JP4173585B2

JP4173585B2 - Production method of ketones

Info

Publication number: JP4173585B2
Application number: JP25052698A
Authority: JP
Inventors: 晃治須田
Original assignee: Shiratori Pharmaceutical Co Ltd
Current assignee: Shiratori Pharmaceutical Co Ltd
Priority date: 1998-09-04
Filing date: 1998-09-04
Publication date: 2008-10-29
Anticipated expiration: 2018-09-04
Also published as: JP2000086567A

Description

【０００１】
【発明の属する技術分野】
本発明はケトン類の製造法に関し、詳細にはエポキシド類から位置選択的にしかも効率よくケトン類を製造する方法に関する。
【０００２】
【従来の技術及び発明が解決しようとする課題】
エポキシド類のカルボニル化合物への異性化反応は重要な反応の一つであり、これまでにもこの反応に関する報告が多くなされている。しかし、これらの報告はフェニルエポキシド誘導体等の比較的高い反応性を有するエポキシドを基質とする場合がほとんどであり、一置換アルキルエポキシドのように活性の低いエポキシド類の異性化反応についての報告は少ない。特に位置選択的な異性化反応については、一置換アルキルエポキシドからアルデヒドへの反応試薬として、強塩基であるリチウム２，２，６，６−テトラメチルピペリジド（ＬｉＴＭＰ）や、遷移金属錯体触媒であるＮｉＢｒ₂（ＰＰｈ₃）₂などが、またケトン類への異性化反応についてはＳｍ試薬、Ｐｄ錯体等の金属試薬が知られているに過ぎない。しかもこれらの試薬を用いた反応は、基質に対して２．５〜５当量もの反応剤を必要とするなど効率や安全性の点で満足のいくものではなかった。
【０００３】
【課題を解決するための手段】
本発明者はケトン類の新たな製造法を見出すべく鋭意研究を行った結果、下記一般式（１）で表されるエポキシド類に、テトラアリールポルフィリントリフルオロメタンスルホネート遷移金属錯体を反応させれば、位置選択性が極めて高く、しかも効率よくケトン類が製造できることを見出し、本発明を完成した。
【０００４】
すなわち本発明は、一般式（１）
【０００５】
【化４】

【０００６】
〔式中、Ｒ¹は有機基を示し、Ｒ²及びＲ³は水素原子又は有機基を示し、Ｒ²が水素原子のときＲ³は水素原子又は置換基を有していてもよいアシル基である〕
で表されるエポキシド類に次式（２）
【０００７】
【化５】
M(tap)SO₃CF₃ （２）
【０００８】
〔式中、Ｍは遷移金属原子を示し、ｔａｐはテトラアリールポルフィリンを示す〕
で表されるテトラアリールポルフィリントリフルオロメタンスルホネート遷移金属錯体を反応させることを特徴とする一般式（３）
【０００９】
【化６】

