WO2009145323A1 - Method for oxidizing alcohol by using polycyclic compound - Google Patents

Method for oxidizing alcohol by using polycyclic compound Download PDF

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WO2009145323A1
WO2009145323A1 PCT/JP2009/059909 JP2009059909W WO2009145323A1 WO 2009145323 A1 WO2009145323 A1 WO 2009145323A1 JP 2009059909 W JP2009059909 W JP 2009059909W WO 2009145323 A1 WO2009145323 A1 WO 2009145323A1
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group
optionally substituted
alkyl
compound
azaadamantane
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PCT/JP2009/059909
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French (fr)
Japanese (ja)
Inventor
好治 岩渕
正俊 澁谷
正樹 富澤
祐二 長田
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日産化学工業株式会社
国立大学法人東北大学
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Priority claimed from JP2008143200A external-priority patent/JP2011153076A/en
Priority claimed from JP2008228721A external-priority patent/JP2011153077A/en
Application filed by 日産化学工業株式会社, 国立大学法人東北大学 filed Critical 日産化学工業株式会社
Publication of WO2009145323A1 publication Critical patent/WO2009145323A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
    • C07C51/23—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups
    • C07C51/235—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of —CHO groups or primary alcohol groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/516—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of nitrogen-containing compounds to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
    • C07C51/255—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of compounds containing six-membered aromatic rings without ring-splitting
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/39—Preparation of carboxylic acid esters by oxidation of groups which are precursors for the acid moiety of the ester
    • C07C67/40—Preparation of carboxylic acid esters by oxidation of groups which are precursors for the acid moiety of the ester by oxidation of primary alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a method for oxidizing alcohol with oxygen using a polycyclic compound.
  • Oxidation reaction by air is expected as an ideal oxidation process from the viewpoint of safety and environmental harmony.
  • Examples of the method for oxidizing alcohols using air as an oxidizing agent include examples using palladium compounds (for example, see Non-Patent Document 1 and Non-Patent Document 4), examples using cobalt complexes (for example, see Non-Patent Document 2), ruthenium.
  • Examples using compounds for example, see Non-Patent Document 6
  • examples using 2,2,6,6-tetramethylpyridine-N-oxyl (TEMPO) and its derivatives for example, Patent Document 1 and Non-Patent Document 3) 5, 7, 8, 9, 10, 11) are known.
  • TEMPO 2,2,6,6-tetramethylpyridine-N-oxyl
  • TEMPO 2,2,6,6-tetramethylpyridine-N-oxyl
  • TEMPO 2,2,6,6-tetramethylpyridine-N-oxyl
  • TEMPO 2,2,6,6-tetramethylpyridine-N-oxyl
  • An object of the present invention is to provide a method for oxidizing alcohol with oxygen, which does not require a toxic heavy metal compound or the like in any alcohol oxidation, and is highly economical and safe for the environment.
  • the present inventors have found an oxidation method using a polycyclic compound as a catalyst and oxygen as an oxidizing agent, thereby completing the present invention.
  • R 1 represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a mercapto group, an amino group, a formyl group, a carboxyl group, a sulfo group, a C 1-12 alkyl group, a C 3-12 cyclo group.
  • R 4 and R 5 each independently represent the same meaning as R 1 , or R 4 and R 5 may be taken together to form a methylene which may be substituted with R 1
  • R a is halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, C 1- 6 alkylsulfenyl C 1-6 alkyl group, C 1-6 haloalkoxy group, C 1-6 alkylsulfenyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 haloalkylsulfenyl Phenyl group, C 1-6 haloalkylsulfinyl group, C 1-6 haloalkylsulfonyl group, C 2-6 alkenyl group, C 2-6 haloalkenyl group, C 2
  • R 3 may be the same or different from each other, and represents a hydrogen atom, a fluorine atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, provided that R 3 Any one or more of them is a fluorine atom or a hydroxy group
  • NO represents NO.
  • Represents N-OH, or represents N + ( O)
  • X ⁇ represents F ⁇ , Cl -, Br -, I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2 ) 2 N - Table in representing a) -, CH 3 CO 2 - , CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O - or
  • alcohols such as primary alcohols and secondary alcohols are oxidized with an oxygen-containing gas such as oxygen gas or air under mild conditions without the need for heating or toxic heavy metal oxides.
  • oxygen-containing gas such as oxygen gas or air
  • the compound, ketone compound and / or carboxylic acid compound can be produced almost selectively in high yield.
  • the polycyclic compound used in the present invention is represented by the above formula (1).
  • the notation method of each group in Formula (1) is as follows.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the expression “halo” also represents these halogen atoms.
  • C a -C b alkyl represents a linear or branched hydrocarbon group having a carbon number of a to b, such as methyl group, ethyl group, n-propyl group, i-propyl group.
  • n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1, 1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 1,1-dimethylbutyl group, 1,3
  • Specific examples include -dimethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b haloalkyl refers to a linear or branched hydrocarbon group comprising a to b carbon atoms, in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom.
  • the halogen atoms when substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other.
  • fluoromethyl group chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, chlorofluoromethyl group, dichloromethyl group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethyl group, trichloromethyl Group, bromodifluoromethyl group, bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl Group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2 -Fl group, 2-chloro-2,2-
  • C a -C b cycloalkyl represents a cyclic hydrocarbon group having a to b carbon atoms, and forms a monocyclic or complex ring structure having 3 to 6 members. I can do it. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms.
  • cyclopropyl group 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2- Specific examples include methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, bicyclo [2.2.1] heptan-2-yl group, etc. , Each selected range of carbon atoms.
  • C a -C b halocycloalkyl represents a cyclic hydrocarbon group having a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom.
  • a monocyclic or complex ring structure from 3 to 6 membered rings can be formed.
  • Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the substitution with a halogen atom may be a ring structure part, a side chain part, They may be both, and when substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other.
  • 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group, 2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methyl Cyclopropyl group, 2,2-dibromo-1-methylcyclopropyl group, 2,2,3,3-tetrafluorocyclobutyl group, 2- (trifluoromethyl) cyclohexyl group, 3- (trifluoromethyl) cyclohexyl group , 4- (trifluoromethyl) cyclohexyl group and the like are listed as specific examples, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b alkenyl is a linear or branched chain having a carbon number of a to b, and an unsaturated carbon having one or more double bonds in the molecule.
  • vinyl group 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-pentenyl group, 2- Methyl-2-butenyl group, 3-methyl-2-butenyl group, 2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenyl group, 2-methyl-2-pentenyl group, Specific examples include 2,4-dimethyl-2,6-heptadienyl group, 3,7-dimethyl-2,6-octadienyl group and the like, and each is selected within the range of the designated number of carbon atoms
  • C a -C b haloalkenyl is a straight chain or branched chain consisting of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and Represents an unsaturated hydrocarbon group having one or more double bonds in the molecule.
  • the halogen atoms may be the same as or different from each other.
  • C a -C b cycloalkenyl represents a cyclic unsaturated hydrocarbon group having 1 to 2 carbon atoms and having 1 to 2 carbon atoms.
  • a monocyclic or complex ring structure from a member ring to a six-membered ring can be formed. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the double bond may be either endo- or exo-.
  • 2-cyclopenten-1-yl group, 3-cyclopenten-1-yl group, 2-cyclohexen-1-yl group, 3-cyclohexen-1-yl group, bicyclo [2.2.1] -5-hepten-2- Specific examples include yl groups and the like, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b halocycloalkenyl refers to a cyclic one having 1 to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom.
  • it represents an unsaturated hydrocarbon group having two or more double bonds, and can form a monocyclic or complex ring structure having 3 to 6 members.
  • Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the double bond may be either endo- or exo-.
  • substitution by a halogen atom may be a ring structure part, a side chain part or both of them, and when substituted by two or more halogen atoms, those halogen atoms May be the same as or different from each other.
  • a 2-chlorobicyclo [2.2.1] -5-hepten-2-yl group and the like are given as specific examples, and each group is selected within the range of the designated number of carbon atoms.
  • C a -C b alkynyl represents a linear or branched chain consisting of a to b carbon atoms and an unsaturated carbonization having one or more triple bonds in the molecule.
  • ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1,1-dimethyl-2 Specific examples include -propynyl group, 2-hexynyl group and the like, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b haloalkynyl as used herein is a straight or branched chain consisting of a to b carbon atoms, wherein a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and Represents an unsaturated hydrocarbon group having one or more triple bonds in the molecule.
  • these halogen atoms may be the same as or different from each other.
  • Specific examples include 2-chloroethynyl group, 2-bromoethynyl group, 2-iodoethynyl group, 3-chloro-2-propynyl group, 3-bromo-2-propynyl group, 3-iodo-2-propynyl group and the like. Each of which is selected for each specified number of carbon atoms.
  • phenyl group o-methylphenyl group, m-methylphenyl group, p-methylphenyl group, o-chlorophenyl group, m-chlorophenyl group, p-chlorophenyl Group, o-fluorophenyl group, p-fluorophenyl group, o-methoxyphenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-cyanophenyl group, ⁇ -naphthyl group, ⁇ -naphthyl group, o- Biphenylyl group, m-biphenylyl group, p-biphenylyl group, 1-anthryl group, 2-anthryl group, 9-anthryl group, 1-phenanthryl group, 2-phenanthryl group, 3-phenanthryl group, 4-phenanthryl group, 9- Phenanthryl
  • benzyl group optionally substituted by R a , benzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, o-chlorobenzyl group, m-chlorobenzyl group, p-chlorobenzyl Group, o-fluorobenzyl group, p-fluorobenzyl group, o-methoxybenzyl group, p-methoxybenzyl group, p-nitrobenzyl group, p-cyanobenzyl group.
  • the alcohol compound to be oxidized is not particularly limited, and includes various alcohol compounds. Among these alcohol compounds, menthol, 4-methoxybenzyl alcohol and the like are preferable.
  • Examples of the polycyclic compound represented by (1) used in the present invention include 2-azaadamantane-N-oxyl (AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO). And 2-azaadamantane-N-oxyl compounds in which a hydroxy group or a fluorine atom is independently substituted at the 5-position and / or the 7-position.
  • AZADO 2-azaadamantane-N-oxyl
  • 1-methyl-2-azaadamantane-N-oxyl 1-methyl-2-azaadamantane-N-oxyl
  • 2-azaadamantane-N-oxyl compounds in which a hydroxy group or a fluorine atom is independently substituted at the 5-position and / or the 7-position.
  • AZADO 1-fluoro-2-azaadamantane-N-oxyl (1-F-AZADO), 5-fluoro-2-azaadamantane-N-oxyl (5-F-AZADO), 5-fluoro-1 -Methyl-2-azaadamantane-N-oxyl (5-F-1-Me-AZADO), 5,7-difluoro-1-methyl-2-azaadamantane-N-oxyl (5,7-F 2 -1 -Me-AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 1-methyl-5-hydroxy-2-azaadamantane-N-oxyl (1-Me-5-OH) -AZADO), 5-methoxy-1-methyl-2-azaadamantane-N-oxyl (5-MeO-1-Me-AZADO), 5-hydroxy-2-azaadamantane-N-oxyl (5-OH-AZADO) ), 9-azabic
  • N-hydroxy compounds include N-hydroxy-1-fluoro-2-azaadamantane (1-F-AZADOH), N-hydroxy-5-fluoro-2 -Azaadamantane (5-F-AZADOH), N-hydroxy-5-fluoro-1-methyl-2-azaadamantane (5-F-1-Me-AZADOH), N-hydroxy-5,7-difluoro-1 -Methyl-2-azaadamantane (5,7-F 2 -1-Me-AZADOH), N-hydroxy-1-methyl-2-azaadamantane (1-Me-AZADOH), N-hydroxy-1-methyl- 5-hydroxy-2-azaadamantane (1-Me-5-OH-AZADOH), N-hydroxy-5-methoxy-1-methyl-2-azaadamantane (5-MeO-1-Me-AZADOH), N- Hydroxy-5-hydroxy-2-azaadamantane (5-OH-AZADOH), N-N-hydroxy-1-fluoro-2-azaadamantan
  • Polycyclic compounds in which NO represents N + ( ⁇ O) X ⁇ that is, oxoammonium salts include, for example, 2-azaadamantane-N-oxoammonium salt (AZADO + X ⁇ ), 1-methyl-2-azaadamantane -N- oxo ammonium salts (1-Me-AZADO + X -), 5 -position and / or 7-position hydroxy group or a fluorine atom each independently are substituted 2-aza-adamantan -N- oxo ammonium salts Among them, for example, AZADO + X ⁇ , 1-fluoro-2-azaadamantane-N-oxoammonium salt (1-F-AZADO + X ⁇ ), 5-fluoro-2-azaadamantane-N-oxoammonium salt (5-F-AZADO + X -), 5- fluoro-1-methyl-2-aza-adamantan -N
  • X - as the F -, Cl -, Br - , I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2) 2 N -, CH 3 CO 2 -, CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O -, CF 3 SO 2 O 2- and the like can be mentioned, and Cl-or NO 3- is preferred.
  • the amount of the polycyclic compound used is preferably 0.01 mol% to 50 mol%, more preferably 0.1 mol% to 10 mol%, based on the substrate alcohol.
  • nitrite compound of the present invention examples include nitrites such as lithium nitrite, sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite; ethyl nitrite, isoamyl nitrite, isobutyl nitrite, Nitrite esters such as tertiary butyl nitrate, normal butyl nitrite, isopropyl nitrite, normal propyl nitrite, and adamantyl nitrite. Of these, sodium nitrite and tertiary butyl nitrite are preferable.
  • the amount of the nitrite compound to be used is 1 mol% to 100 mol%, preferably, for example, 1 mol% to 50 mol% with respect to the substrate alcohol.
  • Nitric acid may be used in place of the nitrous acid compound.
  • the amount of nitric acid used is in accordance with the amount of nitrite compound.
  • the oxidation reaction of the present invention is characterized in that it can be carried out under mild conditions, and the reaction temperature can also be carried out at room temperature. Furthermore, it can be carried out in the range of ⁇ 10 ° C. to 200 ° C.
  • As the reaction pressure normal pressure (atmospheric pressure) is sufficient, but the reaction can be carried out in a reduced pressure state or a pressurized state in the range of 0.01 to 10 MPa (gauge pressure) as necessary.
  • the oxidation reaction is preferably performed at room temperature and normal pressure.
  • the reaction time is not necessarily constant depending on the alcohol compound as a substrate to be used and the reaction conditions, but is usually 1 minute to 100 hours, preferably 5 minutes to 24 hours.
  • a solvent can be used as necessary.
  • the solvent is not limited as long as it does not inhibit the progress of the reaction, and is water, alcohols (for example, methanol, ethanol, propanol, butanol, octanol, etc.), cellosolves (for example, methoxyethanol, ethoxyethanol, etc.), aprotic Polar organic solvents (eg, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, tetramethylurea, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, etc.), ethers (eg, diethyl ether, diisopropyl ether, t- Butyl methyl ether, tetrahydrofuran, dioxane, etc.), aliphatic hydrocarbons (eg pentane, hexane, c-hexane, oc
  • an alcohol having an amino substituent which does not easily undergo an oxidation reaction, can be used as a substrate.
  • concentration of the alcohol compound as a substrate in the solvent is preferably 1 to 99% by mass, and more preferably 5 to 50% by mass except when alcohol is used as the solvent.
  • oxygen gas 100% oxygen
  • air can be used as oxygen as an oxidizing agent.
  • 1-Me-AZADO can be produced by the method described in International Patent Application Publication WO2006 / 001387A1 pamphlet.
  • 5-F-1-Me-AZADO can be produced by the method represented by the following scheme.
  • 1-Methyl-N-benzyloxycarbonyl-2-azaadamantane 6 can be produced according to International Patent Application Publication WO2006 / 001387A1 pamphlet.
  • 5,7-F 2 -1-Me-AZADO can be produced by the method represented by the following scheme.
  • 5-MeO-1-Me-AZADO can be produced by the method represented by the following scheme.
  • 5-F-AZADO can be produced by the method represented by the following scheme.
  • the carboxylic acid compound represented by the formula (19) can be produced by a method according to, for example, J. Org. Chem., Vol. 39, No. 26, p3822 (1974).
  • 1-F-AZADO can be produced by a method represented by the following scheme.
  • 1-hydroxy-N-benzyloxycarbonyl-2-azaadamantane 31 can be produced according to the description in J. Am. Chem. Soc., 2006, 128, p8412-8413.
  • Non-commercial nitrous acid compounds can be produced according to Synthesis, 2004, 11, 1747-1749.
  • the oxoammonium nitrate of the present invention comprises N 2 -oxyl compound represented by the following formula (2) or N-hydroxy compound represented by the following formula (3) obtained as described above, and NO 2 (nitrogen dioxide). ), N 2 O 4 (dinitrogen tetroxide) or a nitrous acid compound.
  • Examples of the method for producing oxoammonium nitrate of the present invention include a method in which an N-oxyl compound represented by the formula (2) is reacted with NO 2 or N 2 O 4 gas in a solvent.
  • it can be carried out by a method in which NO 2 gas is blown into a diethyl ether solution of the N-oxyl compound represented by the formula (2) and reacted at room temperature.
  • the oxoammonium nitrate of the present invention can be obtained by reacting the compound represented by the formula (2) under the same conditions as in the above-mentioned alcohol oxidation in the absence of the substrate alcohol.
  • Example 1 Production of catalyst Production of 1-methyl-N-trifluoroacetyl-2-azaadamantane (7) 1-methyl-N-benzyloxycarbonyl-2-aza produced according to International Patent Application Publication WO2006 / 001387A1 Pamphlet Pd / C (189 mg) containing 5% by mass of Pd was added to a solution of adamantane 6 (1.89 g, 6.61 mmol) in MeOH (0.1 M, 66 mL), and the mixture was stirred for 2 hours under H 2 stream. The reaction solution was filtered through Celite (registered trademark manufactured by Celite Corporation), and the solvent was removed under reduced pressure.
  • Celite registered trademark manufactured by Celite Corporation
  • Tetrahydropyran (88.5 mL) and benzyl alcohol 91.6 mL (885 mmol) were added to the reaction solution, and heated and refluxed until the disappearance of endo-bicyclo [3.3.1] non-6-ene-3-carbonylazide was confirmed. did. After allowing to cool, water and ethyl acetate were added for liquid separation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated.
  • N-trifluoroacetyl-2-azaadamantane 22 500 mg, 2.14 mmol
  • CCl 4 -MeCN-H 2 O 1.65 M; 1.3 mL-1.1 M; 1.9 mL-1.1 M; 1.9 mL
  • NaIO 4 1.05 g, 4.90 mmol
  • RuCl 3 44 mg, 0.214 mmol
  • 5-fluoro-N-trifluoroacetyl-2-azaadamantane (25) 5-hydroxy-N-trifluoroacetyl-2-azaadamantane 23 (549 mg, 2.20 mmol) of CH 2 Cl 2 (1.43 M, 1.5 mL) DAST (0.58 mL, 4.40 mmol) was added to the solution at ⁇ 78 ° C., the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. Then, after diluting with Et 2 O, H 2 O was added and extracted with AcOEt, and the organic layer was washed with H 2 O and dried over MgSO 4 .
  • N-benzyloxycarbonyl-1-fluoro-2-azaadamantane (32) 1-hydroxy-N-benzyloxycarbonyl-2-azaadamantane 31 (227 mg, 0.79 mmol) in CH 2 Cl 2 (1.43 M, 0.55 mL) DAST (0.32 mL, 2.37 mmol) was added to the solution at ⁇ 78 ° C., the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. Then, after diluting with Et 2 O, H 2 O was added and extracted with AcOEt. The organic layer was washed with H 2 O and dried over MgSO 4 , and the solvent was distilled off under reduced pressure.
  • Example 2 Oxygen Oxidation Using N-Oxyl Compound Sodium nitrite (5 mol% of alcohol compound) or tartar nitrite was added to acetic acid solution (0.33 mol / L) or methylene chloride solution (0.33 mol / L) of alcohol compound. Addition of Libutyl (30 mol% of alcohol compound) and 5-fluoro-2-azaadamantane-N-oxyl (5 mol% of alcohol compound) and confirmation of the disappearance of the raw material alcohol with oxygen balloon attached at room temperature Stir vigorously until After completion of the reaction, water and methylene chloride were added for liquid separation, and the organic layer was washed with water to obtain the desired ketone or aldehyde.
  • t-Bu tertiary butyl group
  • AZADO 2-azaadamantane-N-oxyl
  • 1-F-AZADO 1-fluoro-2-azaadamantane-N-oxyl
  • 5-F-AZADO 5-Fluoro-2-azaadamantane-N-oxyl
  • 1-Me-AZADO 1-methyl-2-azaadamantane-N-oxyl
  • 1-Me-5-F-AZADO 1-methyl-5-fluoro- 2-Azaadamantane-N-oxyl
  • 5,7-F 2 -1-Me-AZADO 5,7-difluoro-1-methyl-2-azaadamantane-N-oxyl
  • 1-Me-5-OH-AZADO 1-methyl-5-hydroxy-2-azaadamantane-N-oxyl
  • 5-MeO-1-Me-AZADO 5-methoxy-1-methyl-2-azaadamantane-N-oxyl
  • 5-OH-AZADO 5-meth
  • Entry is the example number
  • substrate is the substrate
  • product is the product
  • cat is the catalyst
  • Time (h) is the reaction time (unit: time)
  • Yield is the yield
  • recover represents raw material recovery
  • methyl ester represents methyl ester
  • carboxylic acid represents carboxylic acid
  • trace represents trace amount
  • balloon represents balloon
  • rt represents room temperature
  • ref represents reference.
  • NaNO 2 in the reaction formula is sodium nitrite
  • FeCl 3 ⁇ 6H 2 O is ferric chloride ⁇ hexahydrate
  • AcOH is acetic acid
  • t-BuONO is tertiary butyl nitrite
  • CH 2 N 2 represents diazomethane.
  • NR indicates that the reaction did not proceed
  • ⁇ indicates that the reaction was not measured
  • GC yield indicates the measurement result of the yield by the gas chromatography fluff method. .
  • Example 3 Reaction example 3 in which the solvent for the oxidation reaction was changed 3-1 MeCN / AcOH solvent
  • 2-octanol (3.91 g), 2-azaadamantane-N-oxyl (0.0229 g), acetonitrile (7.8 g ), Acetic acid (3.6 g) and NaNO 2 (0.831 g) in this order, and the inside of the reaction vessel was purged with oxygen, and then in an oxygen atmosphere (0.1 MPa) (gauge pressure, the same applies hereinafter) at room temperature. Stir for 4 hours.
  • the yield of the desired 2-octanone was 98% (GC yield (measurement of yield by gas chromatography method, the same applies hereinafter)).
  • Example 4 Reaction in a system using an N-hydroxy-2-azaadamantane compound
  • 2-octanol (1.30 g), N-hydroxy-2-azaadamantane (0.0154 g), acetic acid (3.9 g) and NaNO 2 (0.415 g) was sequentially added, and the inside of the reaction vessel was purged with oxygen, and then stirred at room temperature for 15 hours in an oxygen atmosphere (0.1 MPa).
  • the target yield of 2-octanone was 89% (GC yield).
  • Example 5 Reaction in a system using nitric acid
  • 2-octanol 0.392 g
  • 2-azaadamantane-N-oxyl AZADO
  • acetic acid 1.2 g
  • 65% by mass nitric acid An aqueous solution (0.0288 g) was sequentially added, and the reaction vessel was purged with oxygen, and then stirred at room temperature in an oxygen atmosphere (0.1 MPa) for 7 hours.
  • the yield of the desired 2-octanone was 99%.
  • Example 6 Preparation Example of Oxoammonium Halide Salt
  • Example 6-1 Preparation of Chloride Salt Chlorine at room temperature in a solution of 1-Me-AZADO (1920 mg, 11.55 mmol) in CCl 4 (23.1 mL, 0.5 M) Gas was blown in and stirred vigorously. The precipitated crystals were collected by filtration with a glass filter, washed with cooled Et 2 O, and dried under reduced pressure to obtain 1-Me-AZADO + Cl ⁇ (2316 mg, 99%).
  • Example 6-2 Using the preparation bromine bromide, in the same manner as in Example 6-1, 1-Me-AZADO + Br - ( actual counter ions Br 3 -) was obtained.
  • Example 7 Preparation of oxoammonium nitrate NO 2 gas generated by adding copper powder to concentrated HNO 3 to Et 2 O solution (red) of 5-F-AZADO (16 mg, 0.094 mmol) in a water bath Infused. After confirming that the color of the solution became transparent, the precipitated solid was filtered. Thereafter, the precipitated yellow solid was thoroughly washed with Et 2 O. The obtained solid was dried under reduced pressure with a vacuum pump to obtain 5-F-AZADO + NO 3 ⁇ (20.5 mg, 0.088 mmol, 94%) as a yellow solid.
  • Example 9 Oxygen oxidation using oxoammonium nitrate
  • Oxoammonium nitrate of 5-fluoro-2-azaadamantane (5 mol% of the alcohol compound) was added to an acetic acid or methylene chloride solution of the alcohol compound, and the starting alcohol compound at room temperature. The mixture was stirred vigorously until disappearance was confirmed. After completion of the reaction, water and methylene chloride were added for liquid separation, and the organic layer was washed with water to obtain the desired ketone or aldehyde.
  • 2-octanol (1.30 g), 2-azaadamantane-N-oxoammonium nitrate (0.0214 g), acetic acid (3.91 g) and NaNO 2 (0.413 g) were added to the reaction vessel in the order shown on the left.
  • the inside of the reaction vessel was purged with oxygen, and then stirred at room temperature in an oxygen atmosphere (0.1 MPa) for 15 hours.
  • the target yield of 2-octanone was 92% (GC yield).
