A palladium-catalyzed decarboxylative [5+3] cycloaddition reaction

Abstract

The present invention uses 5-vinyl oxazolidine-2,4-dione as an allyl zwitterion precursor, and provides a method for preparing a compound of formula I by a palladium-catalyzed decarboxylation [5+3] cycloaddition reaction. The preparation method comprises reacting a compound of formula II and a compound of formula III in the presence of a palladium catalyst and a chiral phosphine ligand, wherein the structures of formula I, formula II and formula III are as follows: wherein the definition of the substituent is as defined in the specification.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a palladium-catalyzed decarboxylation [5+3] cycloaddition reaction. Technical Background

[0002] Palladium-catalyzed decarboxylative cycloaddition reactions are one of the important tools for synthesizing carbocyclic and heterocyclic compounds and natural products. Generally speaking, palladium-catalyzed decarboxylative cycloaddition reactions start with the reaction of a palladium catalyst with an allylpalladium zwitterion precursor, and the resulting allylpalladium zwitterion intermediate reacts with an electrophilic reagent to complete the construction of the cyclic compound. Obviously, allylpalladium zwitterion precursors play a key role in palladium-catalyzed decarboxylative cycloaddition reactions. Designing and synthesizing new allylpalladium zwitterion precursors with appropriate reactivity is an important task and key scientific issue in the research of new palladium-catalyzed decarboxylative cycloaddition reactions. Summary of the invention

[0003] The present invention designs and uses 5-vinyloxazolidine-2,4-dione as an allyl zwitterion precursor to provide a palladium-catalyzed decarboxylation [5+3] cycloaddition reaction, specifically, a method for preparing a compound of formula I. The preparation method comprises reacting a compound of formula II and a compound of formula III in the presence of a palladium catalyst and a chiral phosphine ligand, wherein the structures of formula I, formula II and formula III are as follows:

[0004]

[0005] Among them, R 1 , R 2 and R 3 Each is independently selected from optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, and R is selected from H, halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or halo-substituted C1-C4 alkoxy;

[0006] The palladium catalyst is Pd2dba3·CHCl3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct);

[0007] The chiral phosphine ligand is:

[0008]

[0009] Furthermore, the present invention also provides a method for preparing a compound of formula II, comprising: step (1) reacting compound S1 with vinyl magnesium bromide to prepare compound S2; step (2) ring-closing compound S2 to prepare compound II. The structures of S1 and S2 are as follows:

[0010] Among them, R 1The definition of is as defined in formula II.

[0011] Beneficial Effects of the Invention

[0012] The reaction substrate used in the invention is cheap and easily available, the reaction conditions are mild, the reaction yield is high, the enantioselectivity is excellent, and the medium-ring heterocyclic compound which is difficult to obtain is synthesized. DETAILED DESCRIPTION

[0013] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0014] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0015] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0016] If the compounds of the formula I described herein are capable of forming geometrical isomers, such as E / Z isomers, both the pure isomers and mixtures thereof can be used in the compositions according to the invention.

[0017] If the compounds of the formula I described herein have one or more chiral centers and therefore exist as enantiomers or diastereomers, the pure enantiomers, racemates or diastereomers can be used in the compositions of the invention.

[0018] If the compounds of the formula I according to the invention have functional groups which can be ionized, they can also be used in the form of their agriculturally acceptable salts or mixtures thereof.

[0019] The term "alkyl" as used herein (and in other groups comprising alkyl, such as alkoxy) denotes in each case a straight-chain or branched alkyl group having generally 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms.

[0020] Examples of C1-C4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl (sec-butyl), isobutyl and tert-butyl.

[0021] In the present invention, halogen is usually fluorine, chlorine, bromine or iodine, preferably fluorine, bromine or chlorine. Accordingly, this also applies to halogen combined with other structures, such as haloalkyl.

