EP1165512A2 - Method for arylating aza-heterocycles with activated aromatic compounds in the presence of cesium carbonate - Google Patents

Method for arylating aza-heterocycles with activated aromatic compounds in the presence of cesium carbonate

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Publication number
EP1165512A2
EP1165512A2 EP00916872A EP00916872A EP1165512A2 EP 1165512 A2 EP1165512 A2 EP 1165512A2 EP 00916872 A EP00916872 A EP 00916872A EP 00916872 A EP00916872 A EP 00916872A EP 1165512 A2 EP1165512 A2 EP 1165512A2
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Prior art keywords
group
indole
atoms
aza
general formula
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German (de)
French (fr)
Inventor
Hubert Barth
Klaus Steiner
Hans-Jürgen BETCHE
Simon Schneider
Ulrich Bayer
Manfred Westermayer
Ulrike Wolfsperger
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Goedecke GmbH
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Goedecke GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
    • 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
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms

Definitions

  • the invention relates to a method for nucleophilic substitution on activated aromatics of the general formula XIV
  • Rl, R2, R3, R4 and R5 are the same or different and are a hydrogen atom, a nitro group, a cyano group, an alkoxycarbonyl group with up to 5 C atoms, an aldehyde group, an alkylcarbonyl group with up to 5 C atoms, an arylcarbonyl group or mean an amide group, where the radicals Rl to R5 cannot all be a hydrogen atom at the same time and HAL for a halogen atom, but especially a fluorine atom, with nucleophiles such as alcohols, amines, sulfoximides, CH-acidic compounds of the formulas V to XI
  • HETN denotes an aromatic aza heterocycle with a total of 5 or 6 ring atoms, where up to 3 ring atoms can be nitrogen atoms and up to two further aromatic carbon rings may be fused to the heterocycle and Rl to R5 have the meaning given above.
  • 1- (Benzotriazol-1-yl) -2, -dinitrobenzene can be obtained in 96% yield by boiling benzotriazole with 2,4-dinitrochlorobenzene in toluene for 9 days (A.R. Katritzky, J. Wu, Synthesis 1994, 597).
  • 4-heterocyclically substituted nitrobenzenes and benzaldehydes can be obtained by reacting the respective aza heterocycles, e.g. Benzotriazole, 1, 2, 4-triazole or benzimidazole with 4-fluorobenzaldehyde or 4-fluoro- or 4-chloro-benzaldehyde can be obtained in DMSO or DMF at 100 ° C (DJ Gale, JFK Wilshire, Aust. J. Chem. 23, 1063, 1970; J. Rosevear, JKF Wilshire, Aust. J. Chem. 44, 1097, 1991).
  • Benzotriazole, 1, 2, 4-triazole or benzimidazole with 4-fluorobenzaldehyde or 4-fluoro- or 4-chloro-benzaldehyde can be obtained in DMSO or DMF at 100 ° C (DJ Gale, JFK Wilshire, Aust. J. Chem. 23, 1063, 1970; J. Roseve
  • Nitrophenylazoles can by Ullmann condensation of azoles with aryl halides in pyridine in the presence of potassium carbonate and copper (II) oxide at high temperatures and long reaction times (MA Khan, JB Polya, J. Chem. Soc. (C), 1970, 85; AK Khan , EK Rocha, Chem. Pharm.
  • nucleophiles V to X also react with 2-fluoronitrobenzene at room temperature in the cesium carbonate / dimethylformide system: illustration 1
  • R 1 to R 5 have the meaning given above and HAL stands for a halogen atom, but in particular for a fluorine atom, investigated in the system cesium carbonate / dimethyl formamide.
  • dimethylformamide instead of dimethylformamide, other dipolar aprotic solvents such as e.g. Dimethylacetamide, acetonitrile, dimethyl sulfoxide, acetone or N-methylpyrrolidone can be used, but the reaction times at room temperature are then significantly longer and the yields are often lower.
  • dipolar aprotic solvents such as e.g. Dimethylacetamide, acetonitrile, dimethyl sulfoxide, acetone or N-methylpyrrolidone
  • the suspension is poured onto water, the product is extracted with ethyl acetate and the crude product obtained after evaporation of the organic phase is purified using the methods customary in organic chemistry, for example by crystallization or chromatography.
  • the invention is illustrated and explained by the following exemplary embodiments:
  • Example 9 N-2-cyanophenyldiphenylsulfoximide from 2 fluorobenzonitrile and diphenylsulfoximide at 80 ° C for 8 h / toluene -ethanol 10 + 1 / 74.3% / mp 160 ° C
  • Example 10 N-2-cyanophenyldiphenylsulfoximide from 2 fluorobenzonitrile and diphenylsulfoximide at 80 ° C for 8 h / toluene -ethanol 10 + 1 / 74.3% / mp 160 ° C
  • Example 10 N-2-cyanophenyldiphenylsulfoximide from 2 fluorobenzonitrile and diphenylsulfoximide at 80 ° C for 8 h / toluene -ethanol 10 + 1 / 74.3% / mp 160 ° C
  • Example 10 N-2-cyanophenyldiphenylsulfoximide from 2 fluorobenzon
  • N-4-nitrophenyldiphenylsulfoximide from 4-fluoronitrobenzene and diphenylsulfoximide 64 h / toluene -ethanol 10 + 0.5 / 64.1% / mp 166 ° C
  • Example 16 1 - (4-Ethoxycarbonylphenyl) indole from ethyl 4-fluorobenzoate and indole at 80 ° C
  • Example 36 1- (2-nitrophenyl) indole-2-carboxylic acid ethyl ester from 2-fluoronitrobenzene and indole-2-carboxylic acid ethyl ester 58 h / toluene / 47.9% / mp 90 ° C.
  • Example 37 1- (4-nitrophenyl) indole-2-carboxylic acid ethyl ester from 4-fluoronitrobenzene and indole-2-carboxylic acid ethyl ester at 80 ° C.

Abstract

The invention relates to a method for producing N-aryl-aza-heterocycles of general formula (I) in which: R1, R2, R3, R4 and R5 are the same or different and represent a hydrogen atom, a nitro group, a cyano group, an alkoxycarbonyl group with up to 5 C atoms, an aldehyde group, an alkylcarbonyl group with up to 5 C atoms, an arylcarbonyl group or an amide group, whereby the radicals R1 to R5 can not all be a hydrogen atom at the same time, and; HETN represents an aromatic aza-heterocycle with 5 or 6 ring atoms, whereby up to 3 ring atoms can be nitrogen atoms, and up to two additional aromatic carbon rings can be fused to the heterocycle. The inventive N-aryl-aza-heterocycles are produced by reacting, at room temperature, aza-heterocycles with activated aromatic compounds of general formula (XIV), in which HAL represents a halogen atom, while using cesium carbonate and without adding additional catalysts.

