JP3896483B2 - Method for producing cyclic ketones - Google Patents

Description

（式中、Ｒ^１〜Ｒ^６は、それぞれ反応に関与しない基を示す。環Ａは、単環もしくは縮合多環の芳香環基を示し、その環を構成する原子には、窒素、酸素またはイオウから選ばれる原子を含んでいてもよく、また環が反応に関与しない基で置換されていてもよい。）で表されるカルボン酸を、一般式（II）
ＭＸｍ・Ｌｎ （II）
（式中、Ｍはビスマス、ガリウム、インジウム、希土類元素から選ばれる金属イオンを示し、Ｘはアニオンを示し、ＬはＭに配位力のある中性分子を示す。ｍは金属Ｍの原子価数であり、ｎは０〜１０の整数である。）
で表されるルイス酸の触媒量の存在下に環化反応させることにより一般式（III）
【化４】

（式中、Ｒ^１〜Ｒ^６及び環Ａは、それぞれ前記と同じ意味である。）で表される環状ケトン類を製造する方法である。
【０００７】
【発明の実施の形態】
本発明の製造方法に原料として用いられる前記一般式（Ｉ）で表されるカルボン酸は、４位が芳香環基で置換されたラク酸類骨格を有するものであり、置換基Ｒ^１〜Ｒ^６は、いずれも本発明の環化反応に悪影響を及ぼさないものであればよく、何ら制限されない。
一般式（Ｉ）において、Ｒ^１〜Ｒ^６は、いずれもラク酸骨格のアルキレン鎖に結合するものであり環化反応に関与しない基であって、例えば、水素原子、ハロゲン原子、メチル、エチル、プロピル、ｔ−ブチルなどのアルキル基、メトキシ、エトキシなどのアルコキシ基、エステル基、シアノ基などが挙げられる。
【０００８】
また、一般式（Ｉ）において環Ａは、単環もしくは縮合多環の芳香環基であり、環を構成する原子には、異項原子として窒素、酸素またはイオウ原子を含む芳香環であってもよい。また、それらの環は、本発明の環化反応に関与しない基で置換されていてもよい。ただし、これらの芳香環基は一般式（Ｉ）に示すように、ラク酸部位が直接結合した炭素原子に結合する２つ（両隣）の原子のうちの少なくとも１個は、脱水環化反応に不可欠な水素原子が結合した炭素原子でなければならない。芳香環基Ａの具体例としては、例えば、フェニル基、１−ナフチル基、５，６，７，８−テトラヒドロ−２−ナフチル基、２−アンスリル基、２−フェナンスリル基、１−ピレニル基、３−チエニル基、２−チアンスリル基、３−フリル基、２−キサンテニル基、３−ピロリル基、３Ｈ−インドール−２−イル基、２−ピリジル基、６−キノリル基、２−カルバゾリル基などが挙げられる。
【０００９】
芳香環基Ａに置換してもよい基の例としては、ハロゲン原子、メチル、エチル、プロピル、ｔ−ブチルなどのアルキル基、ビニル、１−プロペニル、１−ブテニルなどのアルケニル基、エチニル、１−プロピニルなどのアルキニル基、フェニル、ナフチル、トリルなどのアリール基、メトキシ、エトキシなどのアルコキシ基、フェノキシなどのアリールオキシ基、メチルチオなどのアルキルチオ基、フェニルチオなどのアリールチオ基、パーフルオロアルキル基などが挙げられる。
【００１０】
次に、本発明の製法に用いられるルイス酸触媒は、一般式（II）
ＭＸｍ・Ｌｎ （II）
で表される金属化合物である。
一般式（II）において、Ｍは金属イオンであり、ビスマス、ガリウム、インジウム、およびスカンジウム、サマリウム、イッテルビウムなどの希土類元素から選ばれる。
