EP1529024A1 - Method for the production of acetylene alcohols - Google Patents

Method for the production of acetylene alcohols

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Publication number
EP1529024A1
EP1529024A1 EP03792224A EP03792224A EP1529024A1 EP 1529024 A1 EP1529024 A1 EP 1529024A1 EP 03792224 A EP03792224 A EP 03792224A EP 03792224 A EP03792224 A EP 03792224A EP 1529024 A1 EP1529024 A1 EP 1529024A1
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Prior art keywords
ketone
lithium
radical
alkyl
general formula
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EP03792224A
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German (de)
French (fr)
Inventor
Jochem Henkelmann
Alois Kindler
Jan-Dirk Arndt
Katrin Klass
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a process for the preparation of acetylene alcohols by monoethynylation of a ketone by reacting an alkyl halide with lithium.
  • a monolithium acetylide complex is reacted with the corresponding carbonyl compound in an inert organic solvent (CH 642 936).
  • the active lithium acetylide ammonia complex is prepared by evaporating ammonia from a lithium acetylide ammonia solution at -30 to -20 ° C and replacing it with an organic solvent.
  • the reaction of lithium amide with acetylene in an inert organic solvent is mentioned.
  • No. 2,472,310 describes a method for the ethynylation of rapidly aldolizing ketones, such as, for example, ⁇ -ionone, under basic conditions.
  • the lithium acetylene-ammonia complex required for this is shown by introducing acetylene into liquid ammonia at -40 ° C. and simultaneously adding lithium (OA Shavrygina, DV Nazarova, SM Makin, Zh. Org. Khim. 1966, 2, 1566-1568).
  • a disadvantage of the processes mentioned is the low selectivity of the lithium acetylide formation, since the lithium acetylide can be present as mono- or dilithium acetylide or as a mixture of the two components.
  • Another disadvantage is the low temperature required to keep the ammonia liquid and the solvent exchange after lithium acetylide formation.
  • US 2,425,201 discloses a process for the production of ⁇ , ⁇ -unsaturated ketones using calcium acetylidene. The ethynylation takes place at temperatures from -70 to -40 ° C.
  • DE 10 81 883 describes a process for the preparation of ethyl ionol by reacting sodium acetylide with ⁇ -ionone in an organic solvent. To increase the acetylene concentration tion in the reaction mixture, acetylene is used under pressure. Compared to the unpressurized procedure, ethynyl ionol is obtained in an improved yield.
  • the preparation of lithium acetylide is based on the reaction of lithium with naphthalene and acetylene, a naphthalene radical anion being first formed by electron transfer, which then acts as a base and forms the lithium acetylide with acetylene.
  • the reaction with ⁇ -ionone then gives the desired ehinyl ionol in 90% yield (K. Suga, S. Watenabe, T. Suzuki, Can. J. Chem. 1968, 46, 3041-3045).
  • the use of semi-stoichiometric amounts of naphthalene based on ⁇ -ionone is not advantageous here.
  • a catalytic process for the preparation of alkyl lithium compounds is also known.
  • Lithium forms a radical anion in the presence of 4,4-di-tert-butylphenyl as a catalyst by simple electron transfer, which forms the corresponding alkyl lithium species by reaction with alkyl halides (PK Freeman, L. L: Hutchinson, Tetrahedron Letters, 1976, 22, 1849-1852; PK Freeman, LL: Hutchinson, J. Org. Chem. 1983, 48, 4705-4713).
  • naphthalene can also be used as a catalyst.
  • the alkyl lithium compound obtained in the reaction is preferably used for the alkylation of various electrophiles (M. Yus, D. Ramon, J. Chem. Soc., Chem. Comm. 1991, 398-400; TR van den Ancker, MJ Hdgson , J. Chem. Soc, Perkin Trans. 1, 1999, 2869-2870).
  • the object of the invention was to develop an economical process for the production of acetylene alcohols which does not have the disadvantages described in the prior art. Surprisingly, the object was achieved according to the invention by a one-pot process for the preparation of acetylene alcohols of the general formula I.
  • R 1 , R 2 can each independently be the same or different and are hydrogen, a saturated or a mono- or polyunsaturated C 1 -C 3 o-alkyl, aryl, cycloalkylalkyl or cycloalkyl radical, which can optionally be substituted or a group of the general formula (II) can mean
  • R 3 , R 4 can each independently be the same or different and are hydrogen or a saturated or a mono- or polyunsaturated C ⁇ -C 3 o-alkyl, aryl, cycloalkylalkyl or cycloalkyl radical, which can be optionally substituted and the dashed line Line can mean an additional double bond
  • the reaction of lithium with alkyl halide preferably takes place in the presence of catalytic amounts of naphthalene or 4,4'-di-tert-butylbiphenyl.
