CN111454150B - Synthesis method of (S) -2-aryl propionate compound - Google Patents

Synthesis method of (S) -2-aryl propionate compound Download PDF

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CN111454150B
CN111454150B CN202010190577.9A CN202010190577A CN111454150B CN 111454150 B CN111454150 B CN 111454150B CN 202010190577 A CN202010190577 A CN 202010190577A CN 111454150 B CN111454150 B CN 111454150B
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毛建友
关海星
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Abstract

The invention discloses a synthesis method of (S) -2-aryl propionate compounds, which comprises the steps of reacting a compound shown in a formula I and a compound shown in a formula II serving as raw materials under the condition of visible light with a chiral ligand shown in a formula III, a nickel catalyst, a photocatalyst, a reducing agent and alkali to obtain the (S) -2-aryl propionate compounds shown in a formula IV. The method has the advantages of cheap and easily-obtained raw materials, convenient generation, mild conditions, environmental protection and safety, wherein the photocatalyst can be recycled, the production cost is greatly reduced, meanwhile, the test operation is simple, the generated waste is less, and the method can be developed into an industrial production method.

Description

Synthesis method of (S) -2-aryl propionate compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of (S) -2-aryl propionate compounds.
Background
The 2-aryl propionic acid compounds are widely used non-steroidal anti-inflammatory drugs and have excellent antipyretic, anti-inflammatory and analgesic effects. The 2-methyl acetic acid side chain of the anti-inflammatory drug has stronger activity and less side effect than that of the (R) -configuration when the side chain exists in the (S) -configuration. Thus, countries around the world are increasingly inclined to use a single chiral isomer. There are three current methods for obtaining a single chiral pure compound: resolution, chiral source approach and asymmetric synthesis. Both of the first two methods have certain disadvantages, which in turn limits their industrial applications. For example, the first method wastes one-half of the isomer, and the second method uses rare chiral natural compound starting materials. In recent decades, the invention and application of asymmetric catalysis provide new ideas and methods for synthesizing 2-aryl propionic acid compounds with single configuration.
The target product similar compounds in the invention have been reported, and specific examples are as follows:
1. according to the document x.dai, n.a.strotman, g.c.fu, j.am.chem.soc.2008,130,3302-3303, the reaction scheme is as follows:
Figure BDA0002415732950000011
the method takes alpha-bromo-carboxylic ester and aryl silicon reagent as raw materials, and the (S) -2-aryl propionate compound is obtained by reaction in the presence of a catalyst nickel and a chiral nitrogen ligand. This reaction requires an aryl silicon reagent as a raw material, which is difficult to prepare and difficult to store for a long time.
2. The reaction scheme is as follows according to the documents Z.Huang, Z.Liu, S.Zhou Jianrong, JAm ChemSec 2011,133, 15882-15885:
Figure BDA0002415732950000012
the method takes silicon-based ketone acetal and aryl trifluoromethanesulfonate as raw materials, and the (S) -2-aryl propionate compounds are obtained through reaction in the presence of a palladium catalyst and an axial chiral phosphorus ligand. The raw materials of the reaction need to be synthesized in advance, so that the reaction cost is increased.
3. According to the documents J.Mao, F.Liu, M.Wang, L.Wu, B.Zheng, S.Liu, J.Zhong, Q.Bian, P.J.Walsh, J.am.chem.Soc.2014,136,17662-17668, the reaction scheme is as follows:
Figure BDA0002415732950000021
the method takes alpha-bromo-carboxylic ester and aryl-format reagent as raw materials, and the (S) -2-aryl propionate compound is obtained by reaction in the presence of a cobalt catalyst and a bisoxazolin chiral ligand. The reaction needs an aryl-formatted reagent which is extremely sensitive to air and water as a raw material, so that the reaction risk is increased, the reaction is carried out at the temperature of 80 ℃ below zero, the conditions are harsh, and the method is not suitable for industrial application.
4. According to the documents m.jin, l.adak, m.nakamura, j.am.chem.soc.2015,137,7128-7134, the reaction scheme is as follows:
Figure BDA0002415732950000022
the method takes alpha-chloro carboxylic ester and aryl format reagent as raw materials, and the (S) -2-aryl propionic ester compound is obtained by reaction in the presence of an iron catalyst and a chiral phosphorus ligand. The reaction requires aryl-formatted reagents which are extremely sensitive to air and water as raw materials, so that the reaction risk is increased.
Therefore, the novel catalytic system is developed to realize the asymmetric synthesis of the 2-aryl propionic acid ester compound to replace the prior synthesis process, and the method has important significance for realizing the industrial production of the (S) -2-aryl propionic acid compound and the derivative thereof.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a synthesis method of (S) -2-aryl propionate compounds, which does not need to use organic metal reagents with harsh conditions and has the advantages of cheap and easily obtained raw materials, simple operation and convenient production.
