English

• The development of a metal-free catalytic system that can perform organic transformations in water with low catalyst loading is one of the most challenging endeavors in organic synthesis and green chemistry [1-4]. Researchers are exploring water-tolerant catalysts and catalyst-free systems to improve environmental friendliness and produce green pharmaceuticals and functional biomolecules such as proteins [5-10]. To achieve high catalytic efficiency in organic transformations, it is crucial that the catalyst is both stable in water and does not bind directly to the substrate and the product during the reaction process [11-14]. In response to this challenge, researchers are exploring water-tolerant catalysts or catalyst-free systems in water. In recent decades, significant progress has been made with the discovery of water-tolerant Lewis acids such as copper salts, lanthanide triflates, and indium complexes to catalyze less reactive substrates in water [15-19]. However, the use of these expensive and/or toxic metal complexes in high catalytic loadings, leading to disposal issues.

  Inspired by Yamamoto’s work, we aim to exploit the water-tolerant nature of B(C₆F₅)₃ to develop a new catalytic system based on this model using the Mukaiyama-aldol reaction as a model system [20, 21]. The Mukaiyama-aldol reaction first reported by Mukaiyama and Narasaka over 50 years ago is one of the most powerful organic reactions in organic synthesis as it provides efficient access to synthetically useful β–hydroxy carbonyl compounds and traditionally involves water-sensitive Lewis acids, such as titanium chloride, tin tetrachloride, BF₃ (Fig. 1A) [22-37]. Moreover, the use of water-tolerant Lewis acids such as indium complexes, lanthanide triflates, copper salts, or Lewis base to catalyze this reaction in aqueous media have also been explored [38]. In 2014, Zhou and co-workers reported a catalyst-free, on-water protocol for Mukaiyama aldol reaction facilitated by C-F···H—O interaction between the fluorinated silyl enol ether and the hydrogen-bond network of water at the phase boundary [39]. Conventionally, Lewis acids activate carbonyl compounds by coordinating with their lone pairs. This activation mode has been well studied and includes X-ray structures of the benzaldehyde-BF₃ complex obtained by Reetz and the methacrolein-BF₃ complex by Corey, as well as low-temperature 2D NMR studies (Fig. 1B) [40, 41]. More recently, König disclosed the distinct "water-accelerated" effect on photochemical reaction (Fig. 1C). In water, the formation of aggregates between the coupling partners led to an oil-water phase boundary through depressing substrate melting points. Therefore, the reactants interacted with water via hydrogen bonds to accelerate the desired photochemical transformations [42]. Subsequently, Bae et al. also discovered a water accelerated effect on the [2 + 2] cycloaddition between (hetero)arylated ethenesulfonyl fluorides and inert heteroaromatics, likely due to the water-induced confined cage [43]. Herein, we report an unexpected discovery of "water" accelerated catalytic system using B(C₆F₅)₃ as the catalyst for Mukaiyama-aldol reactions (Fig. 1D). The reactions likely proceeded through a new activation mode where the carbonyl group is activated by water molecule protons generated by the hydrogen bonding network of B(C₆F₅)₃. The new catalytic system works well with a wide range of substrates and requires low catalyst loading (0.5–1 mol%).

  Figure 1

  

  Figure 1.  (A) First Mukaiyama-aldol reaction developed by Mukaiyama and Narasaka. (B) Previous evidences of the inner-sphere activation mode by direct coordination. (C) Recent advance in "water" accelerated photochemical reactions. (D) This work: "Water" accelerated B(C₆F₅)₃ catalyzed Mukaiyama-aldol reaction via outer-sphere activation.

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  We initiated our study by investigating the Mukaiyama-aldol reaction between benzenepropanal 1 and silyl enol ether 2a in 1.0 mL water using 5 mol% of B(C₆F₅)₃ as the catalyst (Table 1). The reaction was performed at 22 ℃ and stopped after 12 h, resulting in the detection of β–hydroxy-α, α-dimethyl-methyl ester 3 product (entry 1). Further optimization of the reaction conditions, including a reduction of the catalyst loading from 5 mol% to 1 mol%, resulted in a quantitative yield of 3 after 12 h (entries 2 and 3). However, when the catalyst loading was reduced to 0.5 mol%, the yield of 3 decreased to 28% (entry 4). By increasing the amount of 2a to 1.5 equiv., a 0.5 mol% catalyst loading was found to be effective (entries 5 and 6). With a slight adjustment to the reaction parameters using 1 mol% catalyst loading, the reaction was completed in just 8 h with an 85% yield of 3 (entries 8 and 9).

