Modular, Tricomponent, and Concurrent One‐Pot Synthesis of Libraries of γ‐Keto Sulfones and γ‐Keto Phosphine Oxides using Brønsted Acidic Eutectic Mixtures

Abstract

A modular, three‐component, and sustainable one‐pot/one‐step protocol has been developed for the efficient and regioselective synthesis of libraries of γ‐keto sulfones and γ‐keto phosphine oxides through concurrent C—C and C—X bond formation (X = S or P). The acidic eutectic mixture ChCl/p‐TSA·H₂O (1:2) (ChCl = choline chloride; p‐TSA = p‐toluenesulfonic acid) serves as both promoter and reaction medium. This transformation involves a cascade process comprising three consecutive steps: i) hydration of terminal alkynes to methyl ketones; ii) Claisen–Schmidt condensation with aldehydes, and iii) sulfa‐Michael or phospha‐Michael additions using sodium sulfinates or secondary phosphine oxides, respectively. The methodology provides high yields (up to 99%), excellent atom economy, and operational simplicity, as the products are isolated without the use of any toxic volatile organic solvents or tedious chromatographic purification. Its modular nature accommodates a broad range of substrates, including electron‐rich and electron‐deficient components, demonstrating robustness and versatility (112 examples). Furthermore, the protocol enables scalable (tenfold) and recyclable (five cycles) synthesis of biologically relevant γ‐keto derivatives under green conditions (E‐factor ≤ 10), offering a general strategy for sustainable and modular C—C and C—X bond‐forming reactions.

This study presents a sustainable, metal‐free, one‐pot synthesis of γ‐keto sulfones and phosphine oxides using a ChCl/p‐TSA·H₂O eutectic mixture. The method enables regioselective C—C and C—X bond formation under mild conditions, aligning with Green Chemistry Principles. With a broad substrate scope (112 examples), scalability, and recyclability, it offers a practical, eco‐friendly alternative for fine chemical synthesis.

1. Introduction

Through billions of years of optimization, nature has developed the ability to synthesize a wide variety of biological materials with high structural complexity and specific functions, employing a convergent modular approach base on a limited number of highly selective and efficient chemical reactions, along with a small library of building blocks or molecular modules (20 amino acids and a few sugars and nucleobases). Inspired by nature, contemporary synthetic chemistry adopts this synthetic modular strategy, which involves the stepwise reaction of multiple functional building blocks, to efficiently and simply create libraries of chemical compounds exhibiting broad functional diversity and specific properties.^{[ 1} , ² , ³ , ⁴ , ^{5 ]} Although the definition of modular chemical is inherently subjective, it can be viewed as a convergent approach to generate target compounds with architectural complexity through sequence‐defined reactions between diverse interchangeable building blocks (see Scheme  1a). However, despite the significant synthetic advantages of modular syntheses, they face substantial challenges arising from the need to integrate robust and convergent chemical reactions that fulfill key criteria, including high efficiency, selectivity, versatility, operational simplicity, and atom economy. Notably, these challenges have been successfully addressed in the field of natural product total synthesis, where modular approaches often outperform conventional linear methods in terms of conciseness and yield.^{[ 6} , ^{7 ]} Nevertheless, this strategy has found limited application in other areas of chemistry, a shortcoming particularly pronounced in the context of Green and Sustainable Chemistry.

Scheme 1.

a) Schematic representation of the stepwise and concurrent modular synthesis of multiple building blocks. b) General synthetic methodologies for g‐keto sulfones and g‐keto phosphine oxides. c) Three‐component synthetic pathways leading to g‐keto sulfones and g‐keto phosphine oxides. d) One‐pot two‐step synthesis of g‐keto sulfones in acidic DES. e) Three‐component, modular, one‐pot concurrent synthesis of g‐keto sulfones and g‐keto phosphine oxides promoted by the acidic DES [ChCl/p‐TSA·H2O (1:2)].

In this context, the recent development of one‐pot tandem synthetic protocols applied to the synthesis of high‐value‐added organic products, performed in more sustainable and greener solvents,^{[ 8 ]} provides an effective platform for integrating modular chemistry with the 12 Principles of Green Chemistry.^{[ 9} , ¹⁰ , ¹¹ , ¹² , ^{13 ]} These processes offer significant sustainability advantages over conventional stepwise approaches by minimizing or even eliminating the purification steps required for intermediate isolation.^{[ 14} , ^{15 ]} Our research group has actively contributed to this field by developing highly efficient and selective one‐pot tandem protocols that integrate diverse synthetic methodologies under mild, bench‐top conditions and in green solvents, such as water and deep eutectic solvents (DESs).^{[ 16} , ^{17 ]} These protocols encompass a wide range of synthetic approaches, including: i) biocatalysis, ii) polar organometallic chemistry, iii) transition metal catalysis, and iv) organocatalysis, offering versatile and sustainable strategies for synthesizing complex chemical products under environmentally friendly conditions.^{[ 18} , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ^{25 ]} More recently, the reactivity of Lewis acid‐based DESs as sustainable reaction media and promoters for various organic transformations has been explored.^{[ 26} , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ^{34 ]} In this context, our group has actively employed FeCl₃‐based acidic eutectic mixtures to activate unsaturated organic substrates (e.g., alkynes and alkenes) in reactions such as: i) Meyer–Schuster isomerization of propargylic alcohols into enals and enones,^{[ 35 ]} ii) hydration of terminal and internal alkynes to produce ketones,^{[ 36 ]} and iii) Friedel–Crafts benzylation for synthesizing substituted 1,1‐diarylalkanes.^{[ 37 ]}

