CN114835655A - Method for synthesizing optically active trifluoromethyl acrylate compound - Google Patents

Abstract

The invention discloses a method for synthesizing optically active trifluoromethacrylate compounds, belonging to the technical field of organic chemistry. Using MBH carbonate and oxazolone as starting materials, in the presence of L-tertiary leucine and cyclohexyl-derived chiral bifunctional tertiary amine urea-phosphonamide/ester catalyst, through allyl alkylation reaction, A highly optically active trifluoromethacrylate compound is obtained. The reaction process of the invention has excellent enantioselectivity, does not need to use transition metals or stoichiometric oxidants; the reaction raw materials are readily available, the catalyst structure is simple, the catalytic efficiency is high, the reaction conditions are mild, and the post-treatment is simple.

Description

A kind of method for synthesizing optically active trifluoromethacrylate compounds

technical field

The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a method for synthesizing trifluoromethacrylate compounds.

Background technique

As an important method for the synthesis of chiral trifluoromethacrylate-containing compounds, it has been extensively studied in the past few decades. The introduction of perfluoroalkyl functional groups into the parent molecule can significantly affect its chemical, physical, and biological properties, and many of the known chiral molecules containing trifluoromethyl groups are of great utility.

The chiral parts of many drug molecules contain stereotrifluoromethyl groups, and the construction of compounds containing stereotrifluoromethyl groups is still a research hotspot. Therefore, it is very important to develop a cost-effective method for synthesizing optically active trifluoromethacrylates.

SUMMARY OF THE INVENTION

In order to overcome the above technical defects, the present invention provides a method for synthesizing optically active trifluoromethacrylate compounds with simple starting materials. Optically active trifluoromethacrylates were synthesized using MBH carbonate as the starting material, followed by non-allyl alkylation with oxazolone in the presence of a chiral bifunctional tertiary amine urea-phosphonate catalyst. compound.

Based on the above purpose, the present invention uses MBH carbonate 1 and oxazolone 2 as starting materials, and then uses a chiral bifunctional tertiary amine urea-phosphonate compound as a catalyst to undergo asymmetric allyl alkylation reaction, Synthesis of optically active trifluoromethacrylates with high yield and high enantioselectivity.

A method for synthesizing an optically active trifluoromethacrylate compound, comprising the steps of: using MBH carbonate 1 and oxazolone 2 as raw materials, derivatizing a chiral bifunctional tertiary amine urea-phosphine in L-tertiary leucine In the presence of such a catalyst, the trifluoromethacrylate-based compound 3 is obtained through asymmetric allyl alkylation reaction.

The reaction equation is as follows:

Wherein: R ¹ is selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, thienyl; R ² is selected from C1-C4 alkyl.

Further, in the above technical solution, R ¹ is selected from 2-F, 3-Me, 2-thienyl, and 3-thienyl; R ² is selected from Me, Et.

Further, in the above-mentioned technical scheme, the catalyst is selected from C1-C8, and the specific structural formula is as follows:

Further, in the above technical solution, the catalyst is preferably selected from C1 or C6.

Further, in the above technical solution, the molar ratio of the MBH carbonate 1, the oxazolone 2 and the catalyst is 1:1-1.5:0.05-0.10; the preferred molar ratio is 1:1.5:0.10.

Further, in the above technical solution, the reaction temperature is 0-30°C, preferably 25°C.

Further, in the above technical solution, the reaction is carried out in an air atmosphere.

Further, in the above-mentioned technical scheme, the reaction is carried out in an organic solvent, and the reaction solvent is selected from toluene, dichloromethane, tetrahydrofuran, mesitylene, chlorobenzene, pentafluorobenzene, m-xylene, o-xylene or ether; preferably The reaction solvent is toluene.

Invention Beneficial Effects:

The invention takes MBH carbonate as a starting material and asymmetric allyl alkylation of oxazolone to obtain optical trifluoromethacrylate compounds in one pot, the raw materials are simple and easy to obtain, the catalyst structure is simple and the catalytic efficiency is high, The reaction conditions are mild, the post-treatment is simple, the catalyst can be recycled and reused, and the product yield and enantioselectivity are good to excellent.

Detailed ways

The technical solutions of the present invention will be described in further detail below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

Investigation of reaction conditions

A typical procedure was as follows: Morita-Baylis-Hillman carbonate 1 (0.1 mmol, 1.0 eq and catalyst C1 (0.76 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (1.0 mL) followed by 4-tert-butyl -2-Trifluoromethyloxazol-5(2H)-one 2 (0.15 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 72 h and monitored by TLC. After the complete reaction of the starting materials, the reaction mixture was directly The product was obtained by gradient elution of PE/EA=50:1-20:1 on a silica gel column.

