CN115872900A - Method for generating and capturing alkyl free radical, product thereof and application of product - Google Patents
Method for generating and capturing alkyl free radical, product thereof and application of product Download PDFInfo
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Abstract
The application provides a method for generating and capturing alkyl free radicals, and a product and application of the product, wherein the method comprises the following steps: carrying out a photocatalytic reaction on primary alkyl ethylbenzene and a capture reagent under the condition of a photocatalyst; the primary alkyl ethylbenzene has the following structure:
Description
Technical Field
The application belongs to the technical field of organic compound synthesis, and particularly relates to a method for generating and capturing alkyl free radicals, a product thereof and application of the product.
Background
With the understanding of people on the mechanism of photocatalysis and the development of a photo-oxidation-reduction catalyst, the photo-oxidation-reduction catalysis initiated by visible light is rapidly developed, and remarkable achievement is achieved, so that the modern free radical chemistry is thoroughly changed. Among them, alkyl radicals play an indispensable role in the development of novel synthesis methods under photo/electrochemical catalysis.
Typically, precursors of alkyl radicals undergo a single electron transfer with the aid of a photoredox catalyst to produce transient alkyl radicals capable of participating in various bond formation processes in a chemically and stereoselective manner. Despite the developments that have resulted in a large number of alkyl radical precursors that have essentially heteroatom groups that can be modified by functional groups to reduce the energy barrier between the excited states of the substrate and the photosensitizer, the use of common, commercially available, pure alkyl backbone chemicals to generate alkyl radicals in a precisely controlled manner has received little attention. The direct generation of alkyl radicals from simple, non-activated pure alkyl precursors remains a significant challenge in photo-redox catalysis due to the high oxidation potential of the pure alkyl backbone.
Disclosure of Invention
Based on this, it is an object of the present application to provide a method for generation and capture of alkyl radicals to solve the technical problem existing in the prior art that the direct generation of alkyl radicals from simple non-activated pure alkyl precursors remains a significant challenge in photo-redox catalysis.
It is a further object of the present application to provide a product made by the above process.
It is a further object of the present application to provide the use of the above-mentioned products.
In order to achieve the purpose, the technical scheme adopted by the application is as follows:
a method of alkyl radical generation and capture comprising the steps of:
carrying out a photocatalytic reaction on primary alkyl ethylbenzene and a capture reagent under the condition of a photocatalyst;
the primary alkyl ethylbenzene has the following structure:
R 1 any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, alkoxy, alkenylalkyl, alkynylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, silylalkyl, halogen, phthalimidyl, and hydrogen atom;
the capture reagent contains an unsaturated bond or an electron withdrawing group.
Optionally, the method for performing a photocatalytic reaction of the primary alkyl-ethylbenzene and the capture reagent under the condition of the photocatalyst comprises the following steps:
mixing the first-grade alkyl ethylbenzene, the capture reagent, the photocatalyst solution and the additive, and carrying out a photocatalytic reaction under the irradiation of blue light.
Optionally, the capture reagent is benzylidene malononitrile;
the structure of the product of the photocatalytic reaction by light is as follows:
optionally, the photocatalyst is an acridine salt photocatalyst.
Alternatively, the general structural formula of the acridine salt catalyst is as follows:
wherein, X is any one of tetrafluoroborate anion, hexafluorophosphate anion and perchlorate anion;
ar is aryl or substituted aryl;
R 2 、R 3 each independently is any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkenylalkyl, alkynylalkyl, cyanoalkyl.
Optionally, the additive comprises water and an oxidizing agent.
Optionally, the molar ratio of the photocatalyst, the oxidant and the water is (0.1-20): (0.2-40);
and/or the oxidizing agent comprises at least one of persulfates, monoxides, quinones, potassium permanganate, peroxy compounds, oxygen, and N-fluorobenzenesulfonylimide.
Optionally, the product of the photo-catalytic reaction comprises one of the following structural formulas:
and, a product produced by the method of alkyl radical generation and capture as described above.
And the application of the product in the synthesis of drug intermediates, the preparation of functional materials and metal ligands.
