One‐Pot Morita–Baylis–Hillman/Allylic Substitution in Deep Eutectic Solvents: Access to γ‐Hydroxy Derivatives via Sequential C—C and C—X (X = P, N, S, B, Si) Bond Formation

Abstract

A sustainable one‐pot sequential C—C/C—X (X = P, N, S, B, Si) bond‐forming strategy for synthesizing functionalized γ‐hydroxy derivatives using ChCl/Gly (1:2) (ChCl = choline chloride and Gly = glycerol) deep eutectic solvent (DES) is reported. The methodology combines 1) an atom‐economical Morita–Baylis–Hillman reaction for C—C bond formation and 2) subsequent nucleophilic functionalization to afford diverse γ‐hydroxy derivatives in good yields under mild, air/moisture‐tolerant conditions. The DES system enables straightforward product isolation via water‐induced precipitation, eliminating, in most of the cases, chromatographic purification. Notably, sulfinic acid reactivity displays striking stoichiometric control: 2 equiv. RSO₂H yields γ‐hydroxy sulfones, while 1 equiv. selectively produces (E)‐allylic sulfones (Z/E >1:99). Scalability is demonstrated through a fivefold multigram synthesis of γ‐hydroxy amine 7aaa (96% yield), a pivotal intermediate for synthesizing antibacterial arylureas. The process exhibits outstanding green metrics (E‐factor = 2.6), aligning with industrial benchmarks for bulk chemicals. This work establishes a practical, waste‐minimized approach to privileged heteroatom‐rich scaffolds, merging step economy with sustainable solvent technology.

Sustainable one‐pot synthesis of functionalized γ‐hydroxy derivatives in deep eutectic solvents. A green, sequential C—C/C—X bond‐forming strategy enables diverse γ‐hydroxy derivatives via Morita–Baylis–Hillman and nucleophilic functionalization in ChCl/Gly deep eutectic solvent. Scalable, chromatography‐free isolation and exceptional stoichiometric control (e.g., RSO₂H) deliver heteroatom‐rich scaffolds with industrial‐level green metrics (E‐factor = 2.6). A waste‐minimized route to bioactive intermediates.

1. Introduction

In recent years, the chemical industry has faced growing demands to develop efficient and sustainable synthetic routes for high‐value products, from commodity chemicals to pharmacologically active drugs.^{[ 1} , ² , ³ , ⁴ , ⁵ , ^{6 ]} This shift aligns with the 12 Principles of Green Chemistry,^{[ 7} , ⁸ , ⁹ , ^{10 ]} particularly through the adoption of multistep one‐pot protocols. By combining multiple transformations in a single vessel, these tandem reactions minimize solvent waste, reduce energy consumption, and enhance atom economy by eliminating intermediate purification steps.^{[ 11} , ^{12 ]} Their inherent efficiency also supports waste prevention, as exemplified by traditional multicomponent one‐pot protocols like the Passerini,^{[ 13} , ¹⁴ , ^{15 ]} Ugi,^{[ 16} , ¹⁷ , ^{18 ]} or Biginelli^{[ 19} , ^{20 ]} reactions. Despite these advances, a critical gap persists in designing one‐pot systems that integrate tandem C—C and C‐heteroatom (C—X) bond formations under mild and sustainable conditions,^{[ 21 ]} especially for highly functionalized allylic derivatives, which are pivotal in pharmaceutical^{[ 22} , ^{23 ]} and materials science.^{[ 24} , ^{25 ]}

