One pot, three component 1,3 dipolar cycloaddition: Regio and diastereoselective synthesis of spiropyrrolidinyl indenoquinoxaline derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.05.087

A competent and highly discriminating one-pot synthesis of highly diversified novel functionalized indenoquinoxalone grafted spiropyrrolidine linked chromene-3-carbonitrile conjugates accumulating three pharmocophoric cores, heterocyclic indenoquinoxalone, pyrrolidines and chromene-3-carbonitrile in a single molecular framework by means of 1,3-dipolar cycloaddition reaction between indenoquinoxalone, proline/benzyl amine and chromene-3-carbonitrile in ethanol under classical and microwave conditions is described. The three component 1,3-dipolar cycloaddition reaction proceeds via in situ generation of azomethine ylides by the decarboxylative condensation of indenoquinoxalone with proline/benzyl amine and their selectivity towards the endo cyclic double bonds of dipolarophile (chromene-3-carbonitrile) leading to the formation of highly functionalised regio- and diastereoselective molecular hybrids. This methodology exemplifies the green chemistry protocol such as mild reaction conditions, high yields, one-pot procedure and operational simplicity.

Full text of DOI:10.1016/j.tetlet.2018.05.087

Accepted Manuscript
One pot, Three Component 1,3 Dipolar Cycloaddition: Regio and Diastereose-
lective Synthesis of Spiropyrrolidinyl Indenoquinoxaline Derivatives
Priyabrata Pattnaik, Sabita Nayak, Deepak Ranjan Mishra, Pravati Panda,
Bishnu Prasad Raiguru, Nilima Priyadarsini Mishra, Seetaram Mohapatra, N
Arjunreddy Mallampudi, Chandra Shekhar Purohit
PII:
S0040-4039(18)30725-1
https://doi.org/10.1016/j.tetlet.2018.05.087
TETL 50034
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 April 2018
28 May 2018
29 May 2018
Please cite this article as: Pattnaik, P., Nayak, S., Ranjan Mishra, D., Panda, P., Prasad Raiguru, B., Priyadarsini
Mishra, N., Mohapatra, S., Arjunreddy Mallampudi, N., Shekhar Purohit, C., One pot, Three Component 1,3 Dipolar
Cycloaddition: Regio and Diastereoselective Synthesis of Spiropyrrolidinyl Indenoquinoxaline Derivatives,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.087
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One pot, Three Component 1,3 Dipolar Cycloaddition: Regio and
Diastereoselective Synthesis of Spiropyrrolidinyl Indenoquinoxaline
Derivatives
Priyabrata Pattnaik,1 Sabita Nayak,1,* Deepak Ranjan Mishra,1 Pravati Panda,1 Bishnu Prasad
Raiguru,1 Nilima Priyadarsini Mishra,1 Seetaram Mohapatra,1 N Arjunreddy Mallampudi,2
Chandra Shekhar Purohit3
1Department of Chemistry, Ravenshaw University, Cuttack, Odisha, India
2Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
3School of Chemical Sciences, National Institute of Science education and Research,
Bhubaneswar, Odisha, India, 751 005
Email id: sabitanayak18@gmail.com
ABSTRACT
A competent and highly discriminating one-pot synthesis of highly diversified novel
functionalized indenoquinoxalone grafted spiropyrrolidine linked chromene-3-carbonitrile
conjugates accumulating three pharmocophoric cores, heterocyclic indenoquinoxalone,
pyrrolidines and chromene-3-carbonitrile in a single molecular framework by means of 1,3-dipolar
cycloaddition reaction between indenoquinoxalone, proline/benzyl amine and chromene-3-
carbonitrile in ethanol under classical and microwave conditions is described. The three
component 1,3-dipolar cycloaddition reaction proceeds via in situ generation of azomethine ylides
by the decarboxylative condensation of indenoquinoxalone with proline/benzyl amine and their
selectivity towards the endo cyclic double bonds of dipolarophile (chromene-3-carbonitrile)
leading to the formation of highly functionalised regio- and diastereoselective molecular hybrids.
This methodology exemplifies the green chemistry protocol such as mild reaction conditions,
high yields, one-pot procedure and operational simplicity.
Keywords: Spiro compounds, Nitrogenheterocycles, cycloaddition, azomethine ylides,
multicomponent reactions

