CN117603105A - Method for iron-catalyzed non-activated olefin selective difunctional reaction - Google Patents
Method for iron-catalyzed non-activated olefin selective difunctional reaction Download PDFInfo
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- CN117603105A CN117603105A CN202311619054.1A CN202311619054A CN117603105A CN 117603105 A CN117603105 A CN 117603105A CN 202311619054 A CN202311619054 A CN 202311619054A CN 117603105 A CN117603105 A CN 117603105A
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 46
- 150000001336 alkenes Chemical class 0.000 title claims abstract description 40
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 28
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 16
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical group [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 16
- -1 beta-halogenated aryl ethylene Chemical class 0.000 claims description 15
- 229910052742 iron Inorganic materials 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000003446 ligand Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 8
- 239000005977 Ethylene Substances 0.000 claims description 8
- 229910052796 boron Inorganic materials 0.000 claims description 8
- 229960002089 ferrous chloride Drugs 0.000 claims description 8
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical group Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- JTYRBFORUCBNHJ-UHFFFAOYSA-N 1-bromo-1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexane Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br JTYRBFORUCBNHJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 3
- PBGVMIDTGGTBFS-UHFFFAOYSA-N but-3-enylbenzene Chemical compound C=CCCC1=CC=CC=C1 PBGVMIDTGGTBFS-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012039 electrophile Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 5
- 229910052723 transition metal Inorganic materials 0.000 abstract description 5
- 150000003624 transition metals Chemical class 0.000 abstract description 5
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 23
- 239000000047 product Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 239000011521 glass Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 7
- 229910052731 fluorine Chemical class 0.000 description 7
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical class [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Chemical class 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000007306 functionalization reaction Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000006452 multicomponent reaction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- YMOONIIMQBGTDU-VOTSOKGWSA-N [(e)-2-bromoethenyl]benzene Chemical class Br\C=C\C1=CC=CC=C1 YMOONIIMQBGTDU-VOTSOKGWSA-N 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/02—Addition
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for performing iron-catalyzed non-activated olefin selective difunctional reaction, which belongs to the technical field of catalytic synthesis. The whole method is simple, easy and safe, the product of coupling non-activated olefin and halogenated compound is directly obtained by a one-step method, under the optimized reaction condition, the yield of the separated target product can reach up to 95 percent, and the defect that the guiding group needs to be introduced in the traditional transition metal catalytic multi-component coupling reaction is overcome.
Description
Technical Field
The invention belongs to the technical field of catalytic synthesis, and particularly relates to a method for iron-catalyzed non-activated olefin selective difunctional reaction.
Background
The organic tandem reaction and the multicomponent reaction are important synthetic strategies in organic chemistry, and multi-site reaction products can be economically and efficiently synthesized in one step through the strategies, and the method has been widely developed and applied in the fields of medicine synthesis, functional material preparation, organic molecular framework construction and the like. In the field of olefin dual carbon functionalization, traditional transition metal catalyzed reactions can achieve complex molecular synthesis by constructing two adjacent carbon-carbon bonds simultaneously, however, the regioselectivity of the newly formed two carbon-carbon bonds tends to be unsatisfactory, which prevents the application of the dual functionalization strategy in organic synthesis. This defect can be attributed to the weak resonance effect of the in-situ generated alkyl radicals, which results in such alkyl radicals having extremely high reactivity, thereby initiating occurrence of various side reactions. Transition metal catalyzed three component olefin reactions often rely on the use of a director strategy to achieve good regioselectivity, however, the introduction of a director and removal or conversion of the director affects the economy and atomic economy of the reaction step. In addition, the multicomponent reactions developed so far mainly use transition metal catalysts of nickel, palladium, copper, etc., which are either expensive or biotoxic with an effect on the later modification of the drug. Thus, the development of environmentally friendly and efficient processes for the difunctional functionalization of non-activated olefins without the aid of directing groups, in particular the use of cost-effective, green, non-toxic iron as catalyst, is of great importance.
Disclosure of Invention
The invention aims to solve the technical problems that: the method for the iron-catalyzed non-activated olefin selective difunctional reaction solves the technical problems that guiding groups are required to be introduced and selectivity is insufficient in the traditional transition metal-catalyzed multicomponent coupling reaction.