In this context, the Morita–Baylis–Hillman (MBH) reaction,^{[ 26} , ²⁷ , ^{28 ]} an iconic organic transformation that couples electron‐poor alkenes (e.g., α,β‐unsaturated carbonyls) with carbon electrophiles (e.g., aldehydes), stands out as a powerful green tool for constructing densely functionalized allylic alcohols (MBH adducts).^{[ 29} , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ^{36 ]} This process is uniquely suited for sustainable one‐pot methodologies, as it 1) proceeds with perfect atom economy, 2) is organocatalyzed by nontoxic tertiary amines (e.g., DABCO,^{[ 37} , ^{38 ]} DBU,^{[ 38} , ^{39 ]} or quinuclidines^{[ 38} , ^{40 ]}) in line with safer catalysis processes; and 3) generates highly functionalized C3 synthons, reducing waste through efficient downstream synthetic applications.^{[ 41} , ⁴² , ^{43 ]} Despite these advantages, conventional MBH protocols often rely on volatile organic solvents (e.g., CH₂Cl₂ and THF), compromising their green credentials. While recent efforts have explored alternative solvents (e.g., micellar solutions,^{[ 44} , ^{45 ]} ionic liquids,^{[ 46} , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ^{53 ]} supercritical CO₂,^{[ 54 ]} sulfolane,^{[ 55 ]} biobased solvents,^{[ 56 ]} aqueous media,^{[ 57} , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ^{62 ]} and deep eutectic solvents (DESs)^{[ 63} , ⁶⁴ , ^{65 ]}), these systems face limitations, such as narrow substrate scope, or inefficient recyclability, especially when MBH adducts are intended to be further functionalized in tandem processes (e.g., as intermediates in one‐pot methodologies). Thus, the development of convenient and sustainable MBH‐based one‐pot systems remains a critical challenge.

In this regard, allylic alcohols derived from MBH reactions (MBH adducts) are ideal precursors for constructing C—X (X = P, N, S, B, Si) bonds, which are ubiquitous in pharmaceuticals (e.g., P‐containing antivirals),^{[ 66} , ^{67 ]} agrochemicals (S‐based fungicides),^{[ 68 ]} and functional materials (Si‐based polymers).^{[ 69} , ^{70 ]} Recent studies have demonstrated significant advances in the functionalization of MBH adducts via nucleophilic substitution pathways (S_N2 or S_N2′) employing diverse ionic nucleophiles.^{[ 41} , ⁷¹ , ⁷² , ^{73 ]} Moreover, these adducts have also been employed in the synthesis of cyclic compounds through various annulation processes.^{[ 42} , ^{74 ]} Such approaches have enabled the design of numerous catalytic and noncatalytic methodologies, yielding structurally diverse scaffolds including functionalized methacrylates, cinnamates, nitrogen‐containing heterocycles, and indole‐based frameworks.^{[ 75 ]} Among the diverse methodologies available, nucleophilic addition to activated MBH adducts using main‐group nucleophiles offers an efficient route for the formation of C—X (X = P, N, S, B, Si) bonds. This process proceeds with full atom economy (or water elimination) and typically occurs in the absence of metal catalysts. The synthetic potential of MBH adducts in C—P bond formation has been explored to a limited extent.^{[ 76 ]} For instance, Loh, Xie, and coworkers demonstrated the phosphorylation of MBH adducts using secondary phosphine oxide nucleophiles under neat conditions, yielding allylic organophosphorus compounds via dehydration with high efficiency (typically >95:5 Z/E selectivity).^{[ 77 ]} Similarly, Pirat, Virieux, and collaborators achieved allylic phosphorylation to synthesize (γ‐hydroxyalkyl)phosphine oxide derivatives through a three‐component reaction involving an aldehyde, an electron‐deficient alkene, and a tertiary amino phosphine in water.^{[ 78 ]} In the context of C—N bond formation, the reaction of amines with MBH adducts provides a convenient route to β‐amino carbonyl derivatives. While several methodologies describe amine addition to MBH adducts, most cases result in mixtures of regio‐ and stereoisomers.^{[ 79} , ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ^{89 ]} However, Ranu et al. developed an efficient metal‐free protocol for this transformation in water at room temperature, producing α‐dehydro‐β‐amino esters and nitriles with high yield and selectivity.^{[ 90 ]} On the other hand, allyl sulfones are highly valuable in organic synthesis^{[ 91} , ⁹² , ^{93 ]} and exhibit notable biological activities.^{[ 94} , ^{95 ]} These compounds are typically synthesized via nucleophilic addition of sulfur sources, such as sulfonates,^{[ 96} , ⁹⁷ , ⁹⁸ , ^{99 ]} arenesulfonyl cyanides,^{[ 100 ]} p‐toluenesulfonylmethyl isocyanide,^{[ 101 ]} sulfinyl chlorides,^{[ 102 ]} sulfonylhydrazides,^{[ 103 ]} or DABCO·(SO₂)₂ (DABSO),^{[ 104 ]} to MBH adducts. However, such C—S bond‐forming reactions often generate undesirable by‐products. In contrast, Xie et al. reported a metal‐free dehydrative cross‐coupling of sulfinic acids with MBH adducts, affording allylic sulfones in high yields with excellent selectivity under mild aqueous conditions. Notably, these products could be isolated by simple filtration, avoiding chromatographic purification.^{[ 105 ]} MBH adducts have also been employed as precursors for C—B and C—Si bond formation. Almost simultaneously, Kabalka et al.^{[ 106 ]} and Ramachandran et al.^{[ 107 ]} reported the S_N2′ borylation of MBH acetates using Pd(OAc)₂ and CuCl as catalysts, respectively. Later, Song and collaborators achieved direct borylation of MBH allylic alcohols via a [Cu(OTf)₂/base] catalytic system to access functionalized trisubstituted allylic boronates.^{[ 108 ]} Allylsilanes are key intermediates in the synthesis of natural products and bioactive compounds.^{[ 109} , ¹¹⁰ , ^{111 ]} Among the methodologies for their preparation,^{[ 112} , ¹¹³ , ¹¹⁴ , ¹¹⁵ , ¹¹⁶ , ¹¹⁷ , ^{118 ]} the use of silicon–boron reagents, capable of transferring nucleophilic silicon to electrophiles, stands out. These reactions are typically catalyzed by transition metals such as Pd(0),^{[ 119} , ¹²⁰ , ^{121 ]} Rh(I),^{[ 119} , ¹²² , ¹²³ , ^{124 ]} or Cu(I),^{[ 119} , ¹²⁵ , ¹²⁶ , ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ , ^{132 ]} as well as N‐heterocyclic carbenes (NHCs).^{[ 133 ]} In this context, Li et al. developed an efficient and regioselective synthesis of functionalized allylsilanes via the reaction of MBH adducts with Me₂PhSiBpin, catalyzed by the system [Cu(OTf)₂/pyridine] in methanol.^{[ 134 ]} Very recently and using the same Si‐based reagent, Zhu and collaborators described the silylation of α,β‐unsaturated acceptors in aqueous media using chitosan/cellulose composite copper gelatinous microbeads.^{[ 135 ]}

