Catalyst-free, solvent-promoted and scalable multicomponent synthesis of 3-aminoalkylated indoles via a mannich-type reaction

Article abstract of DOI:10.5560/ZNB.2014-3313

A catalyst-free, solvent-promoted and scalable three-component Mannich-type reaction of indoles, aromatic aldehydes and secondary amines for the synthesis of 3-(1-dialkylaminoalkyl)-1H-indoles has been developed. The protocol provided a mild, simple and highly atom-economic alternative to prepare the title compounds, and the corresponding products could be obtained in good to excellent yields in most cases.

Full text of DOI:10.5560/ZNB.2014-3313

Catalyst-free, Solvent-promoted and Scalable Multicomponent Synthesis
of 3-Aminoalkylated Indoles via a Mannich-type Reaction
Jian-Fei Cao, Yan-Li Chen, Zhi Guan, and Yan-Hong He
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
P. R. China
Reprint requests to Dr. Zhi Guan or Dr. Yan-Hong He. Fax: +86-23-68254091.
E-mail: guanzhi@swu.edu.cn (Zhi Guan) or heyh@swu.edu.cn (Yan-Hong He)
Z. Naturforsch. 2014, 69b, 721 – 727 / DOI: 10.5560/ZNB.2014-3313
Received November 14, 2013
A catalyst-free, solvent-promoted and scalable three-component Mannich-type reaction of indoles,
aromatic aldehydes and secondary amines for the synthesis of 3-(1-dialkylaminoalkyl)-1H-indoles
has been developed. The protocol provided a mild, simple and highly atom-economic alternative to
prepare the title compounds, and the corresponding products could be obtained in good to excellent
yields in most cases.
Key words: Solvent-promoted, Scalable, Multicomponent Synthesis, 3-Aminoalkylated Indoles
Introduction
been reported [29]. Kumar and co-workers reported
L-proline-catalyzed Mannich-type reactions for the
Indole is probably the most ubiquitous motif in na- synthesis of 3-(1-dialkylaminoalkyl)-1H-indoles using
ture [1]. A large number of natural and synthetic in- a cyclic amine under solvent-free conditions [30]. They
dole derivatives have been found a venerable value in also reported that the aminoalkylation of N-substituted
pharmaceutical and medical applications since they are indoles could be carried out in good yields in wa-
able to bind with high affinity to many receptors [2 – 8]. ter in the presence of a surfactant [31]. In the course
Among them, 3-substituted indole derivatives have at- of developing new catalysts for the synthesis of 3-
tracted much attention due to the broad scope of their aminoalkylated indoles, we unexpectedly found that
biological activities [9 – 12]. Although Friedel-Crafts these compounds could be prepared without catalyst,
alkylation of indole has been widely employed for and that solvents had an extraordinary effect on the re-
the preparation of 3-substituted indole derivatives, the action. This catalyst-free approach offers a less expen-
methods often suffer from drastic reaction conditions sive and much simpler method for 3-amino-alkylated
(high temperature, strong acid/base) and regioselec- indoles, and the procedure is also scalable. Therefore,
tivity problems [13 – 15]. In recent years, some tran- we wish to report this catalyst-free, one-pot, three-
sition metal catalysts have emerged as an alternative component reaction in this article.
to the conventional catalysts for Friedel-Crafts alky-
lation of indoles. However, most of the substrates Results and Discussion
were limited to electron-neutral or electron-deficient
alkenes [16 – 26]. The Mannich reaction is another
Initial studies were undertaken using indole, pyrro-
straightforward and powerful tool employed in the syn- lidine and benzaldehyde in a model reaction with-
thesis of alkylated indoles [27], especially in the syn- out catalyst in different solvents. As shown in Ta-
thesis of indoles by aminoalkylation. Mannich reac- ble 1, solvents had a remarkable effect on the reaction.
tions of aldehydes, primary amines, and indoles cat- When the reaction was carried out in toluene, THF,
alyzed by carboxylic acids in water [28] and the con- 1,4-dioxane, n-butyl acetate, isopropyl ether, DMSO,
densation of heteroaryl amines, aromatic aldehydes, MTBE, CHCl3, or MeCN at 30 ◦C, the desired prod-
and indoles under solvent-free but thermal conditions uct 4a was only obtained in low yields of 11 – 46%
to prepare 3-(1-dialkylaminoalkyl)-1H-indoles have (Table 1, entries 3 – 13). However, polar protic solvents
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J.-F. Cao et al. · Multicomponent Synthesis of 3-Aminoalkylated Indoles
100
Table 1. Solvent and temperature screening for the catalyst-
free three-component reactiona.
