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Article

A Concise Approach to N-Substituted Rhodanines through a Base-Assisted One-Pot Coupling and Cyclization Process

by
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
2
State Key Laboratory of Molecular Engineering and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
3
The Institutes of Integrative Medicine of Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(5), 1138; https://doi.org/10.3390/molecules25051138
Submission received: 9 February 2020 / Revised: 27 February 2020 / Accepted: 2 March 2020 / Published: 4 March 2020
(This article belongs to the Section Organic Chemistry)
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Versions Notes

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.

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 [1,2,3,4]. As a prime example, N-substituted rhodanines serve as versatile and useful subunits for numerous biological compounds, which are used in several pharmaceutical agents [5,6,7,8,9]. N-substituted rhodanines and their related heterocycles have been identified as synthetic building blocks and structural scaffolds which possess a unique biomolecular interaction profile [10,11,12,13,14]. However, as pan-assay interference 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.
Multicomponent processes are undoubtedly one of the most efficient approaches to forming several important motifs in modern organic synthesis and pharmaceutical synthesis [24,25,26]. For example, rhodanines have been successfully synthesized through multicomponent processes [27,28,29,30,31,32,33]. 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−d) [32,34,35,36]. As a continuation of drug synthesis and interest in the synthetic methodology of N-substituted rhodanines, we decided to investigate the multicomponent reaction of a primary amine 1, carbon disulphide 2, and methyl (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).

2. Results and Discussion

2.1. Optimization of Reaction Conditions

Our investigation started with the three-component reaction of 4-Methylbenzylamine 1a, carbon disulphide 2, and 4-methoxyphenyl (2-chloroacetyl)carbamate 3a (Table 1). First, when the mixture 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 2−7). The results showed that most of these bases could promote the reaction, and Et3N 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 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).

2.2. Optimization of Substrate Conditions

To further investigate the limitations of this three-component system, various N-acetyl-2-chloroacetamides 3a–3k were examined under the above-optimized reaction conditions (Scheme 2). When contacting esters 3a–3d were used, the desired product 4a was obtained in excellent yield. However, when contacting amides 3e–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.

2.3. Substrate Scope Study

Next, we turned our attention to investigate the scope and limitations of three-component reactions of a primary amine 1, carbon disulphide 2, 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 2,2′-(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 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.

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.

2.5. Plausible Mechanism

On the basis of the mechanistic studies and previous results [37,38], a possible mechanism is proposed in Scheme 5. The initial step in this reaction is the nucleophilic attack of amine 1 on carbon disulphide 2 to afford the key intermediate A, which subsequently reacts with 3 to form another intermediate, B, releasing 1 equiv. of protons from the reaction between 1 and 2. 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 B to D. 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 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–3h could not progress. Therefore, it can be considered that B quickly undergoes isomerization to C, which, in turn, undergoes an intramolecular six-member ring cyclization and deprotonation to afford D. Then, the nucleophilic attack of thionamide on carbonyl produces the five-member ring intermediate E. Next, C–N bond cleavage of E generates 5-unsubstituted rhodanine 4 and intermediate F. Protonation and isomerization of F forms carbamate 5.

