Organocatalytic synthesis of N-substituted 5-arylidene rhodanines

Article abstract of DOI:10.14233/ajchem.2017.20279

A simple and efficient synthesis of N-substituted 5-arylidene rhodanines has been developed via aldol condensation of N-substituted rhodanines with aromatic aldehydes using L-proline as the catalyst in water at room temperature. The attractive features of

Full text of DOI:10.14233/ajchem.2017.20279

Asian Journal of Chemistry; Vol. 29, No. 3 (2017), 623-625
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20279
Organocatalytic Synthesis of N-Substituted 5-Arylidene Rhodanines
*
N.S. DEVI and NIRADA DEVI
Department of Chemistry, Cotton College, Guwahati-781 001, India
*Corresponding author: E-mail: devichemcotton@gmail.com
Received: 1 September 2016; Accepted: 29 November 2016;
Published online: 30 December 2016;
AJC-18214
A simple and efficient synthesis of N-substituted 5-arylidene rhodanines has been developed via aldol condensation of N-substituted
rhodanines with aromatic aldehydes using L-proline as the catalyst in water at room temperature. The attractive features of this protocol
are simple experimental procedures, cleaner reactions, column free, high yield and avoid the use of toxic solvents.
Keywords: N-Substituted 5-arylidene rhodanines, L-Proline, Aldol condensation, Room temperature.
used as catalyst in different organic reactions due to its experi-
mental simplicity, non toxicity, ease of handling, cost effec-
tiveness and recyclability [13-15]. Inspired by the unique
reactivity of L-proline, we explore the synthesis of N-substituted
5-arylidene rhodanine via aldol condensation reaction of N-
substituted rhodanine and aromatic aldehyde in aqueous media
using L-proline as catalyst (Scheme-I).
INTRODUCTION
The importance of N-functionalized 5-arylidene rhodanines
are known to exhibit outstanding biological activities such as
anti-inflammatory [1], antiviral [2] and anti-HIV [3]. Moreover,
they are found to be inhibitor of many targets such as aldose
reductase [4], dynamin GTPase [5] and hepatitis C virus (HCV)
[6]. In view of their unique bioactivities, various methods have
been developed for their synthesis, which include (i) conden-
sation of N-substituted-rhodanines with aromatic aldehyde in
presence of alumina [7] or in presence of base [8], (ii) heating
the reaction mixture of bis(carboxymethyl)trithiocarbonate,
primary amines and aromatic aldehyde using triethylamine as
the base [9], (iii) a multicomponent reaction of primary amines,
aldehydes, ethyl chloroacetate and carbon disulfide in presence
of potassium hydroxide or 1-butyl-3-methyl imidazolium acetate
[10] and (iv) reaction of amines, carbon disulfide and arylpro-
piolates in the presence of tributylphosphine under an argon
atmosphere [11].
Although the above reported methods are valuable, most
of them suffer from one or more drawbacks like the use of
environmentally unfavourable solvents, heating at high tempe-
rature, tedious work-up procedures, non-recovery of the catalysts,
column purification for product, limited substrate scope and
low yields of the desired products. Therefore, the development
of a simple, mild, economic and environmentally friendly method
for the synthesis of N-substituted 5-arylidene rhodanine is
highly desirable.
O2N
NO2
S
S
S
S
L
-proline
N
+ H
CH3
N
water, r.t
6h
CH3
O
O
O
(1a)
(1)
(a)
Scheme-I: Aldol condensation reaction of 3-methyl-2-thioxothiazolidin-
4-one and 4-nitrobenzaldehyde
EXPERIMENTAL
All the compounds were commercial grade and were used
without further purification. 1H NMR spectra were recorded
on 400/600 MHz in CDCl3 and 13C NMR spectra were recorded
on 100/150 MHz in CDCl3 using TMS as internal standard.
IR spectra were recorded in KBr.High-resolution mass spectral
analysis (HRMS) data were recorded using ESI mode (Q-TOF
type Mass Analyzer).
