JP2020070240A - Method for producing α-fluoroalkyl ketone and β-fluoroalkyl alcohol - Google Patents

Abstract

To provide a method for producing α-fluoroalkyl ketone and β-fluoroalkyl alcohol conveniently, inexpensively and efficiently.SOLUTION: A method for producing α-fluoroalkyl ketone represented by formula (II) (where Ris a fluoroalkyl group) includes reacting an alkyne compound represented by formula (I) (where Ris a chain hydrocarbon group, cyclic aliphatic hydrocarbon group, aromatic hydrocarbon group, heterocyclic group, -OR, -NRR, Ris a hydrogen atom, trialkylsilyl group, diallyl alkylsilyl group, or triallylsilyl group), in the presence of a radical initiator, with a fluoroalkyl sulfonic acid.SELECTED DRAWING: None

Description

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

  In the organic fluorine compound, the similarity effect (mimic effect) of steric molecular recognition on the living body side, which is derived from the fact that the atomic radii of fluorine and hydrogen are almost the same, the C—F bond is stronger than the C—H bond. Therefore, fluorine, such as an effect that can protect the metabolic site and avoid toxicity associated therewith (blocking effect), and an effect that promotes absorption and transport in the body by improving lipophilicity (lipophilic effect), The effects derived from the characteristic size and electronic properties of atoms are known. Many chemical and agrochemical products have been developed by chemical modification adapted to these effects. Then, a method for introducing a fluoroalkyl group, which is a mimic substituent of an alkyl group, has been developed. Α-Fluoroalkylketone compounds, which are compounds in which a fluoroalkyl group is introduced at the α-position of a ketone, and β-fluoroalkyl alcohol compounds, in which a fluoroalkyl group is introduced at the β-position of a hydroxy group, are intermediates for medical and agricultural chemicals and liquid crystal materials. It is extremely useful as a raw material.

  As a method for producing an α-fluoroalkylketone compound, (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), (2) Alkene A method of reacting a perfluoroalkylating agent and an oxidizing agent (see Non-Patent Document 4), (3) a method of causing a photoredox catalyst and an electrophilic perfluoroalkylating agent to act on an alkyne (Non-Patent Document 5), (4) ) A method is known in which a radical initiator acts on a vinyl fluoroalkane sulfonate 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. Tomita, R.; Yasu, Y.; 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 an activator of a ketone 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 use only one of the two fluoroalkyl groups of the fluoroalkanesulfonic anhydride. Alternatively, there are problems in that an expensive fluoroalkylating agent is required.
In view of the above problems, it is an object of the present invention to provide a method for producing α-fluoroalkyl ketone and β-fluoroalkyl alcohol that is simpler, cheaper, and efficient.

  The present inventor, as a result of intensive studies to solve the above problems, using an alkyne compound that is relatively easily available as a starting material, in the presence of a radical initiator, by reacting an inexpensive fluoroalkyl sulfonic acid, , Α-fluoroalkyl ketone was found to efficiently obtain β-fluoroalkyl alcohol by reducing the α-fluoroalkyl ketone, and the present invention has been completed.

（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 cycloaliphatic hydrocarbon group which may have a substituent; an aromatic which may have a substituent. hydrocarbon group; optionally substituted heterocyclic _{group; -OR 3; -NR 4 R 4} '; and or may have a substituent group chain hydrocarbon group having a substituent Optionally combined cycloaliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group and at least one group selected from a heterocyclic group optionally substituted. R ₂ represents a hydrogen atom; a trialkylsilyl group; an allyldialkylsilyl group; an alkyldiallylsilyl group; or a triallylsilyl group, and R ₃ represents a hydrogen atom; which may have a substituent. A chain hydrocarbon group; a cycloaliphatic hydrocarbon group which may have a substituent; a substituent An optionally substituted aromatic hydrocarbon group; a heterocyclic group which may have a substituent; or a chain hydrocarbon group which may have a substituent, and a ring which may have a substituent R ₄ represents a group combined with an aliphatic hydrocarbon group, an aromatic hydrocarbon group which may have a substituent and at least one group selected from a heterocyclic group which may have a substituent, and R ₄ And R _{4 ′} are each independently a hydrogen atom; a chain hydrocarbon group which may have a substituent; a cyclic aliphatic hydrocarbon group which may have a substituent; Optionally aromatic hydrocarbon group; heterocyclic group optionally having substituent group; or chain hydrocarbon group optionally having substituent group, and cyclic aliphatic group optionally having substituent group Selected from an aromatic hydrocarbon group, an aromatic hydrocarbon group which may have a substituent and a heterocyclic group which may have a substituent That the alkyne compound and at least one group represented by represents.) The groups combined, in the presence of a radical initiator, fluoroalkyl sulfonic acid _(R f _SO 3 H) (wherein, the R _f, fluoroalkyl (II) which is reacted with

