Efficient synthesis of 3-substituted indoles through a domino gold(I) chloride catalyzed cycloisomerization/C3-functionalization of 2-(alkynyl)anilines

Article abstract of DOI:10.1016/j.tet.2009.09.019

An efficient synthesis of 3-substituted indoles by a sequential approach involving gold(I) chloride catalyzed cycloisomerization/bis-addition and conjugate addition of 2-(alkynyl)anilines has been accomplished. A variety of 2-(alkynyl)anilines, aldehydes,

Full text of DOI:10.1016/j.tet.2009.09.019

Tetrahedron 65 (2009) 9244–9255
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of 3-substituted indoles through a domino gold(I) chloride
catalyzed cycloisomerization/C3-functionalization of 2-(alkynyl)anilines
*
C. Praveen, K. Karthikeyan, P.T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2009
Received in revised form 2 September 2009
Accepted 3 September 2009
Available online 9 September 2009
An efficient synthesis of 3-substituted indoles by a sequential approach involving gold(I) chloride cat-
alyzed cycloisomerization/bis-addition and conjugate addition of 2-(alkynyl)anilines has been accom-
plished. A variety of 2-(alkynyl)anilines, aldehydes, isatins and nitroolefins undergo this overall process
in good to excellent yields. This methodology represents an effective alternative to the classical C3-
functionalization of indoles.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
HN
1.1. Natural occurrence and pharmacological activity
of 3-substituted indoles
H
N
NH2
NH2
NH2
The 3-substituted indole nucleus is prevalent in numerous
natural products and is extremely important in medicinal chem-
istry.1 For example, two diastereoisomeric tris-indole alkaloids,
occurring as enantiomeric pairs, designated as (ꢀ)–gelliusinus A
and B I (Fig. 1) represent the major components of a deep water
Caledonian sponge2 and vibrindole A II is a metabolite of the ma-
rine bacterium, Vibrio parahaemalyticus is isolated from the toxic
mucus of the boxfish Ostracion cubicus.3 In animals, serotonin4 III
(5-hydroxytryptamine) is a crucial neurotransmitter in the central
nervous system.5
Br
HO
N
H
Gelliusines A and B I
NH2
Me
NH
HO
1.2. Synthetic methods, applications and biological
properties of bis(indolyl)methanes, di(indolyl)-
indolin-2-ones and 2-indolyl-1-nitroalkanes
N
N
H
H
Serotonin III
Vibrindole A II
Bis(indolyl)methanes constitute an important class of hetero-
cyclic compounds that display diverse pharmacological activities
and are useful in the treatment of fibromyalgia, chronic fatigue and
irritable bowel syndrome.6 They are known to promote beneficial
oestrogen metabolism7 and induce apoptosis in human cancer
cells. Thus the development of high-throughput methods for the
synthesis of bis(indolyl)methanes remains a topic of paramount
importance in view of their versatile biological and pharmacolog-
ical properties. Bis(indolyl)methanes have been prepared mainly by
the reaction of indole with carbonyl compounds in the presence of
Figure 1. Representatives of 3-substituted indoles.
Lewis acids such as LiClO4,8 InCl3,9 I2,10 CuBr2,11 [RE(PFO)3],12
ZrCl4,13 and Bronsted acids such as sulphamic acid,14,15 PTSA,16
KHSO4.17 All the synthetic avenues to bis(indolyl)methanes com-
prise reaction between pre-constructed indole skeletons with al-
dehydes (or their acetals), ketones, a-ketoacids, imines, iminium
salts or nitrones.18 On the other-hand 3,30-diaryloxindoles, a basic
framework widely found in clinical drugs and biologically active
substances have been shown to possess antiproliferative, antibac-
terial, antiprotozoal and antiinflammatory activities.19 These com-
pounds have also been used as laxatives20 and lead molecules for
Ca2þ depletion mediated inhibition of translation initiation.21 The
* Corresponding author. Tel.: þ91 44 24911329; fax: þ91 44 24911539.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.019

C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
9245
3,3-di(indolyl)indolin-2-ones can be formed by the reaction of
isatin and indoles under acidic conditions for long reaction times or
catalyzed by KAl(SO4)2 under microwave conditions.22 Only a few
methodologies have been accommodated for the synthesis of
di(indolyl)indolin-2-ones.20,23 2-Indolyl-1-nitroalkanes have be-
come important synthetic intermediates and can be readily con-
verted into tryptamines by reduction reactions.24 Various methods
for the synthesis of 2-indolyl-1-nitroalkanes have been developed.
For example, they can be prepared from indoles and nitroolefins by
Michael addition reaction promoted by several catalysts25 or
through a microwave assisted reaction of indoles with nitro-
olefins,26 and by the reaction of sulphonyl indoles with nitro-
alkanes in the presence of sodium hydride.27
acetonitrile at room temperature. Under this condition only the
cycloisomerized product that, 2-phenyl indole was obtained as the
sole product (85% isolated yield). Bis-addition, under these condi-
tions proved to be ineffective, even when the reaction was carried
out for 24 h. By elevating the temperature to 80 ꢁC, we were able to
obtain the bis-addition product (8d) in high yield in a short reaction
time (Table 1, entry 4). When the same reaction was performed
using 2 mol % of AuCl, only 40% of the product (8d) was formed, and
35% of the starting material, 2-(phenylethynyl)aniline (1a) was
recovered. So we inferred that 2 mol % of AuCl was ineffective for
the complete cycloisomerization of o-(phenylethynyl)aniline. Tol-
uene, methanol and dichloromethane gave only 38%, 20%, and 50%
of the product, respectively. Needless to say, in the absence of
catalyst, the cycloisomerization did not proceed at all. The possi-
bility of participation of Au(III) as a catalytic species, (via. oxidation
of Au(I) to Au(III)) was ruled out by performing the same reaction
using 5 mol % of AuCl3 in acetonitrile under reflux followed by the
addition of aldehyde led to the formation of only 40% of the product
(8d). This observation suggested that the catalytic activity of AuCl is
1.3. Gold catalysts in sequential cycloisomerization/C3-
functionalization process of 2-(alkynyl)anilines
In recent years, intramolecular cyclization of o-ethynylanilines
followed by C3-functionalization leading to 3-substituted indoles
have been developed with remarkable improvements in terms of
efficiency and scope of application.28 More recently it has been
shown that the alkynophilic Lewis acidity of Au(I) and Au(III)
present new opportunities for the cycloisomerization of wide array
of alkynes-tethered nucleophiles.29 The unique reactivity of Au(I)
and Au(III) with allenes and alkynes opened the doors to the dis-
covery and invention of new reactions.30 But, participation of Au(I)
and Au(III) in intramolecular cyclization/C3-functionalization of
o-ethynylanilines to 3-substituted indoles was less explored.31
Recently Au(III) catalyzed sequential cycloisomerization/conjugate
Table 1
Gold(I) catalyzed synthesis of bis(indolyl)methanes from 2-(phenylethynyl)aniline
1a and aldehyde 2
Entry
ArCHO2
Producta
Time (h)
Yieldb
CHO
R1
R2
R4
R3
addition of o-ethynylanilines with a,b
-enones32 and Au(III) cata-
1
2
3
4
R1¼H, R2¼OMe, R3¼OH, R4¼Br 2a
R1¼Br, R2¼H, R3¼OMe, R4¼OMe 2b
R1¼H, R2¼H, R3¼COOH, R4¼H 2c
R1¼H, R2¼H, R3¼Ph, R4¼H 2d
8a
8b
8c
8d
2.0
2.0
1.5
1.5
76
79
65
80
lyzed bis-arylation were reported.33 Stimulated by the growing
interest in the development of gold catalysis,34 and the ongoing
exploration of the novel synthetic process of nitrogen containing
heterocycles,35 using gold(I) chloride,35c,d we found that AuCl ef-
fectively catalyses the sequential cycloisomerization/C3-function-
alization of 2-ethynylanilines with a wide range of aldehydes,
isatins35c and nitrostyrenes. Herein, we disclose the application of
AuCl in the synthesis of some 3-substituted indoles using sequen-
tial cycloisomerization/C3-functionalization strategy (Scheme 1).36
CHO
2e
5
8e
4.0
53
N
Me
CHO
O
6
7
8f
1.0
3.5
85
59
2f
O
Br
R
H
CHO
N
Ar
ArCHO 2
2g
8g
5
N
Cl
Bis-addition
R
N
CHO
H
O
8
8h
0.5
83
R1
O
2h
H
N
O
N
R
H
R1
[Au]
6
NH
Et
N
3
R
HN
R
Cycloisomerization
Bis-addition
NH2
9
8i
8j
0.5
0.5
77
76
2i
1
CHO
CHO
NO2
R
Ar
10
Ar
2j
NO2
4
7
Cl
Michael addition
N
H
N
11
8k
8l
0.5
1.5
82
Scheme 1.
Ph
N
2k
OHC
2. Results and discussion
Me
2.1. Optimization of reaction conditions for the synthesis
of bis(indolyl)methanes
12
d
O
2l
a
We initiated our studies by reacting o-(phenylethynyl) aniline
(1a) and biphenyl-4-carbaldehyde (2d) with 5 mol % AuCl in
Isolated yield.
b
The products were characterized by IR, 1H NMR,13 C NMR and mass spectra.

9246
C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
superior to that of AuCl3 in this domino process. Based on these
observations, we used a procedure that utilizes 5 mol % of AuCl in
acetonitrile under reflux, followed by the addition of 0.5 equiv of
aldehyde, for the synthesis of bis(indolyl)methanes (Scheme 2).
(9). Subsequent nucleophilic attack of the tethered amino group
leads to ring closure to afford cyclized intermediate (10), followed
by Proto-deauration affording indole (11) and AuCl. The later acti-
vates the carbonyl oxygen of the aldehyde and carries out an
electrophilic addition reaction at C3 of the indole (11) giving in-
termediate (12). After loss of water, an azafulvene derivative (13) is
generated, which reacts further with a second molecule of indole to
form the bis(indolyl)methane (8).
H
N
Ph
Ar
Ph
1) 5 mol % AuCl, MeCN, reflux, 1h
Ph
2.2. Gold(I) catalyzed synthesis of di(indolyl)indolin-2-ones
2) 0.5 eq ArCHO 2, reflux
N
NH2
1a
H
With an efficient protocol for the gold catalyzed synthesis of
bis(indolyl)methanes in hand, we next set out to apply the same
reaction conditions for the synthesis of di(indolyl)indolin-2-ones
from various 2-ethynylanilines and isatins (Scheme 4).19 The results
of which are summarized in Table 2.
8
Scheme 2.
Under these conditions, the reaction proceeded smoothly with
a wide range of functionalized aldehydes, including those con-
taining ether, phenol, carboxylic acid, polyaromatic and hetero-
aromatic groups. The results are summarized in Table 1. The results
revealed that electron deficiency and the nature of the araldehyde
had marked effect on this conversion. Aldehydes with electron
withdrawing groups gave lower yields of the products (entry 3)
than those with electron releasing counterparts (entries 1–2). This
observation was in good agreement with other bis-addition pro-
tocols.8,37 Moreover this method is chemoselective. For example,
when a 1:1 mixture of biphenyl-4-carbaldehyde (2d) and aceto-
phenone (2l) was allowed to react with 2-(phenylethynyl)aniline
(1a) in the presence of AuCl in acetonitrile, it was found that only
3,30-(biphenyl-4-ylmethylene)bis(2-phenyl-1H-indole) (8d) was
obtained, while acetophenone did not give the corresponding
product (8l). On the basis of the above results we extended our
methodology for the synthesis of bis(indolyl)methanes derived
from aldehydes with structural diversity including polycyclic and
heteroaromatic. Most of these aldehydes gave good yields of
products. However the low yields in the case of (8e) and (8g) may
be attributed to the lower reactivity of their corresponding alde-
hydes (2e and 2g) towards bis-addition. The 1H NMR spectra of
compounds (8a–8k) in DMSO-d6 consisted of a characteristic sin-
glet due to the methine proton (–CH–Ar) in the region of 5.8–
6.7 ppm. Another characteristic feature of the 1H NMR spectra was
the appearance of a singlet at dH 11.3–11.5 ppm, which corresponds
to two indole-NH protons. These observations confirm the forma-
tion of bis(indolyl)methanes.