^a Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), catalyst (0.01 mmol), ultra-dry toluene (1.0 mL), 25°C. ^b Yield by flash column chromatography. ^c ee by HPLC, ^d dr by ¹ H NMR spectroscopy.

During the screening of reaction conditions, the influence of different catalysts on the reaction was first investigated (entries 1-8), and finally catalyst C1 was determined as the best catalyst. Under the action of C2 catalyst, the α-allyl alkylation product was obtained. , and then investigated the effect of solvent on the reaction (entries 9-12), and finally determined that anhydrous toluene was the best solvent, the reaction temperature was 25 °C, and the catalyst dosage was 10 mol%.

The synthesis route of typical catalyst C1 is represented by the reaction equation as follows:

Under nitrogen protection, in a 15mL round bottom flask, add 1.0g of 2-aminocyclohexanol A to 20mL of dichloromethane to dissolve, then dropwise add 1.84mL of 3,5-bistrifluoromethylisosulfide, and quickly monitor the plate . After the completion of the reaction, spin-dried column chromatography, eluted with dichloromethane/methanol=60/1, to obtain Intermediate B in a yield of 81%.

Under nitrogen protection, in a 15 mL round-bottom flask, 2.0 g of intermediate B was added to 30 mL of dichloromethane to dissolve, then 0.903 mL of EDC and 315.2 mg of DMAP were added in sequence, and then 1.56 g of diphenylphosphine benzoic acid was added, and the reaction was carried out at room temperature for 8 h. The dot plate monitoring reaction is completed. Quenching by adding water, extracting with dichloromethane, drying and spin drying, column chromatography to obtain a white solid catalyst C1, the yield is 78%, and the melting point is 168.3-169.2°C.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.17-8.08 (m, 1H), 7.90 (s, 2H), 7.59 (s, 1H), 7.41 (pd, J=7.5, 1.7 Hz,2H),7.37-7.17(m,9H),7.12(t,J＝7.4Hz,2H),6.90(td,J＝4.8,2.3Hz,1H),4.91(td,J＝9.9,4.2Hz , 1H), 2.30(s, 1H), 1.92-1.09(m, 8H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 181.2, 168.5, 140.7, 139.6 (d, J=21.3 Hz), 136.7 (d, J=4.6 Hz), 134.2, 134.0, 133.6 (d, J=16.6 Hz), 132.8 ,131.8(q,J＝33.5Hz),131.3,129.3,129.1,128.9,128.8,128.7,123.2(q,J＝272.8Hz),118.4,76.0,57.7,31.4,30.5,24.0.

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-62.90. ³¹ P NMR (162 MHz, CDCl ₃ ) δ-4.24. HRMS (ESI) calcd. for C ₃₄ H ₃₀ F ₆ O ₂ N ₂ PS ([M+H] ⁺ ):675.1664,found:675.1666.

Example 1

Morita-Baylis-Hillman carbonate 1 (1 mmol, 1.0 eq) and catalyst C1 (7.6 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (5.0 mL), followed by 4-tert-butyl-2-tris Fluoromethyloxazol-5(2H)-one 2 (1.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 72 h. After monitoring the complete reaction of the raw materials by TLC, the solvent was removed under reduced pressure, and the solvent was directly separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=1/50-1/20) to obtain a colorless oily product 3aa , the yield was 82%; HPLC CHIRALPAK OD-H, n-Hexane/2-propanol=96/4, flow rate=0.8mL/min, λ=210nm, retention time: 9.166min(major), 4.717min( minor); 97% ee, dr=10:1; [α] ³⁰ _D = -25.8 (c 1.5, CHCl ₃ ); ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.34-7.08 (m, 5H), 6.60 (s,1H), 6.48(s,1H), 5.11(s,1H), 3.67(s,3H), 1.13(s,9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.0, 166.4, 161.4, 135.3 , 132.9, 130.9, 130.7, 128.5, 128.4, 121.8 (q, J=286.3 Hz), 100.9 (q, J= 29.9 Hz), 52.7, 47.4, 35.0, 26.3; ¹⁹ F NMR (565 MHz, CDCl ₃ )δ- 75.08; HRMS(ESI) calcd. for C ₁₉ H ₂₀ F ₃ O ₄ N[M+H] ⁺ : 384.14 17, found: 384.1422.