Introduction
Multicomponent reactions (MCRs) are very appealing since they can be utilized as
cornerstones to prepare combinational structures. These reactions with privileged properties
and have received significant interest in organic synthesis and regarded as the green tool box
for the construction of nitrogen containing five membered heterocycles in one-pot, which
constitute the central skeleton of numerous bioactive molecules as well as natural products.1,2
These reactions enable uniquely powerful one-step access to products of high complexity and
diversity, containing a structure or substructure of all starting materials. MCRs, besides
facilitating expedient creation of chemical libraries of structurally diverse drug-like
compounds, play a key role in combinatorial and diversity-oriented synthesis.3,4
Synthesis of polycyclic compounds with pyrrolidine and pyrrolizidine rings has attracted the
attention of synthetic organic chemists because of their highly pronounced biological
activities.5-8 The 1,3-dipolar cycloaddition (1,3-DC) reactions of azomethine ylides with
olefin is an elegant and efficient methodology for regio- and stereoselective synthesis of
structurally complex pyrrolidine and spiropyrrolidine heterocycles from relatively simple
precursors. Nitrogen containing heterocycles constructed through 1,3-dipolar cycloaddition of
azomethine ylides generated in situ from the decarboxylative condensation of carbonyl
compounds with α-amino acids have been well documented and are widely applied in organic
synthesis for the construction of important cluster of significant bioactive compounds such as
S33084, S33138, SAR-405838, RO2468, DS-3032b and Flduxoin shows MDM-2 inhibitory
activities.9-12 In recent years, spiro indenoquinoxaline-pyrrolidines, prepared from 1,3-DC
between azomethine ylides with olefinic dipolarophiles, have attracted the increasing
interests due to their potentially pronounced biological activities such as acetylcholine
esterase inhibitory activity, anticancer, antioxidant, and antitubercular properties.13-16 The
abundance of natural and unnatural bioactive spiroquinoxaline pyrrolizine derivatives have
encouraged the design and synthesis of novel spirocyclic indenoquinoxaline with relevant
and notable medicinal properties.
.
Figure 1. Some important bioactive pyrrolidine containing molecules

On the other hand, pyrans and chromenes are important classes of heterocycles because of
their core fragments are incorporated in a large variety of natural products and biologically
active compounds. They are of considerable interest as they display a broad range of
pharmaceutical properties such as anti-tumor, anti-cancer, anti-microbial, anti-fungal and
anti-HIV character.17,18Among the different types of chromenes, we focused on 3-cyano-2H-
chromene scaffolds due to their interesting biological activities, such as antimicrobial and
antioxidant and anticancer.19, 20
Literature survey reveals a large number of reports on 1,3-dipolar cycloaddition reaction of
indenoqunioxaline derivatives with nitro olefins, α, β-unsaturated carbonyl, α, β-unsaturated
ester and α, β-unsaturated nitrile compounds etc.13-16 Despite of these recent advances, to the
best of our knowledge
a
stereoselective 1,3dipolar cycloaddition reaction of
indenoqunioxalone derivatives with cyclic α, β-unsaturated nitrile has not yet been reported.
As continuation of our interest in developing new methodology for the synthesis of highly
functionalized spiro compounds and chromene-3-carbonitrile containing heterocycles we
have reported a three component 1,3-dipolar cycloaddition reaction to form spiropyrrolidinyl
indenoquinoxaline derivatives.
Herein we report the first, efficient, atom economic, high yielding, regio- and
diasteroselective multicomponent protocol for facile synthesis of highly substituted spiro-
indenoquinoxaline pyrrolizine fused chromene-3-carbonitrile scaffold by the reaction of
indenoquinoxalone, proline/benzylamine and chromene-3-carbonitrile in ethanol under
conventional heating/microwave irradiation. It is interesting that regio- and sterospecifically a
single product was obtained.
Results and Discussion
Initially the 2H-chromene-3-carbonitrile derivatives 3(a-i) utilised for 1,3-dipolar
cycloaddition were prepared by the treatment of acrylonitrile 2 with salicylaldehydes 1(a-i)
in the presence of DABCO under solvent free conditions in a single step following oxa-
Michael-Aldol reaction. Synthesized 2H-chromene-3-carbonitrile derivatives were
characterised by 1H, 13C and HRMS spectra (Scheme 1).21
Scheme 1. Synthesis of 2H-chromene-3-carbonitriles

