JP7187018B2 - Method for producing α-fluoroalkyl ketone and β-fluoroalkyl alcohol - Google Patents

Description

The present invention relates to a method for producing an α-fluoroalkyl ketone compound, and further to a method for producing a β-fluoroalkyl alcohol compound derived from the obtained α-fluoroalkyl ketone compound.

Organofluorine compounds have a similarity effect (mimic effect) in three-dimensional molecular recognition on the part of the living body derived from the fact that the atomic radii of fluorine and hydrogen are almost the same, and the C-F bond is stronger than the C-H bond. Therefore, fluorine such as the effect of protecting the metabolic site and avoiding the accompanying toxicity (blocking effect), and the effect of promoting absorption and transport in the body by improving fat solubility (lipid solubility effect) Effects derived from the characteristic size and electronic properties of atoms are known. Numerous medical and agricultural products have been developed by chemical modifications adapted to these effects. A method for introducing a fluoroalkyl group, which is a mimic substituent of an alkyl group, is being developed. α-fluoroalkyl ketone compounds, which are compounds in which a fluoroalkyl group is introduced at the α-position of a ketone, and β-fluoroalkyl alcohol compounds, which are compounds in which a fluoroalkyl group is introduced at the β-position of a hydroxyl group, are used as pharmaceutical and agrochemical intermediates and liquid crystal materials. It is extremely useful as a raw material for

Methods for producing α-fluoroalkyl ketone compounds include (1) a method using an external perfluoroalkylating agent for an enolate derived from a ketone (see Non-Patent Documents 1, 2 and 3, and Patent Document 1); (3) A method of acting a photoredox catalyst and an electrophilic perfluoroalkylating agent on alkyne (Non-Patent Document 5), (4 ) A method is known in which a radical initiator acts on a vinylfluoroalkanesulfonate derived from a ketone using a fluoroalkanesulfonic anhydride and a base, or from an alkyne using trimethylsilyl triflate (see Patent Document 2). there is

JP 2008-24674 A JP 2017-149652 A

Umemoto, T.; Ishihara, S., Tetrahedron Lett. 1990, 31, 3579-3582. Eisenberger, P.; Gischig, S.; Togni, A., Chem. Eur. J. 2006, 12, 2579-2586. Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C., Angew. Chem. Int. Ed. 2011, 50, 6119-6122. Koike, T.; Akita, M., Angew. Chem. Int. Ed. 2014, 53, 7144-7148. Malpani, Y.; Biswas, B.K.; Han, H.S.; Jung, Y.S.; Han, S.B., Org. Lett., 2018, 20, 1693-1697

However, the above method (1) requires a ketone activator in addition to the fluoroalkylating agent, and the above method (2) requires a stoichiometric amount of an oxidizing agent. The method (3) requires an expensive fluoroalkylating agent, and the method (4) can only use one of the two fluoroalkyl groups of the fluoroalkanesulfonic anhydride. Alternatively, each had a problem in that an expensive fluoroalkylating agent was required.
In view of the problems described above, it is an object of the present invention to provide a method for producing α-fluoroalkyl ketones and β-fluoroalkyl alcohols simply, inexpensively and efficiently.

As a result of intensive studies aimed at solving the above problems, the present inventors have found that by reacting an inexpensive fluoroalkylsulfonic acid in the presence of a radical initiator, using a relatively easily available alkyne compound as a starting material, , α-fluoroalkyl ketones can be efficiently obtained by reducing them to β-fluoroalkyl alcohols, thereby completing the present invention.

（式中、Ｒ_１は、置換基を有していてもよい鎖状炭化水素基；置換基を有していてもよい環状脂肪族炭化水素基；置換基を有していてもよい芳香族炭化水素基；置換基を有していてもよい複素環基；－ＯＲ_３；－ＮＲ_４Ｒ_４’；又は置換基を有していてもよい鎖状炭化水素基と、置換基を有していてもよい環状脂肪族炭化水素基、置換基を有していてもよい芳香族炭化水素基及び置換基を有していてもよい複素環基から選ばれる少なくとも１種の基とが複合した基を表し、Ｒ_２は、水素原子；トリアルキルシリル基；アリルジアルキルシリル基；アルキルジアリルシリル基；又はトリアリルシリル基を表し、Ｒ_３は、水素原子；置換基を有していてもよい鎖状炭化水素基；置換基を有していてもよい環状脂肪族炭化水素基；置換基を有していてもよい芳香族炭化水素基；置換基を有していてもよい複素環基；又は置換基を有していてもよい鎖状炭化水素基と、置換基を有していてもよい環状脂肪族炭化水素基、置換基を有していてもよい芳香族炭化水素基及び置換基を有していてもよい複素環基から選ばれる少なくとも一つの基とが複合した基を表し、Ｒ_４及びＲ_４’は、それぞれ独立に、水素原子；置換基を有していてもよい鎖状炭化水素基；置換基を有していてもよい環状脂肪族炭化水素基；置換基を有していてもよい芳香族炭化水素基；置換基を有していてもよい複素環基；又は置換基を有していてもよい鎖状炭化水素基と、置換基を有していてもよい環状脂肪族炭化水素基、置換基を有していてもよい芳香族炭化水素基及び置換基を有していてもよい複素環基から選ばれる少なくとも一つの基とが複合した基を表す。）で表されるアルキン化合物と、ラジカル開始剤存在下に、フルオロアルキルスルホン酸（Ｒ_ｆＳＯ_３Ｈ）（式中、Ｒ_ｆは、フルオロアルキル基を表す。）と反応させる式（II）