R2
R3
R1
N
O
1) 5 mol% AuCl , MeCN, reflux, 1h
R3
R2
NH
R4
R2
R1
R1
NH2
N
2)
O
N
R4
H
O
14
15
16
Scheme 4.
Table 2
Gold(I) catalyzed synthesis of di(indolyl)indolin-2-ones from 2-ethynylanilines 14
and isatin 15a
Entry
R1
R2
R3
R4
Time (h)
Productb
Yieldc (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
nBu
H
H
Cl
Me
CN
H
H
Me
H
H
H
H
H
Me
H
H
1.0
0.5
1.5
0.5
3.0
7.0
16a
16b
16c
16d
16e
16f
83
89
80
91
67
70
H
H
a
All reactions were carried out using 0.5 equiv of isatin.
b
c
All the products were characterized by IR, NMR and mass spectroscopies.
Isolated yield.
The substituents on the aniline moiety play a significant role in
the cycloisomerization/bis-addition process. The presence of elec-
tron releasing group, such as methyl in para position to the amino
group enhances the product formation as indicated by a short re-
action time and higher yield (entry 4). Similarly, for a strong elec-
tron withdrawing group, such as cyano, para to amino group,
A tentative mechanistic interpretation (Scheme 3) to explain the
formation of the observed bis(indolyl)methanes (8) might reason-
ably assume a reaction path that implies an initial
p-coordination of
Lewis acidic AuCl with the alkyne residue (1a) to form a
p
-complex
AuCl
_
AuCl
Ph
Ph
AuCl
..
Ph
..
Ph
NH2
N
NH2
NH2
H
+
9
11
10
1a
Ph
H
N
Ar
Ar
Ar
H
H
AuCl
OH
Ph
10
O
11
Ph
Ph
+
-H2O
-AuCl
N
N
H
Ar
H
N
AuCl
13
12
8
Scheme 3.

C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
9247
required a longer reaction time and gave a lower yield (entry 5). The
nature of groups on the triple bond of the 2-ethynylanilines viz. R1,
also affects the product yield. Compound (14) with a phenyl group
on the alkyne, underwent the cycloisomerization/bis-addition
process smoothly in a short reaction time, and the total conversions
were high (entries 1–5). However n-butyl on the alkyne residue
afforded a product with low yield and required a longer reaction
time (entry 6). The formation of di(indolyl)indolin-2-ones (16a–
16f) was ascertained by the appearance of a low intense peak in the
13C NMR spectrum at dC 52.2–59.7 ppm, indicates the presence of
a quaternary carbon. Moreover, no quaternary carbon signal
appeared in the 13C NMR 135 DEPT spectra. Furthermore, all com-
pounds exhibited a 13C peak at dC 175–183 ppm supporting the
presence of an amide carbon.
2-(phenylethynyl)aniline 1a and nitrostyrene 17a with 5 mol %
AuCl in acetonitrile under refluxing condition. To our delight the
reaction proceeded well and gave the desired 2-indolyl-1-nitro-
alkane 18a in excellent yield (Scheme 5, Table 3, entry 1). A con-
trolled experiment in which 2-phenyl indole was exposed to
nitrostyrene 17a in the absence of AuCl does not lead to any
3-alkylated product at all. This finding suggested that AuCl is in-
deed required for the Michael addition step. One-pot synthesis
coupled with the excellent yield of the product, encouraged us to
extend this methodology to a range of 2-(alkynyl)anilines and
nitroolefins (Table 3, entries 1–12). The results revealed that the
groups attached to the nitroolefin have a marked effect on the
yield of the product. The presence of electron withdrawing group
on the nitroolefin gave good yield of the product (Table 3, entry 3)
NO2
Ar
2.3. Gold(I) catalyzed synthesis of 2-indolyl-1-nitroalkanes
R
1) 5 mol % AuCl, MeCN, reflux
R
Since we had already established that 5 mol % of AuCl in ace-
tonitrile under refluxing condition, is optimal for the cyclo-
isomerization of 2-(alkynyl)anilines, we followed the same
reaction condition for the cycloisomerization/Michel addition
process. To begin our study, we carried out the reaction between
2) Ar
N
NH2
(1.0 mmol), reflux
17
H
NO2
18
1
Scheme 5.
Table 3
Gold(I) catalyzed synthesis of 2-(indolyl)-1-nitroalkanes 18 from 2-(alkynyl)aniline 1 and nitroolefin 17
Entry
2-(Alkynyl)aniline 1
Nitroolefin 17
2-(Indolyl)-1-nitroalkane 18a
Time (h)
Yieldb (%)
Ph
NO2
R1
1a
NH2
1
2
3
R1¼Ph17a
18a
18b
18c
3.0
3.0
3.0
85
79
88
R1¼p-MeC6H4 17b
R1¼p-ClC6H4 17c
NO2
MeO
4
5
18d
18e
5.0
5.0
69
72
17d
MeO
O
Br
NO2
17e
O
Br
Ph
N
N
17f
6
7
18f
4.5
0.5
77
93
p-BrC6H4
O2N
Me
17a
18g
1b
NH2
8
9
17a
17b
18h
18i
1.0
1.0
87
80
1c
NH2
NO2
10
18j
6.0
63
17g
1d
F
NH2
a
Isolated yield.
b
The products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.

9248
C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
and the presence of electron releasing group, gave slightly lower
yields (Table 3, entries 1, 2 and entries 4–6). Similarly, the triple
bond of 2-(alkynyl)anilines, possessing methyl or n-butyl group
afforded product with good yield (Table 3, entries 7 and 8). This
observation may be reasoned due to the better electrophilic ac-
tivation of the in situ formed 2-methylindole and 2-nbutylindole
towards nitroolefins. In addition, electron withdrawing sub-
stituent at the amino group of the 2-(alkynyl)anilines underwent
only cycloisomerization and did not gave the Michael addition
product. The reaction of N-substituted(alkynyl)anilines such as 1e
and 1f with nitrostyrene 17a gave only the cycloisomerized
product 11a and 11b (Table 4, entries 1 and 2). This could be at-
tributed due to the electron withdrawing nature of Ac and Ms
groups, which deactivates the formed indole nucleus. On the other
hand alkyne 1g possessing –C(O)CF3, a very strong electron
withdrawing group completely failed to undergo cyclo-
isomerization (Table 4, entry 3). This observation was in sharp
contrast to the other cycloisomerization protocols,38 wherein, the
presence of an acidic proton (in the form of amide instead of
amine) is essential for effective cycloisomerization (Scheme 5).
A mechanistic rationale portraying the probable sequence of
events is given in Scheme 6. Initial coordination of the -acidic
AuCl with the alkynylaniline 1 forms -complex 19. Subsequent
nucleophilic attack of the tethered amino group would leads to ring
closure to afford the cyclized intermediate 20, followed by proto-
deauration affording indole 21 and AuCl. The later again enters the
catalytic loop by interacting with the nitro oxygen of the nitroolefin
17 to form 22, which undergo a conjugate addition with the elec-
p
p
tron rich b-position of the indole 21 giving intermediate 23. After
proton transposition, 24 is generated, which rearranges to form the
Michael adduct 18 and AuCl.
2.4. Gold(I) catalyzed synthesis of 2-indolyl-1-nitroalkanes
from chiral Michael acceptors
On the basis of the above results, coupled with the fact that
indoles and carbohydrates39 are often associated with important
biological properties, we then intended to examine the fate of sugar
derived chiral Michael acceptors.40 However these Michael accep-
tors, towards conjugate addition required longer reaction time
(Table 5, entries 1–3). This may be due to the poor electrophilicity of
the
towards Michael addition. Crude 1H NMR analysis revealed that in
all cases, -gluco isomer was formed as the major product (18k–
18m) and
-ido isomer was formed as the minor product (18k0–
b-carbon atom of these nitroolefins, making them less reactive
Table 4
Gold(I) catalyzed cycloisomerization of N-substituted 2-(alkynyl)anilines 1
D
Entry
1a
2-(alkynyl)aniline 1
Indole derivative 2b
Time (h)
Yieldc (%)
L
18m0). To extend the scope of this methodology, nitrochromene41
17j was subjected to our reaction conditions, since the resultant 2H-
benzopyran derivatives possess important medicinal properties.42
In this case the products were obtained in excellent diaster-
eoselectivity (18n and 18n0). The relative stereochemistry of the
substituents in 18n was unambiguously assigned on the basis of 1-
D NOE experiment. The assignment of relative stereochemistry at
C5 in compounds 18l and 18l0 became difficult, since the coupling
constant values in both diastereoisomers are very close. Inorder to
eliminate the CH2 coupling in C5–H, and to establish the actual
stereochemistry, we intended to convert –CH2NO2 group to nitrile
Ph
Ph
2.5
78
1e
NHAc
Ph
NAc
11a
2a
3.0
6.0
69
1f
Ph
11b
NMs
NHMs
Ph
1g
3
d
d
NHCOCF3
oxide and carry out
a
sequential [3þ2] cycloaddition with
a
Michael addition was checked using nitroolefin 17a.
diethylacetylene dicarboxylate to form the isoxazole ring.43 The
cycloaddition reaction of 18l and 18l0 was separately carried out
with ethylchloroformate, triethylamine and DMAP in dichloro-
methane at room temperature (Scheme 7). The 1H NMR data of the
obtained isoxazole 20a (from 18l) and 20b (from 18l0) turned out to
be informative, it is known that for a given C5-epimeric pair derived
b
c
The products were characterized by IR, 1H NMR, 13C NMR and mass spectra.
Isolated yield.
AuCl
O
Ar
22
N
from
D-glucofuranose, the J4,5 in the
L
-ido isomer is consistently
O
larger than that of the corresponding
D
-gluco isomer.44 The higher
value of J4,5 observed in isoxazole 20b (10.7 Hz) as compared to
isoxazole 20a (9.9 Hz) indicated, the -ido configuration for 20b and
the -gluco configuration for 20a. This assignment was further
supported by comparing the chemical shifts of H3 in 20a and 20b is
reported to be diagnostic such that, in the -ido isomer, it is sig-
nificantly upfield ( w3.6) as compared to that in the -gluco isomer
w4.0).44 In 20b H3 appeared upfield
w3.37 as compared to 20a
at w4.20. From the above facts we were assigned the stereo-
chemistry of the major diastereoisomers 18k–18m and minor di-
astereoisomers 18k0–18m0 as
-gluco and -ido, respectively. In the
O
Ar
R
N
L
17
N
H
O
D
O
N
_
AuCl
21
Ar
R
O
H
L
AuCl
d
D
1
NH2
NH+
(d
d
23
d
_
AuCl
Ar
AuCl
D
L
O
R
1H NMR spectrum of compound 18n, a doublet at 5.06 ppm, triplet
at 5.41 ppm and singlet at 5.68 ppm were assigned to Ha, Hb and Hc
protons, respectively. These assignments of protons were con-
firmed by HMBC spectrum. In HMBC spectrum, the indole NH
makes HMBC correlation with carbon at 111.7, 127.3 and 137.1 ppm
and a proton signal at 5.06 ppm makes the HMBC correlation with
the above same carbons and additionally two more correlation with
carbon at 75.2 ppm (O–CH) and 89.5 ppm (CH–NO2). From this we
have assigned the signal at 5.06 ppm to Ha. The proton Ha
(5.06 ppm) couples with proton at 5.41 ppm and the proton was
assigned as Hb. From these facts signal at 5.68 ppm to Hc. The
N
OH
R
R
19
N
H
NH2
NH2
+
24
20
O
N
Ar
O
R
N
H
18
Scheme 6.