The long-term goal of our research is to expand the useful repertoire of chromene-3-
carbonitrile, which are important as complexity-generating tools in both combinatorial and
diversity-oriented synthesis. Having 2H-chromene-3-carbonitriles in hand, the one-pot
sequential three-component reaction involving, indenoquinoxalone (4), L-proline(5) and
chromene-3-carbonitrile (3a) were investigated to establish the feasibility of the strategy and
optimize the reaction conditions. The reaction was examined by taking an equimolar reaction
mixture in different solvents such as methanol, ethanol, acetonitrile, benzene, toluene and
H2O at different temperature ranging from room temperature to refluxing. As shown in table
1, ethanol as solvent provided higher yield 70% (table 1, entry 5) in case of conventional oil
bath heating. Therefore, ethanol and refluxing condition were chosen as optimal conditions
for all further reactions. The reaction afforded highly substituted spiroproduct 6a as single
diastereoisomer in 70% yield after recrystallisation.
Scheme 2. Model reaction
Table 1: Solvent and temperature for the synthesis of spiroindenoquinoxaline pyrrolidine
fused chromene-3-carbonitrile
Time
(h)
Yield
(%)
Temp
(oC)
Time
(min)
Yield
(%)a
Entry
Solvent
Methanol
Ethanol
CH3CN
Methanol
Ethanol
CH3CN
Temp
r.t
MW
50W
1
2
3
4
5
6
12h
12h
12h
7
n.r
n.r
40 oC
40 oC
40 oC
80 oC
80 oC
80 oC
10
10
10
10
10
10
20%
30%
20%
58%
90%
r.t
50W
r.t
n.r
50W
80 oC
80 oC
80 oC
40%
70%
100W
100W
100W
6
7
35%
50%
Complx
mixture
Complx
mixture
Complex
mixture
Complex
mixture
7
Benzene
100 oC
12
100W
100 oC
10
8
9
Toluene
H2O
100 oC
100 oC
12
12
100W
100W
100 oC
100 oC
10
10
n.r
n.r
aIsolated yields
In order to reduce the reaction time interval as well as to enhance the yield of spiro
cycloadducts, the reactions were subsequently investigated under microwave irradiation. This

