Method for producing carbonyl compound using light energy

Abstract

Provided is a method for producing a carbonyl compound using light energy, the method being characterized by irradiating a substrate with light having a wavelength of 200-420 nm in the presence of a tetrahalomethane to react the substrate. The method, which is for producing a carbonyl compound, e.g., an ester, a lactone, a carboxylic acid, an amide, a thioester, or a ketone, makes it possible to obtain the carbonyl compound directly from a substrate without using a heavy metal or the like in a stoichiometric amount.

Description

Method for producing carbonyl compounds using light energy

[0001] The present invention relates to a method for producing a carbonyl compound using light energy.

[0002] Carbonyl compounds, including lactones and esters, are chemical structures found in a variety of pharmaceuticals and functional materials, and the development of efficient synthetic methods for them is crucial. A typical synthetic method for lactones and esters involves a reaction using a stoichiometric amount of a condensing agent with a carboxylic acid as a substrate (Non-Patent Documents 1 and 2). Meanwhile, only one example of a macrolactonization reaction using an aldehyde as a substrate has been reported, utilizing an NHC catalyst (Non-Patent Document 3). However, this reaction utilizes an NHC catalyst, stoichiometric amounts of an oxidizing agent, and a base, and thus a new method is desired.

[0003] Shiina, I. et. al. Tetrahedron Lett., 2002, 43, 7535Yamaguchi, M. et. al. Bull. Chem. Soc. Jpn., 1979, 52, 1989Hong, J. et al. Angew. Chem. Int. Ed., 2012, 51, 5735

[0004] The present invention has been made to solve the above-mentioned problems, and provides a method for producing carbonyl compounds such as esters, lactones, carboxylic acids, amides, thioesters, and ketones, which can be obtained directly from substrates without using stoichiometric amounts of heavy metals or the like.

[0005] The present inventors have conducted extensive research to solve the above problems and have completed the present invention, which relates to the following [1] to [8].

[0006] [1] A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with an alcohol represented by the following formula (B1) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm:

[0007] [In formula (A1), X １is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0008] [In formula (B1), Y １ is a primary or secondary alkyl group or an arylalkyl group.

[0009] [In formula (C1), X １ and Y １ has the same meaning as the formulas (A1) and (B1).

[0010] [2] A method for producing a carbonyl compound using light energy, comprising irradiating an aldehyde represented by the following formula (A1) with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane to obtain an acyl bromide represented by the following formula (A2), and then reacting the resulting acyl bromide with an alcohol represented by the following formula (B2):

[0011] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0012] [In formula (A2), X １ has the same meaning as formula (A1).

[0013] [In formula (B2), Y ２ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.]

[0014] [In formula (C2), X １ and Y ２ has the same meaning as the formulas (A1) and (B2).

[0015] [3] A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A3) with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane:

[0016] [In formula (A3), R １ ~R ３ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an arylalkyl group, an alkoxy group, an aryloxy group, a heteroaromatic ring group, or an amino group, and R １ and R ２ The carbon-carbon bond between R may be a single bond or a double bond. １ and R ２ may form a ring structure, Z is a divalent organic group, and n is an integer of 1 to 50.

[0017] [In formula (C3), R １ ~R ３ , Z and n are the same as defined in formula (A3).

[0018] [4] A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with water in the presence of a tetrahalomethane by irradiating the aldehyde with light having a wavelength of 200 to 420 nm.

[0019] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0020] [In formula (C4), X １ has the same meaning as formula (A1).

[0021] [5] A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A4) with an amine represented by the following formula (B5) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm:

[0022] [In formula (A4), X ２ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, an adamantyl group, or an amino acid residue.

[0023] [In formula (B5), R ４ and R ５ are each independently a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or an amino acid residue.

[0024] [In formula (C5), X ２ , R ４ and R ５ has the same meaning as the formulas (A4) and (B5).

[0025] [6] A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with a thiol represented by the following formula (B6) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm:

[0026] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0027] [In formula (B6), R ６ represents a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, or an arylalkyl group.

[0028] [In formula (C6), X １and R ６ has the same meaning as in formulas (A1) and (B6).

[0029] [7] A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with a carbon nucleophile in the presence of a tetrahalomethane by irradiating the aldehyde with light having a wavelength of 200 to 420 nm.

[0030] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0031] [In formula (C7), X １ has the same meaning as in formula (A1), and Nu is an added carbon nucleophile.

[0032] [8] A method for producing a carbonyl compound using light energy, comprising reacting an alcohol represented by the following formula (A8) with an alcohol represented by the following formula (B8) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm:

[0033] [In formula (A8), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0034] [In formula (B8), Y ３ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.]

[0035] [In formula (C8), X １ and Y ３ has the same meaning as the formulas (A8) and (B8).

[0036] The present invention makes it possible to synthesize carbonyl compounds such as esters, lactones, carboxylic acids, amides, thioesters, and ketones directly from substrates without using stoichiometric amounts of heavy metals, etc. Compared to using carboxylic acids as substrates, the synthesis step is shortened by one, which offers cost benefits, does not produce hazardous waste, and the progress of the reaction can be controlled by turning light irradiation on and off, making it extremely safe even when produced on an industrial scale.

[0037] Product 3a １ 1 H NMR spectrum of product 3b. １ 1 H NMR spectrum of product 3c. １ 1 H NMR spectrum of product 3d. １ 1 H NMR spectrum of product 3e. １ 1 H NMR spectrum of product 3f. １ 1 H NMR spectrum of product 3g. １ 1 H NMR spectrum of product 3h. １ 1 H NMR spectrum of product 3i. １ 1 H NMR spectrum of product 3j. １ 1 H NMR spectrum of product 3k. １ 1 H NMR spectrum of product 3l. １ 1 H NMR spectrum of product 3m １ 1 H NMR spectrum of product 3n. １ 1 H NMR spectrum of product 3o. １ 1 H NMR spectrum of product 3p. １ 1 H NMR spectrum of product 3q. １ 1 H NMR spectrum of product 3r. １ 1 H NMR spectrum of product 3s. １ 1 H NMR spectrum of product 3t'. １ 1 H NMR spectrum of product 3t'. １３ C NMR spectrum of product 3t. １ 1 H NMR spectrum of product 3u. １1 H NMR spectrum of product 3v. １ 1 H NMR spectrum of product 3w. １ 1 H NMR spectrum of product 3x. １ 1 H NMR spectrum of product 3x. １３ C NMR spectrum of product 3y. １ 1 H NMR spectrum of product 3z. １ 1 H NMR spectrum of product 2m １ 1 H NMR spectrum of product 2m １３ C NMR spectrum of product 3aa. １ 1 H NMR spectrum of product 3aa. １３ C NMR spectrum of product 3ab. １ 1 H NMR spectrum of product 3ab. １３ C NMR spectrum of product 3ac. １ 1 H NMR spectrum of product 3ad. １ 1 H NMR spectrum of product 3ae. １ 1 H NMR spectrum of product A2-1a. １ 1 H NMR spectrum of product 52a. １ 1 H NMR spectrum of product 52a. １３ C NMR spectrum of product 52c. １ 1 H NMR spectrum of product 52c. １３ C NMR spectrum of product S5. １ 1 H NMR spectrum of product S5. １３ C NMR spectrum of product 52d. １ 1 H NMR spectrum of product 52d. １３ C NMR spectrum of product 52f. １ 1 H NMR spectrum of 52 g of product １ 1 H NMR spectrum of product 52h. １ 1 H NMR spectrum of product 52i. １ 1 H NMR spectrum of product 52j.１ 1 H NMR spectrum of product 52j. １３ C NMR spectrum of product S11. １ 1 H NMR spectrum of product S11. １３ C NMR spectrum of product 52k １ 1 H NMR spectrum of product 52k １３ C NMR spectrum of product S14. １ 1 H NMR spectrum of product S14. １３ C NMR spectrum of product S15. １ 1 H NMR spectrum of product S15. １３ C NMR spectrum of product 52l. １ 1 H NMR spectrum of product 52l. １３ C NMR spectrum of product 52m １ 1 H NMR spectrum of product 53a. １ 1 H NMR spectrum of product 53b. １ 1 H NMR spectrum of product 53c. １ 1 H NMR spectrum of product 53c. １３ C NMR spectrum of product 53d. １ 1 H NMR spectrum of product 53e. １ 1 H NMR spectrum of product 53f. １ 1 H NMR spectrum of product 53h. １ 1 H NMR spectrum of product 53i. １ 1 H NMR spectrum of product 53j. １ 1 H NMR spectrum of product 53k １ 1 H NMR spectrum of product 53l. １ 1 H NMR spectrum of product 53m １ 1 H NMR spectrum of product C4-1b. １ 1 H NMR spectrum of product C8-1c. １ 1 H NMR spectrum.

[0038] The present invention is a method for producing a carbonyl compound using light energy, characterized in that a substrate is reacted by irradiating it with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane.

[0039] The inventors' studies have revealed that various carbonyl compounds, such as esters, lactones, carboxylic acids, amides, thioesters, and ketones, can be directly synthesized by irradiating a substrate with light having a wavelength of 200 to 420 nm in the presence of tetrahalomethanes, without using stoichiometric amounts of heavy metals or the like. Compared to using carboxylic acids as substrates, this method has the advantage of shortening the synthesis step by one, thereby offering cost benefits, not producing hazardous waste, and being able to control the progress of the reaction by turning light irradiation on and off, thereby offering the advantages of extremely high safety even when produced on an industrial scale. In particular, since carbonyl compounds such as esters and lactones have chemical structures found in pharmaceuticals and the like, the present invention enables the efficient synthesis of pharmaceuticals and the like.

[0040] Analysis of the esterification reaction mechanism in the Examples described below revealed that carrying out the reaction under conditions in which TEMPO was added reduced the yield, giving only trace amounts of the target product. Furthermore, compounds in which acyl radicals were trapped by TEMPO were observed by mass spectrometry. These results suggest that this is a radical reaction mediated by the acyl radical. That is, as shown in reaction mechanism (I) below, when irradiated with light having a wavelength of 200 to 420 nm, the tetrahalomethane bromotrichloromethane undergoes homolytic cleavage, generating a trichloromethyl radical and a bromo radical. The trichloromethyl radical then cleaves the C-H bond in the acyl moiety of benzaldehyde or the like, generating an acyl radical. This is then coupled with the bromo radical in the system to form acyl bromide, and finally, an addition-elimination reaction of the substrate alcohol yields an ester, a carbonyl compound.

[0041]

[0042] (Tetrahalomethane) The tetrahalomethane used in the present invention can be one that is used as a radical initiator. The tetrahalomethane is not particularly limited as long as it is a compound in which all hydrogen atoms in methane are replaced with halogen atoms, and examples of usable tetrahalomethane include bromotrichloromethane, tetrabromomethane, tetrachloromethane, tetraiodomethane, tetrafluoromethane, bromotrifluoromethane, tribromoiodomethane, and bromochlorodifluoromethane. From the viewpoint of improving the reaction yield, compounds in which all hydrogen atoms in methane are replaced with halogen atoms containing at least one bromine atom are preferably used. Specifically, examples of usable tetrahalomethane include bromotrichloromethane, tetrabromomethane, bromotrifluoromethane, tribromoiodomethane, and bromochlorodifluoromethane. The amount of tetrahalomethane used is preferably 1 to 10 moles, more preferably 1.2 to 8 moles, even more preferably 1.5 to 6 moles, and particularly preferably 2 to 5 moles, per mole of substrate.

[0043] (Light Irradiation) The method for producing a carbonyl compound of the present invention is characterized by irradiating with light having a wavelength of 200 to 420 nm, and not only ultraviolet light but also visible light can be used. If the wavelength of the light irradiation exceeds 420 nm, the reaction yield may decrease, so the wavelength is preferably 415 nm or less, more preferably 410 nm or less, even more preferably 400 nm or less, and particularly preferably 390 nm or less. On the other hand, if the wavelength of the light irradiation is less than 200 nm, safety may be compromised, so the wavelength is preferably 240 nm or more, more preferably 280 nm or more, even more preferably 315 nm or more, and particularly preferably 340 nm or more.

[0044] (Solvent) In the method for producing a carbonyl compound of the present invention, substrates may be reacted neat (without a solvent) or in the presence of a solvent. Reaction in the presence of a solvent is a preferred embodiment. Examples of solvents include halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, and chlorobenzene; hydrocarbon solvents such as benzene, toluene, xylene, cumene, hexane, heptane, and octane; ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile and propionitrile; and amide solvents such as dimethylformamide and N-methylpyrrolidone. The solvents may be used alone or in combination of two or more. Among these, halogenated hydrocarbon solvents and / or hydrocarbon solvents are preferably used, and halogenated hydrocarbon solvents are more preferably used. Among halogenated hydrocarbon solvents, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, and 1,1,2,2-tetrachloroethane are more preferably used, and dichloromethane, 1,2-dichloroethane, and 1,1,2-trichloroethane are even more preferably used. The amount of solvent used is preferably 10 to 1,000 parts by mass, more preferably 20 to 800 parts by mass, even more preferably 40 to 600 parts by mass, and most preferably 60 to 400 parts by mass, per part by mass of the substrate.