（式中、Ｒ_１は、式（Ｉ）と同じ意味を表し、Ｒ_ｆは、前記と同じ意味を表す。）で表されるα－フルオロアルキルケトンの製造方法。
［２］［１］に記載の式（II）で表されるα－フルオロアルキルケトンを還元する又は有機金属試薬と反応させる式（III）

（式中、Ｒ_１及びＲ_ｆは、式（II）と同じ意味を表し、Ｒ’は、水素原子又は有機金属試薬の有機基部分を表す。）で表されるβ－フルオロアルキルアルコールの製造方法。
［３］式（II）中におけるフルオロアルキル基が、アルキル基中の水素原子の６０％以上がフッ素原子で置換されているアルキル基である上記［１］に記載のα－フルオロアルキルケトンの製造方法。
［４］式（III）中におけるフルオロアルキル基が、アルキル基中の水素原子の６０％以上がフッ素原子で置換されているアルキル基である上記［２］に記載のβ－フルオロアルキルアルコールの製造方法。 That is, the present invention is as follows specified by the following matters.
[1] Formula (I)

(In the formula, R ₁ is a chain hydrocarbon group which may have a substituent; a cyclic aliphatic hydrocarbon group which may have a substituent; an aromatic which may have a substituent a hydrocarbon group; a heterocyclic group which may have a substituent; —OR ₃ ; —NR ₄ R _4′ ; or a chain hydrocarbon group which may have a substituent and a substituent at least one group selected from an optionally substituted cyclic aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group and an optionally substituted heterocyclic group _R2 represents a hydrogen atom; a trialkylsilyl group; an allyldialkylsilyl group; an alkyldiallylsilyl group; or a triallylsilyl group; _R3 represents a hydrogen atom; chain hydrocarbon group; optionally substituted cyclic aliphatic hydrocarbon group; optionally substituted aromatic hydrocarbon group; optionally substituted heterocyclic group; or a chain hydrocarbon group optionally having substituents, a cyclic aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents and substituents Represents a group combined with at least one group selected from heterocyclic groups optionally having, R ₄ and R _{4 '} are each independently a hydrogen atom; a chain optionally having a substituent -like hydrocarbon group; cyclic aliphatic hydrocarbon group which may have a substituent; aromatic hydrocarbon group which may have a substituent; heterocyclic group which may have a substituent; or A chain hydrocarbon group optionally having substituents, a cyclic aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents and substituents represents a group combined with at least one group selected from heterocyclic groups which may have.) and a fluoroalkylsulfonic acid (R _f SO ₃ H ) (Wherein, R _f represents a fluoroalkyl group.) to be reacted with formula (II)

(wherein R ₁ has the same meaning as in formula (I), and R _f has the same meaning as above).
[2] Formula (III) in which α-fluoroalkyl ketone represented by formula (II) described in [1] is reduced or reacted with an organometallic reagent

(Wherein, R ₁ and R _f have the same meaning as in formula (II), and R′ represents a hydrogen atom or an organic group portion of an organometallic reagent.) Production of β-fluoroalkyl alcohol represented by Method.
[3] Production of α-fluoroalkyl ketone according to [1] above, wherein the fluoroalkyl group in formula (II) is an alkyl group in which 60% or more of the hydrogen atoms in the alkyl group are substituted with fluorine atoms. Method.
[4] Production of β-fluoroalkyl alcohol according to [2] above, wherein the fluoroalkyl group in formula (III) is an alkyl group in which 60% or more of the hydrogen atoms in the alkyl group are substituted with fluorine atoms. Method.

By using the production method of the present invention, the desired α-fluoroalkyl ketone can be obtained using relatively easily available alkynes, using inexpensive reagents, under mild conditions, and with simple operations. β-fluoroalkyl alcohols can also be readily obtained by reducing the resulting ketones.

The method for producing an α-fluoroalkyl ketone of the present invention is a method of reacting an alkyne represented by formula (I) with a fluoroalkylsulfonic acid in the presence of a radical initiator. It is thought that the addition of fluoroalkylsulfonic acid to alkynes produces vinylfluoroalkanesulfonate as an intermediate in the reaction system. Therefore, the desired α-fluoroalkyl ketone is obtained by immediate rearrangement.

Among the alkynes represented by formula (I) used in the production method of the present invention, R ₁ is a chain hydrocarbon group optionally having substituent(s), a cyclic aliphatic group optionally having substituent(s) aromatic hydrocarbon group optionally having substituent(s), heterocyclic group optionally having substituent(s), —OR ₃ , —NR ₄ R _4′ , or having substituent(s) A chain hydrocarbon group that may be substituted, a cyclic aliphatic hydrocarbon group that may be substituted, an aromatic hydrocarbon group that may be substituted, and a substituent It represents a group combined with at least one group selected from good heterocyclic groups.

