CN114716345A - Method for deoxygenation functionalization and deoxygenation activation of alcohols and alcohol-functionalized materials - Google Patents

Abstract

The invention relates to the field of organic synthesis, and discloses a method for deoxidizing and deoxidizing and activating alcohol and an alcohol-functionalized substance. The method comprises: (1) in a first solvent, in the presence of an activator, the alcohol is Activation by deoxygenation yields the iodide intermediate; (2) functionalizing the iodide intermediate in a second solvent in the presence of a nucleophile. The method provided by the invention is easy to operate and easy to separate and purify.

Description

Method for deoxyfunctionalizing and deoxyactivating alcohols and alcohol-functionalized substances

technical field

The invention relates to the field of organic synthesis, in particular to a method for deoxyfunctionalizing and deoxyactivating alcohol and an alcohol functionalized substance.

Background technique

As a class of inexpensive and readily available compounds, the deoxyfunctionalization of alcohols has always been a research hotspot in the fields of organic synthetic chemistry and medicinal chemistry. According to the formation method of chemical bond breaking during the reaction process, the deoxyfunctionalization of alcohols is mainly divided into polarization reaction process (Tetrahedron Lett. 1985, 26, 757-760; J.Am.Chem.Soc.2020,142,16787-16794) and metal-catalyzed reaction process (J.Am.Chem.Soc.2012,134,14638-14641; Chem.Commun.2015, 51, 2683-2686).

Among them, direct nucleophilic substitution is the most ideal way, and H ₂ O, as the only by-product, has the advantages of both environmental friendliness and atom economy. However, as the hydroxyl group is not easy to leave, the direct nucleophilic substitution functionalization of the alcohol is difficult, and the alcohol needs to be activated first.

Traditional reagents including thionyl chloride, sulfonyl chloride, etc. can activate alcohols, but will produce metered strong acid waste. The Appel reaction and the Garegg–Samuelsson reaction (J.Am.Chem.Soc. 2007, 129, 9566-9567; J. Chem. Soc., Perkin Trans. 1 1980, 2866-2869) are effective methods for hydroxyhalogenation, but Use highly toxic CX4 reagents or generate phosphine oxide by-products that are difficult to isolate. The Mitsunobu reaction (Chem. Rev. 2009, 109, 2551-2651) is a common method for the deoxyfunctionalization of alcohols, but it has the property of alcohol configuration inversion, and it requires an acidic nucleophile, which has some limitations on the range of nucleophiles. It also produces phosphine oxide by-products that are difficult to separate by measurement, which does not conform to the principle of atom economy.

Therefore, it is of great significance to develop a method for the deoxyfunctionalization of alcohols that is safe and easy to operate and separate and purify.

SUMMARY OF THE INVENTION

The purpose of the present invention is to overcome the above-mentioned defects of the prior art, and to provide an alcohol deoxyfunctionalization method that is easy to operate and easy to separate and purify.

In order to achieve the above object, a first aspect of the present invention provides a method for deoxyfunctionalizing an alcohol, the method comprising:

(1) in the first solvent, in the presence of an activator, the alcohol is deoxidized and activated to obtain an iodide intermediate;

(2) in a second solvent, in the presence of a nucleophile, the iodide intermediate is functionalized to obtain an alcohol-functionalized substance;

Wherein, the activator has the structure shown in formula (I);

Wherein, in formula (I),

R ^a , R ^b and R ^c are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and the optional substituents in R ^a , R ^b and R ^c are each independently selected from At least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

A second aspect of the present invention provides an alcohol-functionalized substance selected from at least one of the following compounds:

A third aspect of the present invention provides a method for deoxidizing and activating alcohol, the method comprising:

In the first solvent, in the presence of an activator, the alcohol is deoxidized and activated, and the activator has the structure shown in formula (I);

Wherein, in formula (I),

R ^a , R ^b and R ^c are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and the optional substituents in R ^a , R ^b and R ^c are each independently selected from At least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

Compared with the prior art, the present invention at least has the following advantages:

The method provided by the present invention is easy to operate, easy to separate and purify, and the method of the present invention has a wider range of substrates, a wide range of optional nucleophiles, high product yield, few by-products, and generated by-products (such as silyl ether, Iodine-containing salts) can be distilled or washed to remove or recycled, no acid waste is generated, and no harmful impact on the environment.

In particular, the method provided by the present invention, the partially sulfided product and the aminated product can maintain the optical configuration of the reaction starting substrate alcohol.

Other features and advantages of the present invention will be described in detail in the detailed description section that follows.

Detailed ways

The endpoints of ranges and any values disclosed herein are not limited to the precise ranges or values, which are to be understood to encompass values proximate to those ranges or values. For ranges of values, the endpoints of each range, the endpoints of each range and the individual point values, and the individual point values can be combined with each other to yield one or more new ranges of values that Ranges should be considered as specifically disclosed herein.

In this article, explanations are provided for the following terms:

C _1-20 alkyl refers to the total number of carbon atoms 1-20 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20) alkyl groups of carbon atoms, which can be straight-chain, branched or cyclic alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, etc.

Aryl of C _6-20 refers to an aryl group with a total number of carbon atoms of 6-20 (eg 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). groups, including but not limited to phenyl, naphthyl, anthracenyl, and the like.

"C _1-10 alkyl group", "C _6-15 aryl group", "C _1-5 alkyl group", "C _6-10 aryl group" and the aforementioned "C _1-20 alkyl group" Similar to the definition of "C _6-20 aryl group", only the number of carbon atoms is different.

As previously mentioned, a first aspect of the present invention provides a method for deoxyfunctionalizing an alcohol, the method comprising:

(1) in the first solvent, in the presence of an activator, the alcohol is deoxidized and activated to obtain an iodide intermediate;

(2) in a second solvent, in the presence of a nucleophile, the iodide intermediate is functionalized to obtain an alcohol-functionalized substance;

Wherein, the activator has the structure shown in formula (I);

Wherein, in formula (I),

R ^a , R ^b and R ^c are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and the optional substituents in R ^a , R ^b and R ^c are each independently selected from At least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

According to the present invention, the optional substituent refers to that the substituent may or may not be present. There is no particular limitation on the substitution position and substitution quantity of each optional substituent, and the substitution can be carried out at any position that can be substituted. replace.

Preferably, in formula (I),

R ^a , R ^b and R ^c are each independently selected from substituted or unsubstituted C _1-20 alkyl groups, substituted or unsubstituted C _6-20 aryl groups, and any of R ^a , R ^b and R ^c The optional substituents are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

More preferably, in formula (I),

R ^a , R ^b and R ^c are each independently selected from substituted or unsubstituted C _1-10 alkyl groups, substituted or unsubstituted C _6-15 aryl groups, and any of R ^a , R ^b and R ^c The optional substituents are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

Further preferably, the activator is selected from trimethyl iodide silane, triethyl iodide silane, triisopropyl iodide silane, tri-n-butyl iodide silane, tri-tert-butyl iodide silane, dimethyl tert-butyl iodide At least one of silane, tricyclohexyliodosilane and triphenyliodosilane.

More preferably, the activator is trimethylsilyl iodide.

Preferably, the alcohol is a primary and/or secondary alcohol, the alcohol has the structure shown in formula (II), and the iodide intermediate has the structure shown in formula (II'):

In formula (II) and formula (II'),

R ¹ and R ² are each independently selected from representing hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and the optional substituents in R ¹ and R ² are each independently selected from halogen, alkane At least one of an oxy group, an alkyl group, an aryl group, a heteroaryl group, and an amine group.

Preferably, in formula (II) and formula (II'),

R ¹ and R ² are each independently selected from representing hydrogen, a substituted or unsubstituted C _1-20 alkyl group, and a substituted or unsubstituted C _6-20 aryl group, and R ¹ and R ² are optionally present in The substituents are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

More preferably, in formula (II) and formula (II'),

R ¹ and R ² are each independently selected from representing hydrogen, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _6-15 aryl, and R ¹ and R ² are optionally present in The substituents are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

Further preferably, in formula (II) and formula (II'),

R ¹ and R ² are each independently selected from representing hydrogen, substituted or unsubstituted C _1-5 alkyl, substituted or unsubstituted C _6-10 aryl, and R ¹ and R ² are optionally present in The substituents are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

Further preferably, the alcohol is selected from at least one of the following compounds:

Preferably, the method provided by the present invention is represented by the following formula (1):

In formula (1), HNu and Nu ^- represent at least one nucleophile selected from the group consisting of nitrogen-containing nucleophiles, sulfur-containing nucleophiles, carbon-containing nucleophiles, halogen-containing nucleophiles, and oxygen-containing nucleophiles Reagent; Nu represents at least one group selected from nitrogen-containing groups, sulfur-containing groups, carbon-containing groups, halogen-containing groups, and oxygen-containing groups.