90
80
70
60
50
40
30
CHO
catalyst-free
N
+
+
N
H
solvent
30 oC
N
H
N
H
4a
1a
2a
3
Entry
Solvent
MeOH
EtOH
Toluene
THF
1,4-Dioxane
n-Butyl acetate
Isopropyl ether
H2O
Yieldb (%)
1
2
3
4
5
6
7
8
93
75
45
31
15
13
34
45
24
11
37
46
87
88
0
20
40
60
80
Reaction time (h)
Fig. 1. Time vs. yield curve of the catalyst-free, three-
component reaction in MeOH. Reaction conditions:
benzaldehyde (1.0 mmol), indole (1.0 mmol), pyrrolidine
(1.0 mmol) in MeOH (1.0 mL) at 30 ◦C.
9
DMSO
MTBE
CHCl3
11
12
13
14
15
MeCN
MeOH (25 ◦C)
MeOH (35 ◦C)
Table 2. Solvent volume screening and the scale-up of the
model reactiona.
a
Reaction conditions: benzaldehyde (1.0 mmol), indole (1.0 mmol)
and pyrrolidine (1.0 mmol) in solvent (1.0 mL) at 30 ◦C for 72 h;
isolated yield after silica gel chromatography.
Entry
MeOH (mL)
Yieldb (%)
b
1
2
3
4
5
6
7
2.0
1.5
1.2
1.0
0.7
0.5
0.4
7.0
88
89
91
93
95
93
90
86
(MeOH and EtOH) obviously promoted the reaction,
and good yields of 93% and 75% were obtained, re-
spectively (Table 1, entries 1 and 2). H2O as a polar
protic solvent did not give a good result, probably due
to the poor solubility of substrates (Table 1, entry 8).
Thus, we selected methanol as the optimal solvent for
8 (scale-up) c
a
Reaction conditions: benzaldehyde (1.0 mmol), indole (1.0 mmol)
and pyrrolidine (1.0 mmol) in MeOH at 30 ◦C for 72 h; isolated
b
c
our further study. We then investigated the model re- yield after silica gel chromatography; benzaldehyde (10.0 mmol),
indole (10.0 mmol) and pyrrolidine (10.0 mmol) in MeOH at 30 ◦C
action in MeOH at 25 ◦C, which gave the product in
for 72 h.
a yield of 87% (Table 1, entry 14). The reaction at
35 ◦C provided the product 4a in a yield of 88%, but
a by-product was observed (Table 1, entry 15). In com- 95% was obtained in 0.7 mL MeOH on a 1.0 mmol
parison with the reaction at 30 ◦C which provided the scale (Table 2, entry 5). When the solvent volume was
product in a better yield of 93% (Table 1, entry 1), we more than or less than 0.7 mL, lower yields were ob-
chose 30 ◦C as the optimal temperature for the reac- tained. Thus, we chose 0.7 mL MeOH as an optimal
tion.
The time-course of this reaction was also investi-
solvent volume for 1.0 mmole of substrate.
Next, we attempted to scale up this catalyst-free,
gated (Fig. 1). The reaction was relatively fast in the one-pot, three-component reaction. When the model
initial 24 h, and after that the reaction rate decreased reaction was scaled up to 10.0 mmol under the opti-
markedly. A good yield of 93% was obtained after mized conditions, it worked smoothly giving product
72 h, and prolonging the reaction time to 84 h did not 4a in a good yield of 86% (Table 2, entry 8).
increase the yield.
Finally, various structurally diverse aldehydes, in-
To further optimize the reaction conditions, we ex- doles and secundary amines were tested under opti-
amined the effect of solvent volume on the model re- mized reaction conditions to explore the scope and
action in MeOH at 30 ◦C (Table 2). The best yield of generality of this methodology. As is shown in Table 3,
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J.-F. Cao et al. · Multicomponent Synthesis of 3-Aminoalkylated Indoles
723
Table 3. Scope of the catalyst-free, three-component reac- Table 3. (Continued.)
tiona.
