Nucleophilic reactions in the indole series: displacement of bromine under phase transfer catalysis

Article abstract of DOI:10.1016/j.tet.2008.10.022

A novel synthetic approach for the synthesis of 3-substituted indoles by nucleophilic substitution of 3-bromo derivatives under phase transfer catalysis (PTC) was reported.

Full text of DOI:10.1016/j.tet.2008.10.022

Tetrahedron 64 (2008) 11625–11631
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nucleophilic reactions in the indole series: displacement of bromine
under phase transfer catalysis
*
Paola Barraja, Patrizia Diana, Anna Carbone, Girolamo Cirrincione
`
Dipartimento Farmacochimico, Tossicologico e Biologico, Universita degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic approach for the synthesis of 3-substituted indoles by nucleophilic substitution of 3-
bromo derivatives under phase transfer catalysis (PTC) was reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 29 July 2008
Received in revised form 23 September
2008
Accepted 9 October 2008
Available online 14 October 2008
1. Introduction
methylester and tryptamine, in the presence of mesyl chloride and
triethylamine, gave the corresponding pyrrolo[2,3-b]indole de-
The chemistry of indoles is characterized by their strong ten-
dency to undergo ready electrophilic substitution in the five-
membered ring, preferentially at position 3 but also at position 2.1
Instead, nucleophilic substitutions on the indole system are
much less common and generally involve replacement of the hy-
drogen from the indole five-membered ring. Such substitutions are
made possible by the presence of a group on nitrogen such as hy-
droxyl, methoxy and phenylsulfonyl, which can act as leaving group.
In some cases, competing substitution of hydrogen on the six-
membered ring can take place. Thus, nucleophilic substitutions on
1-methoxyindole-3-carboxyaldehyde by nitrogen and carbon nu-
cleophiles gave 2-substituted indole-3-carboxyaldehydes in low
to excellent yields.2 The same substrate as well as 1-methoxyindole-
2-carboxyaldehyde gave, upon reaction with methoxide or ethoxide
ions, the 2-alkoxyindole-3-carboxyaldehydes and 3-alkoxyindole-
2-carboxyaldehydes, respectively, in high yields.3 The reactivity
of 1-methoxy-6-nitroindole towards nucleophiles was somehow
different; in fact its reaction with methoxide gave 2- and
3-methoxy-6-nitroindoles in 22 and 6% yield, respectively.
Whereas, the same substrate reacted with sodium cyanide giving
7-cyano-6-nitroindole in 15% yield and with diethylmalonate, in the
presence of potassium tert-butoxide, gave a methylene homologa-
tion reaction at position 3, instead of simple nucleophilic sub-
stitution reaction, and diethyl 2-(6-nitroindol-3-yl)methylmalonate
was isolated in 38% yield.4
rivatives in 47 and 45% yields, respectively, by an intramolecular
nucleophilic substitution at the position 2 of the indole system.3a
Indoles substituted at position 1 by aryl sulfonates gave variable
results from the preparative point of view. In fact reaction of
1-tosyloxyindole-3-carboxaldehyde with sodium methoxide gave
3-tosyloxyindole, 3-methoxyindole and 2-methoxyindole-3-car-
boxaldehyde in 16, 12 and 8% yields, respectively;5 whereas, re-
action of 2-nitro-1-phenylsulfonylindole with enolates of
diethylmalonates, lithium dimethylcuprate and indole anion gave
the corresponding 3-substituted 2-nitroindoles in low to high
yields.6 Cyclizing nucleophilic substitutions at position 3 of 1-
phenylsulfonylindoles, bearing at position 2 suitable substituents
having nitrogen, oxygen or sulfur nucleophiles, led to six- or seven-
membered heterocycles annelated to the indole system, with
elimination of the phenylsulfinate moiety, mainly in good yields.7
A further example of a formal nucleophilic replacement of hy-
drogen is furnished by the reaction of 2-carboxyindoles with thiols
and with N-chlorosuccinimide that gave generally good yields of
the corresponding 3-sulfenylindoles.8
Classical nucleophilic substitution involving replacement of
a halogen atom from the five-membered ring of indole was verified
only in a couple of reports related to replacement of halogen from
position 2. In both cases the halogen replacement was assisted by
an electron-withdrawing group in position 3 and by the presence of
a substituent on the indole nitrogen. Thus, 2-chloro-1-methoxy-
methylindole-3-carboxaldehyde reacted with a range of nitrogen,
oxygen and sulfur nucleophiles to give the corresponding
2-substituted indoles in 60–78% yield;9 and 2-iodo-3-nitro-1-
(phenylsulfonyl)indole underwent efficient amination under mild
condition (43–96% yields).10
Reaction of 1-hydroxyindole with 2,3-dihydroindole gave,
together with many other products, 5-(2,3-dihydroindol-1-yl)in-
dole in poor yield.3a Reaction of Nb-acyl-1-hydroxy-tryptophan
We have previously reported aromatic nucleophilic sub-
stitutions on halogenated pyrroles bearing suitable substituents as
* Corresponding author. Tel.: þ39 916161606; fax: þ39 916169999.
E-mail address: gcirrinc@unipa.it (G. Cirrincione).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.022

11626
P. Barraja et al. / Tetrahedron 64 (2008) 11625–11631
useful method to introduce a wide range of functional groups into
the five-membered ring.11 Such reactions proved to be a versatile
instrument to obtain synthons for the synthesis of polycyclic
systems.12–14
Considering that nucleophilic substitution at C-3 of indoles was
verified only in the case of 1-methoxyindole-2-carboxaldehyde,
which is not readily available as it involves a three steps synthesis,
through some extremely unstable intermediates,5 and considering
our interest also in the indole chemistry we approached the study
of nucleophilic substitution as displacement of the bromine atom at
the 3-position of the indole ring. In this paper we wish to describe
the reactivity of 2-substituted-3-bromo indoles towards nitrogen,
oxygen and sulfur nucleophiles.
ammonium salt, such as 2-methoxyethoxy-N,N-bis[2-(2-methoxy-
ethoxy) ethyl]ethanamine (TDA-1), was used.
It was reported that in some experiments in which prolonged
heating was requested, better results were obtained performing
reactions with solid potassium hydroxide as the base and a crown
ether as the catalyst.17 In this light our reactions were conve-
niently carried out by heating under reflux a mixture of 2-
substituted-3-bromoindoles, an excess of the nucleophile, solid
potassium hydroxide and dibenzo-18-crown-6 as phase transfer
catalyst. Thus, sulfur nucleophiles readily reacted with substrates
2a–e and 3a in acetonitrile (Method D) to give the 3-substituted
indoles 4a–e and 5a with a satisfactory increase of the yields
(56–80%) if compared with those obtained under the classical
reaction conditions (Method A). Moreover when 3-bromoindoles
2a–d were reacted under PTC conditions (Method D) with 3-
methyl benzenethiol, compounds 6a–d were obtained (56–74%)
(Scheme 1).
These results encouraged us to prepare other N-methylated
products and 2-substituted indoles 2b–e were methylated as de-
scribed above to give the corresponding 1-methyl derivatives 3b–e
in very good yields (80–92%). These latter easily reacted with 4-
methoxy-benzenethiol under PTC conditions (Method D) yielding
the corresponding products of direct nucleophilic substitution
5b–e (52–62%).
Nitrogen and oxygen nucleophiles needed more severe condi-
tions to react with indoles 2. In fact the displacement of the bro-
mine generally took place after long refluxing time (24–48 h) only
when the amines themselves were used as solvent under PTC
conditions (Method E). In particular pyrrolidine, aniline and mor-
pholine reacted either with 2-(2-nitrophenyl)-1H-indole (2a), giv-
ing derivatives 7a,c,d in moderate to good yields (30–60%), and
with the N-methyl derivative 3a to afford 7e–g in moderate yields
(22–42%). Moreover, 2a reacted with 3-methoxyphenol used as
solvent (Method E), affording 40% yield of the corresponding direct
substitution product 8. All the other substrates gave tars and very
complex mixtures from which it was not possible to isolate the
desired compounds (Table 1).
The 2-ethoxycarbonylindole (2e) reacted with pyrrolidine,
morpholine and 4-methylbenzylamine at 60 ꢀC under PTC condi-
tions using acetonitrile as solvent (Method D) furnishing the amide
derivatives 9a–c (40–55%), respectively, as main products, thus
indicating that the displacement of bromine atom at the 3-position
is disfavoured with respect to reaction of the ethoxycarbonyl
functionality. Moreover using the required amines as solvent and
heating under reflux (Method E), a mixture of compounds was
obtained from which it was possible to isolate the amides 9a–c (20–
35%) and their substitution products 9d–f as main products (45–
60%). It seems that more severe reaction conditions forced the first
formed amides 9a–c to further react with nucleophiles to give 9d–f.
Phase transfer catalysis reactions of 2a–e, with charged nucle-
ophiles such as azido or cyanide ions either using solid reactives,
i.e., sodium azide or sodium cyanide, or using liquid ones to be used
as solvent like trimethylsilyl azide or trimethylsilyl cyanide did not
produce the desired derivatives 10.