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 was performed using silica gel (200–300 mesh) for separation and purification. 1H 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 parts per million relatives to tetramethylsilane or a residual solvent peak (CDCl3: 1H: δ = 7.26 ppm, 13C: δ = 77.00 ppm; DMSO-d6: 1H: 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].
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, 2H), 7.13–7.00 (m, 2H), 4.55 (s, 2H), 2.31 (s, 3H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 166.9, 150.2, 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, 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 10.99 (s, 1H), 4.50 (s, 2H), 3.66 (s, 3H) ppm; 13C NMR (150 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].
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 (q, J = 6.7 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 166.7, 151.6, 61.4, 44.3, 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 × 50 mL). The extract was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give 4a–4al.
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) δ 7.37–7.31 (m, 2H), 7.15–7.09 (m, 2H), 5.15 (s, 2H), 3.96 (s, 2H), 2.32 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 201.0, 173.9, 138.0, 131.7, 129.2 (2C), 129.1 (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) δ 7.47–7.38 (m, 2H), 6.87–6.79 (m, 2H), 5.12 (s, 2H), 3.95 (s, 2H), 3.78 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 201.1, 173.9, 159.5, 130.8 (2C), 127.0, 113.8 (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; 13C NMR (150 MHz, CDCl3) δ 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.
3-([1,1′-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.
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) δ 7.61–7.52 (m, 4H), 5.23 (s, 2H), 4.02 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) 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 −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].
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) δ 7.49–7.42 (m, 2H), 7.03–6.95 (m, 2H), 5.14 (s, 2H), 3.98 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) 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) δ 7.57–7.46 (m, 2H), 7.20–7.12 (m, 2H), 5.17 (s, 2H), 4.00 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) 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-([1,1′-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) δ 7.71–7.67 (m, 1H), 7.60–7.51 (m, 3H), 7.50–7.32 (m, 5H), 5.25 (s, 2H), 3.98 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) 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) δ 7.14–7.05 (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) δ 201.1, 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 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) δ 7.41–7.36 (m, 1H), 7.25–7.15 (m, 2H), 6.95-6.87 (m, 1H), 5.29 (s, 2H), 4.10 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 200.5, 173.5, 132.9, 131.6, 129.8, 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 (m, 1H), 5.17 (s, 2H), 4.06 (s, 2H), 2.43 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 200.9, 173.8, 135.7, 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) δ 7.41–7.31 (m, 1H), 6.48–6.38 (m, 1H), 6.36–7.26 (m, 1H), 5.19 (s, 2H), 4.01 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) 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) δ 7.34–7.17 (m, 2H), 7.03–6.89 (m, 1H), 5.33 (s, 2H), 3.97 (s, 2H) ppm; 13C NMR (150 MHz, CDCl3) 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); [α]D25 = 26.2 (c 1.00, CH3OH); 1H-NMR (400 MHz, CDCl3) δ 7.38–7.27 (m, 2H), 7.50–7.40 (m, 3H), 6.39 (q, J = 7.2 Hz, 1H), 3.79 (q, 2H), 1.86 (d, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 202.1, 173.4, 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); 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), 3.03–2.89 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 200.9, 173.5, 137.3, 128.9 (2C), 128.6 (2C), 126.8, 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) δ 4.06 (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) δ 201.6, 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) δ 201.3, 173.7, 136.2, 127.4, 122.4, 122.2, 119.7, 118.8, 111.9, 111.2, 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 ether/ethyl acetate, 1:1); M.p. 197.6-199.0 °C; 1H-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) δ 4.02 (s, 2H), 3.39 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) 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) δ 4.03–3.92 (m, 4H), 1.69–1.56 (m, 2H), 1.46–1.25 (m, 2H), 1.01–0.89 (m, 3H) ppm; 13C NMR (150 MHz, CDCl3) 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) 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) ppm; 13C NMR (150 MHz, CDCl3) δ 201.2, 173.9, 44.8, 35.4, 31.3, 26.7, 26.4, 22.5, 14.0 ppm; HRMS (ESI): 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) δ 4.08–3.82 (m, 4H), 1.70–1.55 (m, 2H), 1.38–1.02 (m, 14H), 0.98–0.76 (m, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 201.2, 173.9, 44.8, 35.3, 31.9, 29.5, 29.4, 29.3, 29.1, 26.8, 26.7, 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) δ 4.10–3.82 (m, 4H), 1.72–1.54 (m, 2H), 1.44–1.08 (m, 18H), 0.95–0.78 (m, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 201.2, 173.9, 44.8, 35.3, 31.9, 29.6 (2C), 29.5, 29.5, 29.3, 29.1, 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.
3,3′-(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) δ 7.24 (s, 4H), 5.03 (s, 4H), 4.34 (s, 4H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 203.3 (2C), 174.5 (2C), 134.4 (2C), 127.7 (4C), 46.5 (2C), 36.0 (2C) ppm; HRMS (ESI): m/z [M-H]− calcd for C14H12N2O2S4: 366.9709, found: 366.9705.
3,3′-(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].
3,3′-((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.
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 ether/ethyl acetate, 8:1); [α]D25 = 23.6 (c 1.00, CH3OH); 1H-NMR (400 MHz, CDCl3) δ 7.29–7.24 (m, 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) δ 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 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 acetate, 4:1); M.p. 160.7–162.1 °C; 1H-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; 13C 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 5.85–5.65 (m, 1H), 4.00–3.91 (m, 4H), 3.45–3.34 (m, 2H) ppm; 13C NMR (150 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.
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 oC; 1H-NMR (400 MHz, CDCl3) δ 7.15–7.00 (m, 2H), 6.95–6.83 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H); 13C NMR (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: [email protected]).