また、アニオンＸは、その共役酸が高い酸性度を示すものがよく、例えばハロゲンアニオン、パーフルオロアルキルスルホナートアニオン、ビス（パーフルオロアルキルスルホニル）アミドアニオン、トリス（パーフルオロアルキルスルホニル）メチドアニオンなどが挙げられる。
【００１１】
また、本発明に用いられるルイス酸には、反応に悪影響を及ぼさない中性分子が配位していても差し支えない。この中性分子は、一般式（II）におけるＬであり、金属イオンＭに配位する分子であって、例えば水やジエチルエーテルなどのエーテル類が挙げられ、その数ｎは０〜１０である。
本発明で用いられるルイス酸触媒の使用量は、いわゆる触媒量の少量でよく、化合物（Ｉ）に対し０．０００１−５０モル％の範囲で実施できるが、あまりに少ないと反応が有利な速度で進行せず、また、あまりに多いと反応の経済性が悪くなることから、好ましくは０．０１〜３０モル％の範囲であり、より好ましくは０．０５〜１５モル％の範囲である。
【００１２】
また、この環化反応は溶媒を必ずしも必要とするものではないが、溶媒を使用しても良い。使用し得る溶媒としては、芳香族炭化水素系、塩素化炭化水素系、ニトロ化炭化水素系、脂肪族炭化水素系などが挙げられるが、なかでも芳香族炭化水素系、塩素化炭化水素系、ニトロ化炭化水素系溶媒が好ましく、具体的には、トルエン、キシレン、クロロベンゼン、１，２−ジクロロエタン、１，２−ジクロロベンゼン、ニトロメタン、ニトロベンゼン等が例示される。
【００１３】
反応温度としては、あまりに低温では反応が有利な速度では進行せず、一方、あまりに高温では副反応が起こるとともに経済性に劣ることから、一般的には０〜３００℃の範囲から選ばれ、好ましくは６０〜２６０℃の範囲で実施される。反応生成混合物から所望の目的生成物を分離するには、溶媒抽出、再結晶、蒸留、クロマトグラフィー及び昇華の通常の分離精製法を用いることにより容易に達成される。
【００１４】
【実施例】
以下、本発明を実施例によりさらに具体的に説明するが、本発明はこれらの実施例によって何ら限定されるものではない。
実施例１
４−フェニルラク酸４１ｍｇ（０．２５ｍｍｏｌ）及びＢｉ［Ｎ（ＳＯ_２ＣＦ_３）_２］_３３．０ｍｇ（０．００２９ｍｍｏｌ）を、トルエン２ｍｌ中で混合し、これを密閉したガラス容器中、１８０℃の油浴で７時間加熱して環化反応を行った。この反応の終了後、内部標準としてドデカン２０μｌを加え、ガスクロマトグラフィーで分析することにより１−テトラロンが９７％生成していることを確認した。その後、反応混合物をシリカゲルカラムクロマトグラフィーを用いて精製することにより１−テトラロン３２ｍｇ（８８％）を得た。
【００１５】
実施例２〜１４
実施例１における４−フェニルラク酸の環化反応による１−テトラロンの生成において、使用するルイス酸触媒の種類、触媒量、溶媒、反応温度及び反応時間を、それぞれ表１に示すものに代えたこと以外は、実施例１と同様にして環化反応及び生成物の確認を行った。実施例１〜１４で得られた結果を表１に示す。
【００１６】
【表１】

【００１７】
実施例１５〜２６
原料として各種の４−アリールラク酸類０．２５ｍｍｏｌを、また触媒としてＢｉ［Ｎ（ＳＯ_２ＣＦ_３）_２］_３を用い、溶媒には、それぞれｐ−キシレン（実施例１５〜２０及び２４〜２６）またはクロロベンゼン（実施例２１〜２３）２ｍｌを用いて加熱し、環化反応させて得られた結果を、表２及び表３に示す。なお、表中、ａ）は単離収率であり、括弧内は反応混合物をガスクロマトグラフィーで分析し決定した収率である。
【００１８】
【表２】

