A new application of rhodanine as a green sulfur transferring agent for a clean functional group interconversion of amide to thioamide using reusable MCM-41 mesoporous silica

Article abstract of DOI:10.1016/j.tetlet.2013.02.045

A novel thionation protocol for amide compounds, with the system rhodanine/secondary amine has been discovered. Clean and efficient synthesis of a variety of thioamides can be achieved through this simple and convenient method using MCM-41 mesoporous silica as an acid catalyst. For this purpose we have synthesized MCM-41 silica and characterized by using an array of sophisticated analytical techniques like BET, HR TEM, EDX, XRD, 29Si MAS NMR and FTIR. This reaction is therefore a very neat example of a functional group interconversion.

Full text of DOI:10.1016/j.tetlet.2013.02.045

Tetrahedron Letters 54 (2013) 2164–2170
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Tetrahedron Letters
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A new application of rhodanine as a green sulfur transferring agent for a
clean functional group interconversion of amide to thioamide using reusable
MCM-41 mesoporous silica
Suman Ray a, Asim Bhaumik b, Arghya Dutta b, Ray J. Butcher c, Chhanda Mukhopadhyay a,
⇑
a Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India
b Department of Materials Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
c Department of Chemistry, Howard University, Washington, DC 20059, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel thionation protocol for amide compounds, with the system rhodanine/secondary amine has been
discovered. Clean and efficient synthesis of a variety of thioamides can be achieved through this simple
and convenient method using MCM-41 mesoporous silica as an acid catalyst. For this purpose we have
synthesized MCM-41 silica and characterized by using an array of sophisticated analytical techniques like
BET, HR TEM, EDX, XRD, 29Si MAS NMR and FTIR. This reaction is therefore a very neat example of a func-
tional group interconversion.
Received 19 December 2012
Revised 13 February 2013
Accepted 14 February 2013
Available online 22 February 2013
Keywords:
Thioamide
Ó 2013 Elsevier Ltd. All rights reserved.
Rhodanine
MCM-41
Green synthesis
Reusable catalyst
S
Multidrug resistance (MDR) often emerges in the treatment of
cancer following exposure of the patient to chemotherapeutic
agents.1a P-glycoprotein (P-gp, also known as MDR1)1b,c is one such
protein associated with MDR in cancer chemotherapy. In more re-
cent work, it was demonstrated that essentially single-atom
changes, that is, interchanging amide to thioamide functionality
in rosamine/rhodamine structures gave high inhibitor property to
P-gp.1a,d Thioamide drugs, ethionamide (ETH), prothionamide
(PTH), thiacetazone (TAZ) and isoxyl (ISO) (Fig. 1), have been
widely used for many years in the treatment of mycobacterial
infections.1e–i Thioamides1j–o are also essential building blocks for
a variety of chemically and pharmaceutically relevant compounds,
such as thiazolines, betaines, mesoionic rhodanines, etc.1p–r,2–4 The
most exploited route for the synthesis of thioamides involves the
nucleophilic attack of some suitable sulfur-containing agent on
the carbon atom of C@O bond leading to the substitution of oxygen
by the sulfur.5 To effect this transformation, Lawesson’s reagent6
and P4S10, either alone or with additives,7 are the reagents of
choice. Many other useful reagents such as H2S,8 CS2,9 R2PSX,10
(Et2Al)2S,11 NaSH,12 TMS2S,13 elemental sulfur,14 aq ammonium
sulfide,15 SiS2,16 HMDST,17 etc. have also been reported. However,
the uses of these reagents suffer from serious environmental and
S
NH2
H
N
S
NH2
N
H
NH2
N
N
PTH
ETH
HN
CH3
S
O
ISO
NH
O
NH
TAZ
O
Figure 1. Some thioamide containing drug molecules.
operational issues.5 Therefore, the development of novel synthetic
strategies for thionation is of paramount interest.
The use of heterogeneous catalysts in chemical processes would
simplify catalyst removal and minimize the amount of waste
formed. However, a substantial decrease in the activity is fre-
quently observed due to the heterogeneous nature of the materials
in reaction media.18,19 Open framework MCM-41 mesoporous
molecular sieves with high surface areas and large pore sizes and
pore volumes, favouring an easy accessibility of the organic
functions within the insoluble solid, appear attractive for their
⇑
Corresponding author.