  • Tetrahydrofuran can be used as a solvent.
  • a C 1 -C 4 alkyl radical means a methyl, ethyl, propyl, i-propyl, butyl or t-butyl radical.
  • a mono- or polyunsaturated straight-chain or branched C 1 -C 30 -alkyl radical means, for example, unless otherwise stated, a methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptenyl , Octyl, nonyl, decyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-methyl-2-pentenyl, isopropenyl, 1-butenyl, hexenyl , Heptenyl, octenyl, nonenyl, or a decenyl radical or the radicals corresponding to the compounds listed below.
  • Cycloalkyl stands for a 3-7-membered saturated or a mono- or polyunsaturated 3-7-membered ring in which a CH group can be replaced by 0 or NH, as u. a. the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the cycloheptyl ring, preferably the cyclopentyl or the cyclohexyl ring.
  • An aryl radical means a benzyl, phenyl or naphthyl radical.
  • C 1 -C 4 -alkyl can be methyl, ethyl, propyl, i-propyl, butyl, t-butyl, fluorine, chlorine, bromine, iodine, nitro or amino radicals.
  • ketones can be used, for example, for ethynylation:
  • 6-methylheptanone hexahydrofarnesylacetone, diethyl ketone, methyl ethyl ketone, cyclohexanone, methyl t-butyl ketone, pseudo-ionone, methyl hexenone, H-geranylacetone, preferably acetone, methyl vinyl ketone or ⁇ -ionone.
  • an alkyl halide for example 1-chlorobutane at temperatures from -20 to -10 ° C.
  • acetylene gas is introduced to produce lithium acetylide.
  • the ketone is added at 0 to 10 ° C., preferably at 0 ° C. Surprisingly, there is no disproportionation of the lithium acetylide into dilithium acetylide and acetylene.
  • Tetrahydrofuran can be used as the solvent.
  • the process according to the invention enables acetylene alcohols to be prepared in good to very good yields, for example starting from the ketones acetone, ⁇ -ionone or methyl vinyl ketone.
  • the ethynylation products of ß-ionone and methyl vinyl ketone are precursors of vitamin A and astaxanthin synthesis.
  • Trimethylsilyl chloride is used to prepare trimethylsilacetylene.
  • Trimethylsilyacetylene is used to prepare endiins that are active as anti-tumor reagents.
  • the reaction takes place in two 250 ml cervical vessels under argon.
  • 2.4 g (0.34 mol) of lithium wire is cut into small pieces and suspended together with 5.4 g (20 mol) of the catalyst in 200 ml of tetrahydrofuran at -15 ° C.
  • 14.8 g (0.16 mol) of 1-chlorobutane in 20 ml of tetrahydrofuran are added via a dropping funnel within two hours and then stirred for a further two hours.
  • the lithium is separated off by transferring the supernatant solution into a second ml HWS vessel, into which acetylene is then introduced at -15 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a method for producing acetylene alcohols of general formula (I), wherein R1, R2 can independently be identical or different and represent optionally substituted hydrogen, an optionally substituted saturated, monounsaturated or polyunsaturated C1-C30 alkyl radical, aryl radical, cycloalkylalkyl radical, or cycloalkyl radical, or a group of general formula (II), wherein R3, R4 can independently be identical or different and represent optionally substituted hydrogen or an optionally substituted saturated, monounsaturated, or polyunsaturated C1-C30 alkyl radical, aryl radical, cycloalkylalkyl radical, or cycloalkyl radical while the dashed line can represent an additional double bond. Said acetylene alcohols are produced by monoethynylating a ketone of general formula R1-CO-R2 by (a) reacting lithium with a C1-C10 alkyl halide, (b) introducing acetylene gas, and (c) adding the ketone.

Description

Verfahren zur Herstellung von AcetylenalkoholenProcess for the preparation of acetylene alcohols
Beschreibungdescription
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Acetylenalkoholen durch Monoethinylierung eines Ketons durch Umsetzung eines Alkylhalogenids mit Lithium.The present invention relates to a process for the preparation of acetylene alcohols by monoethynylation of a ketone by reacting an alkyl halide with lithium.