Preferably, in step (1), the molar ratio of the activator to alcohol is 1-4:1.

Preferably, in step (1), the conditions for the deoxidation activation include: minus 20° C. to minus 100° C., and the time is 0.5-20 h.

Preferably, in step (1), the deoxidation activation is carried out under protective atmosphere and shading conditions.

According to a preferred embodiment of the present invention, in step (1), the alcohol is a chiral secondary alcohol, the iodide intermediate is a chiral iodide, and the iodide intermediate is the same as the The optical configuration of alcohols is reversed.

According to the present invention, the opposite optical configurations of the two substances means that the optical configurations of the two substances are reversed. For example, when the optical configuration of the alcohol is R type, the optical configuration of the iodide intermediate is S type. .

Preferably, in step (1), the first solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, dioxane and acetonitrile, more preferably dichloromethane.

The present invention does not specifically limit the amount of the first solvent, and those skilled in the art can make a reasonable selection according to requirements.

According to the present invention, step (1) further comprises desolvating the deoxidized activated solution to obtain the iodide intermediate. The present invention has no particular limitation on the specific operation of the precipitation, which can be carried out by using the existing methods of precipitation and solvent removal in the art, as long as the iodide intermediate can be obtained.

According to the present invention, the reaction of step (2) can be carried out without further purification to obtain the iodide intermediate, and the operation is simple.

According to the present invention, in step (1), in addition to the iodide intermediate, although by-products of silanol (such as trimethylsilanol) and silyl ether (such as hexamethylsilyl ether) may also be produced, Both the silanol and silyl ether by-products can be recycled by distillation.

According to the present invention, deoxyfunctionalization of the alcohol refers to deoxyamination, deoxysulfurization, deoxyesterification, deoxyetherification, deoxyhalogenation, deoxycarbonation, deoxyamidation, deoxysulfonamidation, etc. of the alcohol.

Preferably, in step (2), the functionalization is selected from at least one of amination, sulfurization, carbonization, halogenation, amidation, sulfonamidation, esterification and etherification.

More preferably, in step (2), the functionalization is selected from at least one of amination, sulfurization, sulfonamidation, esterification and etherification.

Preferably, in step (2), the nucleophile is selected from at least one of nitrogen-containing nucleophiles, sulfur-containing nucleophiles, carbon-containing nucleophiles, halogen-containing nucleophiles and oxygen-containing nucleophiles kind.

Preferred specific embodiments of the nitrogen-containing nucleophile will be described below.

According to a preferred embodiment of the present invention, the nitrogen-containing nucleophile is selected from the group consisting of azide salts, amides, sulfonamides, primary aliphatic amines, secondary aliphatic amines, primary aromatic amines, secondary aromatic amines and nitrogen at least one of the heteroaromatic rings.

According to the present invention, preferably, the azide salt is selected from at least one of NaN ₃ and TMSN ₃ .

According to the present invention, preferably, the amide is selected from at least one of formamide, acetamide, propionamide, succinimide, and phthalimide.

中的至少一种：According to the present invention, preferably, the sulfonamide is selected from methanesulfonamide, benzenesulfonamide, p-toluenesulfonamide, di-p-toluenesulfonimide and

At least one of:

According to the present invention, preferably, the primary aliphatic amine is selected from n-propylamine, n-butylamine, n-pentylamine, n-hexylamine, benzylamine, 2-phenylethylamine, 3-phenylpropylamine, 4-phenylbutylamine at least one of amines.

According to the present invention, the secondary aliphatic amine includes secondary acyclic or cyclic aliphatic amine, preferably, the secondary aliphatic amine is selected from at least one of the following compounds:

According to the present invention, preferably, the primary aromatic amine is selected from aniline, o-toluidine, m-toluidine, p-toluidine, o-chloroaniline, m-chloroaniline, p-chloroaniline, α-naphthylamine, β-naphthylamine at least one of them.

According to the present invention, preferably, the secondary aromatic amine is selected from at least one of N-methylaniline, N-methylbenzylamine, N-ethylaniline, diphenylamine, indoline, and tetrahydroquinoline kind.

According to the present invention, preferably, the aza aromatic ring is selected from pyrazole, imidazole, oxazole, thiazole, triazole, benzopyrazole, benzimidazole, benzoxazole, benzothiazole, benzotriazole at least one of azoles.

More preferably, the nitrogen-containing nucleophile is selected from at least one of the following compounds:

NaN ₃ ,

Preferred specific embodiments of the sulfur-containing nucleophile will be described below.

According to a preferred embodiment of the present invention, the sulfur-containing nucleophile is selected from aliphatic thiols, substituted or unsubstituted thiophenates, substituted or unsubstituted thiophenols, heteroarylthiols and phenylenes At least one of sodium sulfonate, and the optional substituents in the sulfur-containing nucleophile are each independently selected from at least one of halogen, alkyl, alkoxy, aryl, and amine.

According to the present invention, preferably, the fatty thiol is selected from at least one of ethanethiol, propanethiol, n-butanethiol, benzylthiol, phenylethanethiol, and phenylpropanethiol.

According to the present invention, preferably, the substituted or unsubstituted thiophenate is selected from at least one of sodium thiophenate, potassium thiophenate, lithium thiophenate, and sodium 4-methylthiophenate.

According to the present invention, preferably, the substituted or unsubstituted thiophenol is selected from at least one of the following compounds:

According to the present invention, preferably, the heteroaryl thiol is selected from at least one of the following compounds:

More preferably, the sulfur-containing nucleophile is selected from at least one of the following compounds:

Preferred specific embodiments of the oxygen-containing nucleophile will be described below.

Preferably, the oxygen-containing nucleophile is selected from aliphatic carboxylates, substituted or unsubstituted aromatic carboxylates, substituted or unsubstituted alkyl alcohols, substituted or unsubstituted alkyl alcohol salts, substituted or unsubstituted alkyl alcohols At least one of phenolate, substituted or unsubstituted phenol, and the optional substituents in the oxygen-containing nucleophile are each independently selected from halogen, alkoxy, alkyl, aryl, at least one of the amine groups.

According to the present invention, preferably, the fatty carboxylate is selected from at least one of sodium formate, sodium acetate, potassium acetate, sodium propionate, sodium phenylacetate, and sodium stearate.

According to the present invention, preferably, the substituted or unsubstituted aromatic carboxylate is selected from at least one of sodium benzoate and sodium 3,5-difluorobenzoate.

According to the present invention, preferably, the substituted or unsubstituted alkyl alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, benzyl alcohol, allyl alcohol, propargyl alcohol, chloroethanol, bromoethanol, At least one of trifluoroethanol, ethylene glycol monomethyl ether, and ethylene glycol monoethyl ether.

According to the present invention, preferably, the substituted or unsubstituted alkyl alkoxide is selected from at least one of sodium methoxide, sodium ethoxide, and sodium propoxide.

According to the present invention, preferably, the substituted or unsubstituted phenate is selected from at least one of sodium phenate, sodium o-nitrophenolate, and sodium p-nitrophenolate.

According to the present invention, preferably, the substituted or unsubstituted phenol is selected from phenol, o-cresol, m-cresol, p-cresol, o-chlorophenol, m-chlorophenol, p-chlorophenol, o-methoxyphenol, m- At least one of methoxyphenol and p-methoxyphenol.

More preferably, the oxygen-containing nucleophile is selected from at least one of the following compounds:

Preferably, the halogen-containing nucleophile is selected from at least one of sodium fluoride, potassium fluoride, potassium hydrogen fluoride, sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide, potassium iodide .

Preferably, the carbon-containing nucleophile is selected from at least one of ethyl acetoacetate, malononitrile, diethyl propionate, ethyl cyanoacetate, and 2,4-pentanedione.

More preferably, the nucleophile is selected from at least one of nitrogen-containing nucleophiles, sulfur-containing nucleophiles and oxygen-containing nucleophiles.

According to the present invention, preferably, in step (2), the molar ratio of the amount of the nucleophile to the alcohol is 1-4:1.

According to the present invention, preferably, in step (2), the functionalization conditions include: a temperature of minus 20° C. to plus a zero of 160° C., and a time of 0.5-20 h.

Preferably, the functionalization reaction is carried out in a protective atmosphere. According to the present invention, the protective atmosphere is provided by at least one substance selected from nitrogen and an inert atmosphere.

