Synthesis of tryptamine derivatives via a direct, one-pot reductive alkylation of indoles

Article abstract of DOI:10.1021/jo3010028

An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin.

Full text of DOI:10.1021/jo3010028

Note
pubs.acs.org/joc
Synthesis of Tryptamine Derivatives via a Direct, One-Pot Reductive
Alkylation of Indoles
Marika Righi, Francesca Topi, Silvia Bartolucci, Annalida Bedini, Giovanni Piersanti,*
and Gilberto Spadoni
Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, 61029 Urbino (PU), Italy
S
* Supporting Information
ABSTRACT: An efficient, one-pot reductive alkylation of indoles
with N-protected aminoethyl acetals in the presence of TES/TFA
is reported. It represents the first general method for the direct
synthesis of tryptamine derivatives from indoles and nitrogen-
functionalized acetals. This convergent and versatile approach
employs safe and inexpensive reagents, proceeds under mild
conditions, and tolerates several functional groups. The new
procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor
antagonist, and melatonin.
ryptamines are an important class of biologically active
compounds whose structural motif is embedded in
ing system for our purpose was N-protected aminoacetaldehyde
dimethyl acetal and Et3SiH/TFA as a reagent combination. We
speculated that these reagents and reaction conditions could
also be used for the C-3 reductive alkylation of indoles, in order
to obtain tryptamine derivatives of pharmaceutical interest in a
single step. Although some examples of C-3 reductive alkylation
of indoles are known,11 there are no reports describing the use
of this protocol for the direct synthesis of tryptamine
derivatives. Herein, we describe the optimized conditions,
scope and applications for the selective C-3 reductive alkylation
of indoles with some protected aminoacetaldehydes (glycinal-
dehydes). We envisaged that achieving C-3 reductive alkylation
of indoles with suitable two-carbon nitrogen-containing
electrophiles such as N-protected aminoacetaldehyde dimethyl
acetals, would open up promising perspectives to the rapid and
practical synthesis of tryptamine and its derivatives.
Our investigation began by screening reaction parameters
using 2-methylindole 1a, which is not prone to polymerization,
as the model substrate and N-acetylaminoacetaldehyde
dimethyl acetal 2 with triethylsilane as the reductant, in
DCM (Table 1). As expected, no reaction occurred in the
absence of any acid additive (Table 1, entry 1). In agreement
with previous reports,11 in the presence of 1.5 equiv of
trifluoroacetic acid (TFA), bisindolyl derivative 4 was the major
product instead of the desired tryptamine 3a (Table 1, entry 2).
The amount of TFA required in our C-3 reductive alkylation
protocol could be critical, as it is necessary to activate different
stages of the process. Therefore, we decided to increase the
amount of TFA used, and we repeated the reaction using 3
equiv of TFA. As outlined in Table 1 (entry 3), we observed
formation of the desired 2-methyl-N-acetamidotryptamine in
addition to the bisindolyl derivative 4. Encouraged by this
T
numerous natural products, including commercial drugs1
(Figure 1). In addition, tryptamine is a biosynthetic precursor
of many alkaloid natural products, including approximately
3000 monoterpene indole alkaloids,2 and is frequently used as a
chemical building block in the total synthesis of biologically
active and pharmaceutically important compounds.3 Thus,
there is currently increased interest in tryptamines, and
methods for their synthesis are being studied.4−8
A variety of well-documented traditional and modern
methods for the synthesis of tryptamines have been described,
which can be divided into two broad categories. The first
approach involves a multistep sequence for the introduction of
the ethylene amine side chain in position 3 of the indole ring.
Two of the most important methods in this category utilize an
electrophilic aromatic substitution reaction with oxalyl chloride
followed by amidation and reduction4 or nitroethylation of
indoles followed by reduction.5 The second approach
constructs the pyrrole ring using an annulation method, such
as the Fischer6 indolization of arylhydrazines with a 4-
aminobutanal equivalent or the Larock heteroannulation
between o-haloanilines and an internal alkyne.7 Recently,
Nicolaou et al. reported a new three-step synthesis of
tryptamines starting from N-Boc-protected anilines.8 However,
some drawbacks of the above methodologies, including the
necessary isolation or preparation of reactive intermediates and
the use of multistep reaction sequences (one of which requires
the use of a strong reducing agent), leave room for
improvements.
As part of our ongoing efforts to synthesize melatonin
receptor agonists and antagonists,9 we recently reported an
efficient and selective one-pot reductive amination of anilines
for the rapid assembly of functionalized unsymmetrically
substituted ethylenediamine derivatives.10 A convenient alkylat-
Received: May 18, 2012
Published: June 22, 2012
© 2012 American Chemical Society
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Note
Figure 1. Natural products and pharmaceuticals containing tryptamines.
Table 1. Optimization of the Reaction Parameters
b
yield (%)
a
entry
TFA (equiv)
solvent (0.25 M)
silane
TES
time (h)
3a
4
c
1
2
DCM
DCM
DCM
DCM
CHCl3
toluene
THF
48
16
16
3
NR
NR
91
1.5
3
5
5
5
5
5
5
5
5
5
5
5
5
5
5
TES
3
TES
39
90
45
4
TES
5
TES
3
85
6
TES
3
71
7
TES
16
16
16
16
16
16
16
16
16
16
16
NR
NR
NR
47
NR
NR
NR
8
Et2O
TES
9
dioxane
CH3CN
DMF
TFE
TES
10
11
12
13
14
15
16
17
TES
TES
36
TES
35
H2O
TES
52
11
32
DCM
DCM
DCM
DCM
PMHS
(EtO)3SiH
TMDSO
Ph2SiH2
d
d
a
All reactions were performed at room temperature with 1.1 equiv of acetal, 1.0 equiv of 1a, and 3 equiv of silane in solvent/TFA with no
b
c
d
precautions taken to exclude moisture. Isolated yields. NR: no reaction. A complicated crude mixture was observed.
