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Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex

A nitrogen heterocycle, large sterically hindered technology, applied in the preparation of amino compounds, the preparation of organic compounds, organic compounds/hydrides/coordination complex catalysts, etc., can solve the problems of ineffective catalytic reaction and low reaction activity, Achieve the effect of improving catalytic activity, simple synthesis method, and improving catalytic activity and stability

Inactive Publication Date: 2021-01-12
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In order to overcome the low reactivity of carbene palladium complexes in the above-mentioned prior art, the shortcomings and shortcomings of being unable to efficiently catalyze reactions at room temperature, the primary purpose of the present invention is to provide a large sterically hindered nitrogen heterocyclic carbene palladium complex

Method used

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  • Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex
  • Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex
  • Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex

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Embodiment approach

[0069] One embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

[0070]

[0071]It should be noted that the large sterically hindered nitrogen heterocyclic carbene palladium complex structure of the present invention uses diphenylimidazole as the main ligand skeleton and functionalized allyl as auxiliary ligand. As an auxiliary ligand, the allyl group is not very tightly combined with the metal center, so it is easily activated into zero-valent palladium at room temperature, inserting into the C-Cl bond of the aromatic heterocyclic chloride, and performing oxidation and addition. As a result, the easy-to-leave property of auxiliary ligands also greatly facilitates the reductive elimination step in the catalytic cycle, thereby enhancing the overall catalytic activity. Secondly, two phenyl groups are introduced on the imidazole ring. During the oxidative addition, the phenyl group can ...

Embodiment 1

[0078] Embodiment 1: the synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-1

[0079]

[0080] (1) Synthesis of diamine compound 2a:

[0081]

[0082] 5mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18mmol of tBuONa, 15mmol of 2,6-diisopropylbromobenzene, 1.5mmol of IPrMe·HCl, 0.5mmol Pd(dba) 2 Mix, add 20mL of anhydrous toluene, and react at 110°C for 24h under nitrogen atmosphere. After the reaction was completed, dilute with water, extract 3 times with ethyl acetate, anhydrous Na 2 SO 4 dry. The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether / dichloromethane=10:1). Product yield: 1.70 g, yield: 65%. 1 H NMR (400MHz, CDCl 3 )δ7.06-6.99(m,16H),4.58(s,2H),4.24(s,2H),3.29(dt,J=13.1,6.4Hz,4H),1.23(d,J=6.6Hz,12H ),0.91(d,J=6.5Hz,12H). 13 C NMR (101MHz, CDCl 3 ) δ143.1, 141.3, 140.2, 128.4, 127.8, 127.0, 123.7, 123.4, 69.1, 27....

Embodiment 2

[0093] Embodiment 2: the synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-2

[0094]

[0095] (1) Synthesis of diamine compound 2b:

[0096]

[0097] 5mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18mmol of tBuONa, 15mmol of 2,4,6-triisopropylbromobenzene, 1.5mmol of IPrMe·HCl, 0.5mmol of Pd(dba) 2 Mix, add 20mL of anhydrous toluene, and react at 110°C for 24h under nitrogen atmosphere. After the reaction was completed, dilute with water, extract 3 times with ethyl acetate, anhydrous Na 2 SO 4 dry. The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether / dichloromethane=10:1). Product yield: 2.15 g, yield: 70%. 1 H NMR (400MHz, CDCl 3 )δ7.10–6.94(m,10H),6.86(s,4H),4.57(d,J=4.3Hz,2H), 4.18(s,2H),3.45–3.13(m,4H),2.95–2.63 (m,2H),1.33–1.12(m,24H),0.87(d,J=6.8 Hz,12H). 13 C NMR (101MHz, CDCl 3 )δ 143.7, 143.0, 140.5, 139.0, 128.5,...

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Abstract

The invention belongs to the technical field of organic synthesis and chemical catalysis, and discloses a large-steric-hindrance N-heterocyclic carbene palladium complex, a preparation method thereof,an application of the complex in efficient catalysis of a C-N coupling reaction under a room-temperature air condition, and a synthesis method of sonidegib based on the complex. According to the large-steric-hindrance N-heterocyclic carbene palladium complex, diphenyl imidazole serves as a main ligand framework, functionalized allyl serves as an auxiliary ligand, the functionalized allyl is introduced beside a metal center of a catalyst to serve as an auxiliary ligand, the catalytic activity and stability are remarkably improved, the large-steric-hindrance N-heterocyclic carbene palladium complex can be applied to efficient catalysis of a CN coupling reaction, particularly, the CN coupling reaction can be efficiently catalyzed under the room temperature condition, and the yield can reachup to 99%. The invention also provides a method for synthesizing sonidegib by taking aryl / aliphatic amine and aryl chloride as reactants and a three-step method at room temperature under the catalysisof a palladium catalytic system, the synthetic method has few steps, and the total yield can reach 74.5%.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and chemical catalysis, in particular to a large sterically hindered nitrogen-heterocyclic carbene palladium complex and its preparation method and its application in efficiently catalyzing C-N coupling reactions at room temperature, and Sony Gibbs based on it synthetic method. Background technique [0002] Phosphine ligands and nitrogen heterocyclic carbene (NHC) ligands are strong electron-donating ligands, and their palladium complexes can efficiently catalyze the rate-determining step of oxidative addition, but they have great differences in their three-dimensional structures. . In 1991, Arduengo successfully separated the nitrogen heterocyclic free carbene for the first time [J.Am.Chem.Soc.1991,113,361.]; in 1997, Tolman et al. conducted an in-depth study on the three-dimensional structure of the phosphine ligand, and believed that the phosphine ligand The three-dimensional struct...

Claims

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Application Information

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IPC IPC(8): C07F15/00B01J31/22C07D413/04C07C209/10C07C211/54C07C211/48C07D295/033C07D295/023C07D213/74C07D417/12C07D471/04C07D405/14C07D401/12C07D405/12C07D409/12
CPCC07F15/006B01J31/2273C07D413/04C07C209/10C07D295/033C07D295/023C07D213/74C07D417/12C07D471/04C07D405/14C07D401/12C07D405/12C07D409/12B01J2231/4283B01J2531/824C07C211/54C07C211/48
Inventor 邱立勤欧阳嘉盛
Owner SUN YAT SEN UNIV
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