Palladium-catalyzed synthesis of 2-(aminomethyl)indoles from 3-(o -trifluoroacetamidoaryl)-1-propargylic alcohols and amines

Article abstract of DOI:10.1021/jo401456x

A novel palladium-catalyzed approach to 2-(aminomethyl)indoles from 3-(o-trifluoroacetamidoaryl)-1-propargylic alcohols and amines has been developed.

Full text of DOI:10.1021/jo401456x

Note
pubs.acs.org/joc
Palladium-Catalyzed Synthesis of 2‑(Aminomethyl)indoles from
3‑(o‑Trifluoroacetamidoaryl)-1-propargylic Alcohols and Amines
Sandro Cacchi, Giancarlo Fabrizi, Antonella Goggiamani,* Carmela Molinaro, and Rosanna Verdiglione
̀
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Rome, Italy
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed approach to
2-(aminomethyl)indoles from 3-(o-trifluoroacetamidoaryl)-1-
propargylic alcohols and amines has been developed.
ecently, we reported that the 2-(aminomethyl)indole motif,
a key structural feature present in several biologically active
2 equiv of diethylamine, a decrease in the yield was observed
(Table 1, entry 8). Pleasingly, after some experimentation, we
found that a satisfactory 76% yield could be obtained upon
treatment of 1a with 2 equiv of diethylamine in the presence of
PdCl2(PPh3)2 in DMF at 100 °C after 1 h (Table 1, entry 9).
A brief investigation of other protecting groups (benzyl, acetyl,
and mesyl groups) as wellas of the behavior of 3-(o-aminophenyl)-
1-propargyl alcohol under the conditions described in Table 1,
entry 10 revealed that the trifluoroacetyl derivative provides the
best results. The starting material was recovered in almost
quantitative yield with 1′a and 1′b, and no evidence of indole
derivatives was attained (Table 2, entries 1 and 2). With the acetyl
derivative 1′c, the 2-(aminomethyl)indole 2a was isolated in only
52% yield, and the mesyl derivative 1′d formed a mixture of the
corresponding protected and unprotected 2-(hydroxymethyl)-
indole in 76% overall yield. The reason why no substitution of the
amino for the hydroxy group takes place with the mesyl protecting
group is unclear at the present time.
The best conditions found for 1a [2 equiv of amine, 0.01 equiv
of PdCl2(PPh3)4, 2 equiv of K2CO3, DMF, 100 °C] were then
used when the reaction was extended to include other amines. As
shown in Table 3, a variety of secondary amines can be
successfully employed, even when bulky substituents are close to
the nitrogen atom (Table 3, entries 4 and 5). In the latter case,
the yields are higher than or comparable to those obtained with
the corresponding carbonate esters.2 Even primary amines
appeared to provide better results with the present method,
although the indoles were isolated in low to moderate yields. For
example, treatment of 1a with butylamine and benzylamine
afforded the corresponding indoles in 56 and 50% yield,
respectively (Table 3, entries 6 and 11), while complex reaction
mixtures were obtained when ethyl 3-(o-trifluoroacetamido-
phenyl)-1-propargyl carbonate was treated with the same
amines.2
R
compounds,1 could be assembled by the palladium-catalyzed
reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargylic
carbonates with secondary amines.2 Although the procedure is
simple and the reaction proceeds under mild conditions, it
requires the initial conversion of the hydroxy group of the
corresponding propargylic alcohol into a better leaving group
such as the carbonate. Clearly, a procedure based on the direct
utilization of 3-(o-trifluoroacetamidophenyl)-1-propargylic alco-
hols, eliminating one operative step, would be desirable for
environmental and practical reasons as well as in terms of atom
economy.3 There are also some limitations in the scope of the
reaction that arise from its ineffectiveness with primary amines.
For example, with benzylamine and butylamine, complex
reaction mixtures were obtained that we did not investigate.2
Furthermore, ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic
carbonates bearing an alkyl substituent at the propargylic carbon
undergo an elimination reaction4 to give 2-vinylic indoles instead
of producing the desired 2-(aminomethyl)indole derivative.5
These drawbacks prompted us to investigate further this
transformation, and here we report the results of this study.
We started our study by examining the conversion of 3-
(o-trifluoroacetamidophenyl)-1-propargyl alcohol (1a) and diethyl-
amine into 2-(diethylaminomethyl)indole (2a). The initial
screen was performed using 10 equiv of diethylamine at 80 °C,
investigating the influence of palladium catalysts and solvents on
the reaction outcome. Under the same conditions used with
the corresponding carbonate ester, 2a could be isolated only in
24% yield, the main product being 2-(hydroxymethyl)indole
(3a) (Table 1, entry 1). Moderate yields were obtained with
Pd(OAc)2 and Pd2(dba)3 in DMF (Table 1, entries 2 and 3).
