Facile synthesis of phthalidyl fused spiro thiohydantoins through silica sulfuric acid induced oxidative rearrangement of ninhydrin adducts of thioureas

Article abstract of DOI:10.1016/j.tet.2019.130817

A one-pot three-component sequential synthetic protocol produces structurally and biologically important phthalidyl fused spiro N,N′-disubstituted thiohydantoins from readily available aromatic isothiocyanates, primary amines and ninhydrin. In this three-step synthesis while the initial two steps are catalyst-free, in the final step silica sulfuric acid (SSA) induces an oxidative rearrangement in [3.3.0]-bicyclic 1,2-diol adducts of ninhydrin and thioureas under solvent-free condition to generate the final products spiro-fused thiohydantoins. The adequate acidity of SSA in cooperation with moderate oxidizing property promotes a facile oxidative rearrangement in 1,2-diol intermediates to produce the spiro-fused thiohydantoins with diverse functionalities. Easy recyclability of SSA, good to excellent yield of the products, wider substrate scope, shorter reaction time, solvent-free two steps out of three and high atom economy make this method attractive and practicable.

Full text of DOI:10.1016/j.tet.2019.130817

Journal Pre-proof
Facile synthesis of phthalidyl fused spiro thiohydantoins through silica sulfuric acid
induced oxidative rearrangement of ninhydrin adducts of thioureas
Subhro Mandal, Animesh Pramanik
PII:
S0040-4020(19)31225-6
https://doi.org/10.1016/j.tet.2019.130817
TET 130817
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 September 2019
Revised Date: 20 November 2019
Accepted Date: 21 November 2019
Please cite this article as: Mandal S, Pramanik A, Facile synthesis of phthalidyl fused spiro
thiohydantoins through silica sulfuric acid induced oxidative rearrangement of ninhydrin adducts of
thioureas, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130817.
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Graphical Abstract
Facile synthesis of phthalidyl fused spiro thiohydantoins through silica
sulfuric acid induced oxidative rearrangement of ninhydrin adducts of
thioureas
Subhro Mandala, Animesh Pramanika,*
aDepartment of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009, India
Fax: +91-33-2351-9755; Tel: +91 9830107470
E-mail: pramanikanimesh61@gmail.com
1

Facile synthesis of phthalidyl fused spiro thiohydantoins through silica
sulfuric acid induced oxidative rearrangement of ninhydrin adducts of
thioureas
Subhro Mandala, Animesh Pramanika,*
aDepartment of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009, India
Fax: +91-33-2351-9755; Tel: +91 9830107470
E-mail: pramanikanimesh61@gmail.com
ABSTRACT
A one-pot three-component sequential synthetic protocol produces structurally and
biologically important phthalidyl fused spiro N,N'-disubstituted thiohydantoins from readily
available aromatic isothiocyanates, primary amines and ninhydrin. In this three-step synthesis
while the initial two steps are catalyst-free, in the final step silica sulfuric acid (SSA) induces
an oxidative rearrangement in [3.3.0]-bicyclic 1,2-diol adducts of ninhydrin and thioureas
under solvent-free condition to generate the final products spiro-fused thiohydantoins. The
adequate acidity of SSA in cooperation with moderate oxidizing property promotes a facile
oxidative rearrangement in 1,2-diol intermediates to produce the spiro-fused thiohydantoins
with diverse functionalities. Easy recyclability of SSA, good to excellent yield of the
products, wider substrate scope, shorter reaction time, solvent-free two steps out of three and
high atom economy make this method attractive and practicable.
Keywords: Thiohydantoins, Phthalide, Spiro-fused bi-heterocycles, Heterogeneous solid-
support, Recyclable SSA, Solvent-free oxidative rearrangement
1.
Introduction
2-thioxoimidazolidin-4-ones (thiohydantoins), a class of nitrogen and sulfur
containing heterocyclic analogues of imidazolidine family are found to possess a diverse
1

range of biological and pharmacological activities. For example, N-substituted thiohydantoins
are promising pharmacophores due to their antifungal [1], anti-prostate cancer [2] (compound
I, Fig. 1), and antiandrogenic activities [3] (compound II, Fig. 1). 5-arylidene thiohydantoins
are another group of structural units that act as antimycobacterial agents [4] as well as
NADPH oxidase (NOX) inhibitiors [5]. Moreover, a number of 5-arylidene thiohydantoin
analogues are used for the treatment of schistosomiasis infections [6] (compound III, Fig. 1).
Therefore, the synthesis of thiohydantoin scaffolds and assessment of their biological
activities generate considerable interest among the synthetic and pharmaceutical chemists.
However, a literature survey revealed that only a few synthetic procedures have been reported
for spiro-fused thiohydantoin derivatives [7-10]. These conformationally constrained sulfur
containing bi-heterocyclic spiro frameworks might be significant for exhibiting drug-like
activities inside the living body [7]. Recently, Takahashi and co-workers developed a one-
step synthetic route to produce 3-allyl-2-thiohydantoin-5-spiro-2'-piperidine and evaluated it
as a potential anti-mutagenic agent [8] (compound IV, Fig. 1). In 2009, Rutjes et al. reported
a base catalysed formation of pyrrolidine fused spiro thiohydantoins which were testified as
potential CNS ligands [9] (compound V, Fig. 1). Docsa et al. assembled a novel semirigid
heterocyclic motif by spiro-fusion of glucopyranosyl unit to thiohyantoin ring system and the
preliminary studies revealed this composite as antidiabetic agent [10] (compound VI, Fig. 1).
Because of their biological importance, the synthesis of new spiro-fused thiohydantoin cores
remains an immensely valid exercise. Keeping this in view, we would like to explore the
synthetic aspect of bioactive phthalidyl[11] fused spiro thiohydantoins. The structural
complexity of this spiro-fused skeleton along with its medicinal potential due to the presence
of both bioactive heterocyclic core thiohydantoin and phthalide, stimulated us to design a
general and efficient synthetic strategy, feasible under benign reaction conditions.
2

Fig. 1. Selected bio-active thiohydantoin molecules.
The multicomponent domino reactions have drawn considerable attention of the
synthetic organic chemists due to their inherent ability to introduce structural complexity in
organic molecules through convergent addition of the starting materials. In addition, high
atom economy and short reaction time make this protocol strategically efficient [12,13]. On
the other hand, the implementation of heterogeneous solid-support/catalyst in organic
reactions under solvent-free condition offers several advantages such as elimination of
hazardous solvent and easy recovery and recyclability of the solid-support/catalyst which
make the process economically viable. Moreover, the wide surface area of the solid-support
absorbs more number of reacting substances which can interact rapidly with large number of
catalytic active sites. By virtue of these, the heterogeneous solid-support promotes efficient
organic transformations, and amazingly in some cases in a chemo- or regio-selective manner
[14,15]. Silica sulfuric acid (SiO2-OSO3H or SSA), a familiar heterogeneous acidic solid-
support, easily prepared from silica gel and chlorosulfonic acid, has been exploited in various
organic reactions successfully [16-20]. Now we would like to introduce a facile SSA
mediated solvent-free intramolecular rearrangement of 3a,8a-dihydroxy-2-thioxo-
indenoimidazolones, the [3.3.0]-bicyclic 1,2-diol intermediates derived from the
condensation of thioureas and ninhydrin. The acidic and oxidizing property of SSA
competently assisted the oxidative rearrangement in 1,2-diol intermediates to produce spiro-
3

