CN106854125B - Method for preparing α -fluoro- β -ethynyl ketone compound containing two chiral centers - Google Patents

Method for preparing α -fluoro- β -ethynyl ketone compound containing two chiral centers Download PDF

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CN106854125B
CN106854125B CN201510894813.4A CN201510894813A CN106854125B CN 106854125 B CN106854125 B CN 106854125B CN 201510894813 A CN201510894813 A CN 201510894813A CN 106854125 B CN106854125 B CN 106854125B
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胡向平
张德旸
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Dalian Institute of Chemical Physics of CAS
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Abstract

The invention relates to a method for preparing α -fluorine- β -ethynyl ketone compound containing two chiral centers, belonging to the field of organic synthesis, which comprises the step of synthesizing α -fluorine- β -ethynyl ketone compound containing two chiral centers by catalyzing asymmetric propargyl substitution reaction by fluorinated enol silyl ether and propargyl compounds, wherein the adopted chiral copper catalyst is generated in situ by copper salt and chiral tridentate P, N, N-ligand in various polar and nonpolar solvents.

Description

Method for preparing α -fluoro- β -ethynyl ketone compound containing two chiral centers
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing α -fluoro- β -ethynyl ketone compounds containing two chiral centers.
Background
The fluorine-containing organic compound is widely applied to the fields of medicines, pesticides, materials and the like, so that the development of an effective method for constructing the fluorine-containing organic compound has important significance. Among them, the synthesis of chiral fluorine-containing organic compounds is one of the difficulties and hot spots. [ (a) O' Hagan, d.; harper, d.b.nat.prod.rep.1994,11,123; (b) hiyama, t. organofluorine Compounds, Chemistry and Applications; Springer-Verlag Berlin Heidelberg, 2000; (c) kirsch, p.modern fluoro organic Chemistry; Wiley-VCH Weinheim, 2013; (d) wang, j.; Snnchez-Rosell, m.;
Figure BDA0000870373340000011
J.L.；del Pozo,C.；Sorochinsky,A.E.；Fustero,S.；Soloshonok,V.A.；Liu,H.Chem.Rev.2013,114,2432.]chiral α -fluorinated ketone compounds, particularly the chiral α -tertiary fluorinated ketone compounds, are an important class of fluorine-containing compounds and many studies have been conducted over the past decade, two major synthetic strategies currently include 1) asymmetric electrophilic fluorination with a fluorine source via the α position of the ketone compound [ (a) Ma, j. -a.; char, d.chem.rev.2004,104, 6119; (b) Ibrahim, h.; Togni, a.chem.commun.2004, 1147; (c) lectad, s.; Hamashima, y.; Sodeoka, m.2010,352, 2708; (d) Yang, x. -y.; Wu t.; Phipps, r.j.; tose, f.d.chem.rev.115, 826.]2) by asymmetric alkylation of the α position of the ketocarbonyl group of a fluorinated ketone compound or analog thereof with an alkylating agent [ (a) Mohr, J.T.; Behenna, D.C.; Harned, A.M.; Stoltz, B.M.Angew.chem.int.Ed.2005,44,6924; (B) Nakamura, M.j.a, A.endo, K.; Nakamura, E.Angew.chem.int.Ed.2005,44,7248; (c) Beerlanger,
Figure BDA0000870373340000012
；Cantin,K.；Messe,O.；Tremblay,M.；Paquin,J.J.Am.Chem.Soc.2007,129,1034.]the invention firstly utilizes asymmetric propargyl substitution reaction between fluorinated enol silicon ether and propargyl compounds catalyzed by chiral copper catalysts to synthesize α -fluorine- β -ethynyl ketone compounds containing two chiral centers with high diastereoselectivity and high enantioselectivity, and provides a synthetic route with simple operation, mild reaction conditions, diastereoselectivity and high enantioselectivity for chiral α -fluorine- β -ethynyl ketone compounds.