(In the formula, R ₁ has the same meaning as in formula (I), and R _f has the same meaning as described above.) The method for producing an α-fluoroalkylketone.
[2] Formula (III) for reducing α-fluoroalkylketone represented by formula (II) described in [1] or reacting with an organometallic reagent

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

  By using the production method of the present invention, it is possible to obtain the desired α-fluoroalkylketone by using alkynes that are relatively easily available, under a mild condition with an inexpensive reagent, and by a simple operation. A β-fluoroalkyl alcohol can be easily obtained by reducing the obtained ketone.

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

In the alkynes represented by formula (I) used in the production method of the present invention, R ₁ is a chain hydrocarbon group which may have a substituent, or a cyclic fat which may have a substituent. family hydrocarbon group having optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, -OR 3, a _-NR 4 _R 4 _', or a substituent A chain hydrocarbon group which may have, a cycloaliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent and a substituent which may have a substituent It represents a group combined with at least one kind of group selected from good heterocyclic groups.

  Specific examples of the “chain hydrocarbon group” in the “chain hydrocarbon group which may have a substituent” include an alkyl group, an alkenyl group, an alkynyl group, and the like. It may be a group in which 2 to 3 carbon-carbon bonds in the alkyl group are converted into a double bond, such as an alkadienyl group and an alkatrienyl group.

  The alkyl group may be linear or branched, and specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group. Groups, C1-C10 alkyl groups such as n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like. be able to.

  In addition, the term "C1-10" represents that the group serving as a nucleus has 1 to 10 carbon atoms. This number of carbon atoms does not include the number of carbon atoms present in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. Hereinafter, in the present specification, the terms have the same meaning.

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

  The alkynyl group may be linear or branched, and specifically, ethynyl group, 1-propynyl group, 1-butynyl group, 1-pentynyl group, 1-hexynyl group, 1-heptynyl group. Examples thereof include C2-10 alkynyl groups such as a 1-octynyl group and a 1-nonynyl group.

  As the above-mentioned "group in which 2 to 3 carbon-carbon bonds in the alkyl group are converted into double bonds", specifically, 2 to 3 carbon-carbon bonds in the alkyl group having 1 to 10 carbon atoms. And C4 to C6 alkadienyl groups such as 1,3-butadienyl and alkatrienyl groups such as 1,3,5-hexatrienyl.

  As the "cycloaliphatic hydrocarbon group" in the above "cycloaliphatic hydrocarbon group optionally having substituent (s)", specifically, a monocyclic aliphatic hydrocarbon group having 3 to 10 members or a condensed ring aliphatic Examples thereof include group hydrocarbon groups. Specific examples of the monocyclic aliphatic hydrocarbon group include a saturated or unsaturated cyclic aliphatic hydrocarbon group, such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.

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

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

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

  The condensed cyclic aliphatic hydrocarbon group also includes those condensed with the monocyclic aliphatic hydrocarbon group and an aromatic hydrocarbon which may have a substituent, 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 2.2.1.0] 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 etc. can be illustrated.

  The “aromatic hydrocarbon group” in the above “aromatic hydrocarbon group optionally having substituent (s)” may be monocyclic or condensed polycyclic, and specifically, phenyl group, 1-naphthyl Examples thereof include a group, a 2-naphthyl group, a 1-azurenyl group, a 3-indenyl group, a 1-indanyl group and a 5-tetralinyl group.

  The “heterocyclic group” in the above “heterocyclic group optionally having substituent (s)” specifically includes at least one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Examples thereof include a monocyclic heterocyclic group having 5 to 10 members, a monocyclic aromatic heterocyclic group having 5 to 10 members, and a condensed aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include a benzene ring and a nitrogen atom. Those in which a monocyclic heterocycle containing at least one heteroatom selected from the group consisting of an atom, an oxygen atom and a sulfur atom are condensed are included.

