JP7344518B2 - Method for producing Vilsmeier reagent - Google Patents

Description

The present invention provides a method for producing a Vilsmeier reagent that can be carried out safely and easily at low cost, and the use of the Vilsmeier reagent to produce aromatic aldehydes or aromatic ketones, carboxylic acid halides, and formic acid esters. It's about how to do it.

Vilsmeier reagent is an electrophilic agent that causes addition reactions to electron-rich alkenes and aromatic rings, and is used, for example, for the formylation of aromatic compounds with active groups and the conversion of carboxy groups to haloformyl groups. be done. Vilsmeier reagents are generally formed from a chlorinating agent such as phosgene, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and an amide compound (Patent Document 1).

However, many chlorinating agents are highly toxic, and some produce toxic and corrosive gases upon contact with water, making them difficult to store and dangerous to handle. . In particular, phosgene has a history of being used as an asphyxiating poisonous gas, and when inhaled during use, there was a risk of death. Chlorinating agents other than phosgene are also corrosive; for example, thionyl chloride produces sulfur dioxide and hydrogen chloride as by-products, making treatment of these agents costly.

Patent Document 2 discloses a method for producing a Vilsmeier reagent using safer phthalic acid dichloride as a chlorinating agent. However, the use of phthalic acid dichloride increases costs. In addition, in this method, phthalic anhydride is produced as a by-product, so the process of purifying the target compound is also costly.

By the way, the present inventors have so far developed various photochemical reactions using halogenated hydrocarbons as raw materials. For example, as disclosed in Patent Document 3, a method has been developed for producing urea derivatives and carbonate ester derivatives by blowing decomposition products generated by irradiating chloroform etc. with light into an amine solution or a phenol solution in the presence of oxygen. There is. Further, Patent Document 4 discloses a method for producing a chloroformate by irradiating a mixture containing a halogenated hydrocarbon and an alcohol with light in the presence of oxygen.

International Publication No. 2008/105464 pamphlet Japanese Patent Application Publication No. 2012-136502 Japanese Patent Application Publication No. 2013-181028 International Publication No. 2015/156245 pamphlet

As mentioned above, the Vilsmeier reagent has been known for a long time and is useful, but its production requires a dangerous chlorinating agent, making industrial production and use difficult or difficult. Industrial production and use were carried out under restrictions.
Therefore, the present invention provides a method for producing a Vilsmeier reagent that can be carried out safely and easily at low cost, and uses the Vilsmeier reagent to produce aromatic aldehydes or aromatic ketones, carboxylic acid halides, and formic acid esters. The purpose is to provide a method for manufacturing.

The present inventors have conducted extensive research in order to solve the above problems. As a result, the inventors discovered that a Vilsmeier reagent can be produced by irradiating a composition containing a halogenated hydrocarbon and an amide compound with light in the presence of oxygen, thereby completing the present invention.
The present invention will be described below.

［式中、
Ｒ¹は、水素原子、Ｃ_1-6アルキル基、または置換基を有していてもよいＣ_6-12芳香族炭化水素基を示し、
Ｒ²とＲ³は、独立して、Ｃ_1-6アルキル基、または置換基を有していてもよいＣ_6-12芳香族炭化水素基を示し、また、Ｒ²とＲ³は一緒になって４員以上７員以下の環構造を形成してもよく、
Ｘは、クロロ、ブロモおよびヨードからなる群より選択されるハロゲノ基を示し、
Ｙ^-はカウンターアニオンを示す。］
クロロ、ブロモおよびヨードからなる群から選択される１種以上のハロゲノ基を有するＣ_1-4ハロゲン化炭化水素を含む組成物に酸素存在下で光照射することによりＣ_1-4ハロゲン化炭化水素を分解する工程、および、
Ｃ_1-4ハロゲン化炭化水素の分解物と下記式（ＩＩ）で表されるアミド化合物とを反応させる工程を含むことを特徴とする方法。

［式中、Ｒ¹～Ｒ³は上記と同義を示す。］[1] A method for producing a Vilsmeier reagent, comprising:
The Vilsmeier reagent is a salt represented by the following formula (I),

[In the formula,
R ¹ represents a hydrogen atom, a C _1-6 alkyl group, or a C _6-12 aromatic hydrocarbon group which may have a substituent,
R ² and R ³ independently represent a C _1-6 alkyl group or a C _6-12 aromatic hydrocarbon group which may have a substituent, and R ² and R ³ together represent may form a 4- to 7-membered ring structure,
X represents a halogeno group selected from the group consisting of chloro, bromo and iodo,
Y ^- represents a counter anion. ]
A C _1-4 halogenated hydrocarbon is produced by irradiating a composition containing a C _1-4 halogenated hydrocarbon having one or more halide groups selected from the group consisting of chloro, bromo, and iodo in the presence of oxygen. a step of decomposing the
A method comprising the step of reacting a decomposition product of a C _1-4 halogenated hydrocarbon with an amide compound represented by the following formula (II).

[In the formula, R ¹ to R ³ have the same meanings as above. ]

[2] The method according to [1] above, wherein the light includes light with a wavelength of 180 nm or more and 280 nm or less.

[3] The method according to [1] or [2] above, wherein a C _1-4 polyhalogenated hydrocarbon is used as the C _1-4 halogenated hydrocarbon.

[4] The method according to any one of [1] to [3] above, wherein X is chloro and Y ^- is a chloride ion.

[5] The method according to any one of [1] to [4] above, wherein N,N-dimethylformamide is used as the amide compound represented by formula (II).

[6] The method according to any one of [1] to [5] above, in which the C _1-4 halogenated hydrocarbon is used in an amount of 5 times or more by mole or more relative to the amide compound represented by the formula (II).

[7] A method for producing an aromatic aldehyde or aromatic ketone, comprising:
A step of producing a Vilsmeier reagent by the method according to any one of [1] to [6] above, and
A method comprising the step of reacting the Vilsmeier reagent with an aromatic compound having an active group.

[8] A method for producing a carboxylic acid halide, comprising:
A step of producing a Vilsmeier reagent by the method according to any one of [1] to [6] above, and
A method comprising the step of converting the carboxy group of the carboxylic acid compound into a haloformyl group by reacting the Vilsmeier reagent with a carboxylic acid compound represented by the following formula (III).
R ⁴ -(CO ₂ H) _n (III)
[In the formula, R ⁴ represents an n-valent organic group, and n represents an integer of 1 or more and 4 or less. ]

[9] A method for producing a formic acid ester, comprising:
A step of producing a Vilsmeier reagent by the method according to any one of [1] to [6] above, and
A method comprising the step of reacting the Vilsmeier reagent with a hydroxyl group-containing compound.

According to the method of the present invention, the highly reactive and useful Vilsmeier reagent can be used safely, easily, and at low cost by using halogenated hydrocarbons, which are also used as general-purpose solvents, instead of dangerous compounds such as phosgene. can be manufactured. At this time, only carbon dioxide and hydrogen chloride are produced as by-products, and since they can be discharged outside the system as gases, purification is not necessary in principle. It is also possible to produce aromatic aldehydes or aromatic ketones, carboxylic acid halides, and formic acid esters in the same system using the produced Vilsmeier reagent. Therefore, the present invention is industrially extremely useful as an industrial production technique for aromatic aldehydes or aromatic ketones, carboxylic acid halides, and formic acid esters.

FIG. 1 is a schematic diagram showing an example of the configuration of a reaction apparatus used in the present invention.

In the present invention, first, a composition containing a C _1-4 halogenated hydrocarbon is irradiated with light in the presence of oxygen to decompose the C _1-4 halogenated hydrocarbon.

The C _1-4 halogenated hydrocarbon used in the present invention is a hydrocarbon having 1 or more and 4 or less carbon atoms, and has one or more halide groups selected from the group consisting essentially of chloro, bromo, and iodo. . Such C _1-4 halogenated hydrocarbons are probably decomposed by irradiation light and oxygen, converted to carbonyl halides or carbonyl halide-like compounds, reacted with amide compounds, and then further attacked by halide ions. It is thought that Vilsmeier's reagent is generated. Even if harmful carbonyl halides are generated, carbonyl halides are extremely reactive and will react immediately with the amide compound, and will not leak out of the reaction solution, or even if they do, the amount of leakage will be small. It is believed that there is. The present invention is a technology for producing useful compounds by photodegrading C _1-4 halogenated hydrocarbons, and it has great contributions both industrially and in environmental science.

