Disubstituted Meldrum’s Acid: Another Scaffold with SuFEx-like Reactivity

Abstract

Sulfur Fluoride Exchange (SuFEx) chemistry represents an emerging class of click reactions that has found broad applications in drug discovery and materials science. Traditionally, SuFEx reactivity has been regarded as the exclusive privilege of sulfur and fluorine. Accordingly, the scaffolds exhibiting SuFEx-like reactivity without sulfur or fluorine have remained underdeveloped. Indeed, SuFEx reactions may represent a more generalizable mode of chemical reactivity. By enhancing the electrophilicity of the carbonyl group and increasing the steric hindrance around the carbon center, we identified disubstituted Meldrum’s acid as a novel carbon-based scaffold with SuFEx-like reactivity. Various O-, S-, and N-nucleophiles are viable exchange partners in the presence of Barton’s base or DBU. In addition to the original method, a catalytic protocol was developed and successfully applied to drug derivatization, including the gram-scale modification of acetaminophen.

1. Introduction

The concept of Sulfur Fluoride Exchange (SuFEx) [1,2,3,4,5,6], first introduced by Sharpless and coworkers, represents a unique class of nucleophilic exchange reactions in which stable sulfur(VI) fluoride compounds can be selectively activated under specific environments [7,8,9,10,11,12], in the presence of promoters [13,14], or under catalytic conditions [15,16,17,18,19,20] to form covalent linkages. This "dormant awakening reactivity" has enabled broad applications across chemical biology [21,22,23,24,25,26,27], drug discovery [28,29,30,31,32,33,34,35,36,37,38], and materials science [39,40,41,42,43,44,45,46,47,48,49,50,51,52]. Initially, SuFEx reactivity was attributed to the distinctive characteristics of the S(VI)–F bond (Scheme 1a). Following this paradigm, a variety of building blocks containing an S–F bond have been developed, greatly expanding the SuFEx toolbox [53,54,55,56,57,58,59,60,61,62,63,64,65]. However, the reliance on either sulfur or fluorine elements in SuFEx chemistry has been challenged by recent discoveries. For instance, Zuilhof and coworkers introduced the concept of sulfur-phenolate exchange (SuPhenEx) in their latest work, demonstrating that S(VI) centers can undergo efficient exchange reactions without the involvement of fluorine (Scheme 1b) [66,67,68,69]. In 2023, Moses and coworkers discovered a set of phosphorus-based exchange reactions, termed Phosphorus Fluoride Exchange (PFEx), wherein P(V) fluorides exhibit similar latent reactivity with nucleophiles (Scheme 1c) [70,71,72,73]. These findings suggest that SuFEx-like reactivity may not be limited to S- or F-based systems, but rather represent a more general reactivity mode for robust covalent bond formation. Therefore, it is highly desirable to discover new scaffolds capable of mimicking SuFEx-type reactivity. Herein, we report a carbon-based scaffold, disubstituted Meldrum’s acid, that exhibits SuFEx-like reactivity under mild conditions (Scheme 1d).

Acyl fluorides were the original candidates for this project. However, due to the relatively low steric hindrance around the acyl carbon, acyl fluorides, despite their high exchange reactivity, exhibited significantly lower hydrolytic stability compared to S(VI)–fluorides. This limitation led us to shift our focus to other carbonyl compounds with high intrinsic reactivity. Ultimately, disubstituted Meldrum’s acid was identified as a promising candidate. Although Meldrum’s acid may seem unrelated to SuFEx-like reactivity at first glance, its cyclic ester structure [74,75,76,77,78] endows it with both high electrophilicity and hydrolytic stability. This pairing of electrophilicity and stability strongly resonates with the design principles of conventional SuFEx reagents. (Figure 1). In addition, disubstituted Meldrum’s acids are highly tunable building blocks and can be readily prepared from Meldrum’s acid via alkylations, Michael additions, and reductive Knoevenagel condensations [79,80]. This ease of double substitution imparts remarkable structural diversity to disubstituted Meldrum’s acids, which in turn facilitates multidimensional connectivity via nucleophilic ring-opening reactions. Meanwhile, disubstituted Meldrum’s acids possess markedly enhanced stability relative to their less substituted counterparts. However, several challenges persist in the proposed decarboxylative nucleophilic ring-opening reaction. Notably, while the nucleophilic ring-opening of disubstituted Meldrum’s acids occurs readily [79,81,82,83,84,85,86,87,88,89], only a very limited number of them undergo decarboxylation under mild conditions [90,91,92]. In many cases, decarboxylation still requires elevated temperatures or the use of excess reagents to achieve efficient conversion [93,94,95,96,97,98,99,100,101]. These existing conditions fail to meet the standards of SuFEx chemistry. Therefore, a facile protocol compatible with more complex synthetic settings is highly desirable.

2. Results

Initially, we chose 2a as a nucleophile to investigate the nucleophilic exchange reactions of 1a. A control experiment conducted in the absence of any base showed no formation of the expected product, and 1a remained intact (

Table 1. Optimization of reaction conditions^a.

Entry	Base	Solvent	Time(h)	3ab(%)
1	none	MeCN	4	0
2	Cs2CO3	MeCN	4	2
3	K2CO3	MeCN	4	0
4	K3PO4	MeCN	4	0
5	Na2CO3	MeCN	4	0
6	DMAP	MeCN	4	0
7	TEA	MeCN	4	0
8	DIPEA	MeCN	4	2
9	DBU	MeCN	4	65
10	BTMG	MeCN	4	82
11	BTMG	MeCN	12	100
12	BTMG	Dichloromethane	12	87
13	BTMG	Toluene	12	100
14	BTMG	Tetrahydrofuran	12	100
15	BTMG	N-methyl-pyrrolidinone	12	100
16	BTMG	Dimethyl sulfoxide	12	99
17c	BTMG	Dimethyl sulfoxide	1	87
18d	BTMG	Dimethyl sulfoxide	1	80

^a Reactions were run with 1a (0.10 mmol), p-bromophenol (1.10 equiv), and base (1.10 equiv) in anhydrous acetonitrile (250.0 μL) at rt for 4 h. ^b Yields were determined by ¹H NMR with 1,3,5-trimethoxybenzene as an internal standard. ^c Reactions were run in 5% H₂O–DMSO at 60 °C for 1 h. ^d Reactions were run in 20% H₂O–DMSO at 60 °C for 1 h.