General procedure for the synthesis of N-substituted
5-arylidene rhodanines (1-3)(a-k): A mixture of 3-methyl-
2-thioxothiazolidin-4-one (1) (0.5 mmol), 4-nitro benzaldehyde
(a) (0.6 mmol), L-proline (30 mol %) and water (3 mL) was
taken in a 10 mL round bottom flask. The heterogeneous
reaction mixture was stirred for 6 h at room temperature.After
completion of the reaction (monitored byTLC), the crude solid
Water has been emerging as potential “greener” alterna-
tives to volatile organic solvents and used for many important
organic reactions as it is low-cost, safe, non-toxic and most
abundant solvent [12]. On the other hand, L-proline has been

624 Devi et al.
Asian J. Chem.
product was collected by filtration and recrystallized from
ethanol to give the corresponding (Z)-3-methyl-5-(4-nitro-
benzylidene)-2-thioxothiazolidin-4-one (1a) in 90 % yield.
Spectral and analytical data of selected compounds are given
below.
of spectroscopic analysis (1H NMR, 13C NMR, IR, HRMS),
the structure of the isolated product was determined as (Z)-3-
methyl-5-(4-nitrobenzylidene)-2-thioxothiazolidin-4-one (1a)
(Scheme-I).
To optimize the reaction condition, the effect of catalyst
loading was screened. Increasing L-proline to 30 mol % led
to a higher yield of 90 % (Table-1, entry 2); further increasing
it to 35 mol % did not improve the yield. Different catalysts
such as L-histidine and L-leucine (Table-1, entries 3-4) were
tested for this transformation, from which L-proline (Table-1,
entry 2) was found to be the most effective catalyst. Next, various
solvents were screened for their influence on this reaction. In
water, the reaction proceeded efficiently and gave the desired
product (1a) in highest yield (90 %); while using ethanol, yield
was reduced to 85 % (Table-1, entry 5). Other solvents such as
CH3CN (70 %), dioxane (68 %) and THF (65 %) were less
effective compared to water (Table-1, entries 6-8).
(Z)-3-Methyl-5-(4-nitrobenzylidene)-2-thioxothiazolidin-
1
4-one (1a): Yellow solid; m.p. 210-211 °C; yield 90 %; H
NMR (600 MHz, CDCl3): δ = 3.5 (s, 3H), 7.63 (d, J = 9.0 Hz,
2H), 7.73 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H); 13C NMR (150
MHz, CDCl3): δ = 35.9, 124.7, 127.8, 129.2, 131.1, 139.4,
148.2, 167.6, 191.9; IR (KBr, νmax, neat): 1715, 1574, 1377,
1191 cm-1; HRMS (ESI): calcd. for C17H8N2O3S2 [M+H]+:
280.9986; found: 280.9990.
(Z)-3-Benzylidene-2-thioxothiazolidin-4-one (2c): Yellow
solid; m.p. 155-156 °C (Lit. [11] m.p. 156 °C); yield 90 %; 1H
NMR (400 MHz, CDCl3): δ = 5.30 (s, 2H), 7.24-7.32 (m, 3H),
7.45-7.47 (m, 7H), 7.72 (s, 1H); 13C NMR (100 MHz, CDCl3):
δ = 47.6, 123.0, 128.2, 128.6, 129.0, 129.4, 130.7, 130.9, 133.4,
133.5, 134.9, 167.9, 193.3; IR (KBr, νmax, neat): 1706, 1595,
1343, 1190 cm-1; HRMS (ESI): calcd. for C17H13NOS2 [M+H]+:
312.0511; found: 312.0514.
