TiO2-mediated, one-pot, four-component 1,3-dipolar cycloaddition reaction: A facile synthesis of dispiro-pyrrolidine ring systems

Article abstract of DOI:10.1080/00397910802374091

An expedient regioselective synthesis of dispiroindenoquinoxaline pyrrolidine derivatives mediated by TiO2 in a one-pot, four-component 1,3-dipolar cycloaddition reaction is described. Copyright Taylor & Francis Group, LLC.

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TiO2-Mediated, One-Pot,
Four-Component 1,3-Dipolar
Cycloaddition Reaction: A
Facile Synthesis of Dispiro-
pyrrolidine Ring Systems
A. R. Suresh Babu a & R. Raghunathan a
a Department of Organic Chemistry, University of
Madras, Guindy Campus, Guindy, Chennai, India
Published online: 22 Dec 2008.
To cite this article: A. R. Suresh Babu & R. Raghunathan (2008) TiO2-Mediated,
One-Pot, Four-Component 1,3-Dipolar Cycloaddition Reaction: A Facile Synthesis
of Dispiro-pyrrolidine Ring Systems, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:2, 347-354, DOI:
10.1080/00397910802374091
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Synthetic Communications1, 39: 347–354, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802374091
TiO2-Mediated, One-Pot, Four-Component
1,3-Dipolar Cycloaddition Reaction: A Facile
Synthesis of Dispiro-pyrrolidine Ring Systems
A. R. Suresh Babu and R. Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Guindy, Chennai, India
Abstract: An expedient regioselective synthesis of dispiroindenoquinoxaline
pyrrolidine derivatives mediated by TiO2 in a one-pot, four-component 1,3-
dipolar cycloaddition reaction is described.
Keywords: Azomethine ylide, 1,3-dipolar cycloaddition, indenoquinoxaline,
spiropyrrolidines
INTRODUCTION
Multicomponent 1,3-dipolar cycloadditions reactions are considered to
be one of the most useful processes for the construction of five-membered
heterocyclic ring systems.[1–3] In particular, the chemistry of the azo-
methine ylide has gained significance in recent years for the construction
of nitrogen-containing five-membered heterocycles, which are often the
central ring systems of numerous natural products.[4] Among the various
nitrogen-containing heterocycles, functionalized pyrrolidine alkaloids
constitute classes of compounds with significant biological activity.[5]
Spiro compounds represent an important class of naturally occurring sub-
stances characterized by highly pronounced biological properties.[6–10]
1,3-Indanediones have captured much attention because of their
important pharmacological propertiessuch as anti-inflammatory and
Received April 12, 2008.
Address correspondence to Raghunathan Raghavachary, Department of
Organic Chemistry, University of Madras, Guindy Campus, Guindy, Chennai,
India. E-mail: ragharaghunathan@yahoo.com
347

