JP7764055B2 - Method for producing nucleophilic reaction products and reactant for producing nucleophilic reaction products - Google Patents

Description

The present invention relates to a method for producing a nucleophilic reaction product and a reactant for producing a nucleophilic reaction product.

Carbonyl halide compounds are extremely important reaction raw materials in organic synthesis and are used in a variety of fields. For example, phosgene, a type of carbonyl halide compound, is used in the synthesis of polycarbonates and other compounds (see, for example, Patent Document 1).

However, carbonyl halide compounds such as phosgene are unstable substances and require careful handling from the perspective of safety, etc. Therefore, a method for producing polyureas or carbonate derivatives has been proposed, which comprises the steps of (a) irradiating chloroform or tetrachloroethane with light in the presence of oxygen to obtain a mixture containing phosgene, and (b) reacting the mixture with a primary amine or alcohol having two or more amino groups in the molecule without isolating the phosgene (Patent Document 2).

Japanese Patent Application Laid-Open No. 2000-128976 Patent No. 5900920

The method for producing polyureas or carbonate derivatives described in Patent Document 2 has the advantage that phosgene, which requires careful handling, can be used in the reaction without isolating it. However, because chloroform and tetrachloroethane have low reactivity, obtaining phosgene from these raw materials requires a high level of energy and strong reaction conditions.

The present invention therefore aims to provide a method for producing nucleophilic reaction products and a reactant for producing nucleophilic reaction products, which can be used in reactions without isolating the carbonyl halide compound and can be carried out under mild reaction conditions.

In order to achieve the above object, the method for producing a nucleophilic reaction product of the present invention comprises the steps of:
a halogenated carbonyl compound generating step of reacting a halogen oxide radical with a halogenated hydrocarbon to generate a halogenated carbonyl compound;
and a nucleophilic reaction product production step in which the carbonyl halide compound is reacted with a nucleophilic agent without isolation to produce a nucleophilic reaction product of the carbonyl halide compound and the nucleophilic agent.

The first reactant for producing a nucleophilic reaction product of the present invention is
containing a halogen oxide radical or a halogen oxide radical generator,
The halogen oxide radical is reacted with a halogenated hydrocarbon to generate a halogenated carbonyl compound, which is used in the method for producing a nucleophilic reaction product of the present invention.

The second reactant for producing a nucleophilic reaction product of the present invention is
Contains halogenated hydrocarbons,
The halogenated hydrocarbon is reacted with a halogen oxide radical to generate a halogenated carbonyl compound, which is used in the method for producing a nucleophilic reaction product of the present invention.

The third reactant for producing a nucleophilic reaction product of the present invention is
containing a nucleophile,
The method is characterized in that the nucleophilic agent is reacted with the carbonyl halide compound generated in the carbonyl halide compound generating step and used in the method for producing a nucleophilic reaction product of the present invention.

The present invention provides a method for producing a nucleophilic reaction product and a reactant for producing a nucleophilic reaction product, which allows a carbonyl halide compound to be used in a reaction without isolation and can be carried out under mild reaction conditions.

FIG. 1 is a ¹³ C-NMR spectrum of the deuterated chloroform solution after the reaction in Reference Example 1. FIG. 2 is a spectral diagram showing the ¹ H-NMR spectrum of 1,2,3,4-tetrahydroquinoline and the ¹ H-NMR spectrum of the reaction mixture of Example 1. FIG. 3 is a spectral diagram showing the ¹ H-NMR spectrum of 1,2,3,4-tetrahydroquinoline, the ¹ H-NMR spectrum of the reaction mixture in Example 2, and ^{the 1} H-NMR spectrum of the residue after separation with water in Example 2. FIG. 4 is a spectral diagram showing the ¹ H-NMR spectrum of 1,2,3,4-tetrahydroquinoline, the ¹ H-NMR spectrum of the reaction mixture in Example 3, and the ¹ H-NMR spectrum of the residue after separation with water in Example 3. FIG. 5 is a ¹ H-NMR spectrum diagram when compound 1b (1,2,3,4-tetrahydroisoquinoline) was reacted under condition 2 or condition 3 in Example 4. FIG. 6 is a ¹ H-NMR spectrum of the compound 1c (indoline) reacted under condition 2 in Example 4. FIG. 7 is a ¹ H-NMR spectrum obtained when compound 1d (piperidine) was reacted under condition 2 in Example 4. FIG. 8 is a ¹ H-NMR spectrum diagram when compound 1e (pyrrolidine) was reacted under condition 2 or condition 3 in Example 4. FIG. 9 is a ¹ H-NMR spectrum diagram when phenol (hydroxybenzene) was reacted under condition 2 in Example 5. FIG. 10 is a ¹ H-NMR spectrum obtained when 4-chlorophenol was reacted under Condition 1 in Example 5. FIG. 11 is a ¹ H-NMR spectrum obtained when 4-nitrophenol was reacted under condition 2 in Example 5. FIG. 12 is a ¹ H-NMR spectrum obtained when 1-propanol (n-propyl alcohol) was reacted under Condition 1 in Example 5.

The present invention will be explained in more detail below using examples. However, the present invention is not limited to the following explanation.

In the following, the first reactant for producing a nucleophilic reaction product of the present invention, the second reactant for producing a nucleophilic reaction product of the present invention, and the third reactant for producing a nucleophilic reaction product of the present invention may be collectively referred to as the "reactants for producing a nucleophilic reaction product of the present invention."

In the method for producing a nucleophilic reaction product of the present invention, for example, in the carbonyl halide generation step, the halogen oxide radical may be activated by irradiating it with light.

The method for producing a nucleophilic reaction product of the present invention may, for example, in the carbonyl halide generation step, generate a halogen radical and singlet oxygen from the halogen oxide radical by activation through light irradiation, and further react the singlet oxygen with the halogenated hydrocarbon to generate the carbonyl halide compound.

In the method for producing a nucleophilic reaction product of the present invention, for example, the irradiation light in the light irradiation may be visible light.

In the method for producing a nucleophilic reaction product of the present invention, for example, the halogen oxide radical may be a chlorine dioxide radical.

In the method for producing a nucleophilic reaction product of the present invention, for example, the carbonyl halide compound may be phosgene.

In the method for producing a nucleophilic reaction product of the present invention, for example, the nucleophilic reaction product may be a carbonylation product of the nucleophile.

In the method for producing a nucleophilic reaction product of the present invention, for example, the nucleophile may be at least one selected from the group consisting of amines, carboxylic acids, ammonia, alcohols, phenols, polyols, polyphenols, polyamines, formamide, urea, urea derivatives, carboxylic acid amides, aromatic compounds, α-amino acids, and thiols.

In the method for producing a nucleophilic reaction product of the present invention, for example, the nucleophilic reaction product may be at least one selected from the group consisting of amides, halogenated amides, acid halides, esters, carbonates, polycarbonates, polyurethanes, isocyanates, ureas, urea derivatives, polyureas, halogenated formate esters, carbamates, isocyanides, carbodiimides, cyanides, aromatic aldehydes, α-amino acid N-carboxylic anhydrides (NCAs), and thiocarbonates.

In the present invention, "halogen" is not particularly limited, but examples include fluorine, chlorine, bromine, and iodine.

In the present invention, a "halogenated hydrocarbon" may be, for example, a compound in which all or some of the hydrogen atoms in a hydrocarbon have been replaced with halogen atoms.

In the present invention, chain compounds (e.g., alkanes, unsaturated aliphatic hydrocarbons, etc.) or chain substituents derived from chain compounds (e.g., hydrocarbon groups such as alkyl groups, alkylene groups, and unsaturated aliphatic hydrocarbon groups) may be, for example, linear or branched, and the number of carbon atoms therein is not particularly limited and may be, for example, 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2. In the case of unsaturated hydrocarbon groups, the number of carbon atoms therein may be, for example, 2 to 40, 2 to 32, 2 to 24, 2 to 18, 2 to 12, or 2 to 6. In the present invention, the number of ring members (the number of atoms constituting the ring) of a cyclic compound (e.g., a cyclic saturated hydrocarbon, a non-aromatic cyclic unsaturated hydrocarbon, an aromatic hydrocarbon, a heteroaromatic compound, etc.) or a cyclic group derived from a cyclic compound (e.g., a cyclic saturated hydrocarbon group, a non-aromatic cyclic unsaturated hydrocarbon group, an aryl group, an arylene group, a heteroaryl group, a heteroarylene group, etc.) is not particularly limited, and may be, for example, 5 to 32, 5 to 24, 6 to 18, 6 to 12, or 6 to 10. Furthermore, when isomers exist in a substituent or the like, for example, the type of isomer is not particularly limited, and as a specific example, when simply referring to a "naphthyl group," it may be, for example, a 1-naphthyl group or a 2-naphthyl group.

