A method for synthesizing β-dicarbonyl compounds containing α-chiral trifluoromethyl

Abstract

The invention discloses a method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group in the field of chemical synthesis technology, comprising the following steps: preparing a chiral catalyst I by using nickel trifluoromethanesulfonate and a chiral bis-oxazoline ligand in a toluene solvent; under the protection of an inert gas, sequentially adding trifluoroethylidene malonate, enol silyl ether and hexafluoroisopropanol (HFIP) into a schlenk tube equipped with the chiral catalyst I to react at room temperature; after the reaction is completed, separating by silica gel column chromatography, and concentrating by vacuum distillation to obtain a β-dicarbonyl compound containing an α-chiral trifluoromethyl group. This scheme realizes an asymmetric Mukaiyama-Michael reaction of ethylidene malonate by a chiral nickel-bis-oxazoline complex catalytic system to generate a series of β-dicarbonyl compounds containing an α-chiral trifluoromethyl group, and the reaction conditions of this scheme are relatively mild, and a high yield and high enantioselectivity can be obtained by reacting at room temperature.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular is a method for synthesizing a beta-dicarbonyl compound containing an alpha-chiral trifluoromethyl group. Background Art

[0002] In the field of medicinal chemistry, trifluoromethyl is an important chemical group. It has a wide range of applications in bioactive molecules due to its ability to improve the lipid solubility of organic molecules, good metabolic stability, high electronegativity and bioavailability. However, there are few natural trifluoromethyl compounds and their content in nature is also low, so scientists often develop synthetic trifluoromethyl compounds through artificial synthesis.

[0003] 1,5-dicarbonyl compounds are an important class of synthons, and chiral trifluoromethyl-1,5-dicarbonyl compounds are important synthetic building blocks for constructing complex structural molecules containing chiral trifluoromethyl. At present, the synthesis methods of chiral trifluoromethyl-1,5-dicarbonyl compounds are relatively limited, mainly focusing on the Michael addition reaction of β-CF3-α,β-unsaturated ketones. For example, Zhao Gang's group (J.Org.Chem.2016,81,9973-9982) and Zhang Junliang's group (Org.Lett.2017,19,5102-5105) used dipeptide-derived phosphonium salt catalysts and diamine-phosphine catalysts respectively to successfully construct chiral trifluoromethyl 1,5-dicarbonyl compounds through asymmetric Michael reaction of malonic esters and β-CF3-α,β-unsaturated ketones. However, the chiral catalysts they selected need to be synthesized by themselves, the steps are long, and the cost and difficulty of synthesis are relatively high. In addition, their method is limited in the types of chiral trifluoromethyl 1,5-dicarbonyl compounds, and requires a low reaction temperature (0-20°C) to ensure high enantioselectivity. Therefore, we developed an asymmetric Mukaiyama-Michael reaction of trifluoroethylene malonate catalyzed by nickel triflate and chiral bis-oxazoline, providing a new method for the synthesis of α-chiral trifluoromethyl-containing β-dicarbonyl compounds. Summary of the invention

[0004] In order to solve the problems of single synthesis reaction type of chiral trifluoromethyl compounds, high catalyst preparation cost, harsh reaction conditions and the like in the prior art, the present invention aims to provide a new method for synthesizing α-chiral trifluoromethyl-containing β-dicarbonyl compounds by asymmetric Mukaiyam-Micheal reaction catalyzed by nickel trifluoromethanesulfonate and chiral bis-oxazoline.

[0005] In order to achieve the above object, the technical scheme of the present invention is as follows: a method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group, comprising the following steps:

[0006] S1. Prepare chiral catalyst I. Add nickel trifluoromethanesulfonate, chiral bis-oxazoline ligand and toluene into a dry Schlenk tube and stir to obtain chiral catalyst I.