Specific examples of the "chain hydrocarbon group" in the above "optionally substituted chain hydrocarbon group" include an alkyl group, an alkenyl group, an alkynyl group, and the like. A group in which 2 to 3 carbon-carbon bonds in an alkyl group are converted to double bonds, such as an alkadienyl group or an alkatrienyl group, may also be used.

The alkyl group may be linear or branched, and specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group and t-butyl. C1-10 alkyl groups such as group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, etc. be able to.

The term "C1-10" means that the number of carbon atoms in the base group is 1-10. This number of carbon atoms does not include the number of carbon atoms in substituent groups. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. Hereinafter, in this specification, they are used with the same meaning.

The alkenyl group may be linear or branched, and specifically includes a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1- Examples include C2-10 alkenyl groups such as pentenyl group, 1-hexenyl group, 1-heptenyl group, 1-octenyl group, 1-nonenyl group and 1-decenyl group.

The alkynyl group may be linear or branched, and specifically includes an ethynyl group, 1-propynyl group, 1-butynyl group, 1-pentynyl group, 1-hexynyl group, and 1-heptynyl group. , 1-octynyl group, 1-nonynyl group and other C2-10 alkynyl groups.

As the above-mentioned "group in which 2 to 3 carbon-carbon bonds in the alkyl group are converted to double bonds", specifically, 2 to 3 carbon-carbon bonds in the alkyl group having 1 to 10 carbon atoms is converted to a double bond, alkadienyl groups having 4 to 6 carbon atoms such as 1,3-butadienyl, and alkatrienyl groups such as 1,3,5-hexatrienyl.

As the "cyclic aliphatic hydrocarbon group" in the above "optionally substituted cyclic aliphatic hydrocarbon group", specifically, a 3- to 10-membered monocyclic aliphatic hydrocarbon group or condensed cyclic aliphatic hydrocarbon group group hydrocarbon groups and the like can be exemplified. Specific examples of monocyclic aliphatic hydrocarbon groups include saturated or unsaturated cyclic aliphatic hydrocarbon groups such as cycloalkyl groups, cycloalkenyl groups, and cycloalkadienyl groups.

Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl groups.

Specific examples of the cycloalkenyl group include 1-cyclopentenyl group, 2-cyclopentenyl group, 1-cyclohexenyl group, 1-cyclobutenyl group, 1-cycloheptenyl group and the like.

Specific examples of the cycloalkadienyl group include a 2,4-cyclopentadienyl group, a 2,4-cyclohexadienyl group and a 2,5-cyclohexadienyl group.

Examples of the condensed ring aliphatic hydrocarbon group include those in which the monocyclic aliphatic hydrocarbon group and an optionally substituted aromatic hydrocarbon are condensed, specifically, a 1-indanyl group. , 2-indanyl group, 1,2,3,4-tetrahydronaphthalen-1-yl group, 1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-1-yl group , 1-hydrindanyl group, exo- or endo-tricyclo[5.2.1.0]decan-4-yl group, 2-bornen-5-yl group, 2-norbornen-5-yl group, exo- or endo -tricyclo[5.2.1.0]dec-3-en-8-yl group, 1,2,3,4,5,6,7,8-octahydronaphthalen-1-yl group, tricyclo[6 .2.1.0]undec-4-en-8-yl group, tetracyclo[6.2.1.1.0]dodeca-4-en-9-yl group, bicyclo[2.2.1]hepta -2,5-dien-3-yl group, 3a,4,7,7a-tetrahydroinden-3-yl group and the like can be exemplified.

The "aromatic hydrocarbon group" in the above "optionally substituted aromatic hydrocarbon group" may be monocyclic or condensed polycyclic, and specifically includes a phenyl group, 1-naphthyl group, 2-naphthyl group, 1-azulenyl group, 3-indenyl group, 1-indanyl group, 5-tetralinyl group and the like.

Specifically, the "heterocyclic group" in the above "optionally substituted heterocyclic group" contains at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A 5- to 10-membered monocyclic heterocyclic group, or a 5- to 10-membered monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic ring can be exemplified, and the condensed aromatic heterocyclic group includes a benzene ring and nitrogen It includes condensed monocyclic heterocycles containing at least one heteroatom selected from the group consisting of atoms, oxygen atoms and sulfur atoms.