  • Air is air
  • TBS is tertiary butyldimethylsilyl group
  • Cbz is benzyloxycarbonyl group
  • Bz is benzoyl group
  • Ac is acetyl group
  • Me is methyl group
  • Ph is phenyl group
  • THP is tetrahydro Pyran
  • HFIP represents 1,1,1,3,3,3-hexafluoro-2-propanol
  • DMSO represents dimethyl sulfoxide.
  • 5-F-AZADO + NO 3 - represents an oxo ammonium nitrate 5-fluoro-2-aza-adamantane.
  • the present invention oxidizes various alcohols with oxygen in the air, almost selectively under mild conditions without the need for heating or toxic heavy metal compounds, and provides aldehyde compounds, ketone compounds and / or carboxylic acids.
  • the compound can be produced and is extremely useful industrially.

Abstract

Disclosed is a novel method for oxidizing an alcohol compound. The method for oxidizing an alcohol compound, which is expressed by scheme (1), is characterized by using oxygen in the presence of a polycyclic compound and a nitrous acid compound.

Description

多環式化合物を用いるアルコールの酸化方法Alcohol oxidation method using polycyclic compounds
　本発明は、多環式化合物を用いるアルコールの酸素による酸化方法に関する。 The present invention relates to a method for oxidizing alcohol with oxygen using a polycyclic compound.
　空気による酸化反応は、安全性及び環境調和性という観点から、理想的な酸化プロセスとして期待を集めている。空気を酸化剤として用いるアルコール類の酸化方法としては、パラジウム化合物を用いる例（例えば、非特許文献１及び非特許文献４参照）、コバルト錯体を用いる例（例えば、非特許文献２参照）、ルテニウム化合物を用いる例(例えば、非特許文献６参照)、２，２，６，６－テトラメチルピリジン－Ｎ－オキシル（ＴＥＭＰＯ）およびその誘導体を用いる例（例えば、特許文献１、及び非特許文献３、５、７、８、９、１０、１１参照）が知られている。また、ＴＥＭＰＯのオキソアンモニウム硝酸塩の調製方法としては、二酸化窒素を用いる例（非特許文献１２及び１３参照）が知られている。 Oxidation reaction by air is expected as an ideal oxidation process from the viewpoint of safety and environmental harmony. Examples of the method for oxidizing alcohols using air as an oxidizing agent include examples using palladium compounds (for example, see Non-Patent Document 1 and Non-Patent Document 4), examples using cobalt complexes (for example, see Non-Patent Document 2), ruthenium. Examples using compounds (for example, see Non-Patent Document 6), examples using 2,2,6,6-tetramethylpyridine-N-oxyl (TEMPO) and its derivatives (for example, Patent Document 1 and Non-Patent Document 3) 5, 7, 8, 9, 10, 11) are known. As a method for preparing TEMPO oxoammonium nitrate, examples using nitrogen dioxide (see Non-Patent Documents 12 and 13) are known.
特開2006-176527号公報JP 2006-176527 A
　しかし、従来知られている、空気を酸化剤として用いるアルコール類の酸化方法は、１級アルコールの酸化において反応が複雑化したり、適用できる基質が限られるといった難点を有している。また、従来知られている空気酸化は、酸化反応の際に加熱を必要とするか、有毒な重金属化合物を用いる必要があり、経済性や環境への安全性などの観点から更なる改善が望まれている。 However, the conventionally known methods for oxidizing alcohols using air as an oxidizing agent have drawbacks that the reaction is complicated in the oxidation of primary alcohols and the applicable substrates are limited. In addition, conventionally known air oxidation requires heating during the oxidation reaction or use of a toxic heavy metal compound, and further improvement is desired from the viewpoint of economy and environmental safety. It is rare.
　本発明の目的は、いずれのアルコールの酸化においても、有毒な重金属化合物などを必要とせずに、経済性及び環境への安全性の高い酸素によるアルコールの酸化方法を提供するものである。 An object of the present invention is to provide a method for oxidizing alcohol with oxygen, which does not require a toxic heavy metal compound or the like in any alcohol oxidation, and is highly economical and safe for the environment.
　本発明者らは上記課題を解決すべく鋭意検討した結果、多環式化合物を触媒として用い、酸素を酸化剤とする酸化方法を見いだし、本発明を完成させた。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found an oxidation method using a polycyclic compound as a catalyst and oxygen as an oxidizing agent, thereby completing the present invention.
　すなわち、本発明は以下の要旨を有する。
〔１〕式（１）： That is, the present invention has the following gist.
[1] Formula (1):
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
(式中、R1は、水素原子、ハロゲン原子、ニトロ基、シアノ基、ヒドロキシ基、メルカプト基、アミノ基、ホルミル基、カルボキシル基、スルホ基、C1-12アルキル基、C3-12シクロアルキル基、（C1-12アルキル）オキシ基、（C3-12シクロアルキル）オキシ基、（C1-12アルキル）チオ基、（C3-12シクロアルキル）チオ基、（C1-12アルキル）アミノ基、（C3-12シクロアルキル）アミノ基、ジ（C1-6アルキル）アミノ基、ジ（C3-6シクロアルキル）アミノ基、C1-12アルキルカルボニル基、C3-12シクロアルキルカルボニル基、（C1-12アルキル）オキシカルボニル基、（C3-12シクロアルキル）オキシカルボニル基、（C1-12アルキル）チオカルボニル基、（C3-12シクロアルキル）チオカルボニル基、（C1-12アルキル）アミノカルボニル基、（C3-12シクロアルキル）アミノカルボニル基、ジ（C1-6アルキル）アミノカルボニル基、ジ（C3-6シクロアルキル）アミノカルボニル基、（C1-12アルキル）カルボニルオキシ基、（C3-12シクロアルキル）カルボニルオキシ基、（C1-12アルキル）カルボニルチオ基、（C3-12シクロアルキル）カルボニルチオ基、（C1-12アルキル）カルボニルアミノ基、（C3-12シクロアルキル）カルボニルアミノ基、ジ（C1-12アルキルカルボニル）アミノ基、ジ（C3-12シクロアルキルカルボニル）アミノ基、C1-6ハロアルキル基、C3-6ハロシクロアルキル基、C2-6アルケニル基、C3-6シクロアルケニル基、C2-6ハロアルケニル基、C3-6ハロシクロアルケニル基、C2-6アルキニル基、C2-6ハロアルキニル基、Raで置換されていてもよいベンジル基、Raで置換されていてもよいベンジルオキシ基、Raで置換されていてもよいベンジルチオ基、Raで置換されていてもよいベンジルアミノ基、Raで置換されていてもよいジベンジルアミノ基、Raで置換されていてもよいベンジルカルボニル基、Raで置換されていてもよいベンジルオキシカルボニル基、Raで置換されていてもよいベンジルチオカルボニル基、Raで置換されていてもよいベンジルアミノカルボニル基、Raで置換されていてもよいジベンジルアミノカルボニル基、Raで置換されていてもよいベンジルカルボニルオキシ基、Raで置換されていてもよいベンジルカルボニルチオ基、Raで置換されていてもよいベンジルカルボニルアミノ基、Raで置換されていてもよいジ（ベンジルカルボニル）アミノ基、Raで置換されていてもよいアリール基、Raで置換されていてもよいアリールオキシ基、Raで置換されていてもよいアリールチオ基、Raで置換されていてもよいアリールアミノ基、Raで置換されていてもよいジアリールアミノ基、Raで置換されていてもよいアリールカルボニル基、Raで置換されていてもよいアリールオキシカルボニル基、Raで置換されていてもよいアリールチオカルボニル基、Raで置換されていてもよいアリールアミノカルボニル基、Raで置換されていてもよいジアリールアミノカルボニル基、Raで置換されていてもよいアリールカルボニルオキシ基、Raで置換されていてもよいアリールカルボニルチオ基、Raで置換されていてもよいアリールカルボニルアミノ基、及びRaで置換されていてもよいジ（アリールカルボニル）アミノ基からなる群から選ばれる１以上の置換基を表し、置換基の数が２以上である場合は、それぞれの置換基は同じでも異なっていてもよく、 (In the formula, R 1 represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a mercapto group, an amino group, a formyl group, a carboxyl group, a sulfo group, a C 1-12 alkyl group, a C 3-12 cyclo group. Alkyl group, (C 1-12 alkyl) oxy group, (C 3-12 cycloalkyl) oxy group, (C 1-12 alkyl) thio group, (C 3-12 cycloalkyl) thio group, (C 1-12 Alkyl) amino group, (C 3-12 cycloalkyl) amino group, di (C 1-6 alkyl) amino group, di (C 3-6 cycloalkyl) amino group, C 1-12 alkylcarbonyl group, C 3- 12 cycloalkylcarbonyl group, (C 1-12 alkyl) oxycarbonyl group, (C 3-12 cycloalkyl) oxycarbonyl group, (C 1-12 alkyl) thiocarbonyl group, (C 3-12 cycloalkyl) thiocarbonyl group, (C 1-12 alkyl) aminocarbonyl group, (C 3-12 cycloalkyl ) Aminocarbonyl group, di (C 1-6 alkyl) aminocarbonyl group, di (C 3-6 cycloalkyl) aminocarbonyl group, (C 1-12 alkyl) carbonyloxy group, (C 3-12 cycloalkyl) carbonyl Oxy group, (C 1-12 alkyl) carbonylthio group, (C 3-12 cycloalkyl) carbonylthio group, (C 1-12 alkyl) carbonylamino group, (C 3-12 cycloalkyl) carbonylamino group, di (C 1-12 alkylcarbonyl) amino group, di (C 3-12 cycloalkylcarbonyl) amino group, C 1-6 haloalkyl group, C 3-6 halocycloalkyl group, C 2-6 alkenyl group, C 3- 6 cycloalkenyl group, C 2-6 haloalkenyl group, C 3-6 halocycloalkenyl group, C 2-6 alkynyl group, C 2-6 haloalkynyl group, benzyl group optionally substituted by R a , R benzyloxy group optionally substituted by a , R Good benzylthio group which may be substituted with a, R a in the optionally substituted benzylamino group, optionally substituted with R a dibenzylamino group, R a with an optionally substituted benzyl group , R a in the optionally substituted benzyloxycarbonyl group, R a with optionally substituted benzyl thiocarbonyl group, R a in the optionally substituted benzylamino group, optionally substituted with R a which may dibenzylamino group, R a with optionally substituted benzylcarbonyl group, R a with optionally substituted benzylcarbonyl thio group, R a in the optionally substituted benzylcarbonyl group, optionally substituted with R a di (benzylcarbonyl) amino group, optionally substituted with R a aryl group, optionally substituted with R a aryloxy , R a with an optionally substituted arylthio group, optionally substituted with R a arylamino group, R a in the optionally substituted diarylamino group, R a may arylcarbonyl optionally substituted with group, R a with optionally substituted aryloxycarbonyl group, optionally substituted with R a arylthiocarbonyl group, R a with optionally substituted arylaminocarbonyl group, substituted by R a which may be diarylamino group, R a with optionally substituted arylcarbonyloxy group, R a with optionally substituted aryl carbonyl thio group, which may be substituted by R a arylcarbonylamino group, And one or more substituents selected from the group consisting of di (arylcarbonyl) amino group optionally substituted with R a , wherein the number of substituents is 2 or more Each substituent may be the same or different,
　R4およびR5は、それぞれ独立にR1と同じ意味を表すか、またはR4とR5とが一緒になってR1で置換されていてもよいメチレンを形成していてもよく、
　Raは、ハロゲン、Ｃ1-6アルキル基、Ｃ1-6ハロアルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、Ｃ1-6アルキルスルフェニルＣ1-6アルキル基、Ｃ1-6ハロアルコキシ基、Ｃ1-6アルキルスルフェニル基、Ｃ1-6アルキルスルフィニル基、Ｃ1-6アルキルスルホニル基、Ｃ1-6ハロアルキルスルフェニル基、Ｃ1-6ハロアルキルスルフィニル基、Ｃ1-6ハロアルキルスルホニル基、Ｃ2-6アルケニル基、Ｃ2-6ハロアルケニル基、Ｃ2-6アルケニルオキシ基、Ｃ2-6ハロアルケニルオキシ基、Ｃ2-6アルケニルスルフェニル基、Ｃ2-6アルケニルスルフィニル基、Ｃ2-6アルケニルスルホニル基、Ｃ2-6ハロアルケニルスルフェニル基、Ｃ2-6ハロアルケニルスルフィニル基、Ｃ2-6ハロアルケニルスルホニル基、Ｃ2-6アルキニル基、Ｃ2-6ハロアルキニル基、Ｃ2-6アルキニルオキシ基、Ｃ2-6ハロアルキニルオキシ基、Ｃ2-6アルキニルスルフェニル基、Ｃ2-6アルキニルスルフィニル基、Ｃ2-6アルキニルスルホニル基、Ｃ2-6ハロアルキニルスルフェニル基、Ｃ2-6ハロアルキニルスルフィニル基、Ｃ２～Ｃ６ハロアルキニルスルホニル基、－ＮＯ２、－ＣＮ、ホルミル基、－ＯＨ、－ＳＨ、－ＮH２、－ＳＣＮ、Ｃ1-6アルコキシカルボニル基、Ｃ1-6アルキルカルボニル基、Ｃ1-6ハロアルキルカルボニル基、Ｃ1-6アルキルカルボニルオキシ基、フェニル基、Ｃ1-6アルキルアミノ基またはジＣ1-6アルキルアミノ基であって、
　置換するRaの数は１～５個であり、Raが２個以上の場合は、それぞれの置換基は同じでも異なっていてもよく、
　N-OはN-O・を表すか、N-OHを表すか、またはN+(=O)X-を表し、Ｘ-はF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ -、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-またはCF3SO2O-を表す。)で表される多環式化合物の存在下、亜硝酸化合物または硝酸の存在下（但し、N-OがN+(=O)X-であってX-がNO3 -である場合は、亜硝酸化合物または硝酸の存在下又は非存在下）、アルコール化合物を酸素で酸化することを特徴とする酸化方法。
〔２〕前記多環式化合物の使用量が、アルコール化合物に対して0.1モル％～50モル%である前記〔1〕に記載の酸化方法。
〔３〕前記亜硝酸化合物の使用量が、アルコール化合物に対して１モル％ないし100モル%である前記〔１〕又は〔２〕に記載の酸化方法。
〔４〕前記亜硝酸化合物が式（２） R 4 and R 5 each independently represent the same meaning as R 1 , or R 4 and R 5 may be taken together to form a methylene which may be substituted with R 1 ,
R a is halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, C 1- 6 alkylsulfenyl C 1-6 alkyl group, C 1-6 haloalkoxy group, C 1-6 alkylsulfenyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 haloalkylsulfenyl Phenyl group, C 1-6 haloalkylsulfinyl group, C 1-6 haloalkylsulfonyl group, C 2-6 alkenyl group, C 2-6 haloalkenyl group, C 2-6 alkenyloxy group, C 2-6 haloalkenyloxy group , C 2-6 alkenyl Le phenyl group, C 2-6 alkenylsulfinyl group, C 2-6 alkenyl-sulfonyl group, C 2-6 halo alkenyl Le phenyl group, C 2-6 halo alkenylsulfinyl group, C 2-6 halo alkenylsulfonyl group, C 2-6 Al Alkenyl group, C 2-6 haloalkynyl group, C 2-6 alkynyloxy group, C 2-6 haloalkynyl group, C 2-6 alkyl Nils Le phenyl group, C 2-6 alkynylsulfinyl group, C 2-6 alkynyl Sulfonyl group, C 2-6 haloalkynylsulfenyl group, C 2-6 haloalkynylsulfinyl group, C 2 -C 6 haloalkynylsulfonyl group, —NO 2 , —CN, formyl group, —OH, —SH, —NH 2 , -SCN, C 1-6 alkoxycarbonyl group, C 1-6 alkylcarbonyl group, C 1-6 haloalkylcarbonyl group, C 1-6 alkylcarbonyloxy group, phenyl group, C 1-6 alkylamino group or di A C 1-6 alkylamino group,
The number of R a to be substituted is 1 to 5, and when R a is 2 or more, each substituent may be the same or different,
NO represents NO., N-OH, or N + (= O) X − , where X − represents F − , Cl − , Br − , I − , ClO 2 − , ClO 4 − , IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2) 2 N -, CH 3 CO 2 − , CF 3 CO 2 − , 4-CH 3 C 6 H 4 SO 2 O — or CF 3 SO 2 O — is represented. Presence of a polycyclic compound represented by), the presence of nitrite or nitrate (however, NO is N + (= O) X - a a and wherein X - NO 3 - if it is, the nitrite An oxidation method comprising oxidizing an alcohol compound with oxygen in the presence or absence of a compound or nitric acid.
[2] The oxidation method according to [1], wherein the amount of the polycyclic compound used is 0.1 mol% to 50 mol% with respect to the alcohol compound.
[3] The oxidation method according to [1] or [2], wherein the amount of the nitrous acid compound used is 1 mol% to 100 mol% with respect to the alcohol compound.
[4] The nitrous acid compound is represented by the formula (2)
Figure JPOXMLDOC01-appb-C000006
 （式中、R2は炭素数１から１０のアルキル基を表す）で表される亜硝酸エステル化合物である前記〔１〕～〔３〕に記載の酸化方法。
〔５〕前記亜硝酸化合物が亜硝酸又は亜硝酸塩である前記〔１〕～〔３〕に記載の酸化方法。
〔６〕前記多環式化合物が、下記式
Figure JPOXMLDOC01-appb-C000006
 The oxidation method according to any one of [1] to [3] above, wherein R 2 represents an alkyl group having 1 to 10 carbon atoms.
[5] The oxidation method according to [1] to [3], wherein the nitrous acid compound is nitrous acid or nitrite.
[6] The polycyclic compound is represented by the following formula:
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、Ｒ3はお互いに同一でも異なっていても良く、水素原子、フッ素原子、ヒドロキシ基、炭素数１から３のアルキル基または炭素数１から３のアルコキシ基を表し、かつ、Ｒ3のうちいずれか１つ以上がフッ素原子またはヒドロキシ基であり、N-OはN-O・を表すか、N-OHを表すか、またはN+(=O)X-を表し、Ｘ-はF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ ‐、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-またはCF3SO2O-を表す。）で表される化合物である、前記〔１〕～〔５〕のいずれかに記載の酸化方法。
〔７〕アルコール化合物を酸化してアルデヒド化合物、ケトン化合物及び／又はカルボン酸化合物を製造する前記〔１〕～〔６〕のいずれかに記載の酸化方法。
〔８〕下記式 (Wherein R 3 may be the same or different from each other, and represents a hydrogen atom, a fluorine atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and R 3 Any one or more of which is a fluorine atom or a hydroxy group, NO represents NO., Represents N-OH, or represents N + (= O) X − , X − represents F − , Cl -, Br -, I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2 ) 2 N - Table in representing a) -, CH 3 CO 2 - , CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O - or CF 3 SO 2 O. The oxidation method according to any one of [1] to [5], wherein
[7] The oxidation method according to any one of [1] to [6], wherein an alcohol compound is oxidized to produce an aldehyde compound, a ketone compound and / or a carboxylic acid compound.
[8] The following formula
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、Ｒ3はお互いに同一でも異なっていても良く、水素原子、フッ素原子、ヒドロキシ基、炭素数１から３のアルキル基または炭素数１から３のアルコキシ基を表し、但し、Ｒ3のうちいずれか１つ以上がフッ素原子またはヒドロキシ基であり、N-OはN-O・を表すか、N-OHを表すか、またはN+(=O)X-を表し、Ｘ-はF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ ‐、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-またはCF3SO2O-を表す。）で表されることを特徴とする化合物。 (Wherein R 3 may be the same or different from each other, and represents a hydrogen atom, a fluorine atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, provided that R 3 Any one or more of them is a fluorine atom or a hydroxy group, NO represents NO., Represents N-OH, or represents N + (= O) X − , X − represents F − , Cl -, Br -, I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2 ) 2 N - Table in representing a) -, CH 3 CO 2 - , CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O - or CF 3 SO 2 O. The compound characterized by being made.
　本発明によれば、１級アルコール、２級アルコールなどのアルコールを、加熱や有毒な重金属酸化物を必要とせずに、穏和な条件において、酸素ガス又は空気などの含酸素ガスにより酸化し、アルデヒド化合物、ケトン化合物及び／又はカルボン酸化合物をほぼ選択的に高収率で製造することができる。 According to the present invention, alcohols such as primary alcohols and secondary alcohols are oxidized with an oxygen-containing gas such as oxygen gas or air under mild conditions without the need for heating or toxic heavy metal oxides. The compound, ketone compound and / or carboxylic acid compound can be produced almost selectively in high yield.
　本発明で用いる多環式化合物は、上記した式（１）で表される。式（１）における各基の表記方法は以下の通りである。
　ハロゲン原子としては、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。尚、本明細書中「ハロ」(halo)の表記もこれらのハロゲン原子を表す。 The polycyclic compound used in the present invention is represented by the above formula (1). The notation method of each group in Formula (1) is as follows.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present specification, the expression “halo” also represents these halogen atoms.
　本明細書におけるCa～Cbアルキルとは、炭素原子数がa～b個よりなる直鎖または分岐鎖の炭化水素基を表し、例えばメチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、i-ブチル基、s-ブチル基、t-ブチル基、n-ペンチル基、1-メチルブチル基、2-メチルブチル基、3-メチルブチル基、1-エチルプロピル基、1,1-ジメチルプロピル基、1,2-ジメチルプロピル基、2,2-ジメチルプロピル基、n-ヘキシル基、1-メチルペンチル基、2-メチルペンチル基、1,1-ジメチルブチル基、1,3-ジメチルブチル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b alkyl represents a linear or branched hydrocarbon group having a carbon number of a to b, such as methyl group, ethyl group, n-propyl group, i-propyl group. Group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1, 1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 1,1-dimethylbutyl group, 1,3 Specific examples include -dimethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like, and each is selected within the range of the designated number of carbon atoms.
　本明細書におけるCa～Cbハロアルキルとは、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa～b個よりなる直鎖または分岐鎖の炭化水素基を表し、このとき、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、または互いに異なっていてもよい。例えばフルオロメチル基、クロロメチル基、ブロモメチル基、ヨードメチル基、ジフルオロメチル基、クロロフルオロメチル基、ジクロロメチル基、ブロモフルオロメチル基、トリフルオロメチル基、クロロジフルオロメチル基、ジクロロフルオロメチル基、トリクロロメチル基、ブロモジフルオロメチル基、ブロモクロロフルオロメチル基、ジブロモフルオロメチル基、2-フルオロエチル基、2-クロロエチル基、2-ブロモエチル基、2,2-ジフルオロエチル基、2-クロロ-2-フルオロエチル基、2,2-ジクロロエチル基、2-ブロモ-2-フルオロエチル基、2,2,2-トリフルオロエチル基、2-クロロ-2,2-ジフルオロエチル基、2,2-ジクロロ-2-フルオロエチル基、2,2,2-トリクロロエチル基、2-ブロモ-2,2-ジフルオロエチル基、2-ブロモ-2-クロロ-2-フルオロエチル基、2-ブロモ-2,2-ジクロロエチル基、1,1,2,2-テトラフルオロエチル基、ペンタフルオロエチル基、1-クロロ-1,2,2,2-テトラフルオロエチル基、2-クロロ-1,1,2,2-テトラフルオロエチル基、1,2-ジクロロ-1,2,2-トリフルオロエチル基、2-ブロモ-1,1,2,2-テトラフルオロエチル基、2-フルオロプロピル基、2-クロロプロピル基、2-ブロモプロピル基、2-クロロ-2-フルオロプロピル基、2,3-ジクロロプロピル基、2-ブロモ-3-フルオロプロピル基、3-ブロモ-2-クロロプロピル基、2,3-ジブロモプロピル基、3,3,3-トリフルオロプロピル基、3-ブロモ-3,3-ジフルオロプロピル基、2,2,3,3-テトラフルオロプロピル基、2-クロロ-3,3,3-トリフルオロプロピル基、2,2,3,3,3-ペンタフルオロプロピル基、1,1,2,3,3,3-ヘキサフルオロプロピル基、ヘプタフルオロプロピル基、2,3-ジクロロ-1,1,2,3,3-ペンタフルオロプロピル基、2-フルオロ-1-メチルエチル基、2-クロロ-1-メチルエチル基、2-ブロモ-1-メチルエチル基、2,2,2-トリフルオロ-1-(トリフルオロメチル)エチル基、1,2,2,2-テトラフルオロ-1-(トリフルオロメチル)エチル基、2,2,3,3,4,4-ヘキサフルオロブチル基、2,2,3,4,4,4-ヘキサフルオロブチル基、2,2,3,3,4,4,4-ヘプタフルオロブチル基、1,1,2,2,3,3,4,4-オクタフルオロブチル基、ノナフルオロブチル基、4-クロロ-1,1,2,2,3,3,4,4-オクタフルオロブチル基、2-フルオロ-2-メチルプロピル基、2-クロロ-1,1-ジメチルエチル基、2-ブロモ-1,1-ジメチルエチル基、5-クロロ-2,2,3,4,4,5,5-ヘプタフルオロペンチル基、トリデカフルオロヘキシル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b haloalkyl refers to a linear or branched hydrocarbon group comprising a to b carbon atoms, in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. In this case, when substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, chlorofluoromethyl group, dichloromethyl group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethyl group, trichloromethyl Group, bromodifluoromethyl group, bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl Group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2 -Fluoroethyl group, 2,2,2-trichloroethyl group, 2-bromo-2,2-difluoroethyl group, 2-bromo-2-chloro-2-fluoroethyl group, 2-butyl Lomo-2,2-dichloroethyl group, 1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1 1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2-trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, 2-fluoropropyl Group, 2-chloropropyl group, 2-bromopropyl group, 2-chloro-2-fluoropropyl group, 2,3-dichloropropyl group, 2-bromo-3-fluoropropyl group, 3-bromo-2-chloropropyl group Group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group, 3-bromo-3,3-difluoropropyl group, 2,2,3,3-tetrafluoropropyl group, 2-chloro- 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group, heptafluoropropyl group, 2, 3-dichloro-1,1,2,3,3-pentaph Oropropyl group, 2-fluoro-1-methylethyl group, 2-chloro-1-methylethyl group, 2-bromo-1-methylethyl group, 2,2,2-trifluoro-1- (trifluoromethyl) ethyl Groups, 1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3,4,4, 4-hexafluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, 1,1,2,2,3,3,4,4-octafluorobutyl group, nonafluorobutyl Group, 4-chloro-1,1,2,2,3,3,4,4-octafluorobutyl group, 2-fluoro-2-methylpropyl group, 2-chloro-1,1-dimethylethyl group, 2 Specific examples include -bromo-1,1-dimethylethyl group, 5-chloro-2,2,3,4,4,5,5-heptafluoropentyl group, tridecafluorohexyl group, etc. In the range of the number of carbon atoms.