Building on these findings, we aimed to design a convergent, modular one‐pot concurrent process to generate libraries of highly functionalized target products. Moreover, this synthesis would be carried out using acidic DESs, which are envisioned to selectively promote cascade bond‐forming reactions, including C–C and C–heteroatom bond formation, while also serving as reusable reaction media. Thus, in this work, we report the modular, convergent synthesis of libraries of γ‐keto sulfones and γ‐keto phosphine oxides through a three‐component cascade‐type reaction promoted by a Brønsted acidic eutectic mixture. This protocol involves three concurrent steps such as: i) the regioselective hydration of terminal alkynes to the corresponding methyl ketones; ii) the Claisen–Schmidt condensation between the in situ generated methyl ketones and aromatic aldehydes; and iii) the chemoselective formation of C—S or C—P bonds via hetero‐Michael reactions using sodium sulfinates (NaSO₂R) or secondary phosphine oxides [O = P(H)R₂] as coupling partners. Importantly, this convergent modular approach enables access to γ‐ketone derivatives, an unnatural functional group arrangement that is challenging to achieve with conventional methods.^{[ 38} , ³⁹ , ^{40 ]} Among these 1,4‐bifunctional compounds, γ‐keto sulfones and γ‐keto phosphine oxides are very promising frameworks with particularly diverse medical^{[ 41} , ⁴² , ^{43 ]} and biological^{[ 44} , ⁴⁵ , ⁴⁶ , ^{47 ]} properties, respectively. These materials have been conventionally achieved by using classical sulfa‐^{[ 48} , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ^{53 ]} and phospha‐Michael^{[ 54} , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ^{61 ]} nucleophilic additions, and Stetter reaction^{[ 62} , ⁶³ , ^{64 ]} (see Scheme 1b). However, both methodologies are often limited by the complex preparation of raw materials, which has led to the recent development of multicomponent strategies for the synthesis of both γ‐keto sulfones^{[ 65} , ⁶⁶ , ^{67 ]} and their phosphine oxide analogs^{[ 68 ]} using different synthetic methodologies (see Scheme 1c). In the context of sustainable reaction media in organic synthesis, Brønsted‐acidic deep eutectic solvents (BADESs) are able to promote both the Claisen–Schmidt condensation,^{[ 69 ]} the sulfa‐Michael addition to chalcones,^{[ 70 ]} and the synthesis of γ‐keto sulfones in acidic DESs through a one‐pot, two‐step process involving a [2 + 2] cycloaddition reaction between an aldehyde and an alkyne, followed by the addition of sodium arenesulfinate (Scheme 1d).^{[ 71 ]}

Building on these precedent studies, we present an efficient and economical modular‐multicomponent methodology for synthesizing libraries of γ‐keto sulfones and γ‐keto phosphine oxides from readily available alkynes, aldehydes, and sodium sulfinates or secondary phosphine oxides (see Scheme 1e). This metal‐free, regioselective, and convergent approach is promoted by an acidic Brønsted DES composed of choline chloride (ChCl) and p‐toluenesulfonic acid monohydrate (p‐TSA·H₂O) [ChCl/p‐TSA·H₂O (1:2)]. The reaction proceeds with: i) good to excellent yields (up to 99%), ii) no external volatile organic compound (VOC) solvents, iii) ambient air conditions, iv) no intermediate isolation or purification, and v) high atom economy, aligning with the principles of Green Chemistry. Moreover, this methodology enables the use of alkyl‐substituted sulfinate salts, which provide access to γ‐keto alkylsulfones, derivatives that were unattainable using previously described methodologies in BADES.^{[ 69 ]} To further assess the sustainability of our protocol, we calculated Sheldon's environmental factor (E‐factor; total waste mass/product mass), achieving a value as low as 7.6. Additionally, the ChCl/p‐TSA·H₂O (1:2) DES can be recycled for up to five cycles. Moreover, this methodology was successfully applied to the multigram synthesis (10 mmol scale) of 1‐phenyl‐3‐(phenylsulfonyl)propan‐1‐one [Ph—C(=O)—(CH₂)₂—SO₂Ph], a compound with demonstrated antimicrobial activity.^{[ 71} , ^{72 ]}

