JPWO2013191287A1 - Alcohol oxidation catalyst and alcohol oxidation method using the same - Google Patents

Abstract

An alcohol oxidation catalyst for oxidizing an alcohol, represented by the following general formula (1): ## STR1 ## wherein R1 represents a hydrogen atom or an alkyl group, and R2 has a hydrogen atom and a substituent. Any one selected from the group consisting of an optionally substituted alkyl group having 1 to 5 carbon atoms and an optionally substituted aromatic hydrocarbon group having 6 to 10 carbon atoms, wherein X is hetero; A group containing an atom (excluding a group represented by the following formula: -NO.-). ] The alcohol oxidation catalyst containing at least 1 sort (s) selected from the group which consists of a polycyclic N-oxyl compound represented by these, and its derivative (s).

Description

  The present invention relates to an alcohol oxidation catalyst and an alcohol oxidation method using the same.

  The alcohol oxidation reaction that oxidizes alcohol to carbonyl compounds is one of the most basic reactions used in organic synthesis of high value-added compounds such as pharmaceuticals, agricultural chemicals, fragrances, and chemical products. Methods have been developed. However, the conventional method requires safety and environment such as heating to a high temperature, the need to use toxic and explosive oxidants, and heavy metal and other waste. Had problems with the load.

  Against this background, in recent years, 2,2,6,6-tetramethylpiperidine 1-oxyl (2,2,6,6-tetramethylpiperidine 1-oxyl, hereinafter referred to as “TEMPO”) is toxic. Oxidation of alcohols can be carried out even on a large scale from the viewpoint that alcohols can be oxidized using various co-oxidants under extremely mild conditions from 0 ° C. to room temperature without using highly dangerous reagents. Has attracted attention as a catalyst.

Examples of the co-oxidant include an aqueous sodium hypochlorite aqueous solution (Pier Lucio Anelli et al., The Journal of Organic Chemistry, 1987, Vol. 52, which is inexpensive and environmentally friendly, which is also used in industrial processes. No. 12, p. 2559-2562 (Non-patent Document 1), iodobenzene diacetate (PhI (OAc)) having broad functional group compatibility applicable to alcohols having double bonds and electron-rich aromatic rings. ₂ ) (Antonella De Mico et al., The Journal of Organic Chemistry, 1997, 62, 20, p. 6974-6777 (Non-patent Document 2)) and many other oxidizing agents can be used. It has been reported.

  In addition, recently, the present inventors have developed an N-oxyl (nitroxyl radical) compound having an azaadamantane skeleton (2-azaadamantane N-oxyl (hereinafter referred to as “AZADO”) and 1-methyl-2-azaadamantane N— oxyl (hereinafter referred to as “1-Me-AZADO”)), an N-oxyl compound having an azabicyclo [3.3.1] nonane skeleton (9-azabicyclo [3.3.1] nonane N-oxyl, hereinafter “ABNO”). ], Polycyclic N-oxyl compounds such as N-oxyl compounds having a norazaadamantane skeleton (9-norazaadamantane N-oxyl, hereinafter referred to as “Nor-AZADO”) have higher alcohol oxidation than TEMPO. Catalytic activity And TEMPO has reported that oxidation of bulky secondary alcohol, which does not proceed with oxidation, can also proceed rapidly (Masutoshi Sugaya et al., Journal of the American Chemical Society, 2006, 128, 26, p.8412-8413 (Non-patent Document 3), Masatoshi Sugaya et al., Chemical Communications, 2009, 13, p.1739-1741 (Non-patent Document 4), Sugaya Masatoshi et al., The Journal of Organic Chemistry, 2009, 74, No. 12, p. 4619-4622 (Non-Patent Document 5), Masatoshi Sugaya et al., Synthesis, 2011, No. 21, p. 3418- 3425 (Non-patent Document 6), Masaki Hayashi et al., Chemical and Pharmaceutical Britain, 2011, 5 9, No. 12, p. 1570-1573 (Non-patent Document 7), pamphlet of International Publication No. 2006/001387 (Patent Document 1), Japanese Unexamined Patent Application Publication No. 2009-114143 (Patent Document 2), Japanese Unexamined Patent Application Publication No. 2008-212853. (Patent Document 3), International Publication No. 2012/008228 (Patent Document 4)).

  Journal of the American Chemical Society, 1974, 96:21, p. 6559-6568 (Non-patent Document 8) describes a compound in which two nitroxyl radicals are introduced into an azaadamantane skeleton, but this document describes nothing about using this compound as an alcohol oxidation catalyst. It has not been.

  Among various oxidants commonly used in alcohol oxidation reactions, oxygen (molecular oxygen) not only excels in operability, safety and economy, but also produces an oxidation system that produces only water as a by-product. Therefore, it is positioned as the most ideal oxidizer in recent years when the need for environmental conservation in the chemical industry is screamed. However, in recent years, many air oxidation reactions of alcohol using TEMPO as a catalyst have been studied, but the catalytic activity is not yet sufficient, and it is still difficult to proceed with the oxidation reaction of secondary alcohol quickly. Had the problem of being.

  In contrast, the present inventors catalyzed an N-oxyl compound (5-fluoro-2-azaadamantane N-oxyl, hereinafter referred to as “5-F-AZADO”) in which a fluorine atom is introduced at the 5-position of AZADO. (Mr. Toshiya, Journal of the American Chemical Society, 2011, Vol. 133, No. 17, p. 6497-6500 (Non-patent Document 9), International Publication No. 2009/145323 pamphlet (Patent Document 5)). According to these conditions, it is possible to quickly oxidize secondary alcohols or highly functionalized alcohols even under mild air oxidation conditions of normal temperature and normal pressure using oxygen as an oxidizing agent.

  However, since 5-F-AZADO is a compound in which a fluorine atom is introduced, the production process is complicated. In particular, in the step of introducing a fluorine atom into an azaadamantane skeleton, a C—H oxidation reaction using a heavy metal, It was necessary to carry out a reaction using an expensive fluorinating agent under low temperature conditions, and there was a problem that it was difficult to produce by a synthetic route directed to supplying a large amount of catalyst.

International Publication No. 2006/001387 Pamphlet JP 2009-114143 A JP 2008-212853 A International Publication No. 2012/008228 Pamphlet International Publication No. 2009/145323 Pamphlet

Pier Lucio Anelli et al., The Journal of Organic Chemistry, 1987, 52, 12, p. 2559-2562 Antonella De Mico et al., The Journal of Organic Chemistry, 1997, 62, 20, p. 6974-6777 Masatoshi Sugaya et al., Journal of the American Chemical Society, 2006, 128, 26, p. 8412-8413 Masatoshi Sugaya et al., Chemical Communications, 2009, No. 13, p. 1739-1741 Masatoshi Sugaya et al., The Journal of Organic Chemistry, 2009, 74, 12, p. 4619-4622 Masatoshi Sugaya et al., Synthesis, 2011, No. 21, p. 3418-3425 Masaki Hayashi et al., Chemical and Pharmaceutical Britain, 2011, 59, 12, p. 1570-1573 Rassat et al., Journal of the American Chemical Society, 1974, 96:21, p. 6559-6568 Masatoshi Sugaya et al., Journal of the American Chemical Society, 2011, Vol. 133, No. 17, p. 6497-6500

  The present invention has been made in view of the above-described problems of the prior art, and can exhibit sufficiently high catalytic activity in both secondary alcohol oxidation and air oxidation, and is easy to manufacture. An object of the present invention is to provide an alcohol oxidation catalyst and an alcohol oxidation method using the same.

The present inventors have made intensive studies to achieve the above objective, nitroxyl radical group at the 2-position aza adamantane skeleton (-NO · ^-) have, and, of the aza-adamantane skeleton 6 By using a heteropolycyclic N-oxyl compound in which the methylene carbon at the position is substituted with a heteroatom as an alcohol oxidation catalyst, the substrate is bulky even in air oxidation using oxygen as an oxidizing agent. It has been found that even an alcohol exhibits a sufficiently high alcohol oxidation catalytic activity.

  Furthermore, since the present inventors do not need to introduce | transduce a fluorine atom as a substituent like 5-F-AZADO, such a heteropolycyclic N-oxyl compound does not need to go through a complicated process. Thus, the present invention was completed.

That is, the alcohol oxidation catalyst of the present invention is
An alcohol oxidation catalyst that oxidizes alcohol,
The following general formula (1):

[In Formula (1), R ¹ represents a hydrogen atom or an alkyl group, and R ² has a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may have a substituent, and a substituent. Any one selected from the group consisting of aromatic hydrocarbon groups having 6 to 10 carbon atoms, wherein X is a group containing a hetero atom (excluding a group represented by the following formula: —NO ^· —) ). ]
It contains at least 1 sort (s) selected from the group which consists of the polycyclic N-oxyl compound represented by these, and its derivative (s).

Furthermore, as the alcohol oxidation catalyst of the present invention, X in the general formula (1) is an oxygen atom and the following general formula (2):
-NY- (2)
[In the formula (2), Y represents a group containing a sulfonyl group or an acyl group. ]
It is preferable that it is any one selected from the group consisting of groups represented by:

  The alcohol oxidation method of the present invention is characterized in that alcohol is oxidized in the presence of the alcohol oxidation catalyst and the cooxidant of the present invention, and the cooxidant is more preferably oxygen. .

  In the alcohol oxidation method of the present invention, the alcohol is preferably a primary alcohol or a secondary alcohol, and the amount of the polycyclic N-oxyl compound added is 100 mol of all hydroxy groups in the alcohol. The amount is preferably 0.001 to 150 mol.

  According to the present invention, an alcohol oxidation catalyst that can exhibit sufficiently high catalytic activity both in the oxidation of secondary alcohol and in air oxidation and that is easy to manufacture and an alcohol oxidation method using the same are provided. It becomes possible to provide.

  Hereinafter, the present invention will be described in detail with reference to preferred embodiments thereof.