, entry 1). In addition, either inorganic bases or weaker organic bases resulted in negligible formation of 3a (Table 1, entries 2–8). Further investigation revealed that 1a was completely consumed when a strong inorganic base, such as cesium carbonate, potassium carbonate, or potassium phosphate, was used. In these cases, the nucleophilic ring-opening product, malonate half ester 3a’ was obtained instead of 3a. In the other cases using sodium carbonate, 4-dimethylaminopyridine (DMAP), triethylamine (TEA), and N,N-diisopropylethylamine (DIPEA), most of 1a remained unchanged. Gratifyingly, both nucleophilic substitution and decarboxylation proceeded smoothly at room temperature in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or Barton’s base (2-tert-Butyl-1,1,3,3-tetramethylguanidine, BTMG) (Table 1, entry 9–10). These results were somewhat unexpected, as the decarboxylation of malonate half-esters typically requires elevated temperatures. Next, we extended the reaction time from 4 h to 12 h and evaluated the compatibility of this reaction with a variety of common solvents (Table 1, entries 11–16). To our delight, nearly quantitative yields were obtained in acetonitrile, toluene, tetrahydrofuran (THF), N-methyl-pyrrolidinone (NMP), and dimethyl sulfoxide (DMSO), while a slightly lower yield (87%) was observed in dichloromethane. To evaluate the potential applicability of this transformation in biological settings, aqueous DMSO solutions were tested, and satisfactory yields were obtained (Table 1, entries 17–18). The high efficiency of this transformation across various solvents aligned well with the principles of click chemistry.

With the optimal protocol in hand, the substrate scope was acid and phenolic nucleophiles were well tolerated and α,α-disubstituted phenyl acetates were obtained in excellent isolated yields (3a–3y) (Figure 2). For the Meldrum’s acid component, we focus on evaluating the substrates with a larger alkyl group. The results indicated that a variety of benzyl-substituted substrates afforded excellent yields (3f–3j). Notably, more sterically hindered alkyl substrates (1b–1e) also provided satisfactory results. For phenolic nucleophiles, we examined the influence of functional group tolerance, electronic properties, and steric hindrance. The method demonstrated excellent tolerance toward diverse functional groups. A wide array of α,α-disubstituted phenylacetates bearing diverse functional groups such as halogens (3t, 3x, and 3y), trifluoromethyl (3l), amino (3n), alkoxy (3o and 3w), nitro (3k), ester (3p), aldehyde (3q), alkenyl (3w), and various heterocycles (3m, 3x, and 3y), were obtained in excellent yields. Although the method was generally insensitive to electronic effects, the most electron-deficient phenol, 4-nitrophenol (2k), and the most electron-rich one, 4-dimethylaminophenol (2n), required a more polar solvent, NMP, and a more concentrated condition (0.8 M) to complete the reaction at room temperature. In terms of steric effects, ortho-substituted substrates (2s, 2t, and 2u) and 1-naphthol (2r) reacted smoothly under standard conditions. The only exception was the highly sterically hindered 2,6-dimethylphenol (2v), which required heating at 60 °C to achieve full conversion.

Next, we turned our attention to the use of alcohols, thiols, and amines as nucleophilic partners. Several representative nucleophiles were selected for evaluation. Not surprisingly, no desired α,α-disubstituted acetate products were obtained when alcohols were used as nucleophiles under the standard conditions developed for phenols, even at 40 °C. However, small amounts of the desired products could be detected upon raising the reaction temperature to 60 °C in acetonitrile. Analysis of the reaction mixtures revealed that the major products under these conditions were the non-decarboxylated malonate half-esters. To improve the yield of the expected ester product, we employed NMP as the solvent to promote decarboxylation. Gratifyingly, this subtle adjustment successfully led to the formation of the desired esters (4a, 4b, 4c, and 4d) in high yields from alcohol nucleophiles (Figure 3). Indeed, primary alcohols such as (4-bromophenyl)methanol and 3-phenylpropan-1-ol, as well as secondary diphenylmethanol, reacted smoothly at 60 °C. Furthermore, cyclohexanol, due to its increased steric hindrance, required the use of a less hindered base (DBU) in place of BTMG, along with a slightly higher temperature (80 °C) to afford the product 4d. Interestingly, the reactivity of thiol and thiophenol more closely resembles that of phenols rather than alcohols. Thioesters (4e and 4f) were delivered in excellent yields at room temperature. Encouraged by these results, we further increased the reaction temperature to 100 °C for amidations and confirmed that primary amines were viable nucleophiles under elevated temperature (Figure 3). The corresponding amide products (4g, 4h, 4i, and 4j) were obtained at 100 °C in satisfactory yields. We also investigated a secondary amine (morpholine) as the nucleophile. As a result, 4k was obtained in 62% isolated yield using the conditions for primary amines. As anticipated, the sterically hindered tert-butanol and tert-butylamine did not undergo nucleophilic exchange reactions and failed to yield the desired products 4l and 4m even at 100 °C.

After evaluating the scope of nucleophilic exchange partners, we sought to improve the practicality of the current methodology in scalable synthesis. To avoid the use of stoichiometric amounts of BTMG, we aimed to develop a catalytic protocol for this transformation. Acetaminophen, a widely used over-the-counter (OTC) fever and pain reliever, was selected as the model substrate. Gratifyingly, using a catalytic amount of BTMG in NMP at 60 °C for 12 h, the desired acylated product was obtained in 96% yield on a 2.12 g scale (Scheme 2a). In addition, we are able to isolate the malonate half-ester 5 by using a modified protocol (Scheme 2b). Subsequently, the Curtius rearrangement of 5 successfully delivered the valuable α-amino acid derivatives 6 in 76% yield (Scheme 2c). Further investigation revealed that the isolation of the malonate half-ester 5 was not required. Accordingly, a one-pot synthesis of malonyl monoester amide 7 from 1a and 2 was successfully achieved (Scheme 2d).

Based on the experimental data we obtained, a plausible catalytic cycle is proposed. The reaction proceeds via decarboxylation of the malonate half-ester followed by reprotonation (Scheme 3) [102,103]. The superior results obtained with BTMG, in contrast to inorganic bases, are likely due to its excellent solubility in various organic solvents, which is particularly important for facilitating the decarboxylation. This pathway is distinct from the ketene mechanism observed under thermal conditions (>150 °C) [104,105,106,107]. To further support this mechanistic proposal, the malonate half-ester 3a’ was treated with a stoichiometric amount of BTMG at room temperature. The decarboxylation of 3a’ occurred readily, affording the product 3a (see Supplementary Materials).

3. Materials and Methods

3.1. Reagents and General Methods

All reagents were purchased from commercial sources(Energy Chemical, Shanghai, China) and used without further purification unless otherwise noted. Acetonitrile, N-methyl-pyrrolidinone and dimethyl sulfoxide used in the reactions were anhydrous solvents purchased from commercial suppliers (Energy Chemical, Shanghai, China) and used without further drying (≥99.9%, LC-MS, Energy Chemical, China). The petroleum ether (Energy Chemical, Shanghai, China) used was in a boiling range of 60–90 °C. Other solvents were purified according to standard procedures [108]. All reactions were carried out with oven-dried glassware and monitored by thin-layer chromatography (0.20 mm HP-TLC silica gel 60 GF-254 plates, Leyan, Shanghai, China). Visualization was accomplished with UV light, and/or potassium permanganate, or 2% ninhydrin in ethanol stain followed by heating. Flash column chromatography was performed on 200–300 mesh silica gel (Leyan, Shanghai, China). Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and 5-methyl Meldrum’s acid (2,2,5-trimethyl-1,3-dioxane-4,6-dione) were purchased from Bide Pharm, Shanghai, China, and used without further purification. The deuterated chloroform (CDCl₃) (Energy Chemical, Shanghai, China) used contains 0.03% (v/v) of tetramethylsilane (TMS).