  Specific examples of the heterocyclic group include a 1-piperidinyl group, a 1-morpholinyl group, a 2-pyrrolyl group, a 2-imidazolyl group, a 2-benzimidazolyl group, a 3-pyrazolyl group, a 2-thiazolyl group, and a 3-isothiazolyl group. , 2-oxazolyl group, 3-isoxazolyl group, 4-flazanyl 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, -Indazolinyl group, 2-purinyl group, 1-quinolizinyl 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-phenanthroline-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-triazol-3-y 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 (s) The "group in which at least one group selected from a heterocyclic group which may have a group is combined" means a chain hydrocarbon group which may have the above-mentioned substituent, and a group which has the above-mentioned substituent. At least one group selected from a cycloaliphatic hydrocarbon group which may have an aromatic hydrocarbon group which may have a substituent and a heterocyclic group which may have a substituent, A complex group, specifically, a group in which a chain hydrocarbon group which may have the above-mentioned substituent and a cyclic aliphatic hydrocarbon group which may have the above-mentioned substituent are combined, A chain hydrocarbon group which may have a substituent and an aromatic hydrocarbon group which may have the above substituent There can be preferably exemplified a complex with groups, and heterocyclic group which may have a good chain hydrocarbon group as the above substituent may have the substituent has a complex group.

  As the above-mentioned "group in which a chain hydrocarbon group which may have a substituent and a cycloaliphatic hydrocarbon group which may have a substituent are combined", specifically, a cyclopropylmethyl group And cycloalkylmethyl groups such as cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclooctylmethyl group, cyclononylmethyl group, and cyclodecylmethyl group.

  As 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", specifically, a benzyl group, a phenethyl group , A naphthylmethyl group and the like can be exemplified.

  As the above-mentioned "group in which a chain hydrocarbon group which may have a substituent and the heterocyclic group which may have a substituent" 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. it can.

  The above “chain hydrocarbon group optionally having substituent (s)”, “cyclic aliphatic hydrocarbon group optionally having substituent (s)”, “aromatic hydrocarbon optionally having substituent (s)” The “substituent” in the “group” and “heterocyclic group optionally having substituent (s)” is chemically acceptable and is not particularly limited as long as it 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 , A C1-10 alkyl group 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, 2-methyl-2-propenyl group, etc. A C2-6 alkenyl group;
A C2-6 alkynyl group 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;

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

Hydroxyl group;
A C1-6 alkoxy group such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group or t-butoxy group;
C2-6 alkenyloxy groups such as vinyloxy group, allyloxy group, propenyloxy group or butenyloxy group;
A C2-6 alkynyloxy group such as an ethynyloxy group or a 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-three-membered heteroaryloxy group such as 2-thiazolyloxy group or 2-pyridyloxy group;
5- to 6-membered heteroaryl C1-6 alkyloxy group such as 2-thiazolylmethyloxy group or 2-pyridylmethyloxy group;

Formyl group;
A C1-6 alkylcarbonyl group such as an acetyl group or a 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 group such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group or t-butoxycarbonyl group; methoxycarbonyloxy group, ethoxycarbonyloxy group, a C1-6 alkoxycarbonyloxy group such as an n-propoxycarbonyloxy group, an i-propoxycarbonyloxy group, an n-butoxycarbonyloxy group, or a t-butoxycarbonyloxy group;
Carboxyl group;

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

Amino group;
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;
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;
A C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group or an i-propoxycarbonylamino group;

An aminocarbonyl group which is unsubstituted or has a substituent such as an aminocarbonyl group, a dimethylaminocarbonyl group, a phenylaminocarbonyl group or an N-phenyl-N-methylaminocarbonyl group;
An imino C1-6 alkyl group 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;
A C1-6 alkyl-substituted aminocarbonyloxy group such as an ethylaminocarbonyloxy group or a dimethylaminocarbonyloxy group;