In order to achieve the above purpose, the invention adopts the following technical scheme: there is provided a method for iron-catalyzed non-activated olefin selective difunctional reactions comprising the steps of: in an organic solvent, halogenated fluorinated alkane and beta-halogenated aryl ethylene are used as electrophiles, an iron-containing reagent is used as a catalyst, a boron-containing reagent is used as a reducing reagent, and under the action of alkali and ligand, non-activated alkene is reacted, and a difunctional reaction is selectively carried out, wherein the reaction formula is shown as follows:
wherein: r is R f -X represents a halofluoroalkane; r is R 1 、R 2 、R 3 Represents a substituent on an olefin, R 4 Representing a substituent on an aromatic ring.
The beneficial effects of the technical scheme adopted by the invention are as follows: the transition metal iron is used as a catalyst, the catalyst has the advantages of no toxicity, low cost, environmental friendliness and the like, the bi-pinacol bi-borate is used as a reducing agent, the non-activated olefin can be subjected to regioselective bi-functionalization, two carbon-carbon bonds are constructed, and the product has excellent E/Z selectivity (E: Z > 20:1). Wherein the raw materials (non-activated alkene, beta-bromostyrene derivative and fluorine-containing bromoalkane) are cheap and easy to obtain, and in addition, the non-activated alkene, the beta-bromostyrene derivative and the fluorine-containing bromoalkane are favored in organic synthesis as important reaction blocks in organic synthesis, so that the reaction has very good application prospect. The metal iron has variable valence and is difficult to control, and the coupling reaction using iron as a catalyst is relatively few at present, and the reaction type is single. In addition, the property of the fluorine-containing alkyl free radical is different from that of the common alkyl free radical, and the fluorine atom is introduced into the medicine molecule to modify the property of the medicine, thereby being beneficial to improving the physical and chemical properties of the medicine.
Based on the technical scheme, the invention can also be improved as follows:
further, R f Represents a fluoroalkane, and X represents a halogen.
Further, R 1 、R 2 、R 3 Represents a substituent on an olefin, which is each independently selected from hydrogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 Halogen-substituted alkyl or C 1 -C 20 Alkylaryl groups of (a).
Further, R 4 Represents substituents on the aromatic ring, where the substituents on the aromatic ring are optionally selected from C 1 -C 20 Alkyl groups, halogen atoms, carbonyl groups, silyl ethers, or cyano groups.
Further, the organic solvent is methyl tert-butyl ether, the halofluoroalkane is 1-bromoperfluorohexane, the β -haloaryl ethylene is (E) -4-methylsulfanyl- β -bromostyrene, the iron-containing reagent is ferrous chloride, the boron-containing reagent is bis-pinacolato biborate, the base is lithium tert-butoxide, the ligand is 1, 2-bis (diphenylphosphine) ethane, the non-activated alkene is 4-phenyl-1-butene, allyltrimethylsilane or 1- [ (trans ) -4'- (3-butenyl) [1,1' -dicyclohexyl ] -4-yl ] -4-methylbenzene.
Further, the molar ratio of halogenated fluoroalkane, beta-halogenated aryl ethylene, iron-containing reagent, boron-containing reagent, base, ligand and non-activated alkene is from 2 to 4:1:0.05-0.2:2-3.5:2-3.5:0.05-0.2:2-3.
Further, the molar ratio of halofluoroalkane, β -haloaryl ethylene, iron-containing reagent, boron-containing reagent, base, ligand and non-activated alkene is 3:1:0.1:2.5:2.5:0.1:2.5.
further, methyl tertiary butyl ether requires a pre-drying treatment with sodium prior to use.
Further, the reaction temperature is 75-85 ℃ and the reaction time is 10-14h.
Further, the reaction temperature was 80℃and the reaction time was 12 hours.
The beneficial effects of the invention are as follows:
(1) The low-cost metal iron-catalyzed olefin amphiphilic reagent cross reduction coupling reaction provided by the invention has the advantages that guide groups do not need to be introduced into olefin, the raw material preparation steps are simplified, the application range of a substrate is enlarged, the reaction types of multi-component reaction are enriched, the difficult problems of regional selectivity control and the like in the reaction process are solved, under standard reaction conditions, the yield of a target product after separation can reach 95%, and the E/Z selectivity is more than 20:1, is a universal, efficient, economical and environmentally friendly method for rapidly constructing carbon-carbon bonds.
