JP2011012026A - Method for producing monoallylated product of 1,2-diol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply and selectively producing a monoallylated product of a 1,2-diol.SOLUTION: The production method of a monoallylated product of a 1,2-diol comprises causing a 1,2-diol represented by formula (1) to react with a carboxylic acid allyl ester in the presence of a complex consisting of a palladium compound having a tertiary phosphine coordinated thereto, an organotin compound and a base to obtain a compound represented by formula (2). In formulae (1) and (2), Rand Rare the same or different and are each a hydrogen atom or an organic group. Rand Rmay be linked together to form a ring together with two neighboring carbon atoms.

Description

  The present invention relates to a method for conveniently and selectively producing a monoallylized form of 1,2-diol.

  In organic synthesis, selectively activating and reacting only specific functional groups in a molecule is very important for freely synthesizing a molecule. For example, polyols such as saccharides, inositol, and glycerin are a group of compounds that play an important role in life science as well as lipids and proteins. However, since these compounds have a large number of hydroxyl groups that are difficult to distinguish, it is difficult to selectively modify only specific hydroxyl groups. Among them, meso-1,2-diol and C2 symmetrical-1,2-diol have two hydroxyl groups with the same reactivity, and it is very difficult to selectively modify only one of the hydroxyl groups. It has been known.

  As a method for selectively modifying one of the hydroxyl groups of 1,2-diol, Patent Document 1 discloses an alkane obtained by reacting an alcohol with an alkanediol in the presence of a metal oxide catalyst under subcritical or supercritical conditions. A process for producing diol monoalkyl ethers is described. However, since harsh reaction conditions are required, the problem is that workability is poor.

  Patent Document 2 describes a method for monoallylating a polyol by reacting an allyl halide in a state where a hydroxyl group other than the hydroxyl group to be modified is protected using a protecting group. . However, the work of protecting with a protecting group and removing the protecting group after the reaction requires advanced techniques. In addition, the allyl halide used as an allylating agent is highly toxic and difficult to handle. Met.

  Furthermore, as a method for monoallylating 1,2-diol, Non-Patent Document 1 only describes a method using allyl halide. However, this method is disadvantageous in that allyl halide is highly toxic. That is, the monoallylated compound can be selected from 1,2-diols in a high yield, easily and without the need for attaching / detaching the protecting group, and without using a highly toxic organic halide. The current situation is that no method has been found.

Japanese Patent Laid-Open No. 2004-196783 JP 2006-520812 A

Tetrahedron Letters vol. 50, p1466-1468 (2009)

  Accordingly, an object of the present invention is to provide a method for producing a monoallylized form of 1,2-diol simply and selectively.

  As a result of intensive studies to solve the above problems, the present inventor has found that a complex in which a tertiary phosphine is coordinated with a 1,2-diol and a carboxylic acid allyl ester with a tertiary phosphine, an organotin compound, and a base. It has been found that when the reaction is carried out under the condition, the modification reaction proceeds to only one hydroxyl group without protecting the hydroxyl group with a protecting group, and the monoallyl compound can be selectively produced in a high yield. The present invention has been completed based on these findings.

（式中、Ｒ¹、Ｒ²は、同一又は異なって、水素原子又は有機基を示す。Ｒ¹、Ｒ²は互いに結合して隣接する２つの炭素原子と共に環を形成していてもよい）
で表される１，２−ジオールをカルボン酸アリルエステルと反応させて下記式（２）

（式中、Ｒ¹、Ｒ²は上記に同じ）
で表される化合物を得る１，２−ジオールのモノアリル化体の製造方法を提供する。 That is, the present invention provides a complex in which a tertiary phosphine is coordinated to a palladium compound, an organic tin compound, and a base in the presence of the following formula (1).

