Synthesis of Novel Spiro[indol-2,2′-pyrroles] Using Isocyanide-Based Multicomponent Reaction

Article abstract of DOI:10.1080/00397911.2015.1071396

An efficient and facile method for the synthesis of novel spiro[indole-2,2′-pyrroles] from N-methyl-3-isatin imines, t-butyl isocyanide, and dialkyl acetylenedicarboxylate has been achieved by [3 + 2] cyclo addition reaction. All the products were purifie

Full text of DOI:10.1080/00397911.2015.1071396

This article was downloaded by: [University of Otago]
On: 30 July 2015, At: 05:28
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place,
London, SW1P 1WG
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Novel Spiro[indol-2,2′-pyrroles] Using
Isocyanide-Based Multicomponent Reaction
Venkataprasad Jallia, Suvratha Krishnamurthya, Hiroyoshi Kawasakia, Tetsuji Moriguchia &
Akihiko Tsugea
a Department of Material science, Kyushu Institute of Technology, Kitakyushu, Fukuoka,
Japan
Accepted author version posted online: 20 Jul 2015.
Click for updates
To cite this article: Venkataprasad Jalli, Suvratha Krishnamurthy, Hiroyoshi Kawasaki, Tetsuji Moriguchi & Akihiko
Tsuge (2015): Synthesis of Novel Spiro[indol-2,2′-pyrroles] Using Isocyanide-Based Multicomponent Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2015.1071396
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1071396
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any

form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHESIS OF NOVEL SPIRO[INDOL-2,2’-PYRROLES] USING
ISOCYANIDE-BASED MULTICOMPONENT REACTION
Venkataprasad Jalli1, Suvratha Krishnamurthy1, Hiroyoshi Kawasaki1, Tetsuji Moriguchi1,
Akihiko Tsuge1
1Department of Material science, Kyushu Institute of Technology, Kitakyushu, Fukuoka,
Japan
Corresponding author to Venkataprasad Jalli, E-mail: jvprasad.008@gmail.com
Abstract
An efficient and facile method for the synthesis of novel spiro[indole-2,2'-pyrroles] from
N-methyl-3-isatin imines, t-butyl isocyanide and dialkyl acetylenedicarboxylate has been
achieved by [3+2] cyclo addition reaction. All the products were purified by column
chromatography as yellow solids and confirmed with 1H NMR, 13CNMR, FAB mass, IR.
Compound 11 was further confirmed with X-ray analysis.
R2
R2
R3
R3
R1
R1
N
N
N
COOR 4
+
Benzene, reflux
10-14h
N
O
+
N
O
N
COOR 4
COOR 4
COOR 4
KEYWORDS: Spiro[indole-2,2'-pyrroles], N-methyl-3-isatin imine, [3+2] cyclo
addition, Multicomponent reaction, X-ray crystallography
1

INTRODUCTION
Isatin derivatives have several pharmacological and biological properties such as
anti-HIV,[1] anticancer,[2] anti-mycobacterial,[3] anti-inflammatory,[4] and anticonvulsant
activities.[5] Isatin found to be a prevalent motif in several alkaloids,[6] drugs,[7] dyes,[8]
pesticides and analytical reagents. Spiro compounds having both indole and pyrrole
nucleus is found to be the key structural unit in many natural products such as
Spirotriprostrain A, Spirotriprostrain B and Horsfiline, which were proven to have
anticancer activity. [9] Because of the versatile reactivity of the isatin various methods have
been developed for the synthesis of spiro [indole-pyrroles] using multi component
reactions.[10] However most of these methods were involved the C-3 carbon of isatin in the
formation of spiro heterocycle. Spiro compounds having dipyrrole namely
Amathaspiramide A, Mytraginine psuedoindoxyl as shown below was proven to have
prominent antiviral and anticancer properties.[11] Very few reports were there in the
literature for the synthesis of spiro [indole-2,2’-pyrroles] bearing spiro carbon at C-2
position. [12]
The reported method involved the multistep organic synthesis, used metal
catalysts and tedious workup procedures. As a consequence and our passion towards the
synthesis of novel heterocycles using multi component reactions, in this article we
2

