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Article

A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones

by
Shi-Wei Yu
1,2,
Zhong-Hao Li
1,
Miao-Xin Li
1,
Yu Zeng
1,
Wan-Xin Ye
1,
Jia-Yu Xie
1 and
Zhao-Yang Wang
1,*
1
School of Chemistry, South China Normal University, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, GDMPA Key Laboratory for Process Control and Quality Evaluation of Chiral Pharmaceuticals, Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education, Guangzhou 510006, China
2
Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, 483 Wushan Road, Guangzhou 510642, China
*
Author to whom correspondence should be addressed.
Catalysts 2024, 14(11), 811; https://doi.org/10.3390/catal14110811
Submission received: 19 October 2024 / Revised: 7 November 2024 / Accepted: 10 November 2024 / Published: 11 November 2024
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
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Versions Notes

Abstract

:
An efficient and operationally simple method for the synthesis of α-acyloxy ketones through the readily available 2-methylimidazole-promoted reaction of α-hydroxy ketones and anhydrides is developed. In the reaction, the anhydrides act as both a substrate and a solvent. The new method features good substrate tolerance, mild reaction conditions, readily accessible starting materials, and excellent yields, providing facile and green access to the targets. Importantly, the reaction also avoids the use of reagents with pungent odors, such as pyridine, in traditional esterification, which may promote the development of organocatalysis using nitrogen-containing heterocyclic compounds as catalysts.

1. Introduction

As a kind of significant structural motif simultaneously possessing both the ketone and O-acyl groups adjacent to each other, α-acyloxy ketone compounds are extensively present in a large number of natural products and biological molecules [1,2]. α-acyloxy ketone is also the core unit of some drug molecules (Figure 1), such as Taxol cortisone acetate [3,4], and these molecules containing the moiety of α-acyloxy ketone usually show good anti-cancer, anti-inflammatory, and antibacterial activities [5,6,7].
Moreover, due to the existence of multiple functionalization sites, the α-acyloxy ketone compounds can serve as versatile intermediates via various transformations, such as cyclization, deoxygenation of ester group, Favorskii rearrangement, etc. [8,9,10]. Therefore, the efficient synthesis of α-acyloxy ketones has always been one of the research focuses of scientific researchers [11,12].
As reported before, oxidative coupling reactions between ketones and metal acetates, e.g., Mn(OAc)3, Pb(OAc)4, are the main approach to access α-acyloxy ketones [13,14]. However, these methods suffer from certain disadvantages, such as excessive by-products, poor selectivity, and the use of toxic metal oxidants (Scheme 1a).
With the development of green synthetic chemistry, the exploration of efficient synthesis methods of α-acyloxy ketones that meet the requirements of green chemistry and sustainable chemistry has attracted much attention [15,16,17]. For example, researchers began to use low-toxic, cheap, and easily available iodine reagents [18,19,20,21] (Scheme 1b), and green and efficient photocatalysis methods were developed to synthesize α-acyloxy ketones [22,23] (Scheme 1c).
Although various new methods are constantly being reported, it is still necessary to explore a green synthesis method for α-acyloxy ketones from economical and readily available raw materials through simple operation with excellent yield.
At the same time, many benzoin-type compounds, namely α-hydroxy ketones, are common intermediates in organic synthesis and medicinal chemistry [24,25]. Thus, based on our continuous interest in green chemistry [26,27], especially green synthetic chemistry [28,29,30], herein, we hope to disclose a facile and efficient method for the synthesis of α-acyloxy ketones.
The reaction uses α-hydroxy ketones and anhydrides as raw materials and the cheap and readily available 2-methylimidazole as a basic catalyst (Scheme 1d). Among the reaction systems, the anhydrides can also be used as a solvent. This new approach does not involve any metal catalyst and does not require any oxidant or reductant. It is easy to operate and has excellent yield. Importantly, the reaction also avoids the use of reagents with pungent odors, such as pyridine, as a catalyst in traditional anhydride-based esterification reactions, which is conducive to promoting the development of organocatalysis.