technique is a valuable alternative to conventional heating, introduces energetic radiations in
to the reaction and there by enhances the rate and yields of the reaction and simultaneously
decreases the reaction time. Similar to the conventional heating reactions, an equimolar
reaction mixture in different solvents such as methanol, ethanol, acetonitrile, benzene,
toluene and H2O were subjected to the microwave irradiation. It has been observed that
o
among all the solvents, in ethanol at 100W/80 C for 10 mins, excellent yield of the product
was formed. Increasing the time interval more than 10 mins leads to decrease in the yield of
the product. To our delight in microwave irradiation excellent yield of the product formation
was observed as well as the reaction time period reduced from hours to minutes which
encouraged us to move further.
To check the generality as well as the effectiveness of the developed protocol, a number of
chromene-3-carbonitrile derivatives having substituents such as methoxy, ethoxy, napthyl,
halogens were reacted with indenoquinoxalone and L-proline/benzyl amine using ethanol
under reflux conditions. All of them underwent the reaction smoothly affording the
corresponding spiro cycloadducts. The yields were not improved further even on raising the
temperature over reflux temperature in a sealed tube. The results obtained for both
conventional as well as microwave irradiation methods are summarised in table 2, which
clearly shows that microwave irradiation led to an enhancement in the rate as well as yield of
the products (78-90%) over the conventional thermal method (58-75%).
The 1H NMR spectrum of compound 6a (table 2, entry 1) exhibited a characteristic singlet at
δ 4.63 ppm corresponding to benzylic Ha proton attached to the chromane core and also the
Hb proton of the proline ring appeared as multiplet at δ 4.50 ppm, the 2H-protons of the
chromene-3-carbonitrile appeared as multiplets at 5.27-4.52 ppm in the cycloadduct 6a which
was appeared as singlet in 2H-chromene-3-carbonitrile 3a at 4.82 ppm and all other protons
appeared in respective positions clearly indicates the formation of spiropyrrolidinyl
indenoquinoxalines. Furthermore the characteristic singlet at δ 4.63 ppm corresponding to Ha
proton proved the formation of regio isomer 6a. If the other regioisomer has formed, the Ha
1
proton would have appeared as a multiplet in the H NMR spectrum. The carbon attached to
Ha and Hb protons resonates at 52.7 and 67.8 ppm, the 2-C and 3-C chromene-3-carbonitrile,
-CN and spiro carbon of the cycloadduct appeared at 68.6, 45.0, 119.0 and 75.1 ppm
respectively in 13C NMR spectrum. The three pyrrolidine methylene carbon resonates at 25.6,
27.5 and 48.0 ppm and was confirmed by DEPT-135 NMR spectroscopy. These observed
chemical shift values are in good agreement with the structure of the compound 6a.
Furthermore, the presence of molecular ion peak at m/z 443.1869 (M+1) in the mass
spectrum confirmed the formation of the cycloadduct 6a. The regio- and sterochemical
outcome of the cycloaddition reaction was determined by 2D NMR spectroscopy (COSY and
NOESY). Further extension of this protocol was carried out to delineate the scope of different
chromene-3-carbonitrile 6(b-i) with azomethine ylides generated in situ from
indenoquinoxalone and proline 5/ or benzyl amine 7 under optimised reaction conditions.
These reactions successfully proceeded through [3+2] cycloaddition to produce the
corresponding spiro indenoquinoxaline pyrrolidine fused chromene-3-carbonitrile 6(a-i) and
8(a-h) in good to excellent yields (Table 2).

Scheme 3. Synthesis of compound 6(a-i) and 8(a-h)
Table 2: Synthesis of spiro indenoquinoxaline pyrrolidine fused 3-carbonitrile
Microwave Method
(EtOH, 80 oC, 100W)
Conventional Method
(EtOH, 80 oC)
Producta
Yield(%)b
Yield(%)b
Time (mins)
Entry
Time (h)