Specific examples of the heterocyclic group include 1-piperidinyl group, 1-morpholinyl group, 2-pyrrolyl group, 2-imidazolyl group, 2-benzimidazolyl group, 3-pyrazolyl group, 2-thiazolyl group, and 3-isothiazolyl group. , 2-oxazolyl group, 3-isoxazolyl group, 4-furazanyl group, 2-pyridinyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 3-pyridazinyl group, 2-furanyl group, 2-pyranyl group, 2-thienyl group , 2-benzothiophenyl group, 2-thiopyranyl group, 1-isothiochromenyl group, 2-thiochromenyl group, 9-thioxanthenyl group, 1-thianthrenyl group, 1-phenoxathiinnyl group, 1-pyrrolidinyl group, 5H- 1-pyrindin-5-yl group, indolizin-1-yl group, 1-isoindolyl group, 1-indolyl group, 1-indazolinyl group, 2-purinyl group, 1-quinolidinyl group, 1-isoquinolinyl group, 2-quinolinyl group, 2,6-naphthyridin-1-yl group, 2,7-naphthyridin-1-yl group, 1-phthalazinyl group, 2-quinoxalinyl group, 2-quinazolinyl group, 3-cinnolinyl group, 2-pteridinyl group, 9 -carbazolyl group, 9-β-carbolinyl group, 10-phenanthridinyl group, 9-acridinyl group, 2-perimidinyl group, 1,10-phenanthrolin-2-yl group, 1-phenazinyl group, 1-phenothiazinyl group , 1-phenoxazinyl group, 2-antiridinyl group, 1-isobenzofuranyl group, 2-benzofuranyl group, 1-isochromenyl group, 2-chromenyl group, 9-xanthenyl group, parathiazinyl group, 1,2,4-triazole -3-yl group, 1,2,3-triazol-1-yl group, 5-tetrazolyl group and the like.

The above "chain hydrocarbon group optionally having substituent(s), cyclic aliphatic hydrocarbon group optionally having substituent(s), aromatic hydrocarbon group optionally having substituent(s) and substituent A group combined with at least one group selected from heterocyclic groups which may have a group" means a chain hydrocarbon group which may have a substituent and a At least one group selected from an optionally substituted cyclic aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group and an optionally substituted heterocyclic group It is a compounded group, specifically, a group in which the chain hydrocarbon group which may have one or more substituents and the cyclic aliphatic hydrocarbon group which may have one or more substituents are combined, A group in which a chain hydrocarbon group optionally having substituents and an aromatic hydrocarbon group optionally having substituents described above are combined, and chain hydrocarbons optionally having substituents described above A preferred example is a group in which a group and a heterocyclic group optionally having a substituent are combined.

As the "group in which a chain hydrocarbon group optionally having substituent(s) and a cyclic aliphatic hydrocarbon group optionally having substituent(s) are combined", specifically, a cyclopropylmethyl group , cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclooctylmethyl group, cyclononylmethyl group, cyclodecylmethyl group and the like.

Specific examples of the above-mentioned "group in which a chain hydrocarbon group which may have a substituent and an aromatic hydrocarbon group which may have a substituent are combined" include a benzyl group and a phenethyl group. , a naphthylmethyl group, and the like.

As the above-mentioned "group in which a chain hydrocarbon group optionally having substituent(s) and a heterocyclic group optionally having substituent(s) are combined", specifically, a 2-piperidinylmethyl group , 1-morpholinylmethyl group, 2-pyrrolylmethyl group, 2-imidazolylmethyl group, 2-imidazolidinylmethyl group, 2-benzimidazolylmethyl group, 3-pyrazolylmethyl group, 2-thiazolylmethyl group and the like. can.

The above "chain hydrocarbon group optionally having substituents", "cyclic aliphatic hydrocarbon group optionally having substituents", "aromatic hydrocarbon group optionally having substituents The “substituent” in the “group” and the “heterocyclic group optionally having substituent(s)” is not particularly limited as long as it is chemically acceptable and has the effects of the present invention.

In particular,
methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-heptyl group , C1-10 alkyl groups such as n-octyl group, n-nonyl group or n-decyl group;
vinyl group, 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group or 2-methyl-2-propenyl group, etc. The C2-6 alkenyl group of;
C2-6 alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group or 1-methyl-2-propynyl group;

C3-8 cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or cubanyl group;
C6-10 aryl group such as phenyl group or 1-naphthyl group;
C6-10 aryl C1-6 alkyl group such as benzyl group or phenethyl group;
3-6 membered heterocyclyl group;
3-6 membered heterocyclyl C1-6 alkyl group;

hydroxyl group;
C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy or t-butoxy;
C2-6 alkenyloxy groups such as a vinyloxy group, an allyloxy group, a propenyloxy group or a butenyloxy group;
C2-6 alkynyloxy group such as ethynyloxy group or propargyloxy group;
a C6-10 aryloxy group such as a phenoxy group or a 1-naphthoxy group;
a C6-10 aryl C1-6 alkoxy group such as a benzyloxy group or a phenethyloxy group;
5- to 6-membered heteroaryloxy groups such as a 2-thiazolyloxy group or a 2-pyridyloxy group;
5- to 6-membered heteroaryl C1-6 alkyloxy groups such as 2-thiazolylmethyloxy group or 2-pyridylmethyloxy group;

formyl group;
C1-6 alkylcarbonyl group such as acetyl group or propionyl group;
formyloxy group;
C1-6 alkylcarbonyloxy groups such as acetyloxy group and propionyloxy group;
C6-10 arylcarbonyl group such as benzoyl group;
C6-10 arylcarbonyloxy group such as benzoyloxy group;
C1-6 alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group or t-butoxycarbonyl group; methoxycarbonyloxy group, ethoxycarbonyloxy group, C1-6 alkoxycarbonyloxy groups such as n-propoxycarbonyloxy group, i-propoxycarbonyloxy group, n-butoxycarbonyloxy group, or t-butoxycarbonyloxy group;
Carboxyl group;

