CN104193620A - Method for preparing alpha-hydroxyl-beta-dicarbonyl compound through activating oxygen in air by using hydrazine - Google Patents

Abstract

The present invention relates to a method for the preparation of compound I (the compound shown is achiral at the indicated hydroxylation center, racemic or enantiomerically enriched), which method comprises the addition of organic hydrazine and Compound II was contacted with a gas containing oxygen molecules to obtain compound I with a maximum yield of 98%. Using a chiral base as a catalyst, such as cinchona base, compound II as a substrate, mixed reaction in a solvent, the product is compound I enriched in the counterpart, with a maximum yield of 95% and an ee value of 85%. Solvents include halogenated hydrocarbons, aromatic hydrocarbons, alkanes and ether solvents. Using organic hydrazine compounds to activate molecular oxygen to realize the α-hydroxylation reaction of β-dicarbonyl compounds has high atom economy and is environmentally friendly. The method is a new method for preparing various chiral or achiral α-hydroxyl-β-dicarbonyl compounds by activating molecular oxygen with organic hydrazine compounds.

Description

Method for preparing α-hydroxy-β-dicarbonyl compounds by activating air oxygen with hydrazine

technical field

The invention belongs to the technical field of organic synthesis and relates to a method for preparing chiral and achiral α-hydroxyl-β-dicarbonyl compounds by activating air oxygen with hydrazine. the

technical background

Optically active ɑ-hydroxy-β-dicarbonyl compounds are a very important structural unit, which widely exist in natural products, chiral pharmaceuticals and pesticide intermediates. It is worth mentioning that (S)-5-chloro-1-oxoindene-2-hydroxy-2-carboxylic acid methyl ester is an important intermediate of the pesticide indoxacarb. Direct asymmetric α-hydroxylation of 1,3-dicarbonyl compounds is the simplest and most direct method to obtain such structural units. In recent years, researchers have reported a large number of methods for the asymmetric synthesis of chiral α-hydroxy β-dicarbonyl compounds, which can be divided into two categories: a) metal complexes/active oxygen systems. b) Organic catalyst/active oxygen system. the

For the metal complex/active oxygen system, the literature (Proc.Natl.Acad.Sci.U.S.A. 2004,101,5810–5814) reported that the metal complexes of tartaric acid-derived chiral ligands coordinated with tetravalent Ti are The preparation of chiral α-hydroxyl β-dicarbonyl compounds with catalysts, but the catalysts and oxidants used are expensive, which limits the application of this method. This is also a common problem in metal complex catalysis. In terms of organic catalysis, literature (J.Am.Chem.Soc.2009, 128, 16488-16489) reported a method for asymmetrically catalyzing α-hydroxy-βdicarbonyl compounds with Bronsted acid catalysts derived from chiral phosphoric acid. This method can obtain products with high enantioselectivity (up to 99% ee), but the chiral phosphoric acid used is difficult to synthesize, expensive, and the oxidant nitrosobenzene is highly toxic and unsuitable for industrial production. the

It is worth noting that molecular oxygen has been paid more and more attention by chemists in recent years, and it is the most ideal oxidant because of its wide range of sources and 100% atom economy. In recent years, photooxidation (Photooxygenation) has become an important oxidation method, which realizes the oxidation process by photoactivating molecular oxygen. The literature (J.Am.Chem.Soc.2004,126,8914–8915) reported for the first time the photocatalytic asymmetric α-hydroxylation reaction of aldehydes and ketones, using amino acids as chiral catalysts, and tetraphenylporphyrin as photosensitive agent, and achieved good results. Literature (Chem Asian J. 2012, 7, 2019–2023) reported the first photocatalytic asymmetric α-hydroxylation of β-ketoesters using a cinchona base-derived phase transfer catalyst under mild conditions Oxidation products with moderate enantioselectivities and high yields can be obtained. In addition, the literature (Org.Lett.2008,10,1593–1595) reported that triethyl phosphite (P(OEt) ₃ ) was used as an auxiliary agent, and molecular oxygen was used as an oxidant for the indole substrates. Symmetric α-hydroxylation reaction. However, due to the relatively low catalytic activity of the triethyl phosphite/oxygen system and the harsh environmental requirements for substrates and solvents, the application of this method is limited. Although scientists have done a lot of fruitful work on the α-hydroxylation of β-dicarbonyl compounds, it is still a great challenge to use molecular oxygen as an oxidant to realize the reaction process.

