US3801580A - Process for the alkylation of the pyridine ring - Google Patents

Process for the alkylation of the pyridine ring Download PDF

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US3801580A
US3801580A US00191781A US3801580DA US3801580A US 3801580 A US3801580 A US 3801580A US 00191781 A US00191781 A US 00191781A US 3801580D A US3801580D A US 3801580DA US 3801580 A US3801580 A US 3801580A
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F Minisci
F Bertini
R Galli
A Quilico
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Montedison SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to a process for alkylating pyridine derivatives and, more particularly, to a process for the alkylation of pyridine derivatives having at least one free position of the three that are alpha and gamma with respect to the heterocyclic nitrogen atom.
  • the alkyl derivatives of pyridine may be profitably used in various fields of technology. Particularly interesting is their use as intermediates for dyestuffs, weed killers and pesticides.
  • methylation in the alpha position with respect to the nitrogen may be etfected by passing a mixture of pyridine and methanol in a great excess over a catalyst based on Ni/Ni0 at 300 C.
  • the pyridines may also be methylated by means of a mixture of CO and H in the presence of nickel at a temperature between 150 and 400 C.
  • Another object of this invention is to provide a process for obtaining alkyland cycloalkyl derivatives at high yields with respect to the starting pyridine compound.
  • a process for alklating the pyridine derivatives (including pyridine itself) and for obtaining alkyland cycloalkyl derivatives having the alkyl or cycloalkyl group in a 2, 4 or 6 position with respect to the heterocyclic nitrogen atom, the process consisting essentially in reacting the pyridine derivative in an aqueous solution with a carboxylic acid R*COOH in which R is an alkyl or a cycloalkyl group having from 1 to 17 carbon atoms, in the presence of an alkaline or ammonium persulphate and of catalytic quantities of Ag+ ions, at atmospheric pressure and at temperatures between 40 and 100 C.
  • R*COOH carboxylic acid
  • pyridine derivatives, pyridine compounds, etc. are to be taken as including pyridine itself.
  • the aqueous mixture of pyridine derivative, carboxylic acid and silver salt is heated up to the processing temperature and is treated with the alakline or ammonium persulphate solution.
  • the mixture is refluxed in order to complete the reaction.
  • the time required for this operation is :between 30 and minutes. 'Ihereupon the excess carboxylic acid is recovered from the reaction mixture by distillation or extraction with a solvent, and then is alkalinized in order to separate the mixture of basic products which are fractionated by rectification or by gas chromatography.
  • the reaction may be represented in thte following
  • the pyridine derivative may be conveniently employed in the form of a salt with the same carboxylic acid or by a mineral acid.
  • the salification makes it possible to operate in an aqueous solution with those pyridine derivatives which are only slightly soluble in Water as the free base and to increase the reactivity of the heterocyclic ring.
  • pyridine derivative to be alkylated one may use any compound containing a pyridine ring having at least one of the three positions 2, 4 and 6 free for alkylation.
  • the pyridine derivative employed as starting material may contain various substituents such as for instance: alkyl, cycloalkyl, halogen, cyano, alkoxy, esters (alkoxy carbonyl), amide, etc.
  • the pyridine ring may be joined with aromatic ring systems as, for instance, in the derivatives of quinoline, isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, etc.
  • carboxylic acids suitable for use in this invention are carboxylic acids -RCOOH of the saturated type in which the R group is an alkyl group (which may be either primary, secondary or tertiary) or cycloalkyl, and containing from 1 to 17 carbon atoms.
  • persulphate ions As a source of persulphate ions, one preferably uses a persulphate of ammonium or an alkaline persulphate as, for instance, potassium persulphate.
  • the molar ratio between the pyridine derivative and the persulphate depends on the nature both of the starting pyridine compound and of the end product that one Wishes to obtain. When positions 2,4 or 2,6 are already substituted, only one of the reactive positions of the pyridine ring (alpha and gamma with respect to the heterocyclic nitrogen atom) is free for substitution. It is thus possible to attain without drawbacks total conversion of the starting pyridine derivative, thereby obtaining a single end product. In such a case the ratio between the pyridine derivative and the persulphate is preferably between 1 and 0.2.