[0007]

[0008] S2. Under the protection of inert gas, trifluoroethylidene malonate, enol silyl ether and hexafluoroisopropanol are sequentially placed in a Schlenk tube containing chiral catalyst I, and an asymmetric Mukaiyama-Michael reaction is carried out at room temperature to generate a β-dicarbonyl compound containing an α-chiral trifluoromethyl group, and the reaction formula is:

[0009]

[0010] Wherein, R is selected from phenyl, 2-tolyl, 3-tolyl, 4-chlorophenyl, 4-bromophenyl, 2-naphthyl, TMS is trimethylsilyl, CF3 is trifluoromethyl, and HFIP is hexafluoroisopropanol;

[0011] S3. After the reaction is completed, the product is separated by silica gel column chromatography using an eluent, and then concentrated by vacuum distillation to obtain a β-dicarbonyl compound containing an α-chiral trifluoromethyl group.

[0012] Furthermore, the amount of nickel trifluoromethanesulfonate in S1 is 8-12 mol%.

[0013] Furthermore, the amount of the chiral bisoxazoline ligand in S1 is 10-14 mol%.

[0014] Furthermore, the amount of toluene in S1 is 1-2 mL.

[0015] Furthermore, the chiral bisoxazoline ligand in S1 is a malonate bisoxazoline ligand with a phenyl, benzyl, isopropyl or tert-butyl group at the C4 position.

[0016] Furthermore, the molar ratio of enol silyl ether, trifluoroethylene malonate and hexafluoroisopropanol in S2 is 1.0-1.5:1.0:1.0-2.0.

[0017] Furthermore, the room temperature in S2 is maintained at 20-30° C., and the reaction time is 4-12 hours.

[0018] Furthermore, the eluent in S3 is prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 10-20:1.

[0019] The following beneficial effects are achieved by adopting the above scheme:

[0020] 1. Compared with the prior art, this scheme forms a chiral catalyst I by complexing nickel trifluoromethanesulfonate and chiral bis-oxazoline, uses hexafluoroisopropanol as an additive, combines enol silyl ether and trifluoroethylidene malonate to undergo an asymmetric Mukaiyama-Michael reaction to obtain a β-dicarbonyl compound containing an α-chiral trifluoromethyl group. This scheme provides a new method for the synthesis of β-dicarbonyl compounds containing an α-chiral trifluoromethyl group, and the catalyst in this method has excellent performance, which can enable the reaction to achieve high yield and enantioselectivity at room temperature;

[0021] 2. This scheme has a wide range of applications and can replace raw materials to synthesize a variety of chiral trifluoromethyl compounds. In addition, nickel trifluoromethanesulfonate and chiral bisoxazoline ligands are easy to obtain and do not require additional synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Schematic diagram of a flow chart of an embodiment of the present invention.

[0023] Figure 2 Schematic diagram of the chemical structure of trifluoromethyl compounds generated by different R in the embodiments of the present invention. DETAILED DESCRIPTION

[0024] The following is further described in detail through specific implementation methods:

[0025] The embodiment is basically as shown in the attached Figure 1-Figure 2 As shown:

[0026] A method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group comprises the following steps:

[0027] S1. Prepare chiral catalyst I. Add 10 mol% nickel trifluoromethanesulfonate (Ni(OTf)2), 12 mol% chiral bis-oxazoline ligand (L4) and 2 mL toluene into a dry Schlenk tube, stir, and react at room temperature for 1 hour to obtain chiral catalyst I.

[0028]

[0029] S2. Under nitrogen protection, trifluoroethylene malonate as reactant 1, enol silyl ether as reactant 2 and hexafluoroisopropanol (HFIP) were added to the Schlenk tube in sequence, and the molar ratio of enol silyl ether, trifluoroethylene malonate and hexafluoroisopropanol (HFIP) was 1.5:1.0:2.0, and an asymmetric Mukaiyama-Michael reaction was carried out at 25°C for 8h to generate a solution containing the target product 3, and the reaction formula is as follows:

[0030]

[0031] S3. After the reaction is completed, the solution is separated by silica gel column chromatography using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 15:1. After elution, the solution is concentrated by vacuum distillation to obtain the synthesized α-chiral trifluoromethyl-containing β-dicarbonyl compound.