investigated an efficient and simple route for the synthesis of novel spiro
[indole-2,2’-pyrroles] bearing spiro carbon at C-2 position. Previously we have reported
the novel heterocycles like benzazepine, chromeno [4, 3-b] quinolin-6-ones,
chromeno-pyrimidine-N-oxides and chromeno [4, 3-b] pyridine-2, 5-diones. [13]
OMe
Br
O
MeO
N
H
N
N
Br
H
OH
MeO
OMe
N
O
O
Amathaspiramide A
Mytraginine psuedoindoxyl
Herein we have demonstrated a novel three component [3+2] cyclo addition reaction for
the synthesis of spiro [indole-2,2’-pyrroles] using C-2 carbon atom of isatin.
RESULTS AND DISCUSSIONS
It was already reported in the literature N-methyl isatin reacts with zwitterionic
intermediates generated by the addition of isocyanides to electron withdrawing alkynes,
such as dialkyl acetylenedicarboxylate to form spirooxindoles.[14] We wanted to attempt
the similar reaction using C-2 carbon of isatin. For this purpose we have protected the C2
carbon of isatin by means of ketal formation using ethylene glycol. Now, we have
attempted a three component reaction using the protected N-methyl isatin, dimethyl
3

acetylenedicarboxylate and t-butyl isocyanide in benzene solvent. We have observed many
products in TLC. Hence, we have changed the protecting group to imine using different
anilines. We have attempted a three component reaction by blocking the reactive C-3
carbonyl carbon atom of isatin by means of forming imine with 4-chloroanilines. To
establish three component protocol, we have carried out a three component reaction using
N-methyl isatin-3-(4-chlorophenyl) imine, dimethyl acetylenedicarboxylate and t-Butyl
isocyanide in toluene solvent under refluxing conditions for 24h (Table 1, Entry. 6). After
column chromatography we have obtained the final product as a yellow solid with 60%
yield.
To optimize the reaction conditions we have screened the same reaction in different
solvents and different conditions (Table 1). The choice of the solvent played profound
effect on the reaction yields. No product formation was observed in polar solvents like
MeOH, EtOH (Table 1, Entrys. 1, 2). Halogenated solvents like CHCl3, DCM (Table 1,
Entrys. 3, 4) less yields were observed. Among all the solvents screened benzene (Table 1,
Entry. 7) was found to be the best solvent with 70% yield with less reaction time.
4

With the optimized reaction conditions in hand, we have demonstrated the reaction with
different substituted N-methyl isatin imines and dialkyl acetylene dicarboxylates as shown
in Table 2. We have attempted the reaction with various substituted N-methyl isatin
imines, reaction went smoothly yielded 40-71%.
Substrates like N-methyl isatin-3-(4-bromophenyl) imine, N-methyl
isatin-3-(4-chlorophenyl) imine, N-methyl isatin-3-(3-chlorophenyl) imine, N-methyl
isatin-3-(phenyl) imine were reacted smoothly yielded the products as yellow solids (Table
2, Entrys. 1, 2, 4, 6, 7, 8, 9, 11) with 60-71%. Substrates like N-methyl
isatin-3-(2-chlorophenyl) imine, N-methyl isatin-3-(2,4-dichlorophenyl) imine were less
reactive yielded the products as yellow solids (Table 2, Entrys. 3, 5, 10, 12) with 40-45%.
The reason for low yields of the reaction with substrates isatin-3-(2-chlorophenyl) imine,
N-methyl isatin-3-(2, 4-dichlorophenyl) imine could be steric hindrance of ortho
substitution with t-butyl group. The reaction was also successful with pentyl isocyanide
(Table 2, Entry 13). We had successfully regenerated the isatin carbonyl of final product
13(Scheme 1) using 2M aq. HCl in THF at room temperature. The detailed procedure was
provided in supporting information. However when we had attempted to hydrolyze the
final product 11 possessing t-butyl group using 2M aq.HCl and 4M aq.HCl in THF at room
5

temperature for 24 h, we did not observe any reaction. When the reaction mixture was
heated to 450C, we had observed multiple spots in TLC with very close Rf value.
All the products are novel characterized with 1H NMR, 13CNMR, FAB mass and IR.
Structure of the product 11 was further confirmed by X-ray analysis of as shown in Figure
1. Good crystals were obtained for compound 11 in DCM solvent suitable for XRD. The
molecule does not contain any hydrogen bonding from the X-ray analysis. The molecule
was crystallized in a racemic form with two molecules in the unit cell and it has triclinic
system with space group p-1.
On the basis of well-established chemistry of isocyanides II reactivity with dialkyl
acetylenedicarboxylate I, initial step was the formation of zwitter ionic species as shown in
scheme 1. This was reacted with activated N-methyl isatin imine amide carbonyl III
expected to form a spiro Oxindole IV. This undergoes iminolactones-lactam
rearrangement formed the final product spiro[indole-2,2'-pyrroles].
EXPERIMENTAL
6