  • ratio between the pyridine derivative and the persulphate shall preferably be maintained between 0.5 and 0.1.
  • the molar ratio between the pyridine derivative and the canboxylic acid is between 1 and 0.1.
  • a mineral acid such as for instance sulphuric acid
  • the molar ratio between the Ag+ ion and the ammonium or alkaline persulphate is preferably between 0.01 and 0.1.
  • the catalytic action of the Ag salt is an indispensable condition for ensuring that the reaction will result in yields that are practically acceptable; in the absence of a catalyst the process either does not take place at all or it takes place with very poor yields.
  • EXAMPLE 1 A solution, containing 0.3 mole of pyridine, 0.3 mole of sulphuric acid, 0.5 mole of propionic acid, C H -COOH, and 0.01 mole of silver nitrate in 70 cc. of water, was treated for 30 minutes at 70-80 C. with an aqueous solution saturated with 0.1 mole of ammonium persulphate. This solution was then heated under reflux conditions for a further 30 minutes and thereafter the excess propionic acid was recovered by distillation. The residual solution was alkalinized in order to separate the basic products which turn out to consist of pyridine, 2- ethyl-pyridine and 4-ethyl-pyridine.
  • the yield with respect to the converted pyridine is quantitative, while the yield with reference to the ammonium persulphate is 40%
  • the 2-ethyl-pyridine/4-ethylpyridine ratio was 1.3.
  • EXAMPLE 2 A solution of 0.1 mole of 4-cyano-pyridine, 0.1 mole of sulphuric acid, 0.5 mole of propionic acid and 0.01 mole of silver nitrate was treated in the same way as in Example 1, with an aqueous solution saturated with 0.1 mole of ammonium persulphate.
  • the reaction product thus obtained turned out to consist of three (3) components: 4-cyano-pyridine, Z-ethyl- 4-cyanopyridine and 2,6 diethyl-4-cyano-pyridine.
  • the yield with respect to the converted 4-cyano-pyridine is quantitative; the yield with respect to the ammonium persulphate is 50%; while the monoethyl-derivative/diethylderivative ratio was 4.
  • EXAMPLE 3 This test was carried out by following the same procedure as in Example 2, but using isobutyric acid, (CH )gCH-COH, instead of propionic acid. Here also the yield with respect to the converted 4-cyano-pyridine was quantitative, while the yield with respect to the ammonium persulphate is 60%. The ratio between the 2- isopropyl-4-cyanopyridine and the 2,6-diisopropyl-4- cyano-pyridine is 3.6.
  • EXAMPLE 4 This example was carried out by following the same procedures as in Example 2, but using pivalic acid, (CH CCOOH, instead of propionic acid. The yield proved to be quantitative with respect to the 4-cyanopyridine and 78% with reference to the ammonium persulphate. The 2-t-butyl-4-cyano-pyridine/2,6-di-t-butyl-4- cyano-pyridine ratio is9.
  • EXAMPLE 5 This test was carried out with propionic acid as in Example 2, but using the ethyl ester of isonicotinic acid instead of the 4-cyano-pyridine. A 55% yield of the 2-ethyland the 2,6-diethyl-derivatives was obtained with respect to the ammonium persulphate, the ratio between these two derivatives being 4.8. The yield with respect to the converted isonicotinic acid ethyl ester was prac-, tically quantitative.
  • EXAMPLE 8 0.3 mole of 4-methylpyridine, 0.3 mole of sulphuric acid, 1 mole of valeric acid, CH (CH COOH, and 0.01 mole of silver nitrate in cc. of water were treated for 50 minutes at 80 C. with an aqueous solution saturated with 0.1 mole of ammonium persulphate. At the end of the addition the mixture was left to rest at 80 C. for another 20 minutes. It was then cooled down and then the excess of valeric acid was extracted with ether and then recovered. Thereupon the mixture was alkalinized and in this way there were obtained two basic products: the starting 4-methylpyridine and 2-n-butyl-4- methylpyridine.
