Process for the production of substituted phenylpyridines

Details Process for the production of substituted phenylpyridines Process for the production of substituted phenylpyridines

1999-03-10

2001-01-02

Seaman, D. Margaret (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Utility Patent

active

06169184

ABSTRACT:

DESCRIPTION
The present invention relates to a novel process for preparing substituted phenylpyridines of the formula I
where
R
1
is hydrogen, fluorine, chlorine or haloalkyl,
R
2
is fluorine, chlorine or haloalkyl,
R
3
is hydrogen, halogen or an organic radical that is inert under the reaction conditions,
R
4
is alkyl, haloalkyl, halogen, alkylsulfonyl, haloalkylsulfonyl or haloalkoxy, and
R
5
is hydrogen, halogen, haloalkyl, haloalkoxy, alkylsulfonyl or haloalkylsulfonyl.
The compounds I are intermediates for herbicides, but they can also be used as herbicides in their own right (WO-A 95/02580).
Various synthetic routes are known for preparing phenyl-substituted heterocycles. For instance, 2-bromopyridine can be converted using activated zinc into the corresponding 2-pyridylzinc bromide which can then be coupled with excess iodobenzene in a palladium-catalyzed reaction to give 2-phenylpyridine in moderate yield [THL 33 (1992) 5373; J. Org. Chem. 56 (1991) 1445].
This reaction requires bromoheterocycles which are often difficult to obtain; for example, according to JP-A 81/115776, 2-bromo-3-chloro-5-trifluoromethylpyridine, is obtained in a yield of only 10%. In addition, expensive iodine building blocks are required as aromatic component. Finally, owing to the high cost of the palladium catalyst, laborious recovery procedures are required.
Another method is coupling of a phenylboronic acid with an aromatic or heterocyclic bromine compound (Synthesis 1995, 1421; WO 95/2580). Disadvantages of this method are the low-yield preparation of aromatic boronic acids (Houben Weyl, Methoden der Org. Chemie, IVth edition, Vol. 13/3a, p. 636), which have to be prepared from organometallic precursors, and the use of expensive palladium catalysts.
In addition to halogens, sulfoxides and sulfones are known as further heterocycle leaving groups. According to JP-A 61/280,474, 2-sulfonylpyridines can be coupled with arylmagnesium compounds, but an additional halogen substitution in the Grignard moiety is not mentioned. According to Heterocycles 24 (1986), p. 3337, an additional halogen substitution in the pyridyl sulfone reduces the yield of coupling product, whereas a donor substitution of the Grignard reagent increases the yield.
Pyridyl sulfoxides as leaving groups in the uncatalyzed coupling with Grignard reagents usually only afford bipyridyls [Bull. Chem. Soc. Jpn. 62 (1989) 2338; THL 25 (1384) 2549]. Only in the case of 2-quinoline sulfoxide could the coupling product be isolated at all, in a 20% yield.
It is an object of the present invention to provide a generally applicable process for preparing substituted phenylpyridines of the formula I in high yields and purity from easily obtainable starting materials.
We have found that this object is achieved by a process for preparing substituted phenylpyridines of the formula I, which substituted pyridines of the formula II comprises reacting with an aryl compound of the formula III, if appropriate in the presence of a transition metal catalyst.
The substituents of the formulae II and III are as defined for the formula I; additionally:
n is 1 or 2, and
Y is alkyl, alkenyl or alkynyl, each of which may be substituted by halogen or methoxy; or is cycloalkyl or phenylalkyl; or substituted or unsubstituted phenyl or naphthyl,
M is magnesium or zinc, and
Z is halogen.
Starting materials for the process according to the invention are pyridine derivatives of the formula II which can be obtained for example from 2-halopyridines by reaction with suitable thiolates and subsequent oxidation. With or without transition metal catalysis, they are reacted with Grignard reagents or zinc compounds of the formula III to give phenylpyridines of the formula I.
If R
1
in the formula III is fluorine, the compounds III can for example be obtained by formation of a Grignard reagent from the correspondingly substituted o-fluorobromobenzene with magnesium at from −10 to 60° C.