【００１０】
〔式中、Ｒ¹、Ｒ²及びＲ³は前記と同じ〕
で表されるケトン類の製造法を提供するものである。
【００１１】
【発明の実施の形態】
前記一般式（１）で表されるエポキシド類において、Ｒ¹、Ｒ²及びＲ³で示される有機基としては、置換基を有していてもよい炭化水素基、複素環式基、１若しくは２以上のヘテロ原子を含む官能基を有する炭化水素基、又はこれらの基が結合した基等が挙げられる。ここで炭化水素基としては飽和又は不飽和の炭化水素基が挙げられ、脂肪族基及び芳香族基のいずれも含む。また複素環式基としては、飽和又は不飽和の複素環が挙げられる。１若しくは２以上のヘテロ原子を含む官能基を有する炭化水素基としては、エーテル結合、カルボニル基、アミノ基、チオエーテル結合、チオカルボニル基、エステル結合、アミド結合、カルボキシル基等の官能基を含む炭化水素基が挙げられる。また、これらの基の置換基としてはハロゲン原子、ニトロ基、シアノ基等が挙げられる。これらの基の中でも置換基を有していてもよいアルキル基、アルケニル基、芳香族基、アラルキル基、又はアシル基が特に好ましい。
【００１２】
なお、上記一般式（１）において、Ｒ²が水素原子の場合、Ｒ³は水素原子又は置換基を有していてもよいアシル基を示すが、かかるアシル基としてはアセチル基、プロピオニル基、ブチリル基等のアルカノイル基、ベンゾイル基等のアロイル基が挙げられる。
【００１３】
本発明で用いられるテトラアリルーポルフィリントリフルオロメタンスルホネート遷移金属錯体は、前記一般式（２）で表されるが、式（２）中Ｍで表される遷移金属原子としてはクロム、マンガン、鉄が挙げられるが、鉄が特に好ましい。更に式（２）中、ｔａｐで表されるテトラアリールポルフィリンとしては、市販で安価なテトラフェニルポルフィリン（ｔｐｐ）が好ましいが、その限りではない。
【００１４】
テトラアリールポルフィリントリフルオロメタンスルホネート遷移金属錯体（２）の製造法としては、公知の方法、例えば文献（ＡＲＤＥＮＤ．ＢＯＥＲＳＭＡａｎｄＨＡＲＯＬＤＭ．ＧＯＦＦ，Ｉｎｏｒｇ．Ｃｈｅｍ．，２１，５８１（１９８２））記載の方法又はこれに準じた方法により製造することができる。
【００１５】
本発明の製造法を実施するには、溶媒中、エポキシド類（１）１モルに対し、触媒量、好ましくは０．００１〜０．０１モルのテトラアリールポルフィリントリフルオロメタンスルホネート遷移金属錯体（２）を加え、加熱還流下反応させればよい。
【００１６】
反応溶媒としては、例えば１，２−ジクロロエタン等のハロゲン化炭化水素；ベンゼン、トルエン等の芳香族炭化水素；１，４−ジオキサン等のエーテル類等が挙げられるが、反応時間及び目的とする化合物の収率の観点から特に１，４−ジオキサンを用いるのが好ましい。
【００１７】
反応終了後に反応混合物から目的化合物（３）を単離するには、通常の操作、例えば再結晶、蒸留、抽出、各種クロマトグラフィー等を行えばよい。
【００１８】
【発明の効果】
本発明によれば、エポキシド類より位置選択性が極めて高く、しかも効率よく一般式（３）の構造のケトン類を製造することができる。
【００１９】
【実施例】
以下、実施例を挙げて本発明を更に具体的に説明するが、本発明はこれらに制限されるものではない。
【００２０】
参考例１
Ｆｅ（ｔｐｐ）ＳＯ₃ＣＦ₃の合成
ＴＨＦ（２５ml）にＦｅ（ｔｐｐ）Ｃｌ（２５０mg，０．３６mmol）を溶解し、この溶液にＡｇＳＯ₃ＣＦ₃（１１２mg，１．２ｅｑ．）を一度に加えた。この反応液を２時間還流した後、室温に戻し、濾過により、灰色析出物（ＡｇＣｌ）を除去した。濾液にｎ−ヘキサンを加え、数十時間放置後沈殿物を濾取し、ＣＨ₂Ｃｌ₂とｎ−ヘキサンにより再結晶することで、Ｆｅ（ｔｐｐ）ＳＯ₃ＣＦ₃を
得た。
【００２１】
元素分析（C₄₅H₂₈F₃SFeN₄O₃として）
計算値
C,66.10; H,3.45; N,6.85.
分析値
C,66.00; H,3.58; N,6.94.
λ_max(CH₂Cl₂):671nm(ε2.4×10³), 583nm(2.5×10³),
515nm(1.2×10⁴), 399nm(1.1×10⁵).
【００２２】
参考例２
４−フェニル−１，２−エポキシブタン（１−１ｅ）の合成
４−フェニル−１−ブテン（１０mmol）の塩化メチレン溶液（２０ml）に、氷冷下、ｍ−ＣＰＢＡ（２．４８ｇ，１１mmol）の塩化メチレン溶液を滴下し、室温で３時間攪拌した。反応液を飽和ＮａＨＳＯ₃水溶液、１０％ＮａＯＨ水溶液、飽和ＮａＨＣＯ₃水溶液、飽和ＮａＣｌ水溶液で洗浄し、有機層を分取し無水ＭｇＳＯ₄で乾燥した。溶媒を留去して得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル／ｎ−ヘキサン＝１／３０）で精製することにより４−フェニル−１，２−エポキシブタン（１−１ｅ）を得た。
【００２３】
４−フェニル−１，２−エポキシブタン（１−１ｅ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
7.15-7.31(5H,m,aromatic H), 2.91(1H,dd,J=2.64,7.26Hz,trans-CH ₂-O),
2.67-2.83(1H,m,CHCH₂CH₂Ph), 2.70(2H,t,J=4.5Hz,CH ₂Ph),
2.43(1H,dd,J=2.64,4.95Hz,cis-CH ₂-O),
1.78-1.88(2H,m,CH ₂CH₂Ph).
【００２４】
実施例１
Ｆｅ（ｔｐｐ）ＳＯ₃ＣＦ₃による一置換アルキルエポキシド（１−１）の異性化反応
１，２−エポキシデカン（１−１ａ）（０．１ｇ，０．６４mmol）の１，４−ジオキサン溶液（３ml）にＦｅ（ｔｐｐ）ＳＯ₃ＣＦ₃（１２．８μmol，２mol％）を加え、還流下、原料が消失するまで攪拌した。反応終了後、反応液を室温に戻し、溶媒を減圧留去して得られた残渣をフロリジルカラム（酢酸エチル）により精製してデシルアルデヒド（３−１ａ）を得た。同様に、表１に示す化合物（１−１ｂ）−（１−１ｆ）から（３−１ｂ）−（３−１ｆ）を得た。結果を表１に示した。
【００２５】
デシルアルデヒド（３−１ａ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
9.76(1H,t,J=1.32Hz,CHO), 2.42(2H,t,J=7.26Hz,CH₂CO),
1.63(2H,m,CH ₂CH₂CO), 1.20-1.38(12H,m,CH₂),
0.88(3H,t,J=6.60Hz,CH₃);
¹³C-NMR(67.8MHz,CDCl₃)δ：
14.11, 22.12, 22.70, 29.22, 29.29, 29.42, 31.90, 43.94, 202.66.
【００２６】
テトラデシルアルデヒド（３−１ｂ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
9.76(1H,t,J=1.65Hz,CHO), 2.41(2H,t,J=7.26Hz,CH₂CO),
1.63(2H,m,CH₂CH₂CO), 1.20-1.38(20H,m,CH₂), 0.88(3H,t,J=6.43Hz,CH₃);
¹³C-NMR(67.8MHz,CDCl₃)δ：
14.14, 22.14, 22.73, 29.22, 29.42, 29.49, 29.70, 31.99, 43.95 and 202.78.
【００２７】
９−デセンアルデヒド（３−１ｃ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
9.75(1H,t,J=1.65Hz,CHO), 5.81(1H,ddt,J=16.99,6.60,6.93Hz,CH=CH₂),
4.98(1H,d of m,J=16.99Hz,CH=CH ₂), 4.92(1H,d of m,J=11.88Hz,CH=CH ₂),
2.41(2H,t,J=7.26Hz,CH₂CO), 2.04(2H,dt,J=6.6,6.93Hz,CH ₂CH=CH₂),
1.63(2H,m,CH ₂CH₂CO), 1.23-1.45(8H,m,CH₂);
¹³C-NMR(67.8MHz,CDCl₃)δ：
22.07, 28.84, 28.88, 29.13, 29.20, 33.75, 43.88, 114.28, 138.94, 202.55.
【００２８】
３−フェニルプロピルアルデヒド（３−１ｄ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
9.78(1H,s,CHO), 7.15-7.31(5H,m,aromatic H),
2.93(2H,t,J=7.26Hz,CH₂CO), 2.74(2H,t,J=7.43Hz,CH ₂Ph);
¹³C-NMR(67.8MHz,CDCl₃)δ：
28.09, 45.23, 126.27, 128.26, 128.59, 140.34, 201.47.
【００２９】
４−フェニルブチルアルデヒド（３−１ｅ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
9.72(1H,s,CHO), 7.15-7.31(5H,m,aromatic H),
2.63(2H,t,J=7.43Hz,CH₂CO), 2.42(2H,t,J=6.60Hz,CH ₂Ph),
1.94(2H,m,CH ₂CH₂CO);
¹³C-NMR(67.8MHz,CDCl₃)δ：
23.63, 34.97, 43.09, 126.07, 128.44, 141.20, 202.21.
【００３０】
１，８−ジオクタナール（３−１ｆ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
9.77(2H,t,J=1.65Hz,CHO), 2.44(4H,dt,J=1.65,7.26Hz,CH₂CO),
1.63(4H,m,CH ₂CH₂CO), 1.30-1.41(4H,m,CH₂);
¹³C-NMR(67.8MHz,CDCl₃)δ：
21.82, 28.88, 43.77, 202.57.
【００３１】
【表１】

