JPS6210036A - Production of alpha-substituted ketone - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals, easily in high yield, under mild reaction condition, by reacting a diazonium salt to a silyl enol ether producible easily from a ketone. CONSTITUTION:The objective alpha-substituted ketone of formula III such as benzyl phenyl ketone can be produced by (1) reacting (A) a silyl enol ether of formula I (R<1>-R<3> are H or organic group; R<5>-R<7>) are alkyl, aryl or aralkyl) [e.g. (1-phenylethenyl)oxytrimethylsilane] with (B) a diazonium salt of formula II (R<4> is aryl or heterocyclic group; X is anion forming a diazonium salt) (e.g. benzenediazonium tetrafluoroborate) in a solvent such as pyridine at -50-+50 deg.C, (2) removing diazonium salt from the resultant reaction solution e.g. by washing with water, (3) removing the solvent e.g. by distillation, and (4) separating and purifying the objective alpha-substituted ketone of formula III having aryl or heterocyclic group at the alpha-site (e.g. benzyl phenyl ketone) e.g. by chromatography.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a method for producing α-substituted ketones useful as intermediates for the synthesis of pharmaceutical and agricultural products.

More specifically, it is characterized by reacting silyl enol ethers easily obtained from ketones with a diazonium salt.
This invention relates to a method for producing substituted ketones.

α-Aryl ketones or α-heterocyclic ketones are some extremely important compounds as synthetic intermediates for various pharmaceutical and agricultural products.

[Prior art]

As a method for introducing an aryl group into the α-position of a ketone,
A method of reacting a silyl enol ether of α-haloketone with aryl copper or aryl nickel, a method of reacting an alkali metal enolate of a ketone with aryl copper or aryl nickel, a method of reacting a potassium enolate of a ketone and an aryl halide under light irradiation. Reaction method, reaction of sulfonylazoolefin and aryl copper, α-
Reaction of haloketone and phenylborane, Reaction of hexadienylium iron and silyl enol ether, Reaction of ketone enol ester and phenylmercury in the presence of a palladium catalyst, Reaction of vinylthioether and bromobenzene in the presence of a palladium catalyst. Several methods are known, but most have low yields and require limited raw materials.
- It has problems such as lack of film properties. Recently, a method was discovered in which a ketone tin enolate produced in the reaction system and an aryl bromide are reacted in the presence of a palladium catalyst, but this method requires expensive reagents such as a palladium catalyst and a tin compound, and the product is separated. However, the separation and recovery of the palladium catalyst and tin residue requires complicated operations, and the yield is not necessarily satisfactory.

〔the purpose〕

In view of these facts, the present inventors under mild conditions,
As a result of intensive research and exploration into the development of a method for introducing an aryl group or a heterocyclic group into the α-position of a ketone that proceeds in good yields, we unexpectedly found that diazonium salts are accompanied by the release of nitrogen molecules relative to silyl enol ethers. It was discovered that α-aryl or α-heterocyclic ketones can be obtained by the reaction, and the present invention was completed based on this knowledge. Reactions between diazonium salts and nucleophiles (e.g., Grignard reagents, alkyl enol ethers, lithium enolates, ketene silyl acetals, etc.) are said to give azo or hydrazino compounds without releasing nitrogen molecules, and the present invention This finding can be said to be completely new and unexpected from these conventional techniques.

Accordingly, an object of the present invention is to provide a method for producing α-substituted ketones having an aryl group or a heterocyclic group at the α-position with a high yield by a novel reaction.

〔composition〕

That is, according to the invention, the general formula.

R1C0CR"R"R' (1) (wherein R" Bg and R3 are hydrogen atoms or organic substituents, and R4 is an aryl group or a heterocyclic group) In producing α-substituted ketones having a ring group, the general formula, -RlC(O8i R'R'R')=CH" R
” (II) (wherein R1, RG and R3 are the same as above, and R5, RG and R7 are an alkyl group, an aryl group or an aralkyl group), to the silyl enol ethers represented by the general formula % formula %( ) (wherein R4 is as defined above and X is a diazonium salt-forming anion) is provided.

The novel reaction of the present invention can be represented by formula (1).

R'C(O5iR'R'R')=CH"R3
+R' N 2X -+ll'C0CR2R'R'
+R″R'R' SiX (1) (In the above formula, R1-R7 are the same as above) There is no restriction on the type of silyl enol ether used in the method of the present invention,
In the compound of the general formula (If), substituents R1, R
”, R3 is a hydrogen atom or an organic substituent, for example, an alkyl group, an aralkyl group, an aryl group, an alkenyl group, an alkynyl group, or a heterocyclic group, and R5, RG, R? are an alkyl group, an aryl group, or an aralkyl group Any combination of silyl enol ethers that are groups can be preferably used.Furthermore, silyl enol ethers in which R1 and R2 or R3 are bonded to each other to form a ring structure can also be preferably used. Examples of substituents include alkyl groups such as methyl, ethyl, hexyl, octyl, etc., aralkyl groups such as benzyl, α- or β-phenylethyl, and aryl groups such as phenyl, tolyl, naphthyl, etc., and alkenyl groups. Examples of groups include vinyl, propenyl, furyl, octenyl, styryl, etc.; examples of alkynyl groups include ethynyl, phenylethynyl, etc.

