Regioselective three component domino synthesis of polyhydrospiro[indoline-3,3'-pyrrolizine]-2-one via [3+2] Cycloaddition reaction

Article abstract of DOI:10.14233/ajchem.2019.21737

In present work, we have reported the synthesis and characterisation of novel hexahydrospiro[indoline-3,3′-pyrrolizine]-2-one derivatives in good to excellent yields via [3+2] cycloaddtion reaction in regioselective manner. These compounds were synthesized via multicomponent reaction of substituted 3-cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-one, isatin, L-proline at room temperature. All the synthesized hexahydrospiro molecules were characterized by ¹H and ¹³C NMR, IR spectra, mass spectra and elemental analysis. Regioselectivity in synthesized molecules were also explained on the basis of secondary orbital interactions. A simple and facile methodology is developed which has great importance in synthetic chemistry.

Full text of DOI:10.14233/ajchem.2019.21737

Asian Journal of Chemistry; Vol. 31, No. 3 (2019), 613-616
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21737
Regioselective Three Component Domino Synthesis of
Polyhydrospiro[indoline-3,3'-pyrrolizine]-2-one via [3+2] Cycloaddition Reaction
1,*
2
3
VISHWA DEEPAK TRIPATHI , AKHILESH KUMAR SHUKLA and HASAN SHAMRAN MOHAMMED
1Department of Chemistry, M.K. College (Lalit Narayan Mithila University), Darbhanga-846003, India
2Department of Applied Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow-226025, India
3Department of Chemistry, Science College, Al-Qadisiyah University, Al-Qadisiyah, Iraq
*Corresponding author: E-mail: vishwadeepak66@gmail.com
Received: 3 October 2018;
Accepted: 12 November 2018;
Published online: 31 January 2019;
AJC-19255
In present work, we have reported the synthesis and characterisation of novel hexahydrospiro[indoline-3,3′-pyrrolizine]-2-one derivatives
in good to excellent yields via [3+2] cycloaddtion reaction in regioselective manner. These compounds were synthesized via multicomponent
reaction of substituted 3-cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-one, isatin, L-proline at room temperature. All the synthesized
hexahydrospiro molecules were characterized by 1H and 13C NMR, IR spectra, mass spectra and elemental analysis. Regioselectivity in
synthesized molecules were also explained on the basis of secondary orbital interactions. A simple and facile methodology is developed
which has great importance in synthetic chemistry.
Keywords: Spiropyrrolidine, Dehydroacetic acid, Isatin, Multicomponent reaction, Cycloaddition.
substituted pyrrolidines derivatives [9,10]. Enhancing the effici-
ency and manoeuvrability of reaction is a challenge in organic
synthesis. For a molecule with fascinating structure and excellent
pharmacological properties always promotes synthetic chemists
to develop easy and ecofriendly synthesis [11]. Spirocyclic systems
containing one carbon atom common to two rings are struc-
turally interesting and asymmetric characteristic of the molecule
due to the chiral spiro carbon which is one of the important criteria
of the biological activities [12,13]. The presence of sterically
constrained spiro structure in various natural products also
adds to the interest in the investigations of spiro compounds [14].
The spirooxindole ring system forms the core structure of many
pharmacological agents and alkaloids [15]. For example, spiro-
tryprostatin (Fig. 1), a natural product isolated from the fermen-
tation of Aspergillus funigatus, has been identified as a novel
inhibitor of microtubule assembly [16]. Natural product isoptero-
podine [17] (Fig. 1) has been shown to modulate the function
of muscarinic and serotonin receptors. It has been observed
that incorporation of more than one bioactive heterocyclic
moiety into a single framework may result into the production
of novel heterocycles with enhanced bioactivity [18-20]. Spiro-
oxindoles have been reported to behave as aldose reductase,
INTRODUCTION
In the past several years, significant advances have been
achieved on the development of new synthetic methods to access
spiroindole derivatives. Spiro compounds with attached indole
moiety having all-carbon quaternary stereogenic center has
attracted synthetic organic chemists due to its fascinating struc-
ture and biological importance [1-3]. These polyhydro hetero-
cyclic compounds are important targets among synthetic as
well as medicinal chemist due to its wide range of pharmaco-
logical properties. Spiroindoles and their derivatives have facile
structural similarity the core unit of many naturally occurring
molecules that possess significant biological activities, which
include spasmolitic, diuretic, anticoagulant, anticancer, and
antianaphylactic activities [4].