2. Results

2.1. Optimization of Reaction Conditions

As an important heterocyclic compound, 2-methylimidazole is stable, cheap, and easy to obtain and can be used as a synthon in various synthesis reactions [31,32]. Moreover, it can also be used as a catalyst or additive to effectively promote the reaction [33,34]. Thus, using the reaction of 2-hydroxy-2-phenylacetophenone (1a) and acetic anhydride (2a) as a model under the promotion of 2-methylimidazole, we systematically explored various factors, such as the type and amount of base, reaction time and reaction temperature to optimize the best conditions. The results are shown in Table 1.
First, we examined the amount of base 2-methylimidazole (Entries 1–6). The results show that 2.0 equiv. of 2-methylimidazole can give the best yield (90%, Entry 4). However, further increasing the amount of 2-methylimidazole, does not further increase the yield (Entries 5–6).
Second, we investigated the reaction time (Entries 7–9). It can be found that increasing the reaction time does not increase the yield. However, decreasing the reaction time from 12 h to 10 h is beneficial for improving the yield (Entry 7 vs. Entry 4). It is a pity that, when the reaction time is further reduced to 8 h, the yield is decreased slightly.
In addition, suitably lowering the reaction temperature is beneficial for increasing the yield of 3a (Entry 10 vs. Entry 7, Entry 13 vs. Entry 2). Obviously, too low temperatures are not beneficial for the reaction, e.g., Entry 12. Thus, the suitable temperature should be 120 °C (Entry 10). It is worth noting that acetic anhydride 2a acts as both a substrate and a solvent herein, and its boiling point is 140 °C, so the effect of increasing temperature on the yield is not explored.
Furthermore, we also examined the amount of acetic anhydride 2a (in a sense, it is the ratio of the dosage between reactants). As shown in Entries 14–16, it can be found that neither increasing nor decreasing the amount of 2a may increase the yield (Entries 14–16 vs. Entry 10).
Therefore, the optimal conditions we obtained are as follows: 1a (0.3 mmol), 2a (3 mL), and 2-methylimidazole (0.6 mmol) as the catalyst at 120 °C for 10 h. At this time, the yield is the highest and up to 94% (Entry 10).

2.2. Scope of Substrates

Under the optimized conditions, we systematically investigated the substrate tolerance using different α-hydroxy ketones 1 and anhydrides 2. The results are presented in Table 2.
First, we examined the influence of different α-hydroxy ketones 1 on the reaction yield. Pleasingly, many α-hydroxy ketones 1 can be successfully employed with excellent yields (3a–3o).In particular, as shown in Table 2, when the two side groups of α-hydroxy ketones are both aryls, the yield is usually more than 90% (3a–3d, 91–97%).
When the two side groups of hydroxyketone substrates 1 are different, the yield of the corresponding product is slightly decreased (3e–3o, 62–87%). Interestingly, among them, the α-hydroxy ketone 1, which contains an electron-donating group, exhibits a higher yield than the one with an electron-withdrawing group, such as 3f (85%) vs. 3h (76%), 3j (80%) vs. 3l (70%). Perhaps the remote electron-donating groups in the substrates 1 are beneficial for enhancing the attacking activity of hydroxyl groups in this esterification reaction. It is worth noting that heteroaryl substituted α-hydroxy ketones 1 can also give the corresponding products in good yields, such as 3m (82%).
On the other hand, the influence of different anhydrides 2 on the reaction yield was also explored (Table 2). As anticipated, different substrates 2 can also react in this process to produce corresponding products in good yields (3p–3t, 73–88%). Among them, with the growth of the anhydride carbon chain, the yield will gradually decrease, such as 3a (94%) vs. 3p (88%) vs. 3s (73%).
Similarly, due to the steric effect, when using anhydride containing a large steric hindrance group as substrate 2, the yield will also decrease, such as 3p (88%) vs. 3q (84%) vs. 3r (81%).
It is worth noting that, even if an alkaline catalyst 2-methylimidazole is used in the reaction, the halo-substituted anhydride substrates 2 can also yield the corresponding products in good yields, such as 3t (81%).

2.3. Structural Characterization Analysis

The results demonstrate that the NMR spectral data for the 20 compounds are consistent with the simulated values. For example, the 1H NMR spectra of these compounds exhibit a peak with the integration as one unit near 5.90 ppm, corresponding to the methyne hydrogen in the product. Similarly, in the 13C NMR spectra, there is a peak near 71.0 ppm, which corresponds to the carbon in this methyne.
In addition, product 3, containing fluorine atoms, will lead to the splitting of the peaks of some carbon atoms in the 13C NMR spectra. Taking 3g as an example, the peaks of six carbon atoms are found to be split, and the splitting rule is in line with the reported [35,36], J1 ≈ 255.0 Hz > J2 ≈ 22.5 Hz > J3 ≈ 10.0 Hz > J4 ≈ 3.0 Hz, and the corresponding chemical shift of the fluorine atoms can be found in 19F NMR spectra as anticipated.
On the other hand, the molecular weights of the newly synthesized compound in products 3 in this experiment were obtained by high-resolution mass spectrometry (HR-MS). For example, the theoretical calculated value of [M − H]− for 3b is 309.1496, while the actual test value is 309.1492 (Figure S1), which is within the allowable range of error.
In addition, we conducted X-ray single-crystal diffraction experiments on compound 3q. The crystallographic data are provided in Table S1 [37], with no A-type or B-type errors, confirming that 3q has the expected structure.
Obviously, the X-ray single-crystal diffraction results of compound 3q in Figure 2 disclose that the molecule contains two benzene rings. Moreover, the ketone and O-acyl groups are adjacent to each other in this molecule, which is fully consistent with the structure of 3q.

