CN114835694B - Method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in aqueous medium - Google Patents
Method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in aqueous medium Download PDFInfo
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- CN114835694B CN114835694B CN202210573524.4A CN202210573524A CN114835694B CN 114835694 B CN114835694 B CN 114835694B CN 202210573524 A CN202210573524 A CN 202210573524A CN 114835694 B CN114835694 B CN 114835694B
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- 238000000034 method Methods 0.000 title claims abstract description 25
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical class C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000012736 aqueous medium Substances 0.000 title claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- MZNSQRLUUXWLSB-UHFFFAOYSA-N 2-ethenyl-1h-pyrrole Chemical compound C=CC1=CC=CN1 MZNSQRLUUXWLSB-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 unsaturated ketone ester compound Chemical class 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 150000004699 copper complex Chemical class 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 7
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical class C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 239000011541 reaction mixture Substances 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 14
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical group [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims 1
- 238000007115 1,4-cycloaddition reaction Methods 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000000047 product Substances 0.000 description 48
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 32
- 238000001228 spectrum Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000006053 organic reaction Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000011968 lewis acid catalyst Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002109 single walled nanotube Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing chiral 3, 4-dihydro-2H-pyrane compounds in an aqueous medium, which comprises the following steps: in the presence of a chiral copper complex catalyst shown in a formula C1 and/or C2, mixing a beta, gamma unsaturated ketone ester compound shown in a formula I and 2-vinyl pyrrole shown in a formula II, and reacting with water as a solvent to obtain a 3, 4-dihydro-2H-pyran compound shown in a formula III. The invention discovers for the first time that the chiral copper complex catalyst can efficiently catalyze the direct asymmetric [4+2] cycloaddition reaction of 2-vinyl pyrrole and beta, gamma unsaturated ketone ester compounds in water, and the reaction can obtain chiral 3, 4-dihydro-2H-pyran compounds with high enantioselectivity and high diastereoselectivity. Moreover, when such aqueous asymmetric [4+2] cycloaddition reactions are scaled up to gram scale, the stereoselectivity and yield of the product can be maintained.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in an aqueous medium.
Background
In the past, most organic reactions were carried out in organic solvents. However, many organic solvents are toxic. In recent years, chemists have begun to study organic reactions in aqueous media. Water has attracted considerable attention from chemists as a safe, inexpensive, readily available solvent. In organic synthesis, water has many advantages as a reaction medium. For example, it may eliminate many redundant steps such as protection and deprotection of mobile functionalities. In addition, the addition of water can also accelerate the reaction speed, improve the chemical selectivity and the stereoselectivity, and reduce the generation of some byproducts in the reaction process.
In recent years, lewis acid catalyzed asymmetric organic reactions have been rapidly developed and have found wide application in the synthesis of natural products and in the pharmaceutical industry. However, many lewis acid catalysts are very sensitive to moisture and readily decompose when exposed to water. With the development of aqueous organic reactions, some lewis acid catalysts have been found to be stable in water and promote asymmetric reactions in the aqueous phase. In 2018, kobayashi's team developed a new catalytic system combining chiral lewis acid and single-walled carbon nanotubes and successfully achieved asymmetric 1, 4-addition of aldoxime to electron-deficient olefin in water.
Chiral 3, 4-dihydro-2H pyranes are widely found in natural products, food flavors and fragrances. In recent years, many subject groups have synthesized such six-membered ring structures by [4+2] cycloaddition reactions. However, they are mostly carried out in organic solvents. The synthesis of such compound structures in the aqueous phase still requires further investigation.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in an aqueous medium.
The invention provides a method for synthesizing chiral 3, 4-dihydro-2H-pyrane compounds in an aqueous medium, which comprises the following steps:
Mixing a beta, gamma unsaturated ketone ester compound shown in a formula I and 2-vinyl pyrrole shown in a formula II in the presence of a chiral copper complex catalyst shown in a formula C1 and/or C2, and reacting with water as a solvent to obtain a3, 4-dihydro-2H-pyran compound shown in a formula III;
wherein Ar is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl;
r is selected from alkyl, substituted alkyl, aryl or substituted aryl.