Therefore, a number of protocols have been developed to
synthesize these structural frameworks via cycloaddition reaction
[5]. The [3+2] cycloadditions have special place in synthetic
chemistry as well for theoretical chemist because it constitutes
one of the most fundamental reactions for regioselective constru-
ction of 5-membered heterocyclic compounds [6-8]. The reaction
of azomethine ylides with various dipolarophils forms highly
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614 Tripathi et al.
Asian J. Chem.
O
General procrdure for synthesis of compounds (4a-y)
(method A): Isatin (147 mg, 1.0 mmol), L-proline ( 115 mg,
1 mmol) and chalcone derivatives (1 mmol) was taken in 50 mL
round bottom flask follwed by the addition of 10 mL of ethanol.
Reaction mixture was allowed to stir at room temperature. The
progress of reaction was monitored by TLC.After completion
of rection, solvent was evaporated under vaccum and poured
in ice-water. Solid residue was filtered off and recrystallized in
ethanol (Scheme-II).
NH
O
MeO
N
N
O
O
O
N
H
N
H
N
O
Elacomine
Horsfiline
Spirostatin B
R1
O
O
H
O
H
R2
O
N
HO
O
NH
O
OH
O
O
N
N
R3
H
R1
O
O
O
H
N
H
O
Alstonisine
Room
Temperature
Stirring
O
O
R1
Designed bio-siosteric
spiropyrrolidine
Isopterodine
R2
N
HO
O
3(a-y)
Fig. 1. Representatives of spiroindole containing compounds
O
Ethanol
COOH
R2
O
O
N
R3
O
O
N
polio virus and rhino virus 3C-proteinase inhibitors [21]. Inspired
from these excellent pharmacological properties and structurally
complex nature of these spiro compounds, here we wish to report
some new bioisosetric analogues of natural spiropyrrolidines
via [3+2] cycloaddition reaction.
N
R3
H
4(a-y)
1
2
Scheme-II: Synthesis of novel hexahydrobenzo[b][1,8]naphthyridines
2′-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-carbonyl)-
1′-(3-methoxyphenyl)-1-propyl-1′,2′,5′,6′,7′,7a′-hexahydro-
spiro[indoline-3,3′-pyrrolizin]-2-one (4a): White solid; m.p.
180 ºC; IR (KBr, νmax, cm-1): 3621, 3020, 2971, 1720, 1604,
1216, 1043. 1H (300 MHz, CDCl3): δ 10.97 (s, 1H,), 7.21 (s, 1H),
7.20-7.04 (m, 4H), 6.80-6.72 (m 3H,), 5.68 (s, 1H), 4.91 (d,
1H, J = 9.4 Hz), 4.57 (t, 1H, J = 8.14 Hz), 4.48 (t, 1H, J = 9.9
Hz), 3.79 (s, 3H), 3.64 (t, 2H, J = 7.5 Hz), 2.58 (t, 1H, J = 7.62
Hz,), 2.28 (s, 3H), 2.14-1.73 (m, 5H), 1.22-1.15 (m, 2H), 1.00
(t, 3H, J = 4.3 Hz). 13C NMR (75MHz, CDCl3): δ 13.7, 22.5,
23.2, 33.4, 38.9, 41.6, 49.7, 51.2, 55.8, 63.4, 65.8, 72.3, 101.5,
103.1, 111.5, 114.8, 116.1, 117.2, 118.4, 119.4, 122.5, 126.6,
129.2, 131.9, 134.4, 140.9, 144.3, 157.8, 163.2, 184.7, 204.4;
MS (ES): m/z (%) 529.1(100) [M+1]+. Anal. calcd. (found) %
for C31H32N2O6: C, 70.44 (70.39); H, 6.10 (6.05); N, 5.30 (5.20).