[0045] (Additives) In a preferred embodiment of the method for producing a carbonyl compound of the present invention, a dehydrating agent such as molecular sieves, magnesium sulfate, or sodium sulfate is added as an additive to the reaction. By using the additive to remove water generated in the reaction system, it is possible to improve the yield of the target product. The amount of additive used is preferably 0.5 to 25 parts by mass, more preferably 1 to 15 parts by mass, even more preferably 1.5 to 10 parts by mass, and particularly preferably 2 to 5 parts by mass, per part by mass of the substrate.

[0046] (Reaction Temperature) The reaction temperature in the method for producing a carbonyl compound of the present invention is adjusted as appropriate depending on the type of substrate, the type of solvent, etc. The reaction temperature is preferably −78° C. to 200° C., more preferably −50° C. to 150° C., even more preferably −20° C. to 120° C., particularly preferably −10° C. to 60° C., and most preferably −5° C. to 35° C.

[0047] (Reaction Time) The reaction time in the method for producing a carbonyl compound of the present invention is adjusted as appropriate depending on the type of substrate, the type of solvent, etc. The reaction time is preferably 1 hour to 1 week, more preferably 2 hours to 5 days, even more preferably 3 hours to 4 days, and particularly preferably 4 hours to 3 days.

[0048] (Inert Gas) The method for producing a carbonyl compound of the present invention is preferably carried out under an inert gas atmosphere, such as nitrogen, argon, helium, neon, or krypton.

[0049] (Production Method 1) The present invention is a method for producing a carbonyl compound using light energy, which is a method for producing a carbonyl compound represented by formula (C1) below, characterized by reacting an aldehyde represented by formula (A1) below with an alcohol represented by formula (B1) below in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm (sometimes referred to as "Production Method 1").

[0050] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0051] [In formula (B1), Y １ is a primary or secondary alkyl group or an arylalkyl group.

[0052] [In formula (C1), X １ and Y １ has the same meaning as the formulas (A1) and (B1).

[0053] In Production Method 1 of the present invention, an ester (C1) can be synthesized by reacting an aldehyde (A1) substrate with an alcohol (B1) by irradiating them with light in the presence of a tetrahalomethane. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperatures, reaction times, and inert gases are as described above. The molar ratio (B1 / A1) of the aldehyde (A1) substrate to the alcohol (B1) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 3.

[0054] In formula (A1) and formula (C1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0055] X １ The primary alkyl group used in may be a linear or branched alkyl group, preferably a primary alkyl group having 1 to 12 carbon atoms, more preferably a primary alkyl group having 1 to 10 carbon atoms, and even more preferably a primary alkyl group having 1 to 8 carbon atoms. Examples of the primary alkyl group include linear or branched alkyl groups such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2-ethylhexyl, n-heptyl, n-octyl, 2-butyloctyl, n-nonyl, and n-decyl. X １ The secondary alkyl group used in X is preferably a secondary alkyl group having 3 to 10 carbon atoms, more preferably a secondary alkyl group having 3 to 8 carbon atoms. Examples of the secondary alkyl group include an isopropyl group, a sec-butyl group, and a sec-pentyl group. １ The tertiary alkyl group used in is preferably a tertiary alkyl group having 4 to 8 carbon atoms, and examples thereof include a tert-butyl group, a tert-pentyl group, and a tert-hexyl group.

[0056] The primary to tertiary alkyl groups may have other substituents, and examples of such other substituents include aryl groups such as phenyl and naphthyl groups; heteroaromatic groups such as pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, pyrazolyl, benzothiazolyl, and benzimidazolyl groups; methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and the like. Alkoxy groups such as silyloxy, isopentyloxy, neopentyloxy, hexyloxy, cyclohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, and dodecyloxy; alkylthio groups such as methylthio, ethylthio, propylthio, and butylthio; arylthio groups such as phenylthio and naphthylthio; tri-substituted silyloxy groups such as tert-butyldimethylsilyloxy and tert-butyldiphenylsilyloxy; acetoxy acyloxy groups such as a propanoyloxy group, a butanoyloxy group, a pivaloyloxy group, and a benzoyloxy group; alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonyl group, a heptyloxycarbonyl group, and an octyloxycarbonyl group; alkylsulfinyl groups such as a methylsulfinyl group and an ethylsulfinyl group; arylsulfinyl groups such as a phenylsulfinyl group; sulfonate groups such as a methylsulfonyloxy group, an ethylsulfonyloxy group, a phenylsulfonyloxy group, a methoxysulfonyl group, an ethoxysulfonyl group and a phenyloxysulfonyl group; an amino group; a hydroxyl group; a cyano group; a nitro group; and halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0057] X １The cycloalkyl group used in is preferably a cycloalkyl group having 3 to 12 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptanyl group, a cyclooctanyl group, a cyclononanyl group, a cyclodecanyl group, etc. These cycloalkyl groups may have other substituents, and as such other substituents, the same substituents as those exemplified in the description of the primary, secondary, and tertiary alkyl groups can be used.

[0058] X １ The alkenyl group used in is preferably an alkenyl group having 2 to 12 carbon atoms, and examples thereof include a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group. These alkenyl groups may have other substituents, and as such other substituents, the same substituents as those exemplified in the description of the primary, secondary, and tertiary alkyl groups can be used.

[0059] X １ The aryl group used in is preferably an aryl group having 6 to 15 carbon atoms, such as a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, etc. These aryl groups may have other substituents, and as such other substituents, the same substituents as those exemplified in the description of the primary, secondary, and tertiary alkyl groups can be used.

[0060] X １ Examples of the heteroaromatic ring group used in the formula (1) include a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazinyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, a benzothiazolyl group, a benzimidazolyl group, etc. These heteroaromatic ring groups may have other substituents, and as such other substituents, the same substituents as those exemplified in the description of the primary to tertiary alkyl groups can be used.

[0061] In formula (B1) and formula (C1), Y １ is a primary or secondary alkyl group or an arylalkyl group.

[0062] Y１ The primary and secondary alkyl groups used in X include １ The same substituents as those exemplified in the explanation of 1 can be used.

[0063] Y １ The arylalkyl group used in is preferably an arylalkyl group having 7 to 15 carbon atoms, such as a benzyl group, a 4-methoxybenzyl group, a phenethyl group, a diphenylmethyl group, etc. These arylalkyl groups may have other substituents, and as such other substituents, the same substituents as those exemplified in the description of the primary, secondary, and tertiary alkyl groups can be used.

[0064] As will be seen from the examples described later, the reaction proceeds smoothly even when the aldehyde (A1) is an aromatic ring aldehyde containing an electron-donating group or an electron-withdrawing group, or an aldehyde having a heteroaromatic ring, and is also applicable to α,β-unsaturated aldehydes. The reaction has been confirmed to proceed with a variety of aliphatic aldehydes, and the ester (C1) can be obtained in high yield even when an aldehyde having a bulky substituent such as an adamantyl group is used. Furthermore, the target ester (C1) can be obtained in good yield whether the alcohol (B1) is a primary alcohol or a secondary alcohol. That is, in Production Method 1 of the present invention, X of the aldehyde (A1) is １ Even if the ester (C1) has a bulky substituent, the reaction with the alcohol (B1) proceeds smoothly, and the ester (C1) can be obtained in good yield.

[0065] (Production Method 2) The present invention relates to a method for producing a carbonyl compound using light energy, which method is characterized by irradiating an aldehyde represented by the following formula (A1) with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane to obtain an acyl bromide represented by the following formula (A2), and then reacting the resulting acyl bromide with an alcohol represented by the following formula (B2) (sometimes referred to as "Production Method 2").

[0066] [In formula (A1), X １is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0067] [In formula (A2), X １ has the same meaning as formula (A1).

[0068] [In formula (B2), Y ２ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.]

[0069] [In formula (C2), X １ and Y ２ has the same meaning as the formulas (A1) and (B2).

[0070] Production method 2 of the present invention is characterized in that an aldehyde (A1) substrate is irradiated with light in the presence of a tetrahalomethane to obtain an acyl bromide (A2), which is then reacted with an alcohol (B2), thereby synthesizing an ester (C2). Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperatures, reaction times, and inert gases for the reaction to obtain the acyl bromide (A2) are as described above. Suitable solvents, additives, reaction temperatures, reaction times, and inert gases for the reaction of the acyl bromide (A2) with the alcohol (B2) are as described above. The molar ratio (B2 / A1) of the aldehyde (A1) substrate to the alcohol (B2) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 3.

[0071] The inventors have found through their investigations that when an alcohol containing an alkene is used in the above-described Production Method 1, a product resulting from the reaction of the alkene with a tetrahalomethane is obtained, making it difficult to synthesize an ester. Therefore, by adopting Production Method 2, in which an aldehyde (A1) is irradiated with light in the presence of a tetrahalomethane to obtain an acyl bromide (A2), which is then reacted with an alcohol (B2) containing an alkene or the like, they have succeeded in obtaining an ester (C2). Production Method 2 of the present invention is applicable to not only alkene-containing alcohols, but also tertiary alcohols, cyclic alcohols, alcohols containing 4-tert-butylphenol, and alcohols containing a protecting group as the alcohol (B2).

[0072] In formula (A1), formula (A2) and formula (C2), X １ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group, and the same substituents as those described in Production Method 1 can be used.

[0073] In formula (B2) and formula (C2), Y ２ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.

[0074] Y ２ The primary to tertiary alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, and arylalkyl groups used in X １ and Y １ The same substituents as those exemplified in the explanation of 1 can be used.

[0075] Y ２The hydroxyalkyl group in which the hydroxy group is protected by a protecting group used in the above means a substituent in which the hydroxy group portion of the hydroxyalkyl group is protected by a protecting group. The alkyl group of the hydroxyalkyl group is preferably an alkyl group having 1 to 10 carbon atoms, and examples thereof include linear and branched alkyl groups such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2-ethylhexyl, n-heptyl, n-octyl, 2-butyloctyl, n-nonyl, and n-decyl. These alkyl groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0076] Examples of the protecting group include an acyl group, an alkoxycarbonyl group, an alkylsilyl group, an alkoxymethyl group, an arylmethyl group, and a tetrahydropyranyl group.

[0077] Examples of the acyl group used as the protecting group include an acetyl (Ac) group, a propionyl group, a butyryl group, an isobutyryl group, a benzoyl group, a dodecanoyl group, and a crotonoyl group. These acyl groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0078] Examples of the alkoxycarbonyl group used as the protecting group include a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an allyloxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonyl group, a heptyloxycarbonyl group, an octyloxycarbonyl group, a benzyloxycarbonyl group, etc. These alkoxycarbonyl groups may have other substituents, and examples of such other substituents include X １The same substituents as those exemplified in the description of the above can be used.

[0079] Examples of the alkylsilyl group used as the protecting group include a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl group, a tert-butyldimethylsilyl (TBS) group, and a tert-butyldiphenylsilyl group. These alkylsilyl groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0080] Examples of the alkoxymethyl group used as the protecting group include a methoxymethyl (MOM) group, an ethoxymethyl group, a benzyloxymethyl group, etc. These alkoxymethyl groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0081] Examples of the arylmethyl group used as the protecting group include a benzyl (Bn) group, a naphthylmethyl group, an anthrylmethyl group, and a phenanthrylmethyl group. These arylmethyl groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the explanation of 1. above can be used, for example, p-methoxybenzyl (MPM) group, p-chlorobenzyl group, etc.

[0082] (Production Method 3) The present invention relates to a method for producing a carbonyl compound using light energy, which is a method for producing a carbonyl compound represented by the following formula (C3) (sometimes referred to as "Production Method 3"), characterized in that an aldehyde represented by the following formula (A3) is reacted with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane:

[0083] [In formula (A3), R １ ~R ３are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an arylalkyl group, an alkoxy group, an aryloxy group, a heteroaromatic ring group, or an amino group, and R １ and R ２ The carbon-carbon bond between R may be a single bond or a double bond. １ and R ２ may form a ring structure, Z is a divalent organic group, and n is an integer of 1 to 50.

[0084] [In formula (C3), R １ ~R ３ , Z and n are the same as defined in formula (A3).

[0085] In Production Method 3 of the present invention, lactone (C3) can be synthesized by reacting an aldehyde (A3) substrate with light in the presence of a tetrahalomethane. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperature, reaction time, and inert gases are as described above. As will be seen from the examples described below, this method is applicable to the synthesis of lactones (C3) with various numbers of ring members, including macrolactones. Because macrolactones have chemical structures found in pharmaceuticals and the like, Production Method 3 of the present invention makes it possible to efficiently synthesize pharmaceuticals and the like.