C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
9249
Table 5
Gold(I) catalyzed sequential cycloisomerization/Michael addition of 2-(alkynyl)anilines with chiral Michael acceptorsa
Entry
2-(Alkynyl)aniline 1
Nitroolefin 3
Nitroadduct 4
Yieldb,c (%)
(dr)d
H
N
H
N
Me
Me
H
O
H
H
O2N
O2N
O2N
O2N
O2N
O
H
H
O
O
1
1b
O
84
88:12 18k/18k’
O
H
O
H
BnO
H
O
O
BnO
D-gluco
BnO
H
H
17h
18k
18k'
L-ido
H
N
H
N
Me
H
Me
H
H
O
O2N
O2N
O
H
H
O
O
2
1b
82
90:10 181/18k’
O
O
O
H
EtO
H
H
O
O
EtO
EtO
D-gluco
H
H
17i
18l'
18l
L-ido
H
H
N
N
Ph
Ph
H
H
O2N
H
H
O
O
3
1a
17h
85
98:2 18m/18m’
O
O
H
H
O
O
BnO
D-gluco
BnO
L-ido
H
H
18m
18m'
H
N
H
N
NO2
Ph
NO2
Ph
NO2
O
4
1a
92
99:1 18n/18n’
O
O
17j
18n'
18n
a
All reactions were carried out for 12 h under reflux in acetonitrile.
b
c
All products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.
Isolated yield.
d
Diastereoisomeric ratio was determined on the basis of crude 1H NMR analysis.
stereochemistry of the diastereoisomers was confirmed by 1-D
NOE experiment. In 1-D NOE measurement, selective irradiation of
Ha proton effected enhancement of the signal of Hb is 3.4%. Irra-
diation of Hb effected enhancement of the signal of Ha (4.9%) and
Hc (11.2%). Irradiation of Hc effected enhancement of the signal of
Hb is 9.6%. These facts shows that the proton Hb cis to Hc and trans
to Ha (Fig. 2).
BRUKER spectrophotometer, respectively. Mass spectra were
recorded using a Thermo Finnigan LCQ Advantage MAX 6000 ESI
mass spectrometer. Elemental analyses were recorded using
a Thermo Finnigan FLASH EA 1112CHN analyzer. Column chroma-
tography was performed on silica gel (100–200 mesh, SRL. India).
Analytical TLC was performed on pre-coated aluminium sheets of
silica gel 60F254 of 0.2 mm thickness (Merck, Germany).
3. Conclusion
4.2. Typical procedure for the preparation of bis(indolyl)-
methanes and di(indolyl)indolin-2-ones
In conclusion Au(I) catalyzed synthesis of some 3-substituted
indole derivatives via sequential cycloisomerization/bis and con-
jugate addition of 2-(alkynyl)anilines with varies electrophiles has
been achieved. Further studies concerning both the mechanism
and possible synthetic applications of this protocol are currently
being carried out.
To a solution of o-ethynylaniline (1.0 mmol) in acetonitrile
(1 mL) was added AuCl (5 mol %) in acetonitrile (1 mL) and refluxed
for 1 h. To this reaction mixture, aldehyde or isatin (0.5 mmol) was
added and refluxed for the specified time (see Tables 1 and 2). After
completion of the reaction as indicated by TLC (petroleum ether/
ethyl acetate), the reaction mixture was concentrated under re-
duced pressure and purified by column chromatography on silica
gel using petroleum ether/ethyl acetate to afford pure product of
bis(indolyl)methanes or di(indolyl)indolin-2-ones.
4. Experimental section
4.1. General
Melting points were determined in capillary tubes and are un-
corrected. Infrared (IR) spectra were recorded on a Perkin–Elmer
FTIR spectrophotometer. 1H NMR (500 MHz) and 13C (75 MHz and
125 MHz) spectra were recorded in CDCl3, DMSO-d6 and acetone-d6
solution with TMS as internal standard on a JEOL spectrometer and
4.2.1. 4-[Bis(2-phenyl-1H-indol-3-yl)methyl]-2-bromo-6-methoxy-
phenol (8a). Brown solid; mp 228–230 ꢁC; Rf¼0.62 (AcOEt/petro-
leum ether 40%). IR (KBr): 3480, 3387, 1493, 1453, 1414, 1274, 1227,
1042, 746, 698 cmꢂ1 1H NMR (500 MHz, DMSO-d6) dH 3.47 (s, 3H,
.
–OCH3), 5.87 (s, 1H, –CH–Ar), 6.66–6.71 (m, 3H, Ar–H), 6.78 (s, 1H,

9250
C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
C
4.69.
37H29BrN2O2: C, 72.43; H, 4.76; N, 4.57. Found: C, 72.52; H, 4.71; N,
H
N
NH
O
H
H
4.2.3. 4-[Bis(2-phenyl-1H-indol-3-yl)methyl]benzoic acid (8c).
Colourless solid; mp 292–294 ꢁC; Rf¼0.19 (AcOEt/petroleum ether
40%). IR (KBr): 3401, 3055, 2923, 2560, 1666, 1606, 1457, 1426, 1294,
743, 696 cmꢂ1. 1H NMR (500 MHz, DMSO-d6) dH 5.96 (s,1H, –CH–Ar),
6.66 (t, 2H, J¼8.4 Hz, Ar–H), 6.85 (d, 2H, J¼8.4 Hz, Ar–H), 6.98 (t, 2H,
J¼8.4 Hz, Ar–H), 7.18–7.25 (m, 14H, Ar–H), 7.35 (d, 2H, J¼8.4 Hz, Ar–
H), 7.80 (s, 1H, –NH), 7.82 (s, 1H, –NH), 11.36 (s, 1H, –COOH). 13C NMR
(75 MHz, DMSO-d6) dC 39.7, 111.4, 113.3, 118.6, 120.5, 121.0, 127.3,
127.9, 128.0, 128.3, 128.5, 128.8, 129.4, 132.5, 135.6, 136.2, 150.8,
167.31. MS(EI): m/z¼519 [MþþHþ]. Anal. Calcd for C36H26N2O2: C,
83.37; H, 5.05; N, 5.40. Found: C, 83.45; H, 4.99; N, 5.44.
O
O2N
O2N
H
H
O
O
EtO
EtO
O
O
18l'
L-ido
D-Gluco
18l
ClCOOEt, DMAP, Et3N
CH2Cl2, rt
ClCOOEt, DMAP, Et3N
CH2Cl2, rt
H
N
NH
O
4.2.4. 3,30-(Biphenyl-4-ylmethylene)bis(2-phenyl-1H-indole) (8d).
Yellow solid; mp 258–260 ꢁC; Rf¼0.43 (AcOEt/petroleum ether
H
H
+
+
-
O
-
O
N
N
O
H
O
EtO
H
50%). IR (KBr): 3398, 1601, 1450, 1306, 1011, 735 cmꢂ1 1H NMR
.
O
EtO
O
O
(500 MHz, DMSO-d6) dH 6.01 (s, 1H, –CH–Ar), 6.67 (t, 2H, J¼7.6 Hz,
Ar–H), 6.99 (t, 4H, J¼7.6 Hz, Ar–H), 7.18–7.22 (m, 8H, Ar–H), 7.27–
7.33 (m, 5H, Ar–H), 7.36–7.41 (m, 4H, Ar–H), 7.58 (d, 2H, J¼8.4 Hz,
Ar–H), 7.65 (d, 2H, J¼7.6 Hz, Ar–H), 11.35 (s, 2H, –NH). 13C NMR
(75 MHz, DMSO-d6) dC 38.6, 111.2, 114.6, 118.4, 120.7, 120.8, 126.3,
127.1, 128.0 (2C), 128.2, 128.7, 129.2, 132.6, 135.3, 136.2, 137.3,
139.6, 144.7. MS(EI): m/z¼550 [Mþ]. Anal. Calcd for C41H30N2: C,
89.42; H, 5.49; N, 5.09. Found: C, 89.55; H, 5.45; N, 4.99.
19b
19a
COOEt
COOEt
COOEt
COOEt
4.2.5. 3,30-[(1-Methyl-1H-indol-2-yl)methylene]bis(2-phenyl-1H-in-
dole) (8e). Brown solid; mp 258–260 ꢁC; Rf¼0.45 (AcOEt/petro-
leum ether 40%). IR (KBr): 3439, 3393, 1454,1306, 744, 696 cmꢂ1. 1H
NMR (500 MHz, DMSO-d6) dH 3.14 (s, 3H, –NCH3), 5.98 (s, 1H, –CH–
Ar), 6.10 (s, 1H, Indolyl-H), 6.62 (t, 2H, J¼7.6 Hz, Ar–H), 6.95–7.04
(m, 4H, Ar–H), 7.18–7.28 (m, 13H, Ar–H), 7.37 (d, 2H, J¼8.4 Hz, Ar–
H), 7.43 (d, 1H, J¼7.6 Hz, Ar–H), 11.3 (s, 2H, –NH). 13C NMR (75 MHz,
DMSO-d6) dC 29.1, 33.5, 101.5, 109.2, 111.2, 118.7, 118.9, 119.7, 119.8,
120.4, 121.0, 126.8, 127.2, 127.8, 128.0, 128.2, 132.4, 134.8, 136.0,
137.3, 143.5. MS(EI): m/z¼528 [MþþHþ]. Anal. Calcd for C38H29N3:
C, 86.50; H, 5.54; N, 7.96. Found: C, 86.46; H, 5.59; N, 7.95.
H
N
NH
O
H
H
O
EtOOC
EtOOC
EtOOC
H
H
O
O
N
N
EtOOC
EtO
EtO
O
20a
O
O
O
20b
Scheme 7.
H
N
4.9 %
4.2.6. 3,30-[(6-Bromo-1,3-benzodioxol-5-yl)methylene]bis(2-phenyl-
Ph
Hb
1H-indole) (8f). Pale yellow solid; mp 222–224 ꢁC; Rf¼0.26 (AcOEt/
11.2 %
Ha
petroleum ether 20%). IR (KBr): 3386, 1474, 1234, 1036, 752 cmꢂ1
.
NO2
4
3
1H NMR (500 MHz, DMSO-d6) dH 6.61 (s, 2H, –OCH2O–), 6.79 (s, 1H,
–CH–Ar), 6.85 (s, 1H, Ar–H), 6.99–7.05 (m, 6H, Ar–H), 7.13 (s, 1H, Ar–
H), 7.20–7.34 (m, 12H, Ar–H), 11.26 (s, 2H, –NH). 13C NMR (75 MHz,
DMSO-d6) dC 26.3, 40.6, 101.8, 110.7, 111.3, 112.7, 114.6, 118.8, 119.6,
120.9, 127.3, 127.9, 128.1, 128.2, 132.7, 136.0, 137.2, 146.6, 146.8.
MS(EI): m/z¼596 [Mþ], 598 [Mþ2]. Anal. Calcd for C36H25BrN2O2: C,
72.37; H, 4.22; N, 4.69. Found: C, 72.49; H, 4.33; N, 4.75.
Hc
O
2
1
Figure 2. NOEs observed for Michael adduct 18n.