Disclosure of Invention
The invention aims to provide a method for synthesizing α -fluoro- β -ethynyl ketone compound containing two chiral centers by asymmetric propargyl reaction of copper-catalyzed fluorinated enol silyl ether and propargyl compound.
The invention provides a method for preparing a chiral α -fluoro- β -ethynyl ketone compound containing two chiral centers, which comprises the following steps of catalyzing fluorinated enol silyl ether and a propargyl compound to be synthesized through asymmetric propargyl substitution reaction in a reaction medium by a chiral copper catalyst in the presence or absence of a base additive, and comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and P, N, N-ligand are stirred in a reaction medium for 0.5 to 2 hours according to the molar ratio of 1:0.1 to 10 to prepare a chiral copper catalyst;
(2) preparing a chiral α -fluoro- β -ethynyl ketone compound, namely dissolving fluorinated enol silyl ether and a propargyl compound in a reaction medium, adding or not adding an alkali additive, then adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, stirring and reacting for 1-36 hours at a certain temperature, and after the reaction is finished, carrying out reduced pressure rotary evaporation and column separation to obtain a α -fluoro- β -ethynyl ketone compound containing two chiral centers;
the molar ratio of the chiral copper catalyst to the fluorinated enol silyl ether is 0.01-100%: 1;
the molar ratio of the alkali additive to the fluorinated enol silyl ether is 0-10: 1;
the molar ratio of the propargyl compound to the fluorinated enol silyl ether is 1-10: 1.
the reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran and ethyl acetate.
The α -fluoro- β -ethynyl ketone compound containing two chiral centers has the following structure:
Figure BDA0000870373340000021
in the formula: r1，R2，R3Is C1-C40 alkylC3-C12 cycloalkyl or substituted C3-C12 cycloalkyl, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms or ester group;
the substituent of the C3-C12 naphthenic base, the substituent of the phenyl or the substituent of the benzyl is C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano respectively.
The fluorinated silyl enol ether has the following structure:
Figure BDA0000870373340000022
in the formula: r1，R2Is the same as R in the structural formula I1，R2The same group; r4，R5，R6Is C1-C40 alkyl, C3-C12 cycloalkyl or substituted C3-C12 cycloalkyl, C2-C40 alkenyl or substituted C2-C40 alkenyl, phenyl and substituted phenyl, benzyl and substituted benzyl, halogen;
the substituent of C3-C12 cycloalkyl, the substituent of C2-C40 alkenyl, the substituent of phenyl or the substituent of benzyl is C1-C40 alkyl, alkoxy of C1-C40, halogen, nitro, ester group or cyano respectively.
The propargyl compound has the following structure:
Figure BDA0000870373340000023
in the formula: r3Is represented by the structural formula I, wherein R is3The same group; x is fluorine, chlorine, bromine, iodine, alkyl carboxylate, alkyl carbonate, alkyl sulfonate, alkyl phosphate, phenyl and substituted phenyl carboxylate, phenyl and substituted phenyl carbonate, phenyl and substituted phenyl sulfonate or phenyl and substituted phenyl phosphate; the substituent on the substituted phenyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
The copper salt is hydrated copper acetate,Hydrated copper sulfate, anhydrous copper acetate, anhydrous copper sulfate, copper triflate, cupric chloride, cuprous acetate, cuprous chloride, cuprous iodide, cuprous perchlorate, copper triflate, Cu (CH)3CN)4BF4、Cu(CH3CN)4ClO4At least one of (1). Preferably hydrated copper acetate, trifluomethane sulfonate, Cu (CH)3CN)4BF4、Cu(CH3CN)4ClO4At least one of (1).
The structural formula of the chiral P, N, N-ligand is as follows:
Figure BDA0000870373340000031
in the formula: r7，R8Is alkyl in H, C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl or benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R9，R10is H, halogen, alkyl of C1-C40, cycloalkyl of C3-C12, phenyl and substituted phenyl, alkoxy of C1-C40, phenoxy, acyl or nitro; the substituent on the substituted phenyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R11is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl or a five-membered or six-membered heterocyclic aromatic group containing one or more than two of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
The alkali additive is various inorganic or organic alkali, preferably N, N-diisopropylethylamine, triethylamine, potassium tert-butoxide, potassium phosphate, KOH, NaOH, K2CO3、Na2CO3Or NaHCO3And the like.