b
a The products were characterised by NMR, IR and Mass spectroscopy. Isolated yield after
purification
As shown in table 2, this protocol could be applied to a large range of different substituted
aromatic rings of 3-cyano-chromene including electron-withdrawing groups (such as chloro
and bromo groups) and electron donating groups (such as methoxy and ethoxy groups) as
well as naphthalene ring. In all cases the reaction proceeded smoothly and only a single
diasteroisomer of spiro-pyrrolidines were afforded in good to excellent yields (78-90%).
From table 2, it is cleared that product yields were dependent on the substituents and their
positions at the aromatic ring of the 3-cyano-chromene. Presence of electron donating groups
gave 85-90% yield (table 2, entries 2-4). However in case of 7-methoxy-3-cyano-chromene
6c (entry 3) excellent yields were obtained over 6b and 6d. Halogenated 3-cyano-chromene
derivatives were also well tolerated and gave better yield of the product 6(e-g) (86-89%).
Presence of halogens such as –Cl and –Br at 6-position of the chromene ring 6e and 6g gave a
slightly better yield (entries 5 & 7, 89%) in comparison to dichlorochromene-3-carbonitrile 6f
(entry 6, 86%). However when both the –I and +I-effect groups such as –Br and –OMe were
present in the aromatic ring of chromene-3-carbonitrile 6h a slight decrease in the yield of the
product formation was observed (entry 8, 80%). Excitingly, naphthalene derivatives 6i
performed exceptionally well to afford excellent yield (entry 9, 90%). In order to extend the
substrate scope of this protocol proline was replaced by pipecolic acid, phenyl alanine and
benzylamine. Unfortunately, in case of pipecolic acid and phenyl alanine, the desired product
was not formed, starting materials remains unreacted even after long period of heating. Only
in case of benzylamine we would able to get the desired product with excellent
diastaeroselectivity which encouraged us to move further. Our experimental results showed
that, a slight decrease in yield of the product formation was observed in case of benzyl amine
in comparison to proline 8(a-h) (entries 10-17, 78-83%). No product formation was observed
in case of napthal-3-carbonitrile when the amine part is changed from proline to benzyl amine
in conventional oil bath heating as well as under microwave irradiation which might be due
to steric effect of the bulky phenyl group. To further probe the usefulness of this single-step
reaction, we examined whether it was compatible with synthetically useful 2-oxo-2H-
chromene-3-carbonitrile as dipolarophile. Regretfully, the expected product is not formed. In
order to further expand the scope of this protocol, indenoquinoxalone was replaced by
ninhydrin, to react with proline/pipecolic acid/benzyl amine/phenyl alanine and chromene-3-
carbonitrile, but we failed to get the cycloaddition product.
The identification of the spiro indenoquinoxaline pyrrolidines 6(a-i) and 8(a-h) was
unequivocally ascertained by their 1H, 13C NMR, IR and HRMS spectra.
A reasonable mechanism of the reaction is given in the scheme 4. From mechanistic
considerations, it is believed that the dipolar cycloaddition reaction of azomethine ylide
generated in situ by the decarboxylative condensation reaction of indenoquinoxalone with
proline to dipolarophile (chromene-3-carbonitrile), could proceed by two possible paths, A or
B, leading to two corresponding regioisomers, as shown in scheme 4. In fact, the reaction
proceeded exclusively by path A, in which the electron-rich carbon of the azomethine ylide
added to the β-carbon of the chromene-3-carbonitrile, resulting a single regioisomer 6a, while

no trace of another regioisomer 6a’’ was detected. Furthermore, this reaction was also found
to be diasteroselective. The 1,3-dipolar cycloaddition of the azomethine ylide with chromene-
3-carbonitrile could proceed by two methods a or b, as shown in scheme 4, but only a single
endo product was obtained (method a), where as exo isomer, such as 6a’ resulting from
method b was not observed. The formation of the regio- and diastereoisomer 6a via method a
is more favorable due to the presence of a secondary orbital interaction (SOI) occurring
between the nitrile group of dipolarophile 3a with those of the azomethine ylide as shown in
scheme 4. This kind of SOI is not possible in method b. Hence, the reaction proceeded via
method a only, leading to regio- and diastereoselective spiropyrrolidinyl indenoquinoxalines
products. The stereochemistry of this cycloaddition was ascertained by 2D NMR (NOESY)
and in which both the protons Ha and Hb are present in trans- orientation. The single crystal
X-ray of compound 6c confirmed both Ha and Hb protons are in trans- orientation which is
shown in figure 2.
Figure 2. ORTEP diagram of compound 6c

