A palladium-catalyzed decarboxylative [3+2] cycloaddition reaction

Abstract

The present invention discloses a method for preparing a compound of formula I by palladium-catalyzed decarboxylative [3+2] cycloaddition reaction using 5-vinyl oxazolidine-2,4-dione as an allyl zwitterion precursor. The preparation method includes 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: R, R 1 and R 2 as defined in the general specification.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a palladium-catalyzed decarboxylative [3+2] cycloaddition reaction. Technical Background

[0002] The palladium-catalyzed decarboxylative cycloaddition reaction is one of the important tools for the synthesis of carbocyclic and heterocyclic compounds and natural products. Generally speaking, the palladium-catalyzed decarboxylative cycloaddition reaction starts from the reaction of a palladium catalyst with an allylpalladium zwitterionic precursor, and the resulting allylpalladium zwitterionic intermediate reacts with an electrophile to complete the construction of a cyclic compound. Obviously, the allylpalladium zwitterionic precursor plays a key role in the palladium-catalyzed decarboxylative cycloaddition reaction. Designing and synthesizing new allylpalladium zwitterionic precursors with appropriate reactivity is an important task and a 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-vinyl oxazolidine-2,4-dione as an allyl zwitterionic precursor to provide a palladium-catalyzed decarboxylative [3+2] cycloaddition reaction. Specifically, a preparation method of a compound of formula I is provided. The preparation method includes 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] Wherein, R, R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl;

[0006] The palladium catalyst is Pd 2 dba 3 ·CHCl 3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct);

[0007] The chiral phosphine ligand is one or more of L1 to L6, and the structures of the L1 to L6 ligands are as follows:

[0008]

[0009] Furthermore, the present invention also provides a method for preparing a corresponding amine by further reducing a compound of formula I, the method including: reacting the compound of formula I with a reducing agent.

[0010] Advantages of the Present Invention

[0011] The reaction substrates used in the present invention are inexpensive and readily available, the reaction conditions are mild, the reaction yield is high, the enantioselectivity and diastereoselectivity are excellent, and heterocyclic compounds that are difficult to obtain are synthesized. Detailed Description of the Invention

[0012] To make the objectives, 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 some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. Unless otherwise clearly stated, in the whole specification and claims, the term "comprising" or its variations such as "comprises" or "comprising" etc. will be understood to include the stated components or steps, without excluding other components or steps.

[0013] In addition, to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0014] Those skilled in the art should understand that the present invention can be implemented without some specific details. In some embodiments, the raw materials, methods, means, etc. well-known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0015] If the compound of formula I described in the present invention can form geometric isomers, such as E / Z isomers, then both the pure isomers and their mixtures can be administered in the compositions of the present invention.

[0016] If the compound of formula I described in the present invention has one or more chiral centers and thus exists as enantiomers or diastereomers, then pure enantiomers, racemates, and diastereomers can be used in the compositions of the present invention.

[0017] If the compound of formula I described in the present invention has functional groups that can be ionized, then they can also be used in the form of their agricultural salts or mixtures thereof.

[0018] As used herein (and in other groups containing alkyl, such as alkoxyalkyl structural moieties), the term "alkyl" in each case represents a straight-chain or branched alkyl having generally 1-20 carbon atoms, often 1-6 carbon atoms, preferably 1-4 carbon atoms.

[0019] The term "C 1 -C 4 " Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl (sec-butyl), isobutyl, and tert-butyl.

[0020] In the present invention, the halogen is usually fluorine, chlorine, bromine or iodine, preferably fluorine, bromine or chlorine. Correspondingly, this also applies to the halogen combined with other structures, such as haloalkyl.

[0021] The term "C 1 -C 4 haloalkyl" refers to C 1 -C 4 alkyl as defined above, where some or all of the hydrogen atoms in these groups can be replaced by the above-mentioned halogen atoms, such as CH 2 F, CHF 2 、CF 3 、CH 2 Cl, CHCl 2 、CCl 3 、chlorofluoromethyl, dichlorofluoromethyl, 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, 2,2,2-trichloroethyl, C 2 F 5 、2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, CH 2 -C 2 F 5 、CF 2 -C 2 F 5 、1-fluoromethyl-2-fluoroethyl, 1-chloromethyl-2-chloroethyl, 1-bromomethyl-2-bromoethyl, 4-fluorobutyl, 4-fluorobutyl, 4-bromobutyl or nonafluorobutyl, but not limited thereto.

