CN114835694A - Method for synthesizing chiral 3, 4-dihydro-2H-pyran compound in aqueous medium - Google Patents
Method for synthesizing chiral 3, 4-dihydro-2H-pyran compound in aqueous medium Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 24
- -1 3, 4-dihydro-2H-pyran compound Chemical class 0.000 title claims abstract description 17
- 239000012736 aqueous medium Substances 0.000 title claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 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
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 150000004699 copper complex Chemical class 0.000 claims abstract description 14
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical class C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 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 11
- 238000002156 mixing Methods 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 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
- 238000004440 column chromatography Methods 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 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
- 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
- 239000003513 alkali Substances 0.000 claims 1
- 150000001879 copper Chemical class 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000007115 1,4-cycloaddition reaction Methods 0.000 abstract description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000000047 product Substances 0.000 description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 32
- 238000001228 spectrum Methods 0.000 description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 239000003480 eluent Substances 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000003643 water by type Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000006053 organic reaction Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 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
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase 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
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001336 alkenes Chemical class 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
- 239000013078 crystal Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000004880 oxines Chemical class 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
- 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
Images
Classifications
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- 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
Abstract
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 as a formula C1 and/or a formula C2, a beta, gamma unsaturated ketone ester compound shown as a formula I and 2-vinyl pyrrole shown as a formula II are mixed, and water is used as a solvent to react to obtain a 3, 4-dihydro-2H-pyran compound shown as 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 ketoester compounds in water, and the reaction can obtain chiral 3, 4-dihydro-2H-pyran compounds with high enantioselectivity and high diastereoselectivity. Moreover, the stereoselectivity and yield of the product can be maintained when such aqueous asymmetric [4+2] cycloaddition reactions are scaled up to gram-scale.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a chiral 3, 4-dihydro-2H-pyran compound 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 investigate organic reactions in aqueous media. Water has attracted the attention of chemists as a safe, inexpensive, readily available solvent. In organic synthesis, water as a reaction medium has many advantages. For example, it may eliminate many redundant steps such as protection and deprotection of the active functional groups. In addition, the addition of water can also accelerate the reaction speed, improve the chemoselectivity and the stereoselectivity and reduce the generation of some byproducts in the reaction process.
In recent years, lewis acid catalyzed asymmetric organic reactions have rapidly developed and are widely used 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. Some lewis acid catalysts have been found to be stable in water and promote asymmetric reactions in the aqueous phase as aqueous organic reactions progress. In 2018, a new catalytic system combining chiral lewis acid and single-walled carbon nanotubes was developed by the group of Kobayashi, and the asymmetric 1, 4-addition of aldoxime to electron-deficient olefin in water was successfully achieved.
Chiral 3, 4-dihydro-2H pyrans are widely found in natural products, food flavors and fragrances. In recent years, many 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 compounds in 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-pyrans in an aqueous medium.
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 as a formula C1 and/or a formula C2, mixing a beta, gamma unsaturated ketone ester compound shown as a formula I and 2-vinyl pyrrole shown as a formula II, and reacting by taking water as a solvent to obtain a 3, 4-dihydro-2H-pyran compound shown as 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 a phenyl group.
Preferably, Ar is selected from substituted or unsubstituted phenyl, naphthyl, thienyl or furyl.
M-0 indicates that Ar is directly bonded to the parent nucleus.
The substituent of the above group is preferably one or more of alkyl, halogen, haloalkyl, alkenyl, alkoxy, and nitro.
Preferably, the number of carbon atoms in the alkyl group, the haloalkyl group, the alkenyl group, and the alkoxy group is 1 to 6, and more preferably 1 to 3.
Preferably, the substituents are selected from one or more of fluoro, chloro, bromo, 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 an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group.
Preferably, the number of carbon atoms in the alkyl group or the alkyl group in the substituted alkyl group is 1 to 6, and 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, R is selected from alkyl, phenyl substituted by alkyl or alkyl substituted by phenyl. The number of carbon atoms in 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 of the present invention is not particularly limited, and may be a general method well known to those skilled in the art, and is preferably prepared according to the following method:
mixing a cupric salt and a base with a ligand shown as a formula L1 or L2 in water for reaction to obtain a reaction mixture containing a chiral copper complex catalyst shown as a formula C1 or C2;
the cupric salt is preferably copper trifluoromethanesulfonate.
