CN106278932B - Cyclic alpha-dehydroaminoketone, chiral cyclic alpha-aminoketone and preparation method thereof - Google Patents
Cyclic alpha-dehydroaminoketone, chiral cyclic alpha-aminoketone and preparation method thereof Download PDFInfo
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Abstract
The invention provides a preparation method of cyclic α -dehydroaminoketone, chiral cyclic α -aminoketone and chiral cyclic α -aminoketone, and the preparation method of the chiral cyclic α -aminoketone comprises the step of reacting cyclic α -dehydroaminoketone represented by the following general formula (1) in an organic solvent under the catalytic action of a diphosphine-rhodium complex in a hydrogen atmosphere to obtain chiral cyclic α -aminoketone represented by the following general formula (2).
Description
Technical Field
The invention relates to a preparation method of cyclic alpha-dehydro amino ketone, chiral cyclic alpha-amino ketone and chiral cyclic alpha-amino ketone. The preparation method of chiral cyclic alpha-amidoketone of the invention is a synthetic method for preparing chiral cyclic alpha-amidoketone by asymmetric catalytic hydrogenation technology under the catalysis of diphosphine-rhodium complex.
Background
The chiral cyclic alpha-aminoketone skeleton is widely present in various drug molecules and physiologically active molecules, and can be used for synthesizing chiral cyclic amino alcohol ligands and drug intermediates of chiral cyclic amines.
Chiral cyclic α -aminoketones are currently obtained mainly by intramolecular Friedel-crafts acylation of chiral chain α -amino acids ((a) D.E.McClure, B.H.Areson, J.H.Jones, J.J.Baldwin, J.Org.Chem.1981,46,2431-2433.(b) M.Kurokawa, T.Watanabe, T.Ishikawa, Helv.Chim.acta 2007,90,574-587.) or asymmetric α -aminoreactions of cyclic ketones ((a) Y.Yamashita, H.Ishitani, S.Kobayashi, Can.J.Chem.2000,78,666-, (b) N.Kumaragarban, K.Juuhur, W.Zanhl, A.
K.A.
J.am.chem.Soc.2002,124,6254-6255, (c) Y.Hayashi, S.Aratake, Y.Imai, K.Hibino, Q. -Y.Chen, J.Yamaguchi, T.Uchimaru, chem.Asian J.2008,3,225-232.), but these methods have disadvantages of low efficiency, poor atom economy, environmental pollution, etc. however, they are difficult to industrialize, and since the product chiral cyclic α -aminoketone is unstable under acid-base conditions and easy to racemize, it is difficult to obtain a product with high enantioselectivity under the above-mentioned relatively severe reaction conditions.
Disclosure of Invention
In order to solve the problems in the prior art, the invention adopts the technology of asymmetric catalytic hydrogenation of the cyclic alpha-dehydroaminoketone for the first time to realize the high-efficiency synthesis of the chiral cyclic alpha-aminoketone. According to the preparation method of the chiral cyclic alpha-aminoketone, the synthesis efficiency is improved, the enantioselectivity is high, the atom economy is good, the synthesis cost is reduced, and the racemization problem does not exist, so that the industrial synthesis of the chiral cyclic alpha-aminoketone is expected to be realized.
The present invention relates to the following.
<1> a cyclic alpha-dehydroaminoketone which is a compound represented by the following general formula (1),
wherein R is one or more than two selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted phenyl, C1-C7 acyl, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxy, C1-C7 acyloxy, amino, mono (C1-C7 alkyl) amino, di (C1-C7 alkyl) amino, C1-C7 acylamino, trimethylsilyl, dihydroxy boron group, diphenyl phosphinyl group, phenyl mercapto, fluorine atom, chlorine atom, bromine atom and iodine atom.
<2> a chiral cyclic alpha-aminoketone which is a compound represented by the following general formula (2),
wherein R is one or more than two selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted phenyl, C1-C7 acyl, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxy, C1-C7 acyloxy, amino, mono (C1-C7 alkyl) amino, di (C1-C7 alkyl) amino, C1-C7 acylamino, trimethylsilyl, dihydroxy boron group, diphenyl phosphinyl group, phenyl mercapto, fluorine atom, chlorine atom, bromine atom and iodine atom,
marked as chiral carbon, which is in R configuration or S configuration.
<3> a method for preparing chiral cyclic alpha-aminoketone, which is characterized in that:
in an organic solvent, under the catalytic action of diphosphine-rhodium complex, the cyclic alpha-dehydroaminoketone represented by the following general formula (1) reacts in a hydrogen atmosphere to obtain chiral cyclic alpha-aminoketone represented by the following general formula (2),
wherein R is one or more than two selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, C1-C7 acyl, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxy, C1-C7 acyloxy, amino, mono (C1-C7 alkyl) amino, di (C1-C7 alkyl) amino, C1-C7 acylamino, trimethylsilyl, dihydroxy boron, diphenyl phosphinyl, phenyl mercapto, fluorine atom, chlorine atom, bromine atom and iodine atom,
in the general formula (2), the symbol denotes a chiral carbon, which is in R configuration or S configuration.
In the method for preparing chiral cyclic alpha-aminoketone of the invention, the diphosphine-rhodium complex is a complex represented by the general formula [ Rh (L) (L') ] X, wherein,
l is any chiral diphosphine ligand selected from the following (R) -BINAP, (R) -Segphos, (R, R) -Quinoxp, (R, R) -Duphos, (S, S) -BenzP, (R, R) -Miniphos, (S) -TCFP and enantiomers thereof:
l' is any one auxiliary diene ligand selected from 1, 5-cyclooctadiene or 2, 5-norbornadiene, and X is selected from SbF6 -Or BF4 -Any one of the anions of (1).