The reaction mechanism of the present invention is as follows:
Figure BDA0002415732950000023
HEH = reducing agent (e.g. 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diethyl ester)
4CzIPN = photocatalyst (e.g. 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile)
SET = single electron transfer
Ln = BiOX = chiral oxazolin ligand
Firstly, the zero-valent nickel Ni (0) and iodobenzene are oxidized and added to generate a divalent nickel complex
Figure BDA0002415732950000031
The other molecule of zero-valent nickel Ni (0) can change chloro-ester into a free radical intermediate through single electron transfer
Figure BDA0002415732950000032
And chloride anions, while zero-valent nickel is oxidized to monovalent nickel Ni (I);
free radical intermediates
Figure BDA0002415732950000033
Can be combined with divalent nickel complexes->
Figure BDA0002415732950000034
Trapping to form trivalent nickel complex
Figure BDA0002415732950000035
Trivalent nickel complex in the conjunction or in the absence of trivalent nickel complexes>
Figure BDA0002415732950000036
The product is obtained after reduction and elimination>
Figure BDA0002415732950000037
And monovalent nickel Ni (I);
the monovalent Ni (I) can be reacted with a photocatalyst 4CzIPN for obtaining an electron ·- Single electron transfer occurs to generate zero-valent nickel Ni (0) and photocatalyst, and then the next cycle is carried out.
Obtaining a photocatalyst 4CzIPN of an electron ·- Is obtained by single electron transfer of a reducing agent and a photocatalyst 4CzIPN which reaches an excited state under blue light irradiation.
Free radical intermediates
Figure BDA0002415732950000038
Or a photocatalyst 4CzIPN which can obtain an electron ·- And single electron transfer with chloro ester (grey path in the mechanism diagram).
The invention specifically adopts the following scheme:
a synthesis method of (S) -2-aryl propionate compounds comprises the following steps of reacting a compound shown in a formula I and a compound shown in a formula II serving as raw materials under the condition of 400-500nm of visible light with a chiral ligand shown in a formula III, a nickel catalyst, a photocatalyst, a reducing agent and alkali to obtain (S) -2-aryl propionate compounds shown in a formula IV:
Figure BDA0002415732950000041
the photocatalyst is selected from one or more of transition metal-containing iridium or ruthenium complex photocatalyst and non-metal organic photocatalyst;
the reducing agent is selected from one or more of dihydropyridine reducing agents or tertiary amine reducing agents;
the alkali is selected from one or more of carbonate inorganic alkali or tertiary amine organic alkali;
R 1 any substituent selected from the group consisting of branched and straight-chain alkyl groups having 1 to 10 carbon atoms, alkyl groups having 1 to 10 carbon atoms and containing ether bonds, cycloalkyl groups having 3 to 6 carbon atoms, benzyl, perbenzyl, 4-substituted benzyl, and 4-substituted benzyl is selected from the group consisting of trifluoromethyl, halogen, and alkoxy groups having 1 to 10 carbon atoms;
R 2 optionally selected from branched and linear alkyl groups of 1 to 10 carbon atoms, benzyl;
ar is optionally selected from phenyl, mono-or poly-substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, indolyl, N-substituted indolyl, benzofuranyl, fluorene, thienyl;
the substituent in the 'mono-substituted or multi-substituted phenyl' is selected from branched and straight-chain alkyl with 1 to 10 carbon atoms, N-dimethylamino, alkoxy with 1 to 10 carbon atoms, trifluoromethoxy, halogen, trifluoromethyl, acetyl, ester group, cyano, boroester group, phenol group, phenyl and pyrrole group;
the substituents in "substituted pyridyl" are selected from halo;
the substituent in the N-substituted indolyl is selected from alkyl with 1-10 carbon atoms;
the substituents in the "substituted naphthyl" are selected from alkoxy groups of 1 to 10 carbon atoms.
Preferably, the photocatalytic agent is selected from tris (2, 2 '-bipyrazinyl) ruthenium di (hydrochloride), tris (4, 4' -di-tert-butyl-2, 2 '-bipyridyl) bis [ (2-pyridyl) phenyl ] iridium (III) hexafluorophosphate, tris (2-phenylpyridine) iridium, (2, 2' -bipyridyl) bis [2- (4-fluorophenyl) pyridine ] iridium (III) hexafluorophosphate, 10-methyl-9-mesityleneacridine perchlorate or 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile; and/or
The reducing agent is selected from diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate, di-tert-butyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate, dimethyl 1, 4-dihydro-2, 6-dimethylpyridine-3, 5-dicarboxylate, N-dicyclohexylmethylamine, triethylamine, N-diisopropylethylamine; and/or
The alkali is selected from N, N-dicyclohexyl methylamine, triethylamine, N-diisopropyl ethylamine, cesium carbonate, sodium carbonate, lithium carbonate and potassium carbonate.