(Wherein R ¹ and R ² are the same or different and represent a hydrogen atom or an organic group. R ¹ and R ² may be bonded to each other to form a ring with two adjacent carbon atoms)
1,2-diol represented by the following formula (2)

(Wherein R ¹ and R ² are the same as above)
A process for producing a monoallylized form of 1,2-diol that yields a compound represented by the formula:

  According to the method for producing a monoallylated product of 1,2-diol according to the present invention, a complex in which a tertiary phosphine is coordinated to a palladium compound is coordinated to a carboxylic acid allyl ester to form π-allyl palladium. Since it acts as an agent, it becomes possible to allylate only one of the hydroxyl groups, and the monoallylation reaction is selectively accelerated to obtain a monoallylated product (monoallyl ether) in a high yield. In addition, since it is possible to omit a complicated process of reacting one hydroxyl group that is not allylated among the two hydroxyl groups of 1,2-diol in a state protected with a protecting group and deprotecting after the reaction, it is a simple process. Monoallylated compounds can be synthesized. Furthermore, since the reaction proceeds under mild conditions at room temperature and normal pressure, it is not necessary to use a harmful organic halide as an allylic agent, so that the workability is excellent. Therefore, the method for producing a monoallylized form of 1,2-diol according to the present invention is very versatile in organic synthesis, and in particular, monoallylation of meso-1,2-diol and C2 symmetrical-1,2-diol. It is useful as a method and can greatly contribute to the synthesis of biofunctional molecules.

  The method for producing a monoallylated form of 1,2-diol according to the present invention comprises a complex in which a tertiary phosphine is coordinated to a palladium compound, an organotin compound, and a base represented by the above formula (1). A 2-diol is reacted with a carboxylic acid allyl ester to obtain a compound represented by the above formula (2).

[1,2-diol]
The 1,2-diol of the present invention is represented by the above formula (1). In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or an organic group. R ¹ and R ² may be bonded to each other to form a ring with two adjacent carbon atoms.

The organic group in R ¹ and R ² may be an organic group that does not inhibit this reaction (for example, an organic group that is non-reactive under the reaction conditions in the present method), such as a hydrocarbon group and / or And groups containing a heterocyclic group.

  The hydrocarbon group and the heterocyclic group also include a hydrocarbon group and a heterocyclic group having a substituent. Examples of the hydrocarbon group include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and a group in which these groups are bonded.

  Examples of the aliphatic hydrocarbon group include 1 to 20 carbon atoms (preferably 1 to 1) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, decyl, and dodecyl groups. 10, more preferably an alkyl group of about 1 to 3); an alkenyl group of about 2 to 20 carbon atoms (preferably 2 to 10, more preferably 2 to 3) such as vinyl, allyl, 1-butenyl group; Examples thereof include alkynyl groups having about 2 to 20 carbon atoms (preferably 2 to 10, more preferably 2 to 3) such as propynyl groups.

As the alicyclic hydrocarbon group, a cycloalkyl group having about 3 to 20 members (preferably 3 to 15 members, more preferably 5 to 8 members) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl groups; Cycloalkenyl groups of about 3 to 20 members (preferably 3 to 15 members, more preferably 5 to 8 members) such as pentenyl and cyclohexenyl groups; perhydronaphthalen-1-yl group, norbornyl, adamantyl, tetracyclo [4 4.0.1, ^2,5 . 1 ^7,10 ] bridged cyclic hydrocarbon groups such as dodecan-3-yl groups. Examples of the aromatic hydrocarbon group include aromatic hydrocarbon groups having about 6 to 14 (preferably 6 to 10) carbon atoms such as phenyl and naphthyl groups.

A group in which an aliphatic hydrocarbon group and an alicyclic hydrocarbon group are bonded to each other includes a cycloalkyl-alkyl group such as cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl group (for example, C _3-20 cycloalkyl-C _{1 -4} alkyl group, etc.). In addition, the group in which the aliphatic hydrocarbon group and the aromatic hydrocarbon group are bonded includes an aralkyl group (for example, a C _7-18 aralkyl group) and an alkyl-substituted aryl group (for example, about 1 to 4 C _{1). -4} alkyl group-substituted phenyl group or naphthyl group).

Preferred hydrocarbon groups include C _1-10 alkyl groups, C _2-10 alkenyl groups, C _2-10 alkynyl groups, C _3-15 cycloalkyl groups, C _6-10 aromatic hydrocarbon groups, C _3-15 A cycloalkyl-C _1-4 alkyl group, a C _7-14 aralkyl group and the like are included.