Halogeno groups such as fluoro, chloro, bromo or iodo groups;
C1-6 haloalkyl groups such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group or perfluoro-n-pentyl group;
C2-6 haloalkenyl groups such as 2-chloro-1-propenyl group or 2-fluoro-1-butenyl group;
C2-6 haloalkynyl groups such as 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group or 5-bromo-2-pentynyl group;
C1-6 haloalkoxy groups such as a trifluoromethoxy group, a 2-chloro-n-propoxy group or a 2,3-dichlorobutoxy group;
C2-6 haloalkenyloxy groups such as 2-chloropropenyloxy group or 3-bromobutenyloxy group;
a C1-6 haloalkylcarbonyl group such as a chloroacetyl group, a trifluoroacetyl group or a trichloroacetyl group;

amino group;
C1-6 alkyl-substituted amino groups such as methylamino group, dimethylamino group or diethylamino group;
C6-10 arylamino group such as anilino group or 1-naphthylamino group;
a C6-10 aryl C1-6 alkylamino group such as a benzylamino group or a phenethylamino group;
formylamino group;
C1-6 alkylcarbonylamino groups such as acetylamino group, propanoylamino group, butyrylamino group or i-propylcarbonylamino group;
C6-10 arylcarbonylamino group such as benzoylamino group;
C1-6 alkoxycarbonylamino groups such as methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group or i-propoxycarbonylamino group;

unsubstituted or substituted aminocarbonyl group such as aminocarbonyl group, dimethylaminocarbonyl group, phenylaminocarbonyl group or N-phenyl-N-methylaminocarbonyl group;
imino C1-6 alkyl groups such as iminomethyl group, 1-iminoethyl group or 1-imino-n-propyl group;
N-hydroxy-iminomethyl group, 1-(N-hydroxyimino)ethyl group, 1-(N-hydroxyimino)-n-propyl group, N-methoxyiminomethyl group or 1-(N-methoxyimino)ethyl group, etc. An unsubstituted or substituted N-hydroxyimino C1-6 alkyl group;

aminocarbonyloxy group;
C1-6 alkyl-substituted aminocarbonyloxy groups such as an ethylaminocarbonyloxy group or a dimethylaminocarbonyloxy group;

mercapto group;
C1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio or t-butylthio;
C1-6 haloalkylthio groups such as a trifluoromethylthio group or a 2,2,2-trifluoroethylthio group;
a C6-10 arylthio group such as a phenylthio group or a 1-naphthylthio group;
5- to 6-membered heteroarylthio groups such as a 2-thiazolylthio group or a 2-pyridylthio group;
C1-6 alkylsulfinyl groups such as a methylsulfinyl group, an ethylsulfinyl group or a t-butylsulfinyl group;
C1-6 haloalkylsulfinyl groups such as a trifluoromethylsulfinyl group or a 2,2,2-trifluoroethylsulfinyl group;
a C6-10 arylsulfinyl group such as a phenylsulfinyl group or a 1-naphthylsulfinyl group;
5- to 6-membered heteroarylsulfinyl groups such as a 2-thiazolylsulfinyl group or a 2-pyridylsulfinyl group;
C1-6 alkylsulfonyl groups such as a methylsulfonyl group, an ethylsulfonyl group or a t-butylsulfonyl group;
C1-6 haloalkylsulfonyl groups such as a trifluoromethylsulfonyl group or a 2,2,2-trifluoroethylsulfonyl group;
a C6-10 arylsulfonyl group such as a phenylsulfonyl group or a 1-naphthylsulfonyl group;
5- to 6-membered heteroarylsulfonyl groups such as a 2-thiazolylsulfonyl group or a 2-pyridylsulfonyl group;
C1-6 alkylsulfonyloxy groups such as a methylsulfonyloxy group, an ethylsulfonyloxy group or a t-butylsulfonyloxy group;
C1-6 haloalkylsulfonyloxy groups such as a trifluoromethylsulfonyloxy group or a 2,2,2-trifluoroethylsulfonyloxy group;

a triC1-6 alkyl-substituted silyl group such as a trimethylsilyl group, a triethylsilyl group or a t-butyldimethylsilyl group;
a tri-C1-6 alkyl-substituted silyloxy group such as a trimethylsilyloxy group, a triethylsilyloxy group or a t-butyldimethylsilyloxy group;
tri-C6-10 aryl-substituted silyl groups such as triphenylsilyl groups;
a tri-C6-10 aryl-substituted silyloxy group such as a triphenylsilyloxy group;
A cyano group, a nitro group, or the like can be exemplified.

In addition, any hydrogen atom in these "substituents" may be substituted with a group having a different structure. Specific examples of the "substituent" in that case include a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a halogeno group, a cyano group, a nitro group, and the like. can do.

