Process for preparing phenethylamines and novel chemical...

Details Process for preparing phenethylamines and novel chemical... Process for preparing phenethylamines and novel chemical...

2000-07-03

2001-07-03

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S374000, C549S366000, C549S440000, C549S467000

Reexamination Certificate

active

06255528

ABSTRACT:

The present invention relates to a novel process for preparing fluorine-containing phenethylamines and to the resulting novel chemical compounds.
BACKGROUND OF THE INVENTION
4-fluorophenethylamine, 4-(trifluoromethoxy)-phenethylamine and other fluorine-containing phenethylamines are intermediates for preparing agrochemicals. J. Am. Chem. Soc. 63, 602 (1941) discloses that 4-fluorophenethylamine can be prepared in a multi-step process. This process gives, starting from p-fluorophenylmagnesium bromide, by addition of ethylene oxide with subsequent hydrolysis, p-fluorophenethyl alcohol which is converted with phosphorus tribromide into p-fluoro. Disadvantageous for using this process on an industrial scale are the high expenditure required for carrying out a Grignard reaction and the multi-step synthesis.
In another process for preparing 4-fluorophenethylamine (see J. Org. Chem. 23, 1979 (1958)), p-fluorobenzylchloride is used as starting material, which is reacted with sodium cyanide to give p-fluorophenylacetonitrile which is then finally reduced using sodium aluminium hydride or lithium aluminium hydride. This process has the disadvantages that some of the required benzyl chlorides are difficult to prepare, and that the handling of sodium aluminium hydride or lithium aluminium hydride requires great safety precautions. Thus, this process is likewise unsuitable for industrial application.
There is therefore still a demand for a process which allows the preparation of fluorine-containing phenethylamines in a simple manner, from easily obtainable starting materials and without any high technical expenditure.
SUMMARY OF THE INVENTION
The present invention, accordingly, provides a process for preparing fluorine-containing phenethylamines of the Formula (I)
in which
one of the radicals R
1
and R
2
represents fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy or pentafluoroethoxy and the other represents hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy or pentafluoroethoxy or
R
1
and R
2
together represent —O—CF
2
—O—, —O—CF
2
—CF
2
— or —O—CF
2
—CF
2
—O— and
R
3
represents hydrogen, chlorine, C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy,
in which in a first step a substituted bromobenzene of the Formula
in which
R
1
, R
2
and R
3
are as defined under Formula (I)
is reacted with acrylamide in the presence of a palladium catalyst,
in a second step the resulting arylacrylamide of the Formula
in which
the radicals R
1
, R
2
and R
3
are as defined under Formula (I)
is hydrogenated catalytically and
in a third step the arylamide obtained in step two of the Formula
in which
R
1
, R
2
and R
3
are as defined under Formula (I)
is rearranged.
The present invention furthermore relates to arylacrylamides of the Formula
in which
one of the radicals R
1
and R
2
represents fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy or pentafluoroethoxy and the other represents hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy or pentafluoroethoxy or
R
1
and R
2
together represent —O—CF
2
—O—, —O—CF
2
—CF
2
— or —O—CF
2
—CF
2
—O— and
R
3
represents hydrogen, chlorine, C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy,
except for the compounds 3-(3-fluorophenyl)-acrylamide, 3-[3-(trifluoromethyl)-phenyl]-acrylamide and 3-[4-(trifluoromethyl)-phenyl]-acrylamide.
The present invention also relates to arylamides of the Formula
in which
one of the radicals R
1
and R
2
represents fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy or pentafluoroethoxy and the other represents hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy or pentafluoroethoxy or
R
1
and R
2
together represent —O—CF
2
—O—, —O—CF
2
—CF
2
— or —O—CF
2
—CF
2
—O— and
R
3
represents hydrogen, chlorine, C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy,
except for the compounds 3-(3-fluorophenyl)-acrylamide, 3-(4-fluorophenyl)-acrylamide, 3-[3-(trifluoromethyl)-phenyl]-acrylamide and 3-[4-(trifluoromethyl)-phenyl]-acrylamide.
DETAILED DESCRIPTION OF THE INVENTION
In the Formulae (I), (II), (III) and (IV), one of the radicals R
1
and R
2
preferably represents a radical from the group consisting of fluorine, trifluoromethyl, trifluoromethoxy, tetrafluoroethoxy and pentafluoroethoxy, and the other radical preferably represents hydrogen, or R
1
and R
2
together preferably represent —O—CF
2
—O—, —O—CF
2
—CF
2
— or —O—CF
2
—CF
2
—O—. R
3
preferably represents hydrogen or chlorine.
In the Formulae (I), (II), (III) and (IV), R
1
and R
3
particularly preferably represent hydrogen and R
2
represents fluorine, trifluoromethyl or trifluoromethoxy, or R
1
represents fluorine, trifluoromethyl or trifluoromethoxy and R
2
and R
3
represent hydrogen or R
1
and R
2
together represent —O—CF
2
—O—, —O—CF
2
—CF
2
— or —O—CF
2
—CF
2
—O— and R
3
represents hydrogen.
Tetrafluoroethoxy radicals are preferably 1,1,2,2-tetrafluoroethoxy radicals.
According to the invention, the fluorine-containing phenethylamines listed in Table 1 are very particularly preferably prepared.
TABLE 1