Stand der Technik ist die kontinuierlich betriebene Ethinylierung von Ketonen mit Acetylen in flüssigem Ammoniak mit katalytischen Mengen Base (meist KOH oder K-Methylat in einem polaren, protischen Solvens; 10-40°C; 20 bar), wie z.B. beschrieben in DE 12 32 573.State of the art is the continuously operated ethynylation of ketones with acetylene in liquid ammonia with catalytic amounts of base (mostly KOH or K-methylate in a polar, protic solvent; 10-40 ° C; 20 bar), e.g. described in DE 12 32 573.
In einem weiteren Verfahren für die 1,2-Ethinylierung α,ß-unge- sättigter Ketone wird ein Monolithiumacetylid-Komplex in einem inerten organischen Lösungsmittel mit der entsprechenden Carbo- nylverbindung umgesetzt (CH 642 936). Der aktive Lithiumacetylid- Ammoniak-Komplex wird hergestellt, indem man Ammoniak aus einer Lithiumacetylid-Ammoniak-Lösung bei -30 bis -20°C abdampft und durch ein organisches Lösungsmittel ersetzt. Als alternatives Verfahren wird die Umsetzung von Lithiumamid mit Acetylen in einem inerten organischen Lösungsmittel angeführt.In a further process for the 1,2-ethynylation of α, β-unsaturated ketones, a monolithium acetylide complex is reacted with the corresponding carbonyl compound in an inert organic solvent (CH 642 936). The active lithium acetylide ammonia complex is prepared by evaporating ammonia from a lithium acetylide ammonia solution at -30 to -20 ° C and replacing it with an organic solvent. As an alternative method, the reaction of lithium amide with acetylene in an inert organic solvent is mentioned.
In US 2,472,310 wird eine Methode zur Ethinylierung von schnell aldolisierenden Ketonen, wie beispielsweise ß-Ionon unter basischen Bedingungen beschrieben. Der dazu benötigte Lithiumacety- lid-Ammoniak-Komplex wird dargestellt, indem bei -40°C Acetylen in flüssigen Ammoniak eingeleitet wird und gleichzeitig Lithium zugegeben wird (O.A. Shavrygina, D.V. Nazarova, S.M. Makin, Zh. Org. Khim. 1966, 2, 1566-1568).No. 2,472,310 describes a method for the ethynylation of rapidly aldolizing ketones, such as, for example, β-ionone, under basic conditions. The lithium acetylene-ammonia complex required for this is shown by introducing acetylene into liquid ammonia at -40 ° C. and simultaneously adding lithium (OA Shavrygina, DV Nazarova, SM Makin, Zh. Org. Khim. 1966, 2, 1566-1568).
Nachteilig bei den genannten Verfahren ist die geringe Selektivi- tat der Lithiumacetylidbildung, da das Lithiumacetylid als Mono- oder Dilithiumacetylid oder als Gemisch der beiden Komponenten vorliegen kann. Ein weiterer Nachteil ist die erforderliche tiefe Temperatur, um den Ammoniak flüssig zu halten und der Lösungsmittelaustausch nach der Lithiumacetylidbildung.A disadvantage of the processes mentioned is the low selectivity of the lithium acetylide formation, since the lithium acetylide can be present as mono- or dilithium acetylide or as a mixture of the two components. Another disadvantage is the low temperature required to keep the ammonia liquid and the solvent exchange after lithium acetylide formation.
US 2,425,201 offenbart ein Verfahren zur Herstellung von α,ß-un- gesättigten Ketonen unter Verwendung von Calciumacetyliden. Die Ethinylierung findet bei Temperaturen von -70 bis -40°C statt.US 2,425,201 discloses a process for the production of α, β-unsaturated ketones using calcium acetylidene. The ethynylation takes place at temperatures from -70 to -40 ° C.
DE 10 81 883 beschreibt ein Verfahren zur Herstellung von Ethi- nylionol durch Umsetzung von Natriumacetylid mit ß-Ionon in einem organischen Lösungsmittel . Zur Steigerung der Acetylenkonzentra- tion im Reaktionsgemisch wird Acetylen unter Druck eingesetzt. Im Vergleich zur drucklosen Fahrweise wird Ethinylionol in verbesserter Ausbeute erhalten.DE 10 81 883 describes a process for the preparation of ethyl ionol by reacting sodium acetylide with β-ionone in an organic solvent. To increase the acetylene concentration tion in the reaction mixture, acetylene is used under pressure. Compared to the unpressurized procedure, ethynyl ionol is obtained in an improved yield.