E-mail address: cmukhop@yahoo.co.in (C. Mukhopadhyay).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.045

S. Ray et al. / Tetrahedron Letters 54 (2013) 2164–2170
2165
Table 1
development and uses as insoluble solid catalyst. MCM-41 displays
a very large specific surface area of approximately 1000 m2 gÀ1
Optimization of reaction conditions for the one-pot synthesis of thioamide 4ja
.
O
This property makes MCM-41 very interesting to be used as a het-
erogeneous catalyst.
O
H
N
S
MCM-41
N
S
O
Rhodanine is an interesting organic molecule with potential
biological activities.20–24 However, the application of this molecule
in organic synthesis was limited in the 3-component reaction with
aldehyde and amine25–28 until recently. We have reported for the
first time the reaction of rhodanine with ketones and secondary
amine with the aid of re-usable heterogeneous silica-pyridine
based catalyst.29 Inspired by these foregoing discussion and given
our interest and experience in heterogeneous catalysis,28–32 we
herein report a novel and convenient approach for thionation of
amides, with rhodanine/secondary amine in the presence of
MCM-41 mesoporous silica as a heterogeneous ‘E’ catalyst (Eco-
friendly, Efficient and Economic) (Scheme 1).
A survey of the literature revealed that no attempt has been
made so far to investigate the general applicability of this potential
thionating agent. Hence, we set out to explore the ability of rhoda-
nine/secondary amine for thionation. In order to ascertain the fea-
sibility of this transformation benzamide was selected as a model
substrate, and conversion to its thio analogue was studied under
a variety of conditions. Several common solvents, viz. DCE, DCM,
toluene, THF, EtOH, MeOH and water were tested (Table 1). Though
the yields of the reaction increased in polar-protic solvent than
aprotic and non polar solvent, the reaction was not satisfactory
in water (Table 1, entry 8), possibly due to less homogeneity of
the reaction mixture. Therefore aqueous-ethanol (1:1 v/v) came
out as a best choice of solvent. Similarly, temperature appears to
play a significant role because there was only 50% thioamide
formation after stirring the reaction mixture at 50–60 °C for 8 h
(Table 1, entry 10) in aqueous ethanol instead of 89% yield at
80–90 °C (Table 1, entry 9).
S
NH
N
Ph
NH2
Ph
NH2
O
S
(2)
O
(5)
(3)
(1)
(4j)
1.2 mmol
1.2 mmol
1 mmol
Entry
Solvent (4 ml)
Temp
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
DCM
DCE
25–30
80–85
90–100
50–55
60–65
60–65
75–80
90–100
75–80
50
36
36
12
14
16
10
10
11
8
15
25
40
38
31
45
85
65
89
50
Toluene
Acetone
THF
MeOH
EtOH
H2O
EtOH/H2O (2 + 2 ml)
EtOH/H2O (2 + 2 ml)
8
a
Reagents and condition: Benzamide (1 mmol), rhodanine (1.2 mmol), mor-
pholine (1.2 mmol), 40 mg MCM-41 different solvents, different temperature, dif-
ferent time, reflux.
b
Isolated yields.
the earlier work where the structure determination mainly relied
on NMR spectroscopy. The conversion of C@O to C@S can be real-
ized from the 13C NMR spectra as the amide carbonyl peak at
around d 160–170 ppm shifted to d 190–210 ppm in the product,
indicating the presence of a thioamide. Gratifyingly, we confirmed
the structure of an unknown compound (4a) unambiguously
through an X-ray single crystal analysis (CCDC 914935) (Fig. 2).
Another intriguing observation is that 10% conversion to thio-
amide was achieved only with rhodanine without any secondary
amine additive, instead of 89% with equimolar quantity of rhoda-
nine and secondary amine. This observation clearly established
that amines have some role in transferring sulfur from rhodanine
to amide. Again the starting materials were mostly unaffected
without MCM-41. Therefore the attenuated acidity of MCM-41
was crucial for this transformation. Good to excellent conversion
was also achieved with different weak and strong homogeneous
acids like AcOH, HCl, H2SO4 etc. However, they required repeated
work-up, neutralization of strong acids and extensive chromato-
graphic purification. Ultimately the isolated yields were very low.