  The hydrocarbon group includes various substituents such as halogen atoms, oxo groups, hydroxyl groups, substituted oxy groups (for example, alkoxy groups, aryloxy groups, aralkyloxy groups, acyloxy groups, etc.), carboxyl groups, substituted oxycarbonyls. Group (alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, etc.), substituted or unsubstituted carbamoyl group, cyano group, nitro group, substituted or unsubstituted amino group, sulfo group, heterocyclic group, etc. May be. The hydroxyl group and carboxyl group may be protected with a protective group commonly used in the field of organic synthesis. In addition, an aromatic or non-aromatic heterocycle may be condensed with the ring of the alicyclic hydrocarbon group or aromatic hydrocarbon group.

The heterocyclic ring constituting the heterocyclic group in R ¹ and R ² includes an aromatic heterocyclic ring and a non-aromatic heterocyclic ring. Examples of such a heterocyclic ring include a heterocyclic ring containing an oxygen atom as a hetero atom (for example, a 3-membered ring such as an oxirane ring, a 4-membered ring such as an oxetane ring, a furan, tetrahydrofuran, oxazole, and a γ-butyrolactone ring). 5-membered ring, 6-membered ring such as 4-oxo-4H-pyran, tetrahydropyran, morpholine ring, condensed ring such as benzofuran, 4-oxo-4H-chromene, chroman ring, 3-oxatricyclo [4.3. 1.1 ^4,8] undecane-2-one ring, 3-oxatricyclo [4.2.1.0 ^4,8] bridged rings such as nonane-2-one ring), a sulfur atom as a hetero atom Heterocycles containing (for example, 5-membered rings such as thiophene, thiazole and thiadiazole rings, 6-membered rings such as 4-oxo-4H-thiopyran ring, and condensed rings such as benzothiophene ring) ), A heterocyclic ring containing a nitrogen atom as a hetero atom (for example, a 5-membered ring such as pyrrole, pyrrolidine, pyrazole, imidazole, triazole ring, 6-membered ring such as pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine ring, indole, Indoline, quinoline, acridine, naphthyridine, quinazoline, condensed rings such as purine rings, etc.). In addition to the substituents that the hydrocarbon group may have, the heterocyclic group includes an alkyl group (eg, a C _1-4 alkyl group such as a methyl or ethyl group), a cycloalkyl group, an aryl group It may have a substituent such as (for example, phenyl, naphthyl group). Moreover, the nitrogen atom which comprises a heterocyclic ring may be protected by the protective group.

R ¹ and R ² may be composed of one or more hydrocarbon groups and / or heterocyclic groups and one or more linking groups. Examples of the linking group include an ether bond (—O—), a thioether bond (—S—), an ester bond (—COO—), an amide bond (—CONH—), and a carbonyl group (—CO—). Examples thereof include a bonded group.

R ¹ and R ² may be the same or different, and may be an aliphatic hydrocarbon group such as a methyl group, an ethyl group, a propyl group, a butyl group or an allyl group, an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, 4- A group in which an aliphatic hydrocarbon group such as a methylphenyl group or a benzyl group is bonded to an aromatic hydrocarbon group, or an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group is preferable. In particular, the present invention relates to a case where R ¹ and R ² which are difficult to selectively monoallylate by other methods represent the same group [particularly, when the compound represented by the formula (1) is a meso form. ] Is useful.

R ¹ and R ² may be bonded to each other to form a ring with two adjacent carbon atoms, and for example, may form an aromatic or non-aromatic ring. Preferred aromatic or non-aromatic rings are about 5 to 12 members, especially about 6 to 10 members. Such a ring includes, for example, a non-aromatic alicyclic ring (a cyclohexane ring or the like which may have a substituent, or an aromatic ring such as a benzene ring which may be condensed). A non-aromatic bridged ring (such as a cycloalkene ring which may have a substituent such as an alkane ring or a cyclohexene ring, and an aromatic ring such as a benzene ring may be condensed). A bridged hydrocarbon ring which may have a substituent such as a norbornene ring), an aromatic ring which may have a substituent such as a benzene ring or a naphthalene ring (including a condensed ring), etc. Can be mentioned. The ring may be a heterocyclic ring, and examples of the heterocyclic ring include the same examples as the heterocyclic ring constituting the heterocyclic group in R ¹ and R ² above. The ring may have a substituent such as an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group, a nitro group, a cyano group, an amino group, or a halogen atom.