Entry Aldehyde
Indole
Amine
Product Yield
(%)b
90
10
Entry Aldehyde
1
Indole
Amine
Product Yield
(%)b
95
11
12
92
86
2
3
97
91
13
14
90
96
4
5
6
95
92
92
15
16
99
97
7
8
9
85
88
86
17
18
19
93
31
28
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J.-F. Cao et al. · Multicomponent Synthesis of 3-Aminoalkylated Indoles
Table 3. (Continued.)
Entry Aldehyde
constants are reported in Hz. High-resolution mass spectra
(Varian 7.0T FTICR-MS) were obtained by use of ESI ion-
ization sources.
Indole
Amine
Product Yield
(%)b
35
20
General procedure for the catalyst-free three-component
reaction for the synthesis of 3-amino alkylated indoles
The aldehyde (1.0 mmol), secondary amine (1.0 mmol),
indole (1.0 mmol), and MeOH (0.7 mL) were sequentially
added into a round-bottom flask to form a clear yellow so-
lution. The resultant mixture was stirred at 30 ◦C for 72 h.
The solvent was removed under reduced pressure, and the
residue was purified by silica gel flash column chromatogra-
phy with petroleum ether-ethyl acetate as eluent to give the
a
Reaction conditions: benzaldehyde (1.0 mmol), indole (1.0 mmol)
and secondary amine (1.0 mmol) in MeOH (0.7 mL) at 30 ◦C for
72 h; b isolated yield after silica gel chromatography.
when pyrrolidine was used as a secondary amine, acti-
vated, unactivated and deactivated indoles reacted with desired product.
aromatic aldehydes bearing either electron-donating
3-(Phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4a)
or electron-withdrawing groups affording the corre-
sponding products in good to excellent yields of
85 – 99% (Table 3, entries 1 – 17). However, when
dimethylamine, piperidine or morpholine was used as
a secondary amine, benzaldehyde and indole gave the
corresponding products in low yields of 28 – 35% (Ta-
ble 3, entries 18 – 20). The position of the substituents
on the benzaldehyde seems to have little effects on the
yields (Table 3, entries 2 – 4).
–
1H NMR (300 MHz, CDCl3): δ(ppm) = 8.42 (s, 1H,
NH), 7.77 (d, J = 7.6 Hz, 1H, ArH), 7.54 (d, J = 7.6 Hz, 2H,
Ph), 7.23 (d, J = 7.3 Hz, 3H, Ph), 7.11 (m, 4H, ArH ), 4.62
(s, 1H, CH), 2.57 (d, J = 9.6 Hz, 4H, NCH2C), 1.77 (s, 4H,
CH2C). – 13C NMR (75 MHz, CDCl3): δ(ppm) = 144.40
(s), 136.08 (s), 128.21 (s), 127.73 (s), 126.60 (s), 122.10
(s), 121.80 (s), 119.69 (s), 119.32 (s), 111.08 (s), 68.00 (s),
53.75 (s), 23.52 (s). – HRMS ((+)-ESI): m/z = 277.1699
(calcd. 276.1703 for C19H30N2, [M+H]+). – HPLC (Hyper-
sil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1):
In conclusion, we have developed a catalyst-free,
three-component Mannich-type reaction for the prepa- tR = 7.26 min.
ration of 3-(1-dialkylaminoalkyl)-1H-indoles under
3-((2-(Chlorophenyl)(pyrrolidin-1-yl)methyl)-1H-indole
(4b)
mild reaction conditions. Solvents had a remarkable ef-
fect on the reaction, and the polar protic solvent MeOH
gave the best results. The procedure is simple and
scalable. Using Mannich-type reactions of aldehydes,
amines and indoles through the loss of a molecule of
water to prepare 3-aminoalkylated indoles was highly
atom-economic. Moreover, in this procedure just a 1 :
1 : 1 molar ratio of the three reactants was sufficient
to obtain good yields in most cases, which makes the
methodology a rather attractive process for the synthe-
sis of 3-aminoalkylated indoles.
