CN117924002A - Method for synthesizing chiral propargyl alcohol compound based on Mn catalytic system - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 29
- -1 propargyl alcohol compound Chemical class 0.000 title claims abstract description 14
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 38
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 35
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000007800 oxidant agent Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 230000001590 oxidative effect Effects 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical class OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000004440 column chromatography Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 14
- 238000010791 quenching Methods 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 238000004809 thin layer chromatography Methods 0.000 claims description 5
- PONXTPCRRASWKW-UHFFFAOYSA-N 1,2-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1C(N)C(N)C1=CC=CC=C1 PONXTPCRRASWKW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 229910052736 halogen Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical group [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 64
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000011572 manganese Substances 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- BDOLQESNFGCNSC-UHFFFAOYSA-N iodylbenzene Chemical compound O=I(=O)C1=CC=CC=C1 BDOLQESNFGCNSC-UHFFFAOYSA-N 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 238000001308 synthesis method Methods 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229910052748 manganese Inorganic materials 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001743 benzylic group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- UFOVULIWACVAAC-UHFFFAOYSA-N 1-ethynyl-2-methoxybenzene Chemical group COC1=CC=CC=C1C#C UFOVULIWACVAAC-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- JQRLYSGCPHSLJI-UHFFFAOYSA-N [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JQRLYSGCPHSLJI-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- OSVXSBDYLRYLIG-UHFFFAOYSA-N chlorine dioxide Inorganic materials O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Abstract
The invention relates to a method for synthesizing chiral propargyl alcohol compound based on Mn catalytic system, which comprises mixing alkyne with oxidant PhIO in organic solvent, adding Salen-Mn (III) catalyst, reacting at low temperature and normal pressure to obtain the product.
Description
Technical Field
The invention relates to a method for synthesizing chiral propargyl alcohol compound based on Mn catalytic system, belonging to the technical field of chemical synthesis.
Background
Chiral tertiary propargyl alcohol is a very important class of building blocks in bioactive molecules, such as glucocorticoid receptor inhibitors, ethinyl estradiol, and the like. At present, the synthesis reaction of chiral propargyl alcohol compounds is single, and is generally synthesized through the addition reaction of alkynyl reagents and carbonyl, but many metal reagents in the reaction are sensitive to air, and are unfavorable for the operation of the reaction.
The oxidation reaction is a very important basic conversion reaction in organic synthesis, and is one of the simplest and direct modes for synthesizing alcohol compounds. Literature Groves,J.T.;Viski,P.;Asymmetric hydroxylation by a chiral iron porphyrin.J.Am.Chem.Soc.1989,111,8537.Hamachi,K.;Irie,R.;Katsuki,T.Asymmetric benzylic oxidation using a Mn-salen complex as catalyst.Tetrahedron Lett.1996,37,4979. et al report oxidation of sp 3 hydrocarbon bonds to alcohols, but this method has the following drawbacks: 1. cyclic substrates are more studied and open-chain substrates are less studied; 2. the oxidation of the secondary carbon-hydrogen bond is mainly carried out, and the effect of the oxidation of the tertiary carbon-hydrogen bond is not ideal; 3. the study object is limited to the oxidation of the benzylic carbon-hydrogen bond and propargyl sp 3 carbon-hydrogen bond, which is yet to be developed. The report of chiral propargyl alcohol obtained based on oxidation reaction is very limited, and non-enzyme catalyzed tertiary propargyl asymmetric oxidation is not reported.
Manganese is abundant in the crust and its valence state is abundant, and is widely used as a reagent or catalyst in oxidation reactions. Wherein, (Salen) Mn can be matched with different oxidants to generate high-activity oxidation species, and is widely applied to oxidation reaction of hydrocarbon bonds.
Therefore, the design of a method for obtaining chiral propargyl alcohol by non-enzymatically catalyzed three-stage propargyl asymmetric oxidation is of great significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing chiral propargyl alcohol compounds based on an Mn catalytic system.
The method has simple conditions, mild reaction conditions and simple reaction equipment.