Ar–H), 6.91 (d, 2H, J¼7.6 Hz, Ar–H), 6.98 (t, 2H, J¼7.6 Hz, Ar–H), 7.19–
7.21 (m, 6H, Ar–H), 7.28–7.29 (m, 4H, Ar–H), 7.34 (d, 2H, J¼8.4 Hz,
Ar–H), 9.30 (s, 1H, –OH), 11.3 (s, 2H, –NH). 13C NMR (75 MHz, DMSO-
d6) dC 56.1, 64.8, 109.0, 111.3, 112.1, 113.8, 118.6, 120.5, 120.9, 124.1,
127.2, 128.0, 128.2, 132.7, 135.3, 136.1, 137.4, 141.9, 148.4. MS(EI):
m/z¼597 [Mþ], 599 [Mþ2]. Anal. Calcd for C36H27BrN2O2: C, 72.14; H,
4.54; N, 4.67. Found: C, 72.22; H, 4.45; N, 4.81.
4.2.7. 3-[Bis(2-phenyl-1H-indol-3-yl)methyl]-2-chloroquinoline (8g).
Yellow solid; mp 232–234 ꢁC; Rf¼0.21 (AcOEt/petroleum ether 40%).
IR (KBr): 3408, 1655, 1025, 750 cmꢂ1. 1H NMR (500 MHz, DMSO-d6)
dH 6.23 (s, 1H, –CH–Ar), 6.63 (t, 2H, J¼7.6 Hz, Ar–H), 6.98 (t, 2H,
J¼8.4 Hz, Ar–H), 7.16–7.23 (m, 12H, Ar–H), 7.37 (d, 2H, J¼8.4 Hz, Ar–
H), 7.52 (t, 1H, J¼8.4 Hz, Ar–H), 7.72 (t, 1H, J¼8.4 Hz, Ar–H), 7.81 (d,
1H, J¼7.6 Hz, Ar–H), 7.86 (d, 1H, J¼8.4 Hz, Ar–H), 8.17 (s, 1H, Qui-
nolinyl-H), 11.42 (s, 2H, –NH). 13C NMR (75 MHz, DMSO-d6) dC 39.5,
111.5, 118.9, 119.5, 121.0, 126.6, 127.2 (2C), 127.3 (2C), 127.9 (2C), 128.1
(2C), 130.2, 132.6, 136.1, 136.8, 138.4, 145.7, 150.6. MS(EI): m/z¼560
[MþþHþ], 562 [Mþ2þHþ]. Anal. Calcd for C38H26ClN3: C, 81.49; H,
4.68; N, 7.50. Found: C, 81.61; H, 4.75; N, 7.60.
4.2.2. 3,30-[(2-Bromo-4,5-dimethoxyphenyl)methylene]bis(2-phenyl-
1H-indole) (8b). Colourless solid; mp 240–242 ꢁC; Rf¼0.17 (AcOEt/
petroleum ether 20%). IR (KBr): 3391, 1602, 1492, 1454, 1377, 1305,
1274, 1149, 744, 699 cmꢂ1. 1H NMR (500 MHz, DMSO-d6) dH 3.30 (s,
3H, –OCH3), 3.73 (s, 3H, –OCH3), 6.06 (s, 1H, –CH–Ar), 6.60–6.80 (m,
3H, Ar–H), 6.97 (t, 2H, J¼7.6 Hz, Ar–H), 7.07 (d, 4H, J¼6.1 Hz, Ar–H),
7.18–7.24(m, 8H, Ar–H),7.31(d, 3H, J¼7.6 Hz,Ar–H),11.21(s,2H, –NH).
13C NMR (75 MHz, DMSO-d6) dC 43.9, 60.8, 61.0, 116.5, 119.8, 120.6,
121.3, 123.9, 124.9, 126.0, 132.3, 133.2 (2C), 133.5, 138.1, 141.0, 141.2,
152.9, 153.3. MS(EI): m/z¼612 [Mþ], 614 [Mþ2]. Anal. Calcd for
4.2.8. 3,30-(1-Naphthylmethylene)bis(phenyl-1H-indole) (8h). Pale
yellow solid; mp 282–284 ꢁC; Rf¼0.20 (AcOEt/petroleum ether 20%).
IR (KBr): 3394, 1451, 1306, 739 cmꢂ1. 1H NMR (500 MHz, DMSO-d6)

C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
9251
dH 6.49 (s, 1H, –CH–Ar), 6.56–6.57 (m, 2H, Ar–H), 6.90–7.03 (m, 2H,
Ar–H), 7.10–7.13 (m, 11H, Ar–H), 7.30 (t, 5H, J¼7.6 Hz, Ar–H), 7.44 (t,
1H, J¼7.6 Hz, Ar–H), 7.50 (d, 1H, J¼9.15 Hz, Ar–H), 7.53 (d, 1H,
J¼6.8 Hz, Ar–H), 7.84 (t, 2H, J¼8.4 Hz, Ar–H), 11.34 (s, 2H, –NH). 13C
NMR (75 MHz, DMSO-d6) dC 37.5, 111.2, 118.5, 120.1, 120.7, 123.1,
125.0, 122.2, 125.7, 126.7, 127.2 (2C), 127.8, 128.1, 128.5, 131.0, 132.6,
133.4, 134.7, 136.1, 140.9. MS(EI): m/z¼524 [Mþ]. Anal. Calcd for
C39H28N2: C, 89.28; H, 5.38; N, 5.34. Found: C, 89.41; H, 5.47; N, 5.48.
ether 25%). IR (KBr): 3411, 3319, 1698, 1605, 1489, 1454, 1351, 741,
696 cmꢂ1 1H NMR (500 MHz, DMSO-d6) dH 2.83 (s, 3H, –NCH3),
.
6.58 (t, 1H, J¼6.8 Hz, Ar–H), 6.64 (t, 2H, J¼6.8 Hz, Ar–H), 6.81 (t, 1H,
J¼7.6 Hz, Ar–H), 6.89–7.09 (m, 11H, Ar–H), 7.23–7.33 (m, 7H, Ar–H),
10.75 (s, 1H, –NH), 11.02 (s, 1H, –NH). 13C NMR (75 MHz, DMSO-d6)
dC 25.9, 52.2, 108.0, 110.2, 110.9, 111.3, 117.8, 118.3, 119.6, 120.4, 121.5,
121.8, 124.8, 125.7, 126.6, 127.1 (2C), 127.4 (2C), 127.7, 128.5 (2C),
128.6, 133.2, 134.0, 134.4, 134.5, 135.3, 135.4, 141.9, 175.5. MS(EI):
m/z¼552 [MþþNaþ]. Anal. Calcd for C37H27N3O: C, 83.91; H, 5.14; N,
7.93. Found: C, 84.01; H, 5.25; N, 7.85.
4.2.9. 3-[Bis(2-phenyl-1H-indol-3-yl)methyl]-9-ethyl-9H-carbazole
(8i). Pale yellow solid; mp 278–280 ꢁC; Rf¼0.23 (AcOEt/petroleum
ether 20%). IR (KBr): 3401,1483,1457,1340,1233, 743 cmꢂ1. 1H NMR
(500 MHz, DMSO-d6) dH 1.26 (t, 3H, J¼7.6 Hz, –NCH2CH3), 4.33 (q,
2H, J¼6.8 Hz, –NCH2CH3), 6.17 (s, 1H, –CH–Ar), 6.58 (t, 2H, J¼8.4 Hz,
Ar–H), 6.88 (d, 2H, J¼7.6 Hz, Ar–H), 6.94–7.00 (m, 3H, Ar–H), 7.15–
7.16 (m, 6H, Ar–H), 7.27 (d, 1H, J¼7.6 Hz, Ar–H), 7.31–7.37 (m, 7H,
Ar–H), 7.44 (d,1H, J¼8.4 Hz, Ar–H), 7.48 (d,1H, J¼7.6 Hz, Ar–H), 7.79
(d, 1H, J¼7.6 Hz, Ar–H), 7.85 (s, 1H, carbazolyl-H), 11.33 (s, 2H, –NH).
13C NMR (75 MHz, DMSO-d6) dC 13.7, 37.0, 39.4, 108.5, 108.9, 111.3,
115.1, 118.4, 119.8, 120.2, 120.8, 122.0, 122.1, 125.5, 126.8, 127.1, 128.0,
128.2, 128.4, 132.8, 135.1, 136.1, 136.3, 138.1, 139.8. MS(EI): m/z¼591
[Mþ]. Anal. Calcd for C43H33N3: C, 87.28; H, 5.62; N, 7.10. Found: C,
87.41; H, 5.70; N, 7.17.
4.2.14. 5-Methyl-3,3-bis(5-chloro-2-phenyl-1H-indol-3-yl)indolin-2-
one (16c). Pink solid; mp 279–281 ꢁC; Rf¼0.46 (AcOEt/petroleum
ether 50%). IR (KBr): 768, 1311, 1464, 1711, 2924, 3419 cmꢂ1. 1H NMR
(500 MHz, DMSO-d6) dH 2.04 (s, 3H, –CH3), 6.89–7.10 (m, 19H, Ar–H),
10.49 (s,1H, –NH–CO–),11.14 (s,1H, –NH),11.21 (s,1H, –NH).13C NMR
(75 MHz, DMSO-d6) dC 31.5, 58.0,114.2,115.3,116.2,117.3,125.1,125.4,
125.8, 126.0, 128.1, 129.0, 131.6, 132.0, 132.3, 132.5, 133.5 (2C), 133.6
(2C), 133.7, 134.2, 135.2, 138.4, 138.5, 138.9, 139.0, 139.1, 142.6, 143.9,
183.0. MS(EI): m/z¼1217 [dimerþNaþ], 1219 [dimerþMþ2þNaþ],
1221 [dimerþMþ4þNaþ]. Anal. Calcd for C37H25ClN3O: C, 74.25; H,
4.21; N, 7.02. Found: C, 74.11; H, 4.25; N, 7.15.
4.2.15. 3,3-Bis(5-methyl-2-phenyl-1H-indol-3-yl)indolin-2-one (16d).
Brown solid; mp 270–272 ꢁC; Rf¼0.38 (AcOEt/petroleum ether 50%).
IR (KBr): 1105,1250,1601, 1706, 1712, 3377, 3409, 3473 cmꢂ1. 1H NMR
(500 MHz, DMSO-d6) dH 2.03 (s, 3H, –CH3), 2.13 (s, 3H, –CH3), 6.80–
7.33 (m, 20H, Ar–H), 10.40 (s, 1H, –NH–CO–), 10.51 (s, 1H, –NH), 10.83
(s, 1H, –NH). 13C NMR (75 MHz, DMSO-d6) dC 21.2, 22.0, 53.4, 109.4,
110.3, 110.5, 110.9, 111.6, 112.6, 120.6, 121.4, 121.7, 122.4, 123.2, 125.1,
125.9, 126.0, 126.4, 126.5, 126.7, 127.5, 127.6, 128.1 (2C), 128.7, 128.9,
129.3, 134.1, 134.4, 134.8, 135.3, 138.8, 141.4, 177.8. MS(EI): m/z¼1109
[dimerþNaþ]. Anal. Calcd for C38H29N3O: C, 83.95; H, 5.38; N, 7.73.
Found: C, 84.05; H, 5.29; N, 7.81.