¹H, ¹⁹F, and ¹³C NMR spectra were recorded on a Bruker AVANCE III 400 MHz spectrometer (Bruker, Billerica, MA, USA) at 298 K and referenced to residual protium in the NMR solvent (CDCl₃, δ 7.26, DMSO-d₆, 2.50 in ¹H NMR) and the carbon resonances of the solvent (CDCl₃, δ 77.16, DMSO-d₆, 39.52 in ¹³C NMR). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. NMR peaks are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), heptet (hept), complex (comp), and approximate (app). High-resolution mass spectra (HRMS) were recorded on a Thermo Fisher Scientific’s Q Exactive UHMR Hybrid Quadrupole-Orbitrap Mass Spectrometer LC/MS (ESI/APCI) (Thermo Fisher, Waltham, MA, USA).

TEAF = triethylammonium formate, TEA = triethylamine, DIPEA = N,N-diisopropylethylamine, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-dimethylaminopyridine, BTMG = 2-tert-butyl-1,1,3,3-tetramethylguanidine, NMI = N-methylimidazole, DPPA = diphenyl azidophosphate, HOBt = 1-hydroxybenzotriazole, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EA = ethyl acetate, DMF = N,N-dimethylformamide, DCM = dichloromethane, DCE = dichloroethane, DMSO = dimethyl sulfoxide, THF = tetrahydrofuran, NMP = N-methyl-pyrrolidinone, TLC = thin-layer chromatography, v/v = volume per volume, equiv = equivalent, w/o = without, rt = room temperature.

3.2. Synthetic Procedures

3.2.1. A General Procedure for the 5-Substituted-5-methyl-1,3-dioxane-4,6-dione

General Procedure: Substituted-Meldrum’s acids were prepared according to the literature procedure [109]. 5-methyl Meldrum’s acid (1.00 equiv) and K₂CO₃ (1.30 equiv) were dissolved in anhydrous DMF, followed by the addition of alkyl bromide (1.20 equiv). The mixture was then heated to 60 °C for 12 h. After reaction completion, the mixture was diluted with 50 mL of EA and 50 mL of water. The organic phase was separated. The aqueous phase was further extracted with 2 × 50 mL of EA. The combined organic layer was separated, washed with saturated aqueous NaHCO₃ solution and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography to afford the purified product.

3.2.2. A General Procedure for the Preparation of the Esters 3

In a 4.0-mL vial, 5,5-substituted-Meldrum’s acid 1 (0.50 mmol, 1.00 equiv), BTMG (94.2 mg, 0.55 mmol, 1.10 equiv) were dissolved in anhydrous MeCN (1.25 mL). The phenol (0.55 mmol, 1.10 equiv) was added and stirred at rt for 12 h. After the reaction was completed, the mixture was diluted with EA (20 mL), washed with 2 M aqueous HCl solution (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography.

4-Bromophenyl isobutyrate (3a): Compound 3a was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl isobutyrate (3a) as a colorless oil (111.8 mg, 92%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 7.5 Hz, 2H), 6.97 (d, J = 7.5 Hz, 2H), 2.79 (hept, J = 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 175.3, 149.9, 132.4 (2C), 123.4 (2C), 118.7, 34.2, 18.9 (2C). HRMS−ESI (m/z) for C₁₀H₁₁BrO₂ [M + Na]⁺: calcd 264.9834 (⁷⁹Br), 266.9814 (⁸¹Br), found 264.9835 (⁷⁹Br), 266.9814 (⁸¹Br).

4-Bromophenyl 2,3-dimethylbutanoate (3b): Compound 3b was prepared according to the general procedure using 1b (100.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 2,3-dimethylbutanoate (3b) as a colorless oil (115.2 mg, 85%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.5 (d, J = 8.8 Hz, 2H), 7.0 (d, J = 8.9 Hz, 2H), 2.5 (m, 1H), 2.1 (m, 1H), 1.3 (d, J = 7.1 Hz, 3H), 1.04 (d, J = 6.8 Hz, 1H), 1.00 (d, J = 6.7 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 174.5, 149.9, 132.4 (2C), 123.4 (2C), 118.7, 46.2, 31.2, 20.7, 19.2, 13.7. HRMS−ESI (m/z) for C₁₂H₁₅BrO₂ [M + Na]⁺: calcd 293.0147 (⁷⁹Br), 295.0127 (⁸¹Br), found 293.0149 (⁷⁹Br), 295.0127 (⁸¹Br).

4-Bromophenyl 2,4-dimethylpentanoate (3c): Compound 3c was prepared according to the general procedure using 1c (107.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 2,4-dimethylpentanoate (3c) as a colorless oil (126.4 mg, 90%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 2.84–2.64 (m, 1H), 1.83–1.64 (comp, 2H), 1.42–1.31 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.2 Hz, 1H), 0.94 (d, J = 6.1 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 175.4, 150.0, 132.5 (2C), 123.5 (2C), 118.9, 43.0, 37.9, 26.2, 22.7, 22.6, 17.5. HRMS−ESI (m/z) for C₁₃H₁₇BrO₂ [M + Na]⁺: calcd 307.0304 (⁷⁹Br), 309.0283 (⁸¹Br), found 307.0304 (⁷⁹Br), 309.0288 (⁸¹Br).

4-Bromophenyl 2-methylpent-4-ynoate (3d): Compound 3d was prepared according to the general procedure using 1d (98.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 2-methylpent-4-ynoate (3d) as a colorless oil (121.9 mg, 90%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 2.91 (m, 1H), 2.59 (comp, 2H), 2.06 (s, 1H), 1.41 (d, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 173.1, 149.9, 132.6 (2C), 123.5 (2C), 119.1, 81.0, 70.5, 39.0, 22.9, 16.4. HRMS−ESI (m/z) for C₁₂H₁₁BrO₂ [M + Na]⁺: calcd 288.9835 (⁷⁹Br), 290.9815 (⁸¹Br), found 288.9831 (⁷⁹Br), 290.9815 (⁸¹Br).

4-Bromophenyl 3-cyclohexyl-2-methylpropanoate (3e): Compound 3e was prepared according to the general procedure using 1e (127.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 3-cyclohexyl-2-methylpropanoate (3e) as a colorless oil (137.7 mg, 85%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 2.84–2.71 (m, 1H), 1.84–1.62 (comp, 6H), 1.37 (comp, 2H), 1.27 (d, J = 6.9 Hz, 3H), 1.23–1.10 (comp, 3H), 0.93 (comp, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 175.5, 150.1, 132.6 (2C), 123.5 (2C), 118.8, 41.6, 37.2, 35.7, 33.5, 33.3, 26.7, 26.4, 26.4, 17.6. HRMS−ESI (m/z) for C₁₆H₂₁BrO₂ [M + Na]⁺: calcd 347.0617 (⁷⁹Br), 349.0596 (⁸¹Br), found 347.0617 (⁷⁹Br), 349.0598 (⁸¹Br).