Mercapto group;
A C1-6 alkylthio group such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group or t-butylthio group;
A C1-6 haloalkylthio group such as a trifluoromethylthio group or a 2,2,2-trifluoroethylthio group;
C6-10 arylthio group such as phenylthio group or 1-naphthylthio group;
5- or 6-membered heteroarylthio group such as 2-thiazolylthio group or 2-pyridylthio group;
A C1-6 alkylsulfinyl group such as a methylsulfinyl group, an ethylsulfinyl group or a t-butylsulfinyl group;
A C1-6 haloalkylsulfinyl group 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- or 6-membered heteroarylsulfinyl group such as 2-thiazolylsulfinyl group or 2-pyridylsulfinyl group;
A C1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group or a t-butylsulfonyl group;
A C1-6 haloalkylsulfonyl group 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- or 6-membered heteroarylsulfonyl group such as 2-thiazolylsulfonyl group or 2-pyridylsulfonyl group;
A C1-6 alkylsulfonyloxy group such as a methylsulfonyloxy group, an ethylsulfonyloxy group or a t-butylsulfonyloxy group;
A C1-6 haloalkylsulfonyloxy group such as a trifluoromethylsulfonyloxy group or a 2,2,2-trifluoroethylsulfonyloxy group;

A tri-C1-6 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;
A tri-C6-10 aryl-substituted silyl group such as a triphenylsilyl group;
A tri C6-10 aryl-substituted silyloxy group such as a triphenylsilyloxy group;
Examples thereof include a cyano group and a nitro group.

  Further, in these “substituents”, any hydrogen atom in the substituent 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.

  In addition, the above-mentioned "3- to 6-membered heterocyclyl group" includes, for example, 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, sulfur atom and boron atom as ring-constituting atoms. The heterocyclyl group may be either monocyclic or polycyclic. In the polycyclic heterocyclyl group, if at least one ring is a hetero ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring or an aromatic ring. 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 2-aziridinyl group, 2-epoxy group, 2-pyrrolidinyl group, 2-tetrahydrofuranyl group, 2-thiazolidinyl group, 2-piperidyl group, and 2-piperazinyl group. , 1-morpholinyl group, 2-dioxolanyl group, 2-dioxanyl group, pinacoronyl boronyl group and the like.

  As the 5-membered heteroaryl group, specifically, 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 can be exemplified.

  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, and a 1,3,5-triazin-2-yl group. You can

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

  As the C1-6 alkyl group of the above 3- to 6-membered heterocyclyl, specifically, 2-aziridinylmethyl group, glycidyl group, 2-pyrrolidylmethyl group, 2-tetrahydrofuranylmethyl group, 2-thiazolidini group. Examples thereof include a rumethyl group, a 2-pyrrolylmethyl group, a 2-furylmethyl group, a 2-imidazolylmethyl group, a 2-pyridylmethyl group and a 4-pyridylmethyl group.

Specific examples of R ₃ of “—OR ₃ ” include the same functional groups as those exemplified as the functional group of R ₁ . Specific examples of "-OR ₃ " include C1 such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group or t-butoxy group. To C6 alkoxy group, vinyloxy group, allyloxy group, C2-6 alkenyloxy group such as propenyloxy group or butenyloxy group, C2-6 alkynyloxy group 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- or 6-membered heteroaryloxy group such as 2-thiazolyloxy group or 2-pyridyloxy group, or thiazoli Rumethyloxy group or pyridylmethyloxy 5-6 membered heteroaryl C1~6 alkyloxy group such like can be exemplified.

As R ₄ and R _{4 ′} of the above-mentioned “—NR ₄ R _{4 ′} ”, specifically, the same functional groups as those exemplified as the functional group of R ₁ can be exemplified. As "-NR ₄ R _{4 '} ", specifically, 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. Group, or a C6-10 aryl C1-6 alkylamino group such as a benzylamino group or a phenethylamino group.

Among R ₁ above, preferably, a cycloaliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a substituent may be present. 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 a substituent may be 1 or 2 or more, and the position of the substituent may be an ortho position, a meta position, or a para position with respect to the position of substitution with the triple bond. Any position may be used.

In formula (I), R ₂ represents a hydrogen atom, a trialkylsilyl group, an allyldialkylsilyl group, an alkyldiallylsilyl group or a triallylsilyl group, and specifically, trimethylsilyl group, triethylsilyl group, tri (n) Examples thereof include -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.

