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Article

Multicomponent Reaction for the Synthesis of β-Ketosulfides in Deep Eutectic Solvents

by
Chiara Falcini
1,
David Jaén-Herrera
1,
Rosario Fernández
1,
Andrés R. Alcántara
2 and
Gonzalo de Gonzalo
1,*
1
Organic Chemistry Department, University of Sevilla, c/Prof. García González, 1, 41012 Sevilla, Spain
2
Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Complutense University of Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
Molecules 2026, 31(4), 745; https://doi.org/10.3390/molecules31040745
Submission received: 27 January 2026 / Revised: 17 February 2026 / Accepted: 19 February 2026 / Published: 22 February 2026
(This article belongs to the Special Issue Ionic Liquids and Deep Eutectic Solvents: From Synthesis to Emerging Applications)
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Abstract

The use of Type III Deep Eutectic Solvents (DESs) as both solvents and cocatalysts enable the one-pot synthesis of several β-ketosulfides, structural motifs commonly found in biologically active compounds, via a multicomponent reaction (MCR) involving 2-bromoketones, alkyl or benzyl halides, and potassium thioacetate in basic medium. Under these conditions, it was possible to avoid not only the use of the non-eco-friendly solvent dimethylformamide (DMF), but also an additional hydrolytic step previously reported for the preparation of these molecules. The MCR conducted in the presence of the DES ChCl:Gly (1:2) was optimized through the evaluation of different reaction parameters. Notably, the non-conventional medium could be recycled up to four times without any appreciable loss of catalytic activity. Environmental metrics, including the E factor, E+ factor, and Global Warming Potential (GWP), were calculated for the process both in the presence and absence of the DES, demonstrating improved environmental performance when the DES was employed.

Graphical Abstract

1. Introduction

β-Ketosulfides constitute a highly valuable class of sulfur-containing organic compounds due to the unique combination of a carbonyl group and a thioether moiety within the same molecular framework. This structural motif provides a versatile platform for further synthetic elaboration, as it integrates the electrophilic reactivity of ketones with the nucleophilic and redox properties of sulfides. Consequently, β-ketosulfides have found widespread application as intermediates in organic synthesis, medicinal chemistry, and materials science [1,2,3]. From a biological perspective, β-ketosulfide derivatives are present in natural products and bioactive molecules. They have been identified in marine fungal metabolites [4], anticancer agents [5], and inhibitors of phospholipases [6]. Furthermore, their selective reduction affords chiral β-hydroxysulfides, which are valuable building blocks in asymmetric synthesis and can serve as precursors for multicomponent reactions and functional polymer modification [7,8,9,10,11,12].
Traditional approaches to β-ketosulfide synthesis typically rely on the direct α-sulfenylation of carbonyl compounds using thiols or disulfides as sulfur sources [13,14]. However, these methodologies often require transition-metal catalysts such as copper [15], indium [16], palladium, or gold complexes [17], or organocatalysts [14], and are frequently performed in hazardous or environmentally problematic solvents such as dimethylformamide [18]. In addition, these protocols may suffer from harsh reaction conditions, poor atom economy, and limited sustainability. A more sustainable strategy was reported by Heredia and co-workers, who described a thiol-free chemoenzymatic synthesis of β-ketosulfides [19]. In this methodology, β-alkylsulfide enol esters were initially prepared via a multicomponent reaction in DMF [20], followed by a lipase-catalyzed hydrolysis step. This approach still involves a non-green solvent and requires a two-step sequence, increasing both operational and environmental complexity.
Nowadays, solvent selection has become a critical parameter in process design. Solvents account for the largest fraction of mass input in fine chemical and pharmaceutical production, often contributing the most significantly to waste generation and environmental impact. Consequently, the development of environmentally benign solvent systems capable of replacing conventional media such as DMF is of great importance.
In 2003, Abbott et al. described Deep Eutectic Solvents for the first time [21]; these neoteric solvents have rapidly gained prominence, due to their versatility and green nature. In fact, DESs have attracted substantial and steadily increasing attention within both academic research and industrial development, as reflected by the rapid expansion of the literature on their synthesis, properties, and applications [22]. These solvents are usually prepared by mixing a hydrogen-bond acceptor (HBA) with one or more hydrogen-bond donors (HBD) in a defined molar ratio, forming a deep eutectic mixture having a melting point significantly lower than that of the pure constituents. These solvents display several desirable properties, including biocompatibility, non-volatility, thermal stability, biodegradability, and low toxicity [23], making them particularly attractive for green synthesis [24,25]. Among the different classes of DESs, those classified as Type III, typically obtained by combining quaternary ammonium salts (for example choline chloride (ChCl)) with a different hydrogen-donor such as glycerol (Gly), ethylene glycol (EG) or urea (U), are the most widely employed in organic synthesis.
Beyond their role as solvents, DESs have shown catalytic activity in a variety of chemical processes. The presence of the hydrogen network enables diverse transformations through hydrogen-bond catalysis, an area of high interest in organic chemistry. A broad range of processes including cycloadditions, condensations, redox and multicomponent reactions can be carried out in the presence of DESs, acting simultaneously as catalysts and solvents. Several studies reported in the literature have consistently demonstrated that the use of DESs in these reactions leads to significantly higher conversions when compared to conventional organic solvents [25,26,27], in addition to the environmental advantages derived from the use of this sustainable type of compounds.
Herein, we present a novel efficient and sustainable one-pot methodology for the synthesis of β-ketosulfides through a multicomponent reaction performed in DESs under mild conditions. The substitution of DMF for a DES in this process enables the direct formation of the β-ketosulfides, thereby eliminating the conventional two-step sequence that requires both DMF and lipase biocatalyzed hydrolysis as previously described [19,20] (Figure 1). This solvent replacement not only simplifies the overall process but also enhances its environmental compatibility. Moreover, the reduced E-factor for the DES-involved process clearly demonstrates that this methodology offers a greener and more sustainable alternative to traditional approaches.

