CN114835655A - Method for synthesizing optically active trifluoromethyl acrylate compound - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 19
- -1 trifluoromethyl acrylate compound Chemical class 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 28
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 12
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 claims abstract description 8
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 5
- 150000003512 tertiary amines Chemical class 0.000 claims abstract description 5
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- ZESXUEKAXSBANL-UHFFFAOYSA-N trifluoromethyl prop-2-enoate Chemical compound FC(F)(F)OC(=O)C=C ZESXUEKAXSBANL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- WACNXHCZHTVBJM-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene Chemical compound FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 abstract description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 229910052723 transition metal Inorganic materials 0.000 abstract 1
- 150000003624 transition metals Chemical class 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 8
- PEIYTIKCYUWXER-UHFFFAOYSA-N 4-tert-butyl-2-(trifluoromethyl)-2H-1,3-oxazol-5-one Chemical compound C(C)(C)(C)C1=NC(OC1=O)C(F)(F)F PEIYTIKCYUWXER-UHFFFAOYSA-N 0.000 description 7
- 238000005712 Baylis-Hillman reaction Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960004592 isopropanol Drugs 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- PQMCFTMVQORYJC-UHFFFAOYSA-N 2-aminocyclohexan-1-ol Chemical compound NC1CCCCC1O PQMCFTMVQORYJC-UHFFFAOYSA-N 0.000 description 1
- UYRPRYSDOVYCOU-UHFFFAOYSA-N 2-diphenylphosphanylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UYRPRYSDOVYCOU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- AFFZTFNQQHNSEG-UHFFFAOYSA-N trifluoromethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC(F)(F)F AFFZTFNQQHNSEG-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0267—Phosphines or phosphonium compounds, i.e. phosphorus bonded to at least one carbon atom, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, the other atoms bonded to phosphorus being either carbon or hydrogen
- B01J31/0268—Phosphonium compounds, i.e. phosphine with an additional hydrogen or carbon atom bonded to phosphorous so as to result in a formal positive charge on phosphorous
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5054—Preparation; Separation; Purification; Stabilisation by a process in which the phosphorus atom is not involved
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention discloses a method for synthesizing an optically active trifluoromethyl acrylate compound, belonging to the technical field of organic chemistry. MBH carbonate and oxazolone are used as initial raw materials, and allyl alkylation reaction is carried out in the presence of L-tert-leucine and cyclohexyl derived chiral bifunctional tertiary amine urea-phosphonamide/ester catalysts to obtain the trifluoromethyl acrylate compound with high optical activity. The reaction process of the invention has excellent enantioselectivity, and does not need to use transition metal or stoichiometric oxidant; the method has the advantages of easily available reaction raw materials, simple catalyst structure, high catalytic efficiency, mild reaction conditions and simple post-treatment.
Description
Technical Field
The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a method for synthesizing a trifluoromethyl acrylate compound.
Background
As an important method for synthesizing compounds containing chiral trifluoromethyl methacrylate, extensive research has been conducted over 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 significant value.
Many chiral sites of drug molecules contain a stereotrifluoromethyl group, and the construction of compounds containing a stereotrifluoromethyl group as a center remains a current research hotspot. Therefore, it is very important to develop a method for economically and efficiently synthesizing an optically active trifluoromethyl acrylate compound.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a method for synthesizing an optically active trifluoromethyl acrylate compound by using simple starting materials. MBH carbonate is used as an initial raw material, and then the MBH carbonate and oxazolone are subjected to non-allyl alkylation reaction in the presence of a chiral bifunctional tertiary amine urea-phosphine catalyst to synthesize the optically active trifluoromethyl acrylate compound.
Based on the purposes, the invention adopts MBH carbonate 1 and oxazolone 2 as starting materials, then adopts chiral bifunctional tertiary amine urea-phosphine ester compounds as catalysts, and synthesizes the optically active trifluoromethyl acrylate compounds through asymmetric allyl alkylation reaction with high yield and high enantioselectivity.
A synthetic method of optically active trifluoromethyl acrylate compounds comprises the following steps: MBH carbonate 1 and oxazolone 2 are used as raw materials, and under the existence of an L-tert-leucine derived chiral bifunctional tertiary amine urea-phosphine catalyst, the trifluoromethyl acrylate compound 3 is obtained through asymmetric allyl alkylation reaction.