6
Switching to Pd(PPh)4 and PdCl2(PPh3)2 in DMF led to the
isolation of 2a in 67% yield (Table 1, entries 4 and 5), and the
addition of K2CO3, particularly with PdCl2(PPh3)2, led to a
further increase in the yield, as the desired indole was isolated in
74% yield (Table 1, entry 7). We then attempted the use of a
lower amount of amine. However, when 1a was treated with
Received: July 5, 2013
© XXXX American Chemical Society
A
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Note
a
Table 1. Optimization Studies for the Reaction of 1a with Diethylamine
b
Yield (%)
Entry
[Pd]
Solvent
Added base
Temp. (°C)
Time (h)
2a
3a
c
1
2
Pd(PPh3)4
Pd(OAc)2
THF
−
−
−
−
80
4
24
55
48
67
67
69
74
65
76
74
46
48
65
64
68
27
38
8
c
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN
DMF
DMF
DMF
80
1.5
5.5
3
d
c
3
Pd2(dba)3
80
c
4
Pd(PPh3)4
80
c
5
PdCl2(PPh3)2
Pd(PPh3)4
−
80
5
13
22
7
c
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
−
K2CO3
K2CO3
K2CO3
80
1.5
1.5
1.5
1
c
7
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PCy3)2
PdCl2(MeCN)2
80
e
8
80
−
−
10
13
−
e
9
100
e
10
11
12
13
14
100
4.5
7.5
1.5
2
e
100
e
100
e
100
−
−
f
e
Hermann cat.
100
3
a
Unless otherwise stated, reactions were carried out on a 0.5 mmol scale under an argon atmosphere using 2 or 10 equiv of Et2NH, 2 equiv of
b
c
d
K2CO3 (when added), and 0.01 equiv of [Pd] in 2 mL of solvent. Yields are given for isolated products. With 10 equiv of Et2NH. With 0.005
equiv of Pd2(dba)3. With 2 equiv of Et2NH. With 0.005 equiv of the Hermann catalyst.7
e
f
a
Table 2. Palladium-Catalyzed Reactions of 1′a−d with Diethylamine
a
Reactions were carried out on a 0.5 mmol scale under an argon atmosphere at 100 °C using 2 equiv of Et2NH, 2 equiv of K2CO3, and 0.01 equiv of
b
c
PdCl2(PPh3)2 in 2 mL of DMF. Yields are given for isolated products. The starting material was recovered in almost quantitative yield.
We next turned our attention to 3-(o-trifluoroacetamidophenyl)-
1-propargylic alcohols bearing an alkyl substituent at the
propargylic carbon. In our previous study,5 the carbonate esters
of these substrates were found to give 2-vinylic indoles instead
of the desired 2-(aminomethyl)indole derivatives. We were
pleased to find that treatment of 1d with diethylamine led to the
isolation of the corresponding aminoindole 2n in good yield
(Table 4, entry 1). A brief optimization study showed that 2n
could be isolated in 77% yield using a 3 equiv excess of
diethylamine (Table 4, entry 4).
propargylic carbon led to the results summarized in Table 5.
Moderate to high yields were obtained in several cases. As a
comparison, the reaction of 1f with N-ethylpiperazine gave the
aminoindole 2q in 52% yield (Table 5, entry 4) and only traces,
if any, of the 2-vinylic derivative, while the related reaction with
the carbonate ester (Scheme 1) produced the corresponding
2-vinylic indole in high yield.5 Interestingly, the reaction met
with failure when 1e was treated with diisopropylamine (Table 5,
entry 6), and with butylamine the indole derivative was isolated
in only 39% yield (Table 5, entry 7). Better results were obtained
when these amines were reacted with the corresponding
carbonate ester at 80 °C in THF in the presence of Pd(PPh3)4.5
The application of these conditions to other amines and
3-(o-trifluoriacetamidoaryl)-1-propargylic alcohols substituted at the
B
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Note
a
Table 3. Synthesis of 2-Aminomethylindoles 2 from 1 and Amines
a
Reactions were carried out on a 0.5 mmol scale at 100 °C in 2 mL of DMF under a nitrogen atmosphere using 2 equiv of the amine, 2 equiv of
b
K2CO3, and 0.01 equiv of PdCl2(PPh3)2. Yields are given for isolated products.
