Facile and convenient synthesis of 5-arylalkylidenerhodanines by electrocatalytic crossed aldol condensation

Article abstract of DOI:10.1080/10426507.2012.717134

An electrochemically induced catalytic crossed Aldol condensation of one equivalent of rhodanine with various aromatic aldehydes and ketones in ethanol in an undivided cell in the presence of sodium bromide as an electrolyte results in the formation of th

Full text of DOI:10.1080/10426507.2012.717134

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Facile and Convenient Synthesis
of 5-Arylalkylidenerhodanines
by Electrocatalytic Crossed Aldol
Condensation
a
b
c
Hojat Veisi , Zahra Vafajoo , Behrooz Maleki & Malek Taher
b
Maghsoodlou
a
Department of Chemistry , Payame Noor University , Tehran , Iran
b
Department of Chemistry , The University of Sistan and
Baluchestan , Zahedan , Iran
c
Department of Chemistry , Hakim Sabzevari University , Sabzevar ,
Iran
Accepted author version posted online: 09 Aug 2012.Published
online: 31 May 2013.
To cite this article: Hojat Veisi , Zahra Vafajoo , Behrooz Maleki & Malek Taher Maghsoodlou (2013):
Facile and Convenient Synthesis of 5-Arylalkylidenerhodanines by Electrocatalytic Crossed Aldol
Condensation, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:6, 672-677
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Phosphorus, Sulfur, and Silicon, 188:672–677, 2013
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Taylor & Francis Group, LLC
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ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.717134
FACILE AND CONVENIENT SYNTHESIS OF
-ARYLALKYLIDENERHODANINES BY
ELECTROCATALYTIC CROSSED ALDOL CONDENSATION
5
1
2
3
Hojat Veisi, Zahra Vafajoo, Behrooz Maleki,
2
and Malek Taher Maghsoodlou
Department of Chemistry, Payame Noor University, Tehran, Iran
Department of Chemistry, The University of Sistan and Baluchestan, Zahedan, Iran
Department of Chemistry, Hakim Sabzevari University, Sabzevar, Iran
1
2
3
GRAPHICAL ABSTRACT
Abstract An electrochemically induced catalytic crossed Aldol condensation of one equivalent
of rhodanine with various aromatic aldehydes and ketones in ethanol in an undivided cell in
the presence of sodium bromide as an electrolyte results in the formation of the corresponding
5-arylalkylidenerhodanines in 80–96% yield with reactions in 40 min.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Electrocatalysis; aldol condensation; rhodanine; aldehydes; ketones
INTRODUCTION
The discovery of novel synthetic methodologies to facilitate the efficient preparation
of compounds of prominent utility is a pivotal focal point of research in modern organic
1
chemistry. The continual upsurge in facile, convenient, and nonpolluting synthetic proce-
dures urges chemists to increase the tools of their arsenal. One approach to address this
challenge involves the development of tandem reactions, which are defined as a one-pot
2
combination of two or more reactions that occur in a specific order. In addition to the intrin-
sic atom economy and selectivity underlying such protocols, the tandem reaction strategy
Received 27 April 2012; accepted 27 July 2012.
We are thankful to the Payame Noor University (PNU) for partial support provided for this work.
Address correspondence to Hojat Veisi, Department of Chemistry, Payame Noor University, 19395-4697
Tehran I.R. of Iran. E-mail: hojatveisi@yahoo.com
6
72