result, we further increased the amount of TFA (5 equiv) to
obtain the desired tryptamine derivative 3a as the only reaction
product in excellent isolated yield (90%) (Table 1, entry 4). A
similar phenomenon was observed in chloroform and toluene,
although the selectivity and yields were lower than in DCM. All
our attempts to improve the yields or the selectivity outcome
by changing the solvent were unsuccessful (Table 1, entries 7−
13). Decreased yields of the desired tryptamine derivative were
observed in trifluoroethanol, DMF, and acetonitrile, and no
reaction occurred with ethereal solvents such as diethyl ether,
THF, and dioxane. Only the bisindolyl adduct 4 was observed
in water. It appears that decreasing the nucleophilicity of the
medium increases the acidity of the system, thus promoting the
reaction. In addition to Et3SiH, other silanes such as Ph2SiH2,
(EtO)3SiH, polymethylhydrosiloxane (PMHS), and tetrame-
thyldisiloxane (TMDS) were also tested as reductants, but
none of them gave appreciable results (Table 1, entries 14−17).
Once reliable conditions to synthesize 2-methyl-N-acetami-
dotryptamine were established, we next investigated the scope
of this reaction using indoles with different substitution
patterns as summarized in Table 2.
A variety of 2-alkyl/aryl-substituted indoles were alkylated
smoothly in good yields, regardless of the length or steric
hindrance of the C-2 substituent (Table 2, entries 1−6).
Interestingly, it was also possible to perform C-3 reductive
alkylation of Nω-acetyl isotryptamine 1g12 to give the
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Note
indole C-3 reductive alkylation strategy could also be extended
to N-alkylated indoles 1o−t,13 independent of the presence of a
C-2 indole substituent to give the corresponding desired
tryptamines 3o−t, although in slightly lower yields (45−77%
yield) and requiring longer reaction times (Table 2, entries 16−
20).
Table 2. Scope of Indoles 1a−t in the C-3 Reductive
Alkylation with 2
Unfortunately, the indole does not afford the desired Nω-
acetyltryptamine. The shortcomings associated with completely
unsubstituted indoles in the reductive alkylation reaction are
likely a manifestation of increased reactivity of the product
toward further reaction with electrophiles present in the
reaction mixture, giving a complicated mixture of dimer and
oligomer products.14
To further expand the potential of this new one-pot single-
step synthesis of tryptamine derivatives, we also investigated an
orthogonal set of easily removable N-protected aminoalkyl
acetals.15 The reaction proceeded well in all cases (Table 3,
b
time
yield
a
entry product
R1
R2
R3
(h)
(%)
1
2
3a
3b
3c
3d
3e
3f
H
Me
But
H
H
H
H
H
H
H
H
H
3
3
6
3
4
4
3
90
70
76
66
74
97
60
H
3
H
cyclopentyl
4
H
t-But
5
H
Bn
6
H
Ph
7
3g
3h
3i
H
CH2CH2NHAc
d
8
H
COOH
COOMe
Me
Me
Me
Me
Ph
NR
NR
85
87
70
63
43
77
50
65
56
45
40
Table 3. Scope of Acetals 5−9 in the Reductive Alkylation of
1a
9
H
10
11
12
13
14
15
16
17
18
19
20
3j
H
5-Me
5-Cl
5-Bpin
5-OMe
6-OMe
H
3
3
3k
3l
H
H
3
c
c
3m
3n
3o
3p
3q
3r
3s
3t
H
2
H
2
Me
Me
Bn
Bn
PMB
Allyl
Me
H
3
H
4
a
b
H
H
16
2
entry
protecting group (Pg)
time (h)
yield (%)
product
c
H
5-OMe
H
1
2
3
4
5
Cbz (5)
Ftal (6)
Ts (7)
16
16
16
16
16
60
78
50
89
3u
3v
3w
3x
H
16
16
H
H
a
Reaction conditions: 2 (1 mmol), 1a−t (1.1 mmol), TFA (5 mmol),
and TES (3 mmol) in DCM (0.25 M) at rt for 3−60 h. Yield after
COCF3 (8)
H (9)
b
c
d
NR
3y
c
d
flash chromatography. DCE at 60 °C. NR: no reaction.
a
Reaction conditions: 5−9 (1 mmol), 1a (1.1 mmol), TFA (5 mmol),
b
and TES (3 mmol) in DCM (0.25 M) at rt for 3−16 h. Yield after
flash chromatography. NR: no reaction. From 3x using base.
c
d
interesting (bis-ethylamino)indole derivative 3g as a single
product in good yield (60%) (Table 2, entry 7); the same
compound 3g could be theoretically obtained by reacting Nω-
acetyltryptamine under the same reaction conditions, but these
attempts gave only polymerization side products. On the
contrary, no reactivity was observed with indoles bearing an
electron-withdrawing group in the C-2 position, such as 2-
indolecarboxylic acid or its ester (Table 2, entries 8 and 9),
even if higher reaction temperatures and prolonged reaction
times were used. A possible reason is that the presence of an
electron-withdrawing group might render the indoles highly
electron-deficient, preventing the electrophilic alkylation. A
similar lack of reactivity was observed with N1-acetyl- and N1-
sulfonylindoles (data not shown). Our synthetic protocol
worked well for indoles with both moderately electron-
donating (i.e., methyl, entry 10) and electron-withdrawing
(i.e., chloro, entry 11) 5-substituents giving the corresponding
tryptamines in high yields. However, when 5-methoxy-2-
methylindole reacted with acetal 2, only 19% yield was
obtained. However, increasing the reaction temperature to 60
°C led to a consistent improvement in the yield of the desired
tryptamine (Table 2, entry 13). Remarkably, the proposed C-3
reductive alkylation also tolerates the presence of a boronate
ester in the indole ring, offering unique, site-specific handles
that can be utilized in cross-coupling methodology for further
functionalization of tryptamines (Table 2, entry 12).