In einem weiteren Verfahren (DE 17 68 877) wird die Herstellung von Acetylenalkoholen durch Umsetzung von Natriu ethanolat mit Acetylen und einem entsprechenden Keton in einem organischen Lösungsmittel unter Druck, bei ca. 14 bar beschrieben. Das Arbeiten unter Druck ist bei diesem Verfahren im Hinblick auf die Sicherheit beim Umgang mit Acetylen und den damit verbundenen Kosten jedoch als deutlicher Nachteil zu sehen.Another process (DE 17 68 877) describes the preparation of acetylene alcohols by reacting sodium ethanolate with acetylene and a corresponding ketone in an organic solvent under pressure at about 14 bar. However, working under pressure is to be seen as a clear disadvantage in terms of safety when handling acetylene and the associated costs.
Anstelle von Lithium in flüssigem Ammoniak ist auch die Verwendung von Natrium möglich, wobei ebenfalls nach der Natriumacety- lidbildung das Keton in einem anderen Lösungsmittel zugegeben werden muss, damit der Ammoniak langsam abdampft (P. Karrer, J. Benz, Helv. Chim. Acta 1948, 31, 390-295).Instead of lithium in liquid ammonia, the use of sodium is also possible, the ketone in another solvent also having to be added after the sodium acetylation, so that the ammonia slowly evaporates (P. Karrer, J. Benz, Helv. Chim. Acta 1948, 31, 390-295).
In einem anderen Verfahren beruht die Darstellung von Lithiumace- tylid auf der Umsetzung von Lithium mit Naphthalin und Acetylen, wobei zuerst durch Elektronenübertragung ein Naphthalin-Radikal- anion gebildet wird, das dann als Base wirkt und mit Acetylen das Lithiumacetylid bildet. Die Umsetzung mit ß-Ionon ergibt dann in 90 %iger Ausbeute das gewünschte Ehinylionol (K. Suga, S. Wata- nabe, T. Suzuki, Can. J. Chem. 1968, 46, 3041-3045). Nicht von Vorteil ist hier die Verwendung von halbstöchiometrischen Mengen Naphthalin bezogen auf ß-Ionon.In another process, the preparation of lithium acetylide is based on the reaction of lithium with naphthalene and acetylene, a naphthalene radical anion being first formed by electron transfer, which then acts as a base and forms the lithium acetylide with acetylene. The reaction with β-ionone then gives the desired ehinyl ionol in 90% yield (K. Suga, S. Watenabe, T. Suzuki, Can. J. Chem. 1968, 46, 3041-3045). The use of semi-stoichiometric amounts of naphthalene based on β-ionone is not advantageous here.
Weiterhin ist ein katalytischer Prozess zur Darstellung von Alkyllithium-Verbindungen bekannt. Lithium bildet in Anwesenheit von 4, 4 -Di-tert-butylphenyl als Katalysator durch einfache Elektronenübertragung ein Radikalanion, welches durch Umsetzung mit Alkylhalogeniden die korrespondierenden Alkyllithium-Spezies bildet (P.K. Freeman, L. L: Hutchinson, Tetrahedron Letters, 1976, 22, 1849-1852; P.K. Freeman, L.L: Hutchinson, J. Org. chem. 1983, 48, 4705-4713). Als Katalysator kann in einigen Fällen auch Naphthalin verwendet werden. Die in der Reaktion gewonnene Alkyl- lithium-Verbindung wird bevorzugt zur Alkylierung verschiedener Elektrophile eingesetzt (M. Yus, D. Ramon, J. Chem. Soc . , Chem. Comm. 1991, 398-400; T.R. van den Ancker, M.J. Hdgson, J. Chem. Soc, Perkin Trans. 1, 1999, 2869-2870).A catalytic process for the preparation of alkyl lithium compounds is also known. Lithium forms a radical anion in the presence of 4,4-di-tert-butylphenyl as a catalyst by simple electron transfer, which forms the corresponding alkyl lithium species by reaction with alkyl halides (PK Freeman, L. L: Hutchinson, Tetrahedron Letters, 1976, 22, 1849-1852; PK Freeman, LL: Hutchinson, J. Org. Chem. 1983, 48, 4705-4713). In some cases, naphthalene can also be used as a catalyst. The alkyl lithium compound obtained in the reaction is preferably used for the alkylation of various electrophiles (M. Yus, D. Ramon, J. Chem. Soc., Chem. Comm. 1991, 398-400; TR van den Ancker, MJ Hdgson , J. Chem. Soc, Perkin Trans. 1, 1999, 2869-2870).
