A facile regio- and stereoselective synthesis of novel spiro[indolin-3,2′-pyrrolidin]-2-one’s via 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1080/00397911.2018.1442866

A facile regio and stereoselective synthesis of novel spiro[indolin-3,2′-pyrrolidin]-2-one’s have been accomplished through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of isatin and benzyl amine with quinoline bearing dipolarophiles in good yields. The synthesized compounds were well characterized through different spectroscopic techniques, such as single crystal XRD, FTIR, NMR, and mass spectral analysis.

Full text of DOI:10.1080/00397911.2018.1442866

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A facile regio- and stereoselective synthesis of
novel spiro[indolin-3,2′-pyrrolidin]-2-one’s via 1,3-
dipolar cycloaddition of azomethine ylides
Kailasam Saravana Mani & Subramaniam Parameswaran Rajendran
To cite this article: Kailasam Saravana Mani & Subramaniam Parameswaran Rajendran
(2018): A facile regio- and stereoselective synthesis of novel spiro[indolin-3,2′-pyrrolidin]-2-
one’s via 1,3-dipolar cycloaddition of azomethine ylides, Synthetic Communications, DOI:
10.1080/00397911.2018.1442866
To link to this article: https://doi.org/10.1080/00397911.2018.1442866
View supplementary material
Published online: 02 Apr 2018.
Submit your article to this journal
Article views: 39
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2018.1442866
A facile regio- and stereoselective synthesis of novel spiro
[indolin-3,20-pyrrolidin]-2-one’s via 1,3-dipolar cycloaddition
of azomethine ylides
Kailasam Saravana Mani and Subramaniam Parameswaran Rajendran
Department of Chemistry, Bharathiar University, Coimbatore, Tamil Nadu, India
ABSTRACT
ARTICLE HISTORY
Received 15 October 2017
A facile regio and stereoselective synthesis of novel spiro[indolin-
3,20-pyrrolidin]-2-one’s have been accomplished through 1,3-dipolar
cycloaddition of azomethine ylides generated in situ from the reaction
of isatin and benzyl amine with quinoline bearing dipolarophiles in
good yields. The synthesized compounds were well characterized
through different spectroscopic techniques, such as single crystal XRD,
FTIR, NMR, and mass spectral analysis.
KEYWORDS
Benzyl amine methanol;
isatin; quinoline
dipolarophiles; spiro[indolin-
3,20-pyrrolidin]-2-one
GRAPHICAL ABSTRACT
Introduction
The spirocyclic oxindoles describe characteristic structural motifs of a variety of medicinal
molecules and biologically dynamic natural products.[1,2] The spiro[pyrrolidin-3,20-
oxindoles] are exemplify by the fused five-membered N-heterocyclic frameworks and
adjoining nitrogen atoms to the spirocenters found in many pharmaceutically
relevant compounds and naturally occurring alkaloids. Natural products that contain
CONTACT Kailasam Saravana Mani
chemsaran.mani@gmail.com
Department of Chemistry, Bharathiar University,
Coimbatore, Tamil Nadu, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental material (IR, 1H-NMR, 13C-NMR and Mass analysis) can be accessed on the publisher’s website.
© 2018 Taylor & Francis

2
K. S. MANI AND S. P. RAJENDRAN
Figure 1. Naturally occurring bioactive spirocyclic oxindoles.
3-spiropyrrolidine oxindole framework (Fig. 1) exhibit significant pharmacological proper-
ties. For example, coerulescine, horsfiline, and elacomine are inhibitors of the mammalian
cell cycle at the G2/M interphase,[3] spirotryprostatin A also showed anticancer activity.[4]
Various biological activities have been found for synthetic spirooxindoles, such as
antidiabetic,[5] acetylcholinesterase (AChE) inhibitory properties,[6] antiviral,[7]
antitumoric,[8] antifungal,[9] antitubercular,[10] antimalarial,[11] and anti-inflammatory[12]
activities.
Azomethine ylides are extremely versatile building blocks in organic synthesis, and are
recognized to take part in 1,3-dipolar cycloaddition reactions with a wide array of
dipolarophiles.[13] Cycloadditions of azomethine ylides to alkenes are well reputable reac-
tions in which pyrrolidines and pyrrolizidines are formed, frequently with a high degree of
stereo chemical control.[14] This mode of cycloaddition simultaneously constructs two car-
bon–carbon bonds and forms ring systems with regio- and stereocontrol.[15] From the
abovementioned significances in the synthesis of spiro oxindoles, herein we report the
synthesis of quinoline substituted spiro[indolin-3,20-pyrrolidin]-2-one through [3 þ 2]
cycloaddition reaction of azomethine ylide generated in situ from isatin and benzyl amine
to quinolinyl chalcones.
Results and discussion
1,3-Dipolar cycloaddition of ylidic species, for example azomethine ylides with
dipolarophiles, is a useful method for the construction of five-membered heterocycles,
such as pyrrolidines and pyrrolizidines.[16] Recently our group reported the synthesis
of bioactive spiro-indenoquinoxaline pyrrolizines through multicomponent reaction
of quinoline derived dipolarophile, ninhydrin, o-phenylenediamine derivatives and
l-proline in methanol.[17] Initially, quinoline based dipolarophile 1(a–f) were synthesized
by the Claizen Schmidt condensation reaction between 2-chloro-3-formyl quinoline
derivatives and acetophenone under alcoholic KOH condition. An equimolar mixture
of dipolarophile 1(a–f), isatin 2, and benzyl amine 3 in methanol condition were allow
to reflux for 6–8 h (Scheme 1). After completion of reaction monitored by TLC, which
afforded a single product, was separated by evaporation of solvent in good yields were
mentioned in Table 1.