When R ¹ and R ² are bonded to each other to form a ring with two adjacent carbon atoms, the ring includes, among others, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and tetrahydronaphthalene. A cycloalkane ring such as a ring; a cycloalkene ring such as cyclohexene; a non-aromatic heterocyclic ring containing a nitrogen atom as a hetero atom such as pyrrolidine; a non-aromatic heterocyclic ring containing an oxygen atom as a hetero atom such as a furan ring; In particular, cycloalkane rings such as cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and tetrahydronaphthalene ring; cycloalkene rings such as cyclohexene ring, non-aromatic heterocycles such as furan ring and pyrrolidine ring are preferable. , Which is preferable in that the reaction easily proceeds.

Specific examples of the 1,2-diol represented by the formula (1) include 2,3-butanediol, 3,4-hexanediol, 5,6-decanediol, 1,2-diphenyl-1, 2-ethanediol, 1,2-bis (4-methylphenyl) -1,2-ethanediol, 1,2-bis (methoxycarbonyl) -1,2-ethanediol, 1,2-cyclobutanediol, 1, 2-cyclopentanediol, 1,2-cyclohexanediol, cyclohexene-4,5-diol, 1,2-cyclooctanediol, 2,3 -dihydroxy-1,2,3,4-tetrahydronaphthalene, N-benzoyl- Examples include 3,4-dihydroxypyrrolidine.

  As the 1,2-diol represented by the formula (1) in the present invention, meso-2,3-butanediol, meso-1,2-cyclopentanediol, meso-1,2-cyclohexanediol, Meso-forms having symmetrical planes in the molecule such as meso-1,2-cyclooctanediol, meso-cyclohexene-4,5-diol, meso-1,2-diphenyl-1,2-ethanediol, dl-1 C2-symmetrical 1,2-diols such as 1,2-bis (4-methylphenyl) -1,2-ethanediol are preferred.

で表される。式中、Ｒ³は水素原子又は炭化水素基を示す。Ｒ³における炭化水素基としては前記Ｒ¹、Ｒ²における炭化水素基と同様の例を挙げることができる。本発明においては、なかでも、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ−ブチル、ｔ−ブチル、ペンチル、ヘキシル、デシル、ドデシル基などの炭素数１〜２０（好ましくは１〜１０、さらに好ましくは１〜３）程度のアルキル基、又はフェニル基が好ましい。また、アルキル基は、ハロゲン原子（フッ素原子等）、アルコキシ基等の置換基を有していてもよい。 [Carboxylic acid allyl ester]
The carboxylic acid allyl ester of the present invention has the following formula (3):

It is represented by In the formula, R ³ represents a hydrogen atom or a hydrocarbon group. Examples of the hydrocarbon group for R ³ include the same examples as the hydrocarbon groups for R ¹ and R ² . In the present invention, among them, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, decyl, dodecyl group, etc., having 1 to 20 carbon atoms (preferably 1 to 10, More preferably, an alkyl group of about 1 to 3) or a phenyl group is preferable. In addition, the alkyl group may have a substituent such as a halogen atom (fluorine atom or the like) or an alkoxy group.

  Among allyl carboxylic acid esters in the present invention, allyl acetate, allyl propionate, allyl butyrate and the like are preferable in terms of availability, handleability, and reactivity.

  The amount of carboxylic acid allyl ester used is, for example, about 1 to 5 mol, preferably about 1.5 to 3.5 mol, per 1 mol of 1,2-diol used as a raw material.

[Complex in which tertiary phosphine is coordinated to palladium compound]
A complex in which a tertiary phosphine is coordinated to a palladium compound is generated by reacting a palladium compound and a tertiary phosphine.