The catalytic reaction conditions in the step (2) are preferably as follows: the temperature is-20 ℃; the reaction medium is methanol; the pressure is normal pressure; the time period required was 12 hours.
The molar ratio of the chiral copper catalyst to the fluorinated silyl enol ether is preferably 1-10%;
the molar ratio of the alkali additive to the fluorinated silyl ether is preferably 2.5: 1;
the mol ratio of the propargyl compound to the fluorinated enol silyl ether is preferably 2.5: 1.
The reaction equation of the invention is as follows:
Figure BDA0000870373340000041
the invention has the following advantages:
1. the starting materials are cheap and easy to obtain.
2. The chiral ligand is simple and convenient to synthesize, the catalyst is cheap and easy to obtain, and the dosage is small.
3. Good reaction activity, high diastereoselectivity and enantioselectivity and mild reaction conditions.
4. The method can conveniently synthesize α -fluoro- β -ethynyl ketone compounds containing two chiral centers, wherein one is a quaternary carbon fluorine-containing chiral center.
Drawings
FIG. 1 nuclear magnetic resonance hydrogen spectrum of compound syn-I-1
FIG. 2 NMR carbon spectrum of compound syn-I-1;
FIG. 3 nuclear magnetic resonance fluorine spectrum of compound syn-I-1;
FIG. 4 NMR Hydrogen Spectroscopy of Compound syn-I-2
FIG. 5 NMR carbon spectra of compound syn-I-2;
FIG. 6 NMR spectra of compound syn-I-2.
Detailed Description
The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent 1100 series HPLC.
Example 1
Cu(CH3CN)4BF4And L-1-1 is complexed as a catalyst to catalyze the reaction to generate a chiral α -fluoro- β -ethynyl ketone product I-1.
The metal precursor Cu (CH) is added into a reaction bottle3CN)4BF4(0.015mmol, 5 mol%) and chiral ligand L-1-1(0.0165mmol, 5.5 mol%), adding 1.0 ml of anhydrous methanol under the protection of nitrogen, and stirring at room temperature for 1 hour. Fluorinated enolsilyl ether II-1(0.30mmol, 1.0equiv), propargyl alcohol ester III-1 (0.75mmol, 2.5equiv) and N, N-diisopropylethylamine (0.75mmol, 2.5equiv) were dissolved in 2.0 ml of anhydrous methanol, and the solution was added to the stirred catalyst solution under nitrogen protection and stirred at-20 ℃ for 12 h. And (3) after the reaction is finished, carrying out reduced pressure rotary evaporation, flushing a silica gel short column on the residue, sending the residue after the rotary evaporation to nuclear magnetism to determine a dr value, and then separating a nuclear magnetism crude sample column to obtain the compound I-1. White solid, 88% yield, 93/7dr (syn/anti), 99% ee (syn),>99％ee(anti).
