阅读说明：本技术 一种芳香苄基酮的合成方法 (Synthetic method of aromatic benzyl ketone ) 是由 王剑 王荣辉 全海迪 杜文婷 徐建宏 王玮 周倩 于 2020-06-08 设计创作，主要内容包括：本发明公开了一种芳香苄基酮的合成方法,所述合成方法包括：以氧气和/或空气为氧化剂,使式(I)所示的芳香苄基化合物在催化体系作用下进行氧化,制得式(II)所示的芳香苄基酮；所述的催化体系为三价铁离子、硝酸根和N-羟基酰亚胺衍生物三者联用并且不含对人体有害的重金属离子,其中三价铁离子与硝酸根的摩尔比为1：0.5-5,三价铁离子与N-羟基酰亚胺衍生物的摩尔比为0.01-0.1:0.03-0.2。本发明方法底物适用性广、原子利用率高、避免了铜、钴等有害重金属的使用,具有高效、经济、环保的特点。Ar-CH<Sub>2</Sub>-R(I)Ar-CO-R(II)。(The invention discloses a synthetic method of aromatic benzyl ketone, which comprises the following steps: oxidizing an aromatic benzyl compound shown in a formula (I) under the action of a catalytic system by taking oxygen and/or air as an oxidant to prepare aromatic benzyl ketone shown in a formula (II); the catalytic system is formed by combining ferric ions, nitrate radicals and N-hydroxyimide derivatives and does not contain heavy metal ions harmful to human bodies, wherein the molar ratio of the ferric ions to the nitrate radicals is 1: 0.5-5, and the mol ratio of the ferric ions to the N-hydroxyimide derivative is 0.01-0.1: 0.03-0.2. The method has the advantages of wide substrate applicability, high atom utilization rate, avoidance of the use of harmful heavy metals such as copper, cobalt and the like, and high efficiency, economy and environmental protection. Ar-CH 2 ‑R(I)Ar‑CO‑R(II)。)

1. A method of synthesizing an aromatic benzyl ketone, the method comprising: oxidizing an aromatic benzyl compound shown in a formula (I) under the action of a catalytic system by taking oxygen and/or air as an oxidant to prepare aromatic benzyl ketone shown in a formula (II); the catalytic system is formed by combining ferric ions, nitrate radicals and N-hydroxyimide derivatives and does not contain heavy metal ions harmful to human bodies, wherein the molar ratio of the ferric ions to the nitrate radicals is 1: 0.5-5, the mol ratio of ferric ions to the N-hydroxyimide derivative is 0.01-0.1: 0.03-0.2;

Ar-CH₂-R(I)Ar-CO-R(II)

wherein Ar is an aromatic ring or a substituted aromatic ring without heteroatoms, the substituent on the substituted aromatic ring is one or more, and each substituent is independently selected from methyl, C5-C12 aryl, amino, alkyl substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, amido or nitro;

r is selected from C1-C12 alkyl or C5-C12 aryl;

or-CH₂-R forms with the adjacent groups on the Ar ring a 5-7 membered heteroatom-free or heteroatom-containing ring a, said 5-7 membered ring a being unsubstituted or substituted by at least one of the following groups: methyl, C5-C12 aryl, amino, alkyl substituted amineThe compound comprises a 5-7-membered aromatic ring A, and optionally, the substituent on the 5-7-membered ring A and the adjacent group on the 5-7-membered ring A can further form a 5-7-membered aromatic ring B which is unsubstituted or substituted by at least one of methyl, C5-C12 aryl, amino, alkyl substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, acylamino and nitro, and when the compound (I) contains the 5-7-membered ring A, whether the 5-7-membered aromatic ring B is contained or not, at least one α position in the 5-7-membered ring A is-CH₂-for reaction to form a carbonyl group;

the C5-C12 aryl is unsubstituted or substituted by substituent groups, and the substituent groups are selected from amino, substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, amido or nitro.

2. The method of synthesis of claim 1, wherein: ar is a benzene ring or a naphthalene ring or an anthracene ring or a phenanthrene ring; the 5-7-membered aromatic ring B is a benzene ring; the heteroatom in ring a is O, N or S; the C5-C12 aryl is unsubstituted or substituted phenyl.