All reagents were purchased from TCI and Sigma Aldrich and used without further
purification. N-methyl isatin imines were synthesized according to the procedure reported
in the literature. All the products were characterized by 1H NMR, C13 NMR, IR, and
Fab-Mass analysis. The NMR spectra were recorded on a Bruker AMX-500 MHz
instrument at room temperature in CDCl3 using TMS as an internal reference. Melting
points were determined by AS ONE instrument. X-ray data for the compound were
collected at room temperature using a Bruker Apex II KY CCD diffractometer with
graphite monochromated MoK radiation ( =0.71073Å) with ω-scan method.
Crystallographic data of 11 has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 1037350 contains the supplementary
crystallographic data for this paper
General Procedure For The Synthesis Of Spiro[Indole-2,2'-Pyrroles] (1-12):
A solution of substituted N-methyl isatin imine (1 mmol), t-Butyl isocyanide (1 mmol)
and dimethyl (or) diethyl acetylenedicarboxylate (1 mmol) in 10ml benzene were
refluxed for 10-14h. After completion of the reaction monitored by TLC, volatiles were
removed under reduced pressure. The crude reaction mixture was subjected to column
7

chromatography using (SiO2, 15% EtOAc/n-Hexane) yielded 40-71% as yellow color
solids in most reactions and some cases as yellow color semi solids were obtained.
Procedure For The Hydrolysis Of Product 13:
Compound 13 (1 mmol) was taken in 10 ml of 2M aq. HCl in THF and stirred at
room temperature for 5h. The reaction mixture was basified with 20% NaHCO3 and
extracted with EtOAC, product was isolated as yellow color solid using column
chromatography using 20% EtOAC/Hexane.
CONCLUSION
An efficient method for the synthesis of novel spiro[indole-2,2'-pyrroles] using
readily available starting materials is reported. The notable advantages of this protocol are
operational simplicity, easily available starting materials, available diversity of each
component, catalyst free and easy work procedure employed. We believed in this protocol
will help in developing novel spiro heterocyclic compounds using C-2 carbon atom of
isatin.
ACKNOWLEDGMENTS
8

We are very thankful to Kyushu Institute of Technology for their kind support and
encouragement. We also thank Dr. Kenji Yoza (Bruker AXS Japan) for experimental
assistance during final stages of the X-ray analysis.
SUPPLEMENTARY DATA
General experimental section, analytical data for compounds 1-12 and the X-ray
analysis of 11 can be accessed on the publisher’s website.
Crystallographic data of 11 has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 1037350 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data
Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336 033;
email: deposit@ccdc.cam.ac.uk].
REFERENCES
1.
(a) Bal, T. R.; Anand, B.; Yogeeswari, P.; Sriram, D. Synthesis and evaluation of
anti-HIV activity of isatin β-thiosemicarbazone derivatives. Article title. Bioorg. Med.
9

Chem. Lett. 2005, 15, 4451-4455; (b) Sriram, D.; Yogeeswari, P.; Myneedu, N. S.;
Saraswat, V. Abacavir prodrugs: Microwave-assisted synthesis and their evaluation of
anti-HIV activities. Article title. Bioorg. Med. Chem. Lett. 2006, 16, 2127-2129; (c)
Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Synthesis, antibacterial, antifungal
and anti-HIV activities of norfloxacin Mannich bases. Article title. Eur. J. Med. Chem.
2000, 35, 249-255; (d) Sriram, D.; Ratan Bal, T.; Yogeeswari, P. Aminopyrimidinimino
isatin analogues: Design of novel non- nucleoside HIV-1 reverse transcriptase inhibitors
with broad-spectrum chemotherapeutic properties. J Pharm. Pharm. Sci. 2005, 8, 565-577.
2.
Gursoy, A.; Karali, N. Synthesis and primary cytotoxicity evaluation of
3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl] hydrazono]-1H-2-indolinones.
Eur. J. Med. Chem. 2003, 38, 633-643.
3.
(a) Karali, N.; Gursoy, A.; Kandemirli, F.; Shvets, N.; Kaynak, F. B.; Ozbey, S.;
Kovalishyn, V.; Dimoglo, A. Synthesis and structure–antituberculosis activity
relationship of 1H-indole-2,3-dione derivatives. Bioorg. Med. Chem. 2007, 15,
5888-5904; (b) Feng, L. S.; Liu, M. L.; Wang, B.; Chai, Y.; Hao, X. Q.; Meng, S.; Guo,
H. Y. Synthesis and in vitro antimycobacterial activity of balofloxacin ethylene isatin
derivatives. Eur. J. Med. Chem. 2010, 45, 3407-3412; (c) Sriram, D.; Yogeeswari, P.;
10

