WO2020050368A1 - Method for preparing vilsmeier reagent - Google Patents

Method for preparing vilsmeier reagent Download PDF

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WO2020050368A1
WO2020050368A1 PCT/JP2019/035031 JP2019035031W WO2020050368A1 WO 2020050368 A1 WO2020050368 A1 WO 2020050368A1 JP 2019035031 W JP2019035031 W JP 2019035031W WO 2020050368 A1 WO2020050368 A1 WO 2020050368A1
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reaction
group
vilsmeier reagent
mmol
halogenated hydrocarbon
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PCT/JP2019/035031
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French (fr)
Japanese (ja)
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明彦 津田
岡添　隆
和田　明宏
森　信明
小西　克彦
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国立大学法人神戸大学
Ａｇｃ株式会社
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Priority to JP2020541302A priority Critical patent/JP7344518B2/en
Publication of WO2020050368A1 publication Critical patent/WO2020050368A1/en

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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention provides a method for producing a Vilsmeier reagent that can be carried out safely and simply at low cost, and the production of an aromatic aldehyde or an aromatic ketone, a carboxylic acid halide, and a formate using the Vilsmeier reagent. How to do it.
  • the Vilsmeier reagents are electrophiles that cause addition reactions to electron-rich alkenes and aromatic rings, for example, for the formylation of aromatic compounds with active groups and the conversion of carboxy groups to haloformyl groups. Is done.
  • the Vilsmeier reagent is generally formed from a chlorinating agent such as phosgene, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and an amide compound (Patent Document 1).
  • chlorinating agents are very toxic, and some produce toxic and corrosive gases on contact with water, making them difficult to store and dangerous to handle.
  • phosgene has a history of being used as a suffocating poisonous gas, and has a risk of death or the like due to inhalation during use.
  • Chlorinating agents other than phosgene are also corrosive, such as thionyl chloride, which produces sulfur dioxide and hydrogen chloride as by-products, and is expensive to treat.
  • Patent Document 2 discloses a method for producing a Vilsmeier reagent using phthalic acid dichloride which is safer as a chlorinating agent.
  • phthalic dichloride increases costs.
  • this method since phthalic anhydride is by-produced, a high cost is required for the purification process of the target compound.
  • Patent Document 3 a method for producing a urea derivative or a carbonate derivative by blowing a decomposition product generated by light irradiation on chloroform or the like in the presence of oxygen into an amine solution or a phenol solution has been developed.
  • 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.
  • the present invention provides a method for producing a Vilsmeier reagent that is safe and simple and can be carried out at low cost, and an aromatic aldehyde or aromatic ketone, a carboxylic acid halide, and a formate ester using the Vilsmeier reagent. It is intended to provide a method of manufacturing.
  • the present inventors have intensively studied to solve the above problems. As a result, they have found 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.
  • 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.
  • the Vilsmeier reagent is a salt represented by the following formula (I): [Where, 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 And may form a ring structure of 4 to 7 members, X represents a halogeno group selected from the group consisting of chloro, bromo and iodo, Y - represents a counter anion.
  • [7] A method for producing an aromatic aldehyde or an aromatic ketone, A step of producing a Vilsmeier reagent by the method according to any one of the above [1] to [6], and Reacting the Vilsmeier reagent with an aromatic compound having an active group.
  • a method for producing a carboxylic acid halide A step of producing a Vilsmeier reagent by the method according to any one of the above [1] to [6], and A method comprising reacting the Vilsmeier reagent with a carboxylic acid compound represented by the following formula (III) to convert a carboxy group of the carboxylic acid compound into a haloformyl group.
  • R 4 - (CO 2 H) n (III) [Wherein, 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 formate ester A step of producing a Vilsmeier reagent by the method according to any one of the above [1] to [6], and Reacting the Vilsmeier reagent with a hydroxyl group-containing compound.
  • a highly reactive and useful Vilsmeier reagent is used in place of a dangerous compound such as phosgene, and a halogenated hydrocarbon which is also used as a general-purpose solvent. Can be manufactured. At this time, only carbon dioxide and hydrogen chloride are by-produced, and since they can be discharged out of the system as gas, purification is not required in principle. It is also possible to produce an aromatic aldehyde or aromatic ketone, a carboxylic acid halide, and a formate 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 ketones, carboxylic acid halides, and formate.
  • FIG. 1 is a schematic diagram illustrating an example of a configuration of a reaction device used in the present invention.
  • the C 1-4 halogenated hydrocarbon used in the present invention is a hydrocarbon having 1 to 4 carbon atoms and having at least one halogeno group selected from a 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 further attacked by halide ions. It is believed that a Vilsmeier reagent is formed. Even if a harmful carbonyl halide is formed, the carbonyl halide reacts immediately with the amide compound due to its extremely high reactivity, and does not leak out of the reaction solution. It is believed that there is.
  • the present invention is a technique for producing a useful compound by photodecomposing a C 1-4 halogenated hydrocarbon, and greatly contributes industrially and environmentally.
  • the C1-4 halogenated hydrocarbon is an alkane, alkene or alkyne having 1 or more and 4 or less carbon atoms substituted with one or more halogeno groups selected from the group consisting essentially of chloro, bromo and iodo. .
  • the C 1-4 halogenated hydrocarbon is considered to be decomposed by the irradiation light and oxygen and to perform the same function as the carbonyl halide.
  • C 1-2 halogenated hydrocarbons are preferred, and halogenomethane is more preferred.
  • alkene or alkyne having one or more unsaturated bonds is preferable so that the decomposition proceeds more easily.
  • a C 1-4 polyhalogenated hydrocarbon having two or more halogeno groups is preferable, and a C 1-2 polyhalogenated hydrocarbon is more preferable.
  • the halogeno group may be transferred with the decomposition, a C 1-4 halogenated hydrocarbon having two or more halogeno groups on the same carbon is preferable.
  • Specific C 1-4 halogenated hydrocarbons include, for example, halomethanes such as dichloromethane, chloroform, dibromomethane, bromoform, iodomethane, diiodomethane; 1,1,2-trichloroethane, 1,1,1-trichloroethane, Haloethanes such as 1,2,2-tetrachloroethane and 1,1,1,2-tetrachloroethane; halopropanes such as 1,1,1,3-tetrachloropropane; tetrachloromethane, tetrabromomethane, tetraiodomethane, Perhaloalkanes such as hexachloroethane and hexabromoethane; and perhaloethenes such as 1,1,2,2-tetrachloroethene and 1,1,2,2-tetrabromoethene.
  • halomethanes such as dich
  • the C1-4 halogenated hydrocarbon may be appropriately selected according to the intended chemical reaction or the desired product, and may be used alone or in combination of two or more. May be. Preferably, only one C 1-4 halogenated hydrocarbon is used depending on the production target compound. Any C 1-4 halogenated hydrocarbon that is liquid at normal pressure or normal temperature or at the reaction temperature can also serve as a solvent. Among the 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 inexpensive chloroform which is also used as a general-purpose solvent is most preferable.
  • a C 1-4 halogenated hydrocarbon once used as a solvent may be recovered and reused.
  • the reaction may be inhibited, so that it is preferable to purify to some extent.
  • the reaction is considered to proceed even if about 1% by volume of water is contained, it is not necessary to perform excessive purification that lowers the productivity.
  • the water content is more preferably 0.5% by volume or less, still more preferably 0.2% by volume or less, and even more preferably 0.1% by volume or less.
  • the recycled C 1-4 halogenated hydrocarbon may include 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 in which the amide compound can be sufficiently converted into the Vilsmeier reagent.
  • the upper limit of the use amount of the C 1-4 halogenated hydrocarbon is not particularly limited, but may be, for example, 200 times or less the molar amount of the amide compound.
  • the amount used is preferably 1-fold or more, 5-fold or more, or 10-fold or more, more preferably 20-fold or more, and even more preferably 25-fold or more. According to the experimental findings by the present inventors, it is observed that the smaller the amount of the amide compound relative to the C 1-4 halogenated hydrocarbon, the higher the production efficiency of the Vilsmeier reagent.
  • a C 1-4 halogenated hydrocarbon When a C 1-4 halogenated hydrocarbon can be used as a solvent, it can be used in an amount of 50 times or more. The amount used is preferably 150 times or less or 100 times or less. The specific amount of the C 1-4 halogenated hydrocarbon to be used may be determined by a preliminary experiment or the like.
  • the oxygen source may be any gas containing oxygen, and for example, air or purified oxygen can be used.
  • the purified oxygen may be used by mixing with an inert gas such as nitrogen or argon. Air can be used in terms of cost and ease.
  • 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. It is also preferable to use substantially only oxygen other than the inevitable impurities.
  • the oxygen content may be appropriately determined depending on the type of the above-mentioned C 1-4 halogenated hydrocarbon or the like.
  • the oxygen content is preferably 15% by volume or more and 100% by volume or less
  • the oxygen content is preferably 90% by volume or more and 100% by volume or less. Note that even when oxygen (oxygen content 100 vol%) is used, the oxygen content can be controlled within the above range by adjusting the flow rate of oxygen into the reaction system.
  • the method for supplying the gas containing oxygen is not particularly limited, and the gas may be supplied into the reaction system from an oxygen cylinder equipped with a flow controller, or may be supplied from the oxygen generator into the reaction system.
  • the reaction according to the present invention may be performed under a gas stream of a gas containing oxygen, but from the viewpoint of increasing the yield of a product, the gas containing oxygen may be supplied into the composition by bubbling. preferable.
  • the amount of the gas containing oxygen may be appropriately determined according to the amount of the C 1-4 halogenated hydrocarbon, the shape of the reaction vessel, and the like.
  • the amount of gas per minute supplied to the reaction vessel with respect to the C 1-4 halogenated hydrocarbon present in the reaction vessel is preferably 5 times or more.
  • the ratio is more preferably 25 times or more, and even more preferably 50 times or more.
  • the upper limit of the ratio is not particularly limited, it is preferably 500 times or less, more preferably 250 times or less, and even more preferably 150 times or less.
  • the amount of oxygen per minute supplied to the reaction vessel with respect to the C 1-4 halogenated hydrocarbon present in the reaction vessel can be 5 times or more and 25 times or less. If the flow rate of the gas is too large, the C 1-4 halogenated hydrocarbon may be volatilized, while if it is too small, the reaction may not easily proceed.
  • a solvent may be added to the composition containing a C 1-4 halogenated hydrocarbon.
  • C 1-4 halogenated hydrocarbon is not liquid at room temperature and atmospheric pressure, C 1-4 can appropriately dissolve the halogenated hydrocarbon, solvent is that and does not inhibit the decomposition of the C 1-4 halogenated hydrocarbons preferable.
  • a solvent examples 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; ethers such as diethyl ether, tetrahydrofuran, and dioxane.
  • 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
  • ethers such as diethyl ether, tetrahydrofuran, and dioxane.
  • System solvent Nitrile solvents such as acetonitrile can be mentioned.
  • the light irradiated to the mixture is preferably light containing short-wavelength light, more preferably light containing ultraviolet light, more specifically light containing light having a wavelength of 180 nm or more and 500 nm or less, and has a peak wavelength of 180 nm or more and 500 nm.
  • Light included in the following range is more preferable.
  • the wavelength of the light may be appropriately determined according to the type of the C 1-4 halogenated hydrocarbon, but is preferably 400 nm or less, more preferably 300 nm or less. When the irradiation light contains light in the above wavelength range, the C 1-4 halogenated hydrocarbon can be efficiently oxidatively photodecomposed.
  • high-energy light including UV-B having a wavelength of 280 to 315 nm and / or UV-C having a wavelength of 180 to 280 nm can be used, and high-energy light including UV-C having a wavelength of 180 to 280 nm can be used. Is preferred. Further, light having a peak wavelength in the range of 280 nm to 315 nm and / or 180 nm to 280 nm is preferable, and light having a peak wavelength in the range of 180 nm to 280 nm is more preferable.
  • the light irradiation means is not particularly limited as long as it can irradiate the light of the above-mentioned wavelength.
  • Examples of the light source including light of such a wavelength range in a wavelength range include, for example, sunlight, a low-pressure mercury lamp, and a medium-pressure mercury. Lamps, high-pressure mercury lamps, ultra-high-pressure mercury lamps, chemical lamps, black light lamps, metal halide lamps, halogen lamps, incandescent lamps and the like. From the viewpoint of reaction efficiency and cost, a low-pressure mercury lamp is preferably used.
  • Conditions such as the intensity of irradiation light and irradiation time may be appropriately set depending on the type and amount of starting material used.
  • a desired light intensity at the shortest distance position of the composition from a light source is 10 mW / cm 2. It is preferably at least 500 mW / cm 2 .
  • the shortest distance between the light source and the halogenated methane is preferably 1 m or less, more preferably 50 cm or less, 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.
  • the shortest distance When light is irradiated from the side of the reaction vessel, the shortest distance may be 1 cm or more or 2 cm or more.
  • the light irradiation time is preferably from 0.5 to 10 hours, more preferably from 1 to 6 hours, even more preferably from 2 to 4 hours.
  • the mode of light irradiation is also not particularly limited, such as a mode in which light is continuously irradiated from the start to the end of the reaction, a mode in which light irradiation and non-irradiation are alternately repeated, and a mode in which light is irradiated only for a predetermined time from the start of the reaction. Either mode can be adopted, but a mode in which light is continuously irradiated from the start to the end of the reaction is preferable.
  • the temperature at which the C 1-4 halogenated hydrocarbon is decomposed is not particularly limited, and may be appropriately adjusted.
  • the temperature may be set to ⁇ 20 ° C. or more and 60 ° C. or less.
  • the temperature is more preferably ⁇ 10 ° C. or higher, still more preferably 0 ° C. or higher or 10 ° C. or higher, and is more preferably 50 ° C. or lower or 40 ° C. or lower, even more preferably 30 ° C. or lower.
  • the reaction may be performed at room temperature without controlling the temperature.
  • the reaction temperature is preferably 10 ° C or lower, more preferably 5 ° C or lower.
  • the reaction may be continued at 10 ° C. or higher and 60 ° C. or lower for 1 minute to 5 hours under general light such as a fluorescent lamp without irradiation of high energy light.
  • the decomposition product of the C 1-4 halogenated hydrocarbon is reacted with the amide compound represented by the formula (II).
  • Step of the reaction with the amide compound may be carried out simultaneously with the decomposition process of the C 1-4 halogenated hydrocarbons, may be performed after the decomposition step of C 1-4 halogenated hydrocarbons.
  • the amide compound may be added to the composition containing the C 1-4 halogenated hydrocarbon.
  • the composition containing a C 1-4 halogenated hydrocarbon may be irradiated with light, and the amide compound may be added while the light 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.
  • the C 1-4 halogenated hydrocarbon is decomposed by light irradiation, and then light irradiation, particularly of high energy light Irradiation may be stopped and an amide compound may be added.
  • this embodiment allows the decomposition of the C 1-4 halogenated hydrocarbon and the reaction with the amide compound to be performed efficiently.
  • this embodiment is particularly suitable for implementing the present invention with a large capacity.
  • amide compound (II) an amide compound represented by the following formula (II) is preferable.
  • the compound represented by the formula (II) may be abbreviated as “amide compound (II)”.
  • 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
  • R 2 and R 3 represent Independently represents a C 1-6 alkyl group or a C 6-12 aromatic hydrocarbon group which may have a substituent
  • R 2 and R 3 together form a 4-membered or more It may form a ring structure of less than or equal to member.
  • C 1-6 alkyl group refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms.
  • it is a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and most preferably methyl.
  • the “C 6-12 aromatic hydrocarbon group” refers to a monovalent aromatic hydrocarbon group having 6 to 12 carbon atoms.
  • phenyl, naphthyl, indenyl and 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, and examples thereof include 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 substituents selected may be mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but may be, for example, from 1 to 5, preferably 3 or less, more preferably 2 or less, and still more preferably 1. When the number of substituents is 2 or more, the substituents may be the same or different.
  • C 1-6 alkoxy group refers to a linear or branched aliphatic hydrocarbonoxy group having 1 to 6 carbon atoms.
  • 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 alkoxy group -2 alkoxy group, more preferably methoxy.
  • halogeno group as the substituent for the C 6-12 aromatic hydrocarbon group may be chloro, bromo, iodo or fluoro.
  • 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.
  • amide compound (II) examples include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-N-phenylformamide, N-methylpyrrolidone (NMP), Examples thereof include 1,3-dimethylimidazolidinone (DMI), tetramethyl urea, tetraethyl urea, and tetrabutyl urea, and DMF is preferred from the viewpoint of versatility and cost.
  • the composition containing the C 1-4 halogenated hydrocarbon and the amide compound is irradiated with light in the presence of oxygen.
  • chloroform which is available at a low cost is most preferable.
  • the manner of mixing the C 1-4 halogenated hydrocarbon and the amide compound is not particularly limited.
  • the entire amount of each compound may be mixed in advance, added in several portions, or added continuously at an arbitrary rate.
  • a solvent that can appropriately dissolve these starting compounds and does not inhibit the reaction of the present invention may be used.
  • examples of such a solvent 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 not particularly limited, and may be appropriately adjusted.
  • the temperature may be -20 ° C or higher and 60 ° C or lower.
  • the temperature is more preferably ⁇ 10 ° C. or more, still more preferably 0 ° C. or more, more preferably 50 ° C. or less or 40 ° C. or less, and even more preferably 30 ° C. or less.
  • the reaction may be performed at room temperature without controlling the temperature.
  • the reaction temperature is preferably 10 ° C or lower, more preferably 5 ° C or lower.
  • FIG. 1 shows one embodiment of a reactor 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 in a tubular reaction vessel 6.
  • the above-mentioned each raw material compound is added into the cylindrical reaction vessel 6, and light is irradiated 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 performed by irradiating light from the means 1.
  • the jacket is preferably made of a material that transmits the short-wavelength light.
  • Light irradiation may be performed from the outside of the reaction vessel.
  • the reaction vessel 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 the effect of the present invention is not impaired, but quartz glass is preferably exemplified.
  • the resulting Vilsmeier reagent is a salt represented by the following formula (I).
  • R 1 to R 3 have the same meanings as described above, X represents a halogeno group selected from the group consisting of chloro, bromo and iodo, and Y ⁇ represents a counter anion. ]
  • Examples of Y ⁇ in formula (I) include, but are not particularly limited to, chloride ions, bromide ions, and iodide ions derived from C 1-4 halogenated hydrocarbons.
  • a compound in which X is chloro and Y - is a chloride ion is preferable from the viewpoint of availability.
  • a compound capable of reacting with the Vilsmeier reagent By further adding a compound capable of reacting with the Vilsmeier reagent to the reaction solution containing the Vilsmeier reagent, it is possible to cause a further reaction to proceed in the same system.
  • a compound capable of reacting with the Vilsmeier reagent can be converted into an aldehyde or a ketone using a Vilsmeier reagent.
  • Such a reaction is known as the Vilsmeier-Haack reaction.
