A kind of preparation method of o-cyanobenzaldehyde

Abstract

The invention discloses a method for preparing o-cyanobenzaldehyde, and belongs to the technical field of organic chemical synthesis methods. Specifically, the method relates to a method for synthesizing o-cyanobenzaldehyde by reacting o-bromobenzaldehyde with non-toxic ferrocyanide under palladium catalysis. The method adjusts the speed of ferrocyanide transferring cyano groups to palladium by adding a cuprous additive, which can not only maintain a faster reaction speed, but also effectively avoid the problem of palladium catalyst deactivation caused by cyano coordination saturation; at the same time, it can effectively reduce the amount of metal palladium catalyst loading; thereby realizing the cyanation reaction of o-bromobenzaldehyde under relatively mild reaction conditions, and effectively avoiding possible side reactions of formyl groups in raw materials and products.

Description

Technical Field

[0001] The invention relates to a method for preparing o-cyanobenzaldehyde, and in particular to a method for synthesizing o-cyanobenzaldehyde by reacting o-bromobenzaldehyde with non-toxic ferrocyanide under palladium catalysis. Background Art

[0002] Aromatic cyano compounds are a very important class of organic compounds. They are important components of dyes, herbicides, pesticides, medicines and many natural products. They are also widely used in organic synthesis. At the same time, aromatic cyano compounds are also important organic synthesis intermediates and can be converted into a series of functional substances such as carboxylic acids, aldehydes, amides, ketones, etc. There are many methods for preparing aromatic cyano compounds that have been reported. Among them, the Sandmeyer reaction and Rosenmund-von Braun reaction using cuprous cyanide are the two most classic methods. These two methods use chemically equivalent CuCN and need to be carried out at very high temperatures, making the reaction conditions harsh and causing heavy metal pollution problems. Since then, in order to develop green and environmentally friendly cyanation reaction pathways, some chemists have focused on the development of new cyanation reagents. These widely used cyanation reagents include sodium cyanide (NaCN), potassium cyanide (KCN), trimethylsilyl cyanide (TMSCN), etc. The first two reagents are highly toxic, while the latter is sensitive to moisture and easily releases toxic gas hydrogen cyanide during the reaction. These problems severely limit the industrialization of the use of such cyanation reagents for aromatic cyanation reactions. In order to overcome these problems, chemists turned to looking for some cyanation reagents that are less toxic or non-toxic and can be easily handled without special precautions as cyanide sources. In 2004, Beller reported the first use of K4Fe(CN)6 (potassium ferrocyanide) as a cyanide source for cyanation of halogenated aromatic hydrocarbons; compared with cyanation reagents such as alkali metal cyanides, potassium ferrocyanide can release cyanide to participate in cyanation reactions under appropriate reaction conditions and is non-toxic; potassium ferrocyanide is widely added to household salt for moisture-proofing, and its safety can be seen. The existing synthetic reaction using potassium ferrocyanide as a cyanation reagent has the main problem of limited substrate range, and the functional groups in the substrate are prone to side reactions, such as being incompatible with the formyl group contained in the reaction raw material structure involved in this patent; due to the strong coordination ability of cyanide with ferrous ions in the structure of potassium ferrocyanide, the cyanide release rate is very slow, resulting in slow reaction speed, long reaction time, and even low yield. Therefore, it is necessary to develop a green, environmentally friendly and efficient method to synthesize cyanobenzaldehyde. The present invention adjusts the speed of ferrocyanide transferring cyano to palladium by adding a cuprous additive, which can not only maintain a faster reaction speed, but also effectively avoid the problem of palladium catalyst deactivation caused by cyano coordination saturation; at the same time, it can effectively reduce the amount of metal palladium catalyst loading; thereby realizing the cyanation reaction of o-bromobenzaldehyde under relatively mild reaction conditions, effectively avoiding the side reactions that may occur in the formyl group in the raw materials and products. Summary of the invention

[0003] The invention aims to provide a green and environmentally friendly method for synthesizing o-cyanobenzaldehyde by cyanation reaction of o-bromobenzaldehyde using non-toxic ferrocyanide as a cyanide source, in view of the defects of the existing cyaniding reagents such as high toxicity, unsafe operation process and waste, harsh reaction conditions and poor compatibility of substrate functional groups.