Table 4. Optimization Studies for the Reaction of 1d with
Diethylamine
behavior depends on the different mechanism involved in the
formation of the carbon−nitrogen bond: with the carbonate
ester, the nitrogen nucleophile attacks the planar allylic terminus
of a π-allylpalladium complex,2 while with the propargylic
alcohol, the carbon−nitrogen bond is formed via nucleophilic
substitution (very likely an SN2-type substitution; vide infra) at a
more hindered secondary carbon atom. In the latter case, steric
effects can play a major role in controlling the reaction outcome,
accounting for the failure in the reaction with the sterically
encumbered diisopropylamine and for the low yield obtained
with butylamine. Butylamine, like other primary amines, shows a
higher tendency to give competitive side reactions under the
conditions used compared with secondary amines. Thus, in the
presence of a hindered electrophilic center, these side reactions may
compete more effectively and prevail over the desired substitution
reaction.
a
b
Entry
Et2NH (equiv)
Added base
Time (h)
Yield of 2n (%)
1
2
3
4
2
2
2
3
K2CO3
Cs2CO3
K3PO4
K2CO3
7.5
7.5
7.5
6.5
63
56
74
77
a
Reactions were carried out on a 0.5 mmol scale at 100 °C in 2 mL of
DMF under a nitrogen atmosphere using 2 or 3 equiv of the amine, 2
equiv of added base, and 0.01 equiv of PdCl2(PPh3)2. Yields are given
b
A possible rationale for this indole synthesis considers the
following elementary steps (Scheme 2; ligands have been
omitted): (a) oxidative addition of the N−H bond to
palladium(0),8 generated via reduction of palladium(II) by the
for isolated products.
Under these conditions, indole derivatives were isolated in
45 and 80% yield, respectively. Most probably, this different
C
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Note
Table 5. Cyclization of 3-(o-Trifluoroacetamidophenyl)-1-propargyl Alcohols Substituted at the Propargylic Carbon To Give
a
Indoles
a
Reactions were carried out on a 0.5 mmol scale at 100 °C in 2 mL of DMF under a nitrogen atmosphere using 3 equiv of the amine, 2 equiv of
b
c
K2CO3, and 0.01 equiv of PdCl2(PPh3)2. Yields are given for isolated products. 1e was recovered in 44% yield.
(reductive elimination of C would afford 2-hydroxymethylindole
Scheme 1. Reaction of a 3-(o-Trifluoroacetamidophenyl)-1-
propargyl Carbonate Bearing an Alkyl Substituent at the
Propargylic Carbon with a Secondary Amine
3); (e) reductive elimination that affords the intermediate E and
regenerates the active palladium catalyst; and (f) base-catalyzed
hydrolysis of the amide bond to give the 2-(aminomethyl)indole
derivative 2.
A mechanism of this type, based on the coordination of HPd+
to the carbon−carbon triple bond followed by a cyclization
step, has been proposed by Tsukada and Yamamoto10 for the
intramolecular hydrocarbonation of a 5-alkynylmalonitrile to
form a cyclopentane derivative. Furthermore, to provide some
experimental support for our proposal, we carried out the
following two experiments: the reaction of the 2-hydroxymethy-
lindole 3a with diethylamine (Scheme 3) and the reaction of
3-(p-trifluoroacetamidophenyl)-2-propyn-1-ol (4) with diethyl-
amine (Scheme 4), both under the standard reaction conditions.
The first reaction, with and without palladium, led to the
recovery of the starting material in almost quantitative yield,11
ruling out the presence of this indole derivative (which may even
be regarded as an allylic derivative)12 in the reaction pathway
leading to 2. The second one led to the recovery of the starting
material in 75% yield with no evidence of the substitution
product,13 ruling out a mechanism in which a palladium-
catalyzed propargylic amination14,15 precedes the cyclization
amine, to afford intermediate A (the acidity of the N−H bond
appears to play a key role in the oxidative addition, as no reaction
was observed when 1′a containing a free N−H bond and its
benzyl derivative 1′b were subjected to cyclization conditions;
Table 2, entries 1 and 2); (b) coordination of the cationic
palladium hydride fragment to the carbon−carbon triple bond to
generate B; (c) intramolecular nucleophilic attack of the anionic
nitrogen9 across the activated carbon−carbon triple bond to give
σ-indolylpalladium intermediate C; (d) direct nucleophilic
substitution of the amino nucleophile for the hydroxy group
assisted by the coordination of the oxygen to palladium to give D
D
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Note
results of the present procedure are significantly better than those
obtained with the corresponding carbonate esters.