  • Example 9 Here Example 8 was repeated, but using 1 mole of ammonium persulphate per 0.1 mole of 4-methylpyridine. In this way there was obtained 2,6-di-n-butyl-4-methylpyridine with a yield of 76% based on the starting 4-methylpyridine.
  • EXAMPLE 10 The same procedures as in Example 8 operating with valeric acid were followed, but using 4-methoxy-pyridine instead of 4-methylpyridine.
  • the yield in 2-n-butyl-4- methoxy-pyridine was quantitative with respect to the converted 4-methoxy-pyridine while it was 32% with respect to the ammonium persulphate.
  • EXAMPLE 11 0.1 mole of quinoline, 1 mole of butyric acid and 0.01 mole of silver nitrate in cc. of water, were treated for 1 hour at 70 C. with an aqueous solution saturated with 0.8 mole of ammonium persulphate. In this way a 67% yield of 2,4-di-n-propyl-quinoline was obtained based on the quinoline used.
  • EXAMPLE 12 0.1 mole of Z-methylquinoline, 0.6 mole of valeric acid and 0.006 mole of silver nitrate in 100 cc. of water, were treated under reflux with an aqueous solution saturated with 0.3 mole of ammonium persulphate for 50 minutes. In this way a 72% yield of 2-methyl-4-n-butyl-quinoline was obtained based on the Z-methylquinoline used.
  • EXAMPLE 15 0.1 mole of 2-chloroquinoline, 0.1 mole of sulphuric acid, 0.01 mole of silver nitrate and 1 mole of butyric acid in 150 cc. of water were treated for 45 minutes at 70 C. with 0.2 mole of an aqueous solution saturated with ammonium persulphate. In this way an 83% yield of 2- chloro-4-n-propylquinoline was obtained.
  • EXAMPLE 16 0.3 mole of isoquinoline, 0.3 mole of sulphuric acid, 1 mole of butyric acid and 0.01 mole of silver nitrate in 130 cc. of water were treated for 70 minutes at 65 C. with an aqueous solution saturated with ammonium persulphate. In this way an 87% yield of l-n-propyl-isoquinoline was obtained with respect to the starting isoquinoline.
  • a process for alkylating a nitrogen heterocyclic compound to obtain alkyl and cycloalkyl derivatives thereof in which the alkyl or cycloalkyl group is in at least one of the 2, 4, and 6 positions with respect to the heterocyclic nitrogen atom comprising reacting a pyridine compound selected from the group consisting of pyridine, quinoline, isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, 4- cyanopyridine, the ethyl ester of isonicotinic acid, 4,4'-dipyridine, 4-methylpyridine, 4-methoxypyridine, 2-methylquinoline, 4-methylquino1ine and 2-ch1oroquinoline in a salified form in an aqueous solution, with a carboxylic acid, RCOOH wherein R is an alkyl or a cycloalcyl group having 1 to 17 carbon atoms,

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Abstract

A PROCESS IS DISCLOSED FOR ALKYLATING PYRIDINE DERIVATIVES (INCLDING PYRIDINE) AND FOR OBTAINING ALKYL- AND CYCLOALKYL-DERIVATIVES OF PYRIDINE IN WHICH THE ALKYL OF CYCLOALKYL GROUP IS IN A 2, 4 OR 6 POSITION WITH RESPECT TO THE HETEROCYCLIC NIITROGEN ATOM, WHEREIN THE PYRIDINE DERIVATIVE IS REACTED IN AN AQUEOUS SOLUTION WITH A CARBOXYLIC ACID, R-COOH, WHEREIN R IS AN ALKYL OR A CYCLOALKYL GROUP HAVING FROM 1 TO 17 CARBON ATOMS, IN THE PRESENCE OF AN ALKALINE OR AMMONIUM PERSULPHATE AND OF CATALYTIC QUANTITIES OF AG+ IONS, AT ATMOSPHERIC PRESSURE AND AT TEMPERATURES BETWEEN 40* C. AND 100* C.