The application provides beneficial effect lies in:
1. according to the method for generating and capturing the alkyl free radicals, primary alkyl ethylbenzene is used as a reaction substrate, the alkyl ethylbenzene is oxidized through single electron transfer, then the carbon-carbon bond breakage is induced under the condition of a photocatalyst through illumination, the alkyl free radicals are generated, and then the alkyl free radicals and a capturing reagent are subjected to synthesis reaction; the method for generating and capturing the alkyl free radicals obviously reduces the production cost for preparing the captured products, and also greatly expands the designability and application prospect of the compounds;
2. the addition product prepared by the method for generating and capturing the alkyl free radical has high functional group, so that the addition product is more diversified in the synthesis of a drug intermediate, the application of a functional material and a metal ligand, can be widely applied to the research fields of organic synthesis chemistry, biochemistry, asymmetric catalysis, pesticides and medicines, can effectively reduce the economic cost for the preparation of the drug intermediate and the functional material when being used for the synthesis of the drug intermediate and the preparation of a chiral ligand and the functional material, is environment-friendly, and is beneficial to application and popularization.
Detailed Description
In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clear, the following embodiments further describe the present application in detail. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
The compounds and derivatives thereof referred to in the examples of the present application are named according to the IUPAC (International Union of pure and applied chemistry) or CAS (chemical abstracts service, columbus, ohio) naming system. Accordingly, the groups of compounds specifically referred to in the examples of the present application are illustrated and described as follows:
with respect to "hydrocarbon group," the minimum and maximum values of the carbon atom content in a hydrocarbon group are indicated by a prefix, e.g., the prefix (Ca-Cb) alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C1-C6) alkyl refers to alkyl groups containing one to six carbon atoms.
"alkoxy" refers to a straight or branched, monovalent, saturated aliphatic chain bonded to an oxygen atom and includes, but is not limited to, groups such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (Ca-Cb) alkoxy means any straight or branched, monovalent, saturated aliphatic chain of alkyl groups containing from "a" to "b" carbon atoms bonded to an oxygen atom.
"alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" means a straight or branched, monovalent, saturated aliphatic chain attached to at least one heteroatom, such as, but not limited to, methylaminoethyl or other similar groups.
"alkenyl" refers to straight or branched chain hydrocarbons having one or more double bonds, including but not limited to, groups such as ethenyl, propenyl, and the like.
"Heteroalkenyl" means a straight or branched chain hydrocarbon with one or more double bonds attached to at least one heteroatom, including but not limited to, for example, vinylaminoethyl or other similar groups.
"alkynyl" refers to a straight or branched chain hydrocarbon with one or more triple bonds, including but not limited to, for example, ethynyl, propynyl, and other similar groups.
"Heteroalkynyl" means a straight or branched chain hydrocarbon with one or more triple bonds attached to at least one heteroatom, including but not limited to, groups such as ethynyl, propynyl, and the like.
"aryl" refers to a cyclic aromatic hydrocarbon including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or different. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b ] indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizyl, quinolyl, quinoxalyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and other similar groups.
"cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group. Cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
"Heterocycloalkyl" means a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different. Heterocycloalkyl groups include, but are not limited to, groups such as azepanyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, and the like.
"cycloalkenyl" refers to an unsaturated, monocyclic or polycyclic alkenyl group with one or more double bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cyclic ethenyl, cyclopropenyl, or other similar groups.
"Heterocycloalkenyl" means an unsaturated, monocyclic or polycyclic alkenyl radical having one or more double bonds, possibly condensed with an aromatic hydrocarbon radical, in which at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
"cycloalkynyl" refers to an unsaturated, monocyclic or polycyclic alkynyl group having one or more triple bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cycloalkynyl, cyclopropynyl, or the like.
"Heterocycloalkynyl" means an unsaturated, monocyclic or polycyclic alkynyl radical having one or more triple bonds, possibly condensed with an aromatic hydrocarbon radical, in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
The method for generating and capturing the alkyl free radical provided by the embodiment of the application comprises the following steps:
carrying out a photocatalytic reaction on primary alkyl ethylbenzene and a capture reagent under the condition of a photocatalyst;
the capture reagent contains an unsaturated bond or an electron withdrawing group.
The primary alkyl ethylbenzene has the following structure:
R 1 is any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, alkoxy, alkenylalkyl, alkynylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, silylalkyl, halogen, phthalimidyl, and hydrogen.
In the primary alkyl ethylbenzene, the connection between phenyl and methyl is stable, and the beta-carbon bond is relatively weak, so that beta-fracture is generated to obtain the product containing R 1 Alkyl radicals of the group.