The invention is realized by the following technical scheme:
a method for synthesizing chiral propargyl alcohol compound based on Mn catalytic system, comprising the following steps:
Mixing alkyne and a catalyst (Salen) Mn in an organic solvent, adding an oxidant, and reacting at low temperature and normal pressure to obtain chiral propargyl alcohol compounds;
The alkyne structure is shown in formula I:
R is selected from alkyl, alkoxy, aryl or halogen.
The structure of the propargyl alcohol compound obtained by the invention is shown as a formula II:
R is selected from alkyl, alkoxy, aryl or halogen.
According to a preferred embodiment of the invention, the organic solvent is toluene, ethyl acetate, methylene chloride, nitromethane or tetrahydrofuran.
Most preferably, the organic solvent is nitromethane.
According to a preferred embodiment of the present invention, the oxidizing agent is iodosobenzene (PhIO).
According to the invention, the molar ratio of alkyne to oxidant is preferably 1 (0.5-3).
Further preferred, the molar ratio of alkyne to oxidant is 1:0.6.
According to a preferred embodiment of the invention, the catalyst (Salen) Mn is C6, and has the structure shown in the following formula III:
According to the invention, C6 is preferably prepared as follows:
0.5mmol of S1 (1.0 eq) is dissolved in 10mL of EtOH, 0.25g of 1, 2-diphenylethylenediamine (0.5 eq) is added, the reaction mixture is placed in an oil bath at 80 ℃ under the protection of nitrogen and stirred for reaction for 6h, the reaction is cooled until a large amount of solids are separated out, and the product S2 is obtained by suction filtration;
0.25mmol of Mn (OAc) 2 (1.0 eq) was added to a mixed solution of 0.25 mmole of S2 (1.0 eq) and 10mL of ethanol, refluxed for 4 hours, cooled to room temperature, suction-filtered to obtain a yellow solid, the obtained yellow solid was redissolved in 10mL of ethanol without water, 0.25mmol of Mn (OAc) 2·4H2 O (1.0 eq) was added, the reaction was left to react at 60℃for 6 hours, 2.0mmol of NaPF 6 (8.0 eq) was added, the reaction was continued for 20 hours, and after the completion of the reaction, the solvent was dried by spin-drying, and catalyst C6 was obtained by thin layer chromatography.
According to the invention, the molar ratio of alkyne to catalyst (Salen) Mn is preferably 1 (0.01 to 2).
Most preferably, the molar ratio of alkyne to catalyst (Salen) Mn is 1:0.05.
According to the invention, the mass volume ratio of alkyne to organic solvent is (20-40): (0.5-5), unit mg/mL.
According to the invention, the reaction time is preferably 2 to 3 hours, and the reaction is carried out at low temperature and normal pressure.
According to the invention, preferably, after the reaction is finished, water quenching reaction is added, an organic phase is separated, an aqueous phase is extracted by ethyl acetate, the organic phases are combined, and the product is obtained through column chromatography separation.
The reaction mechanism of the invention:
Firstly, a catalyst salen-Mn (III) is rapidly oxidized in the presence of an oxidant iodinylidene benzene (PhIO) to generate a pentavalent manganese intermediate, then a substrate participates in a hydrogen atom capturing process mediated by pentavalent manganese species, and the free radical intermediate generated in the process is subjected to free radical hydroxyl transfer with tetravalent manganese species, so that the propargyl alcohol compound is synthesized by asymmetrically oxidizing propargyl sp3 hydrocarbon bond under an Mn catalytic system to generate a product and releasing the catalyst for catalytic circulation.
The invention has the technical characteristics and advantages that:
1. the invention adopts (Salen) Mn as a catalyst, and the propargyl sp3 hydrocarbon bond of alkyne is asymmetrically oxidized under normal pressure and low temperature in the presence of an oxidant to generate chiral propargyl alcohol compound, thus providing a new way for preparing the chiral propargyl alcohol compound.
2. The invention has simple operation, can obtain propargyl alcohol compound with ee value more than or equal to 90% in one step, has no high-temperature high-pressure reaction, mild reaction condition, simple reaction condition and step, low cost, wider substrate selection range and less three wastes, and is suitable for large-scale industrialized production.
Detailed Description
The following is a further illustration of the present invention by way of specific examples, but not by way of limitation.