[0022] The term "C 1 -C 4 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, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

[0023] The term "C 1 -C 4 haloalkoxy" refers to C 1 -C 4 alkoxy as defined above, where some or all of the hydrogen atoms in these groups can be replaced by the above-mentioned halogen atoms, such as OCH 2 F, OCHF 2 、OCF 3, OCH 2 Cl, OCHCl 2 , OCCl 3 , chlorofluoromethoxy, dichlorofluoromethoxy, 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, 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, OCH 2 -C 2 F 5 , OCF 2 -C 2 F 5 , 1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy, 1-bromomethyl-2-bromoethoxy, 4-fluorobutoxy, 4-fluorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

[0024] C 3 -C 6 Cycloalkyl represents a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] As used herein, the term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group, such as phenyl or naphthyl, especially phenyl.

[0026] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic heteroaromatic hydrocarbon group, preferably a monocyclic heteroaromatic group, such as pyridyl, pyrimidinyl, thienyl and furyl, etc., but not limited thereto.

[0027] "Optionally substituted" as used herein means that it can be substituted or unsubstituted. When substituted, the substituents are preferably halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy and C 3 -C 6 cycloalkyl, but not limited thereto.

[0028] The present invention specifically discloses a method for preparing a compound of formula I, which 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. Among them, the structures of formula I, formula II and formula III are as follows:

[0029]

[0030] Wherein, R, R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0031] The palladium catalyst is Pd 2 dba 3 ·CHCl 3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct);

[0032] The chiral phosphine ligand is:

[0033]

[0034] The synthetic route of the reaction is as follows:

[0035]

[0036] Furthermore, in the above technical solution, R is C 1 -C 4 alkyl, C 1 -C 4 alkyl-substituted phenyl, C 1 -C 4 alkoxy-substituted phenyl and halogen-substituted phenyl; most preferably methoxy-substituted phenyl;

[0037] Furthermore, in the above technical solution, R 1 is selected from phenyl optionally substituted by H, halogen or C 1 -C 4 alkyl, naphthyl optionally substituted by H, halogen or C 1 -C 4 alkyl and thiophenyl optionally substituted by H, halogen or C 1 -C 4 alkyl. Preferably phenyl, 4-ClC 6 H 4 、4-BrC 6 H 4 、4-MeC 6 H 4 、2-naphthyl or 3-thienyl;

[0038] Furthermore, in the preferred technical solution, R 2 is selected from those substituted by H, halogen, C1 -C 4 An alkyl-substituted phenyl. Preferably phenyl, 4-FC 6 H 4 、4-MeC 6 H 4 and 2-furyl.

[0039] In the preparation method of formula I above, 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 -10 - 10 °C.

[0040] The present invention also provides a preparation method for further reducing the compound of formula I, which method comprises: reacting the compound of formula I with a reducing agent. The reduction is selected from hydrogen and boride, and the boride is selected from sodium borohydride and potassium borohydride. 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, methanol, ethanol and dioxane. The reaction temperature is -10 - 10 °C, and the reaction time is 1 - 72 h. The reaction route is as follows:

[0041]

[0042] Wherein, R, R 1 and R 2 are as defined above.

[0043] Furthermore, the compound of formula I is prepared according to the above method.

[0044] Examples

[0045] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention. The raw materials in the embodiments are not particularly limited and can all be obtained by purchasing from the market. The yield in the embodiments refers to the isolation yield, and the ee value is obtained by chiral HPLC analysis.