　本明細書におけるCa～Cbシクロアルキルとは、炭素原子数がa～b個よりなる環状の炭化水素基を表し、３員環から６員環までの単環または複合環構造を形成することが出来る。また、各々の環は指定の炭素原子数の範囲でアルキル基によって任意に置換されていてもよい。例えばシクロプロピル基、1-メチルシクロプロピル基、2-メチルシクロプロピル基、2,2-ジメチルシクロプロピル基、2,2,3,3-テトラメチルシクロプロピル基、シクロブチル基、シクロペンチル基、2-メチルシクロペンチル基、3-メチルシクロペンチル基、シクロヘキシル基、2-メチルシクロヘキシル基、3-メチルシクロヘキシル基、4-メチルシクロヘキシル基、ビシクロ[2.2.1]ヘプタン-2-イル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b cycloalkyl represents a cyclic hydrocarbon group having a to b carbon atoms, and forms a monocyclic or complex ring structure having 3 to 6 members. I can do it. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms. For example, cyclopropyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2- Specific examples include methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, bicyclo [2.2.1] heptan-2-yl group, etc. , Each selected range of carbon atoms.
　本明細書におけるCa～Cbハロシクロアルキルとは、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa～b個よりなる環状の炭化水素基を表し、３員環から６員環までの単環または複合環構造を形成することが出来る。また、各々の環は指定の炭素原子数の範囲でアルキル基によって任意に置換されていてもよく、ハロゲン原子による置換は環構造部分であっても、側鎖部分であっても、或いはそれらの両方であってもよく、さらに、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、または互いに異なっていてもよい。例えば2,2-ジフルオロシクロプロピル基、2,2-ジクロロシクロプロピル基、2,2-ジブロモシクロプロピル基、2,2-ジフルオロ-1-メチルシクロプロピル基、2,2-ジクロロ-1-メチルシクロプロピル基、2,2-ジブロモ-1-メチルシクロプロピル基、2,2,3,3-テトラフルオロシクロブチル基、2-(トリフルオロメチル)シクロヘキシル基、3-(トリフルオロメチル)シクロヘキシル基、4-(トリフルオロメチル)シクロヘキシル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b halocycloalkyl represents a cyclic hydrocarbon group having a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. A monocyclic or complex ring structure from 3 to 6 membered rings can be formed. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the substitution with a halogen atom may be a ring structure part, a side chain part, They may be both, and when substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group, 2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methyl Cyclopropyl group, 2,2-dibromo-1-methylcyclopropyl group, 2,2,3,3-tetrafluorocyclobutyl group, 2- (trifluoromethyl) cyclohexyl group, 3- (trifluoromethyl) cyclohexyl group , 4- (trifluoromethyl) cyclohexyl group and the like are listed as specific examples, and each is selected within the range of the designated number of carbon atoms.
　本明細書におけるCa～Cbアルケニルとは、炭素原子数がa～b個よりなる直鎖または分岐鎖で、且つ、分子内に１個または２個以上の二重結合を有する不飽和炭化水素基を表す。例えば、ビニル基、1-プロペニル基、2-プロペニル基、1-メチルエテニル基、2-ブテニル基、1-メチル-2-プロペニル基、2-メチル-2-プロペニル基、2-ペンテニル基、2-メチル-2-ブテニル基、3-メチル-2-ブテニル基、2-エチル-2-プロペニル基、1,1-ジメチル-2-プロペニル基、2-ヘキセニル基、2-メチル-2-ペンテニル基、2,4-ジメチル-2,6-ヘプタジエニル基、3,7-ジメチル-2,6-オクタジエニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b alkenyl is a linear or branched chain having a carbon number of a to b, and an unsaturated carbon having one or more double bonds in the molecule. Represents a hydrogen group. For example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-pentenyl group, 2- Methyl-2-butenyl group, 3-methyl-2-butenyl group, 2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenyl group, 2-methyl-2-pentenyl group, Specific examples include 2,4-dimethyl-2,6-heptadienyl group, 3,7-dimethyl-2,6-octadienyl group and the like, and each is selected within the range of the designated number of carbon atoms.
　本明細書におけるCa～Cbハロアルケニルとは、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa～b個よりなる直鎖または分岐鎖で、且つ、分子内に１個または２個以上の二重結合を有する不飽和炭化水素基を表す。このとき、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、または互いに異なっていてもよい。例えば2,2-ジクロロビニル基、2-フルオロ-2-プロペニル基、2-クロロ-2-プロペニル基、3-クロロ-2-プロペニル基、2-ブロモ-2-プロペニル基、3-ブロモ-2-プロペニル基、3,3-ジフルオロ-2-プロペニル基、2,3-ジクロロ-2-プロペニル基、3,3-ジクロロ-2-プロペニル基、2,3-ジブロモ-2-プロペニル基、2,3,3-トリフルオロ-2-プロペニル基、2,3,3-トリクロロ-2-プロペニル基、1-(トリフルオロメチル)エテニル基、3-クロロ-2-ブテニル基、3-ブロモ-2-ブテニル基、4,4-ジフルオロ-3-ブテニル基、3,4,4-トリフルオロ-3-ブテニル基、3-クロロ-4,4,4-トリフルオロ-2-ブテニル基、3-ブロモ-2-メチル-2-プロペニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b haloalkenyl is a straight chain or branched chain consisting of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and Represents an unsaturated hydrocarbon group having one or more double bonds in the molecule. At this time, when substituted with two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, 2,2-dichlorovinyl group, 2-fluoro-2-propenyl group, 2-chloro-2-propenyl group, 3-chloro-2-propenyl group, 2-bromo-2-propenyl group, 3-bromo-2 -Propenyl group, 3,3-difluoro-2-propenyl group, 2,3-dichloro-2-propenyl group, 3,3-dichloro-2-propenyl group, 2,3-dibromo-2-propenyl group, 2, 3,3-trifluoro-2-propenyl group, 2,3,3-trichloro-2-propenyl group, 1- (trifluoromethyl) ethenyl group, 3-chloro-2-butenyl group, 3-bromo-2- Butenyl group, 4,4-difluoro-3-butenyl group, 3,4,4-trifluoro-3-butenyl group, 3-chloro-4,4,4-trifluoro-2-butenyl group, 3-bromo- A 2-methyl-2-propenyl group or the like is given as a specific example, and is selected within the range of each designated number of carbon atoms.
　本明細書におけるCa～Cbシクロアルケニルとは、炭素原子数がa～b個よりなる環状の、且つ、１個または２個以上の二重結合を有する不飽和炭化水素基を表し、３員環から６員環までの単環または複合環構造を形成することが出来る。また、各々の環は指定の炭素原子数の範囲でアルキル基によって任意に置換されていてもよく、さらに、二重結合はendo-またはexo-のどちらの形式であってもよい。例えば2-シクロペンテン-1-イル基、3-シクロペンテン-1-イル基、2-シクロヘキセン-1-イル基、3-シクロヘキセン-1-イル基、ビシクロ[2.2.1]-5-ヘプテン-2-イル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b cycloalkenyl represents a cyclic unsaturated hydrocarbon group having 1 to 2 carbon atoms and having 1 to 2 carbon atoms. A monocyclic or complex ring structure from a member ring to a six-membered ring can be formed. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the double bond may be either endo- or exo-. For example, 2-cyclopenten-1-yl group, 3-cyclopenten-1-yl group, 2-cyclohexen-1-yl group, 3-cyclohexen-1-yl group, bicyclo [2.2.1] -5-hepten-2- Specific examples include yl groups and the like, and each is selected within the range of the designated number of carbon atoms.
　本明細書におけるCa～Cbハロシクロアルケニルとは、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa～b個よりなる環状の、且つ、１個または２個以上の二重結合を有する不飽和炭化水素基を表し、３員環から６員環までの単環または複合環構造を形成することが出来る。また、各々の環は指定の炭素原子数の範囲でアルキル基によって任意に置換されていてもよく、さらに、二重結合はendo-またはexo-のどちらの形式であってもよい。また、ハロゲン原子による置換は環構造部分であっても、側鎖部分であっても、或いはそれらの両方であってもよく、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、または互いに異なっていても良い。例えば2-クロロビシクロ[2.2.1]-5-ヘプテン-2-イル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b halocycloalkenyl refers to a cyclic one having 1 to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. Alternatively, it represents an unsaturated hydrocarbon group having two or more double bonds, and can form a monocyclic or complex ring structure having 3 to 6 members. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the double bond may be either endo- or exo-. In addition, the substitution by a halogen atom may be a ring structure part, a side chain part or both of them, and when substituted by two or more halogen atoms, those halogen atoms May be the same as or different from each other. For example, a 2-chlorobicyclo [2.2.1] -5-hepten-2-yl group and the like are given as specific examples, and each group is selected within the range of the designated number of carbon atoms.
　本明細書におけるCa～Cbアルキニルの表記は、炭素原子数がa～b個よりなる直鎖または分岐鎖で、且つ、分子内に１個または２個以上の三重結合を有する不飽和炭化水素基を表す。例えば、エチニル基、1-プロピニル基、2-プロピニル基、2-ブチニル基、1-メチル-2-プロピニル基、2-ペンチニル基、1-メチル-2-ブチニル基、1,1-ジメチル-2-プロピニル基、2-ヘキシニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b alkynyl represents a linear or branched chain consisting of a to b carbon atoms and an unsaturated carbonization having one or more triple bonds in the molecule. Represents a hydrogen group. For example, ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1,1-dimethyl-2 Specific examples include -propynyl group, 2-hexynyl group and the like, and each is selected within the range of the designated number of carbon atoms.
　本明細書におけるCa～Cbハロアルキニルとは、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa～b個よりなる直鎖または分岐鎖で、且つ、分子内に１個または２個以上の三重結合を有する不飽和炭化水素基を表す。このとき、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、または互いに異なっていても良い。例えば2-クロロエチニル基、2-ブロモエチニル基、2-ヨードエチニル基、3-クロロ-2-プロピニル基、3-ブロモ-2-プロピニル基、3-ヨード-2-プロピニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 C a -C b haloalkynyl as used herein is a straight or branched chain consisting of a to b carbon atoms, wherein a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and Represents an unsaturated hydrocarbon group having one or more triple bonds in the molecule. At this time, when substituted by two or more halogen atoms, these halogen atoms may be the same as or different from each other. Specific examples include 2-chloroethynyl group, 2-bromoethynyl group, 2-iodoethynyl group, 3-chloro-2-propynyl group, 3-bromo-2-propynyl group, 3-iodo-2-propynyl group and the like. Each of which is selected for each specified number of carbon atoms.
　Raで置換されていてもよいアリール基として、フェニル基、o-メチルフェニル基、m-メチルフェニル基、p-メチルフェニル基、o-クロルフェニル基、m-クロルフェニル基、p-クロルフェニル基、o-フルオロフェニル基、p-フルオロフェニル基、o-メトキシフェニル基、p-メトキシフェニル基、p-ニトロフェニル基、p-シアノフェニル基、α-ナフチル基、β-ナフチル基、o-ビフェニリル基、m-ビフェニリル基、p-ビフェニリル基、1-アントリル基、2-アントリル基、9-アントリル基、1-フェナントリル基、2-フェナントリル基、3-フェナントリル基、4-フェナントリル基、9-フェナントリル基、２－チエニル基、３－チエニル基、２－フリル基、３－フリル基、２－ピラニル基、３－ピラニル基、４－ピラニル基、２－ベンゾフラニル基、３－ベンゾフラニル基、４－ベンゾフラニル基、５－ベンゾフラニル基、６－ベンゾフラニル基、７－ベンゾフラニル基、１－イソベンゾフラニル基、４－イソベンゾフラニル基、５－イソベンゾフラニル基、２－ベンゾチエニル基、３－ベンゾチエニル基、４－ベンゾチエニル基、５－ベンゾチエニル基、６－ベンゾチエニル基、７－ベンゾチエニル基、１－イソベンゾチエニル基、４－イソベンゾチエニル基、５－イソベンゾチエニル基、２－クロメニル基、３－クロメニル基、４－クロメニル基、５－クロメニル基、６－クロメニル基、７－クロメニル基、８－クロメニル基、１－ピロリル基、２－ピロリル基、３－ピロリル基、１－イミダゾリル基、２－イミダゾリル基、４－イミダゾリル基、１－ピラゾリル基、３－ピラゾリル基、４－ピラゾリル基、２－チアゾリル基、４－チアゾリル基、５－チアゾリル基、３－イソチアゾリル基、４－イソチアゾリル基、５－イソチアゾリル基、２－オキサゾリル基、４－オキサゾリル基、５－オキサゾリル基、３－イソオキサゾリル基、４－イソオキサゾリル基、５－イソオキサゾリル基、２－ピリジル基、３－ピリジル基、４－ピリジル基、２－ピラジニル基、２－ピリミジニル基、４－ピリミジニル基、５－ピリミジニル基、３－ピリダジニル基、４－ピリダジニル基、１－インドリジニル基、２－インドリジニル基、３－インドリジニル基、５－インドリジニル基、６－インドリジニル基、７－インドリジニル基、８－インドリジニル基、１－イソインドリル基、４－イソインドリル基、５－イソインドリル基、１－インドリル基、２－インドリル基、３－インドリル基、４－インドリル基、５－インドリル基、６－インドリル基、７－インドリル基、１－インダゾリル基、２－インダゾリル基、３－インダゾリル基、４－インダゾリル基、５－インダゾリル基、６－インダゾリル基、７－インダゾリル基、１－プリニル基、２－プリニル基、３－プリニル基、６－プリニル基、７－プリニル基、８－プリニル基、２－キノリル基、３－キノリル基、４－キノリル基、５－キノリル基、６－キノリル基、７－キノリル基、８－キノリル基、１－イソキノリル基、３－イソキノリル基、４－イソキノリル基、５－イソキノリル基、６－イソキノリル基、７－イソキノリル基、８－イソキノリル基、１－フタラジニル基、５－フタラジニル基、６－フタラジニル基、２－ナフチリジニル基、３－ナフチリジニル基、４－ナフチリジニル基、２－キノキサリニル基、５－キノキサリニル基、６－キノキサリニル基、２－キナゾリニル基、４－キナゾリニル基、５－キナゾリニル基、６－キナゾリニル基、７－キナゾリニル基、８－キナゾリニル基、３－シンノリニル基、４－シンノリニル基、５－シンノリニル基、６－シンノリニル基、７－シンノリニル基、８－シンノリニル基、２－プテニジニル基、４－プテニジニル基、６－プテニジニル基、７－プテニジニル基及び３－フラザニル基が挙げられる。 As the aryl group optionally substituted by R a , phenyl group, o-methylphenyl group, m-methylphenyl group, p-methylphenyl group, o-chlorophenyl group, m-chlorophenyl group, p-chlorophenyl Group, o-fluorophenyl group, p-fluorophenyl group, o-methoxyphenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-cyanophenyl group, α-naphthyl group, β-naphthyl group, o- Biphenylyl group, m-biphenylyl group, p-biphenylyl group, 1-anthryl group, 2-anthryl group, 9-anthryl group, 1-phenanthryl group, 2-phenanthryl group, 3-phenanthryl group, 4-phenanthryl group, 9- Phenanthryl group, 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, 3-pyranyl group, 4-pyranyl group, 2-benzofuranyl group, 3-benzofuranyl group 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothienyl group 3-benzothienyl group, 4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group Group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5-chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group Group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, -Thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4 -Isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4 -Pyridazinyl group, 1-indolidinyl group, 2-indolidinyl group, 3-indolidinyl group, 5-indolidinyl group, 6-indolidinyl group, 7-indolidinyl group, 8-indolidinyl group, 1-isoindolyl group, 4-isoindolyl group, 5 -Isoindolyl group, 1-indolyl group, 2-India Group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, 1-indazolyl group, 2-indazolyl group, 3-indazolyl group, 4-indazolyl group, 5- Indazolyl group, 6-indazolyl group, 7-indazolyl group, 1-purinyl group, 2-purinyl group, 3-prinyl group, 6-purinyl group, 7-purinyl group, 8-purinyl group, 2-quinolyl group, 3- Quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6- Isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl group, 3-naphthyridinyl group, 4-naphthyridinyl group, 2-quinoxalinyl group, 5-quinoxalinyl group, 6-quinoxalinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6-cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-ptenidinyl group, 4-ptenidinyl group, 6-ptenidinyl group, Examples thereof include a 7-ptenidinyl group and a 3-furazanyl group.
　Raで置換されていてもよいベンジル基として、ベンジル基、o-メチルベンジル基、m-メチルベンジル基、p-メチルベンジル基、o-クロルベンジル基、m-クロルベンジル基、p-クロルベンジル基、o-フルオロベンジル基、p-フルオロベンジル基、o-メトキシベンジル基、p-メトキシベンジル基、p-ニトロベンジル基、p-シアノベンジル基が挙げられる。 As the benzyl group optionally substituted by R a , benzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, o-chlorobenzyl group, m-chlorobenzyl group, p-chlorobenzyl Group, o-fluorobenzyl group, p-fluorobenzyl group, o-methoxybenzyl group, p-methoxybenzyl group, p-nitrobenzyl group, p-cyanobenzyl group.
　本発明では、各種アルコールを基質として、触媒として多環式化合物を用い、亜硝酸化合物の存在下、酸素を用いて酸化反応を行うことができる。
　本発明において、酸化されるアルコール化合物としては、特に制限されるものではなく、各種のアルコール化合物が挙げられる。これらアルコール化合物の例としては、なかでも、メントール、４－メトキシベンジルアルコール等が好ましい。 In the present invention, various alcohols can be used as substrates, polycyclic compounds can be used as catalysts, and oxidation can be performed using oxygen in the presence of a nitrite compound.
In the present invention, the alcohol compound to be oxidized is not particularly limited, and includes various alcohol compounds. Among these alcohol compounds, menthol, 4-methoxybenzyl alcohol and the like are preferable.
　本発明に用いられる（１）で表される多環式化合物としては、例えば２－アザアダマンタン－Ｎ－オキシル(AZADO)、1－メチル－２－アザアダマンタン－Ｎ－オキシル(1-Me-AZADO)、5位および／または7位にヒドロキシ基またはフッ素原子がそれぞれ独立して置換している２－アザアダマンタン－Ｎ－オキシル化合物等が挙げられる。また、例えばAZADO、１－フルオロ－２－アザアダマンタン－Ｎ－オキシル(1-F-AZADO)、５-フルオロ－２－アザアダマンタン－Ｎ－オキシル(5-F-AZADO)、５-フルオロ－１－メチル－２－アザアダマンタン－Ｎ－オキシル(5-F-1-Me-AZADO)、５，７－ジフルオロ－１－メチル－２－アザアダマンタン－Ｎ－オキシル(5,7-F2-1-Me-AZADO)、１－メチル－２－アザアダマンタン－Ｎ－オキシル（1-Me-AZADO）、１－メチル－５-ヒドロキシ－２－アザアダマンタン－Ｎ－オキシル(1-Me-5-OH-AZADO)、５－メトキシ－１－メチル－２－アザアダマンタン－Ｎ－オキシル(5-MeO-1-Me-AZADO)、5－ヒドロキシ－２－アザアダマンタン－Ｎ－オキシル（5-OH-AZADO）、9-アザビシクロ[3.3.1]ノナンN-オキシル(ABNO)等が挙げられ、特に、例えば5-F-AZADOが好ましい。 Examples of the polycyclic compound represented by (1) used in the present invention include 2-azaadamantane-N-oxyl (AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO). And 2-azaadamantane-N-oxyl compounds in which a hydroxy group or a fluorine atom is independently substituted at the 5-position and / or the 7-position. Further, for example, AZADO, 1-fluoro-2-azaadamantane-N-oxyl (1-F-AZADO), 5-fluoro-2-azaadamantane-N-oxyl (5-F-AZADO), 5-fluoro-1 -Methyl-2-azaadamantane-N-oxyl (5-F-1-Me-AZADO), 5,7-difluoro-1-methyl-2-azaadamantane-N-oxyl (5,7-F 2 -1 -Me-AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 1-methyl-5-hydroxy-2-azaadamantane-N-oxyl (1-Me-5-OH) -AZADO), 5-methoxy-1-methyl-2-azaadamantane-N-oxyl (5-MeO-1-Me-AZADO), 5-hydroxy-2-azaadamantane-N-oxyl (5-OH-AZADO) ), 9-azabicyclo [3.3.1] nonane N-oxyl (ABNO) and the like, and for example, 5-F-AZADO is particularly preferable.
　N-OがN-OHを表す多環式化合物、すなわN-ヒドロキシ化合物としては、Ｎ－ヒドロキシ－１－フルオロ－２－アザアダマンタン (1-F-AZADOH)、Ｎ－ヒドロキシ－５-フルオロ－２－アザアダマンタン (5-F-AZADOH)、Ｎ－ヒドロキシ－５-フルオロ－１－メチル－２－アザアダマンタン (5-F-1-Me-AZADOH)、Ｎ－ヒドロキシ－５，７－ジフルオロ－１－メチル－２－アザアダマンタン (5,7-F2-1-Me-AZADOH)、Ｎ－ヒドロキシ－１－メチル－２－アザアダマンタン（1-Me-AZADOH）、Ｎ－ヒドロキシ－１－メチル－５-ヒドロキシ－２－アザアダマンタン (1-Me-5-OH-AZADOH)、Ｎ－ヒドロキシ－５－メトキシ－１－メチル－２－アザアダマンタン (5-MeO-1-Me-AZADOH)、Ｎ－ヒドロキシ－５-ヒドロキシ－２－アザアダマンタン（5-OH-AZADOH）、Ｎ－ヒドロキシ－9-アザビシクロ[3.3.1]ノナン (ABNOH)等が挙げられ、特に、例えば5-F-AZADOHが好ましい。 Polycyclic compounds in which NO represents N-OH, ie, N-hydroxy compounds include N-hydroxy-1-fluoro-2-azaadamantane (1-F-AZADOH), N-hydroxy-5-fluoro-2 -Azaadamantane (5-F-AZADOH), N-hydroxy-5-fluoro-1-methyl-2-azaadamantane (5-F-1-Me-AZADOH), N-hydroxy-5,7-difluoro-1 -Methyl-2-azaadamantane (5,7-F 2 -1-Me-AZADOH), N-hydroxy-1-methyl-2-azaadamantane (1-Me-AZADOH), N-hydroxy-1-methyl- 5-hydroxy-2-azaadamantane (1-Me-5-OH-AZADOH), N-hydroxy-5-methoxy-1-methyl-2-azaadamantane (5-MeO-1-Me-AZADOH), N- Hydroxy-5-hydroxy-2-azaadamantane (5-OH-AZADOH), N-hydroxy-9-azabicyclo [3.3.1] nonane (ABNOH), etc. In particular, for example, 5-F-AZADOH is preferable.
　N-OがN+(=O)X-を表す多環式化合物、すなわちオキソアンモニウム塩としては、例えば２－アザアダマンタン－Ｎ－オキソアンモニウム塩(AZADO＋X-)、1－メチル－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(1-Me-AZADO＋X-)、5位および／または7位にヒドロキシ基またはフッ素原子がそれぞれ独立して置換している２－アザアダマンタン－Ｎ－オキソアンモニウム塩等が挙げられ、中でも、例えばAZADO＋X-、１－フルオロ－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(1-F-AZADO＋X-)、５-フルオロ－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(5-F-AZADO＋X-)、５-フルオロ－１－メチル－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(5-F-1-Me-AZADO＋X-)、５，７－ジフルオロ－１－メチル－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(5,7-F2-1-Me-AZADO＋X-)、１－メチル－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(1-Me-AZADO＋X-)、１－メチル－５-ヒドロキシ－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(1-Me-5-OH-AZADO＋X-)、５－メトキシ－１－メチル－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(5-MeO-1-Me-AZADO＋X-)、5－ヒドロキシ－２－アザアダマンタン－Ｎ－オキソアンモニウム塩(5-OH-AZADO＋X-)、9-アザビシクロ[3.3.1]ノナン　N-オキソアンモニウム塩(ABNO＋X-)等が挙げられ、特に、例えば5-F-AZADO＋X-が好ましい。 Polycyclic compounds in which NO represents N + (═O) X − , that is, oxoammonium salts include, for example, 2-azaadamantane-N-oxoammonium salt (AZADO + X − ), 1-methyl-2-azaadamantane -N- oxo ammonium salts (1-Me-AZADO + X -), 5 -position and / or 7-position hydroxy group or a fluorine atom each independently are substituted 2-aza-adamantan -N- oxo ammonium salts Among them, for example, AZADO + X − , 1-fluoro-2-azaadamantane-N-oxoammonium salt (1-F-AZADO + X − ), 5-fluoro-2-azaadamantane-N-oxoammonium salt (5-F-AZADO + X -), 5- fluoro-1-methyl-2-aza-adamantan -N- oxo ammonium salts (-5 F-1-Me -AZADO + X -), 5,7- difluoro -1-methyl-2-azaadamantane-N Oxo ammonium salt (5,7-F 2 -1-Me -AZADO + X -), 1- methyl-2-aza-adamantan -N- oxo ammonium salts (-1 Me-AZADO + X -), 1- methyl - 5-hydroxy-2-azaadamantane-N-oxoammonium salt (1-Me-5-OH-AZADO + X − ), 5-methoxy-1-methyl-2-azaadamantane-N-oxoammonium salt (5- MeO-1-Me-AZADO + X -), 5- hydroxy-2-aza-adamantane -N- oxo ammonium salts (5-OH-AZADO + X -), 9- azabicyclo [3.3.1] nonane N- oxoammonium Salt (ABNO + X − ) and the like, and particularly, for example, 5-F-AZADO + X − is preferable.
