EP1716087A1 - Process for c-c coupling between electrophilic substrates and pi-nucleophiles in neutral to basic acqueous or alcoholic solvents without the use of a lewis or proteic acid. - Google Patents

Process for c-c coupling between electrophilic substrates and pi-nucleophiles in neutral to basic acqueous or alcoholic solvents without the use of a lewis or proteic acid.

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Publication number
EP1716087A1
EP1716087A1 EP05701385A EP05701385A EP1716087A1 EP 1716087 A1 EP1716087 A1 EP 1716087A1 EP 05701385 A EP05701385 A EP 05701385A EP 05701385 A EP05701385 A EP 05701385A EP 1716087 A1 EP1716087 A1 EP 1716087A1
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Prior art keywords
compounds
solvent
substituted
reaction
neutral
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German (de)
French (fr)
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Herbert Mayr
Matthias Hofmann
Shinya Minegishi
Nathalie Hampel
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Saltigo GmbH
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Saltigo GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the invention relates to a method for carbon-carbon bond formation by 5 conversion of electrophilic substrates with a solvolysis rate k Et0H (25 ° C)> 10 "6 s " 1 and ⁇ compounds, characterized in that the intermediate carbocations in neutral to basic aqueous or alcoholic solvents or solvent mixtures are generated without the use of a Lewis acid or protonic acid.
  • Lewis acid (or proton acid) induced reactions of electrophiles e.g.
  • metal halides of the formula type MX n such as A1C1 3 , 25 AlBr 3 , BC1 3 , BF 3 , FeCl 3 , TiCl 4 , SnC, SbF 5 , GaCl 3 , ZnCl 2 ( GA Olah, S. Kobayashi, M. Tashiro, J. Am. Chem. Soc. 1972, 94, 7448.) or POCl 3 used in the Workup of the reaction batches can be irreversibly deactivated by hydrolysis.
  • MX n metal halides of the formula type MX n , such as A1C1 3 , 25 AlBr 3 , BC1 3 , BF 3 , FeCl 3 , TiCl 4 , SnC, SbF 5 , GaCl 3 , ZnCl 2 ( GA Olah, S. Kobayashi, M. Tashiro, J. Am. Chem. Soc. 1972, 94, 7448.)
  • Chlorinated hydrocarbons which have a low ability to coordinate with metal halides are frequently used as solvents. Since the Lewis acids 30 are sensitive to moisture, work is carried out with strict exclusion of moisture, which requires great preparative effort.
  • aqueous reaction media has gained great importance in synthetic organic chemistry. CC-linking reactions that are carried out in such solvents can be a great challenge (A. Lubineau, J. Ange, Y. Queneau, Synthesis 1994, 741-760; CJ Li, Chem. Rev. 1993, 93, 2923-2035.). Furthermore, better reactivities and selectivities are often achieved in aqueous media than under anhydrous conditions (S. Kobayashi, K. Manabe, Chem. Eur. J. 2002, 18, 4094-4101; S. Kobayashi, Eur. J. Org. Chem. 1999, 15-27.).
  • Substrates containing acid labile groups such as e.g. Alkyleneol ethers, silyl enol ethers, ketene acetals or enamines can be decomposed by Lewis or protonic acids.
  • the present invention is therefore based on the object of providing a process by which a carbon-carbon bond formation in the sense of a Friedel-Crafts or related reaction is accomplished without the use of a Lewis or protonic acid in non-chlorinated solvents and thus the A large number of additional substrates can be used under moderate reaction conditions, which offers significant ecological and economic advantages compared to the established synthesis options.
  • the relative rate of formation of carbocations can be given, among other things, using the ethanolysis constant k Et0H , ie the rate constant of solvolysis in 100% ethanol at 25 ° C.
  • This parameter has been used in particular to indicate the relative reactivity of alkyl halides, especially of chlorides or bromides.
  • k EtOH 25 ° C.
  • substituents R 1 , R 2 and R 3 on the compounds of type (I) with the specified minimum values of k Et0H which, however, do not constitute an exhaustive list, are substituents which are selected independently of one another from the group of branched or unbranched alkyl , preferably C 1 -C 4 alkyl, especially methyl, aryl, preferably C 6 -C 10 aryl, especially phenyl, substituted aryl, preferably by amino, alkoxy or alkyl substituents, especially 4-methoxyphenyl (anisyl) and 4-methylphenyl ( Tolyl), substituted or unsubstituted heteroaryl, in particular thiophene, furan and pyrrole, branched or unbranched alkenyl, preferably C 2 -C 0 -alkenyl, in particular 3-methylbut-2-enyl, cycloalk-2-enyl, preferably C 4 -C 7 cycloalk-2-eny
  • Halogen represents fluorine, chlorine, bromine or iodine, preferably chlorine and bromine.
  • a compilation of possible leaving groups is shown in list 1.1. List 1.1
  • Halogen ⁇ l . -Br, -ci, -F oxygen substituents -OCH 3 , -OC 2 H 5 , -OCH 2 Ph, -OCH 2 CH CH 2 , -OCH 2 CF 3 0 2 N 0 2 N -0 "@, -O - ⁇ - CI, -0 - ⁇ - N0 2> "0- ⁇ 0 2 ( -OH ⁇ ⁇ N0 2) -O ⁇ Q- oo OO II II II -OC-CH 3 , -0-CC ( CH 3 ) 3 , -OC-CF 3 , -0-CC 3 F 7
  • the ⁇ compounds which can be used as nucleophilic compounds in the process according to the invention are aliphatic ⁇ nucleophiles, such as e.g. substituted alkenes and alkynes, allyl and propargylsilanes, alkyleneol ethers, silylenol ethers, (silyl) ketene acetals and enamines, or aromatic ⁇ -nucleophiles such as e.g. donor-substituted aromatics, heteroaromatics, preferably substituted or unsubstituted furans, thiophenes, pyrroles or indoles.
  • aliphatic ⁇ nucleophiles such as e.g. substituted alkenes and alkynes, allyl and propargylsilanes, alkyleneol ethers, silylenol ethers, (silyl) ketene acetals and enamines, or aromatic
  • the ⁇ compounds used are used as solutions in a concentration range from 0.01 M to 20 M, preferably 0.1 M to 5 M, in particular 0.5 M to 2 M, in the solvents or solvent mixtures listed below.
  • the solvents or solvent mixtures used are or are composed of the group of alcohols, in particular ethanol, methanol, 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoroisopropanol, tetrahydrofuran, water, acetone, acetonitrile and dioxane.
  • acetone-water mixtures preferably 80% aqueous acetone (80A20W (v / v)), acetonitrile / water mixtures, preferably 90% aqueous acetonitrile (90AN10W (v / v)), or pure 2,2,2-trifluoroethanol for use.
  • the intermediate carbocation is captured in a rapid reaction by the corresponding solvent.
  • W water
  • T 2,2,2-trifluoroethanol
  • AN acetonitrile
  • A acetone.
  • the number in front of the respective solvent abbreviation corresponds to the quantity in%.
  • Basic inorganic and organic compounds were used as additives, preferably hydrogen carbonates, carbonates and pyridines, in particular ammonium hydrogen carbonate (NH HCO 3 ), sodium hydrogen carbonate (NaHCO 3 ), ammonium carbonate [(NH) 2 CO 3 ], 2-chloropyridine and 2,6 -Lutidin.
  • NH HCO 3 ammonium hydrogen carbonate
  • NaHCO 3 sodium hydrogen carbonate
  • 2-chloropyridine 2,6 -Lutidin.
  • reaction times are generally 1 second to 2 days, preferably 1 minute to 5 hours.
  • the course of the reaction can be followed, for example, with GCMS or NMR spectroscopic investigations.
  • the electrophile is added so slowly that the heat of reaction can be easily removed.
  • the reaction mixture is preferably stirred at room temperature (rt).
  • the same volume of water is added to the reaction mixture and the aqueous phase is extracted several times with diethyl ether.
  • the combined organic extracts are dried over a drying agent, preferably sodium sulfate or magnesium sulfate, and excess solvent is removed in vacuo.
  • the residues are subjected, for example, to distillation or chromatography on silica gel.
  • the syntheses can be carried out on a larger scale while maintaining the stoichiometry of the substances used.
  • the electrophile is added so slowly that the heat of reaction can be easily removed.
  • the reaction mixture is preferably stirred at room temperature (rt).
  • the same volume of water is added to the reaction mixture and the aqueous phase is extracted several times with diethyl ether.
  • the combined organic extracts are dried over a drying agent, preferably sodium sulfate or magnesium sulfate, and excess solvent is removed in vacuo.
  • the residues are subjected, for example, to distillation or chromatography on silica gel.
  • n H amount of substance electrophile
  • n Nu amount of substance nucleophile
  • Vs 0 i v + Nu total volume of the 1 molar solution of the nucleophile.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The invention relates to a method for establishing carbon-carbon bonds by reacting electropohilic substrates that have a solvolysis rate kEtOH (25°C) > 10<-6> s<-1> and pi compounds. The method is characterized by generating the intermediary carbocations in neutral to alkaline aqueous or alcoholic solvents or solvent mixtures without using a Lewis or Brönsted acid.

Description

VERFAHREN ZUR CC-BINDUNGSKNÜPFUNG ZWISCHEN ELEKTROPHILEN SUBSTRATEN UND PI-NUCLE OPHILEN IN NEUTRALEN BIS BASISCHEN WÄSSRIGEN ODER ALKOHOLISCHEN LÖSUNGSMITTELN 0 HNE DEN EINSATZ EINER LEWIS- ODER PROTONENSÄUREMETHOD FOR CC BINDING BETWEEN ELECTROPHILIC SUBSTRATES AND PI-NUCLE OPHILES IN NEUTRAL TO BASIC AQUEOUS OR ALCOHOLIC SOLVENTS 0 WITHOUT THE USE OF A LEWIS OR PROTONIC ACID
Die Erfindung betrifft ein Verfahren zur Kohlenstoff-Kohlenstoff-Bindungsknüpfung durch 5 Umsetzung von elektrophilen Substraten mit einer Solvolysegeschwindigkeit kEt0H (25 °C) > 10"6 s"1 und π- Verbindungen, dadurch gekennzeichnet, dass die intermediären Carbokationen in neutralen bis basischen wässrigen oder alkoholischen Lösungsmitteln oder Lösungsmittelgemischen erzeugt werden, ohne dass eine Lewissäure oder Protonensäure zum Einsatz kommt.The invention relates to a method for carbon-carbon bond formation by 5 conversion of electrophilic substrates with a solvolysis rate k Et0H (25 ° C)> 10 "6 s " 1 and π compounds, characterized in that the intermediate carbocations in neutral to basic aqueous or alcoholic solvents or solvent mixtures are generated without the use of a Lewis acid or protonic acid.