4.2.10. 3,30-(9H-Fluoren-3-ylmethylene)bis(2-phenyl-1H-indole)
(8j). Colourless solid; mp 244–246 ꢁC; Rf¼0.27 (AcOEt/petroleum
ether 20%). IR (KBr): 3394, 1454, 1306, 741 cmꢂ1. 1H NMR (500 MHz,
DMSO-d6) dH 3.75 (s, 2H, –CH2–), 6.03 (s, 1H, –CH–Ar), 6.64 (t, 2H,
J¼7.6 Hz, Ar–H), 6.98 (d, 4H, J¼7.6 Hz, Ar–H), 7.17–7.24 (m, 8H, Ar–
H), 7.31–7.37 (m, 8H, Ar–H), 7.47 (d, 1H, J¼7.6 Hz, Ar–H), 7.74 (d, 1H,
J¼7.6 Hz, Ar–H), 7.79 (d, 1H, J¼7.6 Hz, Ar–H), 11.35 (s, 2H, –NH). 13C
NMR (75 MHz, DMSO-d6) dC 36.2, 40.08, 114.3, 114.4, 118.5, 119.7,
120.8, 120.9, 125.0, 125.2 (2C), 126.4, 126.6, 127.1, 127.4, 128.0 (2C),
128.2, 132.7, 135.3, 136.3, 139.0, 141.1, 143.0, 144.6. MS(EI): m/z¼562
[Mþ]. Anal. Calcd for C42H30N2: C, 89.65; H, 5.37; N, 4.98. Found: C,
89.75; H, 5.30; N, 5.08.
4.2.16. 3,3-Bis(5-cyano-2-phenyl-1H-indol-3-yl)indolin-2-one (16e).
Colourless solid; mp 320–322 ꢁC; Rf¼0.41 (AcOEt/petroleum ether
4.2.11. 4-[Bis(2-phenyl-1H-indol-3-yl)methyl]-3-(4-chlorophenyl)-1-
phenyl-1H-pyrazole (8k). Pink solid; mp 270–272 ꢁC; Rf¼0.21
(AcOEt/petroleum ether 20%). IR (KBr): 3413, 1598, 1499, 1449, 1212,
50%). IR (KBr): 1200, 1307, 1464, 1717, 2266, 3346, 3404, 3481 cmꢂ1
.
1H NMR (500 MHz, DMSO-d6) dH 6.63–7.63 (m, 20H, Ar–H), 10.69 (s,
1H, –NH–CO–), 11.56 (s, 1H, –NH), 11.76 (s, 1H, –NH). 13C NMR
(75 MHz, DMSO-d6) dC 59.7, 100.5, 100.6, 109.5, 110.8, 111.7, 112.0,
112.3, 120.6, 120.8, 121.8, 123.4, 123.5, 123.6, 125.6, 125.8, 126.3,
126.4,126.8,127.2,127.4, 127.9,128.4,128.5,128.6,132.1,132.4,133.9,
137.2, 138.0, 140.9, 177.4. MS(EI): m/z¼1153 [dimerþNaþ]. Anal.
Calcd for C38H23N5O: C, 80.69; H, 4.10; N, 12.38. Found: C, 80.55; H,
4.15; N, 12.25.
1092, 746, 697 cmꢂ1 1H NMR (500 MHz, DMSO-d6) dH 5.94 (s, 1H,
.
–CH–Ar), 6.71 (t, 2H, J¼7.6 Hz, Ar–H), 6.97 (t, 2H, J¼8.4 Hz, Ar–H), 7.05
(d, 2H, J¼8.4 Hz, Ar–H), 7.15–7.25 (m, 15H, Ar–H), 7.30 (d, 2H,
J¼8.4 Hz, Ar–H), 7.39 (t, 2H, J¼8.4 Hz, Ar–H), 7.66 (d, 2H, J¼7.6 Hz, Ar–
H), 7.83 (s, 1H, Pyrazolyl-H), 11.25 (s, 2H, –NH). 13C NMR (75 MHz,
DMSO-d6) dC 31.25, 111.2, 113.6, 118.1, 118.6, 120.0, 120.8, 126.17 (2C),
127.2, 127.6, 127.7, 127.9, 128.0, 128.4, 129.4, 131.9 (2C), 132.6, 135.1,
136.1, 139.2, 148.9. MS(EI): m/z¼650 [Mþ], 652 [Mþ2]. Anal. Calcd for
C44H31ClN4: C, 81.15; H, 4.80; N, 8.60. Found: C, 80.97; H, 4.75; N, 9.79.
4.2.17. 3,3-Bis(2-butyl-1H-indol-3-yl)indolin-2-one (16f). Brown solid;
mp 199–201 ꢁC; Rf¼0.50 (AcOEt/petroleum ether 25%). IR (KBr): 749,
1459, 1713, 2925, 3385 cmꢂ1. 1H NMR (500 MHz, DMSO-d6) dH 0.59 (t,
3H, J¼6.8 Hz, –CH3), 0.67 (t, 3H, J¼6.8 Hz, –CH3), 0.91–1.42 (m, 8H,
–CH2–CH2–CH3), 2.29–2.35 (m, 4H, Ar–CH2–), 6.39 (d, 1H, J¼7.6 Hz,
Ar–H), 6.50 (t, 1H, J¼6.9 Hz, Ar–H), 6.58 (t, 1H, J¼7.6 Hz, Ar–H), 6.79–
6.90 (m, 5H, Ar–H), 7.12–7.18 (m, 4H, Ar–H), 10.47 (s, 1H, –NH–CO–),
10.70 (s, 1H, –NH), 10.75 (s, 1H, –NH). 13C NMR (75 MHz, DMSO-d6) dC
13.4, 13.5, 22.0, 22.1, 26.4, 26.5, 30.8, 31.3, 52.6, 109.1, 110.1, 110.2, 110.5,
117.3, 117.4, 119.4, 119.7, 120.0, 120.4, 120.9, 125.1, 127.1, 127.5, 127.6,
135.1, 135.2, 135.3, 135.6, 135.8, 137.9, 141.0, 179.0. MS(EI): m/z¼973
[dimerþNaþ]. Anal. Calcd for C32H33N3O: C, 80.81; H, 6.99; N, 8.83.
Found: C, 80.97; H, 7.10; N, 8.72.
4.2.12. 3,3-Bis(2-phenyl-1H-indol-3-yl)indolin-2-one (16a). Red solid;
mp 240–242 ꢁC; Rf¼0.69 (AcOEt/petroleum ether 50%). IR (KBr):
3376, 1719, 1613, 1454, 1328, 746, 700 cmꢂ1. 1H NMR (500 MHz, Ac-
etone-d6) dH 6.65 (t, 2H, J¼6.6 Hz, Ar–H), 6.71 (t, 1H, J¼8.4 Hz, Ar–H),
6.85 (t, 1H, J¼6.9 Hz, Ar–H), 6.92–6.98 (m, 4H, Ar–H), 7.00 (t, 2H,
J¼7.6 Hz, Ar–H), 7.06 (t, 2H, J¼7.6 Hz, Ar–H), 7.16–7.21 (m, 6H, Ar–H),
7.25 (t, 4H, J¼8.4 Hz, Ar–H), 9.36 (s, 1H, –NH–CO–), 9.78 (s, 1H, –NH),
10.11 (s,1H, –NH). 13C NMR (75 MHz, Acetone-d6) dC 54.2,109.9, 111.2,
111.6, 112.3, 113.1, 113.4, 119.1, 119.4, 121.7, 122.3, 122.9, 123.8, 125.4,
126.7, 126.9, 127.5, 127.9, 128.2, 128.6, 129.1, 129.9, 130.1, 134.8, 135.4,
135.9, 136.6, 138.8, 139.1, 141.9, 178.7. MS(EI): m/z¼1053
[dimerþNaþ]. Anal. Calcd for C36H25N3O: C, 83.86; H, 4.89; N, 8.15.
Found: C, 83.97; H, 4.85; N, 8.09.
4.3. Typical procedure for the preparation of 2-indolyl-1-
nitroalkanes
4.2.13. 1-Methyl-3,3-bis(2-phenyl-1H-indol-3-yl)indolin-2-one
(16b). Brown solid; mp 294–296 ꢁC; Rf¼0.40 (AcOEt/petroleum
To a solution of o-ethynylaniline (1.0 mmol) in acetonitrile
(1 mL) under N2 was added AuCl (5 mol %) in acetonitrile (1 mL)

9252
C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
and refluxed for 1 h. To this reaction mixture nitrostyrene
(1.0 mmol) was added and refluxed for the specified time (Table 3
and 5). After completion of the reaction as indicated by TLC, the
reaction mixture was concentrated under reduced pressure and
purified by column chromatography over silica gel (100–200 mesh)
to afford the pure product.
Ar–H), 7.35 (d, 2H, J¼6.9 Hz, Ar–H), 7.38–7.45 (m, 4H, Ar–H), 7.77
(d, 1H, J¼8.4 Hz, Ar–H), 8.31 (s, 1H, –NH). 13C NMR (125 MHz,
CDCl3) dC 41.3, 55.8, 56.1, 76.8, 108.1, 111.7, 112.7, 113.7, 116.0, 119.6,
120.4, 122.4, 127.3, 128.5, 128.6, 128.9, 130.4, 132.0, 136.0, 137.7,
148.6, 148.7. MS(EI): m/z¼481 [MþþHþ], 483 [Mþ2þHþ]. Anal.
Calcd for C24H21BrN2O4: C, 59.89; H, 4.40; N, 5.82. Found: C, 59.80;
H, 4.44; N, 5.82.
4.3.1. 3-(2-Nitro-1-phenylethyl)-2-phenyl-1H-indole (18a). Pale yel-
low solid; mp 148–149 ꢁC; Rf¼0.34 (EtOAc/petroleum ether 20%). IR
4.3.6. 3-(4-Bromophenyl)-4-[1-(2-phenyl-1H-indol-3-yl)-2-nitro-
ethyl]-1-phenyl-1H-pyrazole (18f). Yellow solid; mp 174–176 ꢁC;
Rf¼0.35 (EtOAc/petroleum ether 35%). 1H NMR (500 MHz, CDCl3) dH
4.93 (dd, 1H, J¼6.8, 12.2 Hz, –CH2NO2), 5.10 (dd, 1H, J¼9.2, 12.2 Hz,
–CH2NO2), 5.52 (t, 1H, J¼8.4 Hz, –CH–CH2NO2), 7.17 (t, 1H, J¼6.9 Hz,
Ar–H), 7.22–7.29 (m, 2H, Ar–H), 7.33–7.35 (m, 4H, Ar–H), 7.37–7.45
(m, 8H, Ar–H), 7.59 (d, 2H, J¼7.6 Hz, Ar–H), 7.65 (d, 1H, J¼8.4 Hz,
Ar–H), 7.89 (s, 1H, Pyrazolyl-H), 8.22 (s, 1H, –NH). 13C NMR
(125 MHz, CDCl3) dC 32.5, 78.2, 108.7, 111.7, 119.1, 119.3, 119.5, 120.4,
122.4, 122.6, 126.4, 126.7, 127.1, 128.7 (2C), 128.9, 129.4, 129.5, 131.7,
131.9, 136.0, 136.9, 139.6, 150.2. MS(EI): m/z¼563 [MþþHþ], 565
[MþþHþ]. Anal. Calcd for C31H23N4O2: C, 66.08; H, 4.11; N, 9.94.
Found: C, 65.96; H, 4.15; N, 10.01.
(KBr): 3396, 3056, 1549, 1490, 1453, 1428, 1376, 1308, 746, 698 cmꢂ1
.