[0004] The technical scheme of the invention is: taking o-benzaldehyde as a raw material, ferrocyanide as a cyanide source, cuprous as an additive, selecting a suitable organic solvent and a base, controlling the reaction temperature to be 60-140 DEG C, the reaction time to be 6-48h, and preparing o-cyanobenzaldehyde under the action of a metal palladium catalyst.

[0005] The structural formula of the cyanation reaction is shown below:

[0006]

[0007] The molar ratio of the ferrocyanide as the cyanide source to the reactant o-bromobenzaldehyde is (0.1-1.0):1; the cyanation reagent is any one of potassium ferrocyanide, sodium ferrocyanide and tetramethylammonium ferrohydride.

[0008] The above-mentioned palladium catalyst is composed of palladium and a ligand, and the molar ratio of palladium to the ligand is: 1: (0.5-2); wherein the palladium is any one of palladium chloride, palladium bromide, palladium acetate, palladium hydroxide, and palladium oxide; the ligand is any one of Xantphos (4,5-bis (diphenylphosphine) -9,9-dimethylxanthene), 2- (di-tert-butylphosphine) biphenyl, BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), DPPE (1,2-bis (diphenylphosphino) ethane), and the structural formula of the ligand is shown as follows:

[0009]

[0010] The molar ratio of the palladium catalyst used to the reactant o-bromobenzaldehyde is (0.0001-0.1):1.

[0011] The above-mentioned base is an organic base or an inorganic base, and the molar ratio of the base to the reactant o-bromobenzaldehyde is (0.01-0.10):1; the organic base is any one of DIPEA (N,N-diisopropylethylamine), triethylamine, and triethanolamine; the inorganic base is any one of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, and potassium acetate.

[0012] The cuprous additive is any one of cuprous iodide, cuprous chloride and cuprous bromide; the molar ratio of the halogenated cuprous additive to the reactant o-bromobenzaldehyde is (0.01-0.50):1.

[0013] The organic solvent is any one of DMAC (N,N-dimethylacetamide), DMF (N,N-dimethylformamide) or NMP (N-methylpyrrolidone), and its usage is 1-20 times of the mass of the reactant o-bromobenzaldehyde.

[0014] The reaction temperature of the above method is 60-140°C and the reaction time is 6-48h.

[0015] The present invention adopts a palladium catalyst, in an organic solvent, at 60-140° C., the reaction time is 6-48 hours, and o-bromobenzaldehyde is efficiently converted into o-cyanated benzaldehyde, and the reaction yield is 60% to 96%. Non-toxic green ferrocyanide is used as a cyanide source, which reduces the environmental pollution problem of cyanobenzaldehyde synthesis. Halogenated cuprous is used as an additive to adjust the release rate of cyanide in two cyanide sources, and under the condition of a lower loading of the noble metal palladium catalyst, the reaction speed and the reaction yield are effectively increased, while the compatibility of the reaction with the active functional group (formyl group) in the substrate is increased, and a hundred-gram-level amplification reaction can be performed. The reaction conditions are simple, easy to operate, and the product separation and purification are convenient, and there is a wide range of application prospects. DETAILED DESCRIPTION

[0016] Example 1: Preparation of o-cyanobenzaldehyde

[0017] The specific preparation method is: add a magnetic stirrer, palladium chloride (1mol%, 0.35mg), Xantphos (2mol%, 2.3mg), K4[Fe(CN)6] (0.4eq, 29.5mg), cuprous iodide (15mol%, 5.7mg), o-bromobenzaldehyde (0.2mmol, 37mg), and then add 1ml of a 4mol% DIPEA mixed solution of N,N-dimethylacetamide in an inert atmosphere, and then seal the reaction tube in an inert atmosphere, react at 120°C for 12h, and thin layer chromatography analysis shows that the raw material o-bromobenzaldehyde is completely consumed, stop heating, and cool; add saturated salt water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and separate by column chromatography; the yield of o-cyanobenzaldehyde is 90%. The product is a white solid with a melting point of 103-105°C; 1 H NMR (400MHz, CDCl3) δ: 10.33 (s, 1H), 8.03 (dd, J = 7.6, 1.2 Hz,1H),7.88(dd,J=7.6,1.2Hz,1H),7.78(td,J=7.2,1.2Hz,1H),7.74(td,J=7.2,1.2Hz,1H); 13C NMR (100MHz, CDCl3) δ188.60,136.77,134.27,134.13,133.26,129.67,116.00,113.80.