Preferably, step (2) is carried out in the presence of an alkaline substance.

Preferably, the alkaline substance is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.

Preferably, the amount of the basic substance is 0.5-2 mmol relative to 1 mmol of the nucleophile.

Preferably, step (2) is carried out in the presence of a catalyst.

Preferably, the catalyst is Ag ₂ O.

Preferably, the amount of the catalyst is 1-5 mmol relative to 1 mmol of the nucleophile.

Preferably, in step (2), the second solvent is selected from acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide, dichloromethane, chloroform, dichloroethane, at least one of dioxane. More preferably, it is acetonitrile or N,N-dimethylformamide.

Preferably, in step (2), the amount of the second solvent is 2-20 mL relative to 1 mmol of the alcohol.

According to the method of the present invention, several preferred specific embodiments are provided below.

Embodiment 1

The functionalization is amination, the nucleophile is a nitrogen-containing nucleophile, and the method comprises:

(1) in the first solvent, in the presence of an activator, the alcohol is deoxidized and activated to obtain an iodide intermediate;

(2) Functionalizing the iodide intermediate in a second solvent in the presence of a nitrogen-containing nucleophile.

Preferably, the activator is trimethyliodosilane.

Preferably, the nitrogen-containing nucleophile is selected from the group consisting of azide salts, amides, sulfonamides, primary aliphatic amines, secondary acyclic or cyclic aliphatic amines, primary aromatic amines, secondary aromatic amines and aza aromatic rings at least one of them.

Preferably, the amination functionalization is represented by the following formula (2):

Wherein, in formula (2), R ¹ and R ² are the same as the definitions of the aforementioned R ¹ and R ² ;

R ³ and R ⁴ are each independently selected from at least one of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, acyl, and sulfonyl, or R ³ , R ⁴ and N atoms are cyclized to form Cyclic aliphatic amines or R ³ , R ⁴ and N atoms are cyclized to form nitrogen heteroaromatic rings, and the optional substituents are selected from at least one of halogen, alkyl, alkoxy, aryl, and amine groups .

According to a preferred embodiment of the present invention:

The nitrogen-containing nucleophile is an azide salt; the second solvent is DMF, and the functionalization conditions include: a temperature of 20-60° C. and a time of 2-16 hours.

According to another preferred embodiment of the present invention:

The nitrogen-containing nucleophile is selected from at least one of primary aliphatic amines, secondary (acyclic or cyclic) aliphatic amines, primary aromatic amines, secondary aromatic amines and nitrogen heteroaromatic rings; the second The solvent is acetonitrile, and the functionalization conditions include: heating under reflux, the temperature is 20-100°C, and the time is 0.5-20h.

According to another preferred embodiment of the present invention:

The iodide intermediate is a chiral iodide, the nitrogen-containing nucleophile is an azide salt, the amination reaction product is a chiral azide product, and the chiral azide product is the same as the chiral azide product. The optical configuration of the iodide intermediate is opposite, that is, when the alcohol is a chiral alcohol and the nitrogen-containing nucleophile is an azide salt, the optical configuration of the amination reaction product maintains the alcohol (chiral alcohol) optical configuration.

Embodiment 2

The functionalization is sulfurization, the nucleophile is a sulfur-containing nucleophile, and the method includes:

(1) in the first solvent, in the presence of an activator, the alcohol is deoxidized and activated to obtain an iodide intermediate;

(2) Functionalizing the iodide intermediate in a second solvent in the presence of a sulfur-containing nucleophile.

Preferably, the activator is trimethyliodosilane.

Preferably, the sulfur-containing nucleophile is selected from at least one of aliphatic thiol, substituted or unsubstituted thiophenate, substituted or unsubstituted thiophenol, heteroarylthiol and sodium phenylsulfinate , the optional substituent is selected from at least one of halogen, alkyl, alkoxy, aryl, and amine.

Preferably, the sulfur functionalization reaction is represented by the following formula (3):

Wherein, in formula (3), R ¹ and R ² are the same as the definitions of the aforementioned R ¹ and R ² ;

R ⁵ is selected from alkyl, substituted or unsubstituted phenyl, and heteroaryl, and the optional substituent is selected from at least one of halogen, alkyl, alkoxy, aryl, and amine.

According to a preferred embodiment of the present invention:

The sulfur-containing nucleophile is substituted or unsubstituted thiophenate and/or sodium phenylsulfinate, and step (2) includes:

The iodide intermediate is sulfurized in the second solvent in the presence of a sulfur-containing nucleophile.

Preferably, the vulcanization conditions include: a temperature of 0-45° C. and a time of 0.5-8 h.

According to another preferred embodiment of the present invention:

The sulfur-containing nucleophile is aliphatic thiol, substituted or unsubstituted thiophenol or heteroaromatic thiol, and step (2) includes:

The iodide intermediate is sulfurized in a second solvent in the presence of a sulfur-containing nucleophile and a basic species.

Preferably, the amount of the basic substance is 0.5-2 mmol relative to 1 mmol of the nucleophile.

Preferably, the vulcanization conditions include: a temperature of 0-45° C. and a time of 0.5-8 h.

According to another preferred embodiment of the present invention:

The iodide intermediate is a chiral iodide, the sulfur-containing nucleophile is a substituted or unsubstituted thiophenol, the sulfide reaction product is a chiral sulfide product, and the chiral sulfide product is the same as the chiral sulfide product. The optical configuration of the iodide intermediate is reversed. That is, when the alcohol is a chiral alcohol and the sulfur-containing nucleophile is a substituted thiophenol, the optical configuration of the sulfurization reaction product maintains the optical configuration of the alcohol (chiral alcohol).

Embodiment 3

The functionalization is esterification and/or etherification, the nucleophile is an oxygen-containing nucleophile, and the method comprises:

(1) in the first solvent, in the presence of an activator, the alcohol is deoxidized and activated to obtain an iodide intermediate;

(2) Functionalizing the iodide intermediate in a second solvent in the presence of an oxygen-containing nucleophile.

Preferably, the activator is trimethyliodosilane.

Preferably, the oxygen-containing nucleophile is selected from aliphatic carboxylates, substituted or unsubstituted aromatic carboxylates, substituted or unsubstituted alkyl alcohols, substituted or unsubstituted alkyl alcohol salts, substituted or unsubstituted alkyl alcohols At least one of phenolate, substituted or unsubstituted phenol, and the optional substituent is selected from at least one of halogen, alkoxy, alkyl, aryl, and amine.

Preferably, the oxidative functionalization is represented by the following formula (4):

Wherein, in formula (4), R ¹ and R ² are the same as the definitions of the aforementioned R ¹ and R ² ;

R ⁶ is selected from substituted or unsubstituted alkyl, fatty acyl, substituted or unsubstituted benzoyl, substituted or unsubstituted phenyl, and the optional substituent is selected from halogen, alkoxy, alkyl , at least one of aryl and amine groups.

According to a preferred embodiment of the present invention:

The oxygen-containing nucleophile is aliphatic carboxylates and/or substituted or unsubstituted aromatic carboxylates, the second solvent is DMF, and step (2) includes:

The iodide intermediate is functionalized in the second solvent in the presence of an oxygen-containing nucleophile.

According to another preferred embodiment of the present invention:

The oxygen-containing nucleophile is substituted or unsubstituted phenol, the second solvent is acetonitrile, and step (2) includes:

The iodide intermediate is functionalized in the second solvent in the presence of an oxygen-containing nucleophile and a basic species.

Preferably, the alkaline substance is sodium carbonate.

Preferably, the amount of the basic substance used is 0.5-2 mmol relative to 1 mmol of the nucleophile.

According to another preferred embodiment of the present invention:

The oxygen-containing nucleophile is benzyl alcohol, the second solvent is acetonitrile, and step (2) includes:

In the second solvent, in the presence of an oxygen-containing nucleophile and a catalyst, the iodide intermediate is subjected to a functionalization reaction, which is an etherification reaction.

Preferably, the catalyst is Ag ₂ O.

Preferably, the amount of the catalyst is 1-5 mmol relative to 1 mmol of the nucleophile.

According to the method of the present invention, the method of the present invention further comprises sequentially extracting, drying, and separating and purifying the reaction solution after the functionalization reaction to obtain an alcohol-functionalized substance. The method of the present invention can realize that the functionalized substance can be separated and purified by simple post-processing operation.

Preferably, the extraction conditions include: first diluting with water, then extracting with dichloromethane, and washing the organic liquid with saturated brine.

Preferably, the drying conditions include: drying with a desiccant, such as Na ₂ SO ₄ .