In the examples, oxidant PhIO, available from Shanghai Bai Ka chemical technology Co., ltd.
Example 1: the structural formula of alkyne raw materials is:
example 2: the structural formula of alkyne raw materials is:
example 3: the structural formula of alkyne raw materials is:
example 4: the structural formula of alkyne raw materials is:
example 5: the structural formula of alkyne raw materials is:
example 6: the structural formula of alkyne raw materials is:
Example 7: the structural formula of alkyne raw materials is:
example 8: the structural formula of alkyne raw materials is:
example 9: the structural formula of alkyne raw materials is:
Example 10: the structural formula of alkyne raw materials is:
Example 1-example 10 a specific preparation of alkyne feedstock is as follows:
a) 3-methoxyphenol (3.0 mol,1.0 equiv) and AlCl 3 (6.0 mmol,2.0 equiv) were added sequentially to CH 2Cl2 at 0deg.C, and after 5min of reaction, acid chloride R 1 -COCl (3.3 mmol,1.1 equiv) was added. After completion of the reaction, H 2 O was added, extracted with DCM, the organic phase separated and concentrated;
b) The product from step a) was dissolved in DMF (5 mL) and then ethyl bromide (4.5 mmol,1.5 equiv) and potassium carbonate (6.0 mmol,2.0 equiv) were added to the solution and the mixture was heated at 70℃for 2h. After the reaction is completed, water (20 mL) is added, the organic phase is separated and concentrated, and the obtained mixture is subjected to thin-layer chromatography to obtain S7;
c) 2-Methoxyphenylacetylene (6.0 mmol,2.0 equiv) was dissolved in THF under N 2, and N-BuLi (6.0mmol,2.4mL,2.5M in hexane,2.0equiv) was slowly added dropwise to the reaction solution after the reaction solution cooled to-78deg.C, and after 1 hour of reaction, the substituted acetophenone (3.0 mmol,1.0 equiv) was added to the mixture and slowly warmed to room temperature. After the reaction was completed, a saturated NH 4 Cl solution was added, and the organic phase was separated and concentrated.
D) The resulting mixture was redissolved in CH 2Cl2 (15 mL) and after cooling to-20deg.C Et 3 SiH (6 mmol,2.0 equiv) and BF 3·Et2 O (1.5 mmol,0.5 equiv) were added sequentially and after completion of the reaction saturated NaHCO 3 solution was added the organic phase was separated and concentrated and the resulting mixture was chromatographed by thin layer chromatography to give S8.
The catalysts C1 to C5 used in the comparative examples were prepared as follows:
0.5mmol of ligand aldehyde S3 (1.0 eq) is dissolved in 10mL of EtOH, 0.25g of 1, 2-diphenyl ethylenediamine (0.5 eq) is added, the reaction mixture is placed in an oil bath at 80 ℃ under the protection of nitrogen gas for stirring reaction for 6 hours, the reaction is cooled until a large amount of solids are separated out, and the product S4 is obtained by suction filtration;
0.25mmol of Mn (OAc) 2 (1.0 eq) was added to a mixed solution of 0.25mmol of S4 (1.0 eq) and 10mL of ethanol, refluxed for 4 hours, cooled to room temperature, suction-filtered to obtain a yellow solid, the obtained yellow solid was redissolved in 10mL of ethanol without water, 0.25mmol of Mn (OAc) 2·4H2 O (1.0 eq) was added, the reaction was left to react at 60℃for 6 hours, 2.0mmol of NaPF 6 (8.0 eq) was added, the reaction was continued for 20 hours, and after the completion of the reaction, the solvent was dried by spin-drying, and catalysts C1-C5 were obtained by thin layer chromatography.
The structural formula of the catalyst of C1 is as follows: The structural formula of the catalyst of C2 is as follows: The structural formula of the catalyst of C3 is:/> The structural formula of the catalyst of C4 is:/>The structural formula of the catalyst of C5 is as follows:
example 1: synthesis of 2- (2-Ethoxy-4-methoxyphenyl) -4-phenylbut-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 27.9mg of alkyne and 13.2mg of iodoxybenzene (PhIO) to 1mL of nitromethane, stirring at-25 ℃ for 2 hours, adding 15mL of water to quench the reaction after the reaction is finished, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, and separating by column chromatography to obtain 13.9mg of chiral propargyl alcohol pure product, wherein the yield is 47% and the ee value is 94.68%.
