A fluoroborate-mediated electrochemical [3+2] ring expansion strategy for the synthesis of 1,3-dioxolane and oxazoline derivatives

Abstract

The present invention discloses a fluoroborate-mediated electrochemical [3+2] ring expansion strategy for the synthesis of 1,3-dioxolane and oxazoline derivatives. This innovative, green, and efficient electrochemically induced [3+2] ring expansion strategy utilizes fluoroborate as a Lewis acid and a noble metal cathode catalyst to rapidly incorporate solvent molecules, namely acetone or acetonitrile, into the epoxide backbone at room temperature and pressure, effectively producing high-value-added 1,3-dioxolane and oxazoline derivatives. This method exhibits high yield and efficiency, mild reaction conditions, and strong controllability.

Description

Technical Field

[0001] The present invention belongs to the field of electrochemical synthesis, and in particular relates to a fluoroborate-mediated electrochemical [3+2] ring expansion strategy for synthesizing 1,3-dioxolane and oxazoline derivatives. Background Art

[0002] Organic ring compounds, particularly heterocyclic compounds, play a vital role in human society. For example, more than two-thirds of FDA-approved drugs contain N-heterocyclic hydrocarbons and / or O-heterocyclic hydrocarbon components. The structural configuration of the ring not only influences properties such as three-dimensionality, lipophilicity, and backbone rigidity, but also determines molecular functionality and reactivity. Therefore, in the field of synthetic chemistry, advancing new technologies to enhance and manipulate ring structures is crucial.

[0003] Skeletal ring expansion is an extremely important means to transform common raw materials into structurally complex molecules, which may enhance or optimize the chemical or biological properties of the original base compound. Previous studies have explored the skeleton editing by introducing carbon, nitrogen, oxygen, boron or other molecules into cyclic molecules under different synthetic conditions. It is worth noting that acetone and acetonitrile are widely used as cheap and easily available solvents, as well as key chemical intermediates in organic synthesis, and have important industrial significance. Therefore, the strategic introduction of acetone or acetonitrile molecules in chemical reactions to prepare high-value-added target chemicals has considerable economic prospects and importance.

[0004] 1,3-Dioxolanes and oxazolines are versatile molecules with widespread applications in various fields, including organic synthesis, drug design, pesticide research, and polymer chemistry. They play important roles as coordination reagents, ligands, and building blocks for the synthesis of complex organic molecules. Furthermore, their ability to coordinate with metal ions makes them valuable in organometallic chemistry and catalysis. These molecules can form stable complexes with transition metals and act as efficient catalysts in a variety of chemical reactions. Although these compounds are typically synthesized via traditional thermochemical catalytic pathways, including reactions involving epoxides (or diols) with ketone or nitrile groups, these methods are often limited by low reaction efficiency, harsh conditions, multi-step syntheses, and large catalyst feedstocks. Therefore, exploring novel and efficient ring-expansion pathways to insert small molecules (such as acetone or acetonitrile) to prepare high-value-added macroheterocyclic compounds is an important research direction.

[0005] Electrochemical synthesis pathways have demonstrated numerous advantages across a wide range of fields, including high efficiency, mild reaction conditions, robust controllability, and the ability to utilize renewable energy sources (e.g., solar, hydro, and wind) to generate electricity to drive non-spontaneous chemical reactions. These advantages have made electrosynthesis a highly sought-after method in organic synthesis. Summary of the Invention

[0006] The present invention primarily addresses the technical problem of providing a fluoroborate-mediated electrochemical [3+2] ring expansion strategy for the synthesis of 1,3-dioxolane and oxazoline derivatives. This method, through the synergistic effect of a cathode catalyst and fluoroborate (as a Lewis acid), rapidly incorporates solvent molecules, namely acetone or acetonitrile, into the epoxide backbone at room temperature to produce 1,3-dioxolane or oxazoline derivatives.

[0007] The present invention is implemented through the following technical solutions:

[0008] A fluoroborate-mediated electrochemical [3+2] ring expansion strategy was developed for the synthesis of 1,3-dioxolane and oxazoline derivatives, comprising the following steps:

[0009] An Ag / AgCl electrode, a graphite rod electrode, and a noble metal cathode are used as a reference electrode, a counter electrode, and a working electrode, respectively; the electrolyte is acetone or acetonitrile containing an epoxide and a supporting electrolyte, and the supporting electrolyte is an ionic liquid containing a fluoroborate; an electrochemical reaction is performed, and after the reaction is completed, the reaction solution is concentrated under reduced pressure in a rotary evaporator; the concentrated reaction solution is extracted, and the obtained organic layer is dried, filtered, and concentrated under reduced pressure; the obtained product is purified by silica gel chromatography, and the target product 1,3-dioxolane derivative or oxazoline derivative is extracted by elution.