1
– H NMR (400 MHz, CDCl3): δ(ppm) = 8.19 (s, NH),
8.00 – 7.89 (m, 2H, ArH), 7.31 – 7.21 (m, 4H, Ph), 7.11 (m,
3H, ArH), 5.17 (s, 1H, CH), 2.57 (d, J = 5.9 Hz, NCH2C),
1.84 – 1.70 (m, CH2C). – 13C NMR (75 MHz, CDCl3):
δ(ppm) = 141.25 (s), 136.03 (s), 132.92 (s), 129.48 (d,
J = 12.3 Hz), 127.51 (s), 126.95 (s), 126.53 (s), 122.82 (s),
121.93 (s), 120.11 (s), 119.51 (s), 118.02 (s), 111.08 (s),
63.02 (s), 53.53 (s), 23.61 (s). – HPLC (Hypersil (NH2)
column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1): tR
7.41 min.
=
3-((3-Chlorophenyl)(pyrrolidin-1-yl)methyl)-1H-indole (4c)
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.12 (s, 1H,
Experimental Section
–
NH), 7.83 (d, J = 7.9 Hz, 1H, Ph), 7.57 (t, J = 1.7 Hz,
1H, Ph), 7.50 – 7.41 (m, 1H, Ph), 7.34 (d, J = 8.0 Hz, 1H),
General information
All reagents were purchased from commercial suppliers 7.25 – 7.00 (m, 5H, ArH), 4.59 (s, 1H, CH), 2.55 (d, J =
and used without further purification. Column chromatog- 6.8 Hz, 4H, NCH2C), 1.81 (s, 4H, CH2C). – 13C NMR
raphy was performed on silica gel (100 – 200 mesh), elut- (75 MHz, CDCl3): δ(ppm) = 146.67 (s), 136.14 (s), 134.03
ing with ethyl acetate and petroleum ether. Thin layer chro- (s), 129.53 (s), 127.76 (s), 126.78 (s), 126.32 (s), 125.89 (s),
matography was carried out using Haiyang GF254 silica gel 122.09 (d, J = 6.3 Hz), 119.63 (d, J = 11.4 Hz), 118.81 (s),
TLC plates. NMR spectra were recorded at 300 MHz or 111.18 (s), 67.55 (s), 53.68 (s), 23.58 (s). – HPLC (Hyper-
400 MHz with CDCl3 as solvent. Chemical shifts are ex- sil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1):
pressed in ppm with TMS as internal standard, and coupling tR = 7.50 min.
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J.-F. Cao et al. · Multicomponent Synthesis of 3-Aminoalkylated Indoles
725
3-((4-Chlorophenyl)(pyrrolidin-1-yl)methyl)-1H-indole (4d) 3-((2-Methoxyphenyl)(pyrrolidin-1-yl)methyl)-1H-indole
(4h)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.21 (s, 1H,
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.22 (s, 1H,
NH), 7.77 (d, J = 7.8 Hz, 1H, ArH), 7.45 (d, J = 8.4 Hz,
2H, ArH), 7.27 – 7.04 (m, 6H, ArH), 4.56 (s, 1H, CH),
2.56 – 2.42 (m, 4H, NCH2C), 1.75 (s, 4H, CH2C). – 13C
NMR (75 MHz, CDCl3): δ(ppm) = 143.00 (s), 136.14 (s),
132.09 (s), 129.07 (s), 128.40 (s), 126.30 (s), 122.05 (s),
119.61 (d, J = 18.9 Hz), 111.23 (s), 67.34 (d, J = 3.3 Hz),
53.70 (s), 23.58 (s). – HPLC (Hypersil (NH2) column, 25 ◦C,
254 nm, hexane-2-propanol 4 : 1): tR = 6.97 min.
NH), 7.90 – 7.74 (m, 2H, Ph), 7.26 – 7.16 (m, 2H, Ph),
7.14 – 7.03 (m, 3H, ArH), 6.91 (d, J = 0.9 Hz, 1H, ArH),
6.79 (dd, 1J = 0.84, 2J = 8.2, 0.9 Hz, 1H, ArH), 5.19
(s, 1H, CH), 3.79 (s, 3H, OMe), 2.57 (d, J = 6.0 Hz,
4H, NCH2C), 1.76 (s, 4H, CH2C). – 13C NMR (75 MHz,
CDCl3): δ(ppm) = 156.41 (s), 135.98 (s), 128.63 (s), 127.23
(s), 126.90 (s), 122.54 (s), 121.62 (s), 120.72 (s), 119.96
(s), 119.16 (s), 111.00 (s), 110.66 (s), 58.93 (s), 55.52 (s),
53.66 (s), 23.62 (s). – HPLC (Hypersil (NH2) column, 25 ◦C,
254 nm, hexane-2-propanol 4 : 1): tR = 7.46 min.
