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CN-121974850-A - Method for constructing chiral [2,2] cyclo-tomato compound by cobalt catalysis asymmetric hydrocarbon bond activation

CN121974850ACN 121974850 ACN121974850 ACN 121974850ACN-121974850-A

Abstract

The invention provides a method for constructing a plane chiral [2,2] pair-ring tomato compound by cobalt catalysis and asymmetric hydrocarbon bond activation, which comprises the steps of carrying out asymmetric C-H activation reaction on aryl hydrazone and racemic 4-ethynyl- [2,2] pair-ring tomato under the action of a cobalt catalyst and chiral auxiliary agent, carrying out kinetic resolution on the racemic 4-ethynyl- [2,2] pair-ring tomato, separating to obtain the plane chiral 4-ethynyl- [2,2] pair-ring tomato and the plane chiral 4-isoquinoline- [2,2] pair-ring tomato compound after the reaction is finished, further developing a research technology of catalyzing C-H activation by cheap transition metal, expanding a synthesis strategy of the plane chiral [2,2] pair-ring tomato compound, having wide reaction substrate adaptability and strong product stereoselectivity, synthesizing a plurality of plane chiral [2,2] pair-ring tomato compounds, and having simple and convenient synthesis method, good atomic economy and high synthesis efficiency.

Inventors

  • SHI BINGFENG
  • ZHONG MINGYU
  • YAO QIJUN

Assignees

  • 浙江大学

Dates

Publication Date
20260505
Application Date
20251205

Claims (7)

  1. 1. A method of cobalt-catalyzed asymmetric hydrocarbon bond activation to build a chiral [2,2] pair cycloparaffin compound, comprising: Under the action of cobalt catalyst, chiral auxiliary and solvent, the aryl hydrazone and racemic 4-ethynyl- [2,2] produce asymmetric C-H activation reaction on the cyclop, the racemic 4-ethynyl- [2,2] carries out kinetic resolution on the cyclop, after the reaction is finished, the compounds of the face chiral 4-ethynyl- [2,2] on the cyclop and the face chiral 4-isoquinoline- [2,2] on the cyclop are obtained through separation, and the reaction is synthesized as follows: Wherein R is H, para-position and meta-position alkyl, para-position and meta-position halogen, phenyl, alkoxy, phenoxy, methylthio, cyano, ester, trifluoromethyl, trifluoromethoxy, amide and morpholino, R 1 is alkyl, substituted or unsubstituted aryl, the substituent on the aryl is halogen or alkyl, R 2 is H, 7,15, 16-position bromine substituent.
  2. 2. A method of cobalt-catalyzed asymmetric hydrocarbon bond activation to build a chiral [2,2] pair of cycloparaffins according to claim 1, wherein: R is H, para-and meta-C 1 ～C 4 alkyl, para-and meta-halogen, phenyl, C 1 ～C 4 alkoxy, phenoxy, methylthio, cyano, C 1 ～C 4 alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, C 1 ～C 4 amido, morpholino, R 1 is C 1 ～C 4 alkyl, substituted or unsubstituted phenyl, the substituents on the phenyl groups are F, cl, br or C 1 ～C 4 alkyl, R 2 is H, 7,15, 16-bromo substituent.
  3. 3. The method for preparing the chiral [2,2] cyclo-tomato compound by activating cobalt-catalyzed asymmetric hydrocarbon bonds according to claim 1, wherein the molar ratio of aryl hydrazone, racemic 4-ethynyl- [2,2] cyclo-tomato to cobalt catalyst and chiral auxiliary agent is 1.5-2.0:1:0.08-0.1:0.1-0.2.
  4. 4. A method for preparing a chiral [2,2] pair-cyclotomato compound by activating an asymmetric hydrocarbon bond under the catalysis of cobalt as claimed in claim 1, wherein the cobalt catalyst is cobalt acetate tetrahydrate.
  5. 5. The method for constructing a chiral [2,2] pair of cycloparaffin compound by activating an asymmetric hydrocarbon bond under the catalysis of cobalt according to claim 1, wherein the chiral auxiliary is chiral salicyloxazoline with the following structural formula:
  6. 6. A method for constructing a chiral [2,2] pair of cycloparaffin compound by activating an asymmetric hydrocarbon bond under the catalysis of cobalt according to claim 1, wherein the solvent is a mixed solvent of ethanol and acetonitrile, and the amount of the solvent is 0.8-2.0 mL of ethanol and 0.2-0.5 mL of acetonitrile for every 0.15mmol of aryl hydrazone substrate.
  7. 7. A method for activating and constructing a chiral [2,2] cyclo-tomato compound by using a cobalt-catalyzed asymmetric hydrocarbon bond as claimed in claim 1, wherein the activation reaction temperature is 40-50 ℃ and the reaction time is 84-120 hours.