Further, the fluoroalkyl group represented by R _f is an alkyl group in which all hydrogen atoms are replaced by fluorine atoms (perfluoroalkyl group), but an alkyl group in which some hydrogen atoms are replaced by fluorine atoms is used. It may be a group. The number of carbon atoms is not particularly limited, but the range of C1 to C10 can be preferably exemplified. Specific examples of R _f include 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. group, CF 2 H, CFH 2,} CF 2 CF 2 H, CH 2 CF 3, CH 2 CH 2 CF 3, CH 2 C 2 F 5, CH 2 CH 2 C 2 F 5, CH 2 C 3 F 7, Partially fluorine-substituted alkyl groups such as CH ₂ CH ₂ C ₃ F ₇ , CH ₂ C ₄ F ₉ or CH ₂ CH ₂ C ₄ F ₉ can be exemplified. Among them, an alkyl group in which 60% or more of hydrogen atoms in the alkyl group are substituted with a fluorine atom is preferable, and 70% or more, 80% or more, 90% or more is more preferable. Further, preferably a fluoroalkyl group having C1~C6 Among them, more preferably fluoroalkyl groups C1 to C3, in particular _CF 3, _{CF 2 CF} 2 H are preferred.

In the production method of the present invention, an alkyne compound represented by the formula (I) is reacted with a fluoroalkylsulfonic acid (R _f SO ₃ H) in an organic solvent or without a solvent in the presence of a radical initiator.

  As the organic solvent used, specifically, 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) su Fido, acetonitrile, aprotic polar solvents such as propionitrile or benzonitrile; aliphatic hydrocarbons such as pentane, hexane, cyclopentane or cyclohexane can be exemplified, and among them, organic halogen solvents are preferable, and , Dichloromethane or 1,2-dichloroethane are preferred.

  The amount of these organic solvents 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 the formula (I).

  The radical initiator used is not particularly limited as long as it can generate a fluoroalkyl radical from a vinyl fluoroalkyl sulfonate that 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), azo compound or di (t-butyl) and dimethyl 2,2'-azobis (isobutyrate) can be exemplified peroxide compounds such as peroxide. Of these, azo compounds such as azobisisobutyronitrile are preferable.

The amount of the radical initiator used with respect to the alkyne compound represented by the formula (I) is preferably in the range of 0.01 to 1.0 equivalent by molar ratio. Further, as a method of generating a fluoroalkyl radical from a vinyl fluoroalkyl sulfonate compound which may be generated as an intermediate in the reaction system, a method of adding an azo compound and heating or a condition of irradiating light or A condition in which an oxide is added and light is irradiated can also be used. When using triethylborane, it is sufficient that a trace amount of molecular oxygen is present.
In the method of the present invention, it is preferable that a radical initiator such as an azo compound is added and heated, and the heating temperature is preferably from 30 ° C. to the boiling point of the solvent used, and the radical polymerization initiator used is It is more preferable to heat to a temperature at which it can be cleaved or more, and the range of 40 to 100 ° C, 50 to 90 ° C, and 60 to 80 ° C can be preferably exemplified.

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

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

  After the reaction, an acid such as acetic acid or hydrochloric acid or water is added to inactivate the reaction reagent and insoluble matter is removed, and then an ordinary operation is performed to obtain an α-fluoroalkylketone compound represented by the formula (II). Can also be purified and isolated, but without such an isolation and purification step, reduction is carried out by adding a reducing agent or the like to the reaction system, and then a known distillation method, extraction, crystallization, recrystallization is performed. 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 it can reduce the ketone without reducing the fluoroalkyl group, and specifically, sodium borohydride, sodium cyanoborohydride, hydride Sodium triacetoxyborohydride, lithium borohydride, lithium triethylborohydride, lithium tri (s-butyl) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, bis (2-methoxyethoxy) aluminum hydride sodium, hydrogen Reduction with metal hydrides such as nickel borohydride, zinc borohydride, 2-picoline borane complex, borane complex such as borane dimethyl sulfide complex, reduction with hydrogen using palladium, ruthenium complex, etc., isopropanol, cyclohexanol as hydrogen source To, it may be exemplified aluminum alkoxide, a lanthanoid alkoxide, a zirconium alkoxide, a Meerwein-Podorufu, Vale reduction or the like using ruthenium complexes, and the like.

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

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the scope of 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 nitrogen substitution was carried out. 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 and analyzed by ¹ H-NMR. As a result, 1- (4-chlorophenyl) -3,3,4,4-tetrafluorobutane- 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 nitrogen substitution was carried out. 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 the mixture was stirred at room temperature for 30 minutes. Then, saturated aqueous ammonium chloride 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 and analyzed by ¹ H-NMR. As a result, 1- (4-chlorophenyl) -3,3,4,4-tetrafluoropentane-1- The yield of oats 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. 56%) was obtained.

