JPS6116376B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an efficient method for producing acetylenic ketones, and more particularly to a method for producing acetylenic ketones by reacting terminal acetylenes with an organic halide and carbon monoxide in the presence of a catalyst. It is something. Acetylenic ketones are a group of useful compounds that serve as raw materials for the production of important heterocyclic compounds as intermediates for pharmaceuticals and agricultural chemicals. Traditional methods for synthesizing this type of compound often involve
Because highly reactive reagents such as organolithium and Grignard reagents are used that react with the ketone group itself, its synthesis requires a multi-step reaction process.
Naturally, the yield is also low. In addition, the conventional method requires the use of highly reactive organolithium and Griard reagents, which limits the types of acetylenic ketones that can be produced; the resulting acetylenic ketones are heterocyclic compounds. Many of them are unsuitable as raw materials. Therefore, in this sense, the conventional method cannot be applied as a general method for producing acetylenic ketones as raw materials for producing heterocyclic compounds. Furthermore, in the case of conventional methods, one of the starting materials is an acid halide,
It is necessary to employ compounds with acyl groups such as aldehydes and esters, but the synthesis of such compounds often requires complicated steps, and therefore conventional methods are far from being industrially superior. I couldn't say it. The present inventors were conducting various studies on carbonylation reactions of organic halides, and found that
When carrying out the carbonylation reaction of an organic halide in the presence of a terminal acetylene compound, surprisingly, the organic group R ¹ - from the halogen compound R ¹ X (R ¹ and X are as described below) , the acetylene group R ² C≡C- with the terminal hydrogen removed from the terminal acetylene compound R ² C≡CH (R ² is as described below) and carbon monoxide are simultaneously directly bonded, and the general formula We have discovered the completely new fact that acetylenic ketones having the structure represented by the following can be produced in good yield, and have completed the present invention based on this knowledge. That is, according to the present invention, the general formula R ¹ X (wherein,
R ¹ represents an organic group selected from an aryl group, an alkenyl group directly connected to X at the carbon part of the olefin double bond, and a heterocyclic group, and these organic groups may have a substituent, and represents a halogen selected from bromine and ^iodine ) ^; a terminal acetylene compound represented by a group selected from an alkynyl group, a heterocyclic group, an alkoxycarbonyl group, an alkoxy group, an alkylthio group, an alkoxyalkyl group, and an organosilyl group, and carbon monoxide,
General formula characterized by reaction in the presence of a palladium compound A method for producing acetylenic ketones represented by the formula (wherein R ¹ and R ² have the same meanings as above) is provided. The reaction of the present invention is novel, and its elementary reaction is represented by the following formula. The reaction of the present invention generally proceeds without any particular restriction on the types of R ¹ and R ² , but it is important to note that active substitutions that inhibit the dehydrohalogenation reaction of the elementary reaction (iii) above are required. R ¹ and R ² having groups are excluded from the chemical common sense point of view. The active substituent in this case includes those having a hydrogen atom more active than the hydrogen atom of the acetylene group, such as a hydroxyl group or a simple amino group. Therefore, the term "substituent inert to the reaction" as used herein is an expression used to exclude such active substituents and specify the reaction of the present invention within a range that can be carried out. Examples of the organic group R ¹ in the organic halide R ¹ X used in the present invention include aryl groups such as phenyl and naphthyl, vinyl, propenyl,
It includes organic groups such as alkenyl groups such as allyl and butadienyl, and heterocyclic groups such as thienyl, furyl, and pyridyl, and these organic groups may have substituents that are inert to the reaction, and in this case, Examples of substituents inert to the reaction include dialkylamino groups, carbamoyl groups, acyl groups, alkoxy groups, alkoxycarbonyl groups, halogen atoms, sulfonyl groups, sulfinyl groups, sulfenyl groups, cyano groups, acyloxy groups, and silyl groups. , nitro group, formyl group, etc. Halogen X includes bromine and iodine. Examples of organic halides include aromatic halides such as iodobenzene, bromobenzene, and bromnaphthalene, and substituents thereof having a substituent inert to the reaction on the aromatic nucleus, β-bromostyrene, and β-bromovinyl. Ketone, iodoethylene,
Unsaturated halides such as 1-bromo-1-propene, β-phenylethynyl bromide, 1,2-dibromoethylene, heterocyclic halides in which the halogen atom X is bonded to furan, thiophene, pyrrole, pyridine, etc., and these and various substituted forms of. Terminal acetylene compound R ² C≡ used in the present invention