fused N,N'-disubstituted thiohydantoins through a number of bond-breaking and bond-
formation on the surface of the solid-support.
2.
Results and Discussion
In search of an optimal reaction condition, an exploratory study was initiated by
taking 1,2-diol intermediate 5a as the model substrate (Scheme 1, Table 1). A typical one-pot
sequential addition of phenyl isothiocyanate 1, benzylamine 2 and ninhydrin 4 at open-air
delivered N-benzyl-N'-phenyl-3a,8a-dihydroxy-2-thioxo-indenoimidazolone intermediate 5a
in almost quantitative yield (Scheme 1). First, the rapid formation of N-benzyl-N'-
phenylthiourea 3a was achieved within 2-3 minutes by successive addition of phenyl
isothiocyanate 1 (1.0 mmol) and benzylamine 2 (1.0 mmol) under neat condition at 0 °C.
Then the crude product 3a (1.0 mmol) and ninhydrin 4 (1.0 mmol) were dissolved in 10 mL
chloroform and the resulting mixture was refluxed for 15 minutes to produce the
condensation product 5a. Subsequently, the intermediate 5a which preferentially persists in
bicyclo[3.3.0]-hemiketal form was screened in presence of various solvents, solid-supports
and catalysts at different temperatures to find out the optimal reaction condition for
rearrangement in the final step of the synthesis (Table 1). Initially, 5a (1.0 mmol) was
dissolved in different polar protic solvents such as water and ethanol, and the reaction
mixtures were refluxed without adding any catalyst. But in both the cases no product was
formed even after 10 h of refluxing (Table 1, entries 1 and 2). A Similar outcome was also
observed in refluxing acetic acid medium containing 5a (Table 1, entry 3). Surprisingly,
when 1 mol% of sulfuric acid was added as catalyst to acetic acid a new compound was
generated from 5a upon 6 h of reflux. Chromatographic purification and spectroscopic
analysis revealed the formation of the desired product 6a, although the yield was only 20%
(Table 1, entry 4). The sulfuric acid which acts as a proton source, as well as an oxidizing
agent, was suitable to promote the product formation by virtue of these properties.
4

Unfortunately, further addition of sulfuric acid resulted adversely as the reaction mixture was
charred due to high acidity (Table 1, entries 5 and 6). Then we looked for an effective acid-
catalyst which will display oxidizing property without damaging the reaction mass at elevated
temperature. Therefore, we implemented melamine sulfonic acid (MSA), PEG sulfonic acid
(PEG-OSO3H) and silica sulfuric acid (SSA) as different heterogeneous solid-supports. A
uniform composition of 5a (1.0 mmol) and heterogeneous solid-support (300 mg) was heated
at 80 °C in absence of solvent. In case of MSA and PEG-OSO3H very low yield of 6a was
observed even after 10 h of continuous heating (Table 1, entries 7 and 8). However, an
effective result was evolved in case of SSA after 2 h of heating which produced 6a in ~ 50%
yield (Table 1, entry 9). Interestingly, when the amount of SSA was enhanced to 400 mg, the
yield of 6a was also increased to ~65% (Table 1, entry 10). Likewise, 600 mg of SSA load
boosted the yield up to ~75 %, which remained unchanged till the addition of 700 mg of SSA
(Table 1, entries 11-13). Surprisingly, further addition of SSA caused a sharp fall in the
product yield (Table 1, entries 14 and 15). This observation suggested that the presence of
moderately strong sulfonic acid group on the surface of SSA causes decomposition of the
product 6a at high temperature. Upon lowering the reaction temperature from 80 °C to 65 °C
the yield of the product 6a was improved up to ~ 83% using 600 mg of SSA (Table 1, entries
16 and 17). But further lowering of the reaction temperature caused worsening of the product
yield (Table 1, entry 18). Therefore, a series of studies established that the maximum yield of
6a (~ 83%) can be obtained through heating of 5a (1.0 mmol) at 65 °C for 2 h in presence of
600 mg of SSA under solvent-free condition.
5

O
O
OH
OH
O
N C S
OH
N
4
1
Oxidative
Rearrangement
S
N
HN
HN
(1.0 mmol)
O
S
(1.0 mmol)
N
HO N
S
a
O
b
NH2
O
(1.0 mmol)
3a
5a
6a
2
Scheme 1. (a) Neat condition, 0 °C, 2-3 min; (b) CHCl3, reflux, 15 min. Yields in the initial
two steps are quantitative.
Table 1
Optimization of reaction conditions for the synthesis of 3-benzyl-1-phenyl-2-thioxo-3'H-
spiro[imidazolidine-4,1'-isobenzofuran]-3',5-dione 6a from 5a.a
Entry
Solvent
(10 mL)
H2O
Catalyst/ solid-support
Amount Temp.(°C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
-
-
-
100
80
10
10
10
6
-
EtOH
AcOH
AcOH
AcOH
AcOH
-
-
-
-
-
110
110
110
110
80
-
H2SO4
H2SO4
H2SO4
MSA
PEG-OSO3H
SSA
1 mol %
2 mol %
3 mol %
300 mg
300 mg
300 mg
20
18
12
15
17
50
6
6
10
10
2
-
80
-
80
6

10
11
12
13
14
15
16
17
18
-
-
-
-
-
-
-
-
-
SSA
SSA
SSA
SSA
SSA
SSA
SSA
SSA
SSA
400 mg
500 mg
600 mg
700 mg
800 mg
1000 mg
600 mg
600 mg
600 mg
80
80
80
80
80
80
70
65
60
2
2
2
2
2
2
2
2
2
65
70
75
75
68
45
80
83
75
aSubstrate 5a (1.0 mmol) was treated with different catalysts or solid-support or in different solvents
and heated at different temperatures (bold row 17 indicates the optimized reaction conditions).
bIsolated yield of 6a in the final step
The substrate scope of the present synthetic strategy was thoroughly investigated
under the optimized reaction condition (Table 1, entry 17). Initially, a series of N,N'-
disubstituted thioureas (3a-w) were synthesized by addition of differently substituted
aromatic isothiocyanates 1 with primary amines 2. Then the mixtures of thioureas 3 and
ninhydrin 4 in chloroform were refluxed for 15 minutes to produce a broad spectrum of 1,2-
diol intermediates 5a-w (Table 2). It was observed that the nucleophilicity of the two nitrogen
atoms of the disubstituted thioureas (3a-w) are different. The nitrogen atom attached to the
aryl group is less nucleophilic due to the lone pair delocalization with the aromatic ring
which makes the nitrogen a hard centre. On the other hand, the nitrogen atom attached to the
aliphatic group is more nucleophilic and acts as a soft centre. In case of ninhydrin, the
presence of two strong electron-withdrawing carbonyl groups makes the C-2 centre as a hard
site. Thereafter a preferential hard-hard interaction occurred during the condensation of
ninhydrin and thioureas to produce particularly one isomeric 1,2-diol intermediate through a
regioselective reaction (Table 2, 5a-w). All the intermediates 5a-w with electron-withdrawing
7

as well as electron-donating substituents were successfully rearranged by SSA to the desired
spiro-fused thiohydantoins 6a-w under the optimized reaction conditions in good to excellent
yield (Table 2). In general, the presence of sterically hindered substituents at R caused
13
lowering of the overall yield of the products (Compounds 6f, 6g and 6u, Table 2). The C
NMR spectra of the purified solid products 6a-w displayed three characteristic carbon peaks
at ~ δ 166.6, 166.0 and 91.0 indicating the lactone carbonyl carbon, amide carbonyl carbon
and spiro carbon respectively. This novel synthetic strategy was further extended to
synthesize a series of new spiro-fused hydantoin derivatives (7a-f) using SSA (Table 3)
instead of the strongly oxidizing NaIO4 as reported earlier [21].
1
The structures of the synthesized compounds 6 and 7 were confirmed by FTIR, H
13
and C NMR spectroscopy, HRMS and elemental analysis. Moreover, single-crystal X-ray
diffraction analysis confirmed the formation of compounds 6a and 6c (Fig. 2).
Table 2
Library synthesis of N,N'-disubstituted-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-diones 6 from 5.a
___________________________________________________________________________
8

S
S
S
N
S
N
N
N
O
O
O
O
N
N
N
N
O
O
O
O
O
O
O
O
6h (84%)
6e (85%)
6f (68%)
6g (70%)
S
N
N
O
O
S
S
N
N
O
S
N
N
O
O
N
Cl
O
O
O
O
N
OH
O
O
O
6l (82%)
6i (84%)
6j (78%)
6k (75%)
O
O
S
N
N
O
S
N
N
O
O
S
N
N
O
S
N
O
O
O
O
N
N
O
O
O
O
6n (79%)
6p (84%)
6o (86%)
6m (85%)
F
F
O
S
O
O
S
S
S
N
N
N
O
N
F
O
O
N
N
N
N
O
O
O
O
O
O
O
O
6t (88%)
6q (82%)
6r (87%)
6s (90%)
Cl
Cl
Cl
Cl
O
Cl
O
Cl
O
S
S
N
N
O
S
N
N
N
N
O
O
O
O
O
6w (86%)
6u (70%)
6v (85%)
___________________________________________________________________________
a Isolated yields (%) of 6 in the final step; yields in the initial two steps are quantitative.
9