Contents of the invention

The technical problem to be solved in the present invention is to provide a new method for preparing ɑ-hydroxyl-β-dicarbonyl compounds by activating air oxygen with hydrazine, using hydrazine/alkali/molecular oxygen-containing gas/solvent system, which can not only prepare the external elimination very efficiently ɑ-hydroxyl-β-dicarbonyl compound, and when the external base is chiral cinchona base, the ɑ-hydroxyl-β-dicarbonyl compound with high enantioselectivity can be obtained. the

A kind of method that hydrazine activates air oxygen to prepare α-hydroxy-β-dicarbonyl compound, concrete steps are as follows:

Using compound II as the reaction raw material, in the solvent, under the condition of alkali as the catalyst and organic hydrazine as the activator, the compound II is reacted with the gas containing molecular oxygen, the reaction temperature is -70°C to 50°C, and the reaction time is 2 hours to 4 days, obtain compound I, wherein, the consumption of alkali is 0.1 molar equivalent～3 molar equivalent of compound II; The chemical formula of compound I and compound II is as follows:

The specific synthetic route is as follows:

In compound I and compound II:

* represents the chiral center of compound I;

_R is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle;

R ₂ is a hydrogen atom, an alkyl group, a cycloalkyl group, a benzene ring, a 5-aromatic heterocycle or a 6-aromatic heterocycle;

_R3 is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle;

R and _R together form an optionally substituted linking chain of 3-6 members, including at least one carbon atom member, optionally including not more than two carbon members in the form of C=0 _, optionally including A member selected from nitrogen and oxygen, and optionally fused with a benzene ring, a 5-membered aromatic heterocycle, or a 6-membered aromatic heterocycle, each ring being optionally substituted.

In compound I and compound II:

R ₁ is an alkoxy group;

R ₂ is an alkyl group;

_R3 is optionally substituted phenyl, or _R2 and _R3 may together form an optionally substituted linking chain of 3-4 carbon members optionally fused to an optionally substituted phenyl ring.

Compound II is compound IIa:

The specific synthetic route is as follows:

_R is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle;

R ₄ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle;

R ₅ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle;

R ₆ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle;

R ₇ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle;

n is a natural number of 0-3. the

The chemical formula III of described organohydrazine is as follows:

Wherein, _R is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, an aromatic ring, a 5-membered heterocycle or a 6-membered heterocycle;

R ₂ is alkyl, cycloalkyl, alkoxy, aromatic ring, 5-membered heterocycle or 6-membered heterocycle.

The alkali is one or both of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium methoxide, and sodium ethoxide. Mix the above. Described base is achiral organic base, refers to triethylamine, diisopropylethylamine, tert-butylamine, pyridine, piperidine, imidazole, tetramethylguanidine, diazabicyclo, triethylenediamine One or two or more are mixed; the base is a chiral organic base, which refers to cinchonine cinchonine, cinchonine, quinine, quinidine, dihydrocinchonine, dihydrocinchonine, dihydroquinine, dihydroquinine, One or a mixture of two or more derivatives of hydroquinidine and dihydroquinidine. the

The solvent is one or a mixture of two or more of halogenated hydrocarbons, aromatic hydrocarbons, alkanes and ethers;

The halogenated hydrocarbon is one or a mixture of two or more of methylene chloride, chloroform, carbon tetrachloride, methylene bromide, 1,2-dibromoethane, and 1,2-dichloroethane;

The aromatic hydrocarbon is one or a mixture of two or more of benzene, toluene, para-xylene, m-xylene, p-xylene, diphenylmethane, and tetrahydronaphthalene;

One or more mixtures of the alkane n-hexane, cyclohexane, and ethane;