Lewis-Säure- (oder auch Protonen-Säure-) induzierte Umsetzungen von Elektrophilen, wie z.B.Lewis acid (or proton acid) induced reactions of electrophiles, e.g.
10 Alkylhalogeniden mit π-Verbindungen wie z.B. Arenen oder Heteroarenen (Friedel-Crafts- Alkylierungen: C. Friedel, J.M. Crafts, J. Chem. Soc. 1877, 32, 725; C.C. Price, Org. React. 1946, 3, 1-82; G.A. Olah, Friedel-Crafts and Related Reactions, Wiley, New York, 1963-1964, Bd. 1 und 2; R. Taylor, Electrophilic Aromatic Substitution, Wiley, New York, 1990, S. 187-203.), oder anderen ungesättigten Systemen stellen wichtige CC-verknüpfende Reaktionen zur Einführung von10 alkyl halides with π compounds such as Arenes or heteroarenes (Friedel-Crafts alkylations: C. Friedel, JM Crafts, J. Chem. Soc. 1877, 32, 725; CC Price, Org. React. 1946, 3, 1-82; GA Olah, Friedel-Crafts and Related Reactions, Wiley, New York, 1963-1964, Vol. 1 and 2; R. Taylor, Electrophilic Aromatic Substitution, Wiley, New York, 1990, pp. 187-203.), or other unsaturated systems represent important CC- linking reactions to the introduction of
15 Alkylsubstiruenten in Arene oder andere π-Systeme dar.15 alkyl substituents in arenes or other π systems.
Bei diesen häufig als Friedel-Crafts-, Hoaglin-Hirsch- (R.I. Hoaglin, D.H. Hirsch, J. Am. Chem. Soc. 1949, 71, 3468-3472.), Hosomi-Sakurai- (A. Hosomi, Acc. Chem. Res. 1988, 21, 200-206; I. Fleming, J. Dunogues, R. Smithers, The Electrophilic Substitution of Allylsilanes and Vinylsilanes, in: Organic Reactions, A. S. Kende (Hrsg.), Wiley, New York, 1989, Vol. 37, 57- 20 575.) oder Mukaiyama-Reaktionen (T. Mukaiyama, M. Murakami, Synthesis 1987, 1043-1054; R. Mahrwald, Chem. Rev. 1999, 99, 1095-1120; M.T. Reetz, W.F. Maier, H. Heimbach, Chem. Ber. 1980, 113, 3734-3740; M.T. Reetz, W.F. Maier, I. Chatziiosifidis, A. Giannis, H. Heimbach, U. Löwe, Chem. Ber. 1980, 113, 3741-3757.) bezeichneten Verfahren werden zur Aktivierung der elektrophilen Substrate üblicherweise Metallhalogenide des Formeltyps MXn, wie z.B. A1C13, 25 AlBr3, BC13, BF3, FeCl3, TiCl4, SnC , SbF5, GaCl3, ZnCl2 (G.A. Olah, S. Kobayashi, M. Tashiro, J. Am. Chem. Soc. 1972, 94, 7448.) oder POCl3 eingesetzt, die bei der Aufarbeitung der Reaktionsansätze durch Hydrolyse irreversibel desaktiviert werden.These are often called Friedel-Crafts-, Hoaglin-Hirsch- (RI Hoaglin, DH Hirsch, J. Am. Chem. Soc. 1949, 71, 3468-3472.), Hosomi-Sakurai- (A. Hosomi, Acc. Chem Res. 1988, 21, 200-206; I. Fleming, J. Dunogues, R. Smithers, The Electrophilic Substitution of Allylsilanes and Vinylsilanes, in: Organic Reactions, AS Kende (ed.), Wiley, New York, 1989, Vol. 37, 57-20575.) Or Mukaiyama reactions (T. Mukaiyama, M. Murakami, Synthesis 1987, 1043-1054; R. Mahrwald, Chem. Rev. 1999, 99, 1095-1120; MT Reetz, WF Maier, H. Heimbach, Chem. Ber. 1980, 113, 3734-3740; MT Reetz, WF Maier, I. Chatziiosifidis, A. Giannis, H. Heimbach, U. Löwe, Chem. Ber. 1980, 113, 3741- 3757.) are usually used to activate the electrophilic substrates, metal halides of the formula type MX n , such as A1C1 3 , 25 AlBr 3 , BC1 3 , BF 3 , FeCl 3 , TiCl 4 , SnC, SbF 5 , GaCl 3 , ZnCl 2 ( GA Olah, S. Kobayashi, M. Tashiro, J. Am. Chem. Soc. 1972, 94, 7448.) or POCl 3 used in the Workup of the reaction batches can be irreversibly deactivated by hydrolysis.
Als Lösungsmittel werden häufig chlorierte Kohlenwasserstoffe eingesetzt, die ein geringes Koordinierungsvermögen gegenüber Metallhalogeniden aufweisen. Da die Lewis-Säuren 30 feuchtigkeitsempfindlich sind, wird unter striktem Feuchtigkeitsausschluss gearbeitet, was großen präparativen Aufwand verursacht.Chlorinated hydrocarbons which have a low ability to coordinate with metal halides are frequently used as solvents. Since the Lewis acids 30 are sensitive to moisture, work is carried out with strict exclusion of moisture, which requires great preparative effort.
Der Einsatz von wässrigen Reaktionsmedien hat große Bedeutung in der synthetischen organischen Chemie erlangt. CC-verknüpfende Reaktionen, die in solchen Lösungsmitteln durchgeführt werden können, stellen hierbei eine große Herausforderung dar (A. Lubineau, J. Ange, Y. Queneau, Synthesis 1994, 741-760; C.J. Li, Chem. Rev. 1993, 93, 2923-2035.). Desweiteren werden in wässrigen Medien oft bessere Reaktivitäten und Selektivitäten erzielt als unter wasserfreien Bedingungen (S. Kobayashi, K. Manabe, Chem. Eur. J. 2002, 18, 4094-4101; S. Kobayashi, Eur. J. Org. Chem. 1999, 15-27.).The use of aqueous reaction media has gained great importance in synthetic organic chemistry. CC-linking reactions that are carried out in such solvents can be a great challenge (A. Lubineau, J. Ange, Y. Queneau, Synthesis 1994, 741-760; CJ Li, Chem. Rev. 1993, 93, 2923-2035.). Furthermore, better reactivities and selectivities are often achieved in aqueous media than under anhydrous conditions (S. Kobayashi, K. Manabe, Chem. Eur. J. 2002, 18, 4094-4101; S. Kobayashi, Eur. J. Org. Chem. 1999, 15-27.).
Die Anwendungsbreite von Friedel-Crafts-Reaktionen ist aus einer Vielzahl von Gründen begrenzt.The scope of Friedel-Crafts reactions is limited for a variety of reasons.
Viele Heteroaromaten eignen sich nicht für die Friedel-Crafts-Alkylierung. Weiterhin stören auch zahlreiche funktionelle Gruppen wie -OH, -OR, -NH2, -NR2, die von der Lewis-Säure komplexiert werden, den Reaktionsverlauf (T. Laue, A. Piagens, Namens- und Schlagwort-Reaktionen der organischen Chemie, Teubner, Stuttgart, 1994, S. 128-132.).Many heteroaromatics are not suitable for Friedel-Crafts alkylation. Furthermore, numerous functional groups such as -OH, -OR, -NH 2 , -NR 2 , which are complexed by the Lewis acid, interfere with the course of the reaction (T. Laue, A. Piagens, name and keyword reactions in organic chemistry , Teubner, Stuttgart, 1994, pp. 128-132.).
Beim Einsatz von Alkoholen als Elektrophile ist in einigen Fällen bekannt, dass Lewis-Säuren durch Protonen-Säuren, insbesondere H2SO oder HF, ersetzt werden können. Jedoch ergeben sich vor allem beim Einsatz von HF erhebliche Nachteile. HF ist stark giftig und korrosiv.When alcohols are used as electrophiles, it is known in some cases that Lewis acids can be replaced by protonic acids, in particular H 2 SO or HF. However, there are considerable disadvantages, especially when using HF. HF is very toxic and corrosive.
Substrate, die säurelabile Gruppen, wie z.B. Alkylenolether, Silylenolether, Ketenacetale oder Enamine beinhalten, können durch Lewis- oder Protonensäuren zersetzt werden.Substrates containing acid labile groups such as e.g. Alkyleneol ethers, silyl enol ethers, ketene acetals or enamines can be decomposed by Lewis or protonic acids.
Der vorliegenden Erfindung liegt daher die Aufgabe zugrunde, ein Verfahren bereitzustellen, durch welches eine Kohlenstoff-Kohlenstoff-Bindungsknüpfung im Sinne einer Friedel-Crafts- oder dazu verwandten Reaktion ohne die Verwendung einer Lewis- oder Protonen-Säure in nichtchlorierten Lösungsmitteln bewerkstelligt wird und somit den Einsatz einer Vielzahl zusätzlicher Substrate unter moderaten Reaktionsbedingungen erlaubt, was gegenüber den etablierten Synthesemöglichkeiten prägnante ökologische und ökonomische Vorteile bietet.The present invention is therefore based on the object of providing a process by which a carbon-carbon bond formation in the sense of a Friedel-Crafts or related reaction is accomplished without the use of a Lewis or protonic acid in non-chlorinated solvents and thus the A large number of additional substrates can be used under moderate reaction conditions, which offers significant ecological and economic advantages compared to the established synthesis options.
Diese Aufgabe wird gelöst durch den Einsatz von Verbindungen des allgemeinen Formeltyps (I),This object is achieved by using compounds of the general formula type (I),
welche Solvolysegeschwindigkeiten von kEt0H > 10' s" (25 °C) aufweisen.which have solvolysis speeds of k Et0H > 10 ' s " (25 ° C).