In the present invention, the salt is not particularly limited and may be, for example, an acid addition salt or a base addition salt. The acid that forms the acid addition salt may be, for example, an inorganic acid or an organic acid, and the base that forms the base addition salt may be, for example, an inorganic base or an organic base. The inorganic acid is not particularly limited and examples thereof include sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorite acid, hypochlorous acid, hypobromous acid, hypoiodous acid, fluorite acid, chlorous acid, bromous acid, iodous acid, fluoric acid, chloric acid, bromic acid, iodic acid, perfluoric acid, perchloric acid, perbromic acid, and periodic acid. The organic acid is not particularly limited and examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The inorganic base is not particularly limited, and examples thereof include ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and hydrogen carbonates, and more specific examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxide, and calcium carbonate. The organic base is not particularly limited, and examples thereof include ethanolamine, triethylamine, and tris(hydroxymethyl)aminomethane.

The following provides a more detailed explanation of embodiments of the present invention, using examples. However, the present invention is not limited to the following embodiments.

[1. Method for producing nucleophilic reaction products]
As described above, the method for producing a nucleophilic reaction product of the present invention is characterized by comprising a carbonyl halide compound generation step of reacting a halogen oxide radical with a halogenated hydrocarbon to generate a carbonyl halide compound, and a nucleophilic reaction product production step of reacting the carbonyl halide compound with a nucleophile without isolating it to produce a nucleophilic reaction product of the carbonyl halide compound and the nucleophile. The method for producing a nucleophilic reaction product of the present invention will be described in more detail below with examples.

[1-1. Carbonyl halide compound generation process]
In the halogenated carbonyl compound generating step, as described above, a halogen oxide radical is reacted with a halogenated hydrocarbon to generate a halogenated carbonyl compound. The halogenated carbonyl compound generating step may be carried out in a reaction system different from that in the nucleophilic reaction product producing step, or may be carried out in the same reaction system as that in the nucleophilic reaction product producing step.

[1-1-1. Halogen oxide radicals]
The halogen oxide radical is not particularly limited, and examples thereof include halogen oxide radicals such as _F2O ^. (oxygen difluoride radical), _{F2O2 .} (dioxygen difluoride radical ^{), ClO2.} ₍ ^chlorine dioxide radical), _BrO2 ^. (bromine dioxide radical), _{and I2O5} ^. (iodine(V) oxide). The halogen oxide radicals may be any one type, or two or more types may be used in combination.

The method for obtaining the halogen oxide radicals is not particularly limited. For example, the halogen oxide radicals may be generated from a source of the halogen oxide radicals (hereinafter sometimes referred to as the "radical source" or simply the "source"). The present invention may further include, for example, a halogen oxide radical generation step in which the halogen oxide radicals are generated from the radical source. The halogen oxide radical generation step may be carried out, for example, prior to the carbonyl halide compound generation step or simultaneously with the carbonyl halide compound generation step. Furthermore, the halogen oxide radical generation step may be carried out, for example, in a reaction system different from that of the carbonyl halide compound generation step, or may be carried out in the same reaction system as that of the carbonyl halide compound generation step.

The radical generation source is not particularly limited and can be selected appropriately depending on, for example, the type of halogen oxide radical. The halogen oxide radical generation source may be, for example, one type, or multiple types may be used in combination.

The radical source is, for example, a compound containing oxygen and a halogen, and specific examples include, for example, a halous acid (HXO ₂ ) or a salt thereof. The salt of the halous acid is not particularly limited, and examples thereof include metal salts, and examples of the metal salts include alkali metal salts, alkaline earth metal salts, and rare earth salts. The halogen oxide radical source may also be, for example, a compound containing oxygen, a halogen, and a Group 1 element (e.g., at least one selected from the group consisting of H, Li, Na, K, Rb, and Cs), and examples thereof include, for example, a halous acid or an alkali metal salt thereof. When the halogen oxide radical is the chlorine dioxide radical, its generating source is not particularly limited and may be, for example, chlorous acid (HClO ₂ ) or a salt thereof, specifically, for example, sodium chlorite (NaClO ₂ ), lithium chlorite (LiClO ₂ ), potassium chlorite (KClO ₂ ), magnesium chlorite (Mg(ClO ₂ ) ₂ ), calcium chlorite (Ca(ClO ₂ ) ₂ ), etc. Among these, sodium chlorite (NaClO ₂ ) is preferred from the viewpoints of cost, ease of handling, etc. For example, the same method can be adopted for other halogen oxide radical generating sources. Examples of other halogen oxide radical generating sources include bromates such as sodium bromite, and iodates such as sodium iodite.

The reaction system for the halogen oxide radical generation process may be, for example, a gas phase, a liquid phase, a solid phase, or a two-phase system consisting of a gas phase and a liquid phase. The liquid phase may be, for example, an aqueous phase, an organic phase, a two-phase system consisting of an aqueous phase and an organic phase, or a mixed phase of water and an organic solvent. An example of using an aqueous phase for the reaction system is dissolving the radical generation source (e.g., a halous acid or its salt, e.g., sodium chlorite) in water together with an acid (e.g., hydrochloric acid) to form an acidic aqueous solution, from which halogen oxide radicals (e.g., chlorine dioxide gas) can be generated. These halogen oxide radicals can be activated, for example, by irradiation with light, and used in the subsequent carbonyl halide compound generation process.

In the halogen oxide radical generation process, the reaction system may or may not be irradiated with light. In the present invention, "not irradiating" the reaction system with light includes, but is not limited to, shading the reaction system to prevent light from entering the reaction system. In the present invention, "not irradiating" the reaction system with light may or may not involve shading the reaction system to prevent light from entering the reaction system. In the present invention, "not irradiating" the reaction system with light may mean, for example, that the reaction system is not actively irradiated with light using a light source or the like, but that natural light, room light, or the like is incident on the reaction system. For example, not irradiating the reaction system with light allows the reaction to be carried out simply and at low cost.

The concentration of the source in the aqueous phase is not particularly limited. When the source is the compound, the concentration, when converted into the halogen oxide ion concentration, is, for example, 0.0001 mol/L or more at the lower limit and 1 mol/L or less at the upper limit. When converted into the number of moles of halogen oxide ions, the concentration, when converted into the number of moles of halogen oxide ions, is, for example, 1/100,000 times or more and 1,000 times or less the number of moles of the raw material. When the source is a halous acid or a halous acid salt (e.g., chlorous acid or chlorite), the concentration, when converted into the concentration of a halous acid ion (e.g., chlorite ion (ClO ₂ ⁻ )), is, for example, 0.0001 mol/L or more at the lower limit and 1 mol/L or less at the upper limit. Furthermore, when the concentration of the source is converted into the number of moles of haloid ions (for example, chlorite ions (ClO ₂ ⁻ )), the lower limit is, for example, 1/100,000 times or more the number of moles of the raw material, and the upper limit is 1,000 times or less. For example, the above concentrations can also be applied to other sources.

The aqueous phase may further contain at least one of a Lewis acid and a Bronsted acid, which may be reacted with the halogen oxide ions to generate the halogen oxide radicals. The at least one of the Lewis acid and the Bronsted acid may be, for example, at least one of a Lewis acid and a Bronsted acid containing a Group 1 element. The halogen oxide ions may be, for example, chlorite ions (ClO ₂ ⁻ ). The aqueous phase may contain, for example, only one of the Lewis acid and the Bronsted acid, or both, or one substance may serve as both the Lewis acid and the Bronsted acid. Only one type of Lewis acid or one type of Bronsted acid may be used, or multiple types may be used in combination. In the present invention, the term "Lewis acid" refers to, for example, a substance that acts as a Lewis acid with respect to a source of halogen oxide radicals.

The concentration of at least one of the Lewis acid and the Bronsted acid in the aqueous phase is not particularly limited and can be set appropriately depending on, for example, the type of polymer to be modified. For example, the lower limit of the concentration is 0.0001 mol/L or more, and the upper limit is 1 mol/L or less.

The Bronsted acid is not particularly limited and may be, for example, an inorganic acid or an organic acid, and specific examples include trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. The acid dissociation constant pK _a of the Bronsted acid is, for example, 10 or less. The lower limit of the pK _a is not particularly limited and is, for example, −10 or more.

The aqueous phase preferably contains, for example, the halogen oxide ion and the Bronsted acid, and is, for example, an aqueous phase in which the compound and the Bronsted acid (e.g., hydrochloric acid) are dissolved in an aqueous solvent. Specifically, when the halogen oxide radical is a chlorine dioxide radical, the aqueous phase preferably contains, for example, a chlorite ion (ClO ₂ ⁻ ) and a Bronsted acid, and is, for example, an aqueous phase in which the sodium chlorite (NaClO ₂ ) and the Bronsted acid (e.g., hydrochloric acid) are dissolved in an aqueous solvent.

In the aqueous phase, for example, the Lewis acid, the Bronsted acid, the radical generating source, etc. may be dissolved or insoluble in the aqueous solvent. In the latter case, they may be dispersed in the aqueous solvent or precipitated.

The halogen oxide radical generating step is not particularly limited. For example, the halogen oxide radical (e.g., chlorine dioxide radical) can be spontaneously generated from the halogen oxide ion (e.g., chlorite ion) by adding a source of the halogen oxide radical to the aqueous solvent. The aqueous phase preferably contains the source dissolved in the aqueous solvent, and is preferably allowed to stand. In the halogen oxide radical generating step, the generation of the halogen oxide radical can be further promoted by, for example, further containing at least one of the Lewis acid and the Bronsted acid. In the halogen oxide radical generating step, the halogen oxide radical can be generated by, for example, irradiating the aqueous phase with light, as described above. However, the halogen oxide radical can also be generated without light irradiation, for example, by simply allowing the aqueous phase to stand.