Preferably, the separation and purification is carried out by column chromatography, and the conditions of the column chromatography include: using 100-200 mesh silica gel, and the eluents are petroleum ether and ethyl acetate.

According to the present invention, in step (2), an iodized salt-containing by-product will be produced, and the iodized salt-containing product can be removed by washing with water, or recycled by a water-layer evaporation crystallization method.

In addition, the present invention may also include other conventional post-processing operation means in the art, which is not particularly limited in the present invention, and can be performed by using existing operations in the art, which should not be construed as a limitation of the present invention by those skilled in the art.

Compared with the classical Appel reaction and the Mitsunobu reaction, the present invention provides an alcohol deoxyfunctionalization method that is easy to operate and easy to purify, has high product yield, few by-products, and produces by-products (such as silicon ethers, iodine-containing products, etc.). salt) can be removed by distillation or washing and recycled, no acid waste is generated, and no harmful impact on the environment.

In addition, the method of the present invention has a wider range of substrates, a wide variety of nucleophiles can be selected, and the reaction with some nucleophiles can maintain the optical configuration of the raw alcohol.

As previously mentioned, a second aspect of the present invention provides an alcohol-functionalized substance selected from at least one of the following compounds:

As mentioned above, a third aspect of the present invention provides a method for deoxidizing and activating an alcohol, the method comprising:

In the first solvent, in the presence of an activator, the alcohol is deoxidized and activated, and the activator has the structure shown in formula (I);

Wherein, in formula (I),

R ^a , R ^b and R ^c are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and the optional substituents in R ^a , R ^b and R ^c are each independently selected from At least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

According to the method described in the third aspect of the present invention, the preferred specific implementations of R ^a , R ^b , and R ^c are the same as the definitions in the foregoing first aspect, and are not repeated here.

According to the method of the third aspect of the present invention, the activator is selected from trimethyliodosilane, triethyliodosilane, triisopropyliodosilane, tri-n-butyliodosilane, tri-tert-butyliodosilane, At least one of dimethyl tert-butyliodosilane, tricyclohexyliodosilane and triphenyliodosilane, more preferably trimethyliodosilane.

According to the method of the third aspect of the present invention, the first solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, dioxane and acetonitrile, more preferably dichloromethane.

According to the method of the third aspect of the present invention, the conditions for the deoxidation activation include: a temperature of minus 20° C. to plus a zero of 100° C., and a time of 0.5-20 h.

According to the method of the third aspect of the present invention, the molar ratio of the activator to the alcohol is 1-4:1.

According to a preferred embodiment of the present invention, the alcohol is an achiral alcohol, and the iodide intermediate obtained by deoxygenation activation is an achiral iodide.

According to another preferred embodiment of the present invention, the alcohol is a racemic alcohol, and the iodide intermediate obtained by deoxygenation activation is a racemic iodide.

According to another preferred embodiment of the present invention, the alcohol is a chiral alcohol, the iodide intermediate obtained by deoxygenation is a chiral iodide, and the optical configuration of the iodide and the alcohol on the contrary.

In the third aspect of the present invention, the preferred situation of the alcohol is the same as that in the first aspect. To avoid redundant description, the present invention will not describe it in detail here.

Using the method of the third aspect of the present invention, the alcohol can be activated to give an iodide intermediate, which can be used for subsequent further processing, such as functionalization (amination, sulfurization, esterification and etherification). Compared with the existing method for activating alcohol substances, the method provided by the present invention has a high product yield, and the generated by-products (such as silyl ether) can be removed or recycled by distillation, without affecting the subsequent functionalization reaction.

The present invention will be described in detail below by way of examples.

In the following examples, the raw materials used are all commercially available products unless otherwise specified.

In the following examples, the specific structures of the involved compounds are shown in Table 1, but the compounds synthesized by this method are not limited to the compounds in Table 1.

In the following example, the reaction involving the ee value of the product all uses chiral alcohol as the raw material to carry out the reaction control, and the specific structure of the chiral product involved is shown in Table 1, but the chiral compound synthesized by this method is not limited to the chiral compounds in Table 1. Chiral compounds.

In the following examples, all reactions involving no product ee value use achiral alcohol or racemic alcohol as raw material.

In the following implementation, the process, conditions, reagents, experimental methods, etc. of the present invention are common knowledge in the art unless otherwise specified.

In the following examples, trimethylsilanol, hexamethyldisilazane, sodium iodide, potassium iodide, ammonium iodide salt by-products will be produced, which can be recycled by distillation or evaporative crystallization methods, but no phosphine oxygen by-products are produced. Product and strong acid waste, which will not be described in detail below.

In the following examples, the performance involved is tested by the following methods:

(1) Yield

Yield=actual production weight of target product/theoretical production weight of target product×100%.

(2) ee value (enantiomeric excess value)

The enantiomeric excess (absolute value of ee value) of the product in the present invention is measured by chiral high performance liquid chromatography and calculated according to the following formula.

ee value=(R-S)/(R+S)×100%

Wherein, R and S are the peak area ratios of the corresponding peaks of the S-configuration product and the R-configuration product in the liquid chromatogram.

In the following examples, unless otherwise specified, room temperature refers to 25±2°C.

Example 1A

The preparation of compound III-1, whose structure is shown in Table 1.

(1) In an 8mL reaction flask, add 0.2mmol of racemic 4-phenyl-2-butanol (I-1), 1mL of dichloromethane as a solvent, dropwise add 0.4mmol of trimethylsilyl iodide, argon Protected at room temperature and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) 1 mL of DMF was added to the iodide intermediate obtained in step (1), 0.4 mmol of nitrogen-containing nucleophile (NaN ₃ , formula N-1) was added, and the reaction was carried out at 60° C. for 12 hours under argon protection. After the reaction is complete, add water to quench, extract, dry, and separate by column chromatography to obtain compound III-1 with a yield of 94%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.36-7.23(m,2H), 7.23-7.12(m,3H), 3.54-3.34(m,1H), 2.83-2.57(m,2H), 1.87-1.65 (m, 2H), 1.26 (d, J=6.5Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 141.3, 128.56, 128.50, 126.1, 57.2, 37.9, 32.4, 19.5.

Example 1B

In a similar manner to Example 1A, the difference is that the consumption of each reaction raw material is different, and the type is the same as that of Example 1A;

Specifically: alcohol I-1 is 0.2 mmol, trimethyliodosilane is 0.2 mmol, and nitrogen-containing nucleophile NaN ₃ is 0.4 mmol;

The rest are the same as in Example 1A, which obtained compound III-1 in a yield of 75%.

Example 1C

In a similar manner to Example 1A, the difference is that the consumption of each reaction raw material is different, and the type is the same as that of Example 1A;

Specifically: alcohol I-1 is 0.2 mmol, trimethyliodosilane is 0.4 mmol, and nitrogen-containing nucleophile NaN ₃ is 0.2 mmol;

The rest are the same as in Example 1A, which obtained compound III-1 in a yield of 83%.

Example 1D

In a manner similar to that of Example 1A, the difference is that an equal volume of dioxane was used to replace the dichloromethane in Example 1A;

The rest are the same as in Example 1A, which obtained compound III-1 in a yield of 80%.

Example 1E

In a similar manner as in Example 1A, the difference is that an equimolar amount of triethyliodosilane is used to replace the trimethyliodosilane in Example 1A;

The rest are the same as in Example 1A, which obtained compound III-1 in a yield of 52%.

Example 1F

In a similar manner to Example 1A, the difference is that equimolar triphenyliodosilane is used instead of trimethyliodosilane in Example 1A;

The rest are the same as in Example 1A, which obtained compound III-1 in a yield of 35%.

Example 1G

In a similar manner to Example 1A, the difference is that the reaction raw material alcohol is a chiral alcohol;

Specifically: the alcohol is chiral (S)-4-phenyl-2-butanol (S-I-1), and the rest are the same as those in Example 1A.

The obtained iodide intermediate is chiral (R)-4-phenyl-2-iodobutane, and in this example, the compound S-III-1 with the configuration maintained is obtained with a yield of 96% and an ee of 86%.

Example 2

The preparation of compound III-2, whose structure is shown in Table 1.