4-Bromophenyl 2-methyl-3-phenylpropanoate (3f): Compound 3f was prepared according to the general procedure using 1f (124.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 2-methyl-3-phenylpropanoate (3f) as a colorless oil (145.2 mg, 91%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.4 Hz, 2H), 7.31 (m, 2H), 7.23 (comp, 3H), 6.79 (d, J = 8.3 Hz, 2H), 3.09 (dd, J = 13.3, 7.7 Hz, 1H), 2.99 (m, 1H), 2.83 (dd, J = 13.3, 6.6 Hz, 1H), 1.32 (d, J = 6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 174.4, 149.8, 139.0, 132.5 (2C), 129.2 (2C), 128.6 (2C), 126.7, 123.4 (2C), 118.9, 41.8, 40.0, 17.1. HRMS−ESI (m/z) for C₁₆H₁₅BrO₂ [M + Na]⁺: calcd 341.0148 (⁷⁹Br), 343.0128 (⁸¹Br), found 341.0149 (⁷⁹Br), 343.0132 (⁸¹Br).

4-Bromophenyl 3-(4-fluorophenyl)-2-methylpropanoate (3g): Compound 3g was prepared according to the general procedure using 1g (133.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 3-(4-fluorophenyl)-2-methylpropanoate (3g) as a colorless oil (151.7 mg, 95%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.8 Hz, 2H), 7.19 (dd, J = 8.3, 5.4 Hz, 2H), 7.00 (t, J = 8.5 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.07 (dd, J = 13.4, 7.7 Hz, 1H), 2.94 (m, 1H), 2.81 (dd, J = 13.4, 6.8 Hz, 1H), 1.31 (d, J = 6.9 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ –116.4. ¹³C NMR (101 MHz, CDCl₃) δ 174.2, 161.9 (d, J_C−F = 244.7 Hz), 149.8, 134.7 (d, J_C−F = 3.2 Hz), 132.6 (2C), 130.6 (d, J_C−F = 7.8 Hz, 2C), 123.4 (2C), 119.0, 115.5 (d, J_C−F = 21.2 Hz, 2C), 41.9, 39.1, 17.0. HRMS−ESI (m/z) for C₁₆H₁₄BrFO₂ [M + Na]⁺: calcd 359.0053 (⁷⁹Br), 361.0033 (⁸¹Br), found 359.0052 (⁷⁹Br), 361.0035 (⁸¹Br).

4-Bromophenyl 3-(3-fluorophenyl)-2-methylpropanoate (3h): Compound 3h was prepared according to the general procedure using 1h (133.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 3-(3-fluorophenyl)-2-methylpropanoate (3h) as a colorless oil (146.7 mg, 87%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.8 Hz, 2H), 7.26 (m, 1H), 7.00 (m, 1H), 6.95 (comp, 2H), 6.83 (d, J = 8.4 Hz, 2H), 3.10 (dd, J = 13.4, 7.7 Hz, 1H), 2.98 (m, 1H), 2.82 (dd, J = 13.4, 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ –113.3. ¹³C NMR (101 MHz, CDCl₃) δ 174.0, 162.9 (d, J_C−F = 246.0 Hz), 149.6, 141.4 (d, J_C−F = 7.2 Hz), 132.4 (2C), 130.0 (d, J_C−F = 8.3 Hz), 124.7 (d, J_C−F = 2.9 Hz), 123.2 (2C), 118.9, 115.9 (d, J_C−F = 21.1 Hz), 113.6 (d, J_C−F = 21.1 Hz), 41.4, 39.4, 17.0. HRMS−ESI (m/z) for C₁₆H₁₄BrFO₂ [M + Na]⁺: calcd 359.0053 (⁷⁹Br), 361.0033 (⁸¹Br), found 359.0052 (⁷⁹Br), 361.0032 (⁸¹Br).

4-Bromophenyl 3-(2fluorophenyl)-2-methylpropanoate (3i): Compound 3i was prepared according to the general procedure using 1i (133.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 3-(2-fluorophenyl)-2-methylpropanoate (3i) as a colorless oil (143.3 mg, 93%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.8 Hz, 2H), 7.25–7.17 (comp, 2H), 7.11–7.00 (comp, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.14–2.99 (comp, 2H), 2.97–2.85 (m, 1H), 1.33 (d, J = 6.6 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ –117.6. ¹³C NMR (101 MHz, CDCl₃) δ 174.1, 161.4 (d, J_C−F = 245.3 Hz), 149.7, 132.4 (2C), 131.5 (d, J_C−F = 4.7 Hz), 128.5 (d, J_C−F = 8.2 Hz), 125.8 (d, J_C−F = 15.7 Hz), 124.1 (d, J_C−F = 3.6 Hz), 123.3 (2C), 118.8, 115.4 (d, J_C−F = 22.1 Hz), 40.2, 33.2 (d, J_C−F = 2.1 Hz), 17.0. HRMS−ESI (m/z) for C₁₆H₁₄BrFO₂ [M + Na]⁺: 359.0053 (⁷⁹Br), 361.0033 (⁸¹Br), found 359.0054 (⁷⁹Br), 361.0033 (⁸¹Br).

4-Bromophenyl 3-cyclohexyl-2-methylpropanoate (3j): Compound 3j was prepared according to the general procedure using 1j (158.0 mg, 0.50 mmol, 1.00 equiv) and p-bromophenol (95.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromophenyl 3-cyclohexyl-2-methylpropanoate (3j) as a colorless oil (168.0 mg, 93%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 3.16 (dd, J = 13.4, 7.7 Hz, 1H), 3.01 (m, 1H), 2.88 (dd, J = 13.4, 7.0 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ –62.8. ¹³C NMR (101 MHz, CDCl₃) δ 173.9, 149.7, 143.1, 132.6 (2C), 129.5 (2C), 129.1 (q, J_C−F = 32.1 Hz), 125.6 (q, J_C−F = 3.8 Hz, 2C), 124.3 (q, J_C−F = 272.0 Hz), 123.3 (2C), 119.1, 41.5, 39.5, 17.1. HRMS−ESI (m/z) for C₁₇H₁₄BrF₃O₂ [M + Na]⁺: calcd 409.0021 (⁷⁹Br), 411.0001 (⁸¹Br), found 409.0025 (⁷⁹Br), 411.0014 (⁸¹Br).

4-Nitrophenyl isobutyrate (3k): Compound 3k was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and p-nitrophenol (76.5 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded 4-nitrophenyl isobutyrate (3k) as a white solid (88.8 mg, 85%). The NMR data of 3k were in agreement with the literature data [109]. R_f = 0.50 (petroleum ether/ethyl acetate = 10/1, v/v). HRMS−ESI (m/z) for C₁₀H₁₁NO₄ [M + Na]⁺: calcd 232.0581, found 232.0580.

