CN102452868B - LJ reacts the application in palladium catalysis cross-coupling reaction - Google Patents

Abstract

The present invention relates to isomerization reaction in a kind of LJ molecule, application in palladium catalysis cross-coupling reaction, application phosphorus pentahalides substitutes palladium series metal catalyst, not only can make existing most of palladium catalysis cross-coupling reaction improve yield, reduce costs, and, in the cross-coupling reaction of new from now on generation C-C key, can substantially not use palladium catalyst series, reach same good effect, be especially more suitable in the industrialization technology of realizing cross-coupling reaction.

Description

Application of LJ Reaction in Palladium-Catalyzed Cross-Coupling Reaction

The present invention relates to a kind of LJ intramolecular isomerization reaction, the application in palladium-catalyzed cross-coupling reaction, application phosphorus pentahalide replaces palladium series metal catalyst, not only can make most of existing palladium-catalyzed cross-coupling reactions improve the yield , reduce cost, and, in the new cross-coupling reaction of generating C-C bonds in the future, palladium series catalysts can be basically not used to achieve the same excellent effect, especially the industrial technology that is more suitable for realizing cross-coupling reactions.

Background technique

Palladium-catalyzed cross-coupling reaction is an important reaction to generate C-C bonds. Powerful anticancer drugs, efficient organic pesticides, and thin-film displays that can emit light by themselves are all composed of complex organic molecules. If there is no palladium-catalyzed cross-coupling reaction , it is very difficult to artificially synthesize these molecules. This is due to the inactive chemical properties of carbon atoms. It is not easy to combine carbon atoms from different molecules with each other. Three scientists from the United States and Japan used palladium atoms as a bridge ", and finally made carbon atoms of different "origins" come together and combine with each other, so that a large number of new medicines and new industrial materials came into being. This outstanding achievement won them the 2010 Nobel Prize in Chemistry. Today, the palladium-catalyzed cross-coupling reaction has been continuously improved, and has gained an important position in the chemical and industrial circles. It is used in the synthesis research and industrial production of many substances, and has already been imperceptibly incorporated into various commodities that are in contact with production and life. However, The problem is that the reagents used for this reaction, such as organozinc, organoboron, and organotin, also require multiple steps to be prepared, which costs a lot of money, especially palladium, which is a precious metal with a higher value than gold, is not suitable for this reaction. The application of large-scale and large-scale industrial production, so at present, scientific research institutions in many countries are developing more direct methods in order to further reduce the cost of preparation.

Contents of the invention

The purpose of the present invention is to use a kind of LJ reaction independently developed in my country and its new law to provide phosphorus pentahalide as a substitute for palladium series catalysts, and to replace palladium catalyzed cross-coupling with alcohols or phenols and their alkali metal salt compounds The organic zinc, organic boron, organic tin and other reagents in the reaction can not only achieve the purpose of palladium-catalyzed cross-coupling reaction, but also greatly reduce the preparation cost, and are more suitable for the industrial design standard of clean production process.

Regarding the LJ reaction, you can refer to the three documents with the application numbers 201010237200.0, 201010264912.1, and 201010258143.4 that the applicant for the patent of the present invention has applied for. The specific invention content of the invention patent application.

7. Application of LJ reaction in palladium-catalyzed cross-coupling reaction

Heck, Negishi, and Suzuki have won the 2010 Nobel Prize in Chemistry for their palladium-catalyzed cross-coupling reaction. The classic "Suzuki reaction" is shown in formula (1)

Ar ¹ -Met+Ar ² -LG+Pd(PPh ₃ ) ₄ →Ar ¹ -Ar ² (1)

1234

In formula (1), Met represents ZnX, B(OH) ₂ , SnR ₃ , 1 represents organic zinc, organoboron, organotin and other compounds; in 2, LG represents halogen, OTf, etc., and 3 represents phosphine-palladium ligand catalyst , 4 things represent the target compound of the reaction, Ar ¹ and Ar ² represent various aryl compounds, alkyl compounds, heterocyclic compounds and the like.