2.4. Mechanism Investigation

Due to the special heteroaromatic structure simultaneously containing two nitrogen atoms in the imidazole ring, imidazole compounds can act as nucleophiles and as an acid/base catalyst. Therefore, the organic catalytic applications of imidazole compounds have attracted widespread attention [38,39]. Based on the results of the control experiments and the reported literature [39,40,41], a possible mechanism is proposed as Scheme 2.
In this reaction, anhydride 2 first reacts with the catalyst 2-methylimidazole (which is labeled as A in Scheme 2) to form acyl imidazole carboxylate B in situ [40]. Subsequently, the intermediate B reacts with α-hydroxy ketone 1 to generate the target product 3 and imidazole carboxylate C after proton transfer [39]. In the end, the intermediate C reacts with the remaining anhydride 2 in the system to obtain the corresponding carboxylic acid D and regenerate intermediate B, which will continue to participate in the reaction and complete the catalytic cycle [41,42].
It is worth noting that we have also tried other common nitrogen-containing heterocyclic compounds as the catalyst for this reaction, and the results of the control experiments shown in Scheme 3 can also provide good evidence for the above mechanism.
For example, some traditional basic catalysts with the structure of nitrogen-containing heterocycles, e.g., pyridine (which only contains a nitrogen atom in its structure, Scheme 3a, though it is more effective than other catalyst systems for the same reaction reactants [43,44]), 4-dimethylaminopyridine (DMAP, which contains two nitrogen atoms but only a nitrogen atom in its ring structure, Scheme 3b), are not as effective as 2-methylimidazole because they lack the efficient recycling process of imidazole carboxylates shown in Scheme 2.
For other imidazole-type basic catalysts with the structure of nitrogen-containing heterocycles, e.g., imidazole (Scheme 3c) and 2-ethyl imidazole (Scheme 3d), it also can be found that the yield of 3a is significantly reduced. This may be caused by the electron-donating effect of the methyl on 2-methylimidazole. Compared with simple imidazole, the presence of methyl can stabilize the positive charge on the nitrogen atom and is more conducive to the formation of intermediates B and C in Scheme 2.
However, for 2-ethylimidazole, when compared with 2-methylimidazole, although the ethyl group also has an electron-donating effect, its large steric hindrance makes it slightly difficult to form intermediate B in Scheme 2, so the effect of 2-ethylimidazole as a catalyst is not as good as 2-methylimidazole.
It should be noted that 2-methylimidazole plays two roles in the reaction. It can not only react with the anhydride to generate intermediate B to promote the reaction (Scheme 2) but also act as a base to continuously neutralize the carboxylic acid generated during the reaction. Therefore, the amount of 2-methylimidazole has a significant effect on the yield of the reaction, which is consistent with the results of condition optimization.
In short, compared with other traditional nitrogen-containing heterocyclic organic catalysts (typically, e.g., pyridine and DMAP), 2-methylimidazole has a better catalytic effect on this esterification reaction due to its interesting reaction mechanism shown in Scheme 2.

2.5. Practicability of Gram-Scale Reaction

Since α-acyloxy ketones are common synthetic intermediates widely used in the fields of organic synthesis and biomedicine [45,46,47], to explore the potential for industrial application, a gram-scale reaction of 2-hydroxy-2-phenylacetophenone (1a) and acetic anhydride (2a) was investigated (Scheme 4).
As shown in Scheme 4, when the reaction scale is increased to ten times, the yield of 3a is decreased by only 2% (92% vs. 94%). Therefore, the method has good practicability and is beneficial to avoid using traditional odorous pyridine as a catalyst for the esterification of anhydrides and alcohols in gram-scale synthesis.
Organocatalysis is an important part of organic synthetic chemistry [48,49]. Organic catalysts are widely used in synthetic reactions due to their good tolerance and excellent catalytic performance [50,51,52], especially some phosphorus [53], sulfur [54], and nitrogen [55] containing organic catalysts have developed recently. Among them, nitrogen-containing organic catalysts are relatively easy to obtain and have been given more attention in different applications, such as [3 + 2] cycloaddition [56], esterification reaction [57], oxidation of aldehydes [58], etc.
Although the development of nitrogen-containing organic catalysts has made great progress, there are still some disadvantages of nitrogen-containing organic catalysts, such as the limited types and relatively complex structures. Therefore, the development of nitrogen-containing organic catalysts with a simple structure and excellent catalytic ability, such as the synthetic reaction using the odorless, cheap, and easy-to-post-process 2-methylimidazole as a catalyst proposed in this paper, is of great significance.