4-(Trifluoromethyl)phenyl isobutyrate (3l): Compound 3l was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 4-(trifluoromethyl)phenol (89.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 40/1, v/v) afforded 4-(trifluoromethyl)phenyl isobutyrate (3l) as a colorless oil (104.4 mg, 90%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 2.82 (hept, J = 7.0 Hz, 1H), 1.33 (d, J = 7.0 Hz, 6H). ¹⁹F NMR (377 MHz, CDCl₃) δ –62.2. ¹³C NMR (101 MHz, CDCl₃) δ175.1, 153.4, 128.1 (q, J_C−F = 31.2 Hz), 126.7 (q, J_C−F = 3.8 Hz, 2C), 126.2 (q, J_C−F = 271.3 Hz), 122.0 (2C), 34.2, 18.8 (2C). HRMS−ESI (m/z) for C₁₁H₁₁F₃O₂ [M + Na]⁺: calcd 255.0603, found 255.0607.

4-(1H-Tetrazol-1-yl)phenyl isobutyrate (3m): Compound 3m was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 4-(1H-tetrazol-1-yl)phenol (89.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded 4-(1H-tetrazol-1-yl)phenyl isobutyrate (3m) as a colorless oil (98.7 mg, 85%). R_f = 0.35 (petroleum ether/ethyl acetate = 10/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 2.85 (hept, J = 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 175.1, 151.9, 140.6, 131.1, 123.5 (2C), 122.5 (2C), 34.2, 18.8 (2C). HRMS−ESI (m/z) for C₁₁H₁₂N₄O₂ [M + Na]⁺: calcd 255.0852, found 255.0854.

4-(Dimethylamino)phenyl isobutyrate (3n): Compound 3n was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 4-(dimethylamino)phenol (75.4 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-(dimethylamino)phenyl isobutyrate (3n) as a white solid (88.0 mg, 85%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). mp 59–60 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 6.93 (d, J = 9.1 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 2.92 (s, 6H), 2.76 (hept, J = 7.0 Hz, 1H), 1.30 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 176.2, 148.7, 141.8, 121.7 (2C), 113.2 (2C), 41.0 (2C), 34.1, 19.0 (2C). HRMS−ESI (m/z) for C₁₂H₁₇NO₂ [M + H]⁺: calcd 208.1332, found 208.1334.

4-Methoxyphenyl isobutyrate (3o): Compound 3o was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 4-methoxyphenol (68.3 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-methoxyphenyl isobutyrate (3o) as a colorless oil (91.2 mg, 94%). The NMR data of 3o were in agreement with the literature data [110]. R_f = 0.40 (petroleum ether/ethyl acetate = 20/1, v/v). HRMS−ESI (m/z) for C₁₁H₁₄O₃ [M + Na]⁺: calcd 217.0835, found 217.0837.

Methyl 4-(isobutyryloxy)benzoate (3p): Compound 3p was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and methyl 4-hydroxybenzoate (83.7 mg, 0.55 mmol, 1.10 equiv) at rt for 4 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded methyl 4-(isobutyryloxy)benzoate (3p) as a colorless oil (100.0 mg, 90%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 9.1 Hz, 2H), 7.15 (d, J = 9.1 Hz, 2H), 3.91 (s, 3H), 2.81 (hept, J = 7.0 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 175.1, 166.4, 154.6, 131.1 (2C), 127.6, 121.6 (2C), 52.2, 34.2, 18.9 (2C). HRMS−ESI (m/z) for C₁₂H₁₄O₄ [M + Na]⁺: calcd 245.0785, found 245.0787.

4-Formylphenyl isobutyrate (3q): Compound 3q was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 4-hydroxybenzaldehyde (67.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-formylphenyl isobutyrate (3q) as a colorless oil (82.6 mg, 86%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 2.83 (hept, J = 6.9 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 190.9, 174.9, 155.7, 133.9, 131.2 (2C), 122.3 (2C), 34.3, 18.8 (2C). HRMS−ESI (m/z) for C₁₁H₁₂O₃ [M + Na]⁺: calcd 215.0679, found 215.0681.

Naphthalen-1-yl isobutyrate (3r): Compound 3r was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and naphthalen-1-ol (79.3 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded naphthalen-1-yl isobutyrate (3r) as a colorless oil (98.6mg, 92%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.00–7.86 (comp, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.60–7.46 (comp, 3H), 7.28 (d, J = 7.4 Hz, 1H), 3.04 (hept, J = 7.0 Hz, 1H), 1.49 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 175.6, 146.7, 134.7, 128.1, 127.0, 126.4, 126.4, 125.9, 125.4, 121.1, 118.0, 34.5, 19.2 (2C). HRMS−ESI (m/z) for C₁₄H₁₄O₂ [M + Na]⁺: calcd 237.0886, found 237.0887.

[1,1’-Biphenyl]-2-yl isobutyrate (3s): Compound 3s was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and [1,1’-biphenyl]-2-ol (93.6 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded [1,1’-biphenyl]-2-yl isobutyrate (3s) as a colorless oil (111.7 mg, 93%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.29 (comp, 8H), 7.13 (d, J = 7.9 Hz, 1H), 2.62 (hept, J = 6.9 Hz, 1H), 1.10 (d, J = 6.8 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 175.4, 147.9, 137.6, 135.2, 130.9, 129.1 (2C), 128.5, 128.1 (2C), 127.4, 126.1, 122.8, 34.1, 18.7 (2C). HRMS−ESI (m/z) for C₁₆H₁₆O₂ [M + Na]⁺: calcd 263.1042, found 263.1044.

2,4-Dibromophenyl isobutyrate (3t): Compound 3t was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 2,4-dibromophenol (138.5 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded methyl 2,4-dibromophenyl isobutyrate (3t) as a colorless oil (137.2 mg, 86%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.7 Hz, 1H), 7.33–7.22 (comp, 2H), 2.86 (hept, J = 7.0 Hz, 1H), 1.36 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 174.2, 148.9, 134.2, 130.3, 127.1, 121.1, 115.3, 34.2, 18.9 (2C). HRMS−ESI (m/z) for C₁₀H₁₀⁷⁹Br₂O₂ [M + Na]⁺: calcd 342.8940, found 342.8944; C₁₀H₁₀⁷⁹Br⁸¹Br O₂ [M + Na]⁺: calcd 344.8920, found 344.8919.

