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

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.


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 [1-4]. 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). 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). Molecules 2020, 25

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).

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, Et 3 N, K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , 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 Et 3 N 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).

Optimization of Substrate Conditions
To further investigate the limitations of this three-component system, various N-acetyl-2chloroacetamides 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

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. 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.

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.

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 Et 3 N, the result showed that the reaction did not proceed (Table 1, Entry 18). Furthermore, when we scaled Et 3 N 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. Et 3 N (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.

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.

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 Et 3 N is needed to scavenge this 1 equiv. of protons being released, and additional excess Et 3 N 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.

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. 1 H NMR and 19 F NMR spectra were recorded on Varian Mercury Plus400 spectrometers, and 13 C 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: 1 H: δ = 7.26 ppm, 13 C: δ = 77.00 ppm; DMSO-d6: 1 H: δ = 2.50 ppm, 13 C: 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.

General Procedure A: Synthesis of 3a-3j [39]
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.

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. 1 H NMR and 19 F NMR spectra were recorded on Varian Mercury Plus400 spectrometers, and 13 C NMR spectra was recorded on Bruker AVANCE600 spectrometer, with CDCl 3 or DMSO-d 6 as solvents. Resonances (δ) are given in parts per million relatives to tetramethylsilane or a residual solvent peak (CDCl 3 : 1 H: δ = 7.26 ppm, 13 C: δ = 77.00 ppm; DMSO-d 6 : 1 H: δ = 2.50 ppm, 13 C: 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.

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].    [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