  • the Vilsmeier reagent converts a carboxy group of a carboxylic acid compound into a haloformyl group.
  • a formic ester is obtained by reacting a hydroxyl group-containing compound with a Vilsmeier reagent.
  • An aromatic compound having an active group is an aromatic compound activated by a substituent or the like.
  • an amino group containing an alkylamino group substituted with an alkyl group or a hydroxyl group strongly activates an aromatic compound.
  • these substituents are referred to as activating groups.
  • compounds such as anthracene in which an aromatic ring is condensed and a conjugated system is expanded, are also activated, and are subjected to aldehyde or ketone formation by a Vilsmeier reagent. It is considered that the ⁇ electron at the activated site is electrophilically reacted with the Vilsmeier reagent, and is converted into an aldehyde or a ketone.
  • the active aromatic compound is not particularly limited as long as it is activated and can be aldehyde or ketonized by the Vilsmeier reagent.
  • C 1-10 such as benzene or naphthalene substituted by the activating group can be used.
  • the amount of the active aromatic compound to be used may be appropriately adjusted, and may be, for example, 0.1 to 1.0 times the mol of the amide compound.
  • the reaction conditions for aldehyde conversion or ketonization may be determined appropriately.
  • the active aromatic compound may be added to the reaction solution after confirming consumption of the amide compound and formation 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.
  • 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.
  • reaction conditions for the aldehyde or ketonization may be appropriately adjusted.
  • the reaction temperature may be -10 ° C. or higher, including the temperature at the time of addition of the active aromatic compound, and the heating and reflux conditions may be employed.
  • the heating and reflux conditions may be employed.
  • R 1 is a hydrogen atom
  • an aromatic aldehyde is obtained
  • R 1 is an alkyl group or an aromatic hydrocarbon group
  • an aromatic ketone is obtained.
  • a saturated sodium carbonate aqueous solution or a saturated sodium bicarbonate aqueous solution is added to the reaction solution after the reaction to stop the reaction, liquid separation is performed, the aqueous layer is extracted with an organic solvent, and the organic layer and the extract are combined to obtain anhydrous sodium sulfate.
  • the target compound, an aromatic aldehyde or aromatic ketone may be purified by a conventional method such as recrystallization, silica gel column chromatography, or distillation.
  • the carboxylic acid compound When the carboxy group of the carboxylic acid compound is converted to a haloformyl group by the Vilsmeier reagent, the carboxylic acid compound may be added to the composition containing the C 1-4 halogenated hydrocarbon and the amide compound before light irradiation. Then, the carboxylic acid compound may be added intermittently or continuously at appropriate times before the light irradiation, during the light irradiation, and 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 to a haloformyl group after the step of producing the Vilsmeier reagent may be performed, or both steps may be performed simultaneously.
  • Examples of the carboxylic acid compound converting a carboxy group to a haloformyl group include a compound represented by the following formula (III).
  • R 4 - (CO 2 H) n (III) [Wherein, 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.
  • Examples thereof include a C 1-18 hydrocarbon group which may have a substituent and the above-mentioned heteroaryl group which may have a substituent. it can.
  • 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.
  • 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 2-18 hydrocarbon group.
  • Hydrocarbon groups corresponding to those having a valence of 4 or more and 4 or less can be mentioned.
  • one or more carbon atoms are —O—, —S—, —NR 5 — (R 5 is a hydrogen atom or And a hetero atom 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. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, and chlorohexane.
  • Halogenated hydrocarbon solvents such as benzene, toluene, chlorobenzene and the like; and ether solvents such as diethyl ether, tetrahydrofuran and dioxane.
  • the amount of the carboxylic acid compound to be used may be appropriately adjusted, and may be, for example, 0.1 to 3.0 times the mol of the amide compound.
  • the conditions for the reaction for converting a carboxy group to a haloformyl group may be determined as appropriate.
  • the reaction temperature can be from 0 ° C. to 50 ° C.
  • the reaction time can be from 10 minutes to 20 hours.
  • Carboxylic acid halides are often highly reactive and unstable, so isolation may be difficult. Therefore, after the reaction of the Vilsmeier reagent 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, a usual post-treatment may be performed, or the target compound may be purified by a conventional method.
  • a compound to be reacted with the carboxylic acid halide such as an alcohol compound or an amine compound
  • the hydroxyl group-containing compound When a formic 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 the amide compound before light irradiation.
  • the hydroxyl group-containing compound may be added intermittently or continuously as appropriate before or after the light irradiation, after the light irradiation, and 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 step of producing the Vilsmeier reagent, or both steps may be performed simultaneously.
  • the hydroxyl group-containing compound may be added as it 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. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, and chlorohexane.
  • Halogenated hydrocarbon solvents such as acetonitrile; ether solvents such as diethyl ether, tetrahydrofuran and dioxane.
  • the hydroxyl group-containing compound is not particularly limited as long as it has at least one reactive hydroxyl group, and examples thereof include an alcohol compound and a phenol compound.
  • Examples of the alcohol compound include C 1-20 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, t-butanol, n-pentanol and isopentanol; 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 thereof include diol compounds such as diol and 1,6-hexanediol; triol compounds such as glycerin; and tetraol compounds such as pentaerythritol.
  • C 1-20 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butan
  • phenol compound examples include monohydric phenol compounds such as phenol, naphthol, cresol, butylphenol, amylphenol, chlorophenol, and bromophenol; catechol, bisphenol AG, bisphenol M, bisphenol S, bisphenol P, bisphenol Z, and the like. Dihydric phenol compounds; trihydric phenol compounds such as trihydroxybenzene can be exemplified.
  • the amount of the hydroxyl group-containing compound used may be appropriately adjusted.
  • the amount of the hydroxyl group-containing compound having one hydroxyl group may be 0.1 to 3.0 times the amide compound. it can.
  • the amount of the hydroxyl group-containing compound having m hydroxyl groups may be adjusted using 1 / m of the amount of the hydroxyl group-containing compound having one hydroxyl group as a guide.
  • the reaction conditions of the Vilsmeier reagent and the hydroxyl group-containing compound may be determined as appropriate.
  • the reaction temperature can be from -10 ° C to 50 ° C, and the reaction time can be from 10 minutes to 20 hours.
  • a saturated sodium carbonate aqueous solution or a saturated sodium bicarbonate aqueous solution is added to the reaction solution after the reaction to stop the reaction, liquid separation is performed, the aqueous layer is extracted with an organic solvent, and the organic layer and the extract are combined to obtain anhydrous sodium sulfate.
  • the formic ester as the target compound may be purified by a conventional method such as recrystallization, silica gel column chromatography, or distillation.
  • Example 1 Production of Vilsmeier Reagent
  • a tubular reaction vessel (diameter 42 mm) equipped with a quartz glass jacket having 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 provided in the quartz glass jacket. , ⁇ 24 ⁇ 120 mm), and purified chloroform (20 mL, 248 mmol) and DMF (1.55 mL, 20 mmol) were added into the reaction vessel.
  • the reaction was carried out at a temperature of 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution.
  • the ratio of residual DMF to the Vilsmeier reagent in the upper layer was about 1: 4 from the peak intensity, and it was estimated that a maximum of 16 mmol of the Vilsmeier reagent was generated.
  • 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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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, pyrrole (0.74 mL, 10 mmol) was added, and the mixture was heated under reflux for 30 minutes.
  • Example 3 Production of 1-methyl-2-pyrrolecarboxaldehyde
  • a chloroform solution (5 mL) of 1-methylpyrrole (0.74 mL, 10 mmol) was used instead of pyrrole, and the aqueous layer was extracted with dichloromethane.
  • a concentrate was obtained in the same manner except that the above procedure was performed.
  • the concentrate was analyzed by 1 H-NMR, it was possible to confirm the formation of 1-methyl-2-pyrrolecarboxaldehyde as a target compound (yield> 99%).
  • Example 4 Production of 2-formylfuran
  • furan (0.73 mL, 10 mmol) was used instead of pyrrole, and after adding furan, the reaction was allowed to proceed at 0 ° C for 30 minutes, and then at room temperature for 2 hours. Then, 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, formation of 2-formylfuran as a target compound could be confirmed (yield: 60%). As described above, no formylation of unsubstituted furan with the Vilsmeier reagent has been reported, but it has been demonstrated that the present invention allows formylation of unsubstituted furan.
  • Example 5 Production of 5-methylfurfural A cylindrical reaction vessel (diameter 42 mm) equipped with a quartz glass jacket having a diameter of 30 mm in the center was prepared, and a low-pressure mercury lamp (manufactured by SEN Light, UVL20PH-6, 20 W, ⁇ 24 ⁇ 120 mm), and purified chloroform (20 mL, 248 mmol) and DMF (3.5 mL, 45 mmol) were added into the reaction vessel. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution.
  • a low-pressure mercury lamp manufactured by SEN Light, UVL20PH-6, 20 W, ⁇ 24 ⁇ 120 mm
  • purified chloroform 20 mL, 248 mmol
  • DMF 3.5 mL, 45 mmol
  • 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, a saturated aqueous solution of sodium carbonate (30 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution separated into two layers was separated, and the aqueous layer was extracted with ethyl acetate. 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, the formation of 5-methylfurfural, which was the target compound, could be confirmed (yield: 80%).
  • Example 6 Production of 2-formylthiophene Purified chloroform (20 mL, 248 mmol) and DMF (1.2 mL, 15 mmol) were added into the reaction vessel of Example 1. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 refluxed for 6 hours.
  • reaction solution was added to a saturated aqueous sodium carbonate solution (30 mL) at 0 ° C., and the mixture was stirred for 30 minutes. Chloroform was added to the reaction solution, the reaction solution separated into two layers was separated, and 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, formation of 2-formylthiophene as a target compound could be confirmed (yield: 61%). As described above, formylation of unsubstituted thiophene with the Vilsmeier reagent has not been reported, but it has been demonstrated that formalization 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. When the concentrate was analyzed by 1 H-NMR, the formation of 5-methyl-2-formylthiophene as the target compound could be confirmed (yield: 56%).
  • Example 8 Preparation of 2-formyl-3-methylthiophene or 2-formyl-4-methylthiophene
  • 3-methylthiophene (0.97 mL, 10 mmol) was used instead of pyrrole to obtain 3-methylthiophene.
  • the heating and refluxing time after the dropwise addition was changed to 2 hours.
  • the yield of 2-formyl-3-methylthiophene was 74%
  • the yield of 2-formyl-4-methylthiophene was 16%.
  • Example 9 Preparation of 2-formyl-3-methylthiophene or 2-formyl-4-methylthiophene Same as Example 8 except that 1-pyrrolidinecarboxaldehyde (1.98 mL, 20 mmol) was used instead of DMF. To give a concentrate. 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
  • a reaction solution containing a Vilsmeier 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. Further, a 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 separated into two layers was separated, and the aqueous layer was extracted with diethyl ether.
  • the organic layer and the extract were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 11 Photoformylation reaction of bipyrrole derivative Purified chloroform (20 mL, 248 mmol) and DMF (0.56 mL, 7.23 mmol) were added into the reaction vessel of Example 1. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 30 minutes.
  • Example 12 Production of bis (pyrrole-2-carboxaldehyde) Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.15 mL, 14.9 mmol) were added. The reaction was carried out at 10 ° C. for 6 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 30 minutes. Thereafter, the reaction vessel was immersed in an ice bath, bipyrrole (420 mg, 3.18 mmol) was added, and the mixture was heated under reflux for 30 minutes.
  • bipyrrole 420 mg, 3.18 mmol
  • 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. The reaction was carried out at 0 ° C. for 5 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to room temperature, benzofuran (1.0 mL, 9 mmol) was added, and the mixture was stirred at 70 ° C. for 30 minutes, and further heated under reflux for 20 hours. Then, a saturated aqueous sodium carbonate solution (20 mL) was added, and the mixture was stirred for 15 minutes.
  • benzofuran 1.0 mL, 9 mmol
  • 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. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 30 minutes. Thereafter, pyrrole (0.7 mL, 10 mmol) was added, and the mixture was heated under reflux for 30 minutes.
  • 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. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the light irradiation was stopped, and the mixture was stirred at 30 ° C. for 30 minutes. Thereafter, pyrrole (0.7 mL, 10 mmol) was added, and the mixture was stirred overnight. Next, the resulting insoluble salts were removed by suction filtration, and the filtrate was concentrated under reduced pressure to obtain the desired 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 into the reaction vessel of Example 1. The reaction was carried out at 10 ° C. for 3 hours while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while stirring the mixed solution. 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 due to the fact that the Vilsmeier reagent was not generated because no amide compound was used.
  • Example 16 Production of benzoyl chloride and amidation thereof Into the reaction vessel of Example 1, purified chloroform (30 mL, 372 mmol), DMF (0.4 mL, 5 mmol) and benzoic acid (1.22 g, 10 mmol) were added. The reaction was carried out at 10 ° C. for 3 hours while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, benzoyl chloride was produced in a yield of 95%.
  • Example 17 Production of benzoyl chloride Into the reaction vessel of Example 1, purified chloroform (30 mL, 372 mmol), DMF (0.4 mL, 5 mmol) and benzoic acid (1.22 g, 10 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, benzoyl chloride was quantitatively formed.
  • 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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, benzoyl chloride was produced in a yield of 8.5%.
  • Example 19 Production of acetyl chloride Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol), DMF (0.4 mL, 5 mmol) and acetic acid (0.57 mL, 10 mmol) were added. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, 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, formation of propionyl chloride was confirmed (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 changed to 2 hours. When the reaction solution was analyzed by 1 H-NMR, it was confirmed that dichloroacetyl chloride was generated quantitatively.
  • Example 22 Production of acryloyl chloride The reaction was carried out in the same manner as in Example 19, except that acrylacetic 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, formation of acryloyl chloride was confirmed (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, formation of maloyl chloride was confirmed (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, formation of 4-nitrobenzoyl chloride was confirmed (yield: 83%).
  • Example 25 Preparation of 4-methoxybenzoyl chloride
  • 4-methoxybenzoic acid (1.52 g, 10 mmol) was used in place of acetic acid, and 3.2 mL (46 mmol) of DMF was used. The reaction was performed. When the reaction solution was analyzed by 1 H-NMR, formation of 4-methoxybenzoyl chloride was confirmed (yield: 89%).
  • Example 26 Production of 2-thiophenecarbonyl chloride
  • 2-thiophenecarboxylic acid (1.28 g, 10 mmol) was used instead of acetic acid, and 2 mL (25 mmol) of DMF was used, and the reaction time was set to 2 hours.
  • the reaction was carried out in the same manner except for the above.
  • the reaction solution was analyzed by 1 H-NMR, formation of 2-thiophenecarbonyl chloride could be confirmed (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-furancarboxylicacetic acid (1.12 g, 10 mmol) was used instead of acetic acid, and the reaction time was changed to 2 hours. Was. When the reaction solution was analyzed by 1 H-NMR, it was confirmed that 2-furancarbonyl chloride was generated quantitatively.
  • Example 28 Production of terephthalic acid dianilide Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol), DMF (2.4 mL, 30 mmol) and terephthalic acid (0.41 g, 2.5 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 formation of terephthalic acid dichloride.
  • 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.
  • the reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution.
  • the reaction solution was analyzed by 1 H-NMR, and the formation of phthalic anhydride was confirmed.
  • phthalic acid dichloride was once generated from phthalic acid, and phthalic acid dichloride was further reacted with DMF to generate phthalic anhydride.
  • Example 30 Production of 2,2,2-trifluoropropionic acid chloride
  • 2,2,2-trifluoropropionic acid (0.87 mL, 10 mmol) was used in place of acetic acid, and DMF was added at 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.
  • the reaction solution was analyzed by 1 H-NMR, it was confirmed that 2,2,2-trifluoropropionic acid chloride was generated quantitatively.
  • Example 31 Preparation of 4-fluorobenzoic acid chloride
  • 4-fluorobenzoic acid 715 mg, 5 mmol
  • acetic acid 0.9 mL (11.6 mmol)
  • DMF dimethyl sulfoxide
  • the reaction was carried out in the same manner except that the reaction time was 2 hours.
  • the reaction solution was analyzed by 1 H-NMR, it was confirmed that 4-fluorobenzoic acid chloride was generated quantitatively.
  • 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 into the reaction vessel of Example 1. . The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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.
  • Example 33 Production of methyl formate Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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.
  • reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture 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.
  • the concentrate was analyzed by 1 H-NMR, formation of methyl formate could be confirmed (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 Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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., and isopropanol (0.77 mL, 10 mmol) was added, followed by stirring at room temperature for 12 hours.
  • reaction solution was added to an ice-cooled saturated aqueous solution of sodium hydrogen carbonate, and the mixture was 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.
  • the concentrate was analyzed by 1 H-NMR, formation of isopropyl formate could be confirmed (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 Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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.
  • reaction solution was added to an ice-cooled saturated aqueous solution of sodium hydrogen carbonate, and the mixture was 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.
  • the concentrate was analyzed by 1 H-NMR, formation of phenyl formate could be confirmed (yield: 82%).
  • Example 38 Production of 2,2,2-trifluoroethanol formate Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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.
  • reaction solution was added to an ice-cooled saturated aqueous solution of sodium hydrogen carbonate, and the mixture was 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.
  • the concentrate was analyzed by 1 H-NMR, formation of 2,2,2-trifluoroethanol formate could be confirmed (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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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., 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 solution of sodium hydrogen carbonate, and the mixture was 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, formation of 1,6-hexanediol diformate could be confirmed (yield: 52%).
  • Example 40 Examination of reaction temperature The reaction temperature at the time of preparing the Vilsmeier reagent was examined. Specifically, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added into the reaction vessel of Example 1. The reaction was carried out for 6 hours while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while adjusting the temperature in the range of 0 to 30 ° C. while stirring the mixed solution. Thereafter, when the stirring was stopped, the reaction solution was separated into two layers. The upper layer was analyzed by 1 H-NMR, and the conversion from DMF to Vilsmeier reagent was determined from the peak intensity. Table 1 shows the results.
  • Example 41 Examination of the amount of the amide compound The optimal amount of the amide compound at the time of 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 into the reaction vessel of Example 1. The reaction was carried out for 5 to 27 hours while controlling the temperature in the range of 0 to 30 ° C. while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while stirring the mixed solution. . Thereafter, when the stirring was stopped, the reaction solution was separated into two layers. The upper layer was analyzed by 1 H-NMR, and the conversion from DMF to Vilsmeier reagent was determined from the peak intensity. Table 2 shows the results.
  • 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. The reaction was carried out at 0 ° C. for 6 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. Thereafter, the reaction vessel was immersed in an ice bath, and furan (0.73 mL, 10 mmol) dissolved in acetone (3 mL) was added dropwise, followed by stirring at 20 ° C for 2 hours.
  • 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. The reaction was carried out at 0 ° C. for 6 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. Thereafter, the reaction vessel was immersed in an ice bath, and furan (0.73 mL, 10 mmol) dissolved in acetonitrile (3 mL) was added dropwise, followed by stirring at 20 ° C. for 2 hours.