Basha, J. S.; Radha, D. R.; Nagaraja, V. Synthesis and antimycobacterial evaluation of
various 7-substituted ciprofloxacin derivatives. Bioorg. Med. Chem. 2005, 13, 5774.
4.
Sridhar, S. K.; Ramesh, A. Synthesis and Pharmacological Activities of
Hydrazones, Schiff and Mannich Bases of Isatin Derivatives. Biol. Pharm. Bull. 2001, 24,
1149-1152.
5.
Verma, M.; Pandeya, S. N.; Singh, K. N.; Stables, J. P. Article title. Acta
Pharm. 2004, 24, 1149.
6.
(a) Batanero, B.; Barba, F. Electrosynthesis of tryptanthrin. Tetrahedron Lett.
2006, 47, 8201; (b) Deng, H.; Konopelski, J. P. Aryllead(IV) Reagents in Synthesis:ꢀ
Formation of the C11 Quaternary Center of N-Methylwelwitindolinone C Isothiocyanate.
Org. Lett. 2001, 3, 3001-3005;(c) Jahng, K. C.; Kim, S. I.; Kim, D. H.; Seo, C. S.; Son, J.
K.; Lee, S. H.; Lee, E. S.; Jahng, Y. One-Pot Synthesis of Simple Alkaloids:
2,3-Polymethylene-4(3H)-quinazolinones, Luotonin A, Tryptanthrin, and Rutaecarpine.
Chem. Pharm. Bull. 2008, 56, 607-609; (d) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.;
Takayama, H. Two new tryptamine-derived alkaloids from Chimonanthus praecox f.
concolor. Tetrahedron. Lett. 2006, 47, 3199-3202; (e) Lee, E. S.; Park, J. G.; Jahang, Y. A
facile synthesis of simple alkaloids—synthesis of
2,3-polymethylene-4(3H)-quinazolinones and related alkaloids.Tetrahedron Lett. 2003,
11

44, 1883-1886; (f) Overman, L. E.; Peterson, E. A. Enantioselective Total Synthesis of the
Cyclotryptamine Alkaloid Idiospermuline. Angew. Chem. Int. Ed. 2003, 42, 2525; (g) Sun,
C.; Lin, X.; Weinreb, S. M. Explorations on the Total Synthesis of the Unusual Marine
Alkaloid Chartelline A. J. Org. Chem. 2006, 71, 3159-3166; (h) Torres, J. C.; Pinto, A. C.;
Garden, S. J.Application of a catalytic palladium biaryl synthesis reaction, via C–H
functionalization, to the total synthesis of Amaryllidaceae alkaloids. Tetrahedron. 2004,
60, 9889-9900; (i) Trost, B. M.; Brennan, M. K. Asymmetric Syntheses of Oxindole and
Indole Spirocyclic Alkaloid Natural Products. Synthesis. 2009, 18, 3003-3025.
7.
(a) Aboul-Fadl, T.; Bin-Jubair, F. A. S.; Aboul-Wafa, O. Schiff bases of
indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis,
antitubercular activity and pharmacophoric model building.Eur. J. Med. Chem. 2010, 45,
4578-4586; (b) Gupta, L.; Sunduru, N.; Verma, A.; Srivastava, S.; Goyal, N.; Chauhan, P.
M. S. Synthesis and biological evaluation of new
[1,2,4]triazino[5,6-b]indol-3-ylthio-1,3,5-triazines and
[1,2,4]triazino[5,6-b]indol-3-ylthio-pyrimidines against Leshmaniadonovani. Eur. J. Med.
Chem. 2010, 45, 2359-2365; (c) Shibinskaya, M. O.; Lyakhov, S. A.; Mazepa, A. V.;
Andronati, S. A.; Turov, A. V.; Zholobak, N. M.; Spivak, N. Y. Synthesis, cytotoxicity,
antiviral activity and interferon inducing ability of
12

