An anti-Michael route for the synthesis of indole-spiro (indene-pyrrolidine) by 1,3-cycloaddition of azomethineylide with indole-derivatised olefins

Article abstract of DOI:10.1002/jhet.3843

One-pot three-component reaction for indole-spiro (indene-pyrrolidine) highly strained molecules were synthesized with moderate yield by 1,3-cycloaddition of unsymmetrical dipolarophiles, prepared from indol-3-yl and 1-acetyl-1H-indol-3-yl derivative with azomethineylide generated through decarboxylative addition of amino acid sarcosine and ninhydrine, which is confirmed by NOESY. Our method is to demonstrate an efficient path in the preparation of strained organic spiro compound, an atom-economical process and eco-friendly toward environment. Viability gives an access to prepare of various spiro pharmaceutical drug molecules.

Full text of DOI:10.1002/jhet.3843

Received: 23 June 2018
DOI: 10.1002/jhet.3843
Revised: 9 January 2019
Accepted: 12 June 2019
A R T I C L E
An anti-Michael route for the synthesis of indole-spiro
indene-pyrrolidine) by 1,3-cycloaddition
(
of azomethineylide with indole-derivatised olefins
Shivaraj Yellappa
Department of Chemistry, Government
Abstract
Science College, Bengaluru, Karnataka,
India
One-pot three-component reaction for indole-spiro (indene-pyrrolidine) highly
strained molecules were synthesized with moderate yield by 1,3-cycloaddition
of unsymmetrical dipolarophiles, prepared from indol-3-yl and 1-acetyl-1H-
indol-3-yl derivative with azomethineylide generated through decarboxylative
addition of amino acid sarcosine and ninhydrine, which is confirmed by
NOESY. Our method is to demonstrate an efficient path in the preparation of
strained organic spiro compound, an atom-economical process and eco-
friendly toward environment. Viability gives an access to prepare of various
spiro pharmaceutical drug molecules.
Correspondence
Shivaraj Yellappa, Department of
Chemistry, Government Science College,
Bengaluru 560 001, Karnataka, India.
Email: shivaraj_y@rediffmail.com
Funding information
Science and Engineering Research Board,
D S T, IN, Grant/Award Number: SB/FT/
CS-009/2012
1
| INTRODUCTION
rings are carbon then it is carbocyclic and if it contains any
one or more hetero atoms then it is said to heterocyclic.
[5]
The indole scaffold represents a “privileged” structural
The design of new spirocyclic compounds is attractive
due to their unique nonplanar structure and enormous
ability to bind with biomolecules because of their
design, well distributed in pharmaceutical drugs and
[1]
natural products. Due to their promising and wide
biological application, its derivatives are important and
applicable in the pharmaceutical field. As a result, new
approaches need to be adopted for synthesis of many
indole derivatives to find out the lead compound. Particu-
larly, C-3-substituted indole derivatives are significant in
building blocks for the preparation of various biologically
active compounds such as antimalarial, inhibitors of HIV-
[
6]
inherent rigid chiral structure. Spiro [indolo-pyrans] is
found to be recognized as good muscle relaxants, anti-
inflammatory agents and also, as pesticides, similarly,
number of spiro [indole-pyrrolidines] exhibits local anes-
thetic and anticonvulsant activities, spiro [indole-pyran/
imidazoles] have been used in treating complication of
[
7]
diabetes or galactosemia.
1,3-Dipolar cycloaddition, which is also known as the
1
, antimicrobial, antioxidant, anticancer, cytotoxic, inhibi-
[
8]
tors of hepatitis C virus, antidiabetic, and neuro protective
activities, conversely, nitrogen and C-3-substituted indole
derivatives possessed important role in biologically active
compounds, chiefly with anti-inflammatory, anticancer,
Huisgen reaction, is one of the significant approaches
[
9]
for the synthesis of five-membered heterocycles present
[
10]
in various natural products.