2. Results and discussion
Thus, 2-aryl or heteroaryl indoles 1a,b,d, conveniently prepared
according to known procedures,15a–c and the commercially avail-
able 2-phenylindole (1c) and 2-ethoxycarbonyl indole (1e) were
selected as substrates for this study, in order to investigate the ef-
fect produced by the substituent adjacent to the reaction centre.
Smooth bromination of the 3-position of indoles 1b,e with N-bro-
mosuccinimide in dimethylformamide, the same procedure that
allowed the isolation of bromo derivatives 2a,c,d,15a,b gave the
corresponding bromoindoles 2b,e in 92–95% yield.
In our first attempts, the experimental conditions used in the
pyrrole series, i.e., dimethylformamide as a solvent, an excess of
the proper nucleophile and stoichiometric amount of triethyl-
amine, to neutralize the hydrobromic acid produced from the
substitution reactions, were applied (Method A),11 but poor results
were obtained. In fact 3-bromo indoles 2a–e, under these condi-
tions, reacted with 4-methoxybenzenethiol, selected as sulfur
nucleophile, to afford compounds 4a–e in moderate yields (30–
40%) and 2a–e reacting with amines (benzylamine, pyrrolidine,
morpholine and aniline) gave no direct nucleophilic substitution
products. However, 2-(2-nitrophenyl)-1H-indole (2a) reacted with
pyrrolidine, used as solvent (Method B), furnishing 7a in very
poor yields (4%). Moreover, upon melting a mixture of 3,5-dime-
thoxyaniline and the 2-substituted indoles 2a–e (Method C) only
the (3,5-dimethoxyphenyl)-2-(2-nitrophenyl)-1H-indol-3-amine
(7b) was obtained in poor yields (5%). Phenols did not react at all
with our substrates 2a–e even with an excess of the nucleophile,
and the starting material was recovered from reaction mixtures
almost entirely.
In order to investigate the effect of the substitution of the pyr-
role nitrogen on the nucleophilic substitution, 2-(2-nitrophenyl)-
1H-indole 2a, which proved to be the most reactive among the
selected 2-substituted indoles, was methylated with iodomethane
using sodium hydride as the base giving the corresponding 1-
methylindole 3a in excellent yields. This latter was reacted with 4-
methoxybenzenethiol according to the previously described
Method A furnishing only 12% yield of 3-[(4-methoxyphenyl)
sulfanyl]-1-methyl-2-(2-nitrophenyl)-1H-indole (5a).
A more promising and versatile approach for aromatic nucleo-
philic substitutions on 3-bromoindoles appeared to us was the
phase transfer catalysis (PTC). Many reports exist on the application
of phase transfer catalysis for the displacement of halogens in ar-
omatic and heteroaromatic compounds by carbon, nitrogen, oxy-
gen and sulfur nucleophiles.16 These reactions can be performed
either in a monophasic solvent system or in a biphasic one. These
latter are generally conducted in benzene or toluene and an
aqueous sodium hydroxide solution (50:50 by weight) at
room temperature or under slight heating, in the presence of
tetrabutylammonium chloride as a catalyst. However, reaction of
2a–e under these conditions, using thiophenols or amines as nu-
cleophiles, did not prove successful, even when another
3. Conclusions
In conclusion, we have reported a method to have access to
nucleophilic substitution at C-3 of the indole ring, offering an in-
strument to prepare functionalized indoles, as useful synthons for
the synthesis of polycyclic heterocycles. From our studies it turns
out that the displacement of bromine by sulfur, nitrogen or oxygen
nucleophiles takes place under phase transfer catalysis even if not
assisted by an electron withdrawing group on the
a-carbon.
Moreover it seems that substitution on the indole nitrogen reduces
the reactivity towards nucleophilic substitution.

P. Barraja et al. / Tetrahedron 64 (2008) 11625–11631
11627
SAr
R1
NR2R3
C6H4-2-NO2
R1
N
R
N
H
N
R
1a-e
7a-g
4a-e (R=H, Ar=C6H4-4-OMe)
5a-e (R=Me, Ar=C6H4-4-OMe)
6a-d (R=H, Ar=C6H4-3-Me)
a R=H, R2-R3= (CH2)4
NHR2R3
b R=R2=H, R3=3,5-(OMe)2-C6H3
ArSH/MeCN
NBS/DMF
Br
c R=R2=H, R3=Ph
d R=H, R2-R3= (CH2)4-O-,
e R=Me, R2-R3= (CH2)4,
f R=Me, R2=H, R3=Ph,
g R=Me, R2-R3=(CH2)4-O-.
Compounds 1-6
a R=H, R1=2-NO2-C6H4
b R=H, R1=2-NH2-C6H4
c R=H, R1=Ph
R1
N
R
d R=H, R1=2-C5H4N
e R=H, R1=CO2Et
2a-e (R=H)
NaH, MeI
3a-e (R=Me)
HO-C6H4-3-OMe
NHR2R3/MeCN
TMSNu
Nu
R1=CO2Et
R4
a R2-R3= (CH2)4, R4=Br
b R2-R3=(CH2)4-O, R4=Br
O-C6H4-3-OMe
C6H4-2-NO2
CONR2R3
c R2=H, R3= Bn-4-Me, R4=Br
R1
N
H
d R2=R3=(CH2)4, R4= N-(CH2)4-
e R2-R3=-(CH2)4-O-, R4= N-(CH2)4-O
N
H
N
R
9a-f
8
10 Nu= CN, N3
f R2= H, R3=Bn-4-Me, R4=NHBn-4-Me
Scheme 1. Nucleophilic substitutions of 3-bromoindoles 2a–e and 3a–e.
4. Experimental
4.1. General
reference). Column chromatography was performed with Merck
silica gel 230–400 mesh ASTM or with a BUCHI SEPACORE chroma-
¨
tography module. 2-(2-Nitrophenyl)-1H-indole 1a,15a 2-(2-amino-
phenyl)-1H-indole 1b,15a 2-pyridinyl indole 1d15c were prepared
according to procedure previously reported. 2-Phenyl-1H-indole 1c
and 2-ethoxycarbonylindole 1e were supplied from Aldrich.
The 3-bromoderivatives 2a,15a 2b,15a 2c15b and 2d15b were pre-
pared according to procedures earlier published.
All melting points were taken on a Buchi-Tottoli capillary appa-
ratusandareuncorrected;IRspectraweredeterminedinbromoform
with a Jasco FT/IR 5300 spectrophotometer; 1H and 13C NMR spectra
were measured at 200 and 50.3 MHz, respectively, in DMSO-d6 or
CDCl3 using a Bruker Avance II 200 spectrometer (TMS as internal
4.1.1. Procedure for the bromination of 2-(2-aminophenyl)-1H-
indole (1b) and 2-ethoxycarbonyl-indole (1e)
Table 1
Direct nucleophilic substitution products of bromoindoles
To a solution of 1b or 1e (5.3 mmol) in anhydrous DMF (10 mL),
a solution of NBS (0.94 g, 5.3 mmol) in anhydrous DMF (4 mL) was
added at room temperature. After 2 h stirring the reaction mixture
was poured onto crushed ice and the precipitate was filtered off and
recrystallized from ethanol to give 2b,e. 2-(2-Aminophenyl)-3-bro-
moindole (2b), obtained in 92% yield showed analytical and spectral
data in agreement to those previously reported.15b
Substrate
Nucleophile
Product
Method (% yields)
A
B
C
D
E
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2e
2e
3a
3a
3a
3a
3b
3c
3d
3e
HS-C6H4-4-OMe
HS-C6H4-3-Me
Pyrrolidine
H2N-C6H3-3,5-(OMe)2
Aniline
4a
6a
7a
7b
7c
7d
8
4b
6b
4c
6c
4d
6d
4e
9d
9e
9f
5a
7e
7f
7g
5b
5c
5d
5e
35
d
0
d
d
4
d
d
d
5
76
74
d
d
d
d
d
80
56
70
58
70
72
56
0
d
d
40
0
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
0
0
0
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
30
60
40
d
d
d
d
d
d
d
60
52
45
d
42
25
22
d
d
d
d
Morpholine
4.1.1.1. 3-Bromo-2-ethoxycarbonylindole (2e). Yield 95%; white
HO-C6H4-3-OMe
HS-C6H4-4-OMe
HS-C6H4-3-Me
HS-C6H4-4-OMe
HS-C6H4-3-Me
HS-C6H4-4-OMe
HS-C6H4-3-Me
HS-C6H4-4-OMe
Pyrrolidine
solid, mp 153–156 ꢀC; IR cmꢁ1: 3296 (NH),1688 (CO),1619 and 1518
35
d
35
d
40
d
30
0
(C]C). 1H NMR (DMSO-d6):
d
1.39 (3H, t, J¼6.6 Hz, CH3), 4.40 (2H, q,
J¼6.6 Hz, CH2), 7.21 (1H, t, J¼7.3 Hz, H-5), 7.38 (1H, t, J¼7.3 Hz, H-6),
7.52 (1H, d, J¼7.3 Hz, H-7), 7.56 (1H, d, J¼7.3 Hz, H-4), 12.25 (1H, s,
NH). 13C NMR (DMSO-d6):
d 14.2 (q), 60.7 (t), 95.9 (s), 113.0 (d),
120.0 (d), 121.1 (d), 123.9 (s), 125.9 (d), 126.8 (s), 135.8 (s), 160.1 (s).
