JP2002047273A - Method for producing dihalogeno cyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a cyclized product of a trihalogenoacetyl halide with a compound having a carbon-carbon multiple bond or a carbon-hetero atom multiple bond by which the cyclized product can be produced without requiring the activation treatment of metallic zinc in an industrially easily usable solvent in high yield. SOLUTION: This method for producing the dihalogeno cyclic compound is characterized in that the reaction is carried out in the presence of the metallic zinc, a metal halide and phosphorus oxychloride when producing the cyclized product by reacting the trihalogenoacetyl halide with the compound having the carbon-carbon multiple bond or the carbon-hetero atom multiple bond.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the reaction of a dihalogenoketene with a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond. These reactions are based on the cyclobutanone ring, cyclobutenone ring, β-
This is one of the important synthetic reactions used when synthesizing a skeleton such as a lactone ring and a β-lactam ring.

[0002]

2. Description of the Related Art A cyclization reaction of a dihalogenoketene with a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond includes, for example, Tetrahe
dron, Vol. 37, no. 17, 29
49 (1981), dihalogenoketene is generated by (1) reaction of dihalogenoacetyl halide with tertiary amine, or (2) reaction of trihalogenoacetyl halide with activated metal zinc. Then, a method of reacting this with olefins or ketones is known.

Further, in the reaction between trihalogenoacetyl halide and activated metal zinc, the surface of the metal zinc is halogenated and the activity is reduced, so that there is a problem that the yield is reduced. Is known to improve the yield by coexisting (J.
Org. Chem. , Vol. 43, no.
14, 2879 (1978)).

[0004]

However, (1)
According to the method, the tertiary amine or a salt thereof, which is a reagent for generating dihalogenoketene, also promotes the polymerization reaction of the obtained dihalogenoketene, so that the selectivity of the target reaction is reduced, or a large amount of by-products is produced. Disadvantages.

On the other hand, when the activated metal zinc is used as in the method (2), for example, an activation treatment using copper sulfate or the like is necessary in advance. Since steps such as filtration and drying are required after the zinc is activated by stirring, it is very disadvantageous when industrially implemented. Further, in the method (2), diethyl ether is usually used as a solvent, but it has a low boiling point and is difficult to handle. In addition, a tar-like substance is generated during the reaction and adheres to the inner wall of the reactor. This is extremely disadvantageous when considering implementation on an industrial scale.

[0006] In addition, it has been found that in the above-mentioned method, if a solvent other than diethyl ether which is industrially easy to use is used, the desired reaction may not be able to proceed in a sufficient yield. As described above, the conventionally known methods for generating dihalogenoketthenes have their respective disadvantages, and it has been industrially difficult to efficiently obtain the desired dihalogeno cyclic compound in any case.

An object of the present invention is to overcome the above-mentioned drawbacks and industrially efficiently produce a cyclization reaction product of a dihalogenoketene and a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond. It is to provide a method.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a trihalogenoacetyl halide and a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond are combined. When the reaction is carried out to produce a cyclized product, a method in which the reaction is carried out in the presence of metal zinc, a metal halide and phosphorus oxychloride is employed. The present inventors have found that the reaction proceeds efficiently even in a solvent that is easily used for the purpose, and have completed the present invention.

That is, the gist of the present invention is to produce a cyclized product by reacting a trihalogenoacetyl halide with a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond. And performing the reaction in the presence of phosphorus oxychloride.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
Examples of the trihalogenoacetyl halide used in the present invention include trichloroacetyl chloride, trichloroacetyl bromide, tribromoacetyl chloride, tribromoacetyl bromide, triiodoacetyl chloride, and triiodoacetyl bromide. To trichloroacetyl chloride is preferred. The amount used varies depending on the desired reaction and the reaction conditions, but is usually 0.1 to 10 times mol based on the compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond to be reacted. And preferably 0.1 to 5 times the molar amount.

As described above as the feature of the present invention, the zinc metal used in the present invention is obtained as it is as a research reagent or industrial chemical without prior activation with copper sulfate or dilute hydrochloric acid. Can be used. Although it is industrially advantageous to use it without activation, there is no problem even if it is activated beforehand. The shape of the metallic zinc is not particularly limited, whether it is a lump, a granule, or a powder, but it is preferable that the metal zinc can be effectively contacted with another reaction substrate, a solvent, or the like, and usually has a large surface area and is uniform in the reaction system. A powdery substance that is easily dispersed in water is used. The amount used depends on the desired reaction and the reaction conditions, but usually, based on trihalogenoacetyl halide,
The molar amount is 0.5 to 10 times, preferably 0.8 to 5 times.