In the method for preparing chiral cyclic alpha-aminoketone of the present invention, the molar ratio of the diphosphine-rhodium complex to the cyclic alpha-dehydroaminoketone represented by general formula (1) is 1/100-1/20000 diphosphine-rhodium complex/cyclic alpha-dehydroaminoketone represented by general formula (1).
In the preparation method of chiral cyclic alpha-aminoketone, the organic solvent is one or more than two selected from ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol and trifluoroethanol.
In the preparation method of the chiral cyclic alpha-aminoketone, the hydrogen pressure is 1-100 bar, the reaction temperature is 0-50 ℃, and the reaction time is 1-48 hours.
As described above, the chiral cyclic α -aminoketone represented by the general formula (2) according to the present invention is obtained from the cyclic α -dehydroaminoketone represented by the general formula (1) according to the present invention as a raw material (hereinafter, may be referred to as "substrate"). In addition, according to the preparation method of the chiral cyclic alpha-aminoketone, the synthesis efficiency is improved, the enantioselectivity is high, the atom economy is good, and the synthesis cost is reduced. Further, the chiral cyclic alpha-aminoketone obtained by the preparation method can be used for synthesizing chiral cyclic amino alcohol ligands and drug intermediates of chiral cyclic amines.
Detailed Description
In the preparation method of chiral cyclic alpha-aminoketone, R in the general formula (1) and the general formula (2) is not changed before and after the reaction.
In the general formula (1) and the general formula (2), R is any one or more selected from a hydrogen atom, a C1-C6 alkyl group, a phenyl group, a substituted phenyl group, a C1-C7 acyl group, a C1-C7 alkoxyacyl group, a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 acyloxy group, an amino group, a mono (C1-C7 alkyl) amino group, a di (C1-C7 alkyl) amino group, a C1-C7 acylamino group, a trimethylsilyl group, a dihydroxyboryl group, a diphenylphosphinyloxy group, a phenylmercapto group, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among them, examples of the C1-C6 alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like; examples of the substituted phenyl group include a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-ethoxyphenyl group, a 3-ethoxyphenyl group, a 4-ethoxyphenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-iodophenyl group, a 3-iodophenyl group, a 4-iodophenyl group, a 1-naphthyl group, a 2-trifluoromethylphenyl group, a 3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group, a 2-furyl group, a 2-thienyl group, a thienyl group, 2-thienyl, 3, 4-dimethoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dichlorophenyl, 3, 4-methyleneoxyphenyl, and the like; examples of the C1-C7 acyl group include formyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group, heptanoyl group, and the like; examples of the C1-C7 alkoxyacyl group include methoxyacyl group, ethoxyacyl group, propoxycarbonyl group, butoxyacyl group, pentoxyacyl group, hexoxyacyl group, and heptyloxyacyl group; examples of the C1-C7 alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and the like; examples of the C1-C7 acyloxy group include formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy and the like; examples of the mono (C1-C7 alkyl) amino group include monomethylamino group, monoethylamino group, monopropylamino group, monobutylamino group, monopentylamino group, monohexylamino group, and monoheptylamino group; examples of the di (C1-C7 alkyl) amino group include a di (C1-C7 alkyl) amino group having two identical alkyl groups such as a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group, a dipentylamino group, a dihexylamino group, and a diheptylamino group, and a di (C1-C7 alkyl) amino group having two different alkyl groups such as a methylethylamino group, an ethylpropylamino group, and a methylpropylamino group; examples of the C1-C7 acylamino group include a formamido group, an acetylamino group, a propionamido group, a butyrylamino group, a pentanoylamino group, a hexanoylamino group, and a heptanoylamino group.
In the general formula (1) and the general formula (2), the Ph-R group may represent a naphthyl group.
In the general formulae (1) and (2), R may be singly substituted, or may be di-, tri-, or tetra-substituted. In the case where R represents "di-, or tri-, or tetra-substituted", each substituent R represents the same meaning as that represented by the above R, and each R is the same group or different groups, respectively. When the Ph-R group represents a naphthyl group, it is one way of "R is disubstituted".
The preparation method is carried out under the catalysis of the diphosphine-rhodium complex. In the present invention, the diphosphine-rhodium complex can be represented by [ Rh (L) (L') ] X. Examples of L include (R) -BINAP, (R) -Segphos, (R, R) -QuinoxP, (R, R) -Duphos, (S, S) -BenzP, (R, R) -Miniphos, (S) -TCFP:
In the production method of the present invention, the hydrogen pressure is not particularly limited as long as the asymmetric catalytic hydrogenation reaction of the present invention can be carried out. However, the hydrogen pressure of the hydrogen atmosphere is set to 1 to 100bar, preferably 1 to 50bar, and more preferably 1 to 20bar, from the viewpoint of the reaction yield and the reaction efficiency.
In the production method of the present invention, the organic solvent is not particularly limited as long as the reaction raw material can be dissolved in the organic solvent and the asymmetric catalytic hydrogenation reaction of the present invention is allowed to proceed. However, the organic solvent is preferably a polar solvent from the viewpoint of reaction yield and reaction efficiency. Among them, one or more solvents selected from ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, and trifluoroethanol are preferable. The solvent mixture of two or more solvents is not particularly limited as long as the kind and ratio of the solvent are appropriately selected as necessary.
The production method of the present invention may be carried out by stirring, and the stirring speed is not particularly limited as long as the reaction of the present invention can be carried out.
In the production method of the present invention, the reaction temperature and the reaction time are not particularly limited as long as the reaction of the present invention can be carried out. However, the reaction temperature may be set to 0 to 50 ℃, preferably 25 to 50 ℃, more preferably 25 to 30 ℃ from the viewpoint of the reaction yield and the reaction efficiency; the reaction time may be set to 1 to 48 hours, preferably 1 to 24 hours, more preferably 1 to 12 hours, and still more preferably 1 to 6 hours.