1H NMR (500 MHz, CDCl3) dH 5.13 (dd, 1H, J¼8.4, 12.2 Hz, –CH2NO2),
5.18 (dd, 1H, J¼7.6, 12.2 Hz, –CH2NO2), 5.32 (t, 1H, J¼8.4 Hz, –CH–
CH2NO2), 7.11 (t,1H, J¼7.6 Hz, Ar–H), 7.22 (t, 2H, J¼8.4 Hz, Ar–H), 7.30
(t, 2H, J¼8.4 Hz, Ar–H), 7.34 (d, 2H, J¼7.6 Hz, Ar–H), 7.39 (d, 1H,
J¼8.4 Hz, Ar–H), 7.42–7.46 (m, 5H, Ar–H), 7.53 (d, 1H, J¼8.4 Hz, Ar–
H), 8.16 (s, 1H, –NH). 13C NMR (125 MHz, CDCl3) dC 30.9, 85.9, 111.1,
112.3, 120.0, 121.0, 122.0, 123.4, 125.7, 127.0, 127.9, 128.4, 128.5, 129.0,
129.1, 132.1, 136.1, 136.2. MS(EI): m/z¼342 [Mþ]. Anal. Calcd for
C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.01; H, 5.49; N,
8.30.
4.3.2. 3-[1-(4-Chlorophenyl)-2-nitroethyl]-2-phenyl-1H-indole
(18b). Yellow solid; mp 116–118 ꢁC; Rf¼0.32 (EtOAc/petroleum
ether 20%). IR (KBr): 3410, 1548, 1490, 1450, 1380, 1207, 1013, 809,
4.3.7. 2-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (18g). Orange
solid; mp 79–81 ꢁC; Rf¼0.45 (EtOAc/petroleum ether 20%). IR (KBr):
3387, 3055, 3025, 1550, 1454, 1370, 770 cmꢂ1. 1H NMR (500 MHz,
CDCl3) dH 2.35 (s, 3H, –CH3), 5.12 (dd, 1H, J¼6.9, 10.7 Hz,
–CHCH2NO2), 5.18–5.25 (m, 2H, –CH2NO2), 7.04 (t, 1H, J¼7.6 Hz, Ar–
H), 7.12 (t, 1H, J¼6.9 Hz, Ar–H), 7.22–7.26 (m, 2H, Ar–H), 7.29–7.34
(m, 4H, Ar–H), 7.39 (d, 1H, J¼8.4 Hz, Ar–H), 7.88 (s, 1H, –NH). 13C
NMR (125 MHz, CDCl3) dC 12.1, 40.6, 79.5, 108.8, 110.8, 118.6, 118.7,
119.8, 121.3, 126.9, 127.3, 128.9, 133.0, 135.5, 139.6. MS(EI): m/z¼280
[Mþ]. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found:
C, 72.78; H, 5.80; N, 10.01.
739, 699 cmꢂ1
.
1H NMR (500 MHz, CDCl3) dH 5.09 (dd, 1H, J¼8.4,
12.2 Hz, –CH2NO2), 5.16 (dd, 1H, J¼7.6, 12.2 Hz, –CH2NO2), 5.27 (t,
1H, J¼7.6 Hz, –CH–CH2NO2), 7.12 (t, 1H, J¼7.6 Hz, Ar–H), 7.21–7.25
(m, 5H, Ar–H), 8.22 (s, 1H, –NH). 13C NMR (125 MHz, CDCl3) dC 40.3,
78.8, 109.1, 111.5, 119.7, 120.4, 122.6, 126.8, 128.7, 128.8, 129.0, 132.0,
133.1, 136.0, 137.0, 138.4. MS(EI): m/z¼376 [Mþ], 378 [Mþ2]. Anal.
Calcd for C22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43. Found: C, 70.00;
H, 4.45; N, 7.59.
4.3.3. 3-[1-(4-Methylphenyl)-2-nitroethyl]-2-phenyl-1H-indole
(18c). Yellow solid; mp 158–160 ꢁC; Rf¼0.31 (EtOAc/petroleum
ether 20%). IR (KBr): 3414, 2921, 1545, 1511, 1451, 1376, 1305, 817,
765, 746 cmꢂ1. 1H NMR (500 MHz, CDCl3) dH 2.30 (s, 3H, –CH3), 5.11
(dd, 1H, J¼8.4, 12.2 Hz, –CH2NO2), 5.16 (dd, 1H, J¼7.6, 12.2 Hz,
–CH2NO2), 5.27 (t, 1H, J¼7.6 Hz, –CH–CH2NO2), 7.11 (t, 1H, J¼8.4 Hz,
Ar–H), 7.21 (t, 1H, J¼8.4 Hz, Ar–H), 7.39 (d, 1H, J¼8.4 Hz, Ar–H),
7.42–7.45 (m, 4H, Ar–H), 7.53 (d, 1H, J¼7.6 Hz, Ar–H), 7.46 (s, 1H,
–NH). 13C NMR (125 MHz, CDCl3) dC 31.8, 40.3, 79.3, 108.7, 111.0,
119.0, 119.9, 121.7, 127.1, 127.4, 129.9, 135.8, 136.6, 137.0, 138.1.
MS(EI): m/z¼356 [Mþ]. Anal. Calcd for C23H20N2O2: C, 77.51; H,
5.66; N, 7.86. Found: C, 77.40; H, 5.50; N, 7.77.
4.3.8. 2-Butyl-3-(2-nitro-1-phenylethyl)-1H-indole (18h). Brown oil;
Rf¼0.55 (EtOAc/petroleum ether 20%). IR (CH2Cl2): 3406, 1552, 1461,
1376, 742, 700 cmꢂ1 1H NMR (500 MHz, CDCl3) dH 0.91 (t, 3H,
.
J¼6.9 Hz, –CH3), 1.35–1.38 (m, 2H, –CH2–CH3), 1.59 (q, 2H, J¼7.6 Hz,
–CH2–CH2–CH3), 2.72–2.77 (m, 2H, –CH2–CH2–CH2–CH3), 5.10 (dd,
1H, J¼7.6, 11.4 Hz, –CH2NO2), 5.20 (t, 1H, J¼7.6 Hz, –CH–CH2NO2),
5.26 (dd, 1H, J¼6.9, 11.4 Hz, –CH2NO2), 7.09 (t, 1H, J¼6.9 Hz, Ar–H),
7.12 (t, 1H, J¼7.6 Hz, Ar–H), 7.22 (t, 1H, J¼6.9 Hz, Ar–H), 7.27–7.33 (m,
5H, Ar–H), 7.37 (d, 1H, J¼7.6 Hz, Ar–H), 7.92 (s, 1H, –NH). 13C NMR
(125 MHz, CDCl3) dC 13.8, 22.5, 25.9, 31.8, 40.3, 78.8, 108.5, 110.7,
118.8,119.7, 121.3, 126.7, 127.0,127.3,128.7,135.5,137.6, 139.6. MS(EI):
m/z¼322 [MþþHþ]. Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N,
8.69. Found: C, 74.55; H, 6.85; N, 8.72.
4.3.4. 3-[1-(6-Bromo-1,3-benzodioxol-5-yl)-2-nitroethyl]-2-phenyl-
1H-indole (18d). Colourless solid; mp 188–190 ꢁC; Rf¼0.35 (EtOAc/
petroleum ether 25%). IR (KBr): 3406, 1549, 1473, 1377, 1236, 1034,
4.3.9. 2-Butyl-3-[1-(4-methylphenyl)-2-nitroethyl]-1H-indole
(18i). Pink solid; mp 86–88 ꢁC; Rf¼0.60 (EtOAc/petroleum ether
10%). IR (KBr): 3400, 2918, 1614, 1550, 1460, 1428, 1378, 1242, 1019,
925, 742 cmꢂ1
.
1H NMR (500 MHz, CDCl3) dH 4.94 (dd, 1H, J¼6.1,
13.0 Hz, –CH2NO2), 5.23 (dd, 1H, J¼10.7, 12.9 Hz, –CH2NO2), 5.55
(dd, 1H, J¼5.3, 10.7 Hz, –CH–CH2NO2), 5.92 (d, 2H, J¼11.4 Hz,
–OCH2O–), 7.05 (s, 1H, Ar–H), 7.09 (s, 1H, Ar–H), 7.18–7.24 (m, 2H,
Ar–H), 7.35 (d, 2H, J¼6.1 Hz, Ar–H), 7.39–7.46 (m, 4H, Ar–H), 7.73 (d,
1H, J¼7.6 Hz, Ar–H), 8.22 (s, 1H, –NH). 13C NMR (125 MHz, CDCl3) dC
41.5, 76.7, 101.8, 108.2, 109.8, 111.6, 113.3, 114.3, 119.8, 120.6, 122.5,
127.3, 128.6, 128.7, 128.9, 131.7, 132.0, 136.0, 137.6, 147.7, 147.8. MS
(EI): m/z¼465 [Mþ], 467 [Mþ2]. Anal. Calcd for C23H17BrN2O4: C,
59.37; H, 3.68; N, 6.02. Found: C, 59.50; H, 3.75; N, 5.99.
817 cmꢂ1
.
1H NMR (500 MHz, CDCl3) dH 0.94 (t, 3H, J¼7.6 Hz,
–(CH2)3CH3); 1.35–1.40 (m, 2H, –(CH2)2–CH2–CH3),1.59 (pentet, 2H,
J¼6.9 Hz, –CH2–CH2–CH2–CH3), 2.32 (s, 3H, Ar–CH3), 2.70–2.76 (m,
2H, –CH2–(CH2)2CH3), 5.10 (dd, 1H, J¼8.4, 11.4 Hz, –CH2NO2), 5.19 (t,
1H, J¼8.4 Hz, –CH–CH2NO2), 5.25 (dd, 1H, J¼6.9, 11.4 Hz, –CH2NO2),
7.05 (t, 1H, J¼8.4 Hz, Ar–H), 7.11–7.15 (m, 3H, Ar–H), 7.23 (d, 2H,
J¼7.6 Hz, Ar–H), 7.28 (d, 1H, J¼8.4 Hz, Ar–H), 7.41 (d, 1H, J¼8.4 Hz,
Ar–H), 7.93 (s, 1H, –NH). 13C NMR (125 MHz, CDCl3) dC 13.8, 21.0,
22.5, 25.9, 31.9, 40.1, 79.0, 108.6, 110.8, 118.9, 119.6, 121.3, 126.7,
127.2, 129.4, 135.5, 136.6 (2C), 137.6. MS(EI): m/z¼336 [MþþHþ].
Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C,
75.05; H, 7.25; N, 8.25.
4.3.5. 3-[1-(2-Bromo-4,5-dimethoxyphenyl)-2-nitroethyl]-2-phenyl-
1H-indole (18e). Pale yellow solid; mp 149–151 ꢁC; Rf¼0.40
(EtOAc/petroleum ether 40%). 1H NMR (500 MHz, CDCl3) dH 3.55
(s, 3H, –OCH3), 3.85 (s, 3H, –OCH3), 4.96 (dd, 1H, J¼6.1, 13.0 Hz,
–CH2NO2), 5.23 (dd, 1H, J¼10.7, 13.0 Hz, –CH2NO2), 5.57 (dd, 1H,
J¼6.1, 10.7 Hz, –CH–CH2NO2), 7.06 (s, 1H, Ar–H), 7.16–7.23 (m, 3H,
4.3.10. 2-(4-Pentylphenyl)-3-[1-(2-fluorophenyl)-2-nitroethyl]-1H-
indole (18j). Brown solid; mp 56–58 ꢁC; Rf¼0.25 (EtOAc/petroleum

C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
9253
ether 20%). IR (KBr): 3410, 2929, 1553, 1488, 1455, 1376, 1223,
745 cmꢂ1. 1H NMR (500 MHz, CDCl3) dH 0.91 (t, 3H, J¼6.9 Hz, –CH3),
1.36–1.37 (m, 4H, –(CH2)2–(CH2)2–CH3), 1.66 (pentet, 2H, J¼7.6 Hz,
–CH2–CH2–(CH2)2–CH3), 2.66 (t, 2H, J¼7.6 Hz, –CH2–(CH2)3–CH3),
5.16 (d, 2H, J¼7.6 Hz, –CH2NO2), 5.56 (t, 1H, J¼8.4 Hz, –CH–CH2NO2),
7.02–7.07 (m, 2H, Ar–H), 7.12 (t, 1H, J¼7.6 Hz, Ar–H), 7.21 (t, 2H,
J¼6.9 Hz, Ar–H), 7.25–7.27 (m, 2H, Ar–H), 7.33 (d, 2H, J¼8.4 Hz, Ar–H),
7.36–7.38 (m, 2H, Ar–H), 7.57 (d,1H, J¼8.4 Hz, Ar–H), 8.14 (s,1H, –NH).