[0086] In formula (A3) and formula (C3), R １ ~R ３ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an arylalkyl group, an alkoxy group, an aryloxy group, a heteroaromatic ring group, or an amino group, and R １ and R ２ The carbon-carbon bond between R may be a single bond or a double bond. １ and R ２ may form a ring structure, Z is a divalent organic group, and n is an integer of 1 to 50.

[0087] R １ ~R ３ The alkyl group used in X １ The same substituents as the primary to tertiary alkyl groups exemplified in the description of R can be used. １ ~R３ The alkenyl group, aryl group, arylalkyl group, and heteroaromatic ring group used in X １ and Y １ The same substituents as those exemplified in the explanation of 1 can be used.

[0088] R １ ~R ３ Examples of the alkoxy group used in include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a hexyloxy group, a cyclohexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group, a decyloxy group, and a dodecyloxy group. Among these, an alkoxy group having 1 to 10 carbon atoms is preferred, an alkoxy group having 1 to 8 carbon atoms is more preferred, and an alkoxy group having 1 to 6 carbon atoms is even more preferred. These alkoxy groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0089] R １ ~R ３ Examples of the arylalkyl group used in the formula (1) include a phenoxy group, a naphthyloxy group, an anthryloxy group, and a phenanthryloxy group. Among these, an aryloxy group having 6 to 14 carbon atoms is preferred, and an aryloxy group having 6 to 10 carbon atoms is more preferred. These aryloxy groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0090] R １ ~R ３ The amino group used in the ２ ), a secondary amino group or a tertiary amino group may also be used. ７ (R ７ is an arbitrary monovalent substituent), and R ７Examples of the secondary amino group include an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, an acetyl group, a benzoyl group, a benzenesulfonyl group, a tert-butoxycarbonyl group, etc. Specific examples of the secondary amino group include R , such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, etc. ７ R is a secondary amino group in which R is an alkyl group, a phenylamino group, a naphthylamino group, etc. ７ and a secondary amino group in which R is an aryl group. ７ The hydrogen atom of the alkyl group or aryl group in the formula (I) may be further substituted with an acetyl group, a benzoyl group, a benzenesulfonyl group, a tert-butoxycarbonyl group, etc. The tertiary amino group is represented by the formula (I) -NR ７ R ８ (R ７ and R ８ is an arbitrary monovalent substituent), and R ８ As for R ７ can be used, and R ７ and R ８ may be the same or different. Specific examples of the tertiary amino group include a dimethylamino group, a diethylamino group, a dibutylamino group, an ethylmethylamino group, a diphenylamino group, and a methylphenylamino group. ７ and R ８ is at least one selected from the group consisting of alkyl groups and aryl groups, and the like.

[0091] R in formula (A3) and formula (C3) １ and R ２ The carbon-carbon bond between R may be a single bond or a double bond, but from the viewpoint of smoothly proceeding with the reaction, a single bond is a preferred embodiment. １ and R ２ may form a ring structure, and the ring structure is preferably an aromatic ring, more preferably a benzene ring or a naphthalene ring, and even more preferably a benzene ring. The ring structure may have other substituents, and examples of such other substituents include X １The same substituents as those exemplified in the description of the above can be used.

[0092] In formula (A3) and formula (C3), Z is a divalent organic group, and n is an integer of 1 to 50. As the divalent organic group, a divalent hydrocarbon group is preferably used, and the structure thereof may contain a bond other than a carbon-carbon bond, such as an ether bond, an ester bond, an amide bond, a sulfonyl bond, a urethane bond, or a thioether bond, and may also contain a double bond, a triple bond, an alicyclic hydrocarbon, a heteroaromatic ring, or the like. The divalent organic group may have other substituents, and such other substituents include X １ The same substituents as those exemplified in the explanation of (1) can be used. Among them, the divalent organic group is preferably an alkylene group which may have a substituent or an arylene group which may have a substituent, and more preferably an alkylene group which may have a substituent. n is preferably an integer of 1 to 40, and more preferably an integer of 1 to 30.

[0093] (Production Method 4) The present invention relates to a method for producing a carbonyl compound using light energy, which is a method for producing a carbonyl compound represented by the following formula (C4) (sometimes referred to as "Production Method 4"), characterized by reacting an aldehyde represented by the following formula (A1) with water in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm.

[0094] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0095] [In formula (C4), X １ has the same meaning as formula (A1).

[0096] In Production Method 4 of the present invention, the carboxylic acid (C4) can be synthesized by reacting the aldehyde (A1) substrate with water by light irradiation in the presence of a tetrahalomethane. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperatures, reaction times, and inert gases are as described above. The mass ratio of the aldehyde (A1) substrate to water (water / A1) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 3.

[0097] In formula (A1) and formula (C4), X １ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group, and the same substituents as those described in Production Method 1 can be used.

[0098] (Production Method 5) The present invention relates to a method for producing a carbonyl compound using light energy, which is a method for producing a carbonyl compound represented by formula (C5) below, characterized by reacting an aldehyde represented by formula (A4) below with an amine represented by formula (B5) below in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm (sometimes referred to as "Production Method 5").

[0099] [In formula (A4), X ２ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, an adamantyl group, or an amino acid residue.

[0100] [In formula (B5), R ４ and R ５ are each independently a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or an amino acid residue.

[0101] [In formula (C5), X ２ , R ４ and R ５ has the same meaning as the formulas (A4) and (B5).

[0102] In Production Method 5 of the present invention, an amide (C5) can be synthesized by reacting a substrate, aldehyde (A4), with an amine (B5) by light irradiation in the presence of a tetrahalomethane. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperature, reaction time, and inert gases are as described above. The molar ratio (B5 / A4) of the substrate, aldehyde (A4), to the amine (B5) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 3. As in Production Method 2, a method in which an acyl bromide is obtained by irradiating a substrate, aldehyde (A4), with light in the presence of a tetrahalomethane, and then the acyl bromide is reacted with an amine (B5) to synthesize an amide (C5) is also a preferred embodiment.

[0103] In formula (A4) and formula (C5), X ２ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, an adamantyl group, or an amino acid residue, and the primary to tertiary alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, heteroaromatic ring groups, and adamantyl groups may be the same as the substituents described in Production Method 1.

[0104] In formula (B5) and formula (C5), R ４ and R ５ are each independently a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or an amino acid residue.

[0105] R ４ and R ５ The primary to tertiary alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, and arylalkyl groups used in X １ and Y １ The same substituents as those exemplified in the explanation of 1 can be used.

[0106] In formula (A4), formula (B5) and formula (C5), X ２ , R ４ and R ５represents a structure in which one amino acid or two or more amino acids are linked by a peptide bond. That is, the aldehyde (A4) may have a peptide structure, the amine (B5) may have a peptide structure, or the amide (C5) obtained by Production Method 5 may have a peptide structure.

[0107] (Production Method 6) The present invention relates to a method for producing a carbonyl compound using light energy, which method comprises reacting an aldehyde represented by the following formula (A1) with a thiol represented by the following formula (B6) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm, to produce a carbonyl compound represented by the following formula (C6) (sometimes referred to as "Production Method 6").

[0108] [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0109] [In formula (B6), R ６ represents a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, or an arylalkyl group.

[0110] [In formula (C6), X １ and R ６ has the same meaning as in formulas (A1) and (B6).

[0111] In Production Method 6 of the present invention, a thioester (C6) can be synthesized by reacting a substrate, aldehyde (A1), with a thiol (B6) by light irradiation in the presence of a tetrahalomethane. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperature, reaction time, and inert gases are as described above. The molar ratio (B6 / A1) of the substrate, aldehyde (A1), to the thiol (B6) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 3. A preferred embodiment, as in Production Method 2, involves irradiating a substrate, aldehyde (A1), with light in the presence of a tetrahalomethane to obtain an acyl bromide (A2), which is then reacted with a thiol (B6) to synthesize a thioester (C6).

[0112] In formula (A1) and formula (C6), X １ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group, and the same substituents as those described in Production Method 1 can be used.

[0113] In formula (B6) and formula (C6), R ６ represents a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, or an arylalkyl group.

[0114] R ６ The primary to tertiary alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, and arylalkyl groups used in X １ and Y １ The same substituents as those exemplified in the explanation of 1 can be used.

[0115] (Production Method 7) The present invention relates to a method for producing a carbonyl compound using light energy, which is a method for producing a carbonyl compound represented by formula (C7) below, characterized by reacting an aldehyde represented by formula (A1) below with a carbon nucleophile in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm (sometimes referred to as "Production Method 7").

[0116] [In formula (A1), X１ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0117] [In formula (C7), X １ has the same meaning as in formula (A1), and Nu is an added carbon nucleophile.

[0118] In Production Method 7 of the present invention, a substrate, aldehyde (A1), and a carbon nucleophile are irradiated with light in the presence of a tetrahalomethane to react with each other, thereby synthesizing a ketone (C7) having a carbon nucleophile added thereto. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperature, reaction time, and inert gases are as described above. The molar ratio of the substrate, aldehyde (A1), to the carbon nucleophile (carbon nucleophile / A1) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 3. A preferred embodiment, as in Production Method 2, is a method in which an acyl bromide (A2) is obtained by irradiating a substrate, aldehyde (A1), with light in the presence of a tetrahalomethane to obtain a ketone (C7), which is then reacted with a carbon nucleophile to synthesize a ketone (C7).

[0119] In formula (A1) and formula (C7), X １ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group, and the same substituents as those described in Production Method 1 can be used.

[0120] In formula (C7), Nu represents an added carbon nucleophile. A compound having a double bond is preferably used as the carbon nucleophile, and examples thereof include an aryl compound having a substituent and an alkene compound having a substituent. The substituents of the aryl compound and the alkene compound are preferably an alkoxy group, an amino group, an alkylsilyl group, or the like.

[0121] Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and an isobutoxy group. Among these, an alkoxy group having 1 to 6 carbon atoms is preferred. These alkoxy groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0122] The amino group may be a primary amino group (—NH ２ ), a secondary amino group or a tertiary amino group may be used. Examples of the secondary amino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a phenylamino group, and a naphthylamino group. Examples of the tertiary amino group include a dimethylamino group, a diethylamino group, a dibutylamino group, an ethylmethylamino group, a diphenylamino group, and a methylphenylamino group. These amino groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0123] Examples of the alkylsilyl group include a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl group, a tert-butyldimethylsilyl (TBS) group, and a tert-butyldiphenylsilyl group. These alkylsilyl groups may have other substituents, and examples of such other substituents include X １ The same substituents as those exemplified in the description of the above can be used.

[0124] The carbon nucleophile is preferably the compound shown below, where the circled area indicates the reactive site.

[0125]

[0126] (Production Method 8) The present invention relates to a method for producing a carbonyl compound using light energy, which is a method for producing a carbonyl compound represented by the following formula (C8) (sometimes referred to as "Production Method 8"), characterized by reacting an alcohol represented by the following formula (A8) with an alcohol represented by the following formula (B8) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm:

[0127] [In formula (A8), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group.

[0128] [In formula (B8), Y ３ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.]

[0129] [In formula (C8), X １ and Y ３ has the same meaning as the formulas (A8) and (B8).

[0130] In Production Method 8 of the present invention, the ester (C8) can be synthesized by reacting the alcohol (A8) as a substrate with the alcohol (B8) by irradiating them with light in the presence of a tetrahalomethane. Suitable tetrahalomethanes, light irradiation, solvents, additives, reaction temperatures, reaction times, and inert gases are as described above. The molar ratio (B8 / A8) of the alcohol (A8) as a substrate to the alcohol (B8) is preferably 1 to 10, more preferably 1.1 to 5, and even more preferably 1.2 to 4.

[0131] In formula (A8) and formula (C8), X １ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group, and the same substituents as those described in Production Method 1 can be used.

[0132] In formula (B8) and formula (C8), Y ３represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which a hydroxy group is protected with a protecting group, and Y ２ The same substituents as those exemplified in the explanation of 1 can be used.

[0133] As explained above, the present invention enables the direct synthesis of carbonyl compounds such as esters, lactones, carboxylic acids, amides, thioesters, and ketones from substrates without using stoichiometric amounts of heavy metals, etc. Compared to using carboxylic acids as substrates, the synthesis step is shortened by one. Because carbonyl compounds such as esters and lactones have chemical structures found in pharmaceuticals and the like, the present invention makes it possible to efficiently synthesize pharmaceuticals and the like.

[0134] Reagents were used as received from the reagent supplier. Heating reactions were performed using an oil bath. Thin-layer chromatography (TLC) was performed using aluminum TLC plates (Merck TLC Silica Gel 60F254). Column chromatography was performed using Kanto Chemical Silica Gel 60N (40-100 mesh, spherical, neutral). IR spectra were recorded on an IRSpirit-T. 1 H and 13 C NMR spectra were recorded on a Varian NMR System PS600 or a Varian 400MR ASW. Chemical shifts in NMR spectra are reported in ppm relative to the internal residual solvent ( 1 H NMR, CDCl3 7.26 ppm, DMSO 2.50 ppm; 13 C NMR, CDCl3 77.0 ppm). The following abbreviations were used to indicate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadband. High-resolution mass spectra were recorded on a Bruker micrOTOF II (ESI-TOF-MS). Photochemical reactions were performed using a photoreactor (EvoluChem TMPhotoRedOx Box) and LEDs (HCK1012-01-013, 380 nm, 18 W, HCK1012-01-011, 365 nm, 18 W) were used.