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Abstract

The purpose of the present invention is to provide: a method for preparing a Vilsmeier reagent, that can be carried out safely, easily, and at a low cost; and a method for producing an aromatic aldehyde or an aromatic ketone, a carboxylic halide, and a formic ester. A method for preparing a Vilsmeier reagent according to the present invention is characterized by comprising: a step for degrading C1-4 halogenated hydrocarbon by irradiating with light, in the presence of an enzyme, a composition that comprises a C1-4 halogenated hydrocarbon having at least one halogen group selected from the group consisting of chlorine, bromine and iodine; and a step for reacting a degraded product of the C1-4 halogenated hydrocarbon with a specific amide compound.

Description

ビルスマイヤー試薬の製造方法Method for producing Vilsmeier reagent
　本発明は、安全かつ簡便に、低コストで実施可能なビルスマイヤー試薬の製造方法と、当該ビルスマイヤー試薬を利用して、芳香族アルデヒドまたは芳香族ケトン、カルボン酸ハロゲン化物、およびギ酸エステルを製造する方法に関するものである。 The present invention provides a method for producing a Vilsmeier reagent that can be carried out safely and simply at low cost, and the production of an aromatic aldehyde or an aromatic ketone, a carboxylic acid halide, and a formate using the Vilsmeier reagent. How to do it.
　ビルスマイヤー（Ｖｉｌｓｍｅｉｅｒ）試薬は求電子剤であり、電子豊富なアルケンや芳香環に付加反応を起こし、例えば、活性基を有する芳香族化合物のホルミル化やカルボキシ基のハロホルミル基への変換などに利用される。ビルスマイヤー試薬は、一般的に、ホスゲン、塩化オキザリル、三塩化リン、五塩化リン、塩化チオニルなどの塩素化剤と、アミド化合物から形成される（特許文献１）。 Vilsmeier reagents are electrophiles that cause addition reactions to electron-rich alkenes and aromatic rings, for example, for the formylation of aromatic compounds with active groups and the conversion of carboxy groups to haloformyl groups. Is done. The Vilsmeier reagent is generally formed from a chlorinating agent such as phosgene, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and an amide compound (Patent Document 1).
　しかし、塩素化剤の多くは非常に毒性が高く、また、水との接触により有毒で腐食性を有する気体を生じるものもあるため、保存が困難であり、取扱いにも危険を伴うことがある。特に、ホスゲンは窒息性の毒ガスとして使用された歴史もあり、使用時における吸引により、死亡などの危険性を伴うものであった。ホスゲン以外の塩素化剤も腐食性を示し、例えば塩化チオニルは副生成物として二酸化硫黄と塩化水素を生じるため、これらの処理にコストを要する。 However, many chlorinating agents are very toxic, and some produce toxic and corrosive gases on contact with water, making them difficult to store and dangerous to handle. . In particular, phosgene has a history of being used as a suffocating poisonous gas, and has a risk of death or the like due to inhalation during use. Chlorinating agents other than phosgene are also corrosive, such as thionyl chloride, which produces sulfur dioxide and hydrogen chloride as by-products, and is expensive to treat.
　特許文献２には、塩素化剤としてより安全なフタル酸二塩化物を用いてビルスマイヤー試薬を製造する方法が開示されている。しかしフタル酸二塩化物を用いるとコストが上がる。また、この方法では無水フタル酸が副生するため、目的化合物の精製プロセスにも高コストがかかる。 Patent Document 2 discloses a method for producing a Vilsmeier reagent using phthalic acid dichloride which is safer as a chlorinating agent. However, using phthalic dichloride increases costs. Further, in this method, since phthalic anhydride is by-produced, a high cost is required for the purification process of the target compound.
　ところで、本発明者らは、これまでハロゲン化炭化水素を原料とする光化学反応を種々開発している。例えば特許文献３に開示されている通り、酸素存在下、クロロホルムなどに光照射して発生した分解生成物をアミン溶液やフェノール溶液に吹き込み、尿素誘導体や炭酸エステル誘導体を製造する方法を開発している。また、特許文献４には、ハロゲン化炭化水素とアルコールを含む混合物に酸素存在下で光照射して、クロロギ酸エステルを製造する方法が開示されている。 By the way, the present inventors have developed various photochemical reactions using halogenated hydrocarbons as raw materials. For example, as disclosed in Patent Document 3, a method for producing a urea derivative or a carbonate derivative by blowing a decomposition product generated by light irradiation on chloroform or the like in the presence of oxygen into an amine solution or a phenol solution has been developed. I have. 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.
国際公開第２００８／１０５４６４号パンフレットWO 2008/105464 pamphlet 特開２０１２－１３６５０２号公報JP 2012-136502 A 特開２０１３－１８１０２８号公報JP 2013-181028 A 国際公開第２０１５／１５６２４５号パンフレットWO 2015/156245 pamphlet
　上述したように、ビルスマイヤー試薬は古くから知られている有用なものであるが、その製造には危険な塩素化剤が必要であり、工業的な製造や使用は困難であるか、或いは厳しい制約の下で工業的な製造や使用が行われていた。
　そこで本発明は、安全かつ簡便に、低コストで実施可能なビルスマイヤー試薬の製造方法と、当該ビルスマイヤー試薬を利用して、芳香族アルデヒドまたは芳香族ケトン、カルボン酸ハロゲン化物、およびギ酸エステルを製造する方法を提供することを目的とする。 As mentioned above, Vilsmeier reagents are useful and long known, but their production requires dangerous chlorinating agents and their industrial production and use are difficult or severe. Industrial production and use were under restrictions.
Accordingly, the present invention provides a method for producing a Vilsmeier reagent that is safe and simple and can be carried out at low cost, and an aromatic aldehyde or aromatic ketone, a carboxylic acid halide, and a formate ester using the Vilsmeier reagent. It is intended to provide a method of manufacturing.
　本発明者らは、上記課題を解決するために鋭意研究を重ねた。その結果、ハロゲン化炭化水素とアミド化合物を含む組成物に酸素存在下で光照射することによりビルスマイヤー試薬を製造できることを見出して、本発明を完成した。
　以下、本発明を示す。 The present inventors have intensively studied to solve the above problems. As a result, they have found 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.
Hereinafter, the present invention will be described.
　［１］　ビルスマイヤー試薬を製造するための方法であって、
　前記ビルスマイヤー試薬が下記式（Ｉ）で表される塩であり、
Figure JPOXMLDOC01-appb-C000003
［式中、
　Ｒ1は、水素原子、Ｃ1-6アルキル基、または置換基を有していてもよいＣ6-12芳香族炭化水素基を示し、
　Ｒ2とＲ3は、独立して、Ｃ1-6アルキル基、または置換基を有していてもよいＣ6-12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Ｃ1-4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Ｃ1-4ハロゲン化炭化水素を分解する工程、および、
　Ｃ1-4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。
Figure JPOXMLDOC01-appb-C000004
［式中、Ｒ1～Ｒ3は上記と同義を示す。］ [1] A method for producing a Vilsmeier reagent,
The Vilsmeier reagent is a salt represented by the following formula (I):
Figure JPOXMLDOC01-appb-C000003
[Where,
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 And may form a ring structure of 4 to 7 members,
X represents a halogeno group selected from the group consisting of chloro, bromo and iodo,
Y - represents a counter anion. ]
Irradiating a composition containing a C 1-4 halogenated hydrocarbon having at least one halogeno group selected from the group consisting of chloro, bromo and iodo in the presence of oxygen with a C 1-4 halogenated hydrocarbon; Decomposing, and
A method comprising reacting a decomposition product of a C 1-4 halogenated hydrocarbon with an amide compound represented by the following formula (II).
Figure JPOXMLDOC01-appb-C000004
Wherein R 1 to R 3 have the same meaning as described above. ]
　［２］　前記光が１８０ｎｍ以上、２８０ｎｍ以下の波長の光を含む上記［１］に記載の方法。 {[2]} The method according to the above [1], wherein the light includes light having a wavelength of 180 nm or more and 280 nm or less.
　［３］　前記Ｃ1-4ハロゲン化炭化水素としてＣ1-4ポリハロゲン化炭化水素を用いる上記［１］または［２］に記載の方法。 [3] The method according to the above [1] or [2], wherein a C 1-4 polyhalogenated hydrocarbon is used as the C 1-4 halogenated hydrocarbon.
　［４］　Ｘがクロロであり、Ｙ-が塩化物イオンである上記［１］～［３］のいずれかに記載の方法。 [4] The method according to any one of the above [1] to [3], wherein X is chloro and Y - is a chloride ion.
　［５］　前記式（ＩＩ）で表されるアミド化合物としてＮ，Ｎ－ジメチルホルムアミドを用いる上記［１］～［４］のいずれかに記載の方法。 {[5]} The method according to any one of the above [1] to [4], wherein N, N-dimethylformamide is used as the amide compound represented by the formula (II).
　［６］　前記式（ＩＩ）で表されるアミド化合物に対して５倍モル以上の前記Ｃ1-4ハロゲン化炭化水素を用いる上記［１］～［５］のいずれかに記載の方法。 [6] The method according to any one of [1] to [5] above, wherein the C 1-4 halogenated hydrocarbon is used in an amount of 5 times or more the amount of the amide compound represented by the formula (II).
　［７］　芳香族アルデヒドまたは芳香族ケトンを製造するための方法であって、
　上記［１］～［６］のいずれかに記載の方法によりビルスマイヤー試薬を製造する工程、および、
　前記ビルスマイヤー試薬と活性基を有する芳香族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。 [7] A method for producing an aromatic aldehyde or an aromatic ketone,
A step of producing a Vilsmeier reagent by the method according to any one of the above [1] to [6], and
Reacting the Vilsmeier reagent with an aromatic compound having an active group.
　［８］　カルボン酸ハロゲン化物を製造するための方法であって、
　上記［１］～［６］のいずれかに記載の方法によりビルスマイヤー試薬を製造する工程、および、
　前記ビルスマイヤー試薬と下記式（ＩＩＩ）で表されるカルボン酸化合物とを反応させることにより、前記カルボン酸化合物のカルボキシ基をハロホルミル基に変換する工程を含むことを特徴とする方法。
　　Ｒ4－（ＣＯ2Ｈ）n　　　　（ＩＩＩ）
［式中、Ｒ4はｎ価の有機基を示し、ｎは１以上４以下の整数を示す。］ [8] A method for producing a carboxylic acid halide,
A step of producing a Vilsmeier reagent by the method according to any one of the above [1] to [6], and
A method comprising reacting the Vilsmeier reagent with a carboxylic acid compound represented by the following formula (III) to convert a carboxy group of the carboxylic acid compound into a haloformyl group.
R 4 - (CO 2 H) n (III)
[Wherein, R 4 represents an n-valent organic group, and n represents an integer of 1 or more and 4 or less. ]
　［９］　ギ酸エステルを製造するための方法であって、
　上記［１］～［６］のいずれかに記載の方法によりビルスマイヤー試薬を製造する工程、および、
　前記ビルスマイヤー試薬と水酸基含有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。 [9] A method for producing a formate ester,
A step of producing a Vilsmeier reagent by the method according to any one of the above [1] to [6], and
Reacting the Vilsmeier reagent with a hydroxyl group-containing compound.
　本発明方法によれば、反応性が高く有用なビルスマイヤー試薬を、ホスゲンといった危険な化合物の代わりに、汎用溶媒としても使われているハロゲン化炭化水素を用い、安全かつ簡便に、低コストで製造することができる。この際に副生するのは二酸化炭素と塩化水素のみであり、それらはガスとして系外に排出することもできるため、精製は原則として必要無い。また、製造されたビルスマイヤー試薬を用い、同一系内で、芳香族アルデヒドまたは芳香族ケトン、カルボン酸ハロゲン化物、およびギ酸エステルを製造することも可能である。よって本発明は、芳香族アルデヒドまたは芳香族ケトン、カルボン酸ハロゲン化物、およびギ酸エステルの工業的な製造技術として、産業上極めて有用である。 According to the method of the present invention, a highly reactive and useful Vilsmeier reagent is used in place of a dangerous compound such as phosgene, and a halogenated hydrocarbon which is also used as a general-purpose solvent. Can be manufactured. At this time, only carbon dioxide and hydrogen chloride are by-produced, and since they can be discharged out of the system as gas, purification is not required in principle. It is also possible to produce an aromatic aldehyde or aromatic ketone, a carboxylic acid halide, and a formate 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 ketones, carboxylic acid halides, and formate.
本発明に用いられる反応装置の構成の一例を示す模式図である。FIG. 1 is a schematic diagram illustrating an example of a configuration of a reaction device used in the present invention.
　本発明では、まず、Ｃ1-4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、Ｃ1-4ハロゲン化炭化水素を分解する。 In the present invention, firstly, by light irradiation in the presence of oxygen to a composition comprising a C 1-4 halogenated hydrocarbons, for decomposing the C 1-4 halogenated hydrocarbons.
　本発明で用いるＣ1-4ハロゲン化炭化水素は、炭素数が１以上４以下の炭化水素であり、クロロ、ブロモおよびヨードから必須的になる群から選択される１種以上のハロゲノ基を有する。かかるＣ1-4ハロゲン化炭化水素は、おそらく照射光と酸素により分解され、ハロゲン化カルボニルまたはハロゲン化カルボニル様の化合物に変換され、アミド化合物と反応した後、更にハロゲン化物イオンの攻撃を受けてビルスマイヤー試薬が生成すると考えられる。たとえ有害なハロゲン化カルボニルが生成しても、ハロゲン化カルボニルは反応性が極めて高いためにアミド化合物と直ぐに反応し、反応液外へは漏出しないか、或いは漏出してもその漏出量は僅かであると考えられる。本発明は、Ｃ1-4ハロゲン化炭化水素を光分解することで有用な化合物を製造する技術であり、工業的にもまた環境科学的にも寄与するところは大きい。 The C 1-4 halogenated hydrocarbon used in the present invention is a hydrocarbon having 1 to 4 carbon atoms and having at least one halogeno group selected from a 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 further attacked by halide ions. It is believed that a Vilsmeier reagent is formed. Even if a harmful carbonyl halide is formed, the carbonyl halide reacts immediately with the amide compound due to its extremely high reactivity, and does not leak out of the reaction solution. It is believed that there is. The present invention is a technique for producing a useful compound by photodecomposing a C 1-4 halogenated hydrocarbon, and greatly contributes industrially and environmentally.
　Ｃ1-4ハロゲン化炭化水素は、クロロ、ブロモおよびヨードから必須的になる群から選択される１種以上のハロゲノ基で置換された、炭素数１以上４以下のアルカン、アルケンまたはアルキンである。上述した通り、本発明においてＣ1-4ハロゲン化炭化水素は照射光と酸素により分解され、ハロゲン化カルボニルと同等の働きをすると考えられる。よってＣ1-2ハロゲン化炭化水素が好ましく、ハロゲノメタンがより好ましい。炭素数が２以上４以下である場合には、分解がより容易に進行するよう、１以上の不飽和結合を有するアルケンまたはアルキンが好ましい。また、２以上のハロゲノ基を有するＣ1-4ポリハロゲン化炭化水素が好ましく、Ｃ1-2ポリハロゲン化炭化水素がより好ましい。さらに、分解に伴ってハロゲノ基が転移する可能性もあるが、同一炭素に２以上のハロゲノ基を有するＣ1-4ハロゲン化炭化水素が好ましい。 The C1-4 halogenated hydrocarbon is an alkane, alkene or alkyne having 1 or more and 4 or less carbon atoms substituted with one or more halogeno groups selected from the group consisting essentially of chloro, bromo and iodo. . As described above, in the present invention, the C 1-4 halogenated hydrocarbon is considered to be decomposed by the irradiation light and oxygen and to perform the same function as the carbonyl halide. Thus, C 1-2 halogenated hydrocarbons are preferred, and halogenomethane is more preferred. When the number of carbon atoms is 2 or more and 4 or less, alkene or alkyne having one or more unsaturated bonds is preferable so that the decomposition proceeds more easily. Further, a C 1-4 polyhalogenated hydrocarbon having two or more halogeno groups is preferable, and a C 1-2 polyhalogenated hydrocarbon is more preferable. Furthermore, although the halogeno group may be transferred with the decomposition, a C 1-4 halogenated hydrocarbon having two or more halogeno groups on the same carbon is preferable.
　具体的なＣ1-4ハロゲン化炭化水素としては、例えば、ジクロロメタン、クロロホルム、ジブロモメタン、ブロモホルム、ヨードメタン、ジヨードメタン等のハロメタン；１，１，２－トリクロロエタン、１，１，１－トリクロロエタン、１，１，２，２－テトラクロロエタン、１，１，１，２－テトラクロロエタン等のハロエタン；１，１，１，３－テトラクロロプロパン等のハロプロパン；テトラクロロメタン、テトラブロモメタン、テトラヨードメタン、ヘキサクロロエタン、ヘキサブロモエタン等のペルハロアルカン；１，１，２，２－テトラクロロエテン、１，１，２，２－テトラブロモエテン等のペルハロエテン等を挙げることができる。 Specific C 1-4 halogenated hydrocarbons include, for example, halomethanes such as dichloromethane, chloroform, dibromomethane, bromoform, iodomethane, diiodomethane; 1,1,2-trichloroethane, 1,1,1-trichloroethane, Haloethanes such as 1,2,2-tetrachloroethane and 1,1,1,2-tetrachloroethane; halopropanes such as 1,1,1,3-tetrachloropropane; tetrachloromethane, tetrabromomethane, tetraiodomethane, Perhaloalkanes such as hexachloroethane and hexabromoethane; and perhaloethenes such as 1,1,2,2-tetrachloroethene and 1,1,2,2-tetrabromoethene.
　Ｃ1-4ハロゲン化炭化水素は目的とする化学反応や所期の生成物に応じて適宜選択すればよく、また、１種を単独で使用してもよいし、２種以上を組み合わせて使用してもよい。また、好適には、製造目的化合物に応じて、Ｃ1-4ハロゲン化炭化水素は１種のみ用いる。常圧で常温または反応温度において液状のＣ1-4ハロゲン化炭化水素であれば、溶媒としての役割も果たすことができる。Ｃ1-4ハロゲン化炭化水素の中でもクロロ基を有する化合物が好ましい。 The C1-4 halogenated hydrocarbon may be appropriately selected according to the intended chemical reaction or the desired product, and may be used alone or in combination of two or more. May be. Preferably, only one C 1-4 halogenated hydrocarbon is used depending on the production target compound. Any C 1-4 halogenated hydrocarbon that is liquid at normal pressure or normal temperature or at the reaction temperature can also serve as a solvent. Among the C 1-4 halogenated hydrocarbons, compounds having a chloro group are preferred.