Scheme 2. Proposed Reaction Mechanism
EXPERIMENTAL SECTION
■
General Methods. Melting points are uncorrected. All of the
reagents, catalysts, and solvents are commercially available and were
used as purchased, without further purification. The appropriate
2-alkynyltrifluoroacetanilides were prepared, usually in high yields,
from 2-iodoaniline via a two-step process involving a trifluoroacetylation
step followed by a Sonogashira cross-coupling with a terminal alkyne.11
Reaction products were purified by flash chromatography using SiO2 as
the stationary phase, eluting with n-hexane/ethyl acetate mixtures.
Typical Procedure for the Cyclization of 1. In a 50 mL Carousel
tube reactor (Radley Discovery Technology) containing a magnetic
stirring bar, PdCl2(PPh3)2 (0.005 mmol) was dissolved at room
temperature with 2.0 mL of DMF. Then, 3-(o-trifluoroacetamidophenyl)-
1-propargylic alcohol 1 (0.5 mmol), amine (1 mmol), and K2CO3
(1 mmol) were added. The mixture was stirred at 100 °C. Then, the
reaction mixture was cooled to room temperature, diluted with Et2O, and
washed with saturated NaHCO3 solution. The organic extract was dried
over Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, n-hexane/EtOAc) to afford
the pure indole derivative 2.
N-((1H-Indol-2-yl)methyl)-N-ethylethanamine (2a).2 Brown oil,
76%, 77.0 mg. 1H NMR (400.13 MHz, CDCl3): δ 8.81 (bs, 1H), 7.62
(d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23−7.13 (m, 2H), 6.41
(s, 1H), 3.80 (s, 2H), 2.64 (q, J = 7.2 Hz, 4H), 1.13 (t, J = 7.2 Hz, 6H).
13C NMR (100.6 MHz, CDCl3): δ 137.4, 136.1, 128.7, 121.3, 120.0,
119.5, 110.7, 100.8, 51.1, 46.9, 11.6.
2-(4-((1H-Indol-2-yl)methyl)piperazin-1-yl)benzonitrile (2b).2
1
Brown wax, 72%, 113.9 mg. H NMR (400.13 MHz, CDCl3): δ 8.56
(bs, 1H), 7.62−7.58 (m, 2H), 7.51−7.49 (m, 1H), 7.37 (d, J = 7.9 Hz,
1H), 7.22−7.18 (m, 1H), 7.15−7.11 (m, 1H), 7.06−7.01 (m, 2H), 6.44
(s, 1H), 3.77 (s, 2H), 3.28−3.26 (m, 4H), 2.75−7.73 (m, 4H). 13C NMR
(100.6 MHz, CDCl3): δ 155.6, 136.2, 135.5, 134.4, 133.8, 128.4, 121.8,
121.7, 120.3, 119.7, 118.7, 118.4, 110.7, 106.0, 101.9, 55.7, 53.2, 51.5.
2-((4-Ethylpiperazin-1-yl)methyl)-1H-indole (2c).2 Pale-yellow oil,
87%, 105.8 mg. 1H NMR (400.13 MHz, CDCl3): δ 8.73 (bs, 1H), 7.58
(d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.19−7.16 (m, 1H), 7.13−
7.10 (m, 1H), 6.40 (s, 1H), 3.69 (s, 2H), 2.57−2.43 (m, 10H), 1.12
(t, J = 7.2 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 136.2, 135.8,
128.4, 121.6, 120.2, 119.6, 110.7, 101.7, 55.9, 53.3, 52.8, 52.3, 12.0.
N-((1H-Indol-2-yl)methyl)-N-isopropylpropan-2-amine (2d).2
Scheme 3. Reaction of 2-Hydroxymethylindole (3a) with
Diethylamine
Scheme 4. Reaction of 2-Phenyl-2-propyn-1-ol 4 with
Diethylamine
1
Pale-yellow oil, 54%, 62.2 mg. H NMR (400.13 MHz, CDCl3): δ
10.54 (bs, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.20−
7.16 (m, 1H), 7.11−7.10 (m, 1H), 6.41 (s, 1H), 4.09 (s, 2H), 3.38−3.32
(m, 2H), 1.24 (d, J = 6.8 Hz, 12H). 13C NMR (100.6 MHz, CDCl3): δ
137.2, 136.0, 128.7, 121.4, 120.1, 119.6, 110.8, 100.9, 48.5, 40.5, 20.8.
