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Phosphine nitrogen ligands with various chiral centers as well as synthesis method and application thereof

A technology of chiral centers and phosphine ligands, applied in organic chemical methods, organic compound/hydride/coordination complex catalysts, chemical instruments and methods, etc., can solve the problems of low reactivity and long reaction time of aromatic aldehydes

Active Publication Date: 2020-12-15
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The three-component coupling reaction of asymmetric terminal alkynes, aldehydes, and amines is an efficient and convenient method for the synthesis of such molecules, but the methods reported previously have the following limitations: terminal alkyne substrates are limited to Substrates with bulky hindrance groups; aromatic aldehydes are less reactive; longer reaction times

Method used

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  • Phosphine nitrogen ligands with various chiral centers as well as synthesis method and application thereof
  • Phosphine nitrogen ligands with various chiral centers as well as synthesis method and application thereof
  • Phosphine nitrogen ligands with various chiral centers as well as synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076]

[0077] Add 1 (2.7111g, 15mmol), 2 (6.6024g, 21mmol), Pd(OAc) successively in the reaction flask with reflux condenser 2 (170.5mg, 0.75mmol), PPh3 (787.5mg, 3mmol), and Na 2 CO 3 (3.2155 g, 30 mmol). The reaction flask was replaced with Ar three times, and 44 mL of a mixed solvent (ethylene glycol dimethyl ether: water = 3:1) was added. The device was placed in an oil bath preheated to 120°C, stirred and refluxed for 24 hours, and the reaction was detected by TLC. Remove from the oil bath, cool to room temperature naturally, add 18mL of water, and extract with 3×40mL dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 (550 mL) to 5:1 (1560 mL) to 4:1 (250 mL)) gave the product 3 (2.8810 g, 58%) as a white solid: mp 131.9-132.6°C (ethyl acetate / petroleum ether); 1 H NMR (400MHz, CDCl 3 )δ7.96(d, J=9.2Hz, 1H, ArH), 7.86(d, J=9.2Hz, ...

Embodiment 2

[0079]

[0080] Under the protection of inert gas, add Pd(OAc) successively to the dry reaction bottle with reflux condenser 2(46.0 mg, 0.2 mmol), rac 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (191.3 mg, 0.3 mmol) and toluene (4 mL). After stirring at room temperature for 30 minutes, 3 (1.3188g, 4mmol), (R)-1-phenyl-1-ethylamine (0.68mL, d=0.940g / mL, 0.6392g, 5.2mmol) / toluene (4mL) were added successively ) and Cs 2 CO 3 (1.8293 g, 5.6 mmol). The mixture was stirred and refluxed in an oil bath preheated to 120° C. for 9 hours, after the completion of the reaction as detected by TLC. The oil bath was removed, cooled to room temperature naturally, the mixture was filtered through a short basic aluminum oxide column (200-300 mesh), and rinsed with 80 mL of ethyl acetate. The filtrate was concentrated, and column chromatography (eluent: petroleum ether / ethyl acetate=4:1 (750mL) to 3:1 (1200mL) to 2:1 (750mL)) gave a yellow solid foam (R, S a )-4a and (R, R a )-4a mixture ...

Embodiment 3

[0082]

[0083] Add (R, S a )-4a and (R,R a )-4a mixture (d.r.=1:1, 887.5mg, 2.15mmol) and 42.9mL HCl (3M MeOH / H 2 O mixed solution). The mixture was stirred at room temperature for 15.5 h, after completion of the reaction as detected by TLC. Add concentrated ammonia water to neutralize to neutral, add 20 mL of water to dilute, and extract with 3×40 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to obtain a yellow solid foam, which is directly used in the next step without purification.

[0084] The crude product obtained in the previous step and 4-dimethylaminopyridine (26.7 mg, 0.215 mmol) were added to the reaction flask. The reaction flask was replaced with Ar three times, and 21.5 mL of DCM, Et 3 N (0.30 mL, d=0.728 g / mL, 0.2184 g, 2.15 mmol), and N-phenylbis(trifluoromethanesulfonyl)imide (784.3 mg, 2.15 mmol). The mixture was stirred at room temperature for 23.5 hours after completion of the reaction by ...

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Abstract

The invention discloses a phosphine-nitrogen ligand with multiple chiral centers as well as a synthesis method and application thereof. The ligand has the axial chirality of a biaryl skeleton and thecentral chirality of chiral amine. The chiral ligand is synthesized from commercialized easily available raw materials through simple five-step reaction, and the finally obtained diastereoisomer product can be separated only through simple column chromatography or re-crystallization. The chiral phosphine nitrogen ligand synthesized by the method can catalyze asymmetric three-component coupling reaction of terminal alkyne, aldehyde and amine, so that the chiral propargyl amine compound with high optical activity is efficiently prepared.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a class of phosphine nitrogen ligands with multiple chiral centers and a synthesis method and application thereof. Background technique [0002] The phosphine nitrogen ligand with axial chirality is an important class of chiral ligands. Since J.M.Brown first disclosed the synthesis of the axial chiral phosphine nitrogen ligand QUINAP in 1993 (Tetrahedron.: Asymmetry 1993, 4, 743. ), this type of ligand has been widely used in different types of asymmetric catalytic reactions (Tetrahedron 2001, 57, 3809; Chem.Soc.Rev.2014, 43, 819; J.Org.Chem.2014, 79, 5391; ACS Catal. 2017, 8, 624.). Although similar axial chiral phosphine nitrogen ligands were subsequently designed and synthesized, most of them require the use of expensive equivalent chiral palladium complexes for resolution and preparation, which limits the application of such ligands. Subsequently, the PINAP ligand (Angew.Che...

Claims

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Application Information

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IPC IPC(8): C07F9/6509C07D237/12B01J31/02C07D237/20C07D295/092C07D295/084C07C213/08C07C215/28
CPCC07F9/650905B01J31/0271C07D237/12C07D237/20C07D295/092C07D295/084C07C213/08C07B2200/07B01J2231/4277C07C215/28B01J31/02
Inventor 麻生明刘琦徐海波
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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