In the present invention, ph represents phenyl.
Preferably, ar is selected from substituted or unsubstituted phenyl, naphthyl, thienyl or furyl.
The above m=0 indicates that Ar is directly connected to the parent nucleus.
The substituents of the above groups are preferably one or more of alkyl, halogen, haloalkyl, alkenyl, alkoxy and nitro.
Preferably, the number of carbon atoms of the alkyl group, the haloalkyl group, the alkenyl group, and the alkoxy group is 1 to 6, more preferably 1 to 3.
Preferably, the substituents are selected from one or more of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, methoxy, ethoxy, nitro and trifluoromethyl.
The R is preferably alkyl, substituted alkyl, aryl or substituted aryl.
Preferably, the number of carbon atoms of the alkyl group or the alkyl group in the substituted alkyl group is 1 to 6, more preferably 1 to 3.
Preferably, the substituent of the substituted alkyl is selected from one or more of halogen and phenyl.
Preferably, the substituent of the substituted aryl is selected from one or more of halogen and alkyl.
Preferably, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl.
Preferably, the R is selected from alkyl, phenyl substituted with alkyl, or alkyl substituted with phenyl. The number of carbon atoms of the alkyl group is preferably 1 to 6, more preferably 1 to 3. The alkyl group also refers to an alkyl group in a phenyl group substituted with an alkyl group, or an alkyl group in an alkyl group substituted with a phenyl group.
The method for preparing the chiral copper complex catalyst is not particularly limited, and may be general methods well known to those skilled in the art, and preferably prepared according to the following method:
mixing cupric salt, alkali and ligand shown in formula L1 or L2 in water for reaction to obtain a reaction mixture containing chiral copper complex catalyst shown in formula C1 or C2;
the cupric salt is preferably copper triflate.
The base is preferably any one or more of triethylamine, N-ethylmorpholine, N-diisopropylethylamine, cesium carbonate, triethylenediamine and potassium tert-butoxide.
Then in the presence of the prepared chiral copper complex catalyst, mixing and reacting the beta, gamma unsaturated ketone ester compound shown in the formula I and the 2-vinyl pyrrole shown in the formula II in water to obtain the chiral 3, 4-dihydro-2H-pyran compound.
Wherein the chiral copper complex may be a reaction product obtained by mixing and reacting copper triflate, a ligand of formula L1 or L2 and a base in water.
Specifically, the method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in an aqueous medium provided by the invention comprises the following steps:
A) Mixing a cupric salt, a base and a ligand shown in formula L1 or L2 in water to obtain a reaction mixture containing a chiral copper complex catalyst shown in formula C1 or C2;
B) And (3) mixing the beta, gamma unsaturated ketone ester compound shown in the formula I and the 2-vinyl pyrrole shown in the formula II with the reaction mixture obtained in the step A) for reaction to obtain the 3, 4-dihydro-2H-pyran compound shown in the formula III.
Further preferably, the method specifically comprises the following steps:
s1): mixing and stirring copper triflate, alkali (preferably potassium tert-butoxide) and a ligand in water for 2 hours to obtain a reaction mixture, wherein the mixture is the chiral copper complex;
s2): adding beta, gamma unsaturated ketoester compounds shown in the formula I into the reaction mixture, and stirring for 20 minutes; subsequently, 2-vinylpyrrole of formula II is added thereto.
Preferably, the dosage of the catalyst is 1-10% of the total molar weight of the beta, gamma unsaturated ketone ester compound and the 2-vinyl pyrrole.
Preferably, the molar ratio of the beta, gamma unsaturated ketone ester compound to the 2-vinyl pyrrole is 1: (1-5).
Preferably, the initial concentration of the beta, gamma unsaturated ketoester compound is 0.1-0.3 mol/L, more preferably 0.1mol/L.
Preferably, the temperature of the reaction is 0 to 25 ℃.
Preferably, the reaction time is 24 to 48 hours.