EXPERIMENTAL
All the reactions were carried out at room temperature,
under ultrasound and microwave condition. Unless otherwise
specified, all the reagents were purchased from Sigma-Aldrich
Chemical Co, Lancaster and used directly without further any
purification. NMR spectra were obtained using Brucker DRX
300MHz spectrometer. Chemical shifts (δ) are given in ppm
relative to TMS, coupling constants (J) in Hz. IR spectra were
taken on VARIAN FT-IR spectrometer as KBr pellets (when
solid). Elemental analysis was preformed using a Perkin Elmer
Autosystem XLAnalyzer. Melting points were measured using
a COMPLAB melting-point apparatus. Reactions were moni-
tored by thin-layer chromatography (TLC) carried out on 0.25
mm silica gel plates visualized with UV light.
RESULTS AND DISCUSSION
General procedure for synthesis of chalcone analogues
(3): Chalcone analogues were synthesized via aldol conden-
sation of substituted benzaldehyde and dehydro acetic acid.
In dry chloroform substituted benzaldehyde (1.0 mmol), dehydro-
acetic acid (1.0 mmol) in the presence of catalytic pyrrolidine
(20 mol %) was taken. Reaction was stirred at room temperature
for 2 h leading to generation of chalcone. Progress of reaction
was monitored by TLC. After completion of reaction solvent
was evaporated under the reduced pressure and residue was
extracted with ethyl acetate and water. The organic layer was
separated and dried over anhydrous Na2SO4 and filtered. The
filtrate was evaporated under vacuum on a rotary evaporator
(Scheme-I).
Our synthetic journey begins by synthesizing a series of
different substituted 3-cinnamoyl-4-hydroxy-6-methyl-2H-
pyran-2-one (3a-y) as substrate for cycloaddition reaction by
condensation of dehydroacteic acid and substituted benzal-
dehydes via Claisen-Schmidt condensation reaction. Further,
efforts were made for synthesis of spiroindoles. Our first objective
was to find optimum reaction condition. We started study in
search of best solvent for synthesis of spiropyrrolidines (4a-y).
To achieve this goal the reaction of (E)-4-hydroxy-3-(3-(2-
methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (3a),
isatin (1) and L-proline (2) was taken as the model reaction.
Various solvents such as methanol, dichloromethane, ethanol,
acetonitrile, chloroform, benzene and DMSO were explored
to check the feasibility of reaction. To our delight, product 4a
was formed in excellent yield. Whereas yield of product was
not satisfactory with other solvents, even at refluxing condition
and prolonged reaction time. Hence ethanol was chosen as
the solvent for reaction. The results are summarized in Table-1.
After optimizing appropriate solvent for reaction, to verify
general procedure for synthesis of spirooxindole we carried
out reaction with different 3-cinnamoyl-4-hydroxy-6-methyl-
OH O
OH O
Piperidine
O
Chloroform
O
O
O
O
R1
Benzaldehydes
R1
Dehydroacetic
acid
3(a-y)
Scheme-I: Synthesis of substituted 3-cinnamoyl-4-hydroxy-6-methyl-2H-
pyran-2-one

Vol. 31, No. 3 (2019)
Regioselective Three Component Domino Synthesis of Polyhydrospiro[indoline-3,3'-pyrrolizine]-2-one 615
TABLE-1
SYNTHESIS OF HEXAHYDROSPIRO[INDOLINE-3,3'-PYRROLIZIN]-2-ONE DERIVATIVES
Method A (room temperature)
