Proline confined FAU zeolite: Heterogeneous hybrid catalyst for the synthesis of spiroheterocycles via a Mannich type reaction

Article abstract of DOI:10.1039/c2gc35822k

A novel l-proline confined FAU zeolite catalyst system has been developed by confinement of l-proline in faujasite zeolite and its catalytic activity has been tested in the aqueous mediated synthesis of novel 1′,3′-di-(4- methylphenyl)-2′,3′,4′,6′-tetrahydro-1′H- spiro[indoline-3,5′-pyrimidin]-2-one (4a) and 1′,3′-di-(4- methylphenyl)-2′,3′,4′,6′-tetrahydro-1′H- spiro[indene-2,5′-pyrimidin]-1(3H)-one (4d) for the first time via the one-pot three-component condensation of lactams/cyclic ketones, amines and aqueous formaldehyde. The recyclability of the novel catalyst system was studied, which resulted in no loss of catalytic activity up to five cycles.

Full text of DOI:10.1039/c2gc35822k

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Proline confined FAU zeolite: heterogeneous hybrid catalyst for synthesis of
spiroheterocycles via mannich type reaction
Kapil Arya,* and Diwan Singh Rawat
Department of Chemistry, University of Delhi, Delhiꢀ110007, India
Email: aryakapil2001@yahoo.com, dsrawat@chemistry.du.ac.in
Novel L-proline confined FAU zeolite catalyst system has been developed by
confinement of L-proline in faujasite zeolite and their catalytic activity been tested in
aqueous mediated synthesis of novel 1', 3'-di-(4-methylphenyl)-2', 3', 4', 6'-tetrahydro-
1'H-spiro[indoline-3,5'-pyrimidin]-2-one (4a) and 1', 3'-di-(4-methylphenyl)-2',3',4',6'-
tetrahydro-1'H-spiro[indene-2,5'-pyrimidin]-1(3H)-one (4d) first time via one pot three-
component condensation of lactams/cyclic ketones, amines and aqueous formaldehyde .
Recyclability of novel catalyst system was studied which resulted in no loss of catalytic
activity upto five cycles
.
Introduction
Organocatalysts, metal-free organic compounds of relatively low molecular weight and
simple structure capable of promoting a reaction in a substoichiometric amount, has received
paramount interest in last few years.1 In particular the use of amino acid proline2 can be regarded
as the simplest ‘enzyme ’and, successfully applied as a catalyst to many organic transformation.3-
6 The main advantages of this method are that the reaction can be performed in a stereoselective
manner, under mild conditions and without the need of any metal. In addition, both enantiomers
of proline are available. The classical Mannich reaction,7 in which an aminomethyl group is
introduced at the a-position to a carbonyl compound, is an important reaction in organic
chemistry.8 The products, so-called Mannich bases,9 are 1,3-amino ketones, which are versatile
intermediates in organic synthesis and have especially proven their value in the synthetic
building blocks and precursors of pharmaceutically valuable alkaloids. The development of
catalytic asymmetric Mannich-type reactions has received increased attention in recent years.10

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Direct catalytic Mannich-type reactions between ketones and imines are catalyzed by
organometallic complexes11 with high enantioselectivity. Moreover, organocatalytic direct
asymmetric Mannich-type reactions have been developed which are catalyzed by Bronsted
16
acids,12 cinchona alkaloids,13 proline derivatives14,15 and linear amino acid derivatives. In this
context, one notable transformation is the proline-catalyzed, one-pot three-component Mannich
reaction using ketones as nucleophiles reported by List and co-workers.14a Other important recent
Mannich transformations, which were independently developed by Enders,17 Westermann,18 and
Cordova,19 for the synthesis of amino sugars and polyhydroxylated amino acids employ
protected dihydroxyacetone derivatives, such as 2,2-dimethyl-1,3-dioxane-5-one, as donors. All
these synthetic procedure serve several drawbacks like long reaction time and use of hazardous
solvents and tedious workup. To the best of our knowledge, scanty reports are available for
synthesis of spiro compounds via sequential introduction of two aminomethyl group on the same
α-carbon of carbonyl moiety. Liang20a reported synthesis of spirohexahydropyrimidines via one-
20b
pot condensation of anilines, formaldehyde, and cyclohexanones, while Mukhopadhyay
reported synthesis of hexahydropyrimidines and its spiro analogues via 1,3-dicarbonyl
compounds in presence of Lewis acid in dichloromethane, but all these procedure do not come
under greener approaches. In addition, when water was produced in the imine formation, most
Lewis acids could not be used in such type of one-pot reactions.20c Therefore, there is a need to
find the most suitable route like one-pot three-component in regard to green chemistry.
Research for efficient, convenient and recyclable catalytic system based on supported
organocatalyst is still a major challenge. Search of green catalyst and our interest in synthesis of
porous zeolite materials,21 prompted us to explore new concept of immobilization in which
organocatalyst such as proline is immobilized on a pure silica mesoporous materials so that the
product purification can be facilitated and the catalyst can be recycled. One method to
immobilize the catalyst is to covalently anchor the proline onto a solid carrier.