6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines. Eur. J. Med. Chem. 2010, 45, 1237; (d)
Bandekar, P. P.; Roopnarine, K. A.; Parekh, V. J.; Mitchell, T. R.; Novak, M. J.; Sinden, R.
R. Antimicrobial Activity of Tryptanthrins in Escherichia coli. J. Med. Chem. 2010, 53,
3558-3565.
8.
(a)Domenech, A.; Domenech-Carbo, M. T.; Sanchez del Rio, M.; Vazquez de
Agredos Pascual, M. L.; Lima, E. Maya Blue as a nanostructured polyfunctional hybrid
organic–inorganic material: the need to change paradigms. New. J. Chem. 2009, 33,
2371-2379; (b) Ferreira, E. S. B.; Hulme, A. N.; McNab, H.; Quye, A. The natural
constituents of historical textile dyes. Chem. Soc. Rev. 2004, 33, 329-336.
9.
(a) Osada, A. H.; Cui, C.B.; Onose, R.; Hanaoka, F. Protein kinase C inhibitors;
Structure—activity relationships in K252c-related compounds. Bioorg. Med. Chem. 1997,
5,193-196; (b) Usui, T.; Kondoh, M.; Cui, C. B.; Mayumi, T.; Osada, H. Tryprostatin A, a
specific and novel inhibitor of microtubule assembly. Biochem. J. 1998, 333, 543-548.
10.
(a) Rehn, S.; Bergman, J.; Stensland, B. The Three-Component Reaction between
Isatin, α-Amino Acids, and Dipolarophiles. Eur. J. Org. Chem. 2004, 2, 413-418; (b) Xie,
Y. M.; Yao, Y. Q.; Sun, H. B.; Yan, T. T.; Liu, J.; Kang, T. R. Facile Synthesis of
Functionalized Spiropyrrolizidine Oxindoles via a Three-Component Tandem
Cycloaddition Reaction. Molecules. 2011, 16, 8745-8757; (c) Chen, G.; Yang, J.; Gao, S.;
13

He, H.; Li, S.; Di, Y.; Lu, Y.; Hao, X. Spiro[pyrrolidine-2,3′-oxindole] derivatives
synthesized by novel regionselective 1,3-dipolar cycloadditions.Mol. Diverse. 2012, 16
151-156; (d) Poornachandran, M.; Muruganantham, R.; Ragunanthan, R. Regioselective
Synthesis of Novel Spirooxindolo and Spiroindano Nitro Pyrrolidines Through 3+2
Cycloaddition reaction. Synth. Commun. 2006, 36, 141-156;(e) Chen, H.; Wang, S. Y.;
Xu, X. P.; Ji, S. J. Facile Three-Component Synthesis of Spirooxindolepyrrololine Ring
Systems via 1,3-Dipolar Cycloaddition with 1,4-Naphthoquinone. Synth. Commun. 2011,
41, 3280-3288.
11.
(a) Morris, B. D.; Prinsep, M. R. Amathaspiramides A−F, Novel Brominated
Alkaloids from the Marine Bryozoan Amathia wilsoni. J. Nat. Prod. 1999, 62, 688-693;
(b) Takayama, H.; Kurihara, M.; Subhadhirasakul, S.; Kitajima, M.; Aimi, N.; Sakai, S. I.
Stereochemical Assignment of Pseudoindoxyl Alkaloids. Heterocycles. 1996, 42, 87-92;
(c) Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.;
Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K. Studies on
the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids:ꢀ
Discovery of Opioid Agonists Structurally Different from Other Opioid Ligan. J. Med.
Chem. 2002, 45, 1949-1956.
14

12.
Kyei, A. S.; Tchabanenko, K.; Baldwin, J. E.; Adlington, R. M. Radical
dearomatising spirocyclisations onto the C-2 position of benzofuran and indole.
Tetrahedron. Lett. 2004, 45, 8931-8934.
13.
(a) Prasad, J. V.; Prabhakar, M.; Manjulatha, K.; Rambabu, D.; Anand Solomon,
K.; Gopi Krishna, G.; Anil Kumar, K. Efficient catalyst-free Domino approach for the
synthesis of novel 2-benzazepine derivatives in water. Tetrahedron Lett. 2010, 23,
3109-3111; (b) Prasad, J. V.; Satyanarayana Reddy, J.; Ravi Kumar, N.; Anand Solomon,
K.; Gopi Krishna, G. An efficient ultrasound promoted catalyst-free protocol for the
synthesis of chromeno[4,3-b]quinolin-6-ones. J. Chem. Sci. 2011, 5, 673-679; (c) Prasad,
J. V.; Satyanarayana Reddy, J.; Anand Solomon, K.; Sravan Kumar, G.; Jagadeesh Babu,
N.; Gopi Krishna, G. Direct access to novel chromeno-pyrimidine-N-oxides via tandem
base catalyzed double nucleophilic addition/dehydration reaction. Tetrahedron Lett. 2013,
11, 1491-1494; (d) Satyanarayana Reddy, J.; Anand Solomon, K.; Prasad, J. V.; Sravan
Kumar, G.; Ramanujam Ganesh, M.; Gopi Krishna, G. Facile eco-friendly synthesis of
novel chromeno[4,3-b]pyridine-2,5-diones and evaluation of their antimicrobial and
antioxidant properties. J. Chem. Sci. 2014, 1, 187-195.
15