Preferably, after the reaction is finished, separation and purification are carried out;
The separation and purification method preferably includes one or more of column chromatography, recrystallization, and distillation.
Specifically, after the reaction is finished, the mixed solution is extracted by ethyl acetate, then is back extracted by saturated saline solution, the organic phase is dried by anhydrous sodium sulfate, and the organic phase is concentrated, and the residue is separated by column chromatography to obtain the 3, 4-dihydro-2H-pyran compound.
The application adopts water as solvent for the first time, chiral copper complex shown in the formula C1 or C2 is used as catalyst, and the product with high enantioselectivity and high diastereoselectivity is obtained through the asymmetric [4+2] cycloaddition reaction of 2-vinyl pyrrole and beta, gamma unsaturated ketoester compound.
Compared with the prior art, the invention provides a method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in an aqueous medium, which comprises the following steps: in the presence of a chiral copper complex catalyst shown in a formula C1 and/or C2, mixing a beta, gamma unsaturated ketone ester compound shown in a formula I and 2-vinyl pyrrole shown in a formula II, and reacting with water as a solvent to obtain a 3, 4-dihydro-2H-pyran compound shown in a formula III. The invention discovers for the first time that the chiral copper complex catalyst can efficiently catalyze the direct asymmetric [4+2] cycloaddition reaction of 2-vinyl pyrrole and beta, gamma unsaturated ketone ester compounds in water, and the reaction can obtain chiral 3, 4-dihydro-2H-pyran compounds with high enantioselectivity and high diastereoselectivity. Moreover, when such aqueous asymmetric [4+2] cycloaddition reactions are scaled up to gram scale, the stereoselectivity and yield of the product can be maintained.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the target product (2R, 4R) -3a in example 1 of the present invention;
FIG. 2 is a chart showing nuclear magnetic resonance of the target product (2R, 4R) -3a in example 1 of the present invention;
FIG. 3 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3b in example 2 of the present invention;
FIG. 4 is a chart showing the nuclear magnetic resonance spectrum of the target product (2R, 4R) -3b in example 2 of the present invention;
FIG. 5 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3c in example 3 of the present invention;
FIG. 6 is a chart showing nuclear magnetic resonance of the target product (2R, 4R) -3c in example 3 of the present invention;
FIG. 7 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3d in example 4 of the present invention;
FIG. 8 is a chart showing the nuclear magnetic resonance spectrum of the target product (2R, 4R) -3d in example 4 of the present invention;
FIG. 9 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3e in example 5 of the present invention;
FIG. 10 is a chart showing the nuclear magnetic resonance spectrum of the target product (2R, 4R) -3e in example 5 of the present invention;
FIG. 11 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3f in example 6 of the present invention;
FIG. 12 is a nuclear magnetic resonance chart of the target product (2R, 4R) -3f in example 6 of the present invention;
FIG. 13 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3g in example 7 of the present invention;
FIG. 14 is a chart showing the nuclear magnetic resonance spectrum of the target product (2R, 4R) -3g in example 7 of the present invention;
FIG. 15 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3h in example 8 of the present invention;
FIG. 16 is a chart showing the nuclear magnetic resonance of the target product (2R, 4R) -3h in example 8 of the present invention;
FIG. 17 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product (2R, 4R) -3i in example 9 of the present invention;
FIG. 18 is a nuclear magnetic resonance chart of the target product (2R, 4R) -3i in example 9 of the present invention;
FIG. 19 is an X-ray single crystal diffraction pattern of the target product (2R, 4R) -3a in example 1 of the present invention
(CCDC-2156149)。
Detailed Description
In order to further illustrate the present invention, the method for synthesizing chiral 3, 4-dihydro-2H-pyran compounds in aqueous medium provided by the present invention will be described in detail with reference to examples.
In the examples below, solvents were purchased from the national drug group; the medicine raw materials are purchased from Shanghai Bi to be available from medical science and technology Co., ltd; chromatographically pure n-hexane and isopropanol were produced by TEDIA company.