Table 3
Library synthesis of N,N'-disubstituted-2-oxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-diones 7 from 5'.a
__________________________________________________________________________________
___________________________________________________________________________
a Isolated yields (%) of 7 in the final step; yields in the initial two steps are quantitative.
C21
C20
C19
S1
C14
C21
C20
C13
C22
C23
S1
C10
C15
C16
C18
N1
C9
C17
C18
C12
C11
C16
C10
N1
C9
C17
C15
C6
C5
C8
O3
C1
O3
O1
O1
C1
C2
C3
C8
C6
C7
O2
C2
C4
C5
C7
C3
C4
O2
6a
6c
Fig. 2. ORTEP diagrams of compounds 6a (CCDC 1858914) & 6c (CCDC 1921631).
Thermal ellipsoids are shown at 50% probability.
10

The surface of the heterogeneous SSA is embedded with a large number of active
sites containing oxo-, -SO3H and -OH functional groups. The sulfonic acid groups rapidly
transfer protons for catalysis of the reaction and also act as a binding and activating group of
the 1,2-diol intermediates 5. The active sites of SSA are also responsible for carrying out
oxidation at the intermediate stage of the reaction. A plausible mechanistic pathway has been
depicted in Scheme 2 to rationalize the product formation, where the dual role of SSA has
been emphasized in the oxidative rearrangement. At first the intermediate 5 gets protonated
from the sulfonic acid group and consequently the central C-C bond is ruptured to furnish
eight-membered amide intermediate A which readily tautomerizes to α-hydroxyketo
intermediate B. Next, the intermediate B experiences SSA assisted oxidation to form eight-
membered intermediate C with vicinal dicarbonyl groups. Thereafter, a nucleophilic attack of
SiO2-OSO3ꢀ causes the breakage of the cyclic amide linkage to produce a substructure D.
Subsequently a facile intramolecular attack of the free NH group of D to one of the vicinal
dicarbonyl groups produces thiohydantoin/hydantoin intermediate E. In the final step, the
nucleophilic attack of the free hydroxyl group of E to the ester carbonyl produces spiro-fused
thiohydantoins/hydantoins 6/7 with simultaneous regeneration of SSA. Therefore, several
bond-breaking and bond-construction on the surface of SSA lead to the facile formation of
spiro-fused N,N'-disubstituted thiohydantoins/hydantoins under mild and solvent-free
conditions.
11

Scheme 2. A plausible mechanistic pathway for the formation of spiro-fused
thiohydantoins/hydantoins 6/7 on the SSA surface.
As SSA has been implemented as solid-support in the synthesis, the ease of
separation, as well as its scope of reusability was examined to assess the industrial viability of
the method. In the present synthesis, the SSA particles were easily separated from the
reaction mixture by sonication in ethylacetate followed by simple filtration. Then
straightforward washing of SSA with ethylacetate made them suitable for application in the
next catalytic cycle. This way the SSA was employed in the synthesis of 6a for six catalytic
cycles. Notably the yield of the product 6a altered from 83% to 80% which showed an
insignificant loss of the catalytic activity of SSA even after repeated applications (Fig. 3).
12

Fig. 3. Recyclability of SSA in the synthesis of 6a.
3.
Conclusions
In conclusion, we have developed a one-pot synthetic method for the construction of
drug-like phthalidyl fused spiro thiohydantoin/hydantoin scaffolds from easily available
starting materials within a short time. The cooperative acidic and oxidizing properties of SSA
have been successfully exploited in the facile synthesis of spiro-fused
thiohydantoins/hydantoins with diverse functionalities. Easy recyclability of SSA, good to
excellent yield of the products, wider substrate scope, solvent-free two steps out of three and
high atom economy make this method attractive and practicable. This multicomponent
synthesis involving SSA represents an effective one-pot general approach to construct
complex spiro-fused thiohydantoins/hydantoins with considerable diversity and variation
from readily available substrates.
4.
Experimental Section
4.1.
General Information
The solvents and chemicals were procured from commercial chemical suppliers and
used without further purification. Melting points were recorded in open capillary tubes and
were uncorrected. Perkin-Elmer 782 spectrophotometer was used for FTIR spectra. Coloumn
13

chromatography was performed with neutral alumina (Merck) and using hexane/ethylacetate
1
solvent system. H (300 MHz & 500 MHz) and 13C NMR (75 MHz & 126 MHz) spectra
were recorded on Bruker instrument (300 MHz & 500 MHz) in CDCl3 and DMSO-d6. Some
1H (400 MHz) and 13C NMR (101 MHz) spectra were recorded on JEOL instrument (400
MHz) in CDCl3. HRMS spectra were recorded using Xevo G2-S QTof instrument. Elemental
analyses (C, H and N) were done in Perkin-Elmer 2400 elemental analyzer. The X-ray
diffraction data for crystallized compounds were collected with MoKα radiation at 296 K
using the Bruker APEX-II CCD System.
4.2.
General procedure for the synthesis of N,N'-disubstituted-3a,8a-dihydroxy-2-
thioxo/oxo-2,3,3a,8a-tetrahydroindeno[1,2-d]imidazol-8(1H)-ones (5a-w/ 5a'-f')
At first, the synthesis of N,N'-disubstituted-thioureas/ureas (3a-w/ 3a'-f') were carried
out within 2-3 minutes by successive addition of substituted isothiocyanate/isocyanate 1/1'
(1.0 mmol) and primary amines 2 (1.0 mmol) under neat condition at 0 °C in a 100 mL round
bottom flask. Then the crude thiourea/urea derivatives (3a-w/ 3a'-f') were dissolved in 10 mL
chloroform. To the above solution 178 mg (1.0 mmol) of ninhydrin 4 was added and the
mixture was subjected to reflux for 15 minutes. Completion of the reaction was monitored by
TLC. Thereafter, chloroform was removed under reduced pressure. Instead of tedious work-
up procedure and chromatographic purification the crude mixture was kept in high vacuum
till solid crystalline intermediate 5 appeared. The resulting solid product 5 was characterized
by 1H and 13C NMR spectroscopy. Presence of two characteristic carbon peaks at ~ δ 90.0 in
13C NMR spectra suggested the formation of 1,2-diol intermediates (5a-w/ 5a'-f').
4.3.
Spectroscopic data of some representative intermediates 5
4.3.1. 3-benzyl-3a,8a-dihydroxy-1-phenyl-2-thioxo-2,3,3a,8a-tetrahydroindeno[1,2-
d]imidazol-8(1H)-one (5a)
14

