Preparation method for green construction of formyloxy group
The synthesis of formyloxy compounds by using benzyl bromide or α-bromophenone compounds, N,N-dimethylformamide and water as raw materials is solved, and the problems of high cost, poor selectivity and environmental pollution in the prior art are achieved, and high selectivity and low cost green synthesis is achieved.
Patent Information
- Application Number
- CN202510550190.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-29
- Publication Date
- 2025-08-05
AI Technical Summary
The methods for synthesizing formyloxy groups in the prior art have high cost, poor selectivity and are unfavorable to the development of drugs or biologically active compounds, and the use of transition metal catalysts is contaminated to the environment.
The benzyl bromide or α-bromophenone compounds, N,N-dimethylformamide and water are used as raw materials, and the reaction is carried out under the protection of argon. By adjusting the dosage ratio of N,N-dimethylformamide and water, the hydrolysis of benzyl bromide is inhibited, nucleophilic addition is achieved, and formyloxy compounds are formed. The final product is obtained after extraction, concentration and column chromatography.
The highly selective synthesis of formyloxy compounds is achieved, which reduces the occurrence of side reactions, reduces production costs, and reduces environmental pollution.
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Figure CN120423952A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a green preparation method for constructing formyloxy groups. Background Art
[0002] The formyloxy group is a unique structural unit whose introduction has significantly impacted the molecular properties of many pharmaceuticals and natural flavorings, such as cephalosporin naphthoate, citronellyl formate, geranyl formate, styryl formate, and benzyl formate, leading to its widespread application in the fragrance industry and drug development. In organic synthesis, it serves as a crucial functional group in synthetic intermediates and can be used to synthesize other biologically active compounds.
[0003] Among the many schemes for synthesizing formyloxy groups, bromohydrocarbons are one of the starting materials for synthesizing formyloxy esters. Currently, there are two developed catalytic synthesis methods: AgBF4 / MeNO2-DMF and fac-Ir(ppy)3. Both methods use transition metals as catalysts, which have disadvantages such as high cost and poor selectivity. In addition, the products synthesized by metal catalysis are not conducive to the development of drugs or biologically active compounds. Summary of the Invention
[0004] In order to solve the problems existing in the above-mentioned prior art, the present invention provides a green preparation method for constructing formyloxy groups, wherein a compound containing formyloxy groups is synthesized using benzyl bromide or α-bromoacetophenone compounds, N,N-dimethylformamide, and H2O. The preparation process is simple and does not require additional catalysts, greatly reduces the occurrence of side reactions, has high selectivity, improves the purity of the final product, and also reduces pollution to the environment and reduces production costs.
[0005] The specific technical solution adopted in the present invention is:
[0006] A green preparation method for constructing formyloxy groups comprises the following steps:
[0007] S1. Add the bromide, N,N-dimethylformamide and water into a reaction tube, and introduce argon as a protective gas;
[0008] S2. Place the reaction tube at 55-65° C. for 4-8 hours to obtain a reaction solution;
[0009] S3, after the reaction solution is cooled to room temperature, it is extracted with ethyl acetate, the organic phase obtained by extraction is dried and concentrated, and then subjected to column chromatography to obtain a compound containing a formyloxy group;
[0010] The brominated compound is a benzyl bromide or an α-bromoacetophenone compound.
[0011] Furthermore, the molar ratio of the bromide to water in step S1 is 1:10-15.
[0012] Furthermore, the amount of N,N-dimethylformamide added in step S1 is 5-8 mL per mol of bromide.
[0013] Furthermore, the eluent used in the column chromatography is a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:10-20.
[0014] The beneficial effects of the present invention are:
[0015] The formyloxy compound in the present invention is synthesized at 60° C. using benzyl bromide or α-bromoacetophenone compounds as substrates, N,N-dimethylformamide as a “C” source, and H2O as an “O” source. The final product is obtained through extraction, concentration, and column chromatography, and its molecular structure is determined by nuclear magnetic resonance (NMR).
[0016] Compared to existing preparation methods, the present invention eliminates the need for a catalyst to inhibit the hydrolysis of benzyl bromide. By simply adjusting the ratio of N,N-dimethylformamide (2.0 mL) to HO (12.0 equiv.), and under argon protection, preventing HO from entering the reaction system, the benzyl bromide is surrounded by a large amount of N,N-dimethylformamide, selectively inhibiting its hydrolysis. This allows for nucleophilic addition of benzyl bromide to N,N-dimethylformamide, resulting in an iminium salt that is then hydrolyzed to yield a compound containing a formyloxy group.