The method for generating and capturing the alkyl free radicals provided by the embodiment of the application takes primary alkyl ethylbenzene as a reaction substrate, oxidizes the alkyl ethylbenzene through single electron transfer, further induces the alkyl ethylbenzene to generate carbon-carbon bond breakage under the condition of a photocatalyst through illumination, generates alkyl free radicals, and then captures the alkyl free radicals by a capture reagent to generate a synthesis reaction.
The reactant primary alkyl ethylbenzene plays a role of a nucleophilic reagent and can attack a compound containing an unsaturated bond or an electron-withdrawing group, so that the primary alkyl ethylbenzene and a capture reagent are subjected to addition reaction, the atom utilization rate of the reactant is effectively improved, the limitation of a substrate can be widened, and a target product with high chemical selectivity and a wide range can be efficiently and greenly prepared.
The method for generating and capturing the alkyl free radicals in the embodiment of the application obviously reduces the production cost for preparing the captured products, and also greatly expands the designability and application prospect of the compounds.
Optionally, the method for performing the photocatalytic reaction of the primary alkyl ethylbenzene and the capture reagent under the condition of the photocatalyst comprises the following steps:
mixing the primary alkyl ethylbenzene, the capture reagent, the photocatalyst solution and the additive, and carrying out a photocatalytic reaction under the irradiation of blue light.
Alternatively, the capture reagent is benzylidene malononitrile, the structure of which is as follows:
The structure of the product of the photocatalytic reaction of primary alkyl ethylbenzene with benzylidene malononitrile is as follows:
R 1 is any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, alkoxy, alkenylalkyl, alkynylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, silylalkyl, halogen, phthalimidyl, and hydrogen.
In particular, R 1 Can be selected from C1-C20 alkyl, C1-C20 heteroalkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C2-C20 alkenyl, C2-C20 heteroalkenyl, C3-C20 cycloalkenyl, C3-C20 heterocycloalkenyl, C2-C20 alkynyl, C2-C20 heteroalkynyl, C3-C20 cycloalkynyl, C3-C20 heteroalkynylAny one of cycloalkynyl, C1-C20 alkoxy, C2-C20 alkenyl (C1-C20) alkyl, C2-C20 alkynyl (C1-C20) alkyl, cyano (C1-C20) alkyl, alkyloxycarbonylalkyl, silylalkyl C3-C20, halogen, phthalimidyl, and hydrogen atom.
When R is 1 In the case of a C1-C20 alkyl group, the C1-C20 alkyl group may be a (C1-C10) alkyl group, a (C1-C5) alkyl group, a (C1-C4) alkyl group, a (C1-C3) alkyl group, a (C1-C2) alkyl group or the like. In some embodiments, the (C1-C20) alkyl group can be specifically any of methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, and the like.
When R is 1 When the (C1-C20) heteroalkyl group is a (C1-C20) heteroalkyl group, the (C1-C10) heteroalkyl group, the (C1-C5) heteroalkyl group, the (C1-C4) heteroalkyl group, the (C1-C3) heteroalkyl group or the (C1-C2) heteroalkyl group may be mentioned. In some embodiments, the heteroatom of the heteroalkyl group may be a halogen or nitrogen atom, or the like.
When R is 1 When it is (C3-C20) cycloalkyl, (C3-C20) cycloalkyl may be (C3-C10) cycloalkyl, (C3-C5) cycloalkyl or (C3-C4) cycloalkyl, etc. In one embodiment, the (C3-C20) cycloalkyl group may be one of cyclopropyl, cyclobutyl, cyclopentyl, and the like.
When R is 1 In the case of (C3-C20) heterocycloalkyl, the (C3-C20) heterocycloalkyl group may be a (C3-C10) heterocycloalkyl group, a (C3-C5) heterocycloalkyl group, a (C3-C4) heterocycloalkyl group or the like. In one embodiment, the heteroatoms in the heterocycloalkyl group can be halogen, nitrogen, and the like.
When R is 1 In the case of (C2-C20) alkenyl, (C2-C20) alkenyl may be (C3-C10) alkenyl, (C3-C5) alkenyl, (C3-C4) alkenyl or (C2-C3) alkenyl, etc. In some embodiments, the (C2-C20) alkenyl group can specifically be ethenyl, propenyl, butenyl, pentenyl, and the like.