[0135] 1. Ester synthesis using aldehydes and alcohols as substrates

[0136] [General Procedure for Photochemical Esterification Reaction (Method A)]

[0137]

[0138] Aldehyde A1 (0.2 mmol), alcohol B1 (0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were added to a 4 mL glass vial. After argon bubbling for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λ = 380 nm) for 36 hours. The reaction mixture was diluted with CHCl and washed with water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give ester C1.

[0139] [General Procedure for Photochemical Esterification Reaction (Method B)]

[0140]

[0141] Aldehyde A1-1a (0.2 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were added to a 4 mL glass vial. After argon bubbling for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λ = 380 nm) for 4 hours. The glass vial was then removed from the photoreactor and cooled at 0 °C for 10 minutes. Next, alcohol B2 (0.26 mmol) was added to the reaction mixture, which was then stirred at room temperature for 24 hours without light irradiation. The reaction mixture was diluted with CHCl and washed with water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give ester C2-1a.

[0142] General Procedure for Photochemical Esterification (Method C)

[0143]

[0144] Aldehyde A1 (0.2 mmol), alcohol B1 (0.26 mmol), tetrabromomethane (199.0 mg, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were added to a 4 mL glass vial. After bubbling with argon for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λ = 365 nm) for 72 hours. The reaction mixture was diluted with CHCl and washed with water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give ester C1.

[0145] Synthesis Example 1 [Butyl benzoate (3a, Method A), Reference 1]

[0146]

[0147] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3a (30.5 mg, 86%) as a colorless liquid. Figure 1 shows the structure of product 3a. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.5, 1.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 4.33 (t, J = 6.6 Hz, 2H), 1.78-1.73 (m, 2H), 1.52-1.45 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).

[0148] Synthesis Examples 2 to 19 [Study of reaction conditions] In Synthesis Example 1, the wavelength of light irradiation, type of solvent, type of tetrahalomethane, amount of 1-butanol 2a, type of additive, and reaction time were changed as shown in Table 1, and the reaction conditions were studied. The yields of product 3a obtained in Synthesis Example 1 and other cases are summarized in Table 1.

[0149]

[0150] Synthesis Example 20 [Butyl 4-methoxybenzoate (3b, Method A), Reference 1]

[0151]

[0152] p-Methoxybenzaldehyde 1b (24.3 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 70:1 to 20:1) to give product 3b (36.1 mg, 87%) as a colorless liquid. Figure 2 shows the structure of product 3b. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 4.29 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 1.76-1.71 (m, 2H), 1.50-1.44 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H).

[0153] Synthesis Example 21 [Butyl 4-(tert-butyl)benzoate (3c, Method A), Reference 2]

[0154]

[0155] 4-(tert-Butyl)benzaldehyde 1c (33.4 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by PTLC (preparative thin-layer chromatography) (hexane / EtOAc = 10:1) to give product 3c (34.4 mg, 73%) as a colorless liquid. Figure 3 shows the chromatographic analysis of product 3c. １ The H NMR spectrum is shown. 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 7.45 (d J = 8.8 Hz, 2H), 4.31 (t, J = 6.6 Hz, 2H), 1.78-1.71 (m, 2H), 1.52-1.42 (m, 2H), 1.34 (s, 9H), 0.98 (t, J = 7.4 Hz, 3H).

[0156] Synthesis Example 22 [Butyl 4-nitrobenzoate (3d, Method C), Reference 1]

[0157]

[0158] p-Nitrobenzaldehyde 1d (30.2 mg, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), tetrabromomethane (199.0 mg, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by PTLC (preparative thin-layer chromatography) (hexane / EtOAc = 10:1) to give product 3d (36.4 mg, 82%) as a colorless liquid. Figure 4 shows the structure of product 3d. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H), 4.38 (t, J = 6.9 Hz, 2H), 1.81-1.76 (m, 2H), 1.52-1.46 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H).

[0159] Synthesis Example 23 [Butyl 4-chlorobenzoate (3e, Method A), Reference 3]

[0160]

[0161] 4-Chlorobenzaldehyde 1e (28.1 mg, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by PTLC (preparative thin-layer chromatography) (hexane / EtOAc = 10:1) to give product 3e (20.8 mg, 49%) as a colorless liquid. Figure 5 shows the structure of product 3e. １ The H NMR spectrum is shown. 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 6.6 Hz, 2H), 1.78-1.71 (m, 2H), 1.52-1.42 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0162] Synthesis Example 24 [Butyl 3-bromobenzoate (3f, Method A), Reference 3]

[0163]

[0164] 3-Bromobenzaldehyde 1f (23.4 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 50:1) to give product 3f (29.7 mg, 58%) as a colorless liquid. Figure 6 shows the chromatographic analysis of product 3f. １ The H NMR spectrum is shown. 1 H NMR (400 MHz, CDCl3) δ 8.17 (t, J = 1.6 Hz, 1H), 7.97 (dt, J = 7.6, 1.4 Hz, 1H), 7.68 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 1.81-1.72 (m, 2H), 1.52-1.43 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0165] Synthesis Example 25 [Butyl 2-bromobenzoate (3g, Method A), Reference 4]

[0166]

[0167] 2-Bromobenzaldehyde 1g (23.1 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 50:1) to give product 3g (31.2 mg, 61%) as a colorless liquid. Figure 7 shows the chromatographic analysis of product 3g. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 7.78 (dd, J = 7.8, 1.8 Hz, 1H), 7.66 (dd, J = 7.2, 1.2 Hz, 1H), 7.36 (td, J = 7.8, 1.2 Hz, 1H), 7.32 (td, J = 7.8, 1.8 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 1.78-1.74 (m, 2H), 1.52-1.46 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).

[0168] Synthesis Example 26 [Butyl thiophene-2-carboxylate (3h, Method A), Reference 5]

[0169]

[0170] 2-Thiophenecarbaldehyde 1h (18.2 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3h (11.6 mg, 31%) as a colorless liquid. Figure 8 shows the chromatographic analysis of product 3h. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 7.80 (dd, J = 3.6, 1.8 Hz, 1H), 7.54 (dd, J = 4.8, 1.2 Hz, 1H), 7.10 (dd, J = 5.4, 3.6 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 1.76-1.71 (m, 2H), 1.49-1.43 (m, 2H), 0.98 (t, J =7.2 Hz, 3H).

[0171] Synthesis Example 27 [Butyl nicotinate (3i, Method A), Reference 1]

[0172]

[0173] 3-Pyridinecarbaldehyde 1i (18.8 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), NaHCO3 (118.0 mg, 1.4 mmol), MS3Å (50 mg), and CHCl2 (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 10:1 to 7:1) to give product 3i (25.1 mg, 70%) as a yellow liquid. Figure 9 shows the structure of product 3i. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 9.22 (d, J = 1.8 Hz, 1H), 8.77 (dd, J = 5.4, 1.8 Hz, 1H), 8.30 (dt, J = 7.8, 1.8 Hz, 1H), 7.40 (ddd, J = 7.8, 4.8, 0.6 Hz, 1H), 4.36 (t, J = 6.9 Hz, 2H), 1.79-1.74 (m, 2H), 1.51-1.45 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).

[0174] Synthesis Example 28 [Butyl cinnamate (3j, Method C), Reference 6]

[0175]

[0176] Cinnamon aldehyde 1j 7 The reaction mixture was 2a (25.2 mg, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), tetrabromomethane (199.0 mg, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL). The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3j (28.5 mg, 70%) as a colorless liquid. Figure 10 shows the solubility of product 3j. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 15.6 Hz, 1H), 7.54-7.52 (m, 2H), 7.40-7.37 (m, 3H), 6.44 (d, J =15.6 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 1.72-1.67 (m, 2H), 1.46-1.41 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H).

[0177] Synthesis Example 29 [Butyl decanoate (3k, Method A), Reference 8]

[0178]

[0179] Decanall 1k 9 The reaction mixture was 2a (37.7 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL). The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3k (44.0 mg, 96%) as a colorless liquid. Figure 11 shows the chromatographic analysis of product 3k. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 4.06 (t, J = 6.9 Hz, 2H), 2.28 (t, J = 7.5 Hz, 2H), 1.66-1.57 (m, 4H), 1.42-1.34 (m, 2H), 1.31-1.25 (m, 12H), 0.93 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H).

[0180] Synthesis Example 30 [Butyl 2-phenylacetate (3l, Method C), Reference 1]

[0181]

[0182] Phenylacetaldehyde 1l (22.9 mg, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), tetrabromomethane (199.0 mg, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3l (20.7 mg, 54%) as a colorless liquid. Figure 12 shows the chromatographic analysis of product 3l. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 7.34-7.31 (m, 2H), 7.29-7.24 (m, 3H), 4.09 (t, J = 6.6 Hz, 2H), 3.61 (s, 2H), 1.62-1.57 (m, 2H), 1.37-1.31 (m, 2H), 0.91 (t, J = 7.5 Hz, 3H).

[0183] Synthesis Example 31 [Butyl 2-ethylhexanoate (3m, Method A), Reference 1]

[0184]

[0185] 2-Ethylhexanal 1m (31.3 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), trichloromethane bromide (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3m (32.0 mg, 80%) as a colorless liquid. Figure 13 shows the chromatographic analysis of product 3m. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 4.08 (t, J = 6.6 Hz, 2H), 2.27-2.23 (m, 1H), 1.64-1.57 (m, 5H), 1.54-1.21 (m, 7H), 0.94 (t, J = 7.8 Hz, 3H), 0.90-0.87 (m, 6H).

[0186] Synthesis Example 32 [Butyl cyclohexanecarboxylate (3n, Method A), Reference 1]

[0187]

[0188] Aldehyde 1n (37.7 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3n (30.4 mg, 82%) as a colorless liquid. Figure 14 shows the chromatographic analysis of product 3n. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 4.05 (t, J = 6.6 Hz, 2H), 2.28 (tt, J = 11.4, 3.6 Hz, 1H), 1.90-1.88 (m, 2H), 1.76-1.73 (m, 2H), 1.64-1.57 (m, 3H), 1.46 -1.34 (m, 4H), 1.31-1.18 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[0189] Synthesis Example 33 [Butyl adamantane-1-carboxylate (3o, Method A), Reference 1]

[0190]

[0191] Aldehyde 1o 10 The reaction mixture was 2a (37.7 μL, 0.2 mmol), 1-butanol 2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL). The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3o (30.4 mg, 82%) as a colorless liquid. Figure 15 shows the chromatographic analysis of product 3o. １The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 4.04 (t, J = 6.6 Hz, 2H), 2.02-2.00 (m, 3H), 1.88 (d, J = 3.0 Hz, 6H), 1.74-1.68 (m, 6H), 1.62-1.57 (m, 2H), 1.41-1.35 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0192] Synthesis Example 34 [Decyl benzoate (3p, Method A), Reference 1]

[0193]

[0194] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 1-decanol 2b (49.6 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3p (54.2 mg, 98%) as a colorless liquid. Figure 16 shows the chromatographic analysis of product 3p. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.5, 1.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 4.32 (t, J = 6.6 Hz, 2H), 1.79-1.74 (m, 2H), 1.47-1.42 (m, 2H), 1.38-1.27 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H).

[0195] Synthesis Example 35 [Nonan-5-yl benzoate (3q, Method A), Reference 11]

[0196]

[0197] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 5-nonal 2c (45.2 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3q (41.9 mg, 84%) as a colorless liquid. Figure 17 shows the chromatographic analysis of product 3q. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.5, 1.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 5.15-5.11 (m, 1H), 1.71-1.61 (m, 4H), 1.39-1.29 (m, 8H), 0.90-0.88 (m, 6H).

[0198] Synthesis Example 36 [2,4-Dimethylpentan-3-yl benzoate (3r, Method A), Reference 12]

[0199]

[0200] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 2,4-dimethyl-3-pentanol 2d (36.4 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3r (30.1 mg, 68%) as a colorless liquid. Figure 18 shows the chromatographic analysis of product 3r. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 8.07 (dd, J = 8.4, 1.2 Hz, 2H), 7.56 (tt, J = 7.5, 1.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 4.85 (t, J = 6.0 Hz, 1H), 2.08-2.00 (m, 2H), 0.96-0.94 (m,12H).

[0201] Synthesis Example 37 [Phenethyl benzoate (3s, Method A), Reference 13]

[0202]

[0203] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 2-phenylethanol 2e (30.6 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 300:1 to 100:1) to give product 3s (32.4 mg, 72%) as a colorless liquid. Figure 19 shows the structure of product 3s. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.02 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.5, 1.5 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.35-7.29 (m, 4H), 7.25-7.24 (m, 1H), 4.54 (t, J = 7.2 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H).