　本発明方法で用いるＣ1-4ハロゲン化炭化水素としては、汎用溶媒としても用いられる安価なクロロホルムが最も好ましい。例えば溶媒としていったん使用したＣ1-4ハロゲン化炭化水素を回収し、再利用してもよい。その際、多量の不純物や水が含まれていると反応が阻害されるおそれがあり得るので、ある程度は精製することが好ましい。例えば、水洗により水や水溶性不純物を除去した後、無水硫酸ナトリウムや無水硫酸マグネシウムなどで脱水することが好ましい。但し、１容量％程度の水が含まれていても反応は進行すると考えられるので、生産性を低下させるような過剰な精製は必要ない。かかる水含量としては、０．５容量％以下がより好ましく、０．２容量％以下がさらに好ましく、０．１容量％以下がよりさらに好ましい。また、上記再利用Ｃ1-4ハロゲン化炭化水素には、Ｃ1-4ハロゲン化炭化水素の分解物などが含まれていてもよい。 As the C 1-4 halogenated hydrocarbon used in the method of the present invention, inexpensive chloroform which is also used as a general-purpose solvent is most preferable. For example, a 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 that it is preferable to purify 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 or anhydrous magnesium sulfate. However, since the reaction is considered to proceed even if about 1% by volume of water is contained, it is not necessary to perform excessive purification that lowers the productivity. The water content is more preferably 0.5% by volume or less, still more preferably 0.2% by volume or less, and even more preferably 0.1% by volume or less. The recycled C 1-4 halogenated hydrocarbon may include a decomposition product of the C 1-4 halogenated hydrocarbon.
　Ｃ1-4ハロゲン化炭化水素の使用量は、アミド化合物をビルスマイヤー試薬へ十分に変換できる範囲で適宜決定すればよいが、例えば、アミド化合物に対して０．１倍モル以上用いればよい。Ｃ1-4ハロゲン化炭化水素の使用量の上限は特に制限されないが、例えば、アミド化合物に対して２００倍モル以下とすることができる。上記使用量としては、１倍モル以上、５倍モル以上または１０倍モル以上が好ましく、２０倍以上がより好ましく、２５倍以上がより更に好ましい。本発明者らによる実験的知見によれば、Ｃ1-4ハロゲン化炭化水素に対するアミド化合物の量が少ない方がビルスマイヤー試薬の生成効率が高い傾向が認められる。また、Ｃ1-4ハロゲン化炭化水素を溶媒として使用できる場合などには、５０倍モル以上用いることもできる。上記使用量としては、１５０倍モル以下または１００倍モル以下が好ましい。Ｃ1-4ハロゲン化炭化水素の具体的な使用量は、予備実験などで決定すればよい。 The amount of the C 1-4 halogenated hydrocarbon to be used may be appropriately determined within a range in which the amide compound can be sufficiently converted into the Vilsmeier reagent. The upper limit of the use amount of the C 1-4 halogenated hydrocarbon is not particularly limited, but may be, for example, 200 times or less the molar amount of the amide compound. The amount used is preferably 1-fold or more, 5-fold or more, or 10-fold or more, more preferably 20-fold or more, and even more preferably 25-fold or more. According to the experimental findings by the present inventors, it is observed that the smaller the amount of the amide compound relative to the C 1-4 halogenated hydrocarbon, the higher the production efficiency of the Vilsmeier reagent. When a C 1-4 halogenated hydrocarbon can be used as a solvent, it can be used in an amount of 50 times or more. The amount used is preferably 150 times or less or 100 times or less. The specific amount of the C 1-4 halogenated hydrocarbon to be used may be determined by a preliminary experiment or the like.
　酸素源としては、酸素を含む気体であればよく、例えば、空気や、精製された酸素を用いることができる。精製された酸素は、窒素やアルゴン等の不活性ガスと混合して使用してもよい。コストや容易さの点からは空気を用いることができる。光照射によるＣ1-4ハロゲン化炭化水素の分解効率を高める観点からは、酸素源として用いられる気体中の酸素含有率は約１５体積％以上１００体積％以下であることが好ましい。また、不可避的不純物以外、実質的に酸素のみを用いることも好ましい。酸素含有率は上記Ｃ1-4ハロゲン化炭化水素などの種類によって適宜決定すればよい。例えば、上記Ｃ1-4ハロゲン化炭化水素としてジクロロメタン、クロロホルム、テトラクロロエチレン等のクロロＣ1-4炭化水素を用いる場合は、酸素含有率は１５体積％以上１００体積％以下であるのが好ましく、ジブロモメタンやブロモホルムなどのブロモＣ1-4炭化水素化合物を用いる場合は、酸素含有率は９０体積％以上１００体積％以下であるのが好ましい。なお、酸素（酸素含有率１００体積％）を用いる場合であっても、反応系内への酸素流量の調節により酸素含有率を上記範囲内に制御することができる。酸素を含む気体の供給方法は特に限定されず、流量調整器を取り付けた酸素ボンベから反応系内に供給してもよく、また、酸素発生装置から反応系内に供給してもよい。 The oxygen source may be any gas containing oxygen, and for example, air or purified oxygen can be used. The purified oxygen may be used by mixing 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 the C 1-4 halogenated hydrocarbon 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. It is also preferable to use substantially only oxygen other than the inevitable impurities. The oxygen content may be appropriately determined depending on the type of the above-mentioned C 1-4 halogenated hydrocarbon or the like. For example, when chloro C 1-4 hydrocarbons such as dichloromethane, chloroform and tetrachloroethylene are used as the C 1-4 halogenated hydrocarbon, the oxygen content is preferably 15% by volume or more and 100% by volume or less, When a bromo C 1-4 hydrocarbon compound such as methane or bromoform is used, the oxygen content is preferably 90% by volume or more and 100% by volume or less. Note that even when oxygen (oxygen content 100 vol%) is used, the oxygen content can be controlled within the above range by adjusting the flow rate of oxygen into the reaction system. The method for supplying the gas containing oxygen is not particularly limited, and the gas may be supplied into the reaction system from an oxygen cylinder equipped with a flow controller, or may be supplied from the oxygen generator into the reaction system.
　なお、「酸素存在下」とは、Ｃ1-4ハロゲン化炭化水素が酸素と接している状態か、上記組成物中に酸素が存在する状態のいずれであってもよい。従って、本発明に係る反応は、酸素を含む気体の気流下で行ってもよいが、生成物の収率を高める観点からは、酸素を含む気体はバブリングにより上記組成物中へ供給することが好ましい。 Here, “in the presence of oxygen” may be either a state where the C 1-4 halogenated hydrocarbon is in contact with oxygen or a state where oxygen is present in the composition. Therefore, the reaction according to the present invention may be performed under a gas stream of a gas containing oxygen, but from the viewpoint of increasing the yield of a product, the gas containing oxygen may be supplied into the composition by bubbling. preferable.
　酸素を含む気体の量は、上記Ｃ1-4ハロゲン化炭化水素の量や、反応容器の形状などに応じて適宜決定すればよい。例えば、反応容器中に存在する上記Ｃ1-4ハロゲン化炭化水素に対する、反応容器へ供給する１分あたりの気体の量を、５容量倍以上とすることが好ましい。当該割合としては、２５容量倍以上がより好ましく、５０容量倍以上がよりさらに好ましい。当該割合の上限は特に制限されないが、５００容量倍以下が好ましく、２５０容量倍以下がより好ましく、１５０容量倍以下がよりさらに好ましい。また、反応容器中に存在する上記Ｃ1-4ハロゲン化炭化水素に対する、反応容器へ供給する１分あたりの酸素の量としては、５容量倍以上２５容量倍以下とすることができる。気体の流量が多過ぎる場合には、上記Ｃ1-4ハロゲン化炭化水素が揮発してしまう虞があり得る一方で、少な過ぎると反応が進行し難くなる虞があり得る。 The amount of the gas containing oxygen may be appropriately determined according to the amount of the C 1-4 halogenated hydrocarbon, the shape of the reaction vessel, and the like. For example, the amount of gas per minute supplied to the reaction vessel with respect to the C 1-4 halogenated hydrocarbon present in the reaction vessel is preferably 5 times or more. The ratio is more preferably 25 times or more, and even more preferably 50 times or more. Although the upper limit of the ratio is not particularly limited, it is preferably 500 times or less, more preferably 250 times or less, and even more preferably 150 times or less. Further, the amount of oxygen per minute supplied to the reaction vessel with respect to the C 1-4 halogenated hydrocarbon present in the reaction vessel can be 5 times or more and 25 times or less. If the flow rate of the gas is too large, the C 1-4 halogenated hydrocarbon may be volatilized, while if it is too small, the reaction may not easily proceed.
　Ｃ1-4ハロゲン化炭化水素を含む組成物には、溶媒を配合してもよい。特にＣ1-4ハロゲン化炭化水素が常温常圧で液体でない場合には、Ｃ1-4ハロゲン化炭化水素を適度に溶解でき、且つＣ1-4ハロゲン化炭化水素の分解を阻害しない溶媒が好ましい。かかる溶媒としては、例えば、アセトン、メチルエチルケトン、メチルイソブチルケトン、シクロヘキサノンなどのケトン系溶媒；酢酸エチルなどのエステル系溶媒；ｎ－ヘキサンなどの脂肪族炭化水素溶媒；ジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒；アセトニトリルなどのニトリル系溶媒を挙げることができる。 A solvent may be added to the composition containing a C 1-4 halogenated hydrocarbon. Especially when C 1-4 halogenated hydrocarbon is not liquid at room temperature and atmospheric pressure, C 1-4 can appropriately dissolve the halogenated hydrocarbon, solvent is that and does not inhibit the decomposition of the C 1-4 halogenated hydrocarbons preferable. Examples of such a solvent 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; ethers such as diethyl ether, tetrahydrofuran, and dioxane. System solvent: Nitrile solvents such as acetonitrile can be mentioned.
　上記混合物に照射する光としては、短波長光を含む光が好ましく、紫外線を含む光がより好ましく、より詳細には１８０ｎｍ以上５００ｎｍ以下の波長の光を含む光が好ましく、ピーク波長が１８０ｎｍ以上５００ｎｍ以下の範囲に含まれる光がより好ましい。なお、光の波長は上記Ｃ1-4ハロゲン化炭化水素の種類に応じて適宜決定すればよいが、４００ｎｍ以下がより好ましく、３００ｎｍ以下がよりさらに好ましい。照射光に上記波長範囲の光が含まれている場合には、上記Ｃ1-4ハロゲン化炭化水素を効率良く酸化的光分解できる。例えば、波長２８０ｎｍ以上３１５ｎｍ以下のＵＶ－Ｂおよび／または波長１８０ｎｍ以上２８０ｎｍ以下のＵＶ－Ｃを含む高エネルギー光を用いることができ、波長１８０ｎｍ以上２８０ｎｍ以下のＵＶ－Ｃを含む高エネルギー光を用いることが好ましい。また、ピーク波長が２８０ｎｍ以上３１５ｎｍ以下および／または１８０ｎｍ以上２８０ｎｍ以下の範囲に含まれる光が好ましく、ピーク波長が１８０ｎｍ以上２８０ｎｍ以下の範囲に含まれる光がより好ましい。 The light irradiated to the mixture is preferably light containing short-wavelength light, more preferably light containing ultraviolet light, more specifically light containing light having a wavelength of 180 nm or more and 500 nm or less, and has a peak wavelength of 180 nm or more and 500 nm. Light included in the following range is more preferable. The wavelength of the light may be appropriately determined according to the type of the C 1-4 halogenated hydrocarbon, but is preferably 400 nm or less, more preferably 300 nm or less. When the irradiation light contains 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 having a wavelength of 280 to 315 nm and / or UV-C having a wavelength of 180 to 280 nm can be used, and high-energy light including UV-C having a wavelength of 180 to 280 nm can be used. Is preferred. Further, light having a peak wavelength in the range of 280 nm to 315 nm and / or 180 nm to 280 nm is preferable, and light having a peak wavelength in the range of 180 nm to 280 nm is more preferable.
　光照射の手段は、上記波長の光を照射できるものである限り特に限定されないが、このような波長範囲の光を波長域に含む光源としては、例えば、太陽光、低圧水銀ランプ、中圧水銀ランプ、高圧水銀ランプ、超高圧水銀ランプ、ケミカルランプ、ブラックライトランプ、メタルハライドランプ、ハロゲンランプ、白熱電球などが挙げられる。反応効率やコストの点から、低圧水銀ランプが好ましく用いられる。 The light irradiation means is not particularly limited as long as it can irradiate the light of the above-mentioned wavelength. Examples of the light source including light of such a wavelength range in a wavelength range include, for example, sunlight, a low-pressure mercury lamp, and a medium-pressure mercury. Lamps, high-pressure mercury lamps, ultra-high-pressure mercury lamps, chemical lamps, black light lamps, metal halide lamps, halogen lamps, incandescent lamps and the like. From the viewpoint of reaction efficiency and cost, a low-pressure mercury lamp is preferably used.
　照射光の強度や照射時間などの条件は、出発原料の種類や使用量によって適宜設定すればよいが、例えば、光源から上記組成物の最短距離位置における所望の光の強度としては１０ｍＷ／ｃｍ2以上５００ｍＷ／ｃｍ2以下が好ましい。また、光源とハロゲン化メタンとの最短距離としては、１ｍ以下が好ましく、５０ｃｍ以下がより好ましく、１０ｃｍ以下または５ｃｍ以下がより更に好ましい。当該最短距離の下限は特に制限されないが、０ｃｍ、即ち、光源をハロゲン化メタン中に浸漬してもよい。反応容器の側面から光照射する場合には、上記最短距離を１ｃｍ以上または２ｃｍ以上とすることもできる。光の照射時間としては、０．５時間以上１０時間以下が好ましく、１時間以上６時間以下がより好ましく、２時間以上４時間以下がよりさらに好ましい。光照射の態様も特に限定されず、反応開始から終了まで連続して光を照射する態様、光照射と光非照射とを交互に繰り返す態様、反応開始から所定の時間のみ光を照射する態様など、いずれの態様も採用できるが、反応開始から終了まで連続して光を照射する態様が好ましい。 Conditions such as the intensity of irradiation light and irradiation time may be appropriately set depending on the type and amount of starting material used. For example, a desired light intensity at the shortest distance position of the composition from a light source is 10 mW / cm 2. It is preferably at least 500 mW / cm 2 . Further, the shortest distance between the light source and the halogenated methane is preferably 1 m or less, more preferably 50 cm or less, 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 of the reaction vessel, the shortest distance may be 1 cm or more or 2 cm or more. The light irradiation time is preferably from 0.5 to 10 hours, more preferably from 1 to 6 hours, even more preferably from 2 to 4 hours. The mode of light irradiation is also not particularly limited, such as a mode in which light is continuously irradiated from the start to the end of the reaction, a mode in which light irradiation and non-irradiation are alternately repeated, and a mode in which light is irradiated only for a predetermined time from the start of the reaction. Either mode can be adopted, but a mode in which light is continuously irradiated from the start to the end of the reaction is preferable.
　Ｃ1-4ハロゲン化炭化水素の分解時の温度も特に限定はされず、適宜調整すればよいが、例えば、－２０℃以上６０℃以下とすることができる。当該温度としては、－１０℃以上がより好ましく、０℃以上または１０℃以上がよりさらに好ましく、また、５０℃以下または４０℃以下がより好ましく、３０℃以下がよりさらに好ましい。或いは、温度制御をすることなく常温で反応を行ってもよい。なお、反応温度が低い場合には、有害なハロゲン化合物ガスが反応系外に漏れ難いという利点がある。かかる観点からは、反応温度は１０℃以下が好ましく、５℃以下がより好ましい。 The temperature at which the C 1-4 halogenated hydrocarbon is decomposed is not particularly limited, and may be appropriately adjusted. For example, the temperature may be set to −20 ° C. or more and 60 ° C. or less. The temperature is more preferably −10 ° C. or higher, still more preferably 0 ° C. or higher or 10 ° C. or higher, and is more preferably 50 ° C. or lower or 40 ° C. or lower, even more preferably 30 ° C. or lower. Alternatively, the reaction may be performed at room temperature without controlling the temperature. When the reaction temperature is low, there is an advantage that harmful halogen compound gas hardly leaks out of the reaction system. From such a viewpoint, the reaction temperature is preferably 10 ° C or lower, more preferably 5 ° C or lower.
　また、高エネルギー光の照射後、高エネルギー光を照射せず、例えば蛍光灯などの一般光の下、１０℃以上６０℃以下で１分間以上５時間以下程度、反応を継続してもよい。 After irradiation with high energy light, the reaction may be continued at 10 ° C. or higher and 60 ° C. or lower for 1 minute to 5 hours under general light such as a fluorescent lamp without irradiation of high energy light.
　本発明では、次に、Ｃ1-4ハロゲン化炭化水素の分解物と式（ＩＩ）で表されるアミド化合物とを反応させる。アミド化合物との反応工程は、Ｃ1-4ハロゲン化炭化水素の分解工程と同時に実施してもよいし、Ｃ1-4ハロゲン化炭化水素の分解工程の後で行ってもよい。 Next, in the present invention, the decomposition product of the C 1-4 halogenated hydrocarbon is reacted with the amide compound represented by the formula (II). Step of the reaction with the amide compound may be carried out simultaneously with the decomposition process of the C 1-4 halogenated hydrocarbons, may be performed after the decomposition step of C 1-4 halogenated hydrocarbons.
　Ｃ1-4ハロゲン化炭化水素の分解工程とアミド化合物との反応工程を同時に実施する場合には、例えば、Ｃ1-4ハロゲン化炭化水素を含む組成物にアミド化合物も配合すればよい。また、Ｃ1-4ハロゲン化炭化水素を含む組成物に光照射し、光照射を継続したままアミド化合物を添加してもよい。これらの場合には、Ｃ1-4ハロゲン化炭化水素の分解物がアミド化合物と速やかに反応することができ、分解物の漏出を抑制できる。 When the step of decomposing the C 1-4 halogenated hydrocarbon and the step of reacting with the amide compound are carried out simultaneously, for example, the amide compound may be added to the composition containing the C 1-4 halogenated hydrocarbon. Alternatively, the composition containing a C 1-4 halogenated hydrocarbon may be irradiated with light, and the amide compound may be added while the light 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.
　Ｃ1-4ハロゲン化炭化水素の分解工程の後にアミド化合物との反応工程を実施する場合には、光照射によりＣ1-4ハロゲン化炭化水素を分解した後、光照射、特に高エネルギー光の照射を停止し、アミド化合物を添加すればよい。アミド化合物によりＣ1-4ハロゲン化炭化水素の分解が阻害される場合には、この態様によりＣ1-4ハロゲン化炭化水素の分解とアミド化合物との反応を効率的に行うことができる。また、Ｃ1-4ハロゲン化炭化水素の分解により副生したハロゲン化水素とアミド化合物との副反応や、アミド化合物への光照射による分解を抑制できる。よってこの態様は、特に大容量での本発明の実施に適している。 When a reaction step with an amide compound is performed after the C 1-4 halogenated hydrocarbon decomposition step, the C 1-4 halogenated hydrocarbon is decomposed by light irradiation, and then light irradiation, particularly of high energy light Irradiation may be stopped and an amide compound may be added. When the decomposition of the C 1-4 halogenated hydrocarbon is inhibited by the amide compound, this embodiment allows the decomposition of the C 1-4 halogenated hydrocarbon and the reaction with the amide compound to be performed efficiently. Further, it is possible to suppress a side reaction between the amide compound and the hydrogen halide by-produced by the decomposition of the C 1-4 halogenated hydrocarbon, and the decomposition of the amide compound by light irradiation. Therefore, this embodiment is particularly suitable for implementing the present invention with a large capacity.