The reaction equation is as follows:
wherein: r is 1 Selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, thienyl; r 2 Selected from C1-C4 alkyl.
Further, the method can be used for preparing a novel materialIn the above technical scheme, R 1 Selected from 2-F, 3-Me, 2-thienyl, 3-thienyl; r 2 Selected from Me and Et.
Further, in the above 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 scheme, the molar ratio of the MBH carbonate 1, oxazolone 2 to 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 scheme, the reaction temperature is 0-30 ℃, preferably 25 ℃.
Further, in the above technical scheme, the reaction is carried out in an air atmosphere.
Further, in the above 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 diethyl ether; preferably, the reaction solvent is toluene.
The invention has the beneficial effects that:
the invention takes MBH carbonate as a starting material to react with asymmetric allyl alkylation of oxazolone in one pot to obtain the optical trifluoromethyl acrylate compound, the raw material is simple and easy to obtain, the catalyst has simple structure/high catalytic efficiency, the reaction condition is mild, the post-treatment is simple, the catalyst can be recycled, and the product yield and the enantioselectivity are good to excellent.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto.
Examination of reaction conditions
A typical operation is as follows: Morita-Baylis-Hillman carbonate 1(0.1mmol,1.0eq and catalyst C1(0.76mg,0.01mmol,0.1eq) was dissolved in super dry toluene (1.0mL) and then 4-tert-butyl-2-trifluoromethyloxazole-5 (2H) -one 2(0.15mmol,1.5eq) was stirred at room temperature for 72H and monitored by TLC after the starting material was completely reacted the reaction mixture was eluted with a gradient PE/EA ═ 50:1-20:1 directly on a short silica gel column to give the product.
a Reaction conditions are as follows: 1(0.1mmol),2(0.15mmol), catalyst (0.01mmol), ultra dry toluene (1.0mL), 25 ℃. b Yield was obtained by flash column chromatography. c The ee is measured by a high performance liquid phase method, d by passing 1 D.r. measured by H NMR spectroscopy.
In the process of screening reaction conditions, the influence of different catalysts on the reaction is firstly examined (entries 1-8), the catalyst C1 is finally determined to be the optimal catalyst, an alpha-allyl alkylation product is obtained under the action of the C2 catalyst, then the influence of a solvent on the reaction is examined (entries 9-12), and finally anhydrous toluene is determined to be the optimal solvent, the reaction temperature is 25 ℃, and the catalyst dosage is 10 mol%.
The synthesis route of the typical catalyst C1 is represented by the following reaction equation:
1.0g of 2-aminocyclohexanol A was dissolved in 20mL of methylene chloride in a 15mL round-bottomed flask under nitrogen, followed by dropwise addition of 1.84mL of 3, 5-bis-trifluoromethyl-isothioxide and rapid spotting of the solution. After completion of the reaction, spin-dry column chromatography eluting with dichloromethane/methanol-60/1 gave intermediate B in 81% yield.
Under the protection of nitrogen, 2.0g of intermediate B is added into 30mL of dichloromethane in a 15mL round-bottom flask to be dissolved, 0.903mL of EDC and 315.2mg of DMAP are added in sequence, 1.56g of diphenylphosphinobenzoic acid is added, the reaction is carried out for 8 hours at room temperature, and the reaction is monitored by a point plate to be finished. Adding water for quenching, extracting by dichloromethane, drying and spin-drying, and carrying out column chromatography to obtain a white solid catalyst C1 with the yield of 78 percent and the melting point of 168.3-169.2 ℃.