[0204] Synthesis Example 38 [3-Bromo-5,5,5-trichloropentyl benzoate (3t', Method A)]

[0205]

[0206] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 3-buten-1-ol 2f (22.1 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 50:1) to give product 3t' (59.2 mg, 79%) as a colorless liquid. Figures 20 and 21 show the structure of product 3t'. １ H NMR and １３ The C NMR spectra are shown below. f = 0.57 (hexane / EtOAc = 10:1); IR (neat) 3064, 2962, 2927, 1719, 1602, 1451, 1315, 1273 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 8.03 (dd, J = 8.4, 1.8 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 4.62-4.59 (m, 1H), 4.57-4.49 (m, 2H), 3.55 (dd, J = 15.6, 4.8 Hz, 1H), 3.34 (dd, J = 15.6, 5.4 Hz, 1H), 2.68-2.62 (m, 1H), 2.36-2.31 (m, 1H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 133.2, 129.8, 129.6, 128.5, 96.8, 62.6, 62.5, 44.6, 38.4; HRMS (ESI TOF) calcd for C 12 H 12 BrCl3O2 [M+Na] + 394.8984, found 394.8988.

[0207] Synthesis Example 39 [But-3-en-1-yl benzoate (3t, Method B), Reference 14]

[0208]

[0209] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 3-buten-1-ol 2f (22.1 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3t (31.5 mg, 89%) as a colorless liquid. Figure 22 shows the structure of product 3t. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.04 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 5.91-5.85 (m, 1H), 5.18 (dd, J = 16.8, 1.2 Hz, 1H), 5.11, (dd, J = 10.2, 1.2 Hz, 1H), 4.38 (t, J = 6.6 Hz, 2H), 2.53 (qt, J = 6.6, 1.2 Hz, 2H).

[0210] Synthesis Example 40 [(E)-3,7-Dimethylocta-2,6-dien-1-yl benzoate (3u, Method B), Reference 11]

[0211]

[0212] Benzaldehyde 1a (20.4 μL, 0.2 mmol), geraniol 2g (45.6 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3u (38.7 mg, 75%) as a colorless liquid. Figure 23 shows the structure of product 3u. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 7.8, 1.2 Hz, 2H), 7.54 (tt, J = 7.2, 1.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 5.48 (td, J = 6.9, 1.2 Hz, 1H), 5.10 (tt, J = 6.9, 1.5 Hz, 1H), 4.85 (d, J = 6.6 Hz, 2H), 2.15-2.11 (m, 2H), 2.09-2.06 (m, 2H), 1.77 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H).

[0213] Synthesis Example 41 [3-Ethylpentan-3-yl benzoate (3v, Method B), Reference 15]

[0214]

[0215] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 2-ethylpentanol 2h (35.5 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3v (10.2 mg, 23%) as a colorless liquid. Figure 24 shows the structure of product 3v. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.00 (dd, J = 9.0, 1.8 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 1.98 (q, J = 7.5 Hz, 6H), 0.88 (t, J = 7.5 Hz, 9H).

[0216] Synthesis Example 42 [Cyclohexyl benzoate (3w, Method B), Reference 13]

[0217]

[0218] Benzaldehyde 1a (20.4 μL, 0.2 mmol), cyclohexanol 2i (27.7 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3w (37.6 mg, 92%) as a colorless liquid. Figure 25 shows the structure of product 3w. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.54 (tt, J = 7.5, 1.5 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 5.06-5.01 (m, 1H), 1.96-1.93 (m, 2H), 1.82-1.77 (m, 2H), 1.63-1.57 (m, 3H), 1.49-1.42 (m, 2H), 1.38-1.32 (m, 1H).

[0219] Synthesis Example 43 [1-Tosylpiperidin-4-yl benzoate (3x, Method B)]

[0220]

[0221] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2j (16, 66.4 mg, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3x (39.2 mg, 54%) as a white solid. Figures 26 and 27 show the structure of product 3x. １ H NMR and １３ The C NMR spectra are shown below. f= 0.32 (hexane / EtOAc = 3:1); mp 181 ℃; IR (neat) 3417, 2970, 2929, 2863, 1714 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 7.92 (dd, J = 8.4, 1.2 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 5.04-5.00 m, 1H), 3.38-3.34 (m, 2H), 3.01-2.97 (m, 2H), 2.45 (s, 3H), 2.09-2.04 (m, 2H), 1.95-1.90 (m, 2H); 13 CNMR (150 Hz, CDCl3) δ 165.5, 143.6, 133.1, 130.1, 129.7, 129.5, 128.3, 127.7, 68.8, 43.4, 30.1, 21.5; HRMS (ESI TOF) calcd for C 19 H 21 NO4S [M+Na] + 382.1084, found 382.1088.

[0222] Synthesis Example 44 [4-(tert-Butyl)phenyl benzoate (3y, Method B), Reference 17]

[0223]

[0224] Benzaldehyde 1a (20.4 μL, 0.2 mmol), 4-tertbutylphenol 2k (39.1 mg, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1) to give product 3y (40.7 mg, 80%) as a white solid. Figure 28 shows the chromatographic analysis of product 3y. １The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.22 (dd, J = 8.4, 1.2 Hz, 2H), 7.64 (tt, J = 7.5, 0.6 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 1.35 (s, 9H).

[0225] Synthesis Example 45 [4-((tert-Butyldimethylsilyl)oxy)butyl benzoate (3z, Method B), Reference 11]

[0226]

[0227] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2L 18 (53.1 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 50:1) to give product 3z (50.8 mg, 82%) as a colorless liquid. Figure 29 shows the structure of product 3z. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.2, 1.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 4.35 (t, J = 6.6 Hz, 2H), 3.68 (t, J = 6.3 Hz, 2H), 1.86-1.82 (m, 2H), 1.70-1.65 (m, 2H), 0.90 (s, 9H), 0.06 (s, 6H).

[0228] Synthesis example 46 [4-((triethylsilyl)oxy)butan-1-ol (2m)]

[0229]

[0230] To a solution of 1,4-butanediol S1 (1.4 mL, 16.0 mmol) in DMF (8.0 mL) was added imidazole (550 mg, 8.0 mmol) at room temperature. TESCl (0.67 mL, 4.0 mmol) was added to the reaction mixture at 0 °C. After stirring at room temperature for 2.5 h, the reaction mixture was treated with saturated aqueous NH4Cl, extracted with hexane / EtOAc = 3:1, washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:hexane / EtOAc = 10:1) to give product 2m (582.9 mg, 71%) as a colorless liquid. Figures 30 and 31 show the chromatographic properties of product 2m. １ H NMR and １３ The C NMR spectra are shown below: Rf = 0.64 (hexane / EtOAc = 1:1); IR (neat) 3339, 2955, 2913, 2877, 1459, 1416, 1387, 1239, 1098, 1011 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 3.67-3.64 (m, 4H), 2.59 (br, 1H), 1.70-1.62 (m, 4H), 0.96 (t, J = 7.8 Hz, 9H), 0.62 (q, J = 7.8 Hz, 6H); 13 C NMR (150 MHz, CDCl3) δ 62.8, 62.6, 30.1, 29.8, 6.6, 4.2; HRMS (ESI TOF) calcd for C 10 H 24 O2SiNa [M + Na]+ 227.1443, found 227.1436.

[0231] Synthesis Example 47 [4-((Triethylsilyl)oxy)butyl benzoate (3aa, Method B)]

[0232]

[0233] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2m (60.4 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 50:1, with 1% EtN) to give product 3aa (30.7 mg, 50%) as a colorless liquid. Figures 32 and 33 show the structure of product 3aa. １ H NMR and １３ The C NMR spectra are shown below. f = 0.32 (hexane / EtOAc = 10:1); IR (neat) 2955, 2913, 2876, 1723, 1273, 1098, 710 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 8.04 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.5, 1.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 4.35 (t, J = 6.6 Hz, 2H), 3.68 (t, J = 6.6 Hz, 2H), 1.87-1.82 (m, 2H), 1.71-1.67 (m, 2H), 0.96 (t, J = 8.1 Hz, 9H), 0.60 (q, J = 8.2 Hz, 6H); 13 C NMR (150 MHz, CDCl3) δ 166.6, 132.8, 130.4, 129.5, 128.3, 64.9, 62.3, 29.4, 25.3, 6.8, 4.4, 4.4; HRMS (ESI TOF) calcd for C 17 H 28 O3Si [M+Na] + 331.1700, found 331.1697.

[0234] Synthesis example 48 [4-(Methoxymethoxy)butyl benzoate (3ab, Method B)]

[0235]

[0236] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2n (19, 35.9 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), NaHCO3 (118.0 mg, 1.4 mmol), MS3Å (50 mg), and CHCl2 (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 10:1 with Et3N) to give product 3ab (44.0 mg, 92%) as a colorless liquid. Figures 34 and 35 show the structure of product 3ab. １ H NMR and １３ The C NMR spectra are shown below. f = 0.24 (hexane / EtOAc = 10:1); IR (neat) 2947, 2884, 1720, 1273, 1110, 1044 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 8.04 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.5, 1.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 4.63 (s, 2H), 4.36 (t, J = 6.6 Hz, 2H), 3.59 (t, J = 6.6 Hz, 2H), 3.36 (s, 3H), 1.90-1.85 (m, 2H), 1.78-1.74 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.6, 132.8, 130.3, 129.5, 128.3, 96.4, 67.2, 64.7, 55.2, 26.4, 25.6; HRMS (ESI TOF) calcd for C 13 H 18 O4 [M+Na] + 261.1097, found 261.1097.

[0237] Synthesis Example 49 [4-(Benzyloxy)butyl benzoate (3ac, Method B), Reference 20]

[0238]

[0239] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2o (21, 45.5 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 20:1) to give product 3ac (50.6 mg, 89%) as a colorless liquid. Figure 36 shows the structure of product 3ac. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.56 (tt, J = 7.5, 1.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 4.2 Hz, 4H), 7.31-7.27 (m, 1H), 4.53 (s, 2H), 4.36 (t, J = 6.6 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 1.91-1.87 (m, 2H), 1.82-1.77 (m, 2H).

[0240] Synthesis Example 50 [4-((4-Methoxybenzyl)oxy)butyl benzoate (3ad, Method B), Reference 22]

[0241]

[0242] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2p (23, 52.1 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 10:1) to give product 3ad (37.8 mg, 60%) as a colorless liquid. Figure 37 shows the structure of product 3ad. １ The H NMR spectrum is shown. 1 H NMR (600 MHz, CDCl3) δ 8.04 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.45 (s, 2H), 4.34 (t, J = 6.6 Hz, 2H), 3.80 (s, 3H), 3.52 (t, J = 6.3 Hz, 2H), 1.89-1.84 (m, 2H), 1.79-1.75 (m, 2H).

[0243] Synthesis Example 51 [4-Acetoxybutyl benzoate (3ae, Method B), Reference 24]

[0244]

[0245] Benzaldehyde 1a (20.4 μL, 0.2 mmol), alcohol 2q (25, 33.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were used in the reaction. The residue was purified by flash chromatography (hexane / EtOAc = 100:1 to 10:1) to give product 3ae (33.1 mg, 70%) as a colorless liquid. Figure 38 shows the structure of product 3ae. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 8.04 (dd, J = 9.0, 1.8 Hz, 2H), 7.56 (tt, J = 7.5, 1.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 4.36 (t, J = 6.3 Hz, 2H), 4.14 (t, J = 6.3 Hz, 2H), 2.05 (s, 3H), 1.88-1.78 (m, 4H).

[0246] Synthesis Example 52 [Analysis of Esterification Reaction Mechanism]

[0247]

[0248] Benzaldehyde A1-1a (20.4 μL, 0.2 mmol), 1-butanol B1-2a (24.0 μL, 0.26 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), TEMPO (93.8 mg, 0.6 mmol), and CHCl (2.0 mL) were added to a 4 mL glass vial. After argon bubbling for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λmax = 380 nm) for 36 hours. The reaction mixture was diluted with CHCl and washed with water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. Compound C1-4a was detected by HRMS (ESI TOF) analysis (C 16 H 23 NO2Na [M + Na]+ 284.1626 (theoretical value), 284.1626 (experimental value). The residue was then purified by flash chromatography (hexane / EtOAc = 100:1) to obtain a trace amount of product C1-3a. Thus, when the reaction was carried out under conditions where TEMPO was added, the yield decreased, and only a trace amount of the desired product C1-3a was obtained. Furthermore, compounds in which the acyl radical was trapped by TEMPO were observed by mass spectrometry. These results suggest that this esterification reaction is a radical reaction mediated by the acyl radical.