　その場合、X-としてはF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ ‐、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-、CF3SO2O-等が挙げられるが、好ましくはCl-またはNO3-である。
　用いる多環式化合物の量は、基質のアルコールに対して好ましくは0.01モル％～50モル%、より好ましくは0.1モル%～10モル%である。 In that case, X - as the F -, Cl -, Br - , I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2) 2 N -, CH 3 CO 2 -, CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O -, CF 3 SO 2 O 2- and the like can be mentioned, and Cl-or NO 3- is preferred.
The amount of the polycyclic compound used is preferably 0.01 mol% to 50 mol%, more preferably 0.1 mol% to 10 mol%, based on the substrate alcohol.
　本発明の亜硝酸化合物としては、例えば、亜硝酸リチウム、亜硝酸ナトリウム、亜硝酸カリウム、亜硝酸カルシウム、亜硝酸バリウム、亜硝酸銀等の亜硝酸塩；亜硝酸エチル、亜硝酸イソアミル、亜硝酸イソブチル、亜硝酸ターシャリーブチル、亜硝酸ノルマルブチル、亜硝酸イソプロピル、亜硝酸ノルマルプロピル、亜硝酸アダマンチル等の亜硝酸エステル等が挙げられる。なかでも、例えば亜硝酸ナトリウム、亜硝酸ターシャリーブチルが好ましい。
　用いる亜硝酸化合物の量としては、基質のアルコールに対して１モル％ないし100モル%、好ましくは、例えば１モル%ないし50モル%である。 Examples of the nitrite compound of the present invention include nitrites such as lithium nitrite, sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite; ethyl nitrite, isoamyl nitrite, isobutyl nitrite, Nitrite esters such as tertiary butyl nitrate, normal butyl nitrite, isopropyl nitrite, normal propyl nitrite, and adamantyl nitrite. Of these, sodium nitrite and tertiary butyl nitrite are preferable.
The amount of the nitrite compound to be used is 1 mol% to 100 mol%, preferably, for example, 1 mol% to 50 mol% with respect to the substrate alcohol.
　なお、亜硝酸化合物の代わりに硝酸を用いても良い。その場合、用いる硝酸の量は、亜硝酸化合物の量に準じる。
　本発明の酸化反応は、穏和な条件で実施できることが特徴であり、反応温度としては、室温で行うこともできるが、必要により、10℃～40℃の範囲、0℃～100℃の範囲、さらには、－10℃～200℃の範囲で実施できる。また、反応圧力として、常圧（大気圧）で充分であるが、必要に応じて、０．０１～１０ＭＰａ(ゲージ圧)の範囲の減圧状態でも加圧状態でも実施できる。酸化反応は、室温で、常圧が行なうのが好ましい。
　反応時間は用いる基質であるアルコール化合物及び反応条件により必ずしも一定しないが、通常1分～100時間であり、好ましくは5分～24時間である。 Nitric acid may be used in place of the nitrous acid compound. In that case, the amount of nitric acid used is in accordance with the amount of nitrite compound.
The oxidation reaction of the present invention is characterized in that it can be carried out under mild conditions, and the reaction temperature can also be carried out at room temperature. Furthermore, it can be carried out in the range of −10 ° C. to 200 ° C. As the reaction pressure, normal pressure (atmospheric pressure) is sufficient, but the reaction can be carried out in a reduced pressure state or a pressurized state in the range of 0.01 to 10 MPa (gauge pressure) as necessary. The oxidation reaction is preferably performed at room temperature and normal pressure.
The reaction time is not necessarily constant depending on the alcohol compound as a substrate to be used and the reaction conditions, but is usually 1 minute to 100 hours, preferably 5 minutes to 24 hours.
　本発明の酸化反応では、必要に応じて溶媒が使用できる。溶媒としては、反応の進行を阻害しないものであれば制限はなく、水、アルコール類（例えばメタノール、エタノール、プロパノール、ブタノール、オクタノール等）、セロソルブ類（例えばメトキシエタノール、エトキシエタノール等）、非プロトン性極性有機溶媒類（例えばジメチルホルムアミド、ジメチルスルホキシド、ジメチルアセトアミド、テトラメチルウレア、スルホラン、Ｎ－メチルピロリドン、N,N-ジメチルイミダゾリジノン等）、エーテル類（例えばジエチルエーテル、ジイソプロピルエーテル、ｔ－ブチルメチルエーテル、テトラヒドロフラン、ジオキサン等）、脂肪族炭化水素類（例えばペンタン、ヘキサン、ｃ－ヘキサン、オクタン、デカン、デカリン、石油エーテル等）、芳香族炭化水素類（ベンゼン、クロロベンゼン、ｏ－ジクロロベンゼン、ニトロベンゼン、トルエン、キシレン、メシチレン、テトラリン等）、ハロゲン化炭化水素類（例えばクロロホルム、ジクロロメタン、ジクロロエタン、四塩化炭素等）、ケトン類（アセトン、メチルエチルケトン、メチルブチルケトン、メチルイソブチルケトン等）、低級脂肪族酸エステル（例えば酢酸メチル、酢酸エチル、酢酸ブチル、プロピオン酸メチル等）、アルコキシアルカン類（例えばジメトキシエタン、ジエトキシエタン等）及びニトリル類（例えばアセトニトリル、プロピオニトリル、ブチロニトリル等）、カルボン酸（酢酸等）等の溶媒が挙げられる。その中でも、例えば、ジクロロメタンおよび酢酸が好ましい。また、基質のアルコールを溶媒として用いることもできる。 In the oxidation reaction of the present invention, a solvent can be used as necessary. The solvent is not limited as long as it does not inhibit the progress of the reaction, and is water, alcohols (for example, methanol, ethanol, propanol, butanol, octanol, etc.), cellosolves (for example, methoxyethanol, ethoxyethanol, etc.), aprotic Polar organic solvents (eg, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, tetramethylurea, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, etc.), ethers (eg, diethyl ether, diisopropyl ether, t- Butyl methyl ether, tetrahydrofuran, dioxane, etc.), aliphatic hydrocarbons (eg pentane, hexane, c-hexane, octane, decane, decalin, petroleum ether, etc.), aromatic hydrocarbons (benzene, chloroben) Zen, o-dichlorobenzene, nitrobenzene, toluene, xylene, mesitylene, tetralin, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.), ketones (acetone, methyl ethyl ketone, methyl butyl ketone, methyl) Isobutyl ketone etc.), lower aliphatic acid esters (eg methyl acetate, ethyl acetate, butyl acetate, methyl propionate etc.), alkoxyalkanes (eg dimethoxyethane, diethoxyethane etc.) and nitriles (eg acetonitrile, propionitrile) , Butyronitrile, etc.) and carboxylic acids (acetic acid etc.). Among these, for example, dichloromethane and acetic acid are preferable. Further, the substrate alcohol may be used as a solvent.
　溶媒として、あるいは添加物として酢酸を用いると、酸化反応が進行し難い、アミノ置換基を有するアルコールを基質として用いることもできる。
　基質であるアルコール化合物の溶媒中の濃度は、アルコールを溶媒として用いる場合以外は、好ましくは１～９９質量％であり、５～５０質量％がより好ましい。
　本発明において、酸化剤となる酸素としては、酸素ガス（１００％の酸素）だけでなく、空気を用いることができる。 When acetic acid is used as a solvent or an additive, an alcohol having an amino substituent, which does not easily undergo an oxidation reaction, can be used as a substrate.
The concentration of the alcohol compound as a substrate in the solvent is preferably 1 to 99% by mass, and more preferably 5 to 50% by mass except when alcohol is used as the solvent.
In the present invention, not only oxygen gas (100% oxygen) but also air can be used as oxygen as an oxidizing agent.
　本発明において、基質であるアルコールの消失と、アルデヒド体、ケトン体またはカルボン酸の生成を確認したあと、溶媒の留去、抽出、再結晶、濾過、デカント、カラムクロマトグラフィー等の通常の精製操作により、目的とするアルデヒド、ケトンまたはカルボン酸化合物を単離することができる。 In the present invention, after confirming the disappearance of the alcohol as a substrate and the formation of an aldehyde, ketone or carboxylic acid, ordinary purification operations such as solvent distillation, extraction, recrystallization, filtration, decantation, column chromatography, etc. The target aldehyde, ketone or carboxylic acid compound can be isolated.
　本発明で用いる多環式化合物の製造方法を以下の反応式で示すが、各製造方法の詳細及び具体例は、後述の実施例中で説明される。
　例えば、1-Me-AZADOは、国際特許出願公開WO2006/001387A1パンフレット記載の方法で製造することができる。
　5-F-1-Me-AZADOは、下記のスキームで表される方法により製造することができる。なお、1-メチル-N-ベンジルオキシカルボニル-2-アザアダマンタン6は、国際特許出願公開WO2006/001387A1パンフレットに従って製造することができる。 The production method of the polycyclic compound used in the present invention is shown by the following reaction formula, and details and specific examples of each production method will be described in Examples described later.
For example, 1-Me-AZADO can be produced by the method described in International Patent Application Publication WO2006 / 001387A1 pamphlet.
5-F-1-Me-AZADO can be produced by the method represented by the following scheme. 1-Methyl-N-benzyloxycarbonyl-2-azaadamantane 6 can be produced according to International Patent Application Publication WO2006 / 001387A1 pamphlet.
Figure JPOXMLDOC01-appb-C000009
 　5,7-F2-1-Me-AZADOは、下記のスキームで表される方法で製造することができる。
Figure JPOXMLDOC01-appb-C000009
 5,7-F 2 -1-Me-AZADO can be produced by the method represented by the following scheme.
Figure JPOXMLDOC01-appb-C000010
 　5-MeO-1-Me-AZADOは、下記のスキームで表される方法で製造することができる。
Figure JPOXMLDOC01-appb-C000010
 5-MeO-1-Me-AZADO can be produced by the method represented by the following scheme.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
 　5-F-AZADOは、下記のスキームで表される方法で製造することができる。なお、式（19）で表されるカルボン酸化合物は、例えばJ. Org. Chem., Vol. 39, No. 26, p3822 (1974)に準じた方法で製造することができる。
Figure JPOXMLDOC01-appb-C000012
 5-F-AZADO can be produced by the method represented by the following scheme. The carboxylic acid compound represented by the formula (19) can be produced by a method according to, for example, J. Org. Chem., Vol. 39, No. 26, p3822 (1974).
Figure JPOXMLDOC01-appb-C000013
 　1-F-AZADOは、下記のスキームで表される方法で製造することができる。なお、１－ヒドロキシ－Ｎ－ベンジルオキシカルボニル－２－アザアダマンタン31は、J.Am.Chem.Soc.,2006,128,p8412-8413の記載に従って製造することができる
Figure JPOXMLDOC01-appb-C000013
 1-F-AZADO can be produced by a method represented by the following scheme. 1-hydroxy-N-benzyloxycarbonyl-2-azaadamantane 31 can be produced according to the description in J. Am. Chem. Soc., 2006, 128, p8412-8413.
Figure JPOXMLDOC01-appb-C000014
 　なお、ABNOについては、J.Am.Chem.Soc.,(1973) 95(19) p6395-6400に製造方法の記載がある。
Figure JPOXMLDOC01-appb-C000014
 ABNO is described in J. Am. Chem. Soc., (1973) 95 (19) p6395-6400.
　亜硝酸化合物のうち市販されていないものについては、Synthesis, 2004, 11, 1747-1749に従って製造することができる。 Non-commercial nitrous acid compounds can be produced according to Synthesis, 2004, 11, 1747-1749.
　本発明のオキソアンモニウム硝酸塩は、上記のようにして得られた下記式（２）で表されるN-オキシル化合物又は下記式（３）で表されるN-ヒドロキシ化合物を、NO2（二酸化窒素）、N2O4（四酸化二窒素）又は亜硝酸化合物と反応させることにより製造することができる。 The oxoammonium nitrate of the present invention comprises N 2 -oxyl compound represented by the following formula (2) or N-hydroxy compound represented by the following formula (3) obtained as described above, and NO 2 (nitrogen dioxide). ), N 2 O 4 (dinitrogen tetroxide) or a nitrous acid compound.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　本発明のオキソアンモニウム硝酸塩の製造方法としては、例えば、式（２）で表されるN-オキシル化合物を溶媒中でNO2又はN2O4ガスと反応させる方法が挙げられる。
　例えば、式（２）で表されるN-オキシル化合物のジエチルエーテル溶液に、室温でNO2ガスを吹き込んで反応させる、といった方法で行うことができる。
　また、式（２）で表される化合物を、前記のアルコール酸化と同じ条件下で、基質のアルコールが存在しない状態で反応させても、本発明のオキソアンモニウム硝酸塩を得ることができる。 Examples of the method for producing oxoammonium nitrate of the present invention include a method in which an N-oxyl compound represented by the formula (2) is reacted with NO 2 or N 2 O 4 gas in a solvent.
For example, it can be carried out by a method in which NO 2 gas is blown into a diethyl ether solution of the N-oxyl compound represented by the formula (2) and reacted at room temperature.
Also, the oxoammonium nitrate of the present invention can be obtained by reacting the compound represented by the formula (2) under the same conditions as in the above-mentioned alcohol oxidation in the absence of the substrate alcohol.
　以下、実施例に基づき、本発明を更に詳細に説明するが、本発明はこれらの実施例により限定して解釈されるものではない。
　なお、実施例では、各化合物は以下のように化学式、若しくは略号で表記した。 EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is limited and interpreted by these Examples.
In the examples, each compound was represented by the chemical formula or abbreviation as follows.
　水：Ｈ２Ｏ、メタノール：ＭｅＯＨ、パラジウム／炭素：Ｐｄ／Ｃ、水素ガス：Ｈ２、炭酸水素ナトリウム：ＮａＨＣＯ３、クロロホルム：ＣＨＣｌ３、炭酸カリウム：Ｋ２ＣＯ３、ジクロロメタン：ＣＨ２Ｃｌ２、酢酸エチル：ＡｃＯＥｔ、硫酸マグネシウム：ＭｇＳＯ４、四塩化炭素：ＣＣｌ４、アセトニトリル：ＭｅＣＮ、過ヨウ素酸ナトリウム：ＮａＩＯ４、三塩化ルテニウム：ＲｕＣｌ３、チオ硫酸ナトリウム：Ｎａ２Ｓ２Ｏ３、ジエチルエーテル：Ｅｔ２Ｏ、エタノール：ＥｔＯＨ、水酸化ナトリウム：ＮａＯＨ、水素化ナトリウム：ＮａＨ、ジメチル硫酸：Ｍｅ２ＳＯ４、タングステン酸ナトリウム・二水和物：Ｎａ２ＷＯ４／２Ｈ２Ｏ。 Water: H 2 O, methanol: MeOH, palladium / carbon: Pd / C, hydrogen gas: H 2 , sodium bicarbonate: NaHCO 3 , chloroform: CHCl 3 , potassium carbonate: K 2 CO 3 , dichloromethane: CH 2 Cl 2 , Ethyl acetate: AcOEt, magnesium sulfate: MgSO 4 , carbon tetrachloride: CCl 4 , acetonitrile: MeCN, sodium periodate: NaIO 4 , ruthenium trichloride: RuCl 3 , sodium thiosulfate: Na 2 S 2 O 3 , diethyl Ether: Et 2 O, ethanol: EtOH, sodium hydroxide: NaOH, sodium hydride: NaH, dimethyl sulfate: Me 2 SO 4 , sodium tungstate dihydrate: Na 2 WO 4 / 2H 2 O.
　また、各化合物の同定に用いた分析方法の略号は、以下の通りである。
ＩＲ：赤外線吸収分析法、ＮＭＲ：核磁気共鳴分析法、ＭＳ：質量分析法、
ＨＲＭＳ（ＥＩ）：高分解能質量分析法（電子イオン化）、Ａｎａｌ：元素分析法。 Abbreviations of analysis methods used for identification of each compound are as follows.
IR: infrared absorption analysis, NMR: nuclear magnetic resonance analysis, MS: mass spectrometry,
HRMS (EI): high resolution mass spectrometry (electron ionization), Anal: elemental analysis.
　実施例１：触媒の製造
　1-メチル-N-トリフルオロアセチル-2-アザアダマンタン(7)の製造
　国際特許出願公開WO2006/001387A1パンフレットに従って製造した1-メチル-N-ベンジルオキシカルボニル-2-アザアダマンタン6 (1.89 g, 6.61 mmol) のMeOH (0.1 M, 66 mL) 溶液に、Pd が５質量% のPd/C (189 mg) を加え、H2気流下2時間攪拌した。反応溶液をセライト（セライト・コーポレーション社製の登録商標）でろ過し、減圧下溶媒を除去した。残渣に飽和NaHCO3 水溶液 を加え、CHCl3で抽出した。有機層をK2CO3で乾燥後、減圧下溶媒を留去し、粗アミン化合物(1 g) を得た。該アミン化合物化合物は精製することなく、次反応に用いた。粗アミン化合物(1 g) のCH2Cl2 (0.2 M，33 mL) 溶液に、氷冷下、トリフルオロ酢酸無水物(1.4 mL, 9.91 mmol) を滴下し、室温に昇温し2時間攪拌した。その後、H2Oを加え、AcOEtにより抽出し、飽和食塩水により洗浄し、MgSO4で乾燥した後、減圧下溶媒を留去した。残渣はシリカゲルカラムクロマトグラフィーにより処理しAcOEt-ヘキサン (1：30 v/v) の流分として1-メチル-N-トリフルオロアセチル-2-アザアダマンタン7 (1.25 g, 5.04 mmol, 収率76%（以下、同様である。）） を無色固体として得た。 Example 1: Production of catalyst Production of 1-methyl-N-trifluoroacetyl-2-azaadamantane (7) 1-methyl-N-benzyloxycarbonyl-2-aza produced according to International Patent Application Publication WO2006 / 001387A1 Pamphlet Pd / C (189 mg) containing 5% by mass of Pd was added to a solution of adamantane 6 (1.89 g, 6.61 mmol) in MeOH (0.1 M, 66 mL), and the mixture was stirred for 2 hours under H 2 stream. The reaction solution was filtered through Celite (registered trademark manufactured by Celite Corporation), and the solvent was removed under reduced pressure. A saturated aqueous NaHCO 3 solution was added to the residue, and the mixture was extracted with CHCl 3 . After drying the organic layer with K 2 CO 3 , the solvent was distilled off under reduced pressure to obtain a crude amine compound (1 g). The amine compound was used for the next reaction without purification. To a solution of the crude amine compound (1 g) in CH 2 Cl 2 (0.2 M, 33 mL) was added dropwise trifluoroacetic anhydride (1.4 mL, 9.91 mmol) under ice cooling, and the mixture was warmed to room temperature and stirred for 2 hours. did. Thereafter, H 2 O was added, extracted with AcOEt, washed with saturated brine, dried over MgSO 4 , and then the solvent was distilled off under reduced pressure. The residue was processed by silica gel column chromatography, and 1-methyl-N-trifluoroacetyl-2-azaadamantane 7 (1.25 g, 5.04 mmol, 76% yield) was obtained as a fraction of AcOEt-hexane (1:30 v / v). (The same applies hereinafter.)) As a colorless solid.
　無色固体の一部をとり、ヘキサンにより再結晶し無色柱状晶を得た。mp 42 ℃，
IR（neat）：ν ＝1693 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.18（br., 1H）, 2.12（br., 2H）, 2.03（br. d, J＝11 Hz, 2H）, 1.89（m, 3H）, 1.85-1.70（m, 3H）, 1.63（s, 3H）, 1.58（br. d, J＝12 .6 Hz, 2H）．13C-NMR（100 MHz, CDCl3）：δ ＝156.1（q, J＝33.7 Hz），116.9（q, J＝292.1 Hz），57.6，50.6（q, J＝4.1 Hz），43.7，35.9，34.4，29.4，26.5 ．
MS m/z: 247 (M+), 190 (100%)．HRMS: Calcd. for C12H16F3NO 247.1184 (M+), Found.: 247.1174． A part of the colorless solid was taken and recrystallized from hexane to obtain colorless columnar crystals. mp 42 ° C,
IR (neat): ν = 1693 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.18 (br., 1H), 2.12 (br., 2H), 2.03 (br. D, J = 11 Hz, 2H), 1.89 (m, 3H) , 1.85-1.70 (m, 3H), 1.63 (s, 3H), 1.58 (br. D, J = 12.6 Hz, 2H). 13 C-NMR (100 MHz, CDCl 3 ): δ = 156.1 (q, J = 33.7 Hz), 116.9 (q, J = 292.1 Hz), 57.6, 50.6 (q, J = 4.1 Hz), 43.7, 35.9, 34.4, 29.4, 26.5.
MS m / z: 247 (M + ), 190 (100%). HRMS: Calcd. For C 12 H 16 F 3 NO 247.1184 (M + ), Found .: 247.1174.
　5-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン(8)及び5, 7-ジヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン(9)の製造
　1-メチル-N-トリフルオロアセチル-2-アザアダマンタン7 (2.271 g, 9.19 mmol) のCCl4-MeCN-H2O (1.65 M; 5.6 mL-1.1 M; 8.4 mL-1.1 M；8.4 mL) 溶液に、NaIO4 (4.52 g，21.1 mmol) 、及びRuCl3 (95 mg，0.460 mmol) を順次加え、60 ℃で9時間激しく攪拌した。その後、飽和NaHCO3 水溶液、及びNa2S2O3水溶液を順次加え、AcOEtにより抽出した。有機層をMgSO4で乾燥した後、減圧下溶媒を留去した。残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン(1：2 v/v) の流分として、白色固体の5-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン8 (1.29 g, 4.87 mmol, 53％) を得た。また同時に、白色固体の5,7-ジヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン9 (340 mg，1.195 mmol，13％) と原料 7 (350 mg, 1.38 mmol, 15％) を得た。 Preparation of 5-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane (8) and 5,7-dihydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane (9) 1-methyl To a solution of -N-trifluoroacetyl-2-azaadamantane 7 (2.271 g, 9.19 mmol) in CCl 4 -MeCN-H 2 O (1.65 M; 5.6 mL-1.1 M; 8.4 mL-1.1 M; 8.4 mL) NaIO 4 (4.52 g, 21.1 mmol) and RuCl 3 (95 mg, 0.460 mmol) were sequentially added, and the mixture was vigorously stirred at 60 ° C. for 9 hours. Thereafter, a saturated NaHCO 3 aqueous solution and a Na 2 S 2 O 3 aqueous solution were sequentially added, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO 4 and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and the white solid 5-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane 8 (1.29) was obtained as a fraction of AcOEt-hexane (1: 2 v / v). g, 4.87 mmol, 53%). At the same time, white solid 5,7-dihydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane 9 (340 mg, 1.195 mmol, 13%) and raw material 7 (350 mg, 1.38 mmol, 15%) Got.
　8の一部をとり，ヘキサンにより再結晶し無色柱状晶を得た。mp 91 ℃，
IR（neat）：ν ＝3428，1692 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.37（br., 1H）, 2.38（br., 1H）, 1.95（br. d, J＝12.5 Hz, 2H）, 1.9-1.7（m, 5H）, 1.69（s, 3H）, 1.63（br. d, J＝13.0 Hz, 1H）, 1.57（br. d, J＝12.1 Hz, 1H）, 1.48（br. d, J＝13.0 Hz, 1H）．13C-NMR（100 MHz, CDCl3）：δ ＝156.1（q, J＝34.6 Hz），116.7（q, J＝291.3 Hz），66.71，66.66，52.3（q, J＝4.9 Hz），51.3，43.3，42.4，34.6，29.0，28.8 ．
MS m/z: 263 (M+), 206 (100%)．HRMS: Calcd. for C12H16F3NO2 263.1133 (M+), Found.: 263.1118．
　９の一部をとり，CHCl3により再結晶し白色針状晶を得た。mp 186 ℃，
IR（neat）：ν ＝3265，1677 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.49（br., 1H）, 1.91（br. d, J＝12.1 Hz, 2H）, 1.88-1.70（m, 8H）, 1.59（s, 3H）, 1.55（br. d, J＝12.1 Hz, 2H）．13C-NMR（100 MHz, CDCl3）：δ ＝157.3（q, J＝33.7 Hz），118.1（q, J＝291.4 Hz），69.2，62.5．54.0（q, J＝4.1 Hz），51.0，50.6，43.0，28.8 ．
MS m/z: 279(M+), 206 (100%)．HRMS: Calcd. for C12H16F3NO3 279.1082 (M+), Found.: 279.1107． A portion of 8 was taken and recrystallized with hexane to obtain colorless columnar crystals. mp 91 ℃,
IR (neat): ν = 3428, 1692 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.37 (br., 1H), 2.38 (br., 1H), 1.95 (br. D, J = 12.5 Hz, 2H), 1.9-1.7 (m, 5H), 1.69 (s, 3H), 1.63 (br. D, J = 13.0 Hz, 1H), 1.57 (br. D, J = 12.1 Hz, 1H), 1.48 (br. D, J = 13.0 Hz, 1H) ). 13 C-NMR (100 MHz, CDCl 3 ): δ = 156.1 (q, J = 34.6 Hz), 116.7 (q, J = 291.3 Hz), 66.71, 66.66, 52.3 (q, J = 4.9 Hz), 51.3, 43.3, 42.4, 34.6, 29.0, 28.8.