Yield 386 mg (~ 96%) as yellow solid; 1H NMR (500 MHz, CDCl3): δppm = 7.82 (d, J
= 7.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H; ), 7.54 (t, J = 7.5 Hz, 1H), 7.44-7.42 (m, 2H), 7.40-
7.37 (m, 5H), 7.28-7.22 (m, 6H), 5.30-5.22 (m, 2H); 13C NMR (126 MHz, CDCl3) δppm
=
193.8, 181.5, 147.8, 137.6, 137.1, 135.6, 132.5, 131.2, 130.5, 129.18, 129.12, 128.5, 127.6,
127.4, 125.4, 125.1, 92.0, 89.7, 46.9.
4.3.2. 3-(4-fluorobenzyl)-3a,8a-dihydroxy-1-phenyl-2-thioxo-2,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(1H)-one (5d)
1
Yield 410 mg (~ 98%) as yellow solid; H NMR (300 MHz, DMSO-d6) δppm = 7.81-
7.75 (m, 2H), 7.70 (s, 1H), 7.63-7.57 (m, 3H), 7.41-7.33 (m, 3H), 7.26-7.22 (m, 4H), 7.09-
6.98 (m, 2H), 5.22 (d, J = 16.5 Hz, 1H), 5.00 (d, J = 16.5 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δppm = 194.5, 180.1, 161.3 (d, J = 240.52 Hz), 159.7, 149.0, 137.3, 136.8, 134.5,
132.9, 131.3, 131.1, 130.9, 129.5 (d, J = 4.12 Hz), 128.6, 128.1, 126.2, 124.4, 114.9 (d, J =
20.92 Hz), 92.0, 91.6, 45.6.
4.3.3. 3-cyclopropyl-3a,8a-dihydroxy-1-phenyl-2-thioxo-2,3,3a,8a-tetrahydroindeno[1,2-
d]imidazol-8(1H)-one (5f)
Yield 335 mg (~ 95%) as white solid; 1H NMR (300 MHz, DMSO-d6) δppm = 8.06 (d,
J = 6.3 Hz, 1H), 7.91-7.86 (m, 1H), 7.77 (d, J = 6.3 Hz, 1H), 7.66-7.55 (m, 2H), 7.29-7.26
13
(m, 4H), 7.05-7.03 (m, 2H), 1.91-1.81 (m, 1H), 0.90-0.88 (m, 2H), 0.71-0.68 (m, 2H); C
NMR (75 MHz, DMSO-d6) δppm = 194.8, 181.8, 148.6, 137.4, 137.2, 133.1, 131.5, 131.1,
128.8, 128.2, 126.4, 124.6, 92.3, 90.9, 27.4, 9.2, 5.3.
4.3.4. 3-butyl-3a,8a-dihydroxy-1-phenyl-2-thioxo-2,3,3a,8a-tetrahydroindeno[1,2-
d]imidazol-8(1H)-one (5i)
1
Yield 364 mg (~ 99%) as yellow solid; H NMR (300 MHz, DMSO-d6) δppm = 7.90
(d, J = 6.9 Hz, 1H), 7.75-7.68 (m, 4H), 7.47-7.40 (m, 3H), 7.23 (s, 2H), 6.72 (d, J = 6.6 Hz,
1H), 3.79-3.74 (m, 2H), 1.87-1.77 (m, 1H), 1.74-1.66 (m, 1H), 1.40-1.30 (m, 2H), 0.95 (t, J =
15

7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δppm = 196.2, 179.0, 148.9, 137.0, 136.8, 132.7,
131.3, 131.2, 128.7, 128.3, 125.7, 124.4, 92.1, 90.1, 43.2, 30.4, 20.2, 14.1.
4.3.5. 3-allyl-3a,8a-dihydroxy-1-phenyl-2-thioxo-2,3,3a,8a-tetrahydroindeno[1,2-
d]imidazol-8(1H)-one (5j)
1
Yield 340 mg (~ 97%) as yellow solid; H NMR (300 MHz, DMSO-d6) δppm = 8.01
(d, J = 7.8 Hz, 1H), 7.90 (t, J = 7.5 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.71-7.60 (m, 3H),
7.43-7.35 (m, 3H), 7.22-7.19 (m, 2H), 5.91-5.79 (m, 1H), 5.16 (d, J = 17.4 Hz, 1H), 5.05 (d, J
= 10.2 Hz, 1H), 4.57-4.52 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δppm = 194.2, 179.0,
148.8, 137.0, 136.9, 134.4, 132.7, 131.1, 130.8, 130.6, 128.3, 127.7, 126.2, 124.1, 116.8,
91.7, 91.1, 45.2.
4.3.6. 3a,8a-dihydroxy-3-(2-hydroxyethyl)-1-phenyl-2-thioxo-2,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(1H)-one (5k)
1
Yield 348 mg (~ 98%) as white solid; H NMR (300 MHz, DMSO-d6) δppm = 8.08-
8.04 (m, 1H), 7.99-7.94 (m, 1H), 7.84-7.79 (m, 1H), 7.74-7.59 (m, 3H), 7.39-7.37 (m, 3H),
7.19-7.18 (m, 2H), 4.95 (s, 1H), 4.04-3.93 (m, 1H), 3.85-3.77 (m, 2H), 3.63-3.53 (m, 1H);
13C NMR (75 MHz, DMSO-d6) δppm = 194.3, 179.1, 149.2, 137.4, 137.1, 133.0, 131.5, 130.8,
128.6, 128.0, 125.7, 124.5, 91.6, 91.2, 58.7, 45.3.
4.3.7. 3a,8a-dihydroxy-1-(4-methoxyphenyl)-3-(pyridin-3-ylmethyl)-2-thioxo-2,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(1H)-one (5p)
1
Yield 425 mg (~ 98%) as yellow solid; H NMR (300 MHz, DMSO-d6) δppm = 8.43-
8.30 (m, 2H), 7.70-7.56 (m, 7H), 7.16-7.07 (m, 3H), 6.89 (s, 2H), 5.16-5.07 (m, 2H), 3.72 (s,
13
3H); C NMR (75 MHz, DMSO-d6) δppm = 194.5, 180.2, 159.1, 149.1, 148.0, 137.1, 135.4,
134.1, 133.1, 132.0, 131.5, 129.8, 126.1, 124.6, 123.3, 114.0, 91.9, 91.4, 55.7, 44.2.
4.3.8. 3a,8a-dihydroxy-1-(2-methoxyphenyl)-3-(4-methylbenzyl)-2-thioxo-2,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(1H)-one (5r)
16

1
Yield 440 mg (~ 98%) as yellow solid; H NMR (300 MHz, DMSO-d6) δppm = 7.68-
7.65 (m, 1H), 7.50-7.49 (m, 3H), 7.38 (d, J = 9.0 Hz, 2H), 7.31-7.22 (m, 2H), 7.05-7.03 (m,
2H), 6.93-6.91 (m, 4H), 5.12 (d, J = 16.2 Hz, 1H), 4.91 (d, J = 16.8 Hz, 1H), 3.36 (s, 3H),
2.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δppm = 193.5, 180.2, 156.1, 148.5, 135.9, 135.4,
135.2, 133.4, 132.1, 130.8, 129.8, 128.4, 127.3, 125.9, 125.8, 123.4, 120.2, 112.4, 92.0, 90.3,
55.4, 45.7, 20.8.
4.4. General procedure for the synthesis of N,N'-disubstituted-2-thioxo-3'H-
spiro[imidazolidine-4,1'-isobenzofuran]-3',5-diones (6a-w) and N,N'-disubstituted-3'H-
spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-triones (7a-f)
The synthesized intermediates (5a-w/ 5a'-f', 1.0 mmol) in 100 mL round bottom flask
(as described earlier) was dissolved in minimum volume of chloroform and then 600 mg of
SSA was added. The mixture was stirred for 5 minutes at room temperature and then dried
under vacuum. These way intermediates 5 were absorbed on the surface of SSA which was
then subjected to heating at 65 °C on an oil bath. After 2 h continuous heating the maximum
conversion of the intermediates was observed (as monitored by TLC). After cooling at room
temperature ethylacetate was added to the mass which was sonicated and then filtered
through Whatman-42 filter paper followed by washing with ethylacetate (4
× 5 ml) to
separate out organic compounds from SSA surface. Then ethylacetate was removed from the
filtrate under vacuum to collect the crude product which was purified over neutral alumina
coloumn chromatography using 20% ethylacetate in hexane as solvent system. The purified
1
solid products 6/7 were characterized by H and 13C NMR spectroscopy. Presence of three
characteristic carbon peaks at δ ~ 166.6, 166.0 & 91.0 in 13C NMR spectra indicates the
lactone carbonyl carbon, amide carbonyl carbon of thiohydantoin ring and spiro carbon
respectively. In addition HRMS values strongly suggested the formation of the desired spiro
derivatives 6/7.
17