On the basis of the ongoing interest in the creation of C—X bonds using MBH adducts, in this work, we report a convenient one‐pot combination of MBH and allylic substitutions in DESs, enabling efficient access to γ‐hydroxy C—X derivatives (X = P, N, S, B, Si) without trace metal contamination (Scheme  1 ). Our strategy capitalizes on 1) the inherent greenness of DES (low cost, biomass‐derived, and biodegradability), 2) the versatility of MBH adducts as allylic precursors, and 3) the preferential formation of γ‐hydroxy products which are often isolable in high purity via aqueous precipitation, thus eliminating the need for volatile organic solvents or chromatographic separations. Notably, both γ‐hydroxy sulfones and vinyl sulfones can be obtained in the case of C—S bond formation simply by adjusting the amount of the corresponding sulfonic salt nucleophile. This protocol operates under ambient conditions (in the presence of air/moisture) with excellent atom economy and broad heteroatom scope, outperforming prior systems dependent on hazardous solvents or energy‐intensive procedures. Furthermore, its robustness is demonstrated through gram‐scale synthesis, highlighting industrial potential.

Scheme 1.

One‐pot combination of MBH and metal‐free allylic substitutions in DESs, providing efficient access to γ‐hydroxy C—X derivatives (X = P, N, S, B, Si).