4-((1H-Indol-3-yl)(pyrrolidin-1-yl)methyl)benzonitrile (4e)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.09 (s, 1H,
3-((4-Nitrophenyl)(pyrrolidin-1-yl)methyl)-1H-indole (4i)
NH), 7.81 (d, J = 7.9 Hz, 1H, NH), 7.69 (d, J = 8.2 Hz,
2H, ArH), 7.58 – 7.55 (m, 2H, ArH), 7.35 (d, J = 8.1 Hz,
1H, Ph), 7.22 – 7.10 (m, 3H, Ph), 4.66 (s, 1H), 2.53 (d,
– 1H NMR (400 MHz, CDCl3): δ(ppm) = 8.19 – 8.10 (m,
3H, ArH), 7.86 – 7.71 (m, 3H, ArH), 7.36 – 7.09 (m, 4H,
ArH, 4.72 (s, 1H, CH), 2.54 (d, J = 2.7 Hz, 4H, NCH2C),
1.87 – 1.77 (m, 4H, CH2C). – 13C NMR (75 MHz, CDCl3):
δ(ppm) = 152.20 (s), 146.57 (s), 136.22 (s), 128.26 (s),
125.98 (s), 123.68 (s), 122.26 (d, J = 14.5 Hz), 119.74 (d,
J = 14.5 Hz), 118.10 (s), 111.28 (s), 53.51 (s), 23.60 (s). –
HPLC (Hypersil (NH2) column, 25 ◦C, 254 nm, hexane-2-
propanol 4 : 1): tR = 6.49 min.
J = 5.0 Hz, 4H, NCH2C), 1.85 – 1.76 (m, 4H, CH2C). – 13
C
NMR (75 MHz, CDCl3): δ(ppm) = 150.11 (s), 136.22 (s),
132.21 (s), 128.32 (s), 127.10 (s), 126.05 (s), 122.22 (d,
J = 6.4 Hz), 119.70 (d, J = 7.4 Hz), 119.16 (s), 118.16 (s),
111.29 (s), 110.15 (s), 67.72 (s), 53.53 (s), 23.59 (s). – HPLC
(Hypersil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol
4 : 1): tR = 8.82 min.
3-(Pyrrolidin-1-yl(4-(trifluoromethyl)phenyl)methyl)-
1H-indole (4j)
3-((3-Methoxyphenyl)(pyrrolidin-1-yl)methyl)-1H-indole
(4f)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.11 (s, 1H,
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.03 (s, 1H,
NH), 7.82 (d, J = 7.9 Hz, 1H, ArH), 7.67 (d, J = 8.1 Hz,
2H, ArH), 7.51 (s, 2H, ArH), 7.31 (d, J = 8.0 Hz, 1H, ArH),
7.20 – 7.08 (m, 3H), 4.64 (s, 1H, CH), 2.52 (d, J = 6.0 Hz,
4H, NCH2C), 1.78 (s, 4H, CH2C). – 13C NMR (75 MHz,
CDCl3): δ(ppm) = 148.60 (s), 136.18 (s), 128.86 (s), 128.54
(s), 127.88 (s), 126.20 (s), 125.64 (s), 125.23 (q, J = 3.8 Hz),
122.93 (s), 122.11 (d, J = 9.2 Hz), 119.68 (d, J = 9.0 Hz),
118.76 (s), 111.19 (s), 67.68 (s), 53.64 (s), 23.58 (s). – HPLC
(Hypersil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol
4 : 1): tR = 9.32 min.
NH), 7.85 (d, J = 7.9 Hz, 1H, ArH), 7.33 – 7.07 (m, 7H,
ArH), 6.70 (m, 1H, ArH), 4.56 (s, 1H, CH), 3.77 (s, 3H,
OMe), 2.54 (d, J = 3.4 Hz, 4H, NCH2C), 1.84 – 1.70 (m, 4H,
CH2C). – 13C NMR (75 MHz, CDCl3): δ(ppm) = 159.54
(s), 146.28 (s), 136.15 (s), 129.19 (s), 126.57 (s), 122.02 (d,
J = 34.1 Hz), 120.25 (s), 119.77 (s), 119.32 (d, J = 11.6 Hz),
113.51 (s), 111.80 (s), 111.15 (s), 68.04 (s), 55.19 (s), 53.79
(s), 23.59 (s). – HPLC (Hypersil (NH2) column, 25 ◦C,
254 nm, hexane-2-propanol 4 : 1): tR = 11.37 min.