There are no particular restrictions on the type of CH. In this case, ^R2 includes alkyl groups such as methyl and ethyl, aryl groups such as phenyl and naphthyl, alkenyl groups such as vinyl, butadienyl and allyl, aralkyl groups such as benzyl and α-phenylethyl, cyclohexyl and cyclooctyl. There are organic groups selected from cycloalkyl groups, alkynyl groups such as ethynyl and phenylethynyl, and various heterocyclic groups such as thienyl, furyl, and pyridyl;
Furthermore, as this R ² , for example, an alkoxycarbonyl group, an alkoxy group, an alkylthio group,
Groups such as an alkoxyalkyl group and an organosilyl group may also be mentioned. Examples of terminal acetylene compounds used in the present invention include methylacetylene, 1-hexyne, phenylacetylene, p-tolylacetylene, vinylacetylene, α- or β
-Terminal acetylenic hydrocarbons such as styrylacetylene, allyl acetylene, benzyl acetylene, phenylpropyne, diacetylene, and β-ethynyl acetylene can be mentioned; I can list things that I have. In the present invention, as mentioned above, in the terminal acetylene compound, the terminal acetylene group HC
The R ² atom bonded to ≡C- may be an oxygen atom other than a carbon atom, a sulfur atom, or a heteroatom such as phosphorus. However, when such a terminal acetylene compound is used as a raw material, although the reaction proceeds, by-products are generated and the yield of the target product is reduced. Therefore, when increasing the yield, it is advantageous to take appropriate measures to suppress the formation of by-products. Examples of the catalyst used in the present invention include zero-valent palladium such as tetrakistriphenylphosphine palladium, tetrakistriphenylarsine palladium, dibenzylideneacetone palladium, carbonyltristriphenylphosphine palladium, maleic anhydride bistriphenylphosphine palladium, etc. Complex, dichlorobistriphenylphosphine palladium, dichlorobisbenzonitrile palladium, dibromobistriphenylarsine palladium, dichloro-1,1'-bisdiphenylphosphinoferocene palladium, dichloro-1,1'-bisdiphenylarsinof Erocene palladium, dichloro-α,ω-bisdiphenylphosphinoalkane palladium (alkanes are linear or branched chains with 1 to 10 carbon atoms), dichloro-α,
Divalent palladium salts or complexes such as α-diphenylphosphino o-xylene palladium, palladium chloride, palladium acetate, bisacetatobistriphenylphosphine palladium, iodophenylbistriphenylphosphine palladium, iodoparatolyl bistriph Organic or hydrogenated palladium complexes such as enylarsine palladium, chlorobenzoylbistriphenylphosphine palladium, iodomethylbistributylphosphine palladium, dimethyl-1,2-bisdiphenylphosphinepalladium, dihydridobistricyclohexylphosphine palladium However, as long as it reacts with an organic halide in the reaction system to produce an organic palladium halide, such a precursor can also be used. These catalysts also contain phosphines, phosphites, phosphinites, tertiary amines,
A ligand such as pyridine bases or bipyridine may be added and used in the reaction. Although the reaction in the present invention proceeds even in the absence of a base, it is generally effective to carry out the reaction in the presence of a conventional hydrogen halide scavenger in order to capture the hydrogen halide that accumulates as the reaction progresses. be.
Various bases can be used as the hydrogen halide scavenger in this case, and both organic bases and inorganic bases can be used. As an organic base, for example, the general formula R ³ ₃ N (wherein R ³ is a hydrogen atom or an organic group, and the organic group is, for example,
Examples include alkyl groups such as methyl, ethyl, propyl, and butyl, cycloalkyl groups such as cyclohexyl, aryl groups such as phenyl and tolyl, allyl groups, benzyl groups, and organic groups having substituents introduced therein. Furthermore, the three ^R3s may be the same or different. Also
R ³ and N may form a ring structure, and further
There are amines represented by polyamines such as diamines and triamines, which may constitute a heteroaromatic ring containing R ³ and N, or may be polyamines such as diamines and triamines in which these monoamines are linked with an appropriate organic chain. , caustic alkalis such as caustic soda, caustic potash, and calcium hydroxide; metal carbonates such as calcium carbonate, sodium carbonate, and sodium bicarbonate; and basic metal oxides such as barium oxide and calcium oxide. Particularly preferred for use in the present invention are trialkylamines. The reaction in the present invention proceeds in the absence of a solvent or in a solvent, and suitable solvents include hexane, benzene, ether, tetrahydrofuran, hexamethylphosphotriamide, dimethylformamide, acetonitrile, acetone, alcohols, carboxylic acids, etc. Any commonly used solvent can be used as long as it does not serve as an active proton source. Water as a solvent is
