阅读说明：本技术 一种含有三氟甲基的3-取代-2-吲哚啉酮类化合物制备方法 (Preparation method of trifluoromethyl-containing 3-substituted-2-indolinone compound ) 是由 周宇涵 李栋 曲景平 冯芮茂 奚灏瀛 张成海 黄文远 于 2021-10-11 设计创作，主要内容包括：本发明公开了一种含有三氟甲基的3-取代-2-吲哚啉酮化合物制备方法,式Ⅱ所示1,1,1-三氟丁-2-烯-2-基酯化合物和式Ⅲ所示3-取代-2-吲哚啉酮化合物在催化剂、手性配体和有机碱存在下反应得到式Ⅰ所示三氟甲基取代的3-取代-2-吲哚啉酮化合物。本发明为1,1,1-三氟丁-2-烯-2-基酯化合物的合成提供了一种方便、低成本的方法。同时1,1,1-三氟丁-2-烯-2-基酯化合物可以应用到3-取代-2-吲哚啉酮化合物的不对称三氟甲基烯丙基化反应,并且反应收率和立体选择性较高。(Hair brushThe invention discloses a preparation method of a trifluoromethyl-containing 3-substituted-2-indolinone compound, which comprises the step of reacting a 1,1, 1-trifluorobut-2-en-2-yl ester compound shown in a formula II with a 3-substituted-2-indolinone compound shown in a formula III in the presence of a catalyst, a chiral ligand and an organic base to obtain the trifluoromethyl-substituted 3-substituted-2-indolinone compound shown in the formula I. The invention provides a convenient and low-cost method for synthesizing the 1,1, 1-trifluorobutan-2-en-2-yl ester compound. Meanwhile, the 1,1, 1-trifluorobutan-2-ene-2-yl ester compound can be applied to the asymmetric trifluoromethyl allylation reaction of the 3-substituted-2-indolinone compound, and the reaction yield and the stereoselectivity are high.)

1. A preparation method of a compound of formula I is characterized in that a compound of formula II and a compound of formula III react in the presence of a catalyst, a chiral ligand and an organic base to obtain the compound of formula I,

wherein G is an amine protecting group;

r is selected from C2-5 alkanoyl, benzoyl or tert-butyloxycarbonyl;

R¹selected from substituted or unsubstituted aryl or heteroaryl;

R³selected from aryl, heteroaryl or alkyl.

2. The method of claim 1, wherein R is¹Is selected from Wherein X is selected from O, S or N (CH)₃) (ii) a n is 1,2, 3,4 and 5, and the wavy line is a connecting position; r²Selected from H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester group or cyano.

3. The method of claim 1, wherein R is³Selected from arylmethyl.

4. The method of claim 1, wherein G is selected from Boc, Fmoc, COOMe, COOEt, COOPh, COOCH₂Ph, Ac, or COPh.

5. The process according to claim 1, characterized in that the catalyst is selected from palladium catalysts, preferably palladium acetate or allylpalladium chloride dimer.

6. The process according to claim 1, characterized in that the chiral ligand is selected from organophosphorus chiral ligands, preferably (R) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, (S) -2,2 '-bis [ bis (4-methylphenyl) phosphine ] -1,1' -binaphthyl or (R) - (+) -4,4 '-bis (diphenylphosphino) -3,3' -bis (1, 2-methylenedioxybenzene).

7. The process of claim 1 wherein the organic base is selected from the group consisting of 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene.

8. The process according to claim 1, wherein the reaction solvent is selected from tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether or acetonitrile.

9. A process according to claim 1, wherein the catalyst is present in an amount of from 5 mol% to 30 mol% and the chiral ligand is present in an amount of from 5 mol% to 30 mol% based on the compound of formula III.

10. A process according to claim 1, wherein the catalyst is present in an amount of 10 mol% and the chiral ligand is present in an amount of 22 mol% based on the compound of formula III.

Technical Field

The invention relates to the field of chemical synthesis, and in particular relates to a preparation method of a trifluoromethyl-containing 3-substituted-2-indolinone compound.