The halogen oxide radical generation process may also be carried out in a manner similar to or analogous to the methods described in, for example, WO2018/110710A1, WO2019/221299A1, WO2019/221300A1, etc.

[1-1-2. Halogenated hydrocarbons and halogenated carbonyl compounds]
The halogenated hydrocarbon may be, for example, a compound in which all or part of the hydrogen atoms of a hydrocarbon have been substituted with halogen atoms, as described above. The halogenated hydrocarbon is not particularly limited, and for example, one type may be used alone, or multiple types may be used in combination. The hydrocarbon is not particularly limited, and may be, for example, a linear or branched alkane, an unsaturated aliphatic hydrocarbon, a cyclic saturated hydrocarbon, a non-aromatic cyclic unsaturated hydrocarbon, an aromatic hydrocarbon, or the like. Examples of the hydrocarbon include methane, ethane, propane, n-butane, 2-methylpropane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, benzene, toluene, and xylene. Examples of the halogenated hydrocarbon include monohalomethane ( _CH3X ), dihalomethane _{( CH2X2 )} , trihalomethane _{( CHX3 )} , tetrahalomethane ( _CX4 ), monohaloethane (C2H5X1), dihaloethane ( _C2H4X2 ), _{trihaloethane} ( _C2H3X3 ), _{and tetrahaloethane (C2H2X4 ) ( wherein} X is a halogen atom ₎ . More specific examples of the halogenated hydrocarbon include fluoromethane ( _CH3F ), difluoromethane ( _CH2F2 ), trifluoromethane ( _CHF3 , also called fluoroform), chloromethane ( _CH3Cl ), dichloromethane ( _CH2Cl2 , also called _methylene chloride), trichloromethane ( _CHCl3 , also called chloroform), tetrachloromethane ( _CCl4 , also called carbon _{tetrachloride), dichloroethane (C2H4Cl2 )} , tetrachloroethane ( _{C2H2Cl4 )} , bromomethane ( _CH3Br ), _{dibromomethane} ( _CH2Br2 , also called methylene bromide), _{tribromomethane ( CHBr3} , also called bromoform) _, tetrabromomethane ( _CBr4 , also called carbon tetrabromide), and _{dibromoethane} ( _C2H4Br ). ₂ ), tetrabromoethane (C ₂ H ₂ Br ₄ ), iodomethane (CH ₃ I), diiodomethane (CH ₂ I ₂ ), triiodomethane (CHI ₃ , also called iodoform), etc. According to the present invention, for example, a halogenated carbonyl compound (e.g., phosgene) can be generated using an inexpensive and easily available halogenated hydrocarbon (e.g., chloroform), so that the reaction can be carried out at low cost and on a large scale.

The carbonyl halide compound generated in the carbonyl halide compound generation process is not particularly limited, but examples include carbonyl difluoride, phosgene (carbonyl dichloride), carbonyl dibromide, carbonyl diiodide, oxalyl chloride, oxalyl bromide, oxalyl iodide, formic acid chloride, formic acid bromide, and formic acid iodide. In the carbonyl halide compound generation process, the halogenated hydrocarbon used as the raw material for the carbonyl halide compound can be appropriately selected depending on the type of carbonyl halide compound of interest. From the standpoints of reaction efficiency, convenience, cost, and the like, it is particularly preferable that the halogenated hydrocarbon be a chlorinated hydrocarbon and the carbonyl halide compound be phosgene.

[1-1-3. Reaction conditions for the carbonyl halide compound generation step]
The reaction conditions for the carbonyl halide compound generating step are not particularly limited, but the step can be carried out, for example, under the following reaction conditions.

First, the reaction system in the carbonyl halide compound generation process may be, for example, a gas phase, a liquid phase, a solid phase, or a two-phase system of a gas phase and a liquid phase. The liquid phase may be, for example, an aqueous phase, an organic phase, a two-phase system of an aqueous phase and an organic phase, or a mixed phase of water and an organic solvent.

From the standpoint of reaction efficiency, convenience, etc., it is preferable to react the halogen oxide radical with the halogenated hydrocarbon in the liquid phase. In this case, for example, a solvent other than the halogenated hydrocarbon may be used, but from the standpoint of reaction efficiency, convenience, etc., it is preferable to use the halogenated hydrocarbon itself as the solvent.

The method for reacting the halogen oxide radicals with the halogenated hydrocarbon in the liquid phase is not particularly limited. For example, the halogen oxide radicals may be introduced into a liquid phase containing the halogenated hydrocarbon. The liquid phase containing the halogenated hydrocarbon may be, for example, the halogenated hydrocarbon itself in liquid form. The method for introducing the halogen oxide radicals into the liquid phase is not particularly limited. For example, when the halogen oxide radicals are gaseous, the halogen oxide radicals may be brought into contact with the liquid phase or blown into the liquid phase. The halogen oxide radicals may be, for example, the halogen oxide radicals generated in the halogen oxide radical generating step. In this case, for example, the reaction system in the halogen oxide radical generating step may be an aqueous phase, and the reaction system in the carbonyl halide compound generating step may be an organic phase. In this case, the method for introducing the halogen oxide radicals generated from the aqueous phase into the organic phase is not particularly limited. For example, the aqueous phase and the organic phase may be directly contacted. In this case, the aqueous phase and the organic phase may be appropriately stirred, etc. Alternatively, the gaseous halogen oxide radicals generated from the aqueous phase may be made to be mobile into the organic phase via the gas phase. In this case, for example, the organic phase may be appropriately stirred to increase the efficiency of introducing the halogen oxide radicals into the organic phase. In this case, for example, an H-shaped tube may be used as a reaction tool or reactor, as in the examples described below. Furthermore, for example, when the reaction is carried out on a larger scale, other reaction tools or reactors suitable for such a purpose may be used.

The concentration of the halogen oxide radicals in the reaction system of the carbonyl halide compound generating step is not particularly limited. For example, when the reaction system is in a liquid phase, the concentration of the halogen oxide radicals may be, for example, 0.0001 mol/L or more, 0.001 mol/L or more, 0.01 mol/L or more, 0.1 mol/L or more, or 1.0 mol/L or more, or may be, for example, 10 mol/L or less, 1.0 mol/L or less, 0.1 mol/L or less, 0.01 mol/L or less, or 0.001 mol/L or less. The concentration of the halogen oxide radicals may be, for example, 0.001 to 10 mol/L, 0.01 to 1 mol/L, or 0.02 to 0.5 mol/L.

Furthermore, for example, as described below, the nucleophilic agent may be present in the reaction system of the carbonyl halide compound generation process, and the nucleophilic reaction product production process may be carried out in the same reaction system as the carbonyl halide compound generation process.

As mentioned above, in the carbonyl halide compound generation process, the halogenated hydrocarbon itself may be used as the solvent, but a solvent other than the halogenated hydrocarbon may also be used. For example, when the nucleophilic reaction product production process is carried out in the same reaction system as the carbonyl halide compound generation process, the other solvent may be used to facilitate dissolution of the nucleophile.

The other solvent is not particularly limited and may be water, an organic solvent, or a mixed solvent of water and an organic solvent. The organic solvent is not particularly limited. For example, only one type of organic solvent may be used, or multiple types may be used in combination. In the present invention, examples of the organic solvent include hydrocarbons (e.g., pentane, hexane, cyclohexane, etc.), nitriles (e.g., acetonitrile, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ketones (e.g., acetone, etc.), ethers (e.g., diethyl ether, THF (tetrahydrofuran), etc.), amides (e.g., DMF (dimethylformamide), DMA (dimethylacetamide), NMP (N-methyl-2-pyrrolidone), etc.), sulfoxides (e.g., DMSO (dimethyl sulfoxide), etc.), halogenated solvents, and fluorous solvents.

A "halogenated solvent" refers to, for example, a solvent in which all or most of the hydrogen atoms of a hydrocarbon have been substituted with halogen. The halogenated solvent may be, for example, a solvent in which 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of the number of hydrogen atoms of the hydrocarbon have been substituted with halogen. The halogenated solvent is not particularly limited, and examples include methylene chloride, chloroform, carbon tetrachloride, carbon tetrabromide, and the fluorous solvents described below.

A "fluorous solvent" is a type of halogenated solvent, e.g., a solvent in which all or most of the hydrocarbon hydrogen atoms have been substituted with fluorine atoms. The fluorous solvent may be, for example, a solvent in which 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of the hydrocarbon hydrogen atoms have been substituted with fluorine atoms. In the present invention, the use of the fluorous solvent has the advantage that, for example, side reactions can be more effectively suppressed or prevented due to the low reactivity of the solvent itself.

Examples of the fluorous solvent include solvents represented by the following chemical formulas (F1) to (F6), and among these, for example, CF ₃ (CF ₂ ) ₄ CF ₃ in which n=4 in the following chemical formula (F1) is preferred.