　アミド化合物としては、下記式（ＩＩ）で表されるアミド化合物が好ましい。以下、式（ＩＩ）で表される化合物を「アミド化合物（ＩＩ）」と略記する場合がある。 As the amide compound, an amide compound represented by the following formula (II) is preferable. Hereinafter, the compound represented by the formula (II) may be abbreviated as “amide compound (II)”.
Figure JPOXMLDOC01-appb-C000005
［式中、Ｒ1は、水素原子（－Ｈ）、Ｃ1-6アルキル基、または置換基を有していてもよいＣ6-12芳香族炭化水素基を示し、Ｒ2とＲ3は、独立して、Ｃ1-6アルキル基、または置換基を有していてもよいＣ6-12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。］
Figure JPOXMLDOC01-appb-C000005
[Wherein, 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 represent 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 form a 4-membered or more It may form a ring structure of less than or equal to member. ]
　本開示において「Ｃ1-6アルキル基」は、炭素数１以上６以下の直鎖状または分枝鎖状の一価飽和脂肪族炭化水素基をいう。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、ｎ－ヘキシル等である。好ましくはＣ1-4アルキル基であり、より好ましくはＣ1-2アルキル基であり、最も好ましくはメチルである。 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. For example, 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.
　「Ｃ6-12芳香族炭化水素基」とは、炭素数が６以上１２以下の一価芳香族炭化水素基をいう。例えば、フェニル、ナフチル、インデニル、ビフェニル基であり、好ましくはフェニルである。Ｃ6-12芳香族炭化水素基は、置換基を有していてもよい。当該置換基は、本発明に係る反応を阻害しないものであれば特に制限されないが、例えば、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲノ基、ニトロ基およびシアノ基からなる群より選択される１以上の置換基を挙げることができる。置換基の数は置換可能である限り特に制限されないが、例えば１以上５以下とすることができ、３以下が好ましく、２以下がより好ましく、１がより更に好ましい。置換基数が２以上である場合、置換基は互いに同一であっても異なっていてもよい。 The “C 6-12 aromatic hydrocarbon group” refers to a monovalent aromatic hydrocarbon group having 6 to 12 carbon atoms. For example, phenyl, naphthyl, indenyl and 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, and examples thereof include 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 substituents selected may be mentioned. The number of substituents is not particularly limited as long as it can be substituted, but may be, for example, from 1 to 5, preferably 3 or less, more preferably 2 or less, and still more preferably 1. When the number of substituents is 2 or more, the substituents may be the same or different.
　「Ｃ1-6アルコキシ基」とは、炭素数１以上６以下の直鎖状または分枝鎖状の脂肪族炭化水素オキシ基をいう。例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｔ－ブトキシ、ｎ－ペントキシ、ｎ－ヘキソキシ等であり、好ましくはＣ1-4アルコキシ基であり、より好ましくはＣ1-2アルコキシ基であり、より更に好ましくはメトキシである。 The “C 1-6 alkoxy group” refers to a linear or branched aliphatic hydrocarbonoxy 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 alkoxy group -2 alkoxy group, more preferably methoxy.
　Ｃ6-12芳香族炭化水素基の置換基としての「ハロゲノ基」は、クロロ、ブロモ、ヨードの他、フルオロであってもよい。 The “halogeno group” as the substituent for the C 6-12 aromatic hydrocarbon group may be chloro, bromo, iodo or fluoro.
　Ｒ2とＲ3が窒素原子と共に一緒になって形成される４員以上７員以下の環構造としては、例えば、ピロリジル基、ピペリジル基、モルホリノ基を挙げることができる。 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.
　具体的なアミド化合物（ＩＩ）としては、例えば、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡ）、Ｎ－メチル－Ｎ－フェニルホルムアミド、Ｎ－メチルピロリドン（ＮＭＰ）、１，３－ジメチルイミダゾリジノン（ＤＭＩ）、テトラメチル尿素、テトラエチル尿素、テトラブチル尿素などを挙げることができ、汎用性やコストなどの観点からＤＭＦが好ましい。 Specific examples of the amide compound (II) include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-N-phenylformamide, N-methylpyrrolidone (NMP), Examples thereof include 1,3-dimethylimidazolidinone (DMI), tetramethyl urea, tetraethyl urea, and tetrabutyl urea, and DMF is preferred from the viewpoint of versatility and cost.
　Ｃ1-4ハロゲン化炭化水素の分解工程とアミド化合物との反応工程を同時に実施する場合、Ｃ1-4ハロゲン化炭化水素とアミド化合物を含む組成物に酸素存在下で光照射する。アミド化合物（ＩＩ）と組み合わせるＣ1-4ハロゲン化炭化水素としては、安価に入手できるクロロホルムが最も好ましい。 When the step of decomposing the C 1-4 halogenated hydrocarbon and the step of reacting the amide compound are simultaneously performed, the composition containing the C 1-4 halogenated hydrocarbon and the amide compound is irradiated with light in the presence of oxygen. As the C 1-4 halogenated hydrocarbon to be combined with the amide compound (II), chloroform which is available at a low cost is most preferable.
　上記Ｃ1-4ハロゲン化炭化水素とアミド化合物の混合態様は特に限定されない。例えば、反応器中、各化合物の全量を予め混合しておいてもよいし、数回に分割して添加してもよいし、任意の速度で連続的に添加してもよい。また、上記Ｃ1-4ハロゲン化炭化水素が常温常圧で液体でない場合には、これら原料化合物を適度に溶解でき、且つ本発明反応を阻害しない溶媒を用いてもよい。かかる溶媒としては、例えば、ｎ－ヘキサンなどの脂肪族炭化水素溶媒；ジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒；アセトニトリルなどのニトリル系溶媒を挙げることができる。 The manner of mixing the C 1-4 halogenated hydrocarbon and the amide compound is not particularly limited. For example, in a reactor, the entire amount of each compound may be mixed in advance, added in several portions, or added continuously at an arbitrary rate. When the C 1-4 halogenated hydrocarbon is not liquid at normal temperature and normal pressure, a solvent that can appropriately dissolve these starting compounds and does not inhibit the reaction of the present invention may be used. Examples of such a solvent include aliphatic hydrocarbon solvents such as n-hexane; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; and nitrile solvents such as acetonitrile.
　反応時の温度も特に限定はされず、適宜調整すればよいが、例えば、－２０℃以上６０℃以下とすることができる。当該温度としては、－１０℃以上がより好ましく、０℃以上がよりさらに好ましく、また、５０℃以下または４０℃以下がより好ましく、３０℃以下がよりさらに好ましい。或いは、温度制御をすることなく常温で反応を行ってもよい。なお、反応温度が低い場合には、有害なハロゲン化合物ガスが反応系外に漏れ難いという利点がある。かかる観点からは、反応温度は１０℃以下が好ましく、５℃以下がより好ましい。 温度 The temperature during the reaction is not particularly limited, and may be appropriately adjusted. For example, the temperature may be -20 ° C or higher and 60 ° C or lower. The temperature is more preferably −10 ° C. or more, still more preferably 0 ° C. or more, more preferably 50 ° C. or less or 40 ° C. or less, and even more preferably 30 ° C. or less. Alternatively, the reaction may be performed at room temperature without controlling the temperature. When the reaction temperature is low, there is an advantage that harmful halogen compound gas hardly leaks out of the reaction system. From such a viewpoint, the reaction temperature is preferably 10 ° C or lower, more preferably 5 ° C or lower.
　また、高エネルギー光の照射後、高エネルギー光を照射せず、例えば蛍光灯などの一般光の下、１０℃以上６０℃以下で１分間以上５時間以下程度、Ｃ1-4ハロゲン化炭化水素の分解物とアミド化合物との反応を継続してもよい。 Further, after irradiation with high energy light, high energy without irradiating the light, for example, under the general light such as a fluorescent lamp, the degree or more to 5 hours or less for 1 minute at 10 ° C. or higher 60 ° C. or less, C 1-4 halogenated hydrocarbons The reaction between the decomposed product of and the amide compound may be continued.
　本発明の製造方法に使用できる反応装置としては、反応容器に光照射手段を備えたものが挙げられる。反応装置には、攪拌装置や温度制御手段が備えられていてもよい。図１に、本発明の製造方法に使用できる反応装置の一態様を示す。図１に示す反応装置は、筒状反応容器６内に光照射手段１を有するものである。筒状反応容器６内に、上記各原料化合物を添加し、当該反応容器６内に酸素を含有する気体を供給または上記混合物に酸素を含有する気体をバブリングしながら（図示せず）、光照射手段１より光を照射して反応を行う。前記光照射手段１をジャケット２等で覆う場合、該ジャケットは、前記短波長光を透過する素材であることが好ましい。また、反応容器の外側から光照射を行ってもよく、この場合、反応容器は、前記短波長光を透過する素材であることが好ましい。前記短波長光を透過する素材としては、本発明の効果を妨げない限り特に限定されないが、石英ガラス等が好ましく挙げられる。 反 応 As a reaction device that can be used in the production method of the present invention, a reaction device provided with a light irradiation means in a reaction container can be mentioned. The reaction device may be provided with a stirring device or a temperature control means. FIG. 1 shows one embodiment of a reactor 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 in a tubular reaction vessel 6. The above-mentioned each raw material compound is added into the cylindrical reaction vessel 6, and light is irradiated 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 performed by irradiating light from the means 1. When the light irradiating 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. Light irradiation may be performed from the outside of the reaction vessel. In this case, the reaction vessel 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 the effect of the present invention is not impaired, but quartz glass is preferably exemplified.
　アミド化合物として上記式（ＩＩ）で表される化合物を用いた場合には、生成するビルスマイヤー試薬は下記式（Ｉ）で表される塩である。 When the compound represented by the above formula (II) is used as the amide compound, the resulting Vilsmeier reagent is a salt represented by the following formula (I).
Figure JPOXMLDOC01-appb-C000006
［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。］
Figure JPOXMLDOC01-appb-C000006
[Wherein, R 1 to R 3 have the same meanings as described above, X represents a halogeno group selected from the group consisting of chloro, bromo and iodo, and Y − represents a counter anion. ]
　式（Ｉ）におけるＹ-としては、Ｃ1-4ハロゲン化炭化水素由来の塩化物イオン、臭化物イオン、およびヨウ化物イオンが挙げられるが、特に制限されない。
　式（Ｉ）で表される塩としては、入手容易性の観点から、Ｘがクロロであり、且つＹ-が塩化物イオンである化合物が好ましい。 Examples of Y − in formula (I) include, but are not particularly limited to, chloride ions, bromide ions, and iodide ions derived from C 1-4 halogenated hydrocarbons.
As the salt represented by the formula (I), a compound in which X is chloro and Y - is a chloride ion is preferable from the viewpoint of availability.
　ビルスマイヤー試薬を含む上記反応液へ更にビルスマイヤー試薬と反応可能な化合物を添加することにより、同一系内で更なる反応を進行せしめることが可能である。例えば、ビルスマイヤー試薬により活性基を有する芳香族化合物をアルデヒド化またはケトン化できることが知られている。かかる反応はビルスマイヤー・ハック反応（Ｖｉｌｓｍｅｉｅｒ－Ｈａａｃｋ　ｒｅａｃｔｉｏｎ）として知られている。また、ビルスマイヤー試薬は、カルボン酸化合物のカルボキシ基をハロホルミル基に変換することが知られている。更に、ビルスマイヤー試薬に水酸基含有化合物を反応させることにより、ギ酸エステルが得られる。 By further adding a compound capable of reacting with the Vilsmeier reagent to the reaction solution containing the Vilsmeier reagent, it is possible to cause a further reaction to proceed in 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. Further, it is known that the Vilsmeier reagent converts a carboxy group of a carboxylic acid compound into a haloformyl group. Further, a formic ester is obtained by reacting a hydroxyl group-containing compound with a Vilsmeier reagent.
　活性基を有する芳香族化合物（以下、「活性芳香族化合物」という）は、置換基などにより活性化された芳香族化合物である。例えば、アルキル基で置換されたアルキルアミノ基を含むアミノ基や水酸基などは、芳香族化合物を強く活性化する。また、アルキルカルボニルアミノ基（－Ｎ（Ｃ＝Ｏ）Ｒ）、アルキルカルボニルオキシ基（－Ｏ（Ｃ＝Ｏ）Ｒ）、エーテル基（－ＯＲ）、アルキル基（－Ｒ）（Ｒはアルキル基を示し、Ｃ1-6アルキル基が好ましい）、および芳香族基も、芳香族化合物を活性化する。以下、これら置換基を活性化基という。また、アントラセンなどのように、芳香族環が縮合して共役系が拡張しているような化合物も活性化されており、ビルスマイヤー試薬によるアルデヒド化やケトン化を受ける。活性化されている部位のπ電子が求電子的にビルスマイヤー試薬と反応し、アルデヒド化やケトン化されると考えられる。 An aromatic compound having an active group (hereinafter, referred to as “active aromatic compound”) is an aromatic compound activated by a substituent or the like. For example, an amino group containing an alkylamino group substituted with an alkyl group or a hydroxyl group strongly activates an aromatic compound. Further, an alkylcarbonylamino group (—N (C ＝ O) R), an alkylcarbonyloxy group (—O (C ＝ O) R), an ether group (—OR), an alkyl group (—R) (R is an alkyl group And a C 1-6 alkyl group is preferred), and aromatic groups also activate aromatic compounds. Hereinafter, these substituents are referred to as activating groups. In addition, compounds such as anthracene, in which an aromatic ring is condensed and a conjugated system is expanded, are also activated, and are subjected to aldehyde or ketone formation by a Vilsmeier reagent. It is considered that the π electron at the activated site is electrophilically reacted with the Vilsmeier reagent, and is converted into an aldehyde or a ketone.
　活性芳香族化合物は、活性化されておりビルスマイヤー試薬によりアルデヒド化またはケトン化される化合物であれば特に制限されないが、例えば、上記活性化基により置換されたベンゼンやナフタレンなどのＣ1-10芳香族炭化水素；フェナンスレンやアントラセンなど、上記活性化基により置換されていてもよい縮合芳香族炭化水素；ピロール、イミダゾール、ピラゾール、チオフェン、フラン、オキサゾール、イソキサゾール、チアゾール、イソチアゾール、チアジアゾール等、上記活性化基により置換されていてもよい５員環ヘテロアリール基；ピリジン、ピラジン、ピリミジン、ピリダジン等、上記活性化基により置換されていてもよい６員環ヘテロアリール；インドール、イソインドール、キノリン、イソキノリン、ベンゾフラン、イソベンゾフラン、クロメン等、上記活性化基により置換されていてもよい縮合ヘテロアリールを挙げることができる。なお、無置換のフランやチオフェンなどは、従来のビルスマイヤー・ハック反応でのアルデヒド化やケトン化の報告例は無いが、本発明方法によればヘテロ元素に隣接する炭素におけるアルデヒド化やケトン化が可能である。 The active aromatic compound is not particularly limited as long as it is activated and can be aldehyde or ketonized by the Vilsmeier reagent. For example, C 1-10 such as benzene or naphthalene substituted by the activating group can be used. Aromatic hydrocarbons; condensed aromatic hydrocarbons which may be substituted by the above activating groups such as phenanthrene and anthracene; pyrrole, imidazole, pyrazole, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, etc. A 5-membered heteroaryl group which may be substituted by an activating group; a 6-membered heteroaryl which may be substituted by the activating group such as pyridine, pyrazine, pyrimidine and pyridazine; indole, isoindole, quinoline, Isoquinoline, benzofuran Isobenzofuran, chromene, etc., can be given good fused heteroaryl optionally substituted by the activation group. In addition, there are no reports of aldehyde conversion or ketonization of unsubstituted furan or thiophene in the conventional Vilsmeier-Hack reaction, but according to the method of the present invention, aldehyde conversion or ketonization at carbon adjacent to a hetero element is performed. Is possible.
　活性芳香族化合物の使用量は適宜調整すればよいが、例えば、アミド化合物に対して０．１倍モル以上１．０倍モル以下とすることができる。 使用 The amount of the active aromatic compound to be used may be appropriately adjusted, and may be, for example, 0.1 to 1.0 times the mol of the amide compound.
　アルデヒド化またはケトン化の反応条件は、適宜決定すればよい。例えば、薄層クロマトグラフィやＮＭＲなどでアミド化合物の消費とビルスマイヤー試薬の生成を確認した後に活性芳香族化合物を反応溶液に添加すればよい。活性芳香族化合物は、そのまま添加してもよいし、活性芳香族化合物の溶液を添加してもよい。活性芳香族化合物溶液の溶媒としては、活性芳香族化合物を適度に溶解でき且つ反応を阻害しないものであれば特に制限されないが、例えば、ジクロロメタン、クロロホルム、四塩化炭素、クロロプロパン、クロロブタン、クロロペンタン、クロロヘキサンなどのハロゲン化炭化水素溶媒；アセトンやメチルエチルケトンなどのケトン系溶媒；アセトニトリルなどのニトリル系溶媒；ベンゼン、トルエン、クロロベンゼンなどの芳香族炭化水素溶媒；ジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒を挙げることができる。アルデヒド化またはケトン化の反応条件も適宜調整すればよいが、例えば、反応温度は、活性芳香族化合物の添加時温度も含め、－１０℃以上、加熱還流条件とすることができ、反応時間は、１０分間以上２０時間以下とすることができる。なお、式（Ｉ）および式（ＩＩ）の化合物においてＲ1が水素原子である場合は芳香族アルデヒドが得られ、Ｒ1がアルキル基または芳香族炭化水素基である場合は芳香族ケトンが得られる。 The reaction conditions for aldehyde conversion or ketonization may be determined appropriately. For example, the active aromatic compound may be added to the reaction solution after confirming consumption of the amide compound and formation 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.For example, 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 the aldehyde or ketonization may be appropriately adjusted. For example, the reaction temperature may be -10 ° C. or higher, including the temperature at the time of addition of the active aromatic compound, and the heating and reflux conditions may be employed. For 10 minutes to 20 hours. In the compounds of the formulas (I) and (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. Can be
　反応後には、通常の後処理や精製をしてもよい。例えば、反応後の反応液に飽和炭酸ナトリウム水溶液や飽和炭酸水素ナトリウム水溶液を加えて反応を停止させ、分液し、水層を有機溶媒で抽出し、有機層と抽出液を合わせて無水硫酸ナトリウムや無水硫酸マグネシウムで乾燥し、減圧濃縮した後、再結晶、シリカゲルカラムクロマトグラフィ、蒸留などの常法により目的化合物である芳香族アルデヒドや芳香族ケトンを精製すればよい。 通常 After the reaction, ordinary post-treatment and purification may be performed. For example, a saturated sodium carbonate aqueous solution or a saturated sodium bicarbonate aqueous solution is added to the reaction solution after the reaction to stop the reaction, liquid separation is performed, the aqueous layer is extracted with an organic solvent, and the organic layer and the extract are combined to obtain anhydrous sodium sulfate. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the target compound, an aromatic aldehyde or aromatic ketone, may be purified by a conventional method such as recrystallization, silica gel column chromatography, or distillation.