Background

3-substituted-2-indolinones are an important molecular skeleton and widely exist in natural products and active molecules. Meanwhile, the derivative is also an important intermediate in the synthesis of organic functional molecules, and the synthesis of active molecules such as (+) -glitazone C, (-) -nicotinamide and the like has the figure of a 3-substituted-2-indolinone intermediate. Therefore, the diversified transformation, especially the asymmetric transformation, of 3-substituted-2-indolinone derivatives has been the research hotspot in the field of organic chemistry

Asymmetric allylation is an important means of building chiral centers. The 3-substituted-2-indolines reported so farAsymmetric allylation of perinone is achieved mainly using dienyl esters or allyl esters as allyl donors under organic small molecule catalytic or transition metal/chiral ligand co-catalytic conditions. For example, Luxin topic groups reported that phosphines catalyze the stereoselective allylation of 3-substituted-2-indolinones and dienyl esters; the Trost topic group reported palladium-catalyzed asymmetric allylation of 3-substituted-2-indolinones and dienyl esters; the Showshinjing problem group reports an organic small molecule catalyst and Pd (PPh)₃)₄A co-catalyzed stereoselective allylation of 3-substituted-2-indolinones and allyl esters. In addition to the above processes, β, γ -ketene and allylhalohydrocarbons can also participate as allyl donors in asymmetric allylation reactions of 3-substituted-2-indolinones.

Although the asymmetric allylation of 3-substituted-2-indolinone derivatives has been advanced, there are still few reports on this reaction as a whole, and there is a need to expand the types of allylation reagents. To our knowledge, the trifluoromethylallylation of 3-substituted-2-indolinones has not been reported so far. The asymmetric trifluoromethylallylation conversion of 3-substituted-2-indolinone derivatives is of great significance considering that the introduction of trifluoromethyl into the active molecule can always positively change the properties.

Disclosure of Invention

The invention provides a widely applicable 1,1, 1-trifluorobutan-2-en-2-yl ester compound of trifluoromethyl substituted alkenyl ester reaction blocks by a synthesis method with low cost and widely available raw materials. The 1,1, 1-trifluorobutan-2-ene-2-yl ester compound is used as an organic synthesis building block and can be applied to asymmetric trifluoromethylallylation reaction of pyrazolone compounds.

A1, 1, 1-trifluorobut-2-en-2-yl ester compound of formula II:

wherein R is selected from C2-5 alkanoyl, benzoyl or tert-butyloxycarbonyl;R¹selected from substituted or unsubstituted aryl or heteroaryl;

preferably, R¹Is selected fromWherein X is selected from O, S or N (CH)₃) (ii) a n is 1,2, 3,4 and 5, and the wavy line is a connecting position;

R²selected from H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester group or cyano;

the 1,1, 1-trifluorobut-2-en-2-yl ester compound shown in the formula II can be prepared according to the following reaction:

a process for preparing a 1,1, 1-trifluorobut-2-en-2-yl ester compound according to the above reaction scheme, comprising the steps of:

(1) under the protection of inert gas, 3-aryl-1-substituted-1-acetone shown in the formula IV and ethyl trifluoroacetate react for 1-24 hours in an organic solvent in the presence of 1.0-3.0 times equivalent of metal hydride, such as sodium hydride, relative to 3-aryl-1-substituted ketone according to the molar ratio of 1: 1-1: 3 under the condition of room temperature to reflux.

(2) And (2) under the protection of inert gas, cooling the reaction liquid in the step (1) to 0-room temperature, slowly dropwise adding 1.0-3.0 times equivalent of acyl chloride or anhydride compound of formula V or formula VI relative to 3-aryl-1 substituted-1-acetone, reacting for 5 minutes-3 hours, adding water for quenching, extracting with ethyl acetate, drying, filtering, removing the solvent by rotary evaporation under reduced pressure, and separating by silica gel column chromatography to obtain the target product.

The organic solvent is selected from ethylene glycol dimethyl ether, tetrahydrofuran, n-hexane, methyl tert-butyl ether or toluene; preferably, the amount ratio of the compound of formula IV to the organic solvent is 1mmol (5-15) mL.

Wherein L is selected from tert-butyl, isopropyl, methyl tert-butyl, ethyl tert-butyl, propyl, isopropyl, or isopropyl,Wherein n is 1,2, 3,4,5, and the wavy line is a connecting position;

R²selected from H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester group or cyano;

a preparation method of a compound of formula I is characterized in that a compound of formula II and a compound of formula III react in the presence of a catalyst, a chiral ligand and an organic base to obtain the compound of formula I,

wherein G is an amine protecting group;

r is selected from C2-5 alkanoyl, benzoyl or tert-butyloxycarbonyl;

R¹selected from substituted or unsubstituted aryl or heteroaryl;

R³selected from aryl, heteroaryl or alkyl.

Preferably, R¹Is selected fromWherein X is selected from O, S or N (CH)₃) (ii) a n is 1,2, 3,4 and 5, and the wavy line is a connecting position;

wherein R is²Selected from H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester group or cyano.

Preferably, R³Selected from arylmethyl.