Pyrrolidine-based natural
products are being used in preventing and treating rheu-
matoid arthritis, asthma, and allergies; and also possess
[2]
antinociceptive, and antipsychotic activities.
[11]
A spiro compounds are one in which same atom is
bonded and bridged to support two or more rings, due to
steric strain in the molecule they always exist in the
anti-influenza virus and anticonvulsant activities.
The
azomethineylide represents the most reactive and versa-
tile classes of 1,3-dipoles and is readily trapped by a range
[3]
[12]
twisted form. The common junction atom called spiro
atom could be carbon or any other hetero atom/s like sili-
of dipolarophiles forming substituted pyrrolidines.
The 1,3-dipolar cycloaddition of azomethineylides,
generated in situ via decarboxylative condensation of
[4]
con, nitrogen, and other atoms. If all the atoms in the
J Heterocyclic Chem. 2019;1–7.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
YELLAPPA
ninhydrine and sarcosine with different olefinicdi-
polarophiles, represents a key approach for the regio-
selective and stereo-selective construction of a various
complex spiro-indoles. Recently, this route has become
significant in combinatorial chemistry due to its process
simplicity, atomic economy, and extension of the scope
of substrates.
in indole-derivatised olefin nitromethane 2a without
acetyl substituent and best moderate in indole-
derivatised olefin dimethylcarboxylate with acetyl sub-
stituent 2g (Figure 1).
TABLE 1 Synthesis of Indole-spiro (indene-pyrrolidine)
derivatives
In the present work, we report the synthesis of indole-
spiro (indene-pyrrolidine) by using 1,3-dipolar cycloaddi-
tion of indole-derivatised olefins with azomethineylide, in
situ via decarboxylative condensation of ninhydrine and
sarcosine in a three-component fashion. Indole-derivatised
olefins were prepared from indole-3-carboxaldehyde and
active methylene compounds through Knoevenagel reac-
tion followed by acetylation. All the synthesized com-
Sl. no
R
R
1
R
2
Product
2a
% Yield
20
1.
2.
3.
4.
5.
NO
2
H
H
CO
2
Et
CO
NO
CO
2
Et
H
H
H
2b
61
CO
2
Et
2
2c
23
CO
2
Me
2
Me
2d
30
NO
CO Et
Me
Et
2
H
MeCO
MeCO
MeCO
MeCO
2e
44
1
pounds were characterized by H-NMR, LC-MS, FT-IR,
and UV-visible spectrophotometer.
6.
2
CO
2
Et
2f
45
7
.
.
CO
2
CO
2
Me
2g
62
8
CO
2
NO
2
2h
47
2
| RESULT AND DISCUSSION
Equimolar mixture of three component system such
as indole-derivatised olefins, sarcosine and ninhydrine
monohydrate afforded the indole-spiro (indene-pyrrolidine)
2a-2h (Scheme 1) in low to moderate yields (Table 1).
The formation of low to moderate yields is due to the
formation of highly strained spiro compounds for different
moieties. It has been found that indole-derivatised olefins
diethylcarboxylate without acetyl 2b and with acetyl 2f
substituent was found to give moderate yield where as in
case of indole-derivatised olefins dimethylcarboxylate
without acetyl 2d and with acetyl 2g substituent were low
to moderate yield, respectively. Low to moderate yields
were observed in indole-derivatised olefins ethyl
nitrocarboxylate without acetyl 2c and with acetyl 2h sub-
stituent; same observation was noticed, in case of indole-
derivatised olefins nitromethane without acetyl 2a and
with acetyl 2e substituent. The least yield has observed
FIGURE 1 Structure of the molecules 2b, 2c, 2f, and 2h
SCHEME 1 Synthetic route for the
synthesis of indole-spiro (indene-
pyrrolidine) derivatives

YELLAPPA
3
1
,3-cycloaddition of unsymmetrical dipolarophiles
carbon-2 is most electrophilic due to presence of same
species at either sides. Sarcosine contains secondary
amino group, which is basic and nucleophilic in nature
due to its lone pair of electron. The amino group with its
lone pair of electrons attacks on oxa group at carbon-2 of
ninhydrine (structure-4) and forms amino alcohol
(structure-4b) which is unstable and undergoes further
reaction. The alcoholic part of structure-4b attacks
internally at its carboxylic group to form cyclic
oxazolidine ring (structure-4c) and ring opening and
closing exist at equilibrium. The two oxa groups on the
ninhydrine ring assist (by –I effect) the oxazolidine ring
to undergo ring opening by decarboxylation to form
azomethineylide (structure-4d). By 1,3-cycloaddition
reaction, the carbon anion of azomethine acts as nucleo-
phile and attacks at one of the olefinic carbon of indole
derivative by anti-Michael addition (confirmed by
such as indole-derivatised olefins with azomethineylide
can occur via two pathways A and B by Michael addition
and anti-Michael addition fashion, respectively, leading
to the formation of regioisomers 5 and 5 as depicted in
Scheme 2. All novel cyclo-adducts obtained by the above
method were confirmed by H-NMR and NOESY.