Preferably, R in the formula I 1 Selected from branched or straight chain alkyl with 1-4 carbon atoms, alkyl with 1-4 carbon atoms containing ether bond, cycloalkyl with 3-6 carbon atoms, benzyl, high benzyl or 4-substituted benzyl, wherein the substituent in the 4-substituted benzyl is selected from trifluoromethyl, halogen and alkoxy with 1-3 carbon atoms; and/or
R in the formula I 2 Optionally selected from branched and straight chain alkyl of 1 to 7 carbon atoms, benzyl; and/or
Ar in the formula II is selected from phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-N, N-dimethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, acetylphenyl, 4-ethoxycarbonylphenyl, 4-cyanophenyl, 4-borocarbonylphenyl, 3-methylphenyl, 3-phenylphenyl, 3-chlorophenyl, 2-methylphenyl, 4-biphenyl, 3-fluoro-4-biphenyl, 4-pyrrolylphenyl, 2-9H-fluorenyl, 2-6-methoxynaphthyl, 1-naphthyl, 5-N-methylindolyl, 5-2-fluoropyridyl, 3-thienyl, 3-benzofuranyl.
Preferably, the nickel-based catalyst is selected from one or more of nickel chloride, nickel bromide, nickel iodide, bis- (1, 5-cyclooctadiene) nickel, nickel (II) bromide-diethylene glycol dimethyl ether complex, nickel diacetone, bis (triphenylphosphine) nickel chloride, (1, 1' -bis (diphenylphosphino) ferrocene) nickel dichloride or nickel chloride-dimethoxyethane complex.
Preferably, the reaction is carried out in a solvent selected from any one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and acetonitrile.
Preferably, the molar ratio of the compound shown in the formula I to the compound shown in the formula II, the nickel-based catalyst, the chiral ligand shown in the formula III, the photocatalyst, the reducing agent and the base is 1: (1-5): (0.01-1): (0.01-1): (0.01-1): (1-5): (1-5).
Preferably, the molar ratio of the compound shown in the formula I to the compound shown in the formula II, the nickel-based catalyst, the chiral ligand shown in the formula III, the photocatalyst, the reducing agent and the base is 1:3:0.1:0.11:0.1:3:3.
preferably, the reaction is carried out under blue light with a wavelength of 400 nm.
Preferably, the reaction temperature is 10 to 50 ℃.
The synthesis method according to claim 1, characterized in that the reaction is carried out in an inert gas or nitrogen atmosphere. The higher benzyl group in the synthesis method means phenylethyl group, and the alkyl group of 1 to 10 carbon atoms containing ether bond means that ether bond is contained in branched or straight chain alkyl group, such as 3-methoxypropyl group.
Advantageous effects
The technical scheme of the invention can at least achieve one of the following beneficial effects:
the method has the advantages of cheap and easily obtained raw materials, convenient generation, mild conditions, environmental protection, safety and the like;
the photocatalyst can be recycled, so that the production cost is greatly reduced;
the invention has simple test operation and less waste generation, and can be developed into an industrial production method;
all raw materials or catalysts used in the method can be dissolved in a solvent, the reaction can be a homogeneous reaction, and the method is more convenient for production and more suitable for industrial production;
the reaction of the invention is green chemistry, and all other byproducts except hydrochloric acid and hydroiodic acid have useful value. The photocatalyst can be recycled, as shown in the following, the by-product 1 and the by-product 2 obtained by the reaction are both valuable by-products, the by-product 1 is a pyridine compound and is one of chemical raw materials, the by-product 2 is dicyclohexyl methylamine hydrochloride or hydroiodide, and dicyclohexyl methylamine can be obtained by alkalization.
Figure BDA0002415732950000051
The invention carries out screening optimization on the synthesis conditions, such as reaction solvent, used alkali, catalyst, reaction temperature and time, and the like, and further improves the reaction yield and ee value.
Drawings
Embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which
FIG. 1 example 1 Hydrogen spectrum of target product
FIG. 2 carbon spectrum of target product in example 1
FIG. 3 Hydrogen spectrum of by-product 1 in example 1
FIG. 4 carbon spectrum of by-product 1 of example 1
FIG. 5 Hydrogen spectrum of by-product 2 of example 1
FIG. 6 carbon spectrum of by-product 2 of example 1
FIG. 7 hydrogen spectrum of recovered photocatalytic reagent of example 1
FIG. 8 carbon spectrum of recovered photocatalytic reagent of example 1
FIG. 9 example 2 hydrogen spectrum of target product
FIG. 10 carbon spectrum of target product in example 2
FIG. 11 example 3 Hydrogen Spectrum of target product
FIG. 12 carbon spectrum of target product in example 3
FIG. 13 example 4 Hydrogen Spectroscopy of target product
FIG. 14 carbon spectrum of target product in example 4
FIG. 15 hydrogen spectrum of target product in example 5
FIG. 16 carbon spectrum of target product in example 5
FIG. 17 example 6 Hydrogen Spectrum of target product
FIG. 18 carbon spectrum of target product in example 6
FIG. 19 example 19 target product hydrogen spectrum
FIG. 20 carbon spectrum of target product in example 19
FIG. 21 example 23 Hydrogen Spectrum of target product
FIG. 22 example 23 carbon spectrum of target product
FIG. 23 example 26 Hydrogen Spectrum of target product
FIG. 24 carbon spectrum of target product in example 26
FIG. 25 example 42 target product Hydrogen Spectrum
FIG. 26 example 42 carbon spectrum of target product
Detailed Description
The invention is further illustrated by the following examples, which are intended to be illustrative and not limiting. It will be understood by those of ordinary skill in the art that these examples are not intended to limit the present invention in any way and that suitable modifications and data transformations may be made without departing from the spirit and scope of the present invention.