Preferably, G is selected from Boc, Fmoc, COOMe, COOEt, COOPh, COOCH₂Ph, Ac, or COPh.

Wherein the catalyst is selected from palladium catalysts, preferably palladium acetate or allylpalladium chloride dimer.

Wherein the chiral ligand is selected from organophosphorus chiral ligands, preferably (R) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, (S) -2,2 '-bis [ bis (4-methylphenyl) phosphine ] -1,1' -binaphthyl or (R) - (+) -4,4 '-bis (diphenylphosphine) -3,3' -bis (1, 2-methylenedioxybenzene).

Wherein the organic base is selected from 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene.

Wherein the reaction solvent is selected from tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether or acetonitrile.

Wherein, the dosage of the catalyst is 5mol percent to 30mol percent of the compound of the formula III, and the dosage of the chiral ligand is 5mol percent to 30mol percent of the compound of the formula III.

Preferably, the amount of catalyst is 10 mol% of the compound of formula III and the amount of chiral ligand is 22 mol% of the compound of formula III

Wherein the molar ratio of the catalyst to the chiral ligand is 1: 1-1: 3.

Wherein the dosage of the organic base is 1.0-3.0 times of the equivalent of the compound shown in the formula III.

The optimal reaction conditions of the invention are as follows: under the protection of argon, Pd (OAc)₂(10 mol%) and (R) -BINAP (22 mol%) were dissolved in THF, stirred at 25 ℃ for five minutes and then cooled to 5 ℃ and then 1,1, 1-trifluorobut-2-en-2-yl acetate (1.5eq), the compound of formula III, 3-substituted-2-indolinone (1.0eq), DBU (1.5eq) were added in that order and the mixture was allowed to react at 5 ℃ for 60 hours with further stirring.

Unless otherwise indicated, the terms used herein have the following meanings.

The term "alkyl" as used herein includes straight chain and branched chain alkyl groups. Reference to a single alkyl group, such as "methyl", is intended to refer only to straight chain alkyl groups, and reference to a single branched alkyl group, such as "isopropyl", is intended to refer only to branched alkyl groups. For example, "C4 lower alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the like. Similar rules apply to other groups used in this specification.

The term "halogen" as used herein includes fluorine, chlorine, bromine, iodine.

The C2-C5 ester group is a group with the following structure: -COOM, wherein M is a C1-C4 alkyl group.

The C1-C4 alkoxy group is a group having the following structure: -O-M₁Wherein，M₁Is C1-C4 alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy.

In the above scheme, the(n-1, 2, 3,4, 5) and the position of the wavy line is a connecting position, wherein (R) is²)_nWhere n ═ 1,2, 3,4,5 means that the substitution of R on the phenyl group can be mono-or multi-substituted, and can be 1,2, 3,4 or 5 substituted. When n is 1, the substituent is monosubstituted, and the monosubstituted substituent can be 2, 3 or 4; when n is 2, 3,4 or 5, the substituent is multi-position substitution, wherein, n is 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-, 3, 5-; n-3 is trisubstituted with the trisubstituted substitution positions being 2, 3, 4-, 2, 3, 5-, 2, 3, 6-, 3,4, 5-.

The invention provides a convenient and low-cost method for synthesizing the 1,1, 1-trifluorobutan-2-en-2-yl ester compound. Meanwhile, the 1,1, 1-trifluorobutan-2-alkene-2-ester compound can be applied to the asymmetric trifluoromethyl allylation reaction of the 3-substituted-2-indolinone compound, and the reaction yield and the stereoselectivity are high.

Detailed Description

The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.

The test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 1

Preparation of 4-phenyl-1, 1, 1-trifluorobut-2-en-2-yl acetate (Compound 1)

(1) 480mg (20.0mmol) of sodium hydride are weighed out by difference method at room temperature into a 250mL Schlenk flask under argon protection, and anhydrous methyl tert-butyl ether (100mL) is added. Subsequently, 2.40g (10.0mmol) of 1- (4-methoxyphenyl) -3-phenylpropan-1-one and 2.0-fold molar amount of ethyl trifluoroacetate (2.4 mL (20.0mmol) of 1- (4-methoxyphenyl) -3-phenylpropan-1-one were added successively. The mixture was left to react at 55 ℃ for 12 hours.

(2) The mixture is cooled to 0 ℃, 1.42mL (20.0mmol) of acetyl chloride with 2.0 times of the molar amount of 1- (4-methoxyphenyl) -3-phenylpropan-1-one is slowly dropped under the protection of argon, and the reaction is continued for 10 minutes at the temperature of 0 ℃. The reaction was quenched by addition of water (10 mL). Extraction was performed with ethyl acetate (3X 100mL), the combined organic phases were washed with saturated brine (2X 50mL), dried over anhydrous magnesium sulfate, and column chromatography was performed to give the title compound in 86% isolated yield using silica gel as the filler and petroleum ether as the eluent.

