A concise approach to n-substituted rhodanines through a base-assisted one-pot coupling and cyclization process

Article abstract of DOI:10.3390/molecules25051138

An efficient approach to obtain functionalized rhodanines was developed through a base-assisted one-pot coupling and continuous cyclization of a primary amine, carbon disulfide, and methyl (2-chloroacetyl)carbamate. This conversion tolerates a broad range of functional groups and can be used to scale the preparation of N-substituted rhodanines in excellent yields.

Full text of DOI:10.3390/molecules25051138

molecules
Article
A Concise Approach to N-Substituted Rhodanines
through a Base-Assisted One-Pot Coupling and
Cyclization Process
Yongxi Liang 1, Mei-Lin Tang 1,2, Zhipeng Huo 1, Chenchen Zhang 1 and Xun Sun 1,3,
*
1
Department of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road,
Shanghai 201203, China; 17111030010@fudan.edu.cn (Y.L.); 14111030017@fudan.edu.cn (M.-L.T.);
18111030010@fudan.edu.cn (Z.H.); 18211030009@fudan.edu.cn (C.Z.)
State Key Laboratory of Molecular Engineering and Institutes of Biomedical Sciences, Fudan University,
220 Handan Road, Shanghai 200433, China
2
3
The Institutes of Integrative Medicine of Fudan University, 12 Wulumuqi Zhong Road,
Shanghai 200040, China
*
Correspondence: sunxunf@shmu.edu.cn; Tel./Fax: +86-21-51980101
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 9 February 2020; Accepted: 2 March 2020; Published: 4 March 2020
Abstract: An efficient approach to obtain functionalized rhodanines was developed through a
base-assisted one-pot coupling and continuous cyclization of a primary amine, carbon disulfide,
and methyl (2-chloroacetyl)carbamate. This conversion tolerates a broad range of functional groups
and can be used to scale the preparation of N-substituted rhodanines in excellent yields.
Keywords: base; one-pot; coupling; cyclization; metal-free
1. Introduction
The exploration of effective approaches to access privileged structural motifs is one of the most
important and urgent requirements in modern organic and pharmaceutical chemistry [
example, N-substituted rhodanines serve as versatile and useful subunits for numerous biological
compounds, which are used in several pharmaceutical agents [ ]. N-substituted rhodanines and
their related heterocycles have been identified as synthetic building blocks and structural scaffolds
which possess a unique biomolecular interaction profile [10 14]. However, as pan-assay interference
1–4]. As a prime
5–9
–
compounds (PAINS), N-substituted rhodanines have been discovered in screening campaigns that have
often been overinterpreted in the past [15]. Epalrestat, an aldose reductase inhibitor which has been
used for the treatment of diabetic neuropathy in clinical practice, exemplifies the importance of these
heterocycles [16,17]. Furthermore, N-substituted rhodanines have been demonstrated to have many
biological activities, such as antiviral [18], antimalarial [19], anti-inflammatory [20], and anticancer
activities (Figure 1) [21]. In addition, N-substituted rhodanines have been utilized in analytical
chemistry to detect heavy metal ions [22,23]. Owing to the importance of N-substituted rhodanine
scaffolds in pharmaceutical chemistry, synthesis methods have attracted a great deal of attention, and a
number of powerful approaches have been reported. Even so, the development of an efficient and
concise process to obtain N-substituted rhodanines is still a challenge in organic and pharmaceutical
synthetic chemistry.
Molecules 2020, 25, 1138; doi:10.3390/molecules25051138
www.mdpi.com/journal/molecules

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Figure 1. Selected pharmaceuticals and representative compounds bearing N-substituted rhodanines.
Multicomponent processes are undoubtedly one of the most efficient approaches to forming
several important motifs in modern organic synthesis and pharmaceutical synthesis [24
For example, rhodanines have been successfully synthesized through multicomponent processes [27
–
–
26].
33].
However, almost all known methods involving multicomponent reactions cannot achieve the synthesis
of 5-unsubstituted rhodanines. Moreover, the known method for obtaining 5-unsubstituted rhodanines
requires long reaction times and harsh reaction conditions (Scheme 1a
of drug synthesis and interest in the synthetic methodology of N-substituted rhodanines, we decided
to investigate the multicomponent reaction of a primary amine , carbon disulphide , and methyl
−
d) [32,34–36]. As a continuation
1
2
(2-chloroacetyl)carbamate 3i to form 5-unsubstituted rhodanines. To the best of our knowledge,
no results through base-assisted one-pot coupling and a continuous cyclization process to obtain
5-unsubstituted rhodanines by the reactions of a primary amine, carbon disulfide, and methyl
(2-chloroacetyl)carbamate have previously been reported (Scheme 1e).

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Scheme 1. Synthesis of 5-unsubstituted rhodanines. (1a–d) previous works. (1e) our work.
2. Results and Discussion
2.1. Optimization of Reaction Conditions
Our investigation started with the three-component reaction of 4-Methylbenzylamine 1a, carbon
disulphide , and 4-methoxyphenyl (2-chloroacetyl)carbamate 3a (Table 1). First, when the mixture
2
was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene in MeCN, the desired product 4a was produced in
74% yield (Table 1, Entry 1). Then, various bases, including N,N-diisopropylethylamine, Et3N, K2CO3,
Na2CO3, K3PO4, and 4-dimethylaminopyridine, were screened, and the results are summarized in
Table 1 (Entries 2
was able to generate 4a in 94% yield (Entry 3). Other solvents were also investigated, and the results
showed that when MeCN was used, the yield of 4a was up to 94% (Entries 8 17). It is worth mentioning
−
7). The results showed that most of these bases could promote the reaction, and Et3N
−
that the base has a great influence on this process. When the reaction was treated in the absence of the
base, the desired product 4a did not form (Entry 18).

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Table 1. Optimization of reaction conditions a.
Yield b (%)
Entry
Solvent
Base
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMA
DBU
DIPEA
Et3N
K2CO3
Na2CO3
K3PO4
DMAP
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
−
74
90
94
82
84
88
80
81
84
86
88
82
84
88
76
74
76
0
EA
acetone
toluene
DCM
DCE
MeOH
EtOH
DMF
MeCN
a
Reaction conditions: 1a (0.5 mmol),
2
(0.5 mmol), 3a (0.5 mmol), base (0.6 mmol), solvent (3 mL), r. t.,
b
10 min.
Isolated yield based on 1a. DMSO = dimethyl sulfoxide; DMA = N,N-dimethylacetamide;
EA = ethyl acetate; DCM = dichloromethane; DCE = dichloroethane; DMF = N,N-dimethylformamide;
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine.
2.2. Optimization of Substrate Conditions
To further investigate the limitations of this three-component system, various
N-acetyl-2-chloroacetamides 3a
(Scheme 2). When contacting esters 3a
yield. However, when contacting amides 3e
–
3k were examined under the above-optimized reaction conditions
3d were used, the desired product 4a was obtained in excellent
3h were used, the reaction would not progress. In contrast,
–
–
when methoxy group- (MeO-) and ethoxy group-(EtO-)substituted N-acetyl-2-chloroacetamides 3i and
3j were examined, an excellent yield of 4a was obtained. However, 2-chloroacetamide 3k could not
promote this three-component reaction. Finally, as a low-cost and effective substrate, 3i, was selected
to investigate the scope of primary amines.