It can be used in a two-phase system of water and an organic solvent that is not mutually soluble. In such a two-phase solvent, an inorganic salt is used as the base, and it is preferable to react with a phase transfer agent such as a quaternary ammonium salt or a quaternary phosphonium salt. When amines which are liquid under the reaction conditions are used as a base component, it is also an advantageous embodiment of the present invention to use them in large excess to function as a solvent. The reaction of the present invention can be carried out under the same conditions as ordinary carbonylation reactions. The partial pressure of carbon monoxide depends on the type of catalyst used, and in general, a higher partial pressure is advantageous because it increases the yield of the target product, but if the partial pressure becomes too high, it has the opposite effect. It reduces the reaction rate and causes equipment disadvantages. Therefore, in the case of the present invention, the partial pressure of carbon monoxide is in the range from below normal pressure to 500 atm, preferably from 1 to 300 atm. The carbon monoxide used may be diluted with an inert gas such as nitrogen or methane. The molar ratio of the organic halide to the terminal acetylene compound is usually selected from the range of 50:1 to 1:50, even if either is in excess, it does not prevent the reaction from occurring. In a preferred embodiment of the present invention, in a solution containing an organic halide and a catalyst,
Under the action of carbon monoxide, the terminal acetylene compound is added dropwise in small portions. When the reaction is carried out in this manner, side reactions such as polymerization of the terminal acetylene compound, which is the starting material, can be prevented. The amount of the base used as necessary may be at least equimolar to the organic halide, and generally ranges from 1 to 50 moles per mole of the organic halide. Of course, it is possible to use a larger amount of base than this, but this does not bring about particularly beneficial results in terms of the reaction. The amount of the catalyst used is not particularly limited, and is generally in the range of 1/10 mol or less, particularly 1/80 to 1/500 mol, per 1 mol of the organic halide. Although the reaction of the present invention may proceed at room temperature depending on the structure of the organic halide, it may be heated up to 300° C. to obtain a preferable reaction rate. In the reaction of the present invention, decomposition and polymerization of acetylene bond raw materials and products occur at too high a temperature.
A preferred reaction temperature is selected from a range of 50 to 200°C. To separate and purify the target ketone compound from the reaction solution obtained by the reaction of the present invention, first, by-produced salts are removed by solid-liquid separation means such as centrifugation or filtration, or by washing the reaction solution with water. , and then by subjecting it to a conventional purification treatment such as distillation. In the method of the present invention, a wide variety of organic halides and terminal acetylene compounds are used, and various ketones can be obtained in good yields.
Further, the reaction operation is easy because it does not require complicated operations and does not use reactive raw materials such as organolithium or Grignard reagents, and the desired ketone can be easily obtained. Next, the present invention will be explained in more detail based on examples. Example 1 14.8 mg of Cl ₂ Pd (AsPh ₃ ) ₂ was placed in a stainless steel (SUS316) autoclave with an internal volume of 27 ml under nitrogen.
(1.88×10 ^-2 mmol), iodobenzene 384mg
(1.88mmol), phenylacetylene 204mg
(2.00mmol), triethylamine 3.0ml
(21.5 mmol) was charged, and after applying a carbon monoxide pressure of 20 atm at room temperature, the reaction was carried out at 120°C. Although the substantial pressure drop stopped after about 1 hour, heating and stirring were continued for another 2 hours. Thereafter, the reaction solution was poured into 50 ml of ether, washed with water, neutralized with dilute hydrochloric acid, washed again with water, dried over anhydrous sodium sulfate, and concentrated. As a result of quantitative determination by gas chromatography, phenylethynylphenyl ketone (bp197.5−199.0
It was found that 314 mg (1.52 mmol) of ℃/13 torr) was produced. This corresponds to a yield of 81% based on the number of moles of iodobenzene charged. Examples 2 to 39 Various ketones were synthesized in the same manner as in Example 1 using specified halides and acetylene compounds under the reaction conditions shown in the following table. In this case, unless otherwise specified, the number of moles of the organic halide, acetylene compound, base, and catalyst to be charged is the same as in Example 1. The results are summarized in the table below. Note that the yield was measured by gas chromatography. This table also shows the results of Example 1. In addition, in the table below, *1 to *6 indicate the following. *1 dpaf...1,1'-bis(diphenylarsino)ferrocene *2 dppb...1,4-bis(diphenylphosphino)butane *3 dppf...1,1'-bis(diphenylphosphino)ferrocene *4 3 times that of Example 1 *5 15 times that of Example 1 *6 0.4 times that of Example 1

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Claims (1)

[Claims] 1 General formula R ¹ X (R ¹ in the formula represents an organic group selected from an aryl group, an alkenyl group directly connected to These organic groups may have a substituent, and X represents a halogen selected from bromine and iodine.
HC≡C-R ² (wherein R ² is an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, a heterocyclic group, an alkoxycarbonyl group, an alkoxy group, an alkylthio group, an alkoxyalkyl group, and A general formula characterized by reacting a terminal acetylene compound (representing a group selected from organosilyl groups) with carbon monoxide in the presence of a palladium compound. A method for producing acetylenic ketones represented by the formula (wherein R ¹ and R ² have the same meanings as above).