(2) The invention uses the environment-friendly organic reagent duplex pinacol biborate as the reducing agent, which can avoid the environmental pollution caused by metals such as zinc, manganese and the like.
(3) The method can carry out post-modification on various natural products and drug molecule derivatives, plays an important role in drug transformation and research and development, and can be widely applied to synthesis of pharmaceutical intermediates and high-added-value fine chemicals.
Drawings
FIG. 1 shows the nuclear magnetic resonance hydrogen spectrum of product 1 1 H-NMR)；
FIG. 2 shows nuclear magnetic resonance spectrum of product 1 13 C-NMR)；
FIG. 3 shows nuclear magnetic resonance fluorine spectrum of product 1 19 F-NMR)；
FIG. 4 shows the nuclear magnetic resonance hydrogen spectrum of product 2 1 H-NMR)；
FIG. 5 shows nuclear magnetic resonance spectrum of product 2 13 C-NMR)；
FIG. 6 shows nuclear magnetic resonance fluorine spectrum of product 2 19 F-NMR)；
FIG. 7 shows the hydrogen nuclear magnetic resonance spectrum of product 3 1 H-NMR)；
FIG. 8 shows nuclear magnetic resonance spectrum of product 3 13 C-NMR)；
FIG. 9 shows nuclear magnetic resonance fluorine spectrum of product 3 19 F-NMR)。
Detailed Description
The following description of the specific embodiments of the present invention is provided to facilitate understanding of the present invention by those skilled in the art, and the examples are not intended to be limiting, and the reagents or apparatus used are not intended to be limiting, and are conventional products available for commercial purchase. It should be understood that the invention is not limited to the specific embodiments, but is capable of numerous modifications within the spirit and scope of the invention as hereinafter defined and defined by the appended claims as will be apparent to those skilled in the art all falling within the true spirit and scope of the invention as hereinafter claimed.
The following test was carried out using a nuclear magnetic resonance spectrometer (400 MHz) from Agilent under the model 400MR DD2.
Example 1
A method for iron-catalyzed non-activated olefin selective difunctional reaction, the reaction equation is as follows:
the method comprises the following specific steps:
(1) 3g of sodium metal was cut into small pieces (50 mg/piece) and placed in a 1L flask, 500mL of methyl tert-butyl ether was added, followed by reflux at 100℃for 3 hours, and distilled methyl tert-butyl ether was collected and stored under sealed conditions;
(2) An 8mL glass bottle to which a magnetic stirrer was added was placed in a glove box, 46mg (1 equivalent) of (E) -4-methylsulfanyl- β -bromostyrene, 2.5mg (0.1 equivalent) of ferrous chloride, 153mg (3 equivalent) of bis (pinacolato) bisborate, 48mg (3 equivalent) of lithium t-butoxide and 8mg (0.1 equivalent) of 1, 2-bis (diphenylphosphine) ethane were weighed, 75. Mu.L (2.5 equivalent) of 4-phenyl-1-butene and 128. Mu.L (3 equivalent) of 1-bromoperfluorohexane were added using a microsyringe, and 1mL of methyl t-butyl ether was then added using a syringe and mixed uniformly;
(3) Taking out the glass bottle from the glove box, and putting the glass bottle into a constant temperature stirrer at 80 ℃ for reaction for 12 hours;
(4) The glass bottle was taken out of the thermostatic stirrer, quenched by addition of 1mL of saturated ammonium chloride solution (concentration 6.95 mol/L), extracted 3 times with 10mL each time with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, finally concentrated in vacuo and purified by petroleum ether: ethyl acetate = 100:2 (v: v) as eluent by flash column chromatography gave 102mg (product 1) as a clear colorless oil in 85% yield.