When R is 1 When the (C2-C20) heteroalkenyl group is a (C2-C20) heteroalkenyl group, the (C2-C20) heteroalkenyl group may be a (C2-C10) heteroalkenyl group, a (C3-C5) heteroalkenyl group, a (C3-C4) heteroalkenyl group, or a (C2-C3) heteroalkenyl group. In some embodiments, the heteroatom of the heteroalkenyl group can be a halogen, a nitrogen atom, a sulfur atom, and the like.
When R is (C3-C20) cycloalkenyl, the (C3-C20) cycloalkenyl group may be (C3-C10) cycloalkenyl, (C3-C5) cycloalkenyl or (C3-C4) cycloalkenyl, and the like. In some embodiments, the (C3-C20) cycloalkenyl group can be cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like.
When R is 1 In the case of (C3-C20) heterocycloalkenyl, the (C3-C20) heterocycloalkenyl may be (C3-C10) heterocycloalkenyl, (C3-C5) heterocycloalkenyl, or (C3-C4) heterocycloalkenyl, etc. In some embodiments, the heteroatom of the heterocycloalkenyl can be a halogen, a nitrogen atom, a sulfur atom, and the like.
When R is 1 When (C2-C20) alkynyl is (C2-C20) alkynyl, the (C2-C20) alkynyl may be (C2-C10) alkynyl, (C3-C5) alkynyl, (C3-C4) alkynyl, or (C2-C3) alkynyl, for example. In some embodiments, the (C2-C20) alkynyl group can be one of ethynyl, propynyl, butynyl, pentynyl, and the like.
When R is 1 In the case of (C2-C20) heteroalkynyl, (C2-C20) heteroalkynyl may be (C2-C10) heteroalkynyl, (C3-C5) heteroalkynyl, (C3-C4) heteroalkynyl, or (C2-C3) heteroalkynyl. In some embodiments, the heteroatom of the heteroalkynyl can be a halogen, nitrogen atom, sulfur atom, and the like.
When R is 1 In the case of (C3-C20) cycloalkynyl, (C3-C20) cycloalkynyl may be (C3-C10) cycloalkynyl, (C3-C5) cycloalkynyl, (C3-C4) cycloalkynyl, etc. In some embodiments, the (C2-C20) cycloalkynyl group can be cyclopropynyl, cyclobutynyl, cyclopentynyl, and the like.
When R is 1 In the case of (C3-C20) heterocycloalkynyl, the (C3-C20) heterocycloalkynyl may be (C3-C10) heterocycloalkynyl, (C3-C5) heterocycloalkynyl, or (C3-C4) heterocycloalkynyl. In some embodiments, the heteroatom of the heterocyclic alkynyl group can be a halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 In the case of the (C1-C20) alkoxy group, the (C1-C20) alkoxy group may be a (C1-C10) alkoxy group, a (C1-C8) alkoxy group, a (C1-C6) alkoxy group, a (C1-C4) alkoxy group, a (C1-C3) alkoxy group, a (C1-C2) alkoxy group or the like. In some embodiments, the (C1-C20) alkoxy group can be, but is not limited to, methyloxy, ethyloxy, propyloxy, and the like.
When R is 1 When it is (C2-C20) alkenyl (C1-C20) alkyl, (C2-C20) alkenyl (C1-C20) alkyl may be (C2-C10) alkenyl (C1-C10) alkyl or (C2-C5) alkenyl (C1-C3)) Alkyl groups, and the like. In some embodiments, the (C2-C20) alkenyl (C1-C20) alkyl can be 2-butenyl, 2-pentenyl, 3-hexenyl, 3-heptenyl, and the like.
When R is 1 In the case of (C2-C20) alkynyl (C1-C20) alkyl, (C2-C20) alkynyl (C1-C20) alkyl may be (C2-C10) alkynyl (C1-C10) alkyl, (C2-C5) alkynyl (C1-C3) alkyl, etc. In some embodiments, the (C2-C20) alkynyl (C1-C20) alkyl can be 2-butynyl, 2-pentynyl, 3-hexynyl, 3-heptynyl, and the like.
When R is 1 When cyano (C1-C20) alkyl is used, cyano (C1-C20) alkyl may be cyano (C1-C10) alkyl, cyano (C1-C5) alkyl, cyano (C1-C4) alkyl, cyano (C1-C3) alkyl, cyano (C1-C2) alkyl, or the like. In some embodiments, cyano (C1-C20) alkyl may be cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, and the like.