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Scheme 2. Optimization of substrate conditions. Reaction conditions: 1a (0.5 mmol),
2 (0.5 mmol),
3a–3k (0.5 mmol), Et3N (0.6 mmol), MeCN (3 mL), r. t., 10 min. Isolated yield based on 1a.
2.3. Substrate Scope Study
Next, we turned our attention to investigate the scope and limitations of three-component
reactions of a primary amine , carbon disulphide , and methyl (2-chloroacetyl)carbamate 3i
First, different substituted benzyl amines 1a 1m were examined under the optimal conditions,
as summarized in Scheme 3. In general, the three-component reactions with various substituted
benzyl amines proceeded smoothly with excellent yields (4a 4m). Other benzyl-type amines
1n 1r were also investigated in this process. The results showed that compounds 4n 4r were
also obtained in excellent yields. Various substituted ethylamines 1s 1w were also examined,
and the desired compounds, 4s 4w, were successfully obtained in excellent yields. A series of linear
primary amines 1x 1ad were examined, and the desired 5-unsubstituted rhodanines 4x 4ad were
also generated in excellent yields. Notably, 1,4-phenylenedimethanamine, propane-1,3-diamine,
and 2,20-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) afforded 4ae
4af, and 4ag in 88%, 89%, and 76%
yields, respectively. When several secondary amines, including 1ah and cyclic secondary amines
1ai 1al, were investigated, the desired compounds, 4ah and 4ai 4al, were also produced in excellent
1
2
.
–
–
–
–
–
–
–
–
,
–
–
yields. It is worth noting that when aniline was investigated, the desired compound, 4am, was not
obtained. The structures of 5-unsubstituted rhodanines 4af (CCDC 1970414) and 4al (CCDC 1970415)
were unambiguously confirmed by X-ray crystallographic analysis.

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Scheme 3. Cont.

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Scheme 3. Scope of amines. Reaction conditions: 1a
(0.6 mmol), MeCN (3 mL), r. t., 10 min. Isolated yield based on 1. 1 (0.25 mmol).
–
1am (0.5 mmol),
2
(0.5 mmol), 3i (0.5 mmol), Et3N
a
2.4. Mechanism Study
To elucidate the mechanism, mechanistic studies were performed (Scheme 4). When 1a
,
2, and 3a
were stirred under standard conditions in the absence of Et3N, the result showed that the reaction did
not proceed (Table 1, Entry 18). Furthermore, when we scaled Et3N up to 0.50 or 0.75 equiv., the desired
product 4a was not yet formed. We found that activity returned after increasing from 1 equiv. to
1.10 equiv. Et3N (Scheme 4b, 90% yield). In the model reaction progress, we obtained the carbamate
product, 5a, in 80% yield (Scheme 4a). The structure of 5a (CCDC 1970413) was confirmed by X-ray
crystallographic analysis.

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Scheme 4. Mechanism study. (a) the model reaction. (b) comparison with different conditions in the
model reaction.
2.5. Plausible Mechanism
On the basis of the mechanistic studies and previous results [37
proposed in Scheme 5. The initial step in this reaction is the nucleophilic attack of amine
disulphide to afford the key intermediate , which subsequently reacts with to form another
intermediate, , releasing 1 equiv. of protons from the reaction between and . Thus, at least 1 equiv.
of Et3N is needed to scavenge this 1 equiv. of protons being released, and additional excess Et3N is
then available to catalyze to . Considering the fact that the desired product 4a was not obtained
when replacing 3a 3d (contacting ester) with 3e 3h (contacting amide), the key lies in the difference in
,
38], a possible mechanism is
1
on carbon
2
A
3
B
1
2
B
D
–
–
electronegativity and polarity between O atom and NH group. The O atom of the ester group does not
affect the isomerization of imide, while NH group does, containing an active hydrogen atom, which
may be the reason why the reaction of 3e
quickly undergoes isomerization to C, which, in turn, undergoes an intramolecular six-member ring
cyclization and deprotonation to afford . Then, the nucleophilic attack of thionamide on carbonyl
produces the five-member ring intermediate . Next, C–N bond cleavage of generates 5-unsubstituted
rhodanine 4 and intermediate F. Protonation and isomerization of F forms carbamate 5.
–3h could not progress. Therefore, it can be considered that B
D
E
E

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Scheme 5. Plausible mechanism.
3. Materials and Methods
3.1. General Information
All starting materials were commercially available and used without further purification unless
otherwise stated. TLC analysis was performed using pre-coated glass plates. Column chromatography
1
was performed using silica gel (200–300 mesh) for separation and purification. H NMR and 19F NMR
spectra were recorded on Varian Mercury Plus400 spectrometers, and 13C NMR spectra was recorded
on Bruker AVANCE600 spectrometer, with CDCl3 or DMSO-d6 as solvents. Resonances (
δ
) are given in
1
parts per million relatives to tetramethylsilane or a residual solvent peak (CDCl3: H:
δ = 7.26 ppm,
1
13C:
δ
= 77.00 ppm; DMSO-d6: H:
δ
= 2.50 ppm, 13C:
δ
= 39.50 ppm). Data are reported as follows:
chemical shift; multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet); coupling constants (Hz);
and integration. HRMS were obtained on an AB Sciex Triple TOF® 5600+. The X-ray crystal-structure
determinations of 4af, 4al, and 5a were obtained on a d8 venture system. Melting points were measured
using a WRX-4 apparatus. Optical rotations were determined on a Rudolph Autopol IV polarimeter.
3.2. General Procedure A: Synthesis of 3a–3j
To a solution of 2-chloroacetamide (1.70 g, 18.2 mmol) in anhydrous 1,2-dichloroethane (20 mL)
was added oxalyl chloride (2 mL) at 0 ◦C, then refluxed in an oil bath at 90 ◦C for 4 h. The reaction
mixture was then cooled to 0 ◦C, and alcohol or amine (18.2 mmol) was added into the reaction mixture.
The reaction mixture was stirred for another 5 min. Upon completion, the solid was filtrated and
washed with 1,2-dichloroethane to give 3a–3j [39].