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The main drawback of this approach is chemical bonding of proline to a solid surface that
may limit the degrees of freedom of the substrate and even change the physicochemical
properties of the proline.22a Hence the leaching of the organocatalyst was unavoidable under
rigorous reaction conditions if the supported immobilized proline catalyst was prepared by
physical adsorption sol gel technique or by having the proline as a thin layer on a support
material. Therefore, a new concept of microporous confined proline catalyst systems has been
adopted for greener catalytic process. Our interest in this area led us to explore confinement of
organocatalyst such as proline in the channels of mesoporous and microporous materials such as
zeolite, silica and Alumina. The key concept of designing and synthesizing such a catalyst
system involves the physical confinement or encapsulation of organocatalyst through a
traditional based hydrolysis of silicate to produce a solid matrix with desired pore sizes or
cavities and channels. The proline acts as both catalyst and reaction media, and the solid matrix
acts as the nanoscale reactor connected with inlets and outlets to contain mesoporous channels
and to allow reactants and products to be transported in or out. The pore size of the Zeolite
should be large enough to contain organocatalyst, while the channel size of the microporous
materials should be small enough to prevent organocatalyst from leaching; however, the channel
size must also be large enough for free transportation of reactant and product. Therefore, they are
intrinsically different from previously reported supported or immobilized organocatalyst.22b,c-23
FAU zeolite contains uniformed distribution of large mesopores in the range of 3-10 nm and
high surface area served as a potentially new support for organocatalyst. Crystalline zeolite
framework exhibited higher hydrothermal stability that makes them suitable for supporting
materials compared to other mesoporous materials without crystalline framework.24 Apart from
this, water has aroused considerable attention in synthetic community and proved to be a
promising solvent in organic synthesis due to its economic, environment friendly and polar
nature.25 In relation to this, significant efforts have been dedicated towards developing organic

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reactions in water with many inherent advantages over reactions in conventional organic
solvents.
As part of our ongoing program to develop potential catalysts and suitable reaction
conditions,26 we developed FAU zeolite confined (L)-proline catalyzed efficient and
environment friendly approach for the first synthesis of novel spiro[indoline-3,5'-pyrimidin]-2-
one (4a) and spiro[indene-2,5'-pyrimidin]-1(3H)-one (4d) by reacting of lactams or cyclic
ketones with amines and aqueous formaldehyde in aqueous medium at room temperature
(Scheme 1).
N
Ar
Ar
N
H
H
L-proline FAU Zeolite (2 mol%)
O
+
Ar-NH2
+
X
Water, r.t., Stirring, 30-45 min.
O
O
1
2
3
4
X
X= Substituted Indole, 1-Indanone, 2-Indanone, Thiazolidinone
13 examples
up to 94% isolated yield
Ar= 4-CH3C6H4, 4-OCH3C6H4, 4-BrC6H4, 3-ClC6H4, 3,4-diCH3C6H3, 4-(CH3)2CHC6H4
Scheme 1 Preparation of spiro heterocycles through Mannich reaction
Results and discussion
L-proline confined zeolite catalyst were synthesized on the basis of the organic-additive-
instant seed technology method.21 A measure amount (10 mol %) of L-proline was added to an
aluminosilicate gel containing 5.40 g of NaOH, 2.58 g of NaAlO2, 3.57 g of SiO2, and 50.0 g of
H2O. The gel was crystallized at 100 °C for 24 hrs. The resultant powder was separated from
solution by centrifugation and then washed completely with deionized (DI) water to remove any
physically absorbed species on the zeolite surface. The synthesized samples were dried at room
temperature for further characterization and catalytic investigations. ICPMS analysis indicates
that the concentration of proline incorporated in the zeolite is (0.80mmol/g, 8 mol %). To
investigate confinement of L-proline on FAU zeolite, UV- Raman spectra of L-proline in solid

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form and on Faujasite Y zeolite were obtained (Fig. 1). Band at 1380 cm-1 corresponding to
symmetric stretching vibration of the carboxylate group of free L-proline shifted to 1390cm-1
after L-proline confined in zeolite. The Raman bands of L-proline became broad and some
characteristic bands disappeared for the adsorbed L- proline. These changes indicate that L-
proline strongly interacts with zeolite and that the carboxylate groups are involved in the
interaction.27 X-ray powder diffraction indicates that unmodified FAU zeolite and the L-proline
confined FAU zeolite have the same structure (Fig. 2). In comparison with the unmodified FAU
zeolite, L-proline confined FAU displays slightly higher 2θ values in all of its diffraction peaks.
Both diffraction patterns match very well with that simulated for faujasite zeolites.28 X-ray
fluorescence analysis shows that the Si/Al ratio is 5.1 for FAU and 5.23 for confined zeolite,
within the range of 5.1-5.2 for faujasite-Y zeolite. There is no evidence for any crystal phases
attributable to L-proline compounds, indicating that L-proline confined zeolite is not highly
crystalline.
Fig. 1 UV-Raman Spectra of (a) L-proline confined in FAU zeolite catalyst system (b) L-proline,
and (c) FAU zeolite