Description

Verfahren zur Arylierung von Aza-Heterocyclen mit aktivierten Aromaten in Gegenwart von Cesiumcarbonat Process for the arylation of aza heterocycles with activated aromatics in the presence of cesium carbonate
Beschreibungdescription
Gegenstand der Erfindung ist ein Verfahren zur nucleophilen Substitution an aktivierten Aromaten der allgemeinen Formel XIVThe invention relates to a method for nucleophilic substitution on activated aromatics of the general formula XIV
in der Rl, R2 , R3 , R4 und R5 gleich oder verschieden sind und ein Wasserstoffatom, eine Nitrogruppe, eine Cyanogruppe, eine Alkoxycarbonylgruppe mit bis zu 5 C Atomen, eine Aldehydgruppe, eine Alkylcarbonylgruppe mit bis zu 5 C-Atomen, eine Arylcarbonylgruppe oder eine Amidgruppe bedeuten, wobei die Reste Rl bis R5 nicht alle gleichzeitig ein Wasserstoffatom sein können und HAL für ein Halogenatom, insbesondere jedoch für ein Fluoratom steht, mit Nucleophilen wie Alkoholen, Aminen, Sulfoximiden, CH-aciden Verbindungen der Formeln V bis XIin which Rl, R2, R3, R4 and R5 are the same or different and are a hydrogen atom, a nitro group, a cyano group, an alkoxycarbonyl group with up to 5 C atoms, an aldehyde group, an alkylcarbonyl group with up to 5 C atoms, an arylcarbonyl group or mean an amide group, where the radicals Rl to R5 cannot all be a hydrogen atom at the same time and HAL for a halogen atom, but especially a fluorine atom, with nucleophiles such as alcohols, amines, sulfoximides, CH-acidic compounds of the formulas V to XI
Abbildung 1illustration 1
VIII IXVIII IX
.COOMe.COOMe
XIXI
< OOMe<OOMe
in dipolar aprotischen Lösungsmitteln, insbesondere Dimethylformamid, unter Verwendung von Cesiumcarbona . Bevorzugt geeignet ist das Verfahren zur Herstellung von Verbindungen der allgemeinen Formel Iin dipolar aprotic solvents, especially dimethylformamide, using cesium carbonate. The process is preferably suitable for the preparation of compounds of the general formula I.
II.
in der HETN einen aromatischen Aza-Heterocyclus mit insgesamt 5 oder 6 Ringatomen bedeutet, wobei bis zu 3 Ringatome Stickstoffatome sein können, und bis zu zwei weitere aromatische Kohlenstoffringe am Heterocyclus ankondensiert sein können und Rl bis R5 die oben genannte Bedeutung haben.in the HETN denotes an aromatic aza heterocycle with a total of 5 or 6 ring atoms, where up to 3 ring atoms can be nitrogen atoms and up to two further aromatic carbon rings may be fused to the heterocycle and Rl to R5 have the meaning given above.
Verbindungen der allgemeinen Formel I spielen eine wichtige Rolle in der medizinischen Chemie. So findet man z.B. die N-Aryl-Aza-Heterocyclus-Substruktur in Substanzen mit antiestrogener (E. Angerer, J. Strohmeier, J. ed. Chem. 30, 131, 1987), mit analgetischer (E.J. Glamkowski et al . , J. Med. Chem. 28, 66, 1985), mit antidiabetischer (R.B.Compounds of general formula I play an important role in medicinal chemistry. So you can find e.g. the N-aryl aza heterocycle substructure in substances with antiestrogenic (E. Angerer, J. Strohmeier, J. ed. Chem. 30, 131, 1987), with analgesic (EJ Glamkowski et al., J. Med. Chem . 28, 66, 1985), with anti-diabetic (RB
Chapleo, G.P. Fagan Ann. Drug Data Rep. 15, 59,1993), mit antimikrobieller (A.G. Kamat, G.S. Gadaginamath, Indian J. Chem., Sect . B, 33, 255, 1994), mit neuroleptischer (J. Perregaard et al . , J. Med. Chem. 35, 1092, 1992), mit antiallergischer (P. Ungast et al . J. Med. Chem. 32, 1360, 1989), mit Angiotensin-II antagonistischer (S. R. Stabler and Jahangir, Syn. Commun. 24, 123, 1994) und mit PDGF- Rezeptor inhibitorischer Wirkung (Brian D. Palmer et al . J. Med. Chem. 41, 5457, 1998) .Chapleo, G.P. Fagan Ann. Drug Data Rep. 15, 59, 1993), with antimicrobial (AG Kamat, GS Gadaginamath, Indian J. Chem., Sect. B, 33, 255, 1994), with neuroleptic (J. Perregaard et al., J. Med Chem. 35, 1092, 1992), with antiallergic (P. Ungast et al. J. Med. Chem. 32, 1360, 1989), with angiotensin-II antagonistic (SR Stabler and Jahangir, Syn. Commun. 24, 123 , 1994) and with PDGF receptor inhibitory activity (Brian D. Palmer et al. J. Med. Chem. 41, 5457, 1998).
Verbindungen der allgemeinen Formel I können nach verschiedenen Methoden hergestellt werden. Eine häufig verwendete Methode besteht in der Umsetzung von Aza- Heterocyclen mit aktivierten Arylhalogeniden in Gegenwart von Katalysatoren und/oder Basen, oder in wenigen Fällen auch ohne weitere Zusätze gemäß Schema 1: Schema 1Compounds of the general formula I can be prepared by various methods. A frequently used method consists in the reaction of aza heterocycles with activated aryl halides in the presence of catalysts and / or bases, or in a few cases also without further additives according to Scheme 1: Scheme 1
So kann z.B. 1- (Benzotriazol-1-yl) -2 , -dinitrobenzol in 96% Ausbeute durch 9-tägiges Kochen von Benzotriazol mit 2,4- Dinitrochlorbenzol in Toluol erhalten werden (A.R. Katritzky, J. Wu, Synthesis 1994, 597) .For example, 1- (Benzotriazol-1-yl) -2, -dinitrobenzene can be obtained in 96% yield by boiling benzotriazole with 2,4-dinitrochlorobenzene in toluene for 9 days (A.R. Katritzky, J. Wu, Synthesis 1994, 597).