Example 2

Preparation of 4- (2-methylphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 2)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (2-methylphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 83%.

Example 3

Preparation of 4- (2-methylphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 3)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (3-methylphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 84%.

Example 4

Preparation of 4- (4-methylphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 4)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (4-methylphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 86%.

Example 5

Preparation of 4- (4-isopropylphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 5)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (4-isopropylphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 86%.

Example 6

Preparation of 4- (2-methoxyphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 6)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (2-methoxyphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 80%.

Example 7

Preparation of 4- (2-naphthyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 7)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (2-naphthyl) propan-1-one, so as to obtain the objective compound with an isolated yield of 85%.

Example 8

Preparation of 4- (4-phenylphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 8)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (4-phenylphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 86%.

Example 9

Preparation of 4- (4-fluorophenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 9)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one with the same molar amount of 1- (4-methoxyphenyl) -3- (4-fluorophenyl) propan-1-one in example 1, to obtain the desired compound in an isolated yield of 89%.

Example 10

Preparation of 4- (3-chlorophenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 10)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one with the same molar amount of 1- (4-methoxyphenyl) -3- (3-chlorophenyl) propan-1-one in example 1, to obtain the desired compound in an isolated yield of 87%.

Example 11

Preparation of 4- (4-bromophenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 11)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (4-bromophenyl) propan-1-one, so as to obtain the desired compound in an isolated yield of 85%.

Example 12

Preparation of 4- (4-trifluoromethylphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 12)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (4-trifluoromethylphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 90%.

Example 13

Preparation of 4- (3,4, 5-trimethoxyphenyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 13)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (3,4, 5-trimethoxyphenyl) propan-1-one, to obtain the desired compound in an isolated yield of 91%.

Example 14

Preparation of 4- (2-thienyl) -1,1, 1-trifluorobut-2-en-2-yl acetate (Compound 14)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) -3- (2-thienyl) propan-1-one, so as to obtain the desired compound in an isolated yield of 88%.

Example 15

Preparation of 1,1, 1-trifluorodec-2-en-2-yl acetate (Compound 15)

The procedure was carried out in the same manner as in example 1 except for replacing 1- (4-methoxyphenyl) -3-phenylpropan-1-one in example 1 with the same molar amount of 1- (4-methoxyphenyl) nonan-1-one, to obtain the desired compound in an isolated yield of 84%.

Example 16

Preparation of 4-phenyl-1, 1, 1-trifluorobut-2-en-2-yl tert-butyl carbonate (Compound 16)

The procedure was carried out in the same manner as in example 1 except for replacing the acetyl chloride in example 1 with the same molar amount of di-tert-butyl dicarbonate, thereby obtaining an isolated yield of the objective compound of 83%.

Example 17

Preparation of 4-phenyl-1, 1, 1-trifluorobut-2-ene-2-benzoic acid ester (Compound 17)

The procedure was carried out in the same manner as in example 1 except for replacing the acetyl chloride in example 1 with the same molar amount of benzoyl chloride, thereby obtaining an isolated yield of the objective compound of 81%.

The following table lists the structures, physical properties and properties of the synthesized specific compounds 1-17¹H NMR data, but the present invention is not limited to these compounds.

Example 18

Asymmetric trifluoromethylallylation reaction of 3-substituted-2-indolinone

Pd (OAc) was added to a 25mL Schlenk flask in sequence under argon₂(5.6mg,10 mol%), (R) -BINAP (34.2mg, 22 mol%) and THF (3mL), the mixture was stirred at 25 ℃ for 5min, the reaction system was cooled to 5 ℃ and 4-aryl-1, 1, 1-trifluorobut-2-en-2-yl acetate 8(0.375mmol,1.5eq), 3-substituted-2-indolinone derivative (0.25mmol) and DBU (57.0mg, 0.375mmol,1.5eq) were added in this order, the mixture was stirred at 5 ℃ for 36-60h, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by silica gel column chromatography to give the desired product.