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Fig. 2 XRD pattern of (a) FAU zeolite, and (b) L-proline confined FAU zeolite
The morphology and particle sizes of L-proline in FAU zeolite were characterized using
high-resolution TEM, as shown in Figure 3. The additional homogeneously distributed dark
spots in L-proline-FAU sample (Fig. 3b) not seen in pure FAU zeolite (Fig. 3a). Figure 3 clearly
indicates that these dark spots are very uniform, in the size range 1.3 + 0.2 nm. This is the same
size as the supercages in FAU zeolite. The L-proline is likely incorporated into the supercages of
FAU zeolite during the hydrothermal crystallization process, and the growth of L-proline is
constrained by the rigid zeolitic framework. Furthermore, due to the structure of FAU zeolite,
with larger supercages tetrahedrally connected by smaller 12-membered rings, once
incorporated, the L-proline is physically confined in the supercages and cannot diffuse out
through the relatively narrow channels. This physical occlusion, supported by the catalytic
results (vide infra), is of significance in the prevention of leaching of the active sites, a common
problem for supported transition-metal catalysts.29

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(a)
(b)
Fig. 3 High resolution TEM image of (a) FAU zeolite, and (b) L-proline confined FAU zeolite
Encouraged by the recent focus on the green chemical theme of eliminating the use of
solvents and importance of aqueous mediated reactions, we began our investigations by treating
various cyclic ketone/ lactams 1, amines 2 and formaldehyde 3 in the presence L-proline
confined FAU zeolite in water at room temperature (Scheme 1). Here we have chosen Mannich
type one pot three component reaction of Indole 1a, 4-methylaniline 2a, formaldehyde 3 as a
simple model substrate. Different solvents such as methanol, NMP, dimethyl formamide (DMF),
dimethyl sulphoxide (DMSO), methyl cyanide (CH3CN), tetrahydrofuran (THF) and water were
explored in presence of different catalyst system. The results are summarized in Table 1.
Table1 Catalyst and Solvent screen for Mannich type reactiona of 1a, 2a and 3 at room
temperature
Entry
1.
Catalyst
Solvent
Water
Yieldb(%)
45
Time (min.)
280
OH
OH
N
H
2.
3.
MeOH
Water
32
48
300
180
N
H
N
Ph
N
N
N
H

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N
Ph
4.
DMSO
30
340
N
N
N
H
HO
5.
6.
Water
Water
42
38
210
180
COOH
N
H
HO
COOMe
Ph
Ph
OH
N
H
7.
8.
Water
Water
30
22
180
240
N
H
N
H
9.
(L)-Proline
(L) -Proline
(L) -Proline
(L) -Proline
(L) -Proline
Water
DMSO
MeOH
CH3CN
THF
80
22
20
89
40
65
42
38
33
94
42
28
32
18
180
300
330
300
360
300
480
400
360
30
10.
11.
12.
13.
14.
15.
16
FAU zeolite
FAU zeolite
FAU zeolite
FAU zeolite
Water
DMSO
MeOH
CH3CN
Water
DMSO
MeOH
CH3CN
THF
17.
18.
19.
20.
21.
22.
23.
L-proline/FAU zeolite
L-proline/FAU zeolite
L-proline/FAU zeolite
L-proline/FAU zeolite
L-proline/FAU zeolite
Neat
120
140
140
180
480
-
Traces of
product
a Experimental conditions: a mixture of Indole (1 mmol, 1 equiv), 4-methylaniline (2 mmol, 2 equiv), formaldehyde
(4 mmol, 4 equiv, 36% aqueous solution), and L-proine/FAU zeolite (2gm, 2 mol %) in 10 mL of water was stirred
at room temperature for appropriate time. The crude product obtained after aqueous workup. b Isolated yields.
It can be seen from the Table 1 that the reaction performed in presence of novel catalyst
system yielded product in very shorter reaction time at room temperature. To find out the