3. A method of synthesis as claimed in claim 1 or 2, characterized in that: the alkoxy is C1-C4 alkoxy; the acyloxy is C1-C4 alkanoyloxy or benzoyloxy; the amido is C1-C4 alkylamido; the alkyl substituted amine group is N, N- (C1-C4 alkyl) amine group.

4. A method of synthesis according to any one of claims 1 to 3, characterized in that: the catalysts added in the reaction system are ferric nitrate and N-hydroxyimide derivatives.

5. The method of synthesis of claim 4, wherein: in the reaction system, the feeding molar ratio of the ferric nitrate, the NHIs and the aromatic benzyl compound is 0.01-0.1:0.03-0.2: 1.

6. A method of synthesis according to any one of claims 1 to 3, characterized in that: the N-hydroxyimide derivative is selected from one of the following: n-hydroxyphthalimide, N ' -dihydroxypyromellitimide, N, N ', N ' -trihydroxyimine cyanuric acid, N-hydroxysuccinimide, N-hydroxy-1, 8-naphthalimide.

7. A method of synthesis according to any one of claims 1 to 3, characterized in that: the oxidation reaction takes oxygen and/or air as an oxidant, namely the oxidation reaction is carried out in oxygen or air or oxygen and air atmosphere, and the pressure of the oxygen and/or air is controlled to carry out the oxidation reaction under normal pressure.

8. A method of synthesis according to any one of claims 1 to 3, characterized in that: the oxidation reaction uses one of the following organic solvents as a reaction solvent: acetic acid, benzonitrile, acetonitrile, ethyl acetate.

9. The method of synthesis of claim 8, wherein: the oxidation reaction is carried out at a temperature of 60-150 ℃.

10. The method of synthesis of claim 9, wherein: the catalysts added into the reaction system are ferric nitrate and N-hydroxyimide derivatives, wherein the feeding molar ratio of the ferric nitrate to the NHIs to the aromatic benzyl compound is 0.01-0.1:0.03-0.2: 1; the N-hydroxyimide derivative is selected from one of the following: n-hydroxyphthalimide, N ' -dihydroxypyromellitimide, N, N ', N ' -trihydroxyimine cyanuric acid, N-hydroxysuccinimide, N-hydroxy-1, 8-naphthalimide.

The technical field is as follows:

the invention relates to a method for generating aromatic benzyl ketone by oxidizing benzylic methylene of aromatic benzyl compound.

(II) background technology:

the reaction of oxidizing the benzyl position of methylene compound to ketone is an important organic reaction and has important application in pharmaceutical, cosmetic, dye synthesis and other related industries. Among the many oxidants available for this oxidation reaction, oxygen is certainly the most inexpensive and readily available oxidant.

The oxidation of methylene or methyl compounds in oxygen or air is known as autoxidation. CN101759542B and CN101759540B use iron, manganese or cobalt and ligands, ethylbenzene or propylbenzene autoxidation obtains corresponding ketone, the metal catalyst used in the reaction mainly uses manganese or cobalt, which is easy to cause pollution, and needs to use large molecular weight bionic ligands and can not be recycled, the reaction system is complex, and the atom economy is low. The autoxidation reaction of p-nitrotoluene disclosed in CN108238946A does not use heavy metal catalyst, but the reaction needs to be carried out under higher pressure, and more than 5 equivalents of alkali are used, which causes waste and has certain safety hazard. CN102656143B directly and selectively oxidizes alkane by using oxygen, the reaction temperature is high, special equipment (bubble column type reactor) is needed, and the substrate is mainly saturated aliphatic hydrocarbon such as cyclohexane. CN107176899A uses ferric nitrate as catalyst and TEMPO as photoinitiator, and oxidizes alcohol or aldehyde under the catalysis of inorganic halide to obtain acid, the substrate is aliphatic alcohol or aldehyde, the alcohol or aldehyde is hydrocarbon oxidation product, and the availability is not as good as hydrocarbon. Furthermore, the use of TEMPO/halides also increases the complexity of the post-treatment and the polluting nature of the waste water.