[0046] Preparation of Compound 1 in Example 1

[0047]

[0048] Add Pd 2 dba 3 ·CHCl 3(2.5 mol%) and (S,S,S)-(3,5-dioxo-4-phosphabicyclo[2,1-a:3,4-a']dinaphthalen-4-yl)bis(1-phenylethyl)amine (L3) (10 mol%) were added to 3-(4-methoxyphenyl)-5-phenyl-5-vinyl-oxazolidine-2,4-dione (0.15 mmol), 1,1-dicyanostyrene (0.1 mmol) and dichloromethane (1.0 mL) in a 25 mL Schlenk tube equipped with a magnetic stir bar. The reaction was stirred at 0 °C under an argon atmosphere. After completion of the reaction, the reaction mixture was purified directly by silica gel column chromatography (ethyl acetate / petroleum ether = 10:1) to give the desired cycloaddition compound 1. Yield 95%, ee value 95%.

[0049] The operating conditions of Examples 2-9 were the same as those of Example 1, except that the reaction raw materials were changed.

[0050]

[0051] Table 1 Reaction results with different raw materials

[0052]

[0053] Table 2 Compounds prepared by the [3+2] addition reaction of the present invention

[0054]

[0055]

[0056] Preparation of amine compound in Example 10

[0057]

[0058] Compound 1 was added to a mixed solution of dichloromethane and methanol (volume ratio = 1:1), and at 0 °C, NaBH 4 was used to reduce Compound 1 to form the amine compound. Yield 75%, ee value 95%. 1 1H NMR (500 MHz, CDCl 3 ): δ = 7.53–7.43 (m, 4H), 7.41–7.27 (m, 8H), 6.88–6.78 (m, 2H), 6.56–6.45 (dd, J = 17.0, 10.5 Hz, 1H), 5.61 (s, 1H), 5.54–5.48 (d, J = 17.0 Hz, 1H), 5.48–5.42 (d, J = 10.5 Hz, 1H), 3.74 (s, 3H), 2.62–2.52 (d, J = 13.5 Hz, 1H), 2.52–2.44 (d, J = 13.5 Hz, 1H), 1.34 (s, 2H).

[0059] Example 1 Preparation of 1,3,5-diphenyl-5-vinyloxazolidine-2,4-dione

[0060] Under -78 °C and argon atmosphere, the Grignard reagent (1.2 equiv.) was added dropwise to an anhydrous tetrahydrofuran solution of ethyl benzoylformate (1.0 equiv.). After the resulting mixture was stirred at -78 °C for 2 hours, it was continuously stirred at -10 °C for 2 hours. The reaction was quenched with NH 4 Cl 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 ethyl 2-hydroxy-2-phenylbut-3-enoate.

[0061] A solution of the intermediate ethyl 2-hydroxy-2-phenylbut-3-enoate (5.0 mmol, 1.0 equiv.), phenyl isocyanate (2.0 equiv.), Et 3 N (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 obtain the product 1,3,5-diphenyl-5-vinyloxazolidine-2,4-dione.

[0062] 5-Vinyloxazolidine-2,4-dione intermediate compounds prepared by the methods of Example 11 and Comparative Example 11

[0063] Table 5 5-Vinyloxazolidine-2,4-dione intermediate compounds

[0064]

[0065]

Claims

1. 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: wherein, R is selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl-substituted phenyl, C 1 -C 4 alkoxy-substituted phenyl or halogen-substituted phenyl; R 1 Selected from phenyl substituted by H, halogen, C 1 -C 4 alkyl, naphthyl substituted by H, halogen, C 1 -C 4 alkyl, and thiophenyl substituted by H, halogen, C 1 -C 4 alkyl; R 2 selected from H, halogen, C 1 -C 4 alkyl-substituted phenyl; The palladium catalyst described is Pd 2 dba 3 ·CHCl 3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct); the chiral phosphine ligand is one or more of L1 to L6, and the structures of the ligands L1 to L6 are as follows:

2. The preparation method according to claim 1, characterized in that, R 1 is phenyl, 4-ClC 6 H 4 、4-BrC 6 H 4 、4-MeC 6 H 4 、2-naphthyl or 3-thienyl.

3. The preparation method according to claim 1, characterized in that, R 2 is phenyl, 4-FC 6 H 4 , 4-MeC 6 H 4 and 2-furyl.

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

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