Encouraged by these results, we applied the reaction conditions
to 2-unsubstituted indole substrate. Gratifingly, the above
entries 1−4), although more slowly. Interestingly, the N-
trifluoroacetyl protecting group proved to be well tolerated to
the reaction conditions and easily removed by simple basic
hydrolysis, directly on the crude reaction mixture, to give
tryptamine 3y in very high yield;16 the same compound was not
obtained by using the simple amino acetal 9.
A wide range of synthetic applications of this procedure can
be envisaged. For instance, the method was extended to the
practical gram-scale synthesis of luzindole (Scheme 1), a widely
used and expensive MT2 melatonin receptor antagonist.
Scheme 1. Multigram-Scale Reductive Alkylation for the
Synthesis of Luzindole and Melatonin
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Note
3H), 2.36 (s, 3H), 2.91 (t, J = 6.5 Hz, 2H), 3.49 (dt, J1 ≈ J2 = 6.5 Hz,
2H), 5.75 (bs, 1H), 7.05−7.17 (m, 2H), 7.25−7.29 (m, 1H), 7.47−
7.51 (m, 1H), 8.44 (bs, 1H). 13C NMR (CDCl3) δ 11.5, 23.3, 24.1,
40.1, 108.3, 110.4, 117.7, 119.3, 121.1, 128.6, 132.1, 135.3, 170.3. Anal.
Calcd for C13H16N2O (216): C, 72.19; H, 7.46; N, 12.95. Found: C,
72.10; H, 7.18; N, 12.94. Data was consistent with that reported in the
literature.18a
Although it constitutes a standard reference compound for
pharmacologists in the melatonin field, the reported multistep
preparation sequences are laborious and give poor overall
yields.17 The single step gram-scale preparation reaction is
conveniently carried out at room temperature under an air
atmosphere with the inexpensive and easily handled starting
material 2-benzylindole in good yield. In order to show the
viability of this method, we also prepared 2-unsubstituted
tryptamine derivatives in gram scale. The treatment of readily
available N-benzyl-5-methoxyindole with acetal 2, followed by
reductive removal of the N1-benzyl group by Na/NH3,
afforded, in acceptable yields, N-acetyl-5-methoxytryptamine
(melatonin), a neurohormone mainly secreted by the pineal
gland and known to play a key role in regulating the body’s
circadian rhythms, including the sleep−wake cycle and mood.18
This chemistry can in principle be easily adapted to provide
access to various analogues of 5-alkoxy- and/or 5-hydroxytrypt-
amine, which may not be readily available otherwise.
In summary, a new, direct, one-pot method for the synthesis
of tryptamine derivatives has been developed, via C-3 reductive
alkylation of indoles and readly available protected glycinalde-
hyde acetals. Protected glycinaldehyde acetals have shown to be
useful two-carbon nitrogen containing electrophiles and could
be utilized to obtain products incorporating the amino ethane
fragment. The present approach constitutes one of the most
efficient, practical, and straightforward methods for a variety of
substituted tryptamines. This powerfully simplified reaction has
enabled the gram-scale synthesis of two important and
biologically active tryptamine derivatives: the neurohormone
melatonin and the reference melatonin receptor antagonist
luzindole. Given the simplicity, efficiency, and functional group
tolerance, this general method is expected to find wide
applications in chemical synthesis in general and in the
construction of tryptamine-based complex molecules.
N-[2-(2-Butyl-1H-indol-3-yl)ethyl]acetamide (3b). Purification by
silica gel column chromatography (cyclohexane/EtOAc 1:1) gave the
product in 70% yield (181 mg): yellowish oil; ESI MS (m/z) 259 [M
1
+ H]+; IR (cm−1, film) 1620; H NMR (CDCl3) δ 0.96 (t, J = 7 Hz,
3H), 1.35−1.50 (m, 2H), 1.58−1.73 (m, 2H), 1.91 (s, 3H), 2.75 (t, J =
7 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H), 3.54 (dt, J1 ≈ J2 = 6.5 Hz, 2H),
5.53 (bs, 1H), 7.07−7.19 (m, 2H), 7.27−7.34 (m, 1H), 7.51−7.55 (m,
1H), 7.98 (bs, 1H); 13C NMR (CDCl3) δ 13.9, 22.6, 23.3, 24.1, 25.8,
32.2, 40.2, 107.9, 110.6, 117.9, 119.2, 121.1, 128.5, 135.4, 136.9, 170.3.
Anal. Calcd for C16H22N2O (258): C, 74.38; H, 8.58; N, 10.84. Found:
C, 74.29; H, 8.45; N, 10.69. Data was consistent with that reported in
the literature.18a
N-(2-(2-Cyclopentyl-1H-indol-3-yl)ethyl)acetamide (3c). Purifica-
tion by silica gel column chromatography (cyclohexane/EtOAc 1:1)
gave the product in 76% yield (205 mg): off-white solid; mp 147−149
1
°C (Et2O); ESI MS (m/z) 271 [M + H]+; IR (cm−1, film) 1654; H
NMR (CDCl3) δ 1.60−2.09 (m, 11H), 2.96 (t, J = 6.5 Hz, 2H), 3.22−
3.39 (m, 1H), 3.54 (dt, J1 ≈ J2 = 6.5 Hz, 2H), 5.62 (bs, 1H), 7.06−7.19
(m, 2H), 7.27−7.35 (m, 1H), 7.50−7.54 (m, 1H), 8.19 (bs, 1H); 13C
NMR (CDCl3) δ 23.4, 24.2, 25.8, 33.6, 36.7, 40.2, 107.8, 110.6, 117.9,
119.3, 121.2, 128.5, 135.4, 139.8, 170.0. Anal. Calcd for C17H22N2O
(270): C, 75.52; H, 8.20; N, 10.36. Found: C, 75.56; H, 8.39; N, 10.64.