ELECTROCATALYTIC CROSSED ALDOL
673
offers significant advantages over conventional linear-type synthesis due to its flexible and
convergent nature.3
Compounds containing the 2-thioxothiazolidin-4-one ring (rhodanine, pKa 5.52)
4
–9
have showed a wide range of pharmacological activities, which includes antimicrobial,
10
10
11
12
13
anticonvulsant, antibacterial, antiviral, anti-diabetic, and anticonvulsant effects. In
addition, rhodanine-based molecules have been popular as small molecule inhibitors of
15
16
17
numerous targets such as HCV NS3 protease, aldose reductase, β-lactamase, UDP-N-
acetylmuramate/L-alanine ligase, antidiabetic agents, cathepsin D, and histidin ede-
carboxylase. The rhodanine moiety has been synthesized by various methods such as the
addition of isothiocyanate to mercaptoacetic acid followed by acidcatalyzed cyclization, or
the reaction of ammonia or primary amines with carbon disulfide and chloroacetic acid in the
18
19
20
21
22
presence of bases. Condensation of aromatic aldehydes or ketones at the nucleophilic C-5
2
2
active methylene has been performed using piperidinium benzoate in refluxing toluene,
23
24
under microwave conditions in the presence of K2CO3/Al2O3, NH4OH/NH4Cl, or
sodium acetate in refluxing glacial acetic acid. Recently, Sim et al. reported the synthe-
sis of 5-arylalkylidene rhodanines in 60–82% yield by heating the reactants suspended in
toluene at 110 C for 3 days. Sing et al. reported the condensation of rhodanine with an
aldehyde (0.1 mmol) by heating in anhydrous EtOH (200 mL) for 6 h at 80 C. Alterna-
25
26
◦
27
◦
tively, rhodanine (0.1 mmol), ketone (0.1 mmol), and NH4OAc (0.2 mmol) were refluxed
in toluene (500 mL) for 3 days (61–92% yield). Obviously, these methods involve long
reaction times, high temperatures, use large quantities of organic solvents, and some give
unsatisfactory yields. Therefore, it is useful to develop new methods, which are simple
and environment friendly for the synthesis of 5-arylalkylidene rhodanines. Also, rhodanine
derivatives have attracted considerable pharmaceutical interest. Therefore, the preparation
of this heterocyclic core unit has attracted the attention of many organic chemists.
RESULTS AND DISCUSSION
Despite the significant synthetic potential and ecological advantages of electrochem-
ical methods, the practical usage of electrochemical procedures is often limited on account
of their technical complexity, and the recently developed electrochemically induced
2
8
29
Knoevenagel and Michael reactions are in compliance with this thesis. In the course
30
of our study on the synthesis of organic compounds, we applied this electrocatalytic
procedure to the synthesis of a number of medicinally relevant rhodanine derivatives. In
the present study we report our results on electrocatalytic tandem chain transformation of
rhodanine 1 and arylaldehydes 2 into 3 under neutral and mild conditions by electrolysis
in an undivided cell. The reaction was performed in ethanol in the presence of sodium
bromide as an electrolyte (Scheme 1).
Scheme 1

6
74
H. VEISI ET AL.
Table 1 Electrocatalytic transformation of rhodanine (1) and benzaldehyde (2) into (3)a
Current density
(mA/cm )
Electricity passed
(F/mol)
Yield
(%)
2
b
I (mA)
Time (min)
5
1
2
4
180
90
40
0.04
0.04
0.04
0.04
67
75
92
72
1
2
5
0
0
0
10
15
a
Using 1 (10 mmol), 2a (10 mmol), NaBr (1 mmol), EtOH (20 mL), iron cathode (5 cm2), graphite anode
2
◦
(
5 cm ), 20 C.
bYield of isolated product.
First, to evaluate the synthetic potential of the procedure proposed and to optimize
the electrolysis conditions, the electrocatalytic tandem transformation of one equivalent of
rhodanine and benzaldehyde into 3 was studied (Table 1).
2
Excellent conversions of the starting compounds were obtained under 4 mA/cm
2
and 10 mA/cm current densities after 0.04 F/mol of electricity was passed. The current
2
2
density of 4 mA/cm (I = 20 mA, electrodes surface 5 cm ) was found to be optimal
for the electrochemically induced chain process and allowed for the highest yield of 3.
2
An increase in the current density up to 10 mA/cm (I = 50 mA) resulted in a slight
decrease in the reaction yield, and this is perhaps as a result of the activation of the
undesired direct electrochemical processes that lead to oligomerization of the starting
material.
After electrolysis, 3 were directly crystallized from the reaction mixture without any
2
further purification. Under the optimal conditions (current density 4 mA/cm , 0.04 F/mol
passed) the electrolysis of one equivalent of 1 and arylaldehydes 2 in ethanol in an undivided
cell affords substituted 3 in 80–96% yield at ambient temperature over a 40-min reaction
period (Table 2).
The following mechanism28b for the electrocatalytic chain transformation of 1
and arylaldehydes 2 into 3 is proposed. The initiation step of the catalytic cycle be-
gins with the deprotonation of a molecule of alcohol at the cathode, which leads to
the formation of an ethoxide anion. The subsequent reaction between the ethoxide an-
ion and 1 gives rise to the corresponding rhodanine anion 4 (Scheme 2). The fol-
lowing process in the solution represents a typical tandem reaction. The Knoevenagel
condensation of anion 4 with arylaldehyde 2 takes place with the elimination of a
hydroxide anion and formation of 3. This novel electrocatalytic chain process offers
an efficient and convenient way to create rhodanine derivatives, the prominent com-
pounds with approved practical utilities and different biomedical applications. We have
used a catalytic amount of EtONa for entry 1 in Table 2 to compare results with
the electrochemical procedure. We could not obtain good results as an electrochemical
procedure.
In addition, to evaluate the chemoselectivity of this method, a control experi-
ment was allowed to proceed under the developed condition utilizing 1 mmol of p-
methoxybenzaldehye and 1 mmol of acetophenone. It was found that rhodanine only reacts
with p-methoxybenzaldehye and leads to the formation of 4-methylbenzylidene rhodanine
as final product and no adduct was obtained from the condensation of rhodanine with ketone
(Scheme 3).