The product 1 was structurally characterized, and the results are shown in fig. 1-3, specifically: 1 H NMR(400MHz,CDCl 3 )δ7.33-7.28(m,4H),7.25-7.18(m,5H),6.43(d,J＝16Hz,1H),6.01(dd,J＝16Hz,J＝9.2Hz,1H),2.80-2.70(m,2H),2.67-2.57(m,1H),2.50(s,3H),2.32-2.17(m,2H),1.99-1.91(m,1H),1.83-1.74(m,1H). 13 C NMR(100MHz,CDCl 3 )δ141.5,137.6,134.1,131.3,130.8,128.4,128.3,126.9,126.6,126.0,37.2,36.1,36.0(t,J＝20Hz),33.2,15.9. 19 F NMR(376MHz,CDCl 3 )δ-80.80(t,J＝9.8Hz,3F),-110.87--113.33(m,2F),-121.70--121.81(m,2F),-122.77--122.89(m,2F),-123.50--123.62(m,2F),-126.06--126.19(m,2F).HRMS(ESI):calcd for C 25 H 20 F 13 S[M-H] - :599.1083,found:599.1082.
example 2
A method for iron-catalyzed non-activated olefin selective difunctional reaction, the reaction equation is as follows:
the method comprises the following specific steps:
(1) 3g of sodium metal was cut into small pieces (50 mg/piece) and placed in a 1L flask, 500mL of methyl tert-butyl ether was added, followed by reflux at 100℃for 3 hours, and distilled methyl tert-butyl ether was collected and stored under sealed conditions;
(2) An 8mL glass bottle added with a magnetic stirrer is placed in a glove box, 1 equivalent of (E) -4-methylthio-beta-bromostyrene, 0.1 equivalent of ferrous chloride, 3 equivalents of bis (pinacolato) bisborate, 3 equivalents of lithium tert-butoxide, 0.1 equivalent of 1, 2-bis (diphenylphosphine) ethane, 2.5 equivalents of allyl trimethylsilane and 3 equivalents of 1-bromoperfluorohexane are weighed, and then 1mL of methyl tert-butyl ether is added with a syringe and uniformly mixed;
(3) Taking out the glass bottle from the glove box, and putting the glass bottle into a constant temperature stirrer at 80 ℃ for reaction for 14h;
(4) The glass bottle was taken out of the thermostatic stirrer, quenched by addition of 1mL of saturated ammonium chloride solution (concentration 6.95 mol/L), extracted 3 times with 10mL each time with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, finally concentrated in vacuo and purified by petroleum ether: ethyl acetate = 100:2 (v: v) as eluent by flash column chromatography gave 101.9mg (product 2) of a clear colorless oil in 95% yield.
The product 2 was structurally characterized, and the results are shown in fig. 4-6, specifically: 1 H NMR(400MHz,CDCl 3 )δ7.38-7.23(m,5H),6.45(d,J＝16Hz,1H),6.02(dd,J＝16,9.2Hz,1H),2.98-2.89(m,1H),2.29-2.17(m,2H),0.95-0.81(m,2H),0.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ137.2,134.2,129.6,128.5,127.3,126.1,39.1(t,J＝20Hz),33.2,24.4,-0.9. 19 F NMR(376MHz,CDCl 3 )δ-80.89--80.97(m,3F),-111.21--113.71(m,2F),-121.77--121.87(m,2F),-122.88--122.94(m,2F),-123.74--123.83(m,2F),-126.17--126.25(m,2F).HRMS(EI):C 20 H 21 F 13 Si[M] + :536.1205,found:536.1200.