4.4.1. 3-benzyl-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-dione
(6a)
Rf=0.50 (Hexane/Ethyl acetate 7:3); Yield 332 mg (~ 83%) as white solid; m.p. 120
°C. IR (KBr): 3100 (Ar-H), 2980 (aliphatic C-H), 1760 (lactone C=O), 1600 (amide C=O),
1150 (C=S) cm-1. 1H NMR (300 MHz, CDCl3) δppm = 7.83 (d, J = 7.8 Hz, 1H), 7.50-7.36 (m,
5H), 7.33-7.27 (m, 2H), 7.04-6.91 (m, 6H), 5.08 (d, J = 15.3 Hz, 1H), 4.50 (d, J = 15.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δppm = 183.5, 166.6, 166.0, 141.0, 135.2, 134.8, 132.7,
131.8, 129.6, 129.2, 128.4, 128.36, 128.34, 128.0, 126.8, 126.2, 123.0, 91.7, 47.4. HRMS
(ESI-TOF): m/z calcd for C23H16N2O3S + H+: 401.0960 [M + H]+; found: 401.0992.
4.4.2. 1-phenyl-3-(pyridin-3-ylmethyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6b)
Rf=0.38 (Hexane/Ethyl acetate 4:6); Yield 320 mg (~ 80%) as white solid; m.p. 160
°C. IR (KBr): 3130 (Ar-H), 2988 (aliphatic C-H), 1755 (lactone C=O), 1590 (amide C=O),
1145 (C=S) cm-1. 1H NMR (500 MHz, CDCl3) δppm = 8.43 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H),
8.00 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.59-7.48 (m, 5H), 7.39 (d, J = 7.0 Hz, 2H),
7.17 (d, J = 7.6 Hz, 1H), 7.13-7.10 (m, 1H), 5.10 (d, J = 15.5 Hz, 1H), 4.66 (d, J = 15.5 Hz,
1H); 13C NMR (126 MHz, CDCl3) δppm = 183.4, 166.3, 165.8, 149.5, 149.3, 140.7, 136.0,
135.2, 132.5, 132.4, 131.1, 129.8, 129.3, 128.2, 126.8, 126.6, 123.3, 122.9, 91.6, 44.7.
Elemental analysis calcd (%) for C22H15N3O3S: C 65.82, H 3.77, N 10.47; found: C 65.78, H
3.80, N 10.40.
4.4.3. 3-phenethyl-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-
dione (6c)
Rf=0.46 (Hexane/Ethyl acetate 7:3); Yield 364 mg (~ 88%) as white solid; m.p. 180
°C. IR (KBr): 3132 (Ar-H), 2970 (aliphatic C-H), 1762 (lactone C=O), 1607 (amide C=O),
1158 (C=S) cm-1. 1H NMR (300 MHz, CDCl3) δppm = 7.99 (d, J = 7.2 Hz, 1H), 7.73-7.65 (m,
18

2H), 7.48-7.44 (m, 3H), 7.41-7.37 (m, 1H), 7.34-7.31 (m, 2H), 7.17-7.11 (m, 3H), 7.00-6.97
(m, 2H), 3.85-3.75 (m, 1H), 3.44-3.34 (m, 1H), 2.93 (t, J = 8.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δppm = 182.7, 166.5, 166.0, 140.9, 137.4, 135.5, 132.4, 129.6, 129.2, 128.6, 128.3,
127.2, 126.7, 126.6, 122.7, 92.3, 45.8, 34.2. HRMS (ESI-TOF): m/z calcd for C24H18N2O3S +
H+: 415.1116 [M + H]+; found: 415.1113.
4.4.4. 3-(4-fluorobenzyl)-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6d).
Rf=0.48 (Hexane/Ethyl acetate 7:3); Yield 334 mg (~ 80%) as white solid; m.p. 152
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.90 (d, J = 7.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.50-
7.43 (m, 4H), 7.34-7.31 (m, 2H), 7.05-6.93 (m, 3H), 6.77-6.69 (m, 2H), 5.06 (d, J = 15.3 Hz,
1H), 4.53 (d, J = 15.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δppm = 183.5, 166.5, 166.0, 162.3
(d, J = 246.00 Hz), 141.0, 135.0, 132.6, 132.0, 131.2, 130.3 (d, J = 8.55 Hz), 129.7, 129.3,
128.3, 126.9, 126.4, 122.9, 115.3 (d, J = 21.75 Hz), 91.7, 46.6. HRMS (ESI-TOF): m/z calcd
for C23H15FN2O3S + H+: 419.0865 [M + H]+; found: 419.0877.
4.4.5. 3-(4-methylbenzyl)-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6e)
Rf=0.51 (Hexane/Ethyl acetate 7:3); Yield 350 mg (~ 85%) as white solid; m.p. 110
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.95 (d, J = 7.5 Hz, 1H), 7.64-7.59 (m, 1H), 7.54-
7.48 (m, 4H), 7.42-7.39 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 6.92 (s, 4H), 5.09 (d, J = 15.0 Hz,
13
1H), 4.63 (d, J = 15.3 Hz, 1H), 2.25 (s, 3H); C NMR (75 MHz, CDCl3) δc = 183.4, 166.7,
166.0, 141.1, 137.7, 134.8, 132.7, 132.1, 131.7, 129.6, 129.2, 129.0, 128.4, 128.3, 126.9,
126.2, 123.0, 91.8, 47.2, 21.0. HRMS (ESI-TOF): m/z calcd for C24H18N2O3S + H+: 415.1116
[M + H]+; found: 415.1196.
4.4.6. 3-cyclopropyl-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-
dione (6f)
19

Rf=0.48 (Hexane/Ethyl acetate 7:3); Yield 240 mg (~ 68%) as white solid; m.p. 194
°C. IR (KBr): 3090 (Ar-H), 2980 (aliphatic C-H), 1750 (lactone C=O), 1590 (amide C=O),
1140 (C=S) cm-1. 1H NMR (400 MHz, CDCl3) δppm = 8.05-8.01 (m, 1H), 7.83-7.79 (m, 1H),
7.75-7.72 (m, 1H), 7.52-7.48 (m, 4H), 7.35-7.33 (m, 2H), 2.59 (s, 1H) , 0.92 (s, 1H), 0.80-
13
0.77 (m, 1H), 0.62 (s, 1H) , 0.54-0.50 (m, 1H); C NMR (101 MHz, CDCl3) δppm = 184.2,
166.5, 166.4, 141.7, 135.4, 132.4, 132.1, 129.6, 129.2, 128.2, 127.2, 126.7, 122.1, 93.0, 27.0,
6.6, 5.0. Elemental analysis calcd (%) for C19H14N2O3S: C 65.13, H 4.03, N 8.00; found: C
65.11, H 4.09, N 7.92.
4.4.7. 3-cyclohexyl-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-
dione (6g)
Rf=0.55 (Hexane/Ethyl acetate 7:3); Yield 275 mg (~ 70%) as white solid; m.p. 126
°C. IR (KBr): 3110 (Ar-H), 2986 (aliphatic C-H), 1755 (lactone C=O), 1592 (amide C=O),
1135 (C=S) cm-1. 1H NMR (300 MHz, CDCl3) δppm = 8.06 (d, J = 6.9 Hz, 1H), 7.85-7.73 (m,
2H), 7.60-7.50 (m, 4H), 7.40-7.36 (m, 2H), 4.38 (s, 1H), 2.07 (d, J = 10.8 Hz, 1H), 1.78-1.53
(m, 5H), 1.34-1.17 (m, 3H), 0.99-0.87 (m, 1H); 13C NMR (75 MHz, CDCl3) δppm = 182.3,
166.8, 166.2, 142.4, 135.1, 132.6, 132.0, 129.4, 129.1, 128.4, 127.2, 126.5, 122.9, 92.3, 58.6,
30.9, 30.4, 26.0, 25.9, 24.9. Elemental analysis calcd (%) for C22H20N2O3S: C 67.33, H 5.14,
N 7.14; found: C 67.24, H 5.21, N 7.10.
4.4.8. 1-phenyl-3-propyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-dione
(6h)
Rf=0.54 (Hexane/Ethyl acetate 7:3); Yield 296 mg (~ 84%) as white solid; m.p. 110
°C. IR (KBr): 3090 (Ar-H), 2972 (aliphatic C-H), 1766 (lactone C=O), 1603 (amide C=O),
1150 (C=S) cm-1. 1H NMR (300 MHz, CDCl3) δppm = 8.08 (d, J = 7.8 Hz, 1H), 7.90-7.76 (m,
2H), 7.58-7.49 (m, 4H), 7.47-7.39 (m, 2H), 3.76-3.66 (m, 1H), 3.31- 3.21 (m, 1H), 1.78-1.54
13
(m, 2H), 0.84 (t, J = 7.4 Hz, 3H); C NMR (75 MHz, CDCl3) δppm = 182.8, 166.6, 166.1,
20