4-Chloro-3-((3-chlorophenyl)(pyrrolidin-1-yl)methyl)-
1H-indole (4k)
3-(Pyrrolidin-1-yl(p-tolyl)methyl)-1H-indole (4g)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.13 (s, 1H,
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.43 (s, 1H,
NH), 7.80 (d, J = 7.8 Hz, 1H, Ph), 7.42 (d, J = 8.0 Hz, NH), 7.54 (s, 1H, ArH), 7.44 (d, J = 7.1 Hz, 2H, ArH), 7.19
2H, Ph), 7.29 – 7.23 (m, 1H, Ph), 7.20 – 7.04 (m, 5H, ArH), (m, 4H, Ph), 7.05 – 7.00 (m, 1H, ArH), 5.40 (s, 1H, CH), 2.55
4.57 (s, 1H, CH), 2.61 – 2.45 (m, 4H, NCH2C), 2.27 (s, 3H, (d, J = 22.4 Hz, 4H, NCH2C), 1.77 (s, 4H, CH2C). – 13C
Me), 1.77 (s, 4H, CH2C). – 13C NMR (75 MHz, CDCl3): NMR (75 MHz, CDCl3): δ(ppm) = 146.90 (s), 137.21 (s),
δ(ppm) = 128.83 (s), 127.55 (s), 121.77 (s), 119.76 (s), 133.97 (s), 129.46 (s), 128.26 (s), 126.70 (d, J = 14.0 Hz),
119.26 (s), 110.94 (s), 67.68 (s), 53.71 (s), 23.49 (s), 21.01 125.73 (s), 124.32 (s), 123.12 (s), 122.24 (s), 121.11 (s),
(s). – HRMS ((+)-ESI): m/z = 290.1857 (calcd. 291.1856 119.26 (s), 110.11 (s), 65.64 (s), 53.89 (s), 23.49 (s). – HPLC
for C20H22N2, [M+H]+). – HPLC (Hypersil (NH2) column, (Hypersil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol
25 ◦C, 254 nm, hexane-2-propanol 4 : 1): tR = 6.90 min.
4 : 1): tR = 7.70 min.
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J.-F. Cao et al. · Multicomponent Synthesis of 3-Aminoalkylated Indoles
4-Chloro-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4l)
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.92 (s, 1H,
23.57 (s), 16.63 (s). – HPLC (Hypersil (NH2) column, 25 ◦C,
254 nm, hexane-2-propanol 4 : 1): tR = 8.15 min.
–
NH), 7.54 (d, J = 7.3 Hz, 2H, Ph), 7.33 (d, J = 2.1 Hz,
1H, Ph), 7.23 (m, 2H, Ph), 7.14 (t, J = 7.3 Hz, 1H, ArH),
7.09 – 6.93 (m, 3H, ArH), 5.44 (s, 1H, CH), 2.57 (td,
J = 9.3,2.8 Hz, 4H, NCH2C), 1.76 (d, J = 13.8 Hz, 4H,
CH2C). – 13C NMR (75 MHz, CDCl3): δ(ppm) = 144.77
(s), 137.23 (s), 128.31 (d, J = 12.2 Hz), 126.66 (s), 125.86
(s), 124.37 (s), 123.29 (s), 122.07 (s), 121.00 (s), 119.84 (s),
110.07 (s), 66.20 (s), 53.99 (s), 23.51 (s). – HPLC (Hyper-
sil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1):
tR = 8.85 min.
7-Methyl-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4p)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.01 (s, 1H,
NH), 7.66 (d, J = 7.9 Hz, 1H, ArH), 7.57 – 7.50 (m, 2H,
ArH), 7.29 – 7.21 (m, 3H, ArH), 7.17 – 7.11 (m, 1H, ArH),
7.04 – 6.92 (m, 2H, ArH), 4.59 (s, 1H, CH), 2.62 – 2.47 (m,
4H, NCH2C), 2.41 (s, 3H, Me), 1.78 (s, 4H, CH2C). – 13C
NMR (75 MHz, CDCl3): δ(ppm) = 144.26 (s), 135.61 (s),
128.23 (s), 127.70 (s), 126.62 (s), 126.00 (s), 122.42 (s),
121.73 (s), 120.23 (s), 119.68 (d, J = 12.0 Hz), 117.44 (s),
68.15 (s), 53.80 (s), 23.56 (s), 16.64 (s). – HPLC (Hyper-
sil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1):
tR = 6.56 min.