Structural validation and experimental data for a portion of the compounds prepared below:

3- (4-Phenylbenzyl) -3- ((E) -1- (4-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

3.44(d,J＝13.2Hz,1H),2.91(d,J＝13.2Hz,1H),2.27(s,3H),1.52(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.8,148.4,140.6,140.1,139.2,137.6,137.5(q,J＝3.7Hz),134.1,133.6,130.4,129.1,129.0,128.7,127.2,127.1,126.8,126.4,124.7,123.6,122.6(q,J＝271.7Hz),121.4(q,J＝33.7Hz),114.9,84.1,58.6,55.6,42.1,28.0,21.1.¹⁹F NMR(377MHz,CDCl₃) δ -63.85(d, J ═ 5.4Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝7.44min,t_minorCalculated value C: 14.07min HRMS (ESI) m/z₃₇H₃₄F₃NNaO₃[M+Na]⁺620.2388, found 620.2386.

3- (4-Phenylbenzyl) -3- ((E) -1- (3-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

J＝15.5,6.2Hz,1H),3.98(d,J＝10.4Hz,1H),3.51(d,J＝13.2Hz,1H),2.98(d,J＝13.2Hz,1H),2.32(s,3H),1.59(s,9H).¹³C NMR(101MHz,CDCl₃)(one aromatic carbon missing)δ176.6,148.4,140.6,140.1,139.2,138.0,137.4(q,J＝3.2Hz),136.5,134.1,130.5,129.9,128.7,128.6,128.2,127.2,127.1,126.8,126.4,126.2,124.8,123.6,122.6(q,J＝270.7Hz),121.50(q,J＝33.7Hz),114.9,84.1,58.6,56.0,41.9,28.0,21.4.¹⁹F NMR(377MHz,CDCl₃) δ -63.84(d, J ═ 5.6Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝6.45min,t_minorCalculated value C: 14.37min HRMS (ESI) m/z₃₇H₃₄F₃NNaO₃[M+Na]⁺620.2388, found 620.2378.

3- (4-Phenylbenzyl) -3- ((E) -1- (2-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

13.0Hz,1H),2.98(d,J＝13.0Hz,1H),2.45(s,3H),1.61(s,9H).¹³C NMR(101MHz,CDCl₃)δ177.1,148.4,140.5,140.0,139.3,138.3(q,J＝6.0Hz),136.4,135.4,133.9,131.1,130.5,128.7,128.6,127.9,127.5,127.2,127.1,126.8,126.4,126.1,124.8,123.4,122.1(q,J＝278.7Hz),120.81(q,J＝33.6Hz),114.8,84.3,59.0,50.5,41.6,28.0,20.5.¹⁹F NMR(376MHz,CDCl₃) Delta-63.80 (d, J ═ 5.1Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 7/3, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝5.43min,t_minorCalculated value C: 10.62min HRMS (ESI) m/z₃₇H₃₄F₃NNaO₃[M+Na]⁺620.2388, found 620.2377.

3- (4-Phenylbenzyl) -3- ((E) -1-phenyl-4, 4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

＝12.2,5.8Hz,1H),3.96(d,J＝10.3Hz,1H),3.46(d,J＝13.1Hz,1H),2.92(d,J＝13.2Hz,1H),1.52(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.6,148.3,140.5,140.0,139.3,137.3(q,J＝6.0Hz),136.7,134.0,130.4,129.1,128.7,128.67,128.3,127.8,127.2,127.1,126.8,126.4,124.6,123.7,122.6(q,J＝271.7Hz),121.6(q,J＝33.8Hz),114.9,84.2,58.6,56.0,42.0,28.0.¹⁹F NMR(376MHz,CDCl₃) Delta-63.91 (d, J ═ 5.8Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝8.05min,t_minorCalculated value C: 19.84min HRMS (ESI) m/z₃₆H₃₂F₃NNaO₃[M+Na]⁺606.2232, found 606.2222.

3- (4-Phenylbenzyl) -3- ((E) -1- (4-tert-butylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

3.87(d,J＝10.4Hz,1H),3.36(d,J＝13.2Hz,1H),2.83(d,J＝13.3Hz,1H),2.76(q,J＝7.8Hz,1H),1.45(s,9H),1.13(d,J＝6.9Hz,6H).¹³C NMR(101MHz,CDCl₃)δ176.7,148.5,148.3,140.6,140.1,139.2,137.4(q,J＝6.1Hz),134.1,133.7,130.4,129.1,128.7,127.1,126.8,126.4,126.3,124.8,123.6,122.3(q,J＝271.7Hz),121.5(q,J＝33.8Hz),121.6,121.2,114.9,84.1,58.7,55.7,41.9,33.7,28.0,23.9.¹⁹F NMR(377MHz,CDCl₃) δ -63.89(d, J ═ 5.9Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝6.16min,t_minorCalculated value C: 12.77min HRMS (ESI) m/z₃₉H₃₈F₃NNaO₃[M+Na]⁺648.2701, found 648.2694.

