Preparation method for tetra-substituted allenoic acid compound based on palladium catalytic system

Patent metadata

Field	Value
Publication number	US-2024199521-A1
Application number	US-202218275291-A
Country	US
Kind code	A1
Filing date	Jan 19, 2022
Priority date	Feb 2, 2021
Publication date	Jun 20, 2024
Grant date	—

Abstract

Disclosed in the present invention is a preparation method for a tetra-substituted allenoic acid compound based on a palladium catalytic system, that is, a highly optically active allenoic acid compound having axial chirality is directly constructed in one step by reacting tertiary propargyl alcohol, carbon monoxide and water in an organic solvent under the action of a palladium catalyst, a chiral bisphosphine ligand, an organophosphoric acid, and an organic additive, and the theoretical yield can reach 100%. The method of the present invention is simple to operate, the raw materials and reagents are readily available, the reaction conditions are mild, the substrate universality is wide, the functional group compatibility is good, the reaction has high enantioselectivity (77%˜96% ee), and the reaction is well compatible with complex natural products or substrates of a drug molecular skeleton. The highly optically active allenoic acid compound obtained by the present invention can be used as an important intermediate for constructing a γ-butyrolactone compound containing a tetra-substituted chiral quaternary carbon center, tetra-substituted allenol, tetra-substituted allenal, tetra-substituted allenyl ketone, tetra-substituted allenami de and other compounds.

First claim

1 . A method for preparing a chiral tetra-substituted allenoic acid compound based on a palladium catalytic system, wherein, in the presence of palladium catalyst, chiral bisphosphine ligand, organophosphoric acid and organic additive, the tertiary propargyl alcohol with different substituents, carbon monoxide and water undergo the asymmetric allenylation reaction in an organic solvent through transition metal catalysis, constructing highly optically active axially chiral allenoic acid compound in one-step synthesis, the reaction process has the following reaction equation (a):

wherein, R 1 is an alkyl, an alkyl with functional group, phenyl, aryl or heterocyclic group; R 2 is an alkyl, an alkyl with functional group, phenyl, aryl or heterocyclic group; R 3 is an alkyl, an alkyl with functional group, phenyl, aryl or heterocyclic group;
in R 1 , R 2 and R 3 , said functional group is selected from carbon-carbon triple bond, hydroxyl, acyl, acyloxy, amide, amino, and silicon group; said aryl group is phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta, and para positions; said heterocyclyl group is furyl or pyridyl group, or furan or pyridine with electron-donating or electron-withdrawing substituents.

2 . The method of claim 1 , wherein, R 1 is a C1-C30 alkyl, a C1-C30 alkyl with functional group at the end, phenyl, aryl or heterocyclic group; R 2 is a C1-C10 alkyl, a C1-C10 alkyl with functional group at the end, phenyl, aryl or heterocyclic group; R 3 is C1-C10 alkyl, a C1-C10 alkyl with functional group at the end, phenyl, aryl or heterocyclic group;
in R 1 , R 2 and R 3 , in said C1-C30 alkyl with functional group at the end or said C1-C10 alkyl with functional group at the end, said functional group is selected from carbon-carbon triple bond, hydroxyl, acyl, acyloxy, amide, amino, silicon group; said aryl group is phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta and para positions, said heterocyclic group is a furanyl or pyridyl group, or furan or pyridine with electron-donating or electron-withdrawing substituents; said electron-withdrawing substituents in the aryl or heterocyclic group include halogen, nitro, ester, carboxyl, acyl, amide, and cyano group, and said electron-donating substituents include alkyl, alkenyl, phenyl, alkoxy group, hydroxyl, amino, silicon group.