When R is 1 When it is an alkyloxycarbonylalkyl group, the alkyloxycarbonylalkyl group may be a (C1-C10) alkyloxycarbonyl (C1-C10) alkyl group, a (C1-C5) alkyloxycarbonyl (C1-C5) alkyl group, a (C1-C4) alkyloxycarbonyl (C1-C4) alkyl group, a (C1-C3) alkyloxycarbonyl (C1-C3) alkyl group, a (C1-C2) alkyloxycarbonyl (C1-C2) alkyl group or the like. In some embodiments, the alkyloxycarbonylalkyl can be specifically ethoxycarbonylethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylmethyl, propoxycarbonylpropyl, propoxycarbonylethyl, propoxycarbonylmethyl, and the like.
Optionally, the photocatalyst is an acridine salt photocatalyst. In some embodiments, the photocatalyst solution is an acetonitrile solution of the photocatalyst, i.e., acetonitrile is the solvent.
Alternatively, the general structural formula of the acridine salt catalyst is as follows:
wherein, X is any one of tetrafluoroborate anion, hexafluorophosphate anion and perchlorate anion;
ar is aryl or substituted aryl;
R 2 、R 3 each independently is any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkenylalkyl, alkynylalkyl, cyanoalkyl.
Optionally, the additive comprises water and an oxidizing agent.
When the reaction substrate is first-grade alkyl ethylbenzene, the capture reagent is benzylidene malononitrile, the photocatalyst is an acridine salt catalyst, and the additive comprises water and an oxidant, the reaction mechanism of the photocatalytic reaction is as follows:
in the chemical reaction formula, the acridine salt catalyst, the oxidant and the water have synergistic effect, wherein the photocatalyst can provide better single-electron oxidation effect, so that the carbon-carbon bond breaking efficiency is improved in the catalytic reaction process, and the oxidant and the water are used for constructing a core alcohol intermediate, so that the catalytic system is low in toxicity, the atom utilization rate and the reaction efficiency are improved, and few byproducts are generated; meanwhile, the reaction process is safe and controllable, and the operation in the preparation production process is simplified.
In some embodiments, the molar ratio of the photocatalyst to the oxidant to the water is (0.1-20): (0.1-20): 0.2-40, and the content ratio of the photocatalyst to the oxidant to the water is controlled, so that the reaction has high catalytic efficiency and the yield of the target product is improved. Preferably, the molar ratio of the photocatalyst to the oxidant to the water is (0.2-20) to 2.5 (1-10), so that the target product with the highest yield can be obtained.
Optionally, the oxidizing agent includes at least one of persulfates, monoxides, quinones, potassium permanganate, peroxy species, oxygen, and N-fluorobenzenesulfonylimide.
Optionally, the product of the photocatalytic reaction comprises one of the following structural formulas:
the addition product prepared by the method for generating and capturing the alkyl free radical has high functional group, so that the addition product is more diversified in the synthesis of a drug intermediate, the application of a functional material and a metal ligand, can be widely applied to the research fields of organic synthesis chemistry, biochemistry, asymmetric catalysis, pesticides and medicines, can effectively reduce the economic cost for the preparation of the drug intermediate and the functional material when being used for the synthesis of the drug intermediate and the preparation of a chiral ligand and the functional material, is environment-friendly, and is beneficial to application and popularization.
The following is illustrated by a number of examples.
Example 1
This example provides a compound, 2- (1-phenylpropyl) malononitrile, and a method for preparing the same, wherein the structural formula of 2- (1-phenylpropyl) malononitrile is shown in the following molecular structural formula I:
the preparation method of the 2- (1-phenylpropyl) malononitrile comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), the capture reagent benzylidenemalononitrile (0.2mmol, 30.8mg) and the oxidant ammonium persulfate (0.5mmol, 114mg) were weighed into an oven-dried 8mL vial equipped with a magnetic star-bar, acetonitrile and water (1 mL and 0.1 mL) were added, followed by alkylethylbenzene (first order) (0.4 mmol) to give a reaction solution.
The structure of alkyl ethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC, and a photocatalytic reaction was performed to obtain a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 81% yield.