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efficiency of novel catalyst system, we tried out the reaction in presence of blank FAU zeolite
(entry 14-17, table 1) in different solvents and obtained very low yield of titled compounds with
increasing reaction time. Apart from this, same reaction was also tried out in neat condition in
absence of any catalyst and solvent (entry 23, table 1) resulting traces of product. Thus, It can be
concluded that the aqueous mediated L-proline FAU zeolite catalyst system is best reaction
medium in which resulted product was obtained in higher yield with shorter reaction time (Table
1).
To search of better reaction parameters, we adjusted the ratio of the reactants, and the
processes are shown in Table 2. The reaction proceeded in water in presence of L-proline FAU
zeolite as catalyst. The amount of arylamines and formaldehyde was up to 2:4 (entry 7). Further
increase in the amounts of amines and formaldehyde resulted in a slight decrease in yield (entries
8 to 13).
Table 2 Effect of molar quantity of arylamine and formaldehyde on product yield
Entry
Indole (1a)
(mmol)
1
4-methylaniline (2a)
Formaldehyde (3)
Yielda (%)
(mmol)
(mmol)
1.
2.
1
1
30
35
40
42
48
65
94
50
58
62
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
3
3
3
1.5
2
3.
4.
2.5
3
5.
6.
3.5
4
7.
8.
3
9.
4
10.
4.5

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11.
12.
1
1
1
3
3
3
5
5.5
6
80
75
68
13.
aIsolated yields
As can be seen from Table 1 and 2, the best result can be obtained by using 2:4 molar
quantities of arylamines and formaldehyde in presence of L-proline FAU zeolite catalyst system
and water as solvent (Table 1, entry 14; Table 2, entry 7).
After optimization of the conditions, to delineate this approach, particularly in regard to
library construction, and in order to check the general applicability of the reaction for the
synthesis of novel spiro heterocycles derivatives, we extended the reaction of aqueous
formaldehyde with electron donating and electron withdrawing groups containing aryl amines
and various lactams/cyclic ketones (Table 3). Aryl amines with electron-withdrawing groups
behave low actively in the reaction, and only medium yields were obtained (entries 8, 12, and
13).
Table 3 Synthesis of spiro heterocycles via one pot reaction of ketone, amine and formaldehyde
Entry
1.
Ketone moiety (X) Amine Product
Time (min.) Yielda (%)
M.P. (oC)
198-200
250-252
176-178
210-212
228-230
285-287
1a
1b
1c
1d
1d
1e
2a
2a
2b
2a
2b
2a
4a
4b
4c
4d
4e
4f
30
20
35
30
40
35
94
90
88
87
90
93
2.
3.
4.
5.
6.

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7.
8.
1f
1a
1a
1a
1d
1d
1d
2a
2c
2f
4g
4h
4i
45
45
35
30
40
35
40
90
65
80
88
78
68
70
184-186
172-174
190-192
183-185
205-207
218-220
246-248
9.
10.
11.
12.
13.
2g
2e
2d
2c
4j
4k
4l
4m
H3CO
O2N
N
H
O
N
H
O
N
H
O
O
1a
1b
1c
1d
OCH3
CH3 H2N
N
H2N
S
O
O
1e
1f
2a
2b
NH2
H2N
H2N
CH3
NH2
H2N
Br
CH3
Cl
2c
2d
2e
2f
2g
a Isolated yield of purified compounds that exhibited physical and spectral properties in accordance with the assigned structure.
A plausible mechanism for the reaction, proposed in Scheme 2. The ketone undergoes
twice α-aminomethylation reactions in succession on the same α-carbon of carbonyl-catalyzed
by proline. The condensation of the resulting substituted propane- 1,3-diamine with
formaldehyde furnishes the desired novel spiro[indoline-3,5'-pyrimidin]-2-one and spiro[indene-
2,5'-pyrimidin]-1(3H)-one. This is first example in which indol-2-one act for enamine-catalysis
without use of H-bond donor catalyst.

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-H2O
Ar-NH2
2
CH2O
H2C
N-Ar
H2
C
3
NH-Ar
COOH
N
H
COOH
H
H
H
COOH
N
H
N
O
N
H
N
N
H
1
Ar
HN
Ar
N
HN
H2
C
H2C
N-Ar
Ar
NH-Ar
Ar
N
H
H2O
COOH
COOH
N
N
N
COOH
0
N
H
H
N
H
N
H
Ar
N
O
N
HCHO
-H2O
Ar
N
H
4
Scheme 2 Plausible mechanism for the Mannich type one pot three component reaction
To the best of our knowledge, this new procedure provides the first example of an
efficient and ecofriendly approach for exclusive synthesis of novel spiro [indoline-3,5'-
pyrimidin]-2-one (4a-c) and spiro[indene-2,5'-pyrimidin]-1(3H)-one (4d-f) derivatives with
higher yield in shorter reaction times . The structures of all the products 4 were established by
IR, 1H NMR, 13C NMR and HRMS spectroscopy.
From economic point of view, the stability and sustained activity of the catalyst are of
great importance. Thus the recovery and reusability of catalyst was investigated in one pot
reaction of Indole-2-one, 4-methyl aniline and aqueous formaldehyde in the presence of L-