Therefore, the reactions were performed employing MCM-41 as
the right choice of catalyst and was demonstrated to be the key
for rendering the reaction clean and obtained good to excellent
yields. We have also used different types of other commonly used
acid catalysts, mainly heterogeneous catalysts to make the work-
up easier like TiO2, SiO2 NP, commercially available macroporous
silica etc. However MCM-41 due to its very large surface area
reproduced better performance than the others. On the basis of
the results obtained above, a plausible reaction scenario for this
reaction is outlined in Scheme 2. The key findings of high signifi-
cance of MCM-41 described in this work are three-fold. Firstly
the attack of secondary amine (3) on C@S of rhodanine (2) is an
acid catalysed reaction27–29 and in this present work MCM-41 per-
forms efficiently as an acid catalyst to afford an in situ intermedi-
ate (6). Secondly the silanol groups present on the surface of MCM-
41 coordinate with the oxygen atom of amide carbonyl which in
turn increases its electrophicity28–30 and attack of –SH of interme-
diate (6) becomes easier affording another in situ intermediate (7).
Subsequent water elimination from (7) is also greatly assisted by
MCM-41 to give the target compound (4). The third high signifi-
cance of MCM-41 is its easy separation by filtration and no addi-
tional work up procedure like neutralization of strong acid or
When the reaction was performed using a stoichiometric
amount (1.0 equiv) of rhodanine, the yield of 4j was slightly re-
duced (74%) than when 1.2 equiv of rhodanine was used (89%).
With the optimal reaction conditions in hand, we extended our
synthetic protocol to examine its generality and substrate scope
(Table 2). A wide range of primary, secondary and tertiary thioam-
ides were readily synthesized from the corresponding amides. In
addition to the amides, ketones could also be converted into
the corresponding thioketones with this present reaction protocol
(Table 2, entries 4u and 4v). It is worthy to mention that a single
crystal structure of thioamide was scarcely reported in most of
O
H
N
O
S
NH
R
NH2
O
S
(2)
(1)
(3)
(1.2 mmol)
(1 mmol)
(1.2 mmol)
Reflux in aqueous
ethanol (2+2 ml),
80-90 °C
MCM-41
O
S
N
S
N
R
NH2
O
(4)
Thioamide
(5)
Scheme 1. Thionation of amide using reusable MCM-41.

2166
S. Ray et al. / Tetrahedron Letters 54 (2013) 2164–2170
Table 2
Table 2 (continued)
Synthesis of thioamidea
Entry
Product
CH3
Time (h)
7
Yieldb (%)
61
Ref.
1n
Entry
Product
Time (h)
9
Yieldb (%)
89
Ref.
—
S
S
S
4s
H3C
N
H
4a
N
N
S
4t
7
89
82
1o
5
N
N
4b
4c
4d
9
8
73
81
71
—
—
—
O
N
S
NC
N
Me
4u
10
S
S
N
N
S
O
4v
12
77
5
MeO
OMe
12
N
N
N
a
Me
Reagents and condition: Different corresponding amides (1 mmol), rhodanine
(1.2 mmol), morpholine (1.2 mmol), 40 mg MCM41 aqueous ethanol (2 + 2 ml),
S
different time, reflux at 80–90 °C.
b
4e
4f
8
7
76
89
—
1j
Isolated yields.
N
O2N
O2N
Me
S
N
S
4g
4h
4i
14
15
8
68
65
70
1l
Me
N
H
N
Me
H
S
1m
1k
N
N
H
H
S
H3C
N
H
S
4j
8
8
7
89
75
82
1k
5
NH2
Figure 2. ORTEP diagram of 4a (CCDC 914935).
S
S
N
CH3
4k
4l
O
HO
O
S
MCM-41
HO
O2N
1j
N
O
R1R2NH
-H /
NH
S
+H
O
S
NH
SH
H
O
R
1R2RN
S
4m
4n
13
10
72
79
1j
1j
N
H
H
O
H2N
(6)
MCM-41
OH
OH
S
-H /
+H
N
O
HO
HO
O
MCM-41
Me
S
-H2O
S
O
+
S
MeO
HO
S
N
H
R
N
H
N
4o
11
73
1j
R
NH2
O
1R2RN
S
C
NR1R2
(5)
Thioamide
(4)
OH
S
S
(7)
NH2
4p
4q
9
9
83
81
—
5
N
Pure covalent bond
H-bond or other weak interactions
N
Scheme 2. Plausible mechanism for thioamide formation.