Die relative Bildungsgeschwindigkeit von Carbokationen kann u.a. mit Hilfe der Ethanolyse- konstante kEt0H, d.h. der Geschwindigkeitskonstante der Solvolyse in 100 % Ethanol bei 25°C angegeben werden. Insbesondere zur Angabe der relativen Reaktivität von Alkylhalogeniden, vor allem von Chloriden oder Bromiden, ist diese Bestimmungsgröße herangezogen worden. Die entsprechenden Werte für kEtOH (25°C) können zahlreichen Veröffentlichungen (J.-P. Dau-Sch idt, H. Mayr, Chem. Ber. 1994, 127, 205-212; Dissertation J.-P. Dau-Schmidt, Medizinische Universität zu Lübeck 1992; P. Vogel, Carbocation Chemistry, Elsevier, Amsterdam, 1985, Kapitel 7; G.A. Olah, P. von R. Schleyer, Carbonium Ions, Vol. 1-5, Interscience, New York, 1968-1976; X. Creary, Advances in Carbocation Chemistry, Vol. 1, JAI, Greenwich, CT, 1989; J.M. Coxon, Advances in Carbocation Chemistry, Vol. 2, JAI, Greenwich, CT, 1995.) entnommen werden. Zur Bestimmung weiterer Solvolyse-geschwindigkeiten kann das bei Winstein und Grunwald (E. Grunwald, S. Winstein, J. Am. Chem. Soc. 1948, 70, 846-854; S. Winstein, E. Grunwald, H.W. Jones, J. Am. Chem. Soc. 1951, 73, 2700-2707.) beschriebene Verfahren verwendet werden.The relative rate of formation of carbocations can be given, among other things, using the ethanolysis constant k Et0H , ie the rate constant of solvolysis in 100% ethanol at 25 ° C. This parameter has been used in particular to indicate the relative reactivity of alkyl halides, especially of chlorides or bromides. The corresponding values for k EtOH (25 ° C.) can be found in numerous publications (J.-P. Dau-Sch idt, H. Mayr, Chem. Ber. 1994, 127, 205-212; dissertation J.-P. Dau-Schmidt , Medical University of Lübeck 1992; P. Vogel, Carbocation Chemistry, Elsevier, Amsterdam, 1985, Chapter 7; GA Olah, P. von R. Schleyer, Carbonium Ions, Vol. 1-5, Interscience, New York, 1968-1976 ; X. Creary, Advances in Carbocation Chemistry, Vol. 1, JAI, Greenwich, CT, 1989; JM Coxon, Advances in Carbocation Chemistry, Vol. 2, JAI, Greenwich, CT, 1995.). To determine further solvolysis rates, Winstein and Grunwald (E. Grunwald, S. Winstein, J. Am. Chem. Soc. 1948, 70, 846-854; S. Winstein, E. Grunwald, HW Jones, J. Methods described in Chem. Soc. 1951, 73, 2700-2707.) Can be used.
Beispiele für die Substituenten R1, R2 und R3 an den Verbindungen des Typs (I) mit den angegebenen Mindestwerten an kEt0H, die jedoch keine erschöpfende Aufzählung darstellen, sind Substituenten, die unabhängig voneinander gewählt sind aus der Gruppe verzweigtes oder unverzweigtes Alkyl, vorzugsweise Cι-C4 Alkyl, insbesondere Methyl, Aryl, vorzugsweise C6-C10- Aryl, insbesondere Phenyl, substituiertes Aryl, vorzugsweise durch Amino-, Alkoxy- oder Alkylsubstiruenten, insbesondere 4-Methoxyphenyl (Anisyl) und 4-Methylphenyl (Tolyl), substituiertes oder unsubstituiertes Heteroaryl, insbesondere Thiophen, Furan und Pyrrol, verzweigtes oder unverzweigtes Alkenyl, vorzugsweise C2-Cι0-Alkenyl, insbesondere 3-Methylbut-2-enyl, Cycloalk-2-enyl, vorzugsweise C4-C7-Cycloalk-2-enyl, insbesondere Cyclopent-2-enyl und Cyclohex-2-enyl, Cyclo-, Bicyclo- und Tricycloalkyl, vorzugsweise C3-C8- Cycloalkyl und C5-C8-Bicyclo- und Tricycloalkyl, Alkoxy, vorzugsweise Methoxy, Ethoxy, Aryloxy oder Wasserstoff. Desweiteren können zwei der Reste R1, R2 und R3 einen Alkylring bilden, vorzugsweise C3-C8-Cycloalkyl und C5-C8-Bicyclo- und Tricycloalkyl.Examples of the substituents R 1 , R 2 and R 3 on the compounds of type (I) with the specified minimum values of k Et0H , which, however, do not constitute an exhaustive list, are substituents which are selected independently of one another from the group of branched or unbranched alkyl , preferably C 1 -C 4 alkyl, especially methyl, aryl, preferably C 6 -C 10 aryl, especially phenyl, substituted aryl, preferably by amino, alkoxy or alkyl substituents, especially 4-methoxyphenyl (anisyl) and 4-methylphenyl ( Tolyl), substituted or unsubstituted heteroaryl, in particular thiophene, furan and pyrrole, branched or unbranched alkenyl, preferably C 2 -C 0 -alkenyl, in particular 3-methylbut-2-enyl, cycloalk-2-enyl, preferably C 4 -C 7 cycloalk-2-enyl, in particular, cyclopent-2-enyl and cyclohex-2-enyl, cyclo, bicyclo-, and tricycloalkyl, C preferably 3 -C 8 - cycloalkyl, and C 5 -C 8 -bicyclo- and tricycloalkyl, alkoxy, preferably methoxy , Ethoxy, aryloxy or hydrogen. Furthermore, two of the radicals R 1 , R 2 and R 3 can form an alkyl ring, preferably C 3 -C 8 cycloalkyl and C 5 -C 8 bicyclo and tricycloalkyl.
X entspricht einer durch die angegebene Solvolysegeschwindigkeit vorgegebenen Abgangsgruppe; insbesondere ist X = Halogen, Alkoxy, vorzugsweise Methoxy, Ethoxy, und Benzyloxy, Alkyl- oder Arylsulfonato, insbesondere Methansulfonato, Trifluormethansulfonato, Benzolsulfonato, p- Toluolsulfonato; es kann aber auch gewählt sein aus der Gruppe substitu-iertes oder unsubstituiertes Phenoxy, Acyloxy, Benzoyloxy, Carbamoyl, Alkyloxycarbonyloxy, Aryloxycarbonyloxy, Siloxy, insbesondere Trimethylsiloxy, Phosphato, Phosphonato, Hypophosphonato, Alkylperoxy, Sulfato, Sulfenyl, Sulfonyl, S-Alkylsulfoxy, S-Arylsulfoxy, Alkylthio, Arylthio, Thiocyanato, Isothiocyanato, Ureato und Imidyl. Synthetisch leicht zugänglich und als sehr effektiv erwiesen haben sich Verbindungen mit X = Halogen. Halogen steht für Fluor, Chlor, Brom oder Iod, bevorzugt für Chlor und Brom. Eine Zusammenstellung möglicher Abgangsgruppen zeigt Aufstellung 1.1. Aufstellung 1.1X corresponds to a leaving group given by the stated solvolysis speed; in particular, X = halogen, alkoxy, preferably methoxy, ethoxy, and benzyloxy, alkyl or aryl sulfonato, especially methanesulfonato, trifluoromethanesulfonato, benzenesulfonato, p-toluenesulfonato; but it can also be selected from the group of substituted or unsubstituted phenoxy, acyloxy, benzoyloxy, carbamoyl, alkyloxycarbonyloxy, aryloxycarbonyloxy, siloxy, especially trimethylsiloxy, phosphato, phosphonato, hypophosphonato, alkylperoxy, sulfato, sulfenyl, sulfonyl, S-alkylsulfoxy, S -Arylsulfoxy, alkylthio, arylthio, thiocyanato, isothiocyanato, urea and imidyl. Compounds with X = halogen have proven to be easily accessible synthetically and have been very effective. Halogen represents fluorine, chlorine, bromine or iodine, preferably chlorine and bromine. A compilation of possible leaving groups is shown in list 1.1. List 1.1
Halogen ~l . -Br , -ci , -F Sauerstoff-Substituenten -OCH3 , -OC2H5 , -OCH2Ph , -OCH2CH=CH2 , -OCH2CF3 02N 02N -0"@ , -O-^-CI , -0-^-N02 > "0-^ 02 ( -OHÖ~N02 ) -O→Q- o o O O II II II II -O-C-CH3 , -0-C-C(CH3)3 , -O-C-CF3 , -0-C-C3F7 Halogen ~ l . -Br, -ci, -F oxygen substituents -OCH 3 , -OC 2 H 5 , -OCH 2 Ph, -OCH 2 CH = CH 2 , -OCH 2 CF 3 0 2 N 0 2 N -0 "@, -O - ^ - CI, -0 - ^ - N0 2> "0- ^ 0 2 ( -OHÖ ~ N0 2) -O → Q- oo OO II II II II -OC-CH 3 , -0-CC ( CH 3 ) 3 , -OC-CF 3 , -0-CC 3 F 7
. 0 O O O 11 II II O-C-NMe, , , -o-c -NH, -O-C-NHPh -O-C-NPh, O O O O O II II II II II -O-C-OMe , -O-C-O.Bu , -O-C-OPh , -O-C-OBn , -O-C-OAc NH II -O-C-CCL , 0 OOO 11 II II OC-NMe,,, -oc -NH, -OC-NHPh -OC-NPh, OOOOO II II II II II -OC-OMe, -OCO.Bu, -OC-OPh, -OC-OBn , -OC-OAc NH II -OC-CCL
-OSi e, , -OSi e2.Bu , -OSiPh3 , -OSi(OEt), , -OSiMe.Ph , -OSi(i-Pr).-OSi e,, -OSi e 2 .Bu, -OSiPh 3 , -OSi (OEt),, -OSiMe.Ph, -OSi (i-Pr).