  Table 1

  

  Table 1.  Optimization of reaction conditions.^a

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  Entry	B(C6F5)3 (mol%)	2a (equiv.)	T (h)	Yield (%)
  1	5	1.2	12	74
  2	3	1.2	12	80
  3	1	1.2	12	84
  4	0.5	1.2	12	28
  5	0.5	1.2	24	52
  6	0.5	1.5	12	85
  7	0.3	1.5	24	50
  8	1	1.2	12	95b
  9	1	1.2	8	95b (85c)
  a Reactions were performed at 0.2 mmol scale in 1.0 mL deionized H2O. Yield is based on 1a and was determined by 1H NMR analysis by using CH3NO2 as an internal standard. b 0.4 mL H2O was used. c Isolated yield.

  Using optimized reaction conditions, the scope of the B(C₆F₅)₃-catalyzed Mukaiyama-aldol reaction in water was evaluated. The reactions of silyl enol ether 2a with a variety of aldehydes, including aliphatic, aromatic, and unsaturated aldehydes, were found to proceed smoothly to the corresponding secondary alcohols (Scheme 1, 3–42). Linear aliphatic aldehydes, such as pentanal and nonanal, were well-accommodated, with good yields (4, 5). Branched aliphatic aldehydes, which increase the steric effects at the α and β positions of the carbonyl group, did not affect the reactions and generated the target products with good to excellent yields (6–10) with good stereo-selectivity observed in several substrates (9, 10). Cyclic substituents attached to the carbonyl group of aldehydes were introduced successfully into the products (11–13). The unchanged conditions were well tolerated for a wide range of functional groups in aromatic aldehydes (14–38). As a typical example, benzaldehyde coupled with 2a to generate the secondary benzylic alcohol with 80% yield (14). Substrates with methyl groups at ortho, meta, and para positions were smoothly converted into the respective products (15–17). A substrate with 3,4-dimethyl groups provided a comparable yield to the mono- methyl compound (18). The electron-rich benzaldehyde with methoxy groups at meta and para positions of the aromatic ring slowed down the process but achieved full conversion with a prolonged reaction time (19, 20). Halogens, which are relevant to pharmaceutical applications, were also examined, and substrates with mono and multiple fluorides, bromides, and chlorides at diverse positions were smoothly converted into the respective products (21–28). Notably, pentafluorobenzaldehyde proceeded in the Mukaiyama-aldol reaction with excellent yield (28). Electron-withdrawing groups, such as 4-trifluoromethyl, 2-trifluoromethoxy, 4-cyano, and 4-nitro, were accommodated to the optimized conditions (29–32). The hydroxyl group and phenyl-protected hydroxyl group were installed into the products, with a higher yield obtained with protection (33, 34). Heterocyclic aldehydes, such as 9-ethyl-carbazolecarbaldehyde, ferrocene carboxaldehyde, 2-furan carboxaldehyde, and 2-thiophene carboxaldehyde, could be coupled with 2a with good yields (35–38). Additionally, the Mukaiyama-aldol product was generated in 75% yield when benzaldehyde dimethyl acetal was treated as a substrate (39). Unsaturated aldehydes were also tolerated, affording the respective products in moderate yields (40, 41). However, when the cinnamaldehyde was selected as the substrate, the target product 42 was isolated in only 27% yield, as the 1,4-addition by-product 42a was formed in 65% yield under standard conditions.

  Scheme 1

  

  Scheme 1.  Scope of carbonyl substrates. Unless other noted, reactions were performed using 0.2 mmol aldehydes, 0.24 mmol 2a and 0.4 mL deionized water in indicated time. Yields are for isolated target products after purification. ^a Gram-scale synthesis. ^b 1.5 equiv. of 2a was added. ^c The yield of 1,4-addition by-product 42a.

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  Next, we turned our attention to the reactions of aromatic ketones under modified conditions (Scheme 2, 43–54). Due to the low reactivity of ketone carbonyls compared to aldehydes, increasing the borane reagent loading to 3 mol% resulted in efficient production of tertiary alcohols. Acetophenone and its derivatives underwent smooth reactions to provide their corresponding Mukaiyama-aldol products in moderate to excellent yields (43–50). The presence of electron-donating substituents at the para position slowed down the process (44, 45), however, a range of halogen substituents was tolerated, yielding β–hydroxy carbonyl compounds that could be further functionalized via cross-coupling reactions (46–49). An electron-withdrawing nitro group was completely consumed within 24 h (50). The polycyclic aromatic β-acetonaphthone was well-accommodated, and with 5 mol% boron catalyst loading, the desired product was obtained in 92% yield (51). Our assessment of other moieties besides methyl showed that the indicated conditions were compatible with a range of other substituents, including ethyl, n-propyl, and phenyl (52–54).

  Scheme 2

  

  Scheme 2.  Unless other noted, reactions were performed using 0.2 mmol indicated carbonyl substrates, 0.24 mmol silyl enol ethers and 0.4 mL deionized water in indicated time. Yields are for isolated target products after purification. ^a 10 mol% B(C₆F₅)₃, 3.0 equiv. 2a and 0.2 mL MeOH were added. ^b 5 mol% B(C₆F₅)₃ and 1.5 equiv. 2a were used. ^c 5 mol% B(C₆F₅)₃ was added. ^d Using 0.1 mL MeOH as co-solvent.