MS m / z: 263 (M + ), 206 (100%). HRMS: Calcd. For C 12 H 16 F 3 NO 2 263.1133 (M + ), Found .: 263.1118.
A portion of 9 was taken and recrystallized with CHCl 3 to obtain white needle crystals. mp 186 ° C,
IR (neat): ν = 3265, 1677 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.49 (br., 1H), 1.91 (br. D, J = 12.1 Hz, 2H), 1.88-1.70 (m, 8H), 1.59 (s, 3H ), 1.55 (br. D, J = 12.1 Hz, 2H). 13 C-NMR (100 MHz, CDCl 3 ): δ = 157.3 (q, J = 33.7 Hz), 118.1 (q, J = 291.4 Hz), 69.2, 62.5.54.0 (q, J = 4.1 Hz), 51.0, 50.6, 43.0, 28.8.
MS m / z: 279 (M + ), 206 (100%). HRMS: Calcd. For C 12 H 16 F 3 NO 3 279.1082 (M + ), Found .: 279.1107.
　5-フルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン(10)の製造
　5-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン8 (184 mg，0.69 mmol) のCH2Cl2 (1.43 M，0.5 mL) 溶液に-78℃下、（ジエチルアミノ）サルファートリフルオリド（三フッ化N,N－ジエチルアミノ硫黄）（以下、DASTと記すこともある）(0.46 mL, 3.5 mmol) を加え、徐々に昇温し０℃で1時間攪拌した。その後Et2Oで希釈した後H2Oを加えて、AcOEtにより抽出し、有機層をH2Oにより洗浄し、MgSO4で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン (1：30 v/v) の流分として、無色固体の5-フルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 10 (183 mg, 定量的) を得た。 Preparation of 5-fluoro-1-methyl-N-trifluoroacetyl-2-azaadamantane (10) 5-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane 8 (184 mg, 0.69 mmol) (Diethylamino) sulfur trifluoride (N, N-diethylaminosulfur trifluoride) (hereinafter sometimes referred to as DAST) at −78 ° C. in a CH 2 Cl 2 (1.43 M, 0.5 mL) solution (0.46 mL, 3.5 mmol) was added, the temperature was gradually raised, and the mixture was stirred at 0 ° C for 1 hour. After dilution with Et 2 O, H 2 O was added and extracted with AcOEt. The organic layer was washed with H 2 O and dried over MgSO 4 . Thereafter, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography. Fluoroacetyl-2-azaadamantane 10 (183 mg, quantitative) was obtained.
　１０の一部をとり、ヘキサンにより再結晶し無色柱状晶を得た。mp 48 ℃，
IR（neat）：ν ＝1698 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.45（br., 1H）, 2.46（br., 1H）, 2.14-2.10（m, 1H）, 2.01-1.95（m, 5H）, 1.94-1.65（m, 6H）,1.56-1.50（m, 1H）．13C-NMR（100 MHz, CDCl3）：δ ＝156.1（q, J＝34.4 Hz）, 116.6（q, J＝290.6 Hz）, 89.8（d, J＝186.8 Hz）, 61.3（d, J＝10.7 Hz）, 52.7（m）, 48.6（d, J＝18.0 Hz）, 42.1（d, J＝1.6 Hz）, 41.1（d, J＝18.8 Hz）, 39.9（d, J＝18.0 Hz）, 34.4（d, J＝1.6 Hz）, 29.6（d, J＝9.0 Hz）, 28.6.
MS m/z: 265 (M+), 190 (100%)．HRMS: Calcd. for C12H15F4NO 265.1090 (M+), Found.: 265.1068． A portion of 10 was taken and recrystallized with hexane to obtain colorless columnar crystals. mp 48 ℃,
IR (neat): ν = 1698 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.45 (br., 1H), 2.46 (br., 1H), 2.14-2.10 (m, 1H), 2.01-1.95 (m, 5H), 1.94- 1.65 (m, 6H), 1.56-1.50 (m, 1H). 13 C-NMR (100 MHz, CDCl 3 ): δ = 156.1 (q, J = 34.4 Hz), 116.6 (q, J = 290.6 Hz), 89.8 (d, J = 186.8 Hz), 61.3 (d, J = 10.7 Hz), 52.7 (m), 48.6 (d, J = 18.0 Hz), 42.1 (d, J = 1.6 Hz), 41.1 (d, J = 18.8 Hz), 39.9 (d, J = 18.0 Hz), 34.4 (D, J = 1.6 Hz), 29.6 (d, J = 9.0 Hz), 28.6.
MS m / z: 265 (M + ), 190 (100%). HRMS: Calcd. For C 12 H 15 F 4 NO 265.1090 (M + ), Found .: 265.1068.
　5フルオロ-1-メチル-2-アザアダマンタン-N-オキシル (11)の製造
　5-フルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 10 (270 mg, 1.02 mmol) のEtOH (6 mL) 溶液にNaOH水溶液 (10質量%溶液, 3 mL) を加えて2時間攪拌した。その後、CHCl3により抽出し、K2CO3で乾燥した後、減圧下溶媒を留去し、粗5-フルオロ-1-メチル-2-アザアダマンタン (165 mg) を得た。本化合物は精製することなく、次反応に用いた。 Preparation of 5-fluoro-1-methyl-2-azaadamantane-N-oxyl (11) 5-fluoro-1-methyl-N-trifluoroacetyl-2-azaadamantane 10 (270 mg, 1.02 mmol) of EtOH (6 To the solution, an aqueous NaOH solution (10 mass% solution, 3 mL) was added and stirred for 2 hours. Thereafter, extraction with CHCl 3 and drying with K 2 CO 3 were performed, and then the solvent was distilled off under reduced pressure to obtain crude 5-fluoro-1-methyl-2-azaadamantane (165 mg). This compound was used in the next reaction without purification.
　粗5-フルオロ-1-メチル-2-アザアダマンタン (165 mg) のMeOH (0.5 M，2 mL) 溶液に、氷冷下ウレアハイドロゲンパーオキシド（以下、UHPと記すこともある）（365 mg, 3.88 mmol）、及びNa2WO4・2H2O（160 mg, 0.485 mmol）を順次加え、室温にて1.5時間攪拌した。その後H2Oを加え、減圧下で溶媒を留去し、残渣はCHCl3により抽出し、K2CO3で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン（1：7 v/v）の流分として黄色針状の5-フルオロ-1-メチル- 2-アザアダマンタン-N-オキシル 11（106 mg, 0.579 mmol, ２工程通しでの収率57％ （for 2 steps））を得た。
IR（neat）：ν ＝1215 cm-1
MS m/z: 184 (M+), 111 (100%)．HRMS: Calcd. for C10H15FNO 184.1138 (M+), Found.: 184.11
26．Anal. Calcd. C11H18NO2：C, 65.19；H, 8.21；N, 7.60. Found：C, 65.27；H, 8.09；N, 7.33. To a solution of crude 5-fluoro-1-methyl-2-azaadamantane (165 mg) in MeOH (0.5 M, 2 mL) under cooling with ice, urea hydrogen peroxide (hereinafter sometimes referred to as UHP) (365 mg, 3.88 mmol) and Na 2 WO 4 · 2H 2 O (160 mg, 0.485 mmol) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. Then H 2 O was added, the solvent was distilled off under reduced pressure, the residue is extracted with CHCl 3, and dried over K 2 CO 3. Thereafter, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography. As a fraction of AcOEt-hexane (1: 7 v / v), yellow needle-shaped 5-fluoro-1-methyl-2-aza Adamantane-N-oxyl 11 (106 mg, 0.579 mmol, 57% yield over 2 steps (for 2 steps)) was obtained.
IR (neat): ν = 1215 cm -1
MS m / z: 184 (M + ), 111 (100%). HRMS: Calcd. For C 10 H 15 FNO 184.1138 (M + ), Found .: 184.11
26. Anal. Calcd. C 11 H 18 NO 2 : C, 65.19; H, 8.21; N, 7.60. Found: C, 65.27; H, 8.09; N, 7.33.
　5-フルオロ-7-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン (12)の製造
　5-フルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 10 (186 mg, 0.70 mmol) のCCl4-MeCN-H2O (1.65 M; 0.42 mL-1.1 M; 0.64 mL-1.1 M；0.64 mL) 溶液に、NaIO4 (344 mg，1.61 mmol)、及びRuCl3H2O(14.5 mg，0.07 mmol) を順次加え、70 ℃で2日激しく攪拌した。その後、飽和NaHCO3 水溶液、及びNa2S2O3水溶液を順次加え、AcOEtにより抽出した。有機層をMgSO4で乾燥した。その後、減圧下溶媒を留去した。残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－Hexane (1：2 v/v) の流分として5-フルオロ-7-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 12 (26 mg, 0.092 mmol, 13％)と原料 (134 mg, 1.38 mmol, 72％) を得た。
IR (neat) :ν= 3415, 1701 cm-1
13C-NMR (150 MHz, CDCl3) :  δ = 156.2 (q, J = 34.4 Hz), 116.4 (q, J = 290.0 Hz), 90.8 (d, J =189.2 Hz), 69.44 (d, J =11.5 Hz), 61.49 (d, J =11.5 Hz), 52.17 (m), 50.6, 47.86 (d, J =17.2 Hz), 47.37 (d, J = 18.0 Hz), 42.15 (d, J = 1.7 Hz), 40.00 (d, J = 19.7 Hz), 28.11.
MS : m/z = 281 (M+), 206 (100%). HRMS Calcd. for C12H15F4NO2 (M+) : 281. 1039, Found. : 281.034. Preparation of 5-fluoro-7-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane (12) 5-fluoro-1-methyl-N-trifluoroacetyl-2-azaadamantane 10 (186 mg, 0.70 mmol) of CCl 4 -MeCN-H 2 O (1.65 M; 0.42 mL-1.1 M; 0.64 mL-1.1 M; 0.64 mL) in solution, NaIO 4 (344 mg, 1.61 mmol), and RuCl 3 H 2 O (14.5 mg, 0.07 mmol) was sequentially added, and the mixture was vigorously stirred at 70 ° C. for 2 days. Thereafter, a saturated NaHCO 3 aqueous solution and a Na 2 S 2 O 3 aqueous solution were sequentially added, and the mixture was extracted with AcOEt. The organic layer was dried with MgSO 4 . Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 5-fluoro-7-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane 12 (26) as AcOEt-Hexane (1: 2 v / v) fraction. mg, 0.092 mmol, 13%) and the raw material (134 mg, 1.38 mmol, 72%).
IR (neat): ν = 3415, 1701 cm -1
13 C-NMR (150 MHz, CDCl 3 ): δ = 156.2 (q, J = 34.4 Hz), 116.4 (q, J = 290.0 Hz), 90.8 (d, J = 189.2 Hz), 69.44 (d, J = 11.5 Hz), 61.49 (d, J = 11.5 Hz), 52.17 (m), 50.6, 47.86 (d, J = 17.2 Hz), 47.37 (d, J = 18.0 Hz), 42.15 (d, J = 1.7 Hz) , 40.00 (d, J = 19.7 Hz), 28.11.
MS: m / z = 281 (M + ), 206 (100%). HRMS Calcd.for C 12 H 15 F 4 NO 2 (M + ): 281. 1039, Found .: 281.034.
　5,7-ジフルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン (13)の製造
　5-フルオロ-7-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 12 (26 mg，0.092 mmol) のCH2Cl2 (1.43 M，0.064 mL) 溶液に-78℃下、DAST (0.061 mL, 0.46 mmol) を加え、徐々に昇温し０℃で1時間攪拌した。その後、Et2Oで希釈した後H2Oを加えて、AcOEtにより抽出し、次いでH2Oにより有機層を洗浄し、MgSO4で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－Hexane (1：3 v/v) の流分として、5,7-ジフルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 13 (14 mg, 0.049 mmol, 54%) を得た。
IR (neat) :ν= 1698 cm-1
MS : m/z = 283 (M+), 208 (100%). HRMS Calcd. for C12H14F5NO2 (M+) : 283. 0996, Found. : 283.0993.．  Preparation of 5,7-difluoro-1-methyl-N-trifluoroacetyl-2-azaadamantane (13) 5-fluoro-7-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane 12 (26 DAST (0.061 mL, 0.46 mmol) was added to a solution of mg, 0.092 mmol) in CH 2 Cl 2 (1.43 M, 0.064 mL) at −78 ° C., the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. Then, after diluting with Et 2 O, H 2 O was added and extracted with AcOEt, and then the organic layer was washed with H 2 O and dried over MgSO 4 . Thereafter, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography. As a fraction of AcOEt-Hexane (1: 3 v / v), 5,7-difluoro-1-methyl-N-trifluoro Acetyl-2-azaadamantane 13 (14 mg, 0.049 mmol, 54%) was obtained.
IR (neat): ν = 1698 cm -1
MS: m / z = 283 (M + ), 208 (100%). HRMS Calcd. For C 12 H 14 F 5 NO 2 (M + ): 283. 0996, Found .: 283.0993.
　5,7-ジフルオロ-1-メチル-2-アザアダマンタン-N-オキシル (14)の製造
　5,7-ジフルオロ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン 13 (20 mg, 0.071 mmol) のEtOH (0.42 mL) 溶液にNaOH 水溶液(10質量%溶液, 0.21 mL) を加えて3時間攪拌した。その後、CHCl3により抽出し、K2CO3で乾燥した後、減圧下溶媒を留去し、粗5,7-ジフルオロ-1-メチル- 2-アザアダマンタン (11 mg) を得た。本化合物は精製することなく、次反応に用いた。 Preparation of 5,7-difluoro-1-methyl-2-azaadamantane-N-oxyl (14) 5,7-difluoro-1-methyl-N-trifluoroacetyl-2-azaadamantane 13 (20 mg, 0.071 mmol ) In EtOH (0.42 mL) was added NaOH aqueous solution (10 mass% solution, 0.21 mL) and stirred for 3 hours. Thereafter, extraction with CHCl 3 and drying with K 2 CO 3 were performed, and then the solvent was distilled off under reduced pressure to obtain crude 5,7-difluoro-1-methyl-2-azaadamantane (11 mg). This compound was used in the next reaction without purification.
　粗5,7-ジフルオロ-1-メチル- 2-アザアダマンタン (11 mg) のMeOH (0.24 M，0.24 mL) 溶液に、氷冷下UHP（22 mg, 0.24 mmol）、及びNa2WO4・2H2O（9.7 mg, 0.029 mmol）を順次加え、室温にて3時間攪拌した。その後H2Oを加え、減圧下溶媒を留去し、残渣はCHCl3により抽出し、K2CO3で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン（1：2 v/v）の流分として5,7-ジフルオロ-1-メチル- 2-アザアダマンタン-N-オキシル 14（3.5 mg, 0.017 mmol, ２工程通しでの収率29％（for 2 steps））を黄色固体として得た。
IR :ν= 1443, 1143 cm-1
　MS : m/z = 281 (M+), 206 (100%). HRMS Calcd. for C10H14F2NO (M+) : 202. 1043, Found. : 202.1043. To a solution of crude 5,7-difluoro-1-methyl-2-azaadamantane (11 mg) in MeOH (0.24 M, 0.24 mL), ice-cooled UHP (22 mg, 0.24 mmol), and Na 2 WO 4 · 2H 2 O (9.7 mg, 0.029 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. Then H 2 O was added, the solvent was evaporated under reduced pressure, the residue is extracted with CHCl 3, and dried over K 2 CO 3. Thereafter, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography. As a fraction of AcOEt-hexane (1: 2 v / v), 5,7-difluoro-1-methyl-2-azaadamantane- N-oxyl 14 (3.5 mg, 0.017 mmol, 29% yield over 2 steps) was obtained as a yellow solid.
IR: ν = 1443, 1143 cm -1
MS: m / z = 281 (M + ), 206 (100%). HRMS Calcd. For C 10 H 14 F 2 NO (M + ): 202. 1043, Found .: 202.1043.
　5-メトキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン（15）の製造
　NaH（82 mg，3.42 mmol）のTHF(テトラヒドロフラン)溶液（1.0 mL）に氷冷下、5-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン（8；300 mg，1.14 mmol）のTHF溶液（2.8 mL）を加え30分攪拌した後に、氷冷下Me2SO4（0.32 mL，3.42 mmol）を滴下し、室温に昇温し4時間攪拌した。3時間経過後、再びNaH（82 mg，3.42 mmol），及びMe2SO4（0.32 mL，3.42 mmol）をさらに加え攪拌した。その後、H2Oを加え、Et2Oにより抽出し、次いで、有機層を食塩水により洗浄し、MgSO4で乾燥した後、減圧下溶媒を留去した。残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン（1：15 v/v）の流分として精製し、Me2SO4との混合物（403 mg）を得た。混合物の一部（333 mg）はさらに精製することなく、次反応に用いた。また混合物の一部をさらにシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン（1：60 v/v）の流分として無色油状5-メトキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン15を得た。
IR（neat）：ν ＝1698 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.39（br., 1H）, 3.24（s, 3H）, 2.38（br., 1H）, 1.96（br. d, J＝12.3 Hz, 2H）, 1.90-1.75（m, 5H）, 1.69（s, 3H）, 1.67（br. d, J＝13.0 Hz, 1H）,1.57（br. d, J＝12.3 Hz, 1H）, 1.51（br. d, J＝13.3 Hz, 1H）．13C-NMR（100 MHz, CDCl3）：δ ＝156.1（q, J＝34.6 Hz），116.7（q, J＝292.2 Hz），70.4，60.2，52.1（q, J＝4.1 Hz），48.2，47.4，39.4，38.3，35.0，29.0，28.7．
MS：m/z＝277（M+），220（100%）．HRMS Calcd. for C13H18F3NO2（M+）：277.1290 Found.：277．1271 Preparation of 5-methoxy-1-methyl-N-trifluoroacetyl-2-azaadamantane (15) To a solution of NaH (82 mg, 3.42 mmol) in THF (tetrahydrofuran) (1.0 mL) under ice-cooling, 5-hydroxy- A THF solution (2.8 mL) of 1-methyl-N-trifluoroacetyl-2-azaadamantane (8; 300 mg, 1.14 mmol) was added and stirred for 30 minutes, and then Me 2 SO 4 (0.32 mL, 3.42) under ice-cooling. mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 4 hours. After 3 hours, NaH (82 mg, 3.42 mmol) and Me 2 SO 4 (0.32 mL, 3.42 mmol) were further added and stirred again. Thereafter, H 2 O was added, extraction was performed with Et 2 O, and then the organic layer was washed with brine and dried over MgSO 4 , and then the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and purified as a flow of AcOEt-hexane (1:15 v / v) to give a mixture (403 mg) with Me 2 SO 4 . A part of the mixture (333 mg) was used in the next reaction without further purification. A part of the mixture was further processed by silica gel column chromatography, and colorless oily 5-methoxy-1-methyl-N-trifluoroacetyl-2-azaadamantane was obtained as a stream of AcOEt-hexane (1:60 v / v). I got 15.
IR (neat): ν = 1698 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.39 (br., 1H), 3.24 (s, 3H), 2.38 (br., 1H), 1.96 (br. D, J = 12.3 Hz, 2H) , 1.90-1.75 (m, 5H), 1.69 (s, 3H), 1.67 (br. D, J = 13.0 Hz, 1H), 1.57 (br. D, J = 12.3 Hz, 1H), 1.51 (br. D , J = 13.3 Hz, 1H). 13 C-NMR (100 MHz, CDCl 3 ): δ = 156.1 (q, J = 34.6 Hz), 116.7 (q, J = 292.2 Hz), 70.4, 60.2, 52.1 (q, J = 4.1 Hz), 48.2, 47.4, 39.4, 38.3, 35.0, 29.0, 28.7.
MS: m / z = 277 (M + ), 220 (100%). HRMS Calcd. For C 13 H 18 F 3 NO 2 (M + ): 277.1290 Found .: 277.1271
　5-メトキシ-1-メチル-2-アザアダマンタン-N-オキシル（16）の製造
　5-メトキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン15のMe2SO4との混合物（333 mg）のEtOH溶液（4 mL）にNaOH水溶液（50質量%溶液，2 mL）を加えて1時間攪拌した。その後、CHCl3により抽出し、有機層をK2CO3で乾燥した後、減圧下溶媒を留去し、粗5-メトキシ-1-メチル-2-アザアダマンタン（135 mg）を得た．本化合物は精製することなく，次反応に用いた。 Preparation of 5-methoxy-1-methyl-2-azaadamantane-N-oxyl (16) A mixture of 5-methoxy-1-methyl-N-trifluoroacetyl-2-azaadamantane 15 with Me 2 SO 4 (333 mg) EtOH solution (4 mL) was added NaOH aqueous solution (50 mass% solution, 2 mL) and stirred for 1 hour. Thereafter, extraction with CHCl 3 was performed, and the organic layer was dried over K 2 CO 3 , and then the solvent was distilled off under reduced pressure to obtain crude 5-methoxy-1-methyl-2-azaadamantane (135 mg). This compound was used in the next reaction without purification.
　粗5-メトキシ-1-メチル-2-アザアダマンタン（135 mg）のMeOH溶液（0.5 M，1.5 mL）に、氷冷下UHP（280 mg，2.96 mmol），及びNa2WO4・2H2O（122 mg，0.37 mmol）を順次加え、室温にて3時間攪拌した。その後、H2Oを加え、減圧下溶媒を留去し、残渣はCHCl3により抽出し、有機層をK2CO3で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン（1：4 v/v）の流分として山吹色針状晶の5-メトキシ-1-メチル-2-アザアダマンタン-N-オキシル（16；105 mg，0.534 mmol, ３工程通しでの収率56％ （for 3 steps））を得た。
IR（neat）：ν ＝1215 cm-1．MS：m/z＝196（M+），196（100%）．HRMS Calcd. for C11H18NO2（M+）：196.1338，Found.：196.1319．Anal. Calcd. C11H18NO2：C, 67.32；H, 9.24；N, 7.14. Found：C, 67.14；H, 9.16；N, 7.10. To a solution of crude 5-methoxy-1-methyl-2-azaadamantane (135 mg) in MeOH (0.5 M, 1.5 mL), ice-cooled UHP (280 mg, 2.96 mmol), and Na 2 WO 4 · 2H 2 O (122 mg, 0.37 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. Thereafter, H 2 O was added, the solvent was distilled off under reduced pressure, the residue was extracted with CHCl 3 , and the organic layer was dried over K 2 CO 3 . Thereafter, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography. As a stream of AcOEt-hexane (1: 4 v / v), 5-methoxy-1-methyl-2 -Azaadamantane-N-oxyl (16; 105 mg, 0.534 mmol, 56% yield over 3 steps (for 3 steps)) was obtained.
IR (neat): ν = 1215 cm −1 . MS: m / z = 196 (M + ), 196 (100%). HRMS Calcd. For C 11 H 18 NO 2 (M + ): 196.1338, Found .: 196.1319. Anal. Calcd. C 11 H 18 NO 2 : C, 67.32; H, 9.24; N, 7.14. Found: C, 67.14; H, 9.16; N, 7.10.
　5-ヒドロキシ-1-メチル-2-アザアダマンタン-N-オキシル（17）の製造
　5-ヒドロキシ-1-メチル-N-トリフルオロアセチル-2-アザアダマンタン（8; 500 mg，1.90 mmol）のMeOH溶液（0.5 M，40 mL）にAmberlyst（アンバーリスト：ローム・アンド・ハース社製の登録商標） A-26（OH form）（5.50 g）を加え，油浴中50 ℃に加熱し40時間攪拌した。その後、セライト（セライト・コーポレーション社製の登録商標）で濾過し、減圧下溶媒を留去し、粗5-ヒドロキシ-1-メチル-2-アザアダマンタン（458 mg）を得た。本化合物は精製することなく、次反応に用いた。 Preparation of 5-hydroxy-1-methyl-2-azaadamantane-N-oxyl (17) 5-hydroxy-1-methyl-N-trifluoroacetyl-2-azaadamantane (8; 500 mg, 1.90 mmol) in MeOH Add Amberlyst (Amberlyst: registered trademark of Rohm and Haas) A-26 (OH form) (5.50 g) to the solution (0.5 M, 40 mL), heat to 50 ° C in an oil bath, and stir for 40 hours did. Thereafter, the mixture was filtered through Celite (registered trademark of Celite Corporation), and the solvent was distilled off under reduced pressure to obtain crude 5-hydroxy-1-methyl-2-azaadamantane (458 mg). This compound was used in the next reaction without purification.