Scheme 4. Proposed mechanism for the formation of 6a

Conclusion
In summary, we have developed an operationally simple, autocatalytic, one-pot, three-
component reaction to synthesize new spiro indenoqunoxaline pyrrolidine by employing
indenoquinoxalone, proline/benzyl amine and chromene-3-carbonitrile. This is the first report
of the preparation of the title compounds by conventional as well as under microwave
irradiation in a highly regio- and steroselective manner. This multicomponent reaction offers
high yield, short reaction time with simple experimental procedure and formation of a single
regio- and sterospecific product. Further the biological activities of the synthesized
compounds are currently under investigation.
Experimental Section
General
Melting points were recorded on SMP10 digital melting point apparatus using open capillary
tubes and uncorrected. IR spectra were recorded on a Nicolet FT-IR500 spectrophotometer
1
using KBr. H NMR spectra were recorded on 400 MHz (100 MHz for 13C NMR) JEOL
NMR spectrometer with CDCl3 as solvent and tetramethylsilane (TMS) as internal standard.
Chemical shifts were reported in parts per million (ppm, δ scale) downfield from TMS at 0.00
1
13
ppm and referenced to the CDCl3 at 7.26 ppm (for H NMR) or 77.00 ppm (for C NMR).
HRMS analysis were conducted on a Brucker micro-TOF-Q-MS analyser. All reagents and
solvents used in this study were commercially available (from Sigma-Aldrich) and were used
without further purification.
Typical experimental procedure
Procedure for the synthesis of chromene-3-carbonitrile 3(a-i)
A neat reaction was carried out by taking substituted salicylaldehydes 1(a-i) (1.0 mmol),
DABCO (0.2 mmol) and acrylonitrile 2 (1.0 mmol) in one pot and stirred in room
temperature to 40 oC for 4-5 h. The progress of the reaction was monitored by TLC checking.
After completion reaction mixture was diluted with water and extracted with EtOAc. The
organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by general silica gel (100-200 mesh) column
chromatography using ethyl acetate/hexane to furnish the pure compound 3(a-i) in 65-93%
yield. All compounds were characterized through IR, NMR and Mass spectral data.
Compound 3a
o
Yield: 93%; Straw yellow solid; m.p.: 53-55 C; IR (KBr, cm-1): 3436, 2215, 1606, 1484,
1459, 1211, 1150,1037, 757; 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.30-7.25 (m, 1H, ArH),
7.18 (s, 1H, CH), 7.12-7.09 (dd, J = 4.0 Hz, 8.0 Hz, 1H, ArH), 6.99-6.95 (m, 1H, ArH), 6.87
13
(d, J = 8.0 Hz, 1H, ArH), 4.82 (s, 2H, CH2); C NMR (CDCl3, 100 MHz): δ (ppm) 154.2,

138.8, 132.7, 128.4, 122.4, 120.0,116.5, 116.4, 103.2, 64.2; HRMS (ESI+): m/z calculated for
C10H7NO [M + H]+: 157.05276; found: 157.05265.
Procedure for the synthesis of spiropyrrolidinyl indenoquinoxaline
derivatives 6(a-i) and 8(a-h)
Procedure A: L-Proline/benzyl amine (1 mmol) and chromene-3-carbonitrile (1 mmol) were
added to a solution of indenoquinoxalone (1 mmol) in EtOH (2 mL) and the mixture were
refluxed for 2-12 h in a sealed tube. The progress of the reaction was monitored by TLC. On
completion of the reaction, the reaction mixture was cooled to room temperature and the solid
mass precipitated out was filtered off followed by washing with cold ethanol to obtain a
crude product, which was further purified by recrystallization from EtOH:CHCl3 (9 : 1)
without carrying out column chromatography to obtain pure compound 6(a-i) as a single
diastereoisomer (58–75%).
Procedure B: L-Proline/benzyl amine (1 mmol) and chromene-3-carbonitrile (1 mmol) were
added into a sealed 10 mL glass tube containing a solution of indenoquinoxalone (1 mmol) in
EtOH (2 mL) and the mixture were irradiated under microwave irradiation (100 W power) at
80 oC for 5–10 minutes. The progress of the reaction was monitored by TLC. On completion
of the reaction, the reaction mixture was cooled to room temperature, whereupon a solid mass
precipitated out. The precipitate was filtered off followed by washing with cold ethanol to
obtain a crude product which was purified just by recrystallization from EtOH:CHCl3 (9:1)
without carrying out column chromatography to obtain pure compound 8(a-h) as a single
diasteroisomer (78–90%).
Compound 6a
Yellow solid; m.p.: 199-201oC; IR (KBr, cm-1): 3434,3052, 2921, 2852, 2227, 1712, 1577,
1488, 1450, 1340, 1307, 1228, 1103, 1051, 958, 761, 669, 574; 1H NMR (CDCl3, 400 MHz):
δ (ppm) 8.25 (d, J = 8.0Hz, 1H, ArH), 8.00-7.97 (m, 1H, ArH), 7.92-7.88 (m, 1H, ArH),
7.87-7.86 (m, 1H, ArH), 7.74-7.57 (m, 4H, ArH), 6.78-6.77 (m, 2H, ArH), 6.32-6.28 (m, 1H,
ArH), 5.93(d, J = 8.0Hz, 1H, OCH2), 5.26 (d, J = 8.0Hz, 1H, OCH2), 4.63 (s, 1H, PhCH),
4.55-4.48 (m, 2H, OCH2, NCH), 3.06 (q, J = 8.0Hz, 1H,CH2), 2.63 (td, J = 4.0Hz, J = 8.0Hz,
1H, CH2), 2.36-2.18 (m, 3H, CH2), 2.12-1.87 (m, 1H, CH2); 13C NMR (CDCl3, 100 MHz): δ
(ppm) 161.6, 153.8, 153.2, 146.2, 141.7, 140.8, 138.2, 132.1, 130.3, 129.6, 129.4, 128.8,
128.8, 128.1, 126.1, 125.8, 122.7, 121.6, 119.0, 117.3, 75.1, 68.6, 67.8, 52.7, 48.0, 45.0, 27.5,
25.6; HRMS(ESI+): m/z calculated forC29H22N4O[M+H] +: 443.1866; found: 443.1869.
Compound 8a
o
Straw yellow solid; m.p.: 247-249 C; IR(KBr, cm-1): 3442, 3261, 2973, 2231, 1710, 1581,
1490, 1457, 1338, 1307, 1228, 1091, 1056, 952, 856, 620, 584; 1H NMR (CDCl3, 400 MHz):
 (ppm) 8.19-8.14 (m, 2H, ArH), 7.98 (d, J = 4.0 Hz, 1H, ArH), 7.88 (d, J = 12.0 Hz, 1H,
ArH), 7.80-7.76 (m, 3H, ArH), 7.68-7.57 (m, 3H, ArH), 7.50 (t, J = 8.0 Hz, 2H, ArH), 7.44-
7.43 (d, J = 8.0 Hz, 1H, ArH), 6.77 (d, J = 4.0Hz, 2H, ArH), 6.34-6.30 (m, 1H, ArH), 6.04 (d,