4-Heterocyclisch substituierte Nitrobenzole und Benzaldehyde können durch Umsetzung der jeweiligen Aza- Heterocyclen wie z.B. Benzotriazol, 1 , 2 , 4-Triazol oder Benzimidazol mit 4-Fluorbenzaldehyd bzw. 4-Fluor- oder 4- Chlor-benzaldehyd in DMSO oder DMF bei 100°C erhalten werden (D.J. Gale, J.F.K. Wilshire, Aust . J. Chem. 23, 1063, 1970; J. Rosevear, J.K.F. Wilshire, Aust. J. Chem. 44, 1097, 1991) .4-heterocyclically substituted nitrobenzenes and benzaldehydes can be obtained by reacting the respective aza heterocycles, e.g. Benzotriazole, 1, 2, 4-triazole or benzimidazole with 4-fluorobenzaldehyde or 4-fluoro- or 4-chloro-benzaldehyde can be obtained in DMSO or DMF at 100 ° C (DJ Gale, JFK Wilshire, Aust. J. Chem. 23, 1063, 1970; J. Rosevear, JKF Wilshire, Aust. J. Chem. 44, 1097, 1991).
Nitrophenylazole können durch Ullmann Kondensation von Azolen mit Arylhaliden in Pyridin in Gegenwart von Kaliumcarbonat und Kupfer (II) oxid bei hohen Temperaturen und langen Reaktionszeiten (M.A. Khan, J.B. Polya, J. Chem. Soc. (C) , 1970, 85; A.K. Khan, E.K. Rocha, Chem. Pharm.Nitrophenylazoles can by Ullmann condensation of azoles with aryl halides in pyridine in the presence of potassium carbonate and copper (II) oxide at high temperatures and long reaction times (MA Khan, JB Polya, J. Chem. Soc. (C), 1970, 85; AK Khan , EK Rocha, Chem. Pharm.
Bull. 25, 3110, 1977) oder aber durch Reaktion von Azolen mit geeigneten Fluor-Nitro-benzolen in DMSO bei höherer Temperatur und in Gegenwart von Kaliumcarbonat hergestellt werden (M.F. Mackay, G.J. Trantino, J.F. Wilshire, Aust. J. Chem. 46, 417, 1993) .Bull. 25, 3110, 1977) or by reacting azoles with suitable fluoronitrobenzenes in DMSO at elevated temperature and in the presence of potassium carbonate (MF Mackay, GJ Trantino, JF Wilshire, Aust. J. Chem. 46, 417, 1993).
1-Arylindole mit aktivierenden Substituenten im Arylteil wurden durch Reaktion von Indol mit aktivierten Arylhaliden in Gegenwart von 37%KF/Al203 und katalytischen Mengen an Kronenether in DMSO bei 120°C erhalten (W.J. Smith, J. Scott Sawyer, Tetrahedron Lett. 37, 299, 1996) .1-Arylindoles with activating substituents in the aryl part were obtained by reacting indole with activated aryl halides in the presence of 37% KF / Al 2 0 3 and catalytic amounts of crown ether in DMSO at 120 ° C (WJ Smith, J. Scott Sawyer, Tetrahedron Lett 37, 299, 1996).
Beschrieben ist auch die Arylierung von Azolen mit aktivierten Arylhaliden in Gegenwart von Basen wie Cesiumcarbonat und Natrium-tert . -butylat , wobei jedoch zusätzlich die Anwesenheit von Palladiumkatalysatoren erforderlich ist und die Reaktion selbst hohe Temperaturen (65° bis 120°C) und lange Reaktionszeiten (3 bis 48The arylation of azoles with activated aryl halides in the presence of bases such as cesium carbonate and sodium tert is also described. -butylate, but the presence of palladium catalysts is also required and the reaction itself high temperatures (65 ° to 120 ° C) and long reaction times (3 to 48
Stunden) erfordert (G. Mann, J.F. Hartwig, M.S. Driver, C. Fernandez-Rivas, J. Am. Chem. Soc . 120, 827, 1998; I.P. Beletskaya, D.V. Davydov, M. Moreno-Manas, Tetrahedron Lett. 39, 5617, 1998) .Hours) (G. Mann, JF Hartwig, MS Driver, C. Fernandez-Rivas, J. Am. Chem. Soc. 120, 827, 1998; IP Beletskaya, DV Davydov, M. Moreno-Manas, Tetrahedron Lett. 39 , 5617, 1998).
Auch ist die Verwendung von Cesiumcarbonat als Reagenz bei Kohlenstoff-Heteroatom-Kupplungsreaktionen bekannt, jedoch müssen zusätzlich immer weitere spezielle Katalysatoren bei solchen Reaktionen verwendet werden (Christopher G. Frost, Paul Mendonca, J. Chem. Soc. , Perkin Trans. 1, 1998, 2615) .The use of cesium carbonate as a reagent in carbon-heteroatom coupling reactions is also known, but additional special catalysts must always be used in such reactions (Christopher G. Frost, Paul Mendonca, J. Chem. Soc., Perkin Trans. 1, 1998 , 2615).
Im allgemeinen kann aus den oben aufgeführten Beispielen gefolgert werden, daß für Arylierungen von Azolen mit aktivierten Arylhalogeniden häufig relativ drastische Bedingungen wie hohe Temperaturen, lange Reaktionszeiten sowie spezielle Katalysatoren erforderlich sind. Im Zusammenhang mit der Synthese einer potentiellen Anti- Cancer-Verbindung wurde von uns die Reaktion von Morpholinopropanol (III) mit o-Nitrofluorbenzol (II) untersucht (Schema 2) :In general, it can be concluded from the examples listed above that arylations of azoles with activated aryl halides often require relatively drastic conditions such as high temperatures, long reaction times and special catalysts. In connection with the synthesis of a potential anti-cancer compound, we examined the reaction of morpholinopropanol (III) with o-nitrofluorobenzene (II) (Scheme 2):
Schema 2Scheme 2
Basierend auf unseren Erfahrungen mit dem System Cesiumcarbonat/Dimethylformamid zur Herstellung von Carbonaten aus Alkoholen und Alkyl/Aryl-Halogeniden (DE 199 05 222.0) und von heterocyclischen Carbamaten aus Aza- Heterocyclen und Alky/Aryl-Halogeniden untersuchten wir, ob dieses System auch für obige Reaktion geeignet ist.Based on our experience with the cesium carbonate / dimethylformamide system for the production of carbonates from alcohols and alkyl / aryl halides (DE 199 05 222.0) and heterocyclic carbamates from aza heterocycles and alky / aryl halides, we examined whether this system was also suitable for the above reaction is suitable.