[0249] Synthesis Example 53 [Benzoyl bromide (A2-1a) 26 ]

[0250]

[0251] Benzaldehyde A1-1a (20.4 μL, 0.2 mmol), bromotrichloromethane (60.0 μL, 0.6 mmol), MS3Å (50 mg), and CHCl (2.0 mL) were added to a 4 mL glass vial. After argon bubbling for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λmax = 380 nm) for 4 hours. The reaction mixture was diluted with CHCl and washed with water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to obtain benzyl bromide (A2-1a). Benzoyl bromide (A2-1a, Ref. 26); 1 H NMR (600 MHz, CDCl3) δ 8.08 (dd, J = 9.0, 1.2 Hz, 2H), 7.70 (tt, J = 7.5, 1.2 Hz, 1H), 7.53-7.50 (m, 2H).

[0252] 2. Lactonization synthesis using aldehydes as substrates

[0253] [Preparation of lactonization reaction precursor]

[0254] Synthesis Example 54 [8-membered ring 2-(4-hydroxybutyl)benzaldehyde (52a)]

[0255]

[0256] To a solution of ester S2 (reference 27, 1.06 g, 5.1 mmol) in CHCl (17.0 mL) was added DIBAL-H (1.03 M in hexane, 14.8 mL, 15.3 mmol) at −78 °C. After stirring at 0 °C for 1 h 30 min, potassium sodium tartrate was added to the reaction mixture. After stirring for 4 h, the mixture was extracted with EtOAc, washed with H2O and brine, and then dried over Na2SO4. The residue was concentrated under reduced pressure to give the diol (0.99 g) as a colorless liquid. Next, MnO (4.4 g, 51.0 mmol) was added to the resulting diol (0.99 g) in CHCl (17.0 mL) at room temperature. After stirring for 12 h at room temperature, the reaction mixture was diluted with EtOAc, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 2:1) to give 52a (687.2 mg) as a colorless liquid in 76% yield over two steps. Figures 40 and 41 show the structure of 52a. １ H NMR and １３ The C NMR spectra are shown below. f = 0.31 (Hexane / EtOAc = 1:1); IR (neat) 3378, 2937, 2863, 1694, 1599, 1209, 1061 cm -1 ; 1 HNMR (600 MHz, CDCl3) δ 10.23 (s, 1H), 7.82 (dd, J = 7.8, 1.8 Hz, 1H), 7.51 (td, J = 7.5, 1.2 Hz, 1H), 7.39 (td, J = 7.5, 1.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 3.71 (t, J = 6.0 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 1.73-1.65 (m, 4H), 1.56 (br, 1H); 13CNMR (100 MHz, CDCl3) δ 192.7, 145.2, 133.7, 133.4, 132.4, 130.9, 126.4, 62.1, 32.1, 32.1, 28.1; HRMS (ESI TOF) calcd for C 11 H 14 O2Na [M + Na] + 201.0891, found 201.0861.

[0257] Synthesis Example 55 [9-membered ring 2-(5-hydroxypentyl)benzaldehyde (52c)]

[0258]

[0259] To a solution of ester S3 (reference 28, 1.26 g, 5.7 mmol) in CHCl (19.0 mL) was added DIBAL-H (1.03 M in hexane, 16.5 mL, 17.0 mmol) at -78 °C. After stirring for 1.5 hours at 0 °C, potassium sodium tartrate was added to the reaction mixture. After stirring for 4 hours, the mixture was extracted with EtOAc, washed with H0 and brine, and then dried over NaSO. The residue was concentrated under reduced pressure, and the resulting diol (1.04 g) was used in the next step without further purification. Next, to a solution of the diol (1.04 g) in CHCl (19.0 mL), MnO 2 (5.0 g, 57.0 mmol) was added at room temperature. After stirring at room temperature for 12 h, the reaction mixture was diluted with EtOAc, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 2:1) to give 52c (929.6 mg) as a colorless liquid in 85% yield over two steps. Figures 42 and 43 show the structure of 52c. １ H NMR and １３ The C NMR spectra are shown below. f = 0.40 (Hexane / EtOAc = 1:1); IR (neat) 3374, 2934, 2860, 1693, 1599, 1209, 1190 cm -1 ; 1HNMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 7.78 (dd, J = 7.6, 1.6 Hz, 1H), 7.45 (td, J = 7.6, 1.6 Hz, 1H), 7.31 (td, J = 7.4, 1.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 3.60 (t, J = 6.6 Hz, 2H), 3.01-2.95 (m, 3H), 1.64-1.54 (m, 4H), 1.46-1.38 (m, 2H); 13 CNMR (100 MHz, CDCl3) δ 192.4, 145.4, 133.7, 133.4, 131.6, 130.8, 126.3, 62.4, 32.3, 32.3, 31.9. 25.5; HRMS (ESI TOF) calcd for C 12 H 16 O2Na [M + Na] + 215.1048, found 215.1040.

[0260] Synthesis Example 56 [10-membered ring 2-(6-hydroxyhexyl)benzaldehyde (52d)]

[0261]

[0262] To a solution of alkyne S4 (reference 29, 2.19 g, 9.4 mmol) in methanol (30.0 mL) was added 10% Pd / C (300.0 mg) at room temperature. Hydrogen gas was bubbled through the reaction mixture, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 3:1) to give S5 (2.11 g) as a colorless liquid in 95% yield. Figures 44 and 45 show the structure of S5. １ H NMR and １３ The C NMR spectra are shown for S5 and R. f = 0.67 (EtOAc); IR (neat) 3385, 2932, 2858, 1723, 1259, 1094 cm -1 ; 1HNMR (600 MHz, CDCl3) δ 7.83 (dd, J = 7.8, 1.2 Hz, 1H), 7.39 (td, J = 7.5, 1.2 Hz, 1H), 7.23-7.20 (m, 2H), 3.87 (s, 3H), 3.60 (t, J = 6.9 Hz, 2H), 2.94-2.91 (m, 2H), 1.97 (br, 1H), 1.61-1.53 ​​(m, 4H), 1.41-1.35 (m, 4H); 13 CNMR (150 MHz, CDCl3) δ 168.1, 144.5, 131.8, 130.8, 130.5, 129.2, 125.6, 62.7, 51.8, 34.2, 32.6, 31.6. 29.3, 25.4; HRMS (ESI TOF) calcd for C 14 H 20 O3Na [M + Na] + 259.1310, found 259.1307.

[0263] Ester S5 (1.35 g, 5.7 mmol) was dissolved in CHCl (19.0 mL) and DIBAL-H (1.03 M, 16.5 mL, 17.0 mmol) in hexane was added at -78 °C. After stirring at 0 °C for 1 h 30 min, the reaction mixture was treated with potassium sodium tartrate. After stirring for an additional 4 h, the mixture was extracted with EtOAc, washed with HO and saturated brine, and dried over NaSO. Concentration under reduced pressure gave the diol (1.01 g) as a colorless liquid, which was used in the next reaction without further purification. The diol (1.01 g) was dissolved in CHCl (19.0 mL) and eluted with MnO at room temperature. 2 (5.0 g, 57.0 mmol) was added. After stirring at room temperature for 6 h, the reaction mixture was diluted with EtOAc, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 2:1) to give 52d (952.8 mg, 81%) as a colorless liquid in two steps. Figures 46 and 47 show the elution of 52d. １ H NMR and １３The C NMR spectra are shown below. f = 0.47 (Hexane / EtOAc = 1:1); IR (neat) 3385, 2932, 2857, 1697, 1599, 1207, 1055 cm -1 ; 1 HNMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.76 (dd, J = 7.6, 1.2 Hz, 1H), 7.43 (td, J = 7.4, 1.6 Hz, 1H), 7.29 (td, J = 7.6, 1.2 Hz, 1H), 7.20 (dd, J = 8.0, 0.8 Hz, 1H), 3.57 (t, J = 6.6 Hz, 2H), 2.98-2.94 (m, 2H), 2.83 (br, 1H), 1.60-1.48 (m, 4H), 1.40-1.30 (m, 4H); 13 CNMR (100 MHz, CDCl3) δ 192.3, 145.5, 133.6, 133.3, 131.4, 130.7, 126.2, 62.4, 32.3, 32.2, 32.0. 29.0, 25.3; HRMS (ESI TOF) calcd for C 13 H 18 O2Na [M + Na] + 229.1204, found 229.1215.

[0264] Synthesis Example 57 [12-membered ring 11-hydroxyundecanal (52f), Reference 30]

[0265]

[0266] Acetal S6 5(328 mg, 1.4 mmol) was dissolved in acetone (14.0 mL) and HO (0.23 mL) and Amberlyst 15 (300 mg) was added at room temperature. After stirring at the same temperature for 16 h, the reaction mixture was diluted with EtOAc, filtered, and dried over NaSO. The residue was concentrated under reduced pressure and purified by flash chromatography (hexane / EtOAc = 3:1) to give 52f (154.3 mg, 59%) as a white solid. Figure 48 shows the structure of product 52f. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 9.77 (t, J = 1.8 Hz, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.42 (td, J = 7.2, 1.8 Hz, 2H), 1.65-1.60 (m, 2H), 1.59-1.55 (m, 3H), 1.37-1.25 (m, 12H).

[0267] Synthesis Example 58 [11-hydroxydodecanal (52 g)]

[0268]

[0269] Acetal S6 (Reference 31, 335.6 mg, 1.44 mmol) was dissolved in CHCl (7.2 mL) and DMSO (1.0 mL) and added with EtN (1.0 mL, 7.2 mmol) and pyridine-sulfur trioxygen complex (344.8 mg, 2.17 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was treated with saturated ammonium chloride solution. The mixture was extracted with EtO, washed with HO and brine, and dried over NaSO. Concentration under reduced pressure gave the aldehyde (329.7 mg) as a yellow liquid, which was used in the next step without purification. The aldehyde (329.7 mg) was dissolved in THF (7.2 mL) and added with MeMgBr (3.0 M in THF, 1.44 mL, 4.82 mmol) at -78 °C. After stirring at 0 °C for 45 min, the reaction mixture was treated with saturated ammonium chloride solution. The mixture was extracted with EtOAc, washed with H2O and saturated brine, and dried over Na2SO4. Concentration under reduced pressure gave the alcohol (332.2 mg) as a yellow liquid, which was used in the next step without purification. The alcohol (332.2 mg) was dissolved in acetone (14.0 mL) and H2O (0.23 mL), and Amberlyst 15 (300 mg) was added at room temperature. After stirring at the same temperature for 22 h, the reaction mixture was diluted with EtOAc, filtered, and dried over Na2SO4. The residue was concentrated under reduced pressure and purified by flash chromatography (hexane / EtOAc = 10:1 to 3:1) to give 52g (186.4 mg, 65% yield over three steps) as a white solid. Figure 49 shows the product 52g. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 9.71 (t, J = 1.8 Hz, 1H), 3.75-3.70 (m, 1H), 2.37 (td, J = 7.2, 1.8 Hz, 2H), 1.82 (br, 1H), 1.60-1.55 (m, 2H), 1.42-1.32 (m, 2H), 1.32-1.21 (m, 12H), 1.13 (d, J = 6.0 Hz, 3H).

[0270] Synthesis Example 59 [13-membered ring 12-hydroxydodecanal (52h), Reference 33]

[0271]

[0272] 1,12-Dodecanediol S7 (450 mg, 2.2 mmol) was dissolved in CHCl (22.0 mL) and DMSO (1.7 mL) and added with EtN (1.6 mL, 11.2 mmol) and pyridine-sulfur trioxygen complex (385.2 mg, 2.4 mmol) at 0 °C. After stirring at room temperature for 18 h, the reaction mixture was treated with saturated ammonium chloride solution. The mixture was extracted with EtO, washed with H0 and brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 4:1 to 2:1) to give 52h (127.5 mg, 29% yield) as a white solid. Figure 50 shows the structure of product 52h. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 9.76 (t, J =2.1 Hz, 1H), 3.64 (t, J = 6.6 Hz, 2H), 2.42 (td, J = 7.5, 1.8 Hz, 2H), 1.65-1.60 (m, 2H), 1.59-1.54 (m, 3H), 1.35-1.23 (m, 14H).

[0273] Synthesis Example 60 [12-Hydroxyoctadecanal (52i), Reference 34]

[0274]

[0275] Diol S8 (350 mg, 1.22 mmol) was dissolved in CHCl (6.1 mL) and TEMPO (9.4 mg, 0.06 mmol) and BAIB (589.4 mg, 1.83 mmol) were added at room temperature. After stirring at the same temperature for 12 h, the reaction mixture was washed with saturated aqueous NaHCO 3 and Na2S2O3. The mixture was extracted with Et2O, washed with H2O, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 10:1 to 5:1) to give 52i (182.9 mg, 53% yield) as a white solid. Figure 51 shows the structure of product 52i. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 9.72 (t, J = 1.8 Hz, 1H), 3.55-3.53 (m, 1H), 2.38 (td, J = 7.5, 1.8 Hz, 2H), 1.61-1.56 (m, 2H), 1.50 (br, 1H), 1.42-1.35 (m, 6H), 1.26-1.24 (m, 20H), 0.85 (t, J = 7.2 Hz, 3H).