SYNTHETIC COMMUNICATIONS®
3
Scheme 1. Synthetic pathway of spiro[indolin-3,20-pyrrolidin]-2-one’s.
1
All the compounds 4a–f were characterised by FTIR, H-NMR, 13C-NMR, 4a included
single crystal XRD, COSY, NOSEY, HSQCE, mass spectral analysis, whereas spectrum
(All characterisation data are presented in supporting information). As a typical analysis,
4a showed FTIR stretching frequency at 3327, 3061 cm−1 for the N‒H group, two C=O
stretching at 1715 and 1617 cm−1 (acetophenone and isatin) whilst the C‒H occurred at
1
2925 cm−1. The H NMR spectrum showed four singlets at δ 8.48, 7.80, 2.71, and 3.91
corresponding to the quinoline C4-H, C5-H isatin ring N–H, and quinoline OCH3 group,
respectively. The benzyl amine N‒H speak at δ 6.49 (J ¼ 7.6 Hz) and seventeen aromatic pro-
tons were found at the region of δ 6.98 to 7–84. The specific regioisomer were decided on the
basis of triplet at δ 4.98 (J ¼ 6.8 Hz) for the C20-H proton and the C30-H proton appeared as
a doublet instead of a triplet at δ 5.03 (J ¼ 10 Hz) and the C40-H proton appeared as a
Table 1. Reaction conditions for the synthesis of spiro[indolin-3,20-pyrrolidin]-2-one’s 4(a–f).
aIsolated yield, Reaction condition: quinoline chalcones 1(1 mmol), isatin 2 (1 mmol), benzyl amine 3 (1 mmol), and methanol
(10 ml).

4
K. S. MANI AND S. P. RAJENDRAN
Figure 2. 1H- and 13C-NMR chemical shift values of compound 4a.
doublet at δ 5.26 (J ¼ 9.6 Hz). The 13C-NMR spectrum showed the presence of four spiro
carbon C20, C30, C40, and C50 peaks at δ 68.66, 62.45, 51.52, and 69.04, respectively (Fig. 2).
The methoxy C9 –OCH3 carbon peaks were at δ 55.62 and quinoline C5 carbon speak at δ
104.81 and isatin ring carbon C7″ at speak at δ 109.46 which were confirmed on the 13C, 1H-
COSY correlation spectrum. The two carbonyl peaks were at δ 196.74 and 181.06,
respectively.
The COSY spectrum of the compound revealed one doublet at δ 5.26 (J ¼ 9.6 Hz), two
singlet at δ 8.48 and 7.80. Two diastereotopic methane proton triplet at δ 5.03 (J ¼ 10 Hz),
δ 4.98 (J ¼ 6.8 Hz). NOESY spectrum of the compound confirmed doublet at δ 6.49
(J ¼ 6 Hz). In the 1H–13C, COSY spectrum, the signal at δ 51.52, 55.62, 62.45, 68.66,
123.33, 123.18, 126.23, 127.12, 127.64, 128.22, 128.46, 129.08, 129.42, 132.97, and 136.79
was assigned to C-40, C-9, C-30, C-50, C-4″, C-6″, C-7, C-5‴, C-6‴, C-60‴, C-50‴, C-6‴,
1
C-4‴, C-5″, and C-4 carbons. Selected H-, 13C-NMR chemical shifts of 4a are given in
based on the above spectral details and its single crystal analysis (Fig. 3), the structure
Figure 3. Molecular structure of 4a; Hydrogen atoms are omitted for clarity (CCDC 1815649).