141.1, 135.4, 132.5, 132.3, 129.5, 129.1, 128.3, 127.2, 126.6, 122.6, 92.2, 46.0, 21.5, 11.1.
HRMS (ESI-TOF): m/z calcd for C19H16N2O3S + H+: 353.0960 [M + H]+; found: 353.1010.
4.4.9. 3-butyl-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-dione
(6i).
Rf=0.54 (Hexane/Ethyl acetate 7:3); Yield 310 mg (~ 84%) as white solid; m.p. 116
°C. 1H NMR (300 MHz, CDCl3) δppm = 7.98 (d, J= 7.5 Hz, 1H), 7.78-7.63 (m, 2H), 7.54-7.40
(m, 4H), 7.31-7.29 (m, 1H), 7.22-7.18 (m, 1H), 3.70-3.60 (m, 1H), 3.26-3.16 (m, 1H), 1.52-
1.32 (m, 2H), 1.21-1.12 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δppm
=
182.8, 166.6, 166.1, 141.1, 135.5, 132.4, 129.5, 129.4, 129.2, 128.3, 127.3, 126.7, 122.7,
92.3, 44.2, 30.2, 19.9, 13.4. HRMS (ESI-TOF): m/z calcd for C20H18N2O3S + H+: 367.1116
[M + H]+; found: 367.1194.
4.4.10. 3-allyl-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-dione (6j)
Rf=0.56 (Hexane/Ethyl acetate 7:3); Yield 274 mg (~ 78%) as white solid; m.p. 120
1
°C. IR (KBr): 3130 (Ar-H), 1750 (lactone C=O), 1600 (amide C=O), 1155 (C=S) cm-1. H
NMR (300 MHz, CDCl3) δppm = 7.92 (d, J = 7.5 Hz, 1H), 7.73-7.61 (m, 2H), 7.45-7.37 (m,
4H), 7.30-7.27 (m, 2H), 5.72-5.59 (m, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.80 (d, J = 17.1 Hz,
13
1H), 4.28 (dd, J = 15.0, 7.0 Hz, 1H), 3.98 (dd, J = 16.4, 6.4 Hz, 1H); C NMR (75 MHz,
CDCl3) δppm = 182.6, 166.5, 166.0, 140.9, 135.2, 132.5, 132.3, 130.8, 129.5, 129.2, 128.2,
127.3, 126.4, 123.0, 119.4, 91.9, 46.7. HRMS (ESI-TOF): m/z calcd for C19H14N2O3S + H+:
351.0803 [M + H]+; found: 351.0812.
4.4.11. 3-(2-hydroxyethyl)-1-phenyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6k)
Rf=0.44 (Hexane/Ethyl acetate 7:3); Yield 265 mg (~ 75%) as white solid; m.p. 110
1
°C. H NMR (500 MHz, CDCl3) δppm = 8.05 (d, J = 7.5 Hz, 1H), 7.84 (t, J = 7.4 Hz, 1H),
7.77 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54-7.47 (m, 3H), 7.38 (d, J = 7.0 Hz, 2H),
21

13
4.00 (dt, J = 14.7, 5.0 Hz, 1H), 3.80-3.71 (m, 2H), 3.53-3.48 (m, 1H), 1.88 (br s, 1H); C
NMR (101 MHz, CDCl3) δppm = 184.0, 166.6, 166.1, 140.7, 135.7, 132.6, 132.5, 129.8,
129.4, 128.3, 127.4, 126.8, 122.9, 92.1, 60.4, 46.6. Elemental analysis calcd (%) for
C18H14N2O4S: C 61.01, H 3.98, N 7.91; found: C 60.96, H 4.05, N 7.81.
4.4.12. 3-(4-chlorobenzyl)-2-thioxo-1-(p-tolyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6l)
Rf=0.49 (Hexane/Ethyl acetate 7:3); Yield 370 mg (~ 82%) as white solid; m.p. 178
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.98 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H),
7.57 (t, J = 7.2 Hz, 1H), 7.37-7.28 (m, 4H), 7.16-7.10 (m, 3H), 7.04-7.01 (m, 2H), 5.11 (d, J
13
= 15.3 Hz, 1H), 4.61 (d, J = 15.3 Hz, 1H), 2.44 (s, 3H); C NMR (75 MHz, CDCl3) δppm
=
183.6, 166.5, 166.1, 140.8, 139.9, 135.0, 133.9, 133.7, 131.9, 129.9, 129.7, 128.5, 127.9,
126.7, 126.3, 122.9, 91.6, 46.5, 21.3. Elemental analysis calcd (%) for C24H17ClN2O3S: C
64.21, H 3.82, N 6.24; found: C 64.24, H 3.89, N 6.19.
4.4.13. 3-(4-methylbenzyl)-2-thioxo-1-(p-tolyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6m)
Rf=0.56 (Hexane/Ethyl acetate 7:3); Yield 364 mg (~ 85%) as white solid; m.p. 160
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.96 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H),
7.52 (t, J = 7.6 Hz, 1H), 7.37-7.28 (m, 4H), 7.14 (d, J = 7.5 Hz, 1H), 6.94 (s, 4H), 5.10 (d, J =
14.7 Hz, 1H), 4.65 (d, J = 15.0 Hz, 1H), 2.44 (s, 3H), 2.27 (s, 3H); 13C NMR (75 MHz,
CDCl3) δppm = 183.5, 166.6, 166.0, 141.0, 139.7, 137.6, 134.7, 132.0, 131.6, 129.9, 129.8,
128.9, 128.3, 127.9, 126.8, 126.0, 122.9, 91.7, 47.1, 21.2, 20.9. Elemental analysis calcd (%)
for C25H20N2O3S: C 70.07, H 4.70, N 6.54; found: C 70.01, H 4.75, N 6.58.
4.4.14. 3-allyl-2-thioxo-1-(p-tolyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-dione
(6n)
22

Rf=0.53 (Hexane/Ethyl acetate 7:3); Yield 288 mg (~ 79%) as white solid; m.p. 140
°C. 1H NMR (300 MHz, CDCl3) δppm = 8.04 (d, J = 7.2 Hz, 1H), 7.85- 7.73 (m, 2H), 7.55 (d,
J = 7.5 Hz, 1H), 7.36-7.26 (m, 4H), 5.84-5.71 (m, 1H), 5.03 (d, J = 10.2 Hz, 1H), 4.92 (d, J =
16.8 Hz, 1H), 4.40 (dd, J = 15.5, 6.7 Hz, 1H), 4.10 (dd, J = 15.3, 6.2 Hz, 1H), 2.43 (s, 3H);
13C NMR (75 MHz, CDCl3) δppm = 182.9, 166.6, 166.1, 140.9, 139.8, 135.2, 132.3, 130.9,
129.9, 127.9, 127.4, 126.4, 123.0, 119.3, 92.0, 46.7, 21.2. Elemental analysis calcd (%) for
C20H16N2O3S: C 65.92, H 4.43, N 7.69; found: C 65.90, H 4.38, N 7.76.
4.4.15. 1-(4-methoxyphenyl)-3-propyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6o)
Rf=0.49 (Hexane/Ethyl acetate 7:3); Yield 330 mg (~ 86%) as white solid; m.p. 100
°C. 1H NMR (300 MHz, CDCl3) δppm = 7.98 (d, J = 7.2 Hz, 1H), 7.78-7.66 (m, 2H), 7.46 (d, J
= 7.5 Hz, 1H), 7.22-7.18 (m, 2H), 6.94 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.66-3.56 (m, 1H),
13
3.21-3.11 (m, 1H), 1.66-1.47 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H); C NMR (75 MHz, CDCl3)
δppm = 183.3, 166.8, 166.1, 160.2, 141.2, 135.4, 132.3, 129.4, 127.3, 126.6, 125.0, 122.6,
114.5, 92.2, 55.4, 46.0, 21.6, 11.2. HRMS (ESI-TOF): m/z calcd for C20H18N2O4S + H+:
383.1065 [M + H]+; found: 383.1076.
4.4.16. 1-(4-methoxyphenyl)-3-(pyridin-3-ylmethyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6p)
Rf=0.36 (Hexane/Ethyl acetate 4:6); Yield 360 mg (~ 84%) as white solid; m.p. 172
1
°C. H NMR (500 MHz, CDCl3) δppm = 8.43 (s, 1H), 8.21 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H),
7.65 (t, J = 7.5 Hz, 1H), 7.58-7.53 (m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 7.5 Hz, 1H),
7.12 (s, 1H), 7.02 (d, J = 8.5 Hz, 2H), 5.08 (d, J = 15.5 Hz, 1H), 4.65 (d, J = 15.5 Hz, 1H),
13
3.84 (s, 3H); C NMR (126 MHz, CDCl3) δppm = 183.9, 166.5, 165.8, 160.3, 149.5, 149.3,
140.7, 136.0, 135.2, 132.3, 131.2, 129.4, 126.8, 126.6, 124.9, 123.3, 122.9, 114.6, 91.6, 55.5,
23