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proline FAU zeolite and result was summarized in Table 4. Result shows that no loss of catalyst
activity was found even after five cyclic times in L-proline FAU catalyst system (Table 4) (Fig.
4). For recycling study of the catalyst, after each cycle catalyst was washed with water and
drayed at 300°C.
Table 4 Comparative Catalyst recycling study using L-proline FAU zeolite catalyst system
(Entry 1, Table 3)
Cycle
Product
Yielda (%)
Time (min.)
Fresh
94
94
94
93
93
93
30
30
31
30
31
30
1st recycle
2nd recycle
3rd recycle
4th recycle
5th recycle
a Isolated yields
Figure 4 L-proline FAU zeolite catalyst recycling study

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Experimental Section
1
IR spectra (KBr) were recorded on a Shimadzu FT IR-8400S spectrophotometer and H
NMR and 13C NMR spectra were recorded on a Bruker DRX-300, at 300.15 and 200 MHz,
respectively, using CDCl3 as solvent. High-resolution mass spectra (HRMS) were obtained on a
Finnigan MAT 8200 system using sector double focus and an electron-impact source with an
ionizing voltage of 70 eV. DIPMS (direct insertion probe mass spectrum) values are reported in
m/z.
General procedure for Synthesis of 1', 3'-di-(4-methylphenyl)-2', 3', 4', 6'-tetrahydro-1'H-
spiro[indoline-3,5'-pyrimidin]-2-one (4a):
A mixture of Indole (1 mmol), 4-methylaniline (2 mmol), formaldehyde (4 mmol, 36% aqueous
solution), and a catalytic amount of L-proline FAU zeolite (2mg, 2 mol% ) in 10 ml of water was
stirred at room temperature for appropriate time mentioned in Table-3. After the completion of
reaction (TLC analysis), reaction mixture was allowed to cool to room temperature. In next step,
reaction mixture was filtered and washed with water and CPME (cyclopentyl methyl ether). The
organic phase was separated and dried over anhydrous Na2SO4 afforded pure crystalline product
(4) with no need of further purification. In the recycling experiment, catalyst was washed
thoroughly with water, dried under vacuum and reused without any pretreatment.
Compounds 4b-g were similarly prepared by the above method and confirmed by spectroscopic
methods.
1', 3'-di-(4-methylphenyl)-2', 3', 4', 6'-tetrahydro-1'H-spiro[indoline-3,5'-pyrimidin]-2-one
(4a): Rf= 0.61 (ethyl acetate/hexane=1:4);1H NMR (300 MHz,CDCl3):δ= 9.02 (s, 1H, NH),
7.99-6.58 (m, 12 H, Ar-H), 4.75 (d, J = 11.4 Hz, 1H), 4.09 (d, J=11.4 Hz, 1H), 3.53 (d, J =12.6
Hz, 2H), 3.27 (d, J =12.6 Hz, 2H), 2.12 ppm (s, 6H, CH3). 13C NMR (200 MHz, CDCl3): δ