2. Results and Discussion

Initial experiments were conducted to investigate the replacement of DMF as solvent in the preparation of β-alkylsulfide enol esters. These valuable molecules are obtained in a MCR combining 2-bromoketones, alkyl iodides and potassium thioacetate in presence of K2CO3 as base, following the procedure described in the literature [20]. Our efforts were focused on the synthesis of 1a using 2-bromoacetophenone and isopropyl iodide in the presence of greener solvents such as DESs. As shown in Table 1, when the reaction was carried out in DMF, 1a was recovered with almost complete conversion after 24 h, but surprisingly, the use of Type III DESs led to the formation of a different product, which was identified as the β-ketosulfide 2a. The preparation of this compound had been previously described by the biocatalyzed hydrolysis of 1a employing a lipase [19]. Thus, the presence of DESs allowed us to avoid one step in the formation of 2a, with a clear better performance in ChCl:Gly (1:2). After 24 h, 83% conversion was observed, as shown in entry 4. The use of ChCl:EG (1:2) also led to a high conversion (70%, entry 3), whereas the urea-based DES, reline [ChCl:U (1:2)], afforded a very low conversion (entry 2), but in a selective process with no 1a formation.
In view of these results, further investigations were carried out. Since the best conversions in product 2a were obtained in polyol-based DESs, the MCR was performed using EG and Gly as an individual reaction medium (entries 5–6). In both cases, only β-ketosulfide 2a was detected, but with lower conversions compared to the corresponding DESs (49% and 43% in EG and Gly, respectively). These results suggest that the hydrogen-bonding network present in the DES plays a significant role in enhancing the catalytic efficiency of this reaction. Other three alcohols were evaluated as solvents for this process: isopropanol (IPA), propane-1,3-diol and 1-butanol (entries 7–9). When IPA and propane-1,3-diol were employed, the conversion was 31% and 56%, respectively, whereas no reaction was observed in 1-butanol. Finally, the reaction was conducted in a 50% v/v water/DMF mixture to determine whether water could be responsible for the formation of product 2a (entry 10). After 24 h, the only product observed was 1a, with a complete conversion, demonstrating that the presence of water does not modify the reaction pathway in the same way as the DESs.
After having established ChCl:Gly (1:2) as the best reaction medium to prepare β-ketosulfide 2a, a study of the effect of the reaction time on this process was conducted, as shown in Figure 2. Conversions were measured using GC/MS after preparing a calibration curve with different concentrations of 2a (see Supporting Information). After one hour, 16% of ketosulfide was observed, without the presence of enol ester 1a, so even at low conversions the process showed complete selectivity. Within two hours, the conversion to β-ketosulfide was more than doubled, with an additional 11% increase over the following two hours. A conversion of 55% was obtained after six hours, reaching 64% at eight hours. The maximum conversion, 83%, was achieved after 24 h.
The effect of the base employed in the MCR process was also assessed. Thus, a set of bases presenting different nature were evaluated in the formation of compound 2a in ChCl:Gly (1:2) (Table 2). Among the inorganic bases tested, potassium carbonate and sodium carbonate (Na2CO3) afforded the highest conversions to 2a (86% and 67% respectively, entries 1–2). In contrast, sodium bicarbonate (NaHCO3) and organic bases including triethylamine (TEA), 1,4-diazabicyclo [2.2.2]octane (DABCO), and pyridine exhibited markedly lower activity, providing conversions lower than 15% (entries 3–6). Additionally, a study on the K2CO3 equivalents used in this reaction was conducted. In the absence of base, no formation of the 2a was detected (entry 7), indicating the pivotal role of the base in this reactivity. The presence of a 0.5 equivalent of K2CO3 led to a moderate conversion (29%, entry 8) whereas increasing the amount of base to 1.0 equivalent resulted in a significantly higher conversion (60%, entry 9). This study demonstrates that two equivalents of base are required to achieve maximum efficiency.