　粗5-ヒドロキシ-1-メチル-2-アザアダマンタン（458 mg）のMeOH溶液（0.5 M，4 mL）に、UHP（715 mg，7.6 mmol）、及びNa2WO4・2H2O（314 mg，0.95 mmol）を順次加え、2時間攪拌した。その後H2Oを加え、減圧下溶媒を留去し、残渣はCHCl3により抽出し、有機層をK2CO3で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルカラムクロマトグラフィーにより処理し、AcOEt－ヘキサン（4：1 v/v）の流分として得た油状物質を分子ふるいクロマトグラフィーにより処理し、橙色固体の5-ヒドロキシ-1-メチル-2-アザアダマンタン-N-オキシル（17；217.5 mg, 1.19 mmol, ２工程通しでの収率63％（ for 2 steps））を得た。
IR（neat）：ν ＝3396 cm-1, MS：m/z＝182（M+），182（100%）．HRMS Calcd. for C10H16NO2（M+）：182.1181，Found.：182.1161．Anal. Calcd. C11H18NO2：C, 65.91；H, 8.85；N, 7.69. Found：C, 65.69；H, 8.83；N, 7.65. To a solution of crude 5-hydroxy-1-methyl-2-azaadamantane (458 mg) in MeOH (0.5 M, 4 mL), UHP (715 mg, 7.6 mmol), and Na 2 WO 4 · 2H 2 O (314 mg) , 0.95 mmol) was added successively and stirred for 2 hours. Thereafter, H 2 O was added, the solvent was distilled off under reduced pressure, the residue was extracted with CHCl 3 , and the organic layer was dried over K 2 CO 3 . Thereafter, the solvent was distilled off under reduced pressure, the residue was treated with silica gel column chromatography, and the oily substance obtained as a stream of AcOEt-hexane (4: 1 v / v) was treated with molecular sieve chromatography to obtain an orange solid. Of 5-hydroxy-1-methyl-2-azaadamantane-N-oxyl (17; 217.5 mg, 1.19 mmol, 63% yield for 2 steps).
IR (neat): ν = 3396 cm −1 , MS: m / z = 182 (M + ), 182 (100%). HRMS Calcd. For C 10 H 16 NO 2 (M + ): 182.1181, Found .: 182.1161. Anal. Calcd. C 11 H 18 NO 2 : C, 65.91; H, 8.85; N, 7.69. Found: C, 65.69; H, 8.83; N, 7.65.
　エンド-ビシクロ[3.3.1]ノン-6-エン- 3-カルボン酸(19)の製造
　1L の3径フラスコに2-アダマンタノン(18) 48.0 g (0.320 mol) とメタンスルホン酸300 g (202 mL, 1.58 M) を加えて溶解した。この溶液に、撹拌下、反応溶液の温度が20℃から35℃以下を保つようにアジ化ナトリウム 22.9 g (0.353 mol) を少量ずつ加えた。その過程でアジ化水素酸および窒素ガスが発生するので、適宜、氷冷水浴で反応温度を下げた。その後、室温で1時間撹拌し、ガスクロマトグラフィーで2-アダマンタノンの消失を確認した。このとき、4-メタンスルホニル-2-アダマンタノン (2)が生成が確認された。次に、反応装置にジムロート冷却管を連結し、50質量%水酸化カリウム水溶液 (450 mL)を徐々に加えた。この際、反応温度は95℃まで上昇した。室温になるまで1時間半撹拌した後、反応液をジエチルエーテル 600 mL で洗浄した。水層に濃塩酸120 mLを注意深く加えて反応液を酸性にすると目的物が晶出した。これを濾取し、水で十分に洗浄後、乾燥して粗エンド-ビシクロ[3.3.1]ノン-6-エン- 3-カルボン酸(19)36.5 g (0.220 mol, 69%)を得た。
エンド-ビシクロ[3.3.1]ノン-6-エン- 3-カルボン酸(19): 1H-NMR (400 MHz, CDCl3):δ＝5.65 (m, 1H), 5.58 (dt, J = 9.5, 3.2 Hz, 1H), 2.57 (t, J = 6.3 Hz, 1H), 2.39 (d, J = 14.0 Hz, 1H), 2.36-2.20 (m, 4H), 2.06 (br s, 1H), 1.78-1.66 (m, 3H), 1.54 (br d, J = 12.3 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ＝ 182.6, 130.6, 129.5, 35.9, 31.9, 31.4, 31.1, 29.8, 28.5, 26.2. IR (neat, cm-1): ν＝1680. MS m/z: 166 (M+), 79 (100%).  HRMS (EI): Calcd. for C10H14O2 166.0994 (M+), found: 166.0989. Production of endo-bicyclo [3.3.1] non-6-ene-3-carboxylic acid (19) In a 1 L 3-diameter flask, 48.0 g (0.320 mol) of 2-adamantanone (18) and 300 g of methanesulfonic acid (202 mL, 1.58 M) was added and dissolved. To this solution, 22.9 g (0.353 mol) of sodium azide was added little by little with stirring so that the temperature of the reaction solution was kept at 20 ° C. to 35 ° C. or lower. During the process, hydrazoic acid and nitrogen gas were generated, and thus the reaction temperature was appropriately lowered with an ice-cold water bath. Thereafter, the mixture was stirred at room temperature for 1 hour, and disappearance of 2-adamantanone was confirmed by gas chromatography. At this time, formation of 4-methanesulfonyl-2-adamantanone (2) was confirmed. Next, a Dimroth condenser was connected to the reaction apparatus, and 50 mass% potassium hydroxide aqueous solution (450 mL) was gradually added. At this time, the reaction temperature rose to 95 ° C. After stirring for 1 hour and a half until reaching room temperature, the reaction solution was washed with 600 mL of diethyl ether. When the reaction solution was acidified by carefully adding 120 mL of concentrated hydrochloric acid to the aqueous layer, the desired product crystallized out. This was collected by filtration, washed thoroughly with water, and dried to obtain 36.5 g (0.220 mol, 69%) of crude endo-bicyclo [3.3.1] non-6-ene-3-carboxylic acid (19). .
Endo-bicyclo [3.3.1] non-6-ene-3-carboxylic acid (19): 1 H-NMR (400 MHz, CDCl 3 ): δ = 5.65 (m, 1H), 5.58 (dt, J = 9.5 , 3.2 Hz, 1H), 2.57 (t, J = 6.3 Hz, 1H), 2.39 (d, J = 14.0 Hz, 1H), 2.36-2.20 (m, 4H), 2.06 (br s, 1H), 1.78- 1.66 (m, 3H), 1.54 (br d, J = 12.3 Hz, 1H). 13 C-NMR (100 MHz, CDCl 3 ): δ = 182.6, 130.6, 129.5, 35.9, 31.9, 31.4, 31.1, 29.8, 28.5, 26.2. IR (neat, cm -1 ): ν = 1680. MS m / z: 166 (M + ), 79 (100%). HRMS (EI): Calcd. For C 10 H 14 O 2 166.0994 ( M + ), found: 166.0989.
　N-ベンジルオキシカルボニル-エンド-ビシクロ[3.3.1]ノン-6-エン-3-イルアミン(20)の製造
　エンド-ビシクロ[3.3.1]ノン-6-エン- 3-カルボン酸 (19) 14.7 g (88.5 mmol) のテトラヒドロピラン (88.5 mL, 1.0 M)溶液（1L ナス形フラスコ中)に、室温下、トリエチルアミン29.8 mL (213 mmol) およびジフェニルホスホリルアジド(DPPA) 21.0 mL (97.4 mmol) を順次加え、同温度で3時間撹拌した。この時点で、反応系内にはエンド-ビシクロ[3.3.1]ノン-6-エン-3-カルボニルアジドが生成していると考えられる。 Preparation of N-benzyloxycarbonyl-endo-bicyclo [3.3.1] non-6-en-3-ylamine (20) Endo-bicyclo [3.3.1] non-6-ene-3-carboxylic acid (19) 14.7 To a solution of g (88.5 mmol) in tetrahydropyran (88.5 mL, 1.0 M) (in a 1 L eggplant-shaped flask), add 29.8 mL (213 mmol) of triethylamine and 21.0 mL (97.4 mmol) of diphenylphosphoryl azide (DPPA) sequentially at room temperature. In addition, the mixture was stirred at the same temperature for 3 hours. At this point, it is considered that endo-bicyclo [3.3.1] non-6-ene-3-carbonylazide is formed in the reaction system.
　この反応液にテトラヒドロピラン(88.5 mL) およびベンジルアルコール 91.6 mL (885 mmol) を加え、エンド-ビシクロ[3.3.1]ノン-6-エン-3-カルボニルアジドの消失が確認されるまで加熱・還流した。放冷後、水および酢酸エチルを加えて分液し、有機層を飽和食塩水溶液で洗浄後、硫酸マグネシウムで乾燥した後、濃縮した。粗生成物をカラムクロマトグラフィー（展開溶媒：酢酸エチル－ヘキサン(1 : 8 v/v))で精製し、N-ベンジルオキシカルボニル-エンド-ビシクロ[3.3.1]ノン-6-エン-3-イルアミン(20) 20.4 g (85%) を得た。
N-ベンジルオキシカルボニル-エンド-ビシクロ[3.3.1]ノン-6-エン-3-イルアミン(20): 1H-NMR (400 MHz, CDCl3): δ＝ 7.38-7.25 (m, 5H), 6.05 (t, J = 7.8 Hz, 1H), 5.92 (d, J = 8.4 Hz, 1H), 5.79 (dt, J = 9.9, 3.2 Hz, 1H), 5.56 (dd, J = 18.5, 12.4 Hz, 2H), 4.03 (m, 1H), 2.43 (dd, J = 18.8, 7.2 Hz, 1H), 2.34 (br s, 1H), 2.18 (br s, 1H), 2.06 (br ｄ, J = 18.1 Hz 1H), 2.00 (dt, J = 14.7, 5.5 Hz, 1H) 1.89-1.66 (m, 4H), 1.55 (br d, J = 12.1 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ＝ 155.5, 136.9, 134.4, 128.8, 128.4, 128.0, 127.9, 66.2, 44.7, 37.5, 34.2, 32.5, 31.0, 27.7, 25.5. IR (neat, cm-1): ν＝ 3434, 1721, 1504. MS m/z: 271 (M+), 91 (100%).  HRMS (EI): Calcd. for C17H21NO2 271.1572 (M+), found: 271.1554. Tetrahydropyran (88.5 mL) and benzyl alcohol 91.6 mL (885 mmol) were added to the reaction solution, and heated and refluxed until the disappearance of endo-bicyclo [3.3.1] non-6-ene-3-carbonylazide was confirmed. did. After allowing to cool, water and ethyl acetate were added for liquid separation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product was purified by column chromatography (developing solvent: ethyl acetate-hexane (1: 8 v / v)), and N-benzyloxycarbonyl-endo-bicyclo [3.3.1] non-6-ene-3- 20.4 g (85%) of ilamine (20) was obtained.
N-benzyloxycarbonyl-endo-bicyclo [3.3.1] non-6-en-3-ylamine (20): 1 H-NMR (400 MHz, CDCl 3 ): δ = 7.38-7.25 (m, 5H), 6.05 (t, J = 7.8 Hz, 1H), 5.92 (d, J = 8.4 Hz, 1H), 5.79 (dt, J = 9.9, 3.2 Hz, 1H), 5.56 (dd, J = 18.5, 12.4 Hz, 2H ), 4.03 (m, 1H), 2.43 (dd, J = 18.8, 7.2 Hz, 1H), 2.34 (br s, 1H), 2.18 (br s, 1H), 2.06 (br d, J = 18.1 Hz 1H) , 2.00 (dt, J = 14.7, 5.5 Hz, 1H) 1.89-1.66 (m, 4H), 1.55 (br d, J = 12.1 Hz, 1H). 13 C-NMR (100 MHz, CDCl 3 ): δ = 155.5, 136.9, 134.4, 128.8, 128.4, 128.0, 127.9, 66.2, 44.7, 37.5, 34.2, 32.5, 31.0, 27.7, 25.5. IR (neat, cm -1 ): ν = 3434, 1721, 1504. MS m / z: 271 (M + ), 91 (100%). HRMS (EI): Calcd. for C 17 H 21 NO 2 271.1572 (M + ), found: 271.1554.
　2-アザアダマンタン(21)の製造
　100 mlナスフラスコ内にN-ベンジルオキシカルボニル-エンド-ビシクロ[3.3.1]ノン-6-エン-3-イルアミン(20) 4.2 g (15.5 mmol) の塩化メチレン(40 ml, 0.4M)溶液を調製し、そこへ、氷冷下、トリフルオロメタンスルホン酸5.8 ml (62 mmol) を加え1時間撹拌した。薄層クロマトグラフィー(TLC)で原料の消失を確認後、氷冷下、トリエチルアミン9.6 ml (68.2 mmol)を加え、中和した後、10質量 % 水酸化ナトリウム水溶液（40ml）を加え1時間攪拌した。その後、CHCl3を加えて抽出し、有機層をMｇSO4で乾燥し、濃縮して粗2-アザアダマンタン(21)を得た。
2-アザアダマンタン（azaadamantane） (21): 1H-NMR (400 MHz, CDCl3): δ＝ 3.13 (s, 2H), 2.04 (s, 2H), 1.94 (d, J = 11.4 Hz, 4H), 1.87 (s, 2H), 1.77 (d, J = 11.4 Hz, ４H). Preparation of 2-azaadamantane (21) N-benzyloxycarbonyl-endo-bicyclo [3.3.1] non-6-en-3-ylamine (20) 4.2 g (15.5 mmol) of methylene chloride in a 100 ml eggplant flask (40 ml, 0.4M) solution was prepared, and trifluoromethanesulfonic acid 5.8 ml (62 mmol) was added there under ice-cooling, and it stirred for 1 hour. After confirming the disappearance of the raw material by thin layer chromatography (TLC), 9.6 ml (68.2 mmol) of triethylamine was added under ice-cooling, neutralized, 10% by weight aqueous sodium hydroxide solution (40 ml) was added, and the mixture was stirred for 1 hour. . Thereafter, CHCl 3 was added for extraction, and the organic layer was dried over MgSO 4 and concentrated to obtain crude 2-azaadamantane (21).
2-azaadamantane (21): 1 H-NMR (400 MHz, CDCl 3 ): δ = 3.13 (s, 2H), 2.04 (s, 2H), 1.94 (d, J = 11.4 Hz, 4H) , 1.87 (s, 2H), 1.77 (d, J = 11.4 Hz, 4H).
　N-トリフルオロアセチル-2-アザアダマンタン(22)の製造
　2-アザアダマンタン 21 (1 g) のCH2Cl2（0.2 M，3 7mL）溶液に，氷冷下 、Et3N (1.5 mL, 10.9 mmol) 、及びトリフルオロ酢酸無水物（1.5 mL, 10.9 mmol）を順次加え、室温に昇温し2.5時間攪拌した。その後、H2Oを加え，AcOEtにより抽出し，有機層を食塩水により洗浄し、MgSO4で乾燥した。その後、減圧下溶媒を留去した。残渣はシリカゲルクロマトグラフィーにより処理しAcOEt－ヘキサン（1：4 v/v）の流分としてN-トリフルオロアセチル-2-アザアダマンタン 22 (1.42 g, 6.09 mmol, 83%)を 黄色油状物として得た。
IR（CHCl3）：ν＝1685 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.76（br., 1H）, 4.23（br., 1H）, 2.14（br., 2H）, 1.83-1.91（m, 10H）．
13C-NMR（100 MHz, CDCl3）：δ=154.1 (q, J = 35.3 Hz), 116.8 (q, J = 288.4 Hz), 49.7 (q, J =  3.3 Hz), 46.2, 36.1, 35.2, 35.1, 26.2.
MS：m/z＝233（M+），233（100%）．HRMS Calcd. for C11H14F3NO（M+）：233.1027，Found.：233.1023． Preparation of N-trifluoroacetyl-2-azaadamantane (22) To a solution of 2-azaadamantane 21 (1 g) in CH 2 Cl 2 (0.2 M, 37 mL), Et 3 N (1.5 mL, 10.9 mmol) and trifluoroacetic anhydride (1.5 mL, 10.9 mmol) were sequentially added, and the mixture was warmed to room temperature and stirred for 2.5 hours. Thereafter, H 2 O was added and extracted with AcOEt, and the organic layer was washed with brine and dried over MgSO 4 . Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography to give N-trifluoroacetyl-2-azaadamantane 22 (1.42 g, 6.09 mmol, 83%) as a yellow oil as a stream of AcOEt-hexane (1: 4 v / v). It was.
IR (CHCl 3 ): ν = 1685 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.76 (br., 1H), 4.23 (br., 1H), 2.14 (br., 2H), 1.83-1.91 (m, 10H).
13 C-NMR (100 MHz, CDCl 3 ): δ = 154.1 (q, J = 35.3 Hz), 116.8 (q, J = 288.4 Hz), 49.7 (q, J = 3.3 Hz), 46.2, 36.1, 35.2, 35.1, 26.2.
MS: m / z = 233 (M + ), 233 (100%). HRMS Calcd. For C 11 H 14 F 3 NO (M + ): 233.102, Found .: 233.01023.
　5-ヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン (23)および5, 7-ジヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン (24)の製造
　N-トリフルオロアセチル-2-アザアダマンタン 22 (500 mg，2.14 mmol）のCCl4－MeCN－H2O (1.65 M；1.3 mL－1.1 M；1.9 mL－1.1 M；1.9 mL) 溶液に、NaIO4（1.05 g，4.90 mmol）、及びRuCl3（44 mg，0.214 mmol）を順次加え、70 ℃で20時間激しく攪拌した。その後、飽和 NaHCO3水溶液、及びNaSO3水溶液を順次加え、AcOEtにより抽出した。次いで、有機層をMgSO4で乾燥した。その後、減圧下溶媒を留去した。残渣はシリカゲルクロマトグラフィーにより処理しAcOEt－ヘキサン（1：2 v/v）の流分として、白色固体の5-ヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン 23 (341 mg，1.37 mmol，64％）を得た。また同時に、白色固体の5,7-ジヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン 24 (70 mg，0.26 mmol，12％）と原料22 (138 mg，0.59 mmol，２０％）を得た。 Preparation of 5-hydroxy-N-trifluoroacetyl-2-azaadamantane (23) and 5,7-dihydroxy-N-trifluoroacetyl-2-azaadamantane (24) N-trifluoroacetyl-2-azaadamantane 22 (500 mg, 2.14 mmol) of CCl 4 -MeCN-H 2 O (1.65 M; 1.3 mL-1.1 M; 1.9 mL-1.1 M; 1.9 mL) in solution, NaIO 4 (1.05 g, 4.90 mmol), and RuCl 3 (44 mg, 0.214 mmol) was sequentially added, and the mixture was vigorously stirred at 70 ° C. for 20 hours. Then, saturated NaHCO 3 aqueous solution and NaSO 3 aqueous solution were sequentially added, and extracted with AcOEt. The organic layer was then dried over MgSO 4 . Thereafter, the solvent was distilled off under reduced pressure. The residue was treated by silica gel chromatography, and the white solid 5-hydroxy-N-trifluoroacetyl-2-azaadamantane 23 (341 mg, 1.37 mmol, 64) was obtained as a stream of AcOEt-hexane (1: 2 v / v). %). Simultaneously, white solid 5,7-dihydroxy-N-trifluoroacetyl-2-azaadamantane 24 (70 mg, 0.26 mmol, 12%) and raw material 22 (138 mg, 0.59 mmol, 20%) were obtained.
　5-ヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン 23 の物性；
IR（neat）：ν＝3425，1681 cm-1
1H-NMR（400 MHz, CDCl3）：δ＝4.97（br., 1H）, 4.43（br., 1H）, 2.04（br, 1H）, 1.92-1.79（m, 8H）, 1.73-1.68（s, 2H）, 1.63（br. d, J＝13.0 Hz, 1H）．
13C-NMR（100 MHz, CDCl3）：δ＝154.0 (q, J = 35.2 Hz), 116.5 (q, J = 288.4 Hz), 66.3, 60.3, 51.5 (q, J = 3.3 Hz), 43.4, 42.9, 42.6, 34.7, 33.8, 28.6.
MS：m/z＝249（M+），249（100%）．HRMS Calcd. for C12H16F3NO2（M+）：249.0977，Found.：249.0956． Properties of 5-hydroxy-N-trifluoroacetyl-2-azaadamantane 23;
IR (neat): ν = 3425, 1681 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.97 (br., 1H), 4.43 (br., 1H), 2.04 (br, 1H), 1.92-1.79 (m, 8H), 1.73-1.68 ( s, 2H), 1.63 (br. d, J = 13.0 Hz, 1H).
13 C-NMR (100 MHz, CDCl 3 ): δ = 154.0 (q, J = 35.2 Hz), 116.5 (q, J = 288.4 Hz), 66.3, 60.3, 51.5 (q, J = 3.3 Hz), 43.4, 42.9, 42.6, 34.7, 33.8, 28.6.
MS: m / z = 249 (M + ), 249 (100%). HRMS Calcd. For C 12 H 16 F 3 NO 2 (M + ): 249.0977, Found .: 249.0956.
　5,7-ジヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン24の物性；
　ＩＲ：ν= 3335, 3197, 2686 cm-1
1H-NMR（400 MHz, CDCl3）：δ = 4.97 (br s, 1H), 4.52 (br s, 1H), 1.87-1.66 (m, 10H).
13C-NMR（100 MHz, CDCl3）：δ = 155.2 (q, J = 35.2 Hz), 118.1 (q, J = 287.6 Hz), 69.4, 53.2 (m), 51.5, 50.3, 43.3, 42.5.
MS : m/z = 265 (M+), 265 (100%). HRMS Calcd. for C11H14F3NO3 (M+) : 265. 0926, Found. : 265.0925  Physical properties of 5,7-dihydroxy-N-trifluoroacetyl-2-azaadamantane 24;
IR: ν = 3335, 3197, 2686 cm -1
1 H-NMR (400 MHz, CDCl 3 ): δ = 4.97 (br s, 1H), 4.52 (br s, 1H), 1.87-1.66 (m, 10H).
13 C-NMR (100 MHz, CDCl 3 ): δ = 155.2 (q, J = 35.2 Hz), 118.1 (q, J = 287.6 Hz), 69.4, 53.2 (m), 51.5, 50.3, 43.3, 42.5.
MS: m / z = 265 (M +), 265 (100%). HRMS Calcd. For C11H14F3NO3 (M +): 265. 0926, Found .: 265.0925
　5-フルオロ-N-トリフルオロアセチル-2-アザアダマンタン (25)の製造
　5-ヒドロキシ-N-トリフルオロアセチル-2-アザアダマンタン 23  (549 mg，2.20 mmol) のCH2Cl2 (1.43 M，1.5 mL） 溶液に-78℃下、DAST (0.58 mL, 4.40 mmol）を加え、徐々に昇温し０℃で1時間攪拌した。その後、Et2Oで希釈した後H2Oを加えて、AcOEtにより抽出し、有機層をH2Oにより洗浄し、MgSO4で乾燥した。その後、減圧下溶媒を留去し、残渣はシリカゲルクロマトグラフィーにより処理し、AcOEt－ヘキサン (1：4 v/v) の流分として、5-フルオロ-N-トリフルオロアセチル-2-アザアダマンタン 25 (457 mg, 1.82mmol, 81%）を白色固体として得た。
IR (neat) : ν =1681 cm-1
1H-NMR (600 MHz, CDCl3) : δ = 5.02 (br s, 1H), 4.48 (br s, 1H), 2.47 (br d, J = 1.8 Hz, 2H), 2.06-1.94 (m, 6H), 1.81-1.77 (m, 2H), 1.73-1.67 (m, 2H).
13C-NMR (150 MHz, CDCl3) :  δ = 154.1 (q, J = 35.6 Hz), 116.6 (q, J = 289.7 Hz), 89.9 (d, J = 187.9 Hz), 52.0 (m), 48.8 (d, J = 11.5 Hz), 41.4 (d, J = 20.1 Hz), 40.7 (d, J = 17.2 Hz), 40.7 (d, J = 17.2 Hz), 34.7 (d, J = 18.6 Hz), 34.7, 33.8, 29.6 (d, J = 10.1 Hz).
MS：m/z＝251（M+），251（100%）．HRMS Calcd. for C11H13F4NO（M+）：251.0933，Found.：251.0919． Preparation of 5-fluoro-N-trifluoroacetyl-2-azaadamantane (25) 5-hydroxy-N-trifluoroacetyl-2-azaadamantane 23 (549 mg, 2.20 mmol) of CH 2 Cl 2 (1.43 M, 1.5 mL) DAST (0.58 mL, 4.40 mmol) was added to the solution at −78 ° C., the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. Then, after diluting with Et 2 O, H 2 O was added and extracted with AcOEt, and the organic layer was washed with H 2 O and dried over MgSO 4 . Thereafter, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel chromatography. As a fraction of AcOEt-hexane (1: 4 v / v), 5-fluoro-N-trifluoroacetyl-2-azaadamantane 25 (457 mg, 1.82 mmol, 81%) was obtained as a white solid.
IR (neat): ν = 1681 cm -1
1 H-NMR (600 MHz, CDCl 3 ): δ = 5.02 (br s, 1H), 4.48 (br s, 1H), 2.47 (br d, J = 1.8 Hz, 2H), 2.06-1.94 (m, 6H ), 1.81-1.77 (m, 2H), 1.73-1.67 (m, 2H).
13 C-NMR (150 MHz, CDCl 3 ): δ = 154.1 (q, J = 35.6 Hz), 116.6 (q, J = 289.7 Hz), 89.9 (d, J = 187.9 Hz), 52.0 (m), 48.8 (d, J = 11.5 Hz), 41.4 (d, J = 20.1 Hz), 40.7 (d, J = 17.2 Hz), 40.7 (d, J = 17.2 Hz), 34.7 (d, J = 18.6 Hz), 34.7 , 33.8, 29.6 (d, J = 10.1 Hz).
MS: m / z = 251 (M + ), 251 (100%). . HRMS Calcd for C 11 H 13 F 4 NO (M +): 251.0933, Found:. 251.0919.