Apply a new law of LJ reaction: when the P atom of the five-coordinated phosphorus (phosphine) compound without phosphorus double bond forms a single bond with at least one O or S atom, under acidic conditions, especially the P atom At the same time as there are electron-withdrawing groups, because of its particularly strong composition or The trend of the double bond group, this kind of compound is very unstable, after heating, it will automatically split into two or more compounds, one of which must be a phosphorus-oxygen double bond four-coordination compound or a phosphorus-sulfur double bond four-coordination compound, and the other One is the compound 8 that forms a new CC bond, so there can be formula (2)

In the reaction process, Ar in the formula (2) ¹ is a compound that can form a carbanion, and Ar ² is a compound that can form a carbanion, so its reactivity is stronger than the activity of the same reaction catalyzed by palladium, Ar ¹ and Ar ² means the same meaning as formula (1).

In formula (2), M ¹ represents elements such as H (hydrogen), Li (lithium), Na (sodium), Al (aluminum), magnesium; M ² represents elements such as Li, Na, Al, magnesium; 5 objects represent alcohol or Phenols or heterocyclic compounds, 6 objects represent hydrocarbon groups or aryl groups or heterocyclic compounds, Z represents halogen or hydrocarbon groups or alkoxy groups or aryloxy groups, X represents halogen, 7 objects represent acyl dihalide compounds, of which there are three Phenyl phosphorus dichloride, trialkoxy phosphorus dichloride, triphenol-based phosphorus dichloride, etc.; 8 and 4 in formula (1) are completely identical compounds, due to the replacement of the reagent: 5 replacements 1, 6 replaced 2, and 7 replaced 3, so on the one hand, the regioselectivity of the "Suzuki reaction" can be completely retained to achieve the same effect. On the other hand, it is precisely because the replacement becomes a cheap and easy-to-prepare reagent, Moreover, it is a reaction reagent with higher reactivity and easier post-reaction treatment, so the preparation cost can be reduced to a large extent, and it is more suitable for industrial design of clean production.

The preparation of compound 8 involves several steps in the following order:

1112

Under acidic conditions, 11 or 12 is unstable and splits automatically after heating:

In formula (3), 8 is the target compound of palladium-catalyzed cross-coupling reaction.

7.1 Preparation of biphenyl

Biphenyl is an important organic raw material, which is widely used in medicine, pesticides, dyes, liquid crystal materials and other fields. Biphenyl exists in coal tar, crude oil and natural gas. The existing synthesis method requires a high temperature of 300 ° C and harsh reaction conditions. " "Suzuki reaction" to prepare biphenyl, the cost is too high, so the LJ reaction is the best choice.

The preparation of biphenyl by the LJ reaction involves several steps in the following order:

7.2 Application of LJ reaction in Suzuki-Miyaura reaction

If the traditional palladium-catalyzed cross-coupling reaction is used to prepare compound 17, the corresponding organoboronic acid compound must be prepared first, the reaction steps are more, and expensive phosphine-palladium ligand catalyst must be used, while the preparation of compound 17 by LJ reaction reduces the cost by 25% %above.

Compound 17 was prepared, comprising several steps in the following order:

7.3 Application of LJ reaction in Stille reaction

If the traditional Stille reaction is used to prepare compound 19, the aryl tin compound must be prepared first, and the reaction steps are increased. Moreover, the expensive phosphine-palladium ligand catalyst must be used, while the LJ reaction reduces the cost by more than 20%.

The preparation of compound 19 involves several steps in the following order:

specific implementation plan

Example 1 Molecular ratio: sodium phenate: PCl ₅ : phenyl lithium = 1: 1: 1

Under the condition of isolating air and water, put 40 grams of PCl ₅ and 200 grams of CCl ₄ into the reactor, start stirring, control the temperature below -15°C, slowly add the calculated amount of sodium phenate, and keep it warm for about 1 hour. In the process, the generated NaCl was continuously filtered out through an external circulation, and 13 compounds were generated at this time, with a yield of 98%.

Throw a calculated amount _of benzene, AlCl3 and 120 grams of _CCl4 into the reaction flask, start stirring, control the temperature and reflux, add dropwise the 13 compound _CCl4 solution of cold insulation, after the dripping is completed, keep the temperature for 1 hour, during the process, continuously The by-product phosphorus oxychloride is distilled out azeotropically, and at the same time, continuously add CCl ₄ solvent. After the reaction reaches the end point, distill off CCl ₄ , add 400 grams of 70% methanol aqueous solution for extraction, cool down, filter, and remove AlCl ₃ ·H ₂ O solid, then distill the mother liquor, crystallize, filter and dry to obtain the biphenyl product with a content of 97% and a yield of 95%.