3 . The method of claim 1 , wherein, said method comprises the following steps:
1) adding a palladium catalyst, a chiral bisphosphine ligand and an organophosphoric acid in sequence into a dried reaction tube, plugging the reaction tube with a rubber stopper, connecting the vacuum pump, replacing with argon under argon atmosphere, adding a functionalized tertiary propargyl alcohol, water, organic additives, and a certain volume of organic solvent; freezing the reaction tube in liquid nitrogen bath, inserting carbon monoxide balloon, replacing with carbon monoxide into the reaction system under the atmosphere of carbon monoxide; after freezing and pumping, when the reaction system returns to the room temperature and melts, putting the reaction tube in the preset low-temperature bath at −20˜80° C. or oil bath and stirring for 4-36 hours; wherein, said organic solvent with a certain volume refers to the amount of functionalized tertiary propargyl alcohol shown in equation (a) as a basis, and said dosage of the organic solvent is 1.0-10.0 mL/mmol; 2) after the completion of the reaction in step 1), raising the reaction tube from the oil bath, after returning to the room temperature, adding a certain volume of ethyl acetate into the reaction tube, filtering the resulting mixture with silica gel short column, washing with a certain amount of ethyl acetate, concentrating, and subjecting to the flash column chromatography, so as to obtain the highly optically active axially chiral allenoic acid compounds; wherein, the certain volume of the ethyl acetate refers to the amount of functionalized tertiary propargyl alcohol shown in equation (a) as a basis, said amount of ethyl acetate is 1.0-100 mL/mmol.

4 . The method of claim 1 , wherein, said palladium catalysts are any one or more of dis-(allyl-palladium chloride), tetra-(triphenylphosphine)palladium, tri-(dibenzylidene-acetone)dipalladium, dis-(cinnamyl-palladium chloride), dis-(dibenzylidene-acetone)monopalladium, palladium chloride, palladium acetate, dis-(triphenylphosphine)palladium chloride and bis-(acetonitrile)palladium chloride.

5 . The method of claim 1 , wherein, said chiral diphosphine ligand is selected from one or more of (R)-L1˜(R)-L4 and its enantiomer (S)-L1˜(S)-L4 in the following structures; wherein, Ar is a phenyl, an aryl or heterocyclic group;
said aryl group is a phenyl group substituted by alkyl or alkoxy group at the ortho, meta, and para positions; said heterocyclic group is thiophene, furan, or pyridine and thiophene substituted by alkyl or alkoxy group, furan substituted by alkyl or alkoxy group, or pyridine substituted by alkyl or alkoxy group:

6 . The method of claim 5 , wherein said chiral diphosphine ligand is selected from (R)-L4 and its enantiomer (S)-L4, the said structure of (R)-L4 is as follows:
Wherein, Ar is 3,5-dialkyl-4-alkoxyphenyl, 3,5-dialkylphenyl, 4-alkylphenyl or phenyl group;

7 . The method of claim 1 , wherein said organophosphoric acid is selected from any one or more of organophosphoric acid 1, organophosphoric acid 2, organophosphoric acid 3, the structure of which is as follows; wherein, R 4 is C1˜C6 alkyl, phenyl or aryl group; said aryl group is a phenyl group substituted by C1˜C6 alkyl at the ortho, meta, and para positions; R 5 is hydrogen, C1˜C6 alkyl, phenyl or aryl group;
said aryl group is a phenyl group substituted by C1˜C6 alkyl at the ortho, meta, and para positions;

8 . The method of claim 1 , wherein, said organic additive is selected from any one or more of 1,1-bis(diphenylphosphine)methane, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, 1,1′-bis(diphenylphosphine)ferrocene, bis(2-diphenylphosphine)ether, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1′-binaphthyl-2,2′-bisdiphenylphosphine, triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-methylphenyl)phosphine, tri(4-fluorophenyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, bromoethane, bromobutane, benzene, fluorobenzene, 1,4-difluorobenzene, hexafluorobenzene, chlorobenzene, 1,4-dichlorobenzene, bromobenzene, 1,4-dibromobenzene, 4-methoxybromobenzene, 4-methylbromobenzene, 4-fluorobromobenzene, 4-trifluoromethylbromobenzene, iodobenzene, trifluorotoluene, aniline, benzenesulfonic acid, phenol, phenylboronic acid; and/or, said organic solvent is selected from any one or more of N-methyl pyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, mesitylene, 4-ethyltoluene, 1,4-diethylbenzene, triethylbenzene, trifluorotoluene, dichloromethane, dibromomethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,2-dibromoethane, chloroform, acetic acid, N,N-dimethylformamide and dimethyl sulfoxide.

9 . The method of claim 1 , wherein, the m

Assignees

• Univ Fudan

Inventors

• Ma Shengming
• Zheng Weifeng
• Qian Hui

Classifications

• B01J2231/50

  Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds · CPC title

• B01J31/0231

  Halogen-containing compounds · CPC title

• B01J31/0258

  Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H · CPC title

• B01J31/2452

  with more than one complexing phosphine-P atom · CPC title

• B01J31/2457

  comprising aliphatic or saturated rings, e.g. Xantphos · CPC title