(1) 0.2 mmol of alcohol I-1 was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, 0.4 mmol of trimethyliodosilane was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-2) was added, and the reaction was carried out at 60° C. for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry over Na ₂ SO ₄ , and obtain compound III-2 with a yield of 91% after column chromatography;

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.32-7.24(m,2H),7.22-7.12(m,3H),2.74-2.45(m,5H),1.84-1.72(m,1H), 1.68-1.55(m,1H),1.53-1.40(m,2H),1.38-1.23(m,4H),1.10(d,J=6.3Hz,3H),0.89(t,J=5.8Hz,3H) . ¹³ C NMR (100MHz, CDCl ₃ ) δ 142.4, 128.3, 125.7, 52.8, 47.3, 38.7, 32.4, 30.1, 29.6, 22.6, 20.4, 14.1.

Example 3

The preparation of compound III-3, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (amine, N-3), and react at 60° C. for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry over Na ₂ SO ₄ , and obtain compound III-3 with a yield of 94% after column chromatography;

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.22(m,2H), 7.21-7.12(m,3H), 2.78-2.66(m,1H), 2.63-2.50(m,5H), ¹³ C NMR (100MHz, CDCl ₃ ) δ 142.8, 128.37, 128.34, 125.6, 58.5, 51.2, 37.3, 32.1, 23.5, 17.7.

Example 4

The preparation of compound III-4, whose structure is shown in Table 1.

(1) 0.2 mmol of alcohol (I-1) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, 0.4 mmol of trimethylsilyl iodide was added dropwise, and the reaction was carried out at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-4) was added, and the reaction was carried out at 60° C. for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry over Na ₂ SO ₄ , and obtain compound III-4 with a yield of 93% after column chromatography;

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.29-7.22(m,2H),7.21-7.13(m,3H),3.75-3.64(m,4H),2.74-2.59(m,2H), ¹³ C NMR (100MHz, CDCl ₃ ) δ 142.6, 128.47, 128.32, 125.7, 67.5, 58.4, 48.7, 35.3, 32.8, 13.9.

Example 5

The preparation of compound 5, whose structure is shown in Table 1.

(1) 0.2 mmol of alcohol (I-1) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, 0.4 mmol of trimethylsilyl iodide was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction was completed, the solvent was evaporated, and 1 mL of acetonitrile was added as the solvent to obtain the iodide intermediate;

(2) 0.4 mmol of nitrogen-containing nucleophile (amine, N-5) was added to the iodide intermediate obtained in step (1), and the reaction was carried out at 60° C. for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry over Na ₂ SO ₄ , and obtain compound III-5 with a yield of 91% after column chromatography;

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.50-7.25(m, 10H), 3.72(d, J=13.4Hz, 1H), 3.57(d, J=13.4Hz, 1H), 2.93-2.74 (m, 3H), 2.27 (s, 3H), 2.08–1.95 (m, 1H), 1.77–1.65 (m, 1H), 1.14 (d, J=6.5Hz, 3H). ¹³ C NMR (100MHz, CDCl) ₃ ) δ143.0, 140.5, 128.81, 128.57, 128.39, 128.29, 126.7, 125.7, 57.61, 57.19, 36.52, 36.13, 33.2, 13.3.

Example 6

The preparation of compound III-6, whose structure is shown in Table 1.

(1) 0.2 mmol of alcohol I-1 was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, 0.4 mmol of trimethylsilyl iodide was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-6) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry over Na ₂ SO ₄ , and obtain compound III-6 with a yield of 93% after column chromatography;

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.26(m,2H),7.22-7.10(m,5H),6.70-6.63(m,1H),6.57-6.48(m,2H), 3.49(h,J＝6.3Hz,1H),2.73(t,J＝7.9Hz,2H),1.88(dtd,J＝14.2,8.0,6.8Hz,1H),1.77(dtd,J＝13.9,7.9, 6.2Hz, 1H), 1.55(s, 1H), 1.22(d, J=6.3Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ147.5, 141.9, 129.2, 128.43, 128.38, 125.8, 116.9, 113.1, 47.8, 38.8, 32.4, 20.8.

Example 7

The preparation of compound III-7, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-7) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry over Na ₂ SO ₄ , and obtain compound III-7 with a yield of 93% after column chromatography.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.27-7.16(m, 5H), 7.15(d, J=1.7Hz, 2H), 6.74(d, J=7.8Hz, 2H), 6.68(t , J=7.2Hz, 1H), 3.97–3.86 (m, 1H), 2.75 (s, 3H), 2.68–2.53 (m, 2H), 1.99–1.89 (m, 1H), 1.82–1.71 (m, 1H) ), 1.12(d, J=6.6Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ150.5, 142.1, 129.1, 128.47, 128.36, 125.8, 116.3, 113.1, 52.7, 36.4, 33.1, 29.8, 16.9.

Example 8

The preparation of compound III-8, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-8) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried over Na ₂ SO ₄ , and separated by column chromatography to obtain compound III-8 with a yield of 46%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.96(s,1H),7.88-7.79(m,1H),7.38-7.33(m,1H),7.31-7.27(m,3H),7.20( t, J=7.2Hz, 1H), 7.08 (d, J=7.3Hz, 2H), 4.49–4.36 (m, 1H), 2.62–2.47 (m, 2H), 2.45–2.32 (m, 1H), 2.26 -2.13 (m, 1H), 1.62 (d, J=6.8Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 144.1, 141.0, 140.3, 133.2, 128.59, 128.35, 126.3, 122.72, 122.13, 120.5, 110.2 ,51.4,37.8,32.3,21.1.

Example 9

The preparation of compound III-9, its structure is shown in Table 1

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-9) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried over Na ₂ SO ₄ , and separated by column chromatography to obtain compound III-9 with a yield of 29%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.57(d,J=5.0Hz,1H),7.43(d,J=12.8Hz,1H),7.30(t,J=7.3Hz,2H), 7.22 (d, J=7.2Hz, 1H), 7.16 (d, J=7.5Hz, 2H), 6.28 (s, 1H), 4.43–4.28 (m, 1H), 2.54–2.44 (m, 2H), 2.38 -2.25(m,1H),2.14-2.01(m,1H),1.54(d,J=6.7Hz,3H). ¹³ C NMR (100MHz, CDCl ₃ )δ141.2,138.9,128.4,127.3,125.9,104.8, 57.3, 38.6, 32.2, 21.5.

Example 10

The preparation of compound III-10, whose structure is shown in Table 1.

(1) Alcohol I-2 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, K ₂ CO ₃ (0.4 mmol) was added, and in this example, the alcohol I-2 part was used as a nucleophile, under argon protection at 60° C. The reaction was carried out for 12 hours. After the reaction was completed, the mixture was washed with dichloromethane and saturated brine, dried over Na ₂ SO ₄ , and separated by column chromatography to obtain compound III-10 with a yield of 80%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.74(d,J=8.0Hz,1H),7.36(d,J=8.3Hz,2H),7.22(t,J=7.7Hz,1H), 7.15(d,J＝8.0Hz,2H),7.10(t,J＝7.5Hz,1H),6.97(d,J＝7.3Hz,1H),4.35(h,J＝6.5Hz,1H),2.36( s, 4H), 1.86–1.72 (m, 2H), 1.38–1.30 (m, 1H), 1.28 (d, J=6.5Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.3, 136.3, 135.1, 133.4, 129.4, 127.98, 127.52, 127.02, 126.6, 125.5, 52.2, 30.0, 24.6, 21.65, 21.54.

Example 11

The preparation of compound III-11, whose structure is shown in Table 1.

(1) Alcohol I-3 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (NaN ₃ ), and react at 60° C. for 12 hours under argon protection. After the reaction is complete, add water to quench, extract, dry, and separate by column chromatography to obtain compound III-11 with a yield of 95%,

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.35-7.29(m,2H),7.21-7.15(m,2H),7.15-7.09(m,1H),5.28(q,J=7.1Hz, 1H), 2.09 (d, J=7.1Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 143.1, 126.5, 125.7, 124.4, 26.8, 24.1.

Example 12

The preparation of compound III-12, whose structure is shown in Table 1.

(1) Alcohol I-4 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (NaN ₃ , N-1), and react at 60° C. for 12 hours under argon protection. After the reaction is complete, add water to quench, extract, dry, and separate by column chromatography to obtain compound III-12 with a yield of 93%,

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.45-7.36(m, 3H), 7.34(d, J=7.2Hz, 2H), 4.35(s, 2H). ¹³ C NMR(100MHz, CDCl ₃ )δ135.4,128.89,128.36,128.27,54.8.

Example 13

The preparation of compound III-13, whose structure is shown in Table 1.

(1) Alcohol I-4 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (amine, N-4), and react at 60° C. for 12 hours under argon protection. After the reaction was completed, the mixture was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-13 with a yield of 90%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.36-7.27(m, 4H), 7.26-7.19(m, 1H), 3.69(t, J=4.7Hz, 4H), 3.48(s, 2H) , 2.42 (t, J=4.7Hz, 4H). ¹³ C NMR (100MHz, CDCl ₃ )δ137.8, 129.2, 128.3, 127.1, 67.0, 63.5, 53.6.