【００３２】
なお、炭素鎖の両端にエポキシ基を有するジエポキシアルカン（１−１ｆ）の反応生成物としては次に示す３つの化合物（５）、（６）及び（７）が考えられるが、分子内にケトンとアルデヒドを併せ持つ化合物（７）については¹H-NMRにおいて確認されなかった。
【００３３】
【化７】

【００３４】
参考例３
ｔｒａｎｓ−３，４−エポキシ−２−デカノン（１−２ｇ）の合成
ｔｒａｎｓ−３−デセン−２−オン（３．０９ｇ，２０mmol）のメタノール溶液（４０ml）に、氷冷下において３０％Ｈ₂Ｏ₂（６ml）と２Ｎ−ＮａＯＨ（６ml）を滴下し、室温に戻し原料が消失するまで攪拌した。反応液を飽和ＮＨ₄Ｃｌ溶液で中和し、エーテルで抽出後、有機層を分取し無水ＭｇＳＯ₄で乾燥した。溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン＝１／３０）で精製することによりｔｒａｎｓ−３，４−エポキシ−２−デカノン（１−２ｇ）を得た。
【００３５】
ｔｒａｎｓ−３，４−エポキシ−２−デカノン（１−２ｇ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
3.17(1H,d,J=1.98Hz,CHCO), 3.08(1H,dt,J=1.98,5.28Hz,CH₂CH-O),
2.05(3H,s,CH₃CO), 1.62(2H,m,CH ₂CH-O), 1.25-1.48(8H,m,CH₂),
0.89(3H,t,J=6.60Hz,CH₃).
【００３６】
参考例４
α，β−エポキシケトン（１−２ｈ）、（１−２ｉ）、（１−２ｊ）の合成
デシルアルデヒド（０．７８ｇ，５mmol）のトルエン溶液を還流し、そこに、１−トリフェニルフォスフォラニリデン−２−プロパノン（１．５９ｇ，５mmol）を一気に加え、原料が消失するまで攪拌した。反応液を室温に戻した後、析出したフォスフィンオキシドを取り除き、溶媒を留去して得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル／ｎ−ヘキサン＝１／３０）で精製することによりｔｒａｎｓ−３−トリデセン−２−オンを得た。これを、参考例３と同様にＨ₂Ｏ₂によりエポキシ化することで（１−２ｈ）を得た。同様に１０−ウンデセン−１−アールから（１−２ｉ）を、３−フェニル−１−プロパナールから（１−２ｊ）を得た。
【００３７】
ｔｒａｎｓ−３，４−エポキシ−２−トリデカノン（１−２ｈ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
3.18(1H,d,J=1.98Hz,CHCO), 3.07(1H,dt,J=1.98,5.45Hz,CH₂CH-O),
2.08(3H,s,CH₃CO), 1.57-1.67(2H,m,CH ₂CH-O), 1.18-1.40(12H,m,CH₂),
0.88(3H,t,J=6.76Hz,CH₂CH ₃).
【００３８】
ｔｒａｎｓ−１３−テトラデセン−３，４−エポキシ−２−オン（１−２ｉ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
5.81(1H,ddt,J=17.08,6.60,6.93Hz,CH=CH₂),
4.98(1H,d of m,J=17.08Hz,CH=CH ₂), 4.93(1H,d of m,J=11.80Hz,CH=CH ₂),
3.18(1H,d,J=1.98Hz,CHCO), 3.07(1H,dt,J=1.98,5.61Hz,CH₂CH-O),
2.06(3H,s,CH₃CO), 2.04(2H,m,CH ₂CH=CH₂), 1.61(2H,m,CH ₂CH-O),
1.30-1.50(12H,m,CH₂).
【００３９】
ｔｒａｎｓ−６−フェニル−３，４−エポキシ−２−ヘキサオン（１−２ｊ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
7.15-7.32(5H,m,aromatic H), 3.15(1H,d,J=1.98Hz,CHCO),
3.07(1H,dt,J=1.98,5.61Hz,CH₂CH-O), 2.77(2H,m,CH ₂Ph),
1.98(3H,s,CH₃CO), 1.93(2H,m,CH ₂CH₂Ph).
【００４０】
参考例５
α，β−エポキシケトン（１−２ｋ）の合成
ｔｒａｎｓ−２−ヘキセナールジエチルアセタール（３．４５ｇ，２０mmol）のｎ−ヘキサン溶液（４０ml）を還流し、この溶液にベンゾトリアゾール（３．５７ｇ，３０mmol）を一気に加え、原料が消失するまで攪拌した。反応液をエーテルで希釈し、飽和Ｎａ₂ＣＯ₃水溶液で洗浄後、有機層を分取し無水ＭｇＳＯ₄で乾燥した。溶媒を留去して得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル／ｎ−ヘキサン＝１／２０）で精製することにより１−（ベンゾトリアゾール−１−イル）−１−エトキシ−２−ヘキセンを得た。次に、得られた１−（ベンゾトリアゾール−１−イル）−１−エトキシ−２−ヘキセン（１．２７ｇ，５mmol）を無水ＴＨＦ（５０ml）に溶解し、−７８℃において、ｎ−ブチルリチウムのｎ−ヘキサン溶液（１．５８Ｍ，５mmol）を滴下した。更に、３０分後、ブロモオクタン（０．９６ml，５．５mmol）を滴下し、原料が消失するまで攪拌した。反応液をエーテルで希釈し、飽和Ｎａ₂ＣＯ₃水溶液で洗浄後、有機層を分取し無水ＭｇＳＯ₄で乾燥した。溶媒を留去して得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル／ｎ−ヘキサン＝１／２０）で精製することにより得られたエノンを参考例３と同様にＨ₂Ｏ₂を用いてエポキシ化することで（１−２ｋ）を得た。