Examples of the heterocyclic group include furyl, chenyl, and the like. In addition, a functional group may be bonded to these substituents, and these functional groups include a halogen atom, an alkoxy group, an alkoxycarbonyl group, a dialkylamino group,
dialkoxymethyl group, thioalkoxy group, nitro group,
Examples include cyano group.

There is no restriction on the type of diazonium used in the present invention, and in the compound of general formula (m), substituent R4 is an aryl group or a heterocyclic group, and X is a diazonium salt-forming anion, for example, an inorganic acid or an organic A residue obtained by removing a hydrogen ion from an acid, or the general formula 1/Q Mm'In (M is a metal cation, ■ is a halogen ion or CN, n, m
, n is a natural number), any combination of diazonium salts which are complex ions for stabilizing diazonium salts can be suitably used. Examples of substituent R4 include phenyl, chlorophenyl, bromophenyl, nitrophenyl,
Tolyl, anisyl, formylphenyl, ethoxycarbonylphenyl, dimethoxymethylphenyl, naphthyl,
Examples include pyridyl, furyl, and chenyl. Also 4
, 4'-biphenylenebisdiazonium salt,
Those containing two diazonium moieties in the same molecule are also suitably used. Examples of X are Cp, H3O4, N0
3, CQO4, BF4, BPh 4, PF6, Ctl
3 CO2, 1/2ZnCQ 4.1/2SnCQ6.
1/2■gCQ4.1/2CdCQ4.1/3Fe(C
N) s, FeCO3, etc. Note that these examples of substituents or functional groups are merely illustrative.
It is not limited to these.

The amount of the diazonium salt used in the present invention is sufficient to be equivalent to or a small excess of the silyl enol ether, but even if the amount is more or less than this, the reaction will not occur.

The solvent used in the reaction of the present invention has an active proton source such as water, alcohols, phenols, carboxylic acids, primary or secondary amines, and is itself reactive with the silyl enol ether or diazonium salt. Except for what you have
Any conventional solvent can be used. Examples of these solvents include hexane, benzene, toluene, acetonitrile, pyridine, tetrahydrofuran, diethyl ether, acetone, dimethylformamide, sulfolane, ethyl acetate, HMPA, etc., but pyridine gives the most favorable results. Moreover, these solvents can also be used in combination.

The reactions of the present invention are carried out at temperatures between -50 DEG and +50 DEG, but depending on the structure of the substrate, higher temperatures may be used to achieve the desired reaction rate.

The target α- from the reaction solution obtained by the reaction of the present invention
Separation and purification of substituted ketones is carried out by removing the diazonium salt by washing with water, etc., removing the solvent by distillation, etc., and then distilling.
This can be carried out by recrystallization, chromatography, etc.

〔effect〕

The method of the present invention uses a novel reaction, and a wide variety of silyl enol ethers and diazonium salts can be used in this reaction, and various α-substituted ketones can be easily obtained in good yields.

〔Example〕

Next, the present invention will be explained in detail with reference to Examples.

Example 1 (l-phenylethynyl)oxytrimethylsilane (0,97mmoQ) was placed in a flask with an internal volume of 20mQ.
and add pyridine 3IIIQ as a solvent. Benzenediazonium tetrafluoroborate (1,3 mmo Q) was added to this mixture, and under a nitrogen atmosphere,
The mixture was stirred at 0°C for 2 hours. The reaction solution was diluted with diethyl ether, washed sequentially with 1.5N hydrochloric acid, water, and saturated saline,
The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oily mixture was separated and purified using silica gel thin layer chromatography to obtain benzyl phenyl ketone (0.68 mmo Q ).

Examples 2 to 8 Table 1 summarizes the results of reactions carried out using various silyl enol ethers, diazonium salts, and solvents according to almost the same formulation as in Example 1.

Table 1 Examples 9 to 14 Reactions were carried out using the combinations shown in Table 2 below. Good reaction results were also obtained in this case.

Table 2 Procedural Neichi - Official book (spontaneous) 61 Kagiken No. 9 Q 7-if Showa 'T3] Rhinoceros June 1st to 3rd

Claims (1)

[Claims] (1) General formula R^1COCR^2R^3R^4 (wherein, R^1, R^2 and R^3 are hydrogen atoms or organic substituents, and R^4 is an aryl group or a heterocyclic group) In producing α-substituted ketones having an aryl group or a heterocyclic group at the α-position represented by
3 (wherein R^1, R^2 and R^3 are the same as above, and R^5, R^6 and R^7 are an alkyl group, an aryl group or an aralkyl group) A method characterized by reacting enol ethers with a diazonium salt represented by the general formula R^4N_2X (wherein R^4 is the same as above and X is a diazonium salt-forming anion).