-0-N=0 , -0-N02 , -0-N=NAr 0 0 O 0 0 11 _ 11 11 11 11 -O-P-0 -O-P-OMe -O-P-OMe -O-P-O-P-0 1 ' 1 > 1 ' I I - 0_ 0_ OMe 0_ 0_ O O O O O II II II II II -O-P-Me -O-P-Ph -O-P-Me -O-P-Me -O-P-Ph -O-P(OEt), OEt OMe Me Ph Ph -O-OfBu-0-N = 0, -0-N0 2 , -0-N = NAr 0 0 O 0 0 11 _ 11 11 11 11 -OP-0 -OP-OMe -OP-OMe -OPOP-0 1 '1> 1 'II - 0_ 0_ OMe 0_ 0_ OOOOO II II II II II -OP-Me -OP-Ph -OP-Me -OP-Me -OP-Ph -OP (OEt), OEt OMe Me Ph Ph -O-OfBu
0 0 0 0 0 II II II II II -O-S-Me , -O-S-Et , -O-S-CH,0F3 , -O-S-CF, , -0-S-C,F„ II II ' II 2 3 II 3 ' II 4 9 0 0 0 O O 0 0 0 0 0 II II II II II -0-S-O e , -0-S-OEt , -0-S-NMe2 , -O-S-Ph , -O-S-Et II ' II ' II 2 O O O Stic stoff-Substituenten0 0 0 0 0 II II II II II -OS-Me, -OS-Et, -OS-CH, 0F 3 , -OS-CF,, -0-SC, F „II II 'II 2 3 II 3 ' II 4 9 0 0 0 OO 0 0 0 0 0 II II II II II -0-SO e, -0-S-OEt, -0-S-NMe 2 , -OS-Ph, -OS-Et II 'II' II 2 OOO Stic substance substituents
^ Θ _Θ TΘ -N-C≡N , -N=N=NI , -NO , -N02 , -N=S-Me O -NR3 mit R = Alkyl ^ Θ _Θ T Θ -NC≡N, -N = N = NI, -NO, -N0 2 , -N = S-Me O -NR 3 with R = alkyl
Die bei dem Verfahren erfindungsgemäß als nucleophile Verbindungen einsetzbaren π- Verbindungen sind aliphatische π-Nucleophile, wie z.B. substituierte Alkene und Alkine, Allyl- und Propargylsilane, Alkylenolether, Silylenolether, (Silyl-) Ketenacetale und Enamine, oder aromatische π-Nucleophile, wie z.B. donorsubstituierte Aromaten, Heteroaromaten, vorzugsweise substituierte oder unsubstituierte Furane, Thiophene, Pyrrole oder Indole.The π compounds which can be used as nucleophilic compounds in the process according to the invention are aliphatic π nucleophiles, such as e.g. substituted alkenes and alkynes, allyl and propargylsilanes, alkyleneol ethers, silylenol ethers, (silyl) ketene acetals and enamines, or aromatic π-nucleophiles such as e.g. donor-substituted aromatics, heteroaromatics, preferably substituted or unsubstituted furans, thiophenes, pyrroles or indoles.
Die eingesetzten π-Verbindungen werden als Lösungen in einem Konzentrationsbereich von 0.01 M bis 20 M, vorzugsweise 0.1 M bis 5 M, insbesondere 0.5 M bis 2 M in den nachfolgend aufgeführten Lösungsmitteln oder Lösungsmittelgemischen eingesetzt.The π compounds used are used as solutions in a concentration range from 0.01 M to 20 M, preferably 0.1 M to 5 M, in particular 0.5 M to 2 M, in the solvents or solvent mixtures listed below.
Die eingesetzten Lösungsmittel oder Lösungsmittelgemische sind oder setzen sich zusammen aus der Gruppe Alkohole, insbesondere Ethanol, Methanol, 2,2,2-Trifluorethanol oder 1,1,1,3,3,3- Hexafluoroisopropanol, Tetrahydrofüran, Wasser, Aceton, Acetonitril und Dioxan.The solvents or solvent mixtures used are or are composed of the group of alcohols, in particular ethanol, methanol, 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoroisopropanol, tetrahydrofuran, water, acetone, acetonitrile and dioxane.
Insbesondere kommen Aceton Wasser-Mischungen, vorzugsweise 80 % wässriges Aceton (80A20W (v/v)), Acetonitril/Wasser-Mischungen, vorzugsweise 90 % wässriges Acetonitril (90AN10W (v/v)), oder reines 2,2,2-Trifluorethanol zum Einsatz.In particular come acetone-water mixtures, preferably 80% aqueous acetone (80A20W (v / v)), acetonitrile / water mixtures, preferably 90% aqueous acetonitrile (90AN10W (v / v)), or pure 2,2,2-trifluoroethanol for use.
Die Solvolyse von Verbindungen des Typs (I) in den oben angeführten Lösungsmitteln oder Lösungsmittelgemischen folgt dem Reaktionsschema gemäß Fig. 1, wobei SOH die nucleophile Komponente in einem der verwendeten Lösungsmitteln ist: Es wurden zahllose Untersuchungen über Geschwindigkeiten und Produkte von SN1 -Reaktionen durchgeführt (J.-P. Dau-Schmidt, H. Mayr, Chem. Ber. 1994, 127, 205-212; Dissertation J.-P. Dau- Schmidt, Medizinische Universität zu Lübeck 1992; P. Vogel, Carbocation Chemistry, Elsevier, Amsterdam, 1985, Kapitel 7; G.A. Olah, P. von R. Schleyer, Carbonium Ions, Vol. 1-5, Interscience, New York, 1968-1976; X. Creary, Advances in Carbocation Chemistry, Vol. 1, JAI, Greenwich, CT, 1989; J.M. Coxon, Advances in Carbocation Chemistry, Vol. 2, JAI, Greenwich, CT, 1995.). Ein beträchtlicher Teil der Kenntnisse über den Zusammenhang zwischen Slruktur und Reaktivität von Carbokationen (R1R2R3C+), den Zwischenstufen dieser Reaktionen, wurde aus Solvolyse-Studien abgeleitet.The solvolysis of compounds of type (I) in the solvents or solvent mixtures mentioned above follows the reaction scheme according to FIG. 1, where SOH is the nucleophilic component in one of the solvents used: Countless studies have been carried out on the speeds and products of S N 1 reactions (J.-P. Dau-Schmidt, H. Mayr, Chem. Ber. 1994, 127, 205-212; dissertation J.-P. Dau-Schmidt , Medical University of Lübeck 1992; P. Vogel, Carbocation Chemistry, Elsevier, Amsterdam, 1985, Chapter 7; GA Olah, P. von R. Schleyer, Carbonium Ions, Vol. 1-5, Interscience, New York, 1968-1976 ; X. Creary, Advances in Carbocation Chemistry, Vol. 1, JAI, Greenwich, CT, 1989; JM Coxon, Advances in Carbocation Chemistry, Vol. 2, JAI, Greenwich, CT, 1995.). Much of the knowledge about the relationship between structure and reactivity of carbocations (R 1 R 2 R 3 C + ), the intermediate stages of these reactions, has been derived from solvolysis studies.
Im zweiten Reaktionsschritt des Reaktionsschemas gemäß Fig. 1 wird in einer schnellen Reaktion das intermediär gebildete Carbokation durch das entsprechende Lösungsmittel abgefangen.In the second reaction step of the reaction scheme according to FIG. 1, the intermediate carbocation is captured in a rapid reaction by the corresponding solvent.
Nach Meinung der Fachwelt sind solche Abfangreaktionen durch Lösungsmittel zu schnell, als dass eine Reaktion zwischen dem intermediär generierten Carbokation und einem eventuell anwesenden π-Nucleophil stattfinden könnte.In the opinion of the experts, such trapping reactions by solvents are too rapid for a reaction between the intermediately generated carbocation and a possibly present π-nucleophile to take place.
Lediglich im speziellen Beispiel des α-(N,N-Dimethylthiocarbamoyl)-4-methoxybenzylkations wurde im Rahmen mechanistischer Untersuchungen gezeigt, dass dieses Intermediat durch π- Nucleophile, die durch N > 6 der Mayr-Skala gekennzeichnet sind, abgefangen werden kann, wenn es solvolytisch in 50 % wässrigem Acetonitril (50AN50W (v/v)) erzeugt wird. Da Nucleophilie- Parameter für Lösungsmittel damals nicht zur Verfügung standen, konnte diese Beobachtung nicht verallgemeinert werden. Weder war es erkennbar, dass dies auch für andere Typen von Carbokationen gelten muss, noch konnten Konsequenzen für die Organische Synthese gezogen werden. Seit der von Richard zitierten Veröffentlichung von Mayr (Angew. Chem. 1994, 106, 990- 1010.) wurden für zahlreiche weitere π-Systeme die Nucleophilie-Parameter N und s publiziert (H. Mayr, B. Kempf, A.R. Ofial, Acc. Chem. Res. 2003, 36, 66-77; B. Kempf, N. Hampel, A.R. Ofial, H. Mayr, Chem. Eur. J. 2003, 9, 2209-2218.). Für zahlreiche nucleophile π-Systeme können die Werte N und s diesen Veröffentlichungen entnommen werden.Only in the specific example of the α- (N, N-dimethylthiocarbamoyl) -4-methoxybenzyl cation was it shown in mechanistic studies that this intermediate can be intercepted by π-nucleophiles, which are characterized by N> 6 of the Mayr scale, if it is solvolytically generated in 50% aqueous acetonitrile (50AN50W (v / v)). Since nucleophilicity parameters for solvents were not available at the time, this observation could not be generalized. It was not apparent that this must also apply to other types of carbocation, nor could any consequences be drawn for organic synthesis. Since the Mayr publication cited by Richard (Angew. Chem. 1994, 106, 990-1010.), the nucleophilicity parameters N and s have been published for numerous other π systems (H. Mayr, B. Kempf, AR Ofial, Acc Chem. Res. 2003, 36, 66-77; B. Kempf, N. Hampel, AR Ofial, H. Mayr, Chem. Eur. J. 2003, 9, 2209-2218.). For numerous nucleophilic π systems, the values N and s can be found in these publications.
Der Durchbruch zu der nun vorliegenden Erfindung kam dadurch zustande, dass mit Hilfe photometrischer Messungen durch konventionelle UV-Vis-Spektroskopie, Stopped-Flow- Methoden und Laser-Flash-Techniken jetzt auch N- und s-Parameter für die erfϊndungsgemäß verwendeten Lösungsmittel und Lösungsmittelgemische ermittelt werden konnten (Tab. 1). Tab. 1The breakthrough to the present invention came about in that with the help of photometric measurements using conventional UV-Vis spectroscopy, stopped-flow methods and laser flash techniques, N and s parameters for the solvents and solvent mixtures used according to the invention are now also available could be determined (Tab. 1). Tab. 1
Solvens a N s W 5.20 0.89 91W9AN 5.16 0.91 80W20AN 5.04 0.89 67W33AN 5.05 0.90 50W50AN 5.05 0.89 33W67AN 5.02 0.90 20W80AN 5.02 0.89 10W90AN 4.56 0.94 20W80A 5.77 0.87 10W90A 5.70 0.85 T 1.23 0.92 90T10W 2.93 0.88 80T20W 3.20 0.88 60T40W 3.42 0.90 50T50W 3.57 0.89 40T60W 3.77 0.88 20T80W 4.78 0.83 10T90W 5.04 0.90 E 7.44 0.90 90E10W 7.03 0.86 80E20W 6.68 0.85 60E40W 6.28 0.87 50E50W 5.96 0.89 40E60W 5.81 0.90 20E80W 5.54 0.94 Solvens a N s 10E90W 5.38 0.91 91E9AN 7.10 0.90 80E20AN 6.94 0.90 67E33AN 6.74 0.89 50E50AN 6.37 0.90 33E67AN 6.06 0.90 20E80AN 5.77 0.92 10E90AN 5.19 0.96 M 7.54 0.92 91M9AN 7.45 0.87 80M20AN 7.20 0.89 67M33AN 7.01 0.91 50M50AN 6.67 0.90 33M67AN 6.38 0.92 20M80AN 6.04 0.94 10M90AN 5.55 0.97Solvens a N s W 5.20 0.89 91W9AN 5.16 0.91 80W20AN 5.04 0.89 67W33AN 5.05 0.90 50W50AN 5.05 0.89 33W67AN 5.02 0.90 20W80AN 5.02 0.89 10W90AN 4.56 0.94 20W80A 5.77 0.87 10W90A 5.70 0.85 T 1.23 0.92 90T10W 2.40 0.8TW 0.85T03.350 0.85T05.350 0.85T05.35 3.77 0.88 20T80W 4.78 0.83 10T90W 5.04 0.90 E 7.44 0.90 90E10W 7.03 0.86 80E20W 6.68 0.85 60E40W 6.28 0.87 50E50W 5.96 0.89 40E60W 5.81 0.90 20E80W 5.54 0.94 Solvents a N s 10E90W 5.38 0.91 91E9AN 7.10 0.90 80E20AN 6.94 0.90 67E33AN 6.74 0.89 50E50AN 6.37 0.90 33E67AN 6.06 0.90 20E80AN 5.77 0.92 10E90AN 5.19 0.96 M 7.54 0.92 91M9AN 7.45 0.87 80M20AN 7.20 0.89 67M33ANM 0.9AN 6.38 0.90 5.55 0.97
a Lösungsmittelgemische sind in Vol-% angegeben (v/v): M = Methanol, E = Ethanol, a Solvent mixtures are given in vol% (v / v): M = methanol, E = ethanol,
W = Wasser, T = 2,2,2-Trifluorethanol, AN = Acetonitril, A = Aceton. Die Zahl vor dem jeweiligen Lösungsmittelkürzel entspricht der Mengenangabe in %.W = water, T = 2,2,2-trifluoroethanol, AN = acetonitrile, A = acetone. The number in front of the respective solvent abbreviation corresponds to the quantity in%.