Example 1
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a10 mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2a (19 mg,0.1 mmol) was added at 0℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated saline, the organic phase was collected, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give white solid (2R, 4R) -3a (26.6 mg,94% yield, 97% ee).
The product (2R, 4R) -3a obtained in example 1 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 1 .1H NMR(500MHz,Acetone)δ10.24(s,1H),7.36-7.34(m,2H),7.32-7.23(m,3H),6.79(dd,J＝4.1,2.6Hz,1H),6.16(s,1H),6.06(dd,J＝3.7,1.7Hz,1H),6.05-6.03(m,1H),5.16(dd,J＝11.5,1.3Hz,1H),3.93(ddd,J＝11.1,6.5,2.3Hz,1H),3.72(s,3H),2.42(ddt,J＝13.5,6.4,1.6Hz,1H),2.14(dt,J＝13.4,11.5Hz,1H).
Analysis of the product (2R, 4R) -3a obtained in example 1 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 2 .13C NMR(125MHz,Acetone)δ162.8,144.9,143.8,130.1,128.7,127.2,126.7,118.2,113.7,107.5,106.5,72.8,51.2,39.2,36.5.
Analysis of the product (2R, 4R) -3a obtained in example 1 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated C 17H17NNaO3 306.1101, measured: 306.1113.
Example 2
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 10mL of the above reaction mixture was sucked into a 1.0mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2b (20.4 mg,0.1 mmol) was added at 25℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated saline, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3b as a yellow oil (28.8 mg,87% yield, 94% ee).
The product (2R, 4R) -3b obtained in example 2 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 3 .1H NMR(500MHz,Acetone)δ10.23(s,1H),7.37-7.32(m,2H),7.30-7.28(m,2H),7.27-7.22(m,1H),6.79-6.78(m,1H),6.15(t,J＝3.6Hz,1H),6.06-6.05(m,1H),6.04(m,1H),5.15(dd,J＝11.6,1.6Hz,1H),4.25-4.13(m,2H),3.92(ddd,J＝11.2,6.5,2.4Hz,1H),2.41(ddt,J＝13.6,6.5,1.7Hz,1H),2.14(dt,J＝13.6,11.4Hz,1H),1.24(t,J＝7.1Hz,3H).
Analysis of the product (2R, 4R) -3b obtained in example 2 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 4 .13C NMR(125MHz,Acetone)δ162.3,145.1,143.8,130.2,128.7,127.2,126.7,118.2,113.6,107.5,106.5,72.8,60.5,39.2,36.5,13.6.
Analysis of the product (2R, 4R) -3b obtained in example 2 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated: c 18H19NNaO3 320.1257, measured value: 320.1264.
Example 3
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2c (21.8 mg,0.1 mmol) was added at 25℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated saline, the organic phase was collected, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3c (28.3 mg,91% yield, 97% ee) as a yellow oily liquid.
The product (2R, 4R) -3c obtained in example 3 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 5 .1H NMR(500MHz,Acetone)δ10.23(s,1H),7.37-7.35(m,2H),7.31-7.23(m,3H),6.80-6.78(m,1H),6.16(t,J＝3.5Hz,1H),6.05-6.03(m,2H),5.15(dd,J＝11.5,1.5Hz,1H),5.08-5.01(m,1H),3.92(ddd,J＝11.2,6.5,2.4Hz,1H),2.41(ddt,J＝13.5,6.5,1.7Hz,1H),2.14(dt,J＝13.5,11.5Hz,1H),1.24(dd,J＝6.3,0.9Hz,6H).
Analysis of the product (2R, 4R) -3c obtained in example 3 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 6 .13C NMR(125MHz,Acetone)δ161.8,145.3,143.9,130.2,128.7,127.2,126.7,118.2,113.4,107.45,106.5,72.7,68.1,39.2,36.6,21.1,21.1.
Analysis of the product (2R, 4R) -3b obtained in example 3 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated: c 19H21NNaO3 334.1414, measured value: 334.1417.
Example 4
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2d (23.2 mg,0.1 mmol) was added at 25℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, saturated saline back extracted, the organic phase was collected, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3d (24.1 mg,74% yield, 96% ee) as a yellow oil.