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=171.6 (C=O), 141.8 (C-N), 134.2, 130.4, 128.4, 124.8, 120.8, 119.7, 116.2, 114.5, 71.5 (CH2),
65.4(CH2), 60.9 (CH2), 50.9 (C), 22.7 ppm (CH3). IR (KBr): 3130, 2970, 1640, 1550, 1420,
1210 cm-1. Mass: m/z 383 [M+]. Analysis: Found (calcd) for C25H25N3O: C, 78.40 (78.30); H,
6.48 (6.57); N, 10.89 (10.96).
1',3'-di-(4-methylphenyl)-5-methoxy-2', 3', 4', 6'-tetrahydro-1'H-spiro[indoline-3,5'-
pyrimidin]-2-one (4b): Rf= 0.66 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ=
9.20 (s, 1H, NH), 7.79-6.43 (m, 11H, Ar-H), 4.78 (d, J = 11.4 Hz, 1H), 4.08 (d, J=11.4 Hz, 1H),
3.70 (s, 3H, OCH3), 3.51 (d, J =12.6 Hz, 2H), 3.38 (d, J =12.6 Hz, 2H), 2.27 ppm (s, 6H, CH3).
13C NMR (200 MHz, CDCl3): δ =175.8 (C=O), 160.3, 145.7 (C-N), 130.4, 127.9, 125.1, 123.4,
120.4, 118.4, 114.3, 112.8, 69.4 (CH2), 64.1 (CH2), 59.8 (CH2), 56.03 (OCH3), 52.7 (C), 20.5
ppm (CH3). IR (KBr): 3170, 2928, 1650, 1540, 1452, 1234, 1150, 811 cm-1. Mass: m/z 413 [M+].
Analysis: Found (calcd) for C26H27N3O2: C, 75.45 (75.52); H, 6.64 (6.58); N, 10.22 (10.16).
1', 3'-di-(4-methoxylphenyl)- 5-nitro-2', 3', 4', 6'-tetrahydro-1'H-spiro[indoline-3,5'-
pyrimidin]-2-one (4c): Rf= 0.75 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 9.38
(s, 1H, NH), 8.09-7.12 (m, 11H, Ar-H), 4.89 (d, J = 11.4 Hz, 1H), 4.15 (d, J=11.4 Hz, 1H), 3.76
13
(s, 6H, OCH3), 3.49 (d, J =12.6 Hz, 2H), 3.35 ppm (d, J =12.6 Hz, 2H). C NMR (200 MHz,
CDCl3): δ =177.8 (C=O), 161.8, 147.2 (C-N), 142.3, 135.7, 132.3, 128.1, 126.9, 124.2, 122.8,
120.3, 118.7, 70.2 (CH2), 67.3(CH2), 61.9 (CH2), 56.38 (OCH3), 51.7 ppm (C). IR (KBr): 3150,
2943, 1660, 1510, 1430, 1220, 1140 cm-1. Mass: m/z 460 [M+]. Analysis: Found (calcd) for
C25H24N4O5: C, 65.15 (65.21); H, 5.33 (5.25); N, 12.08 (12.17).
1',3'-di-(4-methylphenyl)-2',3',4',6'-tetrahydro-1'H-spiro[indene-2,5'-pyrimidin]-1(3H)-one
(4d): Rf= 0.68 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 7.88-6.63 (m, 12H,
Ar-H), 4.83 (d, J = 11.4 Hz, 1H), 4.20 (d, J=11.4 Hz, 1H), 3.60 (d, J =12.6 Hz, 2H), 3.30 (d, J

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=12.6 Hz, 2H), 2.72 (s, 2H, CH2), 2.16 ppm (s, 6H, CH3). 13C NMR (200 MHz, CDCl3): δ =
174.2 (C=O), 142.0 (C-N), 135.8, 132.1, 128.2, 124.9, 121.3, 119.7, 115.8, 113.7, 70.9 (CH2),
65.9 (CH2), 61.5 (CH2), 52.8 (C), 31.7 (CH2), 20.9 ppm (CH3). IR (KBr): 2965, 1650, 1560,
1410, 1230 cm-1. Mass: m/z 382 [M+]. Analysis: Found (calcd) for C26H26N2O: C, 81.72 (81.64);
H, 6.77 (6.85); N, 7.41 (7.32).
1',3'-di-(4-methoxylphenyl)-2',3',4',6'-tetrahydro-1'H-spiro[indene-2,5'-pyrimidin]-1(3H)-
one (4e) : Rf= 0.77 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 8.02-6.91 (m,
12H, Ar-H), 4.92 (d, J = 11.4 Hz, 1H), 4.25 (d, J=11.4 Hz, 1H), 3.68 (d, J =12.6 Hz, 2H), 3.55 (s,
6H, OCH3), 3.28 (d, J =12.6 Hz, 2H), 2.59 ppm (s, 2H, CH2).13C NMR (200 MHz, CDCl3): δ =
171.9 (C=O), 165.2, 145.7 (C-N), 138.9, 135.1, 131.7, 127.5, 123.6, 120.8, 117.2, 113.7, 71.3
(CH2), 68.5 (CH2), 64.2 (CH2), 58.9 (OCH3), 55.6 (C), 32.9 ppm (CH2). IR (KBr): 2965, 1650,
1560, 1410, 1230 cm-1. Mass: m/z 414 [M+]. Analysis: Found (calcd) for C26H26N2O3: C, 75.42
(75.34); H, 6.39 (6.32); N, 6.83 (6.76).
1',3'-di-(4-methylphenyl)-2',3',4',6'-tetrahydro-1'H-spiro[indene-1,5'-pyrimidin]-2(3H)-one
(4f) : Rf= 0.70 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 7.95-6.79 (m, 12H,
Ar-H), 4.80 (d, J = 11.4 Hz, 1H), 4.17 (d, J=11.4 Hz, 1H), 3.76 (d, J =12.6 Hz, 2H), 3.42 (d, J
=12.6 Hz, 2H), 3.29 (s, 2H, CH2), 2.28 ppm (s, 6H, CH3). 13C NMR (200 MHz, CDCl3): δ =
176.4 (C=O), 143.9 (C-N), 134.7, 130.4, 127.3, 124.7, 121.9, 119.8, 116.5, 114.3, 69.2 (CH2),
67.9(CH2), 60.5 (CH2), 54.3 (C), 44.8 (CH2), 22.8 ppm (CH3). IR (KBr): 2965, 1640, 1540,
1390, 1210 cm-1. Mass: m/z 382 [M+]. Analysis: Found (calcd) for C26H26N2O: C, 81.57 (81.64);
H, 6.93 (6.85); N, 7.25 (7.32).
2,3-diphenyl-7,9-di-(4-methylphenyl)-1-thia-3,7,9-triaza-spiro[4,5]decan-4-one(4g): Rf
=
0.75 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 8.12-6.35 (m, 18H, Ar-H), 5.85