Zudem wurden durch Korrelation der von der Arbeitsgruppe Mayr erhaltenen N-Werte mit den Nucleophilie-Werten Nτ, die von der Arbeitsgruppe Kevill (Advances in Quantitative Structure- Property Relationships, Vol. 1, Charton, M. ed., JAI Press, Greenwich, Conneticut, 1996, 81-115) aus Solvolysegeschwmdigkeiten von Methylsulfoniumionen ermittelt wurden, Näherungswerte für zahlreiche weitere Lösungsmittel und Lösungsmittelgemische bestimmt (Tabelle 2). Tab. 2 a Nτ b Nc 70E30W -0.20 6.48 d 30E70W -0.93 5.68 d 95A5W -0.49 6.05 70A30W -0.42 6.16 60A40W -0.52 6.00 50A50W -0.70 5.73 40A60W -0.83 5.54 30A70W -0.96 5.34 20A80W -1.11 5.11 10A90W -1.23 4.93 80D20W -0.46 6.10 70D30W -0.37 6.23 60D40W -0.54 5.97 50D50W -0.66 5.79 40D60W -0.84 5.52 20D80W -1.12 5.10 97T3W e -3.30 1.81 80T20W e -2.19 3.48 80T20E -1.76 4.13 60T40E -0.94 5.37 50T50E -0.64 5.82 40T60E -0.34 6.28 20T80E 0.08 6.91 97H3W e -5.26 -1.15 90H10W e -3.84 0.99 70H30W 6 -2.94 2.35 50H50W e -2.49 3.03 a Lösungsmittelgemische sind in Vol-% angegeben (v/v): M = Methanol, E = Ethanol, W = Wasser, T = 2,2,2-Trifluorethanol, A = Aceton, D = Dioxan, H = l,l,l,3,3,3-Hexafluoro-2- propanol. b Nτ-Werte von Kevill. c Für diese Lösungsmittel (-gemische) wird ein typischer s-Parameter von 0.9 vorgeschlagen. d interpolierter Wert. e Lösungsmittel (-gemische) in Gew.-%.In addition, by correlating the N values obtained by the Mayr group with the nucleophilicity values N τ by the Kevill group (Advances in Quantitative Structure-Property Relationships, Vol. 1, Charton, M. ed., JAI Press, Greenwich , Connecticut, 1996, 81-115) were determined from the solvolysis rates of methylsulfonium ions, approximate values for numerous other solvents and solvent mixtures were determined (Table 2). Tab. 2 a N τ b N c 70E30W -0.20 6.48 d 30E70W -0.93 5.68 d 95A5W -0.49 6.05 70A30W -0.42 6.16 60A40W -0.52 6.00 50A50W -0.70 5.73 40A60W -0.83 5.54 30A70W -0.96 5.34 20A80A -1.11 5 4.93 80D20W -0.46 6.10 70D30W -0.37 6.23 60D40W -0.54 5.97 50D50W -0.66 5.79 40D60W -0.84 5.52 20D80W -1.12 5.10 97T3W e -3.30 1.81 80T20W e -2.19 3.48 80T20E -1.76 4.13 60T40E -0.3.35 5.30 6.28 20T80E 0.08 6.91 97H3W e -5.26 -1.15 90H10W e -3.84 0.99 70H30W 6 -2.94 2.35 50H50W e -2.49 3.03 a Solvent mixtures are given in vol% (v / v): M = methanol, E = ethanol, W = water, T = 2,2,2-trifluoroethanol, A = acetone, D = dioxane, H = l, l, 1,3,3,3-hexafluoro-2-propanol. b N τ values from Kevill. c A typical s parameter of 0.9 is suggested for these solvents (mixtures). d interpolated value. e Solvents (mixtures) in% by weight.
Mit diesen neu ermittelten Parametern ist es nun möglich, die Nucleophilie der erfindungsgemäß eingesetzten Lösungsmittel und Lösungsmittelgemische der Nucleophilie von typischen π-Systemen gegenüberzustellen (vgl. Fig. 2).With these newly determined parameters it is now possible to compare the nucleophilicity of the solvents and solvent mixtures used according to the invention with the nucleophilicity of typical π systems (cf. FIG. 2).
Vergleich der Nucleophilie-Parameter N von Lösungsmitteln (-gemischen) mit N- Parametern typischer π-Systeme; Lösungsmittelgemische sind in Nol.-% angegeben (v/v): M = Methanol, E = Ethanol, W = Wasser, T = 2,2,2-Trifluorethanol, AN = Acetonitril, H = l,l,l,3,3,3-Hexafluoro-2-propanol (weitere Lösungsmittel können den Tab. 1 und 2 entnommen werden).Comparison of the nucleophilicity parameters N of solvents (mixtures) with N parameters of typical π systems; Solvent mixtures are given in% by volume (v / v): M = methanol, E = ethanol, W = water, T = 2,2,2-trifluoroethanol, AN = acetonitrile, H = l, l, l, 3, 3,3-Hexafluoro-2-propanol (further solvents can be found in Tables 1 and 2).
Wenn das fragliche π-System in Fig. 2 oberhalb des jeweiligen Lösungsmittels steht, ist es in der Lage, ein in diesem Lösungsmittel generiertes Carbokation abzufangen. Da die N-Parameter von π- Systemen durch Lösungsmitteleffekte etwas verändert werden, können auch π-Systeme, die in Fig. 2 um bis zu zwei Einheiten unterhalb des jeweiligen Lösungsmittels stehen, die intermediären Carbokationen abfangen.If the π system in question is above the respective solvent in FIG. 2, it is able to trap a carbocation generated in this solvent. Since the N parameters of π systems are changed somewhat by solvent effects, π systems which are up to two units below the respective solvent in FIG. 2 can also intercept the intermediate carbocations.
Bevorzugterweise wurden in dem beanspruchten Verfahren Lösungen von π-Systemen eingesetzt, deren N-Parameter größer als der des jeweils verwendeten Lösungsmittels oder Lösungs- mittelgemisches ist.Solutions of π systems whose N parameters are greater than that of the solvent or solvent mixture used in each case were preferably used in the claimed process.
Vor der Zugabe der Elektrophile der allgemeinen Formel (I) wurden den Lösungen evtl. noch basische Zuschläge zugesetzt, welche die entstehenden Säuren HX (X ist vorzugsweise Halogen, insbesondere Chlor oder Brom) abfangen, die bei den Reaktionen als Nebenprodukte entstehen.Before the addition of the electrophiles of the general formula (I), basic additives were possibly added to the solutions, which intercept the acids HX (X is preferably halogen, in particular chlorine or bromine) which are formed as by-products in the reactions.
Als Zuschläge wurden basische anorganische sowie organische Verbindungen eingesetzt, vorzugsweise Hydrogencarbonate, Carbonate und Pyridine, insbesondere Ammonium- hydrogencarbonat (NH HCO3), Natriumhydrogencarbonat (NaHCO3), Ammoniumcarbonat [(NH )2CO3], 2-Chlorpyridin und 2,6-Lutidin. Die Wahl des Zuschlags wurde im jeweiligen Fall durch Vergleichsexperimente bestimmt.Basic inorganic and organic compounds were used as additives, preferably hydrogen carbonates, carbonates and pyridines, in particular ammonium hydrogen carbonate (NH HCO 3 ), sodium hydrogen carbonate (NaHCO 3 ), ammonium carbonate [(NH) 2 CO 3 ], 2-chloropyridine and 2,6 -Lutidin. The choice of surcharge was determined in each case by comparative experiments.
Die Reaktionszeiten betragen im Allgemeinen 1 Sekunde bis 2 Tage, bevorzugt 1 Minute bis 5 Stunden. Der Verlauf der Reaktion kann beispielsweise mit GCMS- oder NMR-spektroskopischen Untersuchungen verfolgt werden.The reaction times are generally 1 second to 2 days, preferably 1 minute to 5 hours. The course of the reaction can be followed, for example, with GCMS or NMR spectroscopic investigations.
Sämtliche isolierte Produkte wurden durch NMR-spektroskopische Methoden, GCMS, IR und, teilweise, Elementaranalysen eindeutig charakterisiert.All isolated products were clearly characterized by NMR spectroscopic methods, GCMS, IR and, in some cases, elemental analyzes.