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.

References

  1. Berthet, M.; Cheviet, T.; Dujardin, G.; Parrot, I.; Martinez, J. Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry. Chem. Rev. 2016, 116, 15235–15283. [Google Scholar] [CrossRef] [PubMed]
  2. Costantino, L.; Barlocco, D. Privileged structures as leads in medicinal chemistry. Curr. Med. Chem. 2006, 13, 65–85. [Google Scholar] [CrossRef] [PubMed]
  3. Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol. 2010, 14, 347–361. [Google Scholar] [CrossRef] [Green Version]
  4. Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem. Rev. 2017, 117, 7762–7810. [Google Scholar] [CrossRef] [PubMed]
  5. Foye, W.O.; An, S.H. Synthesis of n-glycosylthioureas, N-glycosylrhodanines, and N-glycosyl-2-aminothiazoles and their antimicrobial activity&nbsp. J. Pharm. Sci. 2006, 70, 1059–1064. [Google Scholar]
  6. Tan, W.; Wei, J.; Jiang, X. Thiocarbonyl Surrogate via Combination of Sulfur and Chloroform for Thiocarbamide and Oxazolidinethione Construction. Org. Lett. 2017, 19, 2166–2169. [Google Scholar] [CrossRef]
  7. Tan, W.; Jänsch, N.; Öhlmann, T.; Meyer-Almes, F.-J.; Jiang, X. Thiocarbonyl Surrogate via Combination of Potassium Sulfide and Chloroform for Dithiocarbamate Construction. Org. Lett. 2019, 21, 7484–7488. [Google Scholar] [CrossRef]
  8. Tan, W.; Wang, C.; Jiang, X. Visible-Light-Mediated C(sp3)–H Thiocarbonylation for Thiolactam Preparation with Potassium Sulfide. Chin. J. Chem. 2019, 37, 1234–1238. [Google Scholar] [CrossRef]
  9. Tan, W.; Wang, C.; Jiang, X. Green carbon disulfide surrogate via a combination of potassium sulfide and chloroform for benzothiazine-thione and benzothiazole-thione construction. Org. Chem. Front. 2018, 5, 2390–2394. [Google Scholar] [CrossRef]
  10. Mendgen, T.; Steuer, C.; Klein, C.D. Privileged scaffolds or promiscuous binders: A comparative study on rhodanines and related heterocycles in medicinal chemistry. J. Med. Chem. 2012, 55, 743–753. [Google Scholar] [CrossRef]
  11. Song, M.X.; Zheng, C.J.; Deng, X.Q.; Sun, L.P.; Wu, Y.; Hong, L.; Li, Y.J.; Liu, Y.; Wei, Z.Y.; Jin, M.J.; et al. Synthesis and antibacterial evaluation of rhodanine-based 5-aryloxy pyrazoles against selected methicillin resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA). Eur. J. Med. Chem. 2013, 60, 376–385. [Google Scholar] [CrossRef] [PubMed]
  12. Tomasic, T.; Masic, L.P. Rhodanine as a Privileged Scaffold in Drug Discovery. Curr. Med. Chem. 2009, 16, 1596–1629. [Google Scholar] [CrossRef] [PubMed]
  13. Feng, M.H.; Tang, B.Q.; Liang, S.H.; Jiang, X.F. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200–1216. [Google Scholar] [CrossRef] [PubMed]
  14. Jiang, X. Sulfur Chemistry. In Topics in Current Chemistry Collections; Springer: Berlin, Germany, 2018. [Google Scholar]
  15. Tomašić, T.; Peterlin Mašič, L. Rhodanine as a scaffold in drug discovery: A critical review of its biological activities and mechanisms of target modulation. Expert Opin. Drug Discov. 2012, 7, 549–560. [Google Scholar] [CrossRef] [PubMed]
  16. Li, Q.R.; Wang, Z.; Zhou, W.; Fan, S.R.; Ma, R.; Xue, L.; Yang, L.; Li, Y.S.; Tan, H.L.; Shao, Q.H.; et al. Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway. Neural Regen. Res. 2016, 11, 345–351. [Google Scholar] [PubMed]