Example 14

The preparation of compound III-14, whose structure is shown in Table 1.

(1) Alcohol I-4 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, 0.4 mmol of nitrogen-containing nucleophile (amine, N-7) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-14 with a yield of 92%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.25(m,2H),7.23-7.16(m,5H),6.75-6.66(m,3H),4.49(s,2H),2.97( s, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ149.8, 139.1, 129.3, 128.7, 127.0, 126.8, 116.6, 112.5, 56.7, 38.6.

Example 15

The preparation of compound III-15, whose structure is shown in Table 1.

(1) Alcohol I-5 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (NaN ₃ , N-1), and react at 60° C. for 12 hours under argon protection. After the reaction is complete, add water to quench, extract, dry, and separate by column chromatography to obtain compound III-15 with a yield of 94%,

Nuclear magnetic data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (t, J=7.3 Hz, 2H), 7.35-7.27 (m, 3H), 3.56 (t, J=7.3 Hz, 2H), 2.96 (t , J=7.3Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ )δ138.1, 128.83, 128.72, 126.8, 52.5, 35.4.

Example 16

The preparation of compound III-16, whose structure is shown in Table 1.

(1) Alcohol I-5 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (amine, N-10), and react at 60° C. for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-16 with a yield of 58%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.37-7.27(m,4H), 7.27-7.17(m,6H), 2.95-2.87(m,2H), 2.87-2.80(m,2H), 2.72–2.57 (m, 4H), 1.66 (p, J=8.3, 7.7Hz, 2H), 1.55 (p, J=7.2Hz, 2H), 1.33 (s, 1H). ¹³ C NMR (100MHz, CDCl ₃ )δ142.4,140.1,128.74,128.49,128.43,128.29,126.1,125.7,51.2,49.7,36.4,35.8,29.77,29.21.

Example 17

The preparation of compound III-17, whose structure is shown in Table 1.

(1) Alcohol I-5 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of a nitrogen-containing nucleophile (amine, N-3), and react at 60° C. for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-17 with a yield of 93%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.24(m,2H), 7.24-7.15(m,4H), 2.87-2.79(m,2H), 2.72-2.63(m,2H), 2.59–2.48 (m, 4H), 1.85–1.74 (m, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 140.5, 129.0, 128.68, 128.51, 128.40, 126.0, 63.4, 58.4, 54.2, 39.5, 35.8, 23.4 .

Example 18

The preparation of compound 18, whose structure is shown in Table 1.

(1) Alcohol I-5 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-6) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-18 with a yield of 88%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.35-7.28(m, 2H), 7.24-7.14(m, 5H), 6.71(t, J=7.2Hz, 1H), 6.61(d, J= 7.8Hz, 2H), 3.40 (t, J=7.0Hz, 2H), 2.91 (t, J=6.9Hz, 2H). ¹³ CNMR (100MHz, CDCl ₃ )δ148.0, 139.33, 129.32, 128.82, 128.63, 126.4, 117.5, 113.0, 45.0, 35.5.

Example 19

The preparation of compound III-19, whose structure is shown in Table 1.

(1) Alcohol I-5 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), 1 mL of acetonitrile was added as a solvent, 0.4 mmol of a nitrogen-containing nucleophile (amine, N-7) was added, and the reaction was refluxed at room temperature for 12 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-19 with a yield of 58%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.34-7.17(m, 7H), 6.77-6.67(m, 3H), 3.56(t, J=7.6Hz, 2H), 2.88(s, 3H) , 2.84 (t, J=7.6Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ )δ148.8, 139.8, 129.3, 128.86, 128.58, 126.2, 116.2, 112.1, 54.8, 38.5, 32.9.

The following examples serve to illustrate the preparation of the sulfurization reaction product.

Example 20

The preparation of compound 20, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (thiol, S-1) and K ₂ CO ₃ (0.4 mmol), under argon protection at room temperature The reaction was carried out for 6 hours. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-20 with a yield of 52%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.32-7.24(m,4H), 7.23-7.15(m,6H), 2.89-2.82(m,2H), 2.81-2.65(m,5H), 1.94-1.73(m, 2H), 1.31(d, J=6.7Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 141.9, 140.8, 128.49, 128.46, 128.42, 126.3, 125.8, 39.5, 38.6, 36.5, 33.2, 31.7, 21.5.

Example 21

The preparation of compound 21, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of a sulfur-containing nucleophile (sodium thiophenate, S-2), and react at room temperature for 6 hours under argon protection. After the reaction was completed, the mixture was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-21 with a yield of 90%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.38-7.32(m,2H),7.29-7.22(m,4H),7.22-7.14(m,4H),3.19(h,J=6.7Hz, 1H), 2.83–2.72 (m, 2H), 1.92 (ddt, J=13.6, 9.0, 6.7Hz, 1H), 1.81 (ddt, J=13.7, 9.1, 6.7Hz, 1H), 1.31 (d, J= 6.7Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ141.7, 135.1, 132.0, 128.88, 128.54, 128.47, 126.8, 125.9, 42.5, 38.2, 33.2, 21.2.

Example 22A

The preparation of compound III-22, whose structure is shown in Table 1.

(1) Chiral alcohol S-I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (substituted thiophenol, S-3) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the reaction is complete, use dichloromethane and saturated brine to wash, dry, and obtain compound III-22 with a yield of 96%, 96% ee after column chromatography,

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.24(m,3H),7.21-7.14(m,4H),7.14-7.08(m,2H),3.21(h,J=6.7Hz, 1H), 2.86–2.72 (m, 2H), 2.39 (s, 3H), 1.97 (ddt, J=13.4, 9.2, 6.6Hz, 1H), 1.85 (ddt, J=13.7, 9.1, 6.7Hz, 1H) , 1.32 (d, J=6.7Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ141.6, 139.3, 134.8, 131.2, 130.2, 128.48, 128.41, 126.46, 126.26, 125.9, 41.7, 38.3, 33.1, 21.0, 20.8.

Example 22B

In a manner similar to that of Example 22A, the difference is that an equal volume of dichloromethane was used to replace the acetonitrile in step (2) in Example 22A as the solvent;

The rest are the same as in Example 22A, which obtained compound S-III-22 with a yield of 87% and 88% ee.

Example 22C

In a manner similar to that of Example 22A, the difference is that the room temperature reaction in step (2) in Example 22A was substituted for 6 hours by refluxing at room temperature for 2 hours;

The rest are the same as in Example 22A, which obtained compound S-III-22 with a yield of 95% and 25% ee.

Example 22D

In a similar manner to Example 22A, except that an equimolar amount of racemic alcohol was used instead of the chiral alcohol in Example 22A;

The rest are the same as in Example 22A, which obtained the racemic compound III-22 in a yield of 95%.

Example 23

The preparation of compound III-23, whose structure is shown in Table 1.

(1) Chiral alcohol S-I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (substituted thiophenol, S-4) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound S-III-23 with a yield of 86%, 94% ee,

Nuclear magnetic data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25 (d, J=7.4 Hz, 5H), 7.21-7.12 (m, 3H), 7.08 (d, J=7.8 Hz, 2H), 3.10 (h) , J=6.7Hz, 1H), 2.85–2.69 (m, 2H), 2.31 (s, 3H), 1.96–1.83 (m, 1H), 1.83–1.71 (m, 1H), 1.28 (d, J=6.8 Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ141.7, 137.0, 132.9, 131.0, 129.5, 128.47, 128.38, 125.8, 43.0, 38.1, 33.2, 21.2, 21.1.

Example 24

The preparation of compound III-24, whose structure is shown in Table 1.

(1) Chiral alcohol S-I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (substituted thiophenol, S-5) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the reaction is complete, use dichloromethane and saturated brine to wash, dry, and obtain compound S-III-24 with a yield of 92% and 96% ee after column chromatography.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.47-7.38(m,2H),7.37-7.28(m,2H),7.28-7.17(m,3H),7.03(t,J=8.4Hz, 2H), 3.13 (h, J=6.7Hz, 1H), 2.92–2.75 (m, 2H), 2.04–1.75 (m, 2H), 1.33 (d, J=6.8Hz, 3H). ¹³ C NMR (100MHz) , CDCl ₃ )δ162.3(d,J=247.3Hz),141.6,135.1(d,J=8.1Hz),129.6(d,J=3.4Hz),128.4,125.9,115.9(d,J=21.7Hz ), 43.5, 38.0, 33.1, 21.1.