　ビルスマイヤー試薬によりカルボン酸化合物のカルボキシ基をハロホルミル基に変換する場合には、カルボン酸化合物を上記Ｃ1-4ハロゲン化炭化水素とアミド化合物を含む組成物へ光照射前に添加してもよいし、光照射前から光照射中を経て光照射後にかけてカルボン酸化合物を断続的または連続的に適時添加してよいし、光照射後にカルボン酸化合物を添加してもよい。即ち、ビルスマイヤー試薬の製造工程の後にカルボン酸化合物を添加してカルボキシ基をハロホルミル基に変換する工程を行ってもよいし、両工程を同時に行ってもよい。 When the carboxy group of the carboxylic acid compound is converted to a haloformyl group by the Vilsmeier reagent, the carboxylic acid compound may be added to the composition containing the C 1-4 halogenated hydrocarbon and the amide compound before light irradiation. Then, the carboxylic acid compound may be added intermittently or continuously at appropriate times before the light irradiation, during the light irradiation, and 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 to a haloformyl group after the step of producing the Vilsmeier reagent may be performed, or both steps may be performed simultaneously.
　カルボキシ基をハロホルミル基に変換するカルボン酸化合物としては、例えば、下記式（ＩＩＩ）で表される化合物を挙げることができる。
　　Ｒ4－（ＣＯ2Ｈ）n　　　　（ＩＩＩ）
［式中、Ｒ4はｎ価の有機基を示し、ｎは１以上４以下の整数を示す。］ Examples of the carboxylic acid compound converting a carboxy group to a haloformyl group include a compound represented by the following formula (III).
R 4 - (CO 2 H) n (III)
[Wherein, R 4 represents an n-valent organic group, and n represents an integer of 1 or more and 4 or less. ]
　有機基は、反応を阻害しない限り特に制限されないが、例えば、置換基を有していてもよいＣ1-18炭化水素基および置換基を有していてもよい上記ヘテロアリール基を挙げることができる。置換基としては、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲノ基、ニトロ基およびシアノ基からなる群より選択される１以上の置換基を挙げることができる。また、Ｃ1-18炭化水素基としては、例えば、１価のＣ1-18アルキル基、Ｃ2-18アルケニル基、Ｃ2-18アルキニル基、Ｃ6-18芳香族炭化水素基、および２価以上４価以下のこれらに対応する炭化水素基を挙げることができる。また、Ｃ1-18アルキル基、Ｃ2-18アルケニル基、Ｃ2-18アルキニル基においては、１以上の炭素原子が－Ｏ－、－Ｓ－、－ＮＲ5－（Ｒ5は水素原子またはＣ1-6アルキル基などのアルキル基を示す）などのヘテロ原子で置換されていてもよい。 The organic group is not particularly limited as long as it does not inhibit the reaction. Examples thereof include a C 1-18 hydrocarbon group which may have a substituent and the above-mentioned heteroaryl group which may have a substituent. it 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. 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 2-18 hydrocarbon group. Hydrocarbon groups corresponding to those having a valence of 4 or more and 4 or less can be mentioned. 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 And a hetero atom such as a C 1-6 alkyl group).
　カルボン酸化合物は、そのまま添加してもよいし、カルボン酸化合物の溶液を添加してもよい。カルボン酸化合物溶媒の溶媒としては、カルボン酸化合物を適度に溶解でき且つ反応を阻害しないものであれば特に制限されないが、例えば、ジクロロメタン、クロロホルム、四塩化炭素、クロロプロパン、クロロブタン、クロロペンタン、クロロヘキサンなどのハロゲン化炭化水素溶媒；ベンゼン、トルエン、クロロベンゼンなどの芳香族炭化水素溶媒；ジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒を挙げることができる。 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. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, and chlorohexane. Halogenated hydrocarbon solvents such as benzene, toluene, chlorobenzene and the like; and ether solvents such as diethyl ether, tetrahydrofuran and dioxane.
　カルボン酸化合物の使用量は適宜調整すればよいが、例えば、アミド化合物に対して０．１倍モル以上３．０倍モル以下とすることができる。 使用 The amount of the carboxylic acid compound to be used may be appropriately adjusted, and may be, for example, 0.1 to 3.0 times the mol of the amide compound.
　カルボキシ基をハロホルミル基に変換する反応の条件は、適宜決定すればよい。例えば、反応温度を０℃以上５０℃以下、反応時間を１０分間以上２０時間以下とすることができる。 The conditions for the reaction for converting a carboxy group to a haloformyl group may be determined as appropriate. For example, the reaction temperature can be from 0 ° C. to 50 ° C., and the reaction time can be from 10 minutes to 20 hours.
　カルボン酸ハロゲン化物は反応性が高く不安定である場合が多いため、単離は難しいことがある。よって、ビルスマイヤー試薬とカルボン酸化合物との反応後、アルコール化合物やアミン化合物など、カルボン酸ハロゲン化物と反応させるべき化合物を反応液に添加することが好ましい。当該反応後は通常の後処理を行ってもよく、目的化合物を常法により精製してもよい。 Carboxylic acid halides are often highly reactive and unstable, so isolation may be difficult. Therefore, after the reaction of the Vilsmeier reagent 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, a usual post-treatment may be performed, or the target compound may be purified by a conventional method.
　ビルスマイヤー試薬と水酸基含有化合物を反応させてギ酸エステルを得る場合には、水酸基含有化合物を上記Ｃ1-4ハロゲン化炭化水素とアミド化合物を含む組成物へ光照射前に添加してもよいし、光照射前から光照射中を経て光照射後にかけて水酸基含有化合物を断続的または連続的に適時添加してよいし、光照射後に水酸基含有化合物を添加してもよい。即ち、ビルスマイヤー試薬の製造工程の後に水酸基含有化合物を添加する工程を行ってもよいし、両工程を同時に行ってもよい。水酸基含有化合物は、そのまま添加してもよいし、水酸基含有化合物の溶液を添加してもよい。水酸基含有化合物溶液の溶媒としては、水酸基含有化合物を適度に溶解でき且つ反応を阻害しないものであれば特に制限されないが、例えば、ジクロロメタン、クロロホルム、四塩化炭素、クロロプロパン、クロロブタン、クロロペンタン、クロロヘキサンなどのハロゲン化炭化水素溶媒；アセトニトリルなどのニトリル系溶媒；ジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒を挙げることができる。 When a formic 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 the amide compound before light irradiation. The hydroxyl group-containing compound may be added intermittently or continuously as appropriate before or after the light irradiation, after the light irradiation, and 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 step of producing the Vilsmeier reagent, or both steps may be performed simultaneously. The hydroxyl group-containing compound may be added as it 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. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, chloropropane, chlorobutane, chloropentane, and chlorohexane. Halogenated hydrocarbon solvents such as acetonitrile; ether solvents such as diethyl ether, tetrahydrofuran and dioxane.
　水酸基含有化合物は、反応性水酸基を１以上有する化合物であれば特に制限されず、例えば、アルコール化合物とフェノール化合物を挙げることができる。 The hydroxyl group-containing compound is not particularly limited as long as it has at least one reactive hydroxyl group, and examples thereof include an alcohol compound and a phenol compound.
　アルコール化合物としては、例えば、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｓ－ブタノール、ｔ－ブタノール、ｎ－ペンタノール、イソペンタノールなどのＣ1-20アルコール；トリフルオロメタノール、２－フルオロエタノール、２－クロロエタノール、２－ブロモエタノール、２－ヨードエタノール、２，２，２－フルオロエタノールなどのＣ1-20ハロゲノアルコール；エチレングリコール、プロピレングリコール、１，４－ブタンジオール、１，６－ヘキサンジオールなどのジオール化合物；グリセリンなどのトリオール化合物；ペンタエリスリトールなどのテトラオール化合物などを挙げることができる。 Examples of the alcohol compound include C 1-20 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, t-butanol, n-pentanol and isopentanol; 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 thereof include diol compounds such as diol and 1,6-hexanediol; triol compounds such as glycerin; and tetraol compounds such as pentaerythritol.
　フェノール化合物としては、例えば、フェノール、ナフトール、クレゾール、ブチルフェノール、アミルフェノール、クロロフェノール、ブロモフェノールなどの１価フェノール化合物；カテコール、ビスフェノールＡ～Ｇ、ビスフェノールＭ、ビスフェノールＳ、ビスフェノールＰ、ビスフェノールＺなどの２価フェノール化合物；トリヒドロキシベンゼンなどの３価フェノール化合物を挙げることができる。 Examples of the phenol compound include monohydric phenol compounds such as phenol, naphthol, cresol, butylphenol, amylphenol, chlorophenol, and bromophenol; catechol, bisphenol AG, bisphenol M, bisphenol S, bisphenol P, bisphenol Z, and the like. Dihydric phenol compounds; trihydric phenol compounds such as trihydroxybenzene can be exemplified.
　水酸基含有化合物の使用量は適宜調整すればよいが、例えば、水酸基を１個有する水酸基含有化合物の使用量は、アミド化合物に対して０．１倍モル以上３．０倍モル以下とすることができる。水酸基をｍ個有する水酸基含有化合物の使用量は、１個有する水酸基含有化合物の使用量の１／ｍを目安として調整すればよい。 The amount of the hydroxyl group-containing compound used may be appropriately adjusted. For example, the amount of the hydroxyl group-containing compound having one hydroxyl group may be 0.1 to 3.0 times the amide compound. it can. The amount of the hydroxyl group-containing compound having m hydroxyl groups may be adjusted using 1 / m of the amount of the hydroxyl group-containing compound having one hydroxyl group as a guide.
　ビルスマイヤー試薬と水酸基含有化合物との反応条件は、適宜決定すればよい。例えば、水酸基含有化合物の添加後、反応温度を－１０℃以上５０℃以下、反応時間を１０分間以上２０時間以下とすることができる。 The reaction conditions of the Vilsmeier reagent and the hydroxyl group-containing compound may be determined as appropriate. For example, after the addition of the hydroxyl group-containing compound, the reaction temperature can be from -10 ° C to 50 ° C, and the reaction time can be from 10 minutes to 20 hours.
　反応後には、通常の後処理や精製をしてもよい。例えば、反応後の反応液に飽和炭酸ナトリウム水溶液や飽和炭酸水素ナトリウム水溶液を加えて反応を停止させ、分液し、水層を有機溶媒で抽出し、有機層と抽出液を合わせて無水硫酸ナトリウムや無水硫酸マグネシウムで乾燥し、減圧濃縮した後、再結晶、シリカゲルカラムクロマトグラフィ、蒸留などの常法により目的化合物であるギ酸エステルを精製すればよい。 通常 After the reaction, ordinary post-treatment and purification may be performed. For example, a saturated sodium carbonate aqueous solution or a saturated sodium bicarbonate aqueous solution is added to the reaction solution after the reaction to stop the reaction, liquid separation is performed, the aqueous layer is extracted with an organic solvent, and the organic layer and the extract are combined to obtain anhydrous sodium sulfate. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the formic ester as the target compound may be purified by a conventional method such as recrystallization, silica gel column chromatography, or distillation.
　本願は、２０１８年９月６日に出願された日本国特許出願第２０１８－１６７０３２号に基づく優先権の利益を主張するものである。２０１８年９月６日に出願された日本国特許出願第２０１８－１６７０３２号の明細書の全内容が、本願に参考のため援用される。 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 herein by reference.
　以下、実施例を挙げて本発明をより具体的に説明するが、本発明はもとより下記実施例によって制限を受けるものではなく、前・後記の趣旨に適合し得る範囲で適当に変更を加えて実施することも勿論可能であり、それらはいずれも本発明の技術的範囲に包含される。 Hereinafter, the present invention will be described more specifically with reference to Examples. However, the present invention is not limited to the following Examples, and may be appropriately modified within a range that can conform to the purpose of the preceding and the following. It is, of course, possible to implement them, and all of them are included in the technical scope of the present invention.
　実施例１：　ビルスマイヤー試薬の製造
　中央に直径３０ｍｍの石英ガラスジャケットを装着した筒状反応容器（直径４２ｍｍ）を用意し、石英ガラスジャケットに低圧水銀ランプ（ＳＥＮ　Ｌｉｇｈｔ社製、ＵＶＬ２０ＰＨ－６、２０Ｗ、φ２４×１２０ｍｍ）を入れ、反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（１．５５ｍＬ，２０ｍｍｏｌ）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、温度３０℃で２時間反応を行った。続いて、酸素ガスの供給と光照射を中止し、５０℃で１．５時間反応液を攪拌した。その後、攪拌を中止したところ、反応液は二層に分離していた。
　各層を1Ｈ－ＮＭＲで分析したところ、下層にはビルスマイヤー試薬のピークはほとんど見られなかった。一方、上層にはビルスマイヤー試薬である（クロロメチレン）ジメチルイミニウムクロリドのピークが認められた。また、上層における残留ＤＭＦとビルスマイヤー試薬との比（ＤＭＦ：ビルスマイヤー試薬）は、ピーク強度より約１：４であり、最大で１６ｍｍｏｌのビルスマイヤー試薬が生成していると見積もられた。 Example 1 Production of Vilsmeier Reagent A tubular reaction vessel (diameter 42 mm) equipped with a quartz glass jacket having 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 provided in 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. The reaction was carried out at a temperature of 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, supply of oxygen gas and light irradiation were stopped, and the reaction solution was stirred at 50 ° C. for 1.5 hours. Thereafter, when the stirring was stopped, the reaction solution was separated into two layers.
When each layer was analyzed by 1 H-NMR, almost no peak of the Vilsmeier reagent was found in the lower layer. On the other hand, a peak of (chloromethylene) dimethyliminium chloride, a Vilsmeier reagent, was observed in the upper layer. The ratio of residual DMF to the Vilsmeier reagent in the upper layer (DMF: Vilsmeier reagent) was about 1: 4 from the peak intensity, and it was estimated that a maximum of 16 mmol of the Vilsmeier reagent was generated.
　実施例２：　ピロール－２－カルボキシアルデヒドの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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、反応温度を５０℃に上げ、泡が発生しなくなるまで攪拌した。その後、反応容器をアイスバスに浸漬し、ピロール（０．７４ｍＬ，１０ｍｍｏｌ）を加え、３０分間加熱還流した。次いで、飽和炭酸ナトリウム水溶液（３０ｍＬ）を加え、１５分間攪拌した。二層に分離した反応液を分液し、水層をジエチルエーテルで抽出した。有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、目的化合物であるピロール－２－カルボキシアルデヒドの生成を確認することができた（収率：８２％）。 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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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, pyrrole (0.74 mL, 10 mmol) was added, and the mixture was heated under reflux for 30 minutes. Then, a saturated aqueous solution of sodium carbonate (30 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution separated into two layers was separated, and the aqueous layer was extracted with diethyl ether. 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, formation of pyrrole-2-carboxaldehyde, which was the target compound, could be confirmed (yield: 82%).
　実施例３：　１－メチル－２－ピロールカルボキシアルデヒドの製造
　実施例２において、ピロールの代わりに１－メチルピロール（０．７４ｍＬ，１０ｍｍｏｌ）のクロロホルム（５ｍＬ）溶液を用い、水層をジクロロメタンで抽出した以外は同様にして濃縮物を得た。濃縮物を1Ｈ－ＮＭＲで分析したところ、目的化合物である１－メチル－２－ピロールカルボキシアルデヒドの生成を確認することができた（収率＞９９％）。 Example 3: Production of 1-methyl-2-pyrrolecarboxaldehyde In Example 2, a chloroform solution (5 mL) of 1-methylpyrrole (0.74 mL, 10 mmol) was used instead of pyrrole, and the aqueous layer was extracted with dichloromethane. A concentrate was obtained in the same manner except that the above procedure was performed. When the concentrate was analyzed by 1 H-NMR, it was possible to confirm the formation of 1-methyl-2-pyrrolecarboxaldehyde as a target compound (yield> 99%).
　実施例４：　２－ホルミルフランの製造
　実施例２において、ピロールの代わりにフラン（０．７３ｍＬ，１０ｍｍｏｌ）を用い、フランを添加してから０℃で３０分間、続いて常温で２時間反応させ、水層をジクロロメタンで抽出した以外は同様にして濃縮物を得た。濃縮物を1Ｈ－ＮＭＲで分析したところ、目的化合物である２－ホルミルフランの生成を確認することができた（収率：６０％）。このように、これまでビルスマイヤー試薬による無置換フランのホルミル化は報告されていないが、本発明によれば無置換フランのホルミル化が可能であることが実証された。 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 allowed to proceed at 0 ° C for 30 minutes, and then at room temperature for 2 hours. Then, 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, formation of 2-formylfuran as a target compound could be confirmed (yield: 60%). As described above, no formylation of unsubstituted furan with the Vilsmeier reagent has been reported, but it has been demonstrated that the present invention allows formylation of unsubstituted furan.
　実施例５：　５－メチルフルフラールの製造
　中央に直径３０ｍｍの石英ガラスジャケットを装着した筒状反応容器（直径４２ｍｍ）を用意し、石英ガラスジャケットに低圧水銀ランプ（ＳＥＮ　Ｌｉｇｈｔ社製、ＵＶＬ２０ＰＨ－６、２０Ｗ、φ２４×１２０ｍｍ）を入れ、反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（３．５ｍＬ，４５ｍｍｏｌ）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３時間反応を行った。続いて、反応温度を５０℃に上げ、泡が発生しなくなるまで攪拌した。その後、反応容器を氷浴に浸漬し、２－メチルフラン（０．９ｍＬ，１０ｍｍｏｌ）を加え、０℃で１時間攪拌した。次いで、飽和炭酸ナトリウム水溶液（３０ｍＬ）を加え、１５分間攪拌した。二層に分離した反応液を分液し、水層を酢酸エチルで抽出した。有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、目的化合物である５－メチルフルフラールの生成を確認することができた（収率：８０％）。 Example 5: Production of 5-methylfurfural A cylindrical reaction vessel (diameter 42 mm) equipped with a quartz glass jacket having a diameter of 30 mm in the center was prepared, and a low-pressure mercury lamp (manufactured by SEN Light, UVL20PH-6, 20 W, φ24 × 120 mm), and purified chloroform (20 mL, 248 mmol) and DMF (3.5 mL, 45 mmol) were added into the reaction vessel. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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, a saturated aqueous solution of sodium carbonate (30 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution separated into two layers was separated, and the aqueous layer was extracted with ethyl acetate. 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, the formation of 5-methylfurfural, which was the target compound, could be confirmed (yield: 80%).