3. Materials and Methods

3.1. General Information

1H, 13C, 19F NMR spectra were collected on a Bruker AVANCE NEO-600 MHz, 150 MHz and 564 MHz in Guangzhou, China in CDCl3 using tetramethylsilane (TMS) as an internal standard 19F NMR testing were recorded without proton decoupling.
Mass spectra were recorded on a Thermo Scientific ISQ gas chromatograph-mass spectrometer in Guangzhou, China. High-resolution mass spectra (HR-MS) were obtained with a Thermo Finnigan MAT 95XP mass spectrometer in Wuhan, China. Melting point (m.p.) was measured with a INESA Physico-Optical Instrument Co., Ltd. WRS-1B melting point instrument in Guangzhou, China. Single-crystal X-ray analysis was obtained using Agilent Gemini E in Xiamen, China. Reactions were monitored using thin-layer chromatography (TLC) and visualized with UV light at 254 nm.
All reagents and solvents were purchased from commercial sources and used without further purification. Different α-hydroxy ketones 1 were synthesized according to the literature procedure [59,60], except for 2-hydroxy-2-phenylacetophenone (1a) and 2-hydroxy-1,2-bis(4-methoxyphenyl)ethan-1-one (1d).

3.2. Experimental Procedure for α-Hydroxy Ketones 1

For symmetrical substrates 1 (e.g., 1b–1c), as shown inScheme 5, according to the literature [59], the mixture of aldehyde (1.0 mmol), triethylamine (0.3 mmol), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.05 mmol) and ethanol (10 mL) was stirred at 80 °C for 16 h.
After completion, the solvent was removed under reduced pressure. Subsequently, EtOAc (15 mL) was added to the reaction mixture. The organic layers were extracted with the saturated sodium chloride solution (3 × 15 mL). Then, the organic layer was dried over anhydrous Na2SO4.
Finally, the solvent was removed by reduced pressure. The crude products were purified by column chromatography on silica gel to afford the desired products 1b–1c.
For unsymmetrical substrates 1 (e.g., 1e–1o), as shown inScheme 6, according to the literature [60], the mixture of propiophenone compounds (1.0 mmol), I2 (40 mol%), and DMSO (2 mL) was stirred at 60 °C for 24 h.
After cooling down to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with 0.1 mol/L Na2S2O3 (5 mL) aqueous solution, extracted with ethyl acetate (3 × 5 mL). Then, the organic layers were dried over anhydrous Na2SO4.
Finally, the solvent was removed by reduced pressure. The crude products were purified by column chromatography on silica gel to afford the desired products 1e–1o.

3.3. Experimental Procedure for Compounds 3a–3t

As shown in Scheme 7, α-acyloxy ketones 3a–3t were successfully synthesized. The mixture of α-hydroxy ketones 1a–1o (0.30 mmol, 1.0 equiv.), 2-methylimidazole (0.60 mmol, 2.0 equiv.) and anhydrides 2a–2f (3 mL) under air atmosphere was stirred at 100 °C for 10 h.
After the completion of the reaction, the solvent was removed under reduced pressure. Subsequently, the water (15 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). The combined organic layers were extracted with the saturated sodium chloride solution (25 mL). Then, the organic layer was dried over anhydrous Na2SO4.
Finally, the solvent was removed by reduced pressure. The crude products were purified by column chromatography on silica gel to afford the desired products 3a–3t.