Überraschenderweise wurde gefunden, daß diese Reaktion bei 23 °C innerhalb von 48 Stunden in 82% Ausbeute zu dem gewünschten Produkt (IV) führt.Surprisingly, it was found that this reaction leads to the desired product (IV) in 48% yield at 23 ° C. within 48 hours.
Aufgrund dieses Befundes wurde nun untersucht, ob auch andere Nucleophile wie z.B. die Nucleophile V bis X mit 2- Fluornitrobenzol bei Raumtemperatur im System Cesiumcarbonat/Dirnethylformid miteinander reagieren: Abbildung 1Based on this finding, it has now been investigated whether other nucleophiles such as, for example, the nucleophiles V to X also react with 2-fluoronitrobenzene at room temperature in the cesium carbonate / dimethylformide system: illustration 1
VIII IX XVIII IX X
COOMeCOOMe
< XI<XI
COOMeCOOMe
Es wurde gefunden, daß auch diese Reaktionen bei Raumtemperatur innerhalb von 24 bis 64 Stunden in guten bis sehr guten Ausbeuten die gewünschten Produkte ergeben. Auch führte die Reaktion von 2 , 5-Difluornitrobenzol (XII) mit Malonsäuredimethylester (XI) bei Raumtemperatur im System Cesiumcarbonat/Dimethylformamid nach 24 Stunden in 98% Ausbeute zum gewünschte Produkt XIII (Schema 3) :It has been found that these reactions also give the desired products in good to very good yields at room temperature within 24 to 64 hours. The reaction of 2, 5-difluoronitrobenzene (XII) with dimethyl malonate (XI) at room temperature in the cesium carbonate / dimethylformamide system after 24 hours resulted in the desired product XIII in 98% yield (Scheme 3):
Schema 3Scheme 3
XII XIII Die Herstellung von Verbindung XIII ist in der Literatur beschrieben unter Verwendung von Natriumhydrid in Dimethylsulfoxid bei 100°C in 96% Ausbeute (Li Sun et al . , J. Med. Chem. 41, 2588, 1998) .XII XIII The preparation of compound XIII is described in the literature using sodium hydride in dimethyl sulfoxide at 100 ° C. in 96% yield (Li Sun et al., J. Med. Chem. 41, 2588, 1998).
Ermutigt durch diese Ergebnisse wurde nun die Arylierung von Aza-Heterocyclen mit aktivierten Aromaten der allgemeinen Formel XIVThe arylation of aza heterocycles with activated aromatics of the general formula XIV has now been encouraged by these results
in der R1 bis R5 die oben genannte Bedeutung haben und HAL für ein Halogenatom, insbesondere jedoch für ein Fluoratom steht, in dem System Cesiumcarbonat / Dirnethylformamid untersucht .in which R 1 to R 5 have the meaning given above and HAL stands for a halogen atom, but in particular for a fluorine atom, investigated in the system cesium carbonate / dimethyl formamide.
Überraschenderweise wurde gefunden, daß nahezu alle verwendeten Aza-Heterocyclen schon bei Raumtemperatur in Gegenwart von Cesiumcarbonat/Dimethylformamid mit aktivierten Fluoraromaten der allgemeinen Formel XV zu Verbindungen der allgemeinen Formel I reagieren Surprisingly, it was found that almost all the aza heterocycles used react with activated fluoroaromatics of the general formula XV to give compounds of the general formula I even at room temperature in the presence of cesium carbonate / dimethylformamide
Anstelle von Dimethylformamid können auch andere dipolar aprotische Lösemittel wie z.B. Dimethylacetamid, Acetonitril, Dimethylsulfoxid, Aceton oder N- Methylpyrrolidon, verwendet werden, die Reaktionszeiten bei Raumtemperatur sind dann jedoch deutlich länger und die Ausbeuten oft geringer.Instead of dimethylformamide, other dipolar aprotic solvents such as e.g. Dimethylacetamide, acetonitrile, dimethyl sulfoxide, acetone or N-methylpyrrolidone can be used, but the reaction times at room temperature are then significantly longer and the yields are often lower.
Die Vorgehensweise bei der präparativen Durchführung der Arylierung ist sehr einfach. Man löst equimolare Mengen an Aza-Heterocyclus und aktivierten Aromaten der allgemeinen Formel XIV, insbesondere jedoch der allgemeinen Formel XV, bei Raumtemperatur in einem geeigneten dipolar aprotischen Löungsmittel , insbesondere Dirnethylformamid, fügt einen 2 bis 4 molaren Überschuß an wasserfreiem Cesiumcarbonat hinzu und rührt bei Raumtemperatur solange, bis die Reaktion zu Ende ist. Die Reaktion wird mittels Dünnschichtchromatographie verfolgt . Bei weniger reaktionsfähigen Aromaten muß in wenigen Fällen die Reaktionstemperatur auf ca. 80°C erhöht werden.The procedure for the preparative arylation is very simple. Equimolar amounts of aza-heterocycle and activated aromatics of the general formula XIV, but especially of the general formula XV, are dissolved at room temperature in a suitable dipolar aprotic solvent, in particular dirnethylformamide, a 2 to 4 molar excess of anhydrous cesium carbonate is added and the mixture is stirred at room temperature until the reaction is over. The reaction is followed by thin layer chromatography. In the case of less reactive aromatics, the reaction temperature has to be raised to approximately 80 ° C. in a few cases.