2. Results and Discussion

2.1. Modular and Concurrent One‐Pot Synthesis of γ‐keto Sulfones

For the parametrization experiments, we focused on the multicomponent reaction of phenyl acetylene (1a) and benzaldehyde (2a) with sodium p‐toluenesulfinate (3a) under air conditions as summarized in Table  1 . Initially, having obtained excellent results in the hydration of alkynes using Fe(III)‐based DES,^{[ 36 ]} we began our studies employing the FeCl₃·6H₂O/Gly (3:1; Gly = glycerol) eutectic mixture as both the reaction medium and promoter for the cascade sequence reactions: hydration/Claisen–Schmidt condensation/sulfa‐Michael addition. Thus, using stoichiometric amounts of alkyne and aldehyde (1 mmol) and 1.2 equivalents of the sulfinate salt, the Lewis acidic eutectic mixture FeCl₃·6H₂O/Gly (3:1) was unable to promote the concurrent formation of C—C and C—S bonds to yield the desired γ‐keto sulfone 4aaa (entry 1, Table 1) at 60 °C. Analysis of the crude reaction mixture by ¹H‐NMR revealed the presence of hydration product (acetophenone, ≈22%), Claisen–Schmidt adduct (chalcone, ≈66%), and unreacted benzaldehyde (≈22%). This suggests that under these reaction conditions, hydration occurs rapidly, and the presence of Fe(III) favors the aldol condensation; however, it does not promote the sulfa‐Michael addition. Given the low activity of the Fe(III) Lewis‐based DES in the activation and formation of γ‐keto sulfone 4aaa, but motivated by the orthogonality demonstrated by the sequence of reactions in this one‐pot concurrent process, we decided to explore the activity of Brønsted‐based DESs derived from choline chloride (ChCl) as hydrogen bond acceptor. Thus, the use of eutectic mixtures containing moderately strong and sustainable hydrogen bond donors such as oxalic acid and citric acid (entries 2 and 3 in Table 1, respectively) showed no evidence of forming sulfone 4aaa under the previously described reaction conditions. In contrast, when stronger acids such as trichloroacetic acid (TCA, entry 4 in Table 1) or methanesulfonic acid (MSA, entry 5 in Table 1) were employed, the γ‐keto sulfone 4aaa was obtained with increasing yields correlating to the acid strength (19% for TCA with pK_a = 0.63% and 44% for MSA with pK_a = −1.9). In light of this trend, we decided to use the eutectic mixture ChCl/p‐TSA·H₂O (1:2), containing an even stronger p‐toluenesulfonic acid (pK_a = −2.8. Entry 6, Table 1). Under the previously described conditions (air, 60 °C, and 2 mL of DES), the crude reaction mixture analyzed by ¹H‐NMR after 24 h revealed 87% of the desired γ‐keto sulfone 4aaa along with 13% of the corresponding chalcone intermediate. The γ‐keto sulfone 4aaa precipitated directly in the reaction medium, significantly simplifying purification protocols. A straightforward process involving the addition of water, filtration, and washing the white solid with saturated NaHCO₃ solution, water, and a greener ethereal solvent like cyclopentyl methyl ether (CPME) yielded the desired sulfone 4aaa in a 68% isolated pure yield. Importantly, this approach eliminates the need for tedious and VOC‐consuming silica gel column chromatography.

Table 1.

Parametrization of the aerobic, tricomponent, and concurrent one‐pot synthesis of γ‐keto sulfone (4aaa) using different reaction conditions.

	Eutectic Mixturea)	Eq. 3a	T [°C]	t [h]	4aaa
1	FeCl3·H2O/Gly (3:1)	1.2	60	24	n.d.e)
2	ChCl/oxalic acid (1:1)	1.2	60	24	n.d.e)
3	ChCl/citric acid·H2O (1:1)	1.2	60	24	n.d.e)
4	ChCl/TCA (1:2)	1.2	60	24	19%c)
5	ChCl/MSA (1:2)	1.2	60	24	44%b)
6	ChCl/p‐TSA·H2O (1:2)	1.2	60	24	68%b)
7	ChCl/p‐TSA·H2O (1:2)	1.2	60	48	71%b)
8	ChCl/p‐TSA·H2O (1:2)	1.2	80	24	63%b)
9	ChCl/p‐TSA·H2O (1:2)d)	1.2	60	24	46%b)
10	ChCl/p‐TSA·H2O (1:2)	1.0	60	24	61%b)
11	ChCl/p‐TSA·H2O (1:2)	2.0	60	24	70%b)
12	ChCl/p‐TSA·H2O (1:1)	1.2	60	24	46%b)
13	ChCl/p‐TSA·H2O (2:1)	1.2	60	24	15%c)

^a)General Conditions: 1 mmol of phenyl acetylene (1a), 1.0 mmol of benzaldehyde (2a) and 1.2‐2.0 mmol of sodium p‐toluenesulfinate (3a) are added to 2 mL of the desired acidic eutectic mixture in a sealed vial (without an inert atmosphere), and the mixture is stirred during 24‐48 h hours at the temperature specified in each entry.

^b)Isolated yields.

^c)Determined by ¹H NMR using CHBr₃ as an internal standard.

^d)The volume of the eutectic mixture was reduced from 2 to 1 mL.

^e)Not detected.

When the reaction time was extended to 48 h, neither the conversion nor the final yield of 4aaa (71%, entry 7 in Table 1) showed significant variation. Increasing the reaction temperature to 80 °C or reducing the amount of ChCl/p‐TSA·H₂O (1:2) to 1 mL negatively impacted the yield of γ‐keto sulfone 4aaa (63% and 46%, respectively; entries 8 and 9 in Table 1). Similarly, lowering the equivalents of sodium p‐toluenesulfinate (3a) to 1 equivalent reduced the yield to 61% (entry 10 in Table 1), while no significant improvement was observed when increasing it to 2 equivalent (70%, entry 11 in Table 1). As a compromise between yield and the atom economy of the process, the amount of 3a was fixed at 1.2 equivalents. Finally, other eutectic ratios (1:1 and 2:1) of the ChCl/p‐TSA·H₂O mixture were evaluated. However, decreasing the proportion of p‐toluenesulfonic acid in the eutectic mixture led to a concomitant reduction in the yield of γ‐keto sulfone 4aaa (46% and 15%, respectively; entries 12 and 13 in Table 1).