the NMR hydrogen spectrum, NMR carbon spectrum and NMR fluorine spectrum of the compound syn-I-1 are respectively shown in figure 1, figure 2 and figure 3:
1H NMR(400MHz,CDCl3,syn-I-1):δ8.03(d,J＝7.7Hz,1H),7.50–7.45(m,3H),7.32–7.18(m,5H),4.65(dd,J＝16.0,2.5Hz,1H),3.16–3.08(m,1H),2.96–2.89(m,1H),2.61–2.52(m,1H),2.37(d,J＝2.3Hz,1H),2.09–2.00(m,1H).13C NMR(100MHz,CDCl3,syn-I-1):δ191.3(d,J＝18.8Hz),142.9,134.7(d,J＝4.2Hz),134.4,131.2,130.0,130.0,128.8,128.6,128.1,127.3,95.0(d,J＝189.3Hz),81.1(d,J＝4.0Hz),73.4,41.4(d,J＝22.4Hz),29.6(d,J＝21.9Hz),25.2(d,J＝7.7Hz.19F NMR(376MHz,CDCl3,syn-I-1):δ-158.0(m,1F).HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝85/15,0.8ml/min,254nm,40℃):tR(syn,major)＝18.2min,tR(syn,minor)＝20.3min,tR(anti,major)＝28.2min,tR(anti,minor)＝32.6min。
the structural formula of II-1, III-1, I-1, L-1-1 is as follows:
Figure BDA0000870373340000051
example 2
L-2-1 is used as ligand to react to generate chiral α -fluorine- β -ethynyl ketone product I-1
The ligand L-1-1 in example 1 was replaced with ligand L-2-1, and the procedure was otherwise the same as in example 1. The reaction gave compound I-1 in 70% yield, 75/25dr (syn/anti), 98% ee (syn), 99% ee (anti).
The structural formula of L-2-1 is as follows:
Figure BDA0000870373340000052
example 3
L-2-2 reacts as a ligand to generate a product α -fluoro- β -ethynyl ketone product I-1
The ligand L-2-1 in example 2 was replaced with ligand L-2-2, and the procedure was otherwise the same as in example 1. The reaction gave compound I-1 in 60% yield, 67/33dr (syn/anti), 88% ee (syn), 94% ee (anti).
The structural formula of L-2-2 is as follows:
Figure BDA0000870373340000053
example 4
Cu(OAc)2·H2The complex of O and L-1-1 is used as a catalyst to catalyze the reaction to generate a product α -fluorine- β -ethynyl ketone product I-1
Cu (CH) in example 13CN)4BF4With Cu (OAc)2·H2And O is replaced. The remainder of the procedure is as in example 1 to give compound I-1 in 82% yield, 92/8dr (syn/anti), 98% ee (syn), 99% ee (anti).
Example 5
Without alkali additives to form the product I-1
The compound I-1 was obtained in 8% yield from example 1 by removing the N, N-diisopropylethylamine from example 1, 87/13dr (syn/anti), 58% ee (syn), 63% ee (anti).
Example 6
Triethylamine as alkali additive reacts to generate product I-1
The N, N-diisopropylethylamine of example 1 was replaced with triethylamine. The remainder of the procedure is as in example 1 to give compound I-1 in 70% yield, 86/14dr (syn/anti), 98% ee (syn), 98% ee (anti).
Example 7
III-2 as a substrate to produce a product I-2
The propargyl alcohol ester III-1 from example 1 was replaced by III-2 and the remainder of example 1 gave the product I-2 in 90% yield, 91/9dr (syn/anti), 99% ee (syn), and > 99% ee (anti).
The NMR hydrogen spectrum, NMR carbon spectrum and NMR fluorine spectrum of the compound syn-I-2 are respectively shown in figure 4, figure 5 and figure 6:
1H NMR(400MHz,CDCl3,syn-I-2):δ8.03(d,J＝7.8Hz,1H),7.49(t,J＝7.5Hz,1H),7.44(d,J＝8.4Hz,2H),7.32(t,J＝7.4Hz,1H),7.27(d,J＝8.5Hz,2H),7.21(d,J＝7.7Hz,1H),4.68(dd,J＝14.3,2.4Hz,1H),3.21–3.13(m,1H),2.95–2.88(m,1H),2.65–2.56(m,1H),2.39(d,J＝2.4Hz,1H),2.12–1.98(m,1H).13C NMR(100MHz,CDCl3,syn-I-2):δ190.9(d,J＝18.9Hz),143.0,134.5,134.1,133.4(d,J＝4.7Hz),131.4(d,J＝1.0Hz),131.1,128.8,128.8,128.7,94.7(d,J＝188.7Hz),80.7(d,J＝3.5Hz),73.8,40.9(d,J＝22.9Hz),29.5(d,J＝22.0Hz),25.1(d,J＝7.3Hz).19F NMR(376MHz,CDCl3,syn-I-2):δ-158.0(s,1F).HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝85/15,0.8mL/min,254nm,40℃):tR(syn,major)＝17.5min,tR(syn,minor)＝19.6min,tR(anti,major)＝27.1min,tR(anti,minor)＝31.2min。
the structural formula of III-2 and I-2 is as follows:
Figure BDA0000870373340000061
examples 8 to 28
Reaction substrate suitability
The present invention has a wide substrate applicability, and many substrates can participate in the reaction according to the reaction conditions in example 1, and α -fluoro- β -ethynyl ketone product containing two chiral centers is obtained with high yield, high diastereoselectivity and high enantioselectivity, which has the reaction formula:
Figure BDA0000870373340000062
in examples 8 to 28, when R is1,R2,’R3Substituted, the yields, diastereomeric and enantiomeric excess values are shown in table 1:
TABLE 1
Figure BDA0000870373340000071
Figure BDA0000870373340000081
The invention can conveniently synthesize α -fluoro- β -ethynyl ketone compounds with various substituent groups and two chiral centers, and the enantiomeric excess percentage is more than 99 percent.