[0018] The reaction formula is as follows:

[0019]

[0020] Example 2: Preparation of o-cyanobenzaldehyde

[0021] The specific preparation method is as follows: a magnetic stirrer is added to a clean single-mouth reaction tube, palladium chloride (1 mol%, 0.35 mg), BINAP (2 mol%, 2.5 mg), K4[Fe(CN)6] (0.4 eq, 29.5 mg), cuprous iodide (20 mol%, 7.6 mg), o-bromobenzaldehyde (0.2 mmol, 37 mg), and K2CO3 (4 mol%, 1.1 mg) are added in sequence, and then the reaction tube is sealed in an inert atmosphere, and after reacting at 120° C. for 12 hours, thin layer chromatography analysis shows that the raw material o-bromobenzaldehyde is completely consumed, and heating is stopped and cooled; saturated brine is added, ethyl acetate is extracted, the organic phases are combined, dried over anhydrous sodium sulfate, and separated by column chromatography; the yield of o-cyanobenzaldehyde is 86%.

[0022] The reaction formula is as follows:

[0023]

[0024] Example 3: Preparation of o-cyanobenzaldehyde

[0025] The specific preparation method is as follows: a magnetic stirrer is sequentially added into a clean single-mouth reaction tube, palladium acetate (1 mol%, 44.9 mg), Xantphos (2 mol%, 231.4 mg), K4[Fe(CN)6] (0.4 eq, 2950 mg), cuprous chloride (15 mol%, 297 mg), o-bromobenzaldehyde (20 mmol, 3700 mg), and then 100 mL of a prepared 4 mol% DIPEA mixed solution in N,N-dimethylacetamide is added; then, in an inert atmosphere, the reaction tube is sealed, reacted at 80° C. for 48 hours, and thin-layer chromatography analysis shows that the raw material o-bromobenzaldehyde is completely consumed, and heating is stopped and cooled; saturated brine is added, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, and separated by column chromatography; the yield of o-cyanobenzaldehyde is 88%.

[0026] The reaction formula is as follows:

[0027]

[0028] Example 4: Scale-up preparation of o-cyanobenzaldehyde

[0029] The specific preparation method is as follows: a magnetic stirrer is sequentially added into a clean tetrafluoroethylene-lined reactor, palladium chloride (1 mol%, 3.5 g), Xantphos (2 mol%, 23 g), K4[Fe(CN)6] (0.4 eq, 295 g), cuprous iodide (15 mol%, 57 g), o-bromobenzaldehyde (2 mol, 370 g), and 10 L of a prepared 4 mol% DIPEA mixed solution in N,N-dimethylacetamide, and then the inert reactor is sealed, reacted at 120° C. for 12 hours, and thin layer chromatography analysis shows that the raw material o-bromobenzaldehyde is completely consumed, and heating is stopped and cooled; saturated brine is added, ethyl acetate is extracted, the organic phases are combined, dried over anhydrous sodium sulfate, and separated by column chromatography; the yield of o-cyanobenzaldehyde is 85%.

[0030] The reaction formula is as follows:

[0031]

Claims

1. A method for preparing o-cyanobenzaldehyde, characterized in that: Taking o-bromobenzaldehyde as raw material, potassium ferrocyanide as cyanide source, cuprous as additive, selecting organic solvent and base, controlling reaction temperature at 80-120°C, reaction time at 12-48h, and preparing o-cyanobenzaldehyde under the action of metal palladium catalyst; The molar ratio of ferrocyanide to o-bromobenzaldehyde is: 0.4:1; The palladium catalyst used in the reaction is composed of palladium chloride and a ligand or palladium acetate and a ligand; The ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; The molar ratio of palladium to ligand is 1:2; The organic solvent was N,N-dimethylacetamide and the base was DIPEA; The molar ratio of palladium catalyst to o-bromobenzaldehyde used was 0.01:1; The cuprous additive used is cuprous iodide, and the molar ratio of the cuprous additive to o-bromobenzaldehyde is 0.15:1.

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