【００４１】
ｔｒａｎｓ−４，５−エポキシ−６−テトラデカノン（１−２ｋ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
3.20(1H,d,J=1.98Hz,CHCO), 3.04(1H,m,CH₂CH-O),
2.21-2.49(2H,m,CH₂CO), 1.41-1.68(6H,m,CH ₂CHCO,CH ₂CH ₂CH-O),
1.22-1.33(10H,m,CH₂), 0.98(3H,t,J=7.26Hz,CH₃),
0.88(3H,t,J=6.60Hz,CH₃).
【００４２】
実施例２
Ｆｅ（ｔｐｐ）ＳＯ₃ＣＦ₃によるα，β−エポキシケトン（１−２）の異性化反応
ｔｒａｎｓ−３，４−エポキシ−２−デカノン（１−２ｇ）（０．１ｇ，０．５９mmol）のジオキサン溶液（３ml）にＦｅ（ｔｐｐ）ＳＯ₃ＣＦ₃（１１．８μmol，２mol％）を加え、還流下、原料が消失するまで攪拌した。反応液を室温に戻し、溶媒を減圧留去し、フロリジルカラム（酢酸エチル）により触媒を除去した後、溶媒を減圧留去し化合物１，２−ジケトン（３−２ｇ）を得た。同様に、表２に示す化合物（１−２ｈ）−（１−２ｋ）から（３−２ｈ）−（３−２ｋ）を得た。結果を表２に示した。
【００４３】
２，３−デカンジオン（３−２ｇ）：ｏｉｌ；
IR(neat) 1700cm^-1；
¹H-NMR(270MHz,CDCl₃)δ：
2.73(2H,t,J=7.43Hz,CH₂CO), 2.33(3H,s,CH₃CO),
1.58(2H,m,CH ₂CH₂CO), 1.18-1.35(8H,m,CH₂), 0.88(3H,t,J=6.60Hz,CH₃);
¹³C-NMR(67.8MHz,CDCl₃)δ：
14.05, 22.59, 23.09, 23.70, 29.00, 29.11, 31.64, 35.71, 197.55, 199.48.
MS:170(M⁺,5.7), 127(69.1), 113(3.9), 109(9.1), 97(2.7), 85(3.7), 67(5.4), 57(100.0), 43(33.5).
Exact mass Calcd.for C₁₀H₁₈O₂:170.1307.
Found:170.1312
【００４４】
２，３−トリデカンジオン（３−２ｈ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
2.73(2H,t,J=7.26Hz,CH₂CO), 2.33(3H,s,CH₃CO), 1.58(2H,m,CH ₂CH₂CO), 1.18-1.35(14H,m,CH₂), 0.88(3H,t,J=6.40Hz,CH₃);
¹³C-NMR(67.8MHz,CDCl₃)δ：
14.12, 22.71, 23.11, 23.74, 29.18, 29.34, 29.47, 29.58, 31.93, 35.76, 197.62, 199.55.
Exact mass Calcd.for C₁₃H₂₄O₂: 212.1776.
Found:212.1775
【００４５】
１３−テトラデセン−２，３−ジオン（３−２ｉ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
5.81(1H,ddt,J=16.99,6.60,6.93Hz,CH=CH₂),
4.98(1H,d of m,J=16.99Hz,CH=CH ₂), 4.92(1H,d of m,J=11.88Hz,CH=CH ₂),
2.73(2H,t,J=7.26Hz,CH₂CO), 2.33(3H,s,CH₃CO),
2.04(2H,dt,J=7.1,6.93Hz,CH ₂CH=CH₂), 1.58(2H,m,CH ₂CH₂CO),
1.23-1.40(12H,m,CH₂);
¹³C-NMR(67.8MHz,CDCl₃)δ：
23.07, 23.76, 28.93, 29.13, 29.33, 29.38, 29.42, 33.80, 35.74, 114.14, 139.21, 197.66, 199.57.
Exact mass Calcd.for C₁₄H₂₄O₂:224.1776.
Found:224.1777
【００４６】
６−フェニル−２，３−ヘキサンジオン（３−２ｊ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
7.15-7.31(5H,m,aromatic H), 2.75(2H,t,J=7.26Hz,CH₂CO),
2.64(2H,t,J=7.59Hz,CH ₂Ph), 2.29(3H,s,CH₃CO), 1.93(2H,m,CH ₂CH₂Ph);
¹³C-NMR(67.8MHz,CDCl₃)δ：
23.65, 24.64, 35.04, 126.09, 128.46, 128.50, 141.26, 197.37, 199.06.
Exact mass Calcd.for C₁₂H₁₄O₂:190.0994.
Found:190.0996
【００４７】
５，６−テトラデカンジオン（３−２ｋ）：ｏｉｌ；
¹H-NMR(270MHz,CDCl₃)δ：
2.73(4H,t,J=7.26Hz,CH₂CO), 1.58(4H,m,CH ₂CH₂CO),
1.21-1.41(12H,m,CH₂), 0.92(3H,t,J=7.26Hz,CH₃),
0.88(3H,t,J=6.60Hz,CH₃);
¹³C-NMR(67.8MHz,CDCl₃)δ：
13.82, 14.11, 22.32, 22.68, 23.11, 25.19, 29.13, 29.18, 29.34, 31.84, 35.81, 36.12, 200.18.
【００４８】
【表２】