  Examples of the palladium compound include tetravalent palladium compounds such as sodium hexachloropalladate tetrahydrate and potassium hexachloropalladate; palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, dichlorobis (benzonitrile) palladium, Divalent palladium compounds such as dichlorobis (acetonitrile) palladium, dichlorotetraamminepalladium, dichloro (cycloocta-1,5-diene) palladium, palladium trifluoroacetate, bistriphenylphosphine palladium dichloride complex; tris (dibenzylideneacetone) dipalladium, tris (Dibenzylideneacetone) dipalladium chloroform complex, tetrakistriphenylphosphine palladium complex, etc. Indium compounds, and the like.

  Examples of the tertiary phosphine include triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine, tricyclohexylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, tri (p-tolyl) phosphine, tri (p-anisyl) phosphine, Tris (2-methylphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (4-fluorophenyl) phosphine, 1,2-bis (diphenylphosphino) benzene, BINAP (2,2′-bis (diphenylphosphine) Fino) -1,1′-binaphthyl) and the like. In the present invention, among them, tertiary phosphines (such as triarylphosphine) having high coordination ability such as triphenylphosphine and tris (4-methoxyphenyl) phosphine are preferable.

In the present invention, R ¹ and R ² as substrates are aliphatic hydrocarbon groups such as methyl group, ethyl group and propyl group, or R ¹ and R ² are bonded to each other and adjacent two carbon atoms together with cyclohexane, cyclo When a 1,2-diol that forms a cycloalkane ring such as octane is used, a tertiary phosphine having a high electron donating property (for example, tris (4-methoxyphenyl) phosphine) is preferable. Thereby, the reactivity with respect to the intermediate body C of the intermediate body A ((pi) -allyl palladium) shown below can be improved more. On the other hand, R ¹ and R ² as substrates are electron-withdrawing groups (for example, aromatic hydrocarbon groups such as phenyl group and naphthyl group; alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group) -When using diol, the tertiary phosphine (for example, triphenylphosphine etc.) with low electron donating property is preferable.

  Examples of the combination of the palladium compound and the tertiary phosphine include palladium acetate and tris (4-methoxyphenyl) phosphine, palladium acetate and triphenylphosphine, palladium acetate, and BINAP (2,2′-bis (diphenylphosphino)). -1,1'-binaphthyl) and the like.

  A complex in which a tertiary phosphine is coordinated to a palladium compound can be produced by reacting the palladium compound with a tertiary phosphine in the system, and can be used as it is as an allylating agent. Moreover, you may use the complex (For example, tetrakis (triphenylphosphine) palladium etc.) prepared by making the said palladium compound and tertiary phosphine react beforehand.

  As a usage-amount of a palladium compound, it is 0.01-1 mol with respect to 1 mol of 1, 2-diol used as a raw material, Preferably it is about 0.03-0.5 mol. If the amount of the palladium compound used is too small, the yield of the monoallylated product tends to decrease. On the other hand, if the amount of palladium compound used is too large, it is economically disadvantageous.

  As the usage-amount of a tertiary phosphine, it is 0.01-1 mol with respect to 1 mol of 1,2-diol used as a raw material, Preferably it is about 0.03-0.5 mol. When the amount of the tertiary phosphine used is too small, a sufficient amount of the complex in which the tertiary phosphine is coordinated to the palladium compound is not generated, and the reaction selectivity and the yield of the target compound tend to be lowered. On the other hand, if the amount of tertiary phosphine used is too large, it is economically disadvantageous.

  When a complex obtained by reacting a palladium compound and a tertiary phosphine in advance is used, the amount used is, for example, 0.01 to 1 mol with respect to 1 mol of 1,2-diol used as a raw material. The amount is preferably about 0.03 to 0.5 mol. If the amount of the complex used is too small, the reaction selectivity and the yield of the target compound tend to decrease. On the other hand, if the amount of the complex used is too large, it is economically disadvantageous.

[Organic tin compounds]
In the monoallylation reaction of 1,2-diol of the present invention, an organotin compound is used as a catalyst. Examples of the organic tin compound include compounds in which at least one organic group is bonded to a tetravalent tin atom.