N-(2-(2-tert-Butyl-1H-indol-3-yl)ethyl)acetamide (3d). Purification
by silica gel column chromatography (cyclohexane/EtOAc 1:1) gave
the product in 66% yield (170 mg): amorphous off-white solid; ESI
MS (m/z) 259 [M + H]+; IR (cm−1, film) 1647; 1H NMR (CDCl3) δ
1.50 (s, 9H), 1.95 (s, 3H), 3.14 (t, J = 7 Hz, 2H), 3.59 (dt, J1 ≈ J2 = 7
Hz, 2H), 5.84 (bs, 1H), 7.06−7.20 (m, 2H), 7.32−7.36 (m, 1H),
7.55−7.60 (m, 1H), 8.26 (bs, 1H); 13C NMR (CDCl3) 23.4, 25.4,
30.7, 33.0, 40.5, 106.7, 110.5, 118.0, 119.3, 121.2, 129.7, 134.1, 143.0,
170.2. Anal. Calcd for C16H22N2O (258): C, 74.38; H, 8.58; N, 10.84.
Found: C, 74.45; H, 8.63; N, 11.12.
EXPERIMENTAL SECTION
N-[2-(2-Benzyl-1H-indol-3-yl)ethyl]acetamide (3e). The reaction
was run on 10 mmol (2.07 g) scale. Purification by silica gel column
chromatography (cyclohexane/EtOAc 1:1) gave the product in 74%
yield (2.16 g): white solid; mp 103−104 °C (EtOAc); ESI MS (m/z)
■
General Information. All reactions were run in round-bottom
flasks. Column chromatography purifications were performed in flash
conditions using 230−400 mesh silica gel. Analytical thin-layer
chromatography (TLC) was carried out on silica gel plates (silica
gel 60 F254) that were visualized by exposure to ultraviolet light and an
1
293 [M + H]+; IR (cm−1, film) 1630; H NMR (CDCl3) δ 1.80 (s,
3H), 3.01 (t, J = 6.5 Hz, 2H), 3.54 (dt, J1 ≈ J2 = 6.5 Hz, 2H), 4.13 (s,
2H), 5.48 (bs, 1H), 7.08−7.38 (m, 8 H), 7.55−7.59 (m, 1H), 7.84 (bs,
1H); 13C NMR (CDCl3) δ 23.2, 24.2, 32.2, 40.1, 109.4, 110.7, 118.2,
119.5, 121.6, 126.8. 128.4, 128.5, 128.9, 134.3, 135.7, 138.7, 170.1.
Anal. Calcd for C19H20N2O (292): C, 78.05; H, 6.89; N, 9.58. Found:
C, 78.14; H, 6.75; N, 9.64. Data was consistent with that reported in
the literature.17b
1
aqueous solution of cerium ammonium molybdate (CAM). H NMR
and 13C NMR spectra were recorded at 200/50 MHz on spectrometer
using CDCl3 or DMSO-d6 as solvent. Chemical shifts (scale) are
reported in parts per million (ppm) relative to the central peak of the
solvent. Coupling constants (J values) are given in hertz (Hz). ESI-MS
spectra were taken on an LC−MS instrument. Only molecular ions (M
+ 1) are given for the ESI-MS analysis. Absorbances are reported in
cm−1 for the IR analysis. Melting points were determined on a capillary
melting point apparatus and are uncorrected. Elemental analyses were
within 0.4 of the theoretical values (C, H, N).
N-[2-(2-Phenyl-1H-indol-3-yl)ethyl]acetamide (3f). Purification by
silica gel column chromatography (cyclohexane/EtOAc 1:1) gave the
product in 97% yield (270 mg): yellow solid; mp 114−116 °C
1
(hexane); ESI MS (m/z) 279 [M + H]+; IR (cm−1, film) 1620; H
General Procedure for the Reductive Alkylation of Indoles.
A solution of suitable indole (1 mmol) and acetal (1.1 mmol) in DCM
(2 mL) was added to a solution of trifluoroacetic acid (TFA, 5 mmol)
and triethylsilane (TES, 3 mmol) in DCM (2 mL), and the resulting
mixture was stirred at room temperature for 3−16 h. The reaction was
cooled at 0 °C and carefully neutralized with saturated solution of
NaHCO3 and diluted with DCM. The two phases were separated, and
the aqueous layer was extracted three times with DCM (20 mL). The
combined organic phase was washed with brine, dried over Na2SO4,
filtered, and evaporated on rotary evaporator. The residue was purified
by flash chromatography on silica gel affording desired compounds.
N-[2-(2-Methyl-1H-indol-3-yl)ethyl]acetamide (3a). Purification
by silica gel column chromatography (EtOAc) gave the product in
90% yield (194 mg): yellow solid; mp 83−85 °C (EtOAc); MS (ESI)
NMR (CDCl3) δ 1.77 (s, 3H), 3.14 (t, J = 7 Hz, 2H), 3.56 (dt, J1 ≈ J2
= 7 Hz, 2H), 5.52 (bs, 1H), 7.13−7.27 (m, 2 H), 7.35−7.68 (m, 7H),
8.37 (bs, 1H); 13C NMR (CDCl3) δ 23.1, 24.4, 40.2, 109.7, 111.1,
118.9, 119.8, 122.4, 127.9, 128.0, 129.0, 133.0, 135.4, 136.0, 170.2.