Description

United States Patent Int. Cl. C07d 31/20, 33/30, 35/22 US. Cl. 260-290 R Claims ABSTRACT OF THE DISCLOSURE A process is disclosed for alkylating pyridine derivatives '(inclding pyridine) and for obtaining alkyland cycloalkyl-derivatives of pyridine in which the alkyl of cycloalkyl group is in a 2, 4 or 6 position with respect to the heterocyclic niitrogen atom, wherein the pyridine derivative is reacted in an aqueous solution with a carboxylic acid, RCOOH, wherein R is an alkyl or a cycloalkyl group having from 1 to 17 carbon atoms, in the presence of an alkaline or ammonium persulphate and of catalytic quantities of Ag+ ions, at atmospheric pressure and at temperatures between 40 C. and 100 C.
The present invention relates to a process for alkylating pyridine derivatives and, more particularly, to a process for the alkylation of pyridine derivatives having at least one free position of the three that are alpha and gamma with respect to the heterocyclic nitrogen atom.
The alkyl derivatives of pyridine may be profitably used in various fields of technology. Particularly interesting is their use as intermediates for dyestuffs, weed killers and pesticides.
Various processes are already known for alkylating pyridine and its derivatives. For example, methylation in the alpha position with respect to the nitrogen may be etfected by passing a mixture of pyridine and methanol in a great excess over a catalyst based on Ni/Ni0 at 300 C. The pyridines may also be methylated by means of a mixture of CO and H in the presence of nickel at a temperature between 150 and 400 C. Moreover, it is also known to react the pyridine with carboxylic acids and with their lead salts in the presence of a substance having an active hydrogen as a catalyst, for instance methanol, at a temperature between 80 and 120 C.
All these known processes have, however, the drawback of giving only poor yields of the desired alkyl derivatives.
It is an object of the present invention to provide a process for the alkylation of pyridine derivatives that shall be free of the drawbacks of the known processes and that shall at the same time be simple and cheap.
Another object of this invention is to provide a process for obtaining alkyland cycloalkyl derivatives at high yields with respect to the starting pyridine compound.
According to this invention, a process is provided for alklating the pyridine derivatives (including pyridine itself) and for obtaining alkyland cycloalkyl derivatives having the alkyl or cycloalkyl group in a 2, 4 or 6 position with respect to the heterocyclic nitrogen atom, the process consisting essentially in reacting the pyridine derivative in an aqueous solution with a carboxylic acid R*COOH in which R is an alkyl or a cycloalkyl group having from 1 to 17 carbon atoms, in the presence of an alkaline or ammonium persulphate and of catalytic quantities of Ag+ ions, at atmospheric pressure and at temperatures between 40 and 100 C. For the sake of brevity, unless indicated otherwise by the context the expressions pyridine derivatives, pyridine compounds, etc., are to be taken as including pyridine itself.
According to a preferred embodiment of the invention, the aqueous mixture of pyridine derivative, carboxylic acid and silver salt is heated up to the processing temperature and is treated with the alakline or ammonium persulphate solution. Optionally, the mixture is refluxed in order to complete the reaction. The time required for this operation is :between 30 and minutes. 'Ihereupon the excess carboxylic acid is recovered from the reaction mixture by distillation or extraction with a solvent, and then is alkalinized in order to separate the mixture of basic products which are fractionated by rectification or by gas chromatography.
The reaction may be represented in thte following The pyridine derivative may be conveniently employed in the form of a salt with the same carboxylic acid or by a mineral acid. The salification makes it possible to operate in an aqueous solution with those pyridine derivatives which are only slightly soluble in Water as the free base and to increase the reactivity of the heterocyclic ring. The salification by mineral acids, such as for instance, sulphuric acid, or by strong organic acids, such as halogen-acetic acids (e.g., trichloroacetic acid), becomes necessary in the case of pyridine derivatives which are only slightly basic owing to the presence of electronat-tracting substituents.