[0010] Furthermore, the 1,3-dioxolane derivative is 2,2-dimethyl-4-phenyl-1,3-dioxolane, and the oxazoline derivative is 2-methyl-4-phenyl-oxazoline.

[0011] Furthermore, the concentration of the epoxide in the acetone or acetonitrile is 40-100 mM, and the concentration of the supporting electrolyte is 20-100 mM.

[0012] Furthermore, the concentrated reaction solution is extracted with EtOAc solution, and the obtained organic layer is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained product is purified by silica gel chromatography using petroleum ether / ethyl acetate as eluent to extract the target product 1,3-dioxolane derivative or oxazoline derivative.

[0013] Furthermore, the supporting electrolyte is [emim]BF4, Bu4NBF4 or Et4NBF4.

[0014] Furthermore, the noble metal cathode is a catalyst-loaded carbon felt, and the catalyst loaded on the carbon felt is a single metal catalyst, a bimetallic catalyst or a ternary RhRuPt catalyst; the single metal catalyst is Rh, Pt, Ru, Pd or Au catalyst; the bimetallic catalyst is RhPt or AuPt catalyst.

[0015] Furthermore, the specific preparation steps of the catalyst-loaded carbon felt are as follows: the catalyst is loaded onto the carbon felt by electrodeposition, a graphite rod electrode and an Ag / AgCl electrode are used as the counter electrode and the reference electrode, the electrolyte is an aqueous solution containing a supporting electrolyte and a noble metal salt, and the scanning rate is 0.1 V·s -1 In the case of , CV scans were performed in the potential range of -0.5 to 1.7 V; after the electrodeposition process, the catalyst-loaded carbon felt was washed with deionized water and then dried in air.

[0016] Furthermore, the supporting electrolyte is Na2SO4.

[0017] Furthermore, the noble metal salt is a monometallic salt, a bimetallic salt or a trimetallic salt, the monometallic salt is rhodium nitrate, platinum chlorate hexahydrate, ruthenium nitrosyl nitrate, palladium nitrate dihydrate or chloroauric acid trihydrate; the bimetallic salt is a mixture of rhodium nitrate and platinum chlorate hexahydrate or a mixture of chloroauric acid trihydrate and platinum chlorate hexahydrate; the trimetallic salt is a mixture of rhodium nitrate, platinum chlorate hexahydrate and ruthenium nitrosyl nitrate.

[0018] Furthermore, the concentration of the metal salt in the noble metal salt solution is 2-10 mM.

[0019] The present invention innovatively employs a green and efficient electrochemically induced [3+2] ring-expansion strategy, using fluoroborate as a Lewis acid and a noble metal cathode catalyst to efficiently produce high-value-added 1,3-dioxolane and oxazoline derivatives at room temperature and pressure. Further experimental and computational analysis demonstrates that this synergistic ring-expansion pathway is kinetically superior to a stepwise reaction pathway. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 : Schematic diagram of the electrodeposition method used to prepare metal / alloy nanocatalysts supported on the surface of carbon felt (CF).

[0021] Figure 2 : Ring expansion reaction of 2,2-dimethyl-4-phenyl-1,3-dioxolane and structural characterization of cathode catalyst.

[0022] Figure 3 : Ring expansion reaction of 2-methyl-4-phenyl-oxazoline and structural characterization of cathode catalyst.

[0023] Figure 4 : Theoretical calculations on reaction paths.

[0024] Figure 5 : Schematic diagram of the electrochemical pathway of ring expansion reaction. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is further described in detail below with reference to specific embodiments, but the protection scope of the present invention is not limited to the following embodiments.

[0026] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0027] The following electrochemical experiments were performed in a single-chamber electrolytic cell using a CHI660E electrochemical workstation.

[0028] Preparation of cathode catalyst (catalyst modified carbon felt): Figure 1 As shown, the metal / alloy nanocatalysts were loaded onto carbon felt (1 cm × 1 cm) by electrodeposition, with graphite rod electrodes and Ag / AgCl electrodes (in saturated KCl solution) serving as counter and reference electrodes. The electrolyte was a deionized (DI) aqueous solution containing Na2SO4 (as a supporting electrolyte) and a noble metal salt.