[0032] The following are the 1,5-dicarbonyl compounds containing chiral trifluoromethyl groups generated from different starting materials and their characteristics, yields and enantioselectivities (ee):

[0033] 3aa: (S)-2-(1,1,1-trifluoro-4-oxydeoxy-4-phenylbutan-2-yl)malonic acid diethyl ester, colorless oily liquid, yield 88%, ee 87%, its chemical formula is as follows:

[0034]

[0035] 3ba: S(S)-2-(1,1,1-trifluoro-4-oxydeoxy-4-(2-methylphenyl)butan-2-yl)malonate, colorless oily liquid, yield 69%, ee 77%, its chemical formula is as follows:

[0036]

[0037] 3ca: (S)-2-(1,1,1-trifluoro-4-oxy-4-(3-methylphenyl)butan-2-yl)malonate, colorless oily liquid, yield 79%, ee 85%, its chemical formula is as follows:

[0038]

[0039] 3da: (S)-2-(4-(4-chlorophenyl)-1,1,1-trifluoro-4-oxydebutan-2-yl)malonic acid diethyl ester, colorless oily liquid, yield 89%, ee 86%, its chemical formula is as follows:

[0040]

[0041] 3ea: (S)-2-(4-(4-bromophenyl)-1,1,1-trifluoro-4-oxydebutan-2-yl)malonic acid diethyl ester, white solid, yield 84%, ee 87%, its chemical formula is as follows:

[0042]

[0043] 3fa: (S)-2-(1,1,1-trifluoro-4-(naphthalen-2-yl)-4-oxydeoxybutan-2-yl)malonic acid diethyl ester, white solid, yield 72%, ee 76%, its chemical formula is as follows:

[0044]

[0045] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0046] The above is only an embodiment of the present invention. The common sense such as the known specific structure and characteristics in the scheme is not described in detail here. The ordinary technicians in the relevant field know all the common technical knowledge in the technical field of the invention before the application date or priority date, can know all the existing technologies in the field, and have the ability to apply the conventional experimental means before that date. The ordinary technicians in the relevant field can improve and implement this scheme in combination with their own abilities under the enlightenment given by this application. Some typical known structures or known methods should not become obstacles for ordinary technicians in the relevant field to implement this application. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the protection scope of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the patent. The protection scope required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group, characterized in that: The steps include: S1. Prepare chiral catalyst I. Add nickel trifluoromethanesulfonate, chiral bis-oxazoline ligand and toluene into a dry Schlenk tube and stir to obtain chiral catalyst I. S2. Under the protection of inert gas, trifluoroethylidene malonate, enol silyl ether and HFIP are sequentially placed in a Schlenk tube containing chiral catalyst I, and an asymmetric Mukaiyama-Michael reaction is carried out at room temperature to generate a β-dicarbonyl compound containing an α-chiral trifluoromethyl group, and the reaction formula is: Wherein, R is selected from phenyl, 2-tolyl, 3-tolyl, 4-chlorophenyl, 4-bromophenyl, 2-naphthyl, TMS is trimethylsilyl, CF3 is trifluoromethyl, and HFIP is hexafluoroisopropanol; S3. After the reaction is completed, the β-dicarbonyl compound containing α-chiral trifluoromethyl group is obtained by silica gel column chromatography separation with an eluent, and concentrated by reduced pressure distillation after elution.

2. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The amount of nickel trifluoromethanesulfonate in S1 is 8-12 mol%.

3. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The amount of the chiral bisoxazoline ligand in S1 is 10-14 mol%.

4. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The amount of toluene in the S1 is 1-2 mL.

5. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The chiral bisoxazoline ligand in S1 is a malonate bisoxazoline ligand with a phenyl, benzyl, isopropyl or tert-butyl group at the C4 position.

6. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The molar ratio of enol silyl ether, trifluoroethylene malonate and hexafluoroisopropanol in S2 is 1.0-1.5:1.0:1.0-2.

0.

7. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The room temperature in S2 is maintained at 20-30° C., and the reaction time is 4-12 hours.

8. The method for synthesizing a β-dicarbonyl compound containing an α-chiral trifluoromethyl group according to claim 1, characterized in that: The eluent in S3 is prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 10-20:1.

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