Inclusively, 3 -(1-acetyl-1H-indol-3-yl)-1 -methyl-4 -
nitrospiro [indene-2,2 -pyrrolidine]-1, 3-dione had been
selected as a role model to confirm which regioisomer
exists, either 5 or 5 . The H-NMR shows three peaks at
.84 ppm (m, 1H), 4.91 ppm (d, J = 9.2 Hz, 1H), and
.99 ppm (d, J = 7.2 Hz, 2H) for the proton bonded to
pyrolidine ring at C , C , and C , respectively, as depicted
0
1
0
0
0
0
0
1
5
3
3
2
4
in Figure 2.
But for further confirmation NOESY had been taken
Figure 3). There was correlation signal at 5.84 ppm
x-axis) corresponds to 3.99 ppm (y-axis) and 4.91 ppm (y-
(
(
axis), similarly a signal at 4.91 ppm (x-axis) and 3.99 ppm
(
(
x-axis) correlated to 5.84 ppm (y-axis). Signal at 5.84 ppm
x-axis) was due to proton of C3 which is adjacent to C2
and C4 protons of pyrolidine ring of 5, whereas signals at
.91 ppm (x-axis) and 3.99 ppm (x-axis) were due to pro-
4
tons of C2 and C4, respectively, adjacent to C3 protons of
pyrolidine ring 5. Apart from the above signals, there
were other correlation signals which were insignificance
to assist in confirming the isomers. The above results
reveal that the indene moiety is attached to the pyrolidine
ring at C and thus isomer 5 exists.
1
The mechanism of azomethineylide formation by a
decarboxylative route has been repeatedly described by
[
13,14]
number of authors and is depicted as in Scheme 3.
Ninhydrine (structure-4a) contains two hydroxyl
groups bonded to the carbon atom 2 of cyclopentane ring
in between the two adjacent oxa groups, would undergo
dehydration during heating and form keto group (struc-
ture-4). The three oxa groups of ninhydrine (structure-
4) are electrophilic in nature, but the oxa group at
FIGURE 2 NOESY correlation H-H interactions
SCHEME 2 Synthetic route for the
conversion of azomethineylide to indole-
spiro (indene-pyrrolidine)

4
YELLAPPA
ninhydrine afforded azomethineylide, a highly reactive
unstable intermediate generated in situ by decarboxylative
addition, which underwent 1,3-cycloaddition reaction with
indol-3-yl and 1-acetyl-1H-indol-3-ylderivatives to form
the desired product. All synthesized products had under-
gone anti-Michael addition route which was confirmed by
1
H-NMR and NOESY experiment on selected molecule
0
0
0
3
2
-(1-acetyl-1H-indol-3-yl)-1 -methyl-4 -nitrospiro [indene-
0
,2 -pyrrolidine]-1,3-dione as a role model. Various func-
tional groups are tolerated giving excess to a wide range of
substituted indole-spiro (indene-pyrrolidine). Our exclu-
sive synthetic procedure is quite efficient and provides an
easy access to various pharmaceutical drug molecules.