In the examples, NMR spectra 1 H-NMR and 13 C-NMR was measured using a 400MHz NMR spectrometer from Bruker, deuterated DMSO (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) The specific polarimetry was measured using polarimeter Autopol III polarimeter from luddov usa.
The raw materials used in the following examples were all purchased from the market.
The following reactions were all carried out under irradiation with blue light having a wavelength of 400 to 500 nm.
Example 1
The target compound has the structural formula:
Figure BDA0002415732950000071
in a glove box filled with argon, the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis- (1, 5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) were added to 0.5mLN, N-dimethylacetamide, followed by iodobenzene (61.2mg, 0.3mmol), 2-chloropropionic acid (2, 3-trimethyl-2-butyl) ester (20.6 mg, 0.1mmol), N, N-dicyclohexylmethylamine (58.5mg, 64. Mu.L, 0.3 mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (75.9mg, 0.3mmol), and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol) in this order. Covering the reaction bottleThe reaction mixture was sealed, taken out of the glove box, and placed on a stirrer irradiated with blue light having a wavelength of 400nm at room temperature and 25 ℃ for 48 hours. After the reaction, 10mL of ethyl acetate was added to the reaction solution, a solid precipitated, and the hydrogen spectrum and the carbon spectrum of the by-product 2 (white solid, 66% yield) obtained by filtration were shown in fig. 5 and 6, respectively, and the nmr spectrum data were shown in fig. 5 and 6, respectively: 1 H NMR(400MHz,DMSO-d 6 )δ:8.54(br,1H),3,30-3.23(m,2H),2.61-2.60(m,3H),1.95-1.92(m,4H),1.77-1.74(m,4H),1.58-1.55(m,2H),1.45-1.11(m,8H),1.08-1.01(m,2H).； 13 C{ 1 H}NMR(101MHz,DMSO-d 6 ) Delta 61.6,32.6,28.5,26.6,25.12,25.05,24.8. The filtrate was then washed with saturated brine (5mL × 5), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to give the crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 100) to give the target product represented by formula IV (oily liquid, 19.1mg,77% yield, 90% enantiomeric excess percentage, specific optical rotation [ α] D 20 ＝+22.41(c＝0.424,CHCl 3 ) The value of the specific shift R f =0.54 (petroleum ether: ethyl acetate =50 = 1)), byproduct 1 and photocatalyst, the hydrogen spectrum and carbon spectrum of the target product are respectively shown in fig. 1 and fig. 2, and the nuclear magnetic resonance spectrum data are respectively shown in fig. 1: 1 H NMR(400MHz,CDCl 3 )δ:7.32-7.19(m,5H),3.62(q,J＝7.2Hz,1H),1.47–1.46(m,6H),1.38(s,3H),0.82(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 ) Delta 173.8,141.4,128.6,127.6,126.9,87.2,47.1,38.4,25.1,20.6,20.3,18.2. The hydrogen and carbon spectra of byproduct 1 (white solid, 100% yield) are shown in fig. 3 and 4, respectively, and the nmr spectra data are: 1 H NMR(400MHz,CDCl 3 )δ:8.62(s,1H),4.34(q,J＝7.1Hz,4H),2.79(s，6H),1.37(t,J＝7.1Hz,6H). 13 C{ 1 H}NMR(101MHz,CDCl 3 ) 166.0,162.3,141.0,123.1,61.5,25.0,14.3, the hydrogen and carbon spectra of the recovered photocatalyst (yellow solid, 96% yield, reusable) are respectively shown in FIG. 7 and FIG. 8, and the data of nuclear magnetic resonance spectrum are respectively shown in FIG. 7: 1 H NMR(400MHz,CDCl 3 )δ:8.24–8.18(m,2H),7.75-7.64(m,8H),7.52–7.44(m,2H),7.32(d,J＝7.7Hz,2H),7.23-7.18(m,4H),7.13–7.04(m,8H),6.87–6.78(m,4H),6.68–6.58(m,2H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:145.3,144.7,140.0,138.3,137.0,134.8,127.1,125.9,125.1,124.9,124.6,123.9,122.5,122.1,121.5,121.1,120.5,119.8,116.4,111.8,111.0,110.1,109.6,109.5。
example 2
The target compound has the structural formula:
Figure BDA0002415732950000072
in a glove box filled with argon, the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis- (1, 5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) were added to 0.5mLN, N-dimethylacetamide, followed by 4-methyliodobenzene (65.4mg, 0.3mmol), 2-chloropropionic acid (2, 3-trimethyl-2-butyl) ester (20.6mg, 0.1mmol), N, N-dicyclohexylmethylamine (58.5mg, 64. Mu.L, 0.3 mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (75.9mg, 0.3mmol), and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol) in this order. The reaction bottle cap is covered and sealed, the glove box is taken out and placed on a stirrer irradiated by blue light, and the reaction is carried out for 48 hours at room temperature of 25 ℃. After completion of the reaction, 10mL of ethyl acetate was added to the reaction mixture to precipitate a solid, which was filtered to obtain by-product 2 (white solid, 68% yield). The filtrate was then washed with saturated brine (5mL × 5), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to give the crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 100)] D 20 ＝+13.28(c＝0.700,CHCl 3 ) The value of the ratio shift R f =0.3 (petroleum ether: ethyl acetate = 50)), by-product 1 (white solid, 100% yield), photocatalyst (yellow solid, 92% yield, reusable). The hydrogen spectrum and the carbon spectrum of the target product are respectively shown in fig. 9 and fig. 10, and the nuclear magnetic resonance spectrum data are respectively as follows: 1 H NMR(400MHz,CDCl 3 )δ:7.22(d,J＝8.4Hz,2H),7.11(d,J＝8.3Hz,2H),3.59(q,J＝7.2Hz,1H),2.32(s,3H),1.46–1.44(m,6H),1.38(s,3H),0.86(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:174.0,138.3,136.4,129.2,127.4,87.1,46.7,38.4,25.1,21.3,20.5,20.3,18.3.