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(s, 1H, CH), 5.23 (d, J = 11.4 Hz, 1H), 4.56 (d, J=11.4 Hz, 1H), 4.12 (d, J =12.6 Hz, 2H), 3.89
13
(d, J =12.6 Hz, 2H), 2.38 ppm (s, 6H, CH3). C NMR (200 MHz, CDCl3): δ = 178.7 (C=O),
150.2 (C-N), 141.3, 137.8, 134.2, 130.7, 127.5, 123.7, 119.5, 113.8, 80.5 (CH2), 72.7 (CH2), 60.8
(CH), 54.9 (C), 51.8 (CH2), 21.4 ppm (CH3). IR (KBr): 2965, 1680, 1510, 1360, 1220 cm-1.
Mass: m/z 505 [M+]. Analysis: Found (calcd) for C32H31N3OS: C, 76.12 (76.01); H, 6.09 (6.18);
N, 8.42 (8.31).
1', 3'-di-(4-bromophenyl)-2', 3', 4', 6'-tetrahydro-1'H-spiro[indoline-3,5'-pyrimidin]-2-one
(4h): Rf= 0.74 (ethyl acetate/hexane=1:4);1H NMR (300 MHz,CDCl3):δ= 8.95 (s, 1H, NH),
7.84-6.72 (m, 12 H, Ar-H), 4.68 (d, J = 11.4 Hz, 1H), 4.12 (d, J=11.4 Hz, 1H), 3.58 (d, J =12.6
Hz, 2H), 3.23 (d, J =12.6 Hz, 2H). 13C NMR (200 MHz, CDCl3): δ =172.8 (C=O), 139.5 (C-N),
133.5, 131.3, 127.3, 123.5, 121.2, 118.9, 115.9, 113.8, 111.6, 72.9 (CH2), 69.3 (CH2), 61.8
(CH2), 51.4 ppm (C). IR (KBr): 3120, 2960, 1635, 1510, 1430, 1180, 710 cm-1. Mass: m/z 515
[M+2], 513[M+]. Analysis: Found (calcd) for C23H19Br2N3O: C, 53.72 (53.83); H, 3.75 (3.73);
N, 8.15 (8.19).
1', 3'-di-phenyl-2', 3', 4', 6'-tetrahydro-1'H-spiro[indoline-3,5'-pyrimidin]-2-one (4i): Rf=
0.70 (ethyl acetate/hexane=1:4);1H NMR (300 MHz,CDCl3):δ= 9.12 (s, 1H, NH), 7.95-6.54 (m,
14 H, Ar-H), 4.79 (d, J = 11.4 Hz, 1H), 4.17 (d, J=11.4 Hz, 1H), 3.65 (d, J =12.6 Hz, 2H), 3.31
13
(d, J =12.6 Hz, 2H). C NMR (200 MHz, CDCl3): δ =174.3 (C=O), 141.5 (C-N), 136.3, 133.3,
129.5, 125.9, 123.8, 120.7, 119.8, 116.2, 114.8, 68.3 (CH2), 66.7 (CH2), 61.3 (CH2), 52.8 ppm
(C). IR (KBr): 3150, 2950, 1640, 1530, 1450, 1190. Mass: m/z 355 [M+]. Analysis: Found
(calcd) for C23H21N3O: C, 77.90 (77.72); H, 5.90 (5.96); N, 11.88 (11.82).
1', 3'-di-(4-isopropylphenyl)-2', 3', 4', 6'-tetrahydro-1'H-spiro[indoline-3,5'-pyrimidin]-2-
one (4j): Rf= 0.64 (ethyl acetate/hexane=1:4);1H NMR (300 MHz,CDCl3):δ= 9.05 (s, 1H, NH),