Claims (7)

1. A method for preparing α -fluoro- β -ethynyl ketone compound containing two chiral centers is characterized in that under the condition that alkali additive exists or alkali is not added, a chiral copper catalyst catalyzes fluorinated enol silyl ether and propargyl compound to synthesize through asymmetric propargyl substitution reaction in reaction medium;
the fluorinated silyl enol ether has the following structure:
Figure FDA0002217865210000011
in the formula: r1，R2Is the same as R in the following structural formula I1，R2The same group; r4，R5，R6Is C1-C40 alkyl, C3-C12 cycloalkyl or substituted C3-C12 cycloalkyl, C2-C40 alkenyl or substituted C2-C40 alkenyl, phenyl and substituted phenyl, benzyl and substituted benzyl, halogen;
the substituent of C3-C12 cycloalkyl, the substituent of C2-C40 alkenyl, the substituent of phenyl or the substituent of benzyl is C1-C40 alkyl, alkoxy of C1-C40, halogen, nitro, ester group or cyano respectively;
the chiral α -fluoro- β -ethynyl ketone compound has the following structure:
Figure FDA0002217865210000012
in the formula: r1，R2，R3Is C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group or ester group containing one or more than two of oxygen, sulfur and nitrogen atoms;
the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano;
the propargyl compound has the following structure:
Figure FDA0002217865210000013
in the formula: r3Is represented by the structural formula I, wherein R is3The same group; x is fluorine, chlorine, bromine, iodine, C1-C40 alkyl carboxylic ester, C1-C40 alkyl carbonate, C1-C40 alkyl sulfonate, C1-C40 alkyl phosphate, phenyl and substituted phenyl carboxylic ester, phenyl and substituted phenyl carbonate, phenyl and substituted phenyl sulfonate or phenyl and substituted phenyl phosphate; the substituent on the substituted phenyl is C1-C40 alkyl, C1-C40 alkoxy, halogenOne or more of element, nitryl, ester group or cyano, and the number of the substituent groups is 1-5;
the chiral copper catalyst is prepared from copper salt and P, N, N-ligand, wherein the copper salt is hydrated copper acetate, hydrated copper sulfate, anhydrous copper acetate, anhydrous copper sulfate, copper trifluoromethanesulfonate, copper chloride, cuprous acetate, cuprous chloride, cuprous iodide, cuprous perchlorate, copper trifluoromethanesulfonate, Cu (CH)3CN)4BF4、Cu(CH3CN)4ClO4At least one of;
the structural formula of the chiral P, N, N-ligand is as follows:
Figure FDA0002217865210000021
in the formula: r7，R8Is alkyl in H, C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl or benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R9，R10is H, halogen, alkyl of C1-C40, cycloalkyl of C3-C12, phenyl and substituted phenyl, alkoxy of C1-C40, phenoxy, acyl or nitro; the substituent on the substituted phenyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R11is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl or a five-membered or six-membered heterocyclic aromatic group containing one or more than two of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
2. A process for the preparation of α -fluoro- β -ethynyl ketone compounds containing two chiral centers, as claimed in claim 1, wherein:
the method comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and P, N, N-ligand are stirred in a reaction medium for 0.5 to 2 hours according to the molar ratio of 1:0.1 to 10 to prepare a chiral copper catalyst;
(2) preparing a chiral α -fluoro- β -ethynyl ketone compound, namely dissolving fluorinated enol silyl ether and a propargyl compound in a reaction medium, adding or not adding an alkali additive, then adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, stirring and reacting for 1-36 hours, and after the reaction is finished, carrying out reduced pressure rotary evaporation and column separation to obtain a α -fluoro- β -ethynyl ketone compound containing two chiral centers;
the molar ratio of the chiral copper catalyst to the fluorinated enol silyl ether is 1-10%;
the molar ratio of the alkali additive to the fluorinated enol silyl ether is 2.5: 1;
the molar ratio of the propargyl compound to the fluorinated enol silyl ether is 2.5: 1.