【００１９】
【表３】

【００２０】
【発明の効果】
本発明によれば、特定のルイス酸を用いたから、各種４−フェニルラク酸の環化脱水反応は少量の触媒で容易に進行し、簡易に各種の環状ケトン類を高収率で得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a simple method for producing cyclic ketones useful as synthetic intermediates for physiologically active substances used in pharmaceuticals, agricultural chemicals and the like.
[0002]
[Prior art]
Many methods for producing cyclic ketones by intramolecular cyclization of 4-aryllacric acids have been reported, but almost all of them require an equivalent amount of acid or more. Especially, the method of using concentrated sulfuric acid or polyphosphoric acid for the amount of solvent has been known for a long time and widely used (for example, refer to Non-Patent Documents 1 to 3). Moreover, the method of using polyphosphoric acid ester, methanesulfonic acid, a methanesulfonic acid-5 phosphorus oxide mixture, or anhydrous hydrogen fluoride for the amount of solvents is known (for example, refer nonpatent literatures 4-7). Furthermore, a method using 2 equivalents of trifluoroacetic anhydride and a method using an excess amount of aluminum chloride are also known (for example, see Non-Patent Documents 8 and 9).
On the other hand, as a production method using a catalytic amount of acid, the only method using a perfluoroalkanesulfonic acid polymer (Nafion) is known (for example, see Non-Patent Documents 10 and 11), but a catalytic amount of Lewis acid is used. The manufacturing method using is not known.
[0003]
[Non-Patent Document 1]
Ber. Deutsch. Chem. Ges. 56, p620 (1923)
[Non-Patent Document 2]
Ber. Deutsch. Chem. Ges. 65, p902 (1932)
[Non-Patent Document 3]
Syn. Commun. 21, p981 (1991)
[Non-Patent Document 4]
Tetrahedron, 54, p197 (1998)
[Non-Patent Document 5]
J. et al. Org. Chem. 46, p2974 (1981)
[Non-Patent Document 6]
Heterocycles 43, p127 (1996)
[Non-Patent Document 7]
J. et al. Am. Chem. Soc. 61, p1272 (1939)
[Non-Patent Document 8]
Tetrahedorn Lett. 36, p6413 (1995)
[Non-patent document 9]
J. et al. Chem. Soc. p4647 (1956)
[Non-Patent Document 10]
J. et al. Org. Chem. 56, p3955 (1991)
[Non-Patent Document 11]
Synlett p1067 (1999)
[0004]
[Problems to be solved by the invention]
This invention is made | formed in view of the above-mentioned actual condition in a prior art. That is, an object of the present invention is to provide a method for producing a cyclic ketone inexpensively and easily in a high yield by dehydrating cyclic acid substituted at the 4-position with an aromatic ring.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors have carried out a dehydration cyclization reaction of a lactic acid having a 4-position substituted with an aromatic ring by adding a catalytic amount of a certain Lewis acid. The inventors have found that a cyclic ketone can be obtained rapidly and can be obtained in a high yield, and the present invention has been completed based on these facts.
[0006]
That is, the present invention relates to the general formula (I)
[Chemical 3]

(In the formula, R ^{1 to} R ⁶ each represent a group not involved in the reaction. Ring A represents a monocyclic or condensed polycyclic aromatic ring group, and atoms constituting the ring include nitrogen, oxygen or A carboxylic acid represented by the general formula (II) may contain an atom selected from sulfur and the ring may be substituted with a group not participating in the reaction.
MXm · Ln (II)
(Wherein, M represents bismuth, gallium, indium, a metal ion selected from the rare earth elements, X is denotes an anion, L is .m showing a neutral molecule with a coordinated force M is the metal M (It is a valence number, and n is an integer of 0 to 10.)
By the cyclization reaction in the presence of a catalytic amount of Lewis acid represented by the general formula (III)
[Formula 4]