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing ketones, and more particularly to a method for producing ketones regioselectively and efficiently from epoxides.
[0002]
[Prior art and problems to be solved by the invention]
The isomerization reaction of epoxides to carbonyl compounds is one of important reactions, and there have been many reports on this reaction. However, these reports are mostly based on epoxides having relatively high reactivity, such as phenyl epoxide derivatives, and there are few reports on isomerization reactions of low activity epoxides such as monosubstituted alkyl epoxides. . Especially for regioselective isomerization reaction, as a reaction reagent from monosubstituted alkyl epoxide to aldehyde, lithium 2,2,6,6-tetramethylpiperidide (LiTMP) which is a strong base, transition metal complex catalyst NiBr ₂ (PPh ₃ ) _{2 and the} like, and only metal reagents such as Sm reagent and Pd complex are known for the isomerization reaction to ketones. In addition, the reaction using these reagents is not satisfactory in terms of efficiency and safety, such as requiring 2.5 to 5 equivalents of a reagent relative to the substrate.
[0003]
[Means for Solving the Problems]
As a result of diligent research to find a new production method of ketones, the present inventor reacted a tetraarylporphyrin trifluoromethanesulfonate transition metal complex with an epoxide represented by the following general formula (1). The present inventors have found that regioselectivity is extremely high and that ketones can be produced efficiently, and the present invention has been completed.
[0004]
That is, the present invention provides the general formula (1)
[0005]
[Formula 4]

[0006]
[In the formula, R ¹ represents an organic group, R ² and R ³ represents a hydrogen atom or an organic group, R ³ is an acyl group which may have a hydrogen atom or a substituent when R ² is a hydrogen atom Is)
The epoxide represented by the following formula (2)
[0007]
[Chemical formula 5]
M (tap) SO ₃ CF ₃ (2)
[0008]
[Wherein M represents a transition metal atom and tap represents tetraarylporphyrin]
A tetraarylporphyrin trifluoromethanesulfonate transition metal complex represented by the general formula (3)
[0009]
[Chemical 6]