Prepared derivatives can be used in various therapeutic
applications.
3.1 | Experimental
0
0
FIGURE 3 NOESY for 3 -(1-acetyl-1H-indol-3-yl)-1 -methyl-
4
0
0
-nitrospiro [indene-2, 2 -pyrrolidine]-1, 3-dione
All the chemical reagents used for synthesis were pur-
chased from Sigma Aldrich, Merck, Avra Synthesis Pvt.
Ltd., and SDFCL. Progress of the reaction was evaluated
by thin layer chromatography (TLC) by using petroleum
ether and ethyl acetate as co-solvent mixture.
3.2 | Instrumentation
1
13
H and C NMR spectra were recorded on JEOL Eclipse,
Peabody, MA) and Eclipse plus spectrometers at
(
400 MHz using either deuterated chloroform (CDCl3) or
hexadeuterated dimethyl sulphoxide (DMSO-d ) as sol-
6
vents. Chemical shifts (δ) are given in ppm versus TMS
1
(
H-NMR) as an internal reference. Coupling constants
are given in Hertz (Hz). Spectra of HR-MS were recorded
Q
on ESI- TOF machine. Infrared (IR) spectra were mea-
sured on Agilent FT-IR spectrometer over the range of
SCHEME 3 Tentative synthetic mechanism for the synthesis
of indole-spiro (indene pyrrolidine) derivatives
400 to 4000 per cm. Absorption spectra were carried out
on Shimadzu UV-1800 series. Melting points of all synthe-
sized compounds were determined by open capillary tubes
ꢀ
using Toshiba-melting point apparatus, expressed in C
NOESY) and simultaneously the other olefinic carbon
which carries π-electrons attacks at the iminocarbon
and are uncorrected. Column chromatography was carried
out by using silica gel 60 to 120 and 230 to 400 mesh.
(electron deficient carbon due to adjacent oxa groups and
amino group) and eventually, rearranges to affords
indolyl-spiro (indene-pyrrolidine).
3.3 | General procedure for synthesis
3.3.1 | Indole-3-yl (step 1) derivatives
3
| CONCLUSION
To the round-bottomed flask connected with dean
stark apparatus contained a suspension of indole-
3-carboxaldehyde (1 eq.) in toluene (15 v/w) was added
active methylene compound or nitromethane (1.2 eq.)
A new protocol for the preparation of novel indole-spiro
indene-pyrrolidine) derivatives has been developed.
The reaction of secondary amino-acid sarcosine and
(

YELLAPPA
5
0 0
Diethyl 3 -(1H-indol-3-yl)-1 -methyl-1,3-dioxo-
1,3-dihydrospiro [indene-2,2 -pyrrolidine]-4 ,4 -
at room temperature followed by pipyridine (0.05 eq.),
and acetic acid (0.05 eq.); and heated to reflux for
0
0
0
6
hours. Reaction mixture was cooled to room tempera-
ture and toluene was removed by rotavapor. Water
4 v/w of starting material) was added to the crude com-
dicarboxylate (2b)
ꢀ
1
Yield: 61%; mp: 154-156 C; H NMR (400 MHz, CDCl3) δ
[ppm]: 8.06 (s, 1H), 7.86-7.84 (m, 1H), 7.69-7.66 (m, 3H),
7.57 (d, J = 8 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 7.06-6.97
(m, 3H), 5.36 (s, 1H), 4.56 (d, J = 10 Hz, 1H), 4.38-4.22
(m, 2H), 3.77 (d, J = 10 Hz, 1H), 3.73-3.65 (m, 1H),
(
pound, resulted solid was filtered, washed with water,
methanol and dried to yield compound-2 (Scheme 1) as
a solid.
