Process for the preparation of methylene compounds and the novel compound 2-(2,4-Dichloro-5-fluorobenzyl)thiophene

Methylene compounds are preferably prepared by reducing an aluminum halide complex of the formula ##STR1## in which R.sup.1 represents a C.sub.6 -C.sub.10 -aryl radical which is optionally substituted by 1 to 4 C.sub.1 -C.sub.4 -alkyl radicals, 1 to 4 fluorine, chlorine and/or bromine atoms, one C.sub.1 -C.sub.8 -alkoxy group and/or one acetoxy group, or represents a heteroaryl radical which is optionally substituted by one C.sub.1 -C.sub.4 -alkyl radical and/or one fluorine, chlorine or bromine atom and contains 5 to 10 C atoms and one O or S atom and PA1 R.sup.2 represents a C.sub.1 -C.sub.12 -alkyl radical which is optionally substituted by 1 to 5 fluorine, chlorine and/or bromine atoms, independently of R.sup.1 represents a radical as defined for R.sup.1 and, in the case where R.sup.1 =a C.sub.6 -C.sub.10 -aryl radical which is substituted by 1 to 4 fluorine, chlorine and/or bromine atoms, also represents a furyl or thienyl radical, PA1 Y represents fluorine, chlorine or bromine, with an amineborane of the formula ##STR2## in which R.sup.3 represents C.sub.1 -C.sub.4 -alkyl and PA1 R.sup.4 represents hydrogen or C.sub.1 -C.sub.4 -alkyl and/or with sodium borohydride and/or with potassium borohydride. 2-(2,4-Dichloro-5-fluorobenzyl)thiophene is obtainable in this way for the first time.

The present invention relates to a particularly advantageous process for 
the preparation of methylene compounds. Methylene compounds are important 
intermediates for the preparation of a wide variety of active compounds. 
The present invention also relates to 
2-(2,4-dichloro-5-fluorobenzyl)thiophene which has become available for 
the first time using this process. For example, 
2-(4-fluorobenzyl)thiophene and 2-(4-fluorobenzyl)furan represent 
important building blocks for the preparation of active compounds which 
are leukotriene biosynthesis inhibitors (see U.S. Pat. No. 5,288,751). 
It is known that methylene compounds can be prepared by reduction of 
ketones by the Wolff-Kishner and Huang Minion methods (see J. March, 
Advanced Organic Chemistry, McGraw-Hill, pages 1119-1121 (1977)). These 
methods require the handling of hydrazine, which one seeks to avoid for 
ecological reasons. In addition, reduction processes of these types fail 
with ketones whose hydrazones can be prepared only with difficulty and in 
those cases in which substituents on the ketones can also react with 
hydrazine. 
Furthermore the reduction of ketones with sodium borohydride and 
tert-butylamine-borane in the presence of anhydrous aluminum chloride is 
known (see Synthesis, pages 736-738 (1987) and J. Org. Chem. 54, 491-494 
(1989)). The amounts of aluminum chloride and, in particular, of sodium 
borohydride or tert-butylamine-borane required in these processes are 
extremely high at 3 to 5 mol/mol of ketone, so that this process is 
disadvantageous because of the required amounts of auxiliaries. 
The reduction of ketones with sodium borohydride in trifluoroacetic acid as 
reaction medium has also been described (see Synthesis, pages 763-765 
(1978)). In this case, the industrial handling of trifluoroacetic acid is 
problematic because of its corrosivity, its solubility in water and the 
azeotrope formation with water, and its high price. 
2-(4-Fluorobenzyl)thiophene has been prepared by another synthetic route by 
the action of 2-thienyllithium on 4-fluorobenzyl bromide in the presence 
of tetrakis-(triphenylphosphine)-palladium(0) at -78.degree. C. in diethyl 
ether/tetrahydrofuran. Although the yield is good at 81%, the preparation 
method is extremely elaborate and not very suitable for industrial use 
(see U.S. Pat. No. 5,288,751, Example 12A). 
Ketones can be prepared by acylation of acid halides or anhydrides with 
aromatic or heteroaromatic compounds using aluminium trihalides by the 
Friedel-Crafts method. During the course of this reaction the elimination 
of hydrogen chloride in many cases results in an aluminium halide complex 
which is soluble in the particular reaction medium used. This aluminium 
halide complex is then normally hydrolysed by introduction into ice-water 
to obtain the ketone. Ketone obtained in this way can be reduced with 
boron-hydrogen compounds alone only to the carbinol stage but not to the 
methylene stage (see Houben-Weyl, Methoden der organischen Chemie [Methods 
of Organic Chemistry], Volume 4/1d, page 267 (1981)). 