Allgemeine Arbeitsvorschrift für die Durchfuhrung der Synthesen:General procedure for carrying out the syntheses:
Zu einer Lösung der π-Verbindung in dem jeweils angegebenen Lösungsmittel oder Lösungsmittelgemisch, vorzugsweise einer 0.5 bis 2 molaren Lösung des Nucleophils (welches vorzugsweise in 1.1 bis 10 Äquivalenten bezogen auf das Elektrophil eingesetzt wird), und eventueller Zugabe von vorzugsweise 1 bis 3 Äquivalenten (eq) (bezogen auf das eingesetzte Elektrophil) des basischen Zuschlags, wird das Elektrophil so langsam zugegeben, dass die Reaktionswärme problemlos abgeführt werden kann. Im Falle von Feststoffen werden diese entweder portionsweise zugegeben oder in möglichst wenig inertem Lösungsmittel wie Acetonitril gelöst und tropfenweise zugegeben. Die Reaktionsmischung wird erfindungsgemäß bevorzugt bei Raumtemperatur (rt) gerührt.To a solution of the π-compound in the specified solvent or solvent mixture, preferably a 0.5 to 2 molar solution of the nucleophile (which is preferably used in 1.1 to 10 equivalents based on the electrophile), and possible addition of preferably 1 to 3 equivalents ( eq) (based on the electrophile used) of the basic additive, the electrophile is added so slowly that the heat of reaction can be easily removed. In the case of solids, these are either added in portions or dissolved in as little inert solvent as possible, such as acetonitrile, and added dropwise. According to the invention, the reaction mixture is preferably stirred at room temperature (rt).
Nach beendeter Reaktion wird das Reaktionsgemisch mit demselben Volumen an Wasser versetzt und die wässrige Phase mehrfach mit Diethylether extrahiert. Die vereinigten organischen Extrakte werden über einem Trockenmittel, vorzugsweise Natriumsulfat oder Magnesiumsulfat, getrocknet und überschüssiges Lösungsmittel im Vakuum entfernt.When the reaction is complete, the same volume of water is added to the reaction mixture and the aqueous phase is extracted several times with diethyl ether. The combined organic extracts are dried over a drying agent, preferably sodium sulfate or magnesium sulfate, and excess solvent is removed in vacuo.
Die Rückstände werden zur weiteren Reinigung beispielsweise einer Destillation bzw. einer Chromatographie an Kieselgel unterworfen.For further purification, the residues are subjected, for example, to distillation or chromatography on silica gel.
Eine Durchführung der Synthesen in größerem Maßstab unter Einhaltung der Stöchiometrie der eingesetzten Substanzen ist möglich. The syntheses can be carried out on a larger scale while maintaining the stoichiometry of the substances used.
BeispieleExamples
Allgemeine Arbeitsvorschrift für die Durchführung der Synthesen:General procedure for carrying out the syntheses:
Zu einer Lösung der π-Verbindung in dem jeweils angegebenen Lösungsmittel oder Lösungsmittelgemisch, vorzugsweise einer 0.5 bis 2 molaren Lösung des Nucleophils (welches vorzugsweise in 1.1 bis 10 Äquivalenten bezogen auf das Elektrophil eingesetzt wird), und eventueller Zugabe von vorzugsweise 1 bis 3 Äquivalenten (eq) (bezogen auf das eingesetzte Elektrophil) des basischen Zuschlags, wird das Elektrophil so langsam zugegeben, dass die Reaktionswärme problemlos abgeführt werden kann. Im Falle von Feststoffen werden diese entweder portionsweise zugegeben oder in möglichst wenig inertem Lösungsmittel wie Acetonitril gelöst und tropfenweise zugegeben. Die Reaktionsmischung wird erfindungsgemäß bevorzugt bei Raumtemperatur (rt) gerührt.To a solution of the π-compound in the specified solvent or solvent mixture, preferably a 0.5 to 2 molar solution of the nucleophile (which is preferably used in 1.1 to 10 equivalents based on the electrophile), and possible addition of preferably 1 to 3 equivalents ( eq) (based on the electrophile used) of the basic additive, the electrophile is added so slowly that the heat of reaction can be easily removed. In the case of solids, these are either added in portions or dissolved in as little inert solvent as possible, such as acetonitrile, and added dropwise. According to the invention, the reaction mixture is preferably stirred at room temperature (rt).
Nach beendeter Reaktion wird das Reaktionsgemisch mit demselben Volumen an Wasser versetzt und die wässrige Phase mehrfach mit Diethylether extrahiert. Die vereinigten organischen Extrakte werden über einem Trockenmittel, vorzugsweise Natriumsulfat oder Magnesiumsulfat, getrocknet und überschüssiges Lösungsmittel im Vakuum entfernt.When the reaction is complete, the same volume of water is added to the reaction mixture and the aqueous phase is extracted several times with diethyl ether. The combined organic extracts are dried over a drying agent, preferably sodium sulfate or magnesium sulfate, and excess solvent is removed in vacuo.
Die Rückstände werden zur weiteren Reinigung beispielsweise einer Destillation bzw. einer Chromatographie an Kieselgel unterworfen.For further purification, the residues are subjected, for example, to distillation or chromatography on silica gel.
Beispiele 1 - 2Examples 1-2
Der Allgemeinen Arbeitsvorschrift folgend wurden gemäß des beanspruchten Verfahrens verschiedene Elektrophile mit 2-Methoxypropen (N = 5.41, s = 0.91) analog des nachfolgenden Reaktionsschemas (A) umgesetzt. Die eingesetzten Lösungsmittel(-gemische), Basen, Reaktionsbedingungen und Ausbeuten sind Tab. 3 zu entnehmen.In accordance with the general working procedure, various electrophiles were reacted with 2-methoxypropene (N = 5.41, s = 0.91) in accordance with the process claimed, analogously to the reaction scheme (A) below. The solvents (mixtures), bases, reaction conditions and yields used are shown in Table 3.
t Λ Nr. R1 X nEι UNU t Solvens Vsolv+Nu Base Aus[min] beute [mmol] [mmol] [ml] 1 4-Methoxy- Cl 3.81 25 15 90AN10W 25 2,6- 62 % phenyl Lutidin t Λ No. R 1 X n E ι UNU t Solvent Vsolv + Nu Base From [min] prey [mmol] [mmol] [ml] 1 4-methoxy-Cl 3.81 25 15 90AN10W 25 2.6-62% phenyl lutidine
2 H Br 4.97 25 180 90AN10W 25 2,6- 67 % Lutidin2 H Br 4.97 25 180 90AN10W 25 2.6-67% lutidine
Tab. 3 - nE] = Stoffmenge Elektrophil, nNu = Stoffmenge Nucleophil, VSoiv+Nu = Gesamtvolumen der 1 molaren Lösung des Nucleophils.Tab. 3 - n E] = amount of substance electrophile, n Nu = amount of substance nucleophile, V So i v + Nu = total volume of the 1 molar solution of the nucleophile.
Beispiele 3 - 7Examples 3-7
Gemäß des beanspruchten Verfahrens wurden verschiedene Elektrophile mit 2-Methylfuran (N = 3.61, s = 1.11) in den angegebenen Lösungsmitteln (-gemischen) nach der Allgemeinen Arbeitsvorschrift bei Raumtemperatur (rt) umgesetzt. Die jeweils eingesetzten Lösungsmittel (-gemische), Basen (eq bezogen auf das Elektrophil), Nucleophilkonzentrationen und Ausbeuten sind den Reaktionsgleichungen zu entnehmen.According to the claimed process, various electrophiles were reacted with 2-methylfuran (N = 3.61, s = 1.11) in the specified solvents (mixtures) according to the general procedure at room temperature (rt). The solvents (mixtures), bases (eq based on the electrophile), nucleophile concentrations and yields used can be found in the reaction equations.
Reaktion von 4-Methoxybenzylbromid (4.97 mmol) mit einer 1 molaren Lösung (25 ml) von 2- Methylfuran (25 mmol) in 90 % wässrigem Acetonitril (Beispiel 3):Reaction of 4-methoxybenzyl bromide (4.97 mmol) with a 1 molar solution (25 ml) of 2-methylfuran (25 mmol) in 90% aqueous acetonitrile (Example 3):
rt, 2 h 73 % rt, 2 h 73%
Reaktion von Prenylbromid (6.71 mmol) mit einer 1 molaren Lösung (20 ml) von 2-Methylfuran (20 mmol) in 90 % wässrigem Acetonitril (Beispiel 4):Reaction of prenyl bromide (6.71 mmol) with a 1 molar solution (20 ml) of 2-methylfuran (20 mmol) in 90% aqueous acetonitrile (example 4):
12 % 12%
Reaktion von Chlor-bis(4-methoxyphenyl)methan (3.81 mmol) mit einer 1 molaren Lösung (20 ml) von 2-Methylfuran (20 mmol) in 2,2,2-TrifTuorethanol (Beispiel 5): 85 %Reaction of chlorobis (4-methoxyphenyl) methane (3.81 mmol) with a 1 molar solution (20 ml) of 2-methylfuran (20 mmol) in 2,2,2-trifluoroethanol (example 5): 85%
Reaktion von 4-Methoxybenzylchlorid (12.8 mmol) mit einer 1 molaren Lösung (50 ml) von 2- Methylfuran (50 mmol) in 2,2,2-Trifluorethanol (Beispiel 6):Reaction of 4-methoxybenzyl chloride (12.8 mmol) with a 1 molar solution (50 ml) of 2-methylfuran (50 mmol) in 2,2,2-trifluoroethanol (Example 6):
1 M 2-Methylfuran, TFE 2 eq 2,6-Lutidin rt, 1.5 h 74 %1 M 2-methylfuran, TFE 2 eq 2,6-lutidine rt, 1.5 h 74%
Reaktion von 1-Anisylethylchlorid (5.86 mmol) mit einer 1 molaren Lösung (25 ml) von 2- Methylfuran (25 mmol) in 2,2,2-Trifluorethanol (Beispiel 7):Reaction of 1-anisylethyl chloride (5.86 mmol) with a 1 molar solution (25 ml) of 2-methylfuran (25 mmol) in 2,2,2-trifluoroethanol (Example 7):
1 M 2-Methylfuran, TFE 1.1 e CqH 2 *-,.6υ--Lutidin rt, 30 min 70 %1 M 2-methylfuran, TFE 1.1 e CqH 2 * -,. 6υ - lutidine rt, 30 min 70%
Beispiele 8 - 10Examples 8-10
Der Allgemeinen Arbeitsvorschrift folgend wurden gemäß des beanspruchten Verfahrens verschiedene Elektrophile mit 1,3-Dimethoxybenzol (N = 2.48; s = 1.09) in 2,2,2-Trifluorethanol (TFE) analog des nachfolgenden Reaktionsschemas (B) umgesetzt. Die eingesetzten Basen, Reaktionsbedingungen und Ausbeuten sind Tab. 4 zu entnehmen.Following the general working procedure, various electrophiles were reacted with 1,3-dimethoxybenzene (N = 2.48; s = 1.09) in 2,2,2-trifluoroethanol (TFE) analogously to the reaction scheme (B) below in accordance with the claimed process. The bases, reaction conditions and yields used are shown in Table 4.