The chiral propargyl alcohol prepared in example 1 was pure ：1H NMR(500MHz,Acetone)δ7.57(d,J＝8.6Hz,1H),7.39(ddd,J＝7.0,3.8,2.4Hz,2H),7.36–7.28(m,3H),6.60(d,J＝2.4Hz,1H),6.51(dd,J＝8.6,2.5Hz,1H),4.87(s,1H),4.22-4.12(m,2H),3.79(s,3H),1.87(s,3H),1.45(t,J＝7.0Hz,3H).13CNMR(126MHz,Acetone)δ161.3,158.0,132.1,129.3,128.8,127.2,124.6,105.0,100.9,95.5,81.9,68.2,64.8,55.6,30.7,15.2.HPLC:the ee value was determined by HPLC analysis(ChiralcelOD,i-PrOH/Hexane＝20/80,1.0mL/min,243nm),retention time:tminor＝7.480min,tmajor＝9.243min,ee＝94.68％;[α]D 25＝-37.8(c＝0.23,acetone).HRMS(EI)m/z[M-OH]+calculated for C19H19O2:279.1380,found 279.1383.
Example 2: synthesis of 2- (2-Ethoxy-4-methoxyphenyl) -4- (2-methoxyphenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 31mg of alkyne and 13.2mg of iodoxybenzene (PhIO) and 1mL of nitromethane, stirring at-25 ℃ for 2 hours, adding 15mL of water after the reaction is finished, quenching the reaction, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, and separating by column chromatography to obtain 15.6mg of chiral propargyl alcohol pure product, wherein the yield is 48%, and the ee value is 96.14%.
The chiral propargyl alcohol prepared in example 2 ：1H NMR(500MHz,Acetone)δ7.63(d,J＝8.6Hz,1H),7.34(dd,J＝7.6,1.7Hz,1H),7.29(ddd,J＝8.4,7.5,1.7Hz,1H),6.99(d,J＝8.1Hz,1H),6.90(td,J＝7.5,1.0Hz,1H),6.60(d,J＝2.4Hz,1H),6.51(dd,J＝8.6,2.5Hz,1H),4.76(s,1H),4.22–4.11(m,2H),3.83(s,3H),3.79(s,3H),1.88(s,3H),1.45(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.3,161.0,158.2,134.1,130.3,127.6,127.2,121.1,113.7,111.9,105.0,101.0,99.0,79.0,68.9,64.9,56.0,55.6,30.8,15.1.HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝30/70,1.0mL/min,291nm),retention time:tminor＝9.123min,tmajor＝12.823min,ee＝96.14％;[α]D 25＝-19.9(c＝0.40,acetone).HRMS(EI)m/z[M-OH]+calculated for C20H21O3:309.1485,found309.1490.
Example 3: synthesis of 2- (2-Ethoxy-4-methoxyphenyl) -4- (3-methoxyphenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 31mg of alkyne and 13.2mg of iodoxybenzene (PhIO) and 1mL of nitromethane, stirring at-25 ℃ for 3 hours, adding 15mL of water after the reaction is finished, quenching the reaction, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, and separating by column chromatography to obtain 16.0mg of chiral propargyl alcohol pure product, wherein the yield is 49%, and the ee value is 90.42%.
The chiral propargyl alcohol prepared in example 3 was pure ：1H NMR(500MHz,Acetone)δ7.56(d,J＝8.6Hz,1H),7.24(t,J＝7.9Hz,1H),6.99–6.95(m,1H),6.94–6.88(m,2H),6.59(d,J＝2.4Hz,1H),6.51(dd,J＝8.6,2.4Hz,1H),4.90(s,1H),4.24–4.09(m,2H),3.79(s,3H),3.78(s,3H),1.86(s,3H),1.45(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.3,158.0,141.3,140.9,132.7,129.8,128.5,127.7,127.6,127.2,127.2,123.6,105.0,101.0,96.3,81.8,68.3,64.8,55.6,30.7,15.2.HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝20/80,1.0mL/min,252nm),retention time:tminor＝8.060min,tmajor＝10.080min,ee＝90.42％;[α]D 25＝-24.8(c＝0.43,acetone).HRMS(EI)m/z[M-OH]+calculated for C20H21O3:309.1485,found309.1484.