3- (4-Phenylbenzyl) -3- ((E) -1- (2-methoxyphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

1H),5.90–5.77(m,1H),4.74(d,J＝10.2Hz,1H),3.72(s,3H),3.59(d,J＝13.2Hz,1H),2.93(d,J＝13.2Hz,1H),1.53(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.9,156.6,148.5,140.6,139.9,139.2,137.9(q,J＝6.1Hz),134.3,130.5,128.9,128.7,128.6,128.4,127.3,127.1,126.8,126.4,125.6,125.0,123.1,122.8(q,J＝270.7Hz),121.2(q,J＝33.6Hz),120.3,114.4,110.6,84.0,58.8,55.1,46.5,41.8,28.0.¹⁹F NMR(376MHz,CDCl₃) δ -63.75(d, J ═ 6.0Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝7.30min,t_minorCalculated value C: 12.81min HRMS (ESI) m/z₃₇H₃₄F₃NNaO₄[M+Na]⁺636.2338, found 636.2328.

3- (4-Phenylbenzyl) -3- ((E) -1- (4-Phenylphenyl) -4,4, 4-Trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

J＝10.3Hz,1H),3.48(d,J＝13.2Hz,1H),2.96(d,J＝13.2Hz,1H),1.52(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.6,148.3,140.6,140.5,140.2,140.1,139.3,137.2(q,J＝6.1Hz),135.6,133.9,130.4,129.6,128.8,128.78,128.7,127.5,127.2,127.1,127.0,126.9,126.8,126.4,124.7,123.7,122.5(q,J＝270.7Hz),121.7(q,J＝33.6Hz),115.0,84.2,58.6,55.6,42.1,28.0.¹⁹F NMR(377MHz,CDCl₃) δ -63.93(d, J ═ 5.8Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝12.48min,t_minorCalculated value C: 22.29min HRMS (ESI) m/z₄₂H₃₆F₃NNaO₃[M+Na]⁺682.2545, found value 682.2537.

3- (4-Phenylbenzyl) -3- ((E) -1- (2-naphthyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

5.93–5.83(m,1H),4.14(d,J＝10.2Hz,1H),3.53(d,J＝13.2Hz,1H),2.96(d,J＝13.2Hz,1H),1.48(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.7,148.2,140.5,140.1,139.3,137.3(q,J＝6.1Hz),134.2,133.9,133.0,132.7,130.4,128.8,128.7,128.3,128.0,127.9,127.6,127.2,127.1,127.0,126.8,126.4,126.38,126.3,124.7,123.7,122.6(q,J＝270.7Hz),121.8(q,J＝33.9Hz),115.0,84.2,58.7,56.0,42.1,27.9.¹⁹F NMR(376MHz,CDCl₃) Delta-63.90 (d, J ═ 4.6Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝12.80min,t_minorCalculated value C: 31.70min HRMS (ESI) m/z₄₀H₃₄F₃NNaO₃[M+Na]⁺656.2388, found 656.2388.

3- (4-Phenylbenzyl) -3- ((E) -1- (3-chlorophenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

J＝13.2Hz,1H),2.93(d,J＝13.2Hz,1H),1.53(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.2,148.2,140.5,140.0,139.4,138.7,136.6(q,J＝6.1Hz),134.2,133.7,130.4,129.5,129.1,128.9,128.7,128.0,127.2,127.1,126.9,126.8,126.5,124.3,123.8,122.4(q,J＝270.7Hz),122.1(q,J＝34.3Hz),115.0,84.4,58.3,55.6,41.9,28.0.¹⁹F NMR(376MHz,CDCl₃) δ -63.99(d, J ═ 5.9Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝8.67min,t_minorCalculated value C: 28.00min HRMS (ESI) m/z₃₆H₃₁ClF₃NNaO₃[M+Na]⁺640.1842, found 640.1836.

3- (4-Phenylbenzyl) -3- ((E) -1- (2-chlorophenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

13.0Hz,1H),3.00(d,J＝13.0Hz,1H),1.54(s,9H).¹³C NMR(101MHz,CDCl₃)(two aromatic carbons missing)δ176.7,148.4,140.5,139.6,139.4,137.2(q,J＝7.1Hz),135.3,134.1,133.6,130.5,130.1,128.8,128.7,128.68,127.2,127.0,126.8,126.4,124.6,123.6,122.6(q,J＝270.7Hz),121.80(q,J＝33.7Hz),114.6,84.3,58.5,50.0,42.4,28.0.¹⁹F NMR(376MHz,CDCl₃) Delta-63.90 (d, J ═ 5.3Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝6.85min,t_minorCalculated value C: 13.13min HRMS (ESI) m/z₃₆H₃₁ClF₃NNaO₃[M+Na]⁺640.1842, found 640.1835.