In the present invention, among these, organotin compounds represented by the following formulas (4) and (5) are preferable. In the formula, R ^{4 to} R ⁷ represent an organic group, and X represents a halogen atom.

Examples of the organic group in R ^{4 to} R ⁷ include the same examples as the organic groups in R ¹ and R ² . Specific examples of the organic tin compound include tin (IV) chloride such as dimethyltin dichloride and diphenyltin dichloride; tin (IV) oxide such as dimethyltin oxide, dibutyltin oxide, dihexyltin oxide, and dioctyltin oxide.

  In the present invention, dimethyltin dichloride and dibutyltin oxide are preferred because of their low bulk and excellent ability to coordinate 1,2-diol to the hydroxyl group. Particularly, dimethyltin having high solubility in a solvent and excellent catalytic activity. Dichloride is preferred.

  As usage-amount of organotin, it is 0.01-1 mol with respect to 1 mol of 1, 2-diol used as a raw material, Preferably it is about 0.03-0.5 mol. When the amount of organotin used is too small, it becomes difficult to promote the monoallylation reaction, and the yield of the target compound tends to decrease. On the other hand, if the amount of organotin used is too large, it is economically disadvantageous.

[base]
The base is not particularly limited, and examples thereof include triethylamine, tri-n-propylamine, tri-n-butylamine, tri-s-butylamine, tri-t-butylamine, diisopropylethylamine, dimethylcyclohexylamine, dicyclohexylethylamine, and tribenzyl. Ruamine, N-methylpiperidine, N, N-dimethylaniline, N, N-diethylaniline, 1,4-diazabicyclo [2.2.2] octane, tetramethylethylenediamine, 1,4-dimethylpiperazine, N-methylpyrrolidine , N-methylmorpholine, 1-methyl-2,2,6,6-tetramethylpiperidine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] ] -7-Undecene, pyridine, 2,4-dimethyl Organic bases (amines, nitrogen-containing aromatic heterocyclic compounds) such as rupyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, 2,6-di-t-butylpyridine; sodium methoxide, sodium ethoxide Alkali metal alkoxides such as potassium t-butoxide; alkali metal carbonates such as sodium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal phosphates such as potassium phosphate; lithium hydroxide, hydroxide Examples thereof include alkali metal hydroxides such as sodium and potassium hydroxide.

  In the present invention, alkali metal carbonates (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., especially cesium carbonate) are easily available, and these carbonates are soluble in the reaction solvent. Is low and has an appropriate basicity, and is preferable in that it has an excellent effect of promoting the monoallylation reaction.

  As the usage-amount of a base, it is 0.5-5 mol with respect to 1 mol of 1, 2-diol used as a raw material, Preferably it is 0.8-3 mol, More preferably, it is about 1-2 mol.

[solvent]
The reaction of the present invention is preferably carried out in a solvent. As the reaction solvent, those not involved in the reaction are preferable. For example, DMF (N, N-dimethylformamide), NMP (N-methylpyrrolidone), DMSO (dimethylsulfoxide), THF (tetrahydrofuran), acetonitrile, methanol, ethanol, High polar solvents such as isopropyl alcohol, acetic acid and ethyl acetate; Medium polar solvents such as dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane and diisopropyl ether; Low polarities such as toluene, n-hexane, heptane, chloroform and chlorobenzene A solvent etc. are mentioned.

  In the present invention, in particular, a polar solvent (particularly dichloromethane) such as dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, diisopropyl ether is excellent in solubility of the substrate, and the reaction yield can be improved. This is preferable.

In the monoallylation reaction of 1,2-diol of the present invention, the catalytic cycle is considered to proceed by the mechanism shown below. Ln represents a ligand. Also, have been described when using organic tin compounds represented by R ⁴ R ⁵ SnX ₂ as an organic tin compound, is the same when using the R ⁶ R ⁷ SnO.