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4-Methoxyphenyl (2-chloroacetyl)carbamate (3a): 4-Methoxyphenol (2.26 g, 18.2 mmol) was
used in general procedure A. The crude product was purified from the culture filtrate providing 3a as
a yellow solid in 78% yield (3.46 g, 14.2 mmol). M.p. 149.5–151.3 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
11.45 (s, 1H), 7.20–7.08 (m, 2H), 7.02–6.92 (m, 2H), 4.55 (s, 2H), 3.75 (s, 3H) ppm; 13C NMR (150 MHz,
DMSO-d6)
δ
166.9, 157.1, 150.5, 143.1, 122.6 (2C), 114.5, 114.5, 55.4, 44.3 ppm; HRMS (ESI): m/z [M+H]+
calcd for C10H10ClNO4: 244.0371, found: 244.0370.
p-Tolyl (2-chloroacetyl)carbamate (3b): p-Cresol (1.97 g, 18.2 mmol) was used in general procedure
A. The crude product was purified from the culture filtrate providing 3b as a yellow solid in 91% yield
(3.77 g, 16.6 mmol). M.p. 162.8–164.2 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
11.46 (s, 1H), 7.30–7.16 (m,
166.9, 150.2,
2H), 7.13–7.00 (m, 2H), 4.55 (s, 2H), 2.31 (s, 3H) ppm; 13C NMR (150 MHz, DMSO-d6)
δ
147.5, 135.4, 129.9 (2C), 121.4 (2C), 44.3, 20.4 ppm; HRMS (ESI): m/z [M+H]+ calcd for C10H10ClNO3:
228.0422, found: 228.0423.
Phenyl (2-chloroacetyl)carbamate (3c): Phenol (1.71 g, 18.2 mmol) was used in general procedure
A. The crude product was purified from the culture filtrate providing 3c as a white solid in 88% yield
(3.42 g, 16.0 mmol). M.p. 130.1–132.0 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
11.51 (s, 1H), 7.49–7.40 (m,
2H), 7.33–7.26 (m, 1H), 7.25–7.18 (m, 2H), 4.56 (s, 2H) ppm; 13C NMR (150 MHz, DMSO-d6)
δ
166.9,
150.1, 149.7, 129.6 (2C), 126.1, 121.7 (2C), 44.3 ppm; HRMS (ESI): m/z [M+H]+ calcd for C9H8ClNO3:
214.0265, found: 214.0266. NMR and HRMS data are consistent with those previously reported [40].
2-Bromobenzyl (2-chloroacetyl)carbamate (3d): (2-Bromophenyl)methanol (3.40 g, 18.2 mmol)
was used in general procedure A. The crude product was purified from the culture filtrate providing 3d
as a white solid in 90% yield (5.02 g, 16.4 mmol). M.p. 154.7–156.3 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
11.18 (s, 1H), 7.74–7.62 (m, 1H), 7.60–7.51 (m, 1H), 7.49–7.39 (m, 1H), 7.37–7.26 (m, 1H), 5.20 (s, 2H),
4.49 (s, 2H) ppm; 13C NMR (150 MHz, DMSO-d6)
δ 166.6, 151.2, 134.6, 132.6, 130.5, 130.4, 128.0, 122.8,
66.3, 44.2 ppm; HRMS (ESI): m/z [M-H]− calcd for C10H9BrClNO3: 305.9360, found: 305.9350.
2-Chloro-N-(phenylcarbamoyl)acetamide (3e): Aniline (1.69 g, 18.2 mmol) was used in general
procedure A. The crude product was purified from the culture filtrate providing 3e as a white solid in
73% yield (2.83 g, 13.3 mmol). M.p. 150.4–152.1 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
10.92 (s, 1H),
10.17 (s, 1H), 7.62–7.45 (m, 2H), 7.40–7.32 (m, 2H), 7.18–7.04 (m, 1H), 4.40 (s, 2H) ppm; 13C NMR
(150 MHz, DMSO-d6)
δ 168.6, 150.2, 137.4, 128.9 (2C), 123.8, 119.7 (2C), 43.2 ppm; HRMS (ESI): m/z
[M+H]+ calcd for C9H9ClN2O2: 213.0425, found: 213.0425. NMR and HRMS data are consistent with
those previously reported [39].
2-Chloro-N-(p-tolylcarbamoyl)acetamide (3f): p-Toluidine (1.95 g, 18.2 mmol) was used in
general procedure A. The crude product was purified from the culture filtrate providing 3f as a white
solid in 71% yield (2.93 g, 12.9 mmol). M.p. 183.5–185.1 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
10.89
(s, 1H), 10.10 (s, 1H), 7.46–7.38 (m, 2H), 7.17–7.09 (m, 2H), 4.39 (s, 2H), 2.26 (s, 3H) ppm; 13C NMR
(150 MHz, DMSO-d6) δ 168.6, 150.2, 134.9, 132.9, 129.3 (2C), 119.7 (2C), 43.2, 20.4 ppm; HRMS (ESI): m/z
[M-H]- calcd for C10H11ClN2O2: 225.0436, found: 225.0426. NMR and HRMS data are consistent with
those previously reported [41].
2-Chloro-N-((4-methoxyphenyl)carbamoyl)acetamide (3g): 4-Methoxyaniline (2.24 g, 18.2 mmol)
was used in general procedure A. The crude product was purified from the culture filtrate providing 3g
as a white solid in 70% yield (3.09 g, 12.7 mmol). M.p. 170.7–172.4 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
10.87 (s, 1H), 10.01 (s, 1H), 7.46–7.40 (m, 2H), 6.95–6.87 (m, 2H), 4.38 (s, 2H), 3.73 (s, 3H) ppm; 13C NMR
(150 MHz, DMSO-d6) δ 168.5, 155.8, 150.2, 130.3, 121.6 (2C), 114.1 (2C), 55.2, 43.1 ppm; HRMS (ESI): m/z
[M-H]− calcd for C10H11ClN2O3: 241.0385, found: 241.0381. NMR and HRMS data are consistent with
those previously reported [41].
2-Chloro-N-((5-chloro-2-nitrophenyl)carbamoyl)acetamide (3h): 5-Chloro-2-nitroaniline (3.14 g,
18.2 mmol) was used in general procedure A. The crude product was purified from the culture filtrate
providing 3h as a yellow solid in 42% yield (2.23 g, 7.6 mmol). M.p. 226.8–228.4 ◦C; 1H-NMR (400 MHz,
DMSO-d6)
δ 11.97 (s, 1H), 11.36 (s, 1H),8.61–8.53 (m, 1H), 8.25–8.17 (m, 1H), 7.42–7.35 (m, 1H), 4.41 (s,