[0029] The concentration of Na2SO4 is preferably 0.5M, the noble metal salt is a monometallic salt, a dimetallic salt or a trimetallic salt; the concentration of each metal salt in the electrolyte is 2-10mM, preferably 5mM;

[0030] The single metal salts are rhodium nitrate (Rh(NO3)3), platinum chlorohydrate hexahydrate (H2PtCl6·6H2O), ruthenium nitrosyl nitrate (Ru(NO)(NO3) x (OH) y，x+y＝3 ), palladium nitrate dihydrate (Pd(NO3)2·2H2O) or chloroauric acid trihydrate (HAuCl4·3H2O);

[0031] The double metal salt solution is a mixture of rhodium nitrate (Rh(NO3)3) and platinum chloroate hexahydrate (H2PtCl6·6H2O) or a mixture of chloroauric acid trihydrate (HAuCl4·3H2O) and platinum chloroate hexahydrate (H2PtCl6·6H2O);

[0032] The trimetallic salts are rhodium nitrate (Rh(NO3)3), platinum chloroate hexahydrate (H2PtCl6·6H2O) and ruthenium nitrosyl nitrate (Ru(NO)(NO3) x (OH) y，x+y＝3 ).

[0033] Then, the scan rate was 0.1 V·s -1In the case of , CV scans (50 cycles) were performed in the potential range of -0.5 to 1.7 V. Monometallic catalysts (i.e., Rh, Pt, Ru, Pd, Au) and bimetallic catalysts (i.e., RhPt, AuPt) were also prepared using the above method using the corresponding molar concentrations. Palladium nitrate dihydrate (Pd(NO3)2·2H2O) and chloroauric acid trihydrate (HAuCl4·3H2O) were used as the Pd and Au sources, respectively. After the electrodeposition process, the catalyst-modified carbon felt was rinsed with deionized water and then dried in air to obtain.

[0034] Example 1

[0035] Preparation of Pt-catalyst-modified carbon felt (Pt-NPs / CF): Pt nanocatalysts were loaded onto carbon felt (1 cm × 1 cm) by electrodeposition, with graphite rod electrodes and Ag / AgCl electrodes (in saturated KCl solution) serving as counter and reference electrodes. The electrolyte was a deionized (DI) aqueous solution containing 0.5 M Na2SO4 (as a supporting electrolyte) and 5 mM platinum chlorohydrate (H2PtCl6·6H2O) for the preparation of Pt nanocatalysts. The Pt nanocatalysts were then tested at a scan rate of 0.1 V·s -1 In the case of , CV scans (50 cycles) were performed in the potential range of -0.5 to 1.7 V. After the electrodeposition process, the Pt catalyst-modified carbon felt was washed with deionized water and then dried in air for subsequent testing and characterization.

[0036] Electrochemical ring expansion reaction of 2,2-dimethyl-4-phenyl-1,3-dioxolane: Figure 5 As shown, an Ag / AgCl electrode (in a saturated KCl solution), a graphite rod electrode, and a Pt catalyst-modified carbon felt (Pt-NPs / CF) were used as a reference electrode, a counter electrode, and a working electrode, respectively. In this embodiment, all working electrodes used had the same geometric surface area (1 cm × 1 cm). In the electrochemical reaction, 30 ml of acetone containing epoxide (100 mM) and a supporting electrolyte (ionic liquid containing fluoroborate: [emim] BF4 (1-ethyl-3-methylimidazolium tetrafluoroborate), 100 mM) was used. After the reaction was completed, the reaction solution was concentrated under reduced pressure in a rotary evaporator. The corresponding product was dissolved in EtOAc solvent, shaken thoroughly with deionized water, and then allowed to stand for stratification. After separation, it was shaken thoroughly with a saturated NaHCO3 solution, allowed to stand for stratification, and finally the organic layer product was separated. The obtained organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained product was purified by silica gel chromatography, and the target product 2,2-dimethyl-4-phenyl-1,3-dioxolane was extracted using petroleum ether / ethyl acetate as eluent.

[0037] Figure 2A describes in detail the standard reaction conditions for the electrochemical pathway to generate product 1b. Transmission electron microscopy (TEM) images show that the Pt nanoparticles dispersed by ultrasound present the morphology of metal nanoclusters, see Figure 2 B. High-resolution transmission electron microscopy (HRTEM) analysis shows a lattice fringe with a lattice constant of 0.226 nm, which matches the (111) plane index of the Pt crystal ( Figure 2 C). Scanning electron microscopy (SEM) images and corresponding element distribution maps demonstrate the uniform distribution of Pt elements on the carbon fiber surface, as shown in Figure 2 As shown in DG. Figure 2 As shown in Figure 3, the separation yields of 1b products for different cathode catalysts show the best performance of the Pt-NPs / CF electrode, which achieved a yield of about 95% in one hour of electrochemical reaction. In the supporting electrolytes (SEs) containing fluoroborate, [emim]BF4 (1-ethyl-3-methylimidazolium tetrafluoroborate) showed the highest yield for 1b when paired with the Pt-NPs / CF electrode as the cathode catalyst, as shown in Figure 3. Figure 2 In addition, no signal of product 1b was observed in SEs without fluoroborate (TEAB, tetraethylammonium bromide; TEAI, tetraethylammonium iodide), indicating the key role of SEs containing fluoroborate in the electrochemical ring-expansion reaction.