[0010]
[Wherein R ¹ , R ² and R ³ are the same as above]
A method for producing ketones represented by the formula:
[0011]
DETAILED DESCRIPTION OF THE INVENTION
In the epoxides represented by the general formula (1), as the organic group represented by R ¹ , R ² and R ³ , an optionally substituted hydrocarbon group, heterocyclic group, 1 or Examples thereof include a hydrocarbon group having a functional group containing two or more heteroatoms, or a group in which these groups are bonded. Here, the hydrocarbon group includes a saturated or unsaturated hydrocarbon group, and includes both an aliphatic group and an aromatic group. Examples of the heterocyclic group include saturated or unsaturated heterocycles. Examples of the hydrocarbon group having a functional group containing one or more heteroatoms include a carbon group containing a functional group such as an ether bond, a carbonyl group, an amino group, a thioether bond, a thiocarbonyl group, an ester bond, an amide bond, and a carboxyl group. A hydrogen group is mentioned. Moreover, as a substituent of these groups, a halogen atom, a nitro group, a cyano group, etc. are mentioned. Among these groups, an alkyl group, alkenyl group, aromatic group, aralkyl group or acyl group which may have a substituent is particularly preferable.
[0012]
In the general formula (1), when R ² is a hydrogen atom, R ³ represents a hydrogen atom or an acyl group which may have a substituent. Examples of the acyl group include an acetyl group, a propionyl group, Examples include an alkanoyl group such as a butyryl group and an aroyl group such as a benzoyl group.
[0013]
The tetraallyl-porphyrin trifluoromethanesulfonate transition metal complex used in the present invention is represented by the general formula (2), and the transition metal atom represented by M in the formula (2) includes chromium, manganese, and iron. Among them, iron is particularly preferable. Furthermore, in the formula (2), the tetraarylporphyrin represented by tap is preferably a commercially available and inexpensive tetraphenylporphyrin (tpp), but is not limited thereto.
[0014]
As a method for producing the tetraarylporphyrin trifluoromethanesulfonate transition metal complex (2), a known method, for example, a method described in literature (ARDEN D. BOERSSMA and HAROLD M. GOFF, Inorg. Chem., 21 , 581 (1982)). Or it can manufacture by the method according to this.
[0015]
In order to carry out the production method of the present invention, a catalyst amount, preferably 0.001 to 0.01 mol of tetraarylporphyrin trifluoromethanesulfonate transition metal complex (2) per 1 mol of epoxide (1) in a solvent. And the reaction may be carried out under reflux with heating.
[0016]
Examples of the reaction solvent include halogenated hydrocarbons such as 1,2-dichloroethane; aromatic hydrocarbons such as benzene and toluene; ethers such as 1,4-dioxane, etc., but the reaction time and the target compound From the viewpoint of the yield of 1,4-dioxane is particularly preferred.
[0017]
In order to isolate the target compound (3) from the reaction mixture after completion of the reaction, usual operations such as recrystallization, distillation, extraction, various chromatography and the like may be performed.
[0018]
【The invention's effect】
According to the present invention, ketones having a regioselectivity that is extremely higher than that of epoxides and having a structure of the general formula (3) can be produced efficiently.
[0019]
【Example】
EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.
[0020]
Reference example 1
Synthesis of Fe (tpp) SO ₃ CF ₃ Fe (tpp) Cl (250 mg, 0.36 mmol) was dissolved in THF (25 ml), and AgSO ₃ CF ₃ (112 mg, 1.2 eq.) Was added to the solution all at once. It was. The reaction solution was refluxed for 2 hours, then returned to room temperature, and the gray precipitate (AgCl) was removed by filtration. N-Hexane was added to the filtrate, and after standing for several tens of hours, the precipitate was collected by filtration and recrystallized with CH ₂ Cl ₂ and n-hexane to obtain Fe (tpp) SO ₃ CF ₃ .
[0021]
Elemental analysis (as C ₄₅ H ₂₈ F ₃ SFeN ₄ O ₃ )
Calculated values
C, 66.10; H, 3.45; N, 6.85.
Analysis value
C, 66.00; H, 3.58; N, 6.94.
λ _max (CH ₂ Cl ₂ ): 671 nm (ε2.4 × 10 ³ ), 583 nm (2.5 × 10 ³ ),
515 nm (1.2 × 10 ⁴ ), 399 nm (1.1 × 10 ⁵ ).
[0022]
Reference example 2
Synthesis of 4-phenyl-1,2-epoxybutane (1-1e) To a methylene chloride solution (20 ml) of 4-phenyl-1-butene (10 mmol), m-CPBA (2.48 g, 11 mmol) was cooled with ice. Of methylene chloride was added dropwise and stirred at room temperature for 3 hours. The reaction solution was washed with a saturated aqueous solution of NaHSO ₃ , a 10% aqueous solution of NaOH, a saturated aqueous solution of NaHCO ₃ and a saturated aqueous solution of NaCl, and the organic layer was separated and dried over anhydrous MgSO ₄ . The residue obtained by distilling off the solvent was purified by silica gel chromatography (ethyl acetate / n-hexane = 1/30) to obtain 4-phenyl-1,2-epoxybutane (1-1e).
[0023]
4-phenyl-1,2-epoxybutane (1-1e): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
7.15-7.31 (5H, m, aromatic H), 2.91 (1H, dd, J = 2.64,7.26Hz, trans-C H ₂ -O),
2.67-2.83 (1H, m, C H CH ₂ CH ₂ Ph), 2.70 (2H, t, J = 4.5Hz, C H ₂ Ph),
2.43 (1H, dd, J = 2.64,4.95Hz, cis-C H ₂ -O),
1.78-1.88 (2H, m, C H ₂ CH ₂ Ph).
[0024]
Example 1
Isomerization of mono-substituted alkyl epoxide (1-1) with Fe (tpp) SO ₃ CF ₃ 1,4-dioxane solution of 1,2-epoxydecane (1-1a) (0.1 g, 0.64 mmol) ( 3 ml) was added Fe (tpp) SO ₃ CF ₃ (12.8 μmol, 2 mol%) and stirred under reflux until the raw material disappeared. After completion of the reaction, the reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by a Florisil column (ethyl acetate) to obtain decylaldehyde (3-1a). Similarly, (3-1b)-(3-1f) was obtained from the compound (1-1b)-(1-1f) shown in Table 1. The results are shown in Table 1.
[0025]
Decylaldehyde (3-1a): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
9.76 (1H, t, J = 1.32Hz, CHO), 2.42 (2H, t, J = 7.26Hz, CH ₂ CO),
1.63 (2H, m, C H ₂ CH ₂ CO), 1.20-1.38 (12H, m, CH ₂ ),
0.88 (3H, t, J = 6.60Hz, CH ₃ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
14.11, 22.12, 22.70, 29.22, 29.29, 29.42, 31.90, 43.94, 202.66.
[0026]
Tetradecylaldehyde (3-1b): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
9.76 (1H, t, J = 1.65Hz, CHO), 2.41 (2H, t, J = 7.26Hz, CH ₂ CO),
1.63 (2H, m, CH ₂ CH ₂ CO), 1.20-1.38 (20H, m, CH ₂ ), 0.88 (3H, t, J = 6.43Hz, CH ₃ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
14.14, 22.14, 22.73, 29.22, 29.42, 29.49, 29.70, 31.99, 43.95 and 202.78.
[0027]
9-decenaldehyde (3-1c): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
9.75 (1H, t, J = 1.65Hz, CHO), 5.81 (1H, ddt, J = 16.99,6.60,6.93Hz, C H = CH ₂ ),
4.98 (1H, d of m, J = 16.99Hz, CH = C H ₂ ), 4.92 (1H, d of m, J = 11.88Hz, CH = C H ₂ ),
2.41 (2H, t, J = 7.26Hz, CH ₂ CO), 2.04 (2H, dt, J = 6.6,6.93Hz, C H ₂ CH = CH ₂ ),
1.63 (2H, m, C H ₂ CH ₂ CO), 1.23-1.45 (8H, m, CH ₂ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
22.07, 28.84, 28.88, 29.13, 29.20, 33.75, 43.88, 114.28, 138.94, 202.55.
[0028]
3-phenylpropyl aldehyde (3-1d): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
9.78 (1H, s, CHO), 7.15-7.31 (5H, m, aromatic H),
2.93 (2H, t, J = 7.26Hz, CH ₂ CO), 2.74 (2H, t, J = 7.43Hz, C H ₂ Ph);
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
28.09, 45.23, 126.27, 128.26, 128.59, 140.34, 201.47.
[0029]
4-phenylbutyraldehyde (3-1e): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
9.72 (1H, s, CHO), 7.15-7.31 (5H, m, aromatic H),
2.63 (2H, t, J = 7.43Hz, CH ₂ CO), 2.42 (2H, t, J = 6.60Hz, C H ₂ Ph),
1.94 (2H, m, C H ₂ CH ₂ CO);
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
23.63, 34.97, 43.09, 126.07, 128.44, 141.20, 202.21.
[0030]
1,8-dioctanal (3-1f): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
9.77 (2H, t, J = 1.65Hz, CHO), 2.44 (4H, dt, J = 1.65,7.26Hz, CH ₂ CO),
1.63 (4H, m, C H ₂ CH ₂ CO), 1.30-1.41 (4H, m, CH ₂ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
21.82, 28.88, 43.77, 202.57.
[0031]
[Table 1]