The base is preferably any one or more of triethylamine, N-ethylmorpholine, N-diisopropylethylamine, cesium carbonate, triethylene diamine and potassium tert-butoxide.
Then in the presence of the prepared chiral copper complex catalyst, mixing the beta, gamma unsaturated ketoester compound shown in the formula I and the 2-vinyl pyrrole shown in the formula II in water for reaction to obtain the chiral 3, 4-dihydro-2H-pyran compound.
Wherein the chiral copper complex can be a reaction product obtained by mixing and reacting an unpurified compound, namely copper trifluoromethanesulfonate, a ligand of formula L1 or L2 and a base in water.
Specifically, the method for synthesizing the chiral 3, 4-dihydro-2H-pyran compounds in the aqueous medium comprises the following steps:
A) mixing a cupric salt, a base and a ligand shown as a formula L1 or L2 in water to obtain a reaction mixture containing a chiral copper complex catalyst shown as a formula C1 or C2;
B) mixing beta, gamma unsaturated ketoester compounds shown in formula I and 2-vinyl pyrrole shown in formula II with the reaction mixture obtained in the step A) for reaction to obtain 3, 4-dihydro-2H-pyran compounds shown in formula III.
Further preferably, the method specifically comprises the following steps:
s1): mixing copper trifluoromethanesulfonate, a base (preferably potassium tert-butoxide) and a ligand in water, and stirring for 2 hours to obtain a reaction mixture, wherein the reaction mixture is the chiral copper complex;
s2): adding the beta, gamma unsaturated ketoester compound shown in the formula I into the reaction mixture, and stirring for 20 minutes; subsequently, 2-vinylpyrrole of the 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 ketoester compound to the 2-vinyl pyrrole is 1: (1-5).
Preferably, the initial concentration of the beta, gamma unsaturated ketone ester compound is 0.1-0.3 mol/L, and more preferably 0.1 mol/L.
Preferably, the reaction temperature is 0-25 ℃.
Preferably, the reaction time is 24-48 h.
Preferably, after the reaction is finished, separation and purification are carried out;
the method of separation and purification preferably includes one or more of column chromatography, recrystallization, and distillation.
Specifically, after the reaction is finished, the mixed solution after the reaction is extracted by ethyl acetate, and then is back extracted by saturated saline solution, an organic phase is dried by anhydrous sodium sulfate, 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 a solvent for the first time, adopts a chiral copper complex shown as the formula C1 or C2 as a catalyst, and obtains a product with high enantioselectivity and diastereoselectivity through asymmetric [4+2] cycloaddition reaction of 2-vinyl pyrrole and beta, gamma unsaturated ketoester compounds.