3- (4-Phenylbenzyl) -3- ((E) -1- (4-trifluoromethylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

13.2Hz,1H),2.95(d,J＝13.2Hz,1H),1.52(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.1,148.2,140.5,139.9,139.5,137.8,136.5(q,J＝6.5Hz),133.6,132.0,130.4,129.0,128.8,128.7,127.2,126.9,126.8,126.5,125.8(q,J＝3.7Hz),124.6(q,J＝3.7Hz),124.0(q,J＝28.3Hz),123.7(q,J＝273.7Hz),122.5(q,J＝34.3Hz),122.4(q,J＝270.7Hz),115.0,84.4,58.4,55.8,41.8,27.9.¹⁹F NMR(376MHz,CDCl₃) Delta-62.71 (s,3F), -64.00(d, J-6.0 Hz,3F), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH-95/5, flow rate 0.8mL/min, lambda-254 nm, retention time：t_major＝8.19min,t_minorCalculated value C: 30.42min HRMS (ESI) m/z₃₇H₃₁F₆NNaO₃[M+Na]⁺674.2106, found 674.2104.

3- (4-Phenylbenzyl) -3- ((E) -1- (2-thiophene) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

(m,1H),5.95–5.82(m,1H),4.31(d,J＝10.1Hz,1H),3.46(d,J＝13.0Hz,1H),3.07(d,J＝13.0Hz,1H),1.55(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.4,148.3,140.5,140.3,139.4,138.5,136.9(q,J＝6.7Hz),133.7,130.3,128.9,128.7,127.2,127.1,126.9,126.8,126.6,126.4,125.0,124.4,123.9,122.4(q,J＝270.7Hz),121.6(d,J＝34.0Hz),115.0,84.2,58.6,50.9,42.4,28.0.¹⁹F NMR(376MHz,CDCl₃) δ -64.07(d, J ═ 5.9Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝8.75min,t_minorCalculated value C: 19.80min HRMS (ESI) m/z₃₄H₃₀F₃NNaO₃S[M+Na]⁺612.1796, found 612.1796.

3- (4-methylbenzyl) -3- ((E) -1- (4-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

＝10.3Hz,1H),3.40(d,J＝13.2Hz,1H),2.87(d,J＝13.2Hz,1H),2.31(s,3H),2.17(s,3H),1.57(s,9H).¹³C NMR(101MHz,CDCl₃)(three aromatic carbons missing)δ176.7,148.4,140.1,137.6(q,J＝6.5Hz),137.5,136.0,133.7,131.8,129.8,129.0,128.5,127.4,124.7,123.5,122.6(q,J＝270.7Hz),121.3(q,J＝34.3Hz),114.8,84.0,58.6,55.5,42.1,28.0,21.0.¹⁹F NMR(376MHz,CDCl₃)δ-63.90(d,J＝5.0Hz).HPLC analysis:Daicel CHIRALPAK AD-H, n-hexane/i-PrOH 50/1, flow rate 0.8mL/min, λ 254nm, retention time: t is t_major＝15.20min,t_minorCalculated value C: 26.26min hrms (ESI) m/z₃₂H₃₂F₃NNaO₃[M+Na]⁺558.2232, found 558.2226.

3- (4-methoxybenzyl) -3- ((E) -1- (4-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

1H),3.91(d,J＝10.3Hz,1H),3.64(s,3H),3.35(d,J＝13.3Hz,1H),2.82(d,J＝13.3Hz,1H),2.28(s,3H),1.54(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.8,158.2,148.4,140.1,137.7(q,J＝6.5Hz),137.5,133.7,131.0,129.0,128.98,128.5,127.4,126.9,124.6,123.6,122.6(q,J＝270.7Hz),121.2(q,J＝34.3Hz),114.8,113.2,84.0,58.7,55.4,54.9,41.7,28.0,21.0.¹⁹F NMR(377MHz,CDCl₃) δ -63.85(d, J ═ 5.9Hz), HPLC analysis: Daicel CHIRALPAK AD-H, n-hexane/i-PrOH ═ 9/1, flow rate ═ 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝7.33min,t_minorCalculated value C: 8.11min HRMS (ESI) m/z₃₂H₃₂F₃NNaO₄[M+Na]⁺574.2181, found 574.2173.