348
A. R. S. Babu and R. Raghunathan
anticoagulants.[11] Recent drugs incorporating the pyrrolidine motif have
been identified as candidates with promising anti-HIV4 and antibacterial
activity. Indenoquinoxalines, which are a rare class of nitrogen-containing
heterocycles, also find applications in dyes and pharmaceuticals and as
building blocks for the synthesis of organic semiconductors.[12,13] Bioactivity
of some of the spiro-pyrrolidines has been reported by us recently.[14]
In recent years, there has also been increasing interest in solid-
supported reagents[15] because of the benefits of enhanced reaction rates,
improved yields, cleaner reaction profiles, and greater selectivity. In conti-
nuation of our interest in surface solid-state cycloaddition reactions[16,17]
and with a view to synthesize a rare class of novel dispiroheterocyclic
derivatives, we herein report for the first time TiO2 as an efficient
solid-support catalyst for the synthesis of dispiroindenoquinoxaline
pyrrolidine ring systems in a one-pot, four-component reaction. A
series of dispiro- [indanedione=indeno[1,2-b]quinoxaline]-pyrrolidine ring
systems has been synthesized through regioselective cycloaddition of
2-arylidene-1,3-indanedione 1a–e with the azomethine ylide generated
from ninhydrin 2, 1,2-phenylenediamine 3, and sarcosine 4 in the
presence of TiO2 as catalyst by a decarboxylative route. Bioactivity of
the newly synthesized compounds will be published elsewhere.
RESULTS AND DISCUSSION
Azomethine ylides can be generated by a number of methods, of which the
decarboxylation route is a convenient method for the synthesis of nitrogen-
containing heterocyclic compounds.[18] In this method, an aldehyde and a
primary=secondary amino acid are condensed to generate the reactive
intermediate, which is then trapped by dipolarophiles. The required
dipolarophile 2-arylidene-1,3-indanediones were prepared by the base-
catalyzed condensation of 1,3-indanedione with various benzaldehydes
according to the literature procedure.[19] The multicomponent reaction
was carried out by stirring a mixture of 1 equivalent of ninydrin 2 and 1
equivalent of 1,2-phenylenediamine 3 for 10 min in 10 mL ethanol followed
by the addition of 1 equivalent of sarcosine 4. To this mixture, 1 equivalent
of 2-arylidene-1,3-indanedione 1a–e and 10 mg of TiO2 were then added.
The mixture was then refluxed until completion of the reaction as evi-
denced by thin-layer chromatography (TLC). The reaction proceeded
through the condensation of the ninhydrin 2 and 1,2-phenylenediamine 3
to give indenoquinoxaline-11-one, which then generates an azomethine
ylide with sarcosine 4. The mechanism for the generation of the azomethine
ylide is presented in Scheme 1. The 1,3-dipole so generated subsequently
underwent regioselective cycloaddition reaction with exocyclic double

Dispiro-Pyrrolidine Ring Systems
349
Scheme 1. Mechanism for the generation of azomethine ylide from ninhydrin 2,
1,2-phenylenediamine 3 and sarcosine 4.
bond of the dipolarophile 2-arylidene-1,3-indanedione 1a–e, affording
series of novel 1-N-methyl-spiro[2.110]indeno-[1,2-b]-quinoxaline-
a
spiro[3.200]-indane-100,300-dione-4-aryl-pyrrolidines 5a–e in good yield.
Scheme 2. Reaction of azomethine ylide generated from ninhydrin, O-phenylene
diamine and sarcosine with 2-arylidene 1,3-diones.

350
A. R. S. Babu and R. Raghunathan
The reaction afforded a single product as evidenced by TLC. No traces
of the other regioisomers 6a–e were detected in all the cases studied
(Scheme 2).
The cycloadducts were characterized by various spectroscopic techni-
ques. Thus, the IR spectrum of 5a revealed peaks at 1734 cmꢀ1 due to the
indanedione ring carbonyls. The 1H NMR spectrum of 5a exhibited
peaks at d values 2.11 (s, 3H, -NCH3), 4.04 (t, 1H, Hb), 4.38 (t, 1H,
Hc), 5.32 (t, 1H, Ha), and 6.25–8.62 (m, 17H, ArH). The off-resonance
proton decoupled 13C NMR spectrum of 5a adds conclusive support of
the proposed structure. The pyrrolidine N-methyl and N-methylene
carbon resonated at d 34.54 and 47.09 ppm, whereas the pyrrolidine ring
carbon attached to the phenyl moiety resonated at d 56.22 ppm. The spiro
carbons resonated at d 71.46 and 79.20 ppm. The indanedione ring carbo-
nyls resonated at d 191.12 and 191.43 ppm respectively. These observed
chemical shift values confirmed the proposed structure. The mass spec-
trum of 5a showed a peak at m=z 493.5 (Mþ). Identical results were
obtained for other products. The stereochemical outcome of the cycload-
diton reaction was evidenced based on the spectral and X-ray crystal
analysis of one of the pyrrolizidine analogs in the spiro-indanedione-
indenoquinoxaline series.[20]
.
CONCLUSION
An expedient TiO2-mediated synthesis of a new class of dispiro-
[indanedione=indenoquinoxaline] pyrrolidine ring systems through the
cycloaddition reaction of azomethine ylide generated from 1,2-phenylene-
diamine, ninhydrin, and sarcosine with 2-arylidene-1,3-indanediones was
accomplished for the first time. The cycloaddition is of interest because it
paves the way for the synthesis of a variety of biologically significant
complex dispiro-indanedione-indenoquinoxaline pyrrolidines derivatives
using easily available starting materials.
EXPERIMENTAL
General
All melting points are uncorrected. IR spectra were recorded on a
Shimadzu FT-IR 8300 instrument. Mass spectra were recorded on a Jeol
DX 303 HF spectrometer with Maspec System (msw=9629). 1H and
13C NMR were recorded in CDCl3 using TMS as internal standard on