Am Ende der Reaktion gießt man die Suspension auf Wasser, extrahiert das Produkt mit Essigester und reinigt das nach Eindampfen der organischen Phase erhaltene Rohprodukt mit den in der organischen Chemie üblichen Methoden z.B. durch Kristallisation oder Chromatographie. Die Erfindung wird durch die folgenden Ausführungsbeispiele veranschaulicht und erläutert:At the end of the reaction, the suspension is poured onto water, the product is extracted with ethyl acetate and the crude product obtained after evaporation of the organic phase is purified using the methods customary in organic chemistry, for example by crystallization or chromatography. The invention is illustrated and explained by the following exemplary embodiments:
Beispiel 1example 1
2-Morpholinopropyloxy-nitrobenzol2-morpholinopropyloxy-nitrobenzene
0.57 g 2-Fluornitrobenzol, 0.65 g Morpholinopropanol 3.0 g Cesiumcarbonat und 30 mL Dimethylformamid werden in einem verschlossenen 50 mL Rundkolben 2 Tage bei Raumtemperatur gerührt. Man gießt die Suspension auf 50 mL Wasser, extrahiert die wässrige Phase 3 mal mit jeweils 50 mL Essigester und engt die vereinigten organischen Phasen am Rotavapor ein. Zur Entfernung des Dirnethylformamids, das die chromatographische Trennung stören würde, wird der DMF- haltige Rückstand noch 2 bis 3 mal zusammen mit etwas0.57 g of 2-fluoronitrobenzene, 0.65 g of morpholinopropanol, 3.0 g of cesium carbonate and 30 ml of dimethylformamide are stirred in a sealed 50 ml round-bottomed flask for 2 days at room temperature. The suspension is poured onto 50 ml of water, the aqueous phase is extracted 3 times with 50 ml of ethyl acetate and the combined organic phases are concentrated on a rotavapor. To remove the dirnethylformamide, which would interfere with the chromatographic separation, the DMF-containing residue is added 2 to 3 times with something
Toluol bei 50°C und 30 mbar Vakuum eingeengt. Der ölige Rückstand wird dann an Kieselgel (0.04 bis 0.063 mm) bei 0.1 bar durch Flash-Chromatographie aufgereinigt . Man erhält 0.9 g Öl (82.4%) .Concentrated toluene at 50 ° C and 30 mbar vacuum. The oily residue is then purified on silica gel (0.04 to 0.063 mm) at 0.1 bar by flash chromatography. 0.9 g of oil (82.4%) are obtained.
Die folgenden Beispiele wurden in Analogie zu Beispiel 1 durchgefürt, es sind die folgenden Reaktionsparameter angegeben (Reaktionszeit / Eluent für Chromatographie / Ausbeute / physikal . Angaben) :The following examples were carried out in analogy to Example 1, the following reaction parameters are given (reaction time / eluent for chromatography / yield / physical data):
Beispiel 2Example 2
2-Dimethylaminoethyloxy-nitrobenzol aus 2-Fluornitrobenzol und 2-Dimethylaminoethanol2-Dimethylaminoethyloxy-nitrobenzene from 2-fluoronitrobenzene and 2-dimethylaminoethanol
64 h /Toluol-Ethanol 10 + 2 / 91.8% / Öl64 h / toluene-ethanol 10 + 2 / 91.8% / oil
Beispiel 3Example 3
2-Dimethylaminopropyloxy-nitrobenzol aus 2 - Fluornitrobenzol und 3 -Dimethylaminopropanol 48 h / Methylenchlorid-Methanol 10 + 2 / 58 . 7% / Öl2-dimethylaminopropyloxy-nitrobenzene from 2 - fluoronitrobenzene and 3 -dimethylaminopropanol 48 h / methylene chloride-methanol 10 + 2/58. 7% / oil
Beispiel 4 2- (3.3-Diethoxypropoxy) -nitrobenzol aus 2-Fluornitrobenzol und 3- Hydroxypropionaldehyddiethylacetal 64 h / Hexan-Essigester 10 + 2 / 83.7% / ÖlExample 4 2- (3.3-diethoxypropoxy) nitrobenzene from 2-fluoronitrobenzene and 3-hydroxypropionaldehyde diethylacetal 64 h / hexane-ethyl acetate 10 + 2 / 83.7% / oil
Beispiel 5Example 5
2 -Benzyloxy-nitrobenzol aus 2-Fluornitrobenzol und Benzylalkohol2-Benzyloxy-nitrobenzene from 2-fluoronitrobenzene and benzyl alcohol
24 h / Toluol / 95.7% / Öl24 h / toluene / 95.7% / oil
Beispiel 6Example 6
2 -Benzylamino-nitrobenzol aus 2-Fluornitrobenzol und Benzylamin2-Benzylamino-nitrobenzene from 2-fluoronitrobenzene and benzylamine
64 h / Hexan-Essigester 10 + 2 / 42.7% / Fp 74°C64 h / hexane-ethyl acetate 10 + 2 / 42.7% / mp 74 ° C
Beispiel 7Example 7
4-Fluor-2-nitrophenylmalonsäuredimethylester aus 2, 5 -Difluornitrobenzol und Malonsauredimethylester 24 h / Toluol -Ethanol 10 + 0.5 / 98% / Öl Beispiel 8 N-2 -Nitrophenyl -diphenylsulfoximid aus 2-Fluornitrobenzol und Diphenylsulfoximid 48 h/ Toluol -Ethanol 10 + 2 / 72% / Fp 158°CDimethyl 4-fluoro-2-nitrophenylmalonate from 2,5-difluoronitrobenzene and dimethyl malonate 24 h / toluene-ethanol 10 + 0.5 / 98% / oil Example 8 N-2-nitrophenyldiphenylsulfoximide from 2-fluoronitrobenzene and diphenylethanolsulfox 10 + 2/72% / mp 158 ° C
Beispiel 9 N-2 -Cyanphenyl -diphenylsulfoximid aus 2 Fluorbenzonitril und Diphenylsulfoximid bei 80°C 8 h /Toluol -Ethanol 10 + 1 / 74.3% / Fp 160 °C Beispiel 10Example 9 N-2-cyanophenyldiphenylsulfoximide from 2 fluorobenzonitrile and diphenylsulfoximide at 80 ° C for 8 h / toluene -ethanol 10 + 1 / 74.3% / mp 160 ° C Example 10