Example 2

Morita-Baylis-Hillman carbonate 1b (1 mmol, 1.0 eq) and catalyst C1 (7.6 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (5.0 mL), followed by 4-tert-butyl-2-tris Fluoromethyloxazol-5(2H)-one 2 (1.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 72 h. After monitoring the complete reaction of the raw materials by TLC, the solvent was removed under reduced pressure, and the solvent was directly separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=1/50-1/20) to obtain a colorless oily product 3ab , the yield was 75%; HPLC CHIRALPAK OD-H+IG, n-Hexane/2-propanol=96/4, flow rate=0.8mL/min, λ=210nm, retention time: 16.448min(major), 20.390min (minor); 91% ee, dr=8:1; [α] ³⁰ _D = -88.1 (c 1.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.19 (m, 2H), 7.06(t, J=7.8Hz, 2H), 6.64(s, 1H), 6.46(s, 1H), 5.70(s, 1H), 3.75(s, 3H), 1.25(s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ )δ175.1, 166.1, 161.4, 161.1 (d, J=249.9 Hz), 135.1, 131.4, 131.0, 130.3 (d, J=7.9 Hz), 124.4 (d, J=31.0 Hz), 123.6 (d, J=4.2 Hz), 121.6 (q, J=286.1 Hz), 121.0 (d, J=14.1 Hz), 116.1 (d, J=23.1 Hz), 100.8 (q, J=30.2 Hz), 52.7 , 38.8, 35.1, 26.4; ¹⁹ F NMR (376MHz, CDCl ₃ ) δ–75.61,–114.70; HRMS (ESI) calcd. for C ₁₉ H ₁₉ F ₄ O ₄ N([M+H] ⁺ ): 402.1323, found:402.1318.

Example 3

Morita-Baylis-Hillman carbonate 1c (1 mmol, 1.0 eq) and catalyst C1 (7.6 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (5.0 mL), followed by 4-tert-butyl-2-tris Fluoromethyloxazol-5(2H)-one 2 (1.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 72 h. After monitoring the complete reaction of the raw materials by TLC, the solvent was removed under reduced pressure, and the solvent was directly separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=1/50-1/20) to obtain a colorless oily product 3ac , the yield is 91%; HPLC CHIRALPAK OD-H+IG, n-Hexane/2-propanol=96/4, flow rate=0.8mL/min, λ=210nm, retention time: 14.735min(major), 17.525min (minor); 99% ee, dr=12:1; [α] ³⁰ _D = -24.9 (c 1.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16 (t, J=7.6 Hz, 1H), 7.09–6.98(m, 3H), 6.66(s, 1H), 6.54(s, 1H), 5.14(s, 1H), 3.75(s, 3H), 2.30(s, 3H), 1.21(s , 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 174.9, 166.5, 161.4, 137.9, 135.3, 132.8, 131.4, 130.8, 129.2, 128.2, 127.9, 121.8 (q, J=286.0 Hz), 100.9 (q, J =29.8Hz), 52.7, 47.4, 35.0, 26.3, 21.5; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-75.10; HRMS (ESI) calcd. for C ₂₀ H ₂₂ F ₃ O ₄ N ([M+H] ⁺ ):398.1574,found:398.1578.

Example 4

Morita-Baylis-Hillman carbonate 1d (1 mmol, 1.0 eq) and catalyst C1 (7.6 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (5.0 mL), followed by 4-tert-butyl-2-tris Fluoromethyloxazol-5(2H)-one 2 (1.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 72 h, TLC monitored the complete reaction of the raw materials, and the solvent was removed under reduced pressure to separate and purify directly by flash silica gel column chromatography (petroleum ether/ethyl acetate=1/50-1/20) to obtain a colorless oily product 3ad, which was obtained. HPLC CHIRALPAK OD-H+IG, n-Hexane/2-propa nol=96/4, flow rate=0.8mL/min, λ=210nm, retention time: 15.550min(major), 25.067min( minor); 98% ee, dr=11:1; [α] ³⁰ _D = -35.9 (c 1.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.17 (m, 1H), 7.01 –6.95(m,1H),6.97- 6.89(m,1H),6.69(s,1H),6.54(s,1H),5.49(s,1H),3.79(s,3H),1.21(s,9H) ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.1, 166.1, 161.5, 135.8, 135.5, 131.7, 129.8, 129.0, 127.2, 126.6, 121.6 (q, J=285.7 Hz), 100.4 (q, J=29.8 Hz) , 52.8, 42.6, 35.0, 26.2; ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-75.10; HRMS (ESI) calcd. for C ₁₇ H ₁₈ F ₃ O ₄ NS ([M+H] ⁺ ): 390.0981, found :390.0988.