S. No.
Compound
R1
R2
R3
m.p. (°C)
Time (h)c
5.0
4.5
4.0
4.0
4.0
4.0
4.0
3.0
4.5
4.0
3.0
3.0
4.5
4.5
3.5
4.0
3.0
3.5
3.5
5.0
5.0
5.5
5.0
3.0
4.5
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
3-OMe
2-Cl
4-F
4-F
4-OMe
3-OH
2-OMe
4-NO2
3,4-(OCH3)2
3-OMe
4-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
(CH2)2CH3
CH2Ph
H
(CH2)2CH3
H
(CH2)3CH3
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
CH2Ph
CH2CH3
(CH2)3CH3
H
CH2CH3
H
H
CH3
CH2Ph
CH3
H
(CH2)3CH3
(CH2)2CH3
H
89
90
90
90
90
82
86
86
87
89
94
94
90
89
91
87
93
90
91
91
88
89
92
88
180
191
184
181
186
167
182
163
174
169
182
186
206
201
176
181
186
197
188
159
186
159
184
181
147
4-F
3-OH,4-OCH3
3-OH,4-OCH3
4-Cl
3-OH
4-F
4-NO2
2-Cl
2-OMe
4-Me
4-OH
3-Cl
4-NO2
H
4t
4u
4v
4w
4x
4y
CH3
H
83
Method A = Reaction at room temperature
2H-pyran-2-one derivatives (3a-y), isatin (1) and L-proline (2)
by stirring at room temperature (method A) to afford a series
of novel spiroindoles (4a-y) in excellent yields. The results
are summarized in Table-2.
HOMO of
1,3 - dipole
N
N
HN
O
HN
O
SOI
TABLE-2
OPTIMIZATION OF SOLVENTS
O
No SOI
R1
O
O
O
O
LUMO of
dipolarophile
Entry
Solvent
Methanol
Dichloromethane
Ethanol
Temp. (°C)
Time (h)
Yield (%)a
OH
R1
1
2
3
4
5
6
7
8
RT
Reflux
RT
Reflux
Reflux
Reflux
Reflux
60
4
14
2
10
14
14
14
40 min
78
18
94
32
30
10
28
73
HO
O
Transition state
5b
Unfavourable
Transition state
Favourable
5a
THF
Acetonitrile
Chloroform
Benzene
Fig. 2. Plausible transition states for 1,3-dipolar cycloaddition reaction
DMSOb
(SOI) between orbital of carbonyl group in dipolarophile with
those of dipole. Hence formation of product 5a is more favo-
urable in comparison to 5b.
aIsolated yields of purified fractions; bReaction under microwave
condition.
After characterizing the synthesized spiroindole derivatives,
to explore the effect of substituent on the reactivity of cyclo-
addition we used different groups at R1 position. It was found
that substituent with negative inductive effect tends to facilitate
the reaction.As with N,N-dimethyl group at R1 position decrease
the reaction rate to such a extent that reaction does not complete
even after heating at 80 ºC and product formed in low yield.
Whereas with nitro and halogens at that positions activates the
reaction and reaction complete within 3 h at room temperature
and in 20 min under ultrasonic condition.
The structures of products were confirmed by spectro-
scopic methods (1H NMR, 13C NMR, IR, mass spectroscopy
and elemental analysis). All the spectral data were in good
support with the illustrated structure of spiroindole derivatives.
This cycloaddition reaction proceeds via intermediate forma-
tion of azomathine ylide (Fig. 2). The regioselectivity of synthe-
sized spiroindole derivatives were explained on the basis of
secondary orbital interaction. It is evident from Fig. 2 that the
approach of ylide to dipolarophile can lead to formation of
transition state 5a and 5b leading to product 4a-y, but predomi-
nantly forms transition state 5a. This can be attributed to consi-
dering regioselective approach of HOMO of dipole to the LUMO
of dipolarophile in path-A with secondary orbital interaction
Conclusion
In conclusion, a facile synthesis of 22 membered library
of hexahydrospiro[indoline-3,3′-pyrrolizine]-2-one derivatives

616 Tripathi et al.
Asian J. Chem.
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