -
p r op yl-5-ter t-bu tyltr yp ta m in e (13). To a stirred solution
of 9d (396 mg, 1.83 mmol) in 9 mL of CH3CN were added
K2CO3 (758 mg, 5.49 mmol) and n-PrI (933 mg, 5.49 mmol).
The mixture was stirred at room temperature for 4 h. Di-
chloromethane (60 mL) and water (30 mL) were added. The
organic layer was separated, washed with water, dried,
filtered, and concentrated. The residue was purified by flash
chromatography using 7% methanol, 1% NH4OH in CH2Cl2
to give both monoalkylated product 12 (12.6 mg, 0.05 mmol,
3%) and dialkylated product 13 (410 mg, 1.37 mmol, 75%).
Hydrochloride salt of 12 was prepared. 1H NMR (CDCl3) for
free base: 0.90 (t, J ) 7.0 Hz, 3H), 1.40 (s, 9H), 1.50 (m, 3H),
2.62 (t, J ) 7.0 Hz, 2H), 2.98 (m, 4H), 7.02 (d, J ) 1.5 Hz,
1H), 7.31 (m, 2H), 7.62 (s, 1H), 8.00 (br s, 1H). MS for free
base: 258 (M+). HRMS for hydrochloride: calcd for C17H27N2,
259.2174; found, 259.2176.
To a solution of 16 (91 mg, 0.22 mmol) in 10 mL of methanol
were added Pd/C (5%, 30 mg), and HCO2NH4 (100 mg, 1.59
mmol). The mixture was heated to reflux for 30 min. The
mixture was filtered through a pad of Celite and rinsed with
methanol. The filtrate was concentrated, and the residue was
purified by flash chromatography using 10% methanol, 1%
NH4OH in CH2Cl2 to afford 5-cyclopentyltryptamine (17) (41
mg, 0.18 mmol) in 82% yield. Hydrobromide salt of 17 was
prepared; mp 155-157 °C. 1H NMR (CD3OD) for free base:
0.90 (m, 4H), 1.06 (m, 2H), 1.28 (m, 2H), 2.12 (m, 4H), 2.27
(m, 1H), 6.21 (dd, J ) 9.8, 1.8 Hz, 1H), 6.22 (s, 1H), 6.45 (d, J
) 9.8 Hz, 1H), 6.59 (d, J ) 1.8 Hz, 1H). MS for free base: 228
(M+). HRMS for hydrobromide: calcd for C15H21N2, 229.1705;
found, 229.1699.
5-Cycloh exyltr yp ta m in e (9e). Compound 9e was pre-
pared by the method described for 9b . First, 4-cyclohexyl-
aniline (5e) (15.2 g, 86.7 mmol) was converted to 4-cyclohexyl-
phenylhydrazine hydrochloride (6e) (13.3 g, 58.7 mmol) in 68%
yield.
Then, the Fisher indole cyclization was carried out by
heating a mixture of compound 6e (4.08 g, 18.0 mmol) and 7
(5.24 g, 18.0 mmol) at 60 °C for 30 min in the presence of EtOH
(140 mL) and water (0.12 mL). After the usual workup and
flash chromatography using a 25:25:1 mixture of hexanes,
CH2Cl2, and methanol, compound 8e (24.5 g, 12.1 mmol) was
obtained in 67% yield.
Compound 8e (4.48 g, 12.0 mmol) was then treated with
hydrazine hydrate (12.0 mL) in the presence of 160 mL of
EtOH and 40 mL of H2O at room temperature for 15 h. After
workup, the residue was purified by flash chromatography
using 10% methanol, 1% NH4OH in CH2Cl2 to give 9e (2.80 g,
11.6 mmol) in 96% yield. Hydrochloride salt of 9e was
prepared; mp 227-229 °C. 1H NMR (CDCl3) for free base: 1.20
(br m, 7H), 1.90 (br m, 5H), 2.60 (m, 1H), 2.90 (t, J ) 6.8 Hz,
2H), 3.03 (t, J ) 6.8 Hz, 2H), 7.01 (d, J ) 1.5 Hz, 1H), 7.09
(dd, J ) 8.4, 1.5 Hz, 1H), 7.29 (d, J ) 8.4 Hz, 1H), 7.43 (s,
1H), 8.00 (br s, 1H). MS for free base: 242 (M+). Anal. for the
hydrochloride salt: (C16H23N2Cl) C, H, N.
N-Meth yl-5-ter t-bu tyltr yp ta m in e (10). To a stirred solu-
tion of 5-tert-butyltryptamine (9d ) (358 mg, 1.65 mmol) in 15
mL of THF were added (BOC)2O (378 mg, 1.73 mmol) and 2
N NaOH solution (0.83 mL, 1.66 mmol). The mixture was
stirred at room temperature for 1 h. CH2Cl2 (50 mL) and water
(50 mL) were added. The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (30 mL × 3).
The combined organic layers were dried, filtered, and concen-
trated to a residue that was used for the next step without
further purification.
Hydrochloride salt of 13 was prepared; mp 234-236 °C. 1H
NMR (CDCl3) for free base: 0.98 (t, J ) 7.1 Hz, 6H), 1.45 (s,
9H), 1.60 (m, 4H), 2.60 (t, J ) 7.1 Hz, 4H), 2.93 (m, 4H), 6.98
(d, J ) 1.5 Hz, 1H), 7.32 (m, 2H), 7.63 (s, 1H), 8.18 (br s, 1H.
MS for free base: 300 (M+). Anal. for the hydrochloride salt:
(C20H33N2Cl) C, H, N.
Refer en ces
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To a stirred suspension of LiAlH4 (235 mg, 6.2 mmol) in 15
mL of THF was added dropwise a solution of the residue from
the previous step in 8 mL of THF at 0 °C under nitrogen. The
mixture was warmed to room temperature and stirred for 30
min. It was then heated to reflux for 3 h. Upon cooling,
Na2SO4‚10H2O was slowly added to quench excess LiAlH4. The
suspension sat still for 30 min and then was filtered. The
filtrate was evaporated, and the residue was purified by flash
chromatography using 15% methanol, 1% NH4OH in CH2Cl2
to afford compound 10 (264 mg, 1.15 mmol) in 70% overall
yield. Hydrochloride salt of 10 was prepared; mp 221-223 °C.
1H NMR (CDCl3) for free base: 1.36 (br s, 1H), 1.40 (s, 9H),
2.43 (s, 3H), 2.96 (m, 4H), 7.01 (d, J ) 1.5 Hz, 1H), 7.30 (m,
2H), 7.61 (s, 1H), 7.96 (br s, 1H). MS for free base: 230 (M+).
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sulfonate (403 mg, 3.66 mmol). The mixture was stirred at
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with water, dried, filtered, and then concentrated. Purification
of the residue by flash chromatography using 10% methanol,
1% NH4OH in CH2Cl2 to give N,N-dimethyl-5-tert-butyl-
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