The metal halide used in the present invention includes Mg, Ca, Y, La, Sm, Yb, Ti, Zr,
Cr, Mo, W, Mn, Co, Rh, Ir, Pd, C
Examples include chlorides, bromides, and iodides of metals such as u, Ag, Au, and Pb. Of these, halides of metals belonging to Group 9 such as copper or Group 11 such as cobalt are preferable.
Preference is given to cuprous halides such as cuprous chloride, cuprous bromide, cuprous iodide or cobalt halides such as cobalt chloride, cobalt bromide, cobalt iodide.

The above-mentioned metal halides may be used alone, or may be used by mixing them at an arbitrary ratio. The amount used depends on the intended reaction and the reaction conditions, but is usually 0.01 to 5 times the compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond to be reacted. Molar amount, preferably
It is 0.01 to 2 times the molar amount.

The amount of phosphorus oxychloride used in the present invention is usually 0.1 to 5 times the molar amount of the compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond to be reacted. And preferably 0.5 to 3 times the molar amount. Compounds having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond used in the above reaction include 1-butyne, 2-butyne, phenylacetylene, 1-butene,
Chains of 2-hexene, styrene, cyclopentene, cyclohexene, methylenecyclobutane, methylenecyclohexane, N-protected-4-methylenepiperidine, tetramethylarene, acetone, acetophenone, cyclopentanone, chloral, benzaldehyde, cinnamaldehyde, dicyclohexylcarbodiimide, and the like. Or cyclic, aliphatic or aromatic acetylenes, olefins, ketones, aldehydes or imines (these include halogen atoms, alkoxy groups, trimethylsiloxy groups, amino groups, carbocyclic and aromatic rings, etc.). (Which may be substituted with a substituent)), the cyclization reaction of dichloroketene with [2 + 2] or [2 + 4] to give the desired compound may give rise to a difference in their reactivity. Although the yield of the target compound is different, But the present invention is not particularly limited.

In the present invention, a reaction substrate can be used as a substitute for a solvent, but usually a solvent that does not react with the reaction substrate or an auxiliary agent is used. Examples of the solvent used include ether solvents such as diethyl ether, tert-butyl methyl ether, di-iso-propyl ether, dibutyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; ester solvents such as ethyl acetate; hexane; Hydrocarbon solvents such as heptane and toluene; and halogen solvents such as chloroform, methylene chloride and chlorobenzene. Among them, when an ester solvent is used, tar found when diethyl ether is used as a solvent. It is preferable because the reaction system can maintain a good slurry state from beginning to end without the formation of state substances.

These solvents may be used alone or in combination of two or more. In addition, the amount of zinc and metal halide used may be an amount that can effectively flow, and is usually based on the compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond to be reacted. 3 to 30 times the volume, preferably 5
２５25 times the volume.

The reaction temperature, reaction pressure and reaction time of the present invention are not particularly limited since they differ depending on the type of the desired reaction.
It is determined by the reaction time and the like. Preferably, when a solvent or the like is used, the reaction is performed at a reaction temperature and a reaction pressure at which the solvent can maintain a liquid phase, and other reaction conditions may be set so that the reaction is completed in 0.5 to 50 hours. .

In the reaction method of the present invention, the substrate, the auxiliary agent and the solvent may be contacted in any form and in any order.
Preferably, a metal zinc, a metal halide, and a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond are charged into a solvent, the reaction temperature is set under stirring, and then the trihalogeno dissolved in the solvent is added. It is performed by a method of dropping acetyl halide and phosphorus oxychloride.

The method for removing the reaction product in the present invention may be carried out according to a conventional method. For example, after the reaction is completed, the remaining acid halide and phosphorus oxychloride can be converted into a water-soluble compound by releasing the reaction solution into a basic aqueous solution. And convert it to
If necessary, the precipitated zinc compound is separated by filtration, and the target substance is extracted with an organic solvent or the like. The desired product can be obtained by washing the organic layer with water or the like as necessary and then distilling off the solvent. If necessary, a higher purity target product can be obtained by performing a normal purification method such as recrystallization or column separation.