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2H) ppm; 13C NMR (150 MHz, DMSO-d6)
δ
168.5, 150.4, 139.6, 136.6, 134.3, 127.5, 123.7, 122.1, 43.1 ppm;
HRMS (ESI): m/z [M-H]− calcd for C9H7Cl2N3O4: 289.9741, found: 289.9740.
Methyl (2-chloroacetyl)carbamate (3i): Methanol (0.58 g, 18.2 mmol) was used in general
procedure A. The crude product was purified from the culture filtrate providing 3i as a white solid in
95% yield (2.62 g, 17.3 mmol). M.p. 143.6–145.4 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ 166.7, 152.2, 52.5, 44.3 ppm; HRMS (ESI):
m/z [M+H]+ calcd for C4H6ClNO3:152.0109, found: 152.0109. NMR and HRMS data are consistent
with those previously reported [42].
δ
10.99 (s, 1H), 4.50
(s, 2H), 3.66 (s, 3H) ppm; 13C NMR (150 MHz, DMSO-d6)
Ethyl (2-chloroacetyl)carbamate (3j): Ethanol (0.84 g, 18.2 mmol) was used in general procedure
A. The crude product was purified from the culture filtrate providing 3j as a white solid in 95% yield
(2.86 g, 17.3 mmol). M.p. 45.1–46.2 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
10.94 (s, 1H), 4.48 (s, 2H), 4.12
166.7, 151.6, 61.4, 44.3,
(q, J = 6.7 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (150 MHz, DMSO-d6)
δ
14.1 ppm; HRMS (ESI): m/z [M+H]+ calcd for C5H8ClNO3: 166.0265, found: 166.0264.
3.3. General Procedure B: Synthesis of 4a-4al
A mixture of amine (0.5 mmol) or diamine (0.25 mmol), carbon disulfide (38 mg, 0.5 mmol),
methyl (2-chloroacetyl)carbamate (76 mg, 0.5 mmol), and triethylamine (61 mg, 0.6 mmol) in MeCN
(3 mL) was stirred at room temperature for 10 min. After disappearance of the reactant (monitored
by TLC), added 50 mL water to the mixture, then extracted with ethyl acetate 3 times (3
The extract was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column
chromatography on silica gel to give 4a–4al.
×
50 mL).
3-(4-Methylbenzyl)-2-thioxothiazolidin-4-one (4a): Amine 1a (61 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4a as a red solid in 96% yield (114 mg, 0.48 mmol). TLC Rf = 0.24 (petroleum ether/ethyl acetate, 10:1);
M.p. 71.2–72.7 ◦C; 1H-NMR (400 MHz, CDCl3)
3.96 (s, 2H), 2.32 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ
7.37–7.31 (m, 2H), 7.15–7.09 (m, 2H), 5.15 (s, 2H),
201.0, 173.9, 138.0, 131.7, 129.2 (2C), 129.1
δ
(2C), 47.4, 35.4, 21.2 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H11NOS2: 236.0209, found: 236.0208.
NMR and HRMS data are consistent with those previously reported [33].
3-(4-Methoxybenzyl)-2-thioxothiazolidin-4-one (4b): Amine 1b (69 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4b as a red solid in 91% yield (115 mg, 0.46 mmol). TLC Rf = 0.23 (petroleum ether/ethyl acetate, 10:1);
M.p. 98.1–99.3 ◦C; 1H-NMR (400 MHz, CDCl3)
3.95 (s, 2H), 3.78 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ
7.47–7.38 (m, 2H), 6.87–6.79 (m, 2H), 5.12 (s, 2H),
201.1, 173.9, 159.5, 130.8 (2C), 127.0, 113.8
δ
(2C), 55.3, 47.1, 35.4 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H11NO2S2: 252.0158, found: 252.0158.
NMR and HRMS data are consistent with those previously reported [33].
3-(4-Butylbenzyl)-2-thioxothiazolidin-4-one (4c): Amine 1c (82 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4c as a red oil in 72% yield (101 mg, 0.36 mmol). TLC Rf = 0.24 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
δ
7.41–7.33 (m, 2H), 7.16–7.08 (m, 2H), 5.15 (d, J = 2.5 Hz, 2H), 3.97 (d,
J = 2.9 Hz, 2H), 2.59–2.55 (m, 2H), 1.63–1.51 (m, 2H), 1.38–1.29 (m, 2H), 0.97–0.88 (m, 3H) ppm; 13
NMR (150 MHz, CDCl3) 201.1, 173.9, 143.1, 131.9, 129.1 (2C), 128.6 (2C), 47.4, 35.4, 35.3, 33.5, 22.3,
13.9 ppm; HRMS (ESI): m/z [M-H]− calcd for C14H17NOS2: 278.0679, found: 278.0675.
C
δ
3-([1,10-Biphenyl]-4-ylmethyl)-2-thioxothiazolidin-4-one (4d): Amine 1d (92 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4d as a white solid in 94% yield (141 mg, 0.47 mmol). TLC Rf = 0.21 (petroleum ether/ethyl
acetate, 10:1); M.p. 130.2–131.9 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.61–7.49 (m, 6H), 7.47–7.41 (m, 2H),
7.39–7.32 (m, 1H), 5.23 (s, 2H), 4.00 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ 201.0, 173.9, 141.2, 140.6,
133.7, 129.6 (2C), 128.8 (2C), 127.5, 127.3 (2C), 127.1 (2C), 47.3, 35.4 ppm; HRMS (ESI): m/z [M-H]− calcd
for C16H13NOS2: 298.0366, found: 298.0367.

Molecules 2020, 25, 1138
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3-(4-Fluorobenzyl)-2-thioxothiazolidin-4-one (4e): Amine 1e (63 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4e as a brown oil in 92% yield (111 mg, 0.46 mmol). TLC Rf = 0.29 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
CDCl3)
113.6 ppm; HRMS (ESI): m/z [M-H]− calcd for C10H8FNOS2: 239.9959, found: 239.9958. NMR and
HRMS data are consistent with those previously reported [34].
δ
7.61–7.52 (m, 4H), 5.23 (s, 2H), 4.02 (s, 2H) ppm; 13C NMR (150 MHz,
δ
200.8, 173.7, 138.4, 129.3 (3C), 125.6, 125.6, 47.0, 35.4 ppm; 19F NMR (376 MHz, CDCl3)
δ
−
2-Thioxo-3-(4-(trifluoromethyl)benzyl)thiazolidin-4-one (4f): Amine 1f (88 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4f as a brown solid in 90% yield (131 mg, 0.45 mmol). TLC Rf = 0.31 (petroleum ether/ethyl
acetate, 10:1); M.p. 124.0–125.5 ◦C; 1H-NMR (400 MHz, CDCl3)
5.14 (s, 2H), 3.98 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ
7.49–7.42 (m, 2H), 7.03–6.95 (m, 2H),
δ
200.9, 173.8, 163.3, 161.7, 131.2, 131.1,
130.5, 115.5, 115.3, 46.8, 35.4 ppm; 19F NMR (376 MHz, CDCl3) δ −62.9 ppm; HRMS (ESI): m/z [M-H]−
calcd for C11H8F3NOS2: 289.9927, found: 289.9928. NMR and HRMS data are consistent with those
previously reported [43].
2-Thioxo-3-(4-(trifluoromethoxy)benzyl)thiazolidin-4-one (4g): Amine 1g (96 mg, 0.5 mmol)
was used in general procedure B. The crude product was purified by flash chromatography on silica
gel providing 4g as a brown oil in 90% yield (138 mg, 0.45 mmol). TLC Rf = 0.24 (petroleum ether/ethyl
acetate, 10:1); 1H-NMR (400 MHz, CDCl3)
2H) ppm; 13C NMR (150 MHz, CDCl3)
δ
7.57–7.46 (m, 2H), 7.20–7.12 (m, 2H), 5.17 (s, 2H), 4.00 (s,
δ
200.9, 173.8, 149.1, 133.3, 130.8 (2C), 121.0 (2C), 119.5, 46.8,
35.4 ppm; 19F NMR (376 MHz, CDCl3) δ −58.0 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H8F3NO2S2:
305.9876, found: 305.9875.
4-((4-Oxo-2-thioxothiazolidin-3-yl)methyl)benzonitrile (4h): Amine 1h (66 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4h as a yellow solid in 84% yield (104 mg, 0.42 mmol). TLC Rf = 0.29 (petroleum ether/ethyl
acetate, 6:1); M.p. 158.0–159.8 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.53–7.47 (m, 2H), 7.19–7.13 (m, 2H),
5.21 (s, 2H), 4.04 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 200.7, 173.7, 139.7, 132.4 (2C), 129.6 (2C),
118.4, 112.1, 47.0, 35.5 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H8N2OS2: 247.0005, found: 247.0007.
NMR and HRMS data are consistent with those previously reported [44].
3-([1,10-Biphenyl]-3-ylmethyl)-2-thioxothiazolidin-4-one (4i): Amine 1i (92 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4i as a red oil in 81% yield (121 mg, 0.41 mmol). TLC Rf = 0.30 (petroleum ether/ethyl acetate,
10:1); 1H-NMR (400 MHz, CDCl3)
3.98 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ 7.71–7.67 (m, 1H), 7.60–7.51 (m, 3H), 7.50–7.32 (m, 5H), 5.25 (s, 2H),
δ
201.0, 173.9, 141.6, 140.6, 135.2, 129.0, 128.8 (2C), 128.0
(2C), 127.5, 127.2 (2C), 127.0, 47.6, 35.4 ppm; HRMS (ESI): m/z [M-H]− calcd for C16H13NOS2: 298.0366,
found: 298.0368.
3-(3-Aminobenzyl)-2-thioxothiazolidin-4-one (4j): Amine 1j (61 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4j as a
yellow oil in 91% yield (108 mg, 0.46 mmol). TLC Rf = 0.21 (petroleum ether/ethyl acetate, 3:1); 1H-NMR
(400 MHz, CDCl3) δ7.14–7.05 (m, 1H), 6.85–6.79 (m, 1H), 6.75 (s, 1H), 6.64–6.57 (m, 1H), 5.09 (s, 2H), 3.97 (s,
2H), 3.30 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ201.1, 173.9, 146.6, 135.8, 129.5, 119.2, 115.3, 114.9, 47.6,
35.4 ppm; HRMS (ESI): m/z [M-H]− calcd for C10H10N2OS2: 237.0162, found: 237.0156.
3-(3-Chlorobenzyl)-2-thioxothiazolidin-4-one (4k): Amine 1k (71 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4k as a brown oil in 89% yield (115 mg, 0.45 mmol). TLC Rf = 0.30 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
δ 7.41 (s, 1H), 7.36–7.30 (m, 1H), 7.29–7.22 (m, 2H), 5.14 (s, 2H), 4.01 (s, 2H)
ppm; 13C NMR (150 MHz, CDCl3)
δ 200.8, 173.7, 136.5, 134.4, 129.8, 129.0, 128.4, 127.3, 47.0, 35.4 ppm;
HRMS (ESI): m/z [M-H]− calcd for C10H8ClNOS2: 255.9663, found: 255.9663.
3-(2-Chlorobenzyl)-2-thioxothiazolidin-4-one (4l): Amine 1l (71 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing

