Method for preparing alpha-fluoro-beta-ethynyl ketone compound containing two chiral centers

A technology of ethynyl ketone and chiral center, which is applied in the field of preparing α-fluoro-β-ethynyl ketone compounds containing two chiral centers, achieving the effect of simple synthesis, good reactivity and less dosage

Active Publication Date: 2017-06-16
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are relatively few studies on the second strategy, among which the construction of chiral α-fluoro-β-ethynyl ketone compounds through the asymmetric propargyl substitution reaction of fluorinated ketone compounds or their analogues has not been reported.

Method used

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  • Method for preparing alpha-fluoro-beta-ethynyl ketone compound containing two chiral centers
  • Method for preparing alpha-fluoro-beta-ethynyl ketone compound containing two chiral centers
  • Method for preparing alpha-fluoro-beta-ethynyl ketone compound containing two chiral centers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Cu(CH 3 EN) 4 BF 4 Complexation with L-1-1 acts as a catalyst to catalyze the reaction to generate chiral α-fluoro-β-ethynyl ketone product I-1.

[0049] Add the metal precursor Cu(CH 3 EN) 4 BF 4 (0.015mmol, 5mol%) and chiral ligand L-1-1 (0.0165mmol, 5.5mol%) were added to 1.0ml of anhydrous methanol under nitrogen protection, and stirred at room temperature for 1 hour. Fluorinated enol silyl ether II-1 (0.30mmol, 1.0equiv), propargyl alcohol ester III-1 (0.75mmol, 2.5equiv) and N,N-diisopropylethylamine (0.75mmol, 2.5equiv) Dissolve in 2.0 ml of anhydrous methanol, and then add the solution to the above-mentioned stirred catalyst solution under the protection of nitrogen, and react with stirring at -20° C. for 12 h. After the reaction was completed, the reaction was rotary evaporated under reduced pressure, and the residue was flushed into a short column of silica gel. After the rotary evaporation, the residue was sent to NMR to determine the dr value, and then...

Embodiment 2

[0055] L-2-1 acts as a ligand to generate chiral α-fluoro-β-ethynyl ketone product I-1

[0056] The ligand L-1-1 in Example 1 is replaced by the ligand L-2-1, and the rest are the same as in Example 1. The reaction gave compound I-1 in 70% yield, 75 / 25dr(syn / anti), 98%ee(syn), 99%ee(anti).

[0057] The structural formula of L-2-1 is as follows:

[0058]

Embodiment 3

[0060] L-2-2 reacts as a ligand to generate the product α-fluoro-β-ethynyl ketone product I-1

[0061] The ligand L-2-1 in Example 2 is replaced by the ligand L-2-2, and the rest are the same as in Example 1. Compound Ⅰ-1 was obtained in 60% yield, 67 / 33dr(syn / anti), 88%ee(syn), 94%ee(anti).

[0062] The structural formula of L-2-2 is as follows:

[0063]

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Abstract

The invention provides a method for preparing an alpha-fluoro-beta-ethynyl ketone compound containing two chiral centers, belongs to the field of organic synthesis, and relates to a method for synthesizing an alpha-fluoro-beta-ethynyl ketone compound containing two chiral centers from fluorinated silyl enol ether and a propargyl compound by catalyzing an asymmetric propargyl substitution reaction, wherein the used chiral copper catalyst is generated from a copper salt and a chiral tridentate P,N,N-ligand in various polar and non-polar solvents in an in-situ manner. According to the present invention, with the method, the alpha-fluoro-beta-ethynyl ketone compounds containing two chiral centers and having various substituents can be conveniently synthzied, wherein the enantiomeric excess percentage is up to greater than 99%; and the method has characteristics of easily available raw materials, simple operation, mild reaction condition, high diastereoselectivity, high enantioselectivity, and the like.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a method for preparing alpha-fluoro-beta-ethynyl ketone compounds containing two chiral centers. Background technique [0002] Fluorinated organic compounds are widely used in medicine, pesticides, materials and other fields, so it is of great significance to develop effective methods to construct fluorinated organic compounds. Among them, the synthesis of chiral fluorine-containing organic compounds is one of the difficulties and hot spots. [(a) O'Hagan, D.; Harper, D.B. Nat. Prod. Rep. 1994, 11, 123; (b) Hiyama, T. Organofluorine Compounds, Chemistry and Applications; Springer-Verlag: Berlin Heidelberg, 2000; (c) Kirsch , P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2013; (d) Wang, J.; Snnchez-Roselló, M.; J.L.; del Pozo, C.; Sorochinsky, A.E.; Fustero, S.; Soloshonok, V.A.; Chiral α-fluorinated ketone compounds, especially chiral α-tertiary fluorinated ketone co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B53/00C07C45/00C07C49/683C07C49/697B01J31/22
CPCB01J31/1625B01J2531/004B01J2531/16B01J2531/842C07B53/00C07C45/00C07C49/683C07C49/697
Inventor 胡向平张德旸
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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