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8.02-6.74 (m, 12 H, Ar-H), 4.68 (d, J = 11.4 Hz, 1H), 4.22 (d, J=11.4 Hz, 1H), 3.59 (d, J =12.6
Hz, 2H), 3.23 (d, J =12.6 Hz, 2H), 3.01 (m, 2H), 1.32-1.18 (m, 12H). 13C NMR (200 MHz,
CDCl3): δ =173.5 (C=O), 143.3 (C-N), 139.6, 135.8, 131.6, 128.2, 124.9, 121.8, 118.5, 116.9,
113.5, 65.9 (CH2), 62.3 (CH2), 58.4 (CH2), 55.4 (C), 32.3 (CH), 21.9 (CH3). IR (KBr): 3165,
2930, 1620, 1510, 1445, 1205. Mass: m/z 439 [M+]. Analysis: Found (calcd) for C29H33N3O: C,
79.15 (79.23); H, 7.62 (7.57); N, 9.51 (9.56).
1',3'-di-(3,4-dimethylphenyl)-2',3',4',6'-tetrahydro-1'H-spiro[indene-2,5'-pyrimidin]-1(3H)-
one (4k): Rf= 0.69 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 7.72-6.34 (m,
10H, Ar-H), 4.85 (d, J = 11.4 Hz, 1H), 4.12 (d, J=11.4 Hz, 1H), 3.65 (d, J =12.6 Hz, 2H), 3.35
(d, J =12.6 Hz, 2H), 2.83 (s, 2H, CH2), 2.16 (s, 6H, CH3), 2.08 ppm (s, 6H, CH3). 13C NMR (200
MHz, CDCl3): δ = 178.3 (C=O), 144.1 (C-N), 140.2, 131.8, 129.3, 125.7, 120.8, 118.6, 114.3,
112.5, 72.9 (CH2), 69.1 (CH2), 63.8 (CH2), 53.9 (C), 30.4 (CH2), 21.9 (CH3), 18.2 ppm (CH3). IR
(KBr): 2980, 1635, 1550, 1390, 1210 cm-1. Mass: m/z 410 [M+]. Analysis: Found (calcd) for
C28H30N2O: C, 81.80 (81.91); H, 7.42 (7.37); N, 6.77 (6.82).
1',3'-di-(3-chlorophenyl)-2',3',4',6'-tetrahydro-1'H-spiro[indene-2,5'-pyrimidin]-1(3H)-one
(4l): Rf= 0.75 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 7.95-6.43 (m, 12H, Ar-
H), 4.72 (d, J = 11.4 Hz, 1H), 4.21 (d, J=11.4 Hz, 1H), 3.71 (d, J =12.6 Hz, 2H), 3.53 (d, J =12.6
13
Hz, 2H), 2.77 ppm (s, 2H, CH2). C NMR (200 MHz, CDCl3): δ = 175.2 (C=O), 147.3 (C-N),
141.8, 135.3, 132.8, 128.5, 122.7, 120.1, 117.3, 113.4, 73.9 (CH2), 68.7 (CH2), 62.4 (CH2), 55.9
(C), 28.7 ppm (CH2). IR (KBr): 2990, 1645, 1530, 1360, 1190, 740 cm-1. Mass: m/z 424 [M+2],
422 [M+]. Analysis: Found (calcd) for C24H20Cl2N2O: C, 67.97 (68.09); H, 4.72 (4.76); N, 6.67
(6.62).

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1',3'-di-(4-bromophenyl)-2',3',4',6'-tetrahydro-1'H-spiro[indene-2,5'-pyrimidin]-1(3H)-one
(4m) Rf= 0.78 (ethyl acetate/hexane=1:4).1H NMR (300 MHz,CDCl3):δ= 7.85-6.42 (m, 12H, Ar-
H), 4.63 (d, J = 11.4 Hz, 1H), 4.19 (d, J=11.4 Hz, 1H), 3.74 (d, J =12.6 Hz, 2H), 3.45 (d, J =12.6
Hz, 2H), 2.88 ppm (s, 2H, CH2). 13C NMR (200 MHz, CDCl3): δ = 172.2 (C=O), 142.4 (C-N),
139.7, 135.8, 131.5, 127.6, 121.9, 116.4, 113.8, 110.4, 70.4 (CH2), 67.3 (CH2), 62.5 (CH2), 49.7
(C), 28.4 ppm (CH2). IR (KBr): 3010, 1640, 1530, 1370, 1190, 715 cm-1. Mass: m/z 512 [M+2],
510 [M+]. Analysis: Found (calcd) for C24H20Br2N2O: C, 56.18 (56.27); H, 3.88 (3.94); N, 5.52
(5.47).
Conclusion
In conclusion, we have succeeded in developing novel green catalyst system and tested their
catalytic activity for the Mannich type reaction in aqueous medium , and generate the first report
on the synthesis of a series of novel spiro[indoline-3,5'-pyrimidin]-2-one and spiro[indene-2,5'-
pyrimidin]-1(3H)-one derivatives. In this novel one-pot three-component reaction, six molecules
of reactants are involved and six new covalent bonds are generated which make the reaction
highly atom economic. Functionalisation at the α-position of the carbonyl/ lactam occurs twice
which makes this reaction significant and increases the interest for further modification to
molecular diversity.
Acknowledgement
Authors are thankful to D.S.T., New Delhi for financial support.
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