3- (2-Naphthalenylmethyl) -3- ((E) -1- (4-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

＝8.2Hz,2H),6.90–6.80(m,2H),5.84(dq,J＝15.6,6.2Hz,1H),3.98(d,J＝10.3Hz,1H),3.58(d,J＝13.2Hz,1H),3.04(d,J＝13.2Hz,1H),2.30(s,3H),1.45(s,9H).¹³C NMR(101MHz,CDCl₃)(one aromatic carbon missing)δ176.7,148.2,140.1,137.6(q,J＝6.5Hz),137.5,133.6,133.1,132.6,132.2,129.1,129.06,129.03,128.7,128.1,127.7,127.4,127.2,125.7,125.5,124.7,123.6,122.6(q,J＝270.7Hz),121.5(q,J＝33.3Hz),114.9,84.0,58.7,55.6,42.6,27.9,21.0.¹⁹F NMR(377MHz,CDCl₃) δ -63.84(d, J ═ 5.7Hz), HPLC analysis: Daicel CHIRALPAK OD-H, n-hexane/i-PrOH ═ 95/5, flow rate 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝8.52min,t_minorCalculated value C: 10.88min HRMS (ESI) m/z₃₅H₃₂F₃NNaO₃[M+Na]⁺594.2232, found 594.2231.

3- (4-chlorobenzyl) -3- ((E) -1- (4-methylphenyl) -4,4, 4-trifluorobut-2-ene) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

3.37(d,J＝13.2Hz,1H),2.82(d,J＝13.2Hz,1H),2.29(s,3H),1.54(s,9H).¹³C NMR(101MHz,CDCl₃)δ176.5,148.2,140.0,137.6,137.3(q,J＝6.3Hz),133.5,133.3,132.6,131.3,129.1,129.0,128.8,128.0,126.8,124.6,123.7,122.5(q,J＝270.7Hz),121.5(q,J＝33.9Hz),114.9,84.3,58.5,55.5,41.7,27.9,21.0.¹⁹F NMR(376MHz,CDCl₃) Delta-63.97 (d, J ═ 5.8Hz), HPLC analysis: Daicel CHIRALPAK AD-H, n-hexane/i-PrOH ═ 95/5, flow rate ═ 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝9.51min,t_minorCalculated value C: 13.13min HRMS (ESI) m/z₃₁H₂₉ClF₃NNaO₃[M+Na]⁺578.1686, found 578.1676.

3-benzyl-3- ((E) -1- (2-thienyl) -4,4, 4-trifluorobut-2-en) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

6.83(d,J＝3.6Hz,1H),6.78–6.69(m,2H),5.84(dq,J＝15.5,6.2Hz,1H),4.26(d,J＝10.2Hz,1H),3.39(d,J＝13.0Hz,0H),2.99(d,J＝13.0Hz,0H),1.53(s,9H).¹³CNMR(101MHz,CDCl₃)δ176.3,148.3,140.2,138.6,137.0(q,J＝6.6Hz),134.6,130.0,128.9,127.8,127.1,126.8,126.7,126.6,125.0,124.3,123.9,122.4(q,J＝270.7Hz),121.5(q,J＝34.0Hz),114.9,84.1,58.6,50.8,42.9,28.0.¹⁹F NMR(376MHz,CDCl₃) Delta-64.06 (d, J ═ 5.7Hz), HPLC analysis: Daicel CHIRALPAK AD-H, n-hexane/i-PrOH ═ 95/5, flow rate ═ 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝8.40min,t_minorCalculated value C: 14.22min HRMS (ESI) m/z₂₈H₂₅F₃NNaO₃S[M+Na]536.1483, found 536.1478.

3-phenyl-3- ((E) -1- (4-methylphenyl) -4,4, 4-trifluorobut-2-en) yl-2-oxoindoline-1-carboxylic acid tert-butyl ester

NMR(101MHz,CDCl₃)(three aromatic carbons missing)δ175.4,148.8,139.6,137.6(q,J＝6.8Hz),137.3,137.0,133.3,129.1,128.8,128.6,128.1,127.8,127.6,125.1(q,J＝269.3Hz),122.1(q,J＝33.7Hz),115.0,84.5,60.8,55.0,28.0,21.0.¹⁹F NMR(377MHz,CDCl₃) Delta-64.20 (d, J ═ 6.3Hz), HPLC analysis: Daicel CHIRALPAK AD-H, n-hexane/i-PrOH ═ 50/1, flow rate ═ 0.8mL/min, λ ═ 254nm, retention time: t is t_major＝9.10min,t_minorCalculated value C: 9.92min HRMS (ESI) m/z₃₀H₂₈F₃NNaO₃[M+Na]530.1919, found 530.1911.