  17. Okamoto, H.; Nomura, M.; Nakaya, Y.; Uehara, K.; Saito, K.; Kimura, M.; Chikamori, K.; Ito, S. Effects of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy and gastroparesis. Intern. Med. 2003, 42, 655–664. [Google Scholar] [CrossRef] [Green Version]
  18. Dayam, R.; Sanchez, T.; Clement, O.; Shoemaker, R.; Sei, S.; Neamati, N. Beta-diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors. J. Med. Chem. 2005, 48, 111–120. [Google Scholar] [CrossRef]
  19. Kumar, G.; Parasuraman, P.; Sharma, S.K.; Banerjee, T.; Karmodiya, K.; Surolia, N.; Surolia, A. Discovery of a Rhodanine Class of Compounds as Inhibitors of Plasmodium falciparum Enoyl-Acyl Carrier Protein Reductase. J. Med. Chem. 2007, 50, 2665–2675. [Google Scholar] [CrossRef]
  20. Irvine, M.W.; Patrick, G.L.; Kewney, J.; Hastings, S.F.; MacKenzie, S.J. Rhodanine derivatives as novel inhibitors of PDE4. Bioorg. Med. Chem. Lett. 2008, 18, 2032–2037. [Google Scholar] [CrossRef]
  21. Ali Muhammad, S.; Ravi, S.; Thangamani, A. Synthesis and evaluation of some novel N-substituted rhodanines for their anticancer activity. Med. Chem. Res. 2016, 25, 994–1004. [Google Scholar] [CrossRef]
  22. Lee, C.H.; Chiang, C.L.; Liu, S.J. Electrospun nanofibrous rhodanine/polymethylmethacrylate membranes for the removal of heavy metal ions. Sep. Purif. Technol. 2013, 118, 737–743. [Google Scholar] [CrossRef]
  23. Song, J.; Oh, H.; Kong, H.; Jang, J. Polyrhodanine modified anodic aluminum oxide membrane for heavy metal ions removal. J. Hazard. Mater. 2011, 187, 311–317. [Google Scholar] [CrossRef] [PubMed]
  24. De Graaff, C.; Ruijter, E.; Orru, R.V. Recent developments in asymmetric multicomponent reactions. Chem. Soc. Rev. 2012, 41, 3969–4009. [Google Scholar] [CrossRef] [PubMed]
  25. Domling, A.; Wang, W.; Wang, K. Chemistry and Biology of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083–3135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ramos, L.M.; Rodrigues, M.O.; Neto, B.A.D. Mechanistic knowledge and noncovalent interactions as the key features for enantioselective catalysed multicomponent reactions: A critical review. Org. Biomol. Chem. 2019, 17, 7260–7269. [Google Scholar] [CrossRef] [PubMed]
  27. Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Hosseinpour, R. A simple and effective approach to the synthesis of rhodanine derivatives via three-component reactions in water. Tetrahedron Lett. 2009, 50, 1533–1535. [Google Scholar] [CrossRef]
  28. Attanasi, O.A.; Crescentini, L.D.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.; Behalo, M.S. An efficient one-pot, three-component synthesis of 5-hydrazinoalkylidene rhodanines from 1,2-diaza-1,3-dienes. Org. Lett. 2010, 40, 2265–2268. [Google Scholar]
  29. Azizi, N.; Hasani, M.; Khajeh, M.; Edrisi, M. A straightforward and sustainable one-pot, four-component synthesis of rhodanine derivatives. Tetrahedron Lett. 2015, 56, 1189–1192. [Google Scholar] [CrossRef]
  30. Jacobine, A.M.; Posner, G.H. Three-component, one-flask synthesis of rhodanines (thiazolidinones). J. Org. Chem. 2011, 76, 8121–8125. [Google Scholar] [CrossRef] [Green Version]
  31. Arafa, W.A.A.; Fareed, M.F.; Rabeh, S.A.; Shaker, R.M. Ultrasound mediated green synthesis of rhodanine derivatives: Synthesis, chemical behavior, and antibacterial activity. Phosphorus Sulfur 2016, 191, 1129–1136. [Google Scholar] [CrossRef]
  32. Nasiri, F.; Zolali, A.; Azimian, Z. A novel one-pot solvent-free synthesis of 3-alkyl-2-thioxo-1,3-thiazolidine-4-ones. J. Sulfur. Chem. 2014, 35, 62–66. [Google Scholar] [CrossRef]