First, the alcohol oxidation catalyst of the present invention will be described. The alcohol oxidation catalyst of the present invention is an alcohol oxidation catalyst that oxidizes alcohol,
The following general formula (1):

[In Formula (1), R ¹ represents a hydrogen atom or an alkyl group, and R ² has a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may have a substituent, and a substituent. Or any one selected from the group consisting of aryl groups having 6 to 10 carbon atoms, and X represents a group containing a hetero atom (excluding a group represented by the following formula: —NO ^· —). . ]
Containing at least one selected from the group consisting of a polycyclic N-oxyl compound represented by the formula:

[Polycyclic N-oxyl compound]
The polycyclic N-oxyl compound according to the present invention is a compound represented by the general formula (1). In the general formula (1), R ¹ represents a hydrogen atom or an alkyl group. The alkyl group is preferably an alkyl group having 1 to 5 carbon atoms. Examples of such an alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and an s-butyl group. Group, tert-butyl group, n-pentyl group and isopentyl group. Among these, R ¹ is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom, from the viewpoint of higher activity and easy synthesis.

In the general formula (1), R ² represents a hydrogen atom, an optionally substituted alkyl group having 1 to 5 carbon atoms, and an optionally substituted aromatic group having 6 to 10 carbon atoms. Any one selected from the group consisting of hydrocarbon groups is shown. The alkyl group having 1 to 5 carbon atoms may be linear or branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl. Group, s-butyl group, tert-butyl group, n-pentyl group and isopentyl group. In addition, examples of the aromatic hydrocarbon group having 6 to 10 carbon atoms include groups containing an aromatic ring, and examples thereof include a phenyl group, a tolyl group, a benzyl group, a phenethyl group, and a naphthyl group. Furthermore, examples of the substituent include a hydroxyl group (—OH), an azide group (—N ₃ ), and an acetylene group (—C ₂ ). Among these, R ² is preferably a hydrogen atom or a linear alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or a methyl group, from the viewpoint of higher activity and easy synthesis. More preferred is a hydrogen atom. Further, from the viewpoint that a functional group capable of imparting linking ability to a solid phase and water solubility can be introduced into the alcohol oxidation catalyst of the present invention, R ² is a straight chain having 1 to 5 carbon atoms. A chain alkyl group or a group in which the terminal of the linear alkyl group is substituted with the above-described substituent is preferable, and such a linear alkyl group is more preferably an n-butyl group.

In the general formula (1), X represents a group containing a hetero atom. Examples of the hetero atom include an oxygen atom (O), a nitrogen atom (N), a sulfur atom (S), and a phosphorus atom (P). By incorporating such a heteroatom at the 6-position of the azaadamantane skeleton, an excellent alcohol oxidation catalytic activity is exhibited when the polycyclic N-oxyl compound of the present invention is used as a catalyst. However, as X, a group represented by the following formula: —NO ^· — is excluded. In the present invention, the polycyclic N- oxyl compounds according to the present invention is such -NO · a ^- group represented by (hereinafter referred to nitroxyl radical group) to the position of the 2-position and 6-position of aza-adamantane skeleton Even without two, sufficiently high catalytic activity can be exhibited both in the oxidation of the secondary alcohol and in the air oxidation.

As such X, a sulfur atom or a phosphorus atom is susceptible to oxidation, but from the viewpoint of being less susceptible to oxidation, an oxygen atom and the following general formula (2):
-NY- (2)
It is preferable that it is any one selected from the group consisting of groups represented by: In the general formula (2), Y represents a group containing a sulfonyl group or an acyl group. Examples of the group containing a sulfonyl group (—SO ₂ —) include a tosyl group and a mesyl group, and examples of the acyl group include a benzoyl group, a pivaloyl group, and an acetyl group. Among these, X is an oxygen atom or a group in which Y in the above general formula (2) is a tosyl group (tosylamide group) from the viewpoint that stability tends to be excellent under reaction conditions during synthesis. preferable.

In addition, the polycyclic N-oxyl compound according to the present invention can exhibit higher catalytic activity both in the oxidation of the secondary alcohol and in the air, and is easier to manufacture. From the viewpoint, 6-oxa-2-azaadamantane N-oxyl (hereinafter referred to as 6-oxa-2-azaadamantane N-oxyl), wherein R ¹ and R ² in the formula (1) are hydrogen atoms and X is an oxygen atom, Optionally referred to as “Oxa-AZADO”), N-tosyl-2,6-diazaadamantane N′-oxyl in which R ¹ and R ^{2 in} formula (1) are hydrogen atoms and X is a tosylamide group N-tosyl-2,6-diazaadamantane N' -oxyl, optionally referred to as "N-Ts-AZADO".), ^{R 1} is water in the formula (1) An atom ^{R 2} is an alkyl group X is oxygen atom 7 alkyl-6-oxa-2-aza-adamantan N- oxyl (7-Alkyl-6-oxa -2-azaadamantane N-oxyl, optionally less "7-Alkyl-Oxa-AZADO") is preferred.

Since such a polycyclic N-oxyl compound does not need to introduce a fluorine atom as a substituent unlike 5-F-AZADO, it can be easily produced without going through complicated steps. As a method for producing such a polycyclic N-oxyl compound, from the viewpoint that the polycyclic N-oxyl compound of the present invention can be obtained more easily and reliably,
The following general formula (3):

[In the formula (3), R ¹ has the same meaning as R ¹ in the general formula (1), and Z represents a hydrogen atom, a benzyloxycarbonyl group, an alkyl group, a benzyl group, a group containing a sulfonyl group, and acyl. Any one selected from the group consisting of groups is shown. ]
The azabicyclo [3.3.1] nonane compound represented by general formula (4) is cyclized with a group containing a hetero atom:

[In the formula (4), R ¹ , R ² and X are each independently synonymous with R ¹ , R ² and X in the general formula (1), and Z is in the general formula (3). Is synonymous with Z. ]
Obtaining a polycyclic compound represented by:
And a step of obtaining the polycyclic N-oxyl compound represented by the general formula (1) by oxidizing the polycyclic compound.

In the general formula (3), ^{R 1} has the same meaning as ^{R 1} in the general formula (1). In the general formula (3), Z represents any one selected from the group consisting of a hydrogen atom, a benzyloxycarbonyl group, an alkyl group, a benzyl group, a group containing a sulfonyl group, and an acyl group. Examples of the group containing a sulfonyl group (—SO ₂ —) include a tosyl group and a mesyl group, and examples of the acyl group include a benzoyl group, a pivaloyl group, and an acetyl group. Moreover, as said alkyl group, a C1-C5 alkyl group is mentioned. Among these, a tosyl group is preferable from the viewpoint that side reactions are unlikely to occur during the cyclization reaction and tend to be hardly decomposed.

Such an azabicyclo [3.3.1] nonane compound represented by the general formula (3) includes, for example, acetone dicarboxylic acid, glutaraldehyde or corresponding δ-ketoaldehyde and ammonia as shown in the following reaction step. Condensation reaction is performed using water as a raw material (a in the reaction step). The hydrogen atom in the amino group of the bicyclo compound obtained in the presence of Na ₂ CO ₃ , NaOH, triethylamine, etc. It can be obtained by substituting Z with ZCl, ZBr, ZI) or an anhydride (Z-O-Z) (b in the reaction step).

The method for obtaining the polycyclic compound represented by the general formula (4) by cyclization of the azabicyclo [3.3.1] nonane compound with a group containing a hetero atom is not particularly limited. Among the polycyclic compounds represented by (4), for example, when obtaining a polycyclic compound in which X is an oxygen atom and R ² is a hydrogen atom, first, the azabicyclo [3.3.1] nonane is obtained. The carbonyl group of the compound is reduced to a hydroxy group at room temperature (about 25 ° C.) in the presence of an alkali metal hydride such as lithium aluminum hydride, nickel, platinum, copper, etc., and then iodine is added to the hydroxy group. after the hydrogen atom is iodinated, iodobenzene diacetate (PhI _{(OAc) 2),} La in the presence of an oxidizing agent such as lead acetate (Pb _{(OAc) 4)} Cal manner by deiodination and a method of engaged intramolecular condensation with. Examples of the intramolecular condensation method include a method of stirring using an incandescent bulb of 100 to 500 W while performing light irradiation from about 0 ° C. under ice cooling to about 25 ° C. at room temperature. A suitable example of this reaction step is shown below.

Further, among the polycyclic compounds represented by the general formula (4), for example, when obtaining a polycyclic compound in which X is a group represented by the general formula (2) and R ² is a hydrogen atom. For example, first, the carbonyl group of the azabicyclo [3.3.1] nonane compound in the presence of pyridine is converted to hydroxyamine (NH ₂ OH · HCl, NH ₂ OH, NH ₂ OH · H ₂ SO ₄ , NH ₂ OH · CH ₃ COOH, NH ₂ OH · H ₃ PO _4, etc.) to form an oxime group, and then borohydride for 2 to 3 hours under ice cooling (about 0 ° C.). After reducing the oxime group to an amino group in the presence of sodium, molybdenum oxide or the like, a part of the hydrogen atoms in the amino group is converted to a halogenated salt of Y (Y in Formula (2)) (for example, YCl, YBr, YI) etc. Substituted with Y Te, then after remaining hydrogen atoms in said amino group by the addition of iodine was iodinated, iodobenzene diacetate (PhI _{(OAc) 2),} lead acetate (Pb _{(OAc) 4)} And a method of radically deiodinating in the presence of an oxidant such as intramolecular condensation. The method for intramolecular condensation is as described above. A suitable example of this reaction step is shown below.

Further, among the polycyclic compounds represented by the general formula (4), for example, when obtaining a polycyclic compound in which X is an oxygen atom and R ² is an alkyl group, first, the azabicyclo [3 .3.1] carbonyl group nonane compounds, alkyl lithium or alkyl magnesium, and the like Grignard reagent (e.g. n- butyl Li), and the presence of additives such as CeCl ₃ as necessary, preferably at a temperature -78 Reduction to a hydroxy group and an alkyl group (for example, n-butyl group) within a range of −40 ° C., followed by addition of iodine to iodinate the hydrogen atom of the hydroxy group, followed by iodobenzene diacetate (PhI ( OAc) _2), free-radically method of condensing the molecule by deiodination in the presence of an oxidizing agent such as lead acetate (Pb _(OAc) 4) can be mentioned . The method for intramolecular condensation is as described above. A suitable example of this reaction step is shown below.