　実施例６：　２－ホルミルチオフェンの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（１．２ｍＬ，１５ｍｍｏｌ）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、常温でチオフェン（０．７４ｍＬ，１０ｍｍｏｌ）を滴下し、６時間加熱還流した。次いで、反応液を０℃の飽和炭酸ナトリウム水溶液（３０ｍＬ）に加え、３０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、水層をクロロホルムで抽出した。有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、目的化合物である２－ホルミルチオフェンの生成を確認することができた（収率：６１％）。このように、これまでビルスマイヤー試薬による無置換チオフェンのホルミル化は報告されていないが、本発明によれば無置換チオフェンのホルミル化が可能であることが実証された。 Example 6: Production of 2-formylthiophene Purified chloroform (20 mL, 248 mmol) and DMF (1.2 mL, 15 mmol) were added into the reaction vessel of Example 1. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 refluxed for 6 hours. Then, the reaction solution was added to a saturated aqueous sodium carbonate solution (30 mL) at 0 ° C., and the mixture was stirred for 30 minutes. Chloroform was added to the reaction solution, the reaction solution separated into two layers was separated, and 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, formation of 2-formylthiophene as a target compound could be confirmed (yield: 61%). As described above, formylation of unsubstituted thiophene with the Vilsmeier reagent has not been reported, but it has been demonstrated that formalization of unsubstituted thiophene is possible according to the present invention.
　実施例７：　５－メチル－２－ホルミルチオフェンの製造
　実施例２において、ピロールの代わりに２－メチルチオフェン（０．９７ｍＬ，１０ｍｍｏｌ）を用いた以外は同様にして濃縮物を得た。濃縮物を1Ｈ－ＮＭＲで分析したところ、目的化合物である５－メチル－２－ホルミルチオフェンの生成を確認することができた（収率：５６％）。 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. When the concentrate was analyzed by 1 H-NMR, the formation of 5-methyl-2-formylthiophene as the target compound could be confirmed (yield: 56%).
　実施例８：　２－ホルミル－３－メチルチオフェンまたは２－ホルミル－４－メチルチオフェンの製造
　実施例２において、ピロールの代わりに３－メチルチオフェン（０．９７ｍＬ，１０ｍｍｏｌ）を用い、３－メチルチオフェンを滴下した後の加熱還流時間を２時間にした以外は同様にして濃縮物を得た。濃縮物を1Ｈ－ＮＭＲで分析したところ、２－ホルミル－３－メチルチオフェンの収率は７４％、２－ホルミル－４－メチルチオフェンの収率は１６％であった。 Example 8: Preparation 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 to obtain 3-methylthiophene. Was added in the same manner as above except that the heating and refluxing time after the dropwise addition 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%.
　実施例９：　２－ホルミル－３－メチルチオフェンまたは２－ホルミル－４－メチルチオフェンの製造
　実施例８において、ＤＭＦの代わりに１－ピロリジンカルボキシアルデヒド（１．９８ｍＬ，２０ｍｍｏｌ）を用いた以外は同様にして濃縮物を得た。濃縮物を1Ｈ－ＮＭＲで分析したところ、２－ホルミル－３－メチルチオフェンの収率は１１％、２－ホルミル－４－メチルチオフェンの収率は４％であった。 Example 9: Preparation of 2-formyl-3-methylthiophene or 2-formyl-4-methylthiophene Same as Example 8 except that 1-pyrrolidinecarboxaldehyde (1.98 mL, 20 mmol) was used instead of DMF. To give a concentrate. 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%.
　実施例１０：　３－ホルミルインドールの製造
　実施例２と同様にして、ビルスマイヤー試薬を含む反応液を調製した。当該反応液に、インドール（１．１７ｇ，１０ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液を加え、常温で２時間攪拌した。更に、７．５ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２０ｍＬ）を加え、０℃で１５分間攪拌した。二層に分離した反応液を分液し、水層をジエチルエーテルで抽出した。有機層と抽出液を合わせて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。濃縮物をシリカゲルクロマトグラフィ（溶離液：酢酸エチル／ジクロロエタン＝３／７）に付し、目的化合物である３－ホルミルインドールを得た（収率：７０％）。 Example 10: Production of 3-formylindole In the same manner as in Example 2, a reaction solution containing a Vilsmeier 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. Further, a 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 separated into two layers was separated, and the aqueous layer was extracted with diethyl ether. The organic layer and the 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１１：　ビピロール誘導体の光ホルミル化反応
Figure JPOXMLDOC01-appb-C000007
　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 derivative
Figure JPOXMLDOC01-appb-C000007
Purified chloroform (20 mL, 248 mmol) and DMF (0.56 mL, 7.23 mmol) were added into the reaction vessel of Example 1. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 above bipyrrole derivative (580 mg, 1.81 mmol) dissolved in chloroform (20 mL) was added while cooling the reaction solution with ice, and the mixture was refluxed for 30 minutes. Next, a saturated aqueous solution of sodium carbonate (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 separated into two layers was separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. By recrystallizing using a mixture of dichloromethane and methanol, a formylated bipyrrole derivative was obtained (yield: 66%).
　実施例１２：　ビス（ピロール－２－カルボキシアルデヒド）の製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（１．１５ｍＬ，１４．９ｍｍｏｌ）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、１０℃で６時間反応を行った。続いて、反応温度を５０℃に上げ、３０分間攪拌した。その後、反応容器をアイスバスに浸漬し、ビピロール（４２０ｍｇ，３．１８ｍｍｏｌ）を加え、３０分間加熱還流した。次いで、飽和炭酸ナトリウム水溶液（５０ｍＬ）を加え、１５分間攪拌した。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。残渣をメタノールで洗浄し、1Ｈ－ＮＭＲで分析したところ、目的化合物であるビス（ピロール－２－カルボキシアルデヒド）の生成を確認することができた（収量：２１０ｍｇ，収率：７３％）。 Example 12: Production of bis (pyrrole-2-carboxaldehyde) Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.15 mL, 14.9 mmol) were added. The reaction was carried out at 10 ° C. for 6 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 30 minutes. Thereafter, the reaction vessel was immersed in an ice bath, bipyrrole (420 mg, 3.18 mmol) was added, and the mixture was heated under reflux for 30 minutes. Next, a saturated aqueous solution of sodium carbonate (50 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution separated into two layers was separated, and 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. As a result, formation of the target compound bis (pyrrole-2-carboxaldehyde) was confirmed (yield: 210 mg, 73%).
　実施例１３：　ベンゾフランのホルミル化反応
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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、０℃で５時間反応を行った。続いて、反応温度を室温まで上げ、ベンゾフラン（１．０ｍＬ，９ｍｍｏｌ）を加え、７０℃で３０分間攪拌し、更に２０時間加熱還流した。次いで、飽和炭酸ナトリウム水溶液（２０ｍＬ）を加え、１５分間攪拌した。ジエチルエーテル（１０ｍＬ）を加え、二層に分離した反応液を分液し、水層をジエチルエーテルで抽出した。有機層を抽出液と合わせ、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液、および水で洗浄し、無水硫酸ナトリウムで乾燥した。不溶物を濾別し、濾液を減圧濃縮した。残渣をクロマトグラフィー（溶離液：ヘキサン／ジクロロメタン＝１／１（容量比））に付し、目的化合物である２－ホルミルベンゾフランを得た（収量：３９４ｍｇ，収率：３０％）。 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. The reaction was carried out at 0 ° C. for 5 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to room temperature, benzofuran (1.0 mL, 9 mmol) was added, and the mixture was stirred at 70 ° C. for 30 minutes, and further heated under reflux for 20 hours. Then, a saturated aqueous sodium carbonate solution (20 mL) was added, and the mixture was stirred for 15 minutes. Diethyl ether (10 mL) was added, the reaction solution separated into two layers was separated, and the aqueous layer was extracted with diethyl ether. The organic layer was combined with the extract, washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, and water, and dried over anhydrous sodium sulfate. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography (eluent: hexane / dichloromethane = 1/1 (volume ratio)) to obtain 2-formylbenzofuran as a target compound (yield: 394 mg, 30%).
　実施例１４：　フェニルピロリルケトンの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＮ，Ｎ－ジメチルベンズアミド（３ｇ，２０ｍｍｏｌ）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３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、ピロール（０．７ｍＬ，１０ｍｍｏｌ）を加え、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を加え、３０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、水層をクロロホルムで抽出した。有機層と抽出液を合わせて１５０℃で減圧濃縮した後、シリカゲルカラムクロマトグラフィ（溶離液：ジクロロメタン／酢酸エチル）で精製することにより、目的化合物を得た（収量：０．３２ｇ，収率：９．３％）。 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. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the light irradiation was stopped, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 30 minutes. Thereafter, pyrrole (0.7 mL, 10 mmol) was added, and the mixture was heated under reflux for 30 minutes. Next, a saturated aqueous solution of sodium carbonate was added to the reaction solution, and the mixture was stirred for 30 minutes. Chloroform was added to the reaction solution, the reaction solution separated into two layers was separated, and the aqueous layer was extracted with chloroform. The combined organic layer and extract were concentrated under reduced pressure at 150 ° C., and then purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate) to obtain the desired compound (yield: 0.32 g, 9). .3%).
　実施例１５：　２－アセチルピロールの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＮ，Ｎ－ジメチルアセトアミド（１．７ｇ，２０ｍｍｏｌ）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３時間反応を行った。続いて、光照射を停止し、３０℃で３０分間攪拌した。その後、ピロール（０．７ｍＬ，１０ｍｍｏｌ）を加え、一晩攪拌した。次いで、生じた不溶性塩を吸引濾過により除去し、濾液を減圧濃縮することにより、目的化合物を得た（収量：０．３９ｇ，収率：３６．０％）。 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. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the light irradiation was stopped, and the mixture was stirred at 30 ° C. for 30 minutes. Thereafter, pyrrole (0.7 mL, 10 mmol) was added, and the mixture was stirred overnight. Next, the resulting insoluble salts were removed by suction filtration, and the filtrate was concentrated under reduced pressure to obtain the desired compound (yield: 0.39 g, yield: 36.0%).
　比較例１
　実施例１の反応容器内に精製クロロホルム（３０ｍＬ，３７２ｍｍｏｌ）と安息香酸（１．２２ｇ，１０ｍｍｏｌ）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、１０℃で３時間反応を行った。1Ｈ－ＮＭＲにより反応液を分析したが、反応はまったく進行していなかった。反応が進行しなかった理由は、おそらく、アミド化合物を用いなかったためにビルスマイヤー試薬が生成しなかったことによると考えられる。 Comparative Example 1
Purified chloroform (30 mL, 372 mmol) and benzoic acid (1.22 g, 10 mmol) were added into the reaction vessel of Example 1. The reaction was carried out at 10 ° C. for 3 hours while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while stirring the mixed solution. 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 due to the fact that the Vilsmeier reagent was not generated because no amide compound was used.
　実施例１６：　塩化ベンゾイルの製造とそのアミド化
　実施例１の反応容器内に精製クロロホルム（３０ｍＬ，３７２ｍｍｏｌ）、ＤＭＦ（０．４ｍＬ，５ｍｍｏｌ）および安息香酸（１．２２ｇ，１０ｍｍｏｌ）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、１０℃で３時間反応を行った。1Ｈ－ＮＭＲにより反応液を分析したところ、塩化ベンゾイルが９５％の収率で生成していた。
　上記反応液に常温でアニリン（３．６５ｍＬ，４０ｍｍｏｌ）を加え、常温で１時間攪拌した後、反応液を濾過した。濾液に５％塩酸を加え、ジクロロメタンで抽出した。抽出液を水で洗浄した後、無水硫酸ナトリウムで乾燥し、濾過し、減圧濃縮した。得られた黄褐色濃縮物をアセトン／ｎ－ヘキサン混合溶媒を使って再結晶することにより、ベンズアニリドを得た（単離収率：６１％）。 Example 16: Production of benzoyl chloride and amidation thereof Into the reaction vessel of Example 1, purified chloroform (30 mL, 372 mmol), DMF (0.4 mL, 5 mmol) and benzoic acid (1.22 g, 10 mmol) were added. The reaction was carried out at 10 ° C. for 3 hours while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, 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 the mixture was stirred at room temperature for 1 hour, and then the reaction solution was filtered. The filtrate was added with 5% hydrochloric acid and 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 a mixed solvent of acetone / n-hexane to obtain benzanilide (isolation yield: 61%).
　実施例１７：　塩化ベンゾイルの製造
　実施例１の反応容器内に精製クロロホルム（３０ｍＬ，３７２ｍｍｏｌ）、ＤＭＦ（０．４ｍＬ，５ｍｍｏｌ）および安息香酸（１．２２ｇ，１０ｍｍｏｌ）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。1Ｈ－ＮＭＲにより反応液を分析したところ、塩化ベンゾイルが定量的に生成していた。 Example 17: Production of benzoyl chloride Into the reaction vessel of Example 1, purified chloroform (30 mL, 372 mmol), DMF (0.4 mL, 5 mmol) and benzoic acid (1.22 g, 10 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, benzoyl chloride was quantitatively formed.
　実施例１８：　塩化ベンゾイルの製造
　実施例１の反応容器内にテトラクロロエチレン（３０ｍＬ，２９３ｍｍｏｌ）、ＤＭＦ（０．４ｍＬ，５ｍｍｏｌ）および安息香酸（１．２２ｇ，１０ｍｍｏｌ）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。1Ｈ－ＮＭＲにより反応液を分析したところ、塩化ベンゾイルが収率８．５％で生成していた。 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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, benzoyl chloride was produced in a yield of 8.5%.
　実施例１９：　塩化アセチルの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（０．４ｍＬ，５ｍｍｏｌ）および酢酸（０．５７ｍＬ，１０ｍｍｏｌ）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３時間反応を行った。1Ｈ－ＮＭＲにより反応液を分析したところ、塩化アセチルが収率９０％で生成していた。 Example 19: Production of acetyl chloride Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol), DMF (0.4 mL, 5 mmol) and acetic acid (0.57 mL, 10 mmol) were added. The reaction was carried out at 30 ° C. for 3 hours while irradiating the low pressure mercury lamp with light while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. When the reaction solution was analyzed by 1 H-NMR, acetyl chloride was produced in a yield of 90%.
　実施例２０：　塩化プロピオニルの製造
　実施例１９において、酢酸の代わりにプロピオン酸（０．６７ｍＬ，１０ｍｍｏｌ）を用いた以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、塩化プロピオニルの生成を確認することができた（収率：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, formation of propionyl chloride was confirmed (yield: 90%).
　実施例２１：　ジクロロ塩化アセチルの製造
　実施例１９において、酢酸の代わりにジクロロ酢酸（０．８２ｍＬ，１０ｍｍｏｌ）を用い、反応時間を２時間とした以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、ジクロロ塩化アセチルが定量的に生成していることを確認できた。 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 changed to 2 hours. When the reaction solution was analyzed by 1 H-NMR, it was confirmed that dichloroacetyl chloride was generated quantitatively.
　実施例２２：　塩化アクリロイルの製造
　実施例１９において、酢酸の代わりにアクリル酢酸（０．６９ｍＬ，１０ｍｍｏｌ）を用い、反応時間を２時間とした以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、塩化アクリロイルの生成を確認することができた（収率：１４％）。 Example 22: Production of acryloyl chloride The reaction was carried out in the same manner as in Example 19, except that acrylacetic 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, formation of acryloyl chloride was confirmed (yield: 14%).
　実施例２３：　塩化マロイルの製造
　実施例１９において、酢酸の代わりにマロン酸（１．０４ｇ，１０ｍｍｏｌ）を用い、ＤＭＦを２ｍＬ（２５ｍｍｏｌ）用いた以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、塩化マロイルの生成を確認することができた（収率：８２％）。 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, formation of maloyl chloride was confirmed (yield: 82%).
　実施例２４：　４－ニトロベンゾイルクロリドの製造
　実施例１９において、酢酸の代わりに４－ニトロ安息香酸（１．０４ｍＬ，１０ｍｍｏｌ）を用いた以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、４－ニトロベンゾイルクロリドの生成を確認することができた（収率：８３％）。 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, formation of 4-nitrobenzoyl chloride was confirmed (yield: 83%).
　実施例２５：　４－メトキシベンゾイルクロリドの製造
　実施例１９において、酢酸の代わりに４－メトキシ安息香酸（１．５２ｇ，１０ｍｍｏｌ）を用い、ＤＭＦを３．２ｍＬ（４６ｍｍｏｌ）用いた以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、４－メトキシベンゾイルクロリドの生成を確認することができた（収率：８９％）。 Example 25: Preparation of 4-methoxybenzoyl chloride In Example 19, 4-methoxybenzoic acid (1.52 g, 10 mmol) was used in place of acetic acid, and 3.2 mL (46 mmol) of DMF was used. The reaction was performed. When the reaction solution was analyzed by 1 H-NMR, formation of 4-methoxybenzoyl chloride was confirmed (yield: 89%).
　実施例２６：　２－チオフェンカルボニルクロリドの製造
　実施例１９において、酢酸の代わりに２－チオフェンカルボン酢酸（１．２８ｇ，１０ｍｍｏｌ）を用い、ＤＭＦを２ｍＬ（２５ｍｍｏｌ）用い、反応時間を２時間とした以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、２－チオフェンカルボニルクロリドの生成を確認することができた（収率：９３％）。 Example 26: Production of 2-thiophenecarbonyl chloride In Example 19, 2-thiophenecarboxylic acid (1.28 g, 10 mmol) was used instead of acetic acid, and 2 mL (25 mmol) of DMF was used, and the reaction time was set to 2 hours. The reaction was carried out in the same manner except for the above. When the reaction solution was analyzed by 1 H-NMR, formation of 2-thiophenecarbonyl chloride could be confirmed (yield: 93%).
　実施例２７：　２－フランカルボニルクロリドの製造
　実施例１９において、酢酸の代わりに２－フランカルボン酢酸（１．１２ｇ，１０ｍｍｏｌ）を用い、反応時間を２時間とした以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、２－フランカルボニルクロリドが定量的に生成していることを確認できた。 Example 27: Production of 2-furancarbonyl chloride The reaction was carried out in the same manner as in Example 19, except that 2-furancarboxylicacetic acid (1.12 g, 10 mmol) was used instead of acetic acid, and the reaction time was changed to 2 hours. Was. When the reaction solution was analyzed by 1 H-NMR, it was confirmed that 2-furancarbonyl chloride was generated quantitatively.