The product (2R, 4R) -3d obtained in example 4 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 7 .1H NMR(500MHz,Acetone)δ10.20(s,1H),7.36-7.31(m,2H),7.30-7.20(m,3H),6.77(td,J＝2.6,1.6Hz,1H),6.16-6.12(m,1H),6.03(dd,J＝5.8,2.7Hz,1H),6.00-5.97(m,1H),5.12(dd,J＝11.5,1.5Hz,1H),3.88(ddd,J＝11.2,6.5,2.4Hz,1H),2.39(ddt,J＝13.5,6.4,1.6Hz,1H),2.10(dt,J＝13.5,11.5Hz,1H),1.47(s,9H).
Analysis of the product (2R, 4R) -3d obtained in example 4 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 8 .13C NMR(125MHz,Acetone)δ161.5,145.8,144.0,130.3,128.7,127.2,126.7,118.2,112.9,107.5,106.4,80.7,72.7,39.2,36.6,27.4.
Analysis of the product (2R, 4R) -3d obtained in example 4 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+H ] + calculated: c 20H24NO3 326.1751, measured value: 326.1759.
Example 5
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2e (26.6 mg,0.1 mmol) was added at 0℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated saline, the organic phase was collected, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3e (32.3 mg,90% yield, 97% ee) as a yellow oily liquid.
The product (2R, 4R) -3e obtained in example 5 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 9 .1H NMR(500MHz,Acetone)δ10.23(s,1H),7.43-7.38(m,2H),7.39-7.30(m,5H),7.30-7.21(m,3H),6.79-6.77(m,1H),6.17-6.13(m,1H),6.11(t,J＝1.9Hz,1H),6.03(dd,J＝5.8,2.7Hz,1H),5.22(q,J＝12.4Hz,2H),5.16(dd,J＝11.6,1.5Hz,1H),3.92(ddd,J＝11.2,6.5,2.4Hz,1H),2.41(ddt,J＝13.6,6.5,1.7Hz,1H),2.15(dt,J＝13.5,11.4Hz,1H).
Analysis of the product (2R, 4R) -3e obtained in example 5 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 10 .13C NMR(125MHz,Acetone)δ162.1,144.9,143.7,136.4,130.1,128.7,128.5,128.3,128.1,127.2,126.8,118.3,114.2,107.5,106.5,72.8,66.1,39.3,36.5.
Analysis of the product (2R, 4R) -3e obtained in example 5 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated: c 23H21NNaO3 382.1414, measured value: 382.1418.
Example 6
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2f (23.6 mg,0.1 mmol) was added at 0℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, back-extracted with saturated saline, the organic phase was collected, dried with anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3f (32.3 mg,92% yield, 98% ee) as a yellow oily liquid.
The product (2R, 4R) -3f obtained in example 6 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 11 .1H NMR(500MHz,Acetone)δ10.24(s,1H),7.35-7.29(m,2H),7.13-7.07(m,2H),6.80-6.77(m,1H),6.17-6.14(m,1H),6.04(dd,J＝5.8,2.7Hz,1H),6.02(t,J＝2.0Hz,1H),5.14(dd,J＝11.5,1.5Hz,1H),5.04(hept,J＝6.3Hz,1H),3.94(ddd,J＝11.2,6.5,2.4Hz,1H),2.41(ddt,J＝13.5,6.5,1.7Hz,1H),2.12(dt,J＝13.5,11.4Hz,1H),1.24(dd,J＝6.3,1.2Hz,6H).
Analysis of the product (2R, 4R) -3f obtained in example 6 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 12 .13C NMR(125MHz,Acetone)δ162.6,160.7(d,1J＝242.8Hz),161.8,145.4,139.90-139.87(d,4J＝3.3Hz),130.1,129.05-128.99(d,3J＝8.1Hz),118.3,115.39-115.22(d,2J＝21.7Hz),113.1,107.5,106.5,72.7,68.2,38.5,36.6,21.1,21.1.