2-((4-Methyl-2-phenylpiperazin-1-yl)methyl)-1H-indole (2e).2
1
Brown oil, 53%, 80.9 mg. H NMR (400.13 MHz, CDCl3): δ 8.55
(bs, 1H), 7.59−7.54 (m, 3H), 7.44−7.34 (m, 4H), 7.21−7.10 (m, 2H),
6.34 (s, 1H), 3.90, (d, J = 14.0 Hz, 1H), 3.51−3.49 (m, 1H), 3.17 (d, J =
14.0 Hz, 1H), 2.97−2.82 (m, 4H), 2.44−2.21 (m, 5H). 13C NMR (100.6
MHz, CDCl3): δ 141.4, 136.3, 136.0, 128.8, 128.6, 127.9, 121.4, 120.1,
119.6, 110.7, 101.3, 67.3, 63.7, 55.2, 52.2, 52.1, 45.7.
N-((1H-Indol-2-yl)methyl)butan-1-amine (2f).2 Pale-yellow oil,
56%, 56.6 mg. IR (neat): 3405, 2923, 2857, 1455, 1419, 1338, 1288,
748 cm−1. 1H NMR (400.13 MHz, CDCl3): δ 8.40 (bs, 1H), 7.62 (d, J =
8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.23−7.13 (m, 2H), 6.44 (s, 1H),
3.81 (s, 2H), 2.61−2.57 (m, 1H), 1.64−1.56 (m, 2H), 1.42−1.30
(m, 4H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ
136.1, 136.0, 128.5, 121.7, 120.2, 119.8, 110.7, 101.9, 53.7, 51.2, 29.1,
20.6, 14.1. HRMS (ESI) m/z: calcd for C13H19N2 [M + H]+ 203.1543,
found 203.1549.
step. Taken together, these experiments support the view that the
substitution of the amino group for the hydroxy group involves
an indole intermediate in which palladium can act as alcohol-
activating agent, possibly the intermediate C.
In summary, we have developed a novel palladium-catalyzed
approach to 2-(aminomethyl)indoles from 3-(o-trifluoroaceta-
midoaryl)-1-propargylic alcohols and amines. The procedure is
simple, uses readily available starting materials, and may
represent a useful tool for the synthesis of this class of
compounds. The reaction works well with secondary amines,
even with 3-(o-trifluoroacetamidoaryl)-1-propargylic alcohols
bearing an alkyl substituent at the propargylic carbon. With
primary amines, although moderate yields were obtained, the
N-((1H-Indol-2-yl)methyl)piperidin-1-amine (2g). Yellow wax, 24%,
1
27.5 mg. IR (KBr): 3409, 2933, 1455, 1384, 738 cm−1. H NMR
(400.13 MHz, CDCl3): δ 9.79 (bs, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.40 (d,
J = 8.0 Hz, 1H), 7.22−7.18 (m, 1H), 7.13−7.10 (m, 1H), 6.42 (s, 1H),
5.99 (bs, 1H), 3.86 (s, 2H), 2.67−2.66 (m, 4H), 1.73−1.71 (m, 4H),
E
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Note
1.56−1.54 (m, 2H). 13C NMR (100.6 MHz, CDCl3): δ 136.3, 135.4,
128.3, 121.5, 120.1, 119.5, 110.9, 101.7, 56.3, 54.4, 25.6, 24.1. HRMS
(ESI) m/z: calcd for C14H20N3 [M + H]+ 230.1652, found 230.1647.
N-((1H-Indol-2-yl)methyl)cyclohexanamine (2h). Brown oil, 47%,
58.1, 49.9, 14.2. HRMS (ESI) m/z: calcd for C14H19N2O [M + H]+
231.1492, found 231.1487.
2-(1-(4-(3,4-Dichlorophenyl)piperazin-1-yl)ethyl)-1H-indole (2p).
White solid, mp 116.9−117.6 °C, 52%, 97.3 mg. IR (KBr): 3455,
2937, 2825, 1594, 1455, 1247, 1147, 746 cm−1. 1H NMR (400.13 MHz,
CDCl3): δ 8.59 (bs, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz,
1H), 7.30 (d, J = 8.8 Hz, 1H), 7.24−7.13 (m, 2H), 6.98 (d, J = 3.2 Hz,
1H), 6.75 (dd, J1 = 8.8 Hz, J2 = 3.2 Hz, 1H), 6.41 (s, 1H), 3.95 (q, J = 6.4
Hz, 1H), 3.24−3.14 (m, 4H), 2.75−2.62 (m, 4H), 1.50 (d, J = 6.4 Hz,
3H). 13C NMR (100.6 MHz, CDCl3): δ 150.7, 141.1, 135.8, 132.8,
130.4, 128.5, 122.1, 121.6, 120.3, 119.6, 117.2, 115.3, 110.7, 100.1, 57.7,
49.1, 48.9, 13.8. HRMS (ESI) m/z: calcd for C20H22Cl2N3 [M + H]+
374.1185, found 374.1180.