The molar ratios in which the starting materials II and III are reacted with each other can, for example, be within the range from 0.9 to 1.5, preferably from 1.0 to 1.2, for the ratio of phenyl derivative III to pyridine compound II. The concentration of the starting materials in the solvent is not critical; it is for example from 0.1 to 5 mol/l, preferably from 0.5 to 2 mol/l.
Suitable solvents for these reactions are hydrocarbons, such as pentane, hexane, heptane, cyclohexane, toluene or chlorobenzene, and preferably solvents having electron donor character, in particular solvents having one or more ether oxygens, such as diethyl ether, diisopropyl ether, dibutyl ether, methyl tertbutyl ether, dimethoxyethane, diethoxyheptane, ethylene glycol dimethyl ether, furan, 5,6-dihydro-4H-pyran, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, 4-methyl-1,3-dioxane, anisole, formaldehyde dimethyl acetal, formaldehyde diethyl acetal, acetaldehyde dimethyl acetal, acetaldehyde diethyl acetal, and furthermore triethylamine, hexamethylphosphoric triamide, 1,2-bis(dimethylamino)ethane, N-ethylmorpholine, tribenzylphosphine oxide, dimethyl sulfidre, dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfone, N-methylpyrrolidone or dimethylacetamide. Often, it is advantageous to use mixtures for example of ethers with amines or amides. It may also be advantageous to mix the polar component, for example from 1 to 3 mol % of tetrahydrofuran, triethylamine or N-ethylmorpholine, as an additive into the less polar component, for example benzene, toluene, xylene or naphthalene.
The conversion can be accelerated by the addition of a catalyst, for example of a transition metal. Suitable transition metal catalysts are iron compounds, cobalt compounds, nickel compounds, rhodium compounds, palladium compounds or platinum compounds, in particular nickel(0) compounds, nickel(II) compounds, palladium(0) compounds and palladium(II) compounds. Thus, salts such as nickel chloride, palladium chloride, palladium acetate or even complexes may be used. The only precondition is that the palladium ligands can be displaced by the substrate under the reaction conditions. Phosphine ligands, for example arylalkyl phosphines, such as inter alia methyldiphenylphosphine or isopropyldiphenylphosphine, triarylphosphines, such as inter alia triphenylphosphine, tritolylphosphine or trixylylphosphine, and trihetarylphosphines, such as trifurylphosphine, or dimeric phosphines are particularly suitable. Olefinic ligands, such as inter alia dibenzylideneacetone or salts thereof, cycloocta-1,5-diene or amines such as trialkylamines (for example triethylamine, tetramethylethylenediamine, or N-methylmorpholine) or pyridine are likewise well suited.
If a complex is used this can be employed directly in the reaction. This method can be used for example with bis(triphenylphosphine)nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride, [1,3-bis(diphenylphosphine)propane]nickel(II) chloride, [1,2-bis(diphenylphosphine)ethane]nickel II) chloride, tetrakistriphenylphosphinepalladium(0), bistriphenylphosphinepalladium dichloride, bistriphenylphosphinepalladium diacetate, a dibenzylideneacetonepalladium(0) complex, tetrakismethyldiphenylphosphinepalladium(0) or bis(1,2-diphenylphosphinoethane)palladium dichloride. Alternatively, a suitable ligand can be added to a nickel or palladium salt, thus forming the catalytically active complex in situ. This method is advantageous for example for the abovementioned salts and phosphine liganils, such as trifurylphosphine or tritolylphosphine. Furthermore, nickel complexes or palladium complexes, such as tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium or 1,5-cyclooctadienepalladium dichloride can be further activated by adding ligands such as trifurylphosphine or tritolylphosphine.
Customarily, from 0.001 to 12 mol %, in particular from 001 to mol %, of catalyst are used, based on the starting materials. It is possible to use larger amounts, but this is normally not necessary.
The reaction can be carried out under atm

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