Once the optimal solvent, base, and reaction time were determined, the effect of 2-bromoacetophenone concentration on the reaction was investigated, increasing it from 0.44 M in the standard conditions up to 1.76 M (Figure 3). When the initial concentration was doubled (0.88 M), a 56% conversion of β-ketosulfide 2a was obtained, while a similar value (49%) was observed at 1.32 M of 2-bromoacetophenone. At higher substrate concentrations, the reaction mixture became heterogeneous and difficult to stir, resulting in a lower conversion of 22% after 24 h.
To further investigate the role of ChCl:Gly (1:2) in the MCR, a set of tests on the transformation of β-alkylsulfide enol ester 1a to ketosulfide 2a were carried out (Table 3). When the reaction was conducted in DMF with or without K2CO3 (2.0 equivalents) in the reaction media, no conversion was observed. When moving to a polyol as glycerol as solvent, it was possible to observe some conversion when the reaction was carried out with the base (entry 3, 19%) after 3 h. In the absence of potassium carbonate, no reaction was achieved. Using ChCl:Gly (1:2) as solvent in absence of K2CO3, 2a was not detected (entry 6); whereas a full conversion into β-ketosulfide 2a was achieved when this base was present in the reaction employing the DES (entry 5). These results suggest that the role of K2CO3 is double, as it is necessary for the formation of the β-alkylsulfide enol ester 1a and participates in the hydrolysis, but only in the presence of the DES, indicating that the hydrogen-bonding network of ChCl:Gly (1:2) increases the basicity and/or nucleophilicity of the reaction medium, facilitating the activation of the enol ester toward hydrolysis. This cooperative interaction between the DES and the inorganic base highlights the role of the eutectic medium in modulating the reaction pathway.
After setting the optimized conditions for achieving 2a employing 1.0 equivalent of the corresponding 2-haloketone, 1.0 equivalent of alkyl halide, 1.0 equivalent of potassium thioacetate and 2.0 equivalents of K2CO3 in ChCl:Gly (1:2) at room temperature for 24 h, the scope of this MCR was explored (Figure 4). Different 2-bromoacetophenones presenting substituents in the aromatic ring were initially studied in the presence of isopropyl iodide. The literature reports on α-sulfenylation and related rearrangements indicate that the electronic modulation of the aromatic ring significantly affects both nucleophilic substitution rates and subsequent rearrangement/hydrolysis steps [13,14,15,16,17], something that is observed herein as lower yields are obtained, respecting the model substrate 2a (65% yield). When electron-donating groups are employed (p-methoxy, m-methoxy, or p-methyl), reaction yields range from 42 to 52% and a slight decrease is observed with a p-chloride substituent, with a 30% isolated yield of 2e. Using these haloketones, except for p-methyl derivative, the presence of another product was detected in the reaction with yields ranging from 15 to 23; the compounds were identified as 3b, 3c and 3e (Figure 4), being previously described by Hereida et al. as intermediates for the synthesis of the β-alkylsulfide enol esters [19], indicating a non-completion of the process for these compounds, possibly due to reduced transition-state stabilization, increased steric congestion or altered hydrogen-bonding interactions within the DES network. When the aromatic ring is a naphthyl one, no ketone 2f was obtained. Instead, reaction-intermediate 3f was isolated in 40% yield. A similar substrate-dependent behavior has been reported in related multicomponent and base-triggered rearrangements [19,20].
When isopropyl iodide was replaced by methyl iodide, corresponding β-ketosulfide 2g was obtained in 69% yield. Using electron-donating 2-bromoacetophenones, substituents with slightly higher yields were observed (48–59%) for ketones 2h-j than for those presenting isopropyl group, whereas the p-chloride derivative 2k was obtained with a 34% yield. These slightly higher yields can be explained due to the less steric hindrance of methyl group. The naphthyl derivative 2l was obtained with only a 22% yield.
The reaction of 2-bromoacetophenone was finally tested with other alkyl halides. In general, the lower yields measured for bulkier alkyl halides can be attributed to steric hindrance during nucleophilic substitution and/or DES-assisted hydrolysis. Thus, in the presence of ethyl iodide, the reaction afforded product 2m in 60% yield, while allyl bromide and sec-butyl iodide led to 53% and 43% of the β-ketosulfide, respectively. The use of 2-iodobenzyl bromide afforded 2p with only 15% yield, and for this compound, the formation of a 15% yield of the β-alkylsulfide enol ester 1p was observed. This outcome can be attributed to the steric hindrance of the benzyl group, which likely slows down the reaction process.