2-(1-(4-Ethylpiperazin-1-yl)propyl)-1H-indole (2q). Orange oil,
52%, 70.1 mg. IR (neat): 3279, 2928, 1668, 1437, 1119, 723 cm−1. 1H
NMR (400.13 MHz, DMSO): δ 10.86 (bs, 1H), 7.44 (d, J = 7.6 Hz, 1H),
7.33 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H),
6.21 (s, 1H), 3.86−3.74 (m, 1H), 2.50−2.20 (m, 10H), 1.95−1.75
(m, 2H), 0.93 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.3
Hz, 3H). 13C NMR (100.6 MHz, DMSO): δ 140.9, 136.6, 132.0, 131.9,
128.6, 128.5, 127.1, 120.8, 119.9, 119.1, 111.4, 99.7, 52.6, 46.0. 13C NMR
(100.6 MHz, CDCl3): δ 138.4, 136.3, 128.1, 120.7, 119.8, 119.0, 111.4,
100.6, 64.7, 63.4, 53.2, 52.0, 24.3, 12.4, 11.7. HRMS (ESI) m/z: calcd for
C17H26N3 [M + H]+ 272.2121, found 272.2111.
1
54.0 mg. IR (neat): 3280, 2920, 1655, 1459, 1382, 790, 735 cm−1. H
NMR (400.13 MHz, CDCl3): δ 9.17 (bs, 1H), 7.55 (d, J = 7.6 Hz, 1H),
7.35 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H),
6.34 (s, 1H), 4.01 (s, 2H), 2.60−2.48 (m, 1H), 1.95 (d, J = 11.2 Hz, 2H),
1.76−1.70 (m, 2H), 1.66−1.60 (m, 1H), 1.25−1.10 (m, 6H). 13C NMR
(100.6 MHz, CDCl3): δ 137.3, 136.1, 128.4, 121.4, 120.0, 119.5, 110.9,
100.3, 56.2, 43.8, 31.4, 26.0, 24.9. HRMS (ESI) m/z: calcd for C15H21N2
[M + H]+ 229.1699, found 229.1705.
N-((1H-Indol-2-yl)methyl)pentan-1-amine (2i). Brown oil, 40%,
44.0 mg. IR (neat): 3280, 2928, 1668, 1437, 1385, 723 cm−1. 1H NMR
(400.13 MHz, CDCl3): δ 9.02 (bs, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.32
(d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.32
(s, 1H), 3.95 (s, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.21 (bs, 1H), 1.34−1.22
(m, 6H), 0.91−0.85 (m, 3H). 13C NMR (100.6 MHz, CDCl3): δ 137.6,
136.1, 128.6, 121.3, 120.0, 119.4, 110.8, 100.2, 60.3, 49.4, 46.9, 29.4,
22.5, 14.0. HRMS (ESI) m/z: calcd for C14H21N2 [M + H]+: 217.1699,
found 217.1693.
N-((1H-Indol-2-yl)methyl)-3-methylbutan-2-amine (2j). Brown oil,
52%, 56.2 mg. IR (neat): 3240, 2961, 1667, 1454, 1384, 784 cm−1. 1H
NMR (400.13 MHz, CDCl3): δ 8.91 (bs, 1H), 7.57 (d, J = 8.0 Hz, 1H),
7.36 (d, J = 8.0 Hz, 1H), 7.17−7.07 (m, 2H), 6.36 (s, 1H), 4.05 (d, J =
14.0 Hz, 1H), 3.95 (d, J = 14.0 Hz, 1H), 2.62−2.53 (m, 1H), 2.28 (bs,
1H), 1.86−1.73 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 6.82 Hz,
6H). 13C NMR (100.6 MHz, CDCl3): δ 138.2, 135.9, 128.5, 121.3,
120.0, 119.5, 110.7, 99.8, 57.7, 44.5, 32.3, 19.3, 17.3, 15.8. HRMS (ESI)
m/z: calcd for C14H21N2 [M + H]+ 217.1699, found 217.1694.