[0032]
As the reaction product of diepoxyalkane (1-1f) having an epoxy group at both ends of the carbon chain, the following three compounds (5), (6) and (7) can be considered. The compound (7) having both a ketone and an aldehyde was not confirmed by ¹ H-NMR.
[0033]
[Chemical 7]

[0034]
Reference example 3
Synthesis of trans-3,4-epoxy-2-decanone (1-2 g) To a methanol solution (40 ml) of trans-3-decen-2-one (3.09 g, 20 mmol), 30% H ₂ under ice-cooling. O ₂ (6 ml) and 2N-NaOH (6 ml) were added dropwise, and the mixture was returned to room temperature and stirred until the raw material disappeared. The reaction solution was neutralized with a saturated NH ₄ Cl solution and extracted with ether. The organic layer was separated and dried over anhydrous MgSO ₄ . The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/30) to obtain trans-3,4-epoxy-2-decanone (1-2 g). It was.
[0035]
trans-3,4-epoxy-2-decanone (1-2 g): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
3.17 (1H, d, J = 1.98Hz, CHCO), 3.08 (1H, dt, J = 1.98,5.28Hz, CH ₂ C H -O),
2.05 (3H, s, CH ₃ CO), 1.62 (2H, m, C H ₂ CH-O), 1.25-1.48 (8H, m, CH ₂ ),
0.89 (3H, t, J = 6.60Hz, CH ₃ ).
[0036]
Reference example 4
Synthesis of α, β-epoxyketone (1-2h), (1-2i), (1-2j) in toluene solution of decylaldehyde (0.78 g, 5 mmol) was refluxed, and 1-triphenylphosphoric acid was added thereto. Ranilidene-2-propanone (1.59 g, 5 mmol) was added all at once and stirred until the raw material disappeared. After returning the reaction solution to room temperature, the precipitated phosphine oxide was removed, the solvent was distilled off, and the resulting residue was purified by silica gel chromatography (ethyl acetate / n-hexane = 1/30) to produce trans- 3-Tridecen-2-one was obtained. This was epoxidized with H ₂ O _{2 in the same} manner as in Reference Example 3 to obtain (1-2h). Similarly, (1-2i) was obtained from 10-undecene-1-al and (1-2j) was obtained from 3-phenyl-1-propanal.
[0037]
trans-3,4-epoxy-2-tridecanone (1-2h): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
3.18 (1H, d, J = 1.98Hz, CHCO), 3.07 (1H, dt, J = 1.98,5.45Hz, CH ₂ C H -O),
2.08 (3H, s, CH ₃ CO), 1.57-1.67 (2H, m, C H ₂ CH-O), 1.18-1.40 (12H, m, CH ₂ ),
0.88 (3H, t, J = 6.76Hz, CH ₂ C H ₃ ).
[0038]
trans-13-tetradecene-3,4-epoxy-2-one (1-2i): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
5.81 (1H, ddt, J = 17.08,6.60,6.93Hz, C H = CH ₂ ),
4.98 (1H, d of m, J = 17.08Hz, CH = C H ₂ ), 4.93 (1H, d of m, J = 11.80Hz, CH = C H ₂ ),
3.18 (1H, d, J = 1.98Hz, CHCO), 3.07 (1H, dt, J = 1.98,5.61Hz, CH ₂ C H -O),
2.06 (3H, s, CH ₃ CO), 2.04 (2H, m, C H ₂ CH = CH ₂ ), 1.61 (2H, m, C H ₂ CH-O),
1.30-1.50 (12H, m, CH ₂ ).
[0039]
trans-6-phenyl-3,4-epoxy-2-hexaone (1-2j): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
7.15-7.32 (5H, m, aromatic H), 3.15 (1H, d, J = 1.98Hz, CHCO),
3.07 (1H, dt, J = 1.98,5.61Hz, CH ₂ C H -O), 2.77 (2H, m, C H ₂ Ph),
1.98 (3H, s, CH ₃ CO), 1.93 (2H, m, C H ₂ CH ₂ Ph).
[0040]
Reference Example 5
Synthesis of α, β-epoxyketone (1-2k) A solution of trans-2-hexenal diethyl acetal (3.45 g, 20 mmol) in n-hexane (40 ml) was refluxed and benzotriazole (3.57 g, 30 mmol) was refluxed. ) At a stretch and stirred until the raw material disappeared. The reaction solution was diluted with ether and washed with a saturated aqueous solution of Na ₂ CO ₃ , and the organic layer was separated and dried over anhydrous MgSO ₄ . The residue obtained by distilling off the solvent was purified by silica gel chromatography (ethyl acetate / n-hexane = 1/20) to give 1- (benzotriazol-1-yl) -1-ethoxy-2-hexene. Obtained. Next, the obtained 1- (benzotriazol-1-yl) -1-ethoxy-2-hexene (1.27 g, 5 mmol) was dissolved in anhydrous THF (50 ml), and at −78 ° C., n-butyllithium was dissolved. N-hexane solution (1.58 M, 5 mmol) was added dropwise. Further, after 30 minutes, bromooctane (0.96 ml, 5.5 mmol) was added dropwise and stirred until the raw material disappeared. The reaction solution was diluted with ether and washed with a saturated aqueous solution of Na ₂ CO ₃ , and the organic layer was separated and dried over anhydrous MgSO ₄ . The enone obtained by purifying the residue obtained by distilling off the solvent by silica gel chromatography (ethyl acetate / n-hexane = 1/20) was converted to epoxy using H ₂ O _{2 in the same} manner as in Reference Example 3. (1-2k) was obtained.