[0276] Synthesis Example 61 [Synthesis procedure for 14-membered ring 13-hydroxytridecanal (52j)]

[0277]

[0278] Ester S9 (ref. 35, 299.0 mg, 1.22 mmol) was dissolved in CHCl (6.1 mL) and DIBAL-H (1.03 M in hexane, 2.34 mL, 2.44 mmol) was added at −78 °C. After stirring at the same temperature for 15 min, the reaction mixture was treated with potassium sodium tartrate. After stirring for 22 h, the mixture was extracted with ethyl acetate, washed with H0, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 5:1 to 2:1) to give 52j (95.0 mg, 36% yield) as a white solid. Figures 52 and 53 show the elution of 52j. １ H NMR and １３ The C NMR spectra are shown below. f= 0.32 (Hexane / EtOAc = 2:1); Mp 76 ℃; IR (neat) 3423, 2914, 2848, 1720, 1463, 1103, 1074 cm -1 ; 1 HNMR (600 MHz, CDCl3) δ 9.76 (t, J = 1.8 Hz, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.42 (td, J = 7.2, 1.8 Hz, 2H), 1.65-1.60 (m, 2H), 1.59-1.53 (m, 2H), 1.34-1.26 (m, 16H); 13 CNMR (150 MHz, CDCl3) δ 203.0, 63.1, 43.9, 32.8, 29.6, 29.5, 29.4, 29.3, 29.1, 25.7, 22.1; HRMS (ESI TOF) calcd for C 13 H 26 O2Na [M + Na] + 237.1825, found 237.1827.

[0279] Synthesis Example 62 [Synthesis procedure for 15-membered ring 14-hydroxytetradecanal (52k)]

[0280]

[0281] Ester S10 (36, 606.6 mg, 2.2 mmol) was dissolved in CHCl (7.5 mL) and DIBAL-H (1.03 M in hexane, 6.4 mL, 6.6 mmol) was added at −78 °C. After stirring at 0 °C for 1 h, the reaction mixture was treated with potassium sodium tartrate. After stirring for 2 h, the mixture was extracted with ethyl acetate, washed with H0, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 5:1) to give S11 (503.1 mg, 99% yield) as a white solid. Figures 54 and 55 show the structure of S11. １ H NMR and １３ The C NMR spectra are shown below. For S11; Rf = 0.47 (hexane / EtOAc = 1:1); Mp 38 ℃; IR (neat) 3339, 2980, 2917, 2850, 1718, 1654, 1466, 1370 cm -1 ; 1 HNMR (600 MHz, CDCl3) δ 9.42 (d, J = 8.4 Hz, 1H), 6.80 (dt, J = 15.6, 6.9 Hz, 1H), 6.05 (ddt, J = 15.6, 7.8, 1.5 Hz, 1H), 3.55 (t, J = 6.9 Hz, 2H), 2.29-2.25 (m, 3H), 1.51-1.47 (m, 2H), 1.46-1.41 (m, 2H), 1.27-1.18 (m, 14H); 13 CNMR (150 MHz, CDCl3) δ 194.2, 159.2, 132.7, 62.6, 32.6, 29.4, 29.3, 29.3, 29.2, 29.1, 28.9, 27.6, 25.6; HRMS (ESI TOF) calcd for C 14 H 26 O2Na [M + Na] + 249.1830, found 249.1823.

[0282] Alkene S11 (226.4 mg, 1.0 mmol) was dissolved in methanol (5.0 mL) and 10% Pd / C (30.0 mg) was added at room temperature. Hydrogen gas was bubbled through the reaction mixture, which was then stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 5:1) to give 52k (162.0 mg, 71% yield) as a white solid. Figures 56 and 57 show the 52k product. １ H NMR and １３ The C NMR spectra are shown below. f= 0.58 (hexane / EtOAc =1:1); Mp 86 ℃; IR (neat) 3420, 2917, 2848, 1718, 1462, 1374 cm -1 ; 1 HNMR (600 MHz, CDCl3) δ 9.75 (t, J = 1.8 Hz, 1H), 3.63 (t, J = 6.9 Hz, 2H), 2.41 (td, J =7.2, 1.8 Hz, 2H), 1.64-1.59 (m, 2H), 1.58-1.53 (m, 2H), 1.37-1.25 (m, 18H); 13 CNMR (150 MHz, CDCl3) δ 203.1, 63.1, 43.9, 32.8, 29.6, 29.5, 29.4, 29.3, 29.1, 25.7, 22.0; HRMS (ESI TOF) calcd for C 14 H 28 O2Na [M + Na] + 251.1987, found 251.1980.

[0283] Synthesis Example 63 [16-membered ring 2-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propyl)benzaldehyde (521)]

[0284]

[0285] Methyl 2-iodobenzoate S12 (1.46 mL, 10 mmol) and alkyne S13 (Ref. 37, 2.26 g, 12 mmol) were added to EtN (20.0 mL) at room temperature, followed by the addition of Pd(PPh)Cl (14.0 mg, 0.02 mmol) and CuI (19.0 mg, 0.1 mmol). After stirring at 60 °C for 14 h, the mixture was treated with H2O at room temperature. The mixture was extracted with ethyl acetate, washed with H2O and saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 2:1 to 1:1) to give product S14 (1.25 g, 39% yield) as a colorless liquid. Figures 58 and 59 show the chromatographic properties of S14. １H NMR and １３ The C NMR spectra are shown below. For S14; f = 0.34 (EtOAc); IR (neat) 3448, 2949, 2916, 2873, 1729, 1449, 1296, 1256, 1128, 1085 cm -1 ; 1 HNMR (400 MHz, CDCl3) δ 7.93 (dd, J = 8.0, 1.2 H, 1H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 4.50 (s, 2H), 3.92 (s, 3H), 3.84-3.82 (m, 2H), 3.75-3.72 (m, 4H), 3.70 (s, 4H), 3.63-3.61 (m, 2H); 13 CNMR (100 MHz, CDCl3) δ 166.5, 134.3, 131.9, 131.7, 130.3, 128.1, 123.1, 90.3, 85.0, 72.4, 70.6, 70.5, 70.4, 69.0, 61.8, 59.3, 52.2; HRMS (ESI TOF) calcd for C 17 H 22 O6Na [M + Na] + 345.1314, found 345.1324.

[0286] Alkyne S14 (1.2 g, 3.7 mmol) was dissolved in methanol (15.0 mL) and 10% Pd / C (150.0 mg) was added at room temperature. Hydrogen gas was bubbled through the reaction mixture, which was then stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 1:1) to give product S15 (1.15 g, 95%) as a colorless liquid. Figures 60 and 61 show the structure of S15. １ H NMR and １３ The C NMR spectra are shown below. For S15; f= 0.42 (EtOAc); IR (neat) 3440, 2949, 2916, 2870, 1721, 1451, 1436, 1294, 1259, 1124, 1094 cm -1 ; 1 HNMR (600 MHz, CDCl3) δ 7.85 (dd, J = 7.8, 1.2 Hz, 1H), 7.40 (td, J = 7.5, 1.2 Hz, 1H), 7.26 (d, J= 7.2 Hz, 1H), 7.23 (td, J = 7.2, 1.2 Hz, 1H), 3.87 (s, 3H), 3.71 (t, J = 4.5 Hz, 2H), 3.68-3.64 (m, 6H), 3.60-3.58 (m, 4H), 3.48 (t, J = 6.6 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.62 (br, 1H), 1.91-1.86 (m, 2H); 13 CNMR (150 MHz, CDCl3) δ 168.0, 143.8, 131.8, 131.0, 130.6, 129.4, 125.8, 72.4, 70.7, 70.6, 70.5, 70.3, 69.9, 61.7, 51.8, 31.2, 30.8; HRMS (ESI TOF) calcd for C 17 H 26 O6Na [M + Na] + 349.1627, found 349.1627.

[0287] Ester S15 (801.0 mg, 2.5 mmol) was dissolved in CHCl (8.3 mL) and DIBAL-H (1.03 M, 7.1 mL, 7.4 mmol) in hexane was added at −78 °C. After stirring at 0 °C for 1 h 30 min, the reaction mixture was neutralized by adding potassium sodium tartrate. After stirring for 4 h, the mixture was extracted with EtOAc, washed with H2O and brine, and dried over Na2SO4. The residue was concentrated under reduced pressure to give the diol (472.2 mg) as a colorless liquid, which was used in the next step without purification. The diol (472.2 mg) was dissolved in CHCl (8.3 mL) and MnO (2.2 g, 25.0 mmol) was added at room temperature. After stirring at the same temperature for 6 h, the reaction mixture was diluted with EtOAc, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 1:1 to EtOAc) to give product 52l (420.2 mg, 57% yield over two steps) as a colorless liquid. Figures 62 and 63 show the product 52l. １ H NMR and １３ The C NMR spectra are shown below. f = 0.27 (EtOAc); IR (neat) 3459, 2916, 2868, 1694, 1599, 1453, 1291, 1209, 1120 cm -1 ; 1 HNMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 7.81 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 (td, J = 7.4, 1.6 Hz, 1H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 3.72-3.69 (m, 2H), 3.68-3.64 (m, 6H), 3.61-3.56 (m, 4H), 3.47 (t, J = 6.4 Hz, 2H), 3.10 (t, J = 7.6 Hz, 2H), 1.93-1.86 (m, 2H); 13HRMS (ESI TOF) calcd for C 16 H 24 O5Na [M + Na] + 319.1521, found 319.1520.

[0288] Synthesis Example 64 [17-membered ring 16-hydroxyhexadecanal (52m), Reference 38]

[0289]

[0290] Lactone 53m (376.7 mg, 1.48 mmol) was dissolved in CHCl (7.4 mL) and DIBAL-H (1.03 M, 2.16 mL, 2.22 mmol) in hexane was added at −78 °C. After stirring at the same temperature for 15 min, the reaction mixture was neutralized with potassium sodium tartrate. After stirring for 16 h, the mixture was extracted with EtOAc, washed with H2O, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc = 2:1 to 1:1) to give product 52m (172.0 mg, 45% yield) as a white solid. Figure 64 shows the structure of product 52m. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 9.76 (t, J = 2.1 Hz, 1H), 3.63 (t, J = 6.6 Hz, 2H), 2.41 (td, J = 7.2, 1.8 Hz, 2H), 1.64-1.60 (m, 2H), 1.58-1.53 (m, 2H), 1.35-1.25 (m, 22H).

[0291] General Procedure for Photochemical Lactonization Reactions

[0292]

[0293] Hydroxyaldehyde A3-52 (0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CHCl (20–50 mL, 5–2 mM) were added to a two-neck flask. After bubbling with argon for 5 minutes, the resulting solution was stirred at room temperature under visible light irradiation (λ = 380 nm, 18 W). The reaction mixture was diluted with CHCl and washed with HO. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford lactone C3-53.

[0294] Synthesis Example 65 [3,4,5,6-tetrahydro-1H-benzo[c]oxocin-1-one (53a, 8-membered ring), Reference 27]

[0295]

[0296] The reaction was carried out with hydroxyaldehyde 52a (16.5 μL, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (20 mL) for 9 hours. The residue was purified by flash chromatography to give product 53a (16.9 mg, 96%) as a white solid. Figure 65 shows the structure of product 53a. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 7.43 (t, J = 7.2 Hz, 2H), 7.30 (td, J = 7.8, 0.6 Hz, 1H ), 7.22 (d, J = 7.2 Hz, 1H), 4.18-4.16 (m, 2H), 2.81-2.79 (m, 2H), 1.98-1.94 (m, 2H), 1.85-1.78 (m, 2H).

[0297] Synthesis Example 66 [4,5-Dihydrobenzo[c]oxepin-1(3H)-one (53b, 7-membered ring), Reference 40]

[0298]

[0299] The hydroxyaldehyde 52b (14.8 μL, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH₂Cl₂ (20 mL) were reacted for 7.5 hours. The residue was purified by flash chromatography to give product 53b (10.2 mg, 63%) as a colorless liquid. Figure 66 shows the structure of product 53b. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 7.73 (dd, J = 7.8, 0.6 Hz, 1H), 7.49 (td, J = 7.5, 1.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 4.17 (t, J = 6.3 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.16-2.11 (m, 2H).

[0300] Synthesis Example 67 [4,5,6,7-tetrahydrobenzo[c]oxonin-1(3H)-one (53c, 9-membered ring)]

[0301]

[0302] Hydroxyaldehyde 52c (0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (50 mL) were used in the reaction. The residue was purified by flash chromatography to give product 53c (14.8 mg, 78%) as a colorless liquid. Figures 67 and 68 show the structure of product 53c. １ H NMR and １３ The C NMR spectra are shown below. f = 0.65 (Hexane / EtOAc = 7:1); IR (neat) 2930, 2854, 1717, 1289, 1258, 1124 cm -1 ; 1HNMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.6, 1.6, 1H), 7.38 (td, J = 7.6, 1.6 Hz, 1H), 7.29 (dd, J = 7.6, 1.2 Hz, 1H), 7.20 (dd, J = 7.6, 0.8 Hz, 1H), 4.56 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 6.0 Hz, 2H), 1.92-1.87 (m, 2H), 1.74-1.68 (m, 2H), 1.66-1.60 (m, 2H); 13 CNMR (100 MHz, CDCl3) δ 170.5, 145.4, 131.8, 131.2, 131.0, 130.5, 126.3, 67.0, 35.0, 31.5, 27.6, 26.4; HRMS (ESI TOF) calcd for C 12 H 14 O2Na [M + Na] + 213.0896, found 213.0899.