N-4 -Cyanphenyl -diphenylsulfoximid aus 4 -Fluorbenzonitril und Diphenylsulfoximid 64 h / Toluol-Ethanol 10 + 1 / 61.2% / Fp 159°CN-4-Cyanphenyl-diphenylsulfoximide from 4-fluorobenzonitrile and diphenylsulfoximide 64 h / toluene-ethanol 10 + 1 / 61.2% / mp 159 ° C
Beispiel 11Example 11
N-4-Nitrophenyl -diphenylsulfoximid aus 4-Fluornitrobenzol und Diphenylsulfoximid 64 h / Toluol -Ethanol 10 + 0.5 / 64.1% / Fp 166°CN-4-nitrophenyldiphenylsulfoximide from 4-fluoronitrobenzene and diphenylsulfoximide 64 h / toluene -ethanol 10 + 0.5 / 64.1% / mp 166 ° C
Beispiel 12Example 12
1- (2-Nitrophenyl) -indol aus 2-Fluornitrobenzol und Indol 24 h / Hexan-Essigester 10 + 2 / 90% / 81°C1- (2-nitrophenyl) indole from 2-fluoronitrobenzene and indole 24 h / hexane-ethyl acetate 10 + 2/90% / 81 ° C
Beispiel 13Example 13
1- (4 -Cyanphenyl) -pyrrol aus 4 -Fluorbenzonitril und Pyrrol bei 80°C 8 h / Toluol / 84.1% / 105°C1- (4-cyanophenyl) pyrrole from 4-fluorobenzonitrile and pyrrole at 80 ° C for 8 h / toluene / 84.1% / 105 ° C
Beispiel 14Example 14
1- (4 -Cyanphenyl ) -pyrrol aus 4 -Fluorbenzonitril und Pyrrol (bei Raumtemperatur) 64 h / Toluol / Toluol / 39.1% / 103°-104°C1- (4-cyanophenyl) pyrrole from 4-fluorobenzonitrile and pyrrole (at room temperature) 64 h / toluene / toluene / 39.1% / 103 ° -104 ° C
Beispiel 15Example 15
1- (4 -Cyanphenyl ) -indol aus 4 -Fluorbenzonitril und Indol 64 h / Toluol -Ethanol 10 + 1 / 100% / 93°-94°C1- (4-cyanophenyl) indole from 4-fluorobenzonitrile and indole 64 h / toluene-ethanol 10 + 1/100% / 93 ° -94 ° C
Beispiel 16 1 - (4 -Ethoxycarbonylphenyl ) - indol aus 4 -Fluorbenzoesäureethylester und Indol bei 80 °CExample 16 1 - (4-Ethoxycarbonylphenyl) indole from ethyl 4-fluorobenzoate and indole at 80 ° C
8 h / Hexan-Essigester 10 + 2 / 77 . 2 % / Fp 51 ° C8 h / hexane-ethyl acetate 10 + 2/77. 2% / mp 51 ° C
Beispiel 17Example 17
1- (2-Methoxycarbonylphenyl) -indol aus 2-Fluorbenzoesäuremethylester und Indol1- (2-methoxycarbonylphenyl) indole from 2-fluorobenzoic acid methyl ester and indole
64 h / Toluol / 20% / Öl64 h / toluene / 20% / oil
Beispiel 18Example 18
1- (4-Nitrophenyl) -indol aus 4-Fluornitrobenzol und Indol1- (4-nitrophenyl) indole from 4-fluoronitrobenzene and indole
64 h / Toluol / 98% / Fp 134°C64 h / toluene / 98% / mp 134 ° C
Beispiel 19Example 19
1- (2-Nitrophenyl) -indol-5-carbonsäuremethylester aus 2-Fluornitrobenzol und Indol-5-carbonsäuremethylester1- (2-nitrophenyl) indole-5-carboxylic acid methyl ester from 2-fluoronitrobenzene and indole-5-carboxylic acid methyl ester
64 h / Toluol -Ethanol 10 + 1 / 98% / Fp 89°C64 h / toluene-ethanol 10 + 1/98% / mp 89 ° C
Beispiel 20Example 20
1- (2-Nitrophenyl) -indol-3-carbonsäuremethylester aus 2-Fluornitrobenzol und Indol-3-carbonsäuremethylester1- (2-nitrophenyl) indole-3-carboxylic acid methyl ester from 2-fluoronitrobenzene and indole-3-carboxylic acid methyl ester
24 h / Toluol -Ethanol 10 + 1 / 96% / Fp 155°C24 h / toluene-ethanol 10 + 1/96% / mp 155 ° C
Beispiel 21Example 21
1- (2-Nitrophenyl) -indol-3-carbonitril aus 2-Fluornitrobenzol und Indol-3-carbonitril1- (2-nitrophenyl) indole-3-carbonitrile from 2-fluoronitrobenzene and indole-3-carbonitrile
24 h / Toluol-Ethanol 10 + 1 / 98% / Fp 151°C24 h / toluene-ethanol 10 + 1/98% / mp 151 ° C
Beispiel 22Example 22
1- (Benzotriazol-1-yl) -2 , 4-dinitrobenzol aus Fluor-2 , 4-dinitrobenzol und Benzotriazol 24 h / Toluol -Ethanol 10 + 1 / 85.5% / Fp 185°C1- (benzotriazol-1-yl) -2, 4-dinitrobenzene from fluoro-2, 4-dinitrobenzene and benzotriazole 24 h / toluene-ethanol 10 + 1 / 85.5% / mp 185 ° C
Beispiel 23Example 23
1- (Benzotriazol-1-yl) -2 , 4-dinitrobenzol aus Chlor-2 , 4-dinitrobenzol und Benzotriazol1- (benzotriazol-1-yl) -2, 4-dinitrobenzene from chloro-2, 4-dinitrobenzene and benzotriazole
24 h / Toluol-Ethanol 10 + 1 / 85.5% / Fp 185°C24 h / toluene-ethanol 10 + 1 / 85.5% / mp 185 ° C
Beispiel 24Example 24
1- (4-Nitrophenyl) -indol-3-aldehyd aus 4-Fluornitrobenzol und Indol-3-aldehyd1- (4-nitrophenyl) indole-3-aldehyde from 4-fluoronitrobenzene and indole-3-aldehyde
24 h / Kritallisation beim Aufarbeiten / 91.6% / Fp 269°C24 h / Crystallization during working up / 91.6% / mp 269 ° C
Beispiel 25Example 25
1- (4-Formylphenyl) -indol aus 4 -Fluorbenzaldehyd und Indol 48 h / Toluol / 7.7% / Öl1- (4-formylphenyl) indole from 4-fluorobenzaldehyde and indole 48 h / toluene / 7.7% / oil
Beispiel 26Example 26
1 - ( 2 -Methoxycarbonylphenyl ) - indol aus 2 - Fluorbenzoesäuremethylester und Indol bei 80 ° C1 - (2-methoxycarbonylphenyl) indole from 2-fluorobenzoic acid methyl ester and indole at 80 ° C
8 h / Hexan-Essigester 10 + 2 / 19 . 4 % / Öl8 h / hexane-ethyl acetate 10 + 2/19. 4% / oil
Beispiel 27Example 27
5-Methyl-l- (4-nitrophenyl) -indol aus 4-Fluornitrobenzol und 5-Methylindol 24 h / Toluol / 77.3% / Fp 147°C5-methyl-1- (4-nitrophenyl) indole from 4-fluoronitrobenzene and 5-methyl indole 24 h / toluene / 77.3% / mp 147 ° C.