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  The scope of the method was also examined with respect to silyl enol ethers, which were freshly prepared according to reported procedures (Scheme 2, 55–59). In the case of 4-trifluoromethyl benzaldehyde, the aldol product was obtained in 87% yield when 1-ethoxy-2-methylpropenoxy)trimethylsilane was used (55). However, the yield was lower when bulky ethyl substitutes were used with silyl enol ethers (56). The optimal conditions accommodated cyclic silyl enol ethers, affording the corresponding product in 78% yield (57). The desired product was isolated in 48% yield when 2-naphthaldehyde was reacted with tert–butyl((1-ethoxyvinyl)oxy)dimethylsilane (58). Our strategy was also efficient for vinylogous Mukaiyama-aldol reactions (VMAR), with the expected VMAR product obtained in 44% yield (59).

  To demonstrate the potential for late-stage modification of functionalized natural products and drugs, androsterone was reacted with 4-formylbenzoic acid to yield a derivative bearing an aldehyde group. The subsequent metal-free Mukaiyama-aldol reaction was conducted under aqueous conditions with methanol as a co-solvent to improve the substrate’s solubility, yielding the desired final product in 36% yield (Scheme 2, 60). Similarly, the certified strategy was used to derive L-menthol and to efficiently introduce a β–hydroxy carbonyl moiety under metal-free conditions in water, yielding a single optically pure product in 58% yield (61). Oleyl alcohol and Galactose derivatives were also modified in water with our protocol, albeit in lower yields (62, 63). To demonstrate its practicality, a gram-scale reaction was performed, resulting in the isolation of 1.45 g of the desired product in 88% yield (Scheme 2).

  The activation of H₂O with B(C₆F₅)₃ has been reported previously [44-46]. Danopoulos et al. demonstrated the equilibria in the B(C₆F₅)₃H₂O system in details, which implied the formation of a Lewis acid-base adduct and subsequent ionized by solvent to generate an acidic proton and complementary anion (Fig. 2A) [47]. Piers et al. reported the first B(C₆F₅)₃-catalyzed hydrosilylation of carbonyl compounds in toluene at room temperature [48]. Mechanistic investigation showed that the binding of the substrate and B(C₆F₅)₃ in solution was reversible and exchange rapidly between bound and free substrate. Moreover, the equilibria favored to the adduct of carbonyl compounds and B(C₆F₅)₃ (Fig. 2B). The specific mechanism of B(C₆F₅)₃-catalyzed Mukaiyama-aldol reaction in water involved in the activation model of carbonyl group were evaluated by a series of experiments and analyses. The control experiments disclosed that the desired product was not detected in the absence of borane. Moreover, when toluene was treated as the solvent, the Mukaiyama-aldol reaction occurred in lower efficiency compared with that in water (Fig. 2C). These primary results led further investigations on the catalytic borane species in water, which was effective activating the carbonyl group. When B(C₆F₅)₃ was recrystallized in toluene, the water was added subsequently in the solution. At 4 ℃, the crystalline of B(C₆F₅)₃ with H₂O was obtained, X-Ray analysis confirmed that B(C₆F₅)₃ bound with one water molecule and polarized it to bind with other two water molecules via hydrogen bonding, even more external water molecules overcoming the water-toluene repulsion (Fig. 2D). NMR studies were conducted using ¹¹BNMR, ¹⁹FNMR, and ¹H NMR in deuterated benzene (C₆D₆) (Fig. 2E). The results indicated that, compared to the spectra of B(C₆F₅)₃ in C₆D₆, the addition of 10 equiv. of D₂O effectively prevented B(C₆F₅)₃ from binding with benzaldehyde. Instead, B(C₆F₅)₃ primarily bound with D₂O, as demonstrated by the changes in peak shape and chemical shift in the ¹H NMR. Furthermore, we carried out the Mukaiyama-aldol reaction in D₂O, then extracted the crude sample with C₆D₆. The ¹¹B NMR spectra in C₆D₆ of the crude sample and the mixture of B(C₆F₅)₃, 1 equiv. of benzaldehyde, and 10 equiv. of D₂O were consistent, indicating that the substrate or product was not directly bound to the center of the boron catalyst (see Supporting information for details). Based on these findings, a new model for activating the carbonyl group was proposed. In water, B(C₆F₅)₃ favored an outer-sphere activation model through binding with H₂O, which exhibited Brönsted acidity and delivered net hydrogen bonding to efficiently catalyze the desired reactions.