The ether is one or a mixture of two or more of ether, diethylene glycol dimethyl ether, and methyl tert-butyl ether. the

The formula compound I is based on the base of 0.1 molar equivalents to 5 molar equivalents of the substrate as a catalyst, and under the catalysis of an optional inert solvent, the formula compound II is contacted with usually about 1-5 molar equivalents of hydrazine, and exposed in a gas containing molecular oxygen prepared by reaction. the

The hydrazine compound is preferably methylhydrazine, phenylhydrazine, benzylhydrazine or hydroxyethylhydrazine. the

R ₁ , R ₂ and R ₃ in formula compound I and compound II are additional groups not directly related to the hydroxylation reaction center. Since the reaction conditions of the hydroxylation method of the present invention are relatively mild, there can be various molecular structural features in R ₁ , R ₂ and R ₃ , and only the most reactive functional groups to oxidation conditions are susceptible. Accordingly, the substituents listed for _R1 , _R2 and _R3 in the Summary of the Invention should be considered as describing only a subgroup illustrating the broad applicability of the method of the present invention. Although there is no clear limit to the size of formulas I and II suitable for the method of the present invention, it is worth noting that in these methods of the present invention, in formula compound I and formula compound II, _R is a hydrogen atom, an alkoxy group, Alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle, _each of which is optionally substituted; R is a hydrogen atom, alkyl, cycloalkane Base, benzene ring, 5-aromatic heterocycle or 6-aromatic heterocycle, they are each optionally substituted; _R3 is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, benzene Oxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle, each of which is optionally substituted.

A more preferred method of the present invention comprises using wherein R ₁ is an alkyl group and R ₄ , R ₅ , R ₆ , R ₇ is an alkoxy group or a hydrogen atom, contacting a compound of formula IIa with methylhydrazine and a base for the preparation of The chiral center of is a racemic or enantiomerically enriched compound of formula Ia.

The most preferred method comprises contacting a compound of formula IIa, methylhydrazine and a cinchona base derived catalyst. the

The beneficial effects of the present invention are: the method of the present invention can obtain formula Ia with high yield and enantiomeric excess, and the reaction conditions are milder. The hydroxylation process of the present invention is generally applicable to a wide variety of starting compounds of formula II, which can be obtained using methods known in the art of synthetic organic chemistry. the

Detailed ways

Specific embodiments of the present invention will be described in detail below in conjunction with technical solutions, so that those skilled in the art can better understand the present invention. the

Example 1 Preparation of 5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4mg, 0.1mmol), cesium carbonate (32.5mg, 0.1mmol) and methylhydrazine (12.0mg, 0.26mmol), add 4mL of chloroform, and stir the reaction in air at room temperature. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After reacting for 12 hours, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (21.0 mg, 88% yield). the

Example 2 Preparation of 5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4mg, 0.1mmol), tetramethylguanidine (11.5mg, 0.1mmol) and methylhydrazine (12.0mg, 0.26mmol), add 4mL of chloroform, and stir the reaction in air at room temperature. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After reacting for 6 hours, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (20.3 mg, 88% yield). the

Example 3 Preparation of (S)-5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4mg, 0.1mmol), cinchonine (11.7mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, and add 4mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (19.4 mg, 81% yield, 51% ee). the

Embodiment 3: Preparation (S)-5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4mg, 0.1mmol), dihydrocinchonine (11.7mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, and add 4mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (19.8 mg, 83% yield, 53% ee). the

Example 4 Preparation of (R)-5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4mg, 0.1mmol), quinine (12.9mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, and add 4mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (19.4 mg, 81% yield, 64% ee). the

Example 5 Preparation of (R)-5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, and add 4mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (20.3mg, 85% yield); [α] _D ²⁵ -61.5( c0.07, CHCl ₃ , 67%ee); mp 134-136°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.74 (d, J=8.2Hz, 1H), 7.50 (d, J=0.7Hz, 1H ), 7.43(dd, J＝8.2,0.8Hz, 1H), 3.75(s, 3H), 3.71(d, J＝17.4Hz, 1H), 3.24(d, J＝17.4Hz, 1H); HPLC conditions: Chiralcel OD-H column(250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝10.4min, τ _R (minor)＝8.8min.