J = 8.0Hz, 1H, ArH), 5.67 (d, J = 3.6 Hz, 1H, NCHPh), 5.10 (d, J = 12.0Hz, 1H, OCH2), 4.52
(s, 1H, PhCH), 4.44 (d, J = 12.0 Hz, 1H, OCH2), 2.55-2.54 (m, 1H, NH); 13C NMR (CDCl3,
100 MHz):  (ppm) 163.3, 154.2, 153.4, 149.1, 141.7, 140.8, 137.8, 137.0, 132.9, 130.3,
129.7, 129.4, 129.0, 128.9, 128.7, 128.2, 127.7, 126.6, 125.1, 122.2, 121.9, 120.9, 119.6,
+
117.4, 71.4, 67.1, 65.2, 52.8, 49.1; HRMS(ESI+): m/z calculated for C32H22N4O[M+K] :
517.1425; found: 517.1429.
Acknowledgement
SN and SRM are thankful to CSIR, New Delhi [02(0218)/14/EMR-II], DRDO, New Delhi
ERIP/ER/1203083/M/01 for providing research grant and also thankful to DST-FIST, New
Delhi for providing NMR facility.
References
1. Ganem, B. Acc Chem Res. 2009, 42, 463–472.
2. Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300–1308.
3. Khan, M. M.; Yousuf, R.; Khan, S.; Shafiullah, RSC Adv. 2015, 5, 57883-57905.
4. Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234–
6246.
5. Sirisha, N.; Raghunathan, R. J. Chem. Pharma. Res. 2013, 5, 382-389.
6. Kathiravan, S.; Raghunathan, R. Ind. J. Chem. 2008, 47B, 1117-1119.
7. Sarrafi, Y.; Hamzehlouian, M.; Alimohammadi, K.; Khavasi, H. R. Tetrahedron Lett.
2010, 51, 4734–4737
8. Huang, C.-Y.; Kuo, C.-W.; Kavala, V.; Yao, C.-F. Eur. J. Org. Chem. 2016, 2720–
2734.
9. Rao, J. N. S.; Raghunathan, R. Tetrahedron Lett. 2013, 54, 6568-6573.
10. Rao, J. N. S.; Raghunathan, R. Tetrahedron Lett. 2015, 56, 2276-2279.
11. Nayak, S.; Mishra, S. K.; Bhakta, S.; Panda, P.;
Baral, N.; Mohapatra, S.;
Purohit, C. S.; Satha. P. Lett. Org. Chem. 2016, 13, 11-21.
12. Gollner, A.; Rudolph, D.; Arnhof, H.; Bauer, M.; Blake, S. M.; Boehmelt, G.;
Cockroft, X.-L.; Dahmann, G.; Ettmayer, P.; Gerstberger, T.; Karolyi-Oezguer, J.;
Kessler, D.; Kofink, C.; Ramharter, J.; Rinnenthal, J.; Savchenko, A.; Schnitzer, R.;
Weinstabl, H.; Weyer-Czernilofsky, U.; Wunberg, T.; McConnell, D. B. J. Med.
Chem. 2016, 59, 10147−10162.
13. Akondi, A. M.; Mekala, S.; Kantam, M. L.; Trivedi, R.; Chowhan, L. R.; Das, A. New
J. Chem., 2017, 41, 873-878.
14. Mani, K. S.; Kaminsky, W.; Rajendran, S. P.; New J. Chem., 2018, 42, 301-310.
15. Barkov, A. Y.; Zimnitskiy, N. S.; Kutyashev, I. B.; Korotaev, V. Y.; Sosnovskikh, V.
Y. Chemistry of Heterocyclic Compounds 2017, 53, 1315–1323.
16. (a) Li, M.; Gong, F.-M.; Wen, L.-R.; Li, Z.-R. Eur. J. Chem. 2011, 3482-3490; (b)
Velikorodov, A. V.; Stepkina, N. N.; Shustova, E. A.; Ionova, V. A. Russ. J. Org.
Chem. 2015, 51, 674-679; (c) Barkov, A. Y.; Zimnitskiy, N. S.; Korotaev, V. Y.;
Kutyashev, I. B.; Moshkin, V. S.; Sosnovskikh, V. Y. Chemistry of Heterocyclic