Anal. Calcd for C18H18N2O (278): C, 77.67; H, 6.52; N, 10.06. Found:
C, 77.65; H, 6.45; N, 10.21. Data was consistent with that reported in
the literature.18a
N,N′-[2,2′-(1H-Indole-2,3-diyl)bis(ethane-2,1-diyl)]diacetamide
(3g). Purification by silica gel column chromatography (EtOAc/
MeOH 9:1) gave the product in 60% yield (172 mg): amorphous off-
1
white solid; ESI MS (m/z) 288 [M + H]+; IR (cm−1, film) 1640; H
NMR (DMSO-d6) δ 1.79 (s, 3H), 1.81 (s, 3H), 2.73−2.86 (m, 4H),
3.17−3.40 (m, 4H), 6.90−7.04 (m, 2H), 7.24−7.28 (m, 1H), 7.45−
7.48 (m, 1H), 7.90−7.95 (m, 2H), 10.76 (s, 1H); 13C NMR (DMSO-
d6) δ 23.0, 23.1, 24.7, 26.5, 108.9, 111.1, 118.1, 118.6, 120.7, 128.6,
1
217 [M + H]+; IR (film, cm−1) 1620; H NMR (CDCl3) δ 1.89 (s,
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Note
134.3, 136.0, 169.5, 169.7. Anal. Calcd for C16H21N3O2 (287): C,
66.88; H, 7.37; N, 14.62. Found: C, 66.91; H, 7.56; N,14.91.
N-[2-(2,5-Dimethyl-1H-indol-3-yl)ethyl]acetamide (3j). Purifica-
tion by silica gel column chromatography (EtOAc) gave the product
in 85% yield (196 mg): red viscous oil; ESI MS (m/z) 231 [M + H]+;
(s, 1H), 7.10−7.35 (m, 3H), 7.59−7.63 (m, 1H); 13C NMR (CDCl3)
δ 11.6, 23.3, 24.1, 40.1, 108.4, 110.4, 117.7, 119.3, 121.1, 128.6, 132.1,
135.3, 170.2. Anal. Calcd for C13H16N2O (216): C, 72.19; H, 7.46; N,
12.95. Found: C, 72.08; H, 7.55; N, 12.81. Data was consistent with
that reported in the literature.13
N-[2-(1-Benzyl-1H-indol-3-yl)ethyl]acetamide (3q). Purification by
silica gel column chromatography (EtOAc) gave the product in 65%
yield (190 mg): yellowish oil; ESI MS (m/z) 293 [M + H]+; IR (cm−1,
film) 1630; 1H NMR (CDCl3) δ 1.92 (s, 3H), 2.99 (t, J = 7 Hz, 2H),
3.59 (dt, J1 ≈ J2 = 7 Hz, 2H), 5.30 (s, 2H), 5.62 (bs, 1H), 6.98 (s, 1H),
7.11−7.33 (m, 8H), 7.62−7.66 (m, 1H); 13C NMR (CDCl3) δ 23.3,
25.3, 40.0, 49.9, 109.8, 112.3, 119.0, 119.3, 122.0, 126.1, 126.9, 127.7,
128.1, 128.8, 136.8, 137.6, 170.1. Anal. Calcd for C19H20N2O (292): C,
78.05; H, 6.89; N, 9.58. Found: C, 78.14; H, 6.95; N, 9.39. Data was
consistent with that reported in the literature.13
N-[2-(1-Benzyl-5-methoxy-1H-indol-3-yl)ethyl]acetamide (3r).
The reaction was run on 10 mmol (2.37 g) scale. Purification by
silica gel column chromatography (EtOAc) gave the product in 56%
yield (1.81 g): off-white solid; mp 115 °C (EtOAc/hexane); ESI MS
(m/z) 323 [M + H]+; IR (cm−1, film) 1641; 1H NMR (CDCl3) δ 1.93
(s, 3H), 2.92 (t, J = 7 Hz, 2H), 3.59 (dt, J1 ≈ J2 = 7 Hz, 2H), 3.87 (s,
3H), 5.24 (s, 2H), 5.73 (bs, 1H), 6.85−6.95 (m, 2H), 7.08−7.20 (m,
4H), 7.29−7.32 (m, 3H); 13C NMR (CDCl3) δ 23.4, 25.3, 40.0, 49.4,
55.3, 109.8, 112.1, 114.1, 119.0, 119.2, 121.9, 126.0, 128.1, 128.3,
129.5, 136.7, 159.1, 170.1. Anal. Calcd for C20H22N2O2 (322): C,
74.51; H, 6.88; N, 8.69. Found: C, 74.41; H, 6.99; N, 8.59.
1
IR (cm−1, film) 1650, 2920, 3280; H NMR (CDCl3) δ 1.91 (s, 3H),
2.37 (s, 3H), 2.46 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 3.50 (dt, J1 ≈ J2 =
6.5 Hz, 2H), 5.58 (bs, 1H), 6.97 (d, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz,
1H), 7.28−7.29 (m, 1H), 7.97 (bs, 1H); 13C NMR (CDCl3) δ 11.6,
21.5, 23.3, 24.1, 40.1, 107.9, 110.1, 117.6, 122.6, 128.5, 128.8, 132.2,
133.6, 170.2. Anal. Calcd for C14H18N2O (230): C, 73.01; H, 7.88; N,
12.16. Found: C, 73.03; H, 7.81; N, 12.22 .
N-(2-(5-Chloro-2-methyl-1H-indol-3-yl)ethyl)acetamide (3k). Pu-
rification by silica gel column chromatography (EtOAc) gave the
product in 87% yield (218 mg): pink solid; mp 121−125 °C (Et2O);
ESI MS (m/z) 251 [M + H]+; IR (cm−1, film) 1630; 1H NMR
(CDCl3) δ 1.92 (s, 3H), 2.34 (s, 3H), 2.85 (t, J = 7 Hz, 2H), 3.44 (dt,
J1 ≈ J2 = 7 Hz, 2H), 5.82 (bs, 1H), 7.01−7.18 (m, 1H), 7.43 (1H),
8.66 (bs, 1H); 13C NMR (CDCl3) δ 23.1, 24.4, 40.2, 109.7, 111.1,
118.9, 119.8, 122.4, 127.9, 128.0, 129.0, 133.0, 135.4, 136.0, 170.2.
Anal. Calcd for C13H15ClN2O (250): C, 62.28; H, 6.03; N, 11.17.