In the preparation method of the present invention, the molar ratio of the (diphosphine ligand-rhodium complex/cyclic α -dehydroaminoketone represented by the general formula (1)) is preferably 1/100 to 1/20000, preferably 1/500 to 1/20000, more preferably 1/1000 to 1/20000, further preferably 1/2000 to 1/20000, and particularly preferably 1/10000 to 1/20000.
The main configuration of the chiral cyclic alpha-aminoketone obtained by the preparation method according to the present invention is determined by the configuration of the catalyst (i.e., diphosphine ligand-rhodium complex) used in the preparation method. In other words, in the case where the configuration of the catalyst is determined, the main configuration of the product obtained by the production method according to the present invention is also determined. The main configuration of the product obtained by the production method according to the present invention (i.e., the chiral cyclic α -aminoketone represented by the general formula (2)) is an R configuration or an S configuration.
Compared with the existing preparation method of chiral cyclic alpha-amidoketone, the preparation method of the invention has the advantages of mild reaction conditions, simple and convenient post-treatment, easy synthesis of chiral catalyst, stable property, strong applicability of substrate, great improvement of yield of product, and the like. In addition, according to the preparation method of the invention, the enantiomeric excess of the product can reach 99% at most, and the optical purity is high. The invention provides a feasible method for industrially producing chiral cyclic alpha-aminoketone.
Example (b):
specific examples are given below of the production method of the present invention. It is clear that the scope of protection of the invention is not limited to the examples described below.
In the following examples, the cyclic α -dehydroaminoketones represented by the general formula (1) are represented by 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1 m; the chiral cyclic alpha-aminoketone represented by the general formula (2) is represented by 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l and 2 m.
In addition, as described above, in the method for producing a chiral cyclic α -aminoketone of the present invention, R in the general formula (1) and the general formula (2) does not change before and after the reaction, and therefore, it is needless to say that in the following examples, after the substrate 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m (i.e., the cyclic α -dehydroaminoketone represented by the general formula (1)) is reacted in a hydrogen atmosphere, chiral cyclic α -aminoketones 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m are obtained accordingly.
In the following examples, 1, 5-cyclooctadiene is abbreviated as "cod" and 2, 5-norbornadiene is abbreviated as "nbd" for the sake of convenience.
In the following examples, the yields are values calculated according to the following calculation formulas.
In addition, the theoretical enantiomeric excess percentage (hereinafter referred to as "ee value") is calculated by the following formula:
percent enantiomeric excess { [ S ] - [ R ] |/([ S ] + [ R ]) } × 100%
Wherein [ S ] is the amount of the enantiomer product of S configuration, and [ R ] is the amount of the enantiomer product of R configuration.
In the following examples, the enantiomeric excess percentage was measured by HPLC (high performance liquid chromatography), and the apparatus for performing HPLC measurement was LC-2010 from Shimadzu corporation using a chiral column manufactured by Daiiol corporation.
In the following examples, NMR analysis was performed for each product after synthesis, that is, for each cyclic α -dehydroaminoketone and chiral cyclic α -aminoketone after synthesis (that is, each compound represented by the general formula (1) and the general formula (2)), but for the same product, only the first appearance is described specifically for the sake of simplicity, and the subsequent description is omitted.
In the following examples and applications, the instrument used to perform the nmr analysis was Mercury Plus-400(400MHz,1H；100MHz,13C) spectrometers. In the following application examples, the apparatus used for measuring specific optical rotation is a Rudolph Research Analytical Autopol VI Automatic Polarimeter (using a detection light wavelength of 589nm and an optical path length of 50mm)
Example 1:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, the mixture was stirred at room temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4-phenylmethylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, and then returnedThe temperature is returned to normal temperature and the mixture is stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain the pure product 1 a. The product 1a is recrystallized from dichloromethane and petroleum ether and then directly used for hydrogenation.
The measurement data of 1a are as follows.
1H NMR(400MHz,CDCl3):2.19(s,3H),6.95(d,J＝7.2Hz,1H),7.02-7.07(m,1H),7.26-7.31(m,1H),7.32-7.35(m,1H),7.48(br s,1H),7.48(s,1H)；
13C NMR(100MHz,CDCl3):24.1,122.3,123.6,124.6,127.3,127.4,132.0,135.6,147.0,169.0,193.8.
Example 2:
2.8mg of [ Rh ((R) -BINAP) (nbd) was added to each 50mL reaction tube]SbF6Catalyst, 56mg of substrate 1a [ substrate: catalyst ═ 100:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 2mL of degassed methanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 100bar, violently stirring for 1 hour at 50 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2a, wherein the yield of the product 2a is 99%.
The measurement data of 2a are as follows.
1H NMR(400MHz,CDCl3):2.08(s,3H),2.96(dd,J＝5.6Hz,16.8Hz,1H),3.75(dd,J＝8.2Hz,16.4Hz,1H),4.52-4.58(m,1H),6.39(br s,1H),7.39(t,J＝7.6Hz,1H),7.45(d,J＝7.6Hz,1H),7.63(t,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H)；
13C NMR(100MHz,CDCl3):23.2,35.1,56.8,124.4,126.9,128.1,134.9,135.9,151.7,171.0,203.6.
The conditions for HPLC measurement were as follows. The obtained product is prepared by using DAICEL Chiralpak IE chiral chromatographic column produced by Daiiluo corporation, and n-hexane/isopropanol as mobile phaseProduct ratio) 80/20, mobile phase flow rate 1.0mL/min, detection wavelength 254nm, tmajor＝21.8min,tminor19.2 min. The configuration of product 2a is S. The ee value of 2a was 81% as determined by HPLC.
Example 3:
2.8mg of [ Rh ((R) -Segphos) (nbd) was added to each 50mL reaction tube]SbF6Catalyst, 56mg of substrate 1a [ substrate: catalyst ═ 100:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 2mL of degassed ethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 3bar, violently stirring for 1 hour at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2a, wherein the yield of the product 2a is 99%. HPLC measurement was carried out in the same manner as in example 2. The configuration of product 2a is S, and the ee value of 2a is 53%.