Compounds 2017, 53, 451–459; (d) Barkov, A. Y.; Zimnitskiy, N. S.; Kutyashev,
I. B.; Korotaev, V. Y.; Sosnovskikh, V. Y. Chemistry of Heterocyclic Compounds
2017, 53, 1315–1323; (e) Barkov, A. Y.; Zimnitskiy, N. S.; Kutyashev, I. B.;
Korotaev, V. Y.; Sosnovskikh, V. Y. Chemistry of Heterocyclic Compounds
2018, 54, 43–50; (f) Filatov, A. S.; Knyazev, N. A.; Ryazantsev, M. N.; Suslonov, V.
V.; Larina, A. G.; Molchanov, A. P.; Kostikov, R. R.; Boitsov, V. M.; Stepakov, A. V.
Org. Chem. Front., 2018, 5, 595-605.
17. Dammak, L.; Kammoun, M.; Allouche, N.; Ammar, H.; Abid, S. Org. Commun.
2017, 10, 32-39.
18. Mallikarjuna, R.; Yedukondalu, M.; Varma, P. S. S. D.; Vandana, Manidhar, D. M.
Der Pharma Chemica, 2015, 7, 117-129.
19. Keerthy, H. K.; Garg, M.; Mohan, C. D.; Madan, V.; Kanojia, D.; Shobith, R.;
Nanjundaswamy, S.; Mason, D. J.; Bender, A.; Basappa, Rangappa, K. S.;
Koeffler, H. P. PLoS One 2014, 9, e107118.
20. El-Maghraby, A. M. Org. Chem. Int. 2014, 4, 1-6.
21. Alami, M.; Peyrat, J.-F.; Belachmi, L.; Brion, J.-D. Eur. J. Org. Chem. 2001, 4207-
4212.

Highlights
o Efficient synthesis of spiropyrrolidinylindenoquinoxalines under mild
condition.
o Multiple stereogenic centres were created in a single step by MCR.
o Products are isolated in pure form without column chromatography.
o Highly regio and diastereoselective method.
o Large substrates scope may find application in drug discovery program.