Anal. Calcd for C11H10NO2Br (268.11): C, 49.28; H, 3.76; N, 5.22.
Found: C, 49.00; H, 4.00; N, 5.52.
Morpholine
0
0
0
H2N-Bn-4-Me
HS-C6H4-4-OMe
Pyrrolidine
Aniline
Morpholine
HS-C6H4-4-OMe
HS-C6H4-4-OMe
HS-C6H4-4-OMe
HS-C6H4-4-OMe
d
12
0
0
0
d
d
d
d
56
d
d
d
52
56
60
62
4.1.2. General procedure for the synthesis of 3-bromo-1-methyl-2-
substituted indoles 3a–e
To a solution of the bromoderivatives 2a–e (25 mmol) in an-
hydrous DMF (30 mL), NaH (25 mmol) was added. After 1 h stirring
at room temperature, MeI (1.55 mL, 25 mmol) was added and
stirred for further 2 h at room temperature. The reaction mixture
was then poured onto crushed ice and the solid filtered off and
dried. Recrystallization from ethanol gave the desired 1-methyl 3-
bromo derivatives 3a–e.
Methods: A (Nu/DMF/TEA, reflux, 24 h), B (Nu, reflux, 24 h), C (Nu, 160 ꢀC, 24 h), D
(Nu/KOH/18-crown-6 ether/CH3CN, 60 ꢀC, 6–8 h), E (Nu/KOH/18-crown-6 ether,
reflux, 24 h).

11628
P. Barraja et al. / Tetrahedron 64 (2008) 11625–11631
4.1.2.1. 3-Bromo-1-methyl-2-(2-nitrophenyl)-indole (3a). Yield 95%;
orange solid, mp 108–110 ꢀC; IR cmꢁ1: 1614 and 1573 (C]C), 1527
material, which was purified by chromatography column using
DCM/petroleum ether (1:1) as eluent.
(NO2). 1H NMR (DMSO-d6):
d
3.64 (3H, s, CH3), 7.26 (1H, t, J¼7.5 Hz,
Method C. A mixture of 2-substituted 3-bromoindoles 2a–e
(2.5 mmol), 3,5-dimethoxyaniline (0.76 g, 5 mmol) and sodium
carbonate (0.52 g, 5 mmol) was heated at 160 ꢀC for 24 h. The
mixture was poured onto crushed ice and extracted with DCM. The
oily residue was purified by chromatography column using DCM/
petroleum ether (1:1) as eluent.
H-5), 7.38 (1H, t, J¼7.5 Hz, H-6), 7.52 (1H, d, J¼7.5 Hz, H-7), 7.66 (1H,
d, J¼7.5 Hz, H-4), 7.76 (1H, dd, J¼7.2, 1.3 Hz, H-60), 7.89 (1H, dt,
J¼7.2, 1.3 Hz, H-40), 7.99 (1H, dd, J¼7.2, 1.3 Hz, H-50), 8.31 (1H, dd,
J¼7.2, 1.3 Hz, H-30). 13C NMR (DMSO-d6):
d 31.2 (q), 89.1 (s), 110.6
(d), 118.3 (d), 120.5 (d), 123.0 (d), 124.4 (s), 124.7 (d), 125.9 (s), 131.2
(d), 132.0 (s), 133.6 (d), 133.7 (d), 136.2 (s), 149.4 (s). Anal. Calcd for
C15H11BrN2O2 (331.17): C, 54.40; H, 3.35; N, 8.46. Found: C, 54.58; H,
3.02; N, 8.30.
Method D. A mixture of powdered potassium hydroxide (0.84 g,
10 mmol), dibenzo 18-crown-6 ether (0.15 g, 0.5 mmol) and 2-
substituted 3-bromoindoles 2a–e or 3a–e (5 mmol) in acetonitrile
(20 mL) was stirred at room temperature for 30 min. The required
nucleophile was added (10 mmol) and the reaction mixture was
heated at 60 ꢀC for 6–8 h. Hydrochloric acid (1 N) was added and the
aqueous solution extracted with DCM. The residue was purified by
chromatographycolumnusingDCM/petroleumether(1:1)aseluent.
Method E. A mixture of 2-substituted 3-bromoindoles 2a and 3a
(5 mmol), ten fold excess of the suitable nucleophile (50 mmol),
powdered potassium hydroxide (0.84 g, 10 mmol) and dibenzo 18-
crown-6 ether (0.15 g, 0.5 mmol) was heated under reflux for 24 h.
The mixture was cooled, poured onto crushed ice and neutralized
with 1 N hydrochloric acid. Extraction of the aqueous layer with
DCM furnished an oil, which was purified by chromatography
column using DCM/petroleum ether (1:1) as eluent.
4.1.2.2. 2-(2-Aminophenyl)-3-bromo-1-methylindole (3b). Yield 82-
%; grey oil; IR cmꢁ1: 3467 and 3376 (NH2), 1616 and 1577 (C]C). 1H
NMR (DMSO-d6):
d 3.55 (3H, s, CH3), 4.96 (2H, s, NH2), 6.67 (1H,
dt, J¼7.6, 1.5 Hz, H-50), 6.83 (1H, dd, J¼7.6, 1.5 Hz, H-30), 7.05
(1H, dd, J¼7.6, 1.5 Hz, H-60), 7.14–7.30 (3H, m, H-5, H-6, H-40),
7.48 (1H, d, J¼7.7 Hz, H-7), 7.53 (1H, d, J¼7.7 Hz, H-4). 13C NMR
(DMSO-d6):
d 30.9 (q), 89.1 (s), 110.6 (d), 113.4 (s), 114.9 (d), 115.8
(d), 118.1 (d), 120.0 (d), 122.2 (d), 126.5 (s), 130.2 (d), 131.9 (d),
133.7 (s), 136.4 (s), 147.4 (s). Anal. Calcd for C15H13BrN2 (301.19):
C, 59.82; H, 4.35; N, 8.46. Found: C, 60.01; H, 4.10; N, 8.64.
4.1.2.3. Bromo-1-methyl-2-phenylindole (3c). Yield 80%; grey solid,
mp 70–72 ꢀC; IR cmꢁ1: 1606 and 1574 (C]C). 1H NMR (DMSO-d6):
d
3.66 (3H, s, CH3), 7.21 (1H, t, J¼7.0 Hz, H-5), 7.30 (1H, t, J¼7.0 Hz,
4.1.3.1. 3-[(4-Methoxyphenyl)sulfanyl]-2-(2-nitrophenyl)-indole (4a).
H-6), 7.48–7.58 (7H, m, H-4, H-7, Ph). 13C NMR (DMSO-d6):
d
31.5
Yellow solid, mp 154–156 ꢀC; IR cmꢁ1: 3269 (NH), 1595 and 1574
(q), 88.6 (s), 110.6 (d), 118.3 (d), 120.5 (d), 122.7 (d), 126.3 (s), 128.5
(2ꢂd), 128.8 (d), 129.7 (s), 130.5 (2ꢂd), 136.4 (s), 137.6 (s). Anal.
Calcd for C15H12NBr (286.17): C, 62.96; H, 4.23; N, 4.89. Found: C,
63.24; H, 4.50; N, 4.54.
(C]C),1527 (NO2). 1H NMR (DMSO-d6):
d 3.64 (3H, s, CH3), 6.75 (2H,
d, J¼8.3 Hz, H-300, H-50), 6.94 (2H, d, J¼8.3 Hz, H-200, H-60), 7.09 (1H,
t, J¼7.6 Hz, H-5), 7.22 (1H, t, J¼7.6 Hz, H-6), 7.43 (1H, d, J¼7.6 Hz,
H-7), 7.48 (1H, d, J¼7.6 Hz, H-4), 7.66–7.88 (3H, m, H-40, H-60, H-50),
8.17 (1H, d, J¼8.3 Hz, H-30), 12.07 (1H, s, NH). 13C NMR (DMSO-d6):
4.1.2.4. 3-Bromo-1-methyl-2-(pyridin-2-yl)-indole (3d). Yield 92%;
yellow solid, mp 75–76 ꢀC; IR cmꢁ1: 1589 and 1566 (C]C and
d
55.0 (q), 100.6 (s), 112.0 (2ꢂd), 114.5 (d), 118.8 (d), 120.3 (d), 122.7
(d), 124.7 (d), 126.2 (s), 127.8 (2ꢂd), 128.2 (d), 129.0 (s), 130.2 (d),
133.1 (d), 133.5 (s), 136.3 (s), 138.7 (s), 148.8 (s), 157.4 (s). Anal. Calcd
for C21H16N2O3S (376.43): C, 67.01; H, 4.28; N, 7.44. Found: C, 66.78;
H, 4.02; N, 7.70.