Example 4:
2.2mg of [ Rh ((R, R) -Duphos) (cod) were added to 50mL reaction tubes, respectively]BF4Catalyst, 56mg of substrate 1a [ substrate: catalyst ═ 100:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 2mL of degassed isopropanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 30bar, violently stirring for 12 hours at 50 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2a, wherein the yield of the product 2a is 99%. HPLC determination was carried out in the same manner as in example 2, except that tmajor＝19.0min,tminor21.6 min. The configuration of the product 2a is R, and the ee value of 2a is 65%.
Example 5:
2.3mg of [ Rh ((R, R) -Quinox P) (cod) was added to each 50mL reaction tube]SbF6Catalyst, 112mg of substrate 1a [ substrate: catalyst ═ 200:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 2mL of degassed ethyl acetate under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 50bar, violently stirring for 24 hours at 0 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain a white solid product 2a, wherein the yield of the product 2a is 99%. The product 2a was found to have the configuration R and the ee value of 2a was 71% by HPLC in the same manner as in example 4.
Example 6:
1.7mg of [ Rh ((S, S) -BenzP) (cod) was added to each 50mL reaction tube]SbF6Catalyst, 280mg of substrate 1a [ substrate: catalyst ═ 500:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 2mL of degassed tetrahydrofuran under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 10bar, violently stirring for 48 hours at 0 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain a white solid product 2a, wherein the yield of the product 2a is 99%. HPLC measurement was carried out in the same manner as in example 2. The configuration of product 2a is S, and the ee value of 2a is 79%.
Example 7:
1.5mg of [ Rh ((R, R) -Miniphos) (cod) ] SbF6 catalyst and 11.2g of substrate 1a [ substrate: catalyst ═ 20000:1 (molar ratio) ] are added into 300mL reaction tubes, the reaction tubes are placed in a hydrogenation kettle, the vacuum is pumped for changing hydrogen three times, 30mL of degassed dichloromethane are added under the protection of hydrogen, finally the hydrogen pressure is adjusted to 1bar, the reaction is stopped after vigorous stirring at 25 ℃ for 6 hours, the solvent is concentrated and evaporated to dryness to obtain a white solid product 2a, and the yield of the product 2a is 99%. HPLC measurement was carried out in the same manner as in example 4. The configuration of the product 2a is R, and the ee value of 2a is 92%.
Example 8:
1.5mg of [ Rh ((S) -TCFP) (cod) was added to each of 300mL reaction tubes]SbF6Catalyst, 5.6g of substrate 1a [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 12mL of degassed trifluoroethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 20bar, violently stirring for 1 hour at 30 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain a white solid product 2a, wherein the yield of the product 2a is 99%. HPLC measurement was carried out in the same manner as in example 2. The product 2a has the configuration S, and the ee value of 2a is 98%.
Example 9:
1.5mg of [ Rh ((R) -TCFP) (cod) was added to each of 300mL reaction tubes]SbF6Catalyst, 5.6g of substrate 1a [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 12mL of degassed trifluoroethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 20bar, violently stirring for 1 hour at 30 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain a white solid product 2a, wherein the yield of the product 2a is 99%. HPLC analysis was carried out in the same manner as in example 4, and the configuration of product 2a was R, and ee value of 2a was 98%.
Example 10:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol，Then, 60mml of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then, 60mL of a tetrachloroethylene solution in which 36mmol of 4- (2-methylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added with stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then, returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain the pure product 1 b. The product 1b is recrystallized from dichloromethane and petroleum ether and then directly used for hydrogenation.
The measurement data of 1b are as follows.
1H NMR(400MHz,CDCl3):2.20(s,3H),2.23(s,3H),6.94(t,J＝7.2Hz,1H),7.07(d,J＝8.0Hz,1H),7.16(d,J＝7.2Hz,1H),7.53(br s,1H),7.57(s,1H)；
13C NMR(100MHz,CDCl3):17.3,24.1,121.2,123.0,127.1,127.2,131.3,131.6,137.4,144.7,168.8,194.0.
Example 11:
1.5mg of [ Rh ((S) -TCFP) (cod) was added to each of 300mL reaction tubes]SbF6Catalyst, 6.0g of substrate 1b [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 12mL of degassed trifluoroethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 20bar, violently stirring for 1 hour at 30 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2b, wherein the yield of the product 2b is 99%.
The measurement data of 2b are as follows.
1H NMR(400MHz,CDCl3):2.08(s,3H),2.40(s,3H),2.89(dd,J＝5.6Hz,16.4Hz,1H),3.70(dd,J＝8.0Hz,16.8Hz,1H),4.50-4.56(m,1H),6.31(br s,1H),7.32(d,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.54(s,1H)；
13C NMR(100MHz,CDCl3):21.3,23.2,34.8,57.0,124.3,126.6,134.9,137.2,138.1,149.0,171.0,203.8.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝23.8min,tminor20.1 min. The product 2b has the configuration S, and the ee value of 2b is 99%.
Example 12:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (3-methylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain the pure product 1 c. The product 1c was recrystallized from dichloromethane and petroleum ether and used directly in the hydrogenation.
The measurement data of 1c are as follows.
1H NMR(400MHz,CDCl3):2.18(s,3H),2.27(s,3H),6.70-6.80(m,2H),7.09(t,J＝7.6Hz,1H),7.37(s,1H),7.66(s,1H)；
13C NMR(100MHz,CDCl3):17.6,22.3,120.2,123.7,124.0,127.2,131.6,134.8,146.8,147.5,193.3.
Example 13:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 12.0g of substrate 1c [ substrate: catalyst ═ 20000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed dichloromethane under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 1bar, violently stirring for 6 hours at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2c, wherein the yield of the product 2c is 99%.
The measurement data of 2c are as follows.