3.4. Characterization Data for All Products 3a–3t

We characterized the synthesized compounds 3a–3t by NMR, melting point, etc., and the results are listed in the following.
(1) 2-Oxo-1,2-diphenylethyl acetate (3a), white solid; m.p.: 71–73 °C (71.6 mg, 94%) (90% [45]); 1H NMR (600 MHz, CDCl3), δ, ppm: 2.19 (s, 3H, CH3), 6.87 (s, 1H, CH), 7.33–7.39 (m, 5H, ArH), 7.46 (d, J = 7.8 Hz, 2H, ArH), 7.49 (t, J = 7.2 Hz, 1H, ArH), 7.93 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 20.9, 77.8, 128.7, 128.8, 128.9, 129.2, 129.4, 133.7, 170.5, 193.8.
(2) 2-Oxo-1,2-di-p-tolylethyl acetate (3b), colorless oil (77.0 mg, 91%) (88% [45]); 1H NMR (600 MHz, CDCl3), δ, ppm: 2.20 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.35 (s, 3H, CH3), 6.83 (s, 1H, CH), 7.17 (d, J = 7.8 Hz, 2H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 7.35 (d, J = 7.8 Hz, 2H, ArH), 7.84 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 21.0, 21.3, 21.8, 77.6, 128.8, 129.0, 129.4, 129.9, 131.0, 132.2, 139.4, 144.5, 170.6, 193.4.
(3) 1,2-Bis(4-ethylphenyl)-2-oxoethyl acetate (3c), colorless oil (85.6 mg, 92%); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.20 (t, J = 7.8 Hz, 3H, CH3), 1.21 (t, J = 7.2 Hz, 3H, CH3), 2.20 (s, 3H, CH3), 2.62 (q, J = 7.8 Hz, 2H, CH3), 2.66 (q, J = 7.2 Hz, 2H, CH3), 6.84 (s, 1H, CH), 7.20 (d, J = 7.8 Hz, 2H, ArH), 7.22 (d, J = 8.4 Hz, 2H, ArH), 7.39 (d, J = 7.8 Hz, 2H, ArH), 7.88 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 15.1, 15.4, 21.0, 28.7, 29.1, 77.6, 128.3, 128.8, 128.9, 129.2, 131.2, 132.4, 145.7, 150.6, 170.6, 193.4; ESI-HRMS, m/z: Calcd for C20H21O3 [M − H]−: 309.1496, Found: 309.1492.
(4) 1,2-Bis(4-methoxyphenyl)-2-oxoethyl acetate (3d), colorless oil (91.2 mg, 82%) (66% [61]); 1H NMR (600 MHz, CDCl3), δ, ppm: 2.18 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.80 (s, 1H, CH), 6.83 (d, J = 9.0 Hz, 2H, ArH), 6.88 (d, J = 9.0 Hz, 2H, ArH), 7.38 (d, J = 9.0 Hz, 2H, ArH), 7.92 (d, J = 9.0 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 21.0, 55.4, 55.5, 77.1, 113.9, 114.6, 126.2, 127.6, 130.3, 131.2, 160.4, 163.8, 170.7, 192.2.
(5) 1-Oxo-1-(p-tolyl)propan-2-yl acetate (3e), colorless oil (51.3 mg, 83%) (83% [61]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.50 (d, J = 7.2 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 2.39 (s, 3H, CH3), 5.94 (q, J = 7.2 Hz, 1H, CH), 7.25 (d, J = 7.8 Hz, 2H, ArH), 7.83 (d, J = 7.8 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.3, 20.8, 21.8, 71.4, 128.6, 129.5, 131.9, 144.6, 170.4, 196.4.
(6) 1-(4-Methoxyphenyl)-1-oxopropan-2-yl acetate (3f), colorless oil (56.6 mg, 85%) (73% [61]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.52 (d, J = 7.2 Hz, 3H, CH3), 2.14 (s, 3H, CH3), 3.86 (s, 3H, CH3), 5.94 (q, J = 7.2 Hz, 1H, CH), 6.95 (d, J = 9.0 Hz, 2H, ArH), 7.93 (d, J = 9.0 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.4, 20.8, 55.5, 71.2, 114.0, 127.2, 130.8, 163.9, 170.4, 195.3.