example 3
A method for iron-catalyzed non-activated olefin selective difunctional reaction, the reaction equation is as follows:
the method comprises the following specific steps:
(1) 3g of sodium metal was cut into small pieces (50 mg/piece) and placed in a 1L flask, 500mL of methyl tert-butyl ether was added, followed by reflux at 100℃for 3 hours, and distilled methyl tert-butyl ether was collected and stored under sealed conditions;
(2) An 8mL glass bottle to which a magnetic stirrer was added was placed in a glove box, 1 equivalent of (E) -4-methylsulfanyl-beta-bromostyrene, 0.1 equivalent of ferrous chloride, 3 equivalents of bis (pinacolato) bisborate, 3 equivalents of lithium t-butoxide, 0.1 equivalent of 1, 2-bis (diphenylphosphine) ethane, 2.5 equivalents of 1- [ (trans ) -4'- (3-butenyl) [1,1' -dicyclohexyl ] -4-yl ] -4-methylbenzene and 3 equivalents of 1-bromoperfluorohexane were weighed, and then 1mL of methyl t-butyl ether was added by syringe and mixed uniformly;
(3) Taking out the glass bottle from the glove box, and putting the glass bottle into a constant temperature stirrer at 80 ℃ for reaction for 10 hours;
(4) The glass bottle was taken out of the thermostatic stirrer, quenched by addition of 1mL of saturated ammonium chloride solution (concentration 6.95 mol/L), extracted 3 times with 10mL each time with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, finally concentrated in vacuo and purified by petroleum ether: ethyl acetate = 100:2 (v: v) as eluent by flash column chromatography gave 123.6mg (product 3) as a colorless transparent liquid in 81% yield.
The product 3 was structurally characterized, and the results are shown in fig. 7-9, specifically: 1 H NMR(400MHz,CDCl 3 )δ7.32(d,J＝8.8Hz,2H),7.12(s,4H),6.88(d,J＝8.8Hz,2H),6.38(d,J＝16Hz,1H),5.87(dd,J＝15.6,9.2Hz,1H),3.82(s,3H),2.70-2.61(m,1H),2.49-2.39(m,1H),2.34(s,3H),2.27-2.13(m,2H),1.95-1.91(m,4H),1.86-1.84(m,2H),1.81-1.76(m,4H),1.65-1.57(m,1H),1.48-1.42(m,2H),1.33-1.24(m,2H),1.20-1.16(m,4H),1.06-1.01(m,2H),0.96-0.87(m,2H). 13 C NMR(100MHz,CDCl 3 )δ159.0,144.9,135.1,130.5,130.1,130.0,128.9,127.3,126.6,114.0,55.3,44.2,43.4,42.9,38.0,36.6,36.0(t,J＝21Hz),34.7,34.6,33.7,33.4,33.2,30.4,30.0,30.0,20.9. 19 FNMR(376MHz,CDCl 3 )δ-80.82(t,J＝9.4Hz,3F),-111.00–-113.42(m,2F),-121.70–-121.82(m,2F),-122.77–-122.89(m,2F),-123.52–-123.61(m,2F),-126.07–-126.18(m,2F).HRMS(EI):calcd for C 38 H 43 F 13 O[M] + :762.3106,found:762.3146.
comparative example 1
1, 2-bis (diphenylphosphine) ethane was replaced with 2,2' -bipyridine, with the other conditions being the same as in example 1.
Comparative example 2
Substitution of ferrous chloride for NiBr 2 The other conditions were the same as in example 1.
Comparative example 3
Substitution of ferrous chloride for CuCl 2 The other conditions were the same as in example 1.
Comparative example 4
The ferrous chloride was omitted and the rest of the conditions were the same as in example 1.
Comparative example 5
The lithium tert-butoxide was replaced with sodium tert-butoxide, and the other conditions were the same as in example 1.
Comparative example 6
The lithium tert-butoxide was replaced by potassium methoxide and the rest of the conditions were the same as in example 1.
Comparative example 7
The lithium t-butoxide was omitted and the other conditions were the same as in example 1.
Comparative example 8
The bipartite pinacol biborate was omitted and the other conditions were the same as in example 1.
Yield data for comparative examples 1-8 are shown in table 1.
Table 1 comparison of yields of comparative examples 1-8
| Sequence number | Catalyst | Reducing agent | Alkali | Ligand | Yield rate |
| Comparative example 1 | FeCl 2 | B 2 pin 2 | t-BuOLi | 2,2' -bipyridines | 48％ |
| Comparative example 2 | NiBr 2 | B 2 pin 2 | t-BuOLi | dppe | 17％ |
| Comparative example 3 | CuCl 2 | B 2 pin 2 | t-BuOLi | dppe | n.d. |
| Comparative example 4 | / | B 2 pin 2 | t-BuOLi | dppe | n.d. |
| Comparative example 5 | FeCl 2 | B 2 pin 2 | t-BuONa | dppe | 19％ |
| Comparative example 6 | FeCl 2 | B 2 pin 2 | Potassium methoxide | dppe | 50％ |
| Comparative example 7 | FeCl 2 | B 2 pin 2 | / | dppe | n.d. |
| Comparative example 8 | FeCl 2 | / | t-BuOLi | dppe | n.d. |
Wherein: b (B) 2 pin 2 In the case of the bispinacol bisborate, t-Buoli is lithium tert-butoxide, t-Buona is sodium tert-butoxide, dppe is 1, 2-bis (diphenylphosphine) ethane, and n.d indicates that the product was not detected.