After optimizing the reaction conditions, the modularity of this approach was evaluated by exploring the substrate scope of sulfur sources, alkynes, and aldehydes in this multicomponent reaction. First, the influence of a diverse range of sodium sulfinates was examined (Scheme  2 ), including aromatic (3a–3L), heteroaromatic (3m and 3n), and aliphatic substituents (3o–q). The resulting γ‐keto sulfones (4aaa–4aaq) were generally obtained in good to excellent yields (up to 91%). For aromatic sulfinates (3a–l), the protocol tolerated nonactivated benzene rings (4aab, 65%) and a variety of substituents at the para‐position, including activating [Me (4aaa, 68%), OMe (4aac, 59%)], weakly electron‐donating [Ph (4aad, 76%)], weakly electron‐withdrawing [F (4aae, 69%), Cl (4aaf, 78%), Br (4aag, 76%)], and deactivating [CF₃ (4aah, 61%)] groups, leading to γ‐keto sulfones with yields ranging from 59% to 78%, which suggest that the electronic properties of the sodium sulfinates had only a modest impact on the reaction. However, significant steric effects were observed with 2‐substituted aromatic sulfinates (3i and 3j), resulting in lower yields [4aai (24%) and 4aaj (25%)] due to steric hindrance. Indeed, in both cases, the ¹H‐NMR spectra of the crude reaction mixtures showed the presence of the corresponding chalcone and unreacted sodium sulfinate (3i or 3j, respectively). This observation, together with the absence of signals attributable to phenylacetylene (1a) and benzaldehyde (2a), is consistent with the low reactivity of both sulfinates due to their steric hindrance. Notably, the methodology also accommodated: i) bicyclic aromatic substituents [4aak (70%), 4aal (73%)] and ii) heteroaromatic thienyl frameworks [4aam (76%), 4aan (67%)]. Very importantly, the use of sulfonate salts bearing aliphatic substituents, whether linear [4aao (89%)], branched [4aap (66%)], or cyclic [4aaq (91%)], led to the corresponding γ‐keto sulfones in good yields. This contrasts with previous methodologies described for γ‐keto sulfones in BADES, which were limited to aromatic sulfonate salts.^{[ 70 ]} In alignment with Green Chemistry principles, it is noteworthy that most products (except for 4aai and 4aaj, obtained in yields below 25%) were isolated using a straightforward filtration and washing protocol, without the need for further purification by silica gel column chromatography.

Scheme 2.

Study of the effect of the sodium sulfinate salts (3a‐q) in the modular and concurrent one‐pot synthesis of γ‐keto sulfones 4aaa‐4aaq promoted by the eutectic mixture ChCl/p‐TSA·H2O (1:2) under aerobic conditions. Isolated yields are given in parentheses.

To further explore the substrate compatibility of this modular reaction, we investigated the use of various aromatic aldehydes (2b–t) while keeping the terminal alkyne (Ph—C≡C—H, 1a) constant and employing either aromatic (NaSO₂‐p‐Tolyl, 3a) or aliphatic (NaSO₂Me, 3o) sodium sulfinates (Scheme  3 ). Consistent with previous observations regarding sodium sulfinates (Scheme 2), better yields were generally obtained with the aliphatic sodium sulfinate (3o) compared to its aromatic counterpart, sodium p‐toluenesulfinate (3a).

Scheme 3.

Study of the effect of the aldehydes 2b‐t in the modular and concurrent one‐pot synthesis of γ‐keto sulfones 4aba‐aro promoted by the eutectic mixture ChCl/p‐TSA·H2O (1:2) under aerobic conditions. Isolated yields are given in parentheses.

Regarding the electronic nature of the aldehyde substituents, no clear reactivity pattern emerged, as comparable yields of γ‐keto sulfones were obtained regardless of their electronic characteristics. Using either NaSO₂‐p‐Tolyl (3a) or NaSO₂Me (3o), the reaction proceeded efficiently with aromatic aldehydes bearing substituents at the para‐position, including: i) moderately deactivating groups [F (4aba, 63%), Cl (4aca, 69%), Br (4ada, 64%), I (4aea, 72%; 4aeo, 82%)]; ii) strongly deactivating groups [CF₃ (4afa, 59%; 4afo, 83%) and NO₂ (4aga, 36%)]; and iii) activating groups [Me (4aha, 63%; 4aho, 88%), OMe (4aia, 65%; 4aio, 97%), SMe (4aja, 70%; 4ajo, 84%), and 4‐chlorophenoxy (4aka, 65%; 4ako, 89%)]. Notably, the reaction tolerated potentially competing functionalities such as –OH and allyloxy groups, affording the corresponding γ‐keto sulfones with good yields [4ala (74%), 4alo (78%), 4ama (65%), and 4amo (77%)]. A pronounced steric effect was observed with ortho‐substituted aldehydes, as seen with 2n, which resulted in lower yields for γ‐keto sulfone 4ana (41%) due to steric hindrance. This effect was absent in the meta‐substituted analog 2o, which yielded 4aoa with 71%. The reaction also demonstrated compatibility with di‐[4apa (64%), 4apo (82%), 4aqa (54%), 4aqo (83%), 4ara (53%), 4aro (90%)] and tri‐substituted [4asa (70%)] aromatic aldehydes, as well as heteroaromatic substituents, exemplified by the thienyl‐containing γ‐keto sulfone 4ata (37%). Again, all synthesized sulfones, except for 4aga and 4ata (obtained in low yield), were isolated using a straightforward filtration and washing protocol. The low yields obtained with 4‐nitrobenzaldehyde (2g) and thiophene‐2‐carbaldehyde (2t) were due to the poor solubility of the former in the reaction medium, which prevented proper formation of the corresponding chalcone, and to the occurrence of side reactions involving sulfonation of the thiophene ring present in the intermediate chalcone.