Found: C, 62.35; H, 6.28; N, 11.51.
N-(2-(2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-indol-3-yl)ethyl)acetamide (3l). Purification by silica gel column
chromatography (EtOAc) gave the product in 70% yield (239 mg):
amorphous off-white solid; ESI MS (m/z) 343 [M + H]+; IR (cm−1,
1
film) 1658; H NMR (CDCl3) δ 1.37 (s, 12H), 1.91 (s, 3H), 2.37 (s,
N-[2-(1-(4-Methoxybenzyl)-1H-indol-3-yl)ethyl]acetamide (3s).
Purification by silica gel column chromatography (EtOAc) gave the
product in 45% yield (145 mg): amorphous off-white solid; ESI MS
(m/z) 323 [M + H]+; IR (cm−1, film) 1626; 1H NMR (CDCl3) δ 1.92
(s, 3H), 2.98 (t, J = 6 Hz, 2H), 3.59 (dt, J1 ≈ J2 = 6 Hz, 2H), 3.79 (s,
3H), 5.22 (s, 2H), 5.58 (bs, 1H), 6.82−6.87 (m, 2H), 6.95 (s, 1H),
7.07−7.35 (m, 5H), 7.60−7.64 (m, 1H); 13C NMR (CDCl3) δ 23.4,
25.3, 40.0, 49.4, 55.3, 109.8, 112.1, 114.1, 119.0, 119.2, 121.9, 126.0,
128.1, 128.3, 129.5, 136.7, 159.1, 170.1. Anal. Calcd for C20H22N2O2
(322): C, 74.51; H, 6.88; N, 8.69. Found: C, 74.43; H, 7.11; N, 8.81.
N-[2-(1-Allyl-1H-indol-3-yl)ethyl]acetamide (3t). Purification by
silica gel column chromatography (EtOAc) gave the product in 40%
yield (97 mg): amorphous off-white solid; ESI MS (m/z) 243 [M +
H]+; IR (cm−1, film) 1650; 1H NMR (CDCl3) δ 1.94 (s, 3H), 2.98 (t, J
= 6 Hz, 2H), 3.60 (dt, J1 ≈ J2 = 6 Hz, 2H), 4.69−4.72 (m, 2H), 5.06−
5.25 (m, 2H), 5.77 (bs, 1H), 5.90−6.09 (m, 1H), 6.96 (s, 1H), 7.10−
7.35 (m, 3H), 7.60−7.64 (m, 1H); 13C NMR (CDCl3) δ 23.4, 25.2,
40.0, 48.7, 109.7, 112.0, 117.3, 118.9, 119.1, 121.8, 125.7, 128.0, 133.5,
136.6, 170.1. Anal. Calcd for C15H18N2O (242): C, 74.35; H, 7.49; N,
11.56. Found: C, 74.26; H, 7.24; N, 11.42.
Benzyl 2-(2-Methyl-1H-indol-3-yl)ethylcarbamate (3u). Purifica-
tion by silica gel column chromatography (cyclohexane/EtOAc 8:2)
gave the product in 60% yield (185 mg): yellowish oil; ESI MS (m/z)
309 [M + H]+; IR (cm−1, film) 1700, 2930, 3320; 1H NMR (CDCl3) δ
2.34 (s, 3H), 2.95 (t, J = 7 Hz, 2H), 3.48 (dt, J1 ≈ J2 = 7 Hz, 2H), 4.91
(bs, 1H), 5.15 (s, 2H), 7.08−7.55 (m, 9H), 8.03 (bs, 1H); 13C NMR
(CDCl3) δ 11.5, 24.6, 41.5, 66.6, 108.2, 110.4, 117.8, 119.3, 121.1,
124.2, 128.1, 128.5, 130.5, 132.1, 135.3, 136.7, 156.5. Anal. Calcd for
C19H20N2O2 (308): C, 74.00; H, 6.54; N, 9.08. Found: C, 74.08; H,
6.52; N, 9.11.
3H), 2.91 (t, J = 6.5 Hz, 2H), 3.47 (dt, J1 ≈ J2 = 6.5 Hz, 2H), 5.55 (bs,
1H), 7.25−7.29 (m, 1H), 7.59 (d, J = 8 Hz, 1H), 8.00 (s, 1H), 8.21
(bs, 1H); 13C NMR (CDCl3) δ 11.5, 23.3, 24.0, 24.9, 40.3, 83.5, 109.0,
109.9, 125.4, 127.5, 128.3, 132.2, 137.5, 170.2 (carbon adjacent to
boron was not observed). Anal. Calcd for C19H27BN2O3 (342): C,
66.68; H, 7.95; N, 8.19. Found: C, 66.65; H, 7.98; N, 8.31.
N-[2-(5-Methoxy-2-methyl-1H-indol-3-yl)ethyl]acetamide (3m).
Purification by silica gel column chromatography (cyclohexane/
EtOAc 3:7) gave the product in 63% yield (155 mg): brownish oil;
ESI MS (m/z) 247 [M + H]+; IR (cm−1, film)1630; 1H NMR
(CDCl3) δ 1.91 (s, 3H), 2.36 (s, 3H), 2.88 (t, 2H, J = 6.5 Hz), 3.49
(dt, 2H, J1 ≈ J2 = 6.5 Hz), 3.85 (s, 3H), 5.58 (bs, 1H), 6.76−6.81 (m,
1H), 6.95−6.97 (m, 1H), 7.15−7.19 (m, 1 H), 7.94 (bs, 1H); 13C
NMR (CDCl3) δ 11.6, 23.3, 24.1, 40.0, 56.0, 100.1, 108.2, 110.7,
111.1, 129.0, 130.4, 133.0, 154.0, 170.2. Anal. Calcd for C14H18N2O2
(246): C, 68.27; H, 7.37; N, 11.37. Found: C, 68.25; H, 7.45; N, 11.22.
