Method for producing substituted thiopyridines

Details Method for producing substituted thiopyridines Method for producing substituted thiopyridines

1999-11-17

2001-02-20

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S291000, C546S339000, C546S286000, C546S313000

Reexamination Certificate

active

06191280

ABSTRACT:

The present invention relate to a process for preparing thiopyridines of the formula I
in which
n is 0, 1 or 2
R
1
,R
2
,R
3
and R
4
are identical or different and each is hydrogen, halogen, nitro, cyano; C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
1
-C
6
-alkoxy, C
2
-C
6
-alkenyloxy, C
3
-C
6
-alkynyloxy, C
1
-C
6
-alkylthio, C
2
-C
6
-alkenylthio, C
3
-C
6
-alkynylthio, C
1
-C
6
-alkylsulfinyl, C
2
-C
6
-alkenylsulfinyl, C
3
-C
6
-alkynylsulfinyl, C
1
-C
6
-alkylsulfonyl, C
2
-C
6
-alkenylsulfonyl, C
3
-C
6
-alkynylsulfonyl, it being possible for the alkyl, alkenyl and alkynyl moieties of these groups to carry up to 6 halogen atoms; a C
1
-C
4
-alkylenephenyl, phenyl, phenoxy or naphthyl radical without substitution in the phenyl or naphthyl moiety or with substitution by halogen, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, trifluoromethyl, cyano or nitro; CO
2
R
6
, CONR
7
R
8
, SO
2
NR
7
R
8
or COR
6
; furthermore, if located in adjacent positions on the pyridine ring, they together form a 5- or 6-membered aromatic or aliphatic ring which may contain one or more hetero atoms or may be substituted by halogen, trifluoromethyl, methyl or methoxy;
R
5
is a C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkynyl radical without substitution or with substitution by halogen, C
1
-C
4
-alkoxy, C
1
-C
4
-alkoxycarbonyl, di-(C
1
-C
4
-alkyl)aminocarbonyl, cyano or nitro, a C
3
-C
8
-cycloalkyl radical, a C
1
-C
4
-alkylenephenyl, phenyl or naphthyl radical without substitution in the phenyl or naphthyl moiety or with substitution by halogen, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, trifluoromethyl, cyano or nitro,
R
6
, R
7
and R
8
are identical or different and each is hydrogen;
C
1
-C
6
-alkyl, C
3
-C
6
-cycloalkyl, C
2
-C
6
-alkenyl, C
3
-C
6
-alkynyl, it being possible for these groups to carry up to 6 halogen atoms; a phenyl or C
1
-C
4
-alkylenephenyl radical without substitution in the phenyl moiety or with substitution by halogen, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, trifluoromethyl, cyano or nitro.
The thiopyridines I are important intermediates for preparing crop protection agents having herbicidal activity as disclosed in WO-A-95/02580.
In the literature, the synthesis of pyridine thioethers starting from thiols and halopyridines is usually carried out in the presence of bases (J. Chem. Soc., Perkin Trans., Part I (1980) 648; Bull. Soc. Chim. Belg. 101 (1992) 297).
In GB 2 223 017, the sodium salt of the thio component is reacted with the halopyridine in the presence of copper bronze, affording the corresponding pyridine thioether in 31% yield.
Finally, EP 320448 discloses the reaction of a 2-halopyridine with anilines without the addition of a base to give the corresponding 2-arylaminopyridine in a yield of 11 or 37%. In the same publication, it is furthermore mentioned that, besides anilines, it is also possible to use thiophenols. However, EP-A 320 448 does not give any concrete working example describing the reaction of a 2-halopyridine with a thiophenol.
It is an object of the present invention to provide a simple and economical process for preparing thiopyridine derivatives which in turn are suitable as coupling components for preparing substituted phenylpyridines as described in WO-A-95/02580.
We have found that this object is achieved by the process for preparing thiopyridines of the formula I defined at the outset
which comprises reacting substituted 2-halopyridines of the formula II
in which R
1
, R
2
, R
3
and R
4
are each as defined above and Hal is fluorine, chlorine or bromine, in a first step with a thio compound of the formula III
HS—R
5
  III
in which R
5
is as defined above, in the presence of a copper catalyst to give initially a pyridine thioether of the formula Ia and then oxidizing this stepwise to give the sulfoxide Ib or sulfone Ic