Example 25

The preparation of compound III-25, whose structure is shown in Table 1.

(1) Chiral alcohol S-I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (substituted thiophenol, S-6) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the completion of the reaction, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound S-III-25 with a yield of 91%, 96% ee,

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.18(m,7H),7.18-7.13(m,2H),3.15(h,J=6.7Hz,1H),2.85-2.69(m, 2H), 1.91 (ddt, J=13.4, 9.0, 6.6Hz, 1H), 1.81 (ddt, J=13.8, 9.0, 6.7Hz, 1H), 1.30 (d, J=6.7Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ141.4,133.63,133.32,132.8,128.97,128.46,126.0,42.7,38.1,33.1,21.0.

Example 26

The preparation of compound III-26, whose structure is shown in Table 1.

(1) Chiral alcohol S-I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (substituted thiophenol, S-7) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the reaction is complete, use dichloromethane and saturated brine to wash, dry, and obtain compound S-III-26 with 90% yield and 98% ee after column chromatography.

Nuclear magnetic data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, J=8.5 Hz, 2H), 7.35-7.27 (m, 3H), 7.25-7.16 (m, 4H), 3.19 (h, J= 6.7Hz, 1H), 2.89–2.72 (m, 2H), 1.94 (ddt, J=13.5, 8.9, 6.6Hz, 1H), 1.84 (ddt, J=13.6, 8.7, 6.7Hz, 1H), 1.34 (d , J=6.7Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ141.4, 134.3, 133.4, 132.5, 131.8, 128.4, 126.0, 120.7, 42.6, 38.1, 33.1, 21.0.

Example 27

The preparation of compound III-27, whose structure is shown in Table 1.

(1) Alcohol I-4 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add sulfur-containing nucleophile substituted thiophenol S-5 (0.4 mmol) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-27 with a yield of 91%.

Nuclear magnetic data: ¹ H NMR(400MHz, CDCl ₃ )δ7.29-7.18(m,7H),6.97-6.89(m,2H),4.02(s,2H). ^13C NMR(100MHz, CDCl ₃ )δ162. 1(d,J＝246.6Hz),137.5,133.4(d,J＝8.1Hz),130.7(d,J＝3.3Hz),128.87,128.49,127.2,115.9(d,J＝21.9Hz),40.4.

Example 28

The preparation of compound III-28, whose structure is shown in Table 1.

(1) Alcohol I-5 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (substituted thiophenol, S-5) and K ₂ CO ₃ (0.4 mmol), under argon protection The reaction was carried out at room temperature for 6 hours. After the completion of the reaction, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-28 with a yield of 90%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.63-7.56(m,2H),7.56-7.50(m,2H),7.49-7.39(m,3H),7.28-7.20(m,2H), 3.35 (dd, J=9.2, 6.5 Hz, 2H), 3.13 (dd, J=9.3, 6.4 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.8 (d, J=246.3 Hz), 140.0 ,132.3(d,J＝7.8Hz),131.1(d,J＝3.4Hz),128.56,128.54,126.5,116.0(d,J＝21.9Hz),36.5,35.7.

Example 29

The preparation of compound 29, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of sulfur-containing nucleophile (S-8) and K ₂ CO ₃ (0.4 mmol), and react at room temperature for 6 hours under argon protection . After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-29 with a yield of 88%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.67-7.60(m,1H),7.49-7.42(m,1H),7.35-7.24(m,5H),7.23(d,J=7.3Hz, 3H), 3.98 (h, J=6.8Hz, 1H), 2.94–2.78 (m, 2H), 2.24–2.01 (m, 2H), 1.62 (d, J=6.8Hz, 3H). ¹³ C NMR (100MHz) , CDCl ₃ )δ164.5,151.6,142.0,141.1,128.50,128.43,126.1,124.2,123.8,118.4,109.8,42.9,38.3,33.2,21.8.

Example 30

The preparation of compound III-30, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of a sulfur-containing nucleophile (sodium benzene sulfinate, S-9), and react at room temperature for 10 hours under argon protection. After the reaction was completed, it was washed with dichloromethane and saturated brine, dried, and separated by column chromatography to obtain compound III-30 with a yield of 66%.

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.90-7.83(m,2H),7.70-7.64(m,1H),7.61-7.54(m,2H),7.33-7.26(m,2H), 7.25–7.19 (m, 1H), 7.16–7.10 (m, 2H), 3.11–3.00 (m, 1H), 2.90–2.79 (m, 1H), 2.67–2.56 (m, 1H), 2.40–2.28 (m , 1H), 1.81–1.69(m, 1H), 1.34(d, J=6.9Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ140.1, 137.1, 133.6, 129.13, 129.00, 128.61, 128.32, 126.3, 59.1, 32.4, 30.7, 13.2.

The following examples are used to illustrate the preparation of the oxidation reaction product of the present invention

Example 31

The preparation of compound III-31, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of an oxygen-containing nucleophile (potassium acetate, O-1), and react at room temperature for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry, and obtain compound III-31 with a yield of 90% after column chromatography;

NMR data: ¹ H NMR (400MHz, CDCl ₃ )δ7.31-7.25(m,2H), 7.22-7.15(m,3H), 4.99-4.89(m,1H), 2.72-2.56(m,2H), 2.03(s, 3H), 1.99-1.88(m, 1H), 1.86-1.75(m, 1H), 1.25(d, J=6.3Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ170.8,141.5, 128.43, 128.32, 125.9, 70.5, 37.5, 31.8, 21.3, 20.0.

Example 32

The preparation of compound III-32, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of DMF as a solvent, add 0.4 mmol of an oxygen-containing nucleophile (sodium benzoate, O-2), and react at room temperature for 12 hours under argon protection. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry, and obtain compound III-32 with a yield of 92% after column chromatography;

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ ) δ 8.11 (d, J=7.4Hz, 2H), 7.61 (t, J=7.4Hz, 1H), 7.49 (t, J=7.6Hz, 2H), 7.37–7.30 (m, 2H), 7.28–7.20 (m, 3H), 5.31–5.20 (m, 1H), 2.88–2.72 (m, 2H), 2.23–2.10 (m, 1H), 2.06–1.95 (m , 1H), 1.44 (d, J=6.2Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ166.2, 141.5, 132.8, 130.8, 129.5, 128.50, 128.40, 128.37, 125.9, 71.2, 37.8, 31.9, 20.2 .

Example 33

The preparation of compound III-33, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, trimethylsilyl iodide (0.4 mmol) was added dropwise, and the reaction was carried out at room temperature under argon protection and protected from light for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of an oxygen-containing nucleophile (formula O-3) and K ₂ CO ₃ (0.4 mmol), and react at room temperature under argon protection for 12 Hour. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry, and obtain compound III-33 with a yield of 88% after column chromatography;

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.30-7.23(m,2H),7.20-7.14(m,3H),6.81(s,4H),4.28-4.16(m,1H),3.75( s, 3H), 2.85–2.67 (m, 2H), 2.10–1.97 (m, 1H), 1.90–1.80 (m, 1H), 1.28 (d, J=6.1Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ153.9,152.1,141.9,128.53,128.42,125.8,117.4,114.7,74.0,55.7,38.3,31.8,19.8.

Example 34

The preparation of compound III-34, whose structure is shown in Table 1.

(1) Alcohol I-1 (0.2 mmol) was added to an 8 mL reaction flask, 1 mL of dichloromethane was used as a solvent, 0.4 mmol of trimethylsilyl iodide was added dropwise, and the reaction was performed at room temperature under argon protection and in the dark for 16 hours. After the reaction is complete, the solvent is evaporated to obtain the iodide intermediate;

(2) To the iodide intermediate obtained in step (1), add 1 mL of acetonitrile as a solvent, add 0.4 mmol of oxygen-containing nucleophile (benzyl alcohol, O-4) and 0.8 mmol of Ag ₂ O, under argon protection at 70° C. React for 14 hours. After the reaction is complete, use dichloromethane and saturated brine to extract and wash, dry, and obtain compound III-34 with a yield of 61% after column chromatography;

Nuclear magnetic data: ¹ H NMR (400MHz, CDCl ₃ )δ7.43-7.36(m,4H),7.35-7.29(m,3H),7.21(ddd,J=7.6,5.3,1.7Hz,3H),4.62( d, J=11.7Hz, 1H), 4.49 (d, J=11.7Hz, 1H), 3.63–3.52 (m, 1H), 2.81 (ddd, J=13.7, 9.9, 5.6Hz, 1H), 2.70 (ddd ,J=13.8,9.8,6.5Hz,1H),1.97(dddd,J=13.8,9.8,7.3,5.6Hz,1H),1.80(dddd,J=13.7,9.9,6.5,4.9Hz,1H),1.27 (d, J=6.1 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 142.4, 139.0, 128.46, 128.38, 128.35, 127.72, 127.47, 125.7, 74.1, 70.3, 38.4, 31.8, 19.6.