[0038] Example 2

[0039] Preparation of Rh-catalyst-modified carbon felt (Rh-NPs / CF): Rh nanocatalysts were loaded onto carbon felt (1 cm × 1 cm) by electrodeposition, with graphite rod electrodes and Ag / AgCl electrodes (in saturated KCl solution) serving as counter and reference electrodes. The electrolyte was a deionized (DI) aqueous solution containing 0.5 M Na2SO4 (as a supporting electrolyte) and 5 mM rhodium nitrate solution (Rh(NO3)3) for the preparation of Rh nanocatalysts. The Rh nanocatalysts were then tested at a scan rate of 0.1 V·s -1 In the case of , CV scans (50 cycles) were performed in the potential range of -0.5 to 1.7 V. After the electrodeposition process, the Rh catalyst-modified carbon felt was washed with deionized water and then dried in air for subsequent testing and characterization.

[0040] Electrochemical ring-expansion reaction of 2-methyl-4-phenyl-oxazoline: An Ag / AgCl electrode (in a saturated KCl solution), a graphite rod electrode, and Rh catalyst-modified carbon felt (Rh-NPs / CF) were used as the reference electrode, counter electrode, and working electrode, respectively. In this example, all working electrodes used had the same geometric surface area (1 cm × 1 cm). In the electrochemical reaction, 30 ml of acetonitrile containing 100 mM epoxide and a supporting electrolyte (an ionic liquid containing fluoroborate: [emim]BF4 (1-ethyl-3-methylimidazolium tetrafluoroborate), 100 mM) was used. After completion of the reaction, the reaction solution was concentrated under reduced pressure on a rotary evaporator. The corresponding product was dissolved in EtOAc solvent, shaken thoroughly with deionized water, and then allowed to stand for stratification. After separation, the product was shaken thoroughly with a saturated NaHCO3 solution, allowed to stand for stratification, and finally the organic layer product was separated. The obtained organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained product was purified by silica gel chromatography using petroleum ether / ethyl acetate as eluent to extract the target product 2-methyl-4-phenyl-oxazoline.

[0041] Figure 3 A details the standard reaction conditions for the electrochemical pathway to generate product 2a. Low and high magnification transmission electron microscopy images are shown in Figure 3 BC shows the microstructure of the Rh-NPs sample. The characteristic SEM image shows a hierarchical one-dimensional (1D) structure with interconnected carbon fibers, and the catalyst particles attached to the surface of the carbon fibers ( Figure 3 D). The initial cyclic voltammetry (CV) in the presence of [emim]BF4 shows a sharp redox peak, indicating the occurrence of the target electrochemical coupling reaction ( Figure 3 E). Screening results of the isolated yield of 2a obtained using different cathode catalysts and supporting electrolytes (SEs) ( Figure 3 F) shows that the Rh-NPs / CF electrode exhibits the best performance when paired with [emim]BF4 SE. The purity of the product 2a before and after the 8-h reaction was evaluated by gas chromatography-mass spectrometry (GC-MS) analysis ( Figure 3 G). In the isotope-labeled experiment, the peak shift from m / z = 131 and 161 to m / z = 134 and 164 indicated that deuterated acetonitrile molecules (CD3CN) were successfully introduced into 1a ( Figure 3 HI). Using Rh-NPs / CF cathode catalyst and [emim]BF4 as SE, the cumulative yield of 2a increased steadily with the extension of reaction time, reaching a peak of about 87% after 8 hours ( Figure 3 J).