[
15]
3
0
.43-3.35 (m, 1H), 2.39 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H),
.47 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3)
13
3
.3.2 | 1-acetyl-1H-indol-3-yl (step 2)
δ[ppm]: 200.2, 199.4, 168.3, 167.8, 140.9, 140.1, 136.1,
135.0, 133.5, 130.1, 125.6, 124.5, 123.0, 122.7, 121.8, 118.2,
derivatives
1
15.0, 114.8, 78.4, 64.2, 62.0, 61.1, 59.2, 46.8, 35.4, 13.3,
+
Triethyl amine (1.5 eq.) was added to the solution of
compound-2 (1 eq.) in anhydrous dichloromethane
12.2; ESI-MS : exact mass calculated for C H N O
27 26 2 6
[M + H] : 474.1791, found: 497.1688 (M + Na). IR
(cm ): 3252 (N-H), 2933 (=C-H), 2820 (-C-H), 1704
(C=0), 1592 (C-O), 1347 (C-N); UV-visible (nm):
350, 232, 216.
+
−1
(
20 v/w) at room temperature under nitrogen atmo-
ꢀ
sphere and cooled to 0 C. Acetyl chloride (1.2 eq.) was
added drop wise to the reaction mixture and left stirring
at room temperature for 2 hours. Reaction mixture was
quenched with crushed-ice (20 w/w) and separated
the biphasic layers. Aqueous layer was extracted with
dichloromethane (20 v/w). Combined organic layers
were dried over anhydrous Na SO and concentrated
0
0
0
Ethyl-3 -(1H-indole-3-yl)-1 -methyl-4 -nitro-1,3-dioxo-
0
0
1,3-dihydrospiro[indene-2,2 -pyrolidine]-4 -
carboxylate (2c)
ꢀ
1
Yield: 23%; mp: 182-184 C; H NMR (400 MHz, CDCl3)
δ[ppm]: 8.06 (s, 1H), 7.87-7.86 (m, 1H), 7.72-7.69 (m,
3H), 7.65 (d, J=6.8 Hz, 1H), 7.19-7.18 (m, 1H), 7.11-7.02
2
4
under vacuum to yield compound-3 (Scheme 1) as
a solid.
[
15]
(
m, 3H), 5.78 (s, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.07 (d,
J = 11.6 Hz, 1H), 3.76-3.71 (m, 1H), 3.61-3.57 (m, 1H),
1
3
3
.3.3 | Indole-spiro (indene-pyrrolidine)
2.36 (s, 3H), 0.50-0.47 (m, 3H); C NMR (100 MHz,
CDCl3) δ[ppm]: 201.3, 199.5, 164.0, 141.6, 141.2, 136.5,
1
(step 3) derivatives (2a-h)
36.0, 134.5, 127.7, 125.3, 123.5, 122.6, 122.5, 120.2,
A mixture of compound 2 or 3 (1 equiv.), sarcosine (1.2
equiv.), and ninhydrine (1.2 equiv.) in anhydrous toluene
118.7, 110.6, 106.2, 102.2, 78.3, 62.7, 62.5, 48.8, 35.4,
+
12.7; ESI-MS : exact mass calculated for C H N O6
2
4
21
3
+
-
(50 v/w) was heated to reflux for 16 hours. Dark brown-
[M + H] : 447.1430, found: 470.1328 (M + Na); IR (cm
1
ish reaction mixture was cooled to room temperature and
toluene was removed by concentration under vacuo.
Crude compound was purified by column chromatogra-
phy over silica gel 230 to 400 mesh by using ethyl acetate
in petroleum ether as an eluent to afford compound-5
): 2930(=C-H), 2842 (C-H aliphatic), 1706 (C=0), 1593
(C-O), 1347 (C-N), 1072 (C-O); UV-visible (nm):
257, 234, 214.
0
0
Dimethyl-3 -(1H-indol-3-yl)-1 -methyl-1,3-dioxo-
[16]
0
0
0
(Scheme 1) as a solid.