2. Results and Discussion

Initially, employing the optimized conditions reported by Zhao et al. for MBH reactions in DESs,^{[ 63 ]} we investigated the reaction between benzaldehyde (1a) and acrylonitrile (2a) to yield the desired allylic alcohol 3aa (MBH adduct). The reaction was conducted in the presence of DABCO (as organocatalyst) using ChCl/Gly (1:2) (ChCl = choline chloride and Gly = glycerol) as the sustainable reaction medium. Under these conditions, the desired MBH adduct 3aa was smoothly synthesized using bench conditions (20 °C, open atmosphere) with 93% yield after 5 h of reaction (entry 1, Table  1 ). Interestingly, and in contrast to the previous findings reported by Zhao et al., in our hands, the addition of water (25 wt%) to the reaction medium did not accelerate the reaction (which still required 5 h for completion, as monitored by gas chromatography (GC)) and instead led to a lower yield of 3aa (entry 2, Table 1). Furthermore, reducing the amount of DABCO (entry 3, Table 1), changing the nature of the organocatalyst to DBU or HMTA (entries 4 and 5 of Table 1, respectively), nor altering the reaction medium to ChCl/Urea (1:2) (entry 6, Table 1; note that significantly longer reaction times were required to achieve comparable yields) had a positive impact on the reaction outcome. The reaction using methyl acrylate (2b) under the optimized conditions proved less efficient than with acrylonitrile (2a), yielding only 68% after 5 h of reaction (entry 7, Table 1). However, quantitative conversions (98% by GC; 74% yield) of the MBH adduct 3ab could be achieved when longer reaction times (24 h) and smaller amounts of DES (0.4 mL) were employed (see entry 8, Table 1).

Table 1.

Optimization of reaction conditions for the MBH reaction between benzaldehyde (1a) and acrylonitrile (2a).

Entrya)	DES	H2O [%w]	Organocatalyst [equiv.]	t [h]	Yield [%]b)
1	ChCl/Gly	–	DABCO (1.0)	5	93 (3aa)
2	ChCl/Gly	25	DABCO (1.0)	5	88 (3aa)
3	ChCl/Gly	–	DABCO (0.5)	5	81 (3aa)
4	ChCl/Gly	–	DBU (1.0)	5	ndc)
5	ChCl/Gly	–	HMTA (1.0)	5	ndc)
6	ChCl/Urea	–	DABCO (1.0)	24	98 (3aa)
7d)	ChCl/Gly	–	DABCO (1.0)	5	68 (3ab)
8d)	ChCl/Gly	–	DABCO (1.0)	24	78 (3ab)

^a)General conditions: benzaldehyde (1a, 3.75 mmol), acrylonitrile (2a, 4 mmol), and DABCO (3.75 mmol) were combined with 2.5 mL of the designated DES in an open vial (without inert atmosphere) and stirred at 20 °C for the specified time. Reaction progress was monitored by GC.

^b)Isolated yields.

^c)Not detected.

^d)Methyl acrylate (2b) and 0.4 mL of ChCl/Gly.

Having established the optimal experimental conditions for conducting the MBH reaction using ChCl/Gly (1:2) as the reaction medium and DABCO as the organocatalyst, we proceeded to investigate the one‐pot formation of C—X (X = P, N, S, B, Si) bonds using the generated MBH adduct as a reactive intermediate. To this end, we first examined the formation of C—P bonds through the addition of secondary phosphine oxides. Specifically, our initial study employed diphenylphosphine oxide (4a). When Ph₂P(O)H (1.2 equiv.) was added to the MBH adduct 3aa, generated in situ from the reaction of benzaldehyde (1a) and acrylonitrile (2a) under the previously optimized conditions, thin‐layer chromatography monitoring revealed the complete consumption of the MBH adduct. ¹H‐NMR analysis of the crude reaction mixture indicated the presence of the γ‐hydroxy phosphine oxide derivative 5aaa as major product (85% mol, based on relative integrals) and the allylic phosphine oxide 6aaa in a very minor proportion (7% mol, based on relative integrals. The ³¹P‐NMR spectrum also revealed trace amounts of other unidentified phosphorus‐containing compounds). However, when this second reaction step was conducted at 60 °C, a white solid precipitated from the reaction mixture after 1 h. Following filtration and washing with water, the solid was analyzed by ¹H‐ and ³¹P‐NMR spectroscopy, which confirmed it to be a mixture of the allylic phosphine oxide 6aaa (10%) and the corresponding γ‐hydroxy phosphine oxide derivative 5aaa (90%), as determined by relative integration of the respective signals in the ¹H‐NMR spectrum (see Scheme  2 ).