A process for the preparation of methylene compounds of the formula 
EQU R.sup.1 --CH.sub.2 --R.sup.2 (I) 
in which 
R.sup.1 represents a C.sub.6 -C.sub.10 -aryl radical which is optionally 
substituted by 1 to 4 C.sub.1 -C.sub.4 -alkyl radicals; 1 to 4 fluorine, 
chlorine and/or bromine atoms, one C.sub.1 -C.sub.8 -alkoxy group and/or 
one acetoxy group, or represents a heteroaryl radical which is optionally 
substituted by one C.sub.1 -C.sub.4 -alkyl radical and/or one fluorine, 
chlorine or bromine atom and contains 5 to 10 C atoms and one O or S atom 
and 
R.sup.2 represents a C.sub.1 -C.sub.12 -alkyl radical which is optionally 
substituted by 1 to 5 fluorine, chlorine and/or bromine atoms, 
independently of R.sup.1 represents a radical as defined for R.sup.1 and, 
in the case where R.sup.1 =a C.sub.6 -C.sub.10 -aryl radical which is 
substituted by 1 to 4 fluorine, chlorine and/or bromine atoms, also 
represents a furyl or thienyl radical, 
has now been found, which is characterized in that an aluminium halide 
complex of the formula 
##STR3## 
in which R.sup.1 and R.sup.2 have the abovementioned meaning, and 
Y represents fluorine, chlorine or bromine, 
is reduced with an amineborane of the formula 
##STR4## 
in which R.sup.3 represents C.sub.1 -C.sub.4 -alkyl and 
R.sup.4 represents hydrogen or C.sub.1 -C.sub.4 -alkyl and/or 
with sodium borohydride and/or with potassium borohydride. 
Aluminium halide complexes of the formula (II) can be obtained in principle 
by two routes, namely 
a) by Friedel-Crafts acylation of an aromatic or heteroaromatic compound of 
the formula 
EQU R.sup.1 --H (IV) 
in which 
R.sup.1 has the abovementioned meaning, with acyl compounds of the formula 
EQU R.sup.2 --COX (V) 
in which 
R.sup.2 has the abovementioned meaning, and 
X represents fluorine, chlorine or bromine, or 
b) by Friedel-Crafts acylation of a compound of the formula 
EQU R.sup.2 --H (VI) 
in which 
R.sup.2 has the abovementioned meaning, with an acyl compound of the formul 
a 
EQU R.sup.1 --COX (VII) 
in which 
R.sup.1 and X have the abovementioned meanings. 
Success is not achieved with both routes in all cases, but always is with 
at least one. If R.sup.2 represents an alkyl or aryl radical, route a) is 
preferred, and if R.sup.2 represents a furyl or thienyl radical, route b) 
is. 
This procedure for the preparation of the aluminium halide complex of the 
formula (II) and its reduction according to the invention provides the 
advantage of avoiding additional reaction steps hitherto necessary, for 
example the working up, isolation, purification and drying of the 
particular ketone; the renewed use of aluminium halide in the reduction; 
multistage procedure; handling of large amounts of auxiliaries; handling 
of corrosive and costly chemicals. Isolation of the aluminium halide 
complex of the formula (II) is unnecessary. It can be further processed in 
the form of the reaction mixture resulting from its preparation. 
The process according to the invention is single-stage, starts from readily 
accessible starting compounds, requires only relatively small amounts of 
auxiliaries and requires no corrosive and/or costly chemicals. 
R.sup.1 in the formulae (I), (II), (IV) and (VII) preferably represents a 
phenyl radical which is unsubstituted or substituted by 1 to 4 fluorine, 
chlorine and/or bromine atoms, or represents a heteroaryl radical 
containing 5 C atoms and one S or O atom. 
R.sup.2 in the formulae (I), (II), (V) and (VI) preferably represents a 
phenyl radical which optionally contains 1 to 3 substituents from the 
group consisting of fluorine and chlorine, or, if R.sup.1 represents a 
C.sub.6 -C.sub.10 -aryl radical which is substituted by 1 to 4 fluorine, 
chlorine and/or bromine atoms, also represents a furyl or thienyl radical. 
X in the formulae (V) and (VII) preferably represents chlorine or bromine 
and, independently thereof, Y in formula (III) likewise represents 
chlorine or bromine. 