NH2
N
S
bases is required. Ultimately the reaction is very clean with very
high isolated yield. It is also worth mentioning that after transfer-
ring sulfur to amide rhodanine is converted into 2-aminothiazolid-
inone (5). The thiazolidinone nucleus is known as wonder nucleus
because it gives out different derivatives with all different types of
NH2
4r
11
78
1n
MeO

S. Ray et al. / Tetrahedron Letters 54 (2013) 2164–2170
2167
Step 1
S
O
O
O
-H2S
-H /
+H
R1R2NH
N
H
S
N
S
NH
MCM-41
NR1R2
SH
NR1R2
(5)
S
(6)
Step 2
H2S
S
O
OH
-H2O
-H /
R
+H
R
NH2
R
NH2
NH2
H
S
(4)
(8)
Scheme 3. Another possibility leading to thioamide (4).
Table 3
Optimization of sulfur transferring agent
O
O
S
N
H
N
MCM-41
S
O
N
S
NH
Ph
NH2
Ph
NH2
Figure 4. A representative HRTEM image of MCM-41.
O
S
O
(5)
(2)
(3)
(1)
1 mmol
(4j)
1.2 mmol
1.2 mmol
Another possibility might be the secondary amines first attack
rhodanine expelling H2S as shown in step 1 in Scheme 3. Then a
concomitant attack of H2S on amide and subsequent loss of water
might be proposed. If it would be so then a large amount of H2S
would be released in the environment and a large excess of rhoda-
nine would be required. Since the present reaction was not carried
out in a sealed vessel and only a stoichiometric amount of
(1.0 equiv) rhodanine could afford as high as 74% thiomide (4j), it
might be proposed that loss of H2S in the environment is largely
prevented. Therefore, the expulsion of H2S is not the valid proposi-
tion rather the attack of –SH of intermediate (6) is a more accept-
able proposed mechanism.
We were also interested to know whether the reaction is possi-
ble with H2S gas or not. Therefore, when benzamide was heated at
80–90 °C in the presence of an equivalent amount of Na2S which in
turn produces H2S with water afforded only 15% conversion to thi-
oamide and a large amount of H2S was released into environment
(Table 3). Other sulfur transferring agents were also tested for this
transformation; however rhodanine/amine system was superior in
terms of cleaner reaction, higher isolated yields and environment
compatibility.
Entry
Sulfur sources
Conversionb (%)
Yieldc (%)
1
2
3
4
5
6
7
Rhodanine
P4S10
Na2S
(NH4)2S
NaHS
PSCl3
95
93
25
30
29
76
55
89
71
15
22
20
50
41
CS2
aReagents and condition: Benzamide (1 mmol), different sulfur sources (1.2 mmol),
40 mg MCM-41, aqueous-ethanol (2 + 2 ml), 80À90 °C, 8 h reflux.
Percentage was calculated from 1H NMR spectra (300 MHz).
b
c
Isolated yields.
biological activities.33 Thiazolidin-4-one ring systems are of con-
siderable interest as they are a core structure in various synthetic
pharmaceuticals displaying a broad spectrum of biological activi-
ties.34a–e 2-Imino-thiazolidin-4-ones have been found to have po-
tent anti-inflammatory,35a–c antiviral activities35a,d and antifungal
activity.34b Therefore, in our case the by product 2-aminothiazolid-
inone (5) is also a biologically beneficial compound and therefore
does not cause any detrimental effect to the environment render-
ing the transformation green.
Effect of different secondary amines on the yield of thioamide
was also studied. It was observed that all the cyclic secondary
amines afforded more or less same yields of 4j, albeit the reaction
1400
0.06
(a)
(b)
NLDFT Method
0.05
1200
2 -1
SA 1056.94 m g
Pore diameter 3.56 nm
0.04
1000
Pore Volume = 1.7880 cc/g
800
600
400
200
0
0.03
0.02
0.01
0.00
0.0
0.2
0.4
0.6
0.8
1.0
0
2
4
6
8
10 12 14 16 18 20
Pore width (nm)
Relative pressure (P/P )
0
Figure 3. (a) N2 sorption isotherm and (b) NLDFT pore size distribution of MCM-41.