C _1-4 halogenated hydrocarbon is an alkane, alkene or alkyne having 1 to 4 carbon atoms and substituted with one or more halogeno groups selected from the group consisting essentially of chloro, bromo and iodo. . As mentioned above, in the present invention, C _1-4 halogenated hydrocarbon is decomposed by irradiation light and oxygen, and is considered to function in the same manner as carbonyl halide. Therefore, C _1-2 halogenated hydrocarbons are preferred, and halogenomethanes are more preferred. When the number of carbon atoms is 2 or more and 4 or less, an alkene or alkyne having one or more unsaturated bonds is preferable so that decomposition proceeds more easily. Moreover, C _1-4 polyhalogenated hydrocarbons having two or more halogeno groups are preferred, and C _1-2 polyhalogenated hydrocarbons are more preferred. Further, C _1-4 halogenated hydrocarbons having two or more halogeno groups on the same carbon are preferred, although there is a possibility that halogeno groups may be transferred with decomposition.

Specific C _1-4 halogenated hydrocarbons include, for example, halomethanes such as dichloromethane, chloroform, dibromomethane, bromoform, iodomethane, and diiodomethane; 1,1,2-trichloroethane, 1,1,1-trichloroethane, 1, Haloethane such as 1,2,2-tetrachloroethane, 1,1,1,2-tetrachloroethane; Halopropane such as 1,1,1,3-tetrachloropropane; Tetrachloromethane, tetrabromomethane, tetraiodomethane, Examples include perhaloalkanes such as hexachloroethane and hexabromoethane; perhaloethenes such as 1,1,2,2-tetrachloroethene and 1,1,2,2-tetrabromoethene.

C _1-4 halogenated hydrocarbons may be selected as appropriate depending on the intended chemical reaction and desired product, and one type may be used alone or two or more types may be used in combination. You may. Also, preferably, only one type of C _1-4 halogenated hydrocarbon is used depending on the compound to be produced. Any C _1-4 halogenated hydrocarbon that is liquid at normal pressure and room temperature or reaction temperature can also serve as a solvent. Among C _1-4 halogenated hydrocarbons, compounds having a chloro group are preferred.

The C _1-4 halogenated hydrocarbon used in the method of the present invention is most preferably chloroform, which is inexpensive and can also be used as a general-purpose solvent. For example, the C _1-4 halogenated hydrocarbon once used as a solvent may be recovered and reused. At that time, if a large amount of impurities or water is contained, the reaction may be inhibited, so it is preferable to purify it to some extent. For example, after removing water and water-soluble impurities by washing with water, it is preferable to dehydrate with anhydrous sodium sulfate, anhydrous magnesium sulfate, or the like. However, it is thought that the reaction will proceed even if about 1% by volume of water is contained, so there is no need for excessive purification that would reduce productivity. The water content is more preferably 0.5% by volume or less, even more preferably 0.2% by volume or less, even more preferably 0.1% by volume or less. Further, the recycled C _1-4 halogenated hydrocarbon may contain a decomposition product of the C _1-4 halogenated hydrocarbon.

The amount of the C _1-4 halogenated hydrocarbon to be used may be appropriately determined within a range that allows sufficient conversion of the amide compound into the Vilsmeier reagent, and for example, it may be used in an amount of 0.1 times the mole or more relative to the amide compound. The upper limit of the amount of the C _1-4 halogenated hydrocarbon to be used is not particularly limited, but may be, for example, 200 times the molar amount or less relative to the amide compound. The amount used is preferably at least 1 mole, at least 5 times the mole, or at least 10 times the mole, more preferably at least 20 times, even more preferably at least 25 times. According to the experimental findings of the present inventors, it is recognized that the production efficiency of the Vilsmeier reagent tends to be higher when the amount of the amide compound relative to the C _1-4 halogenated hydrocarbon is smaller. Further, in cases where a C _1-4 halogenated hydrocarbon can be used as a solvent, it can be used in a molar amount of 50 times or more. The above usage amount is preferably 150 times mole or less or 100 times mole or less. The specific amount of C _1-4 halogenated hydrocarbon to be used may be determined through preliminary experiments.

The oxygen source may be any gas containing oxygen, such as air or purified oxygen. Purified oxygen may be used in combination with an inert gas such as nitrogen or argon. Air can be used in terms of cost and ease. From the viewpoint of increasing the decomposition efficiency of C _1-4 halogenated hydrocarbons by light irradiation, the oxygen content in the gas used as the oxygen source is preferably about 15% by volume or more and 100% by volume or less. Further, it is also preferable to use substantially only oxygen other than inevitable impurities. The oxygen content may be appropriately determined depending on the type of the C _1-4 halogenated hydrocarbon. For example, when using a chloroC _1-4 hydrocarbon such as dichloromethane, chloroform, or tetrachloroethylene as the C _1-4 halogenated hydrocarbon, the oxygen content is preferably 15% by volume or more and 100% by volume or less; When using a bromo C _1-4 hydrocarbon compound such as methane or bromoform, the oxygen content is preferably 90% by volume or more and 100% by volume or less. Note that even when using oxygen (oxygen content 100% by volume), the oxygen content can be controlled within the above range by adjusting the oxygen flow rate into the reaction system. The method of supplying the gas containing oxygen is not particularly limited, and it may be supplied into the reaction system from an oxygen cylinder equipped with a flow rate regulator, or may be supplied into the reaction system from an oxygen generator.

Note that "in the presence of oxygen" may be a state in which the C _1-4 halogenated hydrocarbon is in contact with oxygen or a state in which oxygen is present in the composition. Therefore, the reaction according to the present invention may be carried out under a gas flow of oxygen-containing gas, but from the viewpoint of increasing the yield of the product, the oxygen-containing gas may be supplied into the composition by bubbling. preferable.

The amount of the oxygen-containing gas may be appropriately determined depending on the amount of the C _1-4 halogenated hydrocarbon, the shape of the reaction vessel, and the like. For example, it is preferable that the amount of gas supplied to the reaction vessel per minute is at least 5 times the volume of the C _1-4 halogenated hydrocarbon present in the reaction vessel. The ratio is more preferably 25 times the volume or more, even more preferably 50 times the volume or more. The upper limit of the ratio is not particularly limited, but is preferably 500 times the volume or less, more preferably 250 times the volume or less, and even more preferably 150 times the volume or less. Further, the amount of oxygen supplied to the reaction vessel per minute relative to the C _1-4 halogenated hydrocarbon present in the reaction vessel can be 5 times or more and 25 times or less by volume. If the gas flow rate is too large, there is a possibility that the C _1-4 halogenated hydrocarbon will be volatilized, while if it is too small, there is a possibility that the reaction will be difficult to proceed.

A solvent may be added to the composition containing the C _1-4 halogenated hydrocarbon. In particular, when the C _1-4 halogenated hydrocarbon is not liquid at room temperature and normal pressure, a solvent that can appropriately dissolve the C _1-4 halogenated hydrocarbon and does not inhibit the decomposition of the C _1-4 halogenated hydrocarbon is needed. preferable. Examples of such solvents include ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone; ester solvents such as ethyl acetate; aliphatic hydrocarbon solvents such as n-hexane; and ethers such as diethyl ether, tetrahydrofuran, and dioxane. Solvent: Nitrile solvents such as acetonitrile can be mentioned.