The recyclability of ChCl:Gly (1:2) in the synthesis of β-ketosulfide 2a was evaluated over multiple reuse cycles, as shown in Figure 5. After each run, the product was extracted using ethyl acetate, and the DES was dried under vacuum overnight before being reused in the subsequent run. As shown in Figure 5, ChCl:Gly (1:2) retained its catalytic activity for the synthesis of 2a up to four cycles, with no significant changes in conversion. In the fifth cycle, however, the system became very viscous and difficult to stir, resulting in a lower conversion of 49%. A second reaction cycle was also carried out without the addition of K2CO3, but the conversion detected was only 23% after the first DES recycling. Therefore, the addition of the base in each cycle is necessary as it is consumed in the formation of the β-ketosulfide in combination with the DES.
To compare the environmental impact of the two procedures for the synthesis of β-ketosulfide 2a, both the E-factor (kg of waste generated per kg of product [28,29]) and the E+-factor (i.e., the classical E-factor incorporating energy-related CO2 emissions arising from electricity consumption and expressed as kg CO2 per kg of product [30]) were evaluated. E-factor is a widely used green metric because it directly measures the amount of waste generated per unit of product, making it a simple and effective indicator of a process’s environmental impact. Both the E-factor and E+-factor were determined for the one-pot reaction carried out in the presence of ChCl:Gly (1:2) and for the two-step process involving DMF, followed by CalB-catalyzed hydrolysis of enol ester 1a for 24 h at 30 °C in Tris/HCl buffer (see Supplementary Material). Calculations were performed considering three different system boundaries: (i) the reaction alone, (ii) the reaction including the liquid–liquid extractions work-up, and (iii) the complete process, including chromatographic purification. As shown in Table 4, the DES-based reaction outperforms the DMF process across all evaluated metrics. Overall, the one-pot protocol is approximately 4.5 times greener than the two-step route and exhibits a 12% lower overall E+-factor, despite identical purification procedures. The DMF-based process requires approximately 34% more energy (29 h of total stirring versus 24 h) and generates about 5% more waste prior to chromatography, mainly due to the use of buffer/CalB and the additional ethyl acetate required. In both cases, chromatographic purification is the dominant contributor to waste generation, accounting for approximately 97% of the total waste and significantly increasing both E- and E+-factor values. Nevertheless, from a holistic perspective, the DES-based methodology enables a substantially greener core chemistry.
The Global Warming Potential (GWP) has recently emerged as a valuable tool for assessing the environmental sustainability of chemical reactions [31]. GWP quantifies the contribution of a chemical process to climate change, expressed as kilograms of CO2 equivalents (kg CO2 eq) per kilogram of product. This metric accounts for greenhouse gas emissions arising from material inputs (e.g., solvents and reagents), energy consumption (heating and cooling), waste treatment (incineration and wastewater processing), and downstream purification, using CO2 as the reference gas over a 100-year time horizon.
For both processes evaluated for the preparation of ketone 2a, the chromatographic purification step represents the major environmental bottleneck, contributing 1575 kg CO2 eq per kg of product in each case, as expected when operating at the reaction scale. Beyond this dominant contribution, the DES-based process exhibits a lower overall GWP compared to the DMF–CalB procedure. In the latter case, additional contributions of 4.4 kg CO2 eq per kg of product arise from the biocatalytic reaction itself, along with 30 kg CO2 eq per kg of product associated with wastewater treatment. Overall, the one-pot synthesis displays a GWP of 1575 kg CO2 eq per kg of product, compared to 1609 kg CO2 eq per kg of product for the two-step process. This 1% increase in GWP for the latter further demonstrates that the DES-based reaction constitutes a greener alternative, particularly when considering the overwhelming environmental impact of chromatographic purification.

