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CN-121974846-A - Asymmetric synthesis method of axial chiral 2- (hetero) aryl pyridine N-oxide

CN121974846ACN 121974846 ACN121974846 ACN 121974846ACN-121974846-A

Abstract

The invention discloses an asymmetric synthesis method of an axial chiral 2- (hetero) aryl pyridine N-oxide, which comprises the following steps of taking a compound shown in a formula (I) and a compound shown in a formula (II) as raw materials, adding a palladium source, a silver source, a ligand, alkali and a solvent, replacing air by using nitrogen flow or directly operating in a glove box, and reacting to obtain the compound shown in the formula (III), wherein the reaction formula is as follows: Wherein the substituent R 1 is alkyl or hydrogen, the substituent R 2 is hydrogen, cyano, nitro, amido, ester or amino, the substituent R 3 is substituted phenyl, substituted naphthyl, substituted pyridine, substituted quinoline or substituted tetrahydronaphthalene, the hydrogen on the substituted phenyl, substituted naphthyl, substituted pyridine, substituted quinoline or substituted tetrahydronaphthalene is mono-substituted or poly-substituted, X is hydrogen, CH, phenyl or alkyl, and Y is hydrogen, CH, alkyl, difluorophenyl or phenyl. The N-oxide substrate synthesized by the method has the advantages of wide adaptability, mild reaction conditions, simple operation and good regioselectivity and enantioselectivity.

Inventors

  • LOU SHAOJIE
  • Xiong Lenan
  • YE PENG
  • MAO YANGJIE
  • XU DANQIAN
  • XU ZHENYUAN

Assignees

  • 浙江工业大学

Dates

Publication Date
20260505
Application Date
20251223

Claims (5)

  1. 1. An asymmetric synthesis method of an axichiral 2- (hetero) arylpyridine N-oxide is characterized by comprising the following steps of taking pyridine N-oxide shown in a formula (I) and a compound shown in a formula (II) as raw materials, adding a palladium source, a silver source, a ligand, alkali and a solvent, replacing air by using nitrogen flow or directly operating in a glove box, and reacting to obtain the axichiral 2- (hetero) arylpyridine N-oxide shown in a formula (III), wherein the reaction formula is as follows: , Wherein the substituent R 1 is alkyl or hydrogen, the substituent R 2 is hydrogen, cyano, nitro, amido, ester or amino, R 3 is substituted phenyl, substituted naphthyl, substituted pyridine, substituted quinoline or substituted tetrahydronaphthalene, the hydrogen on the substituted phenyl, substituted naphthyl, substituted pyridine, substituted quinoline or substituted tetrahydronaphthalene is mono-or polysubstituted, the substituent is alkoxy, benzyloxy, halogen, monofluoromethyl, difluoromethyl, aldehyde, methoxymethyl ether, ester, ethynyl phenyl, methoxyt-butyldimethylsilyl, chlorophenyl ethynyl, dichlorobenzyloxy or methylphenyloxy, X is hydrogen, CH, phenyl or alkyl, Y is hydrogen, CH, alkyl, difluorophenyl or phenyl; The ligand is one of (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl, (S) -2 '-methoxy-1, 1' -binaphthyl-2-yl diphenylphosphine, (R) -4, 12-bis (diphenylphosphino) - [2.2] naphthacene, (Sp, R) - [2- (diphenylphosphino) ferrocene ] ethyl dicyclohexylphosphine, (Rp, S) - [2- (diphenylphosphino) ferrocene ] ethyl dicyclohexylphosphine, (S) -1- [ (Rp) -2- (dicyclohexylphosphino) -ferrocenyl ] ethyl dicyclohexylphosphine, R-7,7 '-bis (diphenylphosphino) -2,2',3 '-tetrahydro-1, 1' -spirobiindene, (R) - (7 '- (diphenylphosphino) -2,2',3 '-tetrahydro-1, 1' -spiroindene ] -7-yl) diphenylphosphine oxide, (Rp) -1- [ (S) -2- (diphenylphosphino) ferrocene ] ethyl dicyclohexylphosphine.
  2. 2. The asymmetric synthesis of an axichiral 2- (hetero) arylpyridine N-oxide according to claim 1, wherein the palladium source is palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium (0), palladium pivalate, allylpalladium (II) chloride dimer, or palladium trifluoroacetate, and the silver source is silver carbonate, silver acetate, silver phosphate, silver fluoride, silver difluoride, silver nitrate, silver nitrite, silver trifluoroacetate, silver hexafluoroantimonate, or silver tetrafluoroborate.
  3. 3. The method for asymmetric synthesis of an axichiral 2-arylpyridine N-oxide according to claim 2, wherein the base is one of sodium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, 2, 6-dimethylpyridine, cesium carbonate, and the solvent is one of water, dioxane, toluene, benzotrifluoride, dichloromethane, 1, 2-dichloroethane, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide.
  4. 4. The asymmetric synthesis method of an axichiral 2-arylpyridine N-oxide according to claim 3, wherein the solvent is used in a volume amount of 1 to 10 mL/mmol based on the amount of the substance of the compound of formula (II), the ratio of the palladium source to the substance of the compound of formula (II) is 1 to 10mol%, the ratio of the ligand to the substance of the compound of formula (II) is 1 to 12mol%, the ratio of the silver source to the substance of the compound of formula (II) is 0.1 to 3:1, the ratio of the base to the substance of the compound of formula (II) is 1 to 3:1, and the ratio of the pyridine N-oxide of formula (I) to the substance of the compound of formula (II) is 0.5 to 3:1.
  5. 5. The asymmetric synthesis method of an axichiral 2- (hetero) arylpyridine N-oxide according to claim 4, wherein the ratio of the amount of the palladium source to the amount of the compound of the formula (II) is 1 to 5mol%, the ratio of the amount of the ligand to the amount of the compound of the formula (II) is 1.2 to 7mol%, the ratio of the amount of the silver source to the amount of the compound of the formula (II) is 0.1 to 1:1, the ratio of the amount of the base to the amount of the compound of the formula (II) is 2 to 3:1, and the ratio of the amount of the pyridine N-oxide of the formula (I) to the amount of the compound of the formula (II) is 1.5 to 2:1.