The boiling point of the organic solvent is not particularly limited. The organic solvent can be selected appropriately, for example, depending on the temperature conditions of the carbonyl halide compound generating step. When the reaction temperature in the carbonyl halide compound generating step is set to a high temperature, a high-boiling-point solvent can be selected as the organic solvent. Note that, as described below, the present invention does not require heating and can be carried out, for example, at room temperature and atmospheric pressure. In such cases, the organic solvent does not need to be a high-boiling-point solvent, and a solvent with a relatively low boiling point can be used from the standpoint of ease of handling.

When the other solvent is used, the concentration of the halogenated hydrocarbon in the reaction system of the halogenated carbonyl compound generation step is not particularly limited. For example, when the reaction system is in a liquid phase, the concentration of the halogenated hydrocarbon may be, for example, 0.0001 mol/L or more, 0.001 mol/L or more, 0.01 mol/L or more, 0.1 mol/L or more, or 1.0 mol/L or more, or may be, for example, 10 mol/L or less, 1.0 mol/L or less, or 0.1 mol/L or less. The concentration of the halogenated hydrocarbon may be, for example, 0.001 to 10 mol/L, 0.01 to 1.0 mol/L, or 0.02 to 0.5 mol/L.

In the carbonyl halide compound generating step, the reaction system may or may not be irradiated with light. For example, irradiating the reaction system with light can improve the reaction efficiency between the halogen oxide radical and the halogenated hydrocarbon. Specifically, as described above, the halogen oxide radical may be activated by light irradiation in the carbonyl halide generating step. More specifically, as described above, the halogen oxide radical may be activated by light irradiation to generate a halogen radical and singlet oxygen from the halogen oxide radical, and the singlet oxygen may then react with the halogenated hydrocarbon to generate the carbonyl halide compound. For example, when the halogen oxide radical is a chlorine dioxide radical and the halogenated hydrocarbon is chloroform, a reaction such as that shown in Scheme 1 below is believed to occur. In Scheme 1 below, chlorine dioxide gas (chlorine dioxide radical) is activated by light irradiation to generate a chlorine radical and singlet oxygen, and the singlet oxygen reacts with chloroform to generate phosgene. However, the following Scheme 1 is merely an example of a possible reaction mechanism, and the present invention is not limited thereto.

The conditions for the light irradiation are not particularly limited. The wavelength of the irradiation light is not particularly limited, but the lower limit may be, for example, 200 nm or more, 300 nm or more, or 400 nm or more, and the upper limit may be, for example, 800 nm or less, 700 nm or less, 600 nm or less, or 500 nm or less. The wavelength may be, for example, 200 to 800 nm, 300 to 700 nm, 400 to 600 nm, or 400 to 500 nm. The irradiation light may be, for example, ultraviolet light, visible light, or infrared light. However, from the perspective of comprehensive consideration of convenience, safety, reaction efficiency, etc., visible light is preferred. The light irradiation time is not particularly limited, but the lower limit may be, for example, 1 second or more, and the upper limit is not particularly limited, but may be, for example, 1,000 hours or less.

The reaction temperature in the carbonyl halide compound generation step is not particularly limited, and the lower limit is, for example, -20°C or higher, and the upper limit is, for example, 100°C or lower, or 40°C or lower, with a range of, for example, 0 to 100°C or 0 to 40°C. The atmospheric pressure during the reaction is not particularly limited, and the lower limit is, for example, 0.1 MPa or higher, and the upper limit is, for example, 100 MPa or lower, 10 MPa or lower, or 0.5 MPa or lower, with a range of, for example, 0.1 to 100 MPa, 0.1 to 10 MPa, or 0.1 to 0.5 MPa. Examples of reaction conditions for the carbonyl halide compound generation step include a temperature of 0 to 100°C or 0 to 40°C, and a pressure of 0.1 to 0.5 MPa. As mentioned above, in the carbonyl halide compound generation step, the reaction system may or may not be irradiated with light. According to the method for producing a nucleophilic reaction product of the present invention, the carbonyl halide compound generating step or all of the steps including it can be carried out at room temperature (room temperature) and normal pressure (atmospheric pressure) without heating, pressurizing, depressurizing, etc. "Room temperature" is not particularly limited and is, for example, 5 to 35°C. Furthermore, according to the present invention, the carbonyl halide compound generating step or all of the steps including it can be carried out in the atmosphere without, for example, replacing with an inert gas.

The light source for the light irradiation is not particularly limited, and for example, visible light contained in natural light such as sunlight can be used. The use of natural light allows for easy excitation, for example. Furthermore, as the light source, for example, light sources such as xenon lamps, halogen lamps, fluorescent lamps, mercury lamps, and LED lamps can be used instead of or in addition to natural light. However, from the perspective of light absorption efficiency of chlorine dioxide and power saving, LED lamps are preferred, and 365 nm and 405 nm LED lamps are more preferred. In the light irradiation, for example, a filter that cuts out wavelengths other than the required wavelengths can also be used as appropriate.

[1-2. Nucleophilic reaction product production process]
In the method for producing a nucleophilic reaction product of the present invention, the nucleophilic reaction product production step may be carried out after the carbonyl halide compound generation step, or may be carried out simultaneously with the carbonyl halide compound generation step.

The nucleophilic reaction product production step may be carried out in the same reaction system as the carbonyl halide compound generation step, or in a separate reaction system. In the method for producing a nucleophilic reaction product of the present invention, the carbonyl halide compound is reacted with a nucleophile without isolation. Therefore, from the standpoint of convenience, it is preferable to carry out the nucleophilic reaction product production step in the same reaction system as the carbonyl halide compound generation step. Specifically, for example, the nucleophile may be present in advance in the reaction system for the carbonyl halide compound generation step, and the nucleophilic reaction product production step and the carbonyl halide compound generation step may be carried out in this same reaction system. More specifically, for example, the halogenated hydrocarbon and the nucleophile may be dissolved or dispersed in a solvent in advance, and the nucleophilic reaction product production step and the carbonyl halide compound generation step may be carried out in this solvent.

The concentration of the nucleophilic agent in the reaction system of the nucleophilic reaction product production process is not particularly limited. For example, when the reaction system is in a liquid phase, the concentration of the nucleophilic agent may be, for example, 0.0001 mol/L or more, 0.001 mol/L or more, 0.01 mol/L or more, 0.1 mol/L or more, or 1.0 mol/L or more, or may be, for example, 50 mol/L or less, 10 mol/L or less, 5.0 mol/L or less, 1.0 mol/L or less, or 0.1 mol/L or less. The concentration of the nucleophilic agent may be, for example, 0.0001 to 50 mol/L, 0.01 to 10 mol/L, or 0.1 to 1.0 mol/L.

In the nucleophilic reaction product production process, the reaction conditions, such as reaction temperature and reaction time, are not particularly limited. For example, they may be the same as or equivalent to the reaction conditions in a general reaction between a nucleophile and a carbonyl halide compound, or may be set appropriately with reference to such conditions. Furthermore, for example, when the nucleophilic reaction product production process and the carbonyl halide compound generation process are carried out simultaneously in the same reaction system, the reaction conditions for the nucleophilic reaction product production process may be the same as those for the carbonyl halide compound generation process. Furthermore, in the nucleophilic reaction product production process, the reaction system may or may not be irradiated with light. When light is irradiated, the conditions are not particularly limited, but may be the same as those for the carbonyl halide compound generation process, for example.

In the nucleophilic reaction product production process, the term "nucleophile" refers to a substance that readily reacts with or attacks a low-electron-density portion of the molecule to be reacted (the carbonyl halide compound in this invention). In the carbonyl halide compound, the low-electron-density portion is specifically the carbonyl carbon. The nucleophile is preferably a substance containing a high-electron-density portion, such as a Brönsted base (i.e., an electron pair donor), an anion, an aliphatic amine, an aromatic amine (e.g., aniline), hydrazine, diamine, polyamine, ammonia, alcohol, phenol, diol, polyol, polyphenol, aminoalcohol, aromatic compound, amino acid, or thiol.

In the nucleophilic reaction product production process, the raw material nucleophile and the resulting nucleophilic reaction product are not particularly limited and may be similar to or equivalent to, for example, a general reaction between a nucleophile and a carbonyl halide compound. In other words, the method for producing a nucleophilic reaction product of the present invention is applicable to a wide variety of nucleophiles, similar to general reactions between nucleophiles and carbonyl halide compounds, thereby enabling the production of a variety of nucleophilic reaction products. The raw material nucleophile may be, for example, an organic compound or an inorganic substance. Furthermore, only one type of nucleophile may be used, or two or more types may be used in combination. As described above, the nucleophilic reaction product is not particularly limited, and examples thereof include acid halides (e.g., acid fluorides, acid chlorides, acid bromides, or acid iodides), amides, esters, carbonates, polycarbonates, polyurethanes, isocyanates, ureas, polyureas, urea derivatives, halogenated formates (e.g., fluoroformates, chloroformates, bromoformates, or iodoformates), carbonates, carbamates, isocyanides, carbodiimides, cyanides, aldehydes (e.g., aromatic aldehydes), α-amino acid N-carboxylic anhydrides (NCAs), etc. The structures of these nucleophilic reaction products and the structures of the corresponding raw materials (nucleophiles) are not particularly limited, and can be represented, for example, by the chemical formulas shown in Scheme I below. The following Scheme I is a reprint of a diagram (chemical formula) published in the presentation materials (presenter: Akihiko Tsuda, https://shingi.jst.go.jp/var/rev0/0000/9540/2019_kobe-u_1.pdf [search date: February 19, 2021]) at the Kobe University New Technology Briefing [sponsored by: Japan Science and Technology Agency, National Research and Development Agency, Kobe University, held on August 1, 2019], and has been given the title "Scheme I" by the applicant of the present application. In the present invention, a carbonyl halide compound other than phosgene may be used instead of or in addition to the phosgene in the following Scheme I.