3. Materials and Methods

Nuclear magnetic resonance (NMR) spectra were obtained at different frequencies: 300 MHz for 1H-NMR and 75.5 MHz for 13C-NMR. The solvent peak served as the internal reference, with chemical shifts of 7.26 ppm for 1H and 76.95 ppm for 13C, using CDCl3 as the solvent. Column chromatography was conducted on silica gel (Kieselgel 60, Merck, Rahway, NJ, USA), and analytical thin-layer chromatography (TLC) was performed on aluminum-backed plates (1.5 × 5.0 cm) coated with 0.25 mm of silica gel (Silica Gel 60 F254, Merck Rahway, NJ, USA). Compounds were visualized by exposing the plates to UV light. The novel synthesized products were characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. Gas chromatography/mass spectrometry (GC/MS) analyses were carried out using a GC Hewlett Packard 6890 Series II equipped with a Hewlett Packard 5973 chromatograph MS (Agilent Technologies, Santa Clara, CA, USA). Unless otherwise specified, analytical-grade solvents and commercially available reagents were used without further purification.

3.1. General Procedure for the Preparation of the Deep Eutectic Solvents

Deep eutectic solvents were prepared by mixing choline chloride with the corresponding hydrogen bond donors (ethylene glycol, glycerol, or urea) at 1:2 molar ratio in a glass vial. The mixtures were heated at 80 °C on a hotplate and stirred magnetically until a clear liquid was formed (1–2 h), affording eutectic solvents with 100% atom economy.

3.2. General Procedure for the Synthesis of β-Alkylsulfide Enol Esters 1a-p

β-alkylsulfide enol esters 1a-p have been prepared according to the procedure reported [20]. Reactions were conducted in a 4 mL vial, equipped with a magnetic stir bar. To a solution of potassium thioacetate (0.44 mmol) in DMF (1.0 mL), α-bromoketone (0.44 mmol), the alkyl or benzyl halide (0.44 mmol, except for MeI, which was used at 0.88 mmol), and K2CO3 (0.88 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. To recover the product, ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was stirred. The organic phase was separated, and the aqueous phase was extracted with additional ethyl acetate (2 × 2 mL). The combined organic extracts were dried with anhydrous Na2SO4, filtered, and the solvent was removed by evaporation under vacuum. Crude mixtures were purified by column chromatography employing n-hexane/EtOAc (4:1) as eluent.