[0017] The preparation process of the present invention is simple and does not require additional catalysts, which greatly reduces the occurrence of side reactions, while also reducing pollution to the environment and reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 is the reaction equation of the present invention;
[0019] Figure 2 The structural formula and yield of the pure product obtained in Examples 1-8;
[0020] Figure 3 This is the hydrogen spectrum of product 3a in Example 1;
[0021] Figure 4 This is the carbon spectrum of product 3a in Example 1;
[0022] Figure 5 This is the hydrogen spectrum of product 3b in Example 2;
[0023] Figure 6 This is the carbon spectrum of product 3b in Example 2;
[0024] Figure 7This is the hydrogen spectrum of product 3c of Example 3;
[0025] Figure 8 This is the carbon spectrum of product 3c of Example 3;
[0026] Figure 9 This is the 3d hydrogen spectrum of the product of Example 4;
[0027] Figure 10 This is the 3d carbon spectrum of the product of Example 4;
[0028] Figure 11 This is the hydrogen spectrum of the product 3e of Example 5;
[0029] Figure 12 This is the carbon spectrum of product 3e in Example 5;
[0030] Figure 13 This is the hydrogen spectrum of product 4a in Example 6;
[0031] Figure 14 This is the carbon spectrum of product 4a in Example 6;
[0032] Figure 15 This is the hydrogen spectrum of product 4b of Example 7;
[0033] Figure 16 This is the carbon spectrum of product 4b of Example 7;
[0034] Figure 17 This is the hydrogen spectrum of the product 4c of Example 8;
[0035] Figure 18 This is the carbon spectrum of the product 4c in Example 8;
[0036] Figure 19 This is the high resolution mass spectrum (HRMS) of the product 3b of Example 2. DETAILED DESCRIPTION
[0037] The present invention will be further described below with reference to the accompanying drawings and specific embodiments: 1. Specific embodiments
[0039] The silica gel (200-300 mesh) and thin layer chromatography silica gel plate (TLC) used in the column chromatography of the present invention are both domestically produced. The high-resolution mass spectrometer (HRMS) is equipped with an ESI ionization source and a Q-TOF detector, and the nuclear magnetic resonance spectrometer (NMR) is a Varian Mercury plus-400 and an Agilent 600MHz DD2.
[0040] Example 1
[0041] S1. Add 0.3 mmol of 4-methylbenzyl bromide, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0042] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0043] S3. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate. The organic phase obtained by extraction was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 4-tert-butylbenzyl formate was obtained by column chromatography (ethyl acetate / petroleum ether = 1:20).
[0044] Example 2
[0045] S1. Add 0.3 mmol of 3,5-dimethoxybenzyl bromide, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be replaced with argon at least three times.
[0046] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0047] S3. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate. The organic phase obtained by extraction was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 3,5-dimethoxybenzyl formate was obtained by column chromatography (ethyl acetate / petroleum ether = 1:20).
[0048] Example 3
[0049] S1. Add 0.3 mmol of 3-cyanobenzyl bromide, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0050] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0051] S3. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate. The organic phase obtained by extraction was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 3-cyanobenzyl formate was obtained by column chromatography (ethyl acetate / petroleum ether = 1:20).
[0052] Example 4
[0053] S1. Add 0.3 mmol of 2-nitrobenzyl bromide, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0054] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0055] S3. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate. The organic phase obtained by extraction was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 2-nitrobenzyl formate was obtained by column chromatography (ethyl acetate / petroleum ether = 1:10).
[0056] Example 5
[0057] S1. Add 0.3 mmol of 2-naphthylbenzyl bromide, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0058] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0059] S3. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate. The organic phase obtained by extraction was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 2-naphthylmethyl formate was obtained by column chromatography (ethyl acetate / petroleum ether = 1:15).
[0060] Example 6
[0061] S1. Add 0.3 mmol of α-bromoacetophenone, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0062] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0063] S3. After the reaction solution is cooled to room temperature, it is extracted with ethyl acetate. The organic phase obtained by extraction is dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 2-oxo-2-phenylethyl formate is obtained by column chromatography (ethyl acetate / petroleum ether = 1:20).