(7) 1-(4-Fluorophenyl)-1-oxopropan-2-yl acetate (3g), colorless oil (46.0 mg, 73%) (80% [62]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.52 (d, J = 7.2 Hz, 3H, CH3), 2.14 (s, 3H, CH3), 5.91 (q, J = 7.2 Hz, 1H, CH), 7.14–7.16 (m, 2H, ArH), 7.96–7.99 (m, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.2, 20.9, 71.2, 116.1 (d, J = 21.0 Hz), 130.9 (d, J = 3.0 Hz), 131.3 (d, J = 9.0 Hz), 166.1 (d, J = 255.0 Hz), 170.5, 195.5; 19F NMR (564 MHz, CDCl3), δ, ppm: −104.0.
(8) 1-(4-Chlorophenyl)-1-oxopropan-2-yl acetate (3h), colorless oil (51.5 mg, 76%) (90% [61]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.51 (d, J = 6.6 Hz, 3H, CH3), 2.13 (s, 3H, CH3), 5.88 (q, J = 7.2 Hz, 1H, CH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 7.87 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.1, 20.8, 71.4, 129.3, 130.0, 132.8, 140.2, 170.5, 195.9.
(9) 1-(4-Bromophenyl)-1-oxopropan-2-yl acetate (3i), colorless oil (59.9 mg, 74%) (68% [63]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.50 (d, J = 6.6 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 5.87 (q, J = 7.2 Hz, 1H, CH), 7.61 (d, J = 8.4 Hz, 2H, ArH), 7.89 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.1, 20.8, 71.4, 128.9, 130.0, 132.2, 133.2, 170.5, 196.1.
(10) 1-(3-Methoxyphenyl)-1-oxopropan-2-yl acetate (3j), colorless oil (53.3 mg, 80%); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.51 (d, J = 6.6 Hz, 3H, CH3), 2.13 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 5.92 (q, J = 7.2 Hz, 1H, CH), 7.11–7.13 (m, 1H, ArH), 7.35–7.39 (m, 1H, ArH), 7.45 (s, 1H, ArH), 7.50 (d, J = 7.8 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.3, 20.8, 55.6, 71.6, 112.9, 120.2, 121.0, 129.9, 135.8, 160.0, 170.5, 196.8; ; ESI-HRMS, m/z: Calcd for C12H15O4 [M + H]+: 223.0965, Found: 223.0963.
(11) 1-(3-Fluorophenyl)-1-oxopropan-2-yl acetate (3k), colorless oil (39.1 mg, 62%) (97% [64]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.52 (d, J = 7.2 Hz, 3H, CH3), 2.13 (s, 3H, CH3), 5.87 (q, J = 7.2 Hz, 1H, CH), 7.27–7.30 (m, 1H, ArH), 7.44–7.47 (m, 1H, ArH), 7.61–7.63 (m, 1H, ArH), 7.71 (d, J = 7.8 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.1, 20.8, 71.6, 115.4 (d, J = 22.5 Hz), 120.8 (d, J = 21.0 Hz), 124.2 (d, J = 3.0 Hz), 130.6 (d, J = 7.5 Hz), 136.5 (d, J = 6.0 Hz), 163.0 (d, J = 247.5 Hz), 170.5, 195.9; 19F NMR (564 MHz, CDCl3), δ, ppm: −111.3.
(12) 1-(3-Chlorophenyl)-1-oxopropan-2-yl acetate (3l), colorless oil (47.5 mg, 70%) (75% [65]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.51 (d, J = 6.6 Hz, 3H, CH3), 2.13 (s, 3H, CH3), 5.86 (q, J = 7.2 Hz, 1H, CH), 7.40–7.43 (m, 1H, ArH), 7.55 (d, J = 7.8 Hz, 1H, ArH), 7.79 (d, J = 7.8 Hz, 1H, ArH), 7.90 (s, 1H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.1, 20.8, 71.5, 126.7, 128.6, 130.2, 133.6, 135.3, 136.1, 170.5, 195.9.
(13) 1-Oxo-1-(thiophen-2-yl)propan-2-yl acetate (3m), colorless oil (48.7 mg, 82%) (92% [64]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.56 (d, J = 7.2 Hz, 3H, CH3), 2.14 (s, 3H, CH3), 5.73 (q, J = 7.2 Hz, 1H, CH), 7.14–7.16 (m, 1H, ArH), 7.69 (d, J = 4.8 Hz, 1H, ArH), 7.80 (d, J = 4.8 Hz, 1H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 17.8, 20.9, 72.4, 128.4, 132.8, 134.6, 140.6, 170.4, 189.9.