Methyl 3-(isobutyryloxy)-2-naphthoate (3u): Compound 3u was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and methyl 3-hydroxy-2-naphthoate (111.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded methyl 3-(isobutyryloxy)-2-naphthoate (3u) as a white solid (114.7 mg, 84%). R_f = 0.40 (petroleum ether/ethyl acetate = 20/1, v/v). mp 58–59 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63–7.48 (comp, 3H), 3.92 (s, 3H), 2.93 (hept, J = 7.0 Hz, 1H), 1.39 (d, J = 7.1 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ176.1, 165.3, 147.0, 135.7, 133.7, 130.7, 129.1, 128.9, 127.3, 126.6, 122.5, 121.1, 52.3, 34.3, 19.0 (2C). HRMS−ESI (m/z) for C₁₆H₁₆O₄ [M + Na]⁺: calcd 295.0941, found 295.0943.

2,6-Dimethylphenyl isobutyrate (3v): Compound 3v was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 2,6-dimethylphenol (68.2 mg, 0.55 mmol, 1.10 equiv) at 60 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 2,6-dimethylphenyl isobutyrate (3v) as a colorless oil (89.4 mg, 93%). R_f = 0.40 (petroleum ether/ethyl acetate = 40/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.15–6.93 (comp, 3H), 2.87 (hept, J = 7.0 Hz, 1H), 2.13 (s, 6H), 1.36 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 174.7, 148.1, 130.1, 128.6 (2C), 125.7 (2C), 34.3, 19.2 (2C), 16.3 (2C). HRMS−ESI (m/z) for C₁₂H₁₆O₂ [M + Na]⁺: calcd 215.1042, found 215.1041.

2-Oxo-2H-chromen-7-yl isobutyrate (3w): Compound 3w was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 7-hydroxy-2H-chromen-2-one (89.2 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 2-oxo-2H-chromen-7-yl isobutyrate (3w) as a white solid (98.7 mg, 85%). R_f = 0.45 (petroleum ether/ethyl acetate = 20/1, v/v). mp 104–105 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 9.5 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 9.5 Hz, 1H), 2.84 (hept, J = 7.0 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 174.9, 160.4, 154.7, 153.5, 142.9, 128.5, 118.4, 116.6, 116.0, 110.4, 34.2, 18.8 (2C). HRMS−ESI (m/z) for C₁₃H₁₂O₄ [M + Na]⁺: calcd 255.0628, found 255.0628.

5-Bromopyridin-3-yl isobutyrate (3x): Compound 3x was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 5-bromopyridin-3-ol (95.7 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 5-bromopyridin-3-yl isobutyrate (3x) as a colorless oil (100.1 mg, 82%). R_f = 0.45 (petroleum ether/ethyl acetate = 20/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.38 (s, 1H), 7.71 (s, 1H), 2.86 (hept, J = 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 174.6, 147.9, 147.5, 141.6, 132.1, 119.9, 34.1, 18.8 (2C). HRMS−ESI (m/z) for C₉H₁₀BrNO₂ [M + H]⁺: calcd 243.9968 (⁷⁹Br), 245.9947 (⁸¹Br), found 243.9970 (⁷⁹Br), 245.9948 (⁸¹Br).

2-Chloropyrimidin-5-yl isobutyrate (3y): Compound 3y was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 2-chloropyrimidin-5-ol (71.8 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 2-chloropyrimidin-5-yl isobutyrate (3y) as a colorless oil (85.3 mg, 85%). R_f = 0.45 (petroleum ether/ethyl acetate = 20/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 2H), 2.87 (hept, J = 7.0 Hz, 1H), 1.34 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 174.1, 157.1, 152.6 (2C), 145.1, 34.1, 18.7 (2C). HRMS−ESI (m/z) for C₈H₉ClN₂O₂ [M + H]⁺: calcd 201.0426, found 201.0426.

3.2.3. A General Procedure for Alcohols, Thiol, Thiophenol, and Amines

In a 4.0-mL vial, 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (1a) (86.0 mg, 0.50 mmol, 1.00 equiv), BTMG (94.2 mg, 0.55 mmol, 1.10 equiv) were dissolved in anhydrous NMP (625.0 μL). Then, the nucleophile (0.55 mmol, 1.10 equiv) was added, and the mixture was stirred at 60 °C for 12 h. After the reaction was completed, the mixture was diluted with EA (20 mL) and washed with 2 M aqueous HCl solution (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography.

4-Bromobenzyl isobutyrate (4a): Compound 4a was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and (4-bromophenyl)methanol (102.9 mg, 0.55 mmol, 1.10 equiv) at 60 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4-bromobenzyl isobutyrate (4a) as a colorless oil (117.0 mg, 91%). R_f = 0.55 (petroleum ether/ethyl acetate = 20/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 5.06 (s, 2H), 2.59 (hept, J = 7.0 Hz, 1H), 1.18 (d, J = 7.1 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 176.8, 135.3, 131.7 (2C), 129.7 (2C), 122.1, 65.2, 34.0, 19.0 (2C). HRMS−ESI (m/z) for C₁₁H₁₃BrO₂ [M + Na]⁺: calcd 278.9992 (⁷⁹Br), 280.9971 (⁸¹Br), found 278.9991 (⁷⁹Br), 280.9977 (⁸¹Br).

3-Phenylpropyl isobutyrate (4b): Compound 4b was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 3-phenylpropanol (74.9 mg, 0.55 mmol, 1.10 equiv) at 60 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 3-phenylpropyl isobutyrate (4b) as a colorless oil (96.0 mg, 93%). R_f = 0.55 (petroleum ether/ethyl acetate = 20/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.24 (m, 2H), 7.23–7.15 (comp, 3H), 4.09 (t, J = 6.5 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.55 (hept, J = 7.0 Hz, 1H), 1.96 (tt, J = 14.0, 6.5 Hz, 2H), 1.18 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 177.2, 141.3, 128.45 (2C), 128.41 (2C), 126.0, 63.5, 34.1, 32.2, 30.3, 19.0 (2C). HRMS−ESI (m/z) for C₁₃H₁₈O₂ [M + Na]⁺: calcd 229.1199, found 229.1201.

Benzhydryl isobutyrate (4c): Compound 4c was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and diphenylmethanol (101.3 mg, 0.55 mmol, 1.10 equiv) at 60 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded benzhydryl isobutyrate (4c) as a colorless oil (114.4 mg, 90%). R_f = 0.55 (petroleum ether/ethyl acetate = 20/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.27 (comp, 10H), 6.86 (s, 1H), 2.67 (hept, J = 7.0 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 176.0, 140.5 (2C), 128.5 (4C), 127.8 (2C), 127.0 (4C), 76.6, 34.2, 18.9 (2C). HRMS−ESI (m/z) for C₁₇H₁₈O₂ [M + Na]⁺: calcd 277.1199, found 277.1198.

Cyclohexyl isobutyrate (4d): Compound 4d was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and cyclohexanol (55.1 mg, 0.55 mmol, 1.10 equiv) at 80 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded cyclohexyl isobutyrate (4d) as a colorless oil (69.8 mg, 82%). R_f = 0.55 (petroleum ether/ethyl acetate = 20/1, v/v). The NMR data of 4d were in agreement with the literature data [111]. HRMS−ESI (m/z) for C₁₀H₁₈O₂ [M + Na]⁺: calcd 193.1199, found 193.1205.