The reaction of the bromobenzenes of the Formula (II) with acrylamide to give arylacrylamides of the Formula (III) is carried out in the presence of a palladium catalyst, preferably in the presence of a diluent and a reaction auxiliary.
The bromobenzenes of the Formula (II) are either commercially available, or they can be prepared by processes known per se or analogously to these processes.
Suitable palladium catalysts for the first reaction step are, for example, palladium complexes having aryl- or alkylphosphines as ligands. It is possible, for example, to add both the complexes themselves and palladium(II) salts and the free ligands separately.
Suitable diluents for the first reaction step are dipolar aprotic solvents and mixtures comprising these, for example with aliphatic and/or aromatic hydrocarbons and/or ethers. Examples of dipolar aprotic solvents are: nitrites, such as acetonitrile, propionitrile, n- and i-butyronitrile and benzonitrile, amides, such as formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, esters, such as methyl acetate, ethyl acetate and butyl acetate, sulphones, such as sulpholane. It is also possible to use mixtures of dipolar aprotic solvents.
Suitable reaction auxiliaries for the first reaction step are, for example, weak inorganic or organic bases. Preference is given to alkaline earth metal and alkali metal acetates, carbonates and bicarbonates, such as sodium acetate, potassium acetate, calcium acetate and ammonium acetate, sodium carbonate, potassium carbonate and ammonium carbonate, sodium bicarbonate and potassium bicarbonate, and to tertiary amines, such as trimethylamine, triethylamine and tributylamine. Preference is given to using sodium acetate or potassium acetate.
For carrying out the first reaction step, it is possible to use, for example, the bromobenzene of the Formula (II) in question and acrylamide in amounts of from 0.5 to 2 mol of the bromobenzene in question, based on 1 mol of acrylamide. This amount is preferably from 0.9 to 1.1 mol. Particular preference is given to using equimolar amounts of the bromobenzene of the Formula (II) in question and acrylamide. Based on the bromobenzene in question, it is possible to use, for example, from 0.005 to 20 mmol, preferably from 0.1 to 10 mmol, of palladium catalyst and from 1 to 10 equivalents, preferably from 1 to 3 equivalents, of reaction auxiliary. If a palladium(II) salt and free phosphine ligands are employed separately, the molar ratio of palladium(II) salt to phosphine ligands can be, for example, from 1:1 to 1:10, preferably from 1:2 to 1:4. The amount of diluent is not critical. Preference is given to using from 100 to 2000 ml per mole of the bromobcnzene of the Formula (II) in question.
The reaction temperature in the first process step can be varied within a relatively wide range. I

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