Correlation characterization analysis, the result is 1 H NMR(400MHz,Chloroform-d)δ7.49–7.37(m,3H),7.36–7.30(m,2H),3.92(d,J＝6.3Hz,1H),3.15(ddd,J＝10.9,6.3,5.0Hz,1H),2.23–1.96(m,2H),0.94(t,J＝7.3Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ136.53,129.29,128.89,127.86,111.90,48.25,30.05,25.41,11.67.HRMS(ESI-TOF)calculated for C 12 H 12 N 2 (M-H + ):183.0928,found:183.0921。
This result further confirms the molecular structure of the product as in molecular structure I above.
Example 2
This example provides the compound 2- (1-phenyloctyl) malononitrile, the structural formula of which is shown below in molecular formula II:
the preparation method of the 2- (1-phenyloctyl) malononitrile comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), the capture reagent benzylidenemalononitrile (0.2mmol, 30.8mg) and the oxidant ammonium persulfate (0.5mmol, 114mg) were weighed into an oven-dried 8mL vial equipped with a magnetic star-bar, acetonitrile and water (1 mL and 0.1 mL) were added, followed by alkylethylbenzene (first order) (0.4 mmol) to give a reaction solution.
The structure of alkyl ethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC, and a photocatalytic reaction was performed to obtain a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 75% yield.
Correlation characterization analysis, the result is 1 H NMR(400MHz,Chloroform-d)δ7.49–7.37(m,3H),7.37–7.31(m,2H),3.90(d,J＝6.2Hz,1H),3.22(dt,J＝8.9,6.5Hz,1H),2.02(td,J＝8.4,5.8Hz,2H),1.40–1.29(m,3H),1.27–1.14(m,7H),0.88(t,J＝6.9Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ129.28,128.85,127.80,111.91,46.62,32.11,31.65,30.27,29.09,28.92,26.97,22.55,14.04.HRMS(ESI-TOF)calculated for C 17 H 22 N 2 (M-H + ):253.1710,found:253.1709。
This result further confirms the molecular structure of the product as in molecular structure II above.
Example 3
This example provides the compound 2- (2- (4-isobutylphenyl) -1-phenylpropyl) malononitrile, the structural formula of which is shown in molecular structural formula III below, and a process for its preparation, 2- (2- (4-isobutylphenyl) -1-phenylpropyl) malononitrile:
the preparation method of 2- (2- (4-isobutylphenyl) -1-phenylpropyl) malononitrile comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), the capturing agent benzylidenemalononitrile (0.2mmol, 30.8mg) and the oxidizing agent sodium persulfate (0.5mmol, 119mg) were weighed into an oven-dried 8mL vial equipped with a magnetic star-bar, acetonitrile and water (1 mL and 0.1 mL) were added, followed by alkylethylbenzene (first order) (0.4 mmol) to obtain a reaction solution.
The structure of alkyl ethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC, and a photocatalytic reaction was performed to obtain a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 85% yield.
Correlation characterization analysis, the result is 1 H NMR(400MHz,Chloroform-d)δ7.42(dddd,J＝12.5,10.3,6.1,1.9Hz,3H),7.37–7.31(m,2H),3.87(d,J＝6.2Hz,1H),3.33(ddd,J＝11.0,6.2,4.5Hz,1H),2.05(ddd,J＝13.6,11.3,4.4Hz,1H),1.82–1.71(m,1H),1.45(dpd,J＝9.6,6.6,4.3Hz,1H),0.94(dd,J＝10.0,6.6Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ136.67,129.30,128.88,127.88,111.90,44.67,40.89,30.61,25.23,23.34,21.09.HRMS(ESI-TOF)calculated for C 14 H 16 N 2 (M-H + ):211.1241,found:211.1237。
This result further confirms the molecular structure of the product as described above for molecular structure III.
Example 4
This example provides the compound 2- (2-methoxy-1-phenylethyl) malononitrile, the structural formula of which is shown below as molecular structural formula IV, and a process for its preparation:
the preparation method of the 2- (2-methoxy-1-phenethyl) malononitrile comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), the capture reagent benzylidenemalononitrile (0.2mmol, 30.8mg) and the oxidant potassium persulfate (0.5mmol, 135mg) were weighed into an oven-dried 8mL vial equipped with a magnetic star-bar, acetonitrile and water (1 mL and 0.1 mL) were added, followed by alkylethylbenzene (first order) (0.4 mmol) to give a reaction solution.
The structure of the alkylethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC for photocatalytic reaction to give a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 57% yield.