1H NMR(400MHz,CDCl3):2.08(s,1H),2.33(s,1H),2.81(dd,J＝5.2Hz,16.8Hz,1H),3.72(dd,J＝8.0Hz,16.8Hz,1H),4.50-4.55(m,1H),6.29(br s,1H),7.30(t,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.59(d,J＝7.6Hz,1H)；
13C NMR(100MHz,CDCl3):18.0,23.2,34.0,56.8,121.8,128.2,134.6,136.2,136.4,150.8,171.1,204.0。
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column produced by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 85/15, the detection wavelength is 254nm,1.0mL/min, tmajor＝27.8min,tminor25.3 min. The product 2c has the configuration S and the ee value of 2c is 99%.
Example 14:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (3-methylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, 120mL of 1mol/L diluted hydrochloric acid solution is added, the mixture is stirred for 10 minutes, and the organic compounds are extractedAnd washing the organic layer with dichloromethane twice, combining the organic layers, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain the pure product 1 d. The product 1d was recrystallized from dichloromethane and petroleum ether and used directly for hydrogenation.
The measurement data of 1d are as follows.
1H NMR(400MHz,CDCl3):2.18(s,3H),2.40(s,3H),6.70-6.80(m,2H),7.17(d,J＝7.2Hz,1H),7.37(s,1H),7.70(s,1H)；
13C NMR(100MHz,CDCl3):17.6,24.1,123.5,123.8,124.9,127.2,131.6,134.8,138.6,147.2,168.9,194.5.
Example 15:
1.5mg of [ Rh ((S) -TCFP) (cod) was added to each of 300mL reaction tubes]SbF6Catalyst, 6.0g of substrate 1d [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 12mL of degassed ethyl acetate under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 10bar, violently stirring for 1 hour at 30 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain a white solid product 2d, wherein the yield of the product 2d is 99%.
The measurement data of 2d are as follows.
1H NMR(400MHz,CDCl3):2.08(s,3H),2.60(s,3H),2.90(dd,J＝5.6Hz,16.4Hz,1H),3.70(dd,J＝8.0Hz,16.8Hz,1H),4.45-4.55(m,1H),6.37(br s,1H),7.13(d,J＝8.0Hz,1H),7.26(d,J＝6.8Hz,1H),7.47(t,J＝7.6Hz,1H)；
13C NMR(100MHz,CDCl3):18.5,23.2,34.8,56.8,124.2,127.2,129.4,132.4,135.2,147.4,171.1,203.1.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 85/15, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝50.5min,tminor41.1 min. Product ofThe configuration of 2d is S, and the ee value of 2d is 99%.
Example 16:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-methylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain the pure product 1 e. The product 1e was then recrystallized from dichloromethane and petroleum ether and used directly in the hydrogenation.
The measurement data of 1e are as follows.
1H NMR(400MHz,CDCl3):2.20(s,3H),2.28(s,3H),6.82(d,J＝8.0Hz,1H),7.07(d,J＝8.0Hz,1H),7.15(s,1H),7.46(s,1H),7.51(br s,1H)；
13C NMR(100MHz,CDCl3):21.3,24.0,122.1,124.7,124.9,127.7,131.4,135.3,137.3,143.9,168.7,194.0.
Example 17:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 12.0g of substrate 1e [ substrate: catalyst ═ 20000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed dichloromethane under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 5bar, violently stirring for 4 hours at 25 ℃, stopping the reaction, concentrating and evaporating to drynessSolvent to obtain white solid product 2e, wherein the yield of the product 2e is 99%.
The measurement data of 2e are as follows.
1H NMR(400MHz,CDCl3):2.08(s,3H),2.60(s,3H),2.90(dd,J＝5.6Hz,16.4Hz,1H),3.70(dd,J＝8.0Hz,16.8Hz,1H),4.45-4.55(m,1H),6.37(br s,1H),7.13(d,J＝8.0Hz,1H),7.26(d,J＝6.8Hz,1H),7.47(t,J＝7.6Hz,1H)；
13C NMR(100MHz,CDCl3):22.5,23.3,35.0,57.0,124.3,127.2,129.8132.5,139.4,152.2,171.1,204.3.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝24.9min,tminor21.0 min. The product 2e has the configuration S, and the ee value of 2e is 99%.
Example 18
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-ethylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain a pure product 1 f. The product 1f was recrystallized from dichloromethane and petroleum ether and used directly in the hydrogenation.
The measurement data of 1f are as follows.
1H NMR(400MHz,CDCl3):1.19(t,J＝8.0Hz,3H),2.17(s,3H),2.54(q,J＝8.0Hz,2H),6.82(d,J＝7.2Hz,1H),7.04-7.08(m,1H),7.17(s,1H),7.44(s,1H),7.49(br s,1H)；
13C NMR(100MHz,CDCl3):15.4,24.0,28.7,122.1,123.5,124.9,127.8,131.6,134.2,143.7,144.2,168.9,194.0.
Example 19
1.5mg of [ Rh ((S) -TCFP) (cod) was added to each of 300mL reaction tubes]SbF6Catalyst, 6.4g of substrate 1f [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 12mL of degassed methanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 3bar, violently stirring for 1 hour at 30 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2f, wherein the yield of the product 2f is 99%.
The measurement data of 2f are as follows.
1H NMR(400MHz,CDCl3):1.23(t,J＝7.6Hz,3H),2.06(s,3H),2.68(q,J＝7.6Hz,2H),2.89(dd,J＝5.2Hz,16.8Hz,1H),3.70(dd,J＝8.0Hz,16.4Hz,1H),4.51-4.56(m,1H),6.38(br s,1H),7.34(d,J＝7.6Hz,1H),7.44-7.48(m,1H),7.56(s,1H)；13NMR(100MHz,CDCl3):15.7,23.2,28.7,34.8,57.0,123.0,126.7,135.0,136.3,144.5,149.3,171.1,203.9.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝23.0min,tminor19.7 min. The product 2f has the configuration S, the ee value of 2f being 99%.