(Wherein R ^{1 to} R ⁶ and ring A each have the same meaning as described above).
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The carboxylic acid represented by the general formula (I) used as a raw material in the production method of the present invention has a lactic acid skeleton substituted at the 4-position with an aromatic ring group, and substituents R ^{1 to} R ^6. Any of these may be used as long as they do not adversely affect the cyclization reaction of the present invention, and are not limited at all.
In the general formula (I), R ^{1 to} R ⁶ are groups that are bonded to the alkylene chain of the lactic acid skeleton and do not participate in the cyclization reaction, and include, for example, a hydrogen atom, a halogen atom, methyl, ethyl Alkyl groups such as propyl and t-butyl, alkoxy groups such as methoxy and ethoxy, ester groups and cyano groups.
[0008]
In general formula (I), ring A is a monocyclic or condensed polycyclic aromatic ring group, and the atoms constituting the ring are aromatic rings containing nitrogen, oxygen or sulfur atoms as hetero atoms. Also good. Further, these rings may be substituted with a group that does not participate in the cyclization reaction of the present invention. However, as shown in the general formula (I), at least one of the two (both adjacent) atoms bonded to the carbon atom to which the lactic acid moiety is directly bonded is used for these aromatic ring groups in the dehydration cyclization reaction. It must be a carbon atom bonded to an indispensable hydrogen atom. Specific examples of the aromatic ring group A include, for example, phenyl group, 1-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group, 2-anthryl group, 2-phenanthryl group, 1-pyrenyl group, 3-thienyl group, 2-thianthryl group, 3-furyl group, 2-xanthenyl group, 3-pyrrolyl group, 3H-indol-2-yl group, 2-pyridyl group, 6-quinolyl group, 2-carbazolyl group, etc. Can be mentioned.
[0009]
Examples of the group that may be substituted with the aromatic ring group A include a halogen atom, an alkyl group such as methyl, ethyl, propyl, and t-butyl, an alkenyl group such as vinyl, 1-propenyl, and 1-butenyl, ethynyl, 1 -Alkynyl groups such as propynyl, aryl groups such as phenyl, naphthyl and tolyl, alkoxy groups such as methoxy and ethoxy, aryloxy groups such as phenoxy, alkylthio groups such as methylthio, arylthio groups such as phenylthio, perfluoroalkyl groups, etc. Can be mentioned.
[0010]
Next, the Lewis acid catalyst used in the production method of the present invention has the general formula (II)
MXm · Ln (II)
It is a metal compound represented by these.
In the general formula (II), M is a metal ion, selected bismuth, gallium, indium, Contact and scandium, samarium, rare earth elements such as ytterbium.
In addition, the anion X preferably has a high acidity of its conjugate acid, such as a halogen anion, a perfluoroalkylsulfonate anion, a bis (perfluoroalkylsulfonyl) amide anion, a tris (perfluoroalkylsulfonyl) methide anion, and the like. Can be mentioned.
[0011]
In addition, the Lewis acid used in the present invention may be coordinated with a neutral molecule that does not adversely influence the reaction. This neutral molecule is L in the general formula (II), and is a molecule that coordinates to the metal ion M, and examples thereof include ethers such as water and diethyl ether, and the number n is 0 to 10. .
The amount of the Lewis acid catalyst used in the present invention may be a small amount of the so-called catalyst amount and can be carried out in the range of 0.0001-50 mol% with respect to the compound (I). Since it does not proceed, and when the amount is too large, the economic efficiency of the reaction is deteriorated, and therefore it is preferably in the range of 0.01 to 30 mol%, more preferably in the range of 0.05 to 15 mol%.
[0012]
The cyclization reaction does not necessarily require a solvent, but a solvent may be used. Solvents that can be used include aromatic hydrocarbons, chlorinated hydrocarbons, nitrated hydrocarbons, aliphatic hydrocarbons, etc., among which aromatic hydrocarbons, chlorinated hydrocarbons, Nitrated hydrocarbon solvents are preferred, and specific examples include toluene, xylene, chlorobenzene, 1,2-dichloroethane, 1,2-dichlorobenzene, nitromethane, nitrobenzene and the like.
[0013]
As the reaction temperature, the reaction does not proceed at an advantageous rate at an excessively low temperature, while a side reaction occurs at an excessively high temperature and the economy is inferior. Therefore, the reaction temperature is generally selected from the range of 0 to 300 ° C., preferably Is carried out in the range of 60 to 260 ° C. Separation of the desired target product from the reaction product mixture is easily accomplished by using conventional separation and purification methods such as solvent extraction, recrystallization, distillation, chromatography and sublimation.
[0014]
【Example】
EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
Example 1
41 mg (0.25 mmol) of 4-phenyllacric acid and 3.0 mg (0.0029 mmol) of Bi [N (SO ₂ CF ₃ ) ₂ ] ₃ were mixed in 2 ml of toluene, and this was mixed in a sealed glass container. The cyclization reaction was carried out by heating in an oil bath at 7 ° C. for 7 hours. After completion of this reaction, 20 μl of dodecane was added as an internal standard, and analysis by gas chromatography confirmed that 97% of 1-tetralone was produced. Thereafter, the reaction mixture was purified using silica gel column chromatography to obtain 32 mg (88%) of 1-tetralone.
[0015]
Examples 2-14
In the production of 1-tetralone by cyclization of 4-phenyllacric acid in Example 1, the type of Lewis acid catalyst used, the amount of catalyst, the solvent, the reaction temperature, and the reaction time were changed to those shown in Table 1, respectively. Except for this, the cyclization reaction and the product were confirmed in the same manner as in Example 1. The results obtained in Examples 1 to 14 are shown in Table 1.
[0016]
[Table 1]