That is,
1. (A) becomes a zerovalent palladium complex (b) after coordination exchange.
The 2.0 valent palladium complex (b) is coordinated to the carboxylic acid allyl ester to form (c), and then forms intermediate A (π-allyl palladium).
3. 1,2-diol (d) and organotin compound (R ⁴ R ⁵ SnX ₂ ) interact to form intermediate B.
4). Intermediate B is deprotonated with a base to intermediate C.
5). Intermediate C undergoes nucleophilic attack on intermediate A, and the elimination of the zero-valent palladium complex (b) and the organotin compound (R ⁴ R ⁵ SnX ₂ ) results in the monoallylation of 1,2-diol. (E) is formed.

  In the present invention, intermediate A (π-allyl palladium) acts as an allylating agent, so that only one hydroxyl group of 1,2-diol can be allylated, and a monoallylated compound is selectively synthesized. can do.

  In the monoallylation reaction of the 1,2-diol of the present invention, the reaction temperature is usually from 0 ° C. to the boiling point of the solvent used, but it is about 0 ° C. to 50 ° C., especially about 10 ° C. to 30 ° C. Is preferred. The reaction can be performed under normal pressure. The reaction time is usually about 1 to 50 hours, although it depends on the reactivity of the substrate. After completion of the reaction, the desired monoallylated product can be isolated by distilling off the solvent under reduced pressure, distillation, recrystallization, chromatography or the like.

  In the method for producing a monoallylated 1,2-diol according to the present invention, π-allyl palladium formed from a complex in which a tertiary phosphine is coordinated to a carboxylic acid allyl ester and a palladium compound acts as an allylating agent. Therefore, it has a high reaction selectivity, and a monoallylized form of 1,2-diol can be obtained with an excellent yield. Further, it is possible to save the trouble of protecting and deprotecting with a protecting group, and it is not necessary to use a highly toxic organic halide as an allylating agent, so that the workability is excellent. And since the obtained monoallylation body can modify | modify an allyl group easily, its utility value is very high. The method for producing a 1,2-diol monoallylation product according to the present invention can be a highly versatile method for organic synthesis, in particular, a highly versatile monoallylation method of meso-1,2-diol. It greatly contributes to the synthesis of

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Preparation Example 1 (Synthesis of meso-1,2-cyclooctanediol)
In 60 mL of a water / acetone mixed solvent (water: acetone = 5: 1), 75 mmol of 50% N-methylmorpholine-N-oxide and 50 mmol of cyclooctane were added to replace with nitrogen, and 4 wt% OsO ₄ 0.5 mmol was added thereto. And stirred for 18 hours. A suspension of 0.25 g of Na ₂ S ₂ O ₃ and 2.5 g of silica gel was added to 10 mL of water, and the mixture was stirred for 10 minutes. Then, acetone was distilled off under reduced pressure, and concentrated hydrochloric acid was added to the residue to adjust to pH 2. Adjusted. Thereafter, the reaction solution was extracted 6 times with ethyl acetate and filtered through silica gel, and then the solvent was distilled off under reduced pressure to obtain meso-1,2-cyclooctanediol.

Example 1
Meso-1,2-cyclooctanediol 0.5 mmol (74.1 mg) obtained in Preparation Example 1, Cs ₂ CO ₃ 0.75 mmol (244.4 mg), Pd (OAc) ₂ 0.05 mmol (11.2 mg) ), PPh ₃ 0.05 mmol (13.1 mg) and Me ₂ SnCl ₂ 0.05 mmol (11.0 mg) were added and dissolved in ₂ mL of anhydrous CH ₂ Cl ₂ , followed by 1.5 mmol (161.8 μL) of allyl acetate. And stirred at room temperature for 22 hours. Thereafter, water was added to the reaction solution, and extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (trade name “silica gel 60 (70-230 mesh)”, manufactured by MERCK, developing solvent; n- Hexane: ethyl acetate = 10: 1) to obtain meso-1,2-cyclooctanediol monoallyl ether (69 mg, yield: 83%).