Molecules 2020, 25, 1138
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4l as a yellow solid in 94% yield (121 mg, 0.47 mmol). TLC Rf = 0.25 (petroleum ether/ethyl acetate,
8:1); M.p. 73.4–74.6 ◦C; 1H-NMR (400 MHz, CDCl3)
7.41–7.36 (m, 1H), 7.25–7.15 (m, 2H), 6.95-6.87
200.5, 173.5, 132.9, 131.6, 129.8,
δ
(m, 1H), 5.29 (s, 2H), 4.10 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ
128.8, 126.9, 126.9, 45.4, 35.5 ppm; HRMS (ESI): m/z [M-H]− calcd for C10H8ClNOS2: 255.9663, found:
255.9663. NMR and HRMS data are consistent with those previously reported [33].
3-(2-Methylbenzyl)-2-thioxothiazolidin-4-one (4m): Amine 1m (61 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4m as a white solid in 96% yield (114 mg, 0.48 mmol). TLC Rf = 0.31 (petroleum ether/ethyl acetate,
8:1); M.p. 107.0–108.4 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
7.21–7.15 (m, 2H), 7.15–7.06 (m, 1H), 6.95–6.87
200.9, 173.8, 135.7,
(m, 1H), 5.17 (s, 2H), 4.06 (s, 2H), 2.43 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ
132.2, 130.5, 127.6, 126.1, 125.5, 45.2, 35.5, 19.5 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H11NOS2:
236.0209, found: 236.0208.
3-((1H-Indol-5-yl)methyl)-2-thioxothiazolidin-4-one (4n): Amine 1n (73 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4n as a white solid in 91% yield (119 mg, 0.46 mmol). TLC Rf = 0.22 (petroleum ether/ethyl
acetate, 3:1); M.p. 157.8–159.2 ◦C; 1H-NMR (400 MHz, DMSO-d6)
δ
11.11 (s, 1H), 7.54–7.46 (m, 1H),
7.39–7.29 (m, 2H), 7.15–7.06 (m, 1H), 6.43–6.35 (m, 1H), 5.13 (s, 2H), 4.34 (s, 2H) ppm; 13C NMR
(150 MHz, DMSO-d6)
δ 203.2, 174.6, 135.3, 127.4, 125.9, 125.4, 121.4, 119.8, 111.2, 101.0, 47.5, 35.9 ppm;
HRMS (ESI): m/z [M-H]− calcd for C12H10N2OS2: 261.0162, found: 261.0161.
3-(Naphthalen-1-ylmethyl)-2-thioxothiazolidin-4-one (4o): Amine 1o (79 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4o as a yellow oil in 91% yield (124 mg, 0.46 mmol). TLC Rf = 0.29 (petroleum ether/ethyl
acetate, 10:1); 1H-NMR (400 MHz, CDCl3)
δ
8.15–8.08 (m, 1H), 7.91–7.84 (m, 1H), 7.81–7.74 (m, 1H),
7.63–7.47 (m, 2H), 7.42–7.33 (m, 1H), 7.17–7.09 (m, 1H), 5.66 (s, 2H), 4.05 (s, 2H) ppm; 13C NMR
(150 MHz, CDCl3) δ 200.9, 173.7, 133.7, 130.8, 129.2, 128.9, 128.4, 126.5, 125.9, 125.1, 123.9, 122.9, 45.4,
35.4 ppm; HRMS (ESI): m/z [M-H]− calcd for C14H11NOS2: 272.0209, found: 272.0206.
3-(Furan-2-ylmethyl)-2-thioxothiazolidin-4-one (4p): Amine 1p (49 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4p as a red oil in 89% yield (95 mg, 0.45 mmol). TLC Rf = 0.28 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
4.01 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ 7.41–7.31 (m, 1H), 6.48–6.38 (m, 1H), 6.36–7.26 (m, 1H), 5.19 (s, 2H),
δ
200.3, 173.4, 147.7, 142.6, 110.5, 110.5, 40.4, 35.3 ppm;
HRMS (ESI): m/z [M-H]− calcd for C8H7NO2S2: 211.9845, found: 211.9845. NMR and HRMS data are
consistent with those previously reported [45].
3-(Thiophen-2-ylmethyl)-2-thioxothiazolidin-4-one (4q): Amine 1q (57 mg, 0.5 mmol) was used
in general procedure B. The crude product was purified by flash chromatography on silica gel providing
4q as a red solid in 91% yield (104 mg, 0.46 mmol). TLC Rf = 0.22 (petroleum ether/ethyl acetate, 10:1);
M.p. 93.7–95.4 ◦C; 1H-NMR (400 MHz, CDCl3)
3.97 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ
7.34–7.17 (m, 2H), 7.03–6.89 (m, 1H), 5.33 (s, 2H),
δ
200.2, 173.3, 135.8, 129.2, 126.6, 126.4, 41.9, 35.4 ppm;
HRMS (ESI): m/z [M-H]− calcd for C8H7NOS3: 227.9617, found: 227.9619. NMR and HRMS data are
consistent with those previously reported [45].
(S)-3-(1-Phenylethyl)-2-thioxothiazolidin-4-one (4r): Amine 1r (61 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4r as a brown oil in 81% yield (96 mg, 0.41 mmol). TLC Rf = 0.30 (petroleum ether/ethyl acetate, 10:1);
25
[
α
]
= 26.2 (c 1.00, CH3OH); 1H-NMR (400 MHz, CDCl3)
δ
7.38–7.27 (m, 2H), 7.50–7.40 (m, 3H),
202.1, 173.4,
D
6.39 (q, J = 7.2 Hz, 1H), 3.79 (q, 2H), 1.86 (d, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ
138.0, 128.3 (2C), 127.9, 127.6 (2C), 55.2, 34.1, 15.0 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H11NOS2:
236.0209, found: 236.0207. NMR and HRMS data are consistent with those previously reported [46].
3-Phenethyl-2-thioxothiazolidin-4-one (4s): Amine 1s (61 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4s as
a red solid in 92% yield (109 mg, 0.46 mmol). TLC Rf = 0.24 (petroleum ether/ethyl acetate, 10:1);