In the present invention, R, ^R1 , and ^R2 in Scheme I are not particularly limited and may be any atom or atomic group. The structures of R, ^R1 , and ^R2 may be similar to or equivalent to those of a nucleophile or a nucleophilic reaction product in a general reaction in which a nucleophile reacts with a carbonyl halide compound to produce a nucleophilic reaction product. When R, ^R1 , and ^R2 in Scheme I are monovalent groups, R, ^R1 , and ^R2 may each independently represent, for example, a hydrogen atom, a hydroxyl group, a mercapto group (thiol group), a carboxy group, an amino group, or a chain substituent (e.g., a hydrocarbon group such as an alkyl group or an unsaturated aliphatic hydrocarbon group), or a cyclic group (e.g., a cyclic saturated hydrocarbon group, a non-aromatic cyclic unsaturated hydrocarbon group, an aryl group, a heteroaryl group, etc.), and may be substituted or unsubstituted with other substituents. When R, ^R1 , and ^R2 in Scheme I are divalent groups (crosslinked chains), R, ^R1 , and ^R2 may each independently represent, for example, an ether bond (-O-), an ester bond (-COO-), a carbonate bond (-OCOO-), a carbamate bond (-NCOO-), a urea bond (-NCON-), or a chain substituent (e.g., a hydrocarbon group such as an alkylene group or an unsaturated aliphatic hydrocarbon group), or a cyclic group (e.g., a cyclic saturated hydrocarbon group, a non-aromatic cyclic unsaturated hydrocarbon group, an arylene group, a heteroarylene group, etc.), which may or may not be substituted with other substituents. Furthermore, Ar in Scheme I is not particularly limited, and may be, for example, an aromatic compound (e.g., an aromatic hydrocarbon, a heteroaromatic compound, etc.) or a group derived from an aromatic compound (e.g., an aryl group, a heteroaryl group, etc.).

Furthermore, in the present invention, in the nucleophilic reaction product production step, the nucleophilic agent as a raw material and the nucleophilic reaction product as a product are not limited to the substances shown in Scheme I. For example, the nucleophilic agent may be a thiol, and the nucleophilic reaction product may be a thiocarbonate. Alternatively, for example, the nucleophilic agent may be ammonia or an amine, and the nucleophilic reaction product may be a halogenated amide (X—CO—NR ¹ R ² , where X is a halogen, CO is a carbonyl group, and R ¹ and R ² are the same as those in Scheme I). Other examples of the nucleophilic agent include imidazole, phosphonate ester, lactam, imine, hydrazine, pyrrole, triazole, and indole. Examples of the nucleophilic reaction product include carbonyldiimidazole, halogenated phosphate ester (e.g., chlorophosphate ester), imide halide (e.g., imido chloride), and acid halide (e.g., formic acid chloride).

In the nucleophilic reaction product production process, the combination of the raw material nucleophile and the resulting nucleophilic reaction product is not particularly limited, but examples include the combinations listed in Table 1 below. Note that in Table 1 below, when there are two or more types of nucleophilic reaction products for a given raw material nucleophile, the nucleophilic reaction product may be any one type, or any two or more types.

The purification and isolation methods for the nucleophilic reaction product produced in the nucleophilic reaction product production process are not particularly limited, and may be, for example, methods similar to those used in general chemical reactions. Specifically, methods such as separation, recrystallization, distillation, and column chromatography may be used as needed. Furthermore, prior to or simultaneously with the purification and isolation of the nucleophilic reaction product, water, methanol, ethanol, phenol, or an amine may be added as needed to react and consume all of the unreacted carbonyl halide compound. In this way, post-treatment of the nucleophilic reaction product production process can be performed safely without releasing the carbonyl halide compound outside the reaction system.

Furthermore, the method for producing a nucleophilic reaction product of the present invention may or may not include other steps in addition to the carbonyl halide compound generation step and the nucleophilic reaction product production step. The other steps may or may not include, for example, the halogen oxide radical generation step, or may or may not include steps other than the halogen oxide radical generation step.

[2. Reactants for producing nucleophilic reaction products]
As described above, the reactant for producing a nucleophilic reaction product of the present invention includes the first reactant for producing a nucleophilic reaction product of the present invention, the second reactant for producing a nucleophilic reaction product of the present invention, and the third reactant for producing a nucleophilic reaction product of the present invention. The characteristics of each are as described above. That is, the reactant for producing a nucleophilic reaction product of the present invention contains a halogen oxide radical or a halogen oxide radical generator, contains a halogenated hydrocarbon, or contains a nucleophile. The chemical structures of the halogen oxide radical, the halogen oxide radical generator, the halogenated hydrocarbon, and the nucleophile are not particularly limited, but are as described, for example, in "1. Method for producing a nucleophilic reaction product" above.

[3. Uses of the present invention]
As described above, the method for producing a nucleophilic reaction product of the present invention is applicable to a wide variety of nucleophiles, similar to the general reaction between a nucleophile and a carbonyl halide compound, thereby enabling the production of a variety of nucleophilic reaction products. Therefore, the method for producing a nucleophilic reaction product of the present invention is applicable to a very wide range of fields. For example, carbamoyl chloride is an important intermediate in pharmaceuticals, fine chemicals, and resin synthesis. According to the method for producing a nucleophilic reaction product of the present invention, for example, an amine or imine can be used as a nucleophile and reacted with a carbonyl halide compound (e.g., phosgene) to produce the nucleophilic reaction product, carbamoyl chloride. Other industrial fields to which the present invention can be applied include, for example, the polycarbonate industry, the carbamate-related industry, pesticides, dyes, perfumes, pharmaceuticals, and isocyanate production.

Furthermore, as mentioned above, the method for producing nucleophilic reaction products of the present invention allows the carbonyl halide compound to be used in the reaction without isolation, which has advantages such as high safety, shortened work processes, and reduced costs.

Furthermore, as described above, the method for producing a nucleophilic reaction product of the present invention can be carried out under mild reaction conditions. Therefore, for example, the method for producing a nucleophilic reaction product of the present invention can be applied to raw materials that are difficult to use in conventional reactions to produce a nucleophilic reaction product. Specifically, for example, when light is irradiated in the method for producing a nucleophilic reaction product of the present invention, the irradiated light is not particularly limited, as described above, and may be, for example, ultraviolet light, visible light, or infrared light. For example, while conventional reactions require ultraviolet irradiation, if the method for producing a nucleophilic reaction product of the present invention can be used to carry out the reaction using visible light, it would be possible to improve convenience, safety, substrate applicability, reaction time, reaction efficiency, productivity, and the like. Specifically, for example, in conventional reactions, ultraviolet light was required as the excitation light to directly photoexcite chloroform to generate phosgene. However, according to the present invention, for example, instead of directly photoexciting chloroform, phosgene can also be generated by activating chlorine dioxide radicals with visible light and reacting them with chloroform, as described above. Furthermore, for example, reactions that require ultraviolet irradiation are difficult to apply to raw materials that easily absorb ultraviolet light (i.e., are easily decomposed by ultraviolet irradiation), such as aromatic compounds. If such raw materials can be reacted with visible light by the method for producing a nucleophilic reaction product of the present invention, the range of raw materials (nucleophiles) that can be used to produce nucleophilic reaction products will be dramatically expanded.

The following describes examples of the present invention. However, the present invention is not limited to the following examples.

In this example, NMR (nuclear magnetic resonance) spectra were measured using JEOL's ECS400 (product name).

[Reference example 1]
In this example, it was confirmed that phosgene (carbonyl halide) was generated in the reaction system by reacting chlorine dioxide radicals (halogen oxide radicals) with chloroform (halogenated hydrocarbon). More specifically, phosgene was generated by reacting chlorine dioxide radicals with deuterated chloroform according to the following scheme E1.

The reaction of Scheme E1 was carried out as follows. First, 113 mg (0.8 mmol) of sodium chlorite, 5.7 mL of water, and 57 μL of 35% hydrochloric acid were mixed and allowed to stand at room temperature for at least 30 minutes to obtain a sodium chlorite oxidizing solution. This sodium chlorite oxidizing solution contains dissolved chlorine dioxide radicals generated by the disproportionation of chlorous acid. These chlorine dioxide radicals are activated by light irradiation.