3. A process for preparing α -fluoro- β -ethynylketone compounds containing two chiral centers, according to claim 1 or 2, wherein:
the reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran and ethyl acetate.
4. The process for preparing α -fluoro- β -ethynyl ketone compound having two chiral centers according to claim 1 or 2, wherein the base additive is one or more of various inorganic bases or organic bases.
5. The method for preparing α -fluoro- β -ethynyl ketone compound having two chiral centers as claimed in claim 4, wherein the base additive is N, N-diisopropylethylamine, triethylamine, potassium tert-butoxide, KOH, NaOH, K2CO3、Na2CO3Or NaHCO3One or more than two of them.
6. The process for preparing α -fluoro- β -ethynyl ketone compound having two chiral centers as claimed in claim 2, wherein the reaction conditions of step (2) are-20 ℃, methanol as reaction medium, normal pressure and 12 hours.
7. A process for preparing α -fluoro- β -ethynyl ketone compounds containing two chiral centers according to claim 2, wherein:
the copper salt is hydrated copper acetate, trifluoromethanesulfonic acid ketone, Cu (CH)3CN)4BF4、Cu(CH3CN)4ClO4At least one of;
the reaction medium is at least one of methanol and dichloromethane.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001226312A (en) * 1999-12-09 2001-08-21 Ube Ind Ltd Method for producing 3-phenylpropyl ketone compound
CN104513146A (en) * 2013-10-08 2015-04-15 中国科学院大连化学物理研究所 Method for asymmetrically synthesizing chiral beta-acetenyl ketone from beta-ketonic acid
CN104844401A (en) * 2015-06-02 2015-08-19 重庆医科大学 Method for synthesizing 1, 4-diketone compound without catalyst

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001226312A (en) * 1999-12-09 2001-08-21 Ube Ind Ltd Method for producing 3-phenylpropyl ketone compound
CN104513146A (en) * 2013-10-08 2015-04-15 中国科学院大连化学物理研究所 Method for asymmetrically synthesizing chiral beta-acetenyl ketone from beta-ketonic acid
CN104844401A (en) * 2015-06-02 2015-08-19 重庆医科大学 Method for synthesizing 1, 4-diketone compound without catalyst

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Cu-催化炔丙醇酯的不对称转化反应研究;胡向平;《中国化学会全国第十一届有机合成化学学术研讨会论文集》;20141016;第48页 *
GaCl3-catalyzed α-ethynylation reaction of silyl enol ethers;Ryo Amemiya等;《Journal of Organometallic Chemistry》;20031231;第686卷;第94-100页 *
三氯化铁试剂在炔醇衍生物合成中的应用;刘慧娟;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20080715(第7期);第45-57页 *
烯醇硅醚的制备及其在有机合成中的应用;余孝其;《化学试剂》;19921231;第14卷(第1期);第29-35页 *

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