[0017]
Examples 15-26
Various 4-aryllacric acids 0.25 mmol as raw materials, Bi [N (SO ₂ CF ₃ ) ₂ ] ₃ as catalysts, and p-xylene (Examples 15 to 20 and 24-26) as solvents, respectively. Alternatively, Table 2 and Table 3 show the results obtained by heating using 2 ml of chlorobenzene (Examples 21 to 23) to cause cyclization reaction. In the table, a) is the isolated yield, and the value in parentheses is the yield determined by analyzing the reaction mixture by gas chromatography.
[0018]
[Table 2]

[0019]
[Table 3]

[0020]
【The invention's effect】
According to the present invention, since a specific Lewis acid is used, the cyclization dehydration reaction of various 4-phenyl lactic acids proceeds easily with a small amount of catalyst, and various cyclic ketones can be easily obtained in high yield. it can.

Claims (3)

Formula (I)

(Wherein R ^{1 to} R ⁶ each represent a group not involved in the reaction. Ring A represents a monocyclic or condensed polycyclic aromatic ring group, and atoms constituting the ring include nitrogen, oxygen or A carboxylic acid represented by the general formula (II) may contain an atom selected from sulfur and the ring may be substituted with a group not participating in the reaction.
MXm · Ln (II)
(Wherein, M represents bismuth, gallium, indium, a metal ion selected from the rare earth elements, X is denotes an anion, L is .m showing a neutral molecule with a coordinated force M is the metal M (It is a valence number, and n is an integer of 0 to 10.)
By the cyclization reaction in the presence of a catalytic amount of Lewis acid represented by the general formula (III)

(Wherein, R ^{1 to} R ⁶ and ring A have the same meanings as described above, respectively).   The method according to claim 1, wherein the carboxylic acid in which the group not involved in the reaction in the general formula (I) is a group selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, and an ester group is used.   X in the general formula (II) is an anion selected from a halogen anion, a perfluoroalkylsulfonate anion, a bis (perfluoroalkylsulfonyl) amide anion, and a tris (perfluoroalkylsulfonyl) methide anion. The method described.