2168
S. Ray et al. / Tetrahedron Letters 54 (2013) 2164–2170
(100)
(110)
2
4
6
8
10
2θ in degrees
Figure 7. Small angel XRD pattern of MCM-41.
and EDS analyses. EDS chemical analysis confirmed that the ex-
pected MCM-41 silica have successfully developed in this study.38
The 29Si MAS NMR spectral pattern for MCM-41 is shown in
Figure 6, panel a. This pattern is quite broad like amorphous mes-
oporous silica. Three major peaks in this sample at À100.5, À103.0
and À113.9 ppm were observed. These peaks have been assigned
to tetrahedral Q2, Q3 and Q4 silica species, respectively where
Qn = Si(OSi)n(OH)4-n, n = 2–4. High Q4 percentage indicated highly
condensed network.39 Such a high Q4 concentration is of para-
mount importance for the catalytic activity of silica based catalyst,
since reduction of surface silanols introduces high hydrophobicity
(and thus more affinity towards organic substrates).39
Figure 5. EDS analysis of PSNP.
was successful with dimethyl and diethyl amine in very poor yield.
Diallyl amine and the aromatic primary amines were totally unpro-
ductive. Considerably better yield was obtained with cyclohexyl
amine. Therefore cyclic secondary amines were the obvious choice
and thus we selected morpholine as an effective additive with
rhodanine.
N2 adsorption isotherm of the sample is recorded. The irrevers-
ible type IV adsorption isotherms of MCM-41 with H1 hysteresis
loop defined by IUPAC are observed, that is a typical feature of
mesoporous materials (Fig. 3, panel a).36,37
The Brunnauer–Emmett–Teller surface area of the material ob-
tained by using N2 adsorption–desorption isotherm was found out
to be quite high 1057 m2 gÀ1. Pore volume is also very high
(1.79 cc gÀ1). Pore size distribution (PSD) plot employing the non
local density functional theory (NLDFT) suggested a narrow distri-
bution with peak pore dimension of ca. 3.56 nm (Panel b). Sharp in-
crease in N2 uptake at high P/P0 suggested the presence of
interparticle mesopores.
TEM image analysis of the catalyst revealed that the MCM-41
material is composed of uniform ca. 25–30 nm size mostly spher-
ical particles. HRTEM image shows an ordered arrangement of
mesopores. Dimension of the pores is of ca. 3.2 nm (Fig. 4).
The chemical characterization for the MCM-41 was carried out
by EDS analysis. The results of chemical analysis revealed that four
elements –C, O, Si and Cu, existed in MCM-41 (Fig. 5). C and Cu
peaks come from the carbon coated copper grid used for TEM
The chemical structure of MCM-41 was studied using FT-IR
spectroscopy (Fig. 6, panel b). In the IR spectra of the MCM-41 a
strong and broad band in the range of 3500–3400 cmÀ1 corre-
sponds to the hydrogen bonded Si–OH groups and adsorbed water,
another broad band at 1638 cmÀ1 is also due to O–H vibration of
adsorbed water.29 The sharp features around 1092 cmÀ1 and the
absorption peak at 467 cmÀ1 are assigned to asymmetric stretching
and bending vibration of Si–O–Si. The observed results agree with
previously published results in the literatures29 and this confirmed
the similarity in structural characteristics of the developed MCM-
41 by the present method.
Characterization of MCM-41 with X-ray diffraction yields a dif-
fractogram with a limited number of reflections, all situated at low
angles. The MCM-41 material is highly ordered; showing two
strong diffractions for the 100, 110 planes at 2h equal to 2.5°,
4.3° corresponding to 3D-hexagonal mesophase (Fig. 7).39,40 The
reflection for 200 plane is not well resolved. These sharp signals
indicated the long-range order of the uniform hexagonal mesopor-
ous structure, which is the extraordinary characteristic of MCM-41
present in this present sample.