The light irradiated to the above mixture is preferably light containing short wavelength light, more preferably light containing ultraviolet light, more specifically light containing light with a wavelength of 180 nm or more and 500 nm or less, with a peak wavelength of 180 nm or more and 500 nm or more. Light falling within the following ranges is more preferred. The wavelength of the light may be appropriately determined depending on the type of the C _1-4 halogenated hydrocarbon, but is more preferably 400 nm or less, and even more preferably 300 nm or less. When the irradiation light includes light in the above wavelength range, the C _1-4 halogenated hydrocarbon can be efficiently oxidatively photodecomposed. For example, high energy light including UV-B with a wavelength of 280 nm or more and 315 nm or less and/or UV-C with a wavelength of 180 nm or more and 280 nm or less can be used, and high energy light including UV-C with a wavelength of 180 nm or more and 280 nm or less can be used. It is preferable. Furthermore, light having a peak wavelength in a range of 280 nm or more and 315 nm or less and/or 180 nm or more and 280 nm or less is preferable, and light having a peak wavelength in a range of 180 nm or more and 280 nm or less is more preferable.

The means of light irradiation is not particularly limited as long as it can irradiate light with the above-mentioned wavelengths, but examples of light sources that include light in this wavelength range include sunlight, low-pressure mercury lamps, and medium-pressure mercury lamps. lamps, high-pressure mercury lamps, ultra-high-pressure mercury lamps, chemical lamps, black light lamps, metal halide lamps, halogen lamps, and incandescent lamps. From the viewpoint of reaction efficiency and cost, a low-pressure mercury lamp is preferably used.

Conditions such as the intensity of the irradiation light and the irradiation time may be set as appropriate depending on the type of starting material and the amount used, but for example, the desired light intensity at the shortest distance of the composition from the light source is 10 mW/cm ² More than 500 mW/cm ² is preferable. Further, the shortest distance between the light source and the halogenated methane is preferably 1 m or less, more preferably 50 cm or less, and even more preferably 10 cm or less or 5 cm or less. The lower limit of the shortest distance is not particularly limited, but may be 0 cm, that is, the light source may be immersed in halogenated methane. When light is irradiated from the side surface of the reaction container, the shortest distance can be set to 1 cm or more or 2 cm or more. The light irradiation time is preferably 0.5 hours or more and 10 hours or less, more preferably 1 hour or more and 6 hours or less, even more preferably 2 hours or more and 4 hours or less. The mode of light irradiation is not particularly limited, and may include a mode in which light is irradiated continuously from the start of the reaction to the end, a mode in which light irradiation and non-light irradiation are alternately repeated, a mode in which light is irradiated only for a predetermined time from the start of the reaction, etc. Although any embodiment can be adopted, a mode in which light is continuously irradiated from the start to the end of the reaction is preferred.

The temperature at which the C _1-4 halogenated hydrocarbon is decomposed is not particularly limited, and may be adjusted as appropriate, and may be, for example, −20° C. or higher and 60° C. or lower. The temperature is more preferably -10°C or higher, even more preferably 0°C or higher or 10°C or higher, more preferably 50°C or lower or 40°C or lower, even more preferably 30°C or lower. Alternatively, the reaction may be carried out at room temperature without temperature control. Note that when the reaction temperature is low, there is an advantage that harmful halogen compound gas is difficult to leak out of the reaction system. From this point of view, the reaction temperature is preferably 10°C or lower, more preferably 5°C or lower.

Further, after irradiation with high-energy light, the reaction may be continued for about 1 minute to 5 hours at 10° C. to 60° C. without irradiating high-energy light, for example, under general light such as a fluorescent lamp.

In the present invention, next, the decomposition product of C _1-4 halogenated hydrocarbon and the amide compound represented by formula (II) are reacted. The reaction step with the amide compound may be performed simultaneously with the decomposition step of the C _1-4 halogenated hydrocarbon, or may be performed after the decomposition step of the C _1-4 halogenated hydrocarbon.

When the decomposition step of the C _1-4 halogenated hydrocarbon and the reaction step with the amide compound are carried out simultaneously, the amide compound may also be blended into the composition containing the C _1-4 halogenated hydrocarbon, for example. Alternatively, a composition containing a C _1-4 halogenated hydrocarbon may be irradiated with light, and the amide compound may be added while the irradiation is continued. In these cases, the decomposition product of the C _1-4 halogenated hydrocarbon can quickly react with the amide compound, and leakage of the decomposition product can be suppressed.

When carrying out the reaction step with an amide compound after the decomposition step of C _1-4 halogenated hydrocarbons, after decomposing the C _1-4 halogenated hydrocarbons by light irradiation, light irradiation, especially high-energy light, is performed. The irradiation may be stopped and the amide compound may be added. When the decomposition of the C _1-4 halogenated hydrocarbon is inhibited by the amide compound, the decomposition of the C _1-4 halogenated hydrocarbon and the reaction with the amide compound can be efficiently carried out in this embodiment. Further, it is possible to suppress the side reaction between the amide compound and the hydrogen halide produced by the decomposition of the C _1-4 halogenated hydrocarbon, and the decomposition of the amide compound due to light irradiation. This embodiment is therefore particularly suitable for implementing the invention in large volumes.

As the amide compound, an amide compound represented by the following formula (II) is preferable. Hereinafter, the compound represented by formula (II) may be abbreviated as "amide compound (II)".

［式中、Ｒ¹は、水素原子（－Ｈ）、Ｃ_1-6アルキル基、または置換基を有していてもよいＣ_6-12芳香族炭化水素基を示し、Ｒ²とＲ³は、独立して、Ｃ_1-6アルキル基、または置換基を有していてもよいＣ_6-12芳香族炭化水素基を示し、また、Ｒ²とＲ³は一緒になって４員以上７員以下の環構造を形成してもよい。］

[In the formula, R ¹ represents a hydrogen atom (-H), a C _1-6 alkyl group, or a C _6-12 aromatic hydrocarbon group which may have a substituent, and R ² and R ³ are , independently represents a C _1-6 alkyl group or a C _6-12 aromatic hydrocarbon group which may have a substituent, and R ² and R ³ together represent a 4- or more-membered 7 A ring structure having less than one member may be formed. ]

In the present disclosure, "C _1-6 alkyl group" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like. Preferably it is a C _1-4 alkyl group, more preferably a C _1-2 alkyl group, and most preferably methyl.

"C _6-12 aromatic hydrocarbon group" refers to a monovalent aromatic hydrocarbon group having 6 or more and 12 or less carbon atoms. For example, phenyl, naphthyl, indenyl, biphenyl groups, preferably phenyl. The C _6-12 aromatic hydrocarbon group may have a substituent. The substituent is not particularly limited as long as it does not inhibit the reaction according to the present invention, but for example, from the group consisting of a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogeno group, a nitro group, and a cyano group. One or more selected substituents may be mentioned. The number of substituents is not particularly limited as long as they are substitutable, but can be, for example, 1 or more and 5 or less, preferably 3 or less, more preferably 2 or less, and even more preferably 1. When the number of substituents is two or more, the substituents may be the same or different.

"C _1-6 alkoxy group" refers to a linear or branched aliphatic hydrocarbon oxy group having 1 to 6 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, n-hexoxy, etc., preferably C _1-4 alkoxy group, more preferably C _{1 -2} alkoxy group, more preferably methoxy.

The "halogeno group" as a substituent of the C _6-12 aromatic hydrocarbon group may be fluoro in addition to chloro, bromo, and iodo.

Examples of the 4- to 7-membered ring structure formed by R ² and R ³ together with a nitrogen atom include a pyrrolidyl group, a piperidyl group, and a morpholino group.

Specific examples of the amide compound (II) include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-N-phenylformamide, N-methylpyrrolidone (NMP), Examples include 1,3-dimethylimidazolidinone (DMI), tetramethylurea, tetraethylurea, and tetrabutylurea, with DMF being preferred from the viewpoint of versatility and cost.

When the decomposition step of the C _1-4 halogenated hydrocarbon and the reaction step with the amide compound are carried out simultaneously, the composition containing the C _1-4 halogenated hydrocarbon and the amide compound is irradiated with light in the presence of oxygen. The most preferred C _1-4 halogenated hydrocarbon to be combined with the amide compound (II) is chloroform, which is available at low cost.

The mixing mode of the C _1-4 halogenated hydrocarbon and the amide compound is not particularly limited. For example, the entire amount of each compound may be mixed in advance in the reactor, the compounds may be added in several portions, or they may be added continuously at any rate. Further, when the above C _1-4 halogenated hydrocarbon is not liquid at normal temperature and normal pressure, a solvent that can appropriately dissolve these raw material compounds and does not inhibit the reaction of the present invention may be used. Examples of such solvents include aliphatic hydrocarbon solvents such as n-hexane; ether solvents such as diethyl ether, tetrahydrofuran, and dioxane; and nitrile solvents such as acetonitrile.