Example 4:2- (2-Ethoxy-4-methoxyphenyl) -4- (4-methoxyphenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 31mg of alkyne and 13.2mg of iodoxybenzene (PhIO) and 1mL of nitromethane, stirring at-25 ℃ for 3 hours, adding 15mL of water after the reaction is finished, quenching the reaction, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, and separating by column chromatography to obtain 15.3mg of chiral propargyl alcohol pure product, wherein the yield is 47%, and the ee value is 94.64%.
The chiral propargyl alcohol prepared in example 4 was pure ：1H NMR(500MHz,Acetone)δ7.56(d,J＝8.6Hz,1H),7.32(t,J＝5.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.59(d,J＝2.3Hz,1H),6.51(dd,J＝8.6,2.4Hz,1H),4.80(s,1H),4.21–4.12(m,2H),3.79(s,3H),3.79(s,3H),1.86(s,3H),1.45(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.2,160.4,158.0,133.5,127.4,127.2,116.5,114.8,104.9,101.0,93.8,81.9,68.4,64.8,55.6(d,J＝1.1Hz),30.8,15.2.HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝20/80,1.0mL/min,258nm),retention time:tminor＝8.317min,tmajor＝11.507min,ee＝94.64％;[α]D 25＝-9.3(c＝0.45,acetone).HRMS(EI)m/z[M-OH]+calculated for C20H21O3:309.1485,found309.1491.
Example 5:2- (2-Ethoxy-4-methoxyphenyl) -4- (p-tolyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 29.4mg of alkyne and 13.2mg of iodoxybenzene (PhIO), 1mL of nitromethane, stirring at-25 ℃ for 2.5 hours, adding 15mL of water after the reaction is finished, quenching the reaction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, and separating by column chromatography to obtain 14.2mg of chiral propargyl alcohol pure product, wherein the yield is 46%, and the ee value is 93.08%.
The chiral propargyl alcohol prepared in example 5 was pure ：1H NMR(500MHz,Acetone)δ7.58(d,J＝8.6Hz,1H),7.29(d,J＝8.1Hz,2H),7.17(d,J＝8.2Hz,2H),6.61(d,J＝2.4Hz,1H),6.52(dd,J＝8.6,2.4Hz,1H),4.82(s,1H),4.24–4.13(m,2H),3.81(s,3H),2.33(s,3H),1.88(s,3H),1.46(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.3,158.0,138.8,132.0,129.9,127.3,127.2,121.6,105.0,101.0,94.8,82.0,68.3,64.8,55.6,30.7,21.3,15.2.HPLC:the ee value was determined by HPLC analysis(ChiralcelOD,i-PrOH/Hexane＝20/80,1.0mL/min,238nm),retention time:tminor＝7.013min,tmajor＝8.667min,ee＝93.08％;[α]D 25＝-22.7(c＝0.47,acetone).HRMS(EI)m/z[M-OH]+calculated for C20H21O2:293.1536,found 293.1533.
Example 6:2- (2-Ethoxy-4-methoxyphenyl) -4- (4-fluorophenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 29.8mg of alkyne, 13.2mg of iodoxybenzene (PhIO), 1mL of nitromethane, stirring at-25 ℃ for 2.5 hours, adding 15mL of water after the reaction is finished to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, and separating by column chromatography to obtain 14.4mg of chiral propargyl alcohol pure product, wherein the yield is 46%, and the ee value is 92.06%.