Dispiro-Pyrrolidine Ring Systems
351
a Bruker spectrometer at 300 and 75 MHz, respectively. Elemental
analyses were carried out on a Perkin-Elmer 2400 B instrument.
Representative Procedure for TiO2-Supported Synthesis of Dispiro-
indanedione-indenoquinoxaline Pyrrolidines 5a–e
A mixture of ninydrin 2 (1 mmol) and 1,2-phenylenediamine 3 (1 mmol)
was stirred for 10 min in 10 mL ethanol followed by addition of sarcosine
4 (1 mmol). To this mixture, a solution of 2-arylidene-1,3-indanedione 1a
(1 mmol) in 10 ml of ethanol and 10 mg of TiO2 was added. The mixture
was then refluxed until completion of the reaction as evidenced by TLC.
The solvent was removed in vacuo and the crude product was subjected
to column chromatography using petroleum ether–ethyl acetate (4:1) as
eluent.
Reaction Time, Yields, Physical Properties, and Spectroscopic Details for
the Compounds 5a–e
1-N-Methyl-spiro[2.110]indeno-[1,2-b]-quinoxaline-spiro[3.200]indan-
100,300-dione-4-phenyl-pyrrolidine 5a
Time 0.7 h, 0.24 g, 90%, pale yellow powder, mp 164–166 ꢁC; IR (KBr):
1
1734 cmꢀ1, H NMR (300 MHz=CDCl3): d 2.11 (s, 3H), 4.04 (t, 1H,
Hb), 4.38 (t, 1H, Hc), 5.32 (t, 1H, Ha), 6.25–8.62 (m, 17H, ArH); 13C
NMR (75 MHz): d 34.54, 47.09, 56.22, 71.46, 79.20, 124.95, 125.00,
125.06, 126.03, 130.98, 131.34, 131.54, 132.89, 133.69, 133.78, 135.51,
137.17, 138.00, 138.06, 142.85, 143.87, 143.97, 144.43, 150.58, 157.91,
191.12, 191.43 ppm; MS m=z: 493.5 (Mþ). Anal. calcd for C33H23N3O2:
C, 80.30; H, 4.96; N, 8.51. Found: C, 80.13; H, 4.83; N, 8.62.
1-N-Methyl-spiro[2.110]indeno-[1,2-b]-quinoxaline-spiro[3.200]indan-
100,300-dione-4-(p-chlorophenyl)-pyrrolidine 5b
Time 0.7 h, 0.20 g, 85%, pale yellow powder, mp 150–152 ꢁC; IR (KBr):
1
1740 cmꢀ1, H NMR (300 MHz=CDCl3): d 2.14 (s, 3H), 4.06 (t, 1H,
Hb), 4.40 (t, 1H, Hc), 5.34 (t, 1H, Ha), 6.36–8.64 (m, 16H, ArH); 13C
NMR (75 MHz): d 34.65, 47.16, 56.88, 71.58, 79.34, 125.09, 129.21,
129.30, 130.30, 137.28, 138.11, 138.29, 142.80, 143.76, 143.83, 144.57,
150.62, 157.62, 157.80, 191.18, 191.52 ppm; MS m=z. 527 (Mþ). Anal.
calcd. for C33H22N3O2Cl: C, 75.21; H, 4.01; N, 7.97. Found: C, 75.08;
H, 4.17; N, 7.82.