SYNTHETIC COMMUNICATIONS®
5
Scheme 2. Proposed mechanism for the formation of products 4(a–f).
was confirmed as of 30-benzoyl-40-(2-chloro-6-methoxyquinolin-3-yl)-50-phenylspiro
[indoline-3,20-pyrrolidin]-2-one (4a).
A proposed mechanism for the formation of spiropyrrolidinyloxindole heterocycles is
represented in Scheme 2. The azomethine ylide I generated in situ from the reaction of
isatin 2 and benzyl amine 3, has one potential nucleophilic carbon, which undergoes
1,3-dipolar cycloaddition with dipolarophile 1 to afford novel cycloadduct 4 as a single
regioisomer. The proposed mechanism is confirmed in accordance with previous reported
procedures.[18]
Conclusion
In conclusion, we have performed an efficient synthesis of novel spiro heterocycles
using 1,3-dipolar cycloaddition methodology in which the 1,3-dipole generated by 1,5-
prototropic shift is reacted with quinoline chalcones as dipolarophiles under refluxing in
methanol. This method provides an easy access to the spiropyrrolidinyloxindole scaffold
with high regio- and stereoselectivity. The synthesized compounds were well characterized
through different spectroscopic techniques including single crystal XRD, FTIR, NMR, and
mass spectral analysis.
Experimental
All chemicals and reagents were purchased from Sigma-Aldrich and were used as such.
Commercial grade solvents were distilled according to literature procedure. IR Spectra
were recorded on JASCO FT IR 4100 spectrometer using KBr disc and the absorption
1
frequencies quoted in reciprocal centimeters. H- and 13C-NMR spectra were recorded
1
on Bruker advance (400 MHz for H and 100 MHz for 13C) in CDCl3 and DMSO-d6
solvents. The reaction courses were monitored by TLC on silica gel precoated F254 Merck
plates. Chemical shifts are reported in δ values (ppm) downfield from tetramethylsilane
and coupling constants are reported in Hertz (Hz). The following abbreviations are used:
singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). Elemental analyses were

6
K. S. MANI AND S. P. RAJENDRAN
performed on a Perkin Elmer 2400 series II Elemental CHNS analyzer. LC–MS analyses
were performed on waters Q-TOF micro mass spectrometer. Melting point was recorded
in a Guna melting point apparatus and was uncorrected.
Synthesis
An equimolar mixture of quinoline chalcones 1(a–f) (1 mmol), isatin 2 (1 mmol), and
benzyl amine 3 (1 mmol) were refluxed in methanol (10 ml). The progress of the reaction
was monitored using TLC. After completion of the reaction, the solvent was evaporated to
afford a single product 4(a–f) in good yields. The pure product was obtained through
recrystallization using acetonitrile as solvent.
30-Benzoyl-40-(2-chloro-6-methoxyquinolin-3-yl)-50-phenylspiro[indoline-3,20-
pyrrolidin]-2-one (4a)
Brown solid; mp 128–131 °C; IR (KBr) υ (cm−1): 3327, 2925, 1715, 1617; 1H NMR
(400 MHz, CDCl3) (ppm) δ: 8.48 (s, 1H), 7.84 (d, J ¼ 7.6 Hz, 1H), 7.80 (s, 1H),
7.47–6.98 (m, 15H), 6.50 (d, J ¼ 7.6 Hz, 1H), 5.27 (d, J ¼ 9.6 Hz, 1H, Pyrrolidin-H), 5.03
(t, J ¼ 10 Hz, 1H, Pyrrolidin-H), 4.98 (t, J ¼ 6.8 Hz, 1H, Pyrrolidin-H), 3.91 (s, 3H), 2.71
(bs, 1H); 13C NMR (100 MHz, CDCl3) (ppm) δ: 196.745, 181.868, 158.158, 149.019,
142.702, 139.873, 139.159, 136.899, 136.793, 132.975, 131.626, 129.537, 129.426, 129.084,
128.564, 128.463, 128.221, 128.180, 127.690, 127.123, 126.239, 123.334, 123.189, 109.462,
104.815, 69.045, 68.666, 62.456, 55.627, 51.524; Anal. Calcd. for C34H26ClN3O3: C, 72.92;
H, 4.68; N, 7.50; Found: C, 72.94; H, 4.67; N, 7.53.
Acknowledgment
The authors thank SAIF, Cochin University of Science and Technology, Cochin and SAIF, Punjab
University for taking NMR and mass spectral analysis.
References
[1] (a) Santos, M. M. M. Tetrahedron 2014, 70(52), 9735–9757; (b) Singh, G. S.; Desta, Z. Y. Chem.
Rev. 2012, 112(11), 6104–6155; (c) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev.
2012, 41, 7247–7290.
[2] (a) George, R. F.; Ismail, N. S. M.; Stawinski, J.; Girgis, A. S. Eur. J. Med. Chem. 2013, 68,
339–351; (b) Thangamani, A. Eur. J. Med. Chem. 2010, 45(12), 6120–6126.
[3] Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651–12666.
[4] Edmondson, S.; Danishefsky, S. J.; Lorenzino, L. S.; Rosen, N. J. Am. Chem. Soc. 1999, 121(10),
2147–2155.
[5] Murugan, R.; Anbazhagan, S.; Narayanan, S. S. Eur. J. Med. Chem. 2009, 44, 3272–3279.
[6] (a) Kia, Y.; Osman, H.; Kumar, R. S.; Murugaiyah, V.; Basiri, A.; Perumal, S.; Wahab, H. A.;
Bing, C. S. Bioorg. Med. Chem. 2013, 21, 1696–1707; (b) Kia, Y.; Osman, H.; Kumar, R. S.;
Murugaiyah, V.; Basiri, A.; Perumal, S.; Razak, I. A. Bioorg. Med. Chem. Lett. 2013, 23,
2979–2983.
[7] Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Tuntland, T.;
Zhang, K.; Karanewsky, D.; et al. Bioorg. Med. Chem. Lett. 2006, 16, 2109–2112.
[8] Girgis, A. S.; Panda, S. S.; Srour, A. M.; Farag, H.; Ismail, N. S. M.; Elgendy, M.; Abdel-Aziz,
A. K.; Katritzky, A. R. Org. Biomol. Chem. 2015, 13, 6619–6633.
[9] Premachandra, I. D. U. A.; Scott, K. A.; Shen, C.; Wang, F.; Lane, S.; Liu, H.; Van Vranken,
D. L. ChemMedChem 2015, 10, 1672–1686.