44.8. Elemental analysis calcd (%) for C23H17N3O4S: C 64.03, H 3.97, N 9.74; found: C
64.09, H 3.95, N 9.80.
4.4.17. 3-(4-fluorobenzyl)-1-(2-methoxyphenyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6q)
Rf=0.46 (Hexane/Ethyl acetate 7:3); Yield 367 mg (~ 82%) as white solid; m.p. 184
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.88 (d, J = 6.6 Hz, 1H), 7.58-7.53 (m, 1H), 7.51-
7.46 (m, 1H), 7.44-7.39 (m, 1H), 7.31-7.28 (m, 1H), 7.09-7.07 (m, 1H), 7.05-6.98 (m, 4H),
6.74 (t, J = 8.7 Hz, 2H), 4.97 (d, J = 15.9 Hz, 1H), 4.57 (d, J = 15.3 Hz, 1H), 3.78 (s, 3H); 13C
NMR (75 MHz, CDCl3) δppm = 183.6, 166.3, 166.1, 162.2 (d, J = 245.85 Hz), 154.8, 141.7,
134.9, 131.8, 131.5, 130.6, 130.2 (d, J = 8.10 Hz), 130.1, 126.6, 126.1, 122.9, 121.5, 121.1,
115.3 (d, J = 21.67 Hz), 112.2, 91.8, 56.1, 46.6. HRMS (ESI-TOF): m/z calcd for
C24H17FN2O4S + H+: 449.0971 [M + H]+; found: 449.0977.
4.4.18. 1-(2-methoxyphenyl)-3-(4-methylbenzyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6r)
Rf=0.49 (Hexane/Ethyl acetate 7:3); Yield 385 mg (~ 87%) as white solid; m.p. 176
°C. 1H NMR (300 MHz, CDCl3) δppm = 7.94 (d, J = 7.5 Hz, 1H), 7.64-7.47 (m, 3H), 7.38 (d, J
= 6.3 Hz, 1H), 7.20-7.06 (m, 3H), 7.00-6.93 (m, 4H), 5.00 (d, J = 15.0 Hz, 1H), 4.70 (d, J =
13
15.3 Hz, 1H), 3.86 (s, 3H), 2.27 (s, 3H); C NMR (75 MHz, CDCl3) δppm = 183.6, 166.5,
166.3, 154.9, 141.8, 137.6, 134.8, 132.2, 131.6, 131.5, 130.7, 129.0, 128.3, 126.7, 126.0,
123.0, 121.7, 121.1, 112.2, 92.0, 56.1, 47.3, 21.0. HRMS (ESI-TOF): m/z calcd for
C25H20N2O4S + H+: 445.1222 [M + H]+; found: 445.1253.
4.4.19. 1-(4-fluorophenyl)-3-(4-methylbenzyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6s)
Rf=0.48 (Hexane/Ethyl acetate 7:3); Yield 390 mg (~ 90%) as white solid; m.p. 160
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.97 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H),
24

7.53 (t, J = 7.5 Hz, 1H), 7.43-7.39 (m, 2H), 7.27-7.20 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 6.94
(s, 4H), 5.10 (d, J = 15.0 Hz, 1H), 4.64 (d, J= 15.3 Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz,
CDCl3) δppm = 183.3, 166.7, 166.0, 162.8 (d, J = 248.32 Hz), 140.9, 137.8, 134.9, 132.0,
131.8, 130.3, 130.2, 129.1, 128.5, 126.9, 126.3, 123.0, 116.4 (d, J = 22.8 Hz), 91.8, 47.3,
21.0. Elemental analysis calcd (%) for C24H17FN2O3S: C 66.66, H 3.96, N 6.48; found: C
66.64, H 4.03, N 6.40.
4.4.20. 3-allyl-1-(4-fluorophenyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-3',5-
dione (6t)
Rf=0.48 (Hexane/Ethyl acetate 7:3); Yield 324 mg (~ 88%) as white solid; m.p. 148
1
°C. H NMR (300 MHz, CDCl3) δppm = 8.05 (d, J = 6.9 Hz, 1H), 7.85-7.74 (m, 2H), 7.56-
7.54 (m, 1H), 7.41-7.37 (m, 2H), 7.27-7.19 (m, 2H), 5.82-5.69 (m, 1H), 5.03 (d, J = 9.9 Hz,
13
1H), 4.91 (d, J= 16.8 Hz, 1H), 4.42-4.35 (m, 1H), 4.12-4.05 (m, 1H); C NMR (75 MHz,
CDCl3) δppm = 182.5, 166.5, 166.0, 162.8 (d, J = 248.47 Hz), 140.7, 135.3, 132.4, 130.7,
130.2 (d, J = 9.15 Hz), 128.3, 127.3, 126.5, 123.0, 119.5, 116.3 (d, J = 22.87 Hz), 91.9, 46.8.
Elemental analysis calcd (%) for C19H13FN2O3S: C 61.95, H 3.56, N 7.60; found: C 61.87, H
3.66, N 7.68.
4.4.21. 3-cyclopropyl-1-(2,4-dichlorophenyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6u)
Rf=0.40 (Hexane/Ethyl acetate 7:3); Yield 293 mg (~ 70%) as white solid; m.p. 140
1
°C. H NMR (300 MHz, CDCl3) δppm = 8.07 (d, J = 7.5 Hz, 1H), 7.86-7.74 (m, 2H), 7.59-
7.54 (m, 2H), 7.42-7.30 (m, 2H), 2.63-2.60 (m, 1H), 0.94-0.77 (m, 2H), 0.72-0.51 (m, 2H);
13C NMR (75 MHz, DMSO-d6) δppm = 183.2, 166.7, 166.2, 155.7, 141.0, 136.7, 136.3, 133.8,
133.2, 130.1, 129.7, 129.0, 127.9, 126.5, 124.9, 93.4, 27.1, 6.6, 5.0. Elemental analysis calcd
(%) for C19H12Cl2N2O3S: C 54.43, H 2.88, N 6.68; found: C 54.52, H 2.95, N 6.62.
25