To complete our investigation of the substrate scope, we examined the effect of different terminal alkynes (1b–t) while keeping the aldehyde [benzaldehyde (2a)] and sodium sulfinate salts [NaSO₂‐p‐Tolyl (3a) and NaSO₂Me (3o)] constant (Scheme  4 ). As observed with aldehydes (Scheme 3), the aliphatic sulfinate 3o generally provided better yields than the aromatic sulfinate 3a (Scheme 4). However, unlike aldehydes, the electronic characteristics of alkynes significantly influence the course of the reaction. Activating groups on the aromatic ring of alkynes, such as: i) ethers [MeO: 4baa (74%), 4caa (60%), 4daa (76%), 4cao (86%); PhO: 4eaa (73%), 4eao (84%); CF₃O: 4faa (76%), 4fao (72%)]; ii) linear aliphatic hydrocarbon chains [Me: 4gaa (61%), 4gao (87%); n‐pentyl: 4haa (63%)], or branched chains [isopropyl: 4iaa (60%)]; iii) aromatic rings [Ph: 4jaa (69%)]; and iv) amines [NH₂: 4kaa (53%); NMe₂: 4laa (65%), 4lao (67%)], generally result in higher yields compared to their counterparts bearing deactivating groups such as: i) halogens [F: 4maa (67%); Cl: 4naa (62%), 4oaa (50%), 4paa (13%. Determined by ¹ H‐NMR using an internal standard)]; and ii) CF₃: 4qaa (30%)]. This trend is particularly pronounced with strongly deactivating groups, such as CF₃, which also require higher temperatures (80 °C) for the reaction to occur. Additionally, while the position of activating groups on the aromatic ring has little effect on the reaction, as demonstrated by the reactivity of the three isomers [ortho‐ (1d), meta‐ (1c), and para‐ (1b)] of ethynyl anisole, it becomes crucial for deactivating groups. For instance, even at 80 °C, the reactions of 1‐chloro‐3‐ethynylbenzene (1o) and 1‐chloro‐2‐ethynylbenzene (1p) yield less product [4oaa (50%); 4paa (13%)] compared to the para‐isomer (1n), which affords γ‐keto sulfone 4naa in 62% yield. Unfortunately, neither aliphatic aldehydes nor alkynes yielded the corresponding γ‐keto sulfones. This outcome is primarily attributed to the low hydration yields of aliphatic alkynes in acidic DES, as previously observed by our group.^{[ 36 ]} Similarly, the reaction did not proceed when using electron‐deficient alkynes such as methyl propiolate in the presence of benzaldehyde (2a).

Scheme 4.

Study of the effect of the terminal alkynes 1b‐t in the modular and concurrent one‐pot synthesis of γ‐keto sulfones 4baa‐rao promoted by the eutectic mixture ChCl/p‐TSA·H2O (1:2) under aerobic conditions. Isolated yields are given in parentheses.

These findings are consistent with the previous studies reported for the acidic‐DES‐promoted Claisen–Smith reaction,^{[ 69 ]} in which the presence of electron‐donating groups (EDGs) in the ketone (note that in our methodology, the ketone is formed in situ via hydration of the corresponding alkyne) led to higher isolated product yields compared to ketones with electron‐withdrawing groups (EWGs). Notably, both mono‐, di‐, and tri‐substituted aromatic alkynes, as well as naphthalene‐substituted alkynes, react smoothly, yielding the corresponding γ‐keto sulfones in good yields [4raa (56%), 4rao (80%), 4saa (54%), and 4taa (83%)]. However, nonactivated dihalogen‐substituted alkynes require a temperature of 80 °C (see Scheme 4).

Finally, to demonstrate the modularity of our tricomponent and concurrent protocol, we explored the “à la carte” synthesis of γ‐keto sulfones using various combinations of alkynes, aldehydes, and sodium sulfinates (Scheme  5 ). The results showed that all possible combinations of electron‐rich and electron‐poor alkynes and aldehydes are feasible, regardless of the sodium sulfinate used. As expected, the highest yields were obtained by combining electron‐rich alkynes and aldehydes with NaSO₂Me as the sulfinate source. Notably, even in less favorable scenarios, such as combining electron‐poor alkynes and aldehydes with NaSO₂‐p‐Tolyl (3a), moderate yields of up to 62% were achieved. These findings highlight the broad applicability and robustness of our protocol, demonstrating its versatility across diverse substrate combinations.

Scheme 5.

Study of various combinations of alkynes (1n, 1b), aldehydes (2i, 2f, 2o), and sodium sulfinates (3a, 3o) in the modular and concurrent one‐pot synthesis of γ‐keto sulfones promoted by the eutectic mixture ChCl/p‐TSA·H2O (1:2) under aerobic conditions. Isolated yields are given in parentheses.

To study the concurrency of the alkyne hydration/Claisen–Schmidt condensation/sulfa‐Michael addition sequence, the experiments outlined in Scheme  6 were conducted.

Scheme 6.

Control experiments evaluating the reactivity between the phenylacetylene (1a), benzaldehyde (2a), and sodium p‐toluenesulfinate (3a). Isolated yields are given in parentheses.

Firstly, no reaction was observed between sodium p‐toluenesulfinate (3a) and phenylacetylene (1a) or benzaldehyde (2a) (see Equation 1 and 2 in Scheme 6). However, the hydration of phenylacetylene (1a) proceeds rapidly in the presence of ChCl/p‐TSA·H₂O (1:2), forming acetophenone (5a) as the sole product (see Equation 1 in Scheme 6). Additionally, ChCl/p‐TSA·H₂O (1:2) promotes the formation of chalcone 6aa via the direct reaction of phenylacetylene and benzaldehyde (Equation 3 in Scheme 6). The chalcone was isolated as a pure product with a 75% yield. The observation of acetophenone formation via hydration of phenylacetylene strongly suggests that chalcone formation occurs through a Claisen–Schmidt condensation. Finally, the addition of sodium p‐toluenesulfinate to chalcone 6aa in ChCl/p‐TSA·H₂O (1:2) yielded quantitatively (>99%) the desired γ‐keto sulfone 4aaa via a sulfa‐Michael addition process (Equation 4 in Scheme 6).