Scheme 2.

One‐pot sequential C—C (MBH reaction) and C—P bond formation for the synthesis of γ‐hydroxy phosphine oxide 5aaa (major product) and allylic phosphine oxide 6aa (minor product).

The major product, 5aaa, was isolated in pure form through simple recrystallization as a mixture of diastereoisomers in good yield (74%; Scheme  3 ), and its molecular structure was unambiguously confirmed by single‐crystal X‐ray diffraction (SCXRD) (see Figure  1 and the Supporting Information for further experimental details). By varying the substituents on the aromatic ring of the aldehyde, various γ‐hydroxy phosphine oxides were synthesized in good yields containing 1) strongly electron‐withdrawing (EWG) [CF₃; 5baa (60%); Scheme 3], 2) moderately EWG (Cl) at either the para‐ [5caa (68%)] or meta‐positions [5daa (66%)] (Scheme 3), and 3) electron‐donating (EDG) groups such as OMe [5eaa (68%); Scheme 3]. The reaction was also compatible with methyl acrylate [5aba (46%); Scheme 3] and tolerated a range of secondary phosphine oxide nucleophiles [5aab (64%), 5aac (72%), and 5aad (58%); Scheme 3]. Notably, the methodology described herein provides a straightforward route to access γ‐hydroxy phosphine oxide derivatives directly from aldehydes, electron‐deficient alkenes, and secondary phosphine oxides in an environmentally friendly DES. Moreover, obtaining these derivatives in pure form, i.e., free from allylic phosphine oxide counterparts, was achieved simply through filtration and recrystallization.

Scheme 3.

Scope of the one‐pot sequential C—C (MBH reaction) and C—P bond formation for the synthesis of γ‐hydroxy phosphine oxides 5aaa‐5aad.

Figure 1.

SCXRD molecular structure of γ‐hydroxy phosphine oxide 5aaa (30% displacement ellipsoids).

Based on these results, the sequential formation of C—C and C—N bonds was investigated by reacting the in situ generated MBH adduct (from the first‐step C—C bond formation) with various benzylic and aliphatic amines (C—N bond formation; Scheme  4 ) using ChCl/Gly (1:2) as reaction media, under bench‐type conditions and in the absence of metal‐based catalyst. When amines 7a–d (1.5 equiv.) were added to MBH adducts derived from a range of functionalized aldehydes (bearing either EWG or EDG groups) and electron‐poor alkenes (acrylonitrile, 2a, or methyl acrylate, 2b), the corresponding γ‐hydroxy amines were obtained as a mixture of diastereoisomers after 48 h of reaction at 20 °C, in generally good yields (Scheme 4). Using acrylonitrile (2a) as the electron‐poor alkene, this one‐pot methodology proved compatible with 1) nonactivated aldehydes such as benzaldehyde (1a) [8aaa (78%), 8aab (65%), 8aac (87%), and 8aad (47%); Scheme 4], 2) electron‐deficient aldehydes like 4‐(trifluoromethyl)benzaldehyde (1b) [8baa (98%), 8bab (99%), 8bac (68%), and 8bad (58%); Scheme 4], and 3) electron‐rich aldehydes such as 4‐methoxybenzaldehyde (1e) [8eaa (74%), 8eab (68%), 8eac (51%), and 8ead (45%); Scheme 4]. The reaction remained efficient when methyl acrylate (2b) was employed in the MBH step, affording the γ‐hydroxy amine 8aba in good yields (87%; Scheme 4). In general, it can be stated that while the addition of benzylamine (7a), pyrrolidine (7b), and morpholine (7c) to the MBH intermediate adduct affords the corresponding γ‐hydroxy amines in comparable yields, the addition of diallylamine (7d) proceeds with lower efficiency. Notably, γ‐hydroxy amines 8aaa, 8aab, 8aba, 8baa, 8bab, and 8bac could be isolated directly by aqueous precipitation after reaction completion, followed by washing the solid residue with water. The molecular structure of γ‐hydroxy amine 8aaa was confirmed by SCXRD (see Figure  2 and the Supporting Information for further experimental details).