[0020]

The present invention will be described in more detail with reference to the following examples. In the examples, a reaction example of a dihalogenoketene and 4-methylene-N-protected piperidine is described.
Except for the metal halide used in the present invention or the substrate which itself is decomposed by phosphorus oxychloride, olefins or ketones which are usually assumed to be reacted with dihalogenoketene can be easily applied to the present invention.

Example 1 In a 10 ml eggplant flask, 4
0.1 g (0.5 mmol) of -methylene-N-tert-butoxycarbonyl-piperidine, 0.08 g (1.2 mm) of zinc powder (Kanto Chemical Co., Ltd. (purity 90% or more))
ol), cuprous chloride 0.005 g (0.05 mmol:
0.1 mol by volume / 4-methylene-N-tert-butoxycarbonyl-piperidine) and 2 ml of ethyl acetate were charged, and while stirring under ice-cooling, ethyl acetate (0.2 m
l) Trichloroacetyl chloride dissolved in 0.18
g (1 mmol) and 0.16 g of phosphorus oxychloride
(0.16) was added dropwise. After reacting for 5 hours under ice cooling, the resulting 1,1-dichloro-N-tert-butoxycarbonyl-7-azaspiro [3.5] nonane-2-
ON was quantified by high performance liquid chromatography.

Examples 2 to 5 The reaction was carried out in the same manner as in Example 1 except that the kind of the metal halide was changed. (Comparative Examples 1 to 3) The reaction was carried out in the same manner as in Example 1 except that no metal halide and / or phosphorus oxychloride was used.

(Comparative Examples 4 and 5) 20 g of zinc powder was added to water 80
suspended in the solution and bubbling nitrogen through the solution at room temperature.
3.9 g of copper sulfate pentahydrate was added, and the mixture was further stirred at room temperature for about 3 hours. After filtering under a nitrogen stream, washing with water and acetone,
After drying under reduced pressure, it was stored under a nitrogen atmosphere.

The reaction was carried out in the same manner as in Example 1 except that the activated metal zinc was used as the metal zinc, and no metal halide and / or phosphorus oxychloride was used. The results of Examples 1 to 5 and Comparative Examples 1 to 5 are shown in Table 1 below.

[0025]

[Table 1]

As is clear from Comparative Examples 1 to 3, when zinc that is not activated is used, the yield is low even if either the metal halide or phosphorus oxychloride is missing. Also,
Even when zinc activated with copper sulfate was used, the reaction was performed in an acetate solvent, so even when phosphorus oxychloride was added as in Comparative Example 5, the yield was about 56%. The yield is much lower than in Examples 1 to 5.

[0027]

Industrial Applicability According to the present invention, a reaction using a dihalogenoketene can be carried out in an efficient and industrially advantageous manner, and a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond with a trihalogenoacetyl halide. Thus, a dihalogeno cyclic compound can be easily produced.

Continued on the front page (72) Inventor Yuzo Kasuga 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Inside Mitsubishi Chemical Research Laboratory (72) Inventor Uji 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical F-term in Yokohama Research Institute, Inc. (reference) 4C034 CK03 4H039 CA40 CA52 CA62 CH10

Claims (9)

[Claims] 1. A method for producing a cyclized product by reacting a trihalogenoacetyl halide with a compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond, to produce a metal zinc, a metal halide and phosphorus oxychloride. A method for producing a dihalogeno cyclic compound, wherein the reaction is carried out in the presence. 2. The method according to claim 1, wherein the metal halide is a Group 9 or 11 metal.
The method according to claim 1, wherein the method is a halide of a metal selected from the group consisting of: 3. The method according to claim 1, wherein the metal halide is cuprous halide or cobalt halide. 4. The method according to claim 1, wherein the metallic zinc is in a powder form. 5. The method according to claim 1, wherein the trihalogenoacetyl halide is trichloroacetyl chloride. 6. The method according to claim 1, wherein the dihalogenocyclic compound is a dihalogenocyclobutenone, a dihalogenocyclobutanone, a dihalogeno-β-lactone or a dihalogeno-β-lactam. Production method. 7. The compound having a carbon-carbon multiple bond or a carbon-heteroatom multiple bond is a compound selected from the group consisting of acetylenes, olefins, ketones, aldehydes and imines. Claim 1
7. The production method according to 6. 8. The method according to claim 7, wherein the olefin is 4-methylene-N-protected piperidine. 9. The method according to claim 1, wherein the cyclization reaction is carried out in an ester solvent.