Example 6 Preparation of (R)-5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4 mg, 0.1 mmol), dihydroquinine (13.0 mg, 0.04 mmol) and 2-hydroxyethylhydrazine (9.9 mg, 0.13 mmol) into a reaction flask, and add 4 mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (19.9 mg, 83% yield, 63% ee). the

Example 7 Preparation of (R)-5-chloro-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.4 mg, 0.1 mmol), dihydroquinine (13.0 mg, 0.04 mmol) and phenylhydrazine (14.0 mg, 0.13 mmol) into a reaction flask, and add 4 mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (15.6 mg, 65% yield, 53% ee). the

Example 8 Preparation of (R)-5-chloro-2-hydroxyl-1-indanone-2-carboxylic acid methyl ester

Weigh the substrate (22.4 mg, 0.1 mmol), dihydroquinine (13.0 mg, 0.04 mmol) and benzylhydrazine (15.9 mg, 0.13 mmol) into a reaction flask, and add 4 mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (19.4 mg, 81% yield, 61% ee). the

Example 9 Preparation of (R)-5-chloro-2-hydroxyl-1-indanone-2-carboxylic acid methyl ester

Weigh the substrate (22.4 mg, 0.1 mmol), dihydroquinine (13.0 mg, 0.04 mmol) and diphenylazocarbohydrazide (31.2 mg, 0.13 mmol) into a reaction flask, and add 4 mL of chloroform. The reaction temperature was controlled at 15°C, and the reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (12.2 mg, 51% yield, 58% ee). the

Example 10 Preparation of 6-methyl-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (20.4mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (17.2mg, 78% yield); [α] _D ²⁵ -46.2( c0.04, CHCl ₃ , 65%ee); mp 132-134°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.60(s, 1H), 7.50(d, J=7.8Hz, 1H), 7.38(d , J=7.8Hz, 1H), 3.74(s, 3H), 3.68(d, J=17.1Hz, 1H), 3.21(d, J=17.1Hz, 1H), 2.42(s, 3H); HPLC conditions: Chiralcel OD-H column(250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝12.4min, τ _R (minor)＝10.7min.

Example 11 Preparation of 6-methoxy-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.0mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a yellow solid (16.3mg, 69% yield); [α] _D ²⁵ -38.6( c0.06, CHCl ₃ , 78%ee); mp 118-120°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.39(d, J=8.3Hz, 1H), 7.28(m, 1H), 7.21(d , J=8.6Hz, 1H), 3.84(s, 3H), 3.75(s, 3H), 3.65(d, J=16.9Hz, 1H), 3.18(d, J=16.9Hz, 1H); HPLC conditions: Chiralcel OD-H column(250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝15.6min, τ _R (minor)＝13.8min.

Example 12 Preparation of 6-fluoro-2-hydroxyl-1-indanone-2-carboxylic acid methyl ester

Weigh the substrate (20.8mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (18.0mg, 81% yield); [α] _D ²⁵ -46.5(c0 .09, CHCl ₃ , 67%ee); mp 130-132°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.56–7.35 (m, 3H), 3.76 (s, 3H), 3.69 (d, J=17.1 Hz,1H),3.22(d,J＝17.1Hz,1H);HPLC conditions:Chiralcel OD-H column(250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm,τ _R (major)＝13.0min, τ _R (minor)＝10.9min.

Example 13 Preparation of 6-bromo-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (26.9mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a yellow solid (24.1mg, 85% yield); [α] _D ²⁵ -28.3( c0.10, CHCl ₃ , 64%ee); mp119-121℃; ¹ H NMR (500MHz, CDCl ₃ ) δ7.92 (d, J=1.8Hz, 1H), 7.78 (dd, J=8.2, 1.9Hz , 1H), 7.39(d, J=8.2Hz, 1H), 3.75(s, 3H), 3.67(d, J=17.4Hz, 1H), 3.20(d, J=17.4Hz, 1H); HPLC conditions: Chiralcel OD-H column(250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝14.1min, τ _R (minor)＝11.8min.