[0041]
trans-4,5-epoxy-6-tetradecanone (1-2k): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
3.20 (1H, d, J = 1.98Hz, CHCO), 3.04 (1H, m, CH ₂ C H -O),
2.21-2.49 (2H, m, CH ₂ CO), 1.41-1.68 (6H, m, C H ₂ CHCO, C H ₂ C H ₂ CH-O),
1.22-1.33 (10H, m, CH ₂ ), 0.98 (3H, t, J = 7.26Hz, CH ₃ ),
0.88 (3H, t, J = 6.60Hz, CH ₃ ).
[0042]
Example 2
Isomerization of α, β-epoxyketone (1-2) with Fe (tpp) SO ₃ CF ₃ trans-3,4-epoxy-2-decanone (1-2 g) (0.1 g, 0.59 mmol) Fe (tpp) SO ₃ CF ₃ (11.8 μmol, 2 mol%) was added to the dioxane solution (3 ml), and the mixture was stirred under reflux until the raw material disappeared. The reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, the catalyst was removed with a Florisil column (ethyl acetate), and then the solvent was distilled off under reduced pressure to obtain compound 1,2-diketone (3-2 g). Similarly, (3-2h)-(3-2k) was obtained from the compound (1-2h)-(1-2k) shown in Table 2. The results are shown in Table 2.
[0043]
2,3-decanedione (3-2 g): oil;
IR (neat) 1700cm ^-1 ;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
2.73 (2H, t, J = 7.43Hz, CH ₂ CO), 2.33 (3H, s, CH ₃ CO),
1.58 (2H, m, C H ₂ CH ₂ CO), 1.18-1.35 (8H, m, CH ₂ ), 0.88 (3H, t, J = 6.60Hz, CH ₃ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
14.05, 22.59, 23.09, 23.70, 29.00, 29.11, 31.64, 35.71, 197.55, 199.48.
MS: 170 (M ⁺ , 5.7), 127 (69.1), 113 (3.9), 109 (9.1), 97 (2.7), 85 (3.7), 67 (5.4), 57 (100.0), 43 (33.5).
Exact mass Calcd.for C ₁₀ H ₁₈ O ₂ : 170.1307.
Found: 170.1312
[0044]
2,3-tridecanedione (3-2h): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
2.73 (2H, t, J = 7.26Hz, CH ₂ CO), 2.33 (3H, s, CH ₃ CO), 1.58 (2H, m, C H ₂ CH ₂ CO), 1.18-1.35 (14H, m, CH ₂ ), 0.88 (3H, t, J = 6.40Hz, CH ₃ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
14.12, 22.71, 23.11, 23.74, 29.18, 29.34, 29.47, 29.58, 31.93, 35.76, 197.62, 199.55.
Exact mass Calcd.for C ₁₃ H ₂₄ O ₂ : 212.1776.
Found: 212.1775
[0045]
13-tetradecene-2,3-dione (3-2i): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
5.81 (1H, ddt, J = 16.99,6.60,6.93Hz, C H = CH ₂ ),
4.98 (1H, d of m, J = 16.99Hz, CH = C H ₂ ), 4.92 (1H, d of m, J = 11.88Hz, CH = C H ₂ ),
2.73 (2H, t, J = 7.26Hz, CH ₂ CO), 2.33 (3H, s, CH ₃ CO),
2.04 (2H, dt, J = 7.1,6.93Hz, C H ₂ CH = CH ₂ ), 1.58 (2H, m, C H ₂ CH ₂ CO),
1.23-1.40 (12H, m, CH ₂ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
23.07, 23.76, 28.93, 29.13, 29.33, 29.38, 29.42, 33.80, 35.74, 114.14, 139.21, 197.66, 199.57.
Exact mass Calcd.for C ₁₄ H ₂₄ O ₂ : 224.1776.
Found: 224.1777
[0046]
6-phenyl-2,3-hexanedione (3-2j): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
7.15-7.31 (5H, m, aromatic H), 2.75 (2H, t, J = 7.26Hz, CH ₂ CO),
2.64 (2H, t, J = 7.59Hz, C H ₂ Ph), 2.29 (3H, s, CH ₃ CO), 1.93 (2H, m, C H ₂ CH ₂ Ph);
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
23.65, 24.64, 35.04, 126.09, 128.46, 128.50, 141.26, 197.37, 199.06.
Exact mass Calcd.for C ₁₂ H ₁₄ O ₂ : 190.0994.
Found: 190.0996
[0047]
5,6-tetradecanedione (3-2k): oil;
¹ H-NMR (270 MHz, CDCl ₃ ) δ:
2.73 (4H, t, J = 7.26Hz, CH ₂ CO), 1.58 (4H, m, C H ₂ CH ₂ CO),
1.21-1.41 (12H, m, CH ₂ ), 0.92 (3H, t, J = 7.26Hz, CH ₃ ),
0.88 (3H, t, J = 6.60Hz, CH ₃ );
¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ:
13.82, 14.11, 22.32, 22.68, 23.11, 25.19, 29.13, 29.18, 29.34, 31.84, 35.81, 36.12, 200.18.
[0048]
[Table 2]

Claims

General formula (1)

[In the formula, R ¹ represents an organic group, R ² and R ³ represents a hydrogen atom or an organic group, R ³ is an acyl group which may have a hydrogen atom or a substituent when R ² is a hydrogen atom Is)
The epoxide represented by the following formula (2)

[Wherein M represents a transition metal atom and tap represents tetraarylporphyrin]
A tetraarylporphyrin trifluoromethanesulfonate transition metal complex represented by the general formula (3)

[Wherein R ¹ , R ² and R ³ are the same as above]
The manufacturing method of ketones represented by these.