As the pyridine derivative to be alkylated, one may use any compound containing a pyridine ring having at least one of the three positions 2, 4 and 6 free for alkylation. The pyridine derivative employed as starting material may contain various substituents such as for instance: alkyl, cycloalkyl, halogen, cyano, alkoxy, esters (alkoxy carbonyl), amide, etc.
The pyridine ring may be joined with aromatic ring systems as, for instance, in the derivatives of quinoline, isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, etc.
The carboxylic acids suitable for use in this invention are carboxylic acids -RCOOH of the saturated type in which the R group is an alkyl group (which may be either primary, secondary or tertiary) or cycloalkyl, and containing from 1 to 17 carbon atoms.
As a source of persulphate ions, one preferably uses a persulphate of ammonium or an alkaline persulphate as, for instance, potassium persulphate.
The molar ratio between the pyridine derivative and the persulphate depends on the nature both of the starting pyridine compound and of the end product that one Wishes to obtain. When positions 2,4 or 2,6 are already substituted, only one of the reactive positions of the pyridine ring (alpha and gamma with respect to the heterocyclic nitrogen atom) is free for substitution. It is thus possible to attain without drawbacks total conversion of the starting pyridine derivative, thereby obtaining a single end product. In such a case the ratio between the pyridine derivative and the persulphate is preferably between 1 and 0.2.
When more than one of the reactive positions 2, 4 and 6 is free, it is possible to obtain both monoalkylated as well as dialkylated products. -In order to promote the formation of monoalkylation products and to reduce the formation of polyalkylation products, it will be necessary to achieve partial conversions of the starting product. This result may be attained by maintaining the pyridine derivative/persulphate ratio preferably between 3 and 1, while, for obtaining dialkylation products, the
ratio between the pyridine derivative and the persulphate shall preferably be maintained between 0.5 and 0.1.
The molar ratio between the pyridine derivative and the canboxylic acid is between 1 and 0.1. \When, for the salification, a mineral acid such as for instance sulphuric acid is used, in general there are used from 1 to 2 moles of acid per one mole of pyridine derivative.
The molar ratio between the Ag+ ion and the ammonium or alkaline persulphate is preferably between 0.01 and 0.1. The catalytic action of the Ag salt is an indispensable condition for ensuring that the reaction will result in yields that are practically acceptable; in the absence of a catalyst the process either does not take place at all or it takes place with very poor yields.
The following detailed working examples will serve still further to illustrate the invention.
EXAMPLE 1 A solution, containing 0.3 mole of pyridine, 0.3 mole of sulphuric acid, 0.5 mole of propionic acid, C H -COOH, and 0.01 mole of silver nitrate in 70 cc. of water, was treated for 30 minutes at 70-80 C. with an aqueous solution saturated with 0.1 mole of ammonium persulphate. This solution was then heated under reflux conditions for a further 30 minutes and thereafter the excess propionic acid was recovered by distillation. The residual solution was alkalinized in order to separate the basic products which turn out to consist of pyridine, 2- ethyl-pyridine and 4-ethyl-pyridine.
The yield with respect to the converted pyridine is quantitative, while the yield with reference to the ammonium persulphate is 40% The 2-ethyl-pyridine/4-ethylpyridine ratio was 1.3.
EXAMPLE 2 A solution of 0.1 mole of 4-cyano-pyridine, 0.1 mole of sulphuric acid, 0.5 mole of propionic acid and 0.01 mole of silver nitrate was treated in the same way as in Example 1, with an aqueous solution saturated with 0.1 mole of ammonium persulphate.
The reaction product thus obtained turned out to consist of three (3) components: 4-cyano-pyridine, Z-ethyl- 4-cyanopyridine and 2,6 diethyl-4-cyano-pyridine.
The yield with respect to the converted 4-cyano-pyridine is quantitative; the yield with respect to the ammonium persulphate is 50%; while the monoethyl-derivative/diethylderivative ratio was 4.