Table 1: Reaction raw materials, product structural formula and yield of each embodiment

It can be seen from the above that the present invention provides an alcohol deoxyfunctionalization method that is easy to operate and easy to purify. Moreover, the reaction with a partial nucleophile can maintain the configuration of the starting alcohol.

The preferred embodiments of the present invention have been described above in detail, however, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, a variety of simple modifications can be made to the technical solutions of the present invention, including combining various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the content disclosed in the present invention. All belong to the protection scope of the present invention.

Claims (13)

1. A method for deoxygenating a functionalization of an alcohol, the method comprising:

(1) in a first solvent, in the presence of an activating agent, carrying out deoxidation activation on alcohol to obtain an iodo intermediate;

(2) functionalizing the iodo intermediate in a second solvent in the presence of a nucleophile to obtain an alcohol-functionalized material;

wherein the activator has a structure represented by formula (I);

wherein, in the formula (I),

R^a、R^band R^cEach independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and R^a、R^bAnd R^cWherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

2. The process according to claim 1, wherein, in formula (I),

R^a、R^band R^cEach independently selected from substituted or unsubstituted C_1-20Alkyl, substituted or unsubstituted C_6-20And R is an aryl group of^a、R^bAnd R^cWherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine;

preferably, in the formula (I),

R^a、R^band R^cEach independently selected from substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_6-15And R is an aryl group of^a、R^bAnd R^cWherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine;

more preferably, the activator is at least one selected from the group consisting of trimethyliodosilane, triiodosilane, triisopropyliodosilane, tri-n-butyliodosilane, tri-tert-butyliodosilane, dimethyl-tert-butyliodosilane, tricyclohexyliodosilane, and triphenyliodosilane, and more preferably is trimethyliodosilane.

3. The method of claim 1 or 2, wherein the alcohol has a structure represented by formula (II) and the iodide intermediate has a structure represented by formula (II'):

in the formulae (II) and (II'),

R¹and R²Each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and R¹And R²Wherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine;

preferably, in formula (II) and formula (II'),

R¹and R²Each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-20Alkyl, substituted or unsubstituted C_6-20And R is an aryl group of¹And R²Wherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine;

more preferably, in formula (II) and formula (II'),

R¹and R²Each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_6-15And R is an aryl group of¹And R²Wherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

4. The process according to any one of claims 1 to 3, wherein in step (1), the molar ratio of the activator to the alcohol is from 1 to 4: 1;

preferably, in step (1), the deoxidation activation conditions include: the temperature is from minus 20 ℃ to plus 100 ℃, and the time is 0.5 to 20 hours;

preferably, in step (1), the alcohol is a chiral alcohol, the iodide intermediate is a chiral iodide, and the iodide intermediate has an optical configuration opposite to that of the alcohol;

preferably, in step (1), the first solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, chloroform, dioxane and acetonitrile, more preferably dichloromethane.

5. The process of any one of claims 1-4, wherein, in step (2), the functionalization is selected from at least one of amination, sulfurization, carbonization, halogenation, amidation, sulfonylamination, esterification, and etherification;

preferably, the functionalization is selected from at least one of amination, sulfurization, sulfonylamination, esterification, and etherification;

preferably, the nucleophile is selected from at least one of a nitrogen-containing nucleophile, a sulfur-containing nucleophile, a carbon-containing nucleophile, a halogen-containing nucleophile, and an oxygen-containing nucleophile;

more preferably, the nucleophile is selected from at least one of a nitrogen-containing nucleophile, a sulfur-containing nucleophile, and an oxygen-containing nucleophile;

preferably, the nitrogen-containing nucleophile is selected from at least one of azide salts, amides, sulfonamides, primary aliphatic amines, secondary aliphatic amines, primary aromatic amines, secondary aromatic amines, and azaaromatic rings;

preferably, the sulfur-containing nucleophile is selected from at least one of an aliphatic thiol, a substituted or unsubstituted thiophenolate, a substituted or unsubstituted thiophenol, a heteroaromatic thiol, and sodium phenyl sulfinate, and the substituents optionally present in the sulfur-containing nucleophile are each independently selected from at least one of a halogen, an alkyl group, an alkoxy group, an aryl group, an amine group;

preferably, the oxygen-containing nucleophile is selected from at least one of a fatty carboxylate, a substituted or unsubstituted aromatic carboxylate, a substituted or unsubstituted alkyl alcohol, a substituted or unsubstituted alkyl alkoxide, a substituted or unsubstituted phenoxide, a substituted or unsubstituted phenol, and the substituents optionally present in the oxygen-containing nucleophile are each independently selected from at least one of a halogen, an alkoxy group, an alkyl group, an aryl group, an amine group.

6. The process according to any one of claims 1 to 5, wherein, in step (2), the molar ratio of the nucleophilic reagent to the alcohol is from 1 to 4: 1;

preferably, in step (2), the conditions of the functionalization comprise: the temperature is from minus 20 ℃ to minus 160 ℃, and the time is 0.5 to 20 hours.

7. The method of any one of claims 1-6, wherein the functionalization is amination and the nucleophile is a nitrogen-containing nucleophile, the method comprising:

(1) in a first solvent, in the presence of an activating agent, carrying out deoxidation and activation on alcohol to obtain an iodo intermediate;

(2) functionalizing said iodo intermediate in a second solvent in the presence of a nitrogen-containing nucleophile;

preferably, the alcohol is a chiral alcohol, the nitrogen-containing nucleophile is an azide salt, the amination reaction product is a chiral azide product, and the chiral azide product has the same optical configuration as the chiral alcohol.

8. The method of any one of claims 1-6, wherein the functionalization is sulfurization and the nucleophile is a sulfur-containing nucleophile, the method comprising:

(1) in a first solvent, in the presence of an activating agent, carrying out deoxidation and activation on alcohol to obtain an iodo intermediate;

(2) functionalizing said iodo intermediate in a second solvent in the presence of a sulfur-containing nucleophile;

preferably, the alcohol is a chiral alcohol and the sulfur-containing nucleophile is a substituted or unsubstituted thiophenol, the sulfuration reaction product is a chiral sulfuration product, and the chiral sulfuration product has the same optical configuration as the chiral alcohol.

9. The process according to any one of claims 1 to 6, wherein the functionalization is an esterification and/or etherification, the nucleophile is an oxygen-containing nucleophile, the process comprising:

(1) in a first solvent, in the presence of an activating agent, carrying out deoxidation and activation on alcohol to obtain an iodo intermediate;

(2) functionalizing the iodo intermediate in a second solvent in the presence of an oxygen-containing nucleophile.

10. An alcohol functionalized material, characterized in that the material is selected from at least one of the following compounds:

11. a method for deoxygenation activation of an alcohol, the method comprising:

deoxygenating and activating an alcohol in a first solvent in the presence of an activating agent, wherein the activating agent has a structure shown in a formula (I);

wherein, in the formula (I),

R^a、R^band R^cEach independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and R^a、R^bAnd R^cWherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine.

12. The method according to claim 11, wherein, in formula (I),

R^a、R^band R^cEach independently selected from substituted or unsubstituted C_1-20Alkyl, substituted or unsubstituted C_6-20And is aryl ofR^a、R^bAnd R^cWherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine;

preferably, in formula (I),

R^a、R^band R^cEach independently selected from substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_6-15And R is an aryl group of^a、R^bAnd R^cWherein the substituents optionally present are each independently selected from at least one of halogen, alkoxy, alkyl, aryl, heteroaryl, and amine;

more preferably, the activator is at least one selected from the group consisting of trimethyliodosilane, triiodosilane, triisopropyliodosilane, tri-n-butyliodosilane, tri-t-butyliodosilane, dimethyl-t-butyliodosilane, tricyclohexyliodosilane, and triphenyliodosilane, and more preferably is trimethyliodosilane.

13. The process according to claim 11 or 12, wherein the molar ratio of the activator to the alcohol is from 1 to 4: 1;

preferably, the deoxygenation activation conditions include: the temperature is from minus 20 ℃ to plus 100 ℃, and the time is 0.5 to 20 hours;

preferably, the first solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, dioxane, and acetonitrile, more preferably dichloromethane.