Among the polycyclic compounds represented by the general formula (4), for example, when obtaining a polycyclic compound in which X is an oxygen atom and R ² is an alkyl group having a substituent, the Grignard The reagent is, for example, the following formula: BrMg—R ³ —OTHP (wherein R ³ is selected from the group consisting of an alkylene group having 1 to 5 carbon atoms and a divalent aromatic hydrocarbon group having 6 to 10 carbon atoms). OTHP represents a hydroxy group protected with a tetrahydropyranyl group, and examples of R ³ include a butylene group and a group represented by —C ₆ H ₄ —C ₂ H ₄ — An alkyl group having a hydroxy group as a substituent can be introduced by deprotection after intramolecular condensation using a Grignard reagent represented by the following formula: Furthermore, by substituting the obtained hydroxy group, an alkyl group having an azido group (—N ₃ ) or an acetylene group (—C ₂ ) as a substituent can be introduced. In addition, as a method of substituting the hydroxy group with an azide group (—N ₃ ) or an acetylene group (—C ₂ ), a known method can be appropriately employed.

  By oxidizing the amino group (the amino group represented by the following formula: -NZ- in the above reaction step) in the polycyclic compound thus obtained to form a nitroxyl radical group, the above formula (1) The polycyclic N-oxyl compound of this invention represented by these can be obtained.

As such an oxidation method, for example, a urea-hydrogen peroxide adduct, sodium tungstate dihydrate (Na ₂ WO ₄ .2H ₂ O) in an organic solvent (for example, acetonitrile) solution of the polycyclic compound, Examples thereof include a method of adding an oxidizing agent such as NaOCl and stirring at room temperature of about 25 ° C. for 3 to 4 hours, and a method of blowing a gas containing active oxygen such as oxygen and ozone into the solution.

  In the method for producing a polycyclic N-oxyl compound according to the present invention, when an amino group is oxidized as described above, for example, during the reaction step, an amino group represented by the following formula: -NY- Since the reaction product is partially oxidized, among the polycyclic compounds represented by the general formula (1), X is a polycyclic compound according to the present invention in which X is a group represented by the general formula (2). A compound and a polycyclic compound having X as a nitroxyl radical group and having two nitroxyl radical groups in the molecule can be easily obtained in this way. In addition, the polycyclic N-oxyl compound based on this invention can be obtained by isolate | separating such a reaction product by column chromatography etc.

  As mentioned above, although the preferred embodiment of the manufacturing method of the polycyclic N-oxyl compound which concerns on this invention was mentioned as an example, the manufacturing method of the polycyclic N-oxyl compound of this invention is limited to this. Instead, for example, the reaction conditions can be appropriately adjusted according to the raw materials and reaction system used, and if necessary, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography It may further include a step of isolation and purification using a known separation and purification means such as.

  Furthermore, if necessary, a solvent may be used as appropriate, and as such a solvent, a known solvent that does not adversely influence the reaction can be used, for example, aromatic hydrocarbons, aliphatic hydrocarbons, Examples include esters, ethers, aliphatic halogen hydrocarbons, alcohols, amides, organic acids, water, and the like. One of these may be used alone, or two or more may be used in combination. . Among these, as the solvent, methanol, ethanol, propanol, isopropanol, n-butanol, ethyl acetate, butyl acetate, formic acid, acetic acid, hexamethylphosphoric amide, dimethylimidazolidinone, acetonitrile, N, N-dimethylformamide (DMF), dimethylacetamide, N-methylpiperidone, dimethylsulfoxide (DMSO), chloroform, dichloromethane, 1,2-dichloroethane, methylene chloride, dioxane, toluene, benzene, xylene, hexane, cyclohexane, pentane, heptane, tetrahydrofuran (THF) ), Diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxyethane, methylene chloride, and mixtures thereof.

  The alcohol oxidation catalyst of the present invention contains the polycyclic N-oxyl compound and / or its derivative. As the polycyclic N-oxyl compound, one kind may be contained alone, or two or more kinds may be contained in combination.

In addition, examples of the derivative of the polycyclic N-oxyl compound include a hydrate of the polycyclic N-oxyl compound represented by the formula (1) and a polycyclic N-oxyl compound represented by the formula (1). A hydroxylamine compound in which a hydrogen atom is bonded to a nitroxyl radical group therein to form a hydroxylamino group (a group represented by the following formula: —NOH—), and the nitroxyl radical group is an oxoammonium group (the following formula: = N Oxoammonium cation and a salt thereof, which may be a group represented by ═O ⁺ , may be used alone or in combination of two or more.

The salt is preferably a low toxicity salt, for example, a salt of a halogen atom with an anion (for example, Cl ⁻ , Br ⁻ , I ⁻ ), etc .; hydrochloride, hydrobromide, sulfate, formate , Acetate, propionate, fumarate, oxalate, maleate, citrate, succinate, tartrate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfone Inorganic acid salts and organic acid salts such as acid salts; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts, methylamine salts, ethylamine salts, trimethylamine Salt, triethylamine salt, aniline salt, pyridine salt, piperidine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanol Amine salt, dicyclohexylamine salt, N, include a nitrogen atom-containing salts such as N'- dibenzylethylenediamine salt.

  As the alcohol oxidation catalyst of the present invention, the polycyclic N-oxyl compound and / or a derivative thereof may be contained in an effective amount as a catalyst. It may further contain impurities derived from reagents used in the synthesis of N-oxyl compounds and / or derivatives thereof, impurities generated by purification, and the like.

  Next, an alcohol oxidation method using the alcohol oxidation catalyst of the present invention will be described. In the alcohol oxidation method of the present invention, the alcohol as a substrate may be a primary alcohol represented by the following general formula (5) or a secondary alcohol represented by the following general formula (6).

In the general formulas (5) to (6), R ⁴ , R ⁵ , and R ⁶ each independently represent a substituent that does not adversely affect the oxidation reaction. Examples thereof include a branched alkyl group, an optionally substituted cyclic alkyl group, an optionally substituted aromatic group, and an optionally substituted heterocyclic group. In addition, the alcohol according to the alcohol oxidation method of the present invention may be a polyhydric alcohol having a plurality of structural units represented by the general formulas (5) and (6) in the same molecule. From the viewpoint of proceeding more sufficiently, a monoalcohol having one hydroxy group is preferable.

  Examples of the alkyl group in the “optionally substituted linear or branched alkyl group” include an alkyl group having 1 to 16 carbon atoms, and among these, a C 1 to C 8 carbon group is included. Alkyl groups are preferred. Examples of such an alkyl group include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3 , 3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl Group, heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 2-methylheptyl group, 3-methylhexyl group, Ruhepuchiru group, 4-methylheptyl group, 5-methylheptyl group, 6-methylheptyl group, 1-propyl pentyl group, 2-ethylhexyl group, and 5,5-dimethylcyclohexyl are hexyl groups.

  The substituent of the alkyl group is not particularly limited as long as it does not affect the oxidation reaction. For example, the alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group; methoxy group, ethoxy group, C1-C6 alkoxy groups such as propoxy groups; Halogen atoms such as fluorine, chlorine, bromine and iodine; C2-C6 alkenyl groups such as vinyl groups and allyl groups; Carbon numbers such as ethynyl groups and propargyl groups 2-6 alkynyl groups; hydroxy groups; optionally substituted amino groups; optionally substituted sulfonyl groups; cyano groups; nitroso groups; optionally substituted amidino groups; carboxy groups; 7 an alkoxycarbonyl group; an optionally substituted carbamoyl group; an aromatic group; an aromatic heterocyclic group; an acyl group (an optionally substituted alkylcarbonyl group, Be conversion include aryl carbonyl group).

  Examples of the cyclic alkyl group in the “optionally substituted cyclic alkyl group” include cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cyclopeptyl group. . In addition, examples of the substituent of the cyclic alkyl group include the same substituents as those in the “optionally substituted alkyl group”.

  The aromatic group in the “optionally substituted aromatic group” includes, for example, a monocyclic or condensed polycyclic aromatic carbocyclic group, and specifically includes a phenyl group, a naphthyl group, Examples include an aryl group having 2 to 14 carbon atoms such as an anthryl group, an azulenyl group, a phenanthryl group, and an acenaphthylenyl group.

  The heterocyclic ring in the “optionally substituted heterocyclic group” may be a 5-membered monocyclic ring, a 6-membered monocyclic ring, 6-5 or 6-6 An aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as a heteroatom may be used. Specific examples of such heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiadi. Zolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, furazanyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl Group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazonyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group and the like monocyclic aromatic heterocyclic group; benzofuranyl group , Isobenzoxalyl group, 1,2-benzisoxazolyl group, benzothiazolyl group, benzopyranyl group, Zisoisothiazolyl group, 1H-benzotriazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, buteridinyl group, carbazolinyl group, α-carbolinyl group, β-carbolinyl group , Γ-carbolinyl group, acridinyl group, phenoxazinyl group, phenothiazinyl group, phenazinyl group, phenoxathiinyl group, thiantenyl group, phenatolidinyl group, phenatrolinyl group, indolizinyl group, pyrrolo [1,2-b] pyridazinyl group, pyrazolo [ 1,5-a] pyridyl group, imidazo [1,2-a] pyridyl group, imidazo [1,5-a] pyridyl group, imidazo [1,2-b] pyridazinyl group, imidazo [1,2-a] Pyrimidinyl group, 1,2,4-tria B [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b], etc. 8-12 membered fused polycyclic aromatic heterocyclic groups such as a pyridazinyl group. In addition, examples of the substituent of the aromatic group and the heterocyclic group include the same substituents as those in the “optionally substituted alkyl group”.