The temperature during the reaction is also not particularly limited and may be adjusted as appropriate, for example, it can be set to -20°C or more and 60°C or less. The temperature is more preferably -10°C or higher, even more preferably 0°C or higher, more preferably 50°C or lower or 40°C or lower, even more preferably 30°C or lower. Alternatively, the reaction may be carried out at room temperature without temperature control. Note that when the reaction temperature is low, there is an advantage that harmful halogen compound gas is difficult to leak out of the reaction system. From this point of view, the reaction temperature is preferably 10°C or lower, more preferably 5°C or lower.

In addition, after irradiation with high-energy light, C 1-4 halogenated hydrocarbons may be exposed to C _1-4 halogenated hydrocarbons at a temperature of 10°C to 60°C for 1 minute to 5 hours without irradiating high-energy light, for example under general light such as a fluorescent lamp. The reaction between the decomposition product and the amide compound may be continued.

Examples of reaction apparatuses that can be used in the production method of the present invention include those in which a reaction vessel is equipped with a light irradiation means. The reaction apparatus may be equipped with a stirring device and a temperature control means. FIG. 1 shows one embodiment of a reaction apparatus that can be used in the production method of the present invention. The reaction apparatus shown in FIG. 1 has a light irradiation means 1 inside a cylindrical reaction vessel 6. The reaction apparatus shown in FIG. The above raw material compounds are added into the cylindrical reaction vessel 6, and light irradiation is performed while supplying a gas containing oxygen into the reaction vessel 6 or bubbling the gas containing oxygen into the mixture (not shown). The reaction is carried out by irradiating light from means 1. When the light irradiation means 1 is covered with a jacket 2 or the like, the jacket is preferably made of a material that transmits the short wavelength light. Furthermore, the reaction container may be irradiated with light from outside, and in this case, the reaction container is preferably made of a material that transmits the short wavelength light. The material that transmits the short wavelength light is not particularly limited as long as it does not impede the effects of the present invention, but quartz glass and the like are preferably mentioned.

When the compound represented by the above formula (II) is used as the amide compound, the Vilsmeier reagent produced is a salt represented by the following formula (I).

［式中、Ｒ¹～Ｒ³は上記と同義を示し、Ｘは、クロロ、ブロモおよびヨードからなる群より選択されるハロゲノ基を示し、Ｙ^-はカウンターアニオンを示す。］

[In the formula, R ¹ to R ³ have the same meanings as above, X represents a halogeno group selected from the group consisting of chloro, bromo and iodo, and Y ⁻ represents a counter anion. ]

Y ^- in formula (I) includes, but is not particularly limited to, chloride ions, bromide ions, and iodide ions derived from C _1-4 halogenated hydrocarbons.
From the viewpoint of easy availability, the salt represented by formula (I) is preferably a compound in which X is chloro and Y ^- is a chloride ion.

By further adding a compound capable of reacting with the Vilsmeier reagent to the above-mentioned reaction solution containing the Vilsmeier reagent, it is possible to proceed with further reactions within the same system. For example, it is known that an aromatic compound having an active group can be converted into an aldehyde or a ketone using a Vilsmeier reagent. Such a reaction is known as the Vilsmeier-Haack reaction. Furthermore, Vilsmeier's reagent is known to convert the carboxy group of a carboxylic acid compound into a haloformyl group. Furthermore, a formate ester can be obtained by reacting a Vilsmeier reagent with a hydroxyl group-containing compound.

An aromatic compound having an active group (hereinafter referred to as an "active aromatic compound") is an aromatic compound activated by a substituent or the like. For example, amino groups and hydroxyl groups containing alkylamino groups substituted with alkyl groups strongly activate aromatic compounds. Also, alkylcarbonylamino group (-N(C=O)R), alkylcarbonyloxy group (-O(C=O)R), ether group (-OR), alkyl group (-R) (R is an alkyl group C _1-6 alkyl groups are preferred), and aromatic groups also activate aromatic compounds. Hereinafter, these substituents will be referred to as activating groups. Compounds such as anthracene, in which aromatic rings are condensed to extend the conjugated system, are also activated and undergo aldehyde or ketonization using Vilsmeier reagents. It is thought that the π electrons of the activated site electrophilically react with the Vilsmeier reagent, resulting in aldehyde or ketonization.

The active aromatic compound is not particularly limited as long as it is activated and can be aldehyded or ketonized by the Vilsmeier reagent _. Aromatic hydrocarbons; fused aromatic hydrocarbons which may be substituted with the above activating groups, such as phenanthrene and anthracene; pyrrole, imidazole, pyrazole, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, etc. 5-membered heteroaryl group optionally substituted with an activating group; 6-membered heteroaryl optionally substituted with the above-mentioned activating group, such as pyridine, pyrazine, pyrimidine, pyridazine; indole, isoindole, quinoline, Isoquinoline, benzofuran, isobenzofuran, chromene, and other fused heteroaryls which may be substituted with the above-mentioned activating group can be mentioned. Although there are no reports of aldehyde or ketonization of unsubstituted furan or thiophene in the conventional Vilsmeyer-Hack reaction, according to the method of the present invention, the carbon adjacent to the hetero element can be aldehyded or ketonized. is possible.

The amount of the active aromatic compound to be used may be adjusted as appropriate, and may be, for example, from 0.1 times the mole to 1.0 times the mole of the amide compound.

The reaction conditions for aldehydation or ketonization may be determined as appropriate. For example, the active aromatic compound may be added to the reaction solution after confirming the consumption of the amide compound and the production of the Vilsmeier reagent by thin layer chromatography, NMR, or the like. The active aromatic compound may be added as it is, or a solution of the active aromatic compound may be added. The solvent for the active aromatic compound solution is not particularly limited as long as it can appropriately dissolve the active aromatic compound and does not inhibit the reaction, but examples include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, Halogenated hydrocarbon solvents such as chlorohexane; Ketone solvents such as acetone and methyl ethyl ketone; Nitrile solvents such as acetonitrile; Aromatic hydrocarbon solvents such as benzene, toluene, and chlorobenzene; Ether solvents such as diethyl ether, tetrahydrofuran, and dioxane can be mentioned. The reaction conditions for aldehydation or ketonization may be adjusted as appropriate; for example, the reaction temperature may be -10°C or higher, including the temperature at the time of addition of the active aromatic compound, under heating reflux conditions, and the reaction time may be , the duration may be 10 minutes or more and 20 hours or less. In addition, in the compounds of formula (I) and formula (II), when R ¹ is a hydrogen atom, an aromatic aldehyde is obtained, and when R ¹ is an alkyl group or an aromatic hydrocarbon group, an aromatic ketone is obtained. It will be done.

After the reaction, usual post-treatments and purification may be carried out. For example, after the reaction, add a saturated aqueous sodium carbonate solution or a saturated aqueous sodium bicarbonate solution to the reaction solution to stop the reaction, separate the layers, extract the aqueous layer with an organic solvent, combine the organic layer and the extract, and add anhydrous sodium sulfate to the reaction solution. After drying over magnesium sulfate or anhydrous magnesium sulfate and concentrating under reduced pressure, the desired aromatic aldehyde or aromatic ketone may be purified by a conventional method such as recrystallization, silica gel column chromatography, or distillation.

When converting the carboxy group of a carboxylic acid compound into a haloformyl group using a Vilsmeier reagent, the carboxylic acid compound may be added to the composition containing the C _1-4 halogenated hydrocarbon and amide compound before irradiation with light. However, the carboxylic acid compound may be added intermittently or continuously from before the light irradiation to after the light irradiation, or the carboxylic acid compound may be added after the light irradiation. That is, a step of adding a carboxylic acid compound to convert a carboxy group into a haloformyl group may be performed after the Vilsmeier reagent manufacturing step, or both steps may be performed simultaneously.