Example 14 Preparation of 2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (18.9mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (16.7mg, 82% yield); [α] _D ²⁵ -56.1( c0.08, CHCl ₃ , 68%ee); mp134-136℃; ¹ H NMR (500MHz, CDCl ₃ ) δ7.81(d, J=7.7Hz, 1H), 7.68(t, J=7.5Hz, 1H ), 7.50(d, J=7.7Hz, 1H), 7.44(t, J=7.5Hz, 1H), 3.78–3.69(m, 4H), 3.26(d, J=17.2Hz, 1H); HPLC conditions: Chiralcel OD-H column(250×4.6mm), hexane/i-PrOH＝80/20, 1mL/min, 254nm, τ _R (major)＝9.2min, τ _R (minor)＝8.0min.

Example 15 Preparation of 5-bromo 2-hydroxyl-1-indanone-2-methyl carboxylate

Weigh the substrate (26.9mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , The reaction was stirred in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (21.3mg, 75% yield); [α] _D ²⁵ -63.1( c0.08, CHCl ₃ , 66%ee); mp 126-128°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.74–7.63 (m, 2H), 7.58 (dd, J=8.2, 0.6Hz, 1H) ,3.75(s,3H),3.70(d,J=17.4Hz,1H),3.24(d,J=17.4Hz,1H);HPLC conditions:Chiralcel OD-H column(250×4.6mm),hexane/i -PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝15.8min, τ _R (minor)＝13.4min.

Example 16 Preparation of 4-methoxy-2-hydroxyl-1-indanone-2-formic acid methyl ester

Weigh the substrate (22.0mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into the reaction flask, add 0.065mol/L methylhydrazine in chloroform Add 2 mL of the solution, and then add 2 mL of chloroform, control the reaction temperature at 15° C., and stir in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (16.7mg, 71% yield); [α] _D ²⁵ -45.7( c0.07, CHCl ₃ , 67%ee); mp141-143°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.47–7.35 (m, 2H), 7.12 (d, J=7.1Hz, 1H), 3.92 (s,3H),3.74(s,3H),3.66(d,J=17.7Hz,1H),3.12(d,J=17.7Hz,1H);HPLC conditions:ChiralcelOD-H column(250×4.6mm) , hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝14.2min, τ _R (minor)＝16.0min.

Example 17 Preparation of ethyl 2-hydroxy-1-indanone-2-formate

Weigh the substrate (20.4mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a colorless liquid (15.8 mg, 72% yield); [α] _D ²⁵ -41.5 (c0.14, CHCl ₃ , 66%ee); ¹ H NMR (500MHz, CDCl ₃ ) δ7.81 (d, J=7.7Hz, 1H), 7.68 (td, J=7.6, 1.1Hz, 1H), 7.50(d,J=7.7Hz,1H),7.47–7.41(m,1H),4.30–4.13(m,2H),3.73(d,J=17.2Hz,1H),3.26(d,J=17.2Hz , 1H), 1.19 (t, J=7.1Hz, 3H); HPLC conditions:Chiralcel OD-H column (250×4.6mm), hexane/i-PrOH=90/10, 1mL/min, 254nm,τ _R ( major)＝11.0min, τ _R (minor)＝9.6min.

Example 18 Preparation of α, α-diethyl-propyl-2-hydroxyl-1-indanone-formic acid ester

Weigh the substrate (27.4mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a colorless oil (19.4 mg, 67% yield); [α] _D ²⁵ - 23.5 (c0.05, CHCl ₃ , 75%ee); ¹ H NMR (500MHz, CDCl ₃ ) δ7.80 (d, J=7.7Hz, 1H), 7.65 (td, J=7.6, 1.1Hz, 1H) ,7.48(d,J=7.7Hz,1H),7.42(t,J=7.5Hz,1H),4.04(s,1H),3.64(d,J=17.0Hz,1H),3.26(d,J= 17.0Hz, 1H), 1.70(q, J=7.5Hz, 6H), 0.65(t, J=7.5Hz, 9H); HPLC conditions:Chiralcel AS-H column(250×4.6mm), hexane/i-PrOH =80/20, 1mL/min, 254nm, τ _R (major) = 9.1min, τ _R (minor) = 10.9min.