  As the alcohol oxidation method of the present invention, even if the alcohol oxidation catalyst of the present invention is added to a mixture containing the alcohol as a reaction substrate, the alcohol in the solvent containing the alcohol oxidation catalyst of the present invention is used. May be added.

  The mixing ratio of the alcohol oxidation catalyst and the alcohol is such that the addition amount of the polycyclic N-oxyl compound and / or its derivative contained in the alcohol oxidation catalyst is 100 mol of all hydroxy groups in the alcohol. It is preferable that it is 0.001-150 mol, and it is more preferable that it is 0.01-50 mol. When the addition amount of the polycyclic N-oxyl compound and / or derivative thereof is less than the lower limit, the reaction does not proceed, the reaction rate decreases, or the reaction tends to stop halfway, If the upper limit is exceeded, it tends to be difficult to control the reaction rate. Moreover, in this invention, even if the said addition amount of the said polycyclic N-oxyl compound and / or its derivative (s) is as small as 0.01-5.0 mol with respect to 100 mol of all the hydroxyl groups in the said alcohol. It is possible to obtain sufficient activity.

  As the alcohol oxidation method of the present invention, it is preferable to oxidize the alcohol in the presence of a co-oxidant together with the alcohol oxidation catalyst. In the present invention, the co-oxidant is a source of oxidation ability to the alcohol oxidation catalyst of the present invention, and oxidizes the nitroxyl radical group in the polycyclic N-oxyl compound according to the present invention to an oxoammonium group. It refers to what can be done.

  Such a co-oxidant can be appropriately selected from those generally used in an oxidation reaction using TEMPO, and is not particularly limited, and is not limited to peroxyacid, hydrogen peroxide, hypohalous acid. And salts thereof, perhalogenates and salts thereof, persulfates, halides, N-bromosuccinimides and other halogenating agents, trihalogenated isocyanuric acids, diacetoxyiodoalenes, oxygen, and mixtures thereof It is done. Among these, the co-oxidant includes peracetic acid, m-chloroperbenzoic acid, hydrogen peroxide, sodium hypochlorite, lithium hypochlorite, potassium hypochlorite, calcium hypochlorite, Sodium bromite, lithium hypobromite, potassium hypobromite, calcium hypobromite, sodium hydrogen persulfate, sodium periodate, periodic acid, trichloroisocyanuric acid, tribromoisocyanuric acid, N-bromosuccinic acid Imide, N-chlorosuccinimide, chlorine, bromine, iodine, diacetoxyiodobenzene, and oxygen are preferred.

  Further, the alcohol oxidation catalyst of the present invention can exhibit a sufficiently high catalytic activity against the alcohol even under mild air oxidation, and is only excellent in operability, safety and economy. In view of the fact that it is possible to construct an oxidation system that produces only water as a byproduct, oxygen is particularly preferred among the co-oxidants. In addition, as such oxygen, you may supply in the state of air (usually oxygen concentration 18-21 volume%).

  The amount of the co-oxidant added depends on the type of the co-oxidant and cannot be generally stated. For example, when the co-oxidant is oxygen, the total amount of hydroxy groups in the alcohol is 100 mol. On the other hand, the number of oxygen molecules is preferably 100 mol or more. When the addition amount of the co-oxidant is less than the lower limit, the reaction does not proceed, the reaction rate decreases, or the reaction tends to stop in the middle.

  Furthermore, for example, when sodium hypochlorite is used as the co-oxidant, other co-oxidants such as alkali metal halides, quaternary ammonium salts, etc. are used for the purpose of further promoting the reaction. It is preferable to use a combination of additives. Thus, what is used in combination with sodium hypochlorite is preferably tetrabutylammonium chloride, tetrabutylammonium bromide, sodium bromide, potassium bromide, and mixtures thereof. Moreover, as these addition amount, it is preferable that it is 10 mol or less with respect to 100 mol of said sodium hypochlorites.

  Further, for example, even when oxygen is used as the co-oxidant, it is preferable to use other co-oxidants such as copper chloride and iron chloride, and additives in combination for the purpose of further promoting the reaction. . As said additive, it can select suitably from what is generally utilized by the air oxidation reaction which uses TEMPO. As used in combination with oxygen, for example, nitrite compounds such as nitrite and nitrite; inorganic acids; carboxylic acids such as acetic acid, formic acid and propionic acid; bromine; transitions such as copper, iron and ruthenium Metals, and mixtures thereof, among which, from the viewpoint that reaction efficiency is more improved and activity tends to be higher, a mixture of sodium nitrite and acetic acid, a mixture of sodium nitrite and bromine, sodium nitrite And a mixture of iron chloride, copper chloride, and tert-butyl nitrite. Moreover, as these addition amount, when using the mixture of sodium nitrite and an acetic acid, for example, it is preferable that it is 180 mol or less in the total number of moles of a mixture with respect to 100 mol of said oxygen molecules.

  Furthermore, in the alcohol oxidation method of the present invention, a known solvent may be appropriately used as long as the effects of the present invention are not inhibited. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and propionitrile; dichloromethane, chloroform, Halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Amides such as dimethyl sulfoxide; sulfoxides such as dimethyl sulfoxide; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; sulfolane; May be used in combination of two or more be used one kind alone of.

  Moreover, as the solvent, aliphatic hydrocarbons, aromatic hydrocarbons, nitriles, halogenated hydrocarbons, esters, water, and mixtures thereof from the viewpoint that reaction efficiency tends to be further improved. More preferably, dichloromethane, acetonitrile, toluene, ethyl acetate, isopropyl acetate, water, and a mixed solution thereof, dichloromethane, acetonitrile, dichloromethane-water mixed solution, acetonitrile-water mixed solution, toluene-water mixed solution, ethyl acetate are preferable. -A water mixed solution is more preferred.

  Further, in the alcohol oxidation method of the present invention, a buffer may be further added within a range not inhibiting the effects of the present invention. Such buffering agents include alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, alkali metal or alkaline earth metal hydroxides, alkali metals or alkaline earth metals. Phosphates, alkali metal or alkaline earth metal acetates, and the like may be used alone or in combination of two or more. Moreover, as said buffering agent, sodium hydrogencarbonate, sodium carbonate, sodium acetate, and a phosphate are preferable. When these buffering agents are added, the amount added is preferably 500 mol or less with respect to 100 mol of the polycyclic N-oxyl compound and / or its derivative contained in the alcohol oxidation catalyst.

Although the reaction temperature in the alcohol oxidation method of the present invention depends on the type of the alcohol and the co-oxidant used, it cannot be generally stated, but is usually −80 to 120 ° C. and 0 to 40 ° C. Is preferred. Also, the reaction time depends on the reaction temperature and cannot be generally stated, but is usually 2 to 8 hours. Furthermore, the reaction pressure is not particularly limited, and is usually 10 ^{5 to} 3.4 × 10 ⁶ Pa.

  For example, when the co-oxidant is oxygen, the reaction temperature is preferably 0 to 40 ° C., and the reaction time is preferably 2 to 8 hours. In the alcohol oxidation method of the present invention, sufficiently high catalytic activity can be exhibited even under such mild conditions using oxygen as an oxidizing agent.

  The alcohol can be oxidized by such an alcohol oxidation method of the present invention. In addition, the reaction product obtained by oxidation can be isolated by an isolation operation such as extraction, recrystallization, and column chromatography after completion of the reaction.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example.

The compounds obtained in the comparative examples of each example are nuclear magnetic resonance analysis (NMR: ¹ H-NMR, ¹³ C-NMR), infrared absorption analysis (IR), mass spectrometry (MS), and high resolution mass spectrometry. Analysis was performed by the method (electron ionization) (HRMS (EI)) and elemental analysis (Anal.). The multiplicity in ¹ H-NMR is as follows: s = singlet (single line), d = doublelet (double line), t = triplet (triple line), q = quintet (quadruple line), m = multiplet (multiplexing) Line), dd = double doublet, and brs = broad singlet. J represents a coupling constant. In each NMR, CDCl ₃ was used as a solvent.

Example 1
<Synthesis of 6-oxa-2-azaadamantane N-oxyl (6-oxa-2-azaadamantane N-oxyl, Oxa-AZADO)>
(1-1) Synthesis of 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one

  9-tosyl-9-azabicyclo [3.3.1] nonan-3-one was synthesized according to the reaction pathway shown in the above formula. That is, first, a 28% aqueous ammonia solution (19 mL, 274 mmol) was slowly added dropwise to an aqueous solution (200 mL) of acetone dicarboxylic acid (8.0 g, 54.8 mmol) over 15 minutes under ice cooling. To this, 50% aqueous glutaraldehyde solution (10 mL, 55.3 mmol) was slowly added dropwise (one drop every 4 to 5 seconds), followed by stirring at room temperature (25 ° C., the same applies hereinafter) for 24 hours. The stirred reaction solution was dried by lyophilization to obtain orange crude crystals. The obtained crude crystals were used for the next reaction without purification.

  Sodium carbonate (19.0 g, 178 mmol) was added to a mixed solution of the obtained crude crystals (total amount) in dichloromethane (31 mL) and water (62 mL) at room temperature, and then p-toluenesulfonyl chloride (TsCl) was added under ice cooling. A dichloromethane solution (31 mL) of (Ts: tosyl group), 12.5 g, 65.8 mmol) was slowly added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture after stirring is diluted with water (200 mL) to separate the organic layer, and then the aqueous layer is extracted and removed with ethyl acetate. The organic layer is further washed with saturated brine, dried over magnesium sulfate, and reduced in pressure. The solvent was distilled off underneath. The obtained residue was purified by silica gel column chromatography to obtain 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one (5.8 g, yield 36%) as white crystals.

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for 9-tosyl-9-azabicyclo [3.3.1] nonane-3-one obtained are shown below.