　5-フルオロ-2-アザアダマンタン-N-オキシル（26）の製造
　5-フルオロ-N-トリフルオロアセチル-2-アザアダマンタン 25 (457 mg，1.82 mmol）のEtOH (12mL) 溶液にNaOH 水溶液(50質量%，3 mL) を加えて、3時間攪拌した。その後、CHCl3により抽出し、有機層をK2CO3で乾燥した。その後、減圧下溶媒を留去し、粗5-フルオロ-2-アザアダマンタン (268 mg) を得た。本化合物は精製することなく、次反応に用いた。 Preparation of 5-fluoro-2-azaadamantane-N-oxyl (26) A solution of 5-fluoro-N-trifluoroacetyl-2-azaadamantane 25 (457 mg, 1.82 mmol) in EtOH (12 mL) was added NaOH aqueous solution (50 (Mass%, 3 mL) was added and stirred for 3 hours. Then, extracted with CHCl 3, the organic layer was dried over K 2 CO 3. Thereafter, the solvent was distilled off under reduced pressure to obtain crude 5-fluoro-2-azaadamantane (268 mg). This compound was used in the next reaction without purification.
　粗5-フルオロ-2-アザアダマンタン (268 mg) のMeOH (0.5 M, 3 mL)溶液に、氷冷下、UHP (544 mg, 5.78 mmol) 、及びNa2WO4・2H2O (238 mg, 0.722 mmol)を順次加え、室温にて2.5時間攪拌した。その後H2Oを加え、減圧下溶媒を留去し、残渣はCHCl3により抽出し、有機層をK2CO3で乾燥した後、減圧下溶媒を留去し、残渣はシリカゲルクロマトグラフィーにより処理し、Et2O-ヘキサン（1：2 v/v）の流分として、5-フルオロ-2-アザアダマンタン-N-オキシル 26 (214 mg，1.26 mmol, ２工程通しでの収率69％（for 2 steps））を黄色固体として得た。
IR (neat) :ν= 1442, 1347, 1282 cm-1
MS : m/z = 170 (M+), 170 (100%). HRMS Calcd. for C9H13FNO (M+) : 170.0981, Found. : 170.0965．
Anal. Calcd. C9H15FNO：C, 63.51；H, 7.70；N, 8.23. Found：C, 63.32；H, 7.62；N, 8.13. To a solution of crude 5-fluoro-2-azaadamantane (268 mg) in MeOH (0.5 M, 3 mL), ice-cooled UHP (544 mg, 5.78 mmol), and Na 2 WO 4・ 2H 2 O (238 mg , 0.722 mmol) was added sequentially, and the mixture was stirred at room temperature for 2.5 hours. Thereafter, H 2 O was added, the solvent was distilled off under reduced pressure, the residue was extracted with CHCl 3 , the organic layer was dried over K 2 CO 3 , the solvent was distilled off under reduced pressure, and the residue was treated by silica gel chromatography. As a fraction of Et 2 O-hexane (1: 2 v / v), 5-fluoro-2-azaadamantane-N-oxyl 26 (214 mg, 1.26 mmol, 69% yield over two steps ( for 2 steps)) was obtained as a yellow solid.
IR (neat): ν = 1442, 1347, 1282 cm -1
MS: m / z = 170 (M + ), 170 (100%). HRMS Calcd. For C9H13FNO (M + ): 170.0981, Found.: 170.0965.
Anal. Calcd. C 9 H 15 FNO: C, 63.51; H, 7.70; N, 8.23. Found: C, 63.32; H, 7.62; N, 8.13.
　N-ベンジルオキシカルボニル-1-フルオロ-2-アザアダマンタン (32)の製造
　1-ヒドロキシ-N-ベンジルオキシカルボニル-2-アザアダマンタン 31 (227 mg，0.79 mmol) のCH2Cl2 (1.43 M，0.55 mL) 溶液に-78℃下、DAST (0.32 mL, 2.37 mmol) を加え、徐々に昇温し０℃で1時間攪拌した。その後、Et2Oで希釈した後H2Oを加えて、AcOEtにより抽出した。有機層をH2Oにより洗浄し、MgSO4で乾燥後、減圧下溶媒を留去した。残渣はシリカゲルクロマトグラフィーにより処理し、AcOEt－ヘキサン (1：4 v/v) の流分として、油状の 1-フルオロ-N-ベンジルオキシカルボニル-2-アザアダマンタン 32 (211 mg, 0.729 mmol, 92%) を得た。
IR :ν= 1720, 1687, 1392 cm-1
1H-NMR (600 MHz, CDCl3) : δ = 7.37-7.36 (m, 2H), 7.34-7.31 (m, 2H), 7.28-7.26 (m, 1H), 5.19 (s, 2H), 4.62 (m, 1H), 2.32 (br d, 1H,  J =2.5 Hz), 2.13-2.10 (m, 2H), 1.92-1.88 (m, 2H), 1.79-1.69 (m, 4H), 1.61-1.58(m, 2H).
13C-NMR (150 MHz, CDCl3) :  δ = 155.8 (q, J = 2.9 Hz), 136.8, 128.4, 127.7, 127.6, 100 (d,  J =218.0 Hz), 66.9, 53.7, 41.0 (d,  J =20.1), 34.2, 29.9 (d, J =10.1 Hz).
MS m/z: 289 (M+）, 91 (100%)．HRMS: Calcd. for C17H20FNO2 289.1478 (M+), Found: 289.1465． Preparation of N-benzyloxycarbonyl-1-fluoro-2-azaadamantane (32) 1-hydroxy-N-benzyloxycarbonyl-2-azaadamantane 31 (227 mg, 0.79 mmol) in CH 2 Cl 2 (1.43 M, 0.55 mL) DAST (0.32 mL, 2.37 mmol) was added to the solution at −78 ° C., the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. Then, after diluting with Et 2 O, H 2 O was added and extracted with AcOEt. The organic layer was washed with H 2 O and dried over MgSO 4 , and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give oily 1-fluoro-N-benzyloxycarbonyl-2-azaadamantane 32 (211 mg, 0.729 mmol, 92 as AcOEt-hexane (1: 4 v / v) stream. %).
IR: ν = 1720, 1687, 1392 cm -1
1 H-NMR (600 MHz, CDCl 3 ): δ = 7.37-7.36 (m, 2H), 7.34-7.31 (m, 2H), 7.28-7.26 (m, 1H), 5.19 (s, 2H), 4.62 ( m, 1H), 2.32 (br d, 1H, J = 2.5 Hz), 2.13-2.10 (m, 2H), 1.92-1.88 (m, 2H), 1.79-1.69 (m, 4H), 1.61-1.58 (m , 2H).
13 C-NMR (150 MHz, CDCl 3 ): δ = 155.8 (q, J = 2.9 Hz), 136.8, 128.4, 127.7, 127.6, 100 (d, J = 218.0 Hz), 66.9, 53.7, 41.0 (d, J = 20.1), 34.2, 29.9 (d, J = 10.1 Hz).
MS m / z: 289 (M + ), 91 (100%). HRMS: Calcd. For C 17 H 20 FNO 2 289.1478 (M + ), Found: 289.1465.
　1-フルオロ-2-アザアダマンタン-N-オキシル (33)の製造
　1-フルオロ-N-ベンジルオキシカルボニル-2-アザアダマンタン 32 (155 mg，0.535 mmol）のMeOH（6 mL, 0.1M）溶液に、Pd が10質量% のPd／C (16 mg) を加え、H2雰囲気下室温にて2時間攪拌した。反応溶液をセライト（セライト・コーポレーション社製の登録商標）でろ過し、減圧下溶媒を除去した。残渣に飽和Na2CO3水溶液を加え、CHCl3で抽出した。有機層をK2CO3で乾燥後、減圧下溶媒を留去し、粗1-フルオロ-2-アザアダマンタン (70 mg) を得た。本化合物は精製することなく、次反応に用いた。 Preparation of 1-Fluoro-2-azaadamantane-N-oxyl (33) 1-Fluoro-N-benzyloxycarbonyl-2-azaadamantane 32 (155 mg, 0.535 mmol) in a solution of MeOH (6 mL, 0.1M) , Pd / C (16 mg) containing 10% by mass of Pd was added, and the mixture was stirred at room temperature for 2 hours in an H 2 atmosphere. The reaction solution was filtered through Celite (registered trademark manufactured by Celite Corporation), and the solvent was removed under reduced pressure. To the residue was added saturated aqueous Na 2 CO 3 solution, and the mixture was extracted with CHCl 3 . The organic layer was dried over K 2 CO 3 and the solvent was distilled off under reduced pressure to obtain crude 1-fluoro-2-azaadamantane (70 mg). This compound was used in the next reaction without purification.
　粗1-フルオロ-2-アザアダマンタン (70 mg) のMeOH溶液 (0.5 M, 0.9 mL) に、氷冷下UHP (169 mg, 1.8 mmol)、及びNa2WO4・2H2O (74.3 mg, 0.225 mmol) を順次加え、室温にて3時間攪拌した。減圧下溶媒を留去し、残渣はCHCl3により抽出した。有機層をK2CO3で乾燥後、減圧下溶媒を留去した。残渣はシリカゲルクロマトグラフィーにより処理し、Et2O-ヘキサン (1：1 v/v) の流分として、1-フルオロ-2-アザアダマンタン-N-オキシル33 (56 mg, 0.329 mmol, ２工程通しでの収率62％（for 2 steps）) を黄色固体として得た。
IR :ν= 1449, 1323, 1257 cm-1
MS : m/z = 170 (M+), 97 (100%). HRMS Calcd. for C9H13FNO (M+) : 170.0981, Found. : 170.0968
Anal: Calcd. for C9H13FNO: C, 63.51; H, 7.70; N, 8.23．Found: C, 63.44; H, 7.67; N, 8.23． To a solution of crude 1-fluoro-2-azaadamantane (70 mg) in MeOH (0.5 M, 0.9 mL), UHP (169 mg, 1.8 mmol) and Na 2 WO 4・ 2H 2 O (74.3 mg, 0.225 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with CHCl 3 . The organic layer was dried over K 2 CO 3 and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel as a fraction of Et 2 O-hexane (1: 1 v / v) as 1-fluoro-2-azaadamantane-N-oxyl 33 (56 mg, 0.329 mmol, through 2 steps). Yield 62% (for 2 steps)) as a yellow solid.
IR: ν = 1449, 1323, 1257 cm -1
MS: m / z = 170 (M + ), 97 (100%). HRMS Calcd. For C9H13FNO (M + ): 170.0981, Found .: 170.0968
Anal: Calcd. For C 9 H 13 FNO: C, 63.51; H, 7.70; N, 8.23. Found: C, 63.44; H, 7.67; N, 8.23.
　５－ヒドロキシ－２－アザアダマンタン－Ｎ－オキシルの製造
　N-CF3CO-5-OH-AZAD（N-トリフルオロアセチル-5-ヒドロキシ- 2-アザアダマンタン）(616mg)にIPA（イソプロピルアルコール） 3gと6N NaOH水溶液2mLを加え、50℃で4時間攪拌した。GC（ガスクロマトグラフ法による分析）で原料の消失を確認した後、トルエンを加えて分液し、有機層を濃縮した。白色固体として5-OH-AZAD（５－ヒドロキシ－２－アザアダマンタン）粗物426mgを得た。
GC-MS(CI): 154(M+1)
H-NMR: δ = 3.41(2H, s), 2.27(1H, s), 1.2-1.9(12H, m)
　5-OH-AZADから5-OH-AZADO（５－ヒドロキシ－２－アザアダマンタン－Ｎ－オキシル）の製造は、以下のように行なった。 Preparation of 5-hydroxy-2-azaadamantane-N-oxyl N-CF 3 CO-5-OH-AZAD (N-trifluoroacetyl-5-hydroxy-2-azaadamantane) (616 mg) to IPA (isopropyl alcohol) 3 g and 6 mL of 6N NaOH aqueous solution were added and stirred at 50 ° C. for 4 hours. After confirming the disappearance of the raw material by GC (analysis by gas chromatography), toluene was added for liquid separation, and the organic layer was concentrated. As a white solid, 426 mg of a crude 5-OH-AZAD (5-hydroxy-2-azaadamantane) was obtained.
GC-MS (CI): 154 (M + 1)
H-NMR: δ = 3.41 (2H, s), 2.27 (1H, s), 1.2-1.9 (12H, m)
Production of 5-OH-AZADO (5-hydroxy-2-azaadamantane-N-oxyl) from 5-OH-AZAD was performed as follows.
　すなわち、5-OH-AZAD(484mg)のt-ブタノール溶液にＮａＨＣＯ３(5-OH-AZAD に対して0.3eq（0.3当量）（以下、同様である。）)を加え、70℃に加熱した後、過酸化水素水(8.0eq)を加えたところ、2時間の反応で5-OH-AZADから5-OH-AZADOへの転化率は74.6%であった。さらにＮａＨＣＯ３(0.3eq)、及び過酸化水素水(4.0eq)を加え、70℃で2時間撹拌したところ、5-OH-AZADから5-OH-AZADOへの転化率は86.3%まで向上した。その後、反応溶液をトルエン/6N-NaOH水溶液で分液(褐色溶液)した。次いで、水層をジクロロメタンで2回抽出した。有機層を濃縮した後にカラム精製（シリカゲルクロマトグラフィーにより処理）して、黄色固体308mgを得た(得率58%)
GC-MS(CI): 169(M+1) That is, NaHCO 3 (0.3 eq (0.3 equivalents) relative to 5-OH-AZAD (hereinafter the same))) was added to a t-butanol solution of 5-OH-AZAD (484 mg) and heated to 70 ° C. Thereafter, hydrogen peroxide solution (8.0 eq) was added, and the conversion from 5-OH-AZAD to 5-OH-AZADO was 74.6% after 2 hours of reaction. Further, NaHCO 3 (0.3 eq) and hydrogen peroxide solution (4.0 eq) were added and stirred at 70 ° C. for 2 hours. As a result, the conversion rate from 5-OH-AZAD to 5-OH-AZADO was improved to 86.3%. . Thereafter, the reaction solution was separated with a toluene / 6N-NaOH aqueous solution (brown solution). The aqueous layer was then extracted twice with dichloromethane. The organic layer was concentrated and purified by column (treated by silica gel chromatography) to obtain 308 mg of yellow solid (yield: 58%)
GC-MS (CI): 169 (M + 1)
　実施例２：Ｎ－オキシル化合物を用いた酸素酸化
　アルコール化合物の酢酸溶液（0.33mol/L）または塩化メチレン溶液（0.33mol/L）に、亜硝酸ナトリウム（アルコール化合物の５mol％）または亜硝酸ターシャリーブチル（アルコール化合物の３０mol％）および５－フルオロ－２－アザアダマンタン－Ｎ－オキシル(アルコール化合物の５mol％)を加えて室温下、酸素バルーンを付した状態で、原料のアルコールの消失が確認されるまで激しく撹拌した。反応終了後、水と塩化メチレンを加えて分液し、有機層を水洗することにより、目的のケトンまたはアルデヒドを得た。 Example 2 Oxygen Oxidation Using N-Oxyl Compound Sodium nitrite (5 mol% of alcohol compound) or tartar nitrite was added to acetic acid solution (0.33 mol / L) or methylene chloride solution (0.33 mol / L) of alcohol compound. Addition of Libutyl (30 mol% of alcohol compound) and 5-fluoro-2-azaadamantane-N-oxyl (5 mol% of alcohol compound) and confirmation of the disappearance of the raw material alcohol with oxygen balloon attached at room temperature Stir vigorously until After completion of the reaction, water and methylene chloride were added for liquid separation, and the organic layer was washed with water to obtain the desired ketone or aldehyde.
　なお、アルコール化合物として３－フェニル－ｎ－プロパノールおよび４－フェニル－ｎ－ブタノールを用いた場合、3時間撹拌し続けるとカルボン酸が生成したので、これを水酸化ナトリウム水溶液で逆抽出した。次いで、塩酸で中和して再度塩化メチレンで抽出することにより、目的とするカルボン酸を単離した。
　上記と同様にアルコール化合物の酸化反応を行った例を、それぞれの反応式、及び表で示す。 When 3-phenyl-n-propanol and 4-phenyl-n-butanol were used as alcohol compounds, carboxylic acid was produced when stirring was continued for 3 hours, and this was back-extracted with an aqueous sodium hydroxide solution. Subsequently, the objective carboxylic acid was isolated by neutralizing with hydrochloric acid and extracting again with methylene chloride.
The example which performed the oxidation reaction of the alcohol compound similarly to the above is shown by each reaction formula and a table | surface.
　なお、表中、t-Bu：ターシャリーブチル基、AZADO：２－アザアダマンタン－Ｎ－オキシル、1-F-AZADO：１－フルオロ－２－アザアダマンタン－Ｎ－オキシル、5-F-AZADO：５-フルオロ－２－アザアダマンタン－Ｎ－オキシル、1-Me-AZADO：１－メチル－２－アザアダマンタン－Ｎ－オキシル、1-Me-5-F-AZADO：１－メチル－５-フルオロ－２－アザアダマンタン－Ｎ－オキシル、5,7-F2-1-Me-AZADO：５，７－ジフルオロ－１－メチル－２－アザアダマンタン－Ｎ－オキシル、1-Me-5-OH-AZADO：１－メチル－５-ヒドロキシ－２－アザアダマンタン－Ｎ－オキシル、5-MeO-1-Me-AZADO：５－メトキシ－１－メチル－２－アザアダマンタン－Ｎ－オキシル、5-OH-AZADO：5－ヒドロキシ－２－アザアダマンタン－Ｎ－オキシル、ABNO：9-アザビシクロ[3.3.1]ノナンN-オキシルを、それぞれ表す。 In the table, t-Bu: tertiary butyl group, AZADO: 2-azaadamantane-N-oxyl, 1-F-AZADO: 1-fluoro-2-azaadamantane-N-oxyl, 5-F-AZADO: 5-Fluoro-2-azaadamantane-N-oxyl, 1-Me-AZADO: 1-methyl-2-azaadamantane-N-oxyl, 1-Me-5-F-AZADO: 1-methyl-5-fluoro- 2-Azaadamantane-N-oxyl, 5,7-F 2 -1-Me-AZADO: 5,7-difluoro-1-methyl-2-azaadamantane-N-oxyl, 1-Me-5-OH-AZADO : 1-methyl-5-hydroxy-2-azaadamantane-N-oxyl, 5-MeO-1-Me-AZADO: 5-methoxy-1-methyl-2-azaadamantane-N-oxyl, 5-OH-AZADO : 5-hydroxy-2-azaadamantane-N-oxyl, ABNO: 9-azabicyclo [3.3.1] nonane N-oxyl, respectively The
　表中、Entryは実施例の番号を、substrateは基質を、productは生成物を、cat.またはcatalystは触媒を、Time(h)は反応時間（単位：時間）を、Yieldは収率を、recoverは原料回収を、Noteは備考を、methyl esterはメチルエステルを、carboxylic acidはカルボン酸を、traceは痕跡量を、balloonは風船を、rtは室温を、refは参考を、それぞれ表す。 In the table, Entry is the example number, substrate is the substrate, product is the product, cat. Or catalyst is the catalyst, Time (h) is the reaction time (unit: time), Yield is the yield, recover represents raw material recovery, Note represents remarks, methyl ester represents methyl ester, carboxylic acid represents carboxylic acid, trace represents trace amount, balloon represents balloon, rt represents room temperature, and ref represents reference.
　また、濃度や使用量が通常と異なる場合は、注釈を付けて示した。
　さらに、反応式中のNaNO2は亜硝酸ナトリウムを、FeCl3・6H2Oは塩化第二鉄・６水和物を、AcOHは酢酸を、t-BuONOは亜硝酸ターシャリーブチルを、CH2N2はジアゾメタンを表す。
　また、表中、「ＮＲ」は反応が進行しなかったことを示し、「－」は測定しなかったことを示し、「ＧＣ　yield」とは、ガスクロマトフラフ法による収率の測定結果を示す。 In addition, when the concentration and the amount used are different from usual, they are annotated.
Furthermore, NaNO 2 in the reaction formula is sodium nitrite, FeCl 3 · 6H 2 O is ferric chloride · hexahydrate, AcOH is acetic acid, t-BuONO is tertiary butyl nitrite, CH 2 N 2 represents diazomethane.
In the table, “NR” indicates that the reaction did not proceed, “−” indicates that the reaction was not measured, and “GC yield” indicates the measurement result of the yield by the gas chromatography fluff method. .
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　実施例３：酸化反応の溶媒を変更した反応例
３－１　MeCN/AcOH系溶媒
　反応容器に、2-オクタノール（3.91g）、２－アザアダマンタン－N－オキシル（0.0229g）、アセトニトリル（7.8g）、酢酸（3.6g）およびNaNO2（0.831g）を順次に加え、反応容器内を酸素置換した後、酸素雰囲気下（0.1MPa）（ゲージ圧、以下、同様である。）、室温にて4時間撹拌した。目的の2-オクタノンの収率は98%(GC yield（ガスクロマトフラフ法による収率の測定、以下、同様である。)であった。
３－２　H2O/AcOH系溶媒
　反応容器に、2-オクタノール（3.91g）、２－アザアダマンタン－N－オキシル（0.0227g）、H2O（7.81g）、酢酸（3.61g）およびNaNO2（0.827g）を順次に加え、反応容器内を酸素置換した後、酸素雰囲気下（0.1MPa）、室温にて7時間撹拌した。目的とする2-オクタノンの収率は84%（GC yield）であった。 Example 3: Reaction example 3 in which the solvent for the oxidation reaction was changed 3-1 MeCN / AcOH solvent In a reaction vessel, 2-octanol (3.91 g), 2-azaadamantane-N-oxyl (0.0229 g), acetonitrile (7.8 g ), Acetic acid (3.6 g) and NaNO 2 (0.831 g) in this order, and the inside of the reaction vessel was purged with oxygen, and then in an oxygen atmosphere (0.1 MPa) (gauge pressure, the same applies hereinafter) at room temperature. Stir for 4 hours. The yield of the desired 2-octanone was 98% (GC yield (measurement of yield by gas chromatography method, the same applies hereinafter)).
3-2 H 2 O / AcOH solvent In a reaction vessel, add 2-octanol (3.91 g), 2-azaadamantane-N-oxyl (0.0227 g), H 2 O (7.81 g), acetic acid (3.61 g) and NaNO 2 (0.827 g) was sequentially added, and the inside of the reaction vessel was purged with oxygen, and then stirred at room temperature for 7 hours in an oxygen atmosphere (0.1 MPa). The yield of the desired 2-octanone was 84% (GC yield).
　実施例４　Ｎ－ヒドロキシ－２－アザアダマンタン化合物を用いる系での反応
　反応容器に、2-オクタノール（1.30g）、N－ヒドロキシ－２－アザアダマンタン（0.0154g）、酢酸（3.9g）およびNaNO2（0.415g）を順次に加え、反応容器内を酸素置換した後、酸素雰囲気下（0.1MPa）室温にて15時間撹拌した。目的とする2-オクタノンの収率は89%（GC yield）であった。 Example 4 Reaction in a system using an N-hydroxy-2-azaadamantane compound In a reaction vessel, 2-octanol (1.30 g), N-hydroxy-2-azaadamantane (0.0154 g), acetic acid (3.9 g) and NaNO 2 (0.415 g) was sequentially added, and the inside of the reaction vessel was purged with oxygen, and then stirred at room temperature for 15 hours in an oxygen atmosphere (0.1 MPa). The target yield of 2-octanone was 89% (GC yield).
　実施例５：硝酸を用いた系での反応
　反応容器に、2-オクタノール（0.392g）、２－アザアダマンタン－N－オキシル(AZADO)（0.0135g）、酢酸（1.2g）および65質量% 硝酸水溶液（0.0288g）、を順次に加え、反応容器を酸素置換した後、酸素雰囲気下（0.1MPa）室温にて7時間撹拌した。目的とする2-オクタノンの収率は99%であった。 Example 5: Reaction in a system using nitric acid In a reaction vessel, 2-octanol (0.392 g), 2-azaadamantane-N-oxyl (AZADO) (0.0135 g), acetic acid (1.2 g) and 65% by mass nitric acid An aqueous solution (0.0288 g) was sequentially added, and the reaction vessel was purged with oxygen, and then stirred at room temperature in an oxygen atmosphere (0.1 MPa) for 7 hours. The yield of the desired 2-octanone was 99%.
　実施例６　オキソアンモニウムハロゲン化物塩の製造例
実施例６－１：塩化物塩の製造
　1‐Me‐AZADO（1920 mg, 11.55 mmol）のCCl4 （23.1 mL, 0.5 M）溶液中に室温下塩素ガスを吹き込み激しく攪拌した。析出した結晶をグラスフィルターにて濾取し、冷却したEt2Oにより洗浄し、減圧下乾燥を行い、1‐Me‐AZADO+Cl-を得た（2316 mg, 99%）。
実施例６－２：臭化物塩の製造
　臭素を用い、実施例６－１と同様の手法で、1‐Me‐AZADO+Br-（実際のカウンターイオンはBr3 -）を得た。 Example 6 Preparation Example of Oxoammonium Halide Salt Example 6-1: Preparation of Chloride Salt Chlorine at room temperature in a solution of 1-Me-AZADO (1920 mg, 11.55 mmol) in CCl 4 (23.1 mL, 0.5 M) Gas was blown in and stirred vigorously. The precipitated crystals were collected by filtration with a glass filter, washed with cooled Et 2 O, and dried under reduced pressure to obtain 1-Me-AZADO + Cl − (2316 mg, 99%).
Example 6-2: Using the preparation bromine bromide, in the same manner as in Example 6-1, 1-Me-AZADO + Br - ( actual counter ions Br 3 -) was obtained.