[0042] Theoretical calculations of the reaction pathways of the above two examples: Density functional theory (DFT) calculations were performed using the M06-2X functional to gain a deeper understanding of the ring expansion reaction mechanism of styrene oxide (1a) with acetone and acetonitrile as model molecules, as shown in Figure 2. Figure 4 A and Figure 4 C. Through research, it was found that when using various ionic liquids as supporting electrolytes (SE), only those based on tetrafluoroborate (BF4 - ) is the para-anion, and only when the ionic liquid acts as both a supporting electrolyte and a key medium can the ring expansion process of the epoxy substrate be triggered under negative bias. Computational analysis shows that the cooperative ring expansion reaction pathway is more kinetically favorable than the step-by-step reaction pathway, and its ΔΔG 4.0 kcal mol -1 , which helps to produce 2,2-dimethyl-4-phenyl-1,3-dioxolane (1b) ( Figure 4 A). And 23.1kcal mol -1 The lower activation energy barrier value is consistent with the mild reaction conditions used in the electrochemical ring expansion experiments in this invention. Similarly, the reaction between the styrene oxide substrate (1a) and acetonitrile follows a similar pathway ( Figure 4 C). The key [3+2] ring expansion step requires 25.2 kcal mol -1 The activation energy barrier of acetonitrile is slightly higher than that of acetone, which also explains the experimental observation that the reaction rate of acetonitrile is slower than that of acetone. Figure 4 B and Figure 4 D shows the visualization of the electrostatic interactions of the transition state on the electrostatic potential (ESP) surface, indicating that the transition state of the reaction between substrate 1a and acetone exhibits stronger electrostatic attraction.

[0043] Finally, it should be noted that the above-described embodiments merely represent several implementation methods of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made by a person skilled in the art without departing from the spirit of the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention should be based on the appended claims.

Claims

1. A method for synthesizing 1,3-dioxolane and oxazoline derivatives via a fluoroborate-mediated electrochemical [3+2] ring expansion strategy, characterized in that: The following steps are involved: An Ag / AgCl electrode, a graphite rod electrode, and a noble metal cathode were used as the reference electrode, counter electrode, and working electrode, respectively. The electrolyte was acetone or acetonitrile containing an epoxide and a supporting electrolyte, wherein the supporting electrolyte was an ionic liquid containing fluoroborate. The electrochemical reaction was carried out at a current density of 20 mA / cm 2 After the reaction is completed, the reaction solution is concentrated under reduced pressure in a rotary evaporator; the concentrated reaction solution is extracted, the obtained organic layer is dried, filtered, and concentrated under reduced pressure, and the obtained product is purified by silica gel chromatography, and the target product 1,3-dioxolane derivative or oxazoline derivative is extracted by elution; Wherein, the epoxide is styrene oxide, the 1,3-dioxolane derivative is 2,2-dimethyl-4-phenyl-1,3-dioxolane, and the oxazoline derivative is 2-methyl-4-phenyl-oxazoline.

2. The method according to claim 1, wherein: The concentration of the epoxide in the acetone or acetonitrile is 40-100 mM, and the concentration of the supporting electrolyte is 20-100 mM.

3. The method according to claim 1, wherein: The concentrated reaction solution was extracted with EtOAc solution, and the obtained organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained product was purified by silica gel chromatography using petroleum ether / ethyl acetate as eluent to extract the target product 1,3-dioxolane derivative or oxazoline derivative.

4. The method according to claim 1, wherein: The supporting electrolyte is [emim]BF4, Bu4NBF4 or Et4NBF4.

5. The method according to claim 1, wherein: The noble metal cathode is a carbon felt loaded with a catalyst, and the catalyst loaded on the carbon felt is a single metal catalyst, a bimetallic catalyst or a ternary RhRuPt catalyst; the single metal catalyst is Rh, Pt, Ru, Pd or Au catalyst; the bimetallic catalyst is RhPt or AuPt catalyst.

6. The method according to claim 5, characterized in that: The specific preparation steps of the catalyst-loaded carbon felt are as follows: the catalyst is loaded onto the carbon felt by electrodeposition, a graphite rod electrode and an Ag / AgCl electrode are used as the counter electrode and the reference electrode, the electrolyte is an aqueous solution containing a supporting electrolyte and a noble metal salt, and the scanning rate is 0.1 V·s -1 In the case of , CV scans were performed in the potential range of -0.5 to 1.7 V; after the electrodeposition process, the catalyst-loaded carbon felt was washed with deionized water and then dried in air.

7. The method according to claim 6, characterized in that: The supporting electrolyte used in the electrodeposition method is Na2SO4.

8. The method according to claim 6, wherein: The noble metal salt is a monometallic salt, a bimetallic salt or a trimetallic salt. The monometallic salt is rhodium nitrate, platinum chlorate hexahydrate, ruthenium nitrosyl nitrate, palladium nitrate dihydrate or chloroauric acid trihydrate; the bimetallic salt is a mixture of rhodium nitrate and platinum chlorate hexahydrate or a mixture of chloroauric acid trihydrate and platinum chlorate hexahydrate; and the trimetallic salt is a mixture of rhodium nitrate, platinum chlorate hexahydrate and ruthenium nitrosyl nitrate.

9. The method according to claim 6, wherein: The concentration of each metal salt in the electrolyte is 2-10 mM.

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