Example 2 Molecular ratio: 20 compounds: PCl ₅ : Lithium o-toluene=1: 2: 1

Under the protection of nitrogen, put 40 grams of PCl ₅ and 200 grams of CCl ₄ solution into the reactor, start stirring, control the temperature below 20 ° C, drop the calculated amount of 20 compound and o-toluene lithium mixed solution, keep the reaction for 11 hours, the process The LiCl solid produced simultaneously is continuously filtered through the external circulation, and then the temperature is raised to reflux. After the reaction reaches the end point, the phosphorus oxychloride is slowly evaporated, and then the temperature is raised to 160-170°C to sublimate the PCl ₅ , which is recovered and used mechanically. Cool down, wash the remaining PCl ₅ with 5% NaOH alkaline water, add 200 g of CCl ₄ to dissolve and extract, separate layers, collect the organic layer for distillation, cool down, stand still, crystallize, filter, and dry to obtain 17 compounds with a content of 95%. , yield 92%.

Example 3

Molecular ratio: 21 compounds: triphenylphosphine dichloride: alkyl lithium = 1:1:1

Under the condition of isolating air and water, put 40 grams of triphenylphosphine dichloride and 280 grams of n-hexane into the reactor, start stirring, control the temperature below -5°C, slowly add the calculated amount of compound 21, and keep warm for the reaction 1 hour, during the process, the generated LiCl was continuously filtered out through the external circulation, and 18 compounds were generated at this time, with a yield of 98%;

Put the calculated amount of o-methyllithium and 120 grams of n-hexane into the reactor, start stirring, control the temperature and reflux, add dropwise the 18 compound n-hexane solution of cold insulation, after the drop, keep the temperature for 1 hour, during the process, through the external circulation The generated lithium chloride solid was continuously filtered out, and after the reaction reached the end point, the solvent was evaporated, and the distillation substrate was a mixture of compound 19 and triphenylphosphine oxide, and the reaction yield was 95%.

The preparation of embodiment 4 biphenyls

Molecular ratio: lithium phenate: PCl ₅ : phenyl lithium = 1:1～2:1

Under the condition of isolating air and water, 40 grams of PCl ₅ and 400 grams of CCl ₄ are dropped into the reactor, the stirring is started, the temperature is raised to reflux, and the calculated amount of lithium phenate and CCl ₄ mixed solution of phenyllithium is added dropwise. During the process, The by-product phosphorus oxychloride is continuously distilled off azeotropically, at the same time, _CCl solvent is added accordingly, and the LiCl generated synchronously is continuously filtered out through the external circulation, and the gas chromatographic normalization method is used to control and analyze the reaction system. After the PCl ₅ content reaches the requirement (≤1%), it is the end point of the reaction, lower the temperature, wash off the excess PCl ₅ with alkaline water, separate layers, distill, crystallize, filter, and dry to obtain biphenyl with a content of 88% and a yield of 90% %.

Claims (1)

1. Preparation of 17 compounds, including several steps in the following order: Wherein, molecular ratio: 20 compounds: PCl ₅ : o-toluene lithium=1:2:1 Under the protection of nitrogen, put 40 grams of PCl ₅ and 200 grams of CCl ₄ solution into the reactor, start stirring, control the temperature below 20 ° C, drop the calculated amount of 20 compound and o-toluene lithium mixed solution, keep the reaction for 11 hours, the process The LiCl solid produced simultaneously is continuously filtered through the external circulation, and then the temperature is raised to reflux. After the reaction reaches the end point, the phosphorus oxychloride is slowly evaporated, and then the temperature is raised to 160-170°C to sublimate the PCl ₅ , which is recovered and used mechanically. Cool down, wash the remaining PCl ₅ with 5% NaOH alkaline water, add 200 g of CCl ₄ to dissolve and extract, separate layers, collect the organic layer for distillation, cool down, stand still, crystallize, filter, and dry to obtain 17 compounds with a content of 95%. , yield 92%.