14.
Esmaeili, A. A.; Darbanian, M. Reaction between alkyl isocyanides and dialkyl
acetylenedicarboxylates in the presence of N-alkyl isatins: convenient synthesis of
γ-spiro-iminolactones. Tetrahedron. 2003, 59, 5545-5548.
16

Table 1. Effect of solvents for the synthesis of spiro[indole-2,2'-pyrroles] with N-methyl-3-(4-chloro phenyl)
isatin imine, dimethyl acetylenedicarboxylate and t-butyl isocyanide
Cl
Cl
N
N
N
COOMe
+
N
O
+
N
O
N
COOMe
COOMe
COOMe
Entry
Solvent
EtOH
T (0C)
80
Time (h)
24
Yield (%)
1
2
3
4
5
6
7
NRc
NR
20b
20
MeOH
DCM
80
24
60
24
CHCl3
THF
60
24
80
24
50
Toluene
80
24
60
Benzene
80
12
70
a All the reactions were performed with 1 mmol of each reactant and 10ml of solvent
b Isolated yields
c NR no reaction
17

Table 2.Synthesis of novel spiro [indole-2,2'-pyrroles] scaffolds.
R2
R2
R3
R3
R1
R1
N
N
N
N
COOR 4
+
Benzene, reflux
10-14h
N
O
O
+
N
COOR 4
COOR 4
COOR 4
Entrys N-methyl isatin Dialkyl
Yield (%)a
Spiro [indole-2,2'-pyroles]
(1-12)
imine
acetylenedicarboxylate
Cl
Cl
N
N
COOMe
COOMe
N
O
N
1
O
70
COOMe
N
COOMe
Br
Br
N
N
N
COOMe
COOMe
O
N
2
3
O
70
40
COOMe
N
COOMe
Cl
Cl
N
N
COOMe
COOMe
O
N
O
COOMe
N
N
COOMe
Cl
Cl
N
N
N
O
N
COOMe
COOMe
O
COOMe
N
4
60
COOMe
18

Cl
Cl
Cl
Cl
N
N
COOMe
COOMe
N
N
O
N
O
5
6
7
40
60
71
COOMe
COOMe
Cl
Cl
COOE t
COOE t
N
N
N
N
O
N
O
COOEt
COOEt
Cl
Cl
N
COOE t
COOE t
N
N
O
N
O
N
COOEt
COOEt
Br
Br
N
N
N
COOE t
COOE t
O
N
O
8
71
60
45
COOEt
COOEt
N
N
N
COOE t
COOE t
O
N
O
9
COOEt
COOEt
N
N
Cl
Cl
N
N
O
COOE t
COOE t
N
O
10
COOEt
COOEt
N
N
19

N
N
N
N
O
COOE t
COOE t
N
O
11
60
COOEt
COOEt
Cl
Cl
Cl
Cl
Cl
N
N
COOE t
COOE t
N
O
COOEt
N
12
O
45
70
N
COOEt
Cl
N
N
COOE t
COOE t
13c
O
N
N
O
N
COOEt
COOEt
aIsolated yield after column chromatography
cReaction was performed using pentyl isocyanide
20

Scheme 1. Hydrolysis of product 13 to retain isatin carbonyl
Cl
O
N
O
N
2M aq. HCl
O
N
N
COOE t
COOE t
THF, rt
5h
N
COOE t
COOE t
21

Scheme 2. Plausible reaction mechanism for the formation of spiro[indole-2,2’-pyrroles].
O
N
N
COOR4
COOR4
+
N
R4OOC
COOR4
N
R
II
I
III
[3+2] cyclo addition
COOR4
N
R4OOC
R4OOC
R4OOC
N
R1 R2
N
O
R =
N
R3
O
N
N
R
R
IV
intermediate
22

Figure 1. ORTEP plot for the X-ray crystal structure of 11 at 30% probability
23