1 H NMR(400MHz,CDCl 3 )δ8.46(s,1H),8.17-8.08(m,1H),7.90(s,2H),7.59(s, 1H),7.41(pd,J＝7.5,1.7Hz,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(100MHz,CDCl 3 )δ181.2,168.5,140.7,139.6(d,J＝21.3Hz),136.7(d, J＝4.6Hz),134.2,134.0,133.6(d,J＝16.6Hz),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(376MHz,CDCl 3 )δ-62.90. 31 P NMR(162MHz,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(1mmol,1.0eq) and catalyst C1(7.6mg, 0.01mmol,0.1eq) were dissolved in super dry toluene (5.0mL) followed by 4-tert-butyl-2-trifluoromethyloxazole-5 (2H) -one 2(1.5mmol,1.5 eq). Stirring the reaction mixture at room temperature for 72h, monitoring the complete reaction of the raw materials by TLC, removing the solvent under reduced pressure, and directly separating and purifying by flash silica gel column chromatography (petroleum ether/ethyl acetate: 1/50-1/20) to obtain a colorless oily product 3aa with the yield of 82%; HPLC CHIRALPAK OD-H, n-Hexane/2-prop anol (96/4), flow rate (0.8 mL/min), lambda (210 nm), retention time (9.166 min (major)), 4.717min (minor); 97% ee, dr 10: 1; [ alpha ] to] 30 D ＝-25.8(c 1.5, CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.34–7.08(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(100MHz,CDCl 3 )δ175.0,166.4, 161.4,135.3,132.9,130.9,130.7,128.5,128.4,121.8(q,J＝286.3Hz),100.9(q,J＝ 29.9Hz),52.7,47.4,35.0,26.3； 19 F NMR(565MHz,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 (1mmol,1.0eq) and catalyst C1(7.6mg, 0.01mmol,0.1eq) were dissolved in super dry toluene (5.0mL) and then 4-tert-butyl-2-trifluoromethyloxazole-5 (2H) -one 2(1.5mmol,1.5eq) was added. Stirring the reaction mixture at room temperature for 72h, monitoring the complete reaction of the raw materials by TLC, removing the solvent under reduced pressure, and directly separating and purifying by fast silica gel column chromatography (petroleum ether/ethyl acetate: 1/50-1/20) to obtain a colorless oily product 3ab with the yield of 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; [ alpha ] to] 30 D ＝-88.1(c 1.5, CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.37–7.19(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＝249.9Hz),135.1,131.4,131.0, 130.3(d,J＝7.9Hz),124.4(d,J＝31.0Hz),123.6(d,J＝4.2Hz),121.6(q,J＝286.1 Hz),121.0(d,J＝14.1Hz),116.1(d,J＝23.1Hz),100.8(q,J＝30.2Hz),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 (1mmol,1.0eq) and catalyst C1(7.6mg, 0.01mmol,0.1eq) were dissolved in super dry toluene (5.0mL) and then 4-tert-butyl-2-trifluoromethyloxazol-5 (2H) -one 2(1.5mmol )eq). Stirring the reaction mixture at room temperature for 72h, monitoring the complete reaction of the raw materials by TLC, removing the solvent under reduced pressure, and directly separating and purifying by fast silica gel column chromatography (petroleum ether/ethyl acetate: 1/50-1/20) to obtain a colorless oily product 3ac with the yield of 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; [ alpha ] to] 30 D ＝-24.9(c 1.5,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.16(t,J＝7.6Hz,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(100MHz,CDCl 3 )δ174.9,166.5,161.4,137.9,135.3,132.8,131.4, 130.8,129.2,128.2,127.9,121.8(q,J＝286.0Hz),100.9(q,J＝29.8Hz),52.7,47.4, 35.0,26.3,21.5； 19 F NMR(376MHz,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 (1mmol,1.0eq) and catalyst C1(7.6mg, 0.01mmol,0.1eq) were dissolved in super dry toluene (5.0mL) followed by 4-tert-butyl-2-trifluoromethyloxazole-5 (2H) -one 2(1.5mmol,1.5 eq). Stirring the reaction mixture at room temperature for 72h, monitoring the complete reaction of the raw materials by TLC, removing the solvent under reduced pressure, and separating and purifying by direct flash silica gel column chromatography (petroleum ether/ethyl acetate: 1/50-1/20) to obtain a colorless oily product 3ad with the yield of 92%; HPLC CHIRALPAK OD-H + IG, n-Hexane/2-propal 96/4, flow rate 0.8mL/min, λ 210nm, retentivity time 15.550min (major),25.067min (minor); 98% ee, dr 11: 1; [ alpha ] to] 30 D ＝-35.9(c 1.5, CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.24–7.17(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(100MHz,CDCl 3 )δ175.1,166.1,161.5,135.8,135.5,131.7,129.8,129.0, 127.2,126.6,121.6(q,J＝285.7Hz),100.4(q,J＝29.8Hz),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.