Beispiel 28Example 28
5-Nitro-l- (4-nitrophenyl) -indol aus 4-Fluornitrobenzol und 5-Nitroindol5-nitro-1- (4-nitrophenyl) indole from 4-fluoronitrobenzene and 5-nitroindole
24 h / Kristallisation beim Aufarbeiten / 86.9% / Fp 235°C Beispiel 2924 h / crystallization during working up / 86.9% / mp 235 ° C Example 29
5-Chlor- 1- (2-nitrophenyl) -indol aus 2-Fluornitrobenzol und 5-Chlorindol 24 h / Toluol / 71.5% / Fp 142°C5-chloro-1- (2-nitrophenyl) indole from 2-fluoronitrobenzene and 5-chloroindole 24 h / toluene / 71.5% / mp 142 ° C
Beispiel 30Example 30
5-Methoxy-l- (2 -Cyanphenyl) -indol aus 2 -Fluorbenzonitril und 5-Methoxyindol 3 h / Toluol / 100% / Fp 99°C Beispiel 315-methoxy-1- (2-cyanophenyl) indole from 2-fluorobenzonitrile and 5-methoxyindole for 3 h / toluene / 100% / mp 99 ° C. Example 31
1- (2-Nitrophenyl) -pyrrol aus 2-Fluornitrobenzol und Pyrrol1- (2-nitrophenyl) pyrrole from 2-fluoronitrobenzene and pyrrole
64 h / Hexan-Essigester 10 + 2 / 68.6% / Fp 105°C64 h / hexane-ethyl acetate 10 + 2 / 68.6% / mp 105 ° C
Beispiel 32Example 32
5-Methoxy-l- (4-Nitrophenyl) -indol aus 4-Chlornitrobenzol und 5-Methoxyindol bei 80°C5-methoxy-1- (4-nitrophenyl) indole from 4-chloronitrobenzene and 5-methoxyindole at 80 ° C
8 h / Toluol / 27.2% / Fp 187°C8 h / toluene / 27.2% / mp 187 ° C
Beispiel 33Example 33
3 -Methyl -1- (4-nitrophenyl) -indol aus 4-Fluornitrobenzol und 3-Methylindol3-methyl -1- (4-nitrophenyl) indole from 4-fluoronitrobenzene and 3-methyl indole
24 h / Toluol / 84.1% / Fp 146°C24 h / toluene / 84.1% / mp 146 ° C
Beispiel 34Example 34
5-Methoxy-l- (4-Ethoxycarbonylphenyl) -indol aus 4-Fluorbenzoesäureethylester und 5-Methoxyindol bei 80°C5-methoxy-1- (4-ethoxycarbonylphenyl) indole from ethyl 4-fluorobenzoate and 5-methoxyindole at 80 ° C
8 h / Hexan-Essigester 10 + 2 / 68.5% / Öl8 h / hexane-ethyl acetate 10 + 2 / 68.5% / oil
Beispiel 35Example 35
5-Methoxy-l- (4-nitrophenyl) -indol aus 4-Fluornitrobenzol und 5-Methoxyindol5-methoxy-1- (4-nitrophenyl) indole from 4-fluoronitrobenzene and 5-methoxyindole
18 h / Kristallisation beim Aufarbeiten / 88.1% / Fp 188°C18 h / crystallization during working up / 88.1% / mp 188 ° C.
Beispiel 36 1- (2-Nitrophenyl) -indol-2-carbonsäureethylester aus 2-Fluornitrobenzol und Indol-2-carbonsäureethylester 58 h / Toluol / 47.9% / Fp 90°CExample 36 1- (2-nitrophenyl) indole-2-carboxylic acid ethyl ester from 2-fluoronitrobenzene and indole-2-carboxylic acid ethyl ester 58 h / toluene / 47.9% / mp 90 ° C.
Beispiel 37 1- (4-Nitrophenyl) -indol-2-carbonsäureethylester aus 4-Fluornitrobenzol und Indol-2-carbonsäureethylester bei 80°CExample 37 1- (4-nitrophenyl) indole-2-carboxylic acid ethyl ester from 4-fluoronitrobenzene and indole-2-carboxylic acid ethyl ester at 80 ° C.
8 h / Toluol / 78.5% / Fp 135°C8 h / toluene / 78.5% / mp 135 ° C
Beispiel 38Example 38
1- (3 -Nitrophenyl) -indol aus 3-Fluornitrobenzol und Indol bei 80°C1- (3-nitrophenyl) indole from 3-fluoronitrobenzene and indole at 80 ° C
6 h / Hexan-Essigester 10 + 2 / 72.9% / Fp 66°C6 h / hexane-ethyl acetate 10 + 2 / 72.9% / mp 66 ° C
Beispiel 39Example 39
1- (3 -Cyanphenyl ) -indol aus 3 -Fluorbenzonitril und Indol bei 80°C1- (3-cyanophenyl) indole from 3-fluorobenzonitrile and indole at 80 ° C
8 h / Toluol -Ethanol 10 + 1 / 55.8% / Fp 37°C8 h / toluene-ethanol 10 + 1 / 55.8% / mp 37 ° C
Beispiel 40Example 40
1- (2 -Cyanphenyl) -indol aus 2 -Fluorbenzonitril und Indol1- (2-cyanophenyl) indole from 2-fluorobenzonitrile and indole
64 h / Toluol / 100% / Fp 112°C64 h / toluene / 100% / mp 112 ° C
Beispiel 41Example 41
1- (2 -Nitrophenyl) -imidazol aus 2-Fluornitrobenzol und Imidazol 18 h / Toluol -Ethanol 10 + 2 / 92% / Fp 98°-99°C1- (2-nitrophenyl) imidazole from 2-fluoronitrobenzene and imidazole 18 h / toluene-ethanol 10 + 2/92% / mp 98 ° -99 ° C
Beispiel 42Example 42
1- (2 -Nitrophenyl) -benzimidazol aus 2-Fluornitrobenzol und Benzimidazol1- (2-nitrophenyl) benzimidazole from 2-fluoronitrobenzene and benzimidazole
18 h / Toluol -Ethanol 10 + 2 / 98.8% / Öl18 h / toluene-ethanol 10 + 2 / 98.8% / oil
Beispiel 43Example 43
1- (4 -Nitrophenyl) -indazol aus 4-Fluornitrobenzol und Indazol1- (4-nitrophenyl) indazole from 4-fluoronitrobenzene and indazole
18 h / Kristallisation beim Aufarbeiten / 92% / Fp 166°C18 h / crystallization during working up / 92% / mp 166 ° C.