Next, stir bars were placed in both tubes of the H-shaped tube. 1 mL of deuterated chloroform was added to one tube, and 5.7 mL of the sodium chlorite oxidizing solution was added to the other tube. The lids of both tubes of the H-shaped tube were then tightly closed. The H-shaped tube was placed 20 cm from a 405 nm LED lamp (illuminance 90 mW/cm ² ) and the reaction was carried out by irradiating the solution with 400 s laser light while stirring. After the reaction, the deuterated chloroform solution in the H-shaped tube was subjected to ¹³ C-NMR measurement to confirm the generation of phosgene. The ¹³ C-NMR spectrum is shown in Figure 1. The analysis results of the ¹³ C-NMR spectrum are also shown below. As shown below, the generation of phosgene was confirmed by the peak at δ 143.5 ppm. It is believed that chlorine dioxide gas (chlorine dioxide radicals) generated from the sodium chlorite oxidized solution was released into the gas phase in the H-shaped tube and further dissolved in the deuterated chloroform phase, and the chlorine dioxide radicals were further activated by light irradiation and reacted with the deuterated chloroform to generate phosgene.

Results of C-NMR spectrum analysis of the ^deuterated chloroform solution after the reaction in Reference Example 1:
^13C -NMR (100MHz, _CDCl3 ) δ: 143.5ppm

[Example 1]
In this example, a nucleophilic reaction product was produced by the method for producing a nucleophilic reaction product of the present invention. More specifically, as shown in Scheme E2 below, chlorine dioxide radicals (halogen oxide radicals) were reacted with chloroform (halogenated hydrocarbon) to generate phosgene (halogenated carbonyl compound) (halogenated carbonyl compound generation step), and the phosgene was then reacted with tetrahydroquinoline (nucleophile) without isolation to produce carbamoyl chloride (nucleophilic reaction product) (nucleophilic reaction product production step).

In this example, the reaction of Scheme E2 was carried out as follows. First, chloroform (containing 0.3-1.0% ethanol) was separated with water and purified through silica gel and alumina to prepare purified chloroform. This purified chloroform served as a reaction solvent, and a portion of it reacted with chlorine dioxide radicals to produce phosgene. Separately, a sodium chlorite oxidizing solution was prepared by mixing 170 mg (1.2 mmol) of sodium chlorite, 5.7 mL of water, and 86 μL of 35% hydrochloric acid and allowing the mixture to stand at room temperature for at least 30 minutes.

Next, stir bars were placed in both tubes of the H-tube. One tube was charged with 37.6 μL (0.3 mmol, 1 equivalent) of 1,2,3,4-tetrahydroquinoline and 3 mL of the purified chloroform, while the other tube was charged with 5.7 mL (4 equivalents) of the sodium chlorite oxidizing solution. The lids on both tubes were then tightly closed. The H-tube was placed in the center of a ring-shaped LED lamp (illuminance 3.5 mW/cm ² ) with a wavelength of 405 nm, and the mixture was exposed to light for 3 hours while stirring. The LED lamp used was a blue LED light built into an Aldrich microphotochemical reactor (product name: ALDRP2). After distilling off the solvent from the reaction mixture, ^1H -NMR was measured. The yield was calculated from the peak intensity ratio of the ^1H -NMR, confirming that the N-chlorocarbonylated product, carbamoyl chloride, was obtained in 78% yield. 2 shows the ¹ H-NMR spectrum of the mixture after the reaction, together with the ¹ H-NMR spectrum of the starting material, 1,2,3,4-tetrahydroquinoline. The analysis results of each ¹ H-NMR spectrum are also shown below. It is believed that in this example and the following examples, phosgene was generated in the chloroform phase (carbonyl halide compound generation step) through a mechanism similar to that in Reference Example 1, and that the phosgene reacted with a nucleophilic agent to generate a nucleophilic reaction product (nucleophilic reaction product production step).

^1H -NMR spectrum analysis results of 1,2,3,4-tetrahydroquinoline:
^1H -NMR (400MHz, _CDCl3 ) δ: 7.00 (m, 2H), 6.65 (t, J = 7.6Hz, 1H), 6.50 (t, J = 7.6Hz, 1H), 3.32 ( t, J = 5.6Hz, 2H), 2.80 (t, J = 6.4Hz, 2H), 1.98 (tt, J = 5.6, 6.4Hz, 2H)
¹ H-NMR spectrum analysis results of the reaction mixture of Example 1:
^1H -NMR (400MHz, _CDCl3 ) δ: 7.63 (br, 1H), 7.22-7.10 (m, 3H), 3.93 (t, J = 6.4Hz, 2H), 2.80 (t, J = 6.4Hz, 2H), 2.03 (tt, J = 6.4, 6.4Hz, 2H)

[Example 2]
In this example, as shown in Scheme E3 below, chlorine dioxide radicals were reacted with chloroform to generate phosgene, as in Example 1, and the phosgene was then reacted with tetrahydroquinoline without isolation to produce carbamoyl chloride. Note that in this example, instead of the ring-shaped LED lamp used in Example 1, an LED lamp with stronger illuminance (manufactured by Pi Photonics, product name "Hololightkaku") was used as the light source for light irradiation.

In this example, the reaction of Scheme E3 was carried out as follows. First, chloroform (containing amylene) was used as the solvent. This chloroform was not only the reaction solvent, but also reacted with chlorine dioxide radicals to produce phosgene. The sodium chlorite oxidizing solution used was prepared in the same manner as in Example 1.

Next, stir bars were placed in both tubes of the H-shaped tube. One tube was charged with 37.6 μL (0.3 mmol, 1 equivalent) of 1,2,3,4-tetrahydroquinoline, 1 mL of chloroform (containing amylene), and 208 μL (1.5 mmol, 5 equivalents) of triethylamine, while the other tube was charged with 5.7 mL (4 equivalents) of the sodium chlorite oxidizing solution. The caps on both tubes of the H-shaped tube were then tightly closed. This H-shaped tube was placed 20 cm from a 405 nm LED lamp (illuminance: 90 mW/cm ² ) and irradiated with light for 45 minutes while stirring. After distilling off the solvent from the reaction mixture, ^1H -NMR was measured using deuterated chloroform (CDCl ₃₎ as the solvent. Meanwhile, the reaction mixture was separated with water. Specifically, 5 mL of water and 5 mL of dichloromethane were added to the reaction solution to extract the organic layer. After drying with sodium sulfate, the solvent was distilled off. The residue was also subjected to ^1H -NMR measurement using deuterated chloroform (CDCl ₃₎ as the solvent. The yield was calculated from the peak intensity ratio of these ^1H -NMR spectra, confirming that the N-chlorocarbonylated product, carbamoyl chloride, was obtained in 86% yield. Figure 3 shows the ^1H -NMR spectrum of the mixture after the reaction and ^{the 1H} -NMR spectrum of the residue after separation with water, along with the ^1H -NMR spectrum of the starting material, 1,2,3,4-tetrahydroquinoline. The analysis results of each ^1H -NMR spectrum are shown below.

^1H -NMR spectrum analysis results of 1,2,3,4-tetrahydroquinoline:
^1H -NMR (400MHz, _CDCl3 ) δ: 7.00 (m, 2H), 6.65 (t, J = 7.6Hz, 1H), 6.50 (t, J = 7.6Hz, 1H), 3.32 ( t, J = 5.6Hz, 2H), 2.80 (t, J = 6.4Hz, 2H), 1.98 (tt, J = 5.6, 6.4Hz, 2H)
¹ H-NMR spectrum analysis results of the reaction mixture of Example 2:
^1H -NMR (400MHz, _CDCl3 ) δ: 7.38 (br, 1H), 7.01-6.98 (m, 3H), 3.71 (t, J = 6.4Hz, 2H), 2.59 (t, J = 6.4Hz, 2H), 1.82 (tt, J = 6.4, 6.4Hz, 2H)
¹ H-NMR spectrum analysis results of the residue after separation with water in Example 2:
^1H -NMR (400MHz, _CDCl3 ) δ: 7.65 (br, 1H), 7.22-7.10 (m, 3H), 3.92 (t, J = 6.4Hz, 2H), 2.81 (t, J = 6.4Hz, 2H), 2.01 (tt, J = 6.4, 6.4Hz, 2H)

[Example 3]
In this example, carbamoyl chloride was produced from tetrahydroquinoline using the same method as in Example 2, Scheme E3, with slight changes in the amounts of reactants used and the light irradiation time. Specifically, the reaction was carried out under the same conditions as in Example 2, except that the amount of 1,2,3,4-tetrahydroquinoline used was changed from 0.3 mmol to 0.2 mmol, the amount of chloroform (containing amylene) used was changed from 1 mL to 2 mL, the light irradiation time was changed from 45 minutes to 40 minutes, the amount of sodium chlorite used was changed from 17.0 mg to 113 mg (0.8 mmol), and the amount of 35% hydrochloric acid used was changed from 86 μL to 57 μL. The mixture after the reaction was treated in the same manner as in Example 2, and the yield was calculated from the ¹ H-NMR peak intensity ratio in the same manner as in Example 2. It was confirmed that the N-chlorocarbonylated product, carbamoyl chloride, was obtained in a yield of 95%. That is, the yield of carbamoyl chloride was improved from 86% in Example 2 to 95% in this example. FIG. 4 shows the ¹ H-NMR spectrum of 1,2,3,4-tetrahydroquinoline, which is the starting material of this example, the ¹ H-NMR spectrum of the mixture after the reaction, and ^{the 1} H-NMR spectrum of the residue after separation with water, along with the reaction scheme of this example.