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 as a formula C1 and/or a formula C2, a beta, gamma unsaturated ketone ester compound shown as a formula I and 2-vinyl pyrrole shown as a formula II are mixed, and water is used as a solvent to react to obtain a 3, 4-dihydro-2H-pyran compound shown as 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 ketoester compounds in water, and the reaction can obtain chiral 3, 4-dihydro-2H-pyran compounds with high enantioselectivity and high diastereoselectivity. Moreover, the stereoselectivity and yield of the product can be maintained when such aqueous asymmetric [4+2] cycloaddition reactions are scaled up to gram-scale.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a target product (2R,4R) -3a in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the target product (2R,4R) -3a in example 1 of the present invention;
FIG. 3 is a NMR chart of (2R,4R) -3b, a target product in example 2 of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of the target product (2R,4R) -3b in example 2 of the present invention;
FIG. 5 is a NMR chart of (2R,4R) -3c, a target product in example 3 of the present invention;
FIG. 6 is the NMR carbon spectrum of the target product (2R,4R) -3c in example 3 of the present invention;
FIG. 7 is a NMR spectrum of (2R,4R) -3d, a target product in example 4 of the present invention;
FIG. 8 is the NMR carbon spectrum of the target product (2R,4R) -3d in example 4 of the present invention;
FIG. 9 is a NMR chart of (2R,4R) -3e, a target product in example 5 of the present invention;
FIG. 10 is the NMR carbon spectrum of the target product (2R,4R) -3e in example 5 of the present invention;
FIG. 11 is a NMR chart of (2R,4R) -3f, a target product in example 6 of the present invention;
FIG. 12 is a NMR carbon spectrum of the objective compound (2R,4R) -3f of example 6 of the present invention;
FIG. 13 is a NMR chart of (2R,4R) -3g, which is a target product in example 7 of the present invention;
FIG. 14 is a NMR carbon spectrum of (2R,4R) -3g of the objective compound of example 7 of the present invention;
FIG. 15 is the NMR spectrum of the target product (2R,4R) -3h in example 8 of the present invention;
FIG. 16 is the NMR carbon spectrum of the target product (2R,4R) -3h in example 8 of the present invention;
FIG. 17 is a NMR spectrum of (2R,4R) -3i, a target product in example 9 of the present invention;
FIG. 18 is a NMR carbon spectrum of the objective compound (2R,4R) -3i in example 9 of the present invention;
FIG. 19 is an X-ray single crystal diffractogram of the target product (2R,4R) -3a in example 1 of the present invention
(CCDC-2156149)。
Detailed Description
To further illustrate the present invention, the following examples are provided to describe the synthesis of chiral 3, 4-dihydro-2H-pyrans in aqueous medium.
In the following examples, solvents were purchased from the national pharmaceutical group; the raw materials of the medicine are purchased from Shanghai Bide pharmaceutical science and technology Limited; chromatographically pure n-hexane and isopropanol are produced by TEDIA corporation.
Example 1
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was sucked up by syringe into a 10mL reaction tube under stirring, then β, γ unsaturated ketoester 2a (19mg,0.1mmol) was added at 0 ℃, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to obtain white solid (2R,4R) -3a (26.6mg, 94% yield, 97% ee).
The product (2R,4R) -3a obtained in example 1 was analyzed by nuclear magnetic resonance (Bruker AC-300FT) to obtain a nuclear magnetic resonance hydrogen spectrum, which is shown in FIG. 1. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3a obtained in example 1 was analyzed by nuclear magnetic resonance, as shown in FIG. 2. 13 C 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.
The product (2R,4R) -3a obtained in example 1 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated value C 17 H 17 NNaO 3 306.1101, measurement: 306.1113.
example 2
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 10mL of the above reaction mixture was sucked up by a syringe under stirring into a 1.0mL reaction tube, and then β, γ unsaturated ketoester 2b (20.4mg,0.1mmol) was added at 25 ℃, stirred at this temperature for 20 minutes, and then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography using petroleum ether/ethyl acetate as an eluent at a volume ratio of 10/1 to give yellow oily liquid (2R,4R) -3b (28.8mg, 87% yield, 94% ee).
The product (2R,4R) -3b obtained in example 2 was analyzed by nuclear magnetic resonance (Bruker AC-300FT) to obtain a hydrogen nuclear magnetic resonance spectrum, which is shown in FIG. 3. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3b obtained in example 2 was analyzed by nuclear magnetic resonance, as shown in FIG. 4. 13 C 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.
The product (2R,4R) -3b obtained in example 2 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated values: c 18 H 19 NNaO 3 320.1257, measurement: 320.1264.
example 3
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was aspirated into a 10mL reaction tube with a syringe under stirring, then β, γ unsaturated ketoester 2c (21.8mg,0.1mmol) was added at 25 ℃, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give yellow oily liquid (2R,4R) -3c (28.3mg, 91% yield, 97% ee).
The products (2R,4R) -3c obtained in example 3 were analyzed by nuclear magnetic resonance (Bruker AC-300FT) to obtain a hydrogen nuclear magnetic resonance spectrum, which is shown in FIG. 5. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3c obtained in example 3 was analyzed by nuclear magnetic resonance, as shown in FIG. 6. 13 C 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.