N-((1H-Indol-2-yl)methyl)-1-phenylmethanamine (2k). Brown oil,
50%, 59.1 mg. IR (neat): 3283, 2921, 1667, 1455, 749 cm−1. 1H NMR
(400.13 MHz, DMSO): δ 10.93 (bs, 1H), 7.44 (d, J = 7.2 Hz, 1H),
77.40−7.30 (m, 6H), 6.36 (s, 1H), 7.01 (t, J = 6.8 Hz, 1H), 6.94 (t, J =
7.2 Hz, 1H), 6.27 (s, 1H), 3.82 (s, 2H), 3.72 (s, 2H), 2.00 (bs, 1H). 13C
NMR (100.6 MHz, DMSO): δ 140.9, 136.6, 132.0, 131.9, 128.6, 128.5,
127.1, 120.8, 119.9, 119.1, 111.4, 99.7, 52.6, 46.0. HRMS (ESI) m/z:
calcd for C16H17N2 [M + H]+ 237.1386, found 237.1390.
2-((4-Ethylpiperazin-1-yl)methyl)-5-fluoro-1H-indole (2l). Pale-yel-
low solid, mp 102−104 °C, 58%, 75.8 mg. IR (KBr): 2971, 2813, 1488,
1450, 1174, 771 cm−1. 1H NMR (400.13 MHz, CDCl3): δ 8.73 (bs, 1H),
7.24−7.19 (m, 2H), 6.93−6.87 (m, 1H), 6.34 (s, 1H), 3.67 (s, 2H),
2.56−2.42 (m, 10H), 1.11 (t, J = 7.2 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3): δ 157.8 (d, JCF = 232 Hz), 137.6, 132.6, 128.7 (d, JCF = 10 Hz),
111.1 (d, JCF = 10 Hz), 109.7 (d, JCF = 26 Hz), 105.0 (d, JCF = 23 Hz),
101.7 (d, JCF = 4 Hz), 55.8, 53.2, 52.7, 52.3, 12.0. 19F NMR (376.5 MHz,
CDCl3): δ −125.1. HRMS (ESI) m/z: calcd for C15H21FN3 [M + H]+
262.1714, found 262.1719.
2-((4-Ethylpiperazin-1-yl)(phenyl)methyl)-1H-indole (2r).5 Pale-
yellow solid, mp 106−108 °C, 53%, 84.6 mg. 1H NMR (400.13 MHz,
CDCl3): δ 8.60 (bs, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz,
2H), 7.37−7.33 (m, 3H), 7.28 (m, 1H), 7.18−7.11 (m, 1H), 7.09−
7.07 (m, 1H), 6.41 (s, 1H), 4.64 (s, 1H), 2.57−2.45 (m, 10H), 1.11
(t, J = 7.2 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 139.1, 139.0,
136.0, 128.5, 128.4, 128.3, 127.6, 121.6, 120.3, 119.6, 110.8, 101.6, 69.2,
53.0, 52.2, 51.0, 11.8.
N-((1H-Indol-2-yl)(phenyl)methyl)butan-1-amine (2s).5 Pale-yel-
low oil, 39%, 54.3 mg. 1H NMR (400.13 MHz, CDCl3): δ 8.62 (bs, 1H),
7.59 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.39−7.32 (m, 4H),
7.21−7.11 (m, 2H), 6.36 (s, 1H), 5.08 (s, 1H), 2.71−2.66 (m, 2H), 1.84
(bs, 1H), 1.61−1.56 (m, 2H), 1.48−1.38 (m, 2H), 0.93 (t, J = 7.6 Hz,
3H). 13C NMR (100.6 MHz, CDCl3): δ 142.4, 141.1, 135.8, 128.7,
128.6, 127.6, 127.3, 121.5, 120.3, 119.6, 110.9, 100.2, 61.6, 47.8, 32.4,
20.5, 14.1.
2-((4-(4-Fluorophenyl)piperazin-1-yl)(phenyl)methyl)-1H-indole
(2t). Pale-yellow oil, 63%, 121.4 mg. IR (neat): 3399, 2830, 1712, 1455,
1240, 1139, 754 cm−1. 1H NMR (400.13 MHz, CDCl3): δ 8.50 (bs, 1H),
7.59 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.43−7.35 (m, 4H),
7.22−7.18 (m, 1H), 7.17−7.12 (m, 1H), 7.03−7.98 (m, 2H), 6.91−6.87
(m, 2H), 6.47 (s, 1H), 4.72 (s, 1H), 3.19−3.16 (m, 4H), 2.72−2.59 (m,
4H). 13C NMR (100.6 MHz, CDCl3): δ 157.2 (d, JCF = 237 Hz), 147.9,
138.9 (d, JCF = 23 Hz), 136.1, 128.7, 128.4, 128.3, 127.8, 126.7, 121.8,
120.4, 119.8, 117.7 (d, JCF = 7.8 Hz), 115.6 (d, JCF = 22 Hz), 110.9,
101.8, 69.2, 51.3, 50.4. 19F NMR (376.5 MHz, CDCl3): δ −124.4.