¹ H-NMR (400 MHz): δ 7.78 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.50 (s, 2H), 2.71 (Dd, J = 17.2, 6.8 Hz, 2H), 2.43 (s, 3H), 2.35 (d, J = 16.8 Hz, 2H), 1.79-1.46 (m, 6H).
¹³ C-NMR (100 MHz): δ 207.9, 143.6, 137.8, 129.8, 126.9, 49.6, 45.4, 30.4, 21.5, 15.8.
IR (neat [cm < ^-1 >]): 1707, 1351, 1161, 1090.
MS [m / z]: 293 (M ^<+> ), 138 (100%).
HRMS (EI): Calcd. for C ₁₅ H ₁₉ NO ₃ S: 293.1086, found:. 293.1068.

  (1-2) Synthesis of 9-tosyl-9-azabicyclo [3.3.1] nonan-3-ol

  9-tosyl-9-azabicyclo [3.3.1] nonan-3-ol was synthesized according to the reaction pathway shown in the above formula. That is, first, in a tetrahydrofuran solution (THF, 18 mL) of lithium aluminum hydride (194 mg, 5.12 mmol) under ice cooling, 9-tosyl-9-azabicyclo [3.3. 1] A tetrahydrofuran solution (7 mL) of nonan-3-one (1.00 g, 3.41 mmol) was slowly added by cannulation. Subsequently, after stirring this at room temperature for 3 hours, ethyl acetate and water were added slowly slowly in order, and reaction was stopped. Next, a saturated Rochelle salt aqueous solution was added thereto, and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was extracted and removed with ethyl acetate, and the organic layer was further washed with saturated brine, and then dried over magnesium sulfate. The residue was purified using silica gel column chromatography to give 9-tosyl-9-azabicyclo [3.3.1] nonan-3-ol (719 mg, 71% yield) as white crystals. It was.

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for 9-tosyl-9-azabicyclo [3.3.1] nonane-3-ol obtained below are shown.

¹ H-NMR (400 MHz): δ 7.70 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 4.25 (d, J = 10.4 Hz, 2H), 3.72 (m, 1H), 2.42 (s, 3H), 2.36 (m, 2H), 2.13 (qt, J = 13.6, 4.8 Hz, 1H), 1 .62-1.31 (m, 8H).
¹³ C-NMR (100 MHz): δ 142.8, 138.9, 129.6, 126.7, 63.6, 47.1, 34.6, 30.3, 21.4, 13.7.
IR (neat [cm < ^-1 >]): 3510, 1335, 1312, 1162..
MS [m / z]: 295 (M ^<+> ), 140 (100%).
HRMS (EI): Calcd. _{for C 15 H 21 NO 3 S} : 295.1242, found: 295.1233.

  (1-3) Synthesis of N-tosyl-6-oxa-2-azaadamantane

N-tosyl-6-oxa-2-azaadamantane was synthesized according to the reaction pathway shown in the above formula. That is, first, in a cyclohexane (14 mL) solution of 9-tosyl-9-azabicyclo [3.3.1] nonan-3-ol (560 mg, 1.90 mmol) obtained in (1-2) above at room temperature. , Iodine (723 mg, 2.85 mmol) and iodobenzene diacetate (PhI (OAc) ₂ , 950 mg, 2.95 mmol) were added. Subsequently, this reaction liquid was ice-cooled and stirred for 1 hour while irradiating light from a position of 5 to 10 cm from the reaction vessel using a 100 V-100 W incandescent bulb. Next, saturated aqueous sodium hydrogen carbonate and 20% sodium thiosulfate were sequentially added to the reaction solution, and the aqueous layer was extracted and removed with ethyl acetate. The organic layer was further washed with saturated brine, and then dried over magnesium sulfate. Concentrated. The obtained residue was purified by silica gel column chromatography, white crystals of N-tosyl-6-oxa-2-azaadamantane (389 mg, 1.33 mmol, yield 70%), and 9-tosyl-9-azabicyclo [3.3.1] Nonane-3-one (47 mg, 0.160 mmol, 8.5% yield) was obtained as white crystals.

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for the obtained N-tosyl-6-oxa-2-azaadamantane are shown below.

¹ H-NMR (400 MHz): δ 7.74 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.30 (s, 2H), 4.10 (S, 2H), 2.42 (s, 3H), 1.98 (d, J = 12.4 Hz, 4H), 1.75 (d, J = 12.8 Hz, 2H).
¹³ C-NMR (100 MHz): δ 143.2, 138.3, 129.7, 127.0, 66.3, 47.2, 33.9, 21.5.
IR (neat [cm < ^-1 >]): 1345,1165.
MS [m / z]: 293 (M ^<+> ), 293 (100%).
HRMS (EI): Calcd. _{for C 15 H 19 NO 3 S} : 293.1086, found: 293.1083.

  (1-4) Synthesis of 6-oxa-2-azaadamantane N-oxyl (Oxa-AZADO)

  According to the reaction route shown in the above formula, 6-oxa-2-azaadamantane N-oxyl (Oxa-AZADO) was synthesized. That is, first, bis (2-methoxy hydride) was added to a toluene solution (1.5 mL) of N-tosyl-6-oxa-2-azaadamantane (200 mg, 0.682 mmol) obtained in (1-3) above. Ethoxy) aluminum sodium ("Red-Al" manufactured by Sigma-Aldrich, 70% toluene solution, 0.95 mL, 3.41 mmol) was slowly added under ice-cooling, and then heated to reflux for 1.5 hours. The reaction liquid after heating to reflux was cooled to room temperature and diluted with diethyl ether, and water was carefully added thereto under ice-cooling, followed by Celite filtration. The obtained filtrate was added with 10% hydrochloric acid to adjust the pH of the aqueous layer to 1, and then washed with diethyl ether. Next, a 10% aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12, followed by extraction with chloroform. The chloroform layer was dried over potassium carbonate and concentrated under reduced pressure. The obtained 6-oxa-2-azaadamantane was made into an acetonitrile (MeCN) solution (3.4 mL), sodium tungstate dihydrate (112 mg, 0.341 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. . Subsequently, urea / hydrogen peroxide (urea peroxide or UHP (urea hydrogen peroxide), 256 mg, 2.73 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution after stirring, and the organic layer extracted with chloroform was dried over potassium carbonate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-oxa-2-azaadamantane N-oxyl (Oxa-AZADO) (52 mg, 0.337 mmol, yield 50%) as yellow crystals.

  IR, MS, HRMS (EI), Anal. Of Oxa-AZADO obtained below. The results are shown. Activity evaluation was performed using the obtained Oxa-AZADO as a catalyst.

IR (neat [cm < ^-1 >]): 1442, 1338, 1284, 1057.
MS [m / z]: 154 (M ^<+> ), 154 (100%).
HRMS (EI): Calcd. for C ₈ H ₁₂ NO ₂ : 154.0868, found: 154.0858.
Anal. : Calcd. _{for C 8 H 12 NO 2:} C, 62.32; H, 7.84; N, 9.08, found: C, 62.14; H, 7.83; N, 8.96.

(Example 2)
<Synthesis of N-tosyl-2,6-diazaadamantane N′-oxyl (N-tosyl-2,6-diazaadamantane N′-oxyl, N-Ts-AZADO)>
(2-1) Synthesis of 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one oxime

  9-tosyl-9-azabicyclo [3.3.1] nonane-3-one oxime was synthesized according to the reaction pathway shown in the above formula. That is, first, 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one (15.0 g, 51.2 mmol) obtained in the same manner as (1-1) above in ethanol (EtOH) After adding pyridine (17 mL, 205 mmol) and hydroxylammonium chloride (11.0 g, 154 mmol) to the solution (85 mL) at room temperature, the reaction solution was stirred at 60 ° C. for 10 hours. Next, after cooling to room temperature, saturated aqueous sodium hydrogen carbonate was added, and after removing ethanol under reduced pressure, the aqueous layer was extracted and removed from the residue with ethyl acetate. The organic layer was further washed with saturated brine, and then magnesium sulfate. And concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one oxime (15.5 g, 50.3 mmol, yield 98%) was obtained as white crystals. Obtained.

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for 9-tosyl-9-azabicyclo [3.3.1] nonane-3-one oxime obtained are shown below.

¹ H-NMR (400 MHz): δ 9.16 (br s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 4. 32 (br s, 2H), 3.14 (d, J = 16.0 Hz, 1H), 2.58 (dd, J = 15.2, 5.6 Hz, 1H), 2.41 (s, 3H) 2.35 (d, J = 15.6 Hz, 1H), 2.21 (dd, J = 16.2, 6.4 Hz, 1H), 1.78-1.46 (m, 6H).
¹³ C-NMR (100 MHz): δ 157.1, 143.2, 138.2, 129.7, 126.9, 48.7, 47.9, 35.1, 30.8, 29.9, 28. 5, 21.4, 16.3.
IR (neat [cm < ^-1 >]): 3242, 1350, 1162.
MS [m / z]: 308 (M ^<+> ), 291 (100%).
HRMS (EI): Calcd. _{for C 15 H 20 N 2 O} 3 S: 308.1195, found: 308.1183.

  (2-2) Synthesis of N- (9-tosyl-9-azabicyclo [3.3.1] non-3-yl) tosylamide

  N- (9-tosyl-9-azabicyclo [3.3.1] non-3-yl) tosylamide was synthesized according to the reaction pathway shown in the above formula. That is, first, a methanol (MeOH) solution (16 mL) of 9-tosyl-9-azabicyclo [3.3.1] nonane-3-one oxime (1.00 g, 3.25 mmol) obtained in (2-1) above. ) Was added with molybdenum trioxide (VI) (792 mg, 4.88 mmol) and stirred at room temperature for 30 minutes, and then sodium borohydride (369 mg, 9.75 mmol) was added little by little under ice cooling, followed by ice cooling. Stir below. Next, disappearance of 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one oxime as a raw material was confirmed using thin layer chromatography, and then p-toluenesulfonyl chloride (3. 11 g, 16.3 mmol) was added and stirring was continued for another hour. The reaction solution after stirring was filtered through Celite, and then the solvent was distilled off under reduced pressure. The residue was diluted with water and ethyl acetate, the aqueous layer was extracted with ethyl acetate, and the organic layer was further washed with saturated brine. Thereafter, it was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and N- (9-tosyl-9-azabicyclo [3.3.1] non-3-yl) tosylamide (1.18 g, 2.63 mmol, yield 81%) ) Was obtained as white crystals.