S-(4-Fluorophenyl) 2-methylpropanethioate (4e): Compound 4e was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 4-fluorothiophenol (74.5 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded S-(4-fluorophenyl) 2-methylpropanethioate (4e) as a colorless oil (81.2 mg, 82%). R_f = 0.65 (petroleum ether/ethyl acetate = 10/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.33 (m, 2H), 7.14–7.05 (m, 2H), 2.86 (hept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H). ¹⁹F NMR (377 MHz, CDCl₃) δ –111.6. ¹³C NMR (101 MHz, CDCl₃) δ 202.0, 163.5 (d, J = 249.6 Hz), 136.8 (d, J = 8.6 Hz, 2C), 123.3, 116.5 (d, J = 22.2 Hz, 2C), 43.1, 19.5 (2C). HRMS−ESI (m/z) for C₁₀H₁₁FOS [M + H]⁺: calcd 199.0587, found 199.0584.

S-Dodecyl 2-methylpropanethioate (4f): Compound 4f was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and dodecane-1-thiol (111.3 mg, 0.55 mmol, 1.10 equiv) at rt for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 3/1, v/v) afforded S-dodecyl 2-methylpropanethioate (4f) as a colorless oil (51.1 mg, 90%). R_f = 0.60 (petroleum ether/ethyl acetate = 10/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 2.84 (t, J = 7.4 Hz, 2H), 2.72 (hept, J = 6.9 Hz, 1H), 1.65–1.49 (m, 2H), 1.42–1.21 (comp, 18H), 1.18 (d, J = 7.0 Hz, 6H), 0.88 (t, J = 6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 204.5, 43.3, 32.1, 29.8 (3C), 29.7, 29.6, 29.5, 29.3, 29.0, 28.7, 22.8, 19.6 (2C), 14.2. HRMS−ESI (m/z) for C₁₆H₃₂OS [M + H]⁺: calcd 273.2247, found 273.2247.

N-(4-Bromobenzyl)isobutyramide (4g): Compound 4g was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and (4-bromophenyl)methanamine (102.3 mg, 0.55 mmol, 1.10 equiv) at 100 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded N-(4-bromobenzyl)isobutyramide (4g) as a yellow solid (117.4 mg, 92%). R_f = 0.30 (petroleum ether/ethyl acetate = 10/1, v/v). mp 114–115 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.83 (s, 1H), 4.37 (d, J = 5.9 Hz, 2H), 2.38 (hept, J = 6.9 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 177.0, 137.8, 131.9 (2C), 129.5 (2C), 121.4, 42.9, 35.8, 19.7 (2C). HRMS−ESI (m/z) for C₁₁H₁₄BrNO [M + H]⁺: calcd 256.0332 (⁷⁹Br), 258.0312 (⁸¹Br), found 256.0032 (⁷⁹Br), 258.0312 (⁸¹Br).

N-(3-Phenylpropyl)isobutyramide (4h): Compound 4h was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and 3-phenylpropan-1-amine (74.4 mg, 0.55 mmol, 1.10 equiv) at 100 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded N-(3-phenylpropyl)isobutyramide (4h) as a yellow oil (93.4 mg, 91%). R_f = 0.20 (petroleum ether/ethyl acetate = 20/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.24 (m, 2H), 7.23–7.12 (comp, 3H), 5.43 (br, 1H), 3.29 (q, J = 6.5 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.28 (hept, J = 6.9 Hz, 1H), 1.91–1.77 (m, 2H), 1.12 (d, J = 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 177.0, 141.7, 128.6 (2C), 128.5 (2C), 126.2, 39.2, 35.8, 33.5, 31.4, 19.7 (2C). HRMS−ESI (m/z) for C₁₃H₁₉NO [M + H]⁺: calcd 206.1540, found 206.1540.

N-(Heptadecan-9-yl)isobutyramide (4i): Compound 4i was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and heptadecan-9-amine (140.5 mg, 0.55 mmol, 1.10 equiv) at 100 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded N-(heptadecan-9-yl)isobutyramide (4i) as a white solid (146.5 mg, 90%). R_f = 0.50 (petroleum ether/ethyl acetate = 10/1, v/v). mp 85–86 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 5.05 (d, J = 9.2 Hz, 1H), 3.88 (m, 1H), 2.31 (hept, J = 6.9 Hz, 1H), 1.47 (m, 2H), 1.27 (comp, 26H), 1.15 (d, J = 6.9 Hz, 6H), 0.87 (t, J = 6.7 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 176.5, 49.0, 36.1, 35.5 (2C), 32.0 (2C), 29.75 (2C), 29.67 (2C), 29.4 (2C), 26.0 (2C), 22.8 (2C), 19.9 (2C), 14.2 (2C). HRMS−ESI (m/z) for C₂₁H₄₃NO [M + H]⁺: calcd 326.3418, found 326.3418.

N-Cyclohexylisobutyramide (4j): Compound 4j was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and cyclohexanamine (54.5 mg, 0.55 mmol, 1.10 equiv) at 100 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded N-cyclohexylisobutyramide (4j) as a white solid (71.9 mg, 85%). R_f = 0.50 (petroleum ether/ethyl acetate = 10/1, v/v). mp 116–117 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 5.36 (s, 1H), 3.79–3.64 (m, 1H), 2.28 (hept, J = 6.8 Hz, 1H), 1.88 (m, 2H), 1.75–1.64 (m, 2H), 1.64–1.50 (m, 1H), 1.36 (m, 2H), 1.12 (comp, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 176.1, 47.9, 35.9, 33.3 (2C), 25.7, 25.0 (2C), 19.8 (2C). HRMS−ESI (m/z) for C₁₀H₁₉NO [M + H]⁺: calcd 170.1540, found 170.1540.

2-Methyl-1-morpholinopropan-1-one (4k): Compound 4k was prepared according to the general procedure using 1a (86.0 mg, 0.50 mmol, 1.00 equiv) and morpholine (47.9 mg, 0.55 mmol, 1.10 equiv) at 100 °C for 12 h. Purification by flash column chromatography (petroleum ether/ethyl acetate = 3/1, v/v) afforded 2-methyl-1-morpholinopropan-1-one (4k) as a colorless oil (51.1 mg, 62%). R_f = 0.45 (petroleum ether/ethyl acetate = 3/1, v/v). ¹H NMR (400 MHz, CDCl₃) δ 3.74–3.63 (comp, 4H), 3.63–3.56 (m, 2H), 3.50 (m, 2H), 2.74 (hept, J = 6.8 Hz, 1H), 1.11 (d, J = 6.8 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 175.7, 67.1, 66.9, 46.1, 42.2, 30.0, 19.4 (2C). HRMS−ESI (m/z) for C₈H₁₅NO₂ [M + H]⁺: calcd 158.1176, found 158.1176.