Analysis of the product (2R, 4R) -3f obtained in example 6 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated: c 19H20FNNaO3 352.1319, measured value: 352.1326.
Example 7
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then 2g (26.8 mg,0.1 mmol) of β, γ unsaturated ketoester was added at 0℃and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, back-extracted with saturated saline, the organic phase was collected, dried with anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as an eluent to give (2R, 4R) -3g (28.9 mg,80% yield, 91% ee) as a yellow oily liquid.
The product (2R, 4R) -3g obtained in example 7 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 13 .1H NMR(500MHz,Acetone)δ10.27(s,1H),7.93-7.84(m,3H),7.79(s,1H),7.53-7.42(m,3H),6.84-6.77(m,1H),6.20-6.13(m,2H),6.05(dd,J＝5.5,2.7Hz,1H),5.23-5.19(m,1H),5.11-5.02(m,1H),4.10(ddd,J＝11.0,6.4,2.2Hz,1H),2.53-2.46(m,1H),2.32-2.22(m,1H),1.25(d,J＝6.3Hz,6H).
Analysis of the product (2R, 4R) -3g obtained in example 7 by nuclear magnetic resonance gave a nuclear magnetic resonance carbon spectrum thereof as shown in FIG. 14 .13C NMR(125MHz,Acetone)δ161.9,145.4,141.3,133.8,132.7,130.3,128.4,127.6,127.6,126.2,125.8,125.6,125.5,118.2,113.3,107.5,106.5,72.8,68.2,39.4,36.4,21.1
Analysis of the product (2R, 4R) -3g obtained in example 7 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated: c 23H23NNaO3 384.1570, measured value: 384.1571.
Example 8
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester was added at 0℃for 2h (24.4 mg,0.1 mmol), stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, back-extracted with saturated saline, the organic phase was collected, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3h (27.3 mg,81% yield, 98% ee) as a yellow oily liquid.
The product (2R, 4R) -3h obtained in example 8 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 15 .1H NMR(500MHz,CDCl3)δ8.79(s,1H),7.31-7.21(m,4H),7.17-7.13(m,1H),6.68(dd,J＝4.0,2.2Hz,1H),6.47-6.40(m,1H),6.10-6.05(m,2H),6.06-5.99(m,1H),5.97-5.94(m,1H),5.08-5.01(m,1H),5.01-4.96(m,1H),3.35-3.27(m,1H),2.39-2.29(m,1H),1.86(dt,J＝13.6,11.1Hz,1H),1.21(d,J＝6.2Hz,6H).
The product (2R, 4R) -3h obtained in example 8 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum thereof as shown in FIG. 16 .13C NMR(125MHz,CDCl3)δ161.5,143.2,135.9,129.9,129.6,129.1,127.6,126.5,125.2,117.2,112.3,107.1,104.4,71.5,67.9,35.5,32.9,20.8
Analysis of the product (2R, 4R) -3h obtained in example 8 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated: c 21H23NNaO3 360.1570, measured value: 360.1577.
Example 9
Copper triflate (3.6 mg,0.01 mmol), ligand (L1, 4.3mg,0.01 mmol), potassium tert-butoxide (1.1 mg,0.01 mmol) and water (10.0 mL) were added sequentially to a 25mL round bottom flask and stirred at room temperature for 2h. Then 1.0mL of the above reaction mixture was taken up in a 10mL reaction tube with a syringe under stirring, then beta, gamma unsaturated ketoester 2i (22.4 mg,0.1 mmol) was added at 0deg.C, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6 mg,0.2 mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated saline, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was passed through a column with a volume ratio of 10/1 using petroleum ether/ethyl acetate as eluent to give (2R, 4R) -3i as a yellow oil (28.9 mg,91% yield, 99% ee).