Nr. R1 X nEι nNu VSolv+Nu t [min] Base Ausbeute [mmol] [mmol] [ml] H Cl 6.39 25 25 30 1.5 eq 84 % + 7 % 1,2,3-Substi- 2,6-Lutidin tution H Cl 6.39 25 25 30 79 % + 5 % 1,2,3-Substi- tution 10 Me Cl 5.86 25 25 30 1.1 eq 52 % 2,6-Lutidin No. R 1 X n E ι n Nu V Solv + Nu t [min] base yield [mmol] [mmol] [ml] H Cl 6.39 25 25 30 1.5 eq 84% + 7% 1,2,3-Substi- 2,6-lutidine t HCl 6.39 25 25 30 79% + 5% 1,2,3-substitution 10 Me Cl 5.86 25 25 30 1.1 eq 52% 2,6-lutidine
Tab. 4 - nE) = Stoffmenge Elektrophil, nNu = Stoffmenge Nucleophil, VSOI +NU = Gesamtvolumen der 1 molaren Lösung des Nucleophils.Tab. 4 - n E) = amount of substance electrophile, n Nu = amount of substance nucleophile, V SOI + NU = total volume of the 1 molar solution of the nucleophile.
Beispiel 11Example 11
Der Allgemeinen Arbeitsvorschrift folgend wurde gemäß des beanspruchten Verfahrens 4-Methoxybenzylbromid (3.73 mmol) mit einer 1 molaren Lösung (25 ml) von 3-Methylanisol (N = 0.13; s = 1.27) (25 mmol) in 2,2,2-Trifluorethanol (TFE) analog des nachfolgenden Reaktionsschemas umgesetzt. Die eingesetzte Base, die Reaktionsbedingungen und die Ausbeute sind der Reaktionsgleichung zu entnehmen.Following the general working procedure, 4-methoxybenzyl bromide (3.73 mmol) was obtained with a 1 molar solution (25 ml) of 3-methylanisole (N = 0.13; s = 1.27) (25 mmol) in 2,2,2-trifluoroethanol according to the claimed process (TFE) implemented analogously to the reaction scheme below. The base used, the reaction conditions and the yield can be found in the reaction equation.
Gesamtausbeute 97% Beispiele 12 - 13Overall yield 97% Examples 12-13
Der Allgemeinen Arbeitsvorschrift folgend wurden gemäß des beanspruchten Verfahrens verschiedene Elektrophile mit 2-Methylthiophen (N = 1.26; s = 0.96) in 2,2,2-Trifluorethanol (TFE) analog des nachfolgenden Reaktionsschemas (C) umgesetzt. Die eingesetzten Basen, Reaktionsbedingungen und Ausbeuten sind Tab. 5 zu entnehmen.According to the general working procedure, various electrophiles were reacted with 2-methylthiophene (N = 1.26; s = 0.96) in 2,2,2-trifluoroethanol (TFE) analogously to the reaction scheme (C) below in accordance with the claimed process. The bases, reaction conditions and yields used are shown in Table 5.
Raumtemperatur room temperature
Nr. R1 X nEι nNu Vsoivwu t [min] Base Ausbeute [mmol] [mmol] [ml] 12 4-Methoxy- Cl 3.81 20 20 1.1 eq 83 % phenyl 2-Chlor- pyridin 13 Me Cl 5.86 25 25 30 1.1 eq 81 % 2-Chlor- pyridinNo. R 1 X n E ι n Nu Vsoivwu t [min] base yield [mmol] [mmol] [ml] 12 4-methoxy-Cl 3.81 20 20 1.1 eq 83% phenyl 2-chloropyridine 13 Me Cl 5.86 25 25 30 1.1 eq 81% 2-chloropyridine
Tab. 5 - nH = Stoffmenge Elektrophil, nNu = Stoffmenge Nucleophil, Vs0iv+Nu = Gesamtvolumen der 1 molaren Lösung des Nucleophils.Tab. 5 - n H = amount of substance electrophile, n Nu = amount of substance nucleophile, Vs 0 i v + Nu = total volume of the 1 molar solution of the nucleophile.
Beispiele 14 - 17Examples 14-17
Der Allgemeinen Arbeitsvorschrift folgend wurden gemäß des beanspruchten Verfahrens verschiedene Elektrophile mit 1-Methylpyrrol (N = 5.85; s = 1.03) und Pyrrol (N = 4.63; s = 1.00) in 80 % wässrigem Aceton (80A20W) oder Wasser (W) analog des nachfolgenden Reaktionsschemas (D) umgesetzt. Das jeweils verwendete Lösungsmittel (Solvens), die Reaktionsbedingungen und Ausbeuten sind Tab. 6 zu entnehmen.Following the general working procedure, various electrophiles with 1-methylpyrrole (N = 5.85; s = 1.03) and pyrrole (N = 4.63; s = 1.00) in 80% aqueous acetone (80A20W) or water (W) were analogous to that according to the claimed process following reaction scheme (D) implemented. The solvent (solvent) used in each case, the reaction conditions and yields are shown in Table 6.
Nu2 Nu3 Nr. R1 R2 X Y Solvens nE] nNu VSolv+Nu t [h] Ausbeute [mmol] [mmol] [ml] PNU2/PNU3 14 OMe H Br Me 80A20W 4.97 25 25 0.5 49 % / 21 % Nu2 Nu3 No. R 1 R 2 XY Solvents n E] n Nu V Solv + Nu t [h] Yield [mmol] [mmol] [ml] P NU2 / P NU3 14 OMe H Br Me 80A20W 4.97 25 25 0.5 49% / 21 %
15 H Ph Cl Me 80A20W 4.93 25 25 24 47 % / 21 %15 H Ph Cl Me 80A20W 4.93 25 25 24 47% / 21%
16 H Ph Br H 80A20W 4.05 25 25 0.5 81 % / 13 %16 H Ph Br H 80A20W 4.05 25 25 0.5 81% / 13%
17 H Ph Br H W 6.25 25 25 0.5 74 % / 2 %17 H Ph Br H W 6.25 25 25 0.5 74% / 2%
Tab. 6 - nEι = Stoffmenge Elektrophil, nNu = Stoffmenge Nucleophil, Vg^x,, = Gesamtvolumen der 1 molaren Lösung des Nucleophils.Tab. 6 - n E ι = amount of substance electrophile, n Nu = amount of substance nucleophile, Vg ^ x ,, = total volume of the 1 molar solution of the nucleophile.
Beispiel 18Example 18
Der Allgemeinen Arbeitsvorschrift folgend wurde gemäß des beanspruchten Verfahrens 4-Methoxybenzylbromid (2.49 mmol) mit einer 1 molaren Lösung (25 ml) von Ethylprop-1- enylether (cis/trans-Isomerengemisch) (25 mmol) in 90 % wässrigem Acetonitril (90AN10W) analog des nachfolgenden Reaktionsschemas umgesetzt. Die eingesetzte Base, die exakten Reaktionsbedingungen sowie die Ausbeute sind in der Reaktionsgleichung angegeben.Following the general working procedure, 4-methoxybenzyl bromide (2.49 mmol) was mixed with a 1 molar solution (25 ml) of ethyl prop-1-enyl ether (cis / trans isomer mixture) (25 mmol) in 90% aqueous acetonitrile (90AN10W) according to the claimed process. implemented analogously to the reaction scheme below. The base used, the exact reaction conditions and the yield are given in the reaction equation.
Beispiele 19 - 20Examples 19-20
Der Allgemeinen Arbeitsvorschrift folgend wurde gemäß des beanspruchten Verfahrens 4-Methoxybenzylbromid mit 1-Trimethylsiloxycyclopenten (N = 6.57; s = 0.93) und 1-Phenyl-l- trimethylsiloxyethylen (N = 6.22; s = 0.96) in 90 % wässrigem Acetonitril (90AN10W) analog der nachfolgenden Reaktionsschemen umgesetzt. Die eingesetzten Basen, Reaktionsbedingungen und Ausbeuten sind in der jeweiligen Reaktionsgleichung angegeben.Following the general working procedure, 4-methoxybenzyl bromide with 1-trimethylsiloxycyclopentene (N = 6.57; s = 0.93) and 1-phenyl-l-trimethylsiloxyethylene (N = 6.22; s = 0.96) in 90% aqueous acetonitrile (90AN10W) was used in accordance with the claimed process. implemented analogously to the reaction schemes below. The bases, reaction conditions and yields used are given in the respective reaction equation.
Reaktion von 4-Methoxybenzylbromid (1.24 mmol) mit einer 1 molaren Lösung (10 ml) von 1-Trimethylsiloxycyclopenten (10 mmol) in 90 % wässrigem Acetonitril (90AN10W) (Beispiel 19): Reaction of 4-methoxybenzyl bromide (1.24 mmol) with a 1 molar solution (10 ml) of 1-trimethylsiloxycyclopentene (10 mmol) in 90% aqueous acetonitrile (90AN10W) (Example 19):
Reaktion von 4-Methoxybenzylbromid (1.24 mmol) mit einer 1 molaren Lösung (10 ml) von 1- Phenyl-1-trimethylsiloxyethylen (10 mmol) in 90 % wässrigem Acetonitril (90AN10W) (Beispiel 20):Reaction of 4-methoxybenzyl bromide (1.24 mmol) with a 1 molar solution (10 ml) of 1-phenyl-1-trimethylsiloxyethylene (10 mmol) in 90% aqueous acetonitrile (90AN10W) (Example 20):
Beispiel 21Example 21
Der Allgemeinen Arbeitsvorschrift folgend wurde gemäß des beanspruchten Verfahrens Chlor- bis(4-methoxyphenyl)methan (3.81 mmol) mit einer 1 molaren Lösung (25 ml) von Indol (N = 5.80; s = 0.80) (25 mmol) in 80 % wässrigem Aceton (80A20W) analog des nachfolgenden Reaktionsschemas umgesetzt. Die eingesetzte Base, Reaktionsbedingungen und die Ausbeute sind der Reaktionsgleichung zu entnehmen.Following the general working procedure, chlorobis (4-methoxyphenyl) methane (3.81 mmol) was treated with a 1 molar solution (25 ml) of indole (N = 5.80; s = 0.80) (25 mmol) in 80% aqueous solution according to the claimed process Acetone (80A20W) implemented analogous to the following reaction scheme. The base used, reaction conditions and the yield can be found in the reaction equation.