C]N). 1H NMR (DMSO-d6):
d
3.82 (3H, s, CH3), 7.23 (1H, t, J¼7.3 Hz,
H-5), 7.34 (1H, t, J¼8.5 Hz, H-40), 7.46–7.55 (2H, m, H-6, H-7), 7.61
(1H, d, J¼7.3 Hz, H-4), 7.84 (1H, d, J¼7.3 Hz, H-50), 8.02 (1H, dt,
J¼8.5, 1.2 Hz, H-60), 8.80 (1H, d, J¼8.5 Hz, H-30). 13C NMR (DMSO-
d6):
d
31.7 (q), 89.7 (s), 110.7 (d), 118.8 (d), 120.6 (d), 123.2 (d), 123.5
4.1.3.2. 3-[(4-Methoxyphenyl)sulfanyl]-2-(2-aminophenyl)-indole
(d), 126.1 (s), 126.3 (d), 135.8 (s), 136.7 (s), 136.8 (d), 149.1 (s), 149.6
(d). Anal. Calcd for C14H11N2Br (287.16): C, 58.56; H, 3.86; N, 9.76.
Found: C, 58.76; H, 4.05; N, 9.55.
(4b). Brown solid, mp 76–78 ꢀC; IR cmꢁ1: 3429 and 3392 (NH2),
1616 and 1574 (C]C). 1H NMR (200 MHz, DMSO-d6):
d 3.65 (3H, s,
CH3), 4.98 (2H, s, NH2), 6.61 (1H, t, J¼7.3 Hz, H-50), 6.77 (2H, d,
J¼8.7 Hz, H-300, H-500), 6.81 (2H, d, J¼8.7 Hz, H-30, H-60), 6.98 (2H,
d, J¼8.7 Hz, H-200, H-600), 7.02–7.18 (3H, m, H-5, H-6, H-40), 7.42
(1H, d, J¼8.0 Hz, H-7), 7.46 (1H, t, J¼8.0 Hz, H-4), 11.80 (1H, br s,
4.1.2.5. 3-Bromo-2-ethoxycarbonyl-1-methylindole (3e). Yield 90%;
white solid, mp 67–69 ꢀC; IR cmꢁ1: 1613 and 1504 (C]C), 1701
(CO). 1H NMR (DMSO-d6):
d
1.39 (3H, t, J¼6.9 Hz, CH3), 3.97 (3H, s,
NH). 13C NMR (DMSO-d6):
d 55.0 (q), 99.1 (s), 111.9 (d), 114.6
CH3), 4.40 (2H, q, J¼6.9 Hz, CH2), 7.24 (1H, t, J¼7.4 Hz, H-5), 7.42
(2ꢂd), 115.1 (d), 115.8 (d), 115.9 (s), 118.4 (d), 119.9 (d), 121.9 (d),
127.3 (2ꢂd), 129.5 (s), 129.6 (d), 129.7 (d), 131.4 (d), 136.4 (s),
141.7 (s), 146.8 (s), 157.1 (s). Anal. Calcd for C21H18N2OS (346.45):
C, 72.81; H, 5.24; N, 8.09. Found: C, 73.21; H, 5.03; N, 8.34.
(1H, t, J¼7.4 Hz, H-6), 7.56 (1H, d, J¼7.4 Hz, H-7), 7.60 (1H, d,
J¼7.4 Hz, H-4). 13C NMR (DMSO-d6):
d 13.9 (q), 32.4 (q), 60.8 (t), 96.8
(s), 111.1 (d), 120.3 (d), 121.2 (d), 125.3 (s), 125.6 (s), 125.9 (d), 137.5
(s), 160.3 (s). Anal. Calcd for C12H12NO2Br (282.14): C, 51.09; H, 4.29;
N, 9.76. Found: C, 49.80; H, 4.00; N, 10.00.
4.1.3.3. 3-[(4-Methoxyphenyl)sulfanyl]-2-phenylindole (4c). White
solid, mp 163–165 ꢀC; IR cmꢁ1: 3326 (NH),1592 and 1578 (C]C). 1H
4.1.3. General procedure for the preparation of 3-substituted
indoles
NMR (CDCl3):
d
3.69 (3H, s, CH3), 6.75 (2H, d, J¼8.4 Hz, H-300, H-500),
7.05 (2H, d, J¼8.4 Hz, H-200, H-600), 7.15 (1H, t, J¼7.8 Hz, H-5), 7.24
(1H, t, J¼7.8 Hz, H-6), 7.35–7.47 (4H, m, H-7, H-30, H-40, H-50), 7.64
(1H, d, J¼7.8 Hz, H-4), 7.74 (2H, dd, J¼8.1, 1.6 Hz, H-20, H-60), 8.47
Method A. To a solution of 2-substituted 3-bromoindoles 2a–e
(6.3 mmol) in anhydrous DMF (15 mL), stoichiometric amount of
triethylamine (0.8 mL, 6.3 mmol) and the proper nucleophile
(12.6 mmol) were added. The mixture was heated under reflux for
24 h then it was poured onto crushed ice. The aqueous phase was
extracted with DCM, dried and purified by chromatography column
using DCM/petroleum ether (1:1) as eluent.
(1H, br s, NH). 13C NMR (CDCl3):
d 55.3 (q), 100.9 (s), 111.1 (d), 114.6
(2ꢂd), 119.9 (d), 121.0 (d), 123.2 (d), 127.7 (2ꢂd), 128.1 (2ꢂd), 128.6
(d),128.7 (2ꢂd),129.7 (s),131.2 (s),131.5 (s),135.8 (s),141.5 (s),157.5
(s). Anal. Calcd for C21H17NOS (331.43): C, 76.10; H, 5.17; N, 4.23.
Found: C, 76.44; H, 5.00; N, 4.58.
Method B. A mixture of 2-substituted 3-bromoindoles 2a–e
(5 mmol) was heated under reflux for 24 h with an excess of the
proper nucleophile (50 mmol). The mixture was cooled, washed
with 1 N hydrochloric acid. Extraction with DCM afforded a crude
4.1.3.4. 3-[(4-Methoxyphenyl)sulfanyl]-2-pyridin-2-yl-indole (4d).
White solid, mp 130–132 ꢀC; IR cmꢁ1: 3419 (NH), 1594 and 1566
(C]C and C]N). 1H NMR (DMSO-d6):
d 3.65 (3H, s, CH3), 6.81

P. Barraja et al. / Tetrahedron 64 (2008) 11625–11631
11629
(2H, d, J¼8.5 Hz, H-300, H-500), 7.05 (2H, d, J¼8.5 Hz, H-200, H-600),
13C NMR (CDCl3):
d
31.9 (q), 55.2 (q), 102.2 (s), 110.0 (d), 114.4 (d),
7.10 (1H, t, J¼7.7 Hz, H-5), 7.23 (1H, t, J¼7.7 Hz, H-6), 7.40 (1H, t,
J¼8.5 Hz, H-40), 7.55 (1H, d, J¼7.7 Hz, H-7), 7.59 (1H, d, J¼7.7 Hz,
H-4), 7.91 (1H, t, J¼8.5 Hz, H-50), 8.58 (1H, d, J¼8.5 Hz, H-60), 8.73
(1H, d, J¼8.5 Hz, H-30), 12.21 (1H, s, NH). 13C NMR (DMSO-d6):
114.5 (2ꢂd), 120.0 (d), 120.1 (d), 120.9 (d), 123.3 (d), 123.4 (d), 127.6
(2ꢂd), 129.4 (s), 129.7 (s), 136.2 (d), 137.9 (s), 142.0 (s), 149.9 (s),
157.4 (s). Anal. Calcd for C21H18N2OS (346.45): C, 72.81; H, 5.24; N,
8.09. Found: C, 72.60; H, 5.05; N, 8.52.
d
55.0 (q), 99.8 (s), 112.6 (d), 114.9 (2ꢂd), 118.9 (d), 120.4 (d), 122.1
(d), 123.1 (d), 123.3 (d), 127.6 (2ꢂd), 128.2 (s), 130.8 (s), 135.9 (s),
137.0 (d), 139.1 (s), 149.2 (s), 149.3 (d), 157.5 (s). Anal. Calcd for
C20H16N2OS (332.42): C, 72.26; H, 4.85; N, 8.43. Found: C, 72.42;
H, 5.05; N, 8.55.
4.1.3.10. 2-Ethoxycarbonyl-3-[(4-methoxyphenyl)sulfanyl]-1-methyl-
indole (5e). Yellow oil; IR cmꢁ1: 1699 (CO), 1593 and 1574 (C]C).
1H NMR (DMSO-d6):
d
1.29 (3H, t, J¼7.1 Hz, CH3), 3.69 (3H, s, CH3),
3.99 (3H, s, CH3), 4.36 (2H, q, J¼7.1 Hz, CH2), 6.82 (2H, d, J¼8.5 Hz,
H-300, H-500), 7.10–7.19 (3H, m, H-5, H-200, H-600), 7.37 (1H, dt, J¼8.2,
1.2 Hz, H-6), 7.47 (1H, d, J¼8.2 Hz, H-7), 7.65 (1H, d, J¼8.2 Hz, H-4).
4.1.3.5. 2-Ethoxycarbonyl-3-[(4-methoxyphenyl)sulfanyl]-indole (4e).