Molecules 2020, 25, 1138
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M.p. 111.3–112.7 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
7.45–7.15 (m, 5H), 4.25–4.15 (m, 2H), 3.93 (s, 2H),
δ 200.9, 173.5, 137.3, 128.9 (2C), 128.6 (2C), 126.8,
3.03–2.89 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3)
45.7, 35.2, 32.6 ppm; HRMS (ESI): m/z [M-H]− calcd for C11H11NOS2: 236.0209, found: 236.0211.
NMR and HRMS data are consistent with those previously reported [34].
3-(Cyclobutylmethyl)-2-thioxothiazolidin-4-one (4t): Amine 1t (43 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing 4t as
a yellow oil in 93% yield (94 mg, 0.47 mmol). TLC Rf = 0.21 (petroleum ether/ethyl acetate, 10:1); 1H-NMR
(400 MHz, CDCl3) δ4.06 (dd, J = 7.3, 1.6 Hz, 2H), 3.97 (d, J = 1.7 Hz, 2H), 2.80 (dd, J = 14.7, 7.3 Hz, 1H),
2.09–1.92 (m, 2H), 1.75–1.91 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3)
δ201.6, 174.2, 49.4, 35.3, 33.4, 26.2
(2C), 18.3 ppm; HRMS (ESI): m/z [M-H]− calcd for C8H11NOS2: 200.0209, found: 200.0208.
3-(2-(Thiophen-2-yl)ethyl)-2-thioxothiazolidin-4-one (4u): Amine 1u (64 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4u as a brown solid in 92% yield (112 mg, 0.46 mmol). TLC Rf = 0.30 (petroleum ether/ethyl
acetate, 10:1); M.p. 125.5–127.3 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
7.24–7.13 (m, 1H), 7.00–6.90 (m, 1H),
6.91–6.82 (m, 1H), 4.24 (dd, J = 10.6, 4.6 Hz, 2H), 3.95 (d, J = 1.7 Hz, 2H), 3.18 (t, J = 6.7 Hz 2H) ppm;
13C NMR (150 MHz, CDCl3)
δ 200.8, 173.5, 139.2, 127.0, 125.9, 124.3, 45.5, 35.3, 26.6 ppm; HRMS (ESI):
m/z [M-H]− calcd for C9H9NOS3: 241.9774, found: 241.9773.
3-(2-(1H-Indol-3-yl)ethyl)-2-thioxothiazolidin-4-one (4v): Amine 1v (80 mg, 0.5 mmol) was used
in general procedure B. The crude product was purified by flash chromatography on silica gel providing
4v as a yellow solid in 91% yield (126 mg, 0.46 mmol). TLC Rf = 0.26 (petroleum ether/ethyl acetate,
4:1); M.p. 178.0–179.4 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
8.04 (s, 1H), 7.83-7.71 (m, 1H), 7.40–7.30 (m,
1H), 7.24–7.13 (m, 2H), 7.12–7.06 (m, 1H), 4.34–4.21 (m, 2H), 3.87 (s, 2H), 3.11 (dd, J = 9.1, 6.7 Hz, 2H)
ppm; 13C NMR (150 MHz, CDCl3)
201.3, 173.7, 136.2, 127.4, 122.4, 122.2, 119.7, 118.8, 111.9, 111.2,
δ
45.4, 35.4, 22.6 ppm; HRMS (ESI): m/z [M-H]− calcd for C13H12N2OS2: 275.0318, found: 275.0316.
4-(2-(4-Oxo-2-thioxothiazolidin-3-yl)ethyl)benzenesulfonamide (4w): Amine 1w (100 mg,
0.5 mmol) was used in general procedure B. The crude product was purified by flash chromatography
on silica gel providing 4w as a yellow solid in 89% yield (141 mg, 0.45 mmol). TLC Rf = 0.24 (petroleum
◦
1
ether/ethyl acetate, 1:1); M.p. 197.6-199.0 C; H-NMR (400 MHz, DMSO-d6)
δ 7.81–7.71 (m, 2H),
7.47–7.37 (m, 2H), 7.34 (s, 2H), 4.25 (s, 2H), 4.07 (t, J =7.5 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H) ppm; 13C NMR
(150 MHz, DMSO-d6)
δ 203.0, 174.1, 142.5, 141.8, 129.2 (2C), 125.9 (2C), 44.6, 35.8, 31.8 ppm; HRMS
(ESI): m/z [M-H]− calcd for C11H12N2O3S3: 314.9937, found: 314.9934.
3-Methyl-2-thioxothiazolidin-4-one (4x): Amine 1x (16 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4x as
a yellow solid in 96% yield (71 mg, 0.48 mmol). TLC Rf = 0.29 (petroleum ether/ethyl acetate, 10:1);
M.p. 259.4–261.0 ◦C; 1H-NMR (400 MHz, CDCl3)
CDCl3)
δ
4.02 (s, 2H), 3.39 (s, 3H) ppm; 13C NMR (150 MHz,
δ
201.3, 173.8, 35.7, 31.3 ppm; HRMS (ESI): m/z [M-H]− calcd for C4H5NOS2: 145.9740, found:
145.9735. NMR and HRMS data are consistent with those previously reported [34].
3-Butyl-2-thioxothiazolidin-4-one (4y): Amine 1y (37 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing
4y as a yellow oil in 94% yield (89 mg, 0.47 mmol). TLC Rf = 0.21 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
3H) ppm; 13C NMR (150 MHz, CDCl3)
δ 4.03–3.92 (m, 4H), 1.69–1.56 (m, 2H), 1.46–1.25 (m, 2H), 1.01–0.89 (m,
δ
201.2, 173.9, 44.6, 35.3, 28.8, 20.0, 13.7 ppm; HRMS (ESI): m/z
[M-H]− calcd for C7H11NOS2: 188.0209, found: 188.0200. NMR and HRMS data are consistent with
those previously reported [34].
3-Hexyl-2-thioxothiazolidin-4-one (4z): Amine 1z (51 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4z as
a yellow oil in 94% yield (102 mg, 0.47 mmol). TLC Rf = 0.28 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
ppm; 13C NMR (150 MHz, CDCl3)
δ
4.07–3.89 (m, 4H), 1.71–1.55 (m, 2H), 1.37–1.28 (m, 6H), 0.95–0.83 (m, 3H)
201.2, 173.9, 44.8, 35.4, 31.3, 26.7, 26.4, 22.5, 14.0 ppm; HRMS (ESI):
δ