[0022] The term "C1-C4 haloalkyl" refers to a C1-C4 alkyl group as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by the above-mentioned halogen atoms, for example CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, chlorofluoromethyl, dichloromonofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl The invention also includes, but is not limited to, 1-fluoromethyl-2-fluoroethyl, 1-chloromethyl-2-chloroethyl, 1-bromomethyl-2-bromoethyl, 4-fluorobutyl, 4-fluorobutyl, 4-bromobutyl or nonafluorobutyl.

[0023] The term "C1-C4 alkoxy" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms bonded via oxygen at any position in the alkyl group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

[0024] The term "C1-C4 haloalkoxy" refers to a C1-C4 alkoxy group as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by the above-mentioned halogen atoms, for example OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichloromonofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, ethoxy, 2,2,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2-C2F5, OCF2-C2F5, 1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy, 1-bromomethyl-2-bromoethoxy, 4-fluorobutoxy, 4-fluorobutoxy, or nonafluorobutoxy.

[0025] The C3-C6 cycloalkyl group represents a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0026] The term "aryl" as used herein refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group, such as phenyl or naphthyl, especially phenyl.

[0027] The term "heteroaryl" used herein refers to a monocyclic, bicyclic or tricyclic heteroaromatic hydrocarbon group, preferably a monocyclic heteroaromatic group, such as pyridyl, pyrimidinyl, thienyl, etc., but not limited thereto.

[0028] The term "optionally substituted" in the present invention means that the group may be substituted or is substituted. When substituted, the substituent may be halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyclohexyl, etc., but is not limited thereto.

[0029] In the present invention, "Ts" means p-toluenesulfonyl.

[0030] In the present invention, "Cy" means cyclohexyl.

[0031] The present invention specifically discloses a method for preparing a compound of formula I, comprising reacting a compound of formula II and a compound of formula III in the presence of a palladium catalyst and a chiral phosphine ligand, wherein the structures of formula I, formula II and formula III are as follows:

[0032]

[0033] Among them, R 1 , R 2 and R3 Each is independently selected from optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, and R is selected from H, halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or halo-substituted C1-C4 alkoxy;

[0034] The palladium catalyst is Pd2dba3·CHCl3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct);

[0035] The chiral phosphine ligands are L1-L6, and the structures are as follows:

[0036]

[0037] The synthetic route of the reaction is as follows:

[0038]

[0039] Furthermore, in the above technical solution, R 1 is selected from phenyl optionally substituted by H, halogen, C1-C4 alkyl or C3-C6 cycloalkyl, naphthyl optionally substituted by H, halogen, C1-C4 alkyl or C3-C6 cycloalkyl, and thienyl optionally substituted by H, halogen, C1-C4 alkyl or C3-C6 cycloalkyl. Preferably, phenyl, 2-FC6H4, 4-FC6H4, 3-ClC6H4, 4-ClC6H4, 3,4-Cl2C6H3, 3-BrC6H4, 4-BrC6H4, 3-MeC6H4, 4-MeC6H4, 4-isopropylbenzene, 4-CyC6H4, 4-tert-butylbenzene, 2-naphthyl or 3-thienyl;

[0040] Furthermore, in the preferred technical solution, R 2 It is selected from phenyl substituted by H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy or halogenated C1-C4 alkoxy. Phenyl, 3-FC6H4, 4-FC6H4, 3-ClC6H4, 4-ClC6H4, 4-BrC6H4, 4-CF3C6H4, 3-MeC6H4, 4-MeC6H4, 3,5-Me2C6H3, 3-OMeC6H4, 4-OMeC6H4, 4-OCF3C6H4 are preferred.

[0041] Furthermore, in some preferred technical solutions, R 3 is selected from phenyl or heteroaryl substituted by C1-C4 alkyl, preferably phenyl, 4-MeC6H4, 2,4,6-trimethylphenyl, 4-tert-butylphenyl and 4-methoxyphenyl.