3.3. General Procedure for the Synthesis of β-Ketosulfides 2a-p

For the synthesis of β-ketosulfide 2a-p, reactions were conducted in a 4 mL vial, equipped with a magnetic stir bar. The following reagent addition order was used: ChCl:Gly (1:2) (1.0 mL), potassium thioacetate (0.44 mmol), α-bromoketone (0.44 mmol), alkyl or benzyl halide (typically 0.44 mmol, except for MeI, which was used at 0.88 mmol), and K2CO3 (0.88 mmol). The reaction mixture was stirred at room temperature for 24 h. To recover the product, ethyl acetate (2 mL) and water (2 mL) were added. The organic phase was separated, and the aqueous phase was extracted with additional ethyl acetate (2 × 2 mL). The combined organic extracts were dried with anhydrous Na2SO4, filtered, and the solvent was removed by evaporation under vacuum. The crude mixtures were purified by column chromatography, employing n-hexane/EtOAc 4:1 as eluent to achieve the desired ketones 2a-p.

3.4. General Procedure for the Recycling of ChCl:Gly (1:2) in the Synthesis of 2a

For the study on recycling the ChCl:Gly (1:2), the synthesis of β-ketosulfide 2a was conducted in a 4 mL vial, equipped with a magnetic stir bar. The following reagent addition order was used: ChCl:Gly (1:2) (1.0 mL), potassium thioacetate (0.44 mmol), 2-bromoacetophenone (0.44 mmol), isopropyl iodide (0.44 mmol), and K2CO3 (0.88 mmol). The reaction mixture was stirred at room temperature for 24 h. To isolate the product, the reaction mixture was extracted with ethyl acetate (3 × 2 mL). The organic phase was removed from the DES using a pipette. The solvent from the combined organic extracts was evaporated under reduced pressure. Any remaining traces of ethyl acetate in the DES were eliminated by evaporation under vacuum, then the DES was left under vacuum overnight.

4. Conclusions

This work highlights the main role of polyol-based Deep Eutectic Solvents in enabling the sustainable synthesis of β-ketosulfides through a multicomponent one-pot approach. Among the systems evaluated, the DES composed of choline chloride and glycerol (ChCl:Gly, 1:2) demonstrated the highest efficiency under mild reaction conditions. Acting simultaneously as a solvent and co-catalyst, this DES—together with K2CO3—facilitates the direct formation of β-ketosulfides, eliminating the need for additional steps or toxic solvents such as DMF. The developed methodology was successfully extended to a variety of substrates bearing both electron-donating and electron-withdrawing groups, affording the corresponding β-ketosulfides in moderate yields. This one-pot process exemplifies the capacity of DESs to integrate multi-step transformations into a single, efficient reaction medium, thereby reducing solvent usage and improving overall sustainability. Furthermore, the ChCl:Gly (1:2) system can be efficiently recycled up to four times without significant loss of activity, confirming its robustness and reusability. Overall, these findings underscore the potential of DESs as environmentally benign, efficient, and versatile media for organic synthesis, particularly in the preparation of valuable β-ketosulfide derivatives.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules31040745/s1. Figure S1: GC/MS calibration curve for the determination of conversion 2a; Figure S2: 1H-NMR (CDCl3, 300 MHz) of 1b; Figure S3: 13C-NMR (CDCl3, 300 MHz) of 1b; Figure S4: 1H-NMR (CDCl3, 300 MHz) of 1c; Figure S5: 13C-NMR (CDCl3, 300 MHz) of 1c; Figure S6: 1H-NMR (CDCl3, 300 MHz) of 1d; Figure S7: 13C-NMR (CDCl3, 300 MHz) of 1d; Figure S8: 1H-NMR (CDCl3, 300 MHz) of 1e; Figure S9: 13C-NMR (CDCl3, 300 MHz) of 1e; Figure S10: 1H-NMR (CDCl3, 300 MHz) of 1f; Figure S11: 13C-NMR (CDCl3, 300 MHz) of 1f; Figure S12: 1H-NMR (CDCl3, 300 MHz) of 1o; Figure S13: 13C-NMR (CDCl3, 300 MHz) of 1o; Figure S14: 1H-NMR (CDCl3, 300 MHz) of 2b; Figure S15: 13C-NMR (CDCl3, 300 MHz) of 2b; Figure S16: 1H-NMR (CDCl3, 300 MHz) of 2c; Figure S17: 13C-NMR (CDCl3, 300 MHz) of 2c; Figure S18: 1H-NMR (CDCl3, 300 MHz) of 2d; Figure S19: 13C-NMR (CDCl3, 300 MHz) of 2d; Figure S20: 1H-NMR (CDCl3, 300 MHz) of 2e; Figure S21: 13C-NMR (CDCl3, 300 MHz) of 2e; Figure S22: 1H-NMR (CDCl3, 300 MHz) of 2o; Figure S23: 13C-NMR (CDCl3, 300 MHz) of 2o; Figure S24: 1H-NMR (CDCl3, 300 MHz) of 3b; Figure S25: 13C-NMR (CDCl3, 300 MHz) of 3b; Figure S26: 1H-NMR (CDCl3, 300 MHz) of 3c; Figure S27: 13C-NMR (CDCl3, 300 MHz) of 3c; Figure S28: 1H-NMR (CDCl3, 300 MHz) of 3e; Figure S29: 13C-NMR (CDCl3, 300 MHz) of 3e; Figure S30: 1H-NMR (CDCl3, 300 MHz) of 3f; Figure S31: 13C-NMR (CDCl3, 300 MHz) of 3f; Table S1: Summarized results for GWP calculations (both routes, 1 mL lab scale) [1,2,3,10,19,20,29,31,32,33,34,35,36,37].