EXAMPLE 3 This test was carried out by following the same procedure as in Example 2, but using isobutyric acid, (CH )gCH-COH, instead of propionic acid. Here also the yield with respect to the converted 4-cyano-pyridine was quantitative, while the yield with respect to the ammonium persulphate is 60%. The ratio between the 2- isopropyl-4-cyanopyridine and the 2,6-diisopropyl-4- cyano-pyridine is 3.6.
EXAMPLE 4 This example was carried out by following the same procedures as in Example 2, but using pivalic acid, (CH CCOOH, instead of propionic acid. The yield proved to be quantitative with respect to the 4-cyanopyridine and 78% with reference to the ammonium persulphate. The 2-t-butyl-4-cyano-pyridine/2,6-di-t-butyl-4- cyano-pyridine ratio is9.
EXAMPLE 5 This test was carried out with propionic acid as in Example 2, but using the ethyl ester of isonicotinic acid instead of the 4-cyano-pyridine. A 55% yield of the 2-ethyland the 2,6-diethyl-derivatives was obtained with respect to the ammonium persulphate, the ratio between these two derivatives being 4.8. The yield with respect to the converted isonicotinic acid ethyl ester was prac-, tically quantitative.
EXAMPLE 6 In this case the same procedures as in Example 2 were followed, but here using butyric acid,
CH (CH -COOH instead of propionic acid and ethyl isonicotinate instead of 4-cyanopyridine. The yield with respect to the monoand di-n-propylderivatives was 48% with respect to the ammonium persulphate, thereof consisting of the 2-propylderivative and 20% of the 2,6-dipropylderivative.
EXAMPLE 7 By operating according to Example 2 with propionic acid, but using 4,4-dipyridyl (4,4'-dipyridine) instead of 4-cyano-pyridine, the yield with respect to the ammonium persulphate was 45%. 70% of the reaction product consisted of 2-ethyl-4,4'-dipyridyl and 30% consisted of 2,2- diethyl-4,4-dipyridyl.
EXAMPLE 8 0.3 mole of 4-methylpyridine, 0.3 mole of sulphuric acid, 1 mole of valeric acid, CH (CH COOH, and 0.01 mole of silver nitrate in cc. of water were treated for 50 minutes at 80 C. with an aqueous solution saturated with 0.1 mole of ammonium persulphate. At the end of the addition the mixture was left to rest at 80 C. for another 20 minutes. It was then cooled down and then the excess of valeric acid was extracted with ether and then recovered. Thereupon the mixture was alkalinized and in this way there were obtained two basic products: the starting 4-methylpyridine and 2-n-butyl-4- methylpyridine.
The yield with respect to the converted 4-methylpyridine was practically quantitative, while the yield with respect to the ammonium persulphate was 43%.
EXAMPLE 9 Here Example 8 was repeated, but using 1 mole of ammonium persulphate per 0.1 mole of 4-methylpyridine. In this way there was obtained 2,6-di-n-butyl-4-methylpyridine with a yield of 76% based on the starting 4-methylpyridine.
EXAMPLE 10 The same procedures as in Example 8 operating with valeric acid were followed, but using 4-methoxy-pyridine instead of 4-methylpyridine. The yield in 2-n-butyl-4- methoxy-pyridine was quantitative with respect to the converted 4-methoxy-pyridine while it was 32% with respect to the ammonium persulphate.
EXAMPLE 11 0.1 mole of quinoline, 1 mole of butyric acid and 0.01 mole of silver nitrate in cc. of water, were treated for 1 hour at 70 C. with an aqueous solution saturated with 0.8 mole of ammonium persulphate. In this way a 67% yield of 2,4-di-n-propyl-quinoline was obtained based on the quinoline used.
EXAMPLE 12 0.1 mole of Z-methylquinoline, 0.6 mole of valeric acid and 0.006 mole of silver nitrate in 100 cc. of water, were treated under reflux with an aqueous solution saturated with 0.3 mole of ammonium persulphate for 50 minutes. In this way a 72% yield of 2-methyl-4-n-butyl-quinoline was obtained based on the Z-methylquinoline used.