Molecules 2020, 25, 1138
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m/z [M-H]− calcd for C9H15NOS2: 216.0522, found: 216.0512. NMR and HRMS data are consistent
with those previously reported [47].
3-Decyl-2-thioxothiazolidin-4-one (4aa): Amine 1aa (79 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4aa as
a yellow oil in 92% yield (126 mg, 0.46 mmol). TLC Rf = 0.29 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
3H) ppm; 13C NMR (150 MHz, CDCl3)
δ
4.08–3.82 (m, 4H), 1.70–1.55 (m, 2H), 1.38–1.02 (m, 14H), 0.98–0.76 (m,
201.2, 173.9, 44.8, 35.3, 31.9, 29.5, 29.4, 29.3, 29.1, 26.8, 26.7,
δ
22.7, 14.1 ppm; HRMS (ESI): m/z [M-H]− calcd for C13H23NOS2: 272.1148, found: 272.1150.
3-Dodecyl-2-thioxothiazolidin-4-one (4ab): Amine 1ab (93 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4ab
as a yellow oil in 88% yield (133 mg, 0.44 mmol). TLC Rf = 0.25 (petroleum ether/ethyl acetate, 10:1);
1H-NMR (400 MHz, CDCl3)
3H) ppm; 13C NMR (150 MHz, CDCl3)
δ
4.10–3.82 (m, 4H), 1.72–1.54 (m, 2H), 1.44–1.08 (m, 18H), 0.95–0.78 (m,
201.2, 173.9, 44.8, 35.3, 31.9, 29.6 (2C), 29.5, 29.5, 29.3, 29.1,
δ
26.8, 26.7, 22.7, 14.1 ppm; HRMS (ESI): m/z [M-H]− calcd for C15H27NOS2: 300.1461, found: 300.1464.
3-Allyl-2-thioxothiazolidin-4-one (4ac): Amine 1ac (29 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4ac as a
red oil in 91% yield (79 mg, 0.46 mmol). TLC Rf = 0.30 (petroleum ether/ethyl acetate, 10:1); 1H-NMR
(400 MHz, CDCl3)
δ
5.90–5.73 (m, 1H), 5.27 (t, J = 14.6 Hz, 2H), 4.61 (d, J = 5.9 Hz, 2H), 4.00 (s, 2H) ppm;
13C NMR (150 MHz, CDCl3)
δ
200.7, 173.5, 129.4, 119.6, 46.5, 35.4 ppm; HRMS (ESI): m/z [M-H]− calcd
for C6H7NOS2: 171.9896, found: 171.9895. NMR and HRMS data are consistent with those previously
reported [34].
3-(4-((6-Methoxyquinolin-8-yl)amino)pentyl)-2-thioxothiazolidin-4-one (4ad): Amine 1ad
(130 mg, 0.5 mmol) was used in general procedure B. The crude product was purified by flash
chromatography on silica gel providing 4ad as a yellow oil in 88% yield (165 mg, 0.44 mmol).
TLC Rf = 0.29 (petroleum ether/ethyl acetate, 8:1); 1H-NMR (400 MHz, CDCl3)
δ 8.64-8.44 (m, 1H), 7.93
(d, J = 8.2 Hz, 1H), 7.36–7.27 (m, 1H), 6.36 (s, 1H), 6.28 (s, 1H), 6.00 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H),
3.67 (dd, J = 16.3, 9.9 Hz, 1H), 3.59–3.45 (m, 2H), 1.96–1.69 (m, 5H), 1.42–1.21 (m, 4H) ppm; 13C NMR
(150 MHz, CDCl3) δ 159.4, 144.7, 144.3, 135.2, 134.9, 130.0, 129.9, 121.9 (2C), 96.9, 91.9 (2C), 55.2, 47.5,
45.1, 33.6, 26.7, 20.7 ppm; HRMS (ESI): m/z [M-H]− calcd for C18H21N3O2S2: 374.1002, found: 374.1007.
3,30-(1,4-Phenylenebis(methylene))bis(2-thioxothiazolidin-4-one) (4ae): Diamine 1ae (34 mg,
0.25 mmol) was used in general procedure B. The crude product was purified by flash chromatography
on silica gel providing 4ae as a yellow solid in 88% yield (81 mg, 0.22 mmol). TLC Rf = 0.24 (petroleum
ether/ethyl acetate, 4:1); M.p. 266.5–268.3 ◦C; 1H-NMR (400 MHz, DMSO-d6)
4.34 (s, 4H) ppm; 13C NMR (150 MHz, DMSO-d6)
203.3 (2C), 174.5 (2C), 134.4 (2C), 127.7 (4C), 46.5
δ 7.24 (s, 4H), 5.03 (s, 4H),
δ
(2C), 36.0 (2C) ppm; HRMS (ESI): m/z [M-H]− calcd for C14H12N2O2S4: 366.9709, found: 366.9705.
3,30-(Propane-1,3-diyl)bis(2-thioxothiazolidin-4-one) (4af): Diamine 1af (19 mg, 0.25 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4af as a yellow solid in 89% yield (68 mg, 0.22 mmol). TLC Rf = 0.29 (petroleum ether/ethyl
acetate, 3:1); M.p. 122.8–124.5 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 4.08-4.01 (m, 4H), 4.00 (s, 4H), 2.13–2.00
(m, 2H) ppm; 13C NMR (150 MHz, CDCl3)
δ 201.2 (2C), 173.9 (2C), 41.8 (2C), 35.4 (2C), 24.8 ppm;
HRMS (ESI): m/z [M-H]− calcd for C9H10N2O2S4: 304.9552, found: 304.9549. NMR and HRMS data are
consistent with those previously reported [48].
3,30-((Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-thioxothiazolidin-4-one)
(4ag):
Diamine 1ag (37 mg, 0.25 mmol) was used in general procedure B. The crude product was
purified by flash chromatography on silica gel providing 4ag as a yellow oil in 76% yield (72 mg,
0.19 mmol). TLC Rf = 0.29 (petroleum ether/ethyl acetate, 3:1); 1H-NMR (400 MHz, CDCl3)
δ 7.10-6.99
(m, 4H), 6.91–6.81 (m, 4H), 5.41–4.71 (m, 4H), 3.81–3.75 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3)
δ
157.2 (2C), 155.6 (2C), 144.3 (2C), 122.5 (2C), 114.4 (2C), 55.6 (2C) ppm; HRMS (ESI): m/z [M-H]− calcd
for C12H16N2O4S4: 378.9920, found: 378.9917.