The process according to the invention affords the pyridine thioethers of the formula Ia in a surprisingly high yield. The pyridine thioethers Ia formed are so pure that they can generally be oxidized without intermediate isolation with oxidizing agents to give the sulfoxides Ib and Ic.
Hydrogen peroxide in acetic acid or acetic acid/trifluoroacetic acid mixtures has been found to be particularly advantageous for oxidizing the pyridine thioethers Ia stepwise to the sulfoxides Ib and the sulfones Ic. Hypochlorous acid or its alkali metal salt has been found to be particularly suitable for the direct oxidation of pyridine thioethers Ia to sulfones Ic. The thiopyridines I are particularly preferably obtained by initially reacting substituted 2-halopyridines of the formula II
in which R
2
, R
4
and Hal are each as defined above, in a first step with a thio compound of the formula III
HSR
5
  III
in which R
5
is as defined above, in the presence of from 0.001 to 1 mol % of a copper catalyst to give a pyridine thioether of the formula Ia which is then oxidized stepwise to the sulfoxide Ib
or sulfone Ic.
Compounds which are particularly preferred for use as compound II are 2,3,5-trichloropyridine, 5-chloro-2,3-difluoropyridine, 2,3-dichloro-5-difluoromethylpyridine, 2,3-dichloro-5-(3,3,3-trifluoropropyl)pyridine, 2,3-dichloro-5-trifluoromethylpyridine and 2,3-dichloro-5-pentafluoroethylpyridine.
The preparation of the compounds I is exemplified by the reaction starting from 2,3-dichloro-5-trifluoromethylpyridine and thiophenol as nucleophile, using hydrogen peroxide as oxidizing agent, illustrated in the scheme that follows.
It is also possible to use the oxidizing agents mentioned below instead of hydrogen in a similar manner.
Preferred embodiments of the process are specified below:
The reaction of the 2-halopyridines II with a thiol III is advantageously carried out in the presence of a solvent at 80-250° C., preferably 120-200° C., particularly preferably 140-180° C. Solvents that are used for these reactions—depending on the temperature range—are hydrocarbons such as toluene and xylene, chlorinated hydrocarbons such as 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,2-, 1,3- or 1,4-dichlorobenzene, ethers such as 1,4-dioxane or anisole, glycol ethers such as glycol dimethyl ether, glycol diethyl ether or diethylene glycol dimethyl ether, esters such as ethyl acetate, propyl acetate, methyl isobutyrate or isobutyl acetate, carboxamides such as DMF or N-methylpyrrolidone, nitrated hydrocarbons such as nitrobenzene, ureas such as tetraethylurea, tetrabutylurea, dimethylethyleneurea and dimethylpropyleneurea, sulfoxides such as dimethyl sulfoxide, sulfones such as dimethyl sulfone, diethyl sulfone and tetramethylene sulfone, nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; water, or else mixtures of individual solvents.
The reaction is particularly preferably carried out in the melt without the use of a solvent.
The molar ratios in which the starting materials are reacted with each other are generally 0.9-1.4, preferably 0.95-1.1, particularly preferably 0.98-1.04, for the ratio of thiol to 2-halopyridine II. The concentration of the starting materials in the solvent is 0.1-5 mol/l, preferably 0.2-2 mol/l.
Suitable catalysts are copper oxide, salts such as copper(II) chloride, copper sulfate, copper nitrate, copper acetate and copper carbonate. Particular preference is given to using finely dispersed metallic copper, for example copper powder or copper bronze. The molar amount of catalyst, based on the 2-halopyridine II, is 0.001-10, preferably 0.001-1 mol % and particularly preferably 0.001 to 0.1 mol %.
The reaction is preferably carried out under acidic conditions by flushing the hydrogen halide that is eliminated during the reaction out of the reaction mixture by means of an inert gas, for example nitrogen, or by letting it escape into a gas washer under autogenous pressure.
Advantageously, the 2-halopyridine II is added over a period of 10 to 60 min to a mixture of the thiol III and the catalyst at 20-80° C., and the mixture is then stirred for another 0.5 to 12 hours, preferably 1 to 8 hours, at 140-180° C. to allow the reaction to g

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