¹ H-NMR, ¹³ C-NMR, IR, MS, HRMS (EI) of N- (9-tosyl-9-azabicyclo [3.3.1] non-3-yl) tosylamide obtained below Results are shown.

¹ H-NMR (400 MHz): δ 7.67 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 4.39 (d, J = 8.4 Hz, 1H), 4.19 (brs, 1H), 4.16 (brs, 1H), 3.04 (double quantet, J = 18.0, 6.8 Hz, 1H), 2.44 (s, 6H), 2.15 (td, J = 10.2, 6.0 Hz, 2H) 1.82 (m, 1H), 1.51-1.42 (m, 3H), 1.30 (dd, J = 16.4, 2.4 Hz, 2H), 1.15 (m, 2H) .
¹³ C-NMR (100 MHz): δ 143.3, 143.0, 138.6, 137.9, 129.7, 129.6, 126.8, 126.6, 46.9, 45.9, 32. 7, 30.3, 21.5, 14.1.
IR (neat [cm < ^-1 >]): 3279,1331,1162.
MS [m / z]: 448 (M ^<+> ), 293 (100%).
HRMS (EI): Calcd. _{for C 22 H 28 N 2 O} 4 S 2: 448.1490, found: 448.1494.

  (2-3) Synthesis of N, N'-ditosyl-2,6-diazaadamantane

  N, N'-ditosyl-2,6-diazaadamantane was synthesized according to the reaction pathway shown in the above formula. That is, first, N- (9-tosyl-9-azabicyclo [3.3.1] non-3-yl) tosylamide (5.50 g, 12.3 mmol) obtained in (2-2) above, To a solution of 2-dichloroethane (82 mL), iodine (1.56 g, 6.14 mmol) and iodobenzene diacetate (7.89 g, 24.5 mmol) were added at room temperature. Next, the reaction solution was passed through the microreactor using a syringe pump at a flow rate of 0.3 mL / min, and light irradiation was performed from a position of 20 to 30 cm from the microreactor using a 100 V-100 W incandescent bulb. Subsequently, saturated sodium bicarbonate water and 20% sodium thiosulfate were sequentially added to the reaction solution, and the organic layer extracted with chloroform was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized using a dichloromethane-methanol mixed solvent (1: 1), and N, N′-ditosyl-2,6-diazaadamantane (3.85 g, 8.62 mmol, yield 70%). Was obtained as colorless needle crystals. Further, the mother liquor after recrystallization was purified using silica gel column chromatography to obtain N, N′-ditosyl-2,6-diazaadamantane (1.22 g) as a yellow amorphous.

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for the obtained N, N′-ditosyl-2,6-diazaadamantane are shown below.

¹ H-NMR (400 MHz): δ 7.69 (d, J = 8.4 Hz, 4H), 7.27 (d, J = 8.4 Hz, 4H), 4.20 (s, 4H), 2.41 (S, 6H), 1.74 (m, 8H).
¹³ C-NMR (100 MHz): δ 143.4, 138.0, 129.8, 126.9, 47.0, 33.0, 21.5.
IR (neat [cm < ^-1 >]): 1341, 1166.
MS [m / z]: 446 (M ^<+> ), 446 (100%).
HRMS (EI): Calcd. for C ₂₂ H ₂₆ N ₂ O ₄ S ₂ : 446.1334, found: 446.1320.

  (2-4) Synthesis of N-tosyl-2,6-diazaadamantane N'-oxyl (N-Ts-AZADO)

  N-tosyl-2,6-diazaadamantane N'-oxyl (N-Ts-AZADO) was synthesized according to the reaction pathway shown in the above formula. That is, first, bishydride hydride was added to a toluene solution (10.0 mL) of N, N′-ditosyl-2,6-diazaadamantane (2.00 g, 4.48 mmol) obtained in (2-3) above. (2-Methoxyethoxy) aluminum sodium (“Red-Al” manufactured by Sigma-Aldrich, 70% toluene solution, 10.0 mL, 35.9 mmol) was slowly added under ice-cooling, and then heated to reflux for 1 hour. The reaction liquid after heating to reflux was cooled to room temperature and diluted with diethyl ether, and water was carefully added thereto under ice-cooling, followed by Celite filtration. The obtained filtrate was added with 10% hydrochloric acid to adjust the pH of the aqueous layer to 1, and then washed with diethyl ether. Next, 10% aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12, and then sodium chloride was added until saturation, followed by stirring at room temperature for 30 minutes. The organic layer extracted with chloroform was then dried over potassium carbonate and concentrated under reduced pressure. The obtained crude product was made into an acetonitrile solution (22 mL), sodium tungstate dihydrate (739 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 30 min. Subsequently, urea / hydrogen peroxide (urea peroxide or UHP) (3.36 g, 35.8 mmol) was further added, and the mixture was stirred at room temperature for 4 hours. Next, urea / hydrogen peroxide (842 mg, 8.96 mmol) was added again, and the mixture was further stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution after stirring, and the organic layer extracted with chloroform was dried over potassium carbonate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using amine silica gel, and N-tosyl-2,6-diazaadamantane N′-oxyl (N-Ts-AZADO) (223 mg, 0.726 mmol, yield 16%). ) And yellow crystals of 2,6-diazaadamantane N, N′-dioxyl (DiAZADO) (79 mg, 0.470 mmol, yield 10%).

  N-Ts-AZADO obtained below, IR, MS, HRMS (EI), Anal. The results are shown. Activity evaluation was performed using the obtained N-Ts-AZADO as a catalyst.

IR (neat [cm < ^-1 >]): 1343, 1161, 686.
MS [m / z]: 307 (M ^<+> , 100%).
HRMS (EI): Calcd. _{for C 15 H 19 N 2 O} 3 S: 307.1116, found: 307.1098.
Anal. : Calcd. _{for C 15 H 19 N 2 O} 3 S: C, 58.61; H, 6.23; N, 9.11, found: C, 58.61; H, 6.23; N, 8.91.

(Reference Example 1)
<Synthesis of 2,6-diazaadamantane N, N′-dioxyl (2,6-diazadamantane N, N′-dioxyl, DiAZADO)>

  2,6-diazaadamantane-N, N′-dioxyl (DiAZADO) was synthesized according to the reaction route shown in the above formula. That is, first, to a toluene solution (5.0 mL) of N, N′-ditosyl-2,6-diazaadamantane (1.00 g, 2.24 mmol) obtained in (2-3) above, bishydride was added. (2-Methoxyethoxy) aluminum sodium ("Red-Al" manufactured by Sigma-Aldrich, 70% toluene solution, 6.2 mL, 22.4 mmol) was slowly added under ice-cooling, and then heated to reflux for 18 hours. The reaction liquid after heating to reflux was cooled to room temperature and diluted with diethyl ether, and water was carefully added thereto under ice-cooling, followed by Celite filtration. The obtained filtrate was added with 10% hydrochloric acid to adjust the pH of the aqueous layer to 1, and then washed with diethyl ether. Next, 10% aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12, and then sodium chloride was added until saturation, followed by stirring at room temperature for 30 minutes. The organic layer extracted with chloroform was then dried over potassium carbonate and concentrated under reduced pressure. The obtained crude product was made into an acetonitrile solution (11 mL), sodium tungstate dihydrate (369 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature for 30 min. Subsequently, urea / hydrogen peroxide (urea peroxide or UHP) (1.69 g, 17.9 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. Next, urea / hydrogen peroxide (422 mg, 4.48 mmol) was added again, and the mixture was further stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution after stirring, and the organic layer extracted with chloroform was dried over potassium carbonate and concentrated under reduced pressure. The obtained residue was recrystallized from chloroform to obtain light yellow needle-like crystals of 2,6-diazaadamantane-N, N′-dioxyl (146 mg, 0.869 mmol) (DiAZADO). The mother liquor after recrystallization was purified by column chromatography using amine silica gel to obtain yellow crystals of DiAZADO (19 mg, 0.113 mmol) (total yield 44%).

  DiAZADO IR, MS, HRMS (EI), Anal. The results are shown. The activity was evaluated using the obtained DiAZADO as a catalyst.

IR (neat [cm < ^-1 >]): 1423, 1143.
MS [m / z]: 168 (M ^<+> , 100%).
HRMS (EI): Calcd. for C ₈ H ₁₂ N ₂ O ₂ : 168.0899, found: 168.0891.
Anal. : Calcd. _{for C 8 H 12 N 2 O} 2: C, 57.13; H, 7.19; N, 16.66, found: C, 56.86; H, 7.13; N, 16.52.

(Example 3)
<Synthesis of 7-normal butyl-6-oxa-2-azaadamantane N-oxyl (7-n-Butyl-6-oxa-2-azaadamantane N-oxyl, 7-Bu-Oxa-AZADO)>
(3-1) Synthesis of 9-tosyl-3-normalbutyl-9-azabicyclo [3.3.1] nonan-3-ol

  9-tosyl-3-normalbutyl-9-azabicyclo [3.3.1] nonan-3-ol was synthesized according to the reaction pathway shown in the above formula. That is, first, a septum was attached to a 2-necked eggplant flask containing cerium (III) chloride heptahydrate (209 mg, 0.561 mmol) and dried by heating under reduced pressure to obtain gray cerium (III) chloride anhydride. It was. After cooling to room temperature, tetrahydrofuran (1.4 mL) was added with a syringe under ice cooling, and the mixture was stirred at room temperature for 1 hour. Then, this was cooled to -78 degreeC, normal butyllithium (1.56M hexane solution, 327 microliters, 0.510 mmol) was slowly added here with the syringe, and it stirred at the same temperature for 30 minutes. Next, a tetrahydrofuran solution (2.0 mL) of 9-tosyl-9-azabicyclo [3.3.1] nonan-3-one (50 mg, 0.170 mmol) obtained in the same manner as in the above (1-1) was used. It added slowly using the syringe and it stirred at -78 degreeC as it was for 2.5 hours. Subsequently, the reaction solution was slowly added with a saturated aqueous ammonium chloride solution to quench the reaction, and the aqueous layer was extracted and removed with ethyl acetate. The organic layer was further washed with saturated brine, then dried over magnesium sulfate, and reduced pressure. Concentrated in The obtained residue was purified by silica gel column chromatography, and 9-tosyl-3-normalbutyl-9-azabicyclo [3.3.1] nonan-3-ol (55 mg, 0.157 mmol, yield 93%) was obtained. White crystals were obtained.