2.2. Modular and Concurrent One‐Pot Synthesis of γ‐keto Phosphine Oxides

To deeper explore the modularity of the process, we decided to vary the nature of one of the reaction “molecular modules” by using secondary phosphine oxides [HP(O)R₂] instead of the sodium sulfinates previously employed. The eutectic mixture ChCl/p‐TSA·H₂O (1:2) was expected to promote the first two stages of the three‐component process (hydration and Claisen–Schmidt condensation), leading to the formation of the corresponding chalcone. In the presence of HP(O)R₂, this would selectively yield γ‐keto phosphine oxides through a phospha‐Michael addition, forming a new C—P bond (Scheme  7 ). Thus, when the reaction between phenylacetylene (1a), benzaldehyde (2a), and diphenylphosphine oxide (7a) was carried out (using stoichiometric amounts of the three components; see Supporting Information for details) in the presence of the eutectic mixture ChCl/p‐TSA·H₂O (1:2) under previously optimized conditions (i.e., 60 °C, 24 h, and under air atmosphere. See Scheme 7a), the analysis of the crude reaction mixture by ³¹P NMR revealed a signal at 34.3 ppm corresponding to the desired γ‐keto phosphine oxide (8aaa), along with signals for the starting diphenylphosphine oxide (7a, 21.4 ppm) and its addition product with benzaldehyde, [hydroxy(phenyl)methyl]diphenylphosphine oxide (9aa, 30.6 ppm). Relative integration of these signals indicated that [hydroxy(phenyl)methyl]diphenylphosphine oxide (9aa) was the major product (64%), with significant amounts of γ‐keto phosphine oxide (8aaa, 33%) and a minor amount of the starting diphenylphosphine oxide (7a, 3%) also detected (Scheme 7a). Importantly, the desired γ‐keto phosphine oxide (8aaa) was the only observable reaction product after an additional 6 days of reaction. This clearly demonstrates that, in the absence of the diphenylphosphine oxide (7a) starting material, the reaction proceeds via the reaction of [hydroxy(phenyl)methyl]diphenylphosphine oxide (9aa) with acetophenone (5a). These observations suggested that the reaction mechanism might not follow exclusively the sequence of alkyne hydration/Claisen–Schmidt condensation/phospha‐Michael addition. Instead, an alternative cascade could occur, involving: i) hydration of phenylacetylene (1a) to form acetophenone (5a); ii) phospha‐aldol reaction between benzaldehyde (2a) and diphenylphosphine oxide (7a), generating the intermediate α‐hydroxy phosphine oxide (9aa); and iii) acid‐promoted addition of enolate tautomer of acetophenone (5a) to the benzyl carbocation (diphenylphosphoryl)(phenyl)methylium (9aa ⁺ ), derived from water elimination of 9aa (Scheme 7b). The coexistence of these two mechanisms is further supported by control experiments. Specifically, using the eutectic mixture ChCl/p‐TSA·H₂O (1:2) as the reaction medium at 60 °C, the reaction of benzaldehyde (2a) with diphenylphosphine oxide (7a) rapidly yields [hydroxy(phenyl)methyl]diphenylphosphine oxide (9aa), which was isolated in 94% yield (Scheme 7c, Equation (1)). However, the reaction of 9aa with acetophenone (5a), generated via hydration of phenylacetylene (1a), to produce the γ‐keto phosphine oxide (8aaa) is slow, requiring 7 days for completion (>99%. Scheme 7c, Equation (2)). Conversely, the phospha‐Michael addition of diphenylphosphine oxide (7a) to the chalcone intermediate 6aa (Claisen–Schmidt condensation product) occurs rapidly and quantitatively, yielding 8aaa (>99%. Scheme 7c, Equation (3)).

Scheme 7.

a) Reaction between phenylacetylene (1a), benzaldehyde (2a), and sodium diphenylphosphine oxide (7a) in ChCl/p‐TSA·H2O (1:2) under the previous optimized reaction conditions to synthesize γ‐keto sulfones. Yields were determined by ¹H‐ and ^{3 1}P‐NMR analysis of the crude reaction mixtures (relative integration). b) Hydration/phospha‐aldol/addition to benzyl carbocation mechanism. c) Control experiments evaluating the reactivity between the phenylacetylene (1a), benzaldehyde (2a), and sodium diphenylphosphine oxide (7a). Isolated yields are given in parentheses.

This dual reaction pathway (via chalcone or via α‐hydroxy phosphine oxide intermediates) was similarly observed and demonstrated by Su et al. in their synthesis of γ‐keto phosphine oxides through an acid‐promoted three‐component direct phosphorylation of aldehydes.^{[ 68 ]} However, we cannot rule out additional reaction pathways involving the reversible nature of HP(O)R2 addition to carbonyl compounds, which could also account for the formation of 8aa from phenylacetylene (1a) and [hydroxy(phenyl)methyl]diphenylphosphine oxide (9aa).^{[ 72} , ^{73 ]}

Since the formation of the desired γ‐keto phosphine oxide (8aaa) at 60 °C requires 7 days of reaction, the process was studied at different temperatures. At 80 °C, 15% of the reaction intermediate [hydroxy(phenyl)methyl]diphenylphosphine oxide (9aa) remained after 24 h, while the reaction to form 8aaa was complete at 100 °C within the same time frame. Thus, with 100 °C as the optimal temperature for this transformation, the γ‐keto phosphine oxide 8aaa precipitated as a white solid upon water addition, after 24 h of reaction. It was obtained in pure solid form by simple filtration and washing with water, yielding 98% (see Scheme  8 ).

Scheme 8.