Description

Method for constructing chiral [2,2] cyclo-tomato compound by cobalt catalysis asymmetric hydrocarbon bond activation Technical Field The invention relates to the technical field of compound synthesis, in particular to a method for constructing a chiral [2,2] pair-cycloparaffin compound by cobalt catalysis and asymmetric hydrocarbon bond activation. Background [2.2] The p-cycloparaffin consists of two co-planar stacks of benzene rings which interact and are linked at the p-bridgehead carbon atom by ethylene bridges. [2.2] has unique photophysical and optoelectronic properties for cyclopean, an interesting molecule, and has wide application in material science, pharmaceutical chemistry and as a development chiral ligand or organic catalyst, such as surface-mounted MOFs, dopamine D3 receptor antagonist FAUC 418, chiral phosphine ligand phanephos. Therefore, the synthesis of the chiral [2,2] has great practical significance and application prospect on the skeleton of the cyclopean compound. Despite its remarkable importance, the synthesis of optically pure planar chirality [2.2] for cyclopeans remains a considerable challenge in organic synthesis, and current methods rely mainly on chiral High Performance Liquid Chromatography (HPLC) to separate the racemic functionalization [2.2] for chemical resolution of cyclopeans or with stoichiometric chiral reagents. Although recent advances in catalytic kinetic resolution and asymmetric catalysis have increased the feasibility of synthesizing chiral [2.2] pairs of cyclophanes, the structural diversity of the resulting frameworks is still limited. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a method for constructing a plane chiral [2,2] pair-cyclotomato compound by cobalt catalysis and asymmetric hydrocarbon bond activation, and the method uses cheap and high-yield cobalt salt as a catalyst, salicyloxazoline which is easy to synthesize as a chiral auxiliary, aryl hydrazone and racemic 4-ethynyl- [2,2] pair-cyclotomato which are easy to synthesize as substrates, efficiently synthesizes the plane chiral [2,2] pair-cyclotomato, and splits the 4-ethynyl- [2,2] pair-cyclotomato raw material with high enantioselectivity. The technical scheme of the invention is that the method for constructing the chiral [2,2] pair-cyclotomato compound by activating the asymmetric hydrocarbon bond under the catalysis of cobalt comprises the following steps: Under the action of cobalt catalyst, chiral auxiliary and solvent, the aryl hydrazone and racemic 4-ethynyl- [2,2] produce asymmetric C-H activation reaction on the cyclop, the racemic 4-ethynyl- [2,2] carries out kinetic resolution on the cyclop, after the reaction is finished, the compounds of the face chiral 4-ethynyl- [2,2] on the cyclop and the face chiral 4-isoquinoline- [2,2] on the cyclop are obtained through separation, and the reaction is synthesized as follows: Wherein R is H, para-position and meta-position alkyl, para-position and meta-position halogen, phenyl, alkoxy, phenoxy, methylthio, cyano, ester, trifluoromethyl, trifluoromethoxy, amide and morpholino, R 1 is alkyl, substituted or unsubstituted aryl, the substituent on the aryl is halogen or alkyl, R 2 is H, 7,15, 16-position bromine substituent. Preferably, R is H, para-and meta-C 1～C4 alkyl, para-and meta-halogen, phenyl, C 1～C4 alkoxy, phenoxy, methylthio, cyano, C 1～C4 alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, C 1～C4 amido, morpholino, R 1 is C 1～C4 alkyl, substituted or unsubstituted phenyl, the substituents on said phenyl being F, cl, br or C 1～C4 alkyl, R 2 is H, bromo substituent at position 7,15, 16. In the reaction process, the asymmetric C-H activation reaction product can have an ee value of 86% -96% by chiral auxiliary control, and raw materials with an ee value of 40% -99% can be separated Preferably, the molar ratio of the aryl hydrazone substrate, the racemic 4-ethynyl- [2,2] to the cyclopoly, the cobalt catalyst and the chiral auxiliary is 1.5-2.0:1:0.08-0.1:0.1-0.2, and more preferably 1.5:1:0.08:0.1. Preferably, the aryl hydrazone and the racemic 4-ethynyl- [2,2] carry out asymmetric C-H activation reaction on the cyclopean, the racemic 4-ethynyl- [2,2] carries out kinetic resolution on the cyclopean, and after the reaction is finished, the chiral 4-ethynyl- [2,2] cyclopean and the chiral 4-isoquinoline- [2,2] cyclopean compound are obtained through separation. Preferably, the cobalt catalyst is cobalt acetate tetrahydrate. Preferably, the chiral auxiliary is chiral salicyloxazoline, 2- ((R) -4- ((S) -1- (tert-butoxy) ethyl) -4, 5-dihydro-oxazol-2-yl) -6- (tert-butyldimethylsilyl) phenol. Preferably, the solvent is a mixed solvent of ethanol and acetonitrile, and the amount of the solvent is 0.8mL of ethanol and 0.2mL of acetonitrile for each 0.15mmol of aryl hydrazone substrate. Preferably, the temperature of the activation reaction is 40-50 ℃, more preferably 45 ℃, and the reaction time is 84-120 h