Examples of the carboxylic acid compound that converts a carboxy group into a haloformyl group include a compound represented by the following formula (III).
R ⁴ -(CO ₂ H) _n (III)
[In the formula, R ⁴ represents an n-valent organic group, and n represents an integer of 1 or more and 4 or less. ]

The organic group is not particularly limited as long as it does not inhibit the reaction, but examples include a C _1-18 hydrocarbon group that may have a substituent and the above heteroaryl group that may have a substituent. can. Examples of the substituent include one or more substituents selected from the group consisting of a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogeno group, a nitro group, and a cyano group. Further, examples of the C _1-18 hydrocarbon group include a monovalent C _1-18 alkyl group, a C _2-18 alkenyl group, a C _2-18 alkynyl group, a C _6-18 aromatic hydrocarbon group, and a C 1-18 aromatic hydrocarbon group. Corresponding hydrocarbon groups having a valence of more than or equal to 4 and less than or equal to 4 can be mentioned. Furthermore, in the C _1-18 alkyl group, C _2-18 alkenyl group, and C _2-18 alkynyl group, one or more carbon atoms are -O-, -S-, -NR ⁵ - (R ⁵ is a hydrogen atom or (representing an alkyl group such as a C _1-6 alkyl group) may be substituted with a heteroatom such as a C 1-6 alkyl group.

The carboxylic acid compound may be added as it is, or a solution of the carboxylic acid compound may be added. The solvent for the carboxylic acid compound solvent is not particularly limited as long as it can appropriately dissolve the carboxylic acid compound and does not inhibit the reaction, but examples include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, and chlorohexane. Examples include halogenated hydrocarbon solvents such as; aromatic hydrocarbon solvents such as benzene, toluene, and chlorobenzene; and ether solvents such as diethyl ether, tetrahydrofuran, and dioxane.

The amount of the carboxylic acid compound to be used may be adjusted as appropriate, and may be, for example, 0.1 to 3.0 times the mole of the amide compound.

The reaction conditions for converting a carboxy group into a haloformyl group may be determined as appropriate. For example, the reaction temperature can be 0° C. or more and 50° C. or less, and the reaction time can be 10 minutes or more and 20 hours or less.

Isolation of carboxylic acid halides can be difficult because they are often highly reactive and unstable. Therefore, after the Vilsmeier reagent reacts with the carboxylic acid compound, it is preferable to add a compound to be reacted with the carboxylic acid halide, such as an alcohol compound or an amine compound, to the reaction solution. After the reaction, usual post-treatments may be performed, and the target compound may be purified by conventional methods.

When a formic acid ester is obtained by reacting a Vilsmeier reagent with a hydroxyl group-containing compound, the hydroxyl group-containing compound may be added to the composition containing the C _1-4 halogenated hydrocarbon and an amide compound before irradiation with light. The hydroxyl group-containing compound may be added intermittently or continuously from before the light irradiation to after the light irradiation, or the hydroxyl group-containing compound may be added after the light irradiation. That is, the step of adding the hydroxyl group-containing compound may be performed after the Vilsmeier reagent manufacturing step, or both steps may be performed simultaneously. The hydroxyl group-containing compound may be added as is, or a solution of the hydroxyl group-containing compound may be added. The solvent for the hydroxyl group-containing compound solution is not particularly limited as long as it can appropriately dissolve the hydroxyl group-containing compound and does not inhibit the reaction, but examples include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, and chlorohexane. Examples include halogenated hydrocarbon solvents such as; nitrile solvents such as acetonitrile; and ether solvents such as diethyl ether, tetrahydrofuran, and dioxane.

The hydroxyl group-containing compound is not particularly limited as long as it has one or more reactive hydroxyl groups, and examples include alcohol compounds and phenol compounds.

Examples of alcohol compounds include C _1-20 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, t-butanol, n-pentanol, and isopentanol; trifluoro C _1-20 halogeno alcohols such as methanol, 2-fluoroethanol, 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, 2,2,2-fluoroethanol; ethylene glycol, propylene glycol, 1,4-butane Examples include diol compounds such as diol and 1,6-hexanediol; triol compounds such as glycerin; and tetraol compounds such as pentaerythritol.

Examples of phenolic compounds include monohydric phenol compounds such as phenol, naphthol, cresol, butylphenol, amylphenol, chlorophenol, and bromophenol; catechol, bisphenol A to G, bisphenol M, bisphenol S, bisphenol P, and bisphenol Z. Dihydric phenol compounds; trihydric phenol compounds such as trihydroxybenzene can be mentioned.

The amount of the hydroxyl group-containing compound to be used may be adjusted as appropriate, but for example, the amount of the hydroxyl group-containing compound having one hydroxyl group may be 0.1 to 3.0 times the mole of the amide compound. can. The amount of the hydroxyl group-containing compound having m hydroxyl groups may be adjusted to 1/m of the amount of the hydroxyl group-containing compound having one hydroxyl group.

The conditions for the reaction between the Vilsmeier reagent and the hydroxyl group-containing compound may be determined as appropriate. For example, after adding the hydroxyl group-containing compound, the reaction temperature can be set to -10°C or more and 50°C or less, and the reaction time can be set to 10 minutes or more and 20 hours or less.

After the reaction, usual post-treatments and purification may be carried out. For example, after the reaction, add a saturated aqueous sodium carbonate solution or a saturated aqueous sodium bicarbonate solution to the reaction solution to stop the reaction, separate the layers, extract the aqueous layer with an organic solvent, combine the organic layer and the extract, and add anhydrous sodium sulfate to the reaction solution. After drying over magnesium sulfate or anhydrous magnesium sulfate and concentrating under reduced pressure, the target compound, the formate, may be purified by conventional methods such as recrystallization, silica gel column chromatography, and distillation.

This application claims the benefit of priority based on Japanese Patent Application No. 2018-167032 filed on September 6, 2018. The entire contents of the specification of Japanese Patent Application No. 2018-167032 filed on September 6, 2018 are incorporated by reference into this application.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the Examples below, and modifications may be made as appropriate within the scope of the spirit of the preceding and following. Of course, other implementations are also possible, and all of them are included within the technical scope of the present invention.

Example 1: Production of Vilsmeyer reagent A cylindrical reaction vessel (diameter 42 mm) equipped with a quartz glass jacket with a diameter of 30 mm in the center was prepared, and a low-pressure mercury lamp (manufactured by SEN Light, UVL20PH-6, 20 W) was attached to the quartz glass jacket. , φ24×120 mm), and purified chloroform (20 mL, 248 mmol) and DMF (1.55 mL, 20 mmol) were added into the reaction vessel. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at a temperature of 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the supply of oxygen gas and the light irradiation were stopped, and the reaction solution was stirred at 50° C. for 1.5 hours. Thereafter, when stirring was stopped, the reaction solution was separated into two layers.
When each layer was analyzed by ¹ H-NMR, almost no Vilsmeier reagent peak was observed in the lower layer. On the other hand, a peak of (chloromethylene) dimethyliminium chloride, which is a Vilsmeier reagent, was observed in the upper layer. Furthermore, the ratio of residual DMF to Vilsmeier reagent (DMF: Vilsmeier reagent) in the upper layer was about 1:4 based on the peak intensity, and it was estimated that 16 mmol of Vilsmeier reagent was produced at maximum.

Example 2: Production of pyrrole-2-carboxaldehyde Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50°C, and the mixture was stirred until no bubbles were generated. Thereafter, the reaction container was immersed in an ice bath, pyrrole (0.74 mL, 10 mmol) was added, and the mixture was heated under reflux for 30 minutes. Then, saturated aqueous sodium carbonate solution (30 mL) was added and stirred for 15 minutes. The reaction solution was separated into two layers, and the aqueous layer was extracted with diethyl ether. The organic layer and extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that the target compound, pyrrole-2-carboxaldehyde, was produced (yield: 82%).

Example 3: Production of 1-methyl-2-pyrrole carboxaldehyde In Example 2, a solution of 1-methylpyrrole (0.74 mL, 10 mmol) in chloroform (5 mL) was used instead of pyrrole, and the aqueous layer was extracted with dichloromethane. A concentrate was obtained in the same manner except that. Analysis of the concentrate by ¹ H-NMR confirmed the production of the target compound, 1-methyl-2-pyrrolecarboxaldehyde (yield >99%).