EXAMPLE 13 The same procedures were followed as in Example 12, using, however, cyclohexane-carboxylic acid, C H COOH instead of valeric acid. In this way a 68% yield of 2- methyl-4-cyclohexylquinoline Was obtained based on the Z-methylquinoline.
EXAMPLE 14 The same procedures as in Example 12 were followed here, but using 4-methylquinoline instead of 2-methylquinoline. There was obtained similarly 2-n-butyl-4-methylquinoline with a yield of 70%.
EXAMPLE 15 0.1 mole of 2-chloroquinoline, 0.1 mole of sulphuric acid, 0.01 mole of silver nitrate and 1 mole of butyric acid in 150 cc. of water were treated for 45 minutes at 70 C. with 0.2 mole of an aqueous solution saturated with ammonium persulphate. In this way an 83% yield of 2- chloro-4-n-propylquinoline was obtained.
EXAMPLE 16 0.3 mole of isoquinoline, 0.3 mole of sulphuric acid, 1 mole of butyric acid and 0.01 mole of silver nitrate in 130 cc. of water were treated for 70 minutes at 65 C. with an aqueous solution saturated with ammonium persulphate. In this way an 87% yield of l-n-propyl-isoquinoline was obtained with respect to the starting isoquinoline.
What is claimed is:
1. A process for alkylating a nitrogen heterocyclic compound to obtain alkyl and cycloalkyl derivatives thereof in which the alkyl or cycloalkyl group is in at least one of the 2, 4, and 6 positions with respect to the heterocyclic nitrogen atom comprising reacting a pyridine compound selected from the group consisting of pyridine, quinoline, isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, 4- cyanopyridine, the ethyl ester of isonicotinic acid, 4,4'-dipyridine, 4-methylpyridine, 4-methoxypyridine, 2-methylquinoline, 4-methylquino1ine and 2-ch1oroquinoline in a salified form in an aqueous solution, with a carboxylic acid, RCOOH wherein R is an alkyl or a cycloalcyl group having 1 to 17 carbon atoms,
in the presence of an alkaline or ammonium persulphate, and
of catalytic quantities of Ag+ ions,
at atmospheric pressure, and
at temperatures between C. and C.
2. A process according to claim 1, wherein the starting pyridine compound is employed in the form of a salt of a mineral acid.
3. A process according to claim 1, wherein the molar ratio between the pyridine compound and the carboxylic acid varies from 1 to 0.1.
4. A process according to claim 1, wherein the alkaline persulphate is potassium persulphate.
5. A process according to claim 1, wherein the molar ration Ag+ persulphate is from 0.01 to 0.1.
6. A process according to claim 1, wherein the starting pyridine compound has only a single reactive position and wherein the ratio between the pyridine compound and the ammonium persulphate is between 1 and 0.2.
7. A process for obtaining mono-alkylderivatives of pyridine according to claim 1, wherein when the starting pyridine compound has several reactive positions, the molar ratio between the pyridine compound and the ammonium persulphate is between 3 and l.
8. A process for obtaining dialkyl-derivatives of pyridine according to claim 1, wherein when the starting pyridine compound has several reactive positions, the molar ratio between the pyridine compound and the ammonium persulphate is between 0.5 and 0.1.
References Cited UNITED STATES PATENTS 3,428,641 2/l969 Myerly et al 260290 HARRY I. MOATZ, Primary Examiner US. Cl. X.R.
260279 R, 283 R, 294.9, 295 R, 296 D, 297 R
US00191781A 1970-10-27 1971-10-22 Process for the alkylation of the pyridine ring Expired - Lifetime US3801580A (en)

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US4628088A (en) * 1984-07-17 1986-12-09 Eli Lilly And Company Preparation of substituted pyridazines

Cited By (1)

* Cited by examiner, † Cited by third party
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