Figure 6. (a) 29 Si MAS NMR spectra and (b) IR analysis of MCM-41.

S. Ray et al. / Tetrahedron Letters 54 (2013) 2164–2170
2169
90
80
70
60
50
40
References and notes
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0
1
2
3
4
5
6
7
8
9
10 11
Cycles
Figure 8. Recycling of MCM-41 catalyst for the reaction forming 4a.
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catalyst and the optimum amount (40 mg) has been determined
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In the presence of MCM-41 (preheated at 100 °C for 4 h) the
reaction between benzamide, rhodanine and morpholine occurred
with 89% yield of 4j. The same reaction in the presence of MCM-41
after having it exposed to ambient atmosphere for 10 days pro-
duced a similar observation. Obviously, there was no deteriorating
effect of heat, aerial oxygen or moisture towards activity of the cat-
alyst which also provided evidence that the catalyst had the poten-
tial of efficient recycling. The recycled catalyst could be used at
least ten times with almost same efficiency as that of the first
run without any further treatment (Fig. 8). Detailed characteriza-
tion of the catalyst after 5th run showed that it was unaffected un-
der the condition of the reaction. The XRD pattern of the recovered
catalyst showed sharp peaks at 2.6° and 4.4° corresponding to 3D-
hexagonal mesophase indicating that the mesoporous structure of
MCM-41 still remained intact after recycling.
It is the first report of the use of rhodanine as the potential thi-
onating agent for amide and MCM-41 is being used for thionation
purpose also for the first time. Moreover, the entire process was
highly atom-efficient. So the present protocol minimizes the dis-
persal of the harmful chemicals in the environment and maximizes
the use of renewable resources. In this light, this highly efficient
catalytic process41 can also be considered as a green technology.
The unprecedented catalytic performance demonstrated by
MCM-41 holds a significant promise for the achievement of novel
catalyst systems. The new catalytic procedures for the thionation
of amide fulfil the triple bottom-line philosophy of green chemistry
and are important addition to the toolbox of medicinal chemists.
The spectral and analytical data42 of one representative compound
(4a) is provided in the main manuscript.
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We acknowledge UGC for financial support (F. No. 37-398/2009
(S.R.) dated 11-01-2010), CSIR for fellowship (S.R.) and NMR Re-
search Centre, IISc, Bangalore-560012 for the solid state Si-29
MAS NMR spectrum.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
045.

2170
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(1.2 mmol) in EtOH/water (2 + 2 ml) were refluxed at 80–90 °C till
completion using 40 mg of MCM-41 catalyst. The completion of the reaction
was indicated by the disappearance of the starting material in thin layer
chromatography. After completion of the reaction the solvent was evaporated
in a rotary evaporator and the crude product was taken in dichloromethane
and filtered to separate the products as filtrate from the catalyst (residue).
Then the crude product was purified by silica gel column chromatography
where the compound (5) came out from the column with 25%EtOAc/75%
petroleum ether, but thioamide (4) came out with 65%EtOAc/35% petroleum
ether making their separation easy. The thioamides (4) were characterized by
IR, 1H NMR, 13C NMR, CHN and X-ray single crystal analysis.
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42. (Piperidin-1-yl)(pyridin-4-yl)methanethione (4a): Yellow solid, mp 160–162 °C
(DCM/EtOAc 1:1); IR mmax (KBr) 3435, 3013, 2938, 2859, 1586, 1494, 1448,
1286 and 1246 cmÀ1 1H NMR (300 MHz, DMSO-d6) d: 8.54 (2H, d, J = 4.5 Hz),
;
7.19 (2H, d, J = 4.8 Hz), 4.22 (2H, br s), 3.39 (2H, t, J = 5.1 Hz), 1.64 (4H, br s),
1.48 (2H, s); 13C NMR (75 MHz, DMSO-d6) d: 195.3, 150.4, 149.8, 119.6, 53.1,
49.9, 26.7, 25.2, 23.8; Anal. Calcd for C11H14N2S: C, 64.04; H, 6.84; N, 13.58%.
Found C, 64.24; H, 6.91; N, 13.41%.
41. General synthetic procedure for preparation of thioamide (4): In a typical reaction
a
solution of amide (1 mmol), rhodanine (1.2 mmol) and Morpholine