White solid, mp 128–130 ꢀC; IR cmꢁ1: 3302 (NH), 1683 (CO), 1494
13C NMR (DMSO-d6):
d 14.0 (q), 32.2 (q), 55.1 (q), 61.1 (t), 109.4 (s),
and 1572 (C]C). 1H NMR (CDCl3):
d
1.37 (3H, t, J¼7.2 Hz, CH3), 3.73
111.4 (d), 114.6 (2ꢂd), 120.5 (d), 121.2 (d), 125.2 (d), 127.6 (s), 127.7
(s), 129.7 (2ꢂd), 131.1 (s), 138.0 (s), 157.8 (s), 160.9 (s). Anal. Calcd for
C19H19NO3S (341.42): C, 66.84; H, 5.61; N, 4.10. Found: C, 66.55; H,
5.48; N, 4.00.
(3H, s, CH3), 4.42 (2H, q, J¼7.2 Hz, CH2), 6.74 (2H, d, J¼8.5 Hz, H-30,
H-50), 7.09 (1H, t, J¼8.2 Hz, H-5), 7.23 (2H, d, J¼8.5 Hz, H-20, H-60),
7.30 (1H, J¼8.2 Hz, H-6), 7.40 (1H, d, J¼8.2 Hz, H-7), 7.54 (1H, d,
J¼8.2 Hz, H-4), 9.50 (1H, s, NH). 13C NMR (CDCl3):
d 14.2 (q), 55.2
(q), 61.4 (t), 95.2 (s), 112.0 (d), 114.4 (2ꢂd), 114.4 (d), 121.1 (d), 121.7
(d), 125.9 (d), 127.8 (s), 127.9 (s), 129.7 (s), 130.5 (2ꢂd), 130.5 (d),
135.8 (s), 158.2 (s), 161.5 (s). Anal. Calcd for C18H17NO3S (327.40): C,
66.04; H, 5.23; N, 4.28. Found: C, 66.35; H, 5.05; N, 4.55.
4.1.3.11. 3-[(3-Methylphenyl)sulfanyl]-2-(2-nitrophenyl)-indole (6a).
White solid, mp 119–121 ꢀC; IR cmꢁ1: 3369 (NH), 1592 and 1574
(C]C),1519 (NO2). 1H NMR (DMSO-d6):
d 2.12 (3H, s, CH3), 6.72 (1H,
d, J¼7.5 Hz, H-400), 6.82 (1H, s, H-200), 6.84 (1H, d, J¼7.5 Hz, H-500), 7.0
(1H, d, J¼7.5 Hz, H-600), 7.10 (1H, t, J¼7.5 Hz, H-5), 7.25 (1H, t,
J¼7.5 Hz, H-6), 7.41 (1H, d, J¼7.5 Hz, H-7), 7.50 (1H, d, J¼7.5 Hz, H-4),
7.67–7.87 (3H, m, H-60, H-40, H-50), 8.16 (1H, d, J¼6.7 Hz, H-30), 12.14
4.1.3.6. 3-[(4-Methoxyphenyl)sulfanyl]-1-methyl-2-(2-nitrophenyl)-
indole (5a). Orange solid, mp 54–55 ꢀC; IR cmꢁ1: 3269 (NH), 1601
and 1572 (C]C), 1525 (NO2). 1H NMR (DMSO-d6):
d
3.62 (3H, s,
(1H, s, NH). 13C NMR (DMSO-d6):
d 20.8 (q), 98.9 (s), 112.1 (d), 118.7
CH3), 3.64 (3H, s, CH3), 6.74 (2H, d, J¼6.9 Hz, H-300, H-500), 6.90 (2H,
d, J¼6.9 Hz H-200, H-600), 7.16 (1H, t, J¼7.4 Hz, H-5), 7.32 (1H, t,
J¼7.4 Hz, H-6), 7.47 (1H, d, J¼7.4 Hz, H-7), 7.65 (2H, m, H-4, H-60),
7.84 (2H, m, H-40, H-50), 8.23 (1H, dd, J¼7.8, 1.5 Hz, H-30). 13C NMR
(d),120.4 (d), 122.3 (d),122.8 (d),124.7 (d),125.6 (d),125.7 (d), 126.1
(s), 128.6 (d), 129.1 (s), 130.3 (d), 133.1 (d), 133.4 (d), 136.3 (s), 137.9
(s), 138.0 (s), 139.2 (s), 148.6 (s). Anal. Calcd for C21H16N2O2S
(360.43): C, 69.98; H, 4.47; N, 7.77. Found: C, 70.18; H, 4.64; N, 7.92.
(DMSO-d6):
d
31.2 (q), 55.0 (q), 100.5 (s), 110.7 (d), 114.5 (2ꢂd), 118.7
(d), 120.7 (d), 122.7 (d), 124.6 (d), 125.1 (s), 127.9 (2ꢂd), 128.0 (s),
128.4 (s), 131.0 (d), 133.5 (d), 133.6 (d), 137.1 (s), 140.9 (s), 149.3 (s),
157.4 (s). Anal. Calcd for C22H18N2O3S (390.46): C, 67.68; H, 4.65; N,
7.17. Found: C, 68.08; H, 4.32; N, 7.50.
4.1.3.12. 3-[(3-Methylphenyl)sulfanyl]-2-(2-aminophenyl)-indole (6b).
Yellow oil; IR cmꢁ1: 3428, 3388, 3214 (NH and NH2), 1616 and 1574
(C]C). 1H NMR (DMSO-d6):
d 2.16 (3H, s, CH3), 4.98 (2H, s, NH2),
6.59 (1H, t, J¼7.6 Hz, H-50), 6.70–6.87 (4H, m, H-200, H-400, H-500, H-
600), 7.00 (1H, d, J¼7.6 Hz, H-30), 7.02–7.21 (4H, m, H-5, H-6, H-40, H-
60), 7.38 (1H, d, J¼6.8 Hz, H-7), 7.46 (1H, d, J¼6.8 Hz, H-4), 11.81 (1H,
4.1.3.7. 3-[(4-Methoxyphenyl)sulfanyl]-1-methyl-2-(2-aminophenyl)-
indole (5b). Yellow oil; IR cmꢁ1: 3467 and 3378 (NH2), 1616 and
s, NH). 13C NMR (DMSO-d6):
d 20.9 (q), 97.5 (s), 112.0 (d), 115.1 (d),
1576 (C]C). 1H NMR (DMSO-d6):
d
3.60 (3H, s, CH3), 3.64 (3H, s,
115.7 (d), 117.9 (s), 118.3 (d), 119.9 (d), 122.0 (2ꢂd), 125.3 (d), 125.4
(d), 128.6 (d), 129.6 (d), 129.7 (s), 131.3 (d), 136.4 (s), 138.0 (s), 139.0
(s), 142.1 (s), 147.0 (s). Anal. Calcd for C21H18N2S (330.45): C, 76.33;
H, 5.49; N, 8.48. Found: C, 76.03; H, 5.58; N, 8.29.
CH3), 4.97 (2H, s, NH2), 6.61 (1H, d, J¼7.3 Hz, H-50), 6.75 (2H, d,
J¼8.7 Hz, H-300, H-500), 6.83 (1H, d, J¼7.3 Hz, H-30), 7.00 (2H, d,
J¼8.7 Hz, H-200, H-600), 6.97–7.28 (7H, m, H-5, H-6, H-40, H-60), 7.46
(1H, d, J¼8.1 Hz, H-7), 7.55 (1H, d, J¼8.1 Hz, H-4). 13C NMR (DMSO-
d6):
d
31.3 (q), 55.5 (q), 100.3 (s), 111.2 (d), 114.5 (s), 115.0 (2ꢂd),
4.1.3.13. 3-[(3-Methylphenyl)sulfanyl]-2-phenylindole (6c). Yellow
oil; IR cmꢁ1: 3406 (NH), 1590 and 1573 (C]C). 1H NMR (CDCl3):
115.3 (d), 116.1 (d), 119.1 (d), 120.7 (d), 122.5 (d), 128.1 (2ꢂd), 129.6
(s), 130.1 (s), 130.5 (d), 132.4 (d), 137.9 (s), 144.5 (s), 147.9 (s), 157.6
(s). Anal. Calcd for C22H22N2OS (362.49): C, 72.90; H, 6.12; N, 7.73.
Found: C, 73.00; H, 5.92; N, 7.50.
d
2.16 (3H, s, CH3), 6.82 (2H, d, J¼7.0 Hz, H-400, H-600), 6.95 (1H, s, H-
200), 6.99 (1H, t, J¼7.6 Hz, H-5), 7.12 (1H, t, J¼7.0 Hz, H-500), 7.21 (1H,
t, J¼7.6 Hz, H-6), 7.30–7.35 (4H, m, H-7, H-30, H-40, H-50), 7.64 (1H, d,
J¼7.6 Hz, H-4), 7.69 (2H, dt, J¼8.2, 1.8 Hz, H-20, H-60), 8.41 (1H, br s,
4.1.3.8. 3-[(4-Methoxyphenyl)sulfanyl]-1-methyl-2-phenylindole (5c).