[Example 3] to [Example 10]
The reaction was performed in the same manner as in Example 1 except that the alkyne compound used was one shown in Table 1. The results are shown in Table 1.

［実施例１１］

[Example 11]

  Example 1 except that 1-methoxycarbonyl-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene and trifluoromethanesulfonic acid was used instead of 1,1,2,2-tetrafluoroethanesulfonic acid. Was carried out in the same manner as above, and 1- (4-methoxycarbonylphenyl) -3,3,3-trifluoropropan-1-one was obtained with a yield of 56%.

[Example 12] to [Example 15]
The reaction was performed in the same manner as in Example 2 except that the alkyne compound used was one shown in Table 2. The results are shown in Table 2.

［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 the reactor and nitrogen substitution was carried out. 1,2-Dichloroethane (2 ml) and trifluoromethanesulfonic acid (0.07 ml) 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 and analyzed by ¹ H-NMR. As a result, 1- (4-chlorophenyl) -3,3,3-trifluoropropane-1- It was found that the on was obtained in a yield of 75%.

[Example 17] to [Example 26]
The reaction was performed in the same manner as in Example 16 except that the alkyne compound used was one shown in Table 3. The results are shown in Table 3.

  The production method of the present invention uses α-fluoroalkylketone compounds such as α-trifluoromethylketone compounds, which are useful as intermediates and liquid crystal materials for medical and agricultural chemicals, without using existing trifluoromethylation reagents and oxidizing agents. A β-fluoroalkyl alcohol compound such as a β-trifluoromethyl alcohol compound can be efficiently provided.

Claims (4)

Formula (I)

(In the formula, R ₁ is a chain hydrocarbon group which may have a substituent; a cycloaliphatic hydrocarbon group which may have a substituent; an aromatic which may have a substituent. hydrocarbon group; optionally substituted heterocyclic _{group; -OR 3; -NR 4 R 4} '; and or may have a substituent group chain hydrocarbon group having a substituent Optionally combined cycloaliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group and at least one group selected from a heterocyclic group optionally substituted. R ₂ represents a hydrogen atom; a trialkylsilyl group; an allyldialkylsilyl group; an alkyldiallylsilyl group; or a triallylsilyl group, and R ₃ represents a hydrogen atom; which may have a substituent. A chain hydrocarbon group; a cycloaliphatic hydrocarbon group which may have a substituent; a substituent An optionally substituted aromatic hydrocarbon group; a heterocyclic group which may have a substituent; or a chain hydrocarbon group which may have a substituent, and a ring which may have a substituent R ₄ represents a group combined with an aliphatic hydrocarbon group, an aromatic hydrocarbon group which may have a substituent and at least one group selected from a heterocyclic group which may have a substituent, and R ₄ And R _{4 ′} are each independently a hydrogen atom; a chain hydrocarbon group which may have a substituent; a cyclic aliphatic hydrocarbon group which may have a substituent; Optionally aromatic hydrocarbon group; heterocyclic group optionally having substituent group; or chain hydrocarbon group optionally having substituent group, and cyclic aliphatic group optionally having substituent group Selected from an aromatic hydrocarbon group, an aromatic hydrocarbon group which may have a substituent and a heterocyclic group which may have a substituent That the alkyne compound and at least one group represented by represents.) The groups combined, in the presence of a radical initiator, fluoroalkyl sulfonic acid _(R f _SO 3 H) (wherein, the R _f, fluoroalkyl (II) which is reacted with

(In the formula, R ₁ has the same meaning as in formula (I), and R _f has the same meaning as described above.) The method for producing an α-fluoroalkylketone. Formula (III) for reducing or reacting an α-fluoroalkylketone represented by formula (II) according to claim 1 with an organometallic reagent

(Wherein R ₁ and R _f have the same meanings as in formula (II), and R ′ represents a hydrogen atom or an organic group moiety of an organometallic reagent). Method.   The method for producing an α-fluoroalkyl ketone according to claim 1, wherein the fluoroalkyl group in the formula (II) is an alkyl group in which 60% or more of hydrogen atoms in the alkyl group are substituted with fluorine atoms. The method for producing β-fluoroalkyl alcohol according to claim 2, wherein the fluoroalkyl group in the formula (III) is an alkyl group in which 60% or more of hydrogen atoms in the alkyl group are substituted with fluorine atoms.