1,3dihydrospiro [indene-2,2 -pyrrolidine]-4 ,4 -
dicarboxylate (2d)
0
0
0
0
ꢀ
1
3
-(1H-indol-3-yl)-1 -methyl-4 -nitrospiro [indene-2,2 -
Yield: 30%; mp: 180-182 C; H NMR (400 MHz, CDCl3)
δ[ppm]: 8.01 (s, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.65 (m,
3H), 7.57 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H),
7.09-6.99 (m, 3H), 5.37 (s, 1H), 4.59 (d, J = 10.1 Hz, 1H),
3.88-3.62 (m, 4H), 3.11 (s, 3H), 2.49 (s, 3H); C NMR
(100 MHz, CDCl3) δ[ppm]: 201.3, 200.9, 171.3, 169.1,
141.8, 141.1, 136.0, 135.6, 134.5, 127.8, 124.7, 122.3,
122.0, 121.7, 119.8, 118.7, 110.5, 108.4, 79.1, 63.7, 60.9,
pyrrolidine]-1,3-dione (2a)
Yield: 20%; mp: 169-171 C; H NMR (400 MHz, CDCl3)
δ[ppm]: 8.04 (s, 1H), 7.84-7.78 (m, 1H), 7.63-7.62 (m,
H),7.42 (d, J = 7.6, 1H), 7.07-6.99 (m, 3H), 5.87 (q,
ꢀ
1
1
3
3
J = 7.2 Hz), 5.00 (d, J = 8.0 Hz, 1H), 4.00 (d, J = 7.2 Hz,
1
3
2
2
1
5
H), 2.39 (s, 3H); C NMR (100 MHz, CDCl3) δ[ppm]:
03.0, 199.6, 142.1, 140.3, 137.0, 136.5, 135.9, 129.0, 125.1,
23.8, 123.6, 123.3, 121.3, 119.2, 116.5, 114.7, 87.4, 76.32,
+
53.4, 52.2, 48.5, 35.9; ESI-MS : exact mass calculated
+
+
7.4, 47.2, 36.0; ESI-MS : exact mass calculated for
for C H N O [M + H] : 446.1478, found: 469.1375
2
5
22
2
6
+
−1
C H N O [M + H] : 375.1219, found: 398.1115 (M +
(M + Na); IR (cm ): 3279 (N-H), 2963 (=C-H), 1700
(C=0), 1550 (-NO2), 1258 (C-N); UV-visible (nm):
286, 260, 234.
2
1
17 3 4
−
1
Na); IR (cm ): 3279 (N-H), 2963 (=C-H), 1700 (C=0),
550 (-NO2), 1258 (C-N); UV-visible (nm): 397, 234, 214.
1

6
YELLAPPA
0
0
0
0
0
0
3
[
-(1-acetyl-1H-indol-3-yl)-1 -methyl-4 -nitrospiro
Ethyl-3 -(1-acetyl-1H-indole-3-yl)-1 -methyl-4 -nitro-
0
0
0
indene-2,2 -pyrrolidine]-1, 3-dione (2e)
Yield: 44%; mp: 164-166 C; H NMR (400 MHz, CDCl3)
δ [ppm]: 8.10 (d, J = 7.2 Hz, 1H), 7.83-7.81 (m, 1H),
.71-7.69 (m, 3H), 7.39 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H),
.24-7.16 (m, 2H), 5.84 (m, 6.0 Hz, 1H), 4.91 (d, J = 9.2
Hz, 1H), 3.99 (d, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.36
s,3H); C NMR (100 MHz, CDCl3) δ[ppm]: 203.3,
99.3, 168.3, 141.8, 140.4, 136.9, 136.6, 135.3, 128.7,
25.9, 123.9, 123.7, 123.4, 122.3, 118.9, 116.2, 114.5, 86.8,
7.96, 57.3, 47.6, 36.3, 24.0; ESI-MS : exact mass calcu-
lated for C H N O [M + H] : 417.1325, found:
40.1220 (M + Na); IR (cm ): 2925 (=CH), 2823 (-C-H),
703 (C=0), 1549 (-NO2), 1331 (C-N); UV-visible (nm):
99, 292, 234.