HRMS (ESI) m/z: calcd for C25H25FN3 [M + H]+ 386.2027, found
386.2021.
1-(5,7-Dimethyl-1H-indol-2-yl)-N,N-diethylethanamine (2u).
Brown wax, 45%, 55.0 mg. IR (KBr): 3455, 2969, 1600, 1457, 1382,
842, 750 cm−1. 1H NMR (400.13 MHz, CDCl3): δ 8.88 (bs, 1H), 7.24
(s, 1H), 6.84 (s, 1H), 6.29 (s, 1H), 4.25 (q, J = 6.4 Hz, 1H), 2.72−2.64
(m, 2H), 2.59−2.54 (m, 2H), 2.52 (s, 3H), 2.45 (s, 3H), 1.45 (d, J = 6.4
Hz, 3H), 1.13 (t, J = 7.2 Hz, 6H). 13C NMR (100.6 MHz, CDCl3): δ
133.7, 128.8, 128.3, 123.7, 119.8, 117.3, 99.8, 53.2, 43.4, 21.4, 16.7, 13.1,
12.0. HRMS (ESI) m/z: calcd for C16H25N2 [M + H]+ 245.2012, found
245.2018.
2-((4-Ethylpiperazin-1-yl)methyl)-5,7-dimethyl-1H-indole (2m).
Brown wax, 69%, 93.6 mg. IR (KBr): 3299, 2937, 2815, 1450, 1010,
1
750 cm−1. H NMR (400.13 MHz, CDCl3): δ 8.56 (bs, 1H), 7.22
(s, 1H), 6.83 (s, 1H), 6.32 (s, 1H), 3.69 (s, 2H), 2.57−2.44 (m, 16H),
1.12 (t, J = 7.2 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 135.0, 134.2,
129.0, 128.0, 123.9, 119.6, 117.5, 102.1, 55.9, 53.1, 52.6, 52.3, 21.4, 16.7,
12.0. HRMS (ESI) m/z: calcd for C17H26N3 [M + H]+ 272.2121, found
272.2115.
N,N-Diethyl-1-(1H-indol-2-yl)ethanamine (2n). Pale-yellow wax,
77%, 83.3 mg. IR (KBr): 3444, 2969, 1455, 1384, 1299, 784, 736 cm−1.
1H NMR (400.13 MHz, CDCl3): δ 8.71 (bs, 1H), 7.57 (d, J = 7.6 Hz,
1H), 7.36 (d, J = 8.0 Hz, 1H), 7.18−7.07 (m, 2H), 6.33 (s, 1H), 4.17
(q, J = 6.4 Hz, 1H), 2.63−2.43 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H), 1.08
(t, J = 7.2 Hz, 6H). 13C NMR (100.6 MHz, CDCl3): δ 143.3, 135.5,
128.9, 121.1, 120.0, 119.3, 110.5, 99.2, 52.8, 43.3, 13.9, 11.4. HRMS
(ESI) m/z: calcd for C14H21N2 [M + H]+ 217.1699, found 217.1693.
4-(1-(1H-Indol-2-yl)ethyl)morpholine (2o). Brown wax, 60%, 69.1
ASSOCIATED CONTENT
■
1
mg. IR (KBr): 3407, 2861, 1455, 1384, 1114, 750 cm−1. H NMR
S
* Supporting Information
(400.13 MHz, CDCl3): δ 8.63 (bs, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.38 (d,
J = 8.0 Hz, 1H), 7.21−7.10 (m, 2H), 6.38 (s, 1H), 3.86−3.71 (m, 5H),
2.62−2.47 (m, 4H), 1.47 (d, J = 6.8 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3): δ 141.0, 135.8, 128.4, 121.5, 120.2, 119.6, 110.7, 100.2, 67.3,
Copies of 1H and 13C NMR spectra of the products (2a−u). This
material is available free of charge via the Internet at http://pubs.
acs.org.
F
dx.doi.org/10.1021/jo401456x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
AUTHOR INFORMATION
Corresponding Author
*E-mail: antonella.goggiamani@uniroma1.it.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge FIRB Futuro e ricerca 2008 and the
University “La Sapienza”, Rome, for financial support.
■
REFERENCES
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G
dx.doi.org/10.1021/jo401456x | J. Org. Chem. XXXX, XXX, XXX−XXX