[0303] Synthesis Example 68 [3,4,5,6,7,8-Hexahydro-1H-benzo[c]oxecin-1-one (53d, 10-membered ring), Reference 42]

[0304]

[0305] The reaction mixture was treated with hydroxyaldehyde 52d (19.8 μL, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (50 mL) for 24 h. The residue was purified by flash chromatography to give product 53d (17.2 mg, 84%) as a colorless liquid. Figure 69 shows the structure of product 53d. １ The H NMR spectrum is shown. 1HNMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.6, 1.2 Hz, 1H), 7.37 (td, J = 7.6, 1.6 Hz, 1H), 7.27 (td, J = 7.6, 1.6 Hz, 1H), 7.22 (dd, J = 7.6, 0.8 Hz, 1H), 4.43 (t, J = 5.4 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H), 1.83-1.73 (m, 4H), 1.72-1.65 (m, 2H), 1.53-1.47 (m, 2H).

[0306] Synthesis Example 69 [Oxacycloundecan-2-one (53e, 11-membered ring), Reference 36]

[0307]

[0308] Hydroxyaldehyde 52e 17 (17.2 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (50 mL) were used for the reaction for 24 hours. The residue was purified by flash chromatography to give product 53e (14.3 mg, 84%) as a white solid. Figure 70 shows the structure of product 53e. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 4.11 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.68-1.59 (m, 4H), 1.37-1.25 (m, 10H).

[0309] Synthesis Example 70 [Oxacyclododecan-2-one (53f, 12-membered ring), Reference 36]

[0310]

[0311] The hydroxyaldehyde 52f (18.6 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (50 mL) were reacted for 24 hours. The residue was purified by flash chromatography to give the product 53f (14.4 mg, 78%) as a white solid. Figure 71 shows the structure of the product 53f. １ The H NMR spectrum is shown. 1 HNMR (400 MHz, CDCl3) δ 4.10 (t, J = 6.0 Hz, 2H), 2.32 (t, J = 6.8 Hz, 2H), 1.65-1.59 (m, 4H), 1.41-1.23 (m, 12H).

[0312] Synthesis Example 71 [Oxacyclotridecan-2-one (53h, 13-membered ring), Reference 36]

[0313]

[0314] The hydroxyaldehyde 52h (20.0 mg, 0.1 mmol), trichloromethane bromide (29.4 μL, 0.3 mmol), and CHCl (50 mL) were reacted for 24 hours. The residue was purified by flash chromatography to give product 53h (10.7 mg, 54%) as a white solid. Figure 72 shows the structure of product 53h. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 4.10 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 6.9 Hz, 2H), 1.66-1.59 (m, 4H), 1.39-1.27 (m, 14H).

[0315] Synthesis Example 72 [13-Hexyloxacyclotridecan-2-one (53i, 13-membered ring), Reference 44]

[0316]

[0317] The reaction was carried out with hydroxyaldehyde 52i (28.4 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH₂Cl₂ (50 mL) for 24 hours. The residue was purified by flash chromatography to give product 53i (10.9 mg, 39%) as a colorless liquid. Figure 73 shows the structure of product 53i. １ The H NMR spectrum is shown. 1 HNMR (400 MHz, CDCl3) δ 4.94-4.89 (m, 1H), 2.43 (ddd, J = 13.6, 8.4, 3.2 Hz, 1H), 2.28-2.21 (m, 1H), 1.73-1.21 (m, 28H), 0.87 (t, J = 6.8Hz, 3H).

[0318] Synthesis Example 73 [Oxacyclotetradecan-2-one (53j, 14-membered ring), Reference 45]

[0319]

[0320] The reaction was carried out with hydroxyaldehyde 52j (21.4 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (20 mL) for 24 hours. The residue was purified by flash chromatography to give product 53j (12.7 mg, 60%) as a colorless liquid. Figure 74 shows the structure of product 53j. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 4.15 (t, J = 5.4 Hz, 2H), 2.39-2.36 (m, 2H), 1.67-1.63 (m, 4H), 1.44-1.24 (m, 16H).

[0321] Synthesis Example 74 [Oxacyclopentadecan-2-one (53k, 15-membered ring), Reference 46]

[0322]

[0323] The reaction was carried out with hydroxyaldehyde 52k (22.8 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (20 mL) for 24 hours. The residue was purified by flash chromatography to give product 53k (13.5 mg, 60%) as a white solid. Figure 75 shows the structure of product 53k. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 4.14 (t, J = 5.4 Hz, 2H), 2.36-2.34 (m, 2H), 1.70-1.63 (m, 4H), 1.42-1.25 (m, 18H).

[0324] Synthesis Example 75 [3,4,6,7,9,10,13,14-Octahydrobenzo[l][1,4,7,10]tetraoxacyclohexadecan-1(12H)-one (53l, 16-membered ring), Reference 36]

[0325]

[0326] The hydroxyaldehyde 52l (29.4 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH₂Cl₂ (20 mL) were reacted for 24 hours. The residue was purified by flash chromatography to give the product 53l (9.7 mg, 33%) as a pale yellow color. Figure 76 shows the structure of the product 53l. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, DMSO) δ 7.64 (dd, J = 7.8, 1.2 Hz, 1H), 7.48 (td, J = 7.5, 1.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.29 (td, J = 7.5, 1.2 Hz, 1H), 4.39 (t, J = 4.8 Hz, 2H), 3.78 (t, J = 4.8 Hz, 2H), 3.57 (s, 4H), 3.54-3.51 (m, 4H), 3.50-3.47 (m, 2H), 2.93-2.91 (m, 1H), 1.78-1.72 (m, 2H).

[0327] Synthesis Example 76 [Oxacycloheptadecan-2-one (53m, 17-membered ring), Reference 46]

[0328]

[0329] The reaction was carried out with hydroxyaldehyde 52m (25.6 mg, 0.1 mmol), bromotrichloromethane (29.4 μL, 0.3 mmol), and CH2Cl2 (20 mL) for 24 hours. The residue was purified by flash chromatography to give product 53m (19.2 mg, 75%) as a white solid. Figure 77 shows the structure of product 53m. １ The H NMR spectrum is shown. 1 HNMR (600 MHz, CDCl3) δ 4.12 (t, J = 5.7 Hz, 2H), 2.32 (t, J = 6.9 Hz, 2H), 1.67-1.60 (m, 4H), 1.41-1.27 (m, 22H).

[0330] 3. Carboxylic acid synthesis using aldehydes and water as substrates

[0331] Synthesis Example 77 [4-tert-butylbenzoic acid (C4-1b)]

[0332]

[0333] Aldehyde A1-1b (84 μL, 0.5 mmol), bromotrichloromethane (147 μL, 1.5 mmol), CHCl (2.0 mL), and H2O (0.2 mL) were added to a 4 mL glass vial. After argon bubbling for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λmax = 380 nm) for 24 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane and washed with saturated brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:ethyl acetate = 3:1) to give carboxylic acid C4-1b (35 mg, 39%) as a white solid. Figure 78 shows the structure of carboxylic acid C4-1b. １ The H NMR spectrum is shown. 1H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 1.32 (s, 9H).

[0334] 4. Ester synthesis using alcohol as a substrate

[0335] Synthesis example 78 [Decyl benzoate (C8-1c)]

[0336]

[0337] Alcohol A8-1c (51 μL, 0.5 mmol), 1-decanol B8-1c (286 μL, 1.5 mmol), bromotrichloromethane (147 μL, 1.5 mmol), and CHCl (2.0 mL) were added to a 4 mL glass vial. After argon bubbling for 5 minutes, the resulting solution was stirred at room temperature under light irradiation (λmax = 365 nm) for 24 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:ethyl acetate = 10:1) to give ester C8-1c (73 mg, 56%) as a clear liquid. Figure 79 shows the structure of ester C8-1c. １ The H NMR spectrum is shown. 1 H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 (tt, J = 7.2, 1.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 4.31 (t, J = 6.6 Hz, 2H), 1.80-1.73 (m, 2H), 1.46-1.27 (m, 14H), 0.88 (t, J = 6.8 Hz, 3H).

[0338] 5. Reaction of aldehydes with nucleophiles (NU)

[0339] Synthesis Example 79 [Acid anhydride (IIIa)]

[0340]

[0341] As shown in the following reaction formula, benzoic acid was used as the nucleophile (NU) and the reaction was carried out in the same manner as in Synthesis Example 1 to obtain acid anhydride IIIa (yield 45%).

[0342]

[0343] 6. Solvent-free ester synthesis

[0344] Synthesis example 80 [Butyl benzoate (3a)]

[0345]

[0346] In Synthesis Example 1, the reaction between the substrates was carried out neat (without solvent) without using the solvent CH2Cl2, to obtain product 3a (yield 58%), demonstrating that this reaction can also be carried out under solvent-free conditions.

[0347] 7. Ester synthesis using NBS

[0348] Synthesis example 81 [Nonan-5-yl benzoate (3q)]

[0349]

[0350] The reaction was carried out in the same manner as in Synthesis Example 35, except that 0.6 mmol of NBS was used instead of bromotrichloromethane, but product 3q could not be obtained.

[0351] Synthesis example 82 [Phenethyl benzoate (3s)]

[0352]

[0353] The reaction was carried out in the same manner as in Synthesis Example 37, except that 0.6 mmol of NBS was used instead of bromotrichloromethane, but product 3s could not be obtained.

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Claims

1. A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with an alcohol represented by the following formula (B1) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm. [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group. [In formula (B1), Y １ is a primary or secondary alkyl group or an arylalkyl group. [In formula (C1), X １ and Y １ has the same meaning as the formulas (A1) and (B1).

2. A method for producing a carbonyl compound using light energy, comprising irradiating an aldehyde represented by the following formula (A1) with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane to obtain an acyl bromide represented by the following formula (A2), and then reacting the resulting acyl bromide with an alcohol represented by the following formula (B2): [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group. [In formula (A2), X １ has the same meaning as formula (A1). [In formula (B2), Y ２ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.] [In formula (C2), X １ and Y ２ has the same meaning as the formulas (A1) and (B2).

3. A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A3) with light having a wavelength of 200 to 420 nm in the presence of a tetrahalomethane: [In formula (A3), R １ ~R ３ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an arylalkyl group, an alkoxy group, an aryloxy group, a heteroaromatic ring group, or an amino group, and R １ and R ２ The carbon-carbon bond between R may be a single bond or a double bond. １ and R ２ may form a ring structure, Z is a divalent organic group, and n is an integer of 1 to 50. [In formula (C3), R １ ~R ３ , Z and n are the same as defined in formula (A3).

4. A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with water in the presence of a tetrahalomethane by irradiating it with light having a wavelength of 200 to 420 nm, to produce a carbonyl compound represented by the following formula (C4): [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group. [In formula (C4), X １ has the same meaning as formula (A1).

5. A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A4) with an amine represented by the following formula (B5) in the presence of tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm: [In formula (A4), X ２ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, an adamantyl group, or an amino acid residue. [In formula (B5), R ４ and R ５ are each independently a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or an amino acid residue. [In formula (C5), X ２ , R ４ and R ５ has the same meaning as the formulas (A4) and (B5).

6. A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with a thiol represented by the following formula (B6) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm: [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group. [In formula (B6), R ６ represents a hydrogen atom, a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, or an arylalkyl group. [In formula (C6), X １ and R ６ has the same meaning as in formulas (A1) and (B6).

7. A method for producing a carbonyl compound using light energy, comprising reacting an aldehyde represented by the following formula (A1) with a carbon nucleophile in the presence of a tetrahalomethane by irradiating it with light having a wavelength of 200 to 420 nm, and producing a carbonyl compound represented by the following formula (C7): [In formula (A1), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group. [In formula (C7), X １ has the same meaning as in formula (A1), and Nu is an added carbon nucleophile.

8. A method for producing a carbonyl compound using light energy, comprising reacting an alcohol represented by the following formula (A8) with an alcohol represented by the following formula (B8) in the presence of a tetrahalomethane by irradiating them with light having a wavelength of 200 to 420 nm: [In formula (A8), X １ is a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaromatic ring group, or an adamantyl group. [In formula (B8), Y ３ represents a primary to tertiary alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an arylalkyl group, or a hydroxyalkyl group in which the hydroxy group is protected with a protecting group.] [In formula (C8), X １ and Y ３ has the same meaning as the formulas (A8) and (B8).

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