Yellow oil; IR cmꢁ1: 1593 and 1574 (C]C). 1H NMR (DMSO-d6):
NH). 13C NMR (CDCl3):
d 21.3 (q), 99.3 (s), 111.1 (d), 119.9 (d), 121.8
(d), 122.5 (d), 123.2 (d), 125.5 (d), 126.0 (d), 128.0 (2ꢂd), 128.5 (d),
128.6 (2ꢂd), 128.7 (d), 131.2 (s), 131.3 (s), 135.7 (s), 138.5 (s), 138.9
(s), 141.9 (s). Anal. Calcd for C21H17NS (315.43): C, 79.96; H, 5.43; N,
4.44. Found: C, 80.06; H, 5.12; N, 4.24.
d
3.65 (3H, s, CH3), 3.71 (3H, s, CH3), 6.77 (2H, d, J¼8.8 Hz, H-300, H-
500), 6.96 (2H, d, J¼8.7 Hz, H-200, H-600), 7.14 (1H, t, J¼7.1 Hz, H-5),
7.29 (1H, t, J¼7.1 Hz, H-6), 7.47–7.51 (6H, m, Ph, H-7), 7.61 (1H, d,
J¼7.1 Hz, H-4). 13C NMR (DMSO-d6):
d 31.6 (q), 50.1 (q), 99.5 (s),
110.8 (d), 114.6 (2ꢂd), 118.6 (d), 120.7 (d), 122.5 (d), 127.4 (2ꢂd),
128.1 (2ꢂd), 128.7 (d), 128.8 (s), 129.3 (s), 130.1 (s), 130.5 (2ꢂd),
137.1 (s), 145.2 (s), 157.2 (s). Anal. Calcd for C22H19NOS (345.46): C,
76.49; H, 5.54; N, 4.05. Found: C, 76.20; H, 5.73; N, 4.30.
4.1.3.14. 3-[(3-Methylphenyl)sulfanyl]-2-pyridin-2-yl-indole (6d).
Yellow solid, mp 116–118 ꢀC; IR cmꢁ1: 3422 (NH), 1592 and 1569
(C]C and C]N). 1H NMR (CDCl3):
d 2.13 (3H, s, CH3), 6.76 (1H, d,
J¼6.9 Hz, H-600), 6.80 (1H, t, J¼6.9 Hz, H-500), 6.92–7.30 (6H, m, H-5,
H-6, H-7, H-200, H-40), 7.58 (1H, d, J¼6.8 Hz, H-4), 7.61 (1H, t,
J¼7.5 Hz, H-50), 8.52 (1H, d, J¼7.5 Hz, H-60), 8.64 (1H, d, J¼7.5 Hz, H-
4.1.3.9. 3-[(4-Methoxyphenyl)sulfanyl]-1-methyl-2-pyridin-2-yl-in-
dole (5d). Yellow oil; IR cmꢁ1: 1591 and 1566 (C]C and C]N). 1H
30), 10.6 (1H, s, NH). 13C NMR (CDCl3):
d 21.9 (q), 100.8 (s), 112.0 (d),
NMR (CDCl3):
d
3.57 (3H, s, CH3), 3.79 (3H, s, CH3), 6.57 (2H, dd,
120.7 (d),121.4 (d),123.0 (d),123.2 (d),123.3 (d),124.5 (d),126.3 (d),
126.7 (d), 129.2 (d), 132.5 (s), 136.0 (s), 137.4 (d), 138.5 (s), 139.1 (s),
139.4 (s), 149.3 (d), 149.8 (s). Anal. Calcd for C20H16N2S (316.42): C,
75.92; H, 5.10; N, 8.48. Found: C, 76.12; H, 5.33; N, 8.38.
J¼8.7, 1.5 Hz, H-300, H-500), 6.90 (2H, d, J¼8.7, 1.5 Hz, H-200, H-600), 7.06
(1H, t, J¼8.2, H-5), 7.17 (1H, t, J¼8.2 Hz, H-6), 7.20–7.24 (2H, m, H-7,
H-40), 7.32 (1H, d, J¼8.2 Hz, H-4), 7.50–7.65 (3H, m, H-30, H-50, H-60).

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P. Barraja et al. / Tetrahedron 64 (2008) 11625–11631
4.1.3.15. 2-(2-Nitrophenyl)-3-pyrrolidin-1-yl-indole (7a). Brown so-
lid, mp 203–205 ꢀC; IR cmꢁ1: 3328 (NH), 1604 and 1587 (C]C and
(s). Anal. Calcd for C21H17N3O2 (343.38): C, 73.45; H, 4.99; N, 12.24.
Found: C, 73.08; H, 5.16; N, 12.46.
C]N), 1505 (NO2). 1H NMR (CDCl3):
d 1.84–2.00 (2H, m, CH2), 2.14–
2.22 (2H, m, CH2), 3.22–3.31 (2H, m, CH2), 3.80–3.91 (2H, m, CH2),
7.20–7.34 (3H, m, H-5, H-6, H-40), 7.48 (1H, d, J¼7.5 Hz, H-7), 7.58
(1H, d, J¼7.5 Hz, H-50), 8.01 (1H, d, J¼7.5 Hz, H-4), 8.20 (1H, d,
J¼7.5 Hz, H-60), 8.21 (1H, d, J¼7.5 Hz, H-30), 9.97 (1H, s, NH).13C NMR
4.1.3.21. 1-Methyl-3-morpholin-4-yl-2-(2-nitrophenyl)-indole (7g).
Orange solid, mp 182–183 ꢀC; IR cmꢁ1: 1596 and 1567 (C]C), 1490
(NO2). 1H NMR (CDCl3):
d
3.29–3.37 (4H, m, 2ꢂCH2), 3.80–3.84 (4H,
m, 2ꢂCH2), 3.86 (1H, s, CH3), 6.88 (1H, t, J¼7.3 Hz, H-50), 7.24–7.65
(CDCl3):
d
24.7 (2ꢂt), 49.8 (2ꢂt), 111.1 (d), 112.6 (s), 116.7 (d), 121.2
(7H, m, H-4, H-5, H-6, H-7, H-30, H-40, H-60). 13C NMR (CDCl3):
d 31.9
(d), 121.7 (d), 121.9 (d), 122.1 (d), 124.5 (d), 125.2 (s), 129.6 (d), 137.5
(s), 139.6 (s), 141.2 (s), 159.7 (s). Anal. Calcd for C18H17N3O2 (307.35):
C, 70.34; H, 5.58; N, 13.67. Found: C, 70.20; H, 5.84; N, 13.60.
(q), 47.8 (2ꢂt), 66.5 (2ꢂt), 91.1 (s), 109.6 (d), 115.8 (d), 117.5 (d), 119.2
(d), 120.2 (d), 122.5 (d), 127.2 (s), 130.1 (d), 132.7 (d), 136.7 (s), 143.9
(s), 151.5 (s), 152.6 (s). Anal. Calcd for C19H19N3O3 (337.38): C, 67.64;
H, 5.68; N, 12.45. Found: C, 68.04; H, 5.20; N, 12.32.
4.1.3.16. 3-N-(3,5-Dimethoxyphenylamine)-2-(2-nitrophenyl)-indole
(7b). Red solid, mp 156–158 ꢀC; IR cmꢁ1: 3391 (NH), 1591 and 1578
4.1.3.22. 3-(3-Methoxyphenoxy)-2-(2-nitrophenyl)-indole (8). Orange
solid, mp 129–131 ꢀC; IR cmꢁ1: 3396 (NH), 1606 and 1588 (C]C),
(C]C), 1527 (NO2). 1H NMR (DMSO-d6):
d
3.73 (6H, s, 2ꢂCH3), 5.78
(1H, s, NH), 6.07 (2H, d, J¼2.1 Hz, H-200, H-600), 6.44 (1H, J¼2.1 Hz, H-
400), 6.85 (1H, d, J¼7.1 Hz, H-7), 7.23 (1H, t, J¼7.1 Hz, H-5), 7.63 (1H, t,
J¼7.1 Hz, H-6), 7.73 (1H, d, J¼7.1 Hz, H-4), 7.83–7.99 (3H, m, H-40, H-
50, H-60), 8.23 (1H, d, J¼7.8 Hz, H-30), 12.35 (1H, s, NH). 13C NMR
1525 (NO2).1H NMR (CDCl3):
d
3.70 (3H, s, CH3), 6.53 (2H, d, J¼7.6 Hz,
H-400, H-600), 6.56 (1H, s, H-200), 7.05 (1H, t, J¼8.2 Hz, H-5), 7.11 (1H, t,
J¼8.2 Hz, H-6), 7.18–7.47 (4H, H-4, H-7, H-50, H-500), 7.57 (1H, t,
J¼7.6 Hz, H-40), 7.70(1H, d, J¼7.6 Hz, H-60), 7.86 (1H, d, J¼7.6 Hz, H-30),
(DMSO-d6):
d
55.4 (2ꢂq), 95.5 (d), 97.3 (d), 112.6 (d), 120.5 (s), 122.0
8.1 (1H, br s, NH).13C NMR (CDCl3):
d 55.3 (q),101.8 (d),107.8 (s),107.9
(d), 124.3 (d), 125.5 (d), 126.5 (s), 127.9 (d), 128.0 (d), 131.6 (d), 131.8
(d), 134.0 (d), 135.2 (s), 149.4 (s), 150.8 (s), 157.8 (s), 161.2 (s), 161.6
(s), 167.8 (s). Anal. Calcd for C22H19N3O4 (389.41): C, 67.86; H, 4.92;
N, 10.79. Found: C, 67.65; H, 5.15; N, 11.02.