The above-mentioned "3- to 6-membered heterocyclyl group" includes, for example, 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom and a boron atom as ring-constituting atoms. Heterocyclyl groups may be either monocyclic or polycyclic. As long as at least one ring of the polycyclic heterocyclyl group is a heterocyclic ring, the remaining rings may be saturated alicyclic, unsaturated alicyclic or aromatic rings. Specific examples of the "3- to 6-membered heterocyclyl group" include a 3- to 6-membered saturated heterocyclyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered partially unsaturated heterocyclyl group, and the like.

Specific examples of the 3- to 6-membered saturated heterocyclyl group include a 2-aziridinyl group, a 2-epoxy group, a 2-pyrrolidinyl group, a 2-tetrahydrofuranyl group, a 2-thiazolidinyl group, a 2-piperidyl group, and a 2-piperazinyl group. , 1-morpholinyl group, 2-dioxolanyl group, 2-dioxanyl group, pinacolonylboronyl group and the like.

Specific examples of the 5-membered heteroaryl group include a 2-pyrrolyl group, 2-furyl group, 2-thienyl group, 2-imidazolyl group, 3-pyrazolyl group, 2-oxazolyl group, 3-isoxazolyl group, 2- thiazolyl group, 3-isothiazolyl group, 1,2,4-triazol-3-yl group, 1,2,4-oxadiazol-3-yl group, 1,2,4-thiadiazol-3-yl group , 5-tetrazolyl group and the like.

Specific examples of the 6-membered heteroaryl group include a 2-pyridyl group, a 3-pyrazinyl group, a 2-pyrimidinyl group, a 2-pyridazinyl group, a 1,3,5-triazin-2-yl group, and the like. can be done.

Specific examples of the 5- to 6-membered partially unsaturated heterocyclyl group include a 2-oxazolinyl group and a 3-isoxazolinyl group.

Specific examples of the C1-6 alkyl group of the 3- to 6-membered heterocyclyl include a 2-aziridinylmethyl group, a glycidyl group, a 2-pyrrolidylmethyl group, a 2-tetrahydrofuranylmethyl group, and a 2-thiazolidinylmethyl group. methyl group, 2-pyrrolylmethyl group, 2-furylmethyl group, 2-imidazolylmethyl group, 2-pyridylmethyl group, 4-pyridylmethyl group and the like.

As R ₃ of the above “—OR ₃ ”, specifically, the same functional groups as those exemplified as the functional groups of R ₁ can be exemplified. “—OR ₃ ” specifically includes a C1 C2-6 alkenyloxy groups such as ~6 alkoxy group, vinyloxy group, allyloxy group, propenyloxy group or butenyloxy group, C2-6 alkynyloxy groups such as ethynyloxy group or propargyloxy group, phenoxy group or 1-naphthoxy group, etc. C6-10 aryloxy group, C6-10 aryl C1-6 alkoxy group such as benzyloxy group or phenethyloxy group, 5-6 membered heteroaryloxy group such as 2-thiazolyloxy group or 2-pyridyloxy group or thiazolyl 5- to 6-membered heteroaryl C1-6 alkyloxy groups such as methyloxy group or pyridylmethyloxy group can be exemplified.

Specific examples of R ₄ and R 4′ in the above “—NR ₄ R _{4′ ”} include the same functional groups as the functional groups of R ₁ . "-NR ₄ R _4' " specifically includes a C1-6 alkyl-substituted amino group such as a methylamino group, a dimethylamino group or a diethylamino group, a C6-10 arylamino group such as an anilino group or a 1-naphthylamino group. or a C6-10 aryl C1-6 alkylamino group such as a benzylamino group or a phenethylamino group.

Among the above R ₁ , preferably, an optionally substituted cyclic aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, or an optionally substituted It is a heterocyclic group, more preferably an aromatic hydrocarbon group which may have a substituent, and particularly preferably a phenyl group which may have a substituent. Further, the number of substituents on the phenyl group which may have the above substituents may be 1 or 2 or more, and the positions of the substituents are ortho, meta, and para positions with respect to the substitution position with the triple bond. may be at any position.

In formula (I), _R2 represents a hydrogen atom, a trialkylsilyl group, an allyldialkylsilyl group, an alkyldiallylsilyl group, or a triallylsilyl group, specifically a trimethylsilyl group, a triethylsilyl group, a tri(n -butyl)silyl group, t-butyldimethylsilyl group, dimethylphenylsilyl group, diphenylmethylsilyl group, triphenylsilyl group and the like.

Specific examples of the compound represented by formula (I) include compounds represented by the following formulas.

In addition, even if the fluoroalkyl group represented by R _f above is an alkyl group (perfluoroalkyl group) in which all of the hydrogen atoms are substituted with fluorine atoms, an alkyl group in which some of the hydrogen atoms are substituted with fluorine atoms may be a base. The number of carbon atoms is also not particularly limited, but the range of C1 to C10 can be preferably exemplified. R _f is specifically a perfluoroalkyl such as CF ₃ , C ₂ F ₅ , C ₃ F ₇ , C ₄ F ₉ , C ₅ F ₁₁ , C ₆ F ₁₃ , C ₇ F ₁₅ or C ₈ F _{17 groups , CF2H , CFH2 , CF2CF2H , CH2CF3 , CH2CH2CF3 , CH2C2F5 , CH2CH2C2F5 , CH2C3F7 , _} Partially fluorine-substituted alkyl groups such as CH ₂ CH ₂ C ₃ F ₇ , CH ₂ C ₄ F ₉ and CH ₂ CH ₂ C ₄ F ₉ can be exemplified. Among them, an alkyl group in which 60% or more of the hydrogen atoms in the alkyl group are substituted with fluorine atoms is preferable, and 70% or more, 80% or more, and 90% or more is more preferable. Among them, a C1-C6 fluoroalkyl group is preferred, a C1-C3 fluoroalkyl group is more preferred, and CF _{3 and} CF ₂ CF ₂ H are particularly preferred.