Scheme 4.

Scope of the one‐pot sequential C—C (MBH reaction) and C—N bond formation for the synthesis of γ‐hydroxy amines 8aaa‐8ead.

Figure 2.

SCXRD molecular structure of γ‐hydroxy amine 8aaa (30% displacement ellipsoids).

The promising results obtained for both C—P and C—N bond formation on the in situ generated MBH adducts in our one‐pot sequential methodology developed in ChCl/Gly (1:2) encouraged us to extend this approach to C—S bond formation. Thus, under the previous optimized reaction conditions, when benzenesulfinic acid (9a, 2 equiv.) was directly added to the MBH adduct 3aa generated in the first step, the crude reaction mixture (analyzed by ¹H NMR after 62 h at 60 °C) revealed a mixture composed predominantly of the γ‐hydroxy sulfone 10aaa (65%) and the allylic sulfone 11aaa (30%). Trace amounts (5%) of the unreacted intermediate MBH adduct 3aa were also detected. Since Xie et al. had previously described a similar reaction in aqueous media (EtOH/water mixtures),^{[ 105 ]} we decided to add water (1 mL) in the second step. Analysis of the crude mixture by ¹H NMR showed no signals assignable to the MBH adduct (3aa) but confirmed the presence of γ‐hydroxy sulfone 10aaa (84%) and allylic sulfone 11aaa (16%; Scheme  5 ). The former was isolated in pure form as a mixture of diastereoisomers with a 75% yield (Scheme  6 ). When acrylonitrile (2a) was employed as the electron‐poor alkene in the MBH reaction, followed by the addition of benzenesulfinic acid (9a, 2 equiv.) in the second step, this methodology proved compatible with both EWG [10baa (51%); Scheme 6] and EDG [10eaa (49%); Scheme 6] groups on the starting aromatic aldehyde. Furthermore, substituted aromatic sulfinic acids [4‐methylbenzenesulfinic acid (9b) and 4‐chlorobenzenesulfinic acid (9c)] were successfully employed with 1) nonactivated aldehydes [10aab (75%) and 10aac (80%); Scheme 6], 2) electron‐deficient aldehydes [10bab (62%) and 10bac (71%); Scheme 6], and 3) electron‐rich aldehydes [10eab (58%) and 10eac (77%); Scheme 6]. Unfortunately, the reaction was unsuccessful when employing methanesulfinic acid, as no sulfonation product of the MBH intermediate adduct was observed. The molecular structure of γ‐hydroxy sulfone 10baa was confirmed by SCXRD (see Figure  3 and the Supporting Information for further experimental details).

Scheme 5.

One‐pot sequential C—C (MBH reaction) and C—S bond formation for the synthesis of γ‐hydroxy sulfone 10aaa (major product) and allylic sulfone 11aaa (minor product).

Scheme 6.

Scope of the one‐pot sequential C—C (MBH reaction) and C—S bond formation for the synthesis of γ‐hydroxy sulfones 10aaa‐10eac.

Figure 3.

SCXRD molecular structure of γ‐hydroxy sulfone 10baa (30% displacement ellipsoids).