(d),111.7 (d),118.9 (d),120.3 (d),120.8 (s),121.7 (s),123.8 (d),124.7 (d),
128.8 (d), 129.8 (d), 132.0 (d), 132.3 (d), 132.6 (d), 134.5 (s), 146.4 (s),
148.7 (s), 159.5 (s), 160.7 (s). Anal. Calcd for C21H16N2O4 (347.37): C,
69.99; H, 4.48; N, 7.77. Found: C, 70.24; H, 4.64; N, 8.01.
4.1.3.17. 3-N-Phenylamine-2-(2-nitrophenyl)-indole (7c). Yellow oil;
IR cmꢁ1: 3410 and 3403 (NH), 1604 and 1579 (C]C), 1498 (NO2). 1H
4.1.3.23. 3-Bromo-2-(pyrrolidin-1-yl carbonyl)-indole (9a). Yield
40% (Method D), 20% (Method E); white solid, mp 208–210 ꢀC; IR
NMR (DMSO-d6):
d
5.25 (1H, s, NH), 6.52 (1H, d, J¼8.8 Hz, H-7), 7.94–
cmꢁ1: 3125 (NH),1607 (CO).1H NMR (DMSO-d6):
d 1.20–1.23 (4H, m,
7.25 (3H, m, H-5, H-6, H-400), 7.46 (2H, d, J¼8.0 Hz, H-200, H-600), 7.72–
2ꢂCH2), 3.48–3.51 (4H, m, 2ꢂCH2), 7.16 (1H, t, J¼6.8 Hz, H-5), 7.27
8.00 (6H, m, H-4, H-40, H-50, H-60, H-300, H-500), 8.19 (1H, d, J¼8.1 Hz,
(1H, t, J¼6.8 Hz, H-6), 7.43 (1H, d, J¼6.8 Hz, H-7), 7.47 (1H, d,
H-30), 11.82 (1H, s, NH). 13C NMR (DMSO-d6):
d
89.5 (s), 101.5 (d),
J¼6.8 Hz, H-4), 11.90 (1H, br s, NH). 13C NMR (DMSO-d6):
d 23.8 (t),
112.0 (d), 115.7 (d), 118.3 (d), 120.3 (d), 123.0 (2ꢂd), 124.8 (d), 125.6
(s), 126.7 (s), 130.4 (2ꢂd), 131.2 (d), 131.4 (s), 133.3 (d), 133.4 (d),
135.6 (s), 148.0 (s), 148.6 (s). Anal. Calcd for C20H15N3O2 (329.36): C,
72.94; H, 4.59; N, 12.76. Found: C, 73.08; H, 4.76; N, 12.50.
25.5 (t), 45.6 (t), 47.6 (t), 88.6 (s), 112.3 (d), 118.7 (d), 120.5 (d), 123.7
(d),126.0 (s),130.9(s),134.8 (s),160.7(s). Anal. Calcdfor C13H13BrN2O
(293.16): C, 53.26; H, 4.47; N, 9.56. Found: C, 53.48; H, 4.84; N,10.06.
4.1.3.24. 3-Bromo-2-(morpholin-4-yl carbonyl)-indole (9b). Yield
4.1.3.18. 3-Morpholin-4-yl-2-(2-nitrophenyl)-indole
solid, mp 190–192 ꢀC; IR cmꢁ1: 3353 (NH), 1602 and 1584 (C]C),
1501 (NO2). 1H NMR (CDCl3):
(7d). Yellow
55% (Method D), 22% (Method E); white solid, mp 105–110 ꢀC; IR
cmꢁ1: 3246 (NH), 1610 (CO). 1H NMR (DMSO-d6):
d 3.50–3.74 (8H,
d
3.41–3.43 (4H, m, 2ꢂCH2), 3.87–3.90
m, 4ꢂCH2), 7.20 (1H, t, J¼7.2 Hz, H-5), 7.28 (1H, t, J¼7.2 Hz, H-6),
(4H, m, 2ꢂCH2), 6.91 (2H, d, J¼7.3 Hz, H-4, H-7), 7.17–7.36 (4H, m,
7.44 (1H, d, J¼7.2 Hz, H-7), 7.48 (1H, d, J¼7.2 Hz, H-4), 12.03 (1H, br
H-5, H-6, H-40, H-50), 7.58 (1H, d, J¼8.5 Hz, H-60), 8.13 (1H, d,
s, NH). 13C NMR (DMSO-d6):
112.3 (d), 118.8 (d), 120.6 (d), 123.8 (d), 125.8 (s), 129.0 (s), 135.0 (s),
161.3 (s). Anal. Calcd for C13H13BrN2O2 (309.16): C, 50.51; H, 4.24; N,
9.06. Found: C, 50.66; H, 4.40; N, 9.24.
d
60.7 (t), 66.2 (2ꢂt), 69.8 (t), 89.1 (s),
J¼8.5 Hz, H-30), 8.49 (1H, br s, NH). 13C NMR (CDCl3):
d
47.1 (2ꢂt),
66.3 (2ꢂt), 92.3 (s), 111.4 (d), 113.2 (d), 117.9 (d), 119.5 (d), 120.9 (d),
123.8 (d), 127.5 (d), 127.8 (d), 128.6 (s), 131.9 (s), 135.4 (s), 138.8 (s),
153.5 (s). Anal. Calcd for C18H17N3O3 (323.35): C, 66.86; H, 5.30; N,
13.00. Found: C, 66.74; H, 5.00; N, 13.32.
4.1.3.25. 3-Bromo-N-(4-methylbenzyl)-indole-2-carboxamide (9c).
Yield 50% (Method D), 35% (Method E); white solid, mp 207–
208 ꢀC; IR cmꢁ1: 3392 and 3251 (NH), 1626 (CO), 1576 and 1556
4.1.3.19. 1-Methyl-2-(2-nitrophenyl)-3-pyrrolidin-1-yl-indole (7e).
Orange solid, mp 186–187 ꢀC; IR cmꢁ1: 1601 and 1580 (C]C), 1508
(C]C). 1H NMR (DMSO-d6):
d 2.28 (3H, s, CH3), 4.46 (2H, d,
(NO2). 1H NMR (CDCl3):
d
2.05 (4H, m, 2ꢂCH2), 3.38 (4H, m, 2ꢂCH2),
J¼5.4 Hz, CH2), 7.14–7.30 (6H, m, H-5, H-6, H-20, H-30, H-50, H-60),
7.47 (1H, d, J¼8.2 Hz, H-7), 7.51 (1H, d, J¼8.2 Hz, H-4), 8.40 (1H, t,
3.58 (1H, s, CH3), 6.60 (1H, d, J¼7.1 Hz, H-7), 7.16–7.36 (5H, m, H-4,
H-5, H-6, H-40, H-50), 7.58 (1H, d, J¼7.6 Hz, H-60), 8.21 (1H, d,
J¼5.4 Hz, NH), 12.03 (1H, s, NH). 13C NMR (DMSO-d6):
d 20.6 (q),
J¼7.6 Hz, H-30). 13C NMR (CDCl3):
d
25.4 (2ꢂt), 31.1 (q), 47.9 (2ꢂt),
42.4 (t), 90.4 (s), 112.7 (d), 119.4 (d), 120.8 (d), 124.7 (d), 126.6 (s),
127.2 (s), 127.3 (2ꢂd), 128.5 (s), 128.8 (2ꢂd), 134.9 (s), 135.9 (s),
160.0 (s). Anal. Calcd for C21H17BrN2O (343.22): C, 59.49; H, 4.41; N,
8.16. Found: C, 59.36; H, 4.25; N, 8.10.
89.0 (s), 109.4 (d), 111.3 (d), 115.7 (d), 119.2 (d), 120.2 (d), 122.7 (d),
122.8 (d), 126.8 (s), 128.1 (d), 128.6 (s), 130.6 (s), 136.1 (s), 150.7 (s).
Anal. Calcd for C19H19N3O2 (321.38): C, 71.01; H, 5.96; N, 13.07.
Found: C, 71.20; H, 5.80; N, 13.36.