In the production method of the present invention, an alkyne compound represented by formula (I) is reacted with fluoroalkylsulfonic acid (R _f SO ₃ H) in the presence of a radical initiator in an organic solvent or in the absence of solvent.

Specific examples of the organic solvent used include chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, o-dichlorobenzene, 1,3,5-trichlorobenzene, bromobenzene, organic halogen solvents such as iodobenzene, trifluoromethylbenzene, fluorobenzene, or difluorobenzene; aromatic hydrocarbons such as benzene, toluene, xylene or mesitylene; dimethylformamide (DMF), dimethylsulfoxide (DMSO), diethyl ether, Diisopropyl ether, di(n-butyl) ether, monoglyme, diglyme, triglyme, tetrahydrofuran, 1,4-dioxane, anisole, veratrol, diethyl sulfide, di(n-butyl) sulfide, acetonitrile, propionitrile or benzonitrile, etc. Protic polar solvents; aliphatic hydrocarbons such as pentane, hexane, cyclopentane or cyclohexane can be exemplified, among which organic halogen solvents are preferable, and dichloromethane or 1,2-dichloroethane is more preferable.

The amount of these organic solvents to be used is not particularly limited, but is preferably in the range of 0.5 to 20 times the weight of the alkyne compound represented by formula (I).

The radical initiator to be used is not particularly limited as long as it generates a fluoroalkyl radical from the vinyl fluoroalkylsulfonate which is considered to be generated as an intermediate in the reaction system. is a trialkylborane compound such as triethylborane or tributylborane and molecular oxygen, a dialkylzinc such as diethylzinc and molecular oxygen, azobisisobutyronitrile, 2,2′-azobis(4-methoxy-2,4 -dimethylvaleronitrile), 2,2′-azobis(2,4-dimethylvaleronitrile), 2,2′-azobis(2-methylbutyronitrile), 1,1′-azobis(cyclohexane-1-carbonitrile) ), 2,2′-azobis(N-(2-propenyl)-2-methylpropionamide), 2,2′-azobis(N-butyl-2-methylpropionamide), dimethyl 2,2′- Examples include azo compounds such as azobis(isobutyrate) and peroxide compounds such as di(t-butyl) peroxide. Among these, azo compounds such as azobisisobutyronitrile are preferred.

The molar ratio of the radical initiator to the alkyne compound represented by formula (I) is preferably in the range of 0.01 to 1.0 equivalents. In addition, as a method for generating a fluoroalkyl radical from a vinyl fluoroalkylsulfonate compound that may be formed as an intermediate in the reaction system, a method of adding an azo compound and heating, or conditions of light irradiation, A condition of adding an oxide and irradiating light can also be used. When using triethylborane, the presence of molecular oxygen in trace amounts is sufficient.
In the method of the present invention, it is preferable to add a radical initiator such as an azo compound and perform heating, and the heating temperature is preferably from 30° C. to the boiling point of the solvent used. It is more preferable to heat to a temperature higher than the cleavage temperature, and the ranges of 40 to 100°C, 50 to 90°C and 60 to 80°C can be preferably exemplified.

The molar ratio of the fluoroalkylsulfonic acid to the compound represented by formula (I) is preferably in the range of 1.0 to 2.0 equivalents.

Although the reaction temperature in the production method of the present invention is not particularly limited, it is usually -100°C to 150°C. The reaction pressure can be normal pressure or increased pressure. The reaction time is usually 1 minute to 100 hours. In addition, it is desirable to carry out the reaction under sufficient stirring.

After the reaction, an acid such as acetic acid or hydrochloric acid or water is added to deactivate the reaction reagent, and after removing insoluble matter, a normal operation is performed to obtain the α-fluoroalkyl ketone compound represented by formula (II). can be purified and isolated, but without such an isolation and purification step, a reducing agent or the like is added to the reaction system to reduce it, and then a known distillation method, extraction, crystallization, recrystallization The β-fluoroalkyl alcohol compound can be isolated by purification such as chromatography.

The method for reducing the α-fluoroalkyl ketone is not particularly limited as long as the ketone can be reduced without reducing the fluoroalkyl group, and specific examples include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium triethylborohydride, lithium tri(s-butyl)borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, hydrogen Reduction with metal hydrides such as nickel borohydride, zinc borohydride, borane complexes such as 2-picoline borane complex and borane dimethyl sulfide complex, reduction with hydrogen using palladium, ruthenium complexes, etc., isopropanol, cyclohexanol as a hydrogen source Examples thereof include Meerwein-Podolph-Vale reduction using aluminum alkoxide, lanthanide alkoxide, zirconium alkoxide, ruthenium complex, and the like.