Aufgabe der Erfindung war die Entwicklung eines wirtschaftlichen Verfahrens zur Herstellung von Acetylenalkoholen, das die im Stand der Technik beschriebenen Nachteile nicht aufweist . Überraschenderweise wurde die Aufgabe erfindungsgemäß gelöst, durch ein Eintopf-Verfahren zur Herstellung von Acetylenalkoholen der allgemeinen Formel IThe object of the invention was to develop an economical process for the production of acetylene alcohols which does not have the disadvantages described in the prior art. Surprisingly, the object was achieved according to the invention by a one-pot process for the preparation of acetylene alcohols of the general formula I.
wobeiin which
R1, R2 jeweils unabhängig voneinander gleich oder verschieden sein können und Wasserstoff, einen gesättigten oder einen ein oder mehrfach ungesättigten Cι-C3o-Alkyl-, Aryl-, Cycloalkylalkyl- oder Cycloalkylrest bedeuteten, die gegebenenfalls substituiert sein können oder eine Gruppe der allgemeinen Formel (II) bedeuten könnenR 1 , R 2 can each independently be the same or different and are hydrogen, a saturated or a mono- or polyunsaturated C 1 -C 3 o-alkyl, aryl, cycloalkylalkyl or cycloalkyl radical, which can optionally be substituted or a group of the general formula (II) can mean
R4 R 4
wobeiin which
R3 , R4 jeweils unabhängig voneinander gleich oder verschieden sein können und Wasserstoff oder einen gesättigten oder einen ein oder mehrfach ungesättigten Cχ-C3o-Alkyl-, Aryl-, Cycloalkylalkyl- oder Cycloalkylrest bedeuten, die gegebenenfalls substituiert sein können und die gestrichelte Linie eine zusätzliche Doppelbindung bedeuten kann,R 3 , R 4 can each independently be the same or different and are hydrogen or a saturated or a mono- or polyunsaturated Cχ-C 3 o-alkyl, aryl, cycloalkylalkyl or cycloalkyl radical, which can be optionally substituted and the dashed line Line can mean an additional double bond
durch Monoethinylierung eines Ketons der allgemeinen Formel Rx-CO-R2 durchby monoethynylation of a ketone of the general formula R x -CO-R 2
(a) Umsetzung von Lithium mit einem Ci—Cio-Alkylhalogenid(a) Reaction of lithium with a Ci — Cio alkyl halide
(b) Einleiten von Acetylengas (c) Zugabe des Ketons.(b) introducing acetylene gas (c) adding the ketone.
Die Umsetzung von Lithium mit Alkylhalogenid findet bevorzugt in Gegenwart katalytischer Mengen Naphthalin oder 4 , 4 ' -Di-tert- butylbiphenyl statt . Als Lösungsmittel kann dazu Tetrahydrofuran verwendet werden. Unter einem Cι~C -Alkylrest versteht man einen Methyl-, Ethyl, - Propyl-, i-Propyl-, Butyl- oder einen t-Butylrest.The reaction of lithium with alkyl halide preferably takes place in the presence of catalytic amounts of naphthalene or 4,4'-di-tert-butylbiphenyl. Tetrahydrofuran can be used as a solvent. A C 1 -C 4 alkyl radical means a methyl, ethyl, propyl, i-propyl, butyl or t-butyl radical.
Unter einem ein oder mehrfach ungesättigten geradkettigen oder verzweigten Cι-C30-Alkylrest versteht man beispielsweise, wenn nicht anders angegeben einen Methyl, Ethyl, Propyl, Isopropyl, n-Butyl, i-Butyl-, t-Butyl, Pentyl, Hexyl, Heptenyl, Octyl-, Nonyl-, Decyl, 1-Propenyl-, 2-Propenyl-, 2-Methyl-2-propenyl, 1-Pentenyl, l-Methyl-2-Pentenyl-, Isopropenyl-, 1-Butenyl-, Hexenyl-, Heptenyl-, Octenyl-, Nonenyl-, oder einen Decenylrest bzw. die den unten aufgeführten Verbindungen entsprechenden Reste.A mono- or polyunsaturated straight-chain or branched C 1 -C 30 -alkyl radical means, for example, unless otherwise stated, a methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptenyl , Octyl, nonyl, decyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-methyl-2-pentenyl, isopropenyl, 1-butenyl, hexenyl , Heptenyl, octenyl, nonenyl, or a decenyl radical or the radicals corresponding to the compounds listed below.