Author Contributions

Conceptualization, G.d.G. and C.F.; methodology, C.F. and D.J.-H.; formal analysis, A.R.A.; investigation, C.F., D.J.-H. and A.R.A.; resources, G.d.G. and R.F.; writing—original draft preparation, G.d.G. and C.F.; writing—review and editing, G.d.G., R.F. and A.R.A.; funding acquisition, G.d.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the project DECADES funding from the EU’s Horizon Europe Doctoral Network Program under the Marie Skłodowska-Curie, grant agreement no. 101072731.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed at the corresponding author.

Acknowledgments

The text of this manuscript was reviewed and linguistically refined using ChatGPT (OpenAI, GPT-5). The scientific content, data interpretation, and conclusions are entirely the authors’ own work.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 31 00745 g001
Figure 1. Synthesis of β-ketosulfides employing (a) DMF multicomponent reaction plus a CalB-catalyzed hydrolysis [19,20] or (b) a DES-based multicomponent reaction.
Figure 1. Synthesis of β-ketosulfides employing (a) DMF multicomponent reaction plus a CalB-catalyzed hydrolysis [19,20] or (b) a DES-based multicomponent reaction.
Molecules 31 00745 g001
Molecules 31 00745 g002
Figure 2. The effect of the reaction time in the synthesis of β-ketosulfide 2a in ChCl:Gly (1:2). Conversions were determined by GC/MS using a calibration curve (see Supporting Information).
Figure 2. The effect of the reaction time in the synthesis of β-ketosulfide 2a in ChCl:Gly (1:2). Conversions were determined by GC/MS using a calibration curve (see Supporting Information).
Molecules 31 00745 g002
Molecules 31 00745 g003
Figure 3. Study on the substrate concentration effect on the synthesis of product 2a. Conversions were determined by GC/MS using a calibration curve (see Supporting Information).
Figure 3. Study on the substrate concentration effect on the synthesis of product 2a. Conversions were determined by GC/MS using a calibration curve (see Supporting Information).
Molecules 31 00745 g003
Molecules 31 00745 g004
Figure 4. Substrate scope for the preparation of different β-ketosulfides using ChCl:Gly (1:2) as solvent.
Figure 4. Substrate scope for the preparation of different β-ketosulfides using ChCl:Gly (1:2) as solvent.
Molecules 31 00745 g004
Molecules 31 00745 g005
Figure 5. The recycling of the DES ChCl:Gly (1:2) in the MCR procedure for obtaining 2a. Conversions were determined by GC/MS using a calibration curve (see Supporting Information).
Figure 5. The recycling of the DES ChCl:Gly (1:2) in the MCR procedure for obtaining 2a. Conversions were determined by GC/MS using a calibration curve (see Supporting Information).