1,3-dioxo-1,3-Dihydrospiro[indene-2,2 -pyrolidine]-4 -
carboxylate (2h)
ꢀ
1
ꢀ
1
Yield: 47%; mp: 181-183 C; H NMR (400 MHz, CDCl3) δ
[ppm]: 8.28-8.25 (m, 1H), 7.92-7.86 (m, 1H), 7.80-7.78 (m,
3H), 7.61-7.57 (m, 1H), 7.31 (s, 1H), 7.24-7.23 (m, 1H),
7.22-7.17 (m, 1H), 5.65-5.42 (m, 1H), 4.81-4.73 (m, 1H),
4.38-4.33 (m, 1H), 4.12-3.98 (m, 1H), 3.80-3.61 (m, 1H),
2.68-2.55 (m, 3H), 2.41-2.35 (m, 3H), 0.57-0.53 (m, 3H);
C NMR (100 MHz, CDCl3) δ[ppm]: 201.5, 200.2, 168.6,
164.4, 142.0, 141.3, 136.8, 136.1, 134.4, 128.3, 125.4, 123.6,
123.1, 122.8, 120.7, 119.3, 111.2, 106.0, 102.8, 78.1, 63.4,
63.2, 48.5, 36.0, 23.7, 12.8; ESI-MS : exact mass calcu-
7
7
1
3
(
1
1
7
13
+
+
2
3
19
3
5
−
1
+
4
1
2
+
lated for C H N O [M + H] : 489.1536, found:
512.1433 (M + Na); IR (cm ): 3263 (N-H), 2948 (=C-H),
816 (-C-H), 1702 (C=0), 1584 (C-O), 1341 (C-N); UV-
26
23 3 7
−
1
2
0
0
Diethyl-3 -(1-acetyl-1H-indol-3-yl)-1 -methyl-1,3-dioxo-
visible (nm): 230, 291, 299.
0
0
0
1,3 dihydrospiro [indene-2,2 -pyrrolidine]-4 , 4 -
dicarboxylate (2f)
Yield: 45%; mp: 108-110 C; 1 H NMR (400 MHz,
CDCl3) δ [ppm]: 8.27 (d, J = 8.0 Hz, 1H), 7.90-7.89
ACKNOWLEDGMENTS
ꢀ
The authors are grateful to Science and Engineering
Research Board (No. SB/FT/CS-009/2012), DST New
Delhi, India for the financial assistance and also thankful
to DST for the financial assistance through FIST
program.
(
m, 1H), 7.78-7.69 (m, 3H), 7.52 (d, J = 7.6 Hz, 1H),
.36 (s, 1H), 7.25-7.14 (m, 2H), 5.23 (s, 1H), 4.48 (d,
J = 10 Hz, 1H), 4.39-4.24 (m, 2H), 3.80 (d, J = 10 Hz,
7
1
2
H), 3.77-3.67 (m, 1H), 3.44-3.36 (m, 1H), 2.73 (s, 3H),
.39 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 0.48 (t, J = 7.2
ORCID
1
3
Hz, 3H); C NMR (100 MHz, CDCl3) δ[ppm]: 199.7,
Shivaraj Yellappa https://orcid.org/0000-0002-7942-
840X
1
1
1
2
99.1, 169.3, 167.7, 167.2, 140.6, 139.6, 135.4, 135.0,
33.2, 129.6, 125.1, 124.2, 122.5, 122.3, 121.5, 117.8,
15.0, 114.3, 77.5, 64.1, 61.3, 60.3, 59.3, 46.1, 34.7,
REFERENCES
+
3.0, 12.9, 11.9; ESI-MS : exact mass calculated for
[1] T. P. Pathak, K. M. Gligorich, B. E. Welm, M. S. Sigman,
J Amer Chem Soc 2010, 132, 7870.