Cycloalkyl steht für einen 3-7-gliedrigen gesättigten oder einen ein oder mehrfach ungesättigten 3-7-gliedrigen Ring in dem eine CH -Gruppe durch 0 oder NH ersetzt sein kann, wie u. a. den Cyclo- propyl-, Cyclobutyl- Cyclopentyl-, Cyclohexyl- oder den Cyclohep- tylring, vorzugsweise den Cyclopentyl- oder den Cyclohexylring.Cycloalkyl stands for a 3-7-membered saturated or a mono- or polyunsaturated 3-7-membered ring in which a CH group can be replaced by 0 or NH, as u. a. the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the cycloheptyl ring, preferably the cyclopentyl or the cyclohexyl ring.
Unter einem Arylrest versteht man einen Benzyl, Phenyl- oder Naphthylrest .An aryl radical means a benzyl, phenyl or naphthyl radical.
Weitere Substituenten neben Cι~C -Alkyl können Methyl-, Ethyl-, Propyl-, i-Propyl-, Butyl-, t-Butyl-, Fluor-, Chlor-, Brom-, Jod-, Nitro- oder Aminoreste sein.Further substituents in addition to C 1 -C 4 -alkyl can be methyl, ethyl, propyl, i-propyl, butyl, t-butyl, fluorine, chlorine, bromine, iodine, nitro or amino radicals.
Die folgenden Ketone können beispielsweise zur Ethinylierung eingesetzt werden:The following ketones can be used, for example, for ethynylation:
Aceton, Methylvinylketon, ß-Ionon, Tetrahydrogeranylaceton,Acetone, methyl vinyl ketone, ß-ionone, tetrahydrogeranylacetone,
6-Methylheptanon, Hexahydrofarnesylaceton, Diethylketon, Methyl- ethylketon, Cyclohexanon, Methyl-t-butylketon, Pseudoionon, Methylhexenon, H-Geranylaceton, bevorzugt Aceton, Methylvinyl- keton oder ß-Ionon.6-methylheptanone, hexahydrofarnesylacetone, diethyl ketone, methyl ethyl ketone, cyclohexanone, methyl t-butyl ketone, pseudo-ionone, methyl hexenone, H-geranylacetone, preferably acetone, methyl vinyl ketone or β-ionone.
Im ersten Schritt des erfindungsgemäßen Verfahrens wird durch Reaktion von Lithium in Gegenwart katalytischer Mengen (12.5 Mol%) 4, 4' -Di-tert-butylbiphenyl mit einem Alkylhalogenid, beispielsweise 1-Chlorbutan bei Temperaturen von -20 bis -10°C, bevorzugt bei -15°C in situ Alkyllithium generiert. Nach Entfernung des überschüssigen Lithiums aus der Reaktionsmischung durch Filtration wird Acetylengas zur Herstellung von Lithiumacetylid eingeleitet . Als letzter Schritt der Eintopfreaktion erfolgt die Zugabe des Ketons bei 0 bis 10°C, bevorzugt bei 0°C. Überraschenderweise findet keine Disproportionierung des Lithiumacetylids in Dilithium- acetylid und Acetylen statt.In the first step of the process according to the invention, reaction of lithium in the presence of catalytic amounts (12.5 mol%) of 4,4′-di-tert-butylbiphenyl with an alkyl halide, for example 1-chlorobutane at temperatures from -20 to -10 ° C., is preferred generated in situ alkyl lithium at -15 ° C. After removal of the excess lithium from the reaction mixture by filtration, acetylene gas is introduced to produce lithium acetylide. As the last step of the one-pot reaction, the ketone is added at 0 to 10 ° C., preferably at 0 ° C. Surprisingly, there is no disproportionation of the lithium acetylide into dilithium acetylide and acetylene.
Als Lösungsmittel kann hierbei Tetrahydrofuran verwendet werden.Tetrahydrofuran can be used as the solvent.