Example 4: Production of 2-formylfuran In Example 2, furan (0.73 mL, 10 mmol) was used instead of pyrrole, and after adding furan, the reaction was carried out at 0°C for 30 minutes, and then at room temperature for 2 hours. A concentrate was obtained in the same manner except that the aqueous layer was extracted with dichloromethane. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that the target compound, 2-formylfuran, had been produced (yield: 60%). Thus, although formylation of unsubstituted furan using a Vilsmeier reagent has not been reported so far, it has been demonstrated that formylation of unsubstituted furan is possible according to the present invention.

Example 5: Production of 5-methylfurfural A cylindrical reaction vessel (42 mm in diameter) equipped with a quartz glass jacket with a diameter of 30 mm in the center was prepared, and a low-pressure mercury lamp (manufactured by SEN Light, UVL20PH-6, Purified chloroform (20 mL, 248 mmol) and DMF (3.5 mL, 45 mmol) were added to the reaction vessel. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 3 hours while irradiating with light from the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50°C, and the mixture was stirred until no bubbles were generated. Thereafter, the reaction vessel was immersed in an ice bath, 2-methylfuran (0.9 mL, 10 mmol) was added, and the mixture was stirred at 0° C. for 1 hour. Then, saturated aqueous sodium carbonate solution (30 mL) was added and stirred for 15 minutes. The reaction solution was separated into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layer and extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that the target compound, 5-methylfurfural, was produced (yield: 80%).

Example 6: Production of 2-formylthiophene Purified chloroform (20 mL, 248 mmol) and DMF (1.2 mL, 15 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 30 minutes. Thereafter, thiophene (0.74 mL, 10 mmol) was added dropwise at room temperature, and the mixture was heated under reflux for 6 hours. Next, the reaction solution was added to a saturated aqueous sodium carbonate solution (30 mL) at 0°C, and stirred for 30 minutes. Chloroform was added to the reaction solution, the reaction solution was separated into two layers, and the aqueous layer was extracted with chloroform. The organic layer and extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that the target compound, 2-formylthiophene, was produced (yield: 61%). Thus, although formylation of unsubstituted thiophene using a Vilsmeier reagent has not been reported so far, it has been demonstrated that formylation of unsubstituted thiophene is possible according to the present invention.

Example 7: Production of 5-methyl-2-formylthiophene A concentrate was obtained in the same manner as in Example 2, except that 2-methylthiophene (0.97 mL, 10 mmol) was used instead of pyrrole. Analysis of the concentrate by ¹ H-NMR confirmed the production of the target compound, 5-methyl-2-formylthiophene (yield: 56%).

Example 8: Production of 2-formyl-3-methylthiophene or 2-formyl-4-methylthiophene In Example 2, 3-methylthiophene (0.97 mL, 10 mmol) was used instead of pyrrole, and 3-methylthiophene A concentrate was obtained in the same manner except that the heating reflux time after dropping was changed to 2 hours. When the concentrate was analyzed by ¹ H-NMR, the yield of 2-formyl-3-methylthiophene was 74% and the yield of 2-formyl-4-methylthiophene was 16%.

Example 9: Production of 2-formyl-3-methylthiophene or 2-formyl-4-methylthiophene Same as in Example 8 except that 1-pyrrolidinecarboxaldehyde (1.98 mL, 20 mmol) was used instead of DMF. A concentrate was obtained. When the concentrate was analyzed by ¹ H-NMR, the yield of 2-formyl-3-methylthiophene was 11% and the yield of 2-formyl-4-methylthiophene was 4%.

Example 10: Production of 3-formylindole In the same manner as in Example 2, a reaction solution containing Vilsmeier's reagent was prepared. A solution of indole (1.17 g, 10 mmol) in DMF (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Furthermore, 7.5 mol/L aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at 0°C for 15 minutes. The reaction solution was separated into two layers, and the aqueous layer was extracted with diethyl ether. The organic layer and extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to silica gel chromatography (eluent: ethyl acetate/dichloroethane = 3/7) to obtain the target compound, 3-formylindole (yield: 70%).

実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（０．５６ｍＬ，７．２３ｍｍｏｌ）を加えた。混合溶液の攪拌下、酸素ガスを０．５Ｌ／分でバブリングさせつつ、前記低圧水銀ランプにより光照射しながら、３０℃で２時間反応を行った。続いて、光照射を停止し、反応温度を５０℃に上げ、３０分間攪拌した。その後、反応液を氷冷しつつ、上記ビピロール誘導体（５８０ｍｇ，１．８１ｍｍｏｌ）をクロロホルム（２０ｍＬ）に溶解した溶液を添加し、３０分間加熱還流した。次いで、反応液に飽和炭酸ナトリウム水溶液（３０ｍＬ）を加え、１５分間攪拌した。反応液にクロロホルムを加え、二層に分離した反応液を分液し、有機層を無水硫酸ナトリウムで乾燥し、濾過し、濾液を減圧濃縮した。ジクロロメタンのメタノールの混合液を用いて再結晶することにより、ホルミル化されたビピロール誘導体を得た（収率：６６％）。Example 11: Photoformylation reaction of bipyrrole derivatives

Purified chloroform (20 mL, 248 mmol) and DMF (0.56 mL, 7.23 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 30 minutes. Thereafter, a solution of the bipyrrole derivative (580 mg, 1.81 mmol) dissolved in chloroform (20 mL) was added to the reaction solution while cooling it on ice, and the mixture was heated under reflux for 30 minutes. Then, a saturated aqueous sodium carbonate solution (30 mL) was added to the reaction solution, and the mixture was stirred for 15 minutes. Chloroform was added to the reaction solution, the reaction solution was separated into two layers, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A formylated bipyrrole derivative was obtained by recrystallization using a mixture of dichloromethane and methanol (yield: 66%).

Example 12: Production of bis(pyrrole-2-carboxaldehyde) Purified chloroform (20 mL, 248 mmol) and DMF (1.15 mL, 14.9 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the mixture was reacted at 10° C. for 6 hours while being irradiated with light from the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50° C. and stirred for 30 minutes. Thereafter, the reaction container was immersed in an ice bath, bipyrrole (420 mg, 3.18 mmol) was added, and the mixture was heated under reflux for 30 minutes. Then, saturated aqueous sodium carbonate solution (50 mL) was added and stirred for 15 minutes. The reaction solution was separated into two layers, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with methanol and analyzed by ¹ H-NMR, and it was confirmed that the target compound, bis(pyrrole-2-carboxaldehyde), was produced (yield: 210 mg, yield: 73%).

Example 13: Formylation reaction of benzofuran Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the mixture was reacted at 0° C. for 5 hours while being irradiated with light from the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to room temperature, benzofuran (1.0 mL, 9 mmol) was added, stirred at 70° C. for 30 minutes, and further heated under reflux for 20 hours. Then, saturated aqueous sodium carbonate solution (20 mL) was added and stirred for 15 minutes. Diethyl ether (10 mL) was added, the reaction solution was separated into two layers, and the aqueous layer was extracted with diethyl ether. The organic layer was combined with the extract, washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution, and water, and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography (eluent: hexane/dichloromethane = 1/1 (volume ratio)) to obtain the target compound, 2-formylbenzofuran (yield: 394 mg, yield: 30%).

Example 14: Production of phenylpyrrolyl ketone Purified chloroform (20 mL, 248 mmol) and N,N-dimethylbenzamide (3 g, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 3 hours while irradiating with light from the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 30 minutes. Then, pyrrole (0.7 mL, 10 mmol) was added, and the mixture was heated under reflux for 30 minutes. Then, a saturated aqueous sodium carbonate solution was added to the reaction solution, and the mixture was stirred for 30 minutes. Chloroform was added to the reaction solution, the reaction solution was separated into two layers, and the aqueous layer was extracted with chloroform. The organic layer and extract were combined and concentrated under reduced pressure at 150°C, and then purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate) to obtain the target compound (yield: 0.32 g, yield: 9 .3%).