Example 19 Preparation of 2-hydroxyl-1-indanone-2-formic acid isopropyl ester

Weigh the substrate (21.8mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (17.0mg, 73% yield); [α] _D ²⁵ -30.9( c0.06, CHCl ₃ , 61%ee); mp68-74°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.80 (d, J=7.7Hz, 1H), 7.67 (td, J=7.6, 1.0Hz ,1H),7.49(d,J=7.7Hz,1H),7.43(dd,J=11.1,3.9Hz,1H),5.19–4.94(m,1H),3.70(d,J=17.2Hz,1H) , 3.24(d, J=17.2Hz, 1H), 1.20(d, J=6.3Hz, 3H), 1.13(d, J=6.3Hz, 3H); HPLC conditions:Chiralcel OD-H column(250×4.6mm ), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝8.7min, τ _R (minor)＝7.8min.

Example 20 2-Hydroxy-1-indanone-2-formic acid tert-butyl ester

Weigh the substrate (23.1mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into the reaction flask, add 0.065mol/L methylhydrazine in chloroform Add 2 mL of the solution, and then add 2 mL of chloroform, control the reaction temperature at 15° C., and stir in the open air. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (19.2mg, 78% yield); [α] _D ²⁵ -29.5( c0.06, CHCl ₃ , 58%ee); mp128-129°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.79 (d, J=7.7Hz, 1H), 7.64 (d, J=7.5Hz, 1H ),7.48(d,J=7.7Hz,1H),7.42(t,J=7.5Hz,1H),3.65(d,J=17.1Hz,1H),3.22(d,J=17.1Hz,1H), 1.36(s,9H); HPLC conditions:Chiralcel OD-H column(250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm,τ _R (major)＝6.8min,τ _R ( minor) = 6.3min.

Example 21 2-Hydroxy-1-indanone-2-formic acid benzyl ester

Weigh the substrate (26.6mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a colorless solid (21.0 mg, 75% yield); [α] _D ²⁶ -47.6 (c0.04, CHCl ₃ , 60%ee); mp94-97℃; ¹ H NMR (500MHz, CDCl3) δ7.80(d, J=7.7Hz, 1H), 7.65(t, J=7.2Hz, 1H ),7.50–7.39(m,2H),7.33–7.26(m,3H),7.14(dd,J＝6.5,2.8Hz,2H),5.22(d,J＝12.4Hz,1H),5.12(d, J＝12.4Hz, 1H), 3.72(d, J＝17.2Hz, 1H), 3.25(d, J＝17.2Hz, 1H); HPLC conditions:Chiralcel OD-H column(250×4.6mm), hexane/i -PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝19.1min, τ _R (minor)＝15.9min.

Example 22 2-Hydroxy-1-indanone-2-formic acid adamantyl

Weigh the substrate (31.0mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a colorless oil (23.0 mg, 71% yield); [α] _D ²⁵ - 25.0 (c0.05, CHCl ₃ , 66%ee); ¹ H NMR (500MHz, CDCl ₃ ) δ7.79 (d, J=7.7Hz, 1H), 7.65 (td, J=7.6, 1.1Hz, 1H) ,7.48(d,J=7.7Hz,1H),7.42(t,J=7.5Hz,1H),3.66(d,J=17.1Hz,1H),3.22(d,J=17.1Hz,1H),2.12 (s,3H),1.96(d,J=3.1Hz,6H),1.60(d,J=2.6Hz,6H);HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH =90/10, 1mL/min, 254nm, τ _R (major) = 18.2min, τ _R (minor) = 11.3min.