The results of ¹ H-NMR, ¹³ C-NMR, MS, and HRMS (EI) for 9-tosyl-3-normalbutyl-9-azabicyclo [3.3.1] nonane-3-ol obtained below are shown. Show.

¹ H-NMR (400 MHz): δ 7.73 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 4.15 (s, 2H), 2.67 (M, 1H), 2.41 (s, 3H), 1.97 (dd, J = 7.6, 14.6 Hz, 2H), 1.72 (sept, J = 6.8 Hz, 2H), 1 .55 (s, 1H), 1.51 (s, 1H) 1.23 (m, 8H), 0.87 (m, 3H).
¹³ C-NMR (100 MHz): δ 142.7, 138.9, 129.5, 126.9, 67.8, 47.9, 47.4, 47.1, 40.8, 40.6, 29. 0, 28.9, 24.7, 22.9, 21.4, 15.1, 13.9 IR (neat [cm < ^-1 >]): 3502, 1317, 1168.
MS [m / z]: 351 (M ^<+> ), 294 (100%).
HRMS (EI): Calcd. for C ₁₉ H ₂₉ NO ₃ S: 351.1868, found: 351.1890.

  (3-2) Synthesis of N-tosyl-7-normalbutyl-6-oxa-2-azaadamantane

N-tosyl-7-normalbutyl-6-oxa-2-azaadamantane was synthesized according to the reaction pathway shown in the above formula. That is, first, 9-tosyl-3-normalbutyl-9-azabicyclo [3.3.1] nonan-3-ol (36.0 mg, 0.103 mmol) of cyclohexane obtained in (3-1) above ( 0.64 mL) solution was added iodine (39.3 mg, 0.155 mmol) and iodobenzene diacetate (PhI (OAc) ₂ , 53.1 mg, 0.165 mmol) at room temperature. Next, this reaction solution was cooled with water, and stirred for 40 minutes while irradiating light from a position of 5 to 10 cm from the reaction vessel using a 100V-100W incandescent bulb. Next, saturated aqueous sodium hydrogen carbonate and 20% sodium thiosulfate were sequentially added to the reaction solution, and the aqueous layer was extracted and removed with ethyl acetate. The organic layer was further washed with saturated brine, and then dried over magnesium sulfate. Concentrated. The obtained residue was purified by silica gel column chromatography to obtain a colorless oily substance of N-tosyl-7-normalbutyl-6-oxa-2-azaadamantane (26.1 mg, 0.0749 mmol, 73% yield). It was.

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) of the obtained N-tosyl-7-normalbutyl-6-oxa-2-azaadamantane are shown below.

¹ H-NMR (400 MHz): δ 7.74 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.33 (s, 2H), 4.13 (S, 1H), 2.42 (s, 3H), 1.83 (m, 2H), 1.64 (s, 6H), 1.34-1.17 (m, 6H), 0.87 ( t, J = 7.2 Hz, 3H).
¹³ C-NMR (100 MHz): δ 143.2, 138.3, 129.7, 127.0, 70.7, 66, 9, 47.8, 41.8, 37.8, 33.4, 24. 3, 23.1, 21.5, 14.0.
IR (neat [cm < ^-1 >]): 1348,1157.
MS [m / z]: 349 (M ^<+> ), 349 (100%).
HRMS (EI): Calcd. for C ₁₉ H ₂₇ NO ₃ S: 349.1712, found: 349.1706.

  (3-3) Synthesis of 7-normal butyl-6-oxa-2-azaadamantane N-oxyl (7-Bu-Oxa-AZADO)

  According to the reaction route shown in the above formula, 7-normalbutyl-6-oxa-2-azaadamantane N-oxyl (7-Bu-Oxa-AZADO) was synthesized. That is, first, hydrogenation was performed on a toluene solution (0.61 mL) of N-tosyl-7-normalbutyl-6-oxa-2-azaadamantane (102 mg, 0.291 mmol) obtained in (3-2) above. Bis (2-methoxyethoxy) aluminum sodium (“Red-Al” manufactured by Sigma-Aldrich, 70% toluene solution, 0.41 mL, 1.46 mmol) was slowly added under ice-cooling, and then heated to reflux for 0.75 hours. The reaction liquid after heating to reflux was cooled to room temperature, and then sodium bis (2-methoxyethoxy) aluminum hydride (“Red-Al” manufactured by Sigma-Aldrich, 70% toluene solution, 0.41 mL, 1.46 mmol) was slowly added. And then heated to reflux for 1.25 hours. The reaction liquid after heating to reflux was cooled to room temperature and diluted with diethyl ether, and water was carefully added thereto under ice-cooling, followed by Celite filtration. The obtained filtrate was added with 10% hydrochloric acid to adjust the pH of the aqueous layer to 1, and then washed with diethyl ether. Next, a 10% aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12, followed by extraction with chloroform. The chloroform layer was dried over potassium carbonate and concentrated under reduced pressure. The resulting 7-normalbutyl-6-oxa-2-azaadamantane was made into an acetonitrile (MeCN) solution (1.5 mL), and then sodium tungstate dihydrate (48.2 mg, 0.146 mmol) was added, The mixture was stirred at room temperature for 30 minutes. Subsequently, urea / hydrogen peroxide (urea peroxide or UHP, 109 mg, 1.16 mmol) was further added, and the mixture was stirred at room temperature for 3 hours. Further, urea / hydrogen peroxide (59.0 mg, 0.580 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, urea / hydrogen peroxide (59.0 mg, 0.580 mmol) was added every 2 hours, and stirring was performed twice. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution after stirring, and the organic layer extracted with chloroform was dried over potassium carbonate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 7-normalbutyl-6-oxa-2-azaadamantane N-oxyl (7-Bu-Oxa-AZADO) (23 mg, 0.109 mmol, yield 37%). Was obtained as yellow crystals.

  The 7-Bu-Oxa-AZADO obtained below was subjected to IR, MS, HRMS (EI), Anal. The results are shown. Activity evaluation was performed using the obtained 7-Bu-Oxa-AZADO as a catalyst.

IR (neat [cm < ^-1 >]): 2949, 1334.
MS [m / z]: 210 (M ^<+> ), 210 (100%).
HRMS (EI): Calcd. _{for C 12 H 20 NO 2:} 210.1494, found: 210.1496.
Anal. : Calcd. _{for C 12 H 20 NO 2:} C, 68.54; H, 9.59; N, 6.66, found: C, 68.62; H, 9.66; N, 6.63.

(Comparative Example 1)
The activity was evaluated using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a catalyst.

(Comparative Example 2)
Activity evaluation was performed using 2-azaadamantane N-oxyl (AZADO) as a catalyst. AZADO was produced according to the method described in International Publication No. 2009/066735 pamphlet.

(Comparative Example 3)
The activity was evaluated using 1-methyl-2-azaadamantane N-oxyl (1-Me-AZADO) as a catalyst. 1-Me-AZADO was produced according to the method described in International Publication No. 2006/001387.

(Comparative Example 4)
Activity evaluation was performed using 9-norazaadamantane N-oxyl (Nor-AZADO) as a catalyst. Nor-AZADO was produced according to the method described in International Publication No. 2012/008228 pamphlet.

(Comparative Example 5)
Activity evaluation was performed using 5-fluoro-2-azaadamantane N-oxyl, (5-F-AZADO) as a catalyst. In addition, 5-F-AZADO was manufactured in accordance with the method as described in the international publication 2009/145323 pamphlet.

  <Activity evaluation 1>

  First, an oxidation reaction was performed using l-menthol as a substrate according to the reaction pathway shown in the above formula. That is, 1-menthol (184 mg, 1.18 mmol) in acetic acid (AcOH, 1M) solution was prepared by adding the catalysts obtained in Examples 1-2, Reference Example 1 and Comparative Examples 1-5 to 100 mol of the substrate. 1 mol of sodium nitrite was added so as to be 10 mol with respect to 100 mol of the substrate, and the reaction time and air (oxygen concentration 20% by volume, the same applies hereinafter) atmosphere shown in Table 1 at room temperature. (Balloon).

Next, 5 μl of the reaction solution after the reaction is taken, and a sample diluted with 1 ml of acetone is used as a sample. This sample is subjected to gas chromatography (column: HP-5 (30 × 0.32 mm (id); manufactured by Agilent Technologies)). Instrument: Agilent 7890 GC system, manufacturer: Agilent technologies, flame ion detector (FID): 270 ° C., injection: 250 ° C., carrier gas: helium, carrier gas velocity: 25 mL / min, column temperature: 70 ° C. 2 minutes), temperature rise condition: 20 ° C./min to 210 ° C. and then 2 hours at 210 ° C. for 1 minute), residual substrate area area (remaining group mass), produced ketone and / or aldehyde Area area (product amount) of The conversion rate is:
Conversion rate (%) = (product amount / (residual base mass + product amount)) × 100
Calculated by The results are shown in Table 1 together with the reaction time.

  Moreover, about the catalyst obtained in Example 1, 3, the acetic acid solution of 1-menthol (150 mg, 0.961 mmol) was used as the acetic acid solution of the said 1-menthol, and reaction time was made into the time shown in Table 2, respectively. The activity was evaluated in the same manner as above, and the conversion rate was calculated. The obtained results are shown in Table 2 together with the reaction time.