Molecules 2020, 25, 1138
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Ethyl (S)-2-(4-oxo-2-thioxothiazolidin-3-yl)-4-phenylbutanoate (4ah): Amine 1ah (104 mg,
0.5 mmol) was used in general procedure B. The crude product was purified by flash chromatography
on silica gel providing 4ah as a yellow oil in 81% yield (131 mg, 0.41 mmol). TLC Rf = 0.23 (petroleum
25
ether/ethyl acetate, 8:1); [
α
]
= 23.6 (c 1.00, CH3OH); 1H-NMR (400 MHz, CDCl3)
δ 7.29–7.24 (m,
D
2H), 7.21–7.12 (m, 3H), 5.59 (d, J = 8.6 Hz, 1H), 4.27–4.08 (m, 2H), 3.72 (d, J = 18.1 Hz, 1H), 3.55 (d,
J = 18.2 Hz, 1H), 2.82 (dd, J = 13.1, 6.8 Hz, 1H), 2.74–2.50 (m, 3H), 1.28–1.20 (m, 3H) ppm; 13C NMR
(150 MHz, CDCl3) δ 201.2, 173.3, 167.9, 140.2, 128.5 (2C), 128.2 (2C), 126.2, 62.0, 57.7, 34.3, 32.5, 28.2,
14.1 ppm; HRMS (ESI): m/z [M-H]− calcd for C15H17NO3S2: 322.0577, found: 322.0568.
3-Cyclohexyl-2-thioxothiazolidin-4-one (4ai): Amine 1ai (50 mg, 0.5 mmol) was used in general
procedure B. The crude product was purified by flash chromatography on silica gel providing 4ai as a
yellow solid in 91% yield (98 mg, 0.46 mmol). TLC Rf = 0.22 (petroleum ether/ethyl acetate, 10:1); M.p.
120.3–122.1 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
4.86 (t, J = 10.9 Hz, 1H), 3.82 (s, 2H), 2.45-2.15 (m, 2H),
1.94–1.76 (m, 2H), 1.60–1.51 (m, 2H), 1.44–1.31 (m, 2H), 1.32–1.16 (m, 2H) ppm; 13C NMR (150 MHz,
CDCl3)
202.4, 174.3, 58.5, 33.9, 27.5 (2C), 26.0 (2C), 25.0 ppm; HRMS (ESI): m/z [M-H]− calcd for
δ
C9H13NOS2: 214.0366, found: 214.0365. NMR and HRMS data are consistent with those previously
reported [49].
3-(Tetrahydro-2H-pyran-4-yl)-2-thioxothiazolidin-4-one (4aj): Amine 1aj (51 mg, 0.5 mmol) was
used in general procedure B. The crude product was purified by flash chromatography on silica gel
providing 4aj as a white solid in◦92% yield (100 mg, 0.46 mmol). TLC Rf = 0.27 (petroleum ether/ethyl
1
acetate, 4:1); M.p. 160.7–162.1 C; H-NMR (400 MHz, CDCl3)
δ
5.13 (t, J = 12.2 Hz, 1H), 4.08 (d,
J = 11.3 Hz, 2H), 3.86 (s, 2H), 3.46 (t, J = 11.9 Hz, 2H), 2.78–2.61 (m, 2H), 1.60–1.49 (m, 2H) ppm; 13
C
NMR (150 MHz, CDCl3)
δ
202.1, 174.0, 67.6 (2C), 55.3, 33.9, 27.7 (2C) ppm; HRMS (ESI): m/z [M-H]−
calcd for C8H11NO2S2: 216.0158, found: 216.0160. NMR and HRMS data are consistent with those
previously reported [49].
3-(3-Oxocyclobutyl)-2-thioxothiazolidin-4-one (4ak): Amine 1ak (43 mg, 0.5 mmol) was used in
general procedure B. The crude product was purified by flash chromatography on silica gel providing
4ak as a yellow solid in 88% yield (89 mg, 0.44 mmol). TLC Rf = 0.28 (petroleum ether/ethyl acetate,
4:1); M.p. 166.0–167.6 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 201.8, 201.4, 174.2, 51.0 (2C), 41.9, 34.3 ppm; HRMS (ESI):
m/z [M-H]− calcd for C7H7NO2S2: 199.9845, found: 199.9847.
δ
5.85–5.65 (m, 1H), 4.00–3.91 (m, 4H), 3.45–3.34
(m, 2H) ppm; 13C NMR (150 MHz, CDCl3)
3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-thioxothiazolidin-4
-one (4al): Amine 1al (133 mg, 0.5 mmol) was used in general procedure B. The crude product was
purified by flash chromatography on silica gel providing 4al as a white solid in 92% yield (176 mg,
0.46 mmol). TLC Rf = 0.30 (petroleum ether/ethyl acetate, 4:1); M.p. 178.5-180.1 ◦C; 1H-NMR (400 MHz,
CDCl3)
δ 7.68–7.58 (m, 3H), 7.50–7.31 (m, 5H), 7.28 (s, 1H), 6.75 (s, 1H), 4.10 (s, 2H), 3.46 (s, 3H) ppm;
13C NMR (150 MHz, CDCl3)
δ
202.1, 172.0, 168.0, 166.8, 143.0, 137.9, 132.2, 130.8, 130.7, 130.0 (2C),
128.3, 128.2 (2C), 124.4, 121.4, 74.8, 35.8, 34.3 ppm; HRMS (ESI): m/z [M+H]+ calcd for C19H15N3O2S2:
382.0678, found: 382.0681.
3.4. General Procedure for the Synthesis of 4-Methoxyphenyl Carbamate (5a)
A mixture of p-tolylmethanamine (61 mg, 0.5 mmol), carbon disulfide (38 mg, 0.5 mmol),
4-methoxyphenyl (2-chloroacetyl)carbamate (122 mg, 0.5 mmol), and triethylamine (61 mg, 0.6 mmol)
in MeCN (3 mL) was stirred at room temperature for 10 min. After disappearance of the reactant
(monitored by TLC), added 50 mL water to the mixture, and then extracted with ethyl acetate 3 times
(3
×
50 mL). The extract was dried over anhydrous Na2SO4 and evaporated. The residue was purified
by column chromatography on silica gel to afford the product 4a (TLC Rf = 0.24, petroleum ether/ethyl
acetate = 10:1) as a red solid in 94% yield (112 mg, 0.47 mmol) and 5a (TLC Rf = 0.30, petroleum
ether/ethyl acetate = 3:1) as a white solid in 80% yield (67 mg, 0.40 mmol). M.p. 127.3–129.0 C;
1H-NMR (400 MHz, CDCl3)
o
δ
7.15–7.00 (m, 2H), 6.95–6.83 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H); 13C NMR

Molecules 2020, 25, 1138
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(150 MHz, CDCl3)
δ
157.2, 155.5, 144.3, 122.5 (2C), 114.4 (2C), 55.6; HRMS (ESI): m/z [M+H]+ calcd for
C8H9NO3: 168.0655, found: 168.0654.
CCDC 1970414 (4af), CCDC 1970415 (4al), and CCDC 1970413 (5a) contain the Supplementary
Crystallographic Data for this paper. These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax:
+44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
4. Conclusions
In summary, we established an efficient approach for the synthesis of N-substituted rhodanines
via a base-assisted one-pot coupling and continuous cyclization of a primary amine, carbon disulphide,
and methyl (2-chloroacetyl)carbamate. A series of substituted alkyl- and benzylamines were
successively obtained, providing structurally diverse N-substituted rhodanines in outstanding yield.
Further application of this promising method in pharmaceutical synthesis is in progress in our laboratory.
Supplementary Materials: The following are available online. Supporting information including the spectrums
of 1H, 13C-NMR, 19F-NMR, and X-ray Crystallography.
Author Contributions: X.S. directed this project, Y.L. carried out the experiments, M.-L.T. checked and analyzed
the data, and Z.H. and C.Z. revised the paper. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China (81673297 and 81903422)
and Science and Technology Commission of Shanghai Municipality (17JC1400200).
Conflicts of Interest: The authors declare no conflicts of interest.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).