Example 23 α-Methyl-α-phenyl-benzyl-2-hydroxyl-1-indanone-formic acid ester

Weigh the substrate (35.6mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (35.3mg, 95% yield); [α] _D ²⁵ -61.5( c0.12, CHCl ₃ , 85%ee); mp90-92°C; ¹ H NMR (400MHz, DMSO) δ7.90–7.78 (m, 2H), 7.70 (d, J=7.7Hz, 1H), 7.57 ( t,J=7.4Hz,1H),7.23–7.07(m,6H),7.02–6.85(m,4H),6.69(bs,1H),3.76(d,J=17.4Hz,1H),3.20(d , J=17.4Hz, 1H), 2.08(s, 3H); HPLC conditions: Chiralcel OD-H column (250×4.6mm), hexane/i-PrOH=90/10, 1mL/min, 254nm, τ _R ( major)＝19.9min, τ _R (minor)＝15.41min.

Example 24 2-Hydroxy-1-indanone-2-carboxylic acid-(2',7'-dibromo)-9'-fluorene ester

Weigh the substrate (51.2mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4 mL of chloroform, and control the reaction temperature at 15 ℃, open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a white solid (43.2mg, 82% yield); [α] _D ²⁵ -18.8( c0.05, CHCl ₃ , 73%ee); mp168-172°C; ¹ H NMR (500MHz, CDCl ₃ ) δ7.83 (d, J=7.7Hz, 1H), 7.64 (dd, J=13.0, 5.1Hz ,2H),7.56–7.52(m,1H),7.49(dd,J＝8.1,1.5Hz,1H),7.43(m,5H),6.66(s,1H),3.76(d,J＝17.2Hz, 1H), 3.31 (d, J＝17.2Hz, 1H); HPLC conditions: Chiralcel OD-H column (250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major )＝21.9min, τ _R (minor)＝18.6min.

Example 25 Preparation of 2-hydroxy-1-indanone-2-formic acid-9'-methylanthracene

Weigh the substrate (36.6mg, 0.1mmol), dihydroquinine (13.0mg, 0.04mmol) and methylhydrazine (6.0mg, 0.13mmol) into a reaction flask, add 4mL of chloroform, and control the reaction temperature at 15°C , open to the air and stir the reaction. During the reaction, the conversion of the substrate was observed by TLC (thin layer chromatography). After 24 hours of reaction, the solvent was spin-dried and prepared by medium pressure (silica gel column, PE/EtOAc=5/1) to obtain the target product as a yellow solid (30.8mg, 81% yield); [α] _D ²⁵ -20.0( c0.16, CHCl ₃ , 72%ee); mp111-113℃; ¹ H NMR (500MHz, CDCl ₃ ) δ8.45 (s, 1H), 8.12 (d, J=8.1Hz, 2H), 8.05–7.93 (m,2H),7.70(d,J=7.6Hz,1H),7.53(t,J=7.5Hz,1H),7.50–7.42(m,4H),7.33(t,J=7.5Hz,1H) ,7.29–7.23(m,1H),6.36(d,J=12.6Hz,1H),6.00(d,J=12.6Hz,1H),3.49(d,J=17.1Hz,1H),3.11(d, J＝17.1Hz, 1H); HPLCconditions: Chiralcel OD-H column (250×4.6mm), hexane/i-PrOH＝90/10, 1mL/min, 254nm, τ _R (major)＝31.7min, τ _R ( minor) = 25.3 min.

Claims (10)