13C NMR (125 MHz, CDCl3) dC 14.0, 22.5, 30.9, 31.5, 35.6, 35.7, 77.3
(JCꢂF¼3.0 Hz), 107.7, 111.3, 115.8 (JCꢂF¼18.0 Hz), 119.6, 120.2, 122.3,
124.3 (JCꢂF¼3.0 Hz), 126.5 (JCꢂF¼11.0 Hz), 127.2, 128.6, 128.9, 129.1
(JCꢂF¼7.0 Hz), 129.3, 129.5 (2C), 135.8, 137.4, 143.6, 160.5
(JCꢂF¼196.0 Hz). MS(EI): m/z¼430 [MþþHþ]. Anal. Calcd for
C27H27FN2O2: C, 75.33; H, 6.32; N, 6.51. Found: C, 75.25; H, 6.30; N,
6.55.
–NH). 13C NMR (125 MHz, CDCl3) dC 11.8, 26.4, 26.8, 31.0, 35.6, 71.4,
75.5, 79.3, 80.7, 81.6, 104.4, 106.0, 110.0, 111.9, 117.7, 119.4, 121.0,
128.2, 128.5, 128.8, 134.0, 135.6, 136.8. MS(EI): m/z¼454 [MþþHþ].
Anal. Calcd for C25H28N2O6: C, 66.36; H, 6.24; N, 6.19%. Found: C,
66.29; H, 6.27; N, 6.25%.
4.3.15. 3-{(1R)-1-[(5R,6S)-6-Ethoxy-2,2-dimethyltetrahydrofuro[2,3-d]-
[1,3]dioxol-5-yl]-2-nitroethyl}-2-methyl-1H-indole (18l). Yellow solid;
30
[a]
ꢂ129.60 (0.60, CHCl3); mp 160–162 ꢁC; Rf¼0.50 (AcOEt/Petro-
D
leum ether 40%). IR (KBr): 3378, 2957, 2343,1576,1350, 759 cmꢂ1. 1H
NMR (500 MHz, DMSO-d6) dH 1.17–1.19 (m, 6H, –C–CH3, –OCH2CH3),
1.28 (s, 3H, –C–CH3), 2.25 (s, 3H, indole-CH3), 3.45–3.51 (m, 1H,
–OCHHCH3), 3.70–3.75 (m,1H, –OCHHCH3), 3.88 (d,1H, J¼3.1 Hz, C3–
H), 3.97–4.01 (m, 1H, C5–H), 4.60 (dd, 1H, J¼10.7, 3.1 Hz, C4–H), 4.68
(d, 1H, J¼3.8 Hz, C2–H), 4.79 (dd, 1H, J¼12.2, 4.6 Hz, –CHHNO2), 5.01
(t, 1H, J¼11.4 Hz, –CHHNO2), 5.72 (d, 1H, J¼3.8 Hz, C1–H), 6.90 (t, 1H,
J¼7.6 Hz, Ar–H), 6.97 (t,1H, J¼7.6 Hz, Ar–H), 7.23 (d,1H, J¼8.4 Hz, Ar–
H), 7.56 (d,1H, J¼7.6 Hz, Ar–H),10.84 (s,1H, –NH).13C NMR (125 MHz,
DMSO-d6) dC 15.7, 26.7, 27.1, 35.9, 65.0, 76.9, 79.1, 81.4, 81.8, 104.4,
106.6, 111.1, 111.4, 118.3, 118.9, 120.5, 134.1, 135.9. MS(EI): m/z¼391
[MþþHþ]. Anal. Calcd for C20H26N2O6: C, 61.53; H, 6.71; N, 7.17%.
Found: C, 61.65; H, 6.75; N, 7.06%.
4.3.11. 1-Acetyl-2-phenyl-1H-indole (11a). Colourless solid; mp 80–
82 ꢁC; Rf¼0.25 (EtOAc/petroleum ether 10%). IR (KBr): 3065, 1690,
1559, 1367, 761 cmꢂ1 1H NMR (500 MHz, CDCl3) dH 2.07 (s, 3H,
.
–CO–CH3), 6.62 (s, 1H, Indolyl-H), 7.28 (t, 1H, J¼7.6 Hz, Ar–H), 7.35
(t, 1H, J¼7.6 Hz, Ar–H), 7.43–7.47 (m, 5H, Ar–H), 7.56 (d, 1H,
J¼7.6 Hz, Ar–H). 13C NMR (125 MHz, CDCl3) dC 27.9, 111.5, 116.0,
120.3, 123.6, 125.1, 128.6, 128.7, 128.9, 129.0, 134.1, 137.7, 139.7, 171.4.
MS(EI): m/z¼235 [Mþ]. Anal. Calcd for C16H13NO: C, 81.68; H, 5.57;
N, 5.95. Found: C, 81.75; H, 5.45; N, 6.00.
4.3.16. 3-{(1S)-1-[(5R,6S)-6-Ethoxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl]-2-nitroethyl}-2-methyl-1H-indole (18l0). Viscous
28
liquid; [
a
]
62.34 (0.48, CHCl3); Rf¼0.52 (AcOEt/Petroleum ether
D
4.3.12. 1-(Methylsulphonyl)-2-phenyl-1H-indole (11b). Colourless
solid; mp 116–118 ꢁC; Rf¼0.35 (EtOAc/petroleum ether 20%). IR
40%). IR (CH2Cl2): 3416, 2950, 2349, 1559, 1353, 761 cmꢂ1. 1H NMR
(500 MHz, CDCl3) dH 1.28 (t, 3H, J¼6.9 Hz, –OCH2CH3), 1.30 (s, 3H,
–C–CH3), 1.51 (s, 3H, –C–CH3), 2.38 (s, 3H, indole-CH3), 3.09–3.16
(m, 1H, –OCHHCH3), 3.36 (d, 1H, J¼3.1 Hz, C3–H), 3.42–3.48 (m, 1H,
–OCHHCH3), 4.27–4.32 (m, 1H, C5–H), 4.49 (d, 1H, J¼3.8 Hz, C2–H),
4.83 (d, 1H, J¼8.4 Hz, C4–H), 4.95–5.03 (m, 2H, –CH2NO2), 5.98 (d,
1H, J¼3.8 Hz, C1–H), 7.05–7.11 (m, 2H, Ar–H), 7.23 (d, 1H, J¼6.9 Hz,
Ar–H), 7.51 (d, 1H, J¼7.6 Hz, Ar–H), 7.94 (s, 1H, –NH). 13C NMR
(125 MHz, CDCl3) dC 15.3, 26.3, 26.9, 35.4, 65.4, 77.6, 79.2, 81.7, 81.8,
105.2, 105.7, 110.9, 111.8, 118.3, 119.8, 121.2, 134.2, 135.7. MS(EI):
m/z¼391 [MþþHþ]. Anal. Calcd for C20H26N2O6: C, 61.53; H, 6.71; N,
7.17%. Found: C, 61.45; H, 6.65; N, 7.26%.
(KBr): 1654, 1559, 1446, 1367, 1171, 769 cmꢂ1 1H NMR (500 MHz,
.
CDCl3) dH 2.73 (s, 3H, –SO2–CH3), 6.71 (s, 1H, Indolyl-H), 7.33–7.43
(m, 5H, Ar–H), 7.54–7.60 (m, 3H, Ar–H), 8.13 (d, 1H, J¼8.4 Hz, Ar–H).
13C NMR (125 MHz, CDCl3) dC 39.6, 113.1, 115.8, 121.0, 124.6, 125.1,
127.7, 128.9, 130.1, 130.3, 132.0, 138.0, 141.9. MS(EI): m/z¼271 [Mþ].
Anal. Calcd for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16. Found: C,
66.35; H, 4.80; N, 5.21.
4.3.13. 3-{(1R)-1-[(5R,6S)-6-Benzyloxy-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl]-2-nitroethyl}-2-methyl-1H-indole
28
(18k). Yellow solid; [
a]
ꢂ84.66 (0.2, CHCl3); mp 207–209 ꢁC;
D
Rf¼0.45 (AcOEt/Petroleum ether 40%). IR (KBr): 3372, 2937, 2346,
1553, 1350, 751 cmꢂ1. 1H NMR (500 MHz, DMSO-d6) dH 1.21 (s, 3H,
–C–CH3), 1.31 (s, 3H, –C–CH3), 2.24 (s, 3H, Indole-CH3), 4.02 (d, 1H,
J¼3.0 Hz, C3–H), 4.04–4.09 (m, 1H, C5–H), 4.59 (d, 1H, J¼11.4 Hz,
–OCHHPh), 4.64–4.67 (m, 2H, C4–H, –CHHNO2), 4.77 (d, 1H,
J¼11.4 Hz, –OCHHPh), 4.84 (d, 1H, J¼4.2 Hz, C2–H), 5.01 (t, 1H,
J¼11.4 Hz, –CHHNO2), 5.76 (d, 1H, J¼3.8 Hz, C1–H), 6.89 (t, 1H,
J¼6.9 Hz, Ar–H), 6.97 (t, 1H, J¼7.6 Hz, Ar–H), 7.24 (d, 1H, J¼8.4 Hz,
Ar–H), 7.32 (t, 1H, J¼6.8 Hz, Ar–H), 7.38 (t, 2H, J¼8.0 Hz, Ar–H), 7.45
(d, 2H, J¼6.9 Hz, Ar–H), 7.59 (d, 1H, J¼6.5 Hz, Ar–H), 10.85 (s, 1H,
–NH). 13C NMR (125 MHz, DMSO-d6) dC 11.9, 26.7, 27.1, 35.7, 71.0,
76.6, 78.8, 79.7, 80.8, 81.7, 104.4, 106.2, 111.2, 111.3, 118.3, 118.9,
120.5, 128.4, 128.6, 128.9, 134.2, 135.8, 138.2. MS(EI): m/z¼454
[MþþHþ]. Anal. Calcd for C25H28N2O6: C, 66.36; H, 6.24; N, 6.19%.
Found: C, 66.45; H, 6.20; N, 6.16%.