(14) 1-Oxo-1-phenylbutan-2-yl acetate (3n), colorless oil (53.8 mg, 87%) (91% [62]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.01 (t, J = 7.8 Hz, 3H, CH3), 1.81–1.97 (m, 2H, CH2), 2.15 (s, 3H, CH3), 5.80–5.82 (m, 1H, CH), 7.45–7.48 (m, 2H, ArH), 7.57 (t, J = 7.2 Hz, 1H, ArH), 7.93 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 10.0, 20.8, 24.9, 76.5, 128.5, 128.9, 133.6, 135.0, 170.8, 196.7.
(15) 1-Oxo-1-phenylbutan-2-yl acetate (3o), colorless oil (46.9 mg, 71%) (77% [62]); 1H NMR (600 MHz, CDCl3), δ, ppm: 0.93 (t, J = 7.8 Hz, 3H, CH3), 1.45–1.50 (m, 2H, CH2), 1.79–1.83 (m, 2H, CH2), 2.13 (s, 3H, CH3), 5.85–5.87 (m, 1H, CH), 7.44–7.47 (m, 2H, ArH), 7.56 (t, J = 7.2 Hz, 1H, ArH), 7.92 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 13.8, 18.9, 20.7, 33.5, 75.2, 128.4, 128.8, 133.6, 134.8, 170.7, 196.8.
(16) 2-Oxo-1,2-diphenylethyl propionate (3p), colorless oil (70.8 mg, 88%) (99%, [66]); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.19 (t, J = 7.8 Hz, 3H, CH3), 2.44–2.58 (m, 2H, CH2), 6.87 (s, 1H, CH), 7.32–7.41 (m, 5H, ArH), 7.47 (d, J = 7.8 Hz, 2H, ArH), 7.51 (t, J = 7.2 Hz, 1H, ArH), 7.94 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 9.1, 27.5, 77.6, 128.7, 128.8, 128.9, 129.2, 129.4, 133.6, 133.8, 134.8, 174.1, 194.1.
(17) 2-Oxo-1,2-diphenylethyl isobutyrate (3q), white solid; m.p.: 75–77 °C (white solid; m.p.: 80–81 °C [66]) (71.0 mg, 84%); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.22 (d, J = 7.2 Hz, 3H, CH3), 1.38 (d, J = 7.2 Hz, 3H, CH3), 2.70–2.77 (m, 1H, CH), 6.86 (s, 1H, CH), 7.33–7.41 (m, 5H, ArH), 7.48–7.51 (m, 3H, ArH), 7.95 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 18.8, 19.1, 33.9, 77.4, 128.6, 128.7, 128.9, 129.1, 129.3, 133.5, 133.8, 134.8, 176.7, 194.1.
(18) 2-Oxo-1,2-diphenylethyl pivalate (3r), white solid; m.p.: 107–109 °C (m.p.: 110–111 °C [47]) (71.9 mg, 81%); 1H NMR (600 MHz, CDCl3), δ, ppm: 1.29 (s, 9H, 3CH3), 6.80 (s, 1H, CH), 7.33–7.42 (m, 5H, ArH), 7.47 (d, J = 7.8 Hz, 2H, ArH), 7.51 (t, J = 7.2 Hz, 1H, ArH), 7.94 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 27.2, 38.9, 77.4, 128.4, 128.7, 128.9, 129.1, 129.2, 133.5, 134.0, 135.0, 178.2, 194.4.
(19) 2-Oxo-1,2-diphenylethyl butyrate (3s), colorless oil (61.8 mg, 73%) (91% [67]); 1H NMR (600 MHz, CDCl3), δ, ppm: 0.98 (t, J = 7.2 Hz, 3H, CH3), 1.69–1.75 (m, 2H, CH2), 2.40–2.51 (m, 2H, CH2), 6.86 (s, 1H, CH), 7.34–7.41 (m, 5H, ArH), 7.46 (d, J = 7.2 Hz, 2H, ArH), 7.51 (t, J = 7.8 Hz, 1H, ArH), 7.94 (d, J = 7.8 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 13.8, 18.5, 36.0, 77.5, 128.7, 128.9, 129.2, 129.4, 133.6, 133.8, 134.9, 173.3, 194.1.
(20) 2-Oxo-1,2-diphenylethyl 2-chloroacetate (3t), colorless oil (70.0 mg, 81%) (95% [68]); 1H NMR (600 MHz, CDCl3), δ, ppm: 4.19–4.29 (dd, J1 = 42.6 Hz, J2 = 15.0 Hz, 2H, CH2), 6.94 (s, 1H, CH), 7.37–7.41 (m, 5H, ArH), 7.47 (d, J = 7.8 Hz, 2H, ArH), 7.52 (t, J = 7.2 Hz, 1H, ArH), 7.92 (d, J = 7.2 Hz, 2H, ArH); 13C NMR (150 MHz, CDCl3), δ, ppm: 40.8, 79.2, 128.8, 128.9, 129.0, 129.4, 129.8, 133.0, 133.8, 134.3, 167.0, 192.8.
The detailed 1H, 13C, and 19F NMR spectra for all compounds 3a–3t are provided in the Supplementary Materials.