1. a kind of method that hydrazine activates air oxygen to prepare α-hydroxy-β-dicarbonyl compound, it is characterized in that, step is as follows: Using compound II as the reaction raw material, in the solvent, the base is used as a catalyst, and the organic hydrazine is used as an activator to react compound II with a gas containing molecular oxygen. The reaction temperature is -70 ° C to 50 ° C, and the amount of base is 0.1 mole of compound II Equivalent～3 molar equivalents, obtain compound I; The chemical formula of compound I and compound II is as follows: In compound I and compound II: * represents the chiral center of compound I; _R is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle; R ₂ is a hydrogen atom, an alkyl group, a cycloalkyl group, a benzene ring, a 5-aromatic heterocycle or a 6-aromatic heterocycle; _R3 is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle; R and _R together form a linking chain of 3-6 members optionally substituted as described above, including at least one carbon atom member _, optionally including no more than two carbon members in the form of C=0, optionally Contains a member selected from nitrogen and oxygen, and is optionally fused with a benzene ring, a 5-membered aromatic heterocycle, or a 6-membered aromatic heterocycle, each ring being optionally substituted. 2. The method according to claim 1, wherein in compound I and compound II: R ₁ is an alkoxy group; R ₂ is an alkyl group; _R3 is optionally substituted phenyl, or _R2 and _R3 together form an optionally substituted linking chain of 3-4 carbon members optionally fused to an optionally substituted phenyl ring. 3. The method according to claim 2, wherein compound II is compound IIa: _R is a hydrogen atom, alkoxy, alkyl, cycloalkyl, cycloalkoxy, benzene ring, phenoxy ring, 5-aromatic heterocycle or 6-aromatic heterocycle; R ₄ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle; R ₅ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle; R ₆ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle; R ₇ is a hydrogen atom, a halogenated group, an alkyl group, an alkoxy group, a cycloalkyl group, an aromatic ring, a benyloxy group, a 5-membered heterocycle or a 6-membered heterocycle; n is a natural number of 0-3. 4. according to the arbitrary described method of claim 1-3, it is also characterized in that, the chemical formula III of described organic hydrazine is as follows: Wherein, _R is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, an aromatic ring, a 5-membered heterocycle or a 6-membered heterocycle; R ₂ is alkyl, cycloalkyl, alkoxy, aromatic ring, 5-membered heterocycle or 6-membered heterocycle. 5. according to the arbitrary described method of claim 1-3, it is also characterized in that, described alkali is sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide , Potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, or a mixture of two or more. 6. method according to claim 4, it is also characterized in that, described alkali is sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, tert-butanol Potassium, sodium hydride, sodium methoxide, sodium ethoxide, or a mixture of two or more. 7. according to the described method of claim 1,2,3 or 6, it is characterized in that, described alkali is achiral organic base, refers to triethylamine, diisopropylethylamine, tert-butylamine, pyridine, piperidine One or more mixtures of pyridine, imidazole, tetramethylguanidine, diazabicyclo, and triethylenediamine; the base is a chiral organic base, which refers to cinchonine cinchonine, cinchonine, quinine Nine, quinidine, dihydrocinchonine, dihydrocinchonidine, dihydroquinine, dihydroquinidine, derivatives of dihydroquinidine, or a mixture of two or more. 8. the method according to claim 4 is characterized in that, described alkali is achiral organic base, refers to triethylamine, diisopropylethylamine, tert-butylamine, pyridine, piperidine, imidazole, tetramethyl One or two or more of base guanidine, diazabicyclo, and triethylenediamine are mixed; the base is a chiral organic base, which refers to cinchonine cinchonine, cinchonine, quinine, quinidine, One or more mixtures of dihydrocinchonine, dihydrocinchonidine, dihydroquinine, dihydroquinidine, and derivatives of dihydroquinidine. 9. The method according to claim 5, characterized in that, the base is an achiral organic base, referring to triethylamine, diisopropylethylamine, tert-butylamine, pyridine, piperidine, imidazole, tetramethyl One or more mixtures of guanidine, diazabicyclo, and triethylenediamine; the base is a chiral organic base, which refers to cinchonine cinchonine, cinchonine, quinine, quinidine, One or more mixtures of dihydrocinchonine, dihydrocinchonidine, dihydroquinine, dihydroquinidine, and derivatives of dihydroquinidine. 10. according to the described method of claim 1,2,3,6,8 or 9, it is characterized in that, described solvent is one or two or more mixtures in halogenated hydrocarbon, aromatic hydrocarbon, alkane, ether; The halogenated hydrocarbons are methylene chloride, chloroform, carbon tetrachloride, methylene bromide, 1,2-dibromoethane and 1,2-dichloroethane; Described aromatic hydrocarbon is benzene, toluene, adjacent xylene, m-xylene, p-xylene, diphenylmethane and tetrahydronaphthalene; The alkane n-hexane, cyclohexane and ethane; The ethers are ether, diethylene glycol dimethyl ether and methyl tert-butyl ether.