As is apparent from the results shown in Table 1, when TEMPO (Comparative Example 1) was used as a catalyst in an air atmosphere using bulky l-menthol as a substrate, the reaction did not proceed at all, and 1-Me -It was confirmed that the reaction was very slow even when AZADO (Comparative Example 3) was used as a catalyst. In addition, when AZADO (Comparative Example 2) and Nor-AZADO (Comparative Example 4) were used as catalysts, although the conversion rate showed a somewhat high value, a clear deceleration of the reaction was confirmed. On the other hand, when the catalyst of the present invention (Oxa-AZADO (Example 1), N-Ts-AZADO (Example 2)) is used as a catalyst, the oxidation reaction proceeds with almost no reaction stall, It was confirmed that sufficiently high catalytic activity was exhibited to the same extent as 5-F-AZADO (Comparative Example 5) and DiAZADO (Reference Example 1). Further, as is clear from the results shown in Table 2, even when the catalyst of the present invention (7-Bu-Oxa-AZADO (Example 3)) having an alkyl group at the 7-position of the azaazadamantane skeleton was used. The conversion rate and reaction time of the reaction are the same as when using a catalyst having no alkyl group (Oxa-AZADO (Example 1)), and the alkyl group at the 7-position has a great influence on the catalyst activity. Not confirmed. In addition, this makes it possible to impart further functionality to the alcohol oxidation catalyst such as a hydroxy group, an azide group (—N ₃ ) and an acetylene group (—C ₂ ) at the terminal of the alkyl group at the 7-position. It was confirmed that it was possible to introduce a simple group.

  <Activity evaluation 2>

  First, an oxidation reaction was performed using a sugar alcohol derived from fructose as a substrate according to the reaction pathway shown in the above formula. That is, the sugar alcohol (200 mg, 0.796 mmol) was used instead of 1-menthol, the reaction time, and the number of moles of the catalyst obtained in each Example, Reference Example, and Comparative Example with respect to 100 moles of the substrate, respectively. The reaction was conducted in the same manner as in the activity evaluation 1 except that the time and the number of moles shown in Table 3 were used.

Next, after confirming that the reaction was completed or stopped using thin layer chromatography, the reaction solution was diluted with ethyl acetate, saturated aqueous sodium bicarbonate and 20% aqueous sodium thiosulfate solution were added, and the organic layer was extracted with ethyl acetate. Was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the product ketone. From the number of moles of the obtained ketone (product amount) and the number of moles of the substrate used in the reaction (initial base mass), the yield is expressed by the following formula:
Yield (%) = (product amount / initial base mass) × 100
Calculated by The results are shown in Table 3 together with the reaction time and the amount of catalyst.

  As is apparent from the results shown in Table 3, the catalyst of the present invention (Oxa-AZADO (Example 1), N-Ts-AZADO (Example 2)) is 5-F-AZADO (Comparative Example 5) or Similar to DiAZADO (Reference Example 1), it was confirmed that the reaction could be sufficiently advanced even if the amount of catalyst was reduced.

  <Activity evaluation 3>

  According to the reaction route shown in the above formula, the alcohol was oxidized. That is, the yield (%) was obtained in the same manner as in the activity evaluation 2 except that alcohol (0.961 mmol) shown in Table 4 was used as a substrate instead of l-menthol, and the reaction time was set to the time shown in Table 4, respectively. ) The results are shown in Table 4 together with the structure and reaction time of each substrate.

  In Table 4, “a” indicates that the catalyst amount is 3 mol with respect to 100 mol of the substrate, and “b” indicates that the catalyst amount is 5 mol with respect to 100 mol of the substrate. C indicates that 0.4 M acetic acid was used instead of 1 M acetic acid, and d indicates that a mixed solution of 2 molar equivalents of acetic acid and 1 M acetonitrile was used instead of 1 M acetic acid. In Table 4, Me represents a methyl group, Ph represents a phenyl group, Bz represents a benzoyl group, Cbz represents a benzyloxycarbonyl group, and TBS represents a t-butyldimethylsilyl group.

  As is apparent from the results shown in Table 4, the catalyst of the present invention (Oxa-AZADO (Example 1), N-Ts-AZADO (Example 2)) is 5-F-AZADO (Comparative Example 5) or Similar to DiAZADO (Reference Example 1), not only benzyl alcohol (No. 1) and simple aliphatic alcohols (No. 2 to 7), but also alcohols having hetero atoms (No. 8 to 9) and sugar alcohols ( It was confirmed that a wide range of alcohols such as No. 10-11), nucleic acid derivatives (No. 12), and amino alcohols derived from α-amino acids (No. 13) can be oxidized as substrates.

  <Activity evaluation 4>

  First, oxidation reaction of p-methoxybenzyl alcohol was performed according to the reaction route shown in the above formula. That is, to the acetic acid solution (1.3 mL) of p-methoxybenzyl alcohol (181 mg, 1.31 mmol), the catalyst (2.02 mg, 0.0131 mmol) obtained in Example 1 and sodium nitrite (9. 04 mg, 0.131 mmol) was added and stirred at room temperature for 3 hours in an atmosphere. Next, the reaction solution after the reaction was diluted with diethyl ether, saturated aqueous sodium hydrogen carbonate and 20% aqueous sodium thiosulfate solution were added, and the organic layer extracted with diethyl ether was washed with saturated brine and dried over magnesium sulfate. And the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain p-methoxybenzaldehyde (169 mg, 1.24 mmol, yield 93%).

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for the obtained p-methoxybenzaldehyde are shown below.

¹ H-NMR (400 MHz): δ 9.89 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 3.89 (S, 3H).
¹³ C-NMR (100 MHz): δ 190.7, 164.6, 131.9, 129.9, 114.2, 55.5.
IR (neat [cm < ^-1 >]); 1683.
MS [m / z]: 136 (M ^<+> ), 135 (100%).
HRMS (EI): Calcd. for C ₈ H ₈ O ₂ : 136.0524, found: 136.0518.

  <Activity evaluation 5>

  First, the oxidation reaction of N-Cbz-1-prolinol (Cbz: benzyloxycarbonyl group) was performed according to the reaction pathway shown in the above formula. That is, N-Cbz-1-prolinol (> 99% ee (enantiomeric excess), 115 mg, 488 μmol) in acetonitrile solution (488 μL), acetic acid (56 μL, 976 μmol), catalyst obtained in Example 2 (1 .50 mg, 4.88 μmol) and sodium nitrite (3.40 mg, 48.8 μmol) were added, and the mixture was stirred at room temperature in an air atmosphere (balloon) for 4 hours. Next, the reaction solution after the reaction was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate and 20% aqueous sodium thiosulfate were added, and the organic layer extracted with ethyl acetate was washed with saturated brine and dried over magnesium sulfate. And the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain N-Cbz-1-prolinal (> 99% ee (enantiomeric excess), 84 mg, 360 μmol, yield 74%). The enantiomeric excess was determined using chiral HPLC (CHIRALPAC AD-H (manufactured by Daicel chemical industries), isopropanol: hexane = 5: 95, flow rate: 0.5 mL / min).

The results of ¹ H-NMR, ¹³ C-NMR, IR, MS, and HRMS (EI) for the obtained N-Cbz-1-prolinal are shown below.

¹ H-NMR (400 MHz): δ 9.59 (s, 0.5 H), 9.49 (s, 0.5 H), 7.38-7.31 (5 H, m), 5.17 (AB-q) , J = 12.0 Hz, 2H), 4.30 (0.5 H, br-t, J = 5.6 Hz), 4.02 (0.5 H, br-t, J = 5.6 Hz), 2. 16-1.81 (m, 5H).
¹³ C-NMR (100 MHz): δ 200.0, 128.5, 128.1, 128.0, 67.3, 65.2, 64.9, 47.3, 46.7, 27.8, 26. 6, 24.5, 23.7.
IR (neat [cm < ^-1 >]): 2882,1734,1699,1415,1356.
MS [m / z]: 204 ([M-CHO] ^<+> ), 91 (100%).
HRMS (EI): Calcd. _{C 12 H 14 NO 2: 204.1025} , found: 204.1033.

  As described above, according to the present invention, a novel alcohol oxidation catalyst that can exhibit sufficiently high catalytic activity both in the oxidation of a secondary alcohol and in air and that is easy to manufacture and It becomes possible to provide an alcohol oxidation method using the same. Therefore, the present invention can be applied to the catalytic air oxidation reaction of alcohol, which is a means for environmentally synthesize high-value-added organic compounds such as pharmaceuticals, pharmaceutical raw materials, agricultural chemicals, cosmetics, and organic materials. Useful.

Claims (6)

An alcohol oxidation catalyst that oxidizes alcohol,
The following general formula (1):
[In Formula (1), R ¹ represents a hydrogen atom or an alkyl group, and R ² has a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may have a substituent, and a substituent. Any one selected from the group consisting of aromatic hydrocarbon groups having 6 to 10 carbon atoms, wherein X is a group containing a hetero atom (excluding a group represented by the following formula: —NO ^· —) ). ]
An alcohol oxidation catalyst containing at least one selected from the group consisting of a polycyclic N-oxyl compound represented by the formula: X in the general formula (1) is an oxygen atom and the following general formula (2):
-NY- (2)
[In the formula (2), Y represents a group containing a sulfonyl group or an acyl group. ]
The alcohol oxidation catalyst according to claim 1, which is any one selected from the group consisting of groups represented by:   An alcohol oxidation method for oxidizing an alcohol in the presence of the alcohol oxidation catalyst and the co-oxidant according to claim 1.   The alcohol oxidation method according to claim 3, wherein the co-oxidant is oxygen.   The alcohol oxidation method according to claim 3 or 4, wherein the alcohol is a primary alcohol or a secondary alcohol.   The addition amount of the polycyclic N-oxyl compound and / or a derivative thereof is 0.001 to 150 mol with respect to 100 mol of all hydroxy groups in the alcohol. Alcohol oxidation method.