Interestingly, when stoichiometric amounts of the sulfinic acid were employed in the second step of the reaction (i.e., 1 equiv. instead of two), the corresponding (E)‐allyl sulfones were obtained exclusively (no other by‐products were detected spectroscopically, with the corresponding unreacted MBH adduct being the only other species observed) and with complete stereoselectivity, albeit in moderate yields [11aaa (35%), 11aab (33%), 11aad (55%), and 11eaa (30%); Scheme  7 ]. Very importantly, all synthesized (E)‐allyl sulfones precipitated in the reaction mixture upon water addition after reaction completion, enabling isolation of the pure product through simple filtration and washing of the resulting solid with water/ethanol (1:1). The molecular structure of (E)‐allyl sulfone 11eaa was unambiguously confirmed by SCXRD (see Figure  4 and the Supporting Information for further experimental details). It is worth mentioning that our methodology selectively furnishes the corresponding allyl sulfones with total (E)‐stereoselectivity (Z/E > 1/99). In contrast, the approach reported by Xie et al., also based on the use of sulfinic acids as nucleophiles, affords the corresponding allyl sulfones with high Z‐stereoselectivity (Z/E > 95/5).^{[ 105 ]} However, a strong (E)‐selectivity (Z/E > 5/95) was observed by Reddy, Hu, and collaborators in the addition of arenesulfonyl cyanides to nitrile‐based MBH adducts.^{[ 100 ]}

Scheme 7.

Scope of the one‐pot sequential C—C (MBH reaction) and C—S bond formation for the synthesis of (E)‐allyl sulfones 11aaa‐11eaa.

Figure 4.

SCXRD molecular structure of (E)‐allyl sulfone 11eaa (30% displacement ellipsoids).

The applicability of our sequential one‐pot methodology for the formation of C—C and C‐heteroatom bonds in the eutectic mixture ChCl/Gly (1:2) was extended to the generation of C—B bonds. Thus, when B₂pin₂ (12; 1.2 equiv.), Cu(OTf)₂ (10 mol%), and water (10 mL) were added to the MBH adduct 3ba, the ¹¹B‐ and ¹H‐NMR spectra of the crude reaction mixture after 24 h at room temperature revealed the presence of γ‐hydroxy boronate 13ab (>95%) as the sole reaction product (the ¹¹B‐NMR spectrum also displayed a signal at 22 ppm, attributable to the hydrolysis product of 13ab; <5% by relative integration). Direct extraction of the reaction mixture (ethyl acetate or CPME) followed by aqueous washings afforded the γ‐hydroxy boronate 13ab as a pure mixture of diastereoisomers in 68% yield (Scheme  8 ). Notably, in our methodology, the addition of an external base in the second step of the reaction is unnecessary, as the DABCO present in the first step proved to be active, along with Cu(II), in the borylation of MBH adducts. This methodology was found to be compatible with both strong EWG [CF₃, 13bb (81%); NO₂, 13fb (91%, 72 h); Scheme 8] and weakly EWG groups [Cl, 13cb (80%); Scheme 8].The use of aldehydes substituted with EDG groups was not feasible, as the MBH reaction of these with methyl acrylate (2b) did not achieve high conversions (>95%) to the corresponding MBH adducts in any of the cases studied. Similarly, and as previously reported by Song and collaborators,^{[ 108 ]} the use of nitrile‐based MBH adducts resulted in low conversions to the desired γ‐hydroxy boronate derivatives.

Scheme 8.

Scope of the one‐pot sequential C—C (MBH reaction) and C—B bond formation for the synthesis of γ‐hydroxy boronates 13ab‐13fb.

Finally, using the same reaction medium, the eutectic mixture ChCl/Gly (1:2), we investigated the coupling of a C—Si bond‐forming step with the MBH reaction for C—C bond formation. Thus, when benzaldehyde (1a) and acrylonitrile (2a) were employed in the first reaction step, followed by the addition of Me₂PhSiBpin (14, 2 equiv.) as the silylation agent, Cu(OTf)₂ (10 mol%) as the catalyst, water as a cosolvent (0.4 mL), and DABCO (used as the organocatalyst in the MBH reaction), the formation of γ‐hydroxy silane 15aa alongside the corresponding allyl silane (16aa) was observed in an 83/17 molar ratio (determined by relative integration of the corresponding signals in the ¹H‐NMR spectra of the crude reaction mixtures). The major product, 15aa, was isolated as a pure mixture of diastereoisomers by chromatographic separation in 77% yield (Scheme  9 ). This C—Si bond‐forming methodology proved compatible with both electron‐poor aldehydes [15ba (61%) and 15ca (70%); Scheme 9] and electron‐rich aldehydes [15ea (42%); Scheme 9]. Furthermore, it was also compatible with methyl acrylate (2b) as the electron‐poor alkene in the first reaction step (MBH reaction), affording the corresponding γ‐hydroxy silane 15ab in moderate yields (43%; Scheme 9).