5-Methoxy-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole
(4m)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.20 (s, 1H,
5-Bromo-3-(phenyl(pyrrolidin-1-yl)methyl)-1H-indole (4q)
NH), 7.56 – 7.48 (m, 2H, Ph), 7.30 – 7.20 (m, 3H, Ph),
7.17 – 7.06 (m, 3H, ArH), 6.79 (dd, 1J = 2.4, 2J = 8.8,
2.4 Hz, 1H, ArH), 4.53 (s, 1H, CH), 3.83 (s, 3H, OMe),
2.63 – 2.43 (m, 4H, NCH2C), 1.75 (s, 4H, CH2C). – 13C
NMR (75 MHz, CDCl3): δ(ppm) = 153.75 (s), 144.43 (s),
131.35 (s), 128.27 (s), 127.72 (s), 126.93 (s), 126.65 (s),
123.02 (s), 118.97 (s), 111.73 (d, J = 5.0 Hz), 101.87 (s),
68.09 (d, J = 2.9 Hz), 55.97 (d, J = 5.0 Hz), 53.77 (s),
23.58 (s). – HPLC (Hypersil (NH2) column, 25 ◦C, 254 nm,
hexane-2-propanol 4 : 1): tR = 7.92 min.
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.45 (s, 1H,
NH), 7.97 (s, 1H, Ph), 7.51 (d, J = 7.4 Hz, 2H, ArH),
7.29 – 7.14 (m, 4H, Ph), 7.08 (m, 2H, ArH), 4.51 (s, 1H, CH),
2.51 (d, J = 6.1 Hz, 4H, NCH2C), 1.76 (s, 4H, CH2C). –
13C NMR (75 MHz, CDCl3): δ(ppm) = 144.04 (s), 134.69
(s), 128.41 (s), 128.18 (s), 127.64 (s), 126.87 (s), 124.70
(s), 123.35 (s), 122.15 (s), 119.00 (s), 112.68 (d, J =
11.2 Hz), 68.00 (s), 53.84 (s), 23.55 (s). – HPLC (Hyper-
sil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1):
tR = 7.01 min.
4-((5-Methoxy-1H-indol-3-yl)(pyrrolidin-1-yl)methyl)-
benzonitril (4n)
1-(1H-Indol-3-yl)-N,N-dimethyl-1-phenylmethanamine (4r)
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.21 (s, 1H,
– 1H NMR (400 MHz, CDCl3): δ(ppm) = 8.30 – 8.13 (m,
1H, NH), 7.72 (d, J = 7.7 Hz, 1H, ArH), 7.38 – 7.27 (m, 6H,
ArH), 7.24 – 7.16 (m, 2H, ArH), 7.12 (d, J = 7.0 Hz, 1H,
ArH), 4.68 (s, 1H, CH), 2.39 (2×s, 6H, Me). – 13C NMR
(75 MHz, CDCl3): δ(ppm) = 142.10 (s), 136.07 (s), 131.02
(s), 129.57 (s), 128.38 (s), 127.98 (d, J = 8.8 Hz), 126.99
(s), 126.74 (s), 122.71 (s), 121.99 (s), 119.51 (d, J = 1.6 Hz),
116.98 (s), 111.17 (s), 69.21 (s), 44.14 (s). – HPLC (Hyper-
sil (NH2) column, 25 ◦C, 254 nm, hexane-2-propanol 4 : 1):
tR = 7.45 min.