Analysis of results: comparative example 1 the conversion of the bisphosphine ligand dppe to the dinitrogen ligand 2,2' -bipyridine resulted in a decrease in yield. Comparative examples 2 and 3 show that, in the case of nickelWhen the catalyst or copper catalyst is used instead of the iron catalyst, the productivity is greatly reduced, and even the reaction cannot occur. Comparative example 4 shows that this reaction cannot proceed without the addition of iron catalyst. Comparative examples 5 and 6 show that the yield is greatly reduced when sodium tert-butoxide or potassium methoxide is used instead of lithium tert-butoxide. Comparative examples 7 and 8 show that without addition of alkali lithium t-butoxide or reducing agent B 2 pin 2 At this time, the reaction cannot proceed. In view of the above, the selection of standard reaction conditions is advantageous.
Claims (10)
1. A method for iron-catalyzed, non-activated olefin selective difunctional reactions, comprising the steps of: in an organic solvent, halogenated fluorinated alkane and beta-halogenated aryl ethylene are used as electrophiles, an iron-containing reagent is used as a catalyst, a boron-containing reagent is used as a reducing reagent, and under the action of alkali and ligand, non-activated alkene is reacted, and a difunctional reaction is selectively carried out, wherein the reaction formula is shown as follows:
wherein: r is R f -X represents a halofluoroalkane; r is R 1 、R 2 、R 3 Represents a substituent on an olefin, R 4 Representing a substituent on an aromatic ring.
2. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 1 wherein: the R is f Represents a fluoroalkane, and X represents a halogen.
3. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 1 wherein: the R is 1 、R 2 、R 3 Represents a substituent on an olefin, which is each independently selected from hydrogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 Halogen-substituted alkyl or C 1 -C 20 Alkylaryl groups of (a).
4. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 1 wherein: the R is 4 Represents substituents on the aromatic ring, where the substituents on the aromatic ring are optionally selected from C 1 -C 20 Alkyl groups, halogen atoms, carbonyl groups, silyl ethers, or cyano groups.
5. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 1 wherein: the organic solvent is methyl tertiary butyl ether, the halogenated alkane is 1-bromoperfluorohexane, the beta-halogenated aryl ethylene is (E) -4-methylthio-beta-bromostyrene, the iron-containing reagent is ferrous chloride, the boron-containing reagent is bis (pinacolato) biborate, the base is lithium tert-butoxide, the ligand is 1, 2-bis (diphenylphosphine) ethane, and the non-activated olefin is 4-phenyl-1-butene, allyltrimethylsilane or 1- [ (trans ) -4'- (3-butenyl) [1,1' -dicyclohexyl ] -4-yl ] -4-methylbenzene.
6. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 5 wherein: the molar ratio of the halogenated alkane to the beta-halogenated aryl ethylene to the iron-containing reagent to the boron-containing reagent to the alkali to the ligand to the non-activated alkene is 2-4:1:0.05-0.2:2-3.5:2-3.5:0.05-0.2:2-3.
7. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 6 wherein: the molar ratio of the halogenated alkane, the beta-halogenated aryl ethylene, the iron-containing reagent, the boron-containing reagent, the alkali, the ligand and the non-activated olefin is 3:1:0.1:2.5:2.5:0.1:2.5.
8. the method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 5 wherein: the methyl tertiary butyl ether requires a pre-drying treatment with sodium prior to use.
9. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 1 wherein: the reaction temperature is 75-85 ℃, and the reaction time is 10-14h.
10. The method for iron-catalyzed non-activated olefin selective difunctional reaction according to claim 9 wherein: the reaction temperature is 80 ℃ and the reaction time is 12h.
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