[Example 4]
In this example, as shown in Scheme E4 below, various amines (Compound 1 below) were reacted with phosgene instead of tetrahydroquinoline to produce the reaction products carbamoyl chloride (Compound 2 below) and urea derivative (Compound 3 below). In this example, the reaction was carried out under the same reaction conditions as in Example 3 (Condition 1), and further, the reaction was carried out in a system in which the conditions were changed as in Conditions 2 and 3 below. Note that in Conditions 2 and 3 below, the reaction conditions other than those described below were the same as Condition 1 (i.e., the same as in Example 3). Furthermore, in Conditions 2 and 3 below, the term "substrate" refers to the reaction raw material, i.e., Compound 1 in Scheme E4 below (individually, Compound 1b, 1c, 1d, or 1e in Scheme E4 below).

Condition 2: Amount of substrate used: 0.1 mmol, Amount of chloroform used: 5 mL, Amount of triethylamine used: 0.5 mmol
Condition 3: Amount of substrate used: 0.4 mmol, Amount of chloroform used: 1 mL, Amount of triethylamine used: 1.6 mmol, Amount of sodium chlorite used: 57 mg, Amount of 35% hydrochloric acid used: 28 μL

In this example, the treatment of the mixture after the reaction was carried out in the same manner as in Example 2 or 3. Furthermore, ¹ H-NMR was measured in the same manner as in Example 2 or 3, except that tetrachloroethylene C ₂ H ₂ Cl ₄ was used as the internal standard, and the yield was calculated from the peak intensity ratio. As shown in Scheme E4 above, when 1,2,3,4-tetrahydroisoquinoline (Compound 1b) was used as the starting amine (Compound 1), the yield of the corresponding carbamoyl chloride (Compound 2) was 89% under Condition 2, and the yield of the urea derivative (Compound 3) was 48% under Condition 3. Furthermore, when indoline (Compound 1c) was used as the starting amine (Compound 1), no carbamoyl chloride (Compound 2) was produced under either Condition 1 or Condition 2, and the yield of the urea derivative (Compound 3) was 89% under Condition 2. When piperidine (Compound 1d) was used as the starting amine (Compound 1), the yield of the corresponding carbamoyl chloride (Compound 2) was up to 83% under Condition 2. When pyrrolidine (compound 1e) was used as the starting amine (compound 1), the yield of the corresponding carbamoyl chloride (compound 2) was up to 58% under condition 2, and the yield of the urea derivative (compound 3) was up to 42% under condition 3. Furthermore, regardless of whether compounds 1b, 1c, 1d, or 1e were used as starting materials, the conversion rate to the product (the recovery rate of the product and unreacted starting materials combined) was 100%. Figures 5 to 8 show ^1H -NMR charts of the various starting materials and reaction mixtures used in this example, along with the reaction scheme. Figure 5 shows the results when compound 1b (1,2,3,4-tetrahydroisoquinoline) was reacted under condition 2 or condition 3. Figure 6 shows the results when compound 1c (indoline) was reacted under condition 2. Figure 7 shows the results when compound 1d (piperidine) was reacted under condition 2. 8 shows the results when compound 1e (pyrrolidine) was reacted under conditions 2 and 3. The analysis results of each ¹ H-NMR chart are shown below.

Reaction raw material for tetrahydroisoquinoline (1b): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.13-7.00 (m, 3H), 6.99-6.96 (m, 1H), 3.99 (s, 1H), 3.11 (t, J=8.4 Hz, 2H), 2.77 (t, J=8.4 Hz, 2H)
Condition 2 After reaction separation: ¹ H-NMR (400 MHz, CDCl ₃ ) diastereomer mixture δ: 7.10-6.96 (m, 4H), 4.70 (s, 0.8H), 4.60 (s, 1.2H), 3.80-3.76 (m, 1.2H), 3.71-3.66 (m, 0.8H), 2.85-2.78 (m, 2H)
Condition 3 After reaction separation: ¹ H-NMR (400 MHz, CDCl ₃ ) diastereomer mixture δ: 7.10-6.91 (m, 4H), 4.38 (s, 2H), 3.45 (t, J=8.4Hz, 2H), 2.85 (t, J=8.4Hz, 2H)

Reaction raw material for indoline (1c): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.10 (d, J=7.2Hz, 1H), 7.02 (dd, J=7.2, 7.2Hz, 1H), 6.69 (dd, J=7.2, 7.2Hz, 1H) , 6.62 (d, J=7.2Hz, 1H), 3.72 (br, 1H), 3.51 (t, J=8.4Hz, 2H), 3.00 (t, J=8.4Hz, 2H)
Condition 1 After reaction separation treatment (3c): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.85 (d, J=8.4Hz, 2H), 7.22-7.17 (m, 4H), 7.08 (dd, J=7.2, 7.2Hz, 2H), 4.23 (t, J=8.4Hz, 4H), 3.18 (t, J=8.4Hz, 4H)

Piperidine (1d) reaction raw material: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.78 (m, 4H), 1.50 (m, 6H)
Condition 2, after separation (2d): ¹ H-NMR (400 MHz, CDCl ₃ ) diastereomeric mixture δ: 3.57-3.45 (m, 4H), 1.61-1.50 (m, 6H)

Pyrrolidine (1e) reaction raw material: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.80 (m, 4H), 1.66 (m, 4H)
Condition 2 After reaction separation treatment (2e): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.50-3.36 (m, 4H), 1.89-1.82 (m, 4H)
Condition 3 After reaction separation treatment (3e): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.30-3.26 (m, 4H), 1.77-1.72 (m, 4H)

[Example 5]
In this example, as shown in Scheme E5 below, various phenols or alcohols (Compound 4 below) were reacted with phosgene as raw materials in place of various amines to attempt to produce reaction products, phenoxycarbonyl chloride (chloroformate, Compound 5 below) and carbonate (Compound 6 below).

In this example, the reaction of Scheme E5 was carried out in the same manner as in Example 4, except that various phenols or alcohols (Compound 4 in Scheme E5) were used as raw materials instead of various amines, and the amounts of various substances used were appropriately changed. However, in this example, only conditions 1 and 2 were investigated. The mixture after the reaction was treated in the same manner as in Example 4 (i.e., in the same manner as in Example 2 or 3). Furthermore, as in Example 4, ^1H -NMR was measured using deuterated chloroform (CDCl3 ₎ as the solvent for ^1H -NMR and _{tetrachloroethylene} ( _{C2H2Cl4 )} as the internal standard, and the yield was calculated from the peak intensity ratio. As shown in Scheme E5, no production of the corresponding phenoxycarbonyl chloride (Compound 5) was observed when phenol (hydroxybenzene), 4-chlorophenol, or 4-nitrophenol was used as the raw material. On the other hand, the yield of the carbonate (Compound 6) corresponding to the raw material was 99% or higher when phenol (hydroxybenzene) and 4-chlorophenol were used as the raw material (Conditions 1 and 2). Furthermore, when 4-nitrophenol was used as the raw material, the yield of the corresponding carbonate (Compound 6) was 99% or more under Condition 2. When 1-propanol was used as the raw material, the corresponding phenoxycarbonyl chloride (Compound 5) and carbonate (Compound 6) were produced, and the yield of phenoxycarbonyl chloride (Compound 5) was 41% under Condition 2. Regardless of the raw material used, the conversion rate to the product (the recovery rate of the product and unreacted raw material combined) was 100%. Figures 9 to 12 show ^1H -NMR charts of the various raw materials (starting materials) and reaction mixtures used in this example, along with the reaction scheme. Figure 9 shows the results when phenol (hydroxybenzene) was reacted under Condition 2. Figure 10 shows the results when 4-chlorophenol was reacted under Condition 1. Figure 11 shows the results when 4-nitrophenol was reacted under Condition 2. 12 is a diagram showing the case where 1-propanol (n-propyl alcohol) was reacted under Condition 1. The analysis results of each ¹ H-NMR chart are shown below.

Phenol (4a) reaction raw material: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.28 (dd, J=7.8, 8.0 Hz, 2H), 6.99 (t, J=7.8 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H)
Condition 2 After reaction separation treatment (6a): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.43-7.37 (m, 2H), 7.28-7.24 (m, 3H)

4-Chlorophenol (4b) reaction raw material: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.18 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.13 (br, 1H)
Condition 1 After reaction separation treatment (6b): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.38 (d, J = 7.2 Hz, 4H), 7.22 (d, J = 7.2 Hz, 4H)

4-Nitrophenol (4c) reaction raw material: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.17 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 5.85 (br, 1H)
Condition 2 After reaction separation treatment (6c): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.32 (d, J = 9.2 Hz, 4H), 7.48 (d, J = 9.2 Hz, 4H)

1-Propanol (4d) reaction raw material: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.59 (t, J = 6.4 Hz, 2H), 1.57 (tt, J = 9.2 Hz, 2H), 5.85 (br, 1H)
Condition 1 After reaction separation treatment (5d): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.27 (t, J = 6.4 Hz, 2H), 1.71 (tq, J = 6.4, 6.4 Hz, 2H), 0.98 (t, J = 6.4 Hz, 3H)
After reaction separation treatment (6d): ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.98 (t, J = 6.4 Hz, 2H), 1.52 (tq, J = 6.4, 6.4 Hz, 2H), 0.96 (t, J = 6.4 Hz, 3H)

[Example 6]
In this example, as shown in Scheme E6 below, chlorine dioxide radicals were reacted with chloroform to generate phosgene, as in Examples 1 to 3. The phosgene was then reacted with tetrahydroquinoline without isolation to produce carbamoyl chloride. In this example, sunlight was used as the light source for light irradiation instead of the ring-shaped LED lamp in Example 1 and the LED lamps in Examples 2 and 3.