[0042] In some preferred technical solutions, R is selected from H, halogen, C1-C4 alkyl or C1-C4 alkoxy, preferably H, halogen, methyl or methoxy.

[0043] In the above-mentioned preparation method of formula I, the reaction of formula II and formula III is carried out in an organic solvent, and the organic solvent is selected from one or more of dichloromethane, chloroform, dichloroethane, toluene, acetonitrile and dioxane. The reaction temperature is preferably -10-50°C, preferably 0-30°C, and most preferably 20-30°C. The reaction time is 1-96h, preferably 2-24h.

[0044] In some technical schemes, the molar ratio of the palladium catalyst Pd2dba3·CHCl3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct) to the compound of formula II is preferably 1:1-1:6.

[0045] In some technical solutions, the molar ratio of the palladium catalyst Pd2dba3·CHCl3 and the ligand is 1:0.5-1:5.

[0046] The present invention also provides a method for preparing a compound of formula II, comprising: step (1) reacting compound S1 with vinyl magnesium bromide to prepare compound S2; step (2) ring-closing compound S2 to prepare compound II. The structures of S1 and S2 are as follows:

[0047] Among them, R 1 The definition of is as defined in formula II.

[0048] Its synthetic route is as follows:

[0049] Where R 2 is as defined above.

[0050] In step (1) of the preparation method of formula II, S1 and vinyl magnesium bromide are reacted in an organic solvent under low temperature conditions, and the organic solvent is selected from one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane. The low temperature condition refers to the reaction at -78 to -10°C. Preferably, the reaction is carried out under the protection of an inert gas, and the inert gas is selected from nitrogen or argon.

[0051] In step (2) of the preparation method of formula II, S2 reacts with R in an organic solvent. 2 NCO reacts under the catalysis of an organic base to generate a compound of formula II. The organic solvent is a benzene solvent, such as benzene, toluene and xylene, but not limited thereto. The organic base is methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine and butylamine, but not limited thereto. The reaction temperature is 80-140° C., preferably the reflux temperature of the solvent.

[0052] Example

[0053] The technical scheme of the present invention is further described below by specific embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention. The raw materials in the embodiments are not particularly limited and can be purchased from the market. The yield in the embodiments refers to the separation yield, and the ee value is obtained by chiral HPLC analysis.

[0054] Example 1 Preparation of Compound 1

[0055]

[0056] Pd2dba3·CHCl3 (5 mol%) and (S,S,S)-(3,5-dioxa-4-phosphocycloheptyl[2,1-a:3,4-a']dinaphth-4-yl)bis(1-phenylethyl)amine (L3) (20 mol%) were added to an oven-dried 25 ml Schlenk tube equipped with a stirring bar together with 3-(4-chlorophenyl)-5-phenyl-5-vinyloxazolidine-2,4-dione (0.12 mmol), azomethine imine intermediate compound (0.1 mmol) and dichloromethane (1.0 ml). The reaction was stirred at 25° C. under an argon atmosphere for 12 h. The reaction mixture was directly purified by silica gel column chromatography (ethyl acetate / petroleum ether=1:1) to give the desired cycloadduct compound 1. The yield was 91% and the ee value was 92%.

[0057] In Example 2-11, the ligand and solvent were changed, and other reaction conditions remained unchanged.

[0058] Table 1 Effects of ligands and solvents on addition reactions

[0059]

[0060] "-" in the table means the reaction was not processed.

[0061] The operation of Example 12 is similar to that of Example 1, except that the reaction temperature is changed to 0°C and the reaction time is 48 h. The yield of the obtained product is 81% and the ee value is 92%.

[0062] The operation of Example 13 was similar to that of Example 1, except that the reaction temperature was changed to -10°C and the reaction time was 72 h, but Compound 1 was not obtained.

[0063] The operation of Example 14 is similar to that of Example 1, except that Pd2dba3·CHCl3 (2.5 mol %) and the amount of ligand L3 used are 10 mol %, the yield of compound 1 is 47%, and the ee value is 90%.