  Figure 2

  

  Figure 2.  (A) Danopoulos et al.’s equilibria in the B(C₆F₅)_3—H₂O System. (B) Piers et al.’s first B(C₆F₅)₃-catalyzed hydrosilylation of carbonyl compounds. (C) Control experiments. (D) Our crystalline of B(C₆F₅)₃ with H₂O. (E) NMR studies.

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  Based on the result of mechanistic studies, the novel reaction mechanism was proposed, as shown in Fig. 3. Firstly, the boric catalyst B(C₆F₅)₃ exerts the polarization to activate water molecules. The water surface presents hydrogen-bonding donors and acceptors that could dramatically activate carbonyl substrates, which could form complex Ⅰ. Subsequently, nucleophilic silyl enol ethers attack to activated carbon of carbonyl to generate complex Ⅱ. Then, the departure of the TMS group releases the boron catalyst B(C₆F₅)₃·nH₂O along with the forming of the product, thus completing one catalytic cycle.

  Figure 3

  

  Figure 3.  Proposed mechanism.

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  In summary, we have demonstrated the efficiency and practicality of the "water" accelerated B(C₆F₅)₃-catalyzed Mukaiyama-aldol reaction for the synthesis of β–hydroxy carbonyl compounds. This method features several advantages, including: (1) Low catalytic loading, as low as 0.5 mol%; (2) An environmentally friendly, metal-free system; (3) The ability to perform reactions in water; (4) Compatibility with a wide range of carbonyl compounds and silyl enol ethers/ketone silyl acetals; (5) The use of a new catalytic model. This new carbonyl activation approach has the potential to change the way we approach organic transformations.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Zhenguo Zhang: Methodology. Lanyang Li: Methodology. Xinlong Zong: Methodology. Yongheng Lv: Investigation. Shuanglei Liu: Investigation. Liang Ji: Investigation. Xuefei Zhao: Investigation. Zhenhua Jia: Supervision, Project administration, Conceptualization. Teck-Peng Loh: Supervision.

  Acknowledgments

  We thank the financial support from the Start-up Grant of Nanjing Tech University (Nos. 38274017103, 38037037). T.-P. L thank the financial support from Distinguished University Professor grant (Nanyang Technological University) and the Agency for Science, Technology and Research (A*STAR) under its MTC Individual Research Grants (No. M21K2c0114) and RIE2025 MTC Programmatic Fund (No. M22K9b0049).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110504.

  
  
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• 

  Figure 1  (A) First Mukaiyama-aldol reaction developed by Mukaiyama and Narasaka. (B) Previous evidences of the inner-sphere activation mode by direct coordination. (C) Recent advance in "water" accelerated photochemical reactions. (D) This work: "Water" accelerated B(C₆F₅)₃ catalyzed Mukaiyama-aldol reaction via outer-sphere activation.

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  Scheme 1  Scope of carbonyl substrates. Unless other noted, reactions were performed using 0.2 mmol aldehydes, 0.24 mmol 2a and 0.4 mL deionized water in indicated time. Yields are for isolated target products after purification. ^a Gram-scale synthesis. ^b 1.5 equiv. of 2a was added. ^c The yield of 1,4-addition by-product 42a.

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  Scheme 2  Unless other noted, reactions were performed using 0.2 mmol indicated carbonyl substrates, 0.24 mmol silyl enol ethers and 0.4 mL deionized water in indicated time. Yields are for isolated target products after purification. ^a 10 mol% B(C₆F₅)₃, 3.0 equiv. 2a and 0.2 mL MeOH were added. ^b 5 mol% B(C₆F₅)₃ and 1.5 equiv. 2a were used. ^c 5 mol% B(C₆F₅)₃ was added. ^d Using 0.1 mL MeOH as co-solvent.

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  Figure 2  (A) Danopoulos et al.’s equilibria in the B(C₆F₅)_3—H₂O System. (B) Piers et al.’s first B(C₆F₅)₃-catalyzed hydrosilylation of carbonyl compounds. (C) Control experiments. (D) Our crystalline of B(C₆F₅)₃ with H₂O. (E) NMR studies.

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  Figure 3  Proposed mechanism.

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  Table 1.  Optimization of reaction conditions.^a

  Entry	B(C6F5)3 (mol%)	2a (equiv.)	T (h)	Yield (%)
  1	5	1.2	12	74
  2	3	1.2	12	80
  3	1	1.2	12	84
  4	0.5	1.2	12	28
  5	0.5	1.2	24	52
  6	0.5	1.5	12	85
  7	0.3	1.5	24	50
  8	1	1.2	12	95b
  9	1	1.2	8	95b (85c)
  a Reactions were performed at 0.2 mmol scale in 1.0 mL deionized H2O. Yield is based on 1a and was determined by 1H NMR analysis by using CH3NO2 as an internal standard. b 0.4 mL H2O was used. c Isolated yield.

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