Study of the substrate scope in the modular and concurrent one‐pot synthesis of γ‐keto phosphine oxides 8 promoted by the eutectic mixture ChCl/p‐TSA·H2O (1:2) under aerobic conditions. Isolated yields are given in parentheses.

The scope of the reaction was investigated by employing suitable and commercially available terminal alkynes (1) and aldehydes (2), and secondary phosphine oxides (7; see Scheme 8). Firstly, we studied the effect of the different aromatic aldehydes (2c, 2f, 2 h, 2n, 2o), maintaining constant the terminal alkyne (phenyl acetylene, 1a) and the phosphine oxide (diphenylphosphine oxide, 7a; see Scheme 8). As previously noted for γ‐keto sulfones, the electronic nature of the aldehydes employed does not significantly influence the final yield of the desired γ‐keto phosphine oxides. Specifically, the presence of electron‐withdrawing substituents, such as chlorine (8aca) or trifluoromethyl (8afa), or EDGs, such as methyl (8aha), in the para‐position of the aromatic aldehyde has minimal impact on the reaction outcome. However, a pronounced steric effect was observed in our protocol. For instance, when an ortho‐substituted aldehyde (2n) was employed, the reaction time had to be extended to 72 h to achieve quantitative conversion to the desired γ‐keto phosphine oxide (8ana), highlighting the influence of steric hindrance on the reaction efficiency. Secondly, we explored the effect of the terminal alkyne employed (1 g, 1L, 1n, 1o, 1p, 1q, 1u), maintaining constant the aldehyde (benzaldehyde, 2a) and the phosphine oxide (diphenylphosphine oxide, 7a; see Scheme 8). Consistent with our previous observations for the synthesis of γ‐keto sulfones, better yields were obtained when aromatic substituents with EDGs, such as methyl (8gaa) or dimethylamino (8laa), were present in the terminal alkynes. In contrast, the presence of nonactivating groups on the aromatic ring of the alkyne, such as chlorine (8oaa, 8paa) or trifluoromethyl (8qaa), not only reduced the yields of the desired γ‐keto phosphine oxides but also required longer reaction times (up to 72 h). This effect was particularly pronounced when the nonactivating substituents are located in the ortho‐position (8paa), exacerbating steric hindrance. Finally, in the case of 4‐ethynylbenzonitrile (1u), concurrent hydration of the —C≡N bond occurred under our reaction conditions, yielding the corresponding carboxylated γ‐keto phosphine oxide (8uaa) in a moderate yield of 63% after 72 h of reaction. Notably, both γ‐keto phosphine oxides, 8paa and 8uaa, were inaccessible via the other three‐component protocols,^{[ 28 ]} thus, highlighting the unique utility of our one‐pot/one‐step methodology.

To demonstrate the versatility and modularity of this protocol, we explored the synthesis of γ‐keto phosphine oxides using various combinations of alkynes and aldehydes with electron‐donating or EWGs (Scheme 8). The results confirmed the feasibility of all combinations of electron‐rich and electron‐poor alkynes with electron‐rich or electron‐poor aldehydes (see γ‐keto phosphine oxides 8gca, 8gha, 8nha, 8qha, 8nca, 8qfa in Scheme 8), although electron‐deficient alkynes required longer reaction times (8qha and 8qfa in Scheme 8). Remarkably, quantitative yields of γ‐keto phosphine oxides were obtained in all cases, including challenging pairings of electron‐poor alkynes with electron‐deficient aldehydes (see 8nca and 8qfa in Scheme 8). These findings underscore the broad applicability and robustness of our protocol, demonstrating its adaptability to diverse substrates and its potential as a general strategy for synthesizing γ‐keto phosphine oxides without VOC solvents. To further evaluate the scope of this approach, we studied various secondary phosphine oxides (7b–7e) for regioselective C—P bond formation, maintaining constant the alkyne (phenyl acetylene, 1a) and the aldehyde (benzaldehyde, 2a). For mono‐substituted aromatic secondary phosphine oxides, higher yields were obtained with EWGs, such as trifluoromethyl (CF₃, 96%, 8aab), compared to EDGs like methyl (Me, 8aac, 83%) or methoxy (OMe, 8aad, 31%). The method also tolerated bulkier substituents, such as disubstituted 3,5‐dimethylphenyl (8aae, 74%) or 2‐naphthyl (8aaf, 95%), further highlighting its versatility. While the reaction shows good tolerance with various secondary phosphine oxides, other P‐based nucleophiles such as S/Se‐containing phosphine oxides [HP(S/Se)(Ph)₂] or phosphonates [(MeO)₂ P(O)H] were found to be inactive in this transformation.