[0064] The experimental operation conditions of Examples 15-27 are the same as those of Example 1, except that R2 The type of substituents and the reaction scheme are as follows:

[0065]

[0066] The reaction results are shown in Table 2.

[0067] Table 2 Reaction of different 5-vinyloxazolidine-2,4-dione derivatives

[0068]

[0069] The experimental conditions of Examples 28-42 are the same as those of Example 1, except that R 1 The type of substituents and the reaction scheme are as follows:

[0070]

[0071] The reaction results are shown in Table 2.

[0072] Table 3 Reaction of different 5-vinyloxazolidine-2,4-dione derivatives

[0073]

[0074] Examples 43-50 change the 5-vinyloxazolidine-2,4-dione derivative and the azomethine imine intermediate compound, and the operating conditions are the same as those of Example 1. The reaction scheme is as follows:

[0075]

[0076] The reaction results are shown in Table 4.

[0077] Table 4 Reaction results of different methylamine imine intermediates with 5-vinyl oxazolidine-2,4-dione derivatives

[0078]

[0079] Table 5 Compounds of formula I prepared by the present invention and their NMR data

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087] Example 513, Preparation of 5-diphenyl-5-vinyloxazolidine-2,4-dione

[0088] At -78 ° C and argon environment, the Grignard reagent (1.2 equiv.) was added dropwise to an anhydrous tetrahydrofuran solution of ethyl benzoylformate (1.0 equiv.). The resulting mixture was stirred at -78 ° C for 2 hours and then continued to stir at -10 ° C for 2 hours. The reaction was quenched with NH4Cl solution, the organic layer was separated using a separatory funnel, and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with saturated brine (1×100 mL), dried over anhydrous MgSO4, and then the organic solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether=1:15) to obtain the product 2-hydroxy-2-phenylbut-3-enoic acid ethyl ester.

[0089] A solution of the intermediate 2-hydroxy-2-phenylbut-3-enoic acid ethyl ester (5.0 mmol, 1.0 equiv.), phenyl isocyanate (2.0 equiv.), Et3N (5.0 equiv.) and benzene solvent was stirred at 80° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether=1:10) to give the product 3,5-diphenyl-5-vinyloxazolidine-2,4-dione.

[0090] Example 51 and 5-vinyloxazolidine-2,4-dione intermediate compound prepared by the method of Example 51:

[0091] Table 5 5-vinyl oxazolidine-2,4-dione intermediate compounds

[0092]

[0093]

[0094]

[0095]

[0096]

Claims

1. A method for preparing a compound of formula I, characterized in that: The method comprises reacting a compound of formula II and a compound of formula III in the presence of a palladium catalyst and a chiral phosphine ligand, wherein the structures of formula I, formula II and formula III are as follows: in, R 1 is selected from phenyl, naphthyl and thienyl substituted by H, halogen, C1-C4 alkyl or C3-C6 cycloalkyl; R 2 Phenyl substituted by H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy or halo-C1-C4 alkoxy; R 3 Selected from phenyl, 4-MeC6H4, 2,4,6-trimethylphenyl, 4-tert-butylphenyl or 4-methoxyphenyl; R is selected from H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or halogenated C1-C4 alkoxy; The palladium catalyst is Pd2dba3·CHCl3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct); The chiral phosphine ligand is one or more of L1 to L6; the structures of L1 to L6 are as follows:

2. The preparation method according to claim 1, characterized in that: R is selected from H, halogen, C1-C4 alkyl or C1-C4 alkoxy.

3. The preparation method according to claim 1, characterized in that: The reaction is carried out in an organic solvent, and the organic solvent is selected from one or more of dichloromethane, chloroform, dichloroethane, toluene, acetonitrile and dioxane.

4. The preparation method according to any one of claims 1 to 3, characterized in that The compound of formula I is selected from the following compounds,

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