4.3.17. 3-{(1R)-1-[(5R,6S)-6-Benzyloxy-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl]-2-nitroethyl}-2-phenyl-1H-indole
(18m). Colourless solid; [a]
29 102.46 (0.54, CHCl3); mp 240–242 ꢁC;
D
Rf¼0.55 (AcOEt/Petroleum ether 40%). IR (KBr): 3398, 2965, 2385,
1575, 1352, 756 cmꢂ1. 1H NMR (500 MHz, CDCl3) dH 1.28 (s, 3H, –C–
CH3), 1.33 (s, 3H, –C–CH3), 3.83 (d, 1H, J¼3.1 Hz, C3–H), 4.38–4.43
(m, 2H, C2–H, –OCHHPh), 4.52–4.57 (m, 1H, C5–H), 4.60–4.66 (m,
3H, C4–H, –CHHNO2, –OCHHPh), 4.79 (t, 1H, J¼11.4 Hz, –CHHNO2),
5.81 (d, 1H, J¼3.8 Hz, C1–H), 6.98 (t, 1H, J¼6.9 Hz, Ar–H), 7.07 (t, 1H,
J¼7.6 Hz, Ar–H), 7.26–7.36 (m, 9H, Ar–H), 7.51 (d, 1H, J¼7.6 Hz, Ar–
H), 7.55 (d, 2H, J¼6.9 Hz, Ar–H), 9.41 (s, 1H, –NH). 13C NMR
(125 MHz, CDCl3) dC 25.9, 26.4, 34.7, 70.3, 76.1, 78.7, 80.2, 80.9,
103.7, 106.6, 110.7, 111.5, 118.2, 118.8, 121.0, 126.2, 127.2, 127.4, 127.9,
128.1, 128.7, 132.5, 136.1, 137.2, 137.4. MS(EI): m/z¼515 [MþþHþ].
Anal. Calcd for C30H30N2O6: C, 70.02; H, 5.88; N, 5.44%. Found: C,
70.65; H, 5.75; N, 5.36%.
4.3.14. 3-{(1S)-1-[(5R,6S)-6-Benzyloxy-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl]-2-nitroethyl}-2-methyl-1H-indole
4.3.18. 3(S)-(3(R)-Nitro-2(R)-p-tolyl-chroman-4-yl)-2-phenyl-1H-
28
(18k0). Viscous liquid; [
a
]
D
45.73 (0.2, CHCl3); Rf¼0.47 (AcOEt/
indole (18n). Yellow solid; [a]
28 19.08 (1.0, CHCl3); mp 128–130 ꢁC;
D
Petroleum ether 40%). IR (CH2Cl2): 3405, 2950, 2349, 1559, 1353,
761 cmꢂ1. 1H NMR (500 MHz, CDCl3) dH 1.28 (s, 3H, –C–CH3), 1.42 (s,
3H, –C–CH3), 2.26 (s, 3H, indole-CH3), 3.92 (d, 1H, J¼3.1 Hz, C3–H),
4.27–4.31 (m, 1H, C5–H), 4.40 (dd, 1H, J¼3.8, 12.2 Hz, –CHHNO2),
4.52 (d,1H, J¼11.5 Hz, –OCHHPh), 4.66 (dd, 1H, J¼3.0, 9.9 Hz, C4–H),
4.71 (d, 1H, J¼3.8 Hz, C2–H), 4.78–4.84 (m, 2H, –OCHHPh,
–CHHNO2), 5.88 (d,1H, J¼3.8 Hz, C1–H), 6.97 (t,1H, J¼9.9 Hz, Ar–H),
7.04 (t, 1H, J¼7.6 Hz, Ar–H), 7.34–7.50 (m, 6H, Ar–H), 7.94 (s, 1H,
Rf¼0.55 (AcOEt/Petroleum ether 20%). 1H NMR (500 MHz, CDCl3) dH
2.32 (s, 3H, indole-CH3), 5.06 (d, 1H, J¼3.8 Hz, Ha), 5.41 (t, 1H,
J¼3.8 Hz, Hb), 5.68 (br s, 1H, Hc), 6.09 (t, 1H, J¼7.7 Hz, Ar–H), 6.97–
6.99 (m, 1H, Ar–H), 7.07 (d, 1H, J¼7.7 Hz, Ar–H), 7.12–7.20 (m, 7H,
Ar–H), 7.26 (t, 1H, J¼6.9 Hz, Ar–H), 7.38–7.45 (m, 6H, Ar–H), 8.28 (s,
1H, –NH). 13C NMR (125 MHz, CDCl3) dC 21.3, 35.9, 75.2, 90.1, 111.4,
111.7, 116.9, 119.6, 120.6, 121.4, 122.3, 122.7, 125.9, 128.5, 128.7, 128.8,
128.4, 128.6, 128.9, 134.2, 135.8, 138.2. MS(EI): m/z¼461 [MþþHþ].

9254
C. Praveen et al. / Tetrahedron 65 (2009) 9244–9255
6. (a) Bradfield, C. A.; Bjeldanes, L. F. J. Toxicol. Environ. Health 1987, 21, 311; (b)
Dashwood, R. H.; Uyetake, L.; Fong, A. T.; Hendricks, J. D.; Bailey, G. S. Food
Chem. Toxicol. 1987, 27, 385.
Anal. Calcd for C30H24N2O3: C, 78.24; H, 5.25; N, 6.08%. Found: C,
78.45; H, 5.15; N, 6.00%.
7. Zeligs, M. A. J. Med. Food 1998, 1, 67.
8. Yadav, J. S.; Reddy, B. V. S.; Murthy, Ch. V. S. R.; Mahesh Kumar, G.; Madan, Ch.
Synthesis 2001, 783.
4.3.19. 3-[(6-Ethoxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-(2-methyl-1H-indol-3-yl)-methyl]-isoxazole-4,5-dicarboxylic acid
9. Babu, G.; Sridhar, N.; Perumal, P. T. Synth. Commun. 2000, 30, 1609.
10. Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44, 1959.
11. Mo, L.-P.; Ma, Z.-C.; Zhang, Z.-H. Synth. Commun. 2005, 35, 1997.
12. Wang, L.; Han, J.; Tian, H.; Sheng, J.; Fan, Z.; Tang, X. Synlett 2005, 337.
13. Zhang, Z.-H.; Yin, L.; Wang, Y.-M. Synthesis 2005, 1949.
14. (a) Singh, P. R.; Singh, D. U.; Samant, S. D. Synth. Commun. 2005, 35, 2133; (b) Li,
W.-J.; Lin, X.-F.; Wang, J.; Li, G.-L.; Wang, Y.-G. Synth. Commun. 2005, 35, 2765.
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16. Raju, B. C.; Rao, J. M. Indian J. Chem., Sect. B 2008, 47B, 623.
diethyl ester (20a). Viscous liquid; [
a
]
30 139.34 (0.54, CHCl3); Rf¼0.47
D
(AcOEt/Petroleum ether 40%). IR (KBr): 3476, 2931, 2345, 1727, 1556,
1349, 751 cmꢂ1. 1H NMR (500 MHz, CDCl3) dH 1.01 (t, 3H, J¼6.9 Hz,
–COOCH2CH3), 1.12 (t, 3H, J¼7.6 Hz, –COOCH2CH3), 1.27 (s, 3H, –C–
CH3), 1.33 (t, 3H, J¼7.6 Hz, –OCH2CH3), 1.41 (s, 3H, –C–CH3), 2.42 (s,
3H, indole-CH3), 3.16–3.19 (m, 1H, –OCHHCH3), 3.57–3.61 (m, 1H,
–OCHHCH3), 4.05–4.08 (m, 2H, –COOCH2CH3), 4.20 (d, 1H, J¼3.1 Hz,
C3–H), 4.36 (q, 2H, J¼7.6 Hz, –COOCH2CH3), 4.59 (d,1H, J¼3.8 Hz, C2–
H), 4.98 (d, 1H, J¼9.9 Hz, C5–H), 5.26 (dd, 1H, J¼9.9, 3.1 Hz, C4–H),
5.88 (d, 1H, J¼3.8 Hz, C1–H), 6.95 (t, 1H, J¼6.9 Hz, Ar–H), 7.00 (t, 1H,
J¼8.4 Hz, Ar–H), 7.16 (d,1H, J¼6.9 Hz, Ar–H), 7.62 (d,1H, J¼8.4 Hz, Ar–
H), 7.83 (s, 1H, –NH). 13C NMR (125 MHz, CDCl3) dC 13.9, 14.0, 14.9,
26.5, 27.1, 29.8, 34.2, 61.7, 62.8, 65.9, 80.8, 82.3, 82.9,104.9,110.3,111.6,
118.7, 119.4, 120.8, 123.5, 127.6, 133.4, 135.4, 155.6, 156.7, 160.5, 162.9.
MS(EI): m/z¼543 [MþþHþ]. Anal. Calcd for C28H34N2O9: C, 61.98; H,
6.32; N, 5.16%. Found: C, 61.90; H, 6.35; N, 5.31%.
17. Nagarajan, R.; Perumal, P. T. Chem. Lett. 2004, 3, 288.
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Drugovina, V. V.; Yakovleva, L. V.; Bereznyakova, A. I. Khim.-Farm. Zh. 1982, 16,
58; (c) William, C. E. U.S. Patent 3,558,653, 1971; (d) Pajouhesh, H.; Parsons, R.;
Popp, F. D. J. Pharm. Sci. 1983, 72, 318.
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Martinez, E.; Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram, K.;
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24. (a) Kusurkar, R. S.; Alkobati, N. A. H.; Gokule, A. S.; Puranik, V. G. Tetrahedron
2008, 64, 1654; (b) Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1984, 25, 3415;
(c) Osby, J. O.; Ganem, B. Tetrahedron Lett. 1985, 26, 6413.
25. (a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005,
44, 6576; (b) Ballini, R.; Clemente, R. R.; Palmieri, A.; Petrini, M. Adv. Synth.
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4.3.20. 3-[(6-Ethoxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-(2-methyl-1H-indol-3-yl)-methyl]-isoxazole-4,5-dicarboxylic acid
diethyl ester (20b). Yellow solid; [a]
29 618.70 (0.22, CHCl3); mp 188–
D
190 ꢁC; Rf¼0.50 (AcOEt/Petroleum ether 40%). IR (KBr): 3472, 2927,
2331, 1723, 1553, 1347, 751 cmꢂ1. 1H NMR (500 MHz, CDCl3) dH 1.05
(t, 3H, J¼6.9 Hz, –COOCH2CH3), 1.23 (t, 3H, J¼7.6 Hz, –COOCH2CH3),
1.29 (s, 3H, –C–CH3),1.32 (t, 3H, J¼7.6 Hz, –OCH2CH3),1.56 (s, 3H, –C–
CH3), 2.49 (s, 3H, indole-CH3), 2.98–3.01 (m, 1H, –OCHHCH3), 3.32–
3.36 (m, 1H, –OCHHCH3), 3.37 (d, 1H, J¼3.1 Hz, C3–H), 4.20 (q, 2H,
J¼7.6 Hz, –COOCH2CH3), 4.35 (q, 2H, J¼6.9 Hz, –COOCH2CH3), 4.45
(d, 1H, J¼3.8 Hz, C2–H), 5.17 (d, 1H, J¼10.7 Hz, C5–H), 5.45 (dd, 1H,
J¼10.7, 3.1 Hz, C4–H), 5.94 (d, 1H, J¼3.8 Hz, C1–H), 7.03–7.09 (m, 1H,
Ar–H), 7.22 (d, 1H, J¼6.9 Hz, Ar–H), 7.84 (d, 1H, J¼7.6 Hz, Ar–H), 7.86
(s, 1H, –NH). 13C NMR (125 MHz, CDCl3) dC 13.9, 14.0, 15.2, 26.7, 27.1,
29.8, 33.4, 61.6, 62.6, 65.2, 80.1, 81.7, 81.8, 105.5, 106.8, 110.2, 111.9,
115.3, 119.6, 119.9, 121.2, 127.6, 133.2, 135.3, 159.8, 160.9, 163.4, 163.7.
MS(EI): m/z¼543 [MþþHþ]. Anal. Calcd for C28H34N2O9: C, 61.98; H,
6.32; N, 5.16%. Found: C, 61.72; H, 6.31; N, 5.32%.
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Acknowledgements
The authors thank the Council of Scientific and Industrial
Research, New Delhi, for the financial support.
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Supplementary data
30. (a) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J. Tetrahedron 2008, 64, 2755; (b) Morita, N.;
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.09.019.
References and notes
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