ELECTROCATALYTIC CROSSED ALDOL
675
Table 2 Electrocatalytic transformation of rhodanine (1) and arylaldehydes (2) into (3)a
Yield (%)b
mp ( C)
◦
◦
Lit-mp ( C)
Entry
Carbonyl compounds (1)
Time (min)
3
1
2
2
2
1
1
2
3
4
5
6
7
8
9
0.
1.
2.
3.
4.
5.
6.
.
.
.
.
.
.
.
.
.
R1: C6H5-R2: H
40
40
40
40
40
40
40
40
40
40
40
60
60
60
60
60
92
96
90
95
90
85
90
85
90
92
92
85
80
85
90
85
202–204
248–250
232
199–202
245–247
3
R1: 2-MeO-C6H5-R2: H
R1: 4-OH-3-MeO-C6H5-R2: H
R1: 4-MeO-C6H5-R2: H
R1: 4-Me-C6H5-R2: H
R1: 2,4-dichloro-C6H5-R2: H
R1: 2-Cl-C6H5-R2: H
R1: 4-Cl-C6H5-R2: H
R1: 3-NO2-C6H5-R2: H
R1: 4-NO2-C6H5-R2: H
R1: 2-Furyl R2: H
R1: 2-Furyl R2: CH3
Cyclohexylidene
Cyclopentylidene
R1: C6H5-R2: CH3
R1: 4-Cl-C6H5-R2: CH3
4
231–231.5
3
250–253
220–223
230–232
191–192
225–227
261–263
251–252
229–230
242–244
171–174
196–198
165–166
203–205
250–252
3
219–223
3
2
4
231.5–232.5
32
192
32
23
31
23
224–230
263–264
249–250
228–229
1
1
1
1
1
1
1
2
243.5–244.5
24
24
24
172–173
195–196
165–166
24
204
a
2
Using 1 (10 mmol), 2 (10 mmol), NaBr (1 mmol), EtOH (20 mL), iron cathode (5 cm ), graphite anode
2
◦
2
(
5 cm ), 20 C, current density 4 mA/cm , 40 min, electricity passed: 0.04 F/mol.
b
Yield of isolated product.
Scheme 2

6
76
H. VEISI ET AL.
Scheme 3
CONCLUSIONS
In conclusion, the simple electrocatalytic system can produce, under neutral and
mild conditions, a fast and selective tandem crossed Aldol condensation of one equivalent
rhodanine with various aromatic aldehydes and ketones into 3 in excellent yields. This
novel electrocatalytic chain process offers an efficient and convenient way to create rhoda-
nine derivatives, the prominent compounds with approved practical utilities and different
biomedical applications.
EXPERIMENTAL
General Procedure
A solution of rhodanine (1, 3.48 g, 10 mmol), arylaldehyde or ketone 2 (10 mmol),
and NaBr (0.1 g, 1 mmol) in EtOH (20 mL) was electrolyzed in an undivided cell equipped
◦
2
with a magnetic stirrer, a graphite anode, and an iron cathode at 20 C under a constant
2
current density of 4 mA/cm (I = 20 mA, electrodes square 5 cm ) until the catalytic
quantity of 0.04 F/mol of electricity was passed. After the electrolysis was finished, the
solution was filtered to isolate the solid product, which was then rinsed with an ice-cold
EtOH–H2O (9:1, 3 mL), and dried under reduced pressure.
The products are all known compounds; their spectroscopic data was compared with
the original characterization data.23,24,31,32 Selected NMR spectra for compounds 1 and 5
are presented in the Supplemental Materials (Figures S1–S4).
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