Embodiment 5:

Morita-Baylis-Hillman carbonate 1e (1 mmol, 1.0 eq) and catalyst C1 (7.6 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (5.0 mL), followed by 4-tert-butyl-2-tris Fluoromethyloxazol-5(2H)-one 2 (1.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 72 h, TLC monitored the complete reaction of the raw materials, the solvent was removed under reduced pressure, and the solvent was directly separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=1/50-1/20) to obtain a colorless oily product 3ae, which was obtained. The rate was 92%; HPLC CHIRALPAK OD-H+IG, n-Hexane/2-propanol=96/4, flow rate=0.8mL/min, λ=210nm, retention time: 14.127min(major), 16.605min( minor); 99% ee, dr=10:1; [α] ³⁰ _D = -26.4 (c 1.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 (s, 5H), 6.65 (s ,1H),6.50(s,1H),5.18(s,1H),4.18(tt,J=7.3,3.5Hz,2H),1.26(t,J=7.1Hz,3H),1.21(s,9H) ; ¹³ CNMR (150MHz, CDCl ₃ ) δ 174.9, 165.9, 161.4, 135.6, 133.1, 130.7, 130.5, 128.6, 128.4, 121.8 (q, J=286.2 Hz), 100.9 (q, J=29.9 Hz), 61.7, 47.3 , 35.0, 26.3, 14.2; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-75.14; HRMS (ESI) calcd. for C ₂₀ H ₂₂ F ₃ O ₄ N ([M+H] ⁺ ): 398.1574, found: 398.1577 .

Embodiment 6:

Morita-Baylis-Hillman carbonate 1f (1 mmol, 1.0 eq) and catalyst C1 (7.6 mg, 0.01 mmol, 0.1 eq) were dissolved in ultra-dry toluene (5.0 mL), followed by 4-tert-butyl-2-tris Fluoromethyloxazol-5(2H)-one 2 (1.5 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 72 h, after TLC monitoring the complete reaction of the raw materials, the solvent was removed under reduced pressure and the solvent was directly separated and purified by flash silica gel column chromatography (eluent petroleum ether/ethyl acetate=1/50-1/20) to obtain a colorless oil Product 3af, yield 92%; 99% ee, dr=12:1; HPLC CHIRAL PAK OD-H+IG, n-Hexane/2-propanol=96/4, flow rate=0.8 mL/min, λ= 210nm, retention time: 16.695min (major), 21.775min (minor); [α] 30 D=-32.4 (c 1.5, CHCl ₃ ); ¹ H NMR (600MHz, CDCl ₃ )δ7.24 (dd, J= 5.1, 3.0Hz, 1H), 7.18(d, J=3.0Hz, 1H), 7.03–6.96(m, 1H), 6.62(s, 1H), 6.37(s, 1H), 5.34(s, 1H), 3.78(s, 3H), 1.22(s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.1, 166.1, 161.5, 135.8, 135.5, 131.7, 129.8, 129.0, 127.2, 126.6, 121.6 (q, J=285.7 Hz), 100.4 (q, J=29.8 Hz), 52.8, 42.6, 35.0, 26.2. ¹⁹ F NMR (565 MHz, CDCl ₃ ) δ-75.35; HRMS (ESI) calcd. for C ₁₇ H ₁₈ F ₃ O ₄ NS ( [M+H] ⁺ ):390.0981,found:390.0984.

The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments. The above-mentioned embodiments and descriptions only illustrate the principle of the present invention. Without departing from the scope of the principle of the present invention, the present invention will also have various Variations and improvements all fall within the scope of the present invention.

Claims (8)

1. a method for synthesizing optically active trifluoromethacrylate compounds, is characterized in that, comprises the steps: with MBH carbonate 1 and oxazolone 2 as raw materials, in L-tertiary leucine derivation chiral bicarbonate In the presence of a functional group tertiary amine urea-phosphine catalyst, through asymmetric allyl alkylation, trifluoromethacrylate compound 3 is obtained; the reaction equation is as follows:

Wherein: R ¹ is selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, thienyl; R ² is selected from C1-C4 alkyl. 2. The method for synthesizing optically active trifluoromethacrylate compounds according to claim 1, characterized in that: R ¹ is selected from 2-F, 3-Me, 2-thienyl, 3-thienyl; R ² Selected from Me, Et. 3. the method for synthesizing optically active trifluoromethacrylate compounds according to claim 1, is characterized in that: catalyzer is selected from C1-C8, and concrete structural formula is as follows:

4. The method for synthesizing optically active trifluoromethacrylate compounds according to claim 3, wherein the catalyst is selected from C1 or C6. 5. The method for synthesizing optically active trifluoromethacrylate compounds according to claim 1, wherein the molar ratio of the MBH carbonate 1, the oxazolone 2 and the catalyst is 1:1-1.5:0.05- 0.10. 6 . The method for synthesizing optically active trifluoromethacrylate compounds according to claim 1 , wherein the reaction temperature is 0-30° C. 7 . 7. The method for synthesizing an optically active trifluoromethacrylate compound according to claim 1, wherein the reaction is carried out in an air atmosphere. 8. The method for synthesizing optically active trifluoromethacrylate compounds according to any one of claims 1-7, wherein the reaction is carried out in an organic solvent, and the reaction solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, Mesitylene, chlorobenzene, pentafluorobenzene, m-xylene, o-xylene or ether.