  33. Tissaoui, K.; Raouafi, N.; Boujlel, K. Electrogenerated base-promoted synthesis of N-benzylic rhodanine and carbamodithioate derivatives. J. Sulfur. Chem. 2010, 31, 41–48. [Google Scholar] [CrossRef]
  34. Nitsche, C.; Klein, C.D. Aqueous microwave-assisted one-pot synthesis of N-substituted rhodanines. Tetrahedron Lett. 2012, 53, 5197–5201. [Google Scholar] [CrossRef]
  35. Redemann, C.E.; Icke, R.N.; Alles, G.A. Rhodanine. Org. Synth. 1947, 27, 73–76. [Google Scholar]
  36. Yarovenko, V.N.; Nikitina, A.S.; Zavarzin, I.V.; Krayushkin, M.M.; Kovalenko, L.V. A convenient synthesis of N-substituted 2-thioxo-1,3-thiazolidin-4-ones. Synthesis 2006, 2006, 1246–1248. [Google Scholar] [CrossRef]
  37. Ishihara, K.; Ohara, S.; Yamamoto, H. ChemInform Abstract: 3,4,5-Trifluorobenzeneboronic Acid as an Extremely Active Amidation Catalyst. J. Org. Chem. 1996, 61, 4196–4197. [Google Scholar] [CrossRef]
  38. Das, J.; Borah, B.J.; Das, S.K. Base-mediated intramolecular one-pot double-cyclization of epoxide-tethered 2-fluorobenzenesulfonamides: An avenue to 1,4-benzoxazine-fused benzothiaoxazepine-1,1-dioxides. Org. Biomol. Chem. 2020, 18, 220–224. [Google Scholar] [CrossRef]
  39. Shao, K.P.; Zhang, X.Y.; Zhang, X.S.; Xue, D.Q.; Ma, L.Y.; Zhang, Q.R.; Liu, H.M. Synthesis and Antitumor Activity Evaluation of Pyrimidine Analogues Bearing Urea Moiety. Chin. J. Chem. 2014, 32, 443–447. [Google Scholar] [CrossRef]
  40. Vastl, J.; Kartika, R.; Park, K.; Cho, A.E.; Spiegel, D.A. Peptidines: Glycine-amidine-based oligomers for solution- and solid-phase synthesis. Chem. Sci. 2016, 7, 3317–3324. [Google Scholar] [CrossRef] [Green Version]
  41. Loughran, H.M.; Han, Z.; Wrobel, J.E.; Decker, S.E.; Ruthel, G.; Freedman, B.D.; Harty, R.N.; Reitz, A.B. Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress. Bioorg. Med. Chem. Lett. 2016, 26, 3429–3435. [Google Scholar] [CrossRef] [Green Version]
  42. Barron, B.J.; Wong, W.-T.; Chiu, P.; Hii, K.K. “Goldilocks Effect” of Water in Lewis-Brønsted Acid and Base Catalysis. ACS Catal. 2016, 6, 4189–4194. [Google Scholar] [CrossRef]
  43. He, X.Y.; Lu, L.; Qiu, J.; Zou, P.; Yu, F.; Jiang, X.K.; Li, L.; Jiang, S.; Liu, S.; Xie, L. Small molecule fusion inhibitors: Design, synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydrox y)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41. Bioorg. Med. Chem. 2013, 21, 7539–7548. [Google Scholar] [CrossRef] [PubMed]
  44. Pantouris, G.; Syed, M.A.; Fan, C.; Rajasekaran, D.; Cho, T.Y.; Rosenberg, E.M., Jr.; Bucala, R.; Bhandari, V.; Lolis, E.J. An Analysis of MIF Structural Features that Control Functional Activation of CD74. Chem. Biol. 2015, 22, 1197–1205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Kamila, S.; Ankati, H.; Harry, E.; Biehl, E.R. A facile synthesis of novel 3-(aryl/alkyl-2-ylmethyl)-2-thioxothiazolidin-4-ones using microwave heating. Tetrahedron Lett. 2012, 53, 2195–2198. [Google Scholar] [CrossRef]
  46. Rang, K.; Liao, F.-L.; Sandström, J.; Wang, S.-L. Diastereomers of 3-(S)-(1-phenylethyl)-5-methyl-and-5-phenylrhodanine: Crystal structures, conformations, and circular dichroism spectra. Chirality 1997, 9, 568–577. [Google Scholar] [CrossRef]
  47. Yang, L.Y.; Zhang, S.Q.; He, C.; Zhang, J.Q.; Yang, Y.; Zhu, J.; Cui, Y.; Zhao, W.C.; Zhang, H.; Zhang, Y.; et al. Modulating Molecular Orientation Enables Efficient Nonfullerene Small-Molecule Organic Solar Cells. Chem. Mater. 2018, 30, 2129–2134. [Google Scholar] [CrossRef]