TABLE-1
OPTIMIZATION OF REACTION CONDITIONS
O2N
NO2
S
S
(Z)-5-(2,6-Dichlorobenzylidene)-3-benzyl-2-thioxo-
thiazolidin-4-one (2e): Yellow solid; m.p. 113-114 °C; yield
S
[catalyst]
[solvent]
S
+
N
N
CH3
1
CH3
96 %; H NMR (400 MHz, CDCl3): δ = 5.28 (s, 2H), 7.25-
O
7.37 (m, 6H), 7.48 (d, J = 6.6 Hz, 2H), 7.71 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ = 47.8, 128.2, 128.3, 128.5, 128.6, 129.1,
131.0, 131.3, 131.6, 134.1, 134.4, 166.5, 193.3.
O
H
O
(1a)
(a)
(1)
Entry
Catalyst
Solvent
H2O
H2O
H2O
H2O
EtOH
CH3CN
1,4-Dioxane
THF
Yieldb (%)
1
2
3
4
5
6
7
8
L-prolinec
L-proline
L-histidine
L-leucine
L-proline
L-proline
L-proline
L-proline
70
90
65
70
85
70
68
65
(Z)-3-(2-(1H-Indol-3-yl)ethyl)-5-((furan-2-yl)-methylene)-
2-thioxothiazolidin-4-one (4f): Grey solid; m.p. 186-187 °C;
1
yield 75 %; H NMR (400 MHz, CDCl3): δ = 3.13-3.17 (m,
2H), 4.36-4.00 (m, 2H), 6.55–6.59 (m, 1H), 6.81 (d, J = 3.6
Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 7.12-7.20 (m, 2H), 7.33 (d,
J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.69 (s, 1H), 7.80 (d, J = 7.3 Hz,
1H), 8.02 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 22.9,
45.2, 53.5, 111.0, 111.9, 113.4, 118.1, 118.7, 119.0, 119.8,
122.1, 122.2, 127.4, 136.1, 146.9, 150.1, 167.5, 194.7.
(Z)-3-Benzyl-5-[(pyridine-2-yl)methylene]-2-thioxo-
thiazolidin-4-one (2g): Light green solid; m.p. 194-195 °C;
aReaction conditions: (1) (0.5 mmol), (a) (0.6 mmol), catalyst (30 mol
b
%) and solvent (3 mL) at room temperature for 6 h; Isolated yield.
cCatalyst (20 mol %).
Having established the appropriate reaction conditions,
we next explored the substrate scope of N-substituted 5-arylidene
rhodanines using various N-substituted rhodanines and aromatic
aldehydes (Scheme-II). The N-substituted rhodanines (1) con-
densed with aromatic aldehydes possessing electron withdrawing
group such as 4-NO2 (a) and 2-F (b) giving desired N-substituted
5-arylidene rhodanines (1a) and (1b) in 90 % and 87 % yields
respectively. Here, highly electron withdrawing group gave
higher yield of the product irrespective of their position. The
N-substituted rhodanines (2) and (3) were smoothly condensed
with benzaldehyde (c) to give their corresponding N-substituted
5-arylidene rhodanines (2c, 90 %) and (3c, 78 %), respectively.
The N-substituted rhodanine (2) reacted with aromatic aldehydes
having electron donating substituent 4-OCH3 (d) giving its
respective N-substituted 5-arylidene rhodanines (2d, 85 %),
but gave lesser yield as compared to (2e, 96 %) which were
obtained from aromatic aldehyde having electron withdrawing
substituent 2,6-dichloro (e). The condensation reaction is also
successfully applied to heterocyclic aldehyde (f) and (g). The
use of dialdehyde (h) gave molecule containing two differently
space rhodanine rings (2h) in good yield.
1
yield 83 %; H NMR (400 MHz, CDCl3): δ = 5.31 (s, 2H),
7.25-7.34 (m, 4H), 7.44-7.53 (m, 3H), 7.61 (s, 1H), 7.73-7.78
(m, 1H); 13C NMR (100 MHz, CDCl3): δ = 47.1, 123.5, 127.4,
128.0, 128.1, 128.5, 128.6, 129.0, 135.1, 135.7, 149.6, 151.8,
168.0, 199.9.