Example 20
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol，Then, 60mml of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then, 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-phenylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added with stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then, returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, 120mL of 1mol/L diluted hydrochloric acid solution is added, stirring is carried out for 10 minutes, an organic layer is extracted, dichloromethane is used for washing the water phase twice, the organic phase is combined, the solvent is removed by rotary evaporation, and the residue is separated by column chromatography to obtain 1g of a pure product. 1g of product was recrystallized from dichloromethane and petroleum ether and used directly for the hydrogenation.
The measurement data of 1g are as follows.
1H NMR(400MHz,CDCl3):2.20(s,3H),6.99(d,J＝8.0Hz,1H),7.32-7.36(m,1H),7.39-7.45(m,2H),7.47-7.50(m,1H),7.50-7.54(m,3H)7.55-7.58(m,2H)；
13C NMR(100MHz,CDCl3):24.1,122.5,122.6,124.5,126.6,127.9,128.2,129.1,132.1,133.6,140.0,140.5,145.7,168.7,193.4.
Example 21
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 15.8g of substrate 1g [ substrate: catalyst ═ 20000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed tetrahydrofuran under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 8bar, violently stirring for 9 hours at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain 2g of a white solid product, wherein the yield of the 2g of the product is 99%.
The measurement data of 2g are as follows.
1H NMR(400MHz,CDCl3):2.09(s,3H),3.00(dd,J＝5.2Hz,16.8Hz,1H),3.77(dd,J＝8.0Hz,16.8Hz,1H),4.54-4.61(m,1H),6.36(br s,1H),7.37(t,J＝7.2Hz,1H),7.42-7.47(m,2H),7.50(d,J＝8.0Hz,1H),7.55-7.59(m,2H),7.83-7.87(m,1H),7.96(s,1H)；
13C NMR(100MHz,CDCl3):23.2,34.8,57.1,122.5,127.2,127.3,128.1,129.2,135.0,135.4,139.9,141.5,150.5,171.0,203.6.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IA chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, and t ismajor＝14.4min,tminor22.0 min. The product 2g had the configuration S and 2g had an ee of 99%.
Example 22
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-methoxycarbonylphenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain a pure product for 1 hour. The product is recrystallized by dichloromethane and petroleum ether for 1h and then directly used for hydrogenation reaction.
The measurement data for 1h are as follows.
1H NMR(400MHz,CDCl3):2.20(s,3H),3.89(s,3H),7.01(d,J＝7.6Hz,1H),7.51(s,1H),7.57(br s,1H),7.94(s,1H),8.02(d,J＝7.6Hz,1H)；
13C NMR(100MHz,DMSO-d6):23.9,52.8,122.3,122.9,123.1,127.5,128.6,135.8,137.6,152.5,165.9,170.5,192.4.
Example 23:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 14.7g of substrate 1h [ substrate: catalyst ═ 20000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed ethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 6bar, violently stirring for 15 hours at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product for 2 hours, wherein the yield of the product for 2 hours is 99%.
The measurement data for 2h are as follows.
1H NMR(400MHz,CDCl3):2.07(s,3H),3.04(dd,J＝5.6Hz,17.6Hz,1H),3.73-3.82(m,1H),3.93(s,3H),4.51-4.57(m,1H),6.34(br s,1H),7.53(d,J＝8.0Hz,1H),8.26-8.31(m,1H),8.39(s,1H)；
13C NMR(100MHz,CDCl3):23.1,35.0,52.7,57.0,125.9,127.1,130.5,135.2,136.5,155.9,166.2,171.0,202.7.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IA chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, and t ismajor＝14.9min,tminor18.7 min. The product 2h had the configuration S and the ee value of 2h was 99%.
Example 24:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, the mixture was stirred at room temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-fluorophenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, and then returned to normal temperatureWarm and stir for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain a pure product. The product is recrystallized by dichloromethane and petroleum ether and then directly used for hydrogenation reaction.
The measurement data of 1i are as follows.
1H NMR(400MHz,CDCl3):2.18(s,3H),6.86-6.89(m,1H),6.90-6.96(m,1H),7.02-7.06(m,1H),7.47(s,1H),7.48(br s,1H)；
13C NMR(100MHz,CDCl3):24.0,112.3,112.6,120.3,120.5,122.9,123.0,124.6,129.4,132.1,142.2,161.3,163.7,168.6,192.3.
Example 25:
1.5mg of [ Rh ((S) -TCFP) (cod) was added to each of 300mL reaction tubes]SbF6Catalyst, 6.2g of substrate 1i [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 12mL of degassed ethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 12bar, violently stirring for 2 hours at 30 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2i, wherein the yield of the product 2i is 99%.
The measurement data of 2i are as follows.
1H NMR(400MHz,CDCl3):2.09(s,3H),2.97(dd,J＝5.2Hz,16.4Hz,1H),3.71(dd,J＝8.0Hz,16.4Hz,1H),4.52-4.58(m,1H),6.31(br s,1H),7.33-7.39(m,1H),7.40-7.47(m,1H)；
13C NMR(100MHz,CDCl3):23.1,34.3,57.4,110.2,110.4,123.5,123.7,128.4,128.5,147.0,161.4,163.8,171.0,202.6.
The conditions for HPLC measurement were as follows. The obtained product was subjected to DAICEL Chiralpak IE chiral chromatography column (Daiicel Co., Ltd., Japan) with n-hexane/isopropanol (volume ratio) of 80/20 as a mobile phase and a flow rate of 1.0mL/min, detection wavelength 254nm, tmajor＝18.1min,tminor16.6 min. The configuration of the product 2i is S, and the ee value of 2i is 99%.
Example 26:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-chlorophenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added with stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain a pure product 1 j. The product 1j is recrystallized by dichloromethane and petroleum ether and then directly used for hydrogenation reaction.