Further, as a method of obtaining β-fluoroalkyl alcohol from α-fluoroalkyl ketone, a method of reacting an organometallic reagent with a carbonyl group can also be exemplified. The organometallic reagent is not particularly limited as long as it reacts with a carbonyl group, and specific examples thereof include methylmagnesium bromide, phenylmagnesium bromide, methyllithium, and phenyllithium. R' in formula (III) represents an organic group moiety of an organometallic reagent, and specifically includes an alkyl group such as a methyl group, an ethyl group and an n-propyl group, an aryl group such as a phenyl group and a 1-naphthyl group. etc. can be exemplified.

EXAMPLES The present invention will be described in more detail below using examples, but the scope of the present invention is not limited to these examples.
[Example 1]

16.7 mg (0.10 mmol) of azobisisobutyronitrile (AIBN) and 65.4 mg (0.48 mmol) of 1-chloro-4-ethynylbenzene were placed in a reactor, and the reactor was purged with nitrogen. 2 ml of 1,2-dichloroethane and 0.08 ml of 1,1,2,2-tetrafluoroethanesulfonic acid were sequentially added, and the mixture was stirred under heating (80° C.) for 4 hours. Then, after distilling off the solvent, dibromomethane was added to the reaction mixture as an ^internal standard. The yield of 1-one was 81%.
[Example 2]

16.7 mg (0.10 mmol) of AIBN and 65.4 mg (0.48 mmol) of 1-chloro-4-ethynylbenzene were placed in a reactor, and the reactor was purged with nitrogen. 2 ml of 1,2-dichloroethane and 0.08 ml of 1,1,2,2-tetrafluoroethanesulfonic acid were sequentially added, and the mixture was stirred under heating (80° C.) for 4 hours. After cooling to room temperature, 2 ml of methanol and 35.8 mg (0.95 mmol) of sodium borohydride were added and stirred at room temperature for 30 minutes. After that, a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with dichloromethane. After distilling off the solvent, ^{dibromomethane} was added to the reaction mixture as an internal standard. The yield of all was 65%. When the crude product was isolated and purified by silica gel column chromatography, 68 mg (0.27 mmol, yield) of 1-(4-chlorophenyl)-3,3,4,4-tetrafluorobutan-1-ol was obtained. rate of 56%) was obtained.

[Example 3] to [Example 10]
The reaction was carried out in the same manner as in Example 1, except that the alkyne compound shown in Table 1 was used. Table 1 shows the results.

［実施例１１］

[Example 11]

Example 1 except using 1-methoxycarbonyl-4-ethynylbenzene instead of 1-chloro-4-ethynylbenzene and trifluoromethanesulfonic acid instead of 1,1,2,2-tetrafluoroethanesulfonic acid 1-(4-methoxycarbonylphenyl)-3,3,3-trifluoropropan-1-one was obtained with a yield of 56%.

[Example 12] to [Example 15]
The reaction was carried out in the same manner as in Example 2, except that the alkyne compounds shown in Table 2 were used. Table 2 shows the results.

［実施例１６］

[Example 16]

16.7 mg (0.10 mmol) of azobisisobutyronitrile (AIBN) and 105 mg (0.5 mmol) of 1-chloro-4-(2-trimethylsilylethynyl)benzene were placed in a reactor to perform nitrogen substitution. 2 ml of 1,2-dichloroethane and 0.07 ml of trifluoromethanesulfonic acid were sequentially added, and the mixture was stirred under heating (100° C.) for 2 hours. Then, after distilling off the solvent, dibromomethane was added to the reaction mixture as an ^internal standard. A yield of 75% was found to be obtained.

[Example 17] to [Example 26]
The reaction was carried out in the same manner as in Example 16, except that the alkyne compound shown in Table 3 was used. Table 3 shows the results.

The production method of the present invention is an α-fluoroalkyl ketone compound such as an α-trifluoromethyl ketone compound that is useful as an intermediate for pharmaceuticals and agricultural chemicals or a liquid crystal material, without using an existing trifluoromethylating reagent or oxidizing agent. A β-fluoroalkyl alcohol compound such as a β-trifluoromethyl alcohol compound can be efficiently provided.

Claims (2)

Formula (I)

(In the formula, R ₁ is an optionally substituted cyclic aliphatic hydrocarbon group; an optionally substituted aromatic hydrocarbon group; or an optionally substituted heterocyclic represents a ring group, and R ₂ represents a hydrogen atom; a trialkylsilyl group; an allyldialkylsilyl group; an alkyldiallylsilyl group; or a triallylsilyl group. , with a fluoroalkylsulfonic acid (R _f SO ₃ H) (wherein R _f represents a fluoroalkyl group) of formula (II).

(wherein R ₁ has the same meaning as in formula (I), and R _f has the same meaning as above). 2. The method for producing an α-fluoroalkyl ketone according to claim 1, wherein the fluoroalkyl group in formula (II) is an alkyl group in which 60% or more of the hydrogen atoms in the alkyl group are substituted with fluorine atoms.