2.3. Scaling up, Reusability, and E‐Factor

The eutectic mixture ChCl/p‐TSA·H₂O (1:2) serves both as a reaction medium and as a promoter for the synthesis of γ‐keto sulfones and γ‐keto phosphine oxides, significantly simplifying the work‐up processes. Specifically, both γ‐keto sulfones and γ‐keto phosphine oxides can be easily isolated by adding water and filtering the resulting solid. While purifying the former requires the use of a greener ethereal solvent such as CPME, the latter does not require these solvents, as simple washing with water yields the desired pure product. These straightforward isolation procedures eliminate the need for laborious chromatographic purifications, prompting further studies into the scalability and recyclability of the reaction medium. The scalability of the reaction was studied through the synthesis of 1,3‐diphenyl‐3‐(phenylsulfonyl)propan‐1‐one (4aab), a potent antibacterial and antifungal compound active against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Streptococcus faecalis, and Propionibacterium acnes, as well as against Epidermophyton floccosum, Tinea nigra, Candida albicans, Trichophyton rubrum, Microsporum canis, and Aspergillus fumigatus, respectively.^{[ 74} , ^{75 ]} This compound is typically synthesized in two steps from chalcone. First, thiophenol is added in the presence of metallic sodium to generate the corresponding γ‐keto sulfide, which is then oxidized, commonly with hydrogen peroxide in an acidic medium or using meta‐chloroperoxybenzoic acid (m‐CPBA), to afford γ‐keto sulfone 4aab in good yields (≈88%).^{[ 74} , ^{75 ]} To evaluate scalability, the three‐component reaction between phenyl acetylene (1a), benzaldehyde (2a), and sodium benzenesulfinate (3b) (Scheme  9 a,b) was performed on a tenfold scale compared to the previously reported synthesis of 4aab (10 mmol of reactants and 20 mL of the ChCl/p‐TSA·H₂O (1:2) eutectic mixture; see Supporting Information for experimental details). The reaction was heated at 60 °C for 24 h, after which water was added, precipitating γ‐keto sulfone 4aab, which was isolated by filtration in a 71% yield. Notably, no VOCs were used throughout the procedure. This result confirms the scalability of our methodology, enabling its application to gram‐scale synthesis of valuable products. To assess the environmental impact of this method, we calculated the Sheldon environmental factor (E‐Factor; total waste mass/product mass),^{[ 76} , ^{77 ]} obtaining a value of 10.3. This value is significantly lower than previously reported methods for this compound (E‐factor ≈ 300)^{[ 74} , ^{75 ]} and falls within the recommended range for fine chemical synthesis (5–50).

Scheme 9.

a) Scaling‐up studies on the synthesis of 1,3‐diphenyl‐3‐(phenylsulfonyl)propan‐1‐one (4aab). b) Recycling studies on the synthesis of 3‐(diphenylphosphoryl)‐1,3‐diphenylpropan‐1‐one (8aaa). The calculated E‐Factor values for both procedures are also indicated. Isolated yields are given in parentheses.

The recyclability of the reaction medium was examined using the synthesis of 3‐(diphenylphosphoryl)‐1,3‐diphenylpropan‐1‐one (8aaa), as it employs stoichiometric amounts of all three components (phenyl acetylene (1a), benzaldehyde (2a), and diphenylphosphine oxide (7a), (see Scheme 9b), simplifying the recycling process (note that γ‐keto sulfone synthesis requires a 20% mol excess of sulfinate salt). After 24 h at 100 °C, γ‐keto phosphine oxide 8aaa was obtained in 95% yield upon water addition (20 mL) and filtration (although compound 8aaa precipitates, it forms a fine solid under these experimental conditions, which, combined with the viscosity of the reaction medium, prevents its separation by simple filtration). The ChCl/p‐TSA·H₂O (1:2) eutectic mixture was regenerated by evaporating the added water under high vacuum at 60 °C for 8 h and reused in two additional cycles without significant loss of activity (yielding 90% and 80%, respectively). Beyond these cycles, the yield dropped dramatically. This decline in yields from the third cycle onwards is mainly attributed to volume losses of DES during its regeneration steps (although cumulative volume loss remains the primary factor, partial degradation of the DES integrity during successive regeneration cycles cannot be ruled out). These losses of ChCl/p‐TSA·H₂O (1:2) and the corresponding yield reduction can be offset by extending the reaction time. Thus, when the reaction time was increased up to 48 h, the reaction yields remained consistent (above 90%) for up to five consecutive reuse cycles of the eutectic mixture (Scheme 9). Importantly, the E‐factor calculated for these five recycling cycles of 8aaa is 7.6, a very low value that falls within the recommended range for fine chemical synthesis (5–50), approaching that of bulk chemicals (0.1–5).

3. Conclusion

In this work, we have developed an efficient, modular, and environmentally friendly one‐pot strategy for the synthesis of libraries of γ‐keto sulfones and γ‐keto phosphine oxides. This three‐component methodology, involving a terminal alkyne, an aldehyde, and a sulfonate salt or secondary phosphine oxide, uses the acidic eutectic mixture ChCl/p‐TSA·H₂O (1:2) (ChCl = choline chloride; p‐TSA = p‐toluenesulfonic acid) to enable regioselective C—C and C—X bond formation (X = S or P) under mild aerobic conditions. Our metal‐free protocol offers a sustainable alternative to traditional multistep syntheses, aligning with Green Chemistry principles through excellent atom economy, minimal waste generation (water as the sole byproduct), and the elimination of volatile organic solvents. The simple reaction setup and direct product isolation, without chromatographic purification, further enhance its practicality. The robustness of this methodology is demonstrated by its broad substrate scope (112 examples), accommodating diverse terminal alkynes, aromatic aldehydes, and coupling partners (sodium sulfinates and secondary phosphine oxides). It tolerates both electron‐rich and electron‐deficient substituents, achieving high yields even in challenging cases. Importantly, this methodology provides access to aliphatic sulfonate salts, which were shown to be unreactive in previous studies. Notably, the reaction is scalable (tenfold), and the eutectic mixture remains effective over five recycling cycles, demonstrating its potential for larger‐scale applications. Moreover, this applicability was demonstrated in the large‐scale synthesis of 1,3‐diphenyl‐3‐(phenylsulfonyl)propan‐1‐one (4aab), a potent antibacterial and antifungal compound. The compound was isolated in the absence of VOCs with a 71% yield and an E‐Factor of 10.3, which falls within the recommended range for fine chemical synthesis. This adaptability not only underscores its practical relevance but also establishes our approach as a general and sustainable strategy for the synthesis of γ‐keto phosphine oxides and sulfones.

Conflict of Interest

The authors declare no conflict of interest.

Supporting information

Supplementary Material

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.