The measurement data of 1j are as follows.
1H NMR(400MHz,CDCl3):2.19(s,3H),6.87(d,J＝7.6Hz,1H),7.24(dd,J＝2.0Hz,7.6Hz,1H),7.26-7.28(m,1H),7.48(s,1H),7.52(br s,1H)；
13C NMR(100MHz,DMSO-d6):23.9,123.5,123.7,124.1,129.2,131.8,133.9,134.9,145.8,170.3,192.5.
Example 27:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 13.2g of substrate 1j [ substrate: catalyst ═ 20000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed tetrahydrofuran under the protection of hydrogen, and finallyAdjusting the hydrogen pressure to 16bar, vigorously stirring at 25 deg.C for 10 hr, stopping reaction, concentrating and evaporating solvent to obtain white solid product 2j with yield of 2j of 99%.
The measurement data of 2j are as follows.
1H NMR(400MHz,CDCl3):2.08(s,3H),2.96(dd,J＝5.2Hz,16.8Hz,1H),3.71(dd,J＝8.4Hz,16.8Hz,1H),4.48-4.54(m,1H),6.22(br s,1H),7.40(d,J＝8.4Hz,1H),7.59(dd,J＝2.0Hz,8.4Hz,1H),7.73(d,J＝2.0Hz,1H)；
13C NMR(100MHz,CDCl3):23.1,34.5,57.1,124.2,128.2,134.4,135.9,135.9,136.3,149.6,170.9,202.2.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝20.1min,tminor18.4 min. The configuration of product 2j is S, and the ee value of 2j is 99%.
Example 28:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (4-bromophenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added with stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain a pure product 1 k. The product 1k was recrystallized from dichloromethane and petroleum ether and used directly in the hydrogenation.
The measurement data of 1k are as follows.
1H NMR(400MHz,CDCl3):2.19(s,3H),6.82(d,J＝8.4Hz,1H),7.35-7.50(m,4H)；
13C NMR(100MHz,DMSO-d6):23.9,119.8,124.1,124.2,126.1,129.3,133.7,137.9,146.2,170.3,192.5.
Example 29:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 16.0g of substrate 1k [ substrate: catalyst ═ 20000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed ethanol under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 18bar, violently stirring for 22 hours at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to obtain a white solid product 2k, wherein the yield of the product 2k is 99%.
The measurement data of 2k are as follows.
1H NMR(400MHz,CDCl3):2.09(s,3H),2.96(dd,J＝5.2Hz,16.8Hz,1H),3.69(dd,J＝8.0Hz,16.8Hz,1H),4.49-4.55(m,1H),6.38(br s,1H),7.36(d,J＝8.4Hz,1H),7.75(dd,J＝1.6Hz,8.4Hz,1H),7.89(d,J＝1.6Hz,1H)；
13C NMR(100MHz,CDCl3):23.1,34.4,57.0,122.2,127.3,128.5,136.6,138.6,150.1,171.1,202.2.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝20.4min,tminor19.0 min. The product 2k has the configuration S and the ee value of 2k is 99%.
Example 30:
In a 500mL two-necked bottle, anhydrous tris was addedAluminium chloride (AlCl)3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (2-naphthyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain 1L of a pure product. The product 1l was recrystallized from dichloromethane and petroleum ether and used directly for the hydrogenation.
The measurement data of 1l are as follows.
1H NMR(400MHz,CDCl3):2.21(s,3H),7.21(s,1H),7.37(t,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.61(br s,1H),7.64(d,J＝8.0Hz,1H),7.73(d,J＝7.2Hz,1H),7.74(s,1H),7.79(s,1H)；
13C NMR(100MHz,CDCl3):24.2,121.0,125.6,126.6,126.8,128.8,129.7,131.3,132.9,135.3,137.5,140.3,168.6,191.5.
Example 31:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 7.1g of substrate 1l [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed tetrahydrofuran under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 6bar, violently stirring for 5 hours at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain 2l of a white solid product, wherein the yield of the 2l of the product is 99%.
The measurement data of 2l are as follows.
1H NMR(400MHz,CDCl3):2.11(s,3H),2.06-3.13(m,1H),3.95(dd,J＝8.4Hz,16.4Hz,1H),4.63-4.70(m,1H),6.32(br s,1H),7.48-7.54(m,1H),7.58-7.63(m,1H),7.83-7.87(m,2H),7.97(d,J＝8.4Hz,1H),8.33(s,1H)；
13C NMR(100MHz,CDCl3):23.3,34.8,57.5,125.2,125.5,126.7,128.1,129.3,130.7,132.4,132.7,137.9,143.9,171.0,203.8.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝41.3min,tminor35.8 min. The product 2l has the configuration S and the ee value of 2l is 99%.
Example 32:
In a 500mL two-necked flask, anhydrous aluminum trichloride (AlCl) was added3)12mmol, 60 mmol of tetrachloroethylene solvent was added thereto, and the mixture was stirred at ordinary temperature for 1 hour, then 60mL of a tetrachloroethylene solution in which 36mmol of 4- (2, 3-dichlorophenyl) methylene-2-methyl-5 (4H) -oxazolone was dissolved was slowly added under stirring, and after all of the tetrachloroethylene solution was added, the reaction solution was heated, stirred at 100 ℃ for 1 hour, then returned to ordinary temperature and stirred for 2 hours. After the reaction is finished, adding 120mL of 1mol/L diluted hydrochloric acid solution, stirring for 10 minutes, extracting an organic layer, washing the water phase twice by using dichloromethane, combining the organic phase, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain a pure product 1 m. The product 1m is recrystallized by dichloromethane and petroleum ether and then directly used for hydrogenation reaction.
The measurement data of 1m are as follows.