Example 15: Production of 2-acetylpyrrole Purified chloroform (20 mL, 248 mmol) and N,N-dimethylacetamide (1.7 g, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 3 hours while irradiating with light from the low-pressure mercury lamp. Subsequently, light irradiation was stopped, and the mixture was stirred at 30° C. for 30 minutes. Then, pyrrole (0.7 mL, 10 mmol) was added and stirred overnight. Next, the resulting insoluble salt was removed by suction filtration, and the filtrate was concentrated under reduced pressure to obtain the target compound (yield: 0.39 g, yield: 36.0%).

Comparative example 1
Purified chloroform (30 mL, 372 mmol) and benzoic acid (1.22 g, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 10° C. for 3 hours while irradiating with light from the low-pressure mercury lamp. The reaction solution was analyzed by ¹ H-NMR, but the reaction did not proceed at all. The reason why the reaction did not proceed is probably that the Vilsmeier reagent was not produced because no amide compound was used.

Example 16: Production of benzoyl chloride and its amidation Purified chloroform (30 mL, 372 mmol), DMF (0.4 mL, 5 mmol), and benzoic acid (1.22 g, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 10° C. for 3 hours while irradiating with light from the low-pressure mercury lamp. Analysis of the reaction solution by ¹ H-NMR revealed that benzoyl chloride was produced in a yield of 95%.
Aniline (3.65 mL, 40 mmol) was added to the above reaction solution at room temperature, and after stirring at room temperature for 1 hour, the reaction solution was filtered. 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained yellow-brown concentrate was recrystallized using an acetone/n-hexane mixed solvent to obtain benzanilide (isolated yield: 61%).

Example 17: Production of benzoyl chloride Purified chloroform (30 mL, 372 mmol), DMF (0.4 mL, 5 mmol), and benzoic acid (1.22 g, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Analysis of the reaction solution by ¹ H-NMR revealed that benzoyl chloride was quantitatively produced.

Example 18: Production of benzoyl chloride Tetrachloroethylene (30 mL, 293 mmol), DMF (0.4 mL, 5 mmol), and benzoic acid (1.22 g, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Analysis of the reaction solution by ¹ H-NMR revealed that benzoyl chloride was produced in a yield of 8.5%.

Example 19: Production of acetyl chloride Purified chloroform (20 mL, 248 mmol), DMF (0.4 mL, 5 mmol), and acetic acid (0.57 mL, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 3 hours while irradiating with light from the low-pressure mercury lamp. Analysis of the reaction solution by ¹ H-NMR revealed that acetyl chloride was produced in a yield of 90%.

Example 20: Production of propionyl chloride The reaction was carried out in the same manner as in Example 19 except that propionic acid (0.67 mL, 10 mmol) was used instead of acetic acid. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that propionyl chloride was produced (yield: 90%).

Example 21: Production of dichloroacetyl chloride The reaction was carried out in the same manner as in Example 19 except that dichloroacetic acid (0.82 mL, 10 mmol) was used instead of acetic acid and the reaction time was 2 hours. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that dichloroacetyl chloride was quantitatively produced.

Example 22: Production of acryloyl chloride The reaction was carried out in the same manner as in Example 19, except that acrylic acetic acid (0.69 mL, 10 mmol) was used instead of acetic acid and the reaction time was changed to 2 hours. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that acryloyl chloride was produced (yield: 14%).

Example 23: Production of maloyl chloride The reaction was carried out in the same manner as in Example 19, except that malonic acid (1.04 g, 10 mmol) was used instead of acetic acid and 2 mL (25 mmol) of DMF was used. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that maloyl chloride was produced (yield: 82%).

Example 24: Production of 4-nitrobenzoyl chloride The reaction was carried out in the same manner as in Example 19 except that 4-nitrobenzoic acid (1.04 mL, 10 mmol) was used instead of acetic acid. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that 4-nitrobenzoyl chloride was produced (yield: 83%).

Example 25: Production of 4-methoxybenzoyl chloride In the same manner as in Example 19, except that 4-methoxybenzoic acid (1.52 g, 10 mmol) was used instead of acetic acid and 3.2 mL (46 mmol) of DMF was used. The reaction was carried out. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that 4-methoxybenzoyl chloride was produced (yield: 89%).

Example 26: Production of 2-thiophenecarbonyl chloride In Example 19, 2-thiophenecarboxylic acid (1.28 g, 10 mmol) was used instead of acetic acid, 2 mL (25 mmol) of DMF was used, and the reaction time was 2 hours. The reaction was carried out in the same manner except for the following. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that 2-thiophenecarbonyl chloride was produced (yield: 93%).

Example 27: Production of 2-furancarbonyl chloride The reaction was carried out in the same manner as in Example 19, except that 2-furancarboxylic acid (1.12 g, 10 mmol) was used instead of acetic acid and the reaction time was 2 hours. Ta. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that 2-furancarbonyl chloride was quantitatively produced.

Example 28: Production of terephthalic acid dianilide Purified chloroform (20 mL, 248 mmol), DMF (2.4 mL, 30 mmol), and terephthalic acid (0.41 g, 2.5 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50°C, and the mixture was stirred until no bubbles were generated. The reaction solution was analyzed by ¹ H-NMR to confirm the production of terephthalic acid dichloride.
Aniline (3.56 mL, 40 mmol) was added to the above reaction solution at room temperature, and after stirring at room temperature for 10 hours, methanol was added at 0°C. The resulting white precipitate was filtered off to obtain terephthalic acid dianilide as a white powder (isolated yield: 24%).

Example 29: Production of phthalic anhydride Purified chloroform (20 mL, 248 mmol), DMF (0.8 mL, 10 mmol), and phthalic acid (1.66 g, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. The reaction solution was analyzed by ¹ H-NMR to confirm the production of phthalic anhydride. It is believed that in the above reaction, phthalic acid dichloride was once produced from phthalic acid, and then phthalic acid dichloride was further reacted with DMF to produce phthalic anhydride.

Example 30: Production of 2,2,2-trifluoropropionic acid chloride In Example 19, 2,2,2-trifluoropropionic acid (0.87 mL, 10 mmol) was used instead of acetic acid, and DMF was changed to 0. The reaction was carried out in the same manner except that 3 mL (4 mmol) was used, the reaction temperature was 20° C., and the reaction time was 2 hours. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that 2,2,2-trifluoropropionic acid chloride was quantitatively produced.

Example 31: Production of 4-fluorobenzoic acid chloride In Example 19, 4-fluorobenzoic acid (715 mg, 5 mmol) was used instead of acetic acid, 0.9 mL (11.6 mmol) of DMF was used, and the reaction temperature was changed to 20 The reaction was carried out in the same manner except that the temperature was 0.degree. C. and the reaction time was 2 hours. When the reaction solution was analyzed by ¹ H-NMR, it was confirmed that 4-fluorobenzoic acid chloride was quantitatively produced.

Example 32: Production of pentafluorobenzoic acid anilide Purified chloroform (20 mL, 248 mmol), DMF (0.4 mL, 5 mmol), and pentafluorobenzoic acid (1.06 g, 5 mmol) were added to the reaction vessel of Example 1. . While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50°C, and the mixture was stirred until no bubbles were generated.
Aniline (0.46 mL, 5 mmol) was added to the above reaction solution, and the mixture was stirred at room temperature for 3 hours. Then, a saturated aqueous sodium bicarbonate solution was added, the layers were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrate was subjected to silica gel column chromatography (eluent: mixed solvent of ethyl acetate/n-hexane = 1/3 (v/v)) to obtain pentafluorobenzoic acid anilide (isolated yield: 33%).

Example 33: Production of methyl formate Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 30 minutes.
The reaction solution was cooled to 0° C., methanol (0.81 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Next, the reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the layers were separated. The aqueous layer was extracted with chloroform, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Analysis of the concentrate by ¹ H-NMR confirmed the production of methyl formate (yield: 53%).

Example 34: Production of ethyl formate Ethyl formate was obtained in the same manner as in Example 33, except that ethanol (0.79 mL, 10 mmol) was used instead of methanol (yield: 88%).