Data was consistent with that reported in the literature.6d
N-[2-(6-Methoxy-2-phenyl-1H-indol-3-yl)ethyl]acetamide (3n).
Purification by silica gel column chromatography (cyclohexane/
EtOAc 4:6) gave the product in 43% yield (78 mg): brownish oil;
ESI MS (m/z) 309 [M + H]+; IR (cm−1, film) 1625; 1H NMR
(CDCl3) δ 1.76 (s, 3H), 3.09 (t, 2H, J = 7.0 Hz), 3.53 (dt, 2H, J1 ≈ J2
= 7.0 Hz), 3.86 (s, 3H), 5.58 (bs, 1H), 6.79−6.90 (m, 2H), 7.28−7.56
(m, 6H), 8.43 (bs, 1H); 13C NMR (CDCl3) δ 23.2, 24.5, 40.2, 55.7,
94.6, 109.7, 119.6, 123.5, 127.5, 127.7, 129.0,133.1, 134.1,136.8, 156.8,
170.2. Anal. Calcd for C19H20N2O2 (308): C, 74.00; H, 6.54; N, 9.08.
Found: C, 74.11; H, 6.39; N, 9.36.
N-[2-(1,2-Dimethyl-1H-indol-3-yl)ethyl]acetamide (3o). Purifica-
tion by silica gel column chromatography (cyclohexane/EtOAc 3:7)
gave the product in 77% yield (177 mg): pink solid; mp 101−104 °C
(Et2O); ESI MS (m/z) 231 [M + H]+; IR (cm−1, film) 1650; 1H NMR
(CDCl3) δ 1.91 (s, 3H), 2.39 (s, 3H), 2.96 (t, 2H, J = 6.5 Hz), 3.49
(dt, 2H, J1 ≈ J2 = 6.5 Hz), 3.68 (s, 3H), 5.65 (bs, 1H), 7.07−7.31 (m,
3H), 7.51−7.55 (m, 1H); 13C NMR (CDCl3) δ 10.2, 23.4, 24.4, 29.6,
40.3, 107.7, 108.7, 117.7, 119.0, 120.8, 127.7, 133.8, 136.6, 170.0. Anal.
Calcd for C14H18N2O (230): C, 73.01; H, 7.88; N, 12.16. Found: C,
73.11; H, 7.92; N, 12.01. Data was consistent with that reported in the
literature.6d
2-[2-(2-Methyl-1H-indol-3-yl)ethyl]isoindolyn-1,3-dione (3v). Pu-
rification by silica gel column chromatography (cyclohexane/EtOAc
8:2) gave the product in 78% yield (238 mg): pale yellow solid; mp
171−174 °C (hexane); ESI MS (m/z) 305 [M + H]+; IR (cm−1, film)
1
1680; H NMR (CDCl3) δ 2.43 (s, 3H), 3.04−3.12 (m, 2H), 3.87−
3.95 (m, 2H), 7.05−7.15 (m, 2H), 7.24−7.27 (m, 1H), 7.64−7.87 (m,
6H); 13C NMR (CDCl3) δ 11.5, 23.5, 38.3, 107.8, 110.3, 117.9, 119.4,
121.1, 123.1, 128.6, 132.0, 132.2, 133.9, 135.2, 168.4. Anal. Calcd for
C19H16N2O2 (304): C, 74.98; H, 5.30; N, 9.20. Found: C, 75.03; H,
5.53; N, 8.93.
N-[2-(1-Methyl-1H-indol-3-yl)ethyl]acetamide (3p). Purification
by silica gel column chromatography (EtOAc) gave the product in
50% yield (108 mg): yellowish oil; ESI MS (m/z) 217 [M + H]+; IR
(cm−1, film) 1630; 1H NMR (CDCl3) δ 1.94 (s, 3H), 2.97 (t, J = 7 Hz,
2 H), 3.59 (dt, J1 ≈ J2 = 7 Hz, 2H), 3.78 (s, 3H), 5.64 (bs, 1H), 6.90
4 - M e t h y l - N - [ 2 - ( 2 - m e t h y l - 1 H - i n d o l - 3 - y l ) e t h y l ] -
benzenesulfonamide (3w). Purification by silica gel column
chromatography (cyclohexane/EtOAc 7:3) gave the product in 50%
yield (164 mg): brownish solid; mp 135−137 °C (hexane); ESI MS
6355
dx.doi.org/10.1021/jo3010028 | J. Org. Chem. 2012, 77, 6351−6357

The Journal of Organic Chemistry
Note
(m/z) 329 [M + H]+; IR (cm−1, film) 1654; 1H NMR (CDCl3) δ 2.34
(s, 3H), 2.41 (s, 3H), 2.90 (t, J = 6 Hz, 2H), 3.22 (dt, J1 ≈ J2 = 6 Hz,
2H), 4.46 (t, J = 6 Hz, 1H), 6.99−7.33 (m, 6H), 7.61−7.65 (m, 2H),
7.92 (bs, 1H); 13C NMR (CDCl3) δ 11.8, 21.6, 24.7, 43.3, 107.1,
110.5, 117.7, 119.5, 121.4, 127.1, 128.2, 129.7, 132.6, 135.4, 136.9,
143.4. Anal. Calcd for C18H20N2O2S (328): C, 65.83; H, 6.14; N, 8.53.
Found: C, 65.75; H, 6.09; N, 8.46. Data was consistent with that
reported in the literature.6d
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: giovanni.piersanti@uniurb.it.