NH), 7.63 (t, J = 10.2 Hz, 2H, Ph), 7.51 (d, J = 8.3 Hz,
2H, Ph), 7.26 – 7.09 (m, 3H, ArH), 6.83 (dd, 1J = 2.36,
2J = 8.8 Hz, 1H, ArH), 4.57 (s, 1H, CH), 3.85 (s, 3H, OMe),
2.50 (d, J = 6.0 Hz, 4H, NCH2C ), 1.77 (s, 4H, CH2C). –
13C NMR (75 MHz, CDCl3): δ(ppm) = 153.94 (s), 150.08
(s), 132.20 (s), 131.41 (s), 128.22 (s), 126.45 (s), 123.08
(s), 119.18 (s), 117.68 (s), 111.92 (d, J = 3.2 Hz), 110.07
(s), 101.84 (s), 67.74 (d, J = 2.8 Hz), 53.51 (s), 23.59 (s).
– HPLC (Hypersil (NH2) column, 25 ◦C, 254 nm, hexane-2-
propanol 4 : 1): tR = 9.57 min.
3-(Phenyl(piperidin-1-yl)methyl)-1H-indole (4s)
4-((7-Methyl-1H-indol-3-yl)(pyrrolidin-1-yl)methyl)-
benzonitrile (4o)
1
– H NMR (400 MHz, CDCl3): δ(ppm) = 8.07 (s, 1H),
–
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.06 (s, 1H, 7.79 (d, J = 7.8 Hz, 1H, ArH), 7.49 (d, J = 7.2 Hz, 2H, Ph),
NH), 7.66 (m, 3H, ArH), 7.53 (d, J = 8.3 Hz, 2H, ArH), 7.31 – 7.22 (m, 3H, Ph), 7.15 (m, 2H, ArH), 7.06 (m, 2H,
7.26 – 7.18 (m, 1H, ArH), 7.07 – 6.95 (m, 2H, ArH), 4.64 (s, ArH), 4.69 (s, 1H, CH), 2.42 (s, 4H, NCH2C), 1.56 (m, 4H,
1H, CH), 2.52 (d, J = 6.9 Hz, 4H, NCH2C), 2.45 (s, 3H, NCH2C, CH2C), 1.41 (d, J = 5.0 Hz, 2H, CH2). – 13C NMR
Me), 1.79 (s, 4H, CH2C). – 13C NMR (75 MHz, CDCl3): (75 MHz, CDCl3): δ(ppm) = 126.47 (s), 121.80 (s), 120.39
δ(ppm) = 135.71 (s), 132.20 (s), 128.26 (s), 125.51 (s), (s), 119.26 (s), 110.97 (s), 68.58 (s), 52.81 (s), 26.29 (s),
122.79 (s), 121.85 (s), 120.46 (s), 119.96 (s), 119.16 (s), 24.70 (s). – HPLC (Hypersil (NH2) column, 25 ◦C, 254 nm,
117.32 (s), 110.10 (s), 67.81 (d, J = 3.2 Hz), 53.55 (s), hexane-2-propanol 4 : 1): tR = 9.31 min.
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J.-F. Cao et al. · Multicomponent Synthesis of 3-Aminoalkylated Indoles
4-((1H-Indol-3-yl)(phenyl)methyl)morpholine (4t) Supporting information
1H NMR (400 MHz, CDCl3): δ(ppm) = 8.08 (s, 1H,
727
–
The spectra and chromatograms of 4a–4t are given as
Supporting Information available online (DOI: 10.5560/
ZNB.2013-3313).
NH), 7.91 (d, J = 7.9 Hz, 1H, ArH), 7.52 (d, J = 7.5 Hz, 2H,
Ph), 7.31 – 7.25 (m, 3H, Ph), 7.19 – 7.09 (m, 4H, ArH), 4.61
(s, 1H, CH), 3.72 (s, 4H, CCH2O), 2.48 (d, J = 4.2 Hz, 4H,
NCH2C). – 13C NMR (75 MHz, CDCl3): δ(ppm) = 142.45
(s), 136.33 (s), 128.32 (s), 128.16 (d, J = 28.0 Hz), 126.77
(s), 126.48 (s), 122.75 (d, J = 4.1 Hz), 122.02 (s), 120.22
Acknowledgement
Financial support from the National Natural Science
(s), 119.52 (s), 117.12 (s), 111.10 (s), 68.85 (d, J = 5.3 Hz), Foundation of China (no. 21276211) and the Doctoral Foun-
67.31 (s), 52.45 (s). – HPLC (Hypersil (NH2) column, 25 ◦C, dation of Southwest University (SWU112019) are gratefully
254 nm, hexane-2-propanol 4 : 1): tR = 7.92 min.
acknowledged.
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