[0064] Example 7
[0065] S1. Add 0.3 mmol of 3'-nitro-α-bromoacetophenone, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0066] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0067] S3. After the reaction solution is cooled to room temperature, it is extracted with ethyl acetate. The organic phase obtained by extraction is dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 2-(3-nitrophenyl)-2-oxoethyl formate is obtained by column chromatography (ethyl acetate / petroleum ether = 1:10).
[0068] Example 8
[0069] S1. Add 0.3 mmol of α-bromo-4-chloroacetophenone, 2.0 mL of N,N-dimethylformamide, and 3.6 mmol of water sequentially into a pre-dried 25 mL Schlenk tube. The Schlenk tube needs to be purged with argon at least three times.
[0070] S2. Place the Schlenk tube containing the raw materials in a sand bath at 60°C and react for 6 hours to obtain a reaction solution;
[0071] S3. After the reaction solution is cooled to room temperature, it is extracted with ethyl acetate. The organic phase obtained by extraction is dried over anhydrous Na2SO4 and then concentrated under reduced pressure. 2-(4-chlorophenyl)-2-oxoethyl formate is obtained by column chromatography (ethyl acetate / petroleum ether = 1:20).
[0072] Comparative Example 1
[0073] S1. Under argon protection, dissolve 0.15 mmol of benzyl bromide in 1.75 mL of N,N-dimethylformamide (DMF) and add the solution to 4.4 mL of a stirring nitromethane (CH3NO2) solution containing 252 mg (1.3 mmol) of silver tetrafluoroborate (AgBF4).
[0074] S2. Wrap the reaction tube containing the raw materials with aluminum foil (to prevent photoreduction of the silver salt) and allow to react at room temperature for 12 h to obtain a reaction solution;
[0075] S3. The reaction solution was filtered through celite and washed with 40-50 mL of ether (Et2O). The filtrate was washed sequentially with water (3 x 10 mL) and brine (10 mL), and then dried. The solvent was removed in vacuo, and the resulting residue was purified by column chromatography to obtain the benzyl formate.
[0076] The difference between Comparative Example 1 and Example 1 is that the reaction mode is different. In Comparative Example 1, under the catalysis of monovalent silver (Ag(I)), the reaction is changed from a bimolecular nucleophilic substitution reaction (S N 2) Transformation into a unimolecular nucleophilic substitution reaction (S N 1), a quaternary ammonium salt that is easily hydrolyzed is formed at room temperature. Example 1 does not require additional catalysts. By adjusting the ratio of N,N-dimethylformamide (2.0 mL) and H2O (12.0 equiv.), increasing the appropriate reaction temperature (60 ° C), a bimolecular nucleophilic substitution (S N 2) forms a quaternary ammonium salt that can be hydrolyzed into benzyl formate, and also eliminates the use of the highly toxic solvent nitromethane (CH3NO2), simplifies post-processing, reduces pollution to the environment, and is more in line with the requirements of green synthesis.
[0077] 2. Ingredient Testing
[0078] The reaction equations for obtaining the pure substances in Examples 1-8 are shown in Figure 1 , structural formula and yield see Figure 2 , nuclear magnetic resonance (NMR) spectrum 1 H NMR and 13 C NMR see Figure 2-18 HRMS (ESI) m / z of the product 3b of Example 2: [M+Na]+Calcd for C 10 H 12 NaO4 219.0628; Found 219.0624, see Figure 19 .
Claims
1. A green preparation method for constructing formyloxy, characterized in that: The following steps are involved: S1. Add the bromide, N,N-dimethylformamide and water into a reaction tube, and introduce argon as a protective gas; S2. Place the reaction tube at 55-65° C. for 4-8 hours to obtain a reaction solution; S3, after the reaction solution is cooled to room temperature, it is extracted with ethyl acetate, the organic phase obtained by extraction is dried and concentrated, and then subjected to column chromatography to obtain a compound containing a formyloxy group; The bromide is a benzyl bromide or an α-bromoacetophenone compound; The chemical structural formula of the benzyl bromide is The chemical structural formula of the α-bromoacetophenone compound is 2. A green method for preparing formyloxy according to claim 1, characterized in that: The molar ratio of the bromide to water in step S1 is 1:10-15.
3. A green method for preparing formyloxy according to claim 1, characterized in that: The amount of N,N-dimethylformamide added in step S1 is 5-8 mL per mol of bromide.
4. A green method for preparing formyloxy according to claim 1, characterized in that: The eluent used in the column chromatography is a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:10-20.