example 3
The target compound has the structural formula:
Figure BDA0002415732950000081
in a glove box filled with argon, the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis- (1, 5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) were added to 0.5mLN, N-dimethylacetamide, followed by sequentially adding 4-t-butyliodobenzene (78mg, 0.3mmol), 2-chloropropionic acid (2, 3-trimethyl-2-butyl) ester (20.6 mg, 0.1mmol), N, N-dicyclohexylmethylamine (58.5mg, 64. Mu.L, 0.3 mmol), 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diethyl ester (75.9mg, 0.1mmol), and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol). The reaction flask was capped and sealed, the glove box was removed, and the reaction flask was placed on a stirrer with blue light and allowed to react at room temperature of 25 ℃ for 48 hours. After completion of the reaction, 10mL of ethyl acetate was added to the reaction mixture to precipitate a solid, which was filtered to obtain by-product 2 (white solid, 61% yield). The filtrate was then washed with saturated brine (5mL × 5), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to give the crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 100) to obtain the target product represented by formula IV (21mg, 69% yield, 90% enantiomeric excess percentage, specific optical rotation [ α] D 20 ＝+11.49(c＝0.879,CHCl 3 ) The value of the ratio shift R f =0.5 (petroleum ether: ethyl acetate = 50)), by-product 1 (white solid, 100% yield), photocatalyst (yellow solid, 94% yield, reusable). The hydrogen spectrum and the carbon spectrum of the target product are respectively shown in fig. 11 and fig. 12, and the nuclear magnetic resonance spectrum data are respectively shown in the following steps: 1 H NMR(400MHz,CDCl 3 )δ:7.32(d,J＝8.4Hz,2H),7.20(d,J＝8.3Hz,2H),3.61(q,J＝7.2Hz,1H),1.48–1.46(m,6H),1.39(s,3H),1.30(s,9H),0.84(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:174.1,149.7,138.3,127.2,125.4,87.1,46.6,38.4,34.5,31.4,25.1,20.5,20.3,18.2.
example 4
The target compound has the structural formula:
Figure BDA0002415732950000082
in a glove box filled with argon, the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis- (1, 5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) were added to 0.5mLN, N-dimethylacetamide, followed by addition of 4-N, N-dimethyliodobenzene (74.1mg, 0.3mmol), 2-chloropropionic acid (2, 3-trimethyl-2-butyl) ester (20.6mg, 0.1mmol), N, N-dicyclohexylmethylamine (58.5mg, 64. Mu.L, 0.3 mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (75.9mg, 0.3mmol), and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol) in that order. The reaction flask was capped and sealed, the glove box was removed, and the reaction flask was placed on a stirrer with blue light and allowed to react at room temperature of 25 ℃ for 48 hours. After completion of the reaction, 10mL of ethyl acetate was added to the reaction mixture to precipitate a solid, which was filtered to obtain by-product 2 (white solid, 64% yield). The filtrate was washed with saturated brine (5mLx 5), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 100) to give the target product represented by formula IV (21mg, 72% yield, 84% enantiomeric excess percentage, specific optical rotation [ α [. Alpha. ]] D 20 ＝-14.59(c＝0.233,CHCl 3 ) Specific shift value R of the product f =0.3 (petroleum ether: ethyl acetate = 20)) by-product 1 (white solid, 100% yield), photocatalyst (yellow solid, 96% yield, reusable). The hydrogen spectrum and the carbon spectrum of the target product are respectively shown in fig. 13 and 14, and the nuclear magnetic resonance spectrum data are respectively shown in the following steps: 1 H NMR(400MHz,CDCl 3 )δ:7.15(d,J＝8.4Hz,2H),6.69(d,J＝8.3Hz,2H),3.53(q,J＝7.2Hz,1H),2.92(s,6H),1.46–1.42(m,6H),1.38(s,3H),0.88(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:174.5,149.7,129.4,128.2,112.9,86.9,46.1,40.8,38.4,25.2,20.6,20.3,18.3.