The product (2R,4R) -3b obtained in example 3 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated values: c 19 H 21 NNaO 3 334.1414, measurement: 334.1417.
example 4
To a 25mL round bottom flask were added sequentially copper triflate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was aspirated with a syringe under stirring into a 10mL reaction tube, then β, γ unsaturated ketoester 2d (23.2mg,0.1mmol) was added at 25 ℃, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, the organic phase was collected, dried with anhydrous sodium sulfate, concentrated, and the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give a yellow oily liquid (2R,4R) -3d (24.1mg, 74% yield, 96% ee).
Example 4 was performed using nuclear magnetic resonance (Bruker AC-300FT)The product (2R,4R) -3d obtained in (A) was analyzed to obtain a NMR hydrogen spectrum thereof, as shown in FIG. 7. 1 H 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).
The product (2R,4R) -3d obtained in example 4 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 8. 13 C 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.
The product (2R,4R) -3d obtained in example 4 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + H [)] + And (3) calculating the result: c 20 H 24 NO 3 326.1751, measurement: 326.1759.
example 5
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was aspirated into a 10mL reaction tube with a syringe under stirring, then β, γ unsaturated ketoester 2e (26.6mg,0.1mmol) was added at 0 deg.C, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give (2R,4R) -3e (32.3mg, 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-300FT) to obtain a nuclear magnetic resonance hydrogen spectrum thereofAs shown in fig. 9. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3e obtained in example 5 was analyzed by nuclear magnetic resonance, as shown in FIG. 10. 13 C 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.
The product (2R,4R) -3e obtained in example 5 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated values: c 23 H 21 NNaO 3 382.1414, measurement: 382.1418.
example 6
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was aspirated into a 10mL reaction tube with a syringe under stirring, then β, γ unsaturated ketoester 2f (23.6mg,0.1mmol) was added at 0 deg.C, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, back extracted with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give a yellow oily liquid (2R,4R) -3f (32.3mg, 92% yield, 98% ee).
The product (2R,4R) -3f obtained in example 6 was analyzed by nuclear magnetic resonance (Bruker AC-300FT) to obtain a hydrogen nuclear magnetic resonance spectrum, which is shown in FIG. 11. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3f obtained in example 6 was analyzed by nuclear magnetic resonance, as shown in FIG. 12. 13 C 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.
The product (2R,4R) -3f obtained in example 6 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated values: c 19 H 20 FNNaO 3 352.1319, measurement: 352.1326.
example 7
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was aspirated into a 10mL reaction tube with a syringe under stirring, then 2g (26.8mg,0.1mmol) of β, γ unsaturated ketoester was added at 0 deg.C, stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, back extracted with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give (2R,4R) -3g (28.9mg, 80% yield, 91% ee) of yellow oily liquid on the column.
The product (2R,4R) -3 obtained in example 7 was subjected to nuclear magnetic resonance (Bruker AC-300FT)g, the nuclear magnetic resonance hydrogen spectrum of the compound is obtained by analysis, and is shown in figure 13. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3g obtained in example 7 was analyzed by nuclear magnetic resonance, as shown in FIG. 14. 13 C 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 by means of a mass spectrometer (Waters. TM. Q-TOF Premier) gave the result HRMS (ESI) M/z [ M + Na ]] + Calculated values: c 23 H 23 NNaO 3 384.1570, measurement: 384.1571.
example 8
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was aspirated into a 10mL reaction tube with a syringe under stirring, then 2h (24.4mg,0.1mmol) of β, γ unsaturated ketoester was added at 0 deg.C for 2h (24.4mg,0.1mmol), stirred at this temperature for 20 min, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, back extracted with saturated brine, the organic phase was collected, dried with anhydrous sodium sulfate, concentrated, and the residue was chromatographed with petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give a yellow oily liquid (2R,4R) -3h (27.3mg, 81% yield, 98% ee).