Correlation characterization analysis, the result is 1 H NMR(400MHz,Chloroform-d)δ7.50–7.34(m,5H),4.43(d,J＝5.9Hz,1H),3.90–3.75(m,2H),3.48(s,4H). 13 C NMR(101MHz,Chloroform-d)δ134.46,129.25,128.15,112.09,111.61,71.59,59.33,46.44,26.29.HRMS(ESI-TOF)calculated for C 12 H 12 N 2O (M-H + ):199.0877,found:199.0872.
This result further confirms the molecular structure of the product as described above for molecular structure IV.
Example 5
This example provides the compound 2- (2- (1,3-dioxoisoindolin-2-yl) -1-phenylethyl) malononitrile and a process for its preparation, 2- (2- (1,3-dioxoisoindolin-2-yl) -1-phenylethyl) malononitrile having the following molecular structure V:
the preparation method of 2- (2- (1,3-dioxoisoindolin-2-yl) -1-phenylethyl) malononitrile comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), the capture reagent benzylidenemalononitrile (0.2mmol, 30.8 mg) and the oxidant ammonium persulfate (0.5mmol, 114mg) were weighed into an oven-dried 8mL vial equipped with a magnetic star-bar, acetonitrile and water (1 mL) were addedAnd 0.1 mL), followed by addition of alkylethylbenzene (first order) (0.4 mmol) to give a reaction solution.
The structure of alkyl ethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC, and a photocatalytic reaction was performed to obtain a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 48% yield.
Correlation characterization analysis, the result is 1 H NMR(400MHz,Chloroform-d)δ7.87(dd,J＝5.5,3.1Hz,2H),7.76(dd,J＝5.5,3.0Hz,2H),7.42(m,J＝2.8Hz,5H),4.27(d,J＝7.5Hz,2H),4.17(d,J＝6.2Hz,1H),3.92(td,J＝7.5,6.2Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ167.94,134.50,133.79,131.49,129.57,129.40,128.04,123.73,44.85,39.69,27.89.HRMS(ESI-TOF)calculated for C 19 H 13 N 3O (M-H + ):314.0935,found:314.0938。
This result further confirms the molecular structure of the product as the above molecular structure V.
Example 6
This example provides 6,6-dicyano-5-phenylhexyl cyclohexane carboxylate, 6,6-dicyano-5-phenylhexyl cyclohexane carboxylate, having the following molecular structure VI:
5363A method for preparing a 6,6-dicyano-5-phenylhexylcyclohexanecarboxylate comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), capture reagent benzylidenemalononitrile (0.2mmol, 30.8 mg) andthe oxidant potassium persulfate (0.5mmol, 135mg) was weighed into an oven-dried 8mL vial equipped with a magnetometric star-bar, acetonitrile and water (1 mL and 0.1 mL) were added, followed by alkylethylbenzene (first order) (0.4 mmol) to give a reaction solution.
The structure of alkyl ethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC, and a photocatalytic reaction was performed to obtain a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 46% yield.
Correlation characterization analysis, the result is 1 H NMR(400MHz,Chloroform-d)δ7.50–7.35(m,3H),7.35–7.30(m,2H),4.09–3.96(m,2H),3.91(d,J＝6.4Hz,1H),3.23(dt,J＝8.8,6.5Hz,1H),2.25(tt,J＝11.2,3.6Hz,1H),2.12–2.01(m,2H),1.90–1.79(m,2H),1.78–1.70(m,2H),1.70–1.57(m,3H),1.45–1.29(m,4H),1.28–1.16(m,3H). 13 C NMR(101MHz,Chloroform-d)δ176.01,136.41,129.37,128.98,127.78,111.83,111.78,63.29,46.56,43.17,31.73,30.28,28.98,28.23,25.72,25.41,23.52.HRMS(ESI-TOF)calculated for C 21 H 26 N 2O2 (M-H + ):337.1922,found:337.1924。
This result further confirms the molecular structure of the product as that of molecular structure VI described above.
Example 7
This example provides the compound 6,6-dicyano-5-phenylhexyl-3,7-dimethyl octanoate and its preparation, 6,6-dicyano-5-phenylhexyl-3,7-dimethyl octanoate, having the structural formula shown in molecular formula VII below:
the preparation method of 6,6-dicyano-5-phenylhexyl-3,7-dimethyl caprylate comprises the following steps:
s01: the photocatalyst Mes-Acr-PhBF is added 4 (0.01mmol, 4.6 mg), the capture reagent benzylidenemalononitrile (0.2mmol, 30.8mg) and the oxidant ammonium persulfate (0.5mmol, 114mg) were weighed into an oven-dried 8mL vial equipped with a magnetic star-bar, acetonitrile and water (1 mL and 0.1 mL) were added, followed by alkylethylbenzene (first order) (0.4 mmol) to give a reaction solution.