87 % 87%
Beispiele 22 - 46:Examples 22-46:
Der Allgemeinen Arbeitsvorschrift folgend wurden gemäß des beanspruchten Verfahrens die Umsetzungen gemäß Tab. 7 durchgeführt. Nukleophile, Elektrophile sowie deren eingesetzte Stoffmengen n, Lösungsmittel(-gemische) sowie deren Volumina V, gegebenenfalls eingesetzte Basen sowie deren Äquivalente bezogen auf die Stoffmenge des Elektrophils, Reaktionszeit t und die Ausbeuten sind Tab. 7 zu entnehmen. Die Umsetzungen wurden - sofern nicht anders angegeben - bei Raumtemperatur durchgeführt. Tab. 7:Following the general working instructions, the implementations according to Table 7 were carried out in accordance with the claimed process. Nucleophiles, electrophiles and their substance quantities n, solvents (mixtures) as well as their volumes V, possibly used bases as well as their equivalents based on the substance quantity of the electrophile, reaction time t and the yields are shown in Table 7. Unless otherwise stated, the reactions were carried out at room temperature. Tab. 7:
[a] Abbildungen in Anhang Formelanhang - Nucleophile. [b] Abbildungen in Anhang Formelanhang - Elektrophile. [c] Lösungsmittelgemische sind in Vol.-% angegeben, hierin bedeuten: W = Wasser, TFE = 2,2,2-Trifluorethanol, H = 1,1,1,3,3,3-Hexafluoroisopropanol, AN = Acetonitril, A = Aceton. [d] Isoliertes Material, [e] Reaktionstemperatur 85 °C. [a] Figures in Appendix Formula Appendix - Nucleophiles. [b] Figures in Appendix Formula Appendix - Electrophiles. [c] Solvent mixtures are given in% by volume, where: W = water, TFE = 2,2,2-trifluoroethanol, H = 1,1,1,3,3,3-hexafluoroisopropanol, AN = acetonitrile, A = Acetone. [d] Insulated material, [e] reaction temperature 85 ° C.
Formelanhang - Nucleophile zu Tab. 7Formula appendix - nucleophiles to Tab. 7
3-Methylanisol Anisol Dimethylanilin 3-methylanisole anisole dimethylaniline
Mesitylen N-Methylpyrrol PyrrolMesitylene N-methylpyrrole pyrrole
Formelanhang - Elektrophile zu Tab. 7Formula appendix - electrophiles to Tab. 7
p-OMeBnBr p-OMe-α-MeBnCI AniCHCI p-OMeBnBr p-OMe-α-MeBnCI AniCHCI
Ph CHCI 2 (3-CI)(3'-CI)CHCI (3-CI)PhCHCI Ph CHCI 2 (3-CI) (3'-CI) CHCI (3-CI) PhCHCI
(Ani)PhCHCI PhCH2Br Tol CHCI 2 (Ani) PhCHCI PhCH 2 Br Tol CHCI 2

Claims

Patentansprüche : Claims:
1. Verfahren zur KoMenstoff-Kohlenstoff-Bindungsknüpfung durch Umsetzung von Verbindungen des allgemeinen Formeltyps (I)1. Process for the formation of carbon-carbon bonds by reacting compounds of the general formula type (I)
mit π-Verbindungen in neutralen bis basischen wässrigen oder alkoholischen Lösungsmitteln oder Lösungsmittelgemischen, welche eine geringere Nucleophilie aufweisen als das π-Nucleophil, wobei R1, R2 und R3 unabhängig voneinander organische oder metallorganische Reste oder Wasserstoff sind, wobei X eine Abgangsgruppe der Art ist, dass die Verbindungen (I) in Ethanol mit einer Geschwindigkeitskonsante kEtoH > 10"6 s"1 (25 °C) solvolysiert werden, dadurch gekennzeichnet, dass die intermediären Carbokationen in neutralen bis basischen wässrigen oder alkoholischen Lösungsmitteln oder Lösungsmittelgemischen erzeugt werden, ohne dass eine Lewissäure oder Protonensäure verwendet wird. with π compounds in neutral to basic aqueous or alcoholic solvents or solvent mixtures, which have a lower nucleophilicity than the π-nucleophile, where R 1 , R 2 and R 3 are independently organic or organometallic radicals or hydrogen, where X is a leaving group of the Type is that the compounds (I) are solvolysed in ethanol with a rate constant k Et o H > 10 "6 s " 1 (25 ° C), characterized in that the intermediate carbocations in neutral to basic aqueous or alcoholic solvents or solvent mixtures generated without using a Lewis acid or protonic acid.
2. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass R1, R2 und R3 unabhängig voneinander gewählt sind aus der Gruppe verzweigtes oder unverzweigtes Alkyl, substituiertes oder unsubstituiertes Aryl, substituiertes oder unsubstituiertes Heteroaryl, verzweigtes oder unverzweigtes Alk-2-enyl, Cyclo-, Bicyclo- und Tricycloalkyl, Alkoxy, Aryloxy oder Wasserstoff. Desweiteren können zwei der Reste R1, R2 und R3 einen Alkylring bilden.2. The method according to claim 1, characterized in that R 1 , R 2 and R 3 are independently selected from the group consisting of branched or unbranched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, branched or unbranched alk-2-enyl, Cyclo, bicyclo and tricycloalkyl, alkoxy, aryloxy or hydrogen. Furthermore, two of the radicals R 1 , R 2 and R 3 can form an alkyl ring.
3. Verfahren gemäss einem der voranstehenden Ansprüche, dadurch gekennzeichnet, dass X eine Abgangsgruppe ist, gewählt aus der Gruppe Halogen, Alkoxy, Alkyl- oder Arylsulfonato, substituiertes oder unsubstituiertes Phenoxy, Acyloxy, Benzoyloxy, Carbamoyl, Alkyloxycarbonyloxy, Aryloxycarbonyloxy, Siloxy, Phosphato, Phosphonato, Hypophosphonato, Alkylperoxy, Sulfato, Sulfenyl, Sulfonyl, S-Alkylsulfoxy, S- Arylsulfoxy, Alkylthio, Arylthio. Thiocyanato, Isothiocyanato, Ureato und Imidyl.3. The method according to any one of the preceding claims, characterized in that X is a leaving group selected from the group halogen, alkoxy, alkyl or arylsulfonato, substituted or unsubstituted phenoxy, acyloxy, benzoyloxy, carbamoyl, alkyloxycarbonyloxy, aryloxycarbonyloxy, siloxy, phosphato, Phosphonato, Hypophosphonato, Alkylperoxy, Sulfato, Sulfenyl, Sulfonyl, S-Alkylsulfoxy, S-Arylsulfoxy, Alkylthio, Arylthio. Thiocyanato, Isothiocyanato, Ureato and Imidyl.
4. Verfahren gemäss einem der voranstehenden Ansprüche, dadurch gekennzeichnet, dass das verwendete Lösungsmittel bzw. Lösungsmittelgemisch Wasser oder einen Alkohol umfasst. Lösungsmittelkomponeten sind Wasser, Ethanol, Methanol, 2,2,2-Trifluorethanol, l,l,l,3,3,3-Hexafluoro-2-propanol, Tetrahydrofuran, Aceton, Acetonitril und Dioxan.4. The method according to any one of the preceding claims, characterized in that the solvent or solvent mixture used is water or an alcohol includes. Solvent components are water, ethanol, methanol, 2,2,2-trifluoroethanol, l, l, l, 3,3,3-hexafluoro-2-propanol, tetrahydrofuran, acetone, acetonitrile and dioxane.
5. Verfahren gemäss einem der voranstehenden Ansprüche, dadurch gekennzeichnet, dass Verbindungen des Typs (I) mit einer Mischung aus einer π-Verbindung in dem entsprechenden Lösungsmittel oder Lösungsmittelgemisch und evtl. weiteren, basischen anorganischen oder organischen Zusätzen zur Reaktion gebracht werden.5. The method according to any one of the preceding claims, characterized in that compounds of type (I) are reacted with a mixture of a π compound in the corresponding solvent or solvent mixture and possibly further basic inorganic or organic additives.
6. Verfahren gemäss einem der voranstehenden Ansprüche, dadurch gekennzeichnet, dass die als Nucleophil verwendeten π-Verbindungen aliphatische π-Verbindungen aus der Gruppe substituierte Alkene und Alkine, Allyl- und Propargylsilane, Alkylenolether, Silylenolether, (Silyl-) Ketenacetale und Enamine, oder aromatische π-Verbindungen aus der Gruppe der donorsubstituierten oder unsubstituierten Aromaten und Heteroaromaten sind. 6. The method according to any one of the preceding claims, characterized in that the π compounds used as nucleophile are aliphatic π compounds from the group substituted alkenes and alkynes, allyl and propargylsilanes, alkyleneol ethers, silylenol ethers, (silyl) ketene acetals and enamines, or aromatic π compounds from the group of donor-substituted or unsubstituted aromatics and heteroaromatics.
EP05701385A 2004-02-11 2005-02-09 Process for c-c coupling between electrophilic substrates and pi-nucleophiles in neutral to basic acqueous or alcoholic solvents without the use of a lewis or proteic acid. Withdrawn EP1716087A1 (en)

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DE102004006785A DE102004006785A1 (en) 2004-02-11 2004-02-11 Process for C-C bond formation between electrophilic substrates and TT compounds in neutral to basic aqueous or alcoholic solvents without the use of a Lewis or protic acid
PCT/EP2005/001277 WO2005077863A1 (en) 2004-02-11 2005-02-09 METHOD FOR ESTABLISHING CC BONDS BETWEEN ELECTROPHILIC SUBSTRATES AND π - NUCLEOPHILES IN NEUTRAL TO ALKALINE AQUEOUS OR ALCOHOLIC SOLVENTS WITHOUT USING A LEWIS OR BRONSTED ACID

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US10688076B2 (en) 2014-10-23 2020-06-23 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US10689372B2 (en) 2008-11-26 2020-06-23 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US10793529B2 (en) 2008-12-08 2020-10-06 Arena Pharmaceuticals, Inc. Substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators
US11123298B2 (en) 2017-03-01 2021-09-21 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
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US10689372B2 (en) 2008-11-26 2020-06-23 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US11098034B2 (en) 2008-11-26 2021-08-24 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US10793529B2 (en) 2008-12-08 2020-10-06 Arena Pharmaceuticals, Inc. Substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators
US10688076B2 (en) 2014-10-23 2020-06-23 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11000500B2 (en) 2014-10-23 2021-05-11 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11426377B2 (en) 2014-10-23 2022-08-30 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11826337B2 (en) 2014-10-23 2023-11-28 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11123298B2 (en) 2017-03-01 2021-09-21 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
US11826471B2 (en) 2017-03-01 2023-11-28 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
US12098116B2 (en) 2022-02-15 2024-09-24 United Therapeutics Corporation Crystalline prostacyclin (IP) receptor agonist and uses thereof

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