Example 35: Production of isopropyl formate Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 15 minutes.
The reaction solution was cooled to 0° C., isopropanol (0.77 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Then, the reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution and stirred for 30 minutes. The reaction solution was separated, the aqueous layer was extracted with chloroform, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Analysis of the concentrate by ¹ H-NMR confirmed the production of isopropyl formate (yield: 28%).

Example 36: Production of isopropyl formate Isopropyl formate was obtained in the same manner as in Example 35, except that pyridine (1.6 mL, 20 mmol) was added dropwise at 0° C. in addition to isopropanol (yield: 51%).

Example 37: Production of phenyl formate Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 15 minutes.
The reaction solution was cooled to 0° C., phenol (0.94 g, 10 mmol) was added dropwise, and the mixture was stirred at room temperature for 6 hours. Then, the reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution and stirred for 30 minutes. The reaction solution was separated, the aqueous layer was extracted with chloroform, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Analysis of the concentrate by ¹ H-NMR confirmed the formation of phenyl formate (yield: 82%).

Example 38: Production of 2,2,2-trifluoroethanol formic acid Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 30 minutes.
The reaction solution was cooled to 0° C., 2,2,2-trifluoroethanol (0.94 g, 10 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. Then, the reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution and stirred for 30 minutes. The reaction solution was separated, the aqueous layer was extracted with chloroform, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that formic acid 2,2,2-trifluoroethanol was produced (yield: 67%).

Example 39: Production of 1,6-hexanediol diformate Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution and bubbling oxygen gas at a rate of 0.5 L/min, the reaction was carried out at 30° C. for 2 hours while irradiating light with the low-pressure mercury lamp. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50° C., and the mixture was stirred for 15 minutes.
The above reaction solution was cooled to 0° C., 1,6-hexanediol (0.59 g, 5 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution and stirred for 30 minutes. The reaction solution was separated, the aqueous layer was extracted with chloroform, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that 1,6-hexanediol diformate was produced (yield: 52%).

Example 40: Investigation of reaction temperature The reaction temperature during the preparation of the Vilsmeier reagent was investigated. Specifically, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution, the reaction was carried out for 6 hours while bubbling oxygen gas at a rate of 0.5 L/min, irradiating light with the low-pressure mercury lamp, and adjusting the temperature in the range of 0 to 30°C. Thereafter, stirring was stopped, and the reaction solution was separated into two layers. The upper layer was analyzed by ¹ H-NMR, and the conversion rate of DMF to Vilsmeier reagent was determined from the peak intensity. The results are shown in Table 1.

Example 41: Examination of the amount of amide compound The optimal amount of the amide compound when preparing the Vilsmeier reagent was examined. Specifically, purified chloroform (20 mL, 248 mmol) and DMF in the range of 0.78 to 4.68 mL (10 to 60 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution, the reaction was carried out for 5 to 27 hours while bubbling oxygen gas at a rate of 0.5 L/min, irradiating light with the low-pressure mercury lamp, and adjusting the temperature in the range of 0 to 30 ° C. . Thereafter, stirring was stopped, and the reaction solution was separated into two layers. The upper layer was analyzed by ¹ H-NMR, and the conversion rate of DMF to Vilsmeier reagent was determined from the peak intensity. The results are shown in Table 2.

As shown in Tables 1 and 2, it was observed that the production efficiency of the Vilsmeier reagent tended to increase by reducing the amount of DMF relative to chloroform and by setting the reaction temperature relatively low. Furthermore, when the reaction temperature was low, it was observed that harmful halogen compound gas tended to be difficult to leak out of the reaction system.

Example 42: Production of 2-formylfuran Purified chloroform (20 mL, 248 mmol) and DMF (0.78 mL, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution, the reaction was carried out at 0° C. for 6 hours while bubbling oxygen gas at a rate of 0.5 L/min and irradiating light with the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50°C and stirred for 1 hour. Thereafter, the reaction container was immersed in an ice bath, furan (0.73 mL, 10 mmol) dissolved in acetone (3 mL) was added dropwise, and the mixture was stirred at 20° C. for 2 hours. Then, saturated aqueous sodium carbonate solution (15 mL) was added and stirred for 15 minutes. The reaction solution was separated into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layer and extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that the target compound, 2-formylfuran, was produced even though a solvent was used (yield: 30%).

Example 43: Production of 2-formylfuran Purified chloroform (20 mL, 248 mmol) and DMF (0.78 mL, 10 mmol) were added to the reaction vessel of Example 1. While stirring the mixed solution, the reaction was carried out at 0° C. for 6 hours while bubbling oxygen gas at a rate of 0.5 L/min and irradiating light with the low-pressure mercury lamp. Subsequently, the reaction temperature was raised to 50°C and stirred for 1 hour. Thereafter, the reaction vessel was immersed in an ice bath, furan (0.73 mL, 10 mmol) dissolved in acetonitrile (3 mL) was added dropwise, and the mixture was stirred at 20° C. for 2 hours. Then, saturated aqueous sodium carbonate solution (15 mL) was added and stirred for 15 minutes. The reaction solution was separated into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layer and extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed by ¹ H-NMR, it was confirmed that the target compound, 2-formylfuran, was produced even when acetonitrile was used as a solvent (yield: 48%).

1: Light irradiation means, 2: Jacket, 3: Water bath 4: Stirrer, 5: Heat medium or coolant, 6: Cylindrical reaction vessel

Claims (9)

A method for producing a Vilsmeier reagent, the method comprising:
The Vilsmeier reagent is a salt represented by the following formula (I),

[In the formula,
R ¹ represents a hydrogen atom, a C _1-6 alkyl group, or a C _6-12 aromatic hydrocarbon group which may have a substituent,
R ² and R ³ independently represent a C _1-6 alkyl group or a C _6-12 aromatic hydrocarbon group which may have a substituent, and R ² and R ³ together represent may form a 4- to 7-membered ring structure,
X represents chloro ;
Y ^- represents a chloride ion . ]
A step of decomposing the C _1-4 halogenated hydrocarbon by irradiating a composition containing the C _1-4 halogenated hydrocarbon having a chloro group with light in the presence of oxygen, and
A method comprising the step of reacting a decomposition product of a C _1-4 halogenated hydrocarbon with an amide compound represented by the following formula (II).

[In the formula, R ¹ to R ³ have the same meanings as above. ] The method according to claim 1, wherein the light includes light with a wavelength of 180 nm or more and 280 nm or less. The method according to claim 1 or 2, wherein a C _1-4 polyhalogenated hydrocarbon having two or more chloro groups is used as the C _1-4 halogenated hydrocarbon. Claims 1 to 3, wherein a composition containing a C _1-4 halogenated hydrocarbon and an amide compound is irradiated with light in the presence of oxygen, and a step of decomposing the C _1-4 halogenated hydrocarbon and a step of reacting with the amide compound are carried out simultaneously. 3. The method described in any one of 3. 5. The method according to claim 1, wherein N,N-dimethylformamide is used as the amide compound represented by formula (II). The method according to any one of claims 1 to 5, wherein the C _1-4 halogenated hydrocarbon is used in an amount of at least 5 times the molar amount of the amide compound represented by formula (II). A method for producing aromatic aldehydes or aromatic ketones, the method comprising:
A step of producing a Vilsmeier reagent by the method according to any one of claims 1 to 6, and
A method comprising the step of reacting the Vilsmeier reagent with an aromatic compound having an active group. A method for producing a carboxylic acid halide, the method comprising:
A step of producing a Vilsmeier reagent by the method according to any one of claims 1 to 6, and
A method comprising the step of converting the carboxy group of the carboxylic acid compound into a haloformyl group by reacting the Vilsmeier reagent with a carboxylic acid compound represented by the following formula (III).
R ⁴ -(CO ₂ H) _n (III)
[In the formula, R ⁴ represents an n-valent organic group, and n represents an integer of 1 or more and 4 or less. ] A method for producing a formic acid ester, the method comprising:
A step of producing a Vilsmeier reagent by the method according to any one of claims 1 to 6, and
A method comprising the step of reacting the Vilsmeier reagent with a hydroxyl group-containing compound.