Scheme 9.

Scope of the one‐pot sequential C—C (MBH reaction) and C—Si bond formation for the synthesis of γ‐hydroxy silanes 15aa‐15ea.

The synthetic applicability of the one‐pot methodology for the sequential formation of C—C and C—X (X = P, N, S, B, Si) bonds was evaluated through a multigram‐scale synthesis of γ‐hydroxy amine 8aaa, a key intermediate in the preparation of arylureas, which are molecules of significant biological interest due to their antibacterial activity.^{[ 135} , ¹³⁶ , ^{137 ]} Thus, using a fivefold larger scale of starting substrates (20 mmol) and the same reaction conditions previously described for the synthesis of these derivatives (Scheme  10 ), 8aaa was successfully synthesized and isolated in high yield (96%) in pure form directly from the reaction mixture via water‐induced precipitation and filtration of the resulting solid. To assess the environmental impact of this method, we calculated the Sheldon environmental factor (E‐factor; total waste mass/product mass),^{[ 138} , ^{139 ]} obtaining a value of 2.6 (see Supporting Information). This value is very low and falls within the recommended range for bulk chemicals (0.1–5), demonstrating the scalability of our methodology and reinforcing its green credentials.

Scheme 10.

Scaling up studies of the one‐pot sequential C—C (MBH reaction) and C—N bond formation for the synthesis of γ‐hydroxy amine 8aaa.

3. Conclusion

In this work, we have developed a convenient one‐pot sequential C—C and C—X (X = P, N, S, B, Si) bond‐forming methodology to synthesize a wide variety of highly functionalized γ‐hydroxy derivatives using a DES, specifically ChCl/Gly (1:2), as a sustainable reaction medium for all transformations. This two‐step methodology consists of 1) an organocatalytic C—C bond formation step via the MBH reaction, which proceeds with 100% atom economy, and 2) the subsequent direct treatment of the resulting MBH adducts (without the need of tedious and time/energy consuming isolation/purifications steps) with heteroatomic nucleophiles, generating the desired γ‐hydroxy derivatives in good yields and with complete atom economy. Notably, the ChCl/Gly (1:2) eutectic mixture facilitated not only mild reaction conditions (without protective atmospheres in the presence of air/moisture) but also, in some cases, a simple isolation and purification of the products. This was achieved through water‐induced precipitation directly from the reaction medium, followed by filtration, thereby avoiding tedious and volatile organic compound consuming chromatographic purifications. When sulfinic acids (RSO₂H) were used as nucleophiles for C—S bond formation with MBH adducts, the reaction outcome was found to be highly dependent on the stoichiometry of the acid. Remarkably, employing 2 equivalents of RSO₂H produced the anticipated γ‐hydroxy sulfone, while reducing the amount to just 1 equivalent resulted in exclusive formation of the (E)‐allylic sulfone with excellent stereoselectivity (Z/E > 1:99). The synthetic applicability of this methodology was further demonstrated through a multigram‐scale (fivefold) synthesis of γ‐hydroxy amine 8aaa, a key intermediate in the preparation of antibacterial arylureas. The E‐factor for this scaled process was 2.6, a low value within the recommended range for bulk chemicals (0.1–5), highlighting the exceptional green credentials of this methodology.

Supporting Information

All the experimental procedures and characterization details of the synthesised compounds including NMR spectra, are provided in the Supporting Information. The authors have cited additional references within the Supporting Information.^[141–151]

Conflict of Interest

The authors declare no conflict of interest.

Supporting information

Supplementary Material

Ramos‐Martín Marina, del Río Ignacio, García‐Álvarez Joaquín, Presa Soto Alejandro. ChemSusChem. 2025; 19:e202501674. 10.1002/cssc.202501674

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.