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R. T. J. Uday, P. G. V. Siva, D. Rajitha, Y. L. N. Murthy, Arab J
Chem. 2015. In press, Available online 19 February.
+
C H N O [M + H] : 516.1897, found: 539.1792
2
9
28
2
7
−
1
(
(
M + Na); IR (cm ): 3289 (N-H), 2978 (=C-H), 1705
C=0), 1558 (-NO2), 1247 (C-N); UV-visible (nm):
3
03, 295, 233.
[3] T. L. Charlton, An Elementary Latin Dictionary, American
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0
0
Dimethyl-3 -(1-acetyl-1H-indol-3-yl)-1 -methyl-
1
4
Yield: 62%; mp: 103-105 C; H NMR (400 MHz,
CDCl3) δ [ppm]: 8.28 (d, J = 8.0 Hz, 1H), 7.90-7.88
[
4] E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of
Organic Compounds, 1st ed., Wiley & Sons, New York 1994,
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0
,3-dioxo-1,3 dihydrospiro [indene-2,2 -pyrrolidine]-
0
0
,4 -dicarboxylate (2g)
ꢀ
1
[5] G. P. Moss, the Working Party of the International Union of
Pure and Applied Chemistry (IUPAC), Organic Chemistry
Division, Commission on Nomenclature of Organic Chemistry
(
7
m, 1H), 7.77-7.70 (m, 3H), 7.52 (d, J = 7.6 H, 1H),
.35 (s, 1H), 7.24-7.18 (m, 2H), 5.21 (s, 1H), 4.51 (d,
J = 10.0 Hz, 1H), 3.86-3.81 (m, 4H), 3.12 (s, 3H), 2.60
(
III.1), Pure Appl. Chem. 1999). "" (PDF, 71(3), 531–58.
[
6] T. L. Pavlovskaya, F. G. Yaremenko, V. V. Lipson,
S. V. Shishkina, O. V. Shishkin, V. I. Musatov, A. S. Karpenko,
J Org Chem 2014, 10, 117.
1
3
(
s, 3H), 2.40 (s, 3H); C NMR (100 MHz, CDCl3)
δ[ppm]: 202.4, 202.2, 173.8, 172.4, 169.7, 142.2, 140.3,
[7] A. Dandia, H. Taneja, M. Saha, Ind J Chem Technol. 1997,
, 243.
4
1
1
4
36.6, 135.0, 133.0, 128.0, 124.4, 121.5, 121.0, 120.5,
19.6, 117.9, 109.8, 108.3, 77.7, 63.6, 61.4, 54.0, 53.3,
[8] (a) R. Huisgen, Chem Int Ed 1963, 2, 633. (b) R. Huisgen,
Chem Int Ed 1963, 2, 565.
+
7.8, 36.2, 23.6; ESI-MS : exact mass calculated for
[9] P. Albert, 1,3-Dipolar cycloaddition chemistry, John Wiley and
Sons. New York, 1984, Vol. 1, p. 817, Vol 2, p. 704.
+
C H N O [M + H] : 488.1584, found: 511.1479
27
24
2 7
−
1
(
M + Na); IR (cm ): 2930 (=C-H), 2842 (C-H ali-
[
10] (a) V. C. Pham, J. L. Charlton, J Org Chem 1995, 60, 8051.
b) C. W. G. Fiswick, R. J. Foster, R. E. Carr, Tetrahedron Lett
1996, 37, 3915.
phatic), 1706 (C=0), 1593 (C-O), 1347 (C-N), 1072 (C-
O); UV-visible (nm): 293, 233.
(

YELLAPPA
7
[
11] J. Obniska, A. Zeic, A. Zagorska, Acta Pol Pharm 2002,
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SUPPORTING INFORMATION
5
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[
4
[
[
[
[
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Chem 2012, 47, 312.
How to cite this article: Yellappa S. An anti-
Michael route for the synthesis of indole-spiro
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indene-pyrrolidine) by 1,3-cycloaddition of
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