Description

Asymmetric synthesis method of axial chiral 2- (hetero) aryl pyridine N-oxide Technical Field The invention belongs to the technical field of organic chemical synthesis, and particularly relates to an asymmetric synthesis method of an axichiral 2- (hetero) aryl pyridine N-oxide. Background The axial chiral bi (hetero) aryl structure is used as an important chiral framework and has wide application in medicine molecules, pesticide active components and functional materials. At present, the synthesis of the compounds mainly depends on the pre-functionalized pyridine derivatives for asymmetric coupling, but the problems of complex synthesis steps, limited substrate application range, difficult enantioselectivity control and the like generally exist. In particular to pyridine derivatives with functionalized C2 position, side reactions are easy to occur in the reaction process, and the synthesis application potential is further limited. Therefore, a simple and easily obtained pyridine N-oxide is used as a raw material, and an enantioselective arylation strategy of direct C-H bond activation is developed, so that the method has important scientific significance and application value. In recent years, although the catalytic synthesis method of the axial chiral compound is continuously advanced, the efficient construction of the tetra-substituted axial chiral biaryl still faces significant challenges. The existing synthetic routes are mainly divided into two categories, namely asymmetric coupling (such as Suzuki-Miyaura reaction) or dynamic kinetic resolution based on a prefunctionalized substrate (such as halogen or borate), the problems of long steps, low atom economy, high chiral raw material cost and the like exist, and the indirect construction strategy (such as [2+2+2] cycloaddition or oxidative coupling) is adopted, so that biaryl frameworks can be constructed, but the enantioselectivity control capability on the chiral center of a tetrasubstituted axis is insufficient, and the substrate universality is limited. Notably, there is no current mature method capable of achieving de novo construction of tetra-substituted axial chiral biarenes through direct C-H activation. The traditional C-H arylation reaction is mostly limited to the construction of a di-or tri-substituted system, the three-dimensional crowding effect brought by a tetra-substituted structure obviously improves the control difficulty of reaction selectivity, and meanwhile, the dynamic rotation of a high-activity intermediate is easy to cause axial chiral racemization. The technical bottleneck severely restricts the application of the structure in drug development and novel chiral materials (such as asymmetric catalytic ligands). Disclosure of Invention Based on the above problems, the present invention provides an asymmetric synthesis method of an axichiral 2- (hetero) arylpyridine N-oxide. The palladium/silver synergistic catalytic system is adopted to realize the direct enantioselective arylation reaction of the pyridine N-oxide at the C2 position, the strategy has mild reaction conditions, excellent region and enantioselectivity and good functional group compatibility, the method is established to not only overcome the problems of long steps and low efficiency in the traditional synthesis path, but also provide a new idea for the green synthesis of complex axis chiral molecules, and the method has wide application prospect in the fields of drug intermediate development, chiral catalyst customization and the like. The successful implementation of the technology not only provides a new path with high atom economy and simple steps for synthesizing the axial chiral biaryl, but also can be used as a high-performance chiral ligand. The specific technical scheme is as follows: An asymmetric synthesis method of an axial chiral 2- (hetero) aryl pyridine N-oxide comprises the following steps of taking pyridine N-oxide shown in a formula (I) and a compound shown in a formula (II) as raw materials, adding a palladium source, a silver source, a ligand, alkali and a solvent, replacing air by using nitrogen flow or directly operating in a glove box, and reacting to obtain the axial chiral 2- (hetero) aryl pyridine N-oxide shown in the formula (III), wherein the reaction formula is as follows: , Wherein the substituent R 1 is alkyl or hydrogen, the substituent R 2 is hydrogen, cyano, nitro, amido, ester or amino, R 3 is substituted phenyl, substituted naphthyl, substituted pyridine, substituted quinoline or substituted tetrahydronaphthalene, the hydrogen on the substituted phenyl, substituted naphthyl, substituted pyridine, substituted quinoline or substituted tetrahydronaphthalene is mono-or polysubstituted, the substituent is alkoxy, benzyloxy, halogen, monofluoromethyl, difluoromethyl, aldehyde, methoxymethyl ether, ester, ethynyl phenyl, methoxyt-butyldimethylsilyl, chlorophenyl ethynyl, dichlorobenzyloxy or methylphenyloxy, X is hydrogen, CH, phenyl or