example 5
The target compound has the structural formula:
Figure BDA0002415732950000091
in a glove box filled with argon, the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis- (1, 5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) were added to 0.5mLN, N-dimethylacetamide, followed by addition of 4-methoxyiodobenzene (70.2mg, 0.3mmol), 2-chloropropionic acid (2, 3-trimethyl-2-butyl) ester (20.6 mg, 0.1mmol), N, N-dicyclohexylmethylamine (58.5mg, 64. Mu.L, 0.3 mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (75.9mg, 0.3mmol), and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol) in that order. The reaction flask was capped and sealed, the glove box was removed, and the reaction flask was placed on a stirrer with blue light and allowed to react at room temperature of 25 ℃ for 48 hours. After completion of the reaction, 10mL of ethyl acetate was added to the reaction mixture to precipitate a solid, which was filtered to obtain by-product 2 (white solid, 62% yield). The filtrate was washed with saturated brine (5mL × 5), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 100) to give the target product represented by formula IV (14.5mg, 52% yield, 85% enantiomeric excess percentage, specific optical rotation [ α] D 20 ＝+11.10(c0.838,CHCl 3 ) Specific shift value R of the product f =0.3 (petroleum ether: ethyl acetate = 20)), by-product 1 (white solid, 100% yield), photocatalyst (yellow solid, 94% yield, reusable). The hydrogen spectrum and the carbon spectrum nucleus of the target product are respectively shown in FIG. 15 and FIG. 16, and the magnetic resonance spectrum data are respectively shown in the following steps: 1 H NMR(400MHz,CDCl 3 )δ:7.19(d,J＝8.4Hz,2H),6.84(d,J＝8.3Hz,2H),3.79(s，3H),3.57(q,J＝7.2Hz,1H),1.45–1.43(m,6H),1.38(s,3H),0.86(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:174.1,158.5,133.5,128.5,113.9,87.1,55.3,46.2,38.4,25.1,20.5,20.3,18.3.
example 6
The target compound has the structural formula:
Figure BDA0002415732950000092
in a glove box filled with argon, the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis- (1, 5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) were added to 0.5mLN, N-dimethylacetamide, followed by 4-trifluoromethoxyiodobenzene (86.4mg, 0.3mmol), 2-chloropropionic acid (2, 3-trimethyl-2-butyl) ester (20.6mg, 0.1mmol), N, N-dicyclohexylmethylamine (58.5mg, 64. Mu.L, 0.3 mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (75.9mg, 0.3mmol), and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (0.01mmol) in this order. The reaction flask was capped and sealed, the glove box was removed, and the reaction flask was placed on a stirrer with blue light and allowed to react at room temperature of 25 ℃ for 48 hours. After completion of the reaction, 10mL of ethyl acetate was added to the reaction mixture to precipitate a solid, which was filtered to obtain by-product 2 (white solid, 62% yield). The filtrate was washed with saturated brine (5mLx 5), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate =50: 1) to give the target product represented by formula IV (23.9 mg,72% yield, 86% enantiomeric excess percentage, specific optical rotation [ α] D 20 ＝+11.87(c0.716,CHCl 3 ) Specific shift value R of the product f =0.3 (petroleum ether: ethyl acetate = 20)), by-product 1 (white solid, 100% yield), photocatalyst (yellow solid, 93% yield, reusable). The hydrogen spectrum and the carbon spectrum of the target product are respectively shown in FIG. 17 and FIG. 18, and the data of the nuclear magnetic resonance spectrum are respectively shown in the following steps: 1 H NMR(400MHz,CDCl 3 )δ:7.28(d,J＝8.7Hz,2H),7.15(d,J＝8.0Hz,2H),3.64(q,J＝7.2Hz,1H),1.47-1.45(m,6H),1.37(s,3H),0.81(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:173.3,148.1,140.1,128.9,121.1,120.5(q,J＝257Hz),87.6,46.4,38.4,25.0,20.5,20.3,18.1.
referring to the method in example 1, a series of (S) -2-aryl propionate compounds are synthesized respectively by changing the reaction substrate and keeping other raw materials, conditions and operations unchanged, and the yield and the enantiomeric excess percentage can reach more than a medium level. The derivatives synthesized are shown in the following table in particular in examples 7 to 41. The substituents in table 1 are those shown in the following structural formulae.
Figure BDA0002415732950000101
TABLE 1
Figure BDA0002415732950000102
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Figure BDA0002415732950000111
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Figure BDA0002415732950000121
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Figure BDA0002415732950000131
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Figure BDA0002415732950000141
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Figure BDA0002415732950000151
Wherein the hydrogen spectra and carbon spectra of the target products of the above examples 19, 23 and 26 are shown in fig. 19 and 20, fig. 21 and 22, and fig. 23 and 24, respectively, and the nmr data are shown in fig. 1:
1 H NMR(400MHz,CDCl 3 )δ:7.34–7.25(m,3H),7.11–7.07(m,1H),7.02–6.92(m,3H),6.89–6.86(m,1H),3.60(q,J＝7.2Hz,1H),1.45-1.43(m,6H),1.38(s,3H),0.83(s,9H).