The chiral propargyl alcohol prepared in example 6 ：1H NMR(500MHz,Acetone)δ7.55(d,J＝8.6Hz,1H),7.46–7.41(m,2H),7.14–7.09(m,2H),6.59(d,J＝2.4Hz,1H),6.51(dd,J＝8.6,2.5Hz,1H),4.86(s,1H),4.26–4.05(m,2H),3.79(s,3H),1.86(s,3H),1.44(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ164.1,162.1,161.4,158.0,134.2(d,J＝8.4Hz),127.2,127.1,120.9(d,J＝3.5Hz),116.4(d,J＝22.2Hz),105.0,100.9(d,J＝3.3Hz),95.3,80.8,68.2,64.8,55.6,30.6,15.2.19FNMR(471MHz,Acetone)δ-113.36(s).HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝15/85,1.0mL/min,255nm),retention time:tminor＝8.257min,tmajor＝7.743min,ee＝92.06％;[α]D 25＝-17.6(c＝0.37,acetone).HRMS(EI)m/z[M-OH]+calculated for C19H18FO2:297.1285,found 297.1287.
Example 7:4- (4-Chlorophenyl) -2- (2-ethoxy-4-methoxyphenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 31.4mg of alkyne, 13.2mg of iodoxybenzene (PhIO), 1mL of nitromethane, stirring at-25 ℃ for 2.5 hours, adding 15mL of water after the reaction is finished to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, and separating by column chromatography to obtain 15.5mg of chiral propargyl alcohol pure product, wherein the yield is 47%, and the ee value is 90.6%.
The chiral propargyl alcohol prepared in example 7 ：1H NMR(500MHz,Acetone)δ7.55(d,J＝8.6Hz,1H),7.43–7.27(m,5H),6.59(d,J＝2.4Hz,1H),6.51(dd,J＝8.6,2.4Hz,1H),4.90(s,1H),4.24–4.07(m,2H),3.79(s,3H),1.86(s,3H),1.44(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.4,158.0,134.2,133.7,129.5,127.1,126.9,123.4,105.0,100.9,96.8,80.7,68.2,64.8,55.6,30.6,15.2.HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝20/80,1.0mL/min,257nm),retention time:tminor＝6.403min,tmajor＝7.810min,ee＝89.6％;[α]D 25＝-18.1(c＝0.40,acetone).HRMS(EI)m/z[M-OH]+calculated for C19H18ClO2:313.0990,found313.0987.
Example 8:4- (3- (2-Ethoxy-4-methoxyphenyl) -3-hydroxybut-1-yn-1-yl) benzonitrile
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 30.5mg of alkyne, 13.2mg of iodoxybenzene (PhIO), 1mL of nitromethane, stirring at-25 ℃ for 2.5 hours, adding 15mL of water after the reaction is finished to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, and separating by column chromatography to obtain 14.4mg of chiral propargyl alcohol pure product, wherein the yield is 45%, and the ee value is 91.20%.
The chiral propargyl alcohol prepared in example 8 was pure ：1H NMR(500MHz,Acetone)δ7.78–7.71(m,2H),7.57(dt,J＝11.4,5.4Hz,3H),6.59(d,J＝2.4Hz,1H),6.52(dd,J＝8.6,2.5Hz,1H),5.04(s,1H),4.22–4.10(m,2H),3.79(s,3H),1.87(s,3H),1.44(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.5,157.9,133.1,132.9,129.4,127.1,126.6,119.0,112.1,105.1,100.8,100.2,80.5,68.1,64.8,55.6,30.4,15.2.HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝30/70,1.0mL/min,271nm),retention time:tminor＝10.4531min,tmajor＝13.153min,ee＝91.20％;[α]D 25＝-15.8(c＝0.33,acetone).HRMS(EI)m/z[M-OH]+calculated for C20H18NO2:304.1332,found 304.1337.
Example 9:2- (2-Ethoxy-4-methoxyphenyl) -4- (4- (trifluoromethyl) phenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 34.8mg of alkyne, 13.2mg of iodoxybenzene (PhIO), 1mL of nitromethane, stirring at-25 ℃ for 2.5 hours, adding 15mL of water after the reaction is finished to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, and separating by column chromatography to obtain 16.7mg of chiral propargyl alcohol pure product, wherein the yield is 46%, and the ee value is 90.72%.