The structure of alkyl ethylbenzene (primary) is as follows:
s02: the reaction vessel was degassed, backfilled with argon, and the reaction solution was irradiated under a Kessil lamp at 450nm (40W), and the progress of the reaction was monitored by TLC, and a photocatalytic reaction was performed to obtain a mixture.
S03: the mixture was concentrated and then purified by flash column chromatography on silica gel to obtain the desired product in 57% yield.
Correlation characterization analysis, the result is 1 H NMR(500MHz,Chloroform-d)δ7.46–7.34(m,3H),7.34–7.28(m,2H),4.08–3.97(m,2H),3.89(d,J＝6.3Hz,1H),3.21(dt,J＝9.0,6.5Hz,1H),2.26(dd,J＝14.7,5.9Hz,1H),2.11–1.98(m,3H),1.89(h,J＝6.8Hz,1H),1.66(dddd,J＝25.8,12.8,8.5,6.7Hz,2H),1.52(dq,J＝13.3,6.6Hz,1H),1.35–1.22(m,5H),1.20–1.09(m,3H),0.88(dd,J＝9.3,6.6Hz,9H). 13 C NMR(126MHz,Chloroform-d)δ173.25,136.50,129.40,129.03,127.78,111.83,111.77,63.43,46.64,41.85,39.09,36.99,31.79,30.38,30.28,28.27,27.94,24.63,23.62,22.66,22.58,19.73.HRMS(ESI-TOF)calculated for C 24 H 34 N 2 O 2 (M-H + ):381.2548,found:381.2550。
This result further confirms the molecular structure of the product as in molecular structure VII above.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A method for the generation and capture of alkyl radicals, characterized by: the method comprises the following steps:
carrying out a photocatalytic reaction on primary alkyl ethylbenzene and a capture reagent under the condition of a photocatalyst;
the primary alkyl ethylbenzene has the following structure:
the R is 1 Is any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, alkoxy, alkenylalkyl, alkynylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, silylalkyl, halogen, phthalimidyl, and hydrogen;
the capture reagent contains an unsaturated bond or an electron withdrawing group.
2. The method of generating and trapping alkyl radicals of claim 1, wherein: the method for carrying out the photocatalytic reaction on the primary alkyl ethylbenzene and the capture reagent under the condition of the photocatalyst comprises the following steps:
and mixing the primary alkyl ethylbenzene, the capture reagent, the photocatalyst solution and the additive, and carrying out a photocatalytic reaction under the irradiation of blue light.
3. The method for the generation and capture of alkyl radicals as claimed in claim 1 or 2, wherein: the capture reagent is benzylidene malononitrile;
the structure of the product of the photocatalytic reaction is as follows:
4. the method for the generation and capture of alkyl radicals as claimed in claim 1 or 2, wherein: the photocatalyst is an acridine salt photocatalyst.
5. The method for the generation and capture of alkyl radicals as claimed in claim 4, wherein: the structural general formula of the acridine salt catalyst is as follows:
wherein X is any one of tetrafluoroborate anion, hexafluorophosphate anion and perchlorate anion;
ar is aryl or substituted aryl;
R 2 、R 3 each independently is any one of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkenylalkyl, alkynylalkyl, cyanoalkyl.
6. The method of alkyl radical generation and capture as claimed in claim 2 wherein: the additive includes water and an oxidizing agent.
7. The method for the generation and capture of alkyl radicals as claimed in claim 6, wherein: the molar ratio of the photocatalyst to the oxidant to the water is (0.1-20) to (0.2-40);
and/or the oxidizing agent comprises at least one of persulfates, monoxides, quinones, potassium permanganate, peroxy compounds, oxygen and N-fluorobenzenesulfonylimide.
8. The method for the generation and capture of alkyl radicals as claimed in any one of claims 1, 2, 4 to 7, wherein: the product of the photocatalytic reaction comprises one of the following structural formulas:
9. a product produced by the method for the generation and capture of alkyl radicals as claimed in any one of claims 1 to 8.
10. Use of the product of claim 9 in the synthesis of pharmaceutical intermediates, functional materials and metal ligand preparation.
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