SYNTHETIC COMMUNICATIONS®
7
[10] (a) Kumar, R. S.; Rajesh, S. M.; Perumal, S.; Banerjee, D.; Yogeeswari, P.; Sriram, D. Eur. J. Med.
Chem. 2010, 45, 411–422; (b) Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.;
Sriram, D. Eur. J. Med. Chem. 2010, 45, 5653–5661; (c) Karthikeyan, S. V.; Bala, B. D.; Raja,
V. P.; Perumal, S.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2010, 20, 350–353.
[11] Yeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.; Leong, S. Y.; Tan, J.;
Wong, J.; Keller-Maerki, S.; Fischli, C.; et al. J. Med. Chem. 2010, 53, 5155–5164.
[12] Crosignani, S.; Page, P.; Missotten, M.; Colovray, V.; Cleva, C.; Arrighi, J.-F.; Atherall, J.;
Macritchie, J.; Martin, T.; Humbert, Y.; et al. J. Med. Chem. 2008, 51, 2227–2243.
[13] Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7(11), 1105–1150.
[14] Wang, Y.-M.; Zhang, H.-H.; Li, C.; Fanand, T.; Shi, F. Chem. Commun. 2016, 52, 1804–1807.
[15] Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484–4517.
[16] (a) Dandia, A.; Parewa, V.; Kumari, S.; Bansal, S.; Sharma, A. Green Chem. 2016, 18,
2488–2499; (b) Dandia, A.; Jain, A. K.; Laxkar, A. K.; Bhati, D. S. Tetrahedron Letts. 2013,
54(12), 3180–3184; (c) Dandia, A.; Jain, A. K.; Laxkar, A. K. RSC Adv. 2013, 3, 8422–8430;
(d) Dandia, A.; Jain, A. K.; Laxkar, A. K.; Bhati, D. S. Tetrahedron 2013, 69(8), 2062–2069.
[17] Saravana Mani, K.; Kaminsky, W.; Rajendran, S. P. New. J. Chem. 2018, 42, 301–310.
[18] (a) Ranjith Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 12220–12231; (b) Jayashankaran, J.;
Durga, R.; Manian, R. S.; Venkatesan, R.; Raghunathan, R. Tetrahedron 2005, 61, 5595–5598;
(c) Murali, K.; Sparkes, H. A.; Rajendra Prasad, K. J. Eur. J. Med. Chem. 2018, 143, 292–305.