The chiral propargyl alcohol prepared in example 9 was pure ：1H NMR(500MHz,Acetone)δ7.69(d,J＝8.1Hz,2H),7.60(d,J＝8.0Hz,2H),7.56(d,J＝8.6Hz,1H),6.60(d,J＝2.4Hz,1H),6.52(dd,J＝8.6,2.5Hz,1H),4.99(s,1H),4.23–4.11(m,2H),3.80(s,3H),1.88(s,3H),1.45(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.5,158.0,129.9(q,J＝32.4Hz),128.8(d,J＝1.2Hz),127.1,126.7,126.2(q,J＝3.8Hz),124.1,105.0,100.9,100.9,98.5,80.5,68.1,64.8,55.6,30.5,15.2.19F NMR(471MHz,Acetone)δ-63.26(s).HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝30/70,1.0mL/min,242nm),retention time:tminor＝5.090min,tmajor＝5.877min,ee＝89.72％;[α]D 25＝-5.3(c＝0.67,acetone).HRMS(EI)m/z[M-OH]+calculated for C20H18F3O2:347.1253,found 347.1255.
Example 10:4- ([ 1,1' -Biphenyl ] -4-yl) -2- (2-ethoxy-4-methoxyphenyl) but-3-yn-2-ol
Taking a Schlenk reaction tube, adding 6.3mg of catalyst C6, 35.6mg of alkyne and 13.2mg of iodoxybenzene (PhIO), stirring for 2.5 hours at the temperature of minus 25 ℃ with 1mL of nitromethane, adding 15mL of water after the reaction is finished to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, and separating by column chromatography to obtain 16.7mg of chiral propargyl alcohol pure product with the yield of 45% and the ee value of 93.34%.
The chiral propargyl alcohol prepared in example 10 was pure ：1H NMR(500MHz,Acetone)δ7.68–7.63(m,4H),7.58(d,J＝8.6Hz,1H),7.47(dd,J＝15.8,8.1Hz,4H),7.36(t,J＝7.4Hz,1H),6.61(d,J＝2.4Hz,1H),6.52(dd,J＝8.6,2.4Hz,1H),4.93(s,1H),4.24–4.12(m,2H),3.79(s,3H),1.89(s,3H),1.47(t,J＝7.0Hz,3H).13C NMR(126MHz,Acetone)δ161.3,160.5,158.0,130.3,127.1,127.1,125.6,124.5,117.0,115.1,105.0,100.9,95.3,81.9,68.2,64.8,55.6,55.6,30.6,15.2.HPLC:the ee value was determined by HPLC analysis(Chiralcel OD,i-PrOH/Hexane＝35/65,1.0mL/min,267nm),retention time:tminor＝8.410min,tmajor＝11.770min,ee＝93.34％;[α]D 25＝-19.9(c＝0.40,acetone).HRMS(EI)m/z[M-OH]+calculated for C25H23O2:355.1693,found 355.1695.
Comparative example 1
The synthesis method described in example 1 is different in that:
Stirring at 0deg.C for 2-3 hr. The other procedure was as in example 1,
The pure propargyl alcohol product obtained by column chromatography is 14.4mg, the yield is 49%, and the ee value is 85%.
Comparative example 2
The synthesis method described in example 1 is different in that:
Stirring was carried out at 25℃for 2-3 hours, otherwise as in example 1,
The pure propargyl alcohol mg is obtained by column chromatography, the yield is 46%, and the ee value is 83%.
As compared with the examples of the present invention, it can be seen that the reaction temperature of 0℃or too high results in a decrease in the ee value of the product in comparative example 1 and comparative example 2.
Comparative example 3
The synthesis method described in example 1 is different in that:
toluene was used instead of nitromethane, and the procedure of example 1 was followed.
The pure propargyl alcohol product obtained by column chromatography is 15.3mg, the yield is 52%, and the ee value is 36%.
Comparative example 4
The synthesis method described in example 1 is different in that:
the procedure of example 1 was repeated except that methylene chloride was used instead of nitromethane.
The pure propargyl alcohol product obtained by column chromatography is 14.4mg, the yield is 49%, and the ee value is 79%.
Comparative examples 3 and 4 show that the kind of the organic solvent affects the ee value of the product, and the organic solvent of the present invention gives a high ee value of the product, compared with the examples of the present invention.