Examples 2-33, Comparative Examples 1-3
Examples 2 to 33 and Comparative Examples 1 to 3 were reacted in the same manner as in Example 1 except that the conditions were changed as described in the following table (and below). Other reaction conditions are as follows.
Carboxylic acid allyl ester: Allyl acetate, 3.0 eq to 1,2-diol (however, in Examples 19 to 21, 26 to 29, 31 to 33, 2.0 eq to 1,2-diol)
Amount of 1,2-diol used: 0.5 mmol
Amount of Pd compound used: 0.1 eq relative to 1,2-diol
Amount of tertiary phosphine used: 0.1 eq relative to 1,2-diol
Use amount of organotin compound: 0.1 eq with respect to 1,2-diol
Amount of base used: 1.5 eq relative to 1,2-diol
Solvent usage: 2 mL
Reaction temperature: room temperature Reaction time: 22 hours

  As the 1,2-diol used as a raw material, a racemic body was used in Examples 22 to 24 and 33, and a meso body was used in other cases.

The measurement results of the ¹ H-NMR spectrum (300 MHz) of the products (monoallylic compounds) obtained in Examples 1, 25, 26, 27, 28, 29, 30 and 33 are shown below.

Example 1 (Meso-1,2-cyclooctanediol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 1.28-2.02 (m, 12H), 2.57 (s, 1H), 3.48-3.60 (m, 1H), 3.84-4.16 (m, 3H), 5.10-5.32 (m, 2H ), 5.82-6.00 (m, 1H)

Example 25 (meso-1,2-cycloheptanediol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 1.20-1.92 (m, 12H), 2.54 (d, J = 2.4Hz, 1H), 3.40-3.52 (m, 1H), 3.82-4.18 (m, 3H), 5.10- 5.36 (m, 2H), 5.82-6.02 (m, 1H)

Example 26 (Meso-1,2-cyclohexanediol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 1.40-1.70 (m, 5H), 1.70-1.86 (m, 2H), 2.27 (s, 1H), 3.40-3.48 (m, 1H), 3.82 (s, 1H), 3.94-4.16 (m, 3H), 5.12-5.34 (m, 2H), 5.86-6.02 (m, 1H)

Example 27 (Meso-1,2-cyclopentanediol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 1.38-1.92 (m, 7H), 3.70-3.80 (m, 1H), 3.98-4.16 (m, 3H), 5.18-5.32 (m, 2H), 5.86-6.04 (m , 1H)

Example 28 (Meso-3,4-butanediol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 1.00-1.18 (m, 6H), 3.38-3.46 (m, 1H), 3.82-4.16 (m, 4H), 5.12-5.34 (m, 2H), 5.86-6.00 (m , 1H)

Example 29 (meso-cyclohexene-4,5-diol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 1.08-1.18 (m, 6H), 2.20 (s, 1H), 3.18-3.48 (m, 1H), 3.82-3.92 (m, 1H), 3.92-4.04 (m, 1H ), 4.04-4.14 (m, 1H), 5.14-5.32 (m, 2H), 5.84-6.00 (m, 1H)

Example 30 (Meso- 2,3 -dihydroxy-1,2,3,4-tetrahydronaphthalene monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 2.88-3.14 (m, 5H), 3.76-3.86 (m, 1H), 4.06-4.28 (m, 3H), 5.14-5.34 (m, 2H), 5.86-6.00 (m , 1H), 7.00-7.18 (m, 4H)
Example 33 (racemic-1,2-bis (4-methylphenyl) -1,2-ethanediol monoallyl ether)
¹ H-NMR (CDCl ₃ ) δ 2.27 (d, J = 3.6Hz, 6H), 3.53 (s, 1H), 3.74-3.88 (m, 1H), 3.92-4.02 (m, 1H), 4.25 (d, J = 4.1Hz, 1H), 4.65 (d, J = 4.2Hz, 1H), 5.12-5.30 (m, 2H), 5.84-5.98 (m, 1H), 5.84-7.08 (m, 8H)

Claims (1)

In the presence of a complex in which a tertiary phosphine is coordinated to a palladium compound, an organotin compound and a base, the following formula (1)

(Wherein R ¹ and R ² are the same or different and represent a hydrogen atom or an organic group. R ¹ and R ² may be bonded to each other to form a ring with two adjacent carbon atoms)
1,2-diol represented by the following formula (2)

(Wherein R ¹ and R ² are the same as above)
The manufacturing method of the monoallylization body of 1, 2-diol which obtains the compound represented by these.