■
Notes
2,2,2-Trifluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]acetamide
(3x). Purification by silica gel column chromatography (cyclohexane/
EtOAc 7:3) gave the product in 89% yield (240 mg): brownish solid;
mp 98−102 °C (hexane); ESI MS (m/z) 271 [M + H]+; IR (cm−1,
film) 1630; 1H NMR (CDCl3) δ 2.39 (s, 3H), 3.01 (t, J = 6.5 Hz, 2H),
3.63 (dt, J1 ≈ J2 = 6.5 Hz, 2H), 6.50 (bs, 1H), 7.10−7.34 (m, 3H),
7.49−7.53 (m, 1H), 8.01 (bs, 1H); 13C NMR (CDCl3) δ 11.3, 23.5,
40.3, 107.1, 110.6, 115.9 (J = 285 Hz), 117.5, 119.6, 121.4, 128.2,
132.4, 135.4, 157.3 (J = 35 Hz). Anal. Calcd for C13H13F3N2O (270):
C, 57.78; H, 4.85; N, 10.37. Found: C, 57.65; H, 4.79; N, 10.26. Data
was consistent with that reported in the literature.6d
2-(2-Methyl-1H-indol-3-yl)ethanamine (3y). A solution of 3x (1
mmol) and potassium carbonate (5 mmol) in MeOH (20 mL)/H2O
(1.5 mL) was heated to reflux for 2 h. After removal of volatiles under
reduced pressure, to the residue was added water and the mixture
extracted three times with dichloromethane. The combined organic
phases were washed with brine, dried over sodium sulfate, filtered, and
concentrated. The residue was purified by silica gel flash
chromatography (dichloromethane/methanol 95:5): yield 75% (131
mg); mp 95 °C; ESI MS (m/z) 175 [M + H]+, 158 [M + H − NH3]+;
1H NMR (CDCl3) δ 1.83 (bs, 2H), 2.38 (s, 3H), 2.83−3.02 (m, 4H),
The authors declare no competing financial interest.
REFERENCES
■
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7.06−7.17 (m, 2H), 7.25−7.29 (m, 1H), 7.50−7.54 (m, 1H), 8.14 (bs,
1H); 13C NMR (CDCl3) δ 11.7, 28.1, 42.5, 108.8, 110.3, 117.9, 119.1,
120.9, 128.7, 132.0, 135.4. Anal. Calcd for C11H14N2 (174): C, 75.82;
H, 8.10; N, 16.08. Found: C, 75.79; H, 8.17; N, 16.18. Data was
consistent with that reported in the literature.16
́
(6) (a) Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D.
Tetrahedron 2001, 57, 1041−1048. (b) Khedkar, V.; Tillack, A.;
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N-[2,2-bis(2-Methyl-1H-3-yl)ethyl]acetamide (4). Compound 4
was isolated as the major product when 1.5 equiv of TFA was used.
Purification by silica gel column chromatography (cyclohexane/EtOAc
3:7) gave the product in 91% yield (314 mg): yellowish solid; mp
168−170 °C (EtOAc); ESI MS (m/z) 215 [M + H − C9H8NH]+; IR
1
(cm−1, film) 3297, 3209, 1618; H NMR (DMSO-d6) δ 1.74 (s, 3H),
2.32 (s, 6H), 3.93 (dd, J1 ≈ J2 = 7 Hz, 2H), 4.60 (t, J = 7 Hz, 1H),
6.76−6.94 (m, 4H), 7.19 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H),
7.73 (m, 1H), 10.64 (bs, 2H); 13C NMR (DMSO-d6) δ 12.7, 23.0,
34.5, 43.6, 111.2,112.4, 118.8, 119.2, 120.3,128.7, 132.4, 136.0, 170.1.
Anal. Calcd for C22H23N3O (345): C, 76.49; H, 6.71; N, 12.16. Found:
C, 76.59; H, 6.77; N, 12.18.
(7) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689−
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Melatonin. In THF (40 mL) was condensed NH3 (105 mL) at
−78 °C followed by addition of Na (970 mg, 42 mmol). A solution of
3r (2.25 g, 7 mmol) in THF (40 mL) was then added dropwise, and
the mixture was stirred at −33 °C for 1 h. Solid NH4Cl was added, the
bath removed, and the ammonia allowed to evaporate. The solvent
was evaporated under reduced pressure, water (80 mL) was added,
and the aqueous layer was extracted three times with EtOAc (60 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel (EtOAc) to give melatonin as a white solid: yield 92% (1.18
g); mp 117−120 °C; ESI MS (m/z): 233 [M + H]+; IR (cm−1, film)
(8) Nicolaou, K. C.; Krasovskiy, A.; Majumder, U.; Trepanier, V. E.;
Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131, 3690−3699.
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Lucini, V.; Pannacci, M.; Fraschini, F.; Scaglione, F.; Ochoa Sanchez,
R.; Gobbi, G.; Tarzia, G. J. Med. Chem. 2007, 50, 6618−6626.
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Lucini, V.; Pannacci, M.; Caronno, A.; Scaglione, F.; Gobbi, G.;
Spadoni, G.; Bedini, A.; Orlando, P.; Lucarini, S.; Tarzia, G.
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1
1627; H NMR (CDCl3) δ 1.93 (s, 3H), 2.94 (t, J = 7 Hz, 2H), 3.59
(dd, J1 ≈ J2 = 7 Hz, 2H), 3.86 (s, 3H), 5.69 (bs, 1H), 6.87 (d, J = 8.5
Hz, 1H), 7.02 (d, J = 5.0 Hz, 2H), 7.27 (d, J = 8.5 Hz 1H), 8.32 (bs,
1H); 13C NMR (CDCl3) δ 23.4, 25.3, 39.8, 55.9, 100.4, 112.1, 112.4,
112.6, 122.7, 127.7, 131.6, 154.1, 170.2. Anal. Calcd for C13H16N2O2
(232): C, 67.22; H, 6.94; N, 12.06. Found: C, 67.15; H, 6.83; N, 12.26.
Data was consistent with that reported in the literature.18c
(10) Righi, M.; Bedini, A.; Piersanti, G.; Romagnoli, F.; Spadoni, G. J.
Org. Chem. 2011, 76, 704−707.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental details of the reactions and copies of H NMR
and 13C NMR spectra for all substrates and products. This
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Note
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