4.1.3.26. 3-Pyrrolidin-1-yl-2-(pyrrolidin-1-ylcarbonyl)-indole (9d).
4.1.3.20. 3-N-Phenylamine-1-methyl-2-(2-nitrophenyl)-indole (7f).
Orange oil; IR cmꢁ1: 3403 (NH), 1608 and 1578 (C]C), 1498 (NO2).
White solid, mp 205–207 ꢀC; IR cmꢁ1: 3254 (NH), 1601 (CO). 1H
NMR (CDCl3):
d
1.84–1.99 (8H, m, 4ꢂCH2), 3.40–3.56 (8H, m,
1H NMR (DMSO-d6):
d
3.59 (1H, s, CH3), 6.38 (1H, s, NH), 6.89 (1H, d,
4ꢂCH2), 6.90 (1H, t, J¼8.3 Hz, H-5), 7.11 (1H, t, J¼8.3 Hz, H-6), 7.30
(1H, d, J¼8.3 Hz, H-7), 7.82 (1H, d, J¼8.3 Hz, H-4), 9.50 (1H, br s,
J¼7.0 Hz, H-7), 6.89–7.41 (10H, m, Ph, H-4, H-5, H-6, H-40, H-50),
7.56 (2H, d, J¼8.4 Hz, H-60), 8.22 (1H, d, J¼8.4 Hz, H-30). 13C NMR
NH). 13C NMR (CDCl3):
d
23.4 (2ꢂt), 25.9 (2ꢂt), 46.7 (2ꢂt), 52.4
(DMSO-d6):
d
31.2 (q), 89.7 (s), 109.6 (d), 114.6 (d), 118.6 (d), 119.3
(2ꢂt),112.0 (s),112.1 (d),117.4 (d),118.1 (s),121.7 (d),123.3 (d),129.2
(s), 135.4 (s), 164.7 (s). Anal. Calcd for C17H21N3O (283.37): C, 70.06;
H, 7.47; N, 14.83. Found: C, 70.20; H, 7.84; N, 13.96.
(d), 120.4 (d), 121.9 (2ꢂd), 123.0 (d), 124.8 (d), 124.9 (d), 126.8 (s),
127.9 (d), 128.7 (s), 129.8 (2ꢂd), 134.9 (s), 136.5 (s), 139.1 (s), 149.5

P. Barraja et al. / Tetrahedron 64 (2008) 11625–11631
11631
4.1.3.27. 3-Morpholin-4-yl-2-(morpholin-4-ylcarbonyl)-indole (9e).
White solid, mp 273–276 ꢀC; IR cmꢁ1: 3254 (NH), 1589 (CO). 1H
NMR (DMSO-d6):
References and notes
1. Trofimov, B. A.; Nedolya, N. A. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2008; Vol. 3, pp 88–167.
2. Yamada, F.; Shinmyo, D.; Somei, M. Heterocycles 1994, 38, 273–276.
3. (a) Somei, M.; Kawasaki, T.; Fukui, Y.; Yamada, F.; Kobayashi, T.; Aoyama, H.;
Shinmyo, D. Heterocycles 1992, 34, 1877–1884; (b) Yamada, F.; Fukui, Y.; Shin-
myo, D.; Somei, M. Heterocycles 1993, 35, 99–104.
4. Yamada, K.; Kawasaki, T.; Fujita, T.; Somei, M. Heterocycles 2001, 55, 1151–1159.
5. Kawasaki, T.; Kodama, A.; Nishida, T.; Shimizu, K.; Somei, M. Heterocycles 1991,
32, 221–227.
6. Pelkey, E. T.; Barden, T. C.; Gribble, G. W. Tetrahedron Lett. 1999, 40, 7615–7619.
7. Joule, J. A. Prog. Heterocycl. Chem. 1999, 11, 45–65.
d
3.07–3.11 (4H, m, 2ꢂCH2), 3.56–3.61 (8H, m,
4ꢂCH2), 3.70–3.75 (4H, m, 2ꢂCH2), 6.98 (1H, t, J¼8.1 Hz, H-5), 7.13
(1H, t, J¼8.1 Hz, H-6), 7.30 (1H, d, J¼8.1 Hz, H-7), 7.67 (1H, d,
J¼8.1 Hz, H-4), 11.09 (1H, br s, NH). 13C NMR (DMSO-d6):
d 52.5
(2ꢂt), 66.3 (4ꢂt), 66.8 (2ꢂt), 112.0 (d), 118.7 (d), 119.9 (d), 121.9 (s),
122.4 (s), 122.5 (d), 127.5 (s), 134.5 (s), 163.3 (s). Anal. Calcd for
C17H21N3O3 (315.37): C, 64.74; H, 6.71; N, 13.31. Found: C, 64.50; H,
6.94; N, 13.60.
8. Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed, J. E.; Sexton, K. Org. Lett.
2004, 6, 819–821.
9. Comber, M. F.; Moody, C. J. Synthesis 1992, 731–733.
10. Roy, S.; Gribble, G. W. Tetrahedron Lett. 2007, 48, 1003–1005.
11. Cirrincione, G.; Almerico, A. M.; Passannanti, A.; Diana, P.; Mingoia, F. Synthesis
1997, 1169–1173.
12. Passannanti, A.; Diana, P.; Barraja, P.; Mingoia, F.; Lauria, A.; Cirrincione, G.
Heterocycles 1998, 48, 1229–1235.
13. Passannanti, A.; Diana, P.; Mingoia, F.; Barraja, P.; Lauria, A.; Cirrincione, G.
J. Heterocycl. Chem. 1998, 35, 1535–1537.
14. Diana, P.; Passannanti, A.; Barraja, P.; Lauria, A.; Cirrincione, G. Heterocycles
1999, 51, 2103–2109.
15. (a) Cirrincione, G.; Almerico, A. M.; Barraja, P.; Diana, P.; Lauria, A.; Passannanti,
A.; Musiu, C.; Pani, A.; Murtas, P.; Minnei, C.; Marongiu, M. E.; La Colla, P. J. Med.
Chem. 1999, 42, 2561–2568; (b) Almerico, A. M.; Barraja, P.; Diana, P.; Cirrin-
cione, G.; Mingoia, F.; Musiu, C.; Perra, G.; Putzolu, M.; Marongiu, M. E. Il
Farmaco 1998, 53, 409–414; (c) Sugasawa, S.; Terashima, M.; Kanaoka, Y. Chem.
Pharm. Bull. 1956, 4, 16–19.
4.1.3.28. N-(4-Methylbenzyl)-3-[(4-methylbenzyl)amino]-indole-2-
carboxamide (9f). White solid, mp 218–220 ꢀC; IR cmꢁ1: 3261–
3258 (NH), 1626 (CO), 1568 and 1515 (C]C). 1H NMR (DMSO-d6):
d
2.25 (3H, s, CH3), 2.29 (3H, s, CH3), 4.46 (2H, d, J¼5.6 Hz, CH2), 4.55
(2H, d, J¼6.7 Hz, CH2), 6.54 (1H, t, J¼6.7 Hz, NH), 6.89 (1H, t,
J¼8.2 Hz, H-5), 7.05–7.34 (10H, m, H-6, H-7, H-20, H-30, H-50, H-60, H-
200, H-300, H-500, H-600), 7.24 (1H, d, J¼8.2 Hz, H-4), 8.37 (1H, t,
J¼5.6 Hz, NH), 10.60 (1H, br s, NH). 13C NMR (DMSO-d6):
d 20.6
(2ꢂq), 41.7 (t), 50.3 (t), 112.4 (s), 113.8 (d), 118.0 (d), 120.1 (s), 121.3
(d), 124.4 (d), 127.2 (2ꢂd), 127.5 (2ꢂd), 128.8 (2ꢂd), 128.9 (2ꢂd),
133.4 (s), 135.1 (s), 135.6 (s), 135.7 (s), 136.3 (s), 137.6 (s), 162.5 (s).
Anal. Calcd for C25H25N3O (383.49): C, 78.30; H, 6.57; N, 10.96.
Found: C, 78.02; H, 6.14; N, 11.58.
16. See for example: (a) Hiebl, J.; Stanek, M.; Schulte, J. H. International Patent: PCT
WO 2006/108491 A1; Chem. Abstr. 2006, 145, 438601; (b) Wang, X.; Li, Z.; Yang, J.
Synth. Commun. 2001, 31, 1447–1452; (c) Chiou, A.; Markidis, T.; Costantinou-
Kokotou, V.; Verger, R.; Kokotos, G. Org. Lett. 2000, 2, 347–350; (d) Dehmlow, E.
V.; Dehmlow, S. S. In Phase Transfer Catalysis; Dehmlow, E. V.; Dehmlow, S. S.,
Eds.; Chemie: Weinheim, 1983; pp 199–202. (e) Alsaidi, H.; Gallo, R.; Metzger, J.
Synth. Commun. 1980, 921–924.
Acknowledgements
This work was financially supported by Ministero dell’Istruzione
`
17. Gonzalez, A.; Galvez, C. Synth. Commun. 1983, 212–214.
dell’Universita e della Ricerca.