　実施例７：オキソアンモニウム硝酸塩の製造
　5-F-AZADO (16 mg, 0.094 mmol) のEt2O溶液 (赤色)に、濃HNO3に銅粉を加えて発生させたNO2ガスを水浴下で吹き込んだ。溶液の色が透明になったのを確認し、析出した固体をろ過した。その後、析出した黄色い固体をEt2Oでよく洗浄した。得られた固体を真空ポンプで減圧下乾燥し、5-F-AZADO+NO3 － (20.5 mg, 0.088 mmol, 94 %) を黄色固体として得た。 Example 7: Preparation of oxoammonium nitrate NO 2 gas generated by adding copper powder to concentrated HNO 3 to Et 2 O solution (red) of 5-F-AZADO (16 mg, 0.094 mmol) in a water bath Infused. After confirming that the color of the solution became transparent, the precipitated solid was filtered. Thereafter, the precipitated yellow solid was thoroughly washed with Et 2 O. The obtained solid was dried under reduced pressure with a vacuum pump to obtain 5-F-AZADO + NO 3 − (20.5 mg, 0.088 mmol, 94%) as a yellow solid.
　同様に、以下のオキソアンモニウム塩を製造した。
5-F-AZADO+NO3 －
IR (neat): ν =1628, 1372, 1333 cm-1
Anal: Calcd. for C9H13FN2O4: C, 46.55; H, 5.64; N, 12.06．Found: C, 46.26; H, 5.73; N, 11.86．
1-Me-AZADO+NO3 －
IR (neat): ν =1617, 1366, 1333 cm-1
Anal: Calcd. for C10H16N2O4: C, 52.62; H, 7.07; N, 12.27． 
5-F-1-Me-AZADO+NO3 －
IR (neat): ν =1634, 1462, 1334 cm-1
Anal: Calcd. for C10H15FN2O4: C, 48.78; H, 6.14; N, 11.38．Found: C, 48.55; H, 5.99; N, 11.24．
TEMPO+NO3 －
IR (neat): ν =1620, 1470, 1321 cm-1
Anal: Calcd. for C9H18N2O4: C, 49.53; H, 8.31; N, 12.84．Found: C, 49.26; H, 8.07; N, 12.78．
ABNO+NO3 －
IR (neat): ν =1627, 1320 cm-1
AZADO+NO3 －
IR (neat): ν =1633, 1615, 1332 cm-1
　実施例８　AZADOオキソアンモニウム塩化物塩を用いる系
　反応容器に、2-オクタノール（1.30g）、２－アザアダマンタン－N－オキソアンモニウム塩化物塩（0.0187g）、酢酸（3.9g）およびNaNO2（0.417g）を左記の順に加え、反応容器内を酸素置換した後、酸素雰囲気下（0.1MPa）室温にて15時間撹拌した。目的とする2-オクタノンの収率は90%（GC yield）であった。 Similarly, the following oxoammonium salts were prepared.
5-F-AZADO + NO 3 -
IR (neat): ν = 1628, 1372, 1333 cm -1
Anal: Calcd. For C 9 H 13 FN 2 O 4 : C, 46.55; H, 5.64; N, 12.06. Found: C, 46.26; H, 5.73; N, 11.86.
1-Me-AZADO + NO 3 -
IR (neat): ν = 1617, 1366, 1333 cm -1
Anal: Calcd. For C 10 H 16 N 2 O 4 : C, 52.62; H, 7.07; N, 12.27.
5-F-1-Me- AZADO + NO 3 -
IR (neat): ν = 1634, 1462, 1334 cm -1
Anal: Calcd. For C 10 H 15 FN 2 O 4 : C, 48.78; H, 6.14; N, 11.38. Found: C, 48.55; H, 5.99; N, 11.24.
TEMPO + NO 3 -
IR (neat): ν = 1620, 1470, 1321 cm -1
Anal: Calcd. For C 9 H 18 N 2 O 4 : C, 49.53; H, 8.31; N, 12.84. Found: C, 49.26; H, 8.07; N, 12.78.
ABNO + NO 3 -
IR (neat): ν = 1627, 1320 cm -1
AZADO + NO 3 -
IR (neat): ν = 1633, 1615, 1332 cm -1
Example 8 System Using AZADO Oxoammonium Chloride Salt In a reaction vessel, 2-octanol (1.30 g), 2-azaadamantane-N-oxoammonium chloride salt (0.0187 g), acetic acid (3.9 g) and NaNO 2 ( 0.417 g) was added in the order shown on the left, and the inside of the reaction vessel was purged with oxygen, and then stirred at room temperature in an oxygen atmosphere (0.1 MPa) for 15 hours. The target yield of 2-octanone was 90% (GC yield).
　実施例９：オキソアンモニウム硝酸塩を用いた酸素酸化
　アルコール化合物の酢酸又は塩化メチレン溶液に５－フルオロ－２－アザアダマンタンのオキソアンモニウム硝酸塩(アルコール化合物の５mol％)を加えて室温下、原料のアルコール化合物の消失が確認されるまで激しく撹拌した。反応終了後、水と塩化メチレンを加えて分液し、有機層を水洗することにより、目的のケトン又はアルデヒドを得た。 Example 9: Oxygen oxidation using oxoammonium nitrate Oxoammonium nitrate of 5-fluoro-2-azaadamantane (5 mol% of the alcohol compound) was added to an acetic acid or methylene chloride solution of the alcohol compound, and the starting alcohol compound at room temperature. The mixture was stirred vigorously until disappearance was confirmed. After completion of the reaction, water and methylene chloride were added for liquid separation, and the organic layer was washed with water to obtain the desired ketone or aldehyde.
　具体的には、反応容器に、2-オクタノール（1.30g）、２－アザアダマンタン－N－オキソアンモニウム硝酸塩（0.0214g）、酢酸（3.91g）およびNaNO2（0.413g）を左記の順に加え、反応容器内を酸素置換した後、酸素雰囲気下（0.1MPa）室温にて15時間撹拌した。目的とする2-オクタノンの収率は92%（GC yield）であった。 Specifically, 2-octanol (1.30 g), 2-azaadamantane-N-oxoammonium nitrate (0.0214 g), acetic acid (3.91 g) and NaNO 2 (0.413 g) were added to the reaction vessel in the order shown on the left. The inside of the reaction vessel was purged with oxygen, and then stirred at room temperature in an oxygen atmosphere (0.1 MPa) for 15 hours. The target yield of 2-octanone was 92% (GC yield).
　同様に反応を行った例を、表で示す。なお、表中、Entryは実施例の番号を、Substrateは基質を、Time (h)は反応時間（ｈは時間、dayは日）を、Yieldは収率を、recoverは原料回収を、Noteは備考を、traceは痕跡量を、balloonは風船を、rtは室温を、それぞれ表す。また、反応条件が通常と異なる場合は付記した。 Examples of similar reactions are shown in the table. In the table, Entry is the example number, Substrate is the substrate, Time 、 (h) is the reaction time (h is time, day is day), Yield is the yield, recover is the raw material recovery, and Note is Remarks, trace represents the trace amount, balloon represents the balloon, and rt represents the room temperature. In addition, when reaction conditions are different from usual, it is added.
　さらに、表中の以下の各略号は、以下の基、あるいは化合物を表す。
　Airは空気を、TBSはターシャリーブチルジメチルシリル基を、Cbzはベンジルオキシカルボニル基を、Bzはベンゾイル基を、Acはアセチル基を、Meはメチル基を、Phはフェニル基を、THPはテトラヒドロピランを、HFIPは1,1,1,3,3,3-ヘキサフルオロ-2-プロパノールを、DMSOはジメチルスルホキシドを表す。また、5-F-AZADO+NO3 -は、5-フルオロ-2-アザアダマンタンのオキソアンモニウム硝酸塩を表す。
実施例９－１ Further, the following abbreviations in the table represent the following groups or compounds.
Air is air, TBS is tertiary butyldimethylsilyl group, Cbz is benzyloxycarbonyl group, Bz is benzoyl group, Ac is acetyl group, Me is methyl group, Ph is phenyl group, THP is tetrahydro Pyran, HFIP represents 1,1,1,3,3,3-hexafluoro-2-propanol, and DMSO represents dimethyl sulfoxide. Furthermore, 5-F-AZADO + NO 3 - represents an oxo ammonium nitrate 5-fluoro-2-aza-adamantane.
Example 9-1
Figure JPOXMLDOC01-appb-C000024
 実施例９－２
Figure JPOXMLDOC01-appb-C000024
 Example 9-2
Figure JPOXMLDOC01-appb-C000025
 実施例９－３
Figure JPOXMLDOC01-appb-C000025
 Example 9-3
Figure JPOXMLDOC01-appb-C000026
 実施例９－４
Figure JPOXMLDOC01-appb-C000026
 Example 9-4
Figure JPOXMLDOC01-appb-C000027
実施例９－５
Figure JPOXMLDOC01-appb-C000027
Example 9-5
Figure JPOXMLDOC01-appb-C000028
実施例９－６
Figure JPOXMLDOC01-appb-C000028
Example 9-6
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　本発明は、各種のアルコールの酸化を、空気中の酸素により、加熱や有毒な重金属化合物を必要とせずに、穏和な条件でほぼ選択的に行って、アルデヒド化合物、ケトン化合物及び／又はカルボン酸化合物を製造することが可能であり、工業的に極めて有用である。 The present invention oxidizes various alcohols with oxygen in the air, almost selectively under mild conditions without the need for heating or toxic heavy metal compounds, and provides aldehyde compounds, ketone compounds and / or carboxylic acids. The compound can be produced and is extremely useful industrially.
　なお、２００８年５月３０日に出願された日本特許出願２００８－１４３２００号及び２００８年９月５日に出願された日本特許出願２００８－２２８７２１号の明細書、特許請求の範囲、及び要約書の全内容をここに引用し、本発明の明細書の開示として、取り入れるものである。 The specification, claims, and abstract of Japanese Patent Application No. 2008-143200 filed on May 30, 2008 and Japanese Patent Application No. 2008-228721 filed on September 5, 2008 are as follows. The entire contents are hereby incorporated by reference as the disclosure of the specification of the present invention.

Claims (6)

  1. 　式（１）：
    Figure JPOXMLDOC01-appb-C000001
     (式中、R1は、水素原子、ハロゲン原子、ニトロ基、シアノ基、ヒドロキシ基、メルカプト基、アミノ基、ホルミル基、カルボキシル基、スルホ基、直鎖または分岐鎖であるC1-12アルキル基、C3-12シクロアルキル基、（C1-12アルキル）オキシ基、（C3-12シクロアルキル）オキシ基、（C1-12アルキル）チオ基、（C3-12シクロアルキル）チオ基、（C1-12アルキル）アミノ基、（C3-12シクロアルキル）アミノ基、ジ（C1-6アルキル）アミノ基、ジ（C3-6シクロアルキル）アミノ基、C1-12アルキルカルボニル基、C3-12シクロアルキルカルボニル基、（C1-12アルキル）オキシカルボニル基、（C3-12シクロアルキル）オキシカルボニル基、（C1-12アルキル）チオカルボニル基、（C3-12シクロアルキル）チオカルボニル基、（C1-12アルキル）アミノカルボニル基、（C3-12シクロアルキル）アミノカルボニル基、ジ（C1-6アルキル）アミノカルボニル基、ジ（C3-6シクロアルキル）アミノカルボニル基、（C1-12アルキル）カルボニルオキシ基、（C3-12シクロアルキル）カルボニルオキシ基、（C1-12アルキル）カルボニルチオ基、（C3-12シクロアルキル）カルボニルチオ基、（C1-12アルキル）カルボニルアミノ基、（C3-12シクロアルキル）カルボニルアミノ基、ジ（C1-12アルキルカルボニル）アミノ基、ジ（C3-12シクロアルキルカルボニル）アミノ基、C1-6ハロアルキル基、C3-6ハロシクロアルキル基、C2-6アルケニル基、C3-6シクロアルケニル基、C2-6ハロアルケニル基、C3-6ハロシクロアルケニル基、C2-6アルキニル基、C2-6ハロアルキニル基、Raで置換されていてもよいベンジル基、Raで置換されていてもよいベンジルオキシ基、Raで置換されていてもよいベンジルチオ基、Raで置換されていてもよいベンジルアミノ基、Raで置換されていてもよいジベンジルアミノ基、Raで置換されていてもよいベンジルカルボニル基、Raで置換されていてもよいベンジルオキシカルボニル基、Raで置換されていてもよいベンジルチオカルボニル基、Raで置換されていてもよいベンジルアミノカルボニル基、Raで置換されていてもよいジベンジルアミノカルボニル基、Raで置換されていてもよいベンジルカルボニルオキシ基、Raで置換されていてもよいベンジルカルボニルチオ基、Raで置換されていてもよいベンジルカルボニルアミノ基、Raで置換されていてもよいジ（ベンジルカルボニル）アミノ基、Raで置換されていてもよいアリール基、Raで置換されていてもよいアリールオキシ基、Raで置換されていてもよいアリールチオ基、Raで置換されていてもよいアリールアミノ基、Raで置換されていてもよいジアリールアミノ基、Raで置換されていてもよいアリールカルボニル基、Raで置換されていてもよいアリールオキシカルボニル基、Raで置換されていてもよいアリールチオカルボニル基、Raで置換されていてもよいアリールアミノカルボニル基、Raで置換されていてもよいジアリールアミノカルボニル基、Raで置換されていてもよいアリールカルボニルオキシ基、Raで置換されていてもよいアリールカルボニルチオ基、Raで置換されていてもよいアリールカルボニルアミノ基、及びRaで置換されていてもよいジ（アリールカルボニル）アミノ基からなる群から選ばれる１以上の置換基を表し、置換基の数が２以上である場合は、それぞれの置換基は同じでも異なっていてもよく、
    　R4およびR5は、それぞれ独立にR1と同じ意味を表すか、またはR4とR5とが一緒になってR1で置換されていてもよいメチレン基を形成していてもよく、
    　Raは、ハロゲン、Ｃ1-6アルキル基、Ｃ1-6ハロアルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、Ｃ1-6アルキルスルフェニルＣ1-6アルキル基、Ｃ1-6ハロアルコキシ基、Ｃ1-6アルキルスルフェニル基、Ｃ1-6アルキルスルフィニル基、Ｃ1-6アルキルスルホニル基、Ｃ1-6ハロアルキルスルフェニル基、Ｃ1-6ハロアルキルスルフィニル基、Ｃ1-6ハロアルキルスルホニル基、Ｃ2-6アルケニル基、Ｃ2-6ハロアルケニル基、Ｃ2-6アルケニルオキシ基、Ｃ2-6ハロアルケニルオキシ基、Ｃ2-6アルケニルスルフェニル基、Ｃ2-6アルケニルスルフィニル基、Ｃ2-6アルケニルスルホニル基、Ｃ2-6ハロアルケニルスルフェニル基、Ｃ2-6ハロアルケニルスルフィニル基、Ｃ2-6ハロアルケニルスルホニル基、Ｃ2-6アルキニル基、Ｃ2-6ハロアルキニル基、Ｃ2-6アルキニルオキシ基、Ｃ2-6ハロアルキニルオキシ基、Ｃ2-6アルキニルスルフェニル基、Ｃ2-6アルキニルスルフィニル基、Ｃ2-6アルキニルスルホニル基、Ｃ2-6ハロアルキニルスルフェニル基、Ｃ2-6ハロアルキニルスルフィニル基、Ｃ２～Ｃ６ハロアルキニルスルホニル基、－ＮＯ２、－ＣＮ、ホルミル基、－ＯＨ、－ＳＨ、－ＮH２、－ＳＣＮ、Ｃ1-6アルコキシカルボニル基、Ｃ1-6アルキルカルボニル基、Ｃ1-6ハロアルキルカルボニル基、Ｃ1-6アルキルカルボニルオキシ基、フェニル基、Ｃ1-6アルキルアミノ基またはジＣ1-6アルキルアミノ基であって、
    　置換するRaの数は１～５個であり、Raが２個以上の場合は、それぞれの置換基は同じでも異なっていてもよく、
    　N-OはN-O・を表すか、N-OHを表すか、またはN+(=O)X-を表し、Ｘ-はF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ ‐、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-またはCF3SO2O-を表す。)で表される多環式化合物の存在下、亜硝酸化合物または硝酸の存在下（但し、N-OがN+(=O)X-であってX-がNO3 -である場合は、亜硝酸化合物または硝酸の存在下又は非存在下）、アルコール化合物を酸素で酸化することを特徴とする酸化方法。     Formula (1):
    Figure JPOXMLDOC01-appb-C000001
     Wherein R 1 is a hydrogen atom, halogen atom, nitro group, cyano group, hydroxy group, mercapto group, amino group, formyl group, carboxyl group, sulfo group, linear or branched C 1-12 alkyl Group, C 3-12 cycloalkyl group, (C 1-12 alkyl) oxy group, (C 3-12 cycloalkyl) oxy group, (C 1-12 alkyl) thio group, (C 3-12 cycloalkyl) thio group Group, (C 1-12 alkyl) amino group, (C 3-12 cycloalkyl) amino group, di (C 1-6 alkyl) amino group, di (C 3-6 cycloalkyl) amino group, C 1-12 Alkylcarbonyl group, C 3-12 cycloalkylcarbonyl group, (C 1-12 alkyl) oxycarbonyl group, (C 3-12 cycloalkyl) oxycarbonyl group, (C 1-12 alkyl) thiocarbonyl group, (C 3 -12 cycloalkyl) thiocarbonyl group, (C 1-12 alkyl) aminocarbonyl , (C 3-12 cycloalkyl) aminocarbonyl group, di (C 1-6 alkyl) aminocarbonyl group, di (C 3-6 cycloalkyl) aminocarbonyl group, (C 1-12 alkyl) carbonyloxy group, ( C 3-12 cycloalkyl) carbonyloxy group, (C 1-12 alkyl) carbonylthio group, (C 3-12 cycloalkyl) carbonylthio group, (C 1-12 alkyl) carbonylamino group, (C 3-12 Cycloalkyl) carbonylamino group, di (C 1-12 alkylcarbonyl) amino group, di (C 3-12 cycloalkylcarbonyl) amino group, C 1-6 haloalkyl group, C 3-6 halocycloalkyl group, C 2 -6 alkenyl group, C 3-6 cycloalkenyl group, C 2-6 haloalkenyl group, C 3-6 halocycloalkenyl group, C 2-6 alkynyl group, C 2-6 haloalkynyl group, substituted with Ra which may be a benzyl group, optionally substituted by R a There benzyloxy group, R a with an optionally substituted benzylthio group, R a in the optionally substituted benzylamino group, R a in the optionally substituted dibenzylamino group, substituted by R a which may be benzylcarbonyl radical, R a in the optionally substituted benzyloxycarbonyl radical, R a with optionally substituted benzyl thiocarbonyl radical, R a with optionally substituted benzyl aminocarbonyl radical, R a dibenzylaminocarbonyl group optionally substituted with a , a benzylcarbonyloxy group optionally substituted with R a , a benzylcarbonylthio group optionally substituted with R a , and optionally substituted with R a good benzylcarbonyl group, optionally substituted with R a di (benzylcarbonyl) amino group, R a with an optionally substituted aryl group, substituted by R a Also an aryloxy group, R a with an optionally substituted arylthio group, R a with an optionally substituted arylamino group, R a in the optionally substituted diarylamino group, optionally substituted with R a be aryl group, R a with optionally substituted aryloxycarbonyl group, optionally substituted with R a arylthiocarbonyl group, R a with optionally substituted arylaminocarbonyl radical, R optionally substituted diarylamino group in a, R a with optionally substituted arylcarbonyl group, R a in the optionally substituted aryl carbonyl thio group, may be substituted by R a Represents one or more substituents selected from the group consisting of an arylcarbonylamino group and a di (arylcarbonyl) amino group optionally substituted with R a ; When the number of groups is 2 or more, each substituent may be the same or different,
    R 4 and R 5 each independently represent the same meaning as R 1 , or R 4 and R 5 may be taken together to form a methylene group that may be substituted with R 1 ,
    R a is halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, C 1- 6 alkylsulfenyl C 1-6 alkyl group, C 1-6 haloalkoxy group, C 1-6 alkylsulfenyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 haloalkylsulfenyl Phenyl group, C 1-6 haloalkylsulfinyl group, C 1-6 haloalkylsulfonyl group, C 2-6 alkenyl group, C 2-6 haloalkenyl group, C 2-6 alkenyloxy group, C 2-6 haloalkenyloxy group , C 2-6 alkenyl Le phenyl group, C 2-6 alkenylsulfinyl group, C 2-6 alkenyl-sulfonyl group, C 2-6 halo alkenyl Le phenyl group, C 2-6 halo alkenylsulfinyl group, C 2-6 halo alkenylsulfonyl group, C 2-6 Al Alkenyl group, C 2-6 haloalkynyl group, C 2-6 alkynyloxy group, C 2-6 haloalkynyl group, C 2-6 alkyl Nils Le phenyl group, C 2-6 alkynylsulfinyl group, C 2-6 alkynyl Sulfonyl group, C 2-6 haloalkynylsulfenyl group, C 2-6 haloalkynylsulfinyl group, C 2 -C 6 haloalkynylsulfonyl group, —NO 2 , —CN, formyl group, —OH, —SH, —NH 2 , -SCN, C 1-6 alkoxycarbonyl group, C 1-6 alkylcarbonyl group, C 1-6 haloalkylcarbonyl group, C 1-6 alkylcarbonyloxy group, phenyl group, C 1-6 alkylamino group or di A C 1-6 alkylamino group,
    The number of R a to be substituted is 1 to 5, and when R a is 2 or more, each substituent may be the same or different,
    NO represents NO ·, N-OH, or N + (= O) X − , where X − represents F − , Cl − , Br − , I − , ClO 2 − , ClO 4 − , IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2) 2 N -, CH 3 CO 2 − , CF 3 CO 2 − , 4-CH 3 C 6 H 4 SO 2 O — or CF 3 SO 2 O — is represented. Presence of a polycyclic compound represented by), the presence of nitrite or nitrate (however, NO is N + (= O) X - a a and wherein X - NO 3 - if it is, the nitrite An oxidation method comprising oxidizing an alcohol compound with oxygen in the presence or absence of a compound or nitric acid.
  2. 　前記亜硝酸化合物が式（２）
    Figure JPOXMLDOC01-appb-C000002
     （式中、R2は炭素数１から１０のアルキル基を表す）で表される亜硝酸エステル化合物である請求項１に記載の酸化方法。     The nitrous acid compound is represented by the formula (2)
    Figure JPOXMLDOC01-appb-C000002
     The oxidation method according to claim 1, wherein R 2 is a nitrite compound represented by the formula (wherein R 2 represents an alkyl group having 1 to 10 carbon atoms).
  3. 　前記亜硝酸化合物が亜硝酸又は亜硝酸塩である請求項１又は２に記載の酸化方法。 The oxidation method according to claim 1 or 2, wherein the nitrite compound is nitrous acid or nitrite.
  4. 　前記多環式化合物が、下記式
    （式中、Ｒ3はお互いに同一でも異なっていても良く、水素原子、フッ素原子、ヒドロキシ基、炭素数１から３のアルキル基または炭素数１から３のアルコキシ基を表し、但し、Ｒ3のうちいずれか１つ以上がフッ素原子またはヒドロキシ基であり、N-OはN-O・を表すか、N-OHを表すか、またはN+(=O)X-を表し、Ｘ-はF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ ‐、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-またはCF3SO2O-を表す。）で表される化合物である、請求項１～３のいずれかに記載の酸化方法。     The polycyclic compound has the following formula:
    (In the formula, R 3 may be the same or different from each other, and represents a hydrogen atom, a fluorine atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, provided that R 3 Any one or more of which is a fluorine atom or a hydroxy group, NO represents NO., Represents N-OH, or represents N + (= O) X − , X − represents F − , Cl -, Br -, I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2 ) 2 N - Table in representing a) -, CH 3 CO 2 - , CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O - or CF 3 SO 2 O. The oxidation method according to any one of claims 1 to 3, which is a compound to be produced.
  5. 　アルコール化合物を酸化してアルデヒド化合物、ケトン化合物及び／又はカルボン酸化合物を製造する請求項１～４のいずれかに記載の酸化方法。 The oxidation method according to any one of claims 1 to 4, wherein the alcohol compound is oxidized to produce an aldehyde compound, a ketone compound and / or a carboxylic acid compound.
  6. 　下記式
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ3はお互いに同一でも異なっていても良く、水素原子、フッ素原子、ヒドロキシ基、炭素数１から３のアルキル基または炭素数１から３のアルコキシ基を表し、但し、Ｒ3のうちいずれか１つ以上がフッ素原子またはヒドロキシ基であり、N-OはN-O・を表すか、N-OHを表すか、またはN+(=O)X-を表し、Ｘ-はF-、Cl-、Br-、I-、ClO2 -、ClO4 -、IO4 -、NO2 -、NO3 -、SO4 2-、BF4 -、PF6 -、SbCl5 -、SbF6 -、XeF２ ‐、(CF3 SO2) 2N-、CH3CO2 -、CF3CO2 -、4-CH3C6H4SO2O-またはCF3SO2O-を表す。）で表されることを特徴とする化合物。     Following formula
    Figure JPOXMLDOC01-appb-C000004
     (Wherein R 3 may be the same or different from each other, and represents a hydrogen atom, a fluorine atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, provided that R 3 Any one or more of them is a fluorine atom or a hydroxy group, NO represents NO., Represents N-OH, or represents N + (= O) X − , X − represents F − , Cl -, Br -, I -, ClO 2 -, ClO 4 -, IO 4 -, NO 2 -, NO 3 -, SO 4 2-, BF 4 -, PF 6 -, SbCl 5 -, SbF 6 -, XeF 2 -, (CF 3 SO 2 ) 2 N - Table in representing a) -, CH 3 CO 2 - , CF 3 CO 2 -, 4-CH 3 C 6 H 4 SO 2 O - or CF 3 SO 2 O. The compound characterized by being made.
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