  48. Kamila, S.; Biehl, E.R. Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors. Tetrahedron Lett. 2012, 53, 3998–4003. [Google Scholar] [CrossRef]
  49. Harada, K.; Kubo, H.; Abe, J.; Haneta, M.; Conception, A.; Inoue, S.; Okada, S.; Nishioka, K. Discovery of potent and orally bioavailable 17beta-hydroxysteroid dehydrogenase type 3 inhibitors. Bioorg. Med. Chem. 2012, 20, 3242–3254. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
Molecules 25 01138 g001 550
Figure 1. Selected pharmaceuticals and representative compounds bearing N-substituted rhodanines.
Figure 1. Selected pharmaceuticals and representative compounds bearing N-substituted rhodanines.
Molecules 25 01138 g001
Molecules 25 01138 sch001 550
Scheme 1. Synthesis of 5-unsubstituted rhodanines. (1a–d) previous works. (1e) our work.
Scheme 1. Synthesis of 5-unsubstituted rhodanines. (1a–d) previous works. (1e) our work.
Molecules 25 01138 sch001
Molecules 25 01138 sch002 550
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.
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.
Molecules 25 01138 sch002
Molecules 25 01138 sch003a 550Molecules 25 01138 sch003b 550
Scheme 3. Scope of amines. Reaction conditions: 1a–1am (0.5 mmol), 2 (0.5 mmol), 3i (0.5 mmol), Et3N (0.6 mmol), MeCN (3 mL), r. t., 10 min. Isolated yield based on 1. a 1 (0.25 mmol).
Scheme 3. Scope of amines. Reaction conditions: 1a–1am (0.5 mmol), 2 (0.5 mmol), 3i (0.5 mmol), Et3N (0.6 mmol), MeCN (3 mL), r. t., 10 min. Isolated yield based on 1. a 1 (0.25 mmol).
Molecules 25 01138 sch003aMolecules 25 01138 sch003b
Molecules 25 01138 sch004 550
Scheme 4. Mechanism study. (a) the model reaction. (b) comparison with different conditions in the model reaction.
Scheme 4. Mechanism study. (a) the model reaction. (b) comparison with different conditions in the model reaction.
Molecules 25 01138 sch004
Molecules 25 01138 sch005 550
Scheme 5. Plausible mechanism.
Scheme 5. Plausible mechanism.
Molecules 25 01138 sch005
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 25 01138 i001
EntrySolventBaseYield b (%)
1MeCNDBU74
2MeCNDIPEA90
3MeCNEt3N94
4MeCNK2CO382
5MeCNNa2CO384
6MeCNK3PO488
7MeCNDMAP80
8DMSOEt3N81
9DMAEt3N84
10EAEt3N86
11acetoneEt3N88
12tolueneEt3N82
13DCMEt3N84
14DCEEt3N88
15MeOHEt3N76
16EtOHEt3N74
17DMFEt3N76
18MeCN−0
a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), 3a (0.5 mmol), base (0.6 mmol), solvent (3 mL), r. t., 10 min. b 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.

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Liang, Y.; Tang, M.-L.; Huo, Z.; Zhang, C.; Sun, X. A Concise Approach to N-Substituted Rhodanines through a Base-Assisted One-Pot Coupling and Cyclization Process. Molecules 2020, 25, 1138. https://doi.org/10.3390/molecules25051138

AMA Style

Liang Y, Tang M-L, Huo Z, Zhang C, Sun X. A Concise Approach to N-Substituted Rhodanines through a Base-Assisted One-Pot Coupling and Cyclization Process. Molecules. 2020; 25(5):1138. https://doi.org/10.3390/molecules25051138

Chicago/Turabian Style

Liang, Yongxi, Mei-Lin Tang, Zhipeng Huo, Chenchen Zhang, and Xun Sun. 2020. "A Concise Approach to N-Substituted Rhodanines through a Base-Assisted One-Pot Coupling and Cyclization Process" Molecules 25, no. 5: 1138. https://doi.org/10.3390/molecules25051138

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