The product obtained in example 8 (2R,4R) -3h was analyzed by nuclear magnetic resonance (Bruker AC-300FT) to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 15As shown. 1 H NMR(500MHz,CDCl 3 )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 nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3h obtained in example 8 was analyzed by nuclear magnetic resonance, as shown in FIG. 16. 13 C NMR(125MHz,CDCl 3 )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
The (2R,4R) -3h product obtained in example 8 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated values: c 21 H 23 NNaO 3 360.1570, measurement: 360.1577.
example 9
To a 25mL round bottom flask were added copper trifluoromethanesulfonate (3.6mg,0.01mmol), ligand (L1,4.3mg,0.01mmol), potassium tert-butoxide (1.1mg,0.01mmol), water (10.0mL) in that order and stirred at room temperature for 2 h. Then 1.0mL of the above reaction mixture was sucked up by a syringe under stirring into a 10mL reaction tube, and then β, γ unsaturated ketoester 2i (22.4mg,0.1mmol) was added at 0 ℃ and stirred at this temperature for 20 minutes, then 2-vinylpyrrole (18.6mg,0.2mmol) was added, after completion of the reaction (TLC follow-up monitoring), extracted with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed using petroleum ether/ethyl acetate as eluent at a volume ratio of 10/1 to give yellow oily liquid (2R,4R) -3i (28.9mg, 91% yield, 99% ee).
The product (2R,4R) -3i obtained in example 9 was analyzed by nuclear magnetic resonance (Bruker AC-300FT) to obtain a hydrogen nuclear magnetic resonance spectrum, which is shown in FIG. 17. 1 H 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).
The nuclear magnetic resonance carbon spectrum of the product (2R,4R) -3i obtained in example 9 was analyzed by nuclear magnetic resonance, as shown in FIG. 18. 13 C 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.
The (2R,4R) -3i product obtained in example 9 was analyzed by a mass spectrometer (Waters. TM. Q-TOF Premier) to obtain the results HRMS (ESI) M/z [ M + Na ]] + Calculated value C 17 H 19 NNaO 3 S340.0978, measurement: 340.0981.
the above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A method for synthesizing chiral 3, 4-dihydro-2H-pyrans in an aqueous medium, comprising the steps of:
in the presence of a chiral copper complex catalyst shown as a formula C1 and/or a formula C2, mixing a beta, gamma unsaturated ketone ester compound shown as a formula I and 2-vinyl pyrrole shown as a formula II, and reacting by taking water as a solvent to obtain a 3, 4-dihydro-2H-pyran compound shown as 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 of claim 1, wherein Ar is selected from phenyl, naphthyl, thienyl, furyl, or from phenyl, naphthyl, thienyl or furyl substituted with one or more of alkyl, halo, haloalkyl, alkenyl, alkoxy and nitro.
3. The method according to claim 2, wherein the number of carbon atoms in the alkyl group, the haloalkyl group, the alkenyl group, and the alkoxy group is 1 to 6.
4. The method of claim 1, wherein R is selected from alkyl, phenyl substituted with alkyl, or alkyl substituted with phenyl.
5. The method according to claim 4, wherein the number of carbon atoms in the alkyl group is 1 to 6.
6. The method of claim 1, comprising the steps of:
A) mixing a cupric salt and a base with a ligand shown as a formula L1 or L2 in water for reaction to obtain a reaction mixture containing a chiral copper complex catalyst shown as a formula C1 or C2;
B) mixing beta, gamma unsaturated ketoester compounds shown in formula I and 2-vinyl pyrrole shown in formula II with the reaction mixture obtained in the step A) for reaction to obtain 3, 4-dihydro-2H-pyran compounds shown in formula III.
7. The process according to claim 6, wherein the divalent copper salt is selected from copper triflate;
the alkali is selected from one or more of triethylamine, N-ethylmorpholine, N-diisopropylethylamine, cesium carbonate, triethylene diamine and potassium tert-butoxide.
8. The method according to claim 1 or 6, wherein the amount of the catalyst is 1-10% of the total molar amount of the beta, gamma unsaturated ketoester compound and the 2-vinyl pyrrole;
the mol 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, characterized in that, after the reaction is finished, separation and purification are carried out;
the separation and purification method comprises one or more of column chromatography, recrystallization and distillation.
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