Example 5:
Morita-Baylis-Hillman carbonate 1e (1mmol,1.0eq) and catalyst C1(7.6mg, 0.01mmol,0.1eq) were dissolved in super dry toluene (5.0mL) and then 4-tert-butyl-2-trifluoromethyloxazole-5 (2H) -one 2(1.5mmol,1.5eq) was added. Stirring the reaction mixture at room temperature for 72h, monitoring the complete reaction of the raw materials by TLC, removing the solvent under reduced pressure, and separating and purifying by direct fast silica gel column chromatography (petroleum ether/ethyl acetate: 1/50-1/20) to obtain a colorless oily product 3ae with the yield of 92%; HPLC CHIRALPAK OD-H + IG, n-Hexane/2-prop anol 96/4, flow rate 0.8mL/min, λ 210nm, retention time 14.127min (major),16.605min (minor); 99% ee, dr 10: 1; [ alpha ] to] 30 D ＝-26.4(c 1.5, CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.26(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 C NMR (150MHz,CDCl 3 )δ174.9,165.9,161.4,135.6,133.1,130.7,130.5,128.6,128.4, 121.8(q,J＝286.2Hz),100.9(q,J＝29.9Hz),61.7,47.3,35.0,26.3,14.2； 19 F NMR (376MHz,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.
Example 6:
Morita-Baylis-Hillman carbonate 1f (1mmol,1.0eq) and catalyst C1(7.6mg, 0.01mmol,0.1eq) were dissolvedIn extra dry toluene (5.0mL) and then 4-tert-butyl-2-trifluoromethyloxazol-5 (2H) -one 2(1.5mmol,1.5 equiv). Stirring the reaction mixture at room temperature for 72h, monitoring the complete reaction of the raw materials by TLC, removing the solvent under reduced pressure, and separating and purifying by direct flash silica gel column chromatography (eluent petroleum ether/ethyl acetate 1/50-1/20) to obtain a colorless oily product 3af with the yield of 92%; 99% ee, dr 12: 1; HPLC CHIRAL PAK OD-H + IG, n-Hexane/2-propanol 96/4, flow rate 0.8mL/min, λ 210nm, retention time 16.695min (major),21.775min (minor); [ alpha ] to]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(100MHz,CDCl 3 )δ175.1,166.1,161.5, 135.8,135.5,131.7,129.8,129.0,127.2,126.6,121.6(q,J＝285.7Hz),100.4(q,J＝ 29.8Hz),52.8,42.6,35.0,26.2. 19 F NMR(565MHz,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 foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (8)
1. A method for synthesizing an optically active trifluoromethyl acrylate compound is characterized by comprising the following steps: MBH carbonate 1 and oxazolone 2 are taken as raw materials, and are subjected to asymmetric allylic alkylation reaction in the presence of an L-tert-leucine derived chiral bifunctional tertiary amine urea-phosphine catalyst to obtain a trifluoromethyl acrylate compound 3; the reaction equation is as follows:
wherein: r 1 Selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, thienyl; r is 2 Selected from C1-C4 alkyl.
2. The method for synthesizing an optically active trifluoromethyl acrylate compound according to claim 1, wherein: r 1 Selected from 2-F, 3-Me, 2-thienyl, 3-thienyl; r 2 Selected from Me and Et.
3. The method for synthesizing an optically active trifluoromethyl acrylate compound according to claim 1, wherein: the catalyst is selected from C1-C8, and the specific structural formula is as follows:
4. the method for synthesizing an optically active trifluoromethyl acrylate compound according to claim 3, wherein: the catalyst is selected from C1 or C6.
5. The method for synthesizing an optically active trifluoromethyl acrylate compound according to claim 1, wherein: the molar ratio of MBH carbonate 1, oxazolone 2 and catalyst is 1: 1-1.5: 0.05-0.10.
6. The method for synthesizing an optically active trifluoromethyl acrylate compound according to claim 1, wherein: the reaction temperature is 0-30 ℃.
7. The method for synthesizing an optically active trifluoromethyl acrylate compound according to claim 1, wherein: the reaction was carried out under an air atmosphere.
8. The method for synthesizing an optically active trifluoromethyl acrylate compound according to any one of claims 1 to 7, wherein: the reaction is carried out in an organic solvent selected from toluene, dichloromethane, tetrahydrofuran, mesitylene, chlorobenzene, pentafluorobenzene, m-xylene, o-xylene or diethyl ether.
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