N-hydroxyimide derivatives (NHIs) are a class of efficient free radical initiators which, in combination with metal catalysts, catalyze benzylic autoxidation. CN1814615A discloses CrO₃The allylic methylene autoxidation reaction of a/carrier/N-hydroxyphthalimide (NHPI)/dichloromethane system uses heavy metal cadmium which is easy to cause pollution as a co-catalyst. CN104109083B discloses a method for preparing adipic acid by cyclohexane autoxidation under the catalysis of NHIs, which uses cobalt salt and manganese salt which are easy to cause pollution to react to obtain a thorough oxidation product adipic acid. CN106423170A uses cobalt/graphene compound and NHPI to catalyze ethylbenzene autoxidation to acetophenone, although the amount of cobalt used in the reaction is small and the oxygen pressure is mild, the preparation process of the catalyst cobalt/graphene compound is complicated. CN107628947A applies an NHPI/cobalt acetate/oxygen catalytic system in the synthesis of the pemetrexed disodium key intermediate, and directly oxidizes benzyl methyl to carboxyl.

In summary, the autoxidation reaction of the aromatic benzyl compound usually uses cobalt, cadmium, manganese and the like as catalysts, the solution has dark color after the reaction is finished, and heavy metal ions harmful to human bodies are easily complexed with aromatic rings in the product, so that the application of the aromatic benzyl compound in the pharmaceutical and food industries is limited. Therefore, the development of an environment-friendly, high-selectivity and high-efficiency reaction from the perspective of green chemistry has great significance for reducing the cost and expanding the application range of the reaction.

(III) the invention content:

the technical problem to be solved by the invention is to provide a method for synthesizing aromatic benzyl ketone by oxidizing aromatic benzyl compound, which has the characteristics of wide applicability of substrate, high atom utilization rate, avoidance of use of harmful heavy metals such as copper, cobalt and the like, high efficiency, economy and environmental protection.

In order to solve the technical problems, the invention adopts the following technical scheme:

a method of synthesizing an aromatic benzyl ketone, the method comprising: oxidizing an aromatic benzyl compound shown in a formula (I) under the action of a catalytic system by taking oxygen and/or air as an oxidant to prepare aromatic benzyl ketone shown in a formula (II); the catalyst system is formed by combining ferric ions, nitrate radicals and N-hydroxyimide derivatives (NHIs) and does not contain heavy metal ions harmful to human bodies, wherein the molar ratio of the ferric ions to the nitrate radicals is 1: 0.5-5, the mol ratio of ferric ions to the N-hydroxyimide derivative is 0.01-0.1: 0.03-0.2;

Ar-CH₂-R(I) Ar-CO-R(II)

wherein Ar is an aromatic ring or a substituted aromatic ring without heteroatoms, the substituent on the substituted aromatic ring is one or more, and each substituent is independently selected from methyl, C5-C12 aryl, amino, alkyl substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, amido or nitro;

r is selected from C1-C12 alkyl or C5-C12 aryl;

or-CH₂-R forms with the adjacent groups on the Ar ring a 5-7 membered ring A containing no or no heteroatoms, said 5-7 membered ring A being unsubstituted orIs substituted by at least one of methyl, C5-C12 aryl, amino, alkyl substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, amido and nitro, optionally, the substituent on the 5-7 membered ring A can be further substituted with the adjacent group on the 5-7 membered ring A to form a 5-7 membered aromatic ring B which is unsubstituted or substituted by at least one of methyl, C5-C12 aryl, amino, alkyl substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, amido and nitro, and when the formula (I) contains the 5-7 membered ring A, at least one α position in the 5-7 membered ring A is-CH regardless of whether the 5-7 membered aromatic ring B is contained or not, at least one α position in the 5-7 membered ring A is-CH₂-for reaction to form a carbonyl group;

the C5-C12 aryl is unsubstituted or substituted by substituent groups, and the substituent groups are selected from amino, substituted amino, carboxyl, alkoxy, halogen, cyano, acyloxy, amido or nitro.

Preferably, Ar is a benzene ring, a naphthalene ring, an anthracene ring or a phenanthrene ring.

Preferably, the C5-C12 aryl group may be unsubstituted or substituted phenyl.

Preferably, the 5-to 7-membered aromatic ring B is a benzene ring.

Preferably, the heteroatom in ring a is O, N or S.