Bei der erfindungsgemäßen Reaktion wurde ausschließlich die Bildung der Monolithiumacetylid-Spezies beobachtet, während man bei der Umsetzung von käuflichem Alkyllithium, beispielsweise Butyl- lithium, mit Acetylen oberhalb von -25°C eine Disproportionierung zu Acetylen und unlöslichem Dilithiumacetylid beobachtet. Dilithiumacetylid in Tetrahydrofuran steht bei 0°C mit der Mono- acetylid-Spezies im Gleichgewicht, wodurch bei Zugabe eines Elek- trophils das Gleichgewicht verschoben und dadurch die entsprechende ethinylierte Spezies erhalten wird.In the reaction according to the invention, only the formation of the monolithium acetylide species was observed, while disproportionation to acetylene and insoluble dilithium acetylide was observed in the reaction of commercially available alkyllithium, for example butyllithium, with acetylene above -25 ° C. Dilithium acetylide in tetrahydrofuran is in equilibrium with the monoacetylide species at 0 ° C, which, when an electrophile is added, shifts the equilibrium and the corresponding ethynylated species is obtained.
Durch das erfindungsgemäße Verfahren lassen sich Acetylenalko- hole, beispielsweise ausgehend von den Ketonen Aceton, ß-Ionon oder Methylvinylketon problemlos in guten bis sehr guten Ausbeuten herstellen. Die Ethinylierungsprodukte von ß-Ionon und Methylvinylketon stellen Vorprodukte der Vitamin A und der Astaxanthin- Synthese dar.The process according to the invention enables acetylene alcohols to be prepared in good to very good yields, for example starting from the ketones acetone, β-ionone or methyl vinyl ketone. The ethynylation products of ß-ionone and methyl vinyl ketone are precursors of vitamin A and astaxanthin synthesis.
Neben der Umsetzung der erfindungsgemäßen Ketone ist es auch möglich Trimethylsilylchlorid zur Darstellung von Trimethylsilacety- len umzusetzen. Trimethylsilyacetylen wird zur Darstellung von Endiinen eingesetzt, welche als Anti-Tumor-Reagentien aktiv sind.In addition to the implementation of the ketones according to the invention, it is also possible to implement trimethylsilyl chloride to prepare trimethylsilacetylene. Trimethylsilyacetylene is used to prepare endiins that are active as anti-tumor reagents.
Die nachfolgenden Beispiele sollen die Erfindung näher erläutern, ohne sie jedoch darauf zu beschränken:The following examples are intended to explain the invention in more detail, but without restricting it thereto:
BeispieleExamples
Die Reaktion findet in zwei 250 ml-HWS-Gefäßen unter Argon statt. Zuerst wird 2,4 g (0,34 mol) Lithium-Draht in kleine Stücke geschnitten und zusammen mit 5,4 g (20 mol) des Katalysators in 200 ml Tetrahydrofuran bei -15°C suspendiert. Nachdem eine intensive Blaufärbung der Reaktionsmischung aufgetreten ist, wird über einen Tropftrichter 14,8 g (0,16 mol) 1-Chlorbutan in 20 ml Tetrahydrofuran innerhalb von zwei Stunden zugegeben und anschließend noch zwei weitere Stunden gerührt. Die Lithiumabtrennung erfolgt durch Überführung der überstehenden Lösung in ein zweites ml-HWS-Gefäß, in die dann bei -15°C Acetylen (1,5 h) mit einem Strom von 4 1/h eingeleitet wird. Nach der Lithiumacetylidbildung wird 0,18 mol des entsprechenden Ketons in 20 ml Tetrahydrofuran über einen Tropftrichter bei 0°C innerhalb von zwei Stunden zugetropft. Nach Erwärmen auf Raumtemperatur wird durch Zugabe von Wasser hydrolysiert, und die Phasen werden getrennt.The reaction takes place in two 250 ml cervical vessels under argon. First, 2.4 g (0.34 mol) of lithium wire is cut into small pieces and suspended together with 5.4 g (20 mol) of the catalyst in 200 ml of tetrahydrofuran at -15 ° C. After an intense blue coloration of the reaction mixture has occurred, 14.8 g (0.16 mol) of 1-chlorobutane in 20 ml of tetrahydrofuran are added via a dropping funnel within two hours and then stirred for a further two hours. The lithium is separated off by transferring the supernatant solution into a second ml HWS vessel, into which acetylene is then introduced at -15 ° C. (1.5 h) with a stream of 4 l / h. After the formation of lithium acetylide, 0.18 mol of the corresponding ketone in 20 ml of tetrahydrofuran is passed through a dropping funnel at 0 ° C. within two Dripped for hours. After warming to room temperature, the mixture is hydrolyzed by adding water and the phases are separated.