4.4.22. 1-(2,4-dichlorophenyl)-3-propyl-2-thioxo-3'H-spiro[imidazolidine-4,1'-
isobenzofuran]-3',5-dione (6v)
Rf=0.47 (Hexane/Ethyl acetate 7:3); Yield 360 mg (~ 85%) as white solid; m.p. 150
1
°C. H NMR (300 MHz, CDCl3) δppm = 7.98 (d, J = 7.2 Hz, 1H), 7.79-7.67 (m, 2H), 7.51-
7.47 (m, 2H), 7.34-7.24 (m, 2H), 3.67-3.57 (m, 1H), 3.21-3.11 (m, 1H), 1.68-1.42 (m, 2H),
0.75 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δppm = 181.4, 165.9, 165.8, 140.6, 136.8,
135.4, 134.4, 132.4, 131.7, 130.4, 129.1, 127.9, 127.2, 126.6, 122.6, 92.3, 45.9, 21.5, 11.0.
Elemental analysis calcd (%) for C19H14Cl2N2O3S: C 54.17, H 3.35, N 6.65; found: C 54.10,
H 3.43, N 6.59.
4.4.23. 3-butyl-1-(2,4-dichlorophenyl)-2-thioxo-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-
3',5-dione (6w)
Rf=0.52 (Hexane/Ethyl acetate 7:3); Yield 375 mg (~ 86%) as white solid; m.p. 164
1
°C. H NMR (300 MHz, CDCl3) δppm = 8.08 (d, J = 7.5 Hz, 1H), 7.88-7.76 (m, 2H), 7.61-
7.56 (m, 2H), 7.44-7.33 (m, 2H), 3.78-3.68 (m, 1H), 3.34-3.24 (m, 1H), 1.71-1.59 (m, 2H),
1.31-1.19 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δppm = 181.5, 166.0,
165.9, 140.7, 136.9, 135.5, 134.5, 132.5, 131.8, 130.5, 129.2, 128.0, 127.3, 126.7, 122.7,
92.4, 44.3, 30.1, 19.8, 13.4. Elemental analysis calcd (%) for C20H16Cl2N2O3S: C 55.18, H
3.70, N 6.44; found: C 55.13, H 3.77, N 6.35.
4.4.24. 3-(4-methylbenzyl)-1-phenyl-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-
trione (7a)
Rf=0.45 (Hexane/Ethyl acetate 7:3); Yield 350 mg (~ 88%) as white solid; m.p. 134
°C. 1H NMR (300 MHz, CDCl3) δppm = 7.97 (d, J = 7.5 Hz, 1H), 7.66-7.41 (m, 7H), 7.13 (d, J
= 8.4 Hz, 1H), 6.97-6.86 (m, 4H), 4.59 (d, J = 15.0 Hz, 1H), 4.28 (d, J = 15.0 Hz, 1H), 2.28
(s, 3H)
;
13C NMR (75 MHz, CDCl3) δppm = 166.3, 165.7, 154.4, 141.0, 137.7, 134.7, 132.2,
26

131.6, 130.9, 129.2, 129.1, 128.6, 128.5, 127.4, 126.0, 125.7, 122.9, 91.8, 43.8, 20.9. HRMS
(ESI-TOF): m/z calcd for C24H18N2O4 + H+: 399.1345 [M + H]+; found: 399.1374.
4.4.25. 1-phenyl-3-(pyridin-3-ylmethyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-
trione (7b)
Rf=0.35 (Hexane/Ethyl acetate 7:3); Yield 327 mg (~ 85%) as yellow solid; m.p. 144
1
°C. H NMR (300 MHz, CDCl3) δppm = 8.45 (s, 1H), 8.15 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H),
7.67 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.51-7.49 (m, 4H), 7.47-7.40 (m, 2H), 7.15
(d, J = 7.7 Hz, 2H), 4.62 (d, J = 15.6 Hz, 1H), 4.31 (d, J = 15.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δppm = 166.2, 165.6, 154.7, 149.4, 149.5, 140.8, 136.6, 135.3, 132.4, 130.8, 129.7,
129.4, 129.0, 127.5, 127.4, 126.7, 125.9, 123.0, 91.7, 41.7. HRMS (ESI-TOF): m/z calcd for
C22H15N3O4 + H+: 386.1141 [M + H]+; found: 386.1154.
4.4.26. 3-cyclohexyl-1-phenyl-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-trione (7c)
Rf=0.45 (Hexane/Ethyl acetate 7:3); Yield 270 mg (~ 72%) as white solid; m.p. 98 °C.
IR (KBr): 3180 (Ar-H), 2930 (aliphatic C-H), 1740 (lactone C=O), 1640 (amide C=O), 1560
1
(amide -N-(C=O)-N-) cm-1. H NMR (300 MHz, CDCl3) δppm = 8.04 (d, J = 7.2 Hz, 1H),
7.83-7.71 (m, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.48-7.46 (m, 4H), 7.41-7.35 (m, 1H), 3.12-3.01
13
(m, 1H), 1.95-1.54 (m, 8H), 1.07-1.00 (m, 2H); C NMR (126 MHz, CDCl3) δppm = 166.6,
165.7, 153.4, 141.9, 135.2, 132.0, 130.9, 129.1, 128.5, 127.8, 126.4, 125.8, 122.6, 92.6, 54.6,
31.1, 30.8, 25.9, 25.8, 24.8. Elemental analysis calcd (%) for C22H20N2O4: C 70.20, H 5.36, N
7.44; found: C 70.10, H 5.42, N 7.40.
4.4.27. 3-(4-chlorobenzyl)-1-(p-tolyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-
trione (7d).
Rf=0.42 (Hexane/Ethyl acetate 7:3); Yield 364 mg (~ 84%) as white solid; m.p. 120
1
°C. H NMR (500 MHz, CDCl3) δppm = 7.96 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H),
7.56 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.12-7.10 (m, 3H),
27

6.92 (d, J = 8.5 Hz, 2H), 4.57 (d, J = 15.5 Hz, 1H), 4.23 (d, J = 15.5 Hz, 1H), 2.39 (s, 3H);
13C NMR (126 MHz, CDCl3) δppm = 166.3, 165.6, 154.6, 141.0, 138.9, 134.9, 134.1, 134.0,
131.9, 130.0, 129.9, 128.7, 128.1, 127.3, 126.2, 125.6, 122.9, 91.7, 43.3, 21.2. Elemental
analysis calcd (%) for C24H17ClN2O4: C 66.60, H 3.96, N 6.47; found: C 66.54, H 4.05, N
6.42.
4.4.28. 3-cyclopropyl-1-(p-tolyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-trione
(7e)
Rf=0.45 (Hexane/Ethyl acetate 7:3); Yield 226 mg (~ 65%) as white solid; m.p. 158
1
°C. H NMR (400 MHz, CDCl3) δppm = 8.03 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.4 Hz, 1H),
7.72 (t, J = 7.6 Hz, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.32-7.24 (m, 4H), 2.37 (s, 3H), 2.36- 2.33
(m, 1H), 0.92-0.86 (m, 1H), 0.69- 0.57 (m, 2H), 0.55-0.47 (m, 1H); 13C NMR (101 MHz,
CDCl3) δppm = 166.8, 165.6, 154.9, 141.8, 138.9, 135.3, 132.0, 129.9, 128.2, 127.7, 126.6,
125.8, 122.3, 92.9, 22.3, 21.3, 5.1, 4.3. Elemental analysis calcd (%) for C20H16N2O4: C
68.96, H 4.63, N 8.04; found: C, 68.89, H 4.60, N 7.99.
4.4.29. 3-hexyl-1-(p-tolyl)-3'H-spiro[imidazolidine-4,1'-isobenzofuran]-2,3',5-trione
(7f)
Rf=0.62 (Hexane/Ethyl acetate 7:3); Yield 330 mg (~ 84%) as white solid; m.p. 150
°C. 1H NMR (300 MHz, CDCl3) δppm = 8.04 (d, J = 7.2 Hz, 1H), 7.84-7.71 (m, 2H), 7.51 (d, J
= 7.5 Hz, 1H), 7.36-7.25 (m, 4H), 3.36 (ddd, J = 15.4, 8.8, 6.7 Hz, 1H), 3.03 (ddd, J = 14.6,
8.7, 6.4 Hz, 1H), 2.38 (s, 3H), 1.51-1.39 (m, 2H), 1.25-1.14 (m, 6H), 0.82 (t, J = 6.8 Hz, 3H);
13C NMR (126 MHz, CDCl3) δppm = 166.5, 165.8, 154.5, 141.3, 138.7, 135.2, 132.1, 129.8,
128.2, 127.7, 126.5, 125.6, 122.6, 92.4, 40.8, 31.0, 28.9, 26.2, 22.3, 21.2, 13.9. Elemental
analysis calcd (%) for C23H24N2O4: C 70.39, H 6.16, N 7.14; found: C 70.34, H 6.22, N 7.08.
4.5.
Single crystal X-ray Data
4.5.1. Single crystal X-ray structure analysis of 6a (CCDC 1858914)
28