(5Z)-5-(3-[(Z)-(3-Benzyl-4-oxo-2-thioxothiazolidin-5-
ylidene)methyl]benzylidene)-3-benzyl-2-thioxothiazolidin-
1
4-one (2h): Yellow solid; m.p. 174-175 °C; yield 60 %; H
NMR (400 MHz, CDCl3): δ = 5.31 (s, 4H), 7.30-7.33 (m, 6H),
7.45-7.52 (m, 8H), 7.70 (s, 2H); 13C NMR (100 MHz, CDCl3):
δ = 47.7, 125.0, 128.3, 128.7, 129.1, 130.4, 131.4, 131.8, 132.1,
134.6, 134.7, 167.7, 192.4.
RESULTS AND DISCUSSION
With the above expectation, a trial reaction was carried
out by treating N-substituted rhodanine (1) with 4-nitrobenzal-
dehyde (a) in the presence of L-proline (20 mol %) in water at
room temperature. After 6h stirring, a yellow precipitate was
observed, separated by filtration and the product was isolated
(70 % yield) by recrystallization from ethanol. On the basis

Vol. 29, No. 3 (2017)
Organocatalytic Synthesis of N-Substituted 5-Arylidene Rhodanines 625
S
S
S
Conclusion
S
Ar
L-proline
In summary, we have developed a simple, efficient and
novel method for the synthesis of rhodanine derivatives. The
reaction proceeded under mild condition and the desired
products can be obtained by simply recrystallization from
ethanol in good to high yields.
N
+
ArCHO
N
R
R
H2O, rt, 6 h
O
O
(1-4) (a-h)
(a-h)
S
(1-4)
S
Ar1
S
S
R1
N
N
CH3
R
ACKNOWLEDGEMENTS
O
O
1a: R1 = 4-NO2(90%)
1b: R1 = 2-F (87%)
2c: R = C6H5CH2 (90%)
3c: R = allyl (75%)
This study was financially supported by Department of
Science and Technology (DST) (SB/FT/CS-170/2013), New
Delhi, India.
S
Ar1
S
S
S
Ar2
R1
O
N
N
REFERENCES
R
O
O
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2d R1 = 4-OCH3 (85%)
1f: R = CH3 (82%)
2e: R1 = 2,6-dichloro (96%)
4f: indole-3-ethyl (75%)
S
S
S
N
S
N
N
S
S
N
O
2g (83%)
O
O
2h (60%)
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Scheme-II: Substrate scope of N-substituted 5-arylidene rhodaninesa,b
(aReaction conditions: (1-4) (0.5 mmol), (a-h) (0.6 mmol), L-
proline (30 mol %), H2O (3 mL), rt. bIsolated yields)
Subsequently, we investigated the recyclability of the
catalyst. The L-proline is highly soluble in water whereas the
product is insoluble. The products can be directly separated
by filtration. The filtrate containing L-proline can be directly
reused for up to three times without noticeable decrease in
catalytic activity.
A plausible mechanistic pathway is outlined in Scheme-III.
Initially, rhodanine and L-proline formed iminium ion (A).
The nucleophilic attack of enamine (B) to aromatic aldehyde
forming intermediate (C) which upon hydrolysis give aldol
product (1a″) with the release of catalyst, L-proline. The aldol
product (1a″) undergoes a dehydration process to afford product
(1a).
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O
R
N
COO
N
O
S
S
R
R
H
R
O
)
O
N
N
N
N
OH
H
-H 2O
S
OH
Ar
S
S
A
(
S
)
-H 2O
S
S
H2O
Ar
1a''
(
(1a)
COO
OH
N
COOH
N
ArCHO
R
N
R
Ar
N
S
S
S
S
C
(
)
(B)
Scheme-III: A plausible mechanism for the synthesis of N-substituted 5-
arylidene rhodanines