13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:173.4,157.4,143.5,129.82,129.80,123.3,122.6,118.9,118.2,117.4,87.4,47.0,38.4,25.1,20.5,20.3,18.1.
1 H NMR(400MHz,CDCl 3 )δ:7.34–7.25(m,3H),7.11–7.00(m,1H),7.00–6.93(m,3H),6.89–6.86(m,1H),3.60(q,J＝7.2Hz,1H),1.45–1.43(m,6H),1.38(s,3H),0.83(s,9H).
13 C{ 1 H}NMR(101MHz,CDCl 3 )δ:173.2,159.8(d,J＝249.3Hz),142.7(d,J＝7.6Hz),135.7,130.7(d,J＝3.9Hz),129.0(d,J＝2.8Hz),128.5,127.7,127.5(d,J＝13.6Hz),123.7(d,J＝3.2Hz),115.3(d,J＝23.6Hz),87.7,46.6,38.5,25.1,20.6,20.4,18.1.
1 H NMR(400MHz,CDCl 3 )δ7.71–7.65(m,3H),7.40–7.38(m,1H),7.15–7.11(m,2H),3.91(s,3H),3.76(q,J＝7.2Hz,1H),1.54(d,J＝7.2Hz,3H),1.47(s,3H),1.38(s,3H),0.84(s,9H)；
13 C NMR(101MHz,CDCl 3 )δ:174.0,157.6,136.5,133.6,129.3,129.1,127.0,126.5,126.0,118.9,105.7,87.3,55.4,47.0,38.4,25.1,20.6,20.3,18.3.
example 42
In example 1, 0.5mL of N, N-dimethylacetamide was replaced with 0.5mL of acetonitrile, bis- (1, 5-cyclooctadiene) nickel (2.8mg, 0.01mmol) was replaced with nickel chloride (2.4mg, 0.02mmol), the amount of chiral nitrogen ligand represented by formula III was increased to (8mg, 0.02mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (65mg, 3.0eq.) was replaced with triethylamine (50.5mg, 5.0eq.), and N, N-dicyclohexylmethylamine (65uL, 3.0eq.) was replaced with cesium carbonate (162mg, 5.0eq.)
Meanwhile, the reaction time was changed to 12 hours, the reaction temperature was changed to 10 ℃, and other conditions, materials and operations were kept unchanged, to finally obtain the pure target product (oily liquid, 11.1mg,30% yield, 90% enantiomeric excess). Specific shift value R of the product f =0.54 (petroleum ether: ethyl acetate = 50) and the product hydrogen spectrum and carbon spectrum are respectively in fig. 25 and 26, and the spectrum data are respectively: 1 H NMR(400MHz,CDCl 3 )δ:7.32-7.19(m,5H),3.61(q,J＝7.2Hz,1H),1.47–1.46(m,6H),1.37(s,3H),0.82(s,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 ) Delta 173.8,141.4,128.5,127.6,126.9,87.2,47.1,38.4,25.1,20.6,20.2,18.2. The obtained by-product 2 (white solid, 66% yield) was recovered; the resulting byproduct 1 (white solid, 100% yield) was recovered; the photocatalyst was recovered (yellow solid, 96% yield, reusable).
Example 43
2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol) in example 1 was replaced with: 4,4' -di-tert-butyl-2, 2' -bipyridine) bis [ (2-pyridyl) phenyl ] iridium (III) hexafluorophosphate (9.1mg, 0.01mmol), 0.5mL of N, N-dimethylacetamide was replaced with an equal volume of DMSO, bis- (1, 5-cyclooctadiene) nickel (2.8mg, 0.01mmol) was replaced with (1, 1' -bis (diphenylphosphino) ferrocene) nickel dichloride (27.2mg, 0.04mmol), the amount of chiral nitrogen ligand was increased to (16mg, 0.04mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (65mg, 3.0eq.) was replaced with N, N-dicyclohexylmethylamine (65uL, 3.0eq.), N, N-dicyclohexylmethylamine (65uL, 3.0eq.) was replaced with sodium carbonate (52.5mg, 5.0eq.)
The reaction time was changed to 96 hours, the reaction temperature was changed to 50 ℃, and other conditions, materials and operations were kept constant to obtain a pure product (oily liquid, 6.2mg,25% yield, 90% enantiomeric excess). Specific shift value R of the product f =0.54 (petroleum ether: ethyl acetate = 50; the resulting byproduct 2 (white solid, 66% yield) was recovered; the obtained by-product 1 (white solid, 100% yield) was recovered.
Example 44
2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (8mg, 0.01mmol) in example 1 was replaced with: tris (2, 2' -bipyrazinyl) ruthenium bis (hydrochloride) salt (7.5mg, 0.01mmol), 0.5ml N, N-dimethylacetamide was replaced with an equivalent volume of DMF, bis- (1, 5-cyclooctadiene) nickel (2.8mg, 0.01mmol) was replaced with bis (triphenylphosphine) nickel chloride (65.4mg, 0.1mmol), the amount of chiral nitrogen ligand was increased to (40mg, 0.1mmol), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (65mg, 3.0eq.) was replaced with di-tert-butyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (154.5mg, 5.0eq.), and N, N-dicyclohexylmethylamine was increased to (109ul, 5.0eq.)