Molecules 31 00745 g005
Table 1. Solvent screening for the synthesis of β-ketosulfide 2a.
Table 1. Solvent screening for the synthesis of β-ketosulfide 2a.
Molecules 31 00745 i001
EntrySolvent1a (%) 12a (%) 1
1DMF96≤3
2ChCl:U (1:2)≤317
3ChCl:EG (1:2)≤370
4ChCl:Gly (1:2)≤383
5EG≤349
6Gly≤343
7IPA≤331
81-Butanol≤3≤3
9Propane-1,3-diol≤356
10DMF/H2O (1:1)≥97≤3
1 Measured by GC-MS.
Table 2. Base screening for the synthesis of β-ketosulfide 2a.
Table 2. Base screening for the synthesis of β-ketosulfide 2a.
Molecules 31 00745 i002
EntryBaseEquivalents2a (%) 1
1K2CO3283
2Na2CO3267
3NaHCO327
4DABCO215
5TEA214
6Pyridine2≤3
7 K2CO3 0≤3
8 K2CO3 0.529
9 K2CO3 160
1 Measured by GC-MS.
Table 3. Hydrolysis of β-alkylsulfide enol ester 1a.
Table 3. Hydrolysis of β-alkylsulfide enol ester 1a.
Molecules 31 00745 i003
EntryBaseSolvent2a (%) 1
1K2CO3DMF≤3
2NoneDMF≤3
3K2CO3Gly 19
4NoneGly≤3
5K2CO3ChCl:Gly (1:2)97
6NoneChCl:Gly (1:2)≤3
1 Measured by GC-MS.
Table 4. E factor and E+ factor calculations for the synthesis of 2a using DES or a two-step procedure in the presence of DMF and CalB hydrolysis.
Table 4. E factor and E+ factor calculations for the synthesis of 2a using DES or a two-step procedure in the presence of DMF and CalB hydrolysis.
ScenarioE Factor DES (kg/kg)E Factor DMF (kg/kg)E+ Factor DES (kg/kg)E+ Factor DMF (kg/kg)Winner
Reaction alone4.419.615.225.6DES
Reaction + Work up190.6222.9743807DES
Full process6118687677539229DES
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Falcini, C.; Jaén-Herrera, D.; Fernández, R.; Alcántara, A.R.; de Gonzalo, G. Multicomponent Reaction for the Synthesis of β-Ketosulfides in Deep Eutectic Solvents. Molecules 2026, 31, 745. https://doi.org/10.3390/molecules31040745

AMA Style

Falcini C, Jaén-Herrera D, Fernández R, Alcántara AR, de Gonzalo G. Multicomponent Reaction for the Synthesis of β-Ketosulfides in Deep Eutectic Solvents. Molecules. 2026; 31(4):745. https://doi.org/10.3390/molecules31040745

Chicago/Turabian Style

Falcini, Chiara, David Jaén-Herrera, Rosario Fernández, Andrés R. Alcántara, and Gonzalo de Gonzalo. 2026. "Multicomponent Reaction for the Synthesis of β-Ketosulfides in Deep Eutectic Solvents" Molecules 31, no. 4: 745. https://doi.org/10.3390/molecules31040745

APA Style

Falcini, C., Jaén-Herrera, D., Fernández, R., Alcántara, A. R., & de Gonzalo, G. (2026). Multicomponent Reaction for the Synthesis of β-Ketosulfides in Deep Eutectic Solvents. Molecules, 31(4), 745. https://doi.org/10.3390/molecules31040745

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