Comparative example 5
The synthesis method described in example 1 is different in that:
Catalyst C1 was used instead of C6, and the procedure of example 1 was followed.
The pure propargyl alcohol product obtained by column chromatography is 14.2mg, the yield is 48%, and the ee value is 57%.
Comparative example 6
The synthesis method described in example 1 is different in that:
catalyst C2 was used instead of C6, and the procedure of example 1 was followed.
The pure propargyl alcohol product obtained by column chromatography is 14.8mg, the yield is 50%, and the ee value is 68%.
Comparative example 7
The synthesis method described in example 1 is different in that:
catalyst C3 was used instead of C6, and the procedure of example 1 was followed.
The pure propargyl alcohol product obtained by column chromatography is 12.7mg, the yield is 43%, and the ee value is 70%.
Comparative example 8
The synthesis method described in example 1 is different in that:
Catalyst C4 was used instead of C6, and the procedure of example 1 was followed.
The pure propargyl alcohol product obtained by column chromatography is 12.4mg, the yield is 42%, and the ee value is 75%.
Comparative example 9
The synthesis method described in example 1 is different in that:
Catalyst C5 was used instead of C6, and the procedure of example 1 was followed.
The pure propargyl alcohol 13.6mg is obtained by column chromatography, the yield is 46%, and the ee value is 67%.
As can be seen from comparative examples 5 to 9, the ee value of the product is affected by the kind of catalyst, and C1 to C5 results in a decrease in the ee value of the product.
Claims (10)
1. A method for synthesizing chiral propargyl alcohol compound based on Mn catalytic system, comprising the following steps:
Mixing alkyne and a catalyst (Salen) Mn in an organic solvent, adding an oxidant, and reacting at low temperature and normal pressure to obtain chiral propargyl alcohol compounds;
The alkyne structure is shown in formula I:
R is selected from alkyl, alkoxy, aryl or halogen.
2. A process according to claim 1, characterized in that the organic solvent is toluene, ethyl acetate, methylene chloride, nitromethane or tetrahydrofuran, most preferably the organic solvent is nitromethane.
3. The method of claim 1, wherein the oxidizing agent is iodosobenzene (PhIO).
4. The method of claim 1, wherein the molar ratio of alkyne to oxidant is 1 (0.5-3).
5. The method according to claim 1, wherein the catalyst (Salen) Mn is C6, having the structure shown in formula III:
6. the method of claim 5, wherein C6 is prepared as follows:
0.5mmol of S1 (1.0 eq) is dissolved in 10mL of EtOH, 0.25g of 1, 2-diphenylethylenediamine (0.5 eq) is added, the reaction mixture is placed in an oil bath at 80 ℃ under the protection of nitrogen and stirred for reaction for 6h, the reaction is cooled until a large amount of solids are separated out, and the product S2 is obtained by suction filtration;
0.25mmol of Mn (OAc) 2 (1.0 eq) was added to a mixed solution of 0.25 mmole of S2 (1.0 eq) and 10mL of ethanol, refluxed for 4 hours, cooled to room temperature, suction-filtered to obtain a yellow solid, the obtained yellow solid was redissolved in 10mL of ethanol without water, 0.25mmol of Mn (OAc) 2·4H2 O (1.0 eq) was added, the reaction was left to react at 60℃for 6 hours, 2.0mmol of NaPF 6 (8.0 eq) was added, the reaction was continued for 20 hours, and after the completion of the reaction, the solvent was dried by spin-drying, and catalyst C6 was obtained by thin layer chromatography.
7. The process according to claim 1, wherein the molar ratio of alkyne to catalyst (Salen) Mn is 1 (0.01-2).
8. The method according to claim 1, wherein the mass-to-volume ratio of alkyne to organic solvent is (20-40): (0.5-5), unit mg/mL.
9. The process according to claim 1, wherein the reaction time is 2 to 3 hours and the reaction is carried out at low temperature and normal pressure.
10. The method of claim 1, wherein after the reaction is completed, adding water to quench the reaction, separating out an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phases, and separating by column chromatography to obtain the product.
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