In this example, the reaction of Scheme E6 was carried out as follows. First, chloroform (containing amylene) was used as the solvent. This chloroform was not only the reaction solvent, but also reacted with chlorine dioxide radicals to produce phosgene. The sodium chlorite oxidizing solution used was prepared in the same manner as in Example 1.

Next, stir bars were placed in both tubes of the H-shaped tube. Furthermore, 25.1 μL (0.2 mmol, 1 equivalent) of 1,2,3,4-tetrahydroquinoline, 2.0 mL of chloroform (containing amylene), and 138 μL (1.0 mmol, 5 equivalents) of triethylamine were added to one tube, and 5.7 mL (4 equivalents) of the sodium chlorite oxidizing solution was added to the other tube. The lids of both H-shaped tubes were then tightly closed. This H-shaped tube was placed in sunlight and irradiated with sunlight for 2 hours while stirring. The experiment was conducted on March 10, 2021, from 11:20 to 13:20, and the weather was clear. After distilling off the solvent from the reaction mixture, ^1H -NMR was measured using deuterated chloroform (CDCl3 ₎ as the solvent. Meanwhile, the reaction mixture was separated with water. Specifically, 5 mL of water and 5 mL of dichloromethane were added to the solution after the reaction to extract the organic layer, followed by drying with sodium sulfate and distilling off the solvent. ¹ H-NMR was also measured for the residue using deuterated chloroform (CDCl ₃₎ as a solvent. The yield was calculated from the peak intensity ratio of these ¹ H-NMR spectra, confirming that the N-chlorocarbonylated product, carbamoyl chloride, was obtained in a yield of 96%. In other words, this example confirmed that the target product (nucleophilic reaction product) can be produced in extremely high yield by the method for producing a nucleophilic reaction product of the present invention, even when sunlight (natural light) is used instead of an artificial light source.

[Example 7]
In this example, ethylene glycol was selected as the substrate (i.e., raw material or starting material) to react with phosgene in a 1:1 molar ratio. In this example, 0.5 equivalents of chlorine dioxide were allowed to act on ethylene glycol as shown in Scheme E7 below, and the product was obtained in 61% yield. This suggests that chlorine dioxide acted as an initiator and oxygenating agent for the radical chain reaction in this example.

In this example, the reaction of Scheme E7 was carried out as follows. First, stir bars were placed in both tubes of an H-shaped tube. Next, 22.3 μL (0.4 mmol, 1 equivalent) of ethylene glycol, 4 mL of chloroform (containing amylene), and 161 μL (2.0 mmol, 5 equivalents) of pyridine were added to one tube of the H-shaped tube. Furthermore, 5.7 mL (0.5 equivalents) of the sodium chlorite oxidizing solution was added to the other tube of the H-shaped tube. Then, the lids of both tubes of the H-shaped tube were tightly closed. This H-shaped tube was placed 20 cm from a 405 nm LED lamp (illuminance 90 mW/cm ² ) and irradiated with light for 3 hours while stirring to allow the reaction to occur. After the solvent was distilled off from the reaction mixture, ¹ H-NMR was measured using deuterated chloroform (CDCl ₃₎ as a solvent, and the yield was calculated from the peak intensity ratio, confirming that the carbonylated target product, cyclic carbonate, was obtained in a yield of 61%. Note that the identification of the reaction mixture by ¹ H-NMR was performed by comparison with known ¹ H-NMR charts of the starting material (ethylene glycol) and the target product (cyclic carbonate).

In this example, the mechanism by which phosgene (a halogenated carbonyl compound) is generated by the reaction of chlorine dioxide radicals (halogen oxide radicals) with chloroform (a halogenated hydrocarbon) is presumed to proceed via a radical chain reaction, as shown in Scheme II below. In Scheme II below, " ¹ O ₂ ^* " represents an oxygen molecule in a singlet state. Furthermore, in Scheme II below, numbers such as "-3.3" and "-14.8" represent the energy difference (unit: kcal mol ^-1 ) before and after the reaction estimated by DFT calculation (M06-2x/6-311++G(d,p) level). "-60.5 (s)" represents the energy difference (unit: kcal mol ^-1 ) before and after the reaction when singlet oxygen (s) is added. "-23.1 (t)" represents the energy difference (unit: kcal mol ^-1 ) before and after the reaction when triplet oxygen (t) is added. The fact that the energy difference before and after these reactions is a negative value means that the product system (the system after the reaction) is lower in energy (i.e., more stable) than the system before the reaction, suggesting that the reaction proceeds exothermically. Note that in this example, light was irradiated using an LED lamp with a wavelength of 405 nm, but as mentioned above, the present invention is not limited to this.

As described above, the present invention provides a method for producing a nucleophilic reaction product and a reactant for producing a nucleophilic reaction product, which allows the carbonyl halide compound to be used in the reaction without isolation and can be carried out under mild reaction conditions. As described above, the method for producing a nucleophilic reaction product of the present invention allows the carbonyl halide compound to be used in the reaction without isolation, thereby offering advantages such as high safety, shortening of work steps, and cost reduction. Furthermore, as described above, the method for producing a nucleophilic reaction product of the present invention is applicable to a wide variety of nucleophiles, similar to general reactions between nucleophiles and carbonyl halide compounds, thereby enabling the production of a variety of nucleophilic reaction products. Therefore, the method for producing a nucleophilic reaction product of the present invention is applicable to a very wide range of fields. Furthermore, as described above, the method for producing a nucleophilic reaction product of the present invention can be carried out under mild reaction conditions. Therefore, for example, nucleophilic reaction products can be produced by applying the method for producing a nucleophilic reaction product of the present invention to raw materials that have been difficult to use in conventional reactions.

As described above, the present invention is applicable to a wide range of diverse technical fields and has great industrial utility.

This application claims priority based on Japanese Patent Application No. 2021-033809, filed on March 3, 2021, the disclosure of which is incorporated herein in its entirety.

Claims (12)

a halogenated carbonyl compound generating step of reacting a halogen oxide radical with a halogenated hydrocarbon to generate a halogenated carbonyl compound;
a nucleophilic reaction product production step of reacting the carbonyl halide compound with a nucleophilic agent without isolating it to produce a nucleophilic reaction product of the carbonyl halide compound and the nucleophilic agent. A method for producing a nucleophilic reaction product according to claim 1, wherein in the carbonyl halide generating step, the halogen oxide radical is activated by irradiating it with light. A method for producing a nucleophilic reaction product as described in claim 2, wherein in the carbonyl halide generating step, a halogen radical and singlet oxygen are generated from the halogen oxide radical by activation by irradiation with light, and the singlet oxygen is further reacted with the halogenated hydrocarbon to generate the carbonyl halide compound. A method for producing a nucleophilic reaction product according to claim 2 or 3, wherein the light irradiated is visible light. A method for producing a nucleophilic reaction product described in any one of claims 1 to 4, wherein the halogen oxide radical is a chlorine dioxide radical. A method for producing a nucleophilic reaction product according to any one of claims 1 to 5, wherein the carbonyl halide compound is phosgene. A method for producing a nucleophilic reaction product according to any one of claims 1 to 6, wherein the nucleophilic reaction product is a carbonylation product of the nucleophile. A method for producing a nucleophilic reaction product according to any one of claims 1 to 7, wherein the nucleophilic agent is at least one selected from the group consisting of amines, carboxylic acids, ammonia, alcohols, phenols, polyols, polyphenols, polyamines, formamide, urea, urea derivatives, carboxylic acid amides, aromatic compounds, α-amino acids, and thiols. The method for producing a nucleophilic reaction product according to any one of claims 1 to 8, wherein the nucleophilic reaction product is at least one selected from the group consisting of amides, halogenated amides, acid halides, esters, carbonates, polycarbonates, polyurethanes, isocyanates, ureas, urea derivatives, polyureas, halogenated formate esters, carbamates, isocyanides, carbodiimides, cyanides, aromatic aldehydes, α-amino acid N-carboxylic anhydrides (NCAs), and thiocarbonates. containing a halogen oxide radical or a halogen oxide radical generator,
A reactant for producing a nucleophilic reaction product, characterized in that the halogen oxide radical is reacted with a halogenated hydrocarbon to generate a halogenated carbonyl compound, and the reactant is used in the method for producing the nucleophilic reaction product according to any one of claims 1 to 9. Contains halogenated hydrocarbons,
A reactant for producing a nucleophilic reaction product, which is used in the method for producing the nucleophilic reaction product according to any one of claims 1 to 9, by reacting the halogenated hydrocarbon with a halogen oxide radical to generate a halogenated carbonyl compound. containing a nucleophile,
A reactant for producing a nucleophilic reaction product, characterized in that the nucleophilic agent is reacted with the carbonyl halide compound generated in the carbonyl halide compound-generating step, and the reactant is used in the method for producing the nucleophilic reaction product according to any one of claims 1 to 9.