The product (2R, 4R) -3i obtained in example 9 was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereof as shown in FIG. 17 .1H NMR(500MHz,Acetone)δ10.23(s,1H),7.30(dd,J＝4.9,1.4Hz,1H),7.00-6.96(m,2H),6.79(td,J＝2.7,1.6Hz,1H),6.19-6.15(m,1H),6.07(t,J＝2.0Hz,1H),6.06-6.04(m,1H),5.15(dd,J＝11.6,1.6Hz,1H),5.04(hept,J＝6.3Hz,1H),4.28-4.22(m,1H),2.50(ddt,J＝13.5,6.4,1.7Hz,1H),2.23(dt,J＝13.5,11.4Hz,1H),1.24(d,J＝6.3Hz,6H).
Analysis of the product (2R, 4R) -3i obtained in example 9 by nuclear magnetic resonance gave its nuclear magnetic resonance carbon spectrum as shown in FIG. 18 .13C NMR(125MHz,Acetone)δ161.7,146.8,144.8,129.9,126.9,124.0,123.7,118.4,112.9,107.5,106.6,72.7,68.2,36.8,34.5,21.1.
Analysis of the product (2R, 4R) -3i obtained in example 9 using a mass spectrometer (WATERSTM Q-TOF Premier) gave the result HRMS (ESI) M/z [ M+Na ] + calculated C 17H19NNaO3 S340.0978, measured: 340.0981.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (10)
1. A method for synthesizing chiral 3, 4-dihydro-2H-pyrans in an aqueous medium, comprising the steps of:
Mixing beta, gamma unsaturated ketone ester compounds shown in a formula I and 2-vinyl pyrrole shown in a formula II in the presence of a chiral copper complex catalyst shown in a formula C1, and reacting with water as a solvent to obtain 3, 4-dihydro-2H-pyran compounds shown in a formula III;
wherein Ar is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl;
r is selected from alkyl, substituted alkyl, aryl or substituted aryl.
2. The method according to claim 1, wherein Ar is selected from phenyl, naphthyl, thienyl, furyl, or phenyl, naphthyl, thienyl or furyl substituted with one or more of alkyl, halogen, haloalkyl, alkenyl, alkoxy and nitro.
3. The method according to claim 2, wherein the number of carbon atoms of the alkyl group, the haloalkyl group, the alkenyl group, and the alkoxy group is 1 to 6.
4. The method according to claim 1, wherein R is selected from alkyl, phenyl substituted with alkyl, or phenyl substituted alkyl.
5. The method according to claim 4, wherein the number of carbon atoms in the alkyl group is 1 to 6.
6. The method according to claim 1, comprising the steps of:
a) Mixing cupric salt, alkali and a ligand shown in a formula L1 in water for reaction to obtain a reaction mixture containing a chiral copper complex catalyst shown in a formula C1;
B) And (3) mixing the beta, gamma unsaturated ketone ester compound shown in the formula I and the 2-vinyl pyrrole shown in the formula II with the reaction mixture obtained in the step A) for reaction to obtain the 3, 4-dihydro-2H-pyran compound shown in the formula III.
7. The method according to claim 6, wherein the divalent copper salt is selected from copper triflate;
the base is selected from any one or more of triethylamine, N-ethylmorpholine, N-diisopropylethylamine, cesium carbonate, triethylenediamine and potassium tert-butoxide.
8. The method according to claim 1 or 6, wherein the catalyst is used in an amount of 1% to 10% of the total molar amount of beta, gamma unsaturated ketoester compound and 2-vinyl pyrrole;
The molar ratio of the beta, gamma unsaturated ketoester compound to the 2-vinyl pyrrole is 1: (1-5);
The initial concentration of the beta, gamma unsaturated ketoester compound is 0.1-0.3 mol/L.
9. The method according to claim 1 or 6, wherein the temperature of the reaction is 0 to 25 ℃.
10. The method according to claim 1 or 6, wherein after the reaction is completed, separation and purification are performed;
the separation and purification method comprises one or more of column chromatography, recrystallization and distillation.
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| Shuangshuang Zhao et al.."Copper-Catalyzed Stereoselective [4 + 2] Cycloaddition of β,γ-Unsaturated α‑Keto Esters and 2‑Vinylpyrroles in Water".《Organic Letters》.2022,第24卷第4224-4228页. * |
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