In the present invention, the alkoxy group may be a C1-C4 alkoxy group such as methoxy, ethoxy, propoxy, butoxy, etc., or a phenoxy group. The acyloxy may be C1-C4 acyloxy, such as formyloxy, acetyloxy, propionyloxy, butyryloxy, benzoyloxy, etc. The amide group may be a C1-C4 amide group, such as a carboxamide group, an acetamido group, or the like. The alkyl substituted amine group may be an N, N- (C1-C4 alkyl) amine group, such as N, N-dimethylamino group, etc.

In a specific embodiment of the present invention, the aromatic benzyl compound having a 5-to 7-membered ring A includes fluorene, tetrahydronaphthalene, indane, xanthene and isochroman.

In the invention, the catalyst system is formed by combining ferric ions, nitrate and N-hydroxyimide derivatives (NHIs), wherein the nitrate ions are used as a cocatalyst to promote the NHIs to generate free radicals, so that the autooxidation of benzyl (methylene) is promoted, and the dosage of a metal catalyst is reduced. The combination of ferric ion, nitrate radical and N-hydroxyimide derivative (NHIs) means that ferric nitrate and NHIs can be directly added into the reaction system, soluble salt containing ferric ion, salt containing nitrate radical and NHIs can be added, and substances which can simultaneously generate the catalytic components in the reaction process can be added, which belongs to the protection scope of the invention.

Preferably, the catalyst added to the reaction system is ferric nitrate and N-hydroxyimide derivatives (NHIs). Further preferably, in the reaction system, the feeding molar ratio of the ferric nitrate, the NHIs and the aromatic benzyl compound is 0.01-0.1:0.03-0.2: 1. Still more preferably: the feeding molar ratio of the aromatic benzyl compound with the aromatic ring connected with the electron-donating group is 0.01-0.05:0.03-0.1:1, and the feeding molar ratio of the aromatic benzyl compound with the benzene ring connected with the electron-withdrawing group is 0.02-0.1:0.05-0.2: 1.

Preferably, the N-hydroxyimide derivative used in the present invention is selected from one of the following: n-hydroxyphthalimide (NHPI), N ' -dihydroxypyromellitimide (NDHPI), N, N ', N ' -trihydroxyimine cyanuric acid (THICA), N-hydroxysuccinimide (NHSI), N-hydroxy-1, 8-naphthalimide (NHNI), the formula of which is shown below, preferably NHSI, NHPI or NHNI.

The oxidation reaction of the present invention uses oxygen and/or air as an oxidant, i.e. the oxidation reaction is performed in oxygen or air or oxygen and air atmosphere, and preferably the oxidation reaction is performed under normal pressure by controlling the pressure of oxygen and/or air.

In the oxidation reaction of the present invention, an organic solvent with relatively high polarity is preferably used as a reaction solvent, such as acetic acid, benzonitrile, acetonitrile, ethyl acetate, and the like, and further preferably, the organic solvent is acetic acid or benzonitrile.

The oxidation reaction of the present invention is preferably carried out at a temperature of 60 to 150 c, most preferably 100 c. The end point of the oxidation reaction can be monitored by gas chromatography.

After the oxidation reaction is finished, the target product can be obtained by simply post-treating the obtained reaction mixture, for example, after the solvent in the reaction system is evaporated out under reduced pressure, the target product is obtained by column chromatography separation or recrystallization, and the specific post-treatment method can be automatically adjusted according to the property of the target product. In addition, the reaction of the NHSI of the present invention as a catalyst allows the NHSI to be recycled (see example 9: oxidation of 4-nitroacetophenone).

Compared with the prior art, the invention is characterized in that:

(1) the catalyst system used in the invention is the combination of ferric ions, nitrate radicals and N-hydroxyimide derivatives (NHIs), and the harmless metal ferric ions and NHIs of human body are used as catalysts, so that the use of metal ions harmful to human body such as copper, cobalt, manganese and the like and the residue in the product are avoided, and the application of the catalyst system in drug synthesis is facilitated; nitrate ions are used as a cocatalyst to promote the formation of free radicals from NHIs, thereby promoting the autooxidation of benzyl (methylene) groups and reducing the dosage of the metal catalyst.

(2) The method uses oxygen or air as an oxidant, is relatively cheap and green, most of substrates can be oxidized only at mild temperature, and a small part of substrates only need to increase the reaction temperature to promote the increase of the conversion rate.

(IV) specific embodiment:

the following examples are given by way of illustration and are not intended to limit the present invention.