3.2.4. Gram-Scale Preparation of 4-Acetamidophenyl Isobutyrate (3z)

To a 50-mL round-bottom flask, 5,5-dimethyl-Meldrum’s acid 1a (1.72 g, 10.0 mmol, 1.00 equiv), BTMG (34.2 mg, 0.20 mmol, 0.02 equiv) were dissolved in anhydrous NMP (25.0 mL). Then, acetaminophen (1.66 g, 11.0 mmol, 1.10 equiv) was added and stirred at 60 °C for 12 h. After the reaction was completed, the mixture was diluted with EA (100 mL) and washed with 2 × 2 M aqueous HCl solution (50 mL). The organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1, v/v), which afforded 4-acetamidophenyl isobutyrate (3z) as a white solid (2.12 g, 96%). R_f = 0.35 (petroleum ether/ethyl acetate = 3/1, v/v). mp 111−112 °C (petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 2.81 (hept, J = 7.0 Hz, 1H), 2.19 (s, 3H), 1.33 (d, J = 7.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 176.1, 168.5, 147.0, 135.6, 121.8 (2C), 120.9 (2C), 34.1, 24.4, 18.9 (2C). HRMS−ESI (m/z) for C₁₂H₁₅NO₃ [M + H]⁺: calcd 222.1125, found 222.1126.

3.2.5. Synthesis of 4-Acetamidophenyl 2-(((benzyloxy)carbonyl)amino)-2-Methylpropanoate (6)

Step 1: To a 25-mL round-bottom flask, 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (1a) (688.3 mg, 4.0 mmol, 1.00 equiv) and BTMG (753.6 mg, 0.55 mmol, 1.10 equiv) were dissolved in anhydrous DCM (10.0 mL). Then, acetaminophen (665.1 mg, 4.4 mmol, 1.10 equiv) was added, and the mixture was stirred at rt for 4 h. After the reaction was completed, the mixture was diluted with DCM (20 mL) and washed with 2 M aqueous HCl solution (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography (ethyl acetate), which afforded 3-(4-acetamidophenoxy)-2,2-dimethyl-3-oxopropanoic acid (5) as a white solid (912.5 mg, 86%). R_f = 0.20 (dichloromethane /methanol = 40/1, v/v). mp 166–168 °C (petroleum ether). ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (br, s, 1H), 9.98 (s, 1H), 7.61 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 2.04 (s, 3H), 1.46 (s, 6H). ¹³C NMR (101 MHz, DMSO-d₆) δ 173.4, 171.6, 168.2, 145.5, 137.1, 121.4 (2C), 119.9 (2C), 49.4, 23.9, 22.4 (2C). HRMS−ESI (m/z) for C₁₃H₁₆NO₅ [M + H]⁺: calcd 266.1023, found 266.1030.

Step 2: To a 4.0-mL vial, the malonate half-ester 5 (132.5 mg, 0.50 mmol, 1.00 equiv), DPPA (165.1 mg, 0.60 mmol, 1.20 equiv), and TEA (75.9 mg, 0.75 mmol, 1.50 equiv) were dissolved in anhydrous toluene (2.5 mL). The mixture was stirred at 100 °C for 12 h. After it was cooled to rt, benzyl alcohol (108.1 mg, 1.00 mmol, 2.00 equiv) was added and stirred at 100 °C for 12 h. After the reaction was completed, the mixture was diluted with EA (20 mL) and washed with 2 M aqueous HCl solution (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1, v/v), which afforded 4-acetamidophenyl 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoate (6) as a white solid (140.6 mg, 76%). R_f = 0.35 (petroleum ether/ethyl acetate = 1/1, v/v). mp 189–190 °C (petroleum ether). ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.98 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.41–7.26 (comp, 5H), 6.90 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H), 2.05 (s, 3H), 1.49 (s, 6H). ¹³C NMR (101 MHz, DMSO-d₆) δ 173.3, 168.2, 155.3, 145.9, 136.9, 136.8, 128.3 (2C), 127.8 (3C), 121.6 (2C), 119.8 (2C), 65.4, 55.6, 24.9 (2C), 23.9. HRMS−ESI (m/z) for C₂₀H₂₂N₂O₅ [M + H]⁺: calcd 371.1602, found 371.1610.

3.2.6. One-Pot Preparation of 4-Acetamidophenyl 3-((4-bromobenzyl)amino)-2,2-dimethyl-3-oxopropanoate (7)

In a 4.0-mL vial, 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (1a) (86.0 mg, 0.50 mmol, 1.00 equiv) and BTMG (94.2 mg, 0.55 mmol, 1.10 equiv) were dissolved in anhydrous DCM (1.25 mL). Then, acetaminophen (83.1 mg, 0.55 mmol, 1.10 equiv) was added, and the mixture was stirred at rt for 4 h. Then, p-BrBnNH₂ (102.3 mg, 0.55 mmol, 1.10 equiv), EDC·HCl (143.8 mg, 0.75 mmol, 1.50 equiv), and HOBt (101.3 mg, 0.75 mmol, 1.50 equiv) were added, and the mixture was stirred at rt for 6 h. After the reaction was completed, the mixture was diluted with EA (20 mL) and washed with 2 M aqueous HCl solution (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1, v/v), which afforded 4-acetamidophenyl 3-((4-bromobenzyl)amino)-2,2-dimethyl-3-oxopropanoate (7) as a white solid (140.4 mg, 65%). R_f = 0.35 (petroleum ether/ethyl acetate = 3/1, v/v). mp 179–180 °C (petroleum ether). ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 4.29 (d, J = 5.9 Hz, 1H), 2.04 (s, 3H), 1.49 (s, 6H). ¹³C NMR (101 MHz, DMSO-d₆) δ 172.2, 171.5, 168.2, 145.6, 139.0, 137.0, 131.0 (2C), 129.2 (2C), 121.5 (2C), 119.8 (2C), 119.7, 50.0, 41.9, 23.9, 22.7 (2C). HRMS−ESI (m/z) for C₂₀H₂₁BrN₂O₄ [M + H]⁺: calcd 433.0758 (⁷⁹Br), 435.0737 (⁸¹Br), found 433.0766 (⁷⁹Br), 435.0745 (⁸¹Br).

4. Conclusions

We have identified disubstituted Meldrum’s acid as a novel carbon-based scaffold with SuFEx-like reactivity. As exemplified in other SuFEx reactions, phenols are the optimal nucleophilic exchange partners. Notably, thiols and thiophenols, typically prone to oxidation by S(VI) electrophiles in classical SuFEx reactions, exhibit comparable reactivity to phenols in our method. In contrast, alcohols and amines require elevated temperatures to achieve full conversion. Sterically hindered nucleophiles, such as tertiary alcohols or bulky primary and secondary amines, remain challenging and will require the development of new catalytic systems. Alternative activation strategies for disubstituted Meldrum’s acids are currently under investigation in our laboratory and will be reported in due course.

5. Patents

Sun Yat-sen University has filed a patent application.