　実施例２８：　テレフタル酸ジアニリドの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（２．４ｍＬ，３０ｍｍｏｌ）およびテレフタル酸（０．４１ｇ，２．５ｍｍｏｌ）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、反応温度を５０℃に上げ、泡が発生しなくなるまで攪拌した。反応液を1Ｈ－ＮＭＲにより分析し、テレフタル酸ジクロリドの生成を確認した。
　上記反応液に常温でアニリン（３．５６ｍＬ，４０ｍｍｏｌ）を加え、常温で１０時間攪拌した後、０℃でメタノールを添加した。生じた白色沈殿を濾別し、白色粉末であるテレフタル酸ジアニリドを得た（単離収率：２４％）。 Example 28: Production of terephthalic acid dianilide Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol), DMF (2.4 mL, 30 mmol) and terephthalic acid (0.41 g, 2.5 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 formation of terephthalic acid dichloride.
Aniline (3.56 mL, 40 mmol) was added to the above reaction solution at room temperature, stirred at room temperature for 10 hours, and then methanol was added at 0 ° C. The resulting white precipitate was separated by filtration to obtain terephthalic acid dianilide as a white powder (isolation yield: 24%).
　実施例２９：　無水フタル酸の製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（０．８ｍＬ，１０ｍｍｏｌ）およびフタル酸（１．６６ｇ，１０ｍｍｏｌ）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。反応液を1Ｈ－ＮＭＲにより分析し、無水フタル酸の生成を確認した。なお、上記反応では、フタル酸からフタル酸ジクロリドがいったん生成し、更にフタル酸ジクロリドがＤＭＦと反応して無水フタル酸が生成したと考えられる。 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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. The reaction solution was analyzed by 1 H-NMR, and the formation of phthalic anhydride was confirmed. In the above reaction, it is considered that phthalic acid dichloride was once generated from phthalic acid, and phthalic acid dichloride was further reacted with DMF to generate phthalic anhydride.
　実施例３０：　２，２，２－トリフルオロプロピオン酸クロリドの製造
　実施例１９において、酢酸の代わりに２，２，２－トリフルオロプロピオン酸（０．８７ｍＬ，１０ｍｍｏｌ）を用い、ＤＭＦを０．３ｍＬ（４ｍｍｏｌ）用い、反応温度を２０℃とし、反応時間を２時間とした以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、２，２，２－トリフルオロプロピオン酸クロリドが定量的に生成していることを確認できた。 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 in place of acetic acid, and DMF was added at 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 generated quantitatively.
　実施例３１：　４－フルオロ安息香酸クロリドの製造
　実施例１９において、酢酸の代わりに４－フルオロ安息香酸（７１５ｍｇ，５ｍｍｏｌ）を用い、ＤＭＦを０．９ｍＬ（１１．６ｍｍｏｌ）用い、反応温度を２０℃とし、反応時間を２時間とした以外は同様にして反応を行った。反応液を1Ｈ－ＮＭＲで分析したところ、４－フルオロ安息香酸クロリドが定量的に生成していることを確認できた。 Example 31: Preparation 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 set to 20. The reaction was carried out in the same manner except that 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 generated quantitatively.
　実施例３２：　ペンタフルオロ安息香酸アニリドの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（０．４ｍＬ，５ｍｍｏｌ）およびペンタフルオロ安息香酸（１．０６ｇ，５ｍｍｏｌ）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、反応温度を５０℃に上げ、泡が発生しなくなるまで攪拌した。
　上記反応液にアニリン（０．４６ｍＬ，５ｍｍｏｌ）を加え、常温で３時間攪拌した。次いで、飽和炭酸水素ナトリウム水溶液を加え、分液し、有機層を飽和塩化ナトリウム水溶液で洗浄した。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。得られた濃縮物をシリカゲルカラムクロマトグラフィ（溶離液：酢酸エチル／ｎ－ヘキサン＝１／３（ｖ／ｖ）の混合溶媒）に付し、ペンタフルオロ安息香酸アニリドを得た（単離収率：３３％）。 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 into the reaction vessel of Example 1. . The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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. Next, a saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was separated. 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: a mixed solvent of ethyl acetate / n-hexane = 1/3 (v / v)) to obtain pentafluorobenzoic anilide (isolation yield: 33%).
　実施例３３：　ギ酸メチルの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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。
　上記反応液を０℃に冷却し、メタノール（０．８１ｍＬ，１０ｍｍｏｌ）を加え、常温で３０分間攪拌した。次いで、反応液を氷冷した飽和炭酸水素ナトリウム水溶液に加え、分液した。水層をクロロホルムで抽出し、有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、ギ酸メチルの生成を確認することができた（収率：５３％）。 Example 33: Production of methyl formate Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 mixture 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, formation of methyl formate could be confirmed (yield: 53%).
　実施例３４：　ギ酸エチルの製造
　メタノールの代わりにエタノール（０．７９ｍＬ，１０ｍｍｏｌ）を用いた以外は実施例３３と同様にして、ギ酸エチルを得た（収率：８８％）。 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%).
　実施例３５：　ギ酸イソプロピルの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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、１５分間攪拌した。
　上記反応液を０℃に冷却し、イソプロパノール（０．７７ｍＬ，１０ｍｍｏｌ）を加え、常温で１２時間攪拌した。次いで、反応液を氷冷した飽和炭酸水素ナトリウム水溶液に加え、３０分間撹拌した。反応液を分液し、水層をクロロホルムで抽出し、有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、ギ酸イソプロピルの生成を確認することができた（収率：２８％）。 Example 35: Production of isopropyl formate Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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., and isopropanol (0.77 mL, 10 mmol) was added, followed by stirring at room temperature for 12 hours. Then, the reaction solution was added to an ice-cooled saturated aqueous solution of sodium hydrogen carbonate, and the mixture was 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, formation of isopropyl formate could be confirmed (yield: 28%).
　実施例３６：　ギ酸イソプロピルの製造
　イソプロパノールに加えてピリジン（１．６ｍＬ，２０ｍｍｏｌ）を０℃で滴下した以外は実施例３５と同様にして、ギ酸イソプロピルを得た（収率：５１％）。 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%).
　実施例３７：　ギ酸フェニルの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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、１５分間攪拌した。
　上記反応液を０℃に冷却し、フェノール（０．９４ｇ，１０ｍｍｏｌ）を滴下し、常温で６時間攪拌した。次いで、反応液を氷冷した飽和炭酸水素ナトリウム水溶液に加え、３０分間撹拌した。反応液を分液し、水層をクロロホルムで抽出し、有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、ギ酸フェニルの生成を確認することができた（収率：８２％）。 Example 37: Production of phenyl formate Into the reaction vessel of Example 1, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 solution of sodium hydrogen carbonate, and the mixture was 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, formation of phenyl formate could be confirmed (yield: 82%).
　実施例３８：　ギ酸２，２，２－トリフルオロエタノールの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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。
　上記反応液を０℃に冷却し、２，２，２－トリフルオロエタノール（０．９４ｇ，１０ｍｍｏｌ）を滴下し、常温で１２時間攪拌した。次いで、反応液を氷冷した飽和炭酸水素ナトリウム水溶液に加え、３０分間撹拌した。反応液を分液し、水層をクロロホルムで抽出し、有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、ギ酸２，２，２－トリフルオロエタノールの生成を確認することができた（収率：６７％）。 Example 38: Production of 2,2,2-trifluoroethanol formate Purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added to the reaction vessel of Example 1. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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 solution of sodium hydrogen carbonate, and the mixture was 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, formation of 2,2,2-trifluoroethanol formate could be confirmed (yield: 67%).
　実施例３９：　１，６－ヘキサンジオールジホルメートの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）、ＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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、１５分間攪拌した。
　上記反応液を０℃に冷却し、１，６－ヘキサンジオール（０．５９ｇ，５ｍｍｏｌ）を滴下し、常温で１時間攪拌した。次いで、反応液を氷冷した飽和炭酸水素ナトリウム水溶液に加え、３０分間撹拌した。反応液を分液し、水層をクロロホルムで抽出し、有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、１，６－ヘキサンジオールジホルメートの生成を確認することができた（収率：５２％）。 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. The reaction was carried out at 30 ° C. for 2 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. 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., 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 solution of sodium hydrogen carbonate, and the mixture was 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, formation of 1,6-hexanediol diformate could be confirmed (yield: 52%).
　実施例４０：　反応温度の検討
　ビルスマイヤー試薬の調製時における反応温度を検討した。具体的には、実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（１．５６ｍＬ，２０ｍｍｏｌ）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、０～３０℃の範囲で温度を調整しつつ、６時間反応を行った。その後、攪拌を中止したところ、反応液は二層に分離した。上層を1Ｈ－ＮＭＲで分析し、ピーク強度から、ＤＭＦからビルスマイヤー試薬への転化率を求めた。結果を表１に示す。 Example 40: Examination of reaction temperature The reaction temperature at the time of preparing the Vilsmeier reagent was examined. Specifically, purified chloroform (20 mL, 248 mmol) and DMF (1.56 mL, 20 mmol) were added into the reaction vessel of Example 1. The reaction was carried out for 6 hours while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while adjusting the temperature in the range of 0 to 30 ° C. while stirring the mixed solution. Thereafter, when the stirring was stopped, the reaction solution was separated into two layers. The upper layer was analyzed by 1 H-NMR, and the conversion from DMF to Vilsmeier reagent was determined from the peak intensity. Table 1 shows the results.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　実施例４１：　アミド化合物の量の検討
　ビルスマイヤー試薬の調製時におけるアミド化合物の最適量を検討した。具体的には、実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）と、０．７８～４．６８ｍＬ（１０～６０ｍｍｏｌ）の範囲のＤＭＦ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、０～３０℃の範囲で温度を調整しつつ、５～２７時間反応を行った。その後、攪拌を中止したところ、反応液は二層に分離した。上層を1Ｈ－ＮＭＲで分析し、ピーク強度から、ＤＭＦからビルスマイヤー試薬への転化率を求めた。結果を表２に示す。 Example 41: Examination of the amount of the amide compound The optimal amount of the amide compound at the time of 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 into the reaction vessel of Example 1. The reaction was carried out for 5 to 27 hours while controlling the temperature in the range of 0 to 30 ° C. while bubbling oxygen gas at 0.5 L / min and irradiating light with the low-pressure mercury lamp while stirring the mixed solution. . Thereafter, when the stirring was stopped, the reaction solution was separated into two layers. The upper layer was analyzed by 1 H-NMR, and the conversion from DMF to Vilsmeier reagent was determined from the peak intensity. Table 2 shows the results.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　表１，２に示す結果の通り、クロロホルムに対するＤＭＦの量を低減し、また、反応温度を比較的低く設定することにより、ビルスマイヤー試薬の生成効率が高まる傾向が認められた。また、反応温度が低い場合には、有害なハロゲン化合物ガスが反応系外に漏れ難い傾向が認められた。 の 通 り As shown in Tables 1 and 2, it was recognized that the production efficiency of the Vilsmeier reagent tended to increase by reducing the amount of DMF relative to chloroform and setting the reaction temperature relatively low. In addition, when the reaction temperature was low, it was found that harmful halogen compound gas hardly leaked out of the reaction system.
　実施例４２：　２－ホルミルフランの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（０．７８ｍＬ，１０ｍｍｏｌ）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、０℃で６時間反応を行った。続いて、反応温度を５０℃に上げ、１時間攪拌した。その後、反応容器をアイスバスに浸漬し、アセトン（３ｍＬ）に溶解させたフラン（０．７３ｍＬ，１０ｍｍｏｌ）を滴下し、２０℃で２時間撹拌した。次いで、飽和炭酸ナトリウム水溶液（１５ｍＬ）を加え、１５分間攪拌した。二層に分離した反応液を分液し、水層を酢酸エチルで抽出した。有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、溶媒を用いても目的化合物である２－ホルミルフランの生成を確認することができた（収率：３０％）。 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. The reaction was carried out at 0 ° C. for 6 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. Thereafter, the reaction vessel was immersed in an ice bath, and furan (0.73 mL, 10 mmol) dissolved in acetone (3 mL) was added dropwise, followed by stirring at 20 ° C for 2 hours. Then, a saturated aqueous sodium carbonate solution (15 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution separated into two layers was separated, and the aqueous layer was extracted with ethyl acetate. 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, the formation of 2-formylfuran as a target compound could be confirmed even using a solvent (yield: 30%).
　実施例４３：　２－ホルミルフランの製造
　実施例１の反応容器内に精製クロロホルム（２０ｍＬ，２４８ｍｍｏｌ）とＤＭＦ（０．７８ｍＬ，１０ｍｍｏｌ）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、０℃で６時間反応を行った。続いて、反応温度を５０℃に上げ、１時間攪拌した。その後、反応容器をアイスバスに浸漬し、アセトニトリル（３ｍＬ）に溶解させたフラン（０．７３ｍＬ，１０ｍｍｏｌ）を滴下し、２０℃で２時間撹拌した。次いで、飽和炭酸ナトリウム水溶液（１５ｍＬ）を加え、１５分間攪拌した。二層に分離した反応液を分液し、水層を酢酸エチルで抽出した。有機層と抽出液を合わせて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。濃縮物を1Ｈ－ＮＭＲで分析したところ、溶媒としてアセトニトリルを用いても、目的化合物である２－ホルミルフランの生成を確認することができた（収率：４８％）。 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. The reaction was carried out at 0 ° C. for 6 hours while irradiating light with the low-pressure mercury lamp while bubbling oxygen gas at 0.5 L / min while stirring the mixed solution. Subsequently, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. Thereafter, the reaction vessel was immersed in an ice bath, and furan (0.73 mL, 10 mmol) dissolved in acetonitrile (3 mL) was added dropwise, followed by stirring at 20 ° C. for 2 hours. Then, a saturated aqueous sodium carbonate solution (15 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution separated into two layers was separated, and the aqueous layer was extracted with ethyl acetate. 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 the target compound, 2-formylfuran, was produced even when acetonitrile was used as a solvent (yield: 48%).
　１：　光照射手段，　　２：　ジャケット，　　３：　ウォーターバス
　４：　撹拌子，　　５：　熱媒または冷媒，　　６：　筒状反応容器 1: Light irradiation means, 2: Jacket, 3: Water bath 4: Stirrer, 5: Heat medium or refrigerant, 6: Tubular reaction vessel

Claims (9)

  1. 　ビルスマイヤー試薬を製造するための方法であって、
    　前記ビルスマイヤー試薬が下記式（Ｉ）で表される塩であり、
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    　Ｒ1は、水素原子、Ｃ1-6アルキル基、または置換基を有していてもよいＣ6-12芳香族炭化水素基を示し、
    　Ｒ2とＲ3は、独立して、Ｃ1-6アルキル基、または置換基を有していてもよいＣ6-12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Ｃ1-4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Ｃ1-4ハロゲン化炭化水素を分解する工程、および、
    　Ｃ1-4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。
    Figure JPOXMLDOC01-appb-C000002
    ［式中、Ｒ1～Ｒ3は上記と同義を示す。］     A method for producing a Vilsmeier reagent, comprising:
    The Vilsmeier reagent is a salt represented by the following formula (I):
    Figure JPOXMLDOC01-appb-C000001
    [Where,
    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 an optionally substituted C 6-12 aromatic hydrocarbon group, and R 2 and R 3 together To form a ring structure of 4 to 7 members,
    X represents a halogeno group selected from the group consisting of chloro, bromo and iodo,
    Y - represents a counter anion. ]
    Irradiating a composition containing a C 1-4 halogenated hydrocarbon having at least one halogeno group selected from the group consisting of chloro, bromo and iodo in the presence of oxygen with a C 1-4 halogenated hydrocarbon; Decomposing, and
    A method comprising reacting a decomposition product of a C 1-4 halogenated hydrocarbon with an amide compound represented by the following formula (II).
    Figure JPOXMLDOC01-appb-C000002
    [Wherein, R 1 to R 3 have the same meaning as described above. ]
  2. 　前記光が１８０ｎｍ以上、２８０ｎｍ以下の波長の光を含む請求項１に記載の方法。 The method according to claim 1, wherein the light includes light having a wavelength of 180 nm or more and 280 nm or less.
  3. 　前記Ｃ1-4ハロゲン化炭化水素としてＣ1-4ポリハロゲン化炭化水素を用いる請求項１または２に記載の方法。 The method according to claim 1 or 2 using the C 1-4 polyhalogenated hydrocarbons as the C 1-4 halogenated hydrocarbons.
  4. 　Ｘがクロロであり、Ｙ-が塩化物イオンである請求項１～３のいずれかに記載の方法。 The method according to any one of claims 1 to 3, wherein X is chloro and Y - is a chloride ion.
  5. 　前記式（ＩＩ）で表されるアミド化合物としてＮ，Ｎ－ジメチルホルムアミドを用いる請求項１～４のいずれかに記載の方法。 方法 The method according to any one of claims 1 to 4, wherein N, N-dimethylformamide is used as the amide compound represented by the formula (II).
  6. 　前記式（ＩＩ）で表されるアミド化合物に対して５倍モル以上の前記Ｃ1-4ハロゲン化炭化水素を用いる請求項１～５のいずれかに記載の方法。 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 amount of the amide compound represented by the formula (II).
  7. 　芳香族アルデヒドまたは芳香族ケトンを製造するための方法であって、
    　請求項１～６のいずれかに記載の方法によりビルスマイヤー試薬を製造する工程、および、
    　前記ビルスマイヤー試薬と活性基を有する芳香族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。     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 claims 1 to 6, and
    Reacting the Vilsmeier reagent with an aromatic compound having an active group.
  8. 　カルボン酸ハロゲン化物を製造するための方法であって、
    　請求項１～６のいずれかに記載の方法によりビルスマイヤー試薬を製造する工程、および、
    　前記ビルスマイヤー試薬と下記式（ＩＩＩ）で表されるカルボン酸化合物とを反応させることにより、前記カルボン酸化合物のカルボキシ基をハロホルミル基に変換する工程を含むことを特徴とする方法。
    　　Ｒ4－（ＣＯ2Ｈ）n　　　　（ＩＩＩ）
    ［式中、Ｒ4はｎ価の有機基を示し、ｎは１以上４以下の整数を示す。］     A method for producing a carboxylic acid halide, comprising:
    A step of producing a Vilsmeier reagent by the method according to any one of claims 1 to 6, and
    A method comprising reacting the Vilsmeier reagent with a carboxylic acid compound represented by the following formula (III) to convert a carboxy group of the carboxylic acid compound into a haloformyl group.
    R 4 - (CO 2 H) n (III)
    [Wherein, R 4 represents an n-valent organic group, and n represents an integer of 1 or more and 4 or less. ]
  9. 　ギ酸エステルを製造するための方法であって、
    　請求項１～６のいずれかに記載の方法によりビルスマイヤー試薬を製造する工程、および、
    　前記ビルスマイヤー試薬と水酸基含有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。     A method for producing a formate, comprising:
    A step of producing a Vilsmeier reagent by the method according to any one of claims 1 to 6, and
    Reacting the Vilsmeier reagent with a hydroxyl group-containing compound.
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