4. Conclusions

In summary, we successfully developed an oxyacyloxylation of α-hydroxy ketones and anhydrides mediated by 2-methylimidazole. This reaction can efficiently give a series of α-acyloxy ketone derivatives without any metal catalyst, oxidants, or reductants. In the reaction, the anhydrides can act as both a substrate and a solvent. At the same time, this reaction also avoids the use of reagents with pungent odors, such as pyridine, in traditional esterification reactions. Thus, it meets the requirements for the development of green chemistry in many fields. More importantly, the discovery of this new research result is also conducive to promoting the development of organocatalysis using nitrogen-containing heterocyclic compounds as catalysts.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal14110811/s1, and contains the 1H, 13C, and 19F NMR spectra for all compounds 3a–3t.

Author Contributions

Conceptualization, Z.-Y.W.; methodology, S.-W.Y. and Z.-H.L.; formal analysis, S.-W.Y. and M.-X.L.; data curation, Y.Z. and W.-X.Y.; writing-original draft preparation, S.-W.Y.; writing-review and editing, S.-W.Y., J.-Y.X. and Z.-Y.W.; project administration, Z.-Y.W.; funding acquisition, Z.-Y.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Guangdong Basic and Applied Basic Research Foundation (no. 2021A1515012342).

Data Availability Statement

All data supporting the findings of this study are available within the paper and its Supplementary Materials published online.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 14 00811 g001
Figure 1. Some typical bioactive compounds (or drugs) containing the unit of α-acyloxy ketone.
Figure 1. Some typical bioactive compounds (or drugs) containing the unit of α-acyloxy ketone.
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Catalysts 14 00811 sch001
Scheme 1. Serial synthesis reactions for α-acyloxy ketone compounds.
Scheme 1. Serial synthesis reactions for α-acyloxy ketone compounds.
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Figure 2. The crystal structure of 3q (CCDC: 2376760).
Figure 2. The crystal structure of 3q (CCDC: 2376760).
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Catalysts 14 00811 sch002
Scheme 2. Proposed mechanism.
Scheme 2. Proposed mechanism.
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Catalysts 14 00811 sch003
Scheme 3. Control experiments (the amount of each catalyst used is 2.0 equiv.).
Scheme 3. Control experiments (the amount of each catalyst used is 2.0 equiv.).
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Catalysts 14 00811 sch004
Scheme 4. Gram-scale reaction of 3a.
Scheme 4. Gram-scale reaction of 3a.
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Scheme 5. Synthesis route of α-hydroxy ketones 1b–1c.
Scheme 5. Synthesis route of α-hydroxy ketones 1b–1c.
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Scheme 6. Synthesis route of α-hydroxy ketones 1e–1o.
Scheme 6. Synthesis route of α-hydroxy ketones 1e–1o.
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Scheme 7. Synthesis route for compounds 3a–3t.
Scheme 7. Synthesis route for compounds 3a–3t.
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Table 1. Optimization of reaction conditions [a].
Table 1. Optimization of reaction conditions [a].
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EntryDose of 2-Methylimidazole
(Equiv.)		Temp.
(°C)		Time
(h)		Yield
(%) [b]
10140120
21.01401278
31.31401283
42.01401290
53.01401284
64.01401280
72.01401091
82.0140889
92.01401486
102.01201094
112.01001092
122.025100
131.01001282
14 [c]2.01201084
15 [d]2.01201087
16 [e]2.01201090
[a] Reaction conditions: Usually, 1a (0.3 mmol), 2a (3 mL), 2-Methylimidazole (0.6 mmol) at 120 °C for 10 h under air atmosphere. [b] Isolated yield. [c] 2a (1 mL). [d] 2a (2 mL). [e] 2a (4 mL).
Table 2. Substrate scope of various α-hydroxy ketones 1 anhydrides 2 [a,b].
Table 2. Substrate scope of various α-hydroxy ketones 1 anhydrides 2 [a,b].
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Catalysts 14 00811 i003
[a] The reaction generally proceeds under the following conditions: α-hydroxy ketones 1 (0.30 mmol), anhydrides 2 (3 mL), and 2-methylimidazole (0.6 mmol) were reacted at 120 °C for 10 h. [b] Isolated yield.
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MDPI and ACS Style

Yu, S.-W.; Li, Z.-H.; Li, M.-X.; Zeng, Y.; Ye, W.-X.; Xie, J.-Y.; Wang, Z.-Y. A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones. Catalysts 2024, 14, 811. https://doi.org/10.3390/catal14110811

AMA Style

Yu S-W, Li Z-H, Li M-X, Zeng Y, Ye W-X, Xie J-Y, Wang Z-Y. A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones. Catalysts. 2024; 14(11):811. https://doi.org/10.3390/catal14110811

Chicago/Turabian Style

Yu, Shi-Wei, Zhong-Hao Li, Miao-Xin Li, Yu Zeng, Wan-Xin Ye, Jia-Yu Xie, and Zhao-Yang Wang. 2024. "A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones" Catalysts 14, no. 11: 811. https://doi.org/10.3390/catal14110811

APA Style

Yu, S. -W., Li, Z. -H., Li, M. -X., Zeng, Y., Ye, W. -X., Xie, J. -Y., & Wang, Z. -Y. (2024). A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones. Catalysts, 14(11), 811. https://doi.org/10.3390/catal14110811

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