1H NMR(400MHz,CDCl3):2.21(s,3H),7.16(s,2H),7.51(br s,1H),7.61(s,1H)；
13C NMR(100MHz,DMSO-d6):24.0,119.6,122.9,124.6,127.2,129.2,135.5,138.6,147.1,170.8,191.6.
Example 33:
1.5mg of [ Rh ((S, S) -Miniphos) (cod) was added to each 300mL reaction tube]SbF6Catalyst, 7.1g of substrate 1m [ substrate: catalyst ═ 10000:1 (molar ratio)]Placing a reaction test tube in a hydrogenation kettle, vacuumizing for three times to exchange hydrogen, adding 30mL of degassed tetrahydrofuran under the protection of hydrogen, finally adjusting the pressure of the hydrogen to 6bar, violently stirring for 5 hours at 25 ℃, stopping the reaction, concentrating and evaporating the solvent to dryness to obtain 2l of a white solid product, wherein the yield of the product 2m is 99%.
The measurement data of 2m are as follows.
1H NMR(400MHz,CDCl3):2.08(s,3H),3.01(dd,J＝4.8Hz,17.2Hz,1H),3.74(dd,J＝8.0Hz,17.2Hz,1H),4.40-4.46(m,1H),6.17(br s,1H),7.52(d,J＝8.0Hz,1H),7.62(d,J＝8.0Hz,1H)；
13C NMR(100MHz,CDCl3):23.0,34.2,56.8,123.0,130.7,135.0,140.3,151.1,170.8,201.5.
The conditions for HPLC measurement were as follows. Using DAICEL Chiralpak IE chiral chromatographic column manufactured by Daiiluol corporation, the mobile phase is n-hexane/isopropanol (volume ratio) 80/20, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 254nm, tmajor＝16.2min,tminor14.4 min. The product 2m has the configuration S and the ee value of 2m is 99%.
Application example 1
0.95g of Compound 2a was dissolved in 50mL of anhydrous tetrahydrofuran, the reaction was cooled to-78 ℃, 8mL of a 1M borane tetrahydrofuran solution was slowly added dropwise thereto at that temperature, and the reaction was carried out at-78 ℃ for 3 hours after completion of the dropwise addition. The reaction was checked by TLC and quenched by slow dropwise addition of 3mL of methanol at-78 ℃. After the reaction is warmed up to room temperature, the crude product is obtained by rotary evaporation, dichloromethane and water are used for extraction, organic phases are combined, and white solid is obtained by concentration and drying. Column chromatography gave 0.81g of white solid 3a in 86% yield.
Placing 0.81g of the obtained compound 3a in a 100mL reaction bottle, adding 30mL of 3M hydrochloric acid solution, heating and refluxing for 8 hours, cooling to room temperature, adding sodium hydroxide to adjust the pH value to be alkaline, adding dichloromethane for extraction, carrying out organic phase drying and concentration to obtain a white solid, and carrying out column chromatography to obtain 0.47g of a compound 4a, wherein the yield is 75%.
The assay data for product 4a is as follows:
1H NMR(400MHz,CDCl3):2.60(bs,3H),2.70(dd,J＝6.2,15.0Hz,1H),3.10(dd,J＝6.2,15.0Hz,1H),3.40-3.87(m,1H),4.78(d,J＝5.5Hz,1H),7.19-7.41(m,4H)；
13C NMR(100MHz,CDCl3):41.0,56.7,77.1,127.7,126.9,128.9,130.4,143.1,145.3.
[α]D 25＝+62(c 0.5,CHCl3).
the above synthetic amino alcohols are widely used as ligands in organic synthesis, the following references (s.rodri guez-Escrich, l.sol, c.jimeno, c.rodri guez-Escrich, m.a.perc, adv.synth.cal.2008, 350, 2250-2260.).
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (4)
1. A preparation method of chiral cyclic alpha-aminoketone is characterized by comprising the following steps:
in an organic solvent, under the catalytic action of diphosphine-rhodium complex, the cyclic alpha-dehydroaminoketone represented by the following general formula (1) reacts in a hydrogen atmosphere to obtain chiral cyclic alpha-aminoketone represented by the following general formula (2),
wherein R is one or more than two selected from hydrogen atom, C1-C6 alkyl, phenyl, C1-C7 acyl, C1-C7 alkoxyacyl, hydroxyl, C1-C7 alkoxy, C1-C7 acyloxy, amino, mono (C1-C7 alkyl) amino, di (C1-C7 alkyl) amino, C1-C7 acylamino, trimethylsilyl, dihydroxyboranyl, diphenylphosphinyloxy, phenylmercapto, fluorine atom, chlorine atom, bromine atom and iodine atom,
in the general formula (2), the chiral carbon is designated as R configuration or S configuration,
the diphosphine-rhodium complex is a complex represented by a general formula [ Rh (L) (L') ] X,
wherein L is any chiral diphosphine ligand selected from the following (R) -BINAP, (R) -Segphos, (R, R) -Quinoxp, (R, R) -Duphos, (S, S) -BenzP, (R, R) -Miniphos, (S) -TCFP and enantiomer thereof:
l' is any one auxiliary diene ligand selected from 1, 5-cyclooctadiene or 2, 5-norbornadiene,
x is selected from SbF6 -Or BF4 -Any one of the anions of (1).
2. The method of claim 1, wherein the chiral cyclic alpha-aminoketone is produced by reacting a chiral cyclic alpha-aminoketone,
the molar ratio of the diphosphine-rhodium complex to the cyclic alpha-dehydroaminoketone represented by the general formula (1) is 1/100-1/20000.
3. The process for preparing chiral cyclic alpha-aminoketones according to claim 1 or 2,
the organic solvent is one or more selected from ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol and trifluoroethanol.
4. The process for preparing chiral cyclic alpha-aminoketones according to claim 1 or 2,
the hydrogen pressure is 1-100 bar, the reaction temperature is 0-50 ℃, and the reaction time is 1-48 hours.
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