Beispiel 44Example 44
N-2.4-Dinitrophenyl-carbazol aus 2.4-Dinitrofluorbenzol und CarbazolN-2.4-Dinitrophenyl-carbazole from 2.4-dinitrofluorobenzene and carbazole
18 h / Kristallisation beim Aufarbeiten / Fp 189°C18 h / crystallization during working up / mp 189 ° C.
Beispiel 45Example 45
1- (2 -Cyanphenyl) -1,2, 3-triazol aus 2 -Fluorbenzonitril und 1.2.3-Triazol1- (2-cyanophenyl) -1,2, 3-triazole from 2-fluorobenzonitrile and 1.2.3-triazole
24 h / Toluol + Ethanol 10 + 1 / 14.2% / Fp 112 °C24 h / toluene + ethanol 10 + 1 / 14.2% / mp 112 ° C
Beispiel 46Example 46
4- (4 -Cyanphenyl) -1.2.4-triazol aus 4 -Fluorbenzonitril und 1.2.4-Triazol4- (4-cyanophenyl) -1.2.4-triazole from 4-fluorobenzonitrile and 1.2.4-triazole
24 h / Toluol + Ethanol 10 + 2 / 14.2% / Fp 169°C24 h / toluene + ethanol 10 + 2 / 14.2% / mp 169 ° C
Beispiel 47Example 47
5-Chlor-l- (2 -cyanphenyl ) -indol aus 2 -Fluorbenzonitril und 5-Chlorindol 2 h / Toluol / 70.4% / Fp 129-130°C Beispiel 485-chloro-1- (2-cyanophenyl) indole from 2-fluorobenzonitrile and 5-chloroindole for 2 h / toluene / 70.4% / mp 129-130 ° C Example 48
1- (2-Pyridyl) -indol aus 2-Fluorpyridin und Indol bei 80°C1- (2-pyridyl) indole from 2-fluoropyridine and indole at 80 ° C
24 h / Toluol / 84.1% / Fp 58°C 24 h / toluene / 84.1% / mp 58 ° C

Claims

Patentansprücheclaims
1. Verfahren zur nucleophilen Substitution an aktivierten Aromaten der allgemeinen Formel XIV1. Process for nucleophilic substitution on activated aromatics of the general formula XIV
in der Rl, R2 , R3 , R4 und R5 gleich oder verschieden sind und ein Wasserstoffatom, eine Nitrogruppe, eine Cyanogruppe, eine Alkoxycarbonylgruppe mit bis zu 5 C Atomen, eine Aldehydgruppe, eine Alkylcarbonylgruppe mit bis zu 5 C-Atomen, eine Arylcarbonylgruppe oder eine Amidgruppe bedeuten, wobei die Reste Rl bis R5 nicht alle gleichzeitig ein Wasserstoffatom sein können und HAL für ein Halogenatom steht, mit Nucleophilen wie Alkoholen, Aminen, Sulfoximiden, CH- aciden Verbindungen der Formeln V bis XI in which Rl, R2, R3, R4 and R5 are the same or different and are a hydrogen atom, a nitro group, a cyano group, an alkoxycarbonyl group with up to 5 C atoms, an aldehyde group, an alkylcarbonyl group with up to 5 C atoms, an arylcarbonyl group or mean an amide group, where the radicals Rl to R5 cannot all be a hydrogen atom at the same time and HAL represents a halogen atom, with nucleophiles such as alcohols, amines, sulfoximides, CH-acidic compounds of the formulas V to XI
Abbildung 1illustration 1
VIII IXVIII IX
.COOMe.COOMe
< COOMe XI<COOMe XI
in dipolar aprotischen Lösungsmitteln in Gegenwart von Cesiumcarbonat bei Raumtemperatur.in dipolar aprotic solvents in the presence of cesium carbonate at room temperature.
Verfahren gemäß Anspruch 1 zur Herstellung von Verbindungen der allgemeinen Formel IA process according to claim 1 for the preparation of compounds of general formula I.
II.
in der HETN einen aromatischen Aza-Heterocyclus mit insgesamt 5 oder 6 Ringatomen bedeutet, wobei bis zu 3 Ringatome Stickstoffatome sein können, und bis zu zwei weitere aromatische Kohlenstoffringe am Heterocyclus ankondensiert sein können und Rl , R2 , R3 , R4 und R5 die oben genannte Bedeutung haben.in the HETN means an aromatic aza heterocycle with a total of 5 or 6 ring atoms, where up to 3 ring atoms can be nitrogen atoms, and up to two further aromatic carbon rings on the heterocycle can be condensed and Rl, R2, R3, R4 and R5 have the meaning given above.
3. Verfahren gemäß der Ansprüche 1 oder 2 , dadurch gekennzeichnet, daß das Lösungsmittel Aceton,3. The method according to claims 1 or 2, characterized in that the solvent is acetone,
Acetonitril, Dimethylsulfoxid, Dimethylacetamid, N- Methylpyrrolidon oder Dimethylformamid ist.Acetonitrile, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide.
4. Verfahren gemäß der Ansprüche 1 oder 2 , dadurch gekennzeichnet, daß das Lösungsmittel Dimethylformamid ist .4. The method according to claims 1 or 2, characterized in that the solvent is dimethylformamide.
5. Verfahren gemäß der Ansprüche 1 oder 2 , dadurch gekennzeichnet, daß HAL in der allgemeinen Formel XIV ein Fluoratom bedeutet. 5. The method according to claims 1 or 2, characterized in that HAL in the general formula XIV represents a fluorine atom.
EP00916872A 1999-03-30 2000-02-25 Method for arylating aza-heterocycles with activated aromatic compounds in the presence of cesium carbonate Withdrawn EP1165512A2 (en)

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