The reaction time was changed to 48 hours, and the reaction temperature was changedAt 25 ℃ the conditions, materials and operations were kept constant to obtain the pure product (oily liquid, 18.6mg,75% yield, 90% enantiomeric excess). Specific shift value R of the product f =0.54 (petroleum ether: ethyl acetate = 50; the obtained by-product 2 (white solid, 66% yield) was recovered; the obtained by-product 1 (white solid, 100% yield) was recovered.

Claims (2)

1. A synthesis method of (S) -2-aryl propionate compounds is characterized in that under the condition of blue light with the wavelength of 400nm, a compound shown in a formula I and a compound shown in a formula II are used as raw materials, under the condition of a chiral ligand shown in a formula III, a nickel-based catalyst, a photocatalyst, a reducing agent and alkali, in any one or more solvents selected from dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and acetonitrile, the reaction temperature is 10-50 ℃, and the (S) -2-aryl propionate compounds shown in a formula IV are obtained through reaction in a nitrogen atmosphere:
Figure QLYQS_1
the nickel catalyst is selected from one or more of nickel chloride, nickel bromide, nickel iodide, bis- (1, 5-cyclooctadiene) nickel, nickel bromide (II) diethylene glycol dimethyl ether compound, nickel diacetone, bis (triphenylphosphine) nickel chloride, (1, 1' -bis (diphenylphosphino) ferrocene) nickel dichloride or nickel chloride dimethoxyethane compound;
the photocatalyst is selected from one or more of tris (2, 2 '-bipyrazine) ruthenium di (hydrochloride), bis [ (2-pyridyl) phenyl ] iridium (III) hexafluorophosphate of 4,4' -di-tert-butyl-2, 2 '-bipyridine), iridium (tris (2-phenylpyridine), bis [2- (4-fluorophenyl) pyridine ] iridium (III) hexafluorophosphate of 2,2' -bipyridine or 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile;
the reducing agent is selected from one or more of diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate, di-tert-butyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate and dimethyl 1, 4-dihydro-2, 6-dimethylpyridine-3, 5-dicarboxylate;
the alkali is selected from one or more of N, N-dicyclohexyl methylamine, triethylamine, N-diisopropyl ethylamine, cesium carbonate, sodium carbonate, lithium carbonate or potassium carbonate;
the molar ratio of the compound shown in the formula I to the compound shown in the formula II, the nickel-based catalyst, the chiral ligand shown in the formula III, the photocatalyst, the reducing agent and the alkali is 1:3:0.1:0.11:0.1:3:3;
R 1 optionally, the compound is selected from branched chain and straight chain alkyl with 1 to 10 carbon atoms, alkyl with 1 to 10 carbon atoms containing ether bonds, cycloalkyl with 3 to 6 carbon atoms, benzyl or 4-substituted benzyl, wherein the substituent in the 4-substituted benzyl is selected from trifluoromethyl, halogen or alkoxy with 1 to 10 carbon atoms;
R 2 optionally branched and straight chain alkyl of 1 to 10 carbon atoms, benzyl;
ar is optionally selected from phenyl, mono-or poly-substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, indolyl, N-substituted indolyl, benzofuranyl, fluorene or thienyl;
the substituent in the 'mono-substituted or multi-substituted phenyl' is selected from branched chain and straight chain alkyl with 1 to 10 carbon atoms, N, -dimethylamino, alkoxy with 1 to 10 carbon atoms, trifluoromethoxy, halogen, trifluoromethyl, acetyl, ester group, cyano, boron ester group, phenol group, phenyl or pyrrole group;
the substituent in the substituted pyridyl is selected from halogen;
the substituent in the N-substituted indolyl is selected from alkyl with 1 to 10 carbon atoms;
the substituent in the substituted naphthyl is selected from alkoxy with 1 to 10 carbon atoms.
2. The method of claim 1, wherein R in formula I 1 Selected from branched or straight chain alkyl with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms containing ether bond, cycloalkyl with 3 to 6 carbon atoms, benzyl and 4-substituted benzyl, wherein the substituent in the 4-substituted benzyl is selected from trifluoromethyl, halogen or alkoxy with 1 to 3 carbon atoms(ii) a And/or
R in the formula I 2 Optionally selected from branched and linear alkyl of 1 to 7 carbon atoms, benzyl; and/or
Ar in the formula II is selected from phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-N, N-dimethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, acetylphenyl, 4-ethoxycarbonylphenyl, 4-cyanophenyl, 4-borocarbonylphenyl, 3-methylphenyl, 3-phenylphenyl, 3-chlorophenyl, 2-methylphenyl, 4-biphenyl, 3-fluoro-4-biphenyl, 4-pyrrolophenyl, 2-9H-fluorenyl, 1-naphthyl, 5-N-methylindolyl, 3-thienyl or 3-benzofuranyl.
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