MBI MethylbutinolMBI methyl butinol
MVK MethylvinylketonMVK methyl vinyl ketone
VBI VinylbutinolVBI vinyl butinol
Biph 4,4' -Di-tert . -butylbiphenylBiph 4,4'-di-tert. -butylbiphenyl
Naph Naphthalin Naph naphthalene

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von Acetylenalkoholen der allgemei- nen Formel I1. Process for the preparation of acetylene alcohols of the general formula I
wobeiin which
R1, R2 jeweils unabhängig voneinander gleich oder verschieden sein können und Wasserstoff, einen gesättigten oder einen ein oder mehrfach ungesättigten Cι-C3o~Alkyl-, Aryl-, Cycloalkylalkyl- oder Cycloalkylrest bedeuteten, die gegebenenfalls substituiert sein können oder eine Gruppe der allgemeinen Formel (II) bedeuten könnenR 1 , R 2 can each independently be the same or different and are hydrogen, a saturated or a mono- or polyunsaturated C 1 -C 3 alkyl, aryl, cycloalkylalkyl or cycloalkyl radical, which can optionally be substituted or a group of the general formula (II) can mean
R4 R 4
wobeiin which
R3 , R4 jeweils unabhängig voneinander gleich oder verschieden sein können und Wasserstoff oder einen gesättigten oder einen ein oder mehrfach ungesättigten Cι-C3o-Alkyl-, Aryl-, Cycloalkylalkyl- oder Cycloalkylrest bedeuten, die gegebenenfalls substituiert sein können und die gestrichelte Linie eine zusätzliche Doppelbindung bedeuten kann,R 3 , R 4 can each independently be the same or different and are hydrogen or a saturated or a mono- or polyunsaturated C 1 -C 3 o-alkyl, aryl, cycloalkylalkyl or cycloalkyl radical, which can optionally be substituted and the dashed line Line can mean an additional double bond
durch Monoethinylierung eines Ketons der allgemeinen Formel Ri-CO-R2 durchby monoethynylation of a ketone of the general formula R i -CO-R 2
(a) Umsetzung von Lithium mit einem Ci—Cχo-Alkylhalogenid (b) Einleiten von Acetylengas (c) Zugabe des Ketons. (a) Reaction of lithium with a Ci — Cχo-alkyl halide (b) introduction of acetylene gas (c) addition of the ketone.
2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, dass die Umsetzung von Lithium mit dem Cι-Cιo-Alkylhalogenid in Gegenwart katalytischer Mengen Naphthalin oder 4, 4 '-Di-tert-butyl- biphenyl stattfindet.2. The method according to claim 1, characterized in that the reaction of lithium with the -CC-alkyl halide takes place in the presence of catalytic amounts of naphthalene or 4,4'-di-tert-butyl-biphenyl.
3. Verfahren gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass das eingesetzte Keton ausgewählt ist aus der Gruppe Aceton, Methylvinylketon, ß-Ionon, Tetrahydrogeranylaceton, 6-Methylheptanon, Hexahydrofarnesylaceton, Diethylketon, Methylethylketon, Cyclohexanon, Methyl-t-butylketon, Pseudo- ionon, Methylhexenon, H-Geranylaceton. 3. The method according to claim 1 or 2, characterized in that the ketone used is selected from the group acetone, methyl vinyl ketone, β-ionone, tetrahydrogeranylacetone, 6-methylheptanone, hexahydrofarnesylacetone, diethyl ketone, methyl ethyl ketone, cyclohexanone, methyl t-butyl ketone, pseudo - ionone, methylhexenone, H-geranylacetone.
EP03792224A 2002-08-08 2003-07-23 Method for the production of acetylene alcohols Withdrawn EP1529024A1 (en)

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DE10236578 2002-08-08
DE10236578A DE10236578A1 (en) 2002-08-08 2002-08-08 Production of acetylene alcohols, useful in synthesis of compounds such as Vitamin A and astaxanthin, involves mono-ethynylation of ketone by reacting lithium with alkyl halide, adding acetylene gas and then adding ketone
PCT/EP2003/008045 WO2004018399A1 (en) 2002-08-08 2003-07-23 Method for the production of acetylene alcohols

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