352
A. R. S. Babu and R. Raghunathan
1-N-Methyl-spiro[2.110]indeno-[1,2-b]-quinoxaline-spiro[3.200]indan-
100,300-dione-4-(p-methylphenyl)-pyrrolidine 5c
Time 0.8 h, 0.20 g, 82%, pale yellow powder, mp 132–134 ꢀC; IR (KBr):
1
1738 cmꢁ1, H NMR (300 MHz=CDCl3): d 2.02 (s, 3H), 2.12 (s, 3H),
4.04 (t, 1H, Hb), 4.36 (t, 1H, Hc), 5.30 (t, 1H, Ha), 6.64–8.60 (m, 16H,
ArH); 13C NMR (75 MHz): d 24.06, 34.32, 46.96, 56.04, 71.32, 79.06,
124.63, 125.08, 125.17, 126.21, 129.68, 131.22, 131.47, 132.93, 133.54,
133.70, 135.24, 138.08, 138.12, 142.77, 143.70, 143.81, 150.42, 157.81,
191.06, 191.38; MS m=z: 487.5 (Mþ). Anal. calcd. for C34H25N3O2: C,
83.75; H, 5.16; N, 8.61. Found: C, 83.86; H, 5.27; N, 8.47.
1-N-Methyl-spiro[2.110]indeno-[1,2-b]-quinoxaline-spiro[3.200]indan-
100,300-dione-4-(p-methoxyphenyl)-pyrrolidine 5d
Time 0.9 h, 0.20 g, 82%, pale yellow powder, mp 140–141 ꢀC; IR (KBr):
1
1730 cmꢁ1, H NMR (300 MHz=CDCl3): d 2.16 (s, 3H), 3.76 (s, 3H),
4.08 (t, 1H, Hb), 4.38 (t, 1H, Hc), 5.32 (t, 1H, Ha), 6.74–8.62 (m, 16H,
ArH); 13C NMR (75 MHz): d 34.64, 47.02, 55.66, 56.32, 71.43, 79.17,
120.81, 125.30, 126.28, 129.31, 129.40, 131.28, 131.66, 133.54, 133.81,
135.39, 137.26, 138.12, 138.31, 142.78, 143.69, 143.98, 153.18, 157.70,
191.34, 191.52 ppm; MS m=z: 523.5 (Mþ). Anal. calcd. for C34H25N3O3:
C, 77.99; H, 4.81; N, 8.02. Found: C, 77.83; H, 4.95; N, 8.14.
1-N-Methyl-spiro[2.110]indeno-[1,2-b]-quinoxaline-spiro[3.200]indan-
100,300-dione-4-(p-nitrophenyl)-pyrrolidine 5e
Time 0.5 h, 0.20 g, 88%, pale yellow powder, mp 128–130ꢀC; IR (KBr):
1
1742cmꢁ1, H NMR (300 MHz=CDCl3): d 2.18 (s, 3H), 4.12 (t, 1H, Hb),
4.45 (dd, J ¼ 9.0, 7.8 Hz, 1H, Hc), 5.76 (dd, J ¼ 10.2, 7.8 Hz, 1H, Ha),
7.40–8.56 (m, 16H, ArH) ; 13C NMR (75 MHz): d 34.62, 45.02, 59.02,
71.58, 79.27, 122.34, 122.54, 122.73, 126.52, 126.94, 128.18, 129.09, 129.37,
129.64, 130.31, 131.20, 132.57, 134.56, 141.29, 141.66, 142.27, 143.36,
152.82, 160.94, 197.90, 198.33; MS m=z: 538.5 (Mþ). Anal. calcd. for
C33H22N4O4: C, 73.59; H, 4.11; N, 10.40. Found: C, 73.46; H, 4.23; N, 10.56.
ACKNOWLEDGMENTS
A. R. S. thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for the award of a senior research fellowship. R. R. thanks
Department of Science and Technology (DST) and DST-Fund for
Improvement S-T (FIST) for financial assistance.

Dispiro-Pyrrolidine Ring Systems
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