R.sup.3 in formula (III) preferably represents methyl, ethyl or tert-butyl 
and R.sup.4 preferably represents hydrogen, methyl or ethyl. 
Particularly preferred starting materials of the formulae (IV) and (VI) are 
thiophene, benzothiophene, benzofuran, fluorobenzene and 
2,4-dichlorofluorobenzene. 
Particularly preferred starting materials of the formulae (V) and (VII) are 
4-fluorobenzoyl chloride, 4-chlorobenzoyl chloride, 
2,4-dichloro-5-fluorobenzoyl chloride, 2-chloro-4,5-difluorobenzoyl 
chloride, thenoyl chloride and furoyl chloride. 
Particularly preferred amineboranes of the formula (III) are 
dimethylamineborane and tert-butylamineborane. The use of sodium 
borohydride and potassium borohydride is likewise preferred. 
The following methylene compounds of the formula (I) are particularly 
preferably prepared by the process according to the invention: 
2-(4-fluorobenzyl)thiophene, 2-(4-chlorobenzyl)thiophene, 
2-(4-fluorobenzyl)furan, 2-(2,4-dichloro-5-fluorobenzyl)-thiophene, 
2-(2-chloro-4,5-difluorobenzyl)thiophene and 
2-(2,4-dichloro-5-fluorobenzyl)furan. 
The process according to the invention can be carried out by the following 
method, for example: 
An acyl compound of the formula (V) or (VII) is reacted with a compound of 
the formula (IV) or (VI) with addition of an aluminium halide in an inert 
diluent with elimination of hydrogen halide. After removal of the hydrogen 
halide, for example by applying a vacuum, the resulting reaction mixture 
which contains an aluminium halide complex of the formula (II) is reacted 
with an amineborane of the formula (III) or sodium borohydride or 
potassium borohydride, the mixture is hydrolysed with water to eliminate 
the aluminium halide, the aqueous phase is separated off, and the organic 
phase is distilled. 
Suitable inert diluents are solvents which are customary in Friedel-Craft 
acylations and which must additionally be inert to boron-hydrogen 
compounds. Halogenobenzenes and ethers, especially chlorobenzene, 
o-dichlorobenzene and mixtures of chlorobenzene and diglyme, are 
preferred. 
The procedure up to the stage of the reaction mixtures containing the 
aluminium halide complex of the formula (II) can be like that known for 
the preparation of ketones from aromatic compounds and acyl compounds by 
the Friedel-Crafts method (see, for example, Houben-Weyl, Methoden der 
organischen Chemie [Methods of Organic Chemistry], Volume VII/2a, pages 15 
et seq. (1973)). 
The reduction according to the invention of aluminium halide complexes of 
the formula (II) with one of the stated boron-hydrogen compounds can be 
carded out, for example, at 0.degree. to 100.degree. C., preferably at 
50.degree. to 90.degree. C. It is advantageous to use an additional 
solvent in this reduction, for example an ether, especially when the 
boron-hydrogen compound has low solubility in the reaction medium which is 
otherwise present. Preferred additional solvents are tetrahydrofuran, 
diethylene glycol dimethyl ether (diglyme) and ethylene glycol dimethyl 
ether. 
A solution or suspension which contains the boron-hydrogen compound in for 
example, digylme is preferably added to the solution or suspension which 
contains the aluminium halide complex of the formula (II). 
It is perfectly possible for the reaction temperature in the acylation and 
reduction reaction steps to be different. Thus, for example, the reaction 
of an acyl compound of the formula (V) or (VII) with a compound of the 
formula (IV) or (VI) can be started initially in the low temperature 
range, for example at -10.degree. to +10.degree. C., and be raised during 
the course of the reaction to 50.degree. to 110.degree. C. By contrast, 
the reduction can be carried out in the temperature range from 0.degree. 
to 100.degree. C., preferably 50.degree. to 90.degree. C. 
The amount of boron-hydrogen compound to be used per mole of aluminium 
halide complex of the formula (II) can be, for example, 0.5 to 1 mol, 
preferably 0.7 to 0.8 mol. A larger excess of reducing agent does not in 
general improve the result but entails the risk of perhydrogenation of 
aromatic or heterocyclic radicals. 
It is possible for the first time with the process according to the 
invention to prepare 2-(2,4-dichloro-5-fluorobenzyl)thiophene of the 
formula 
##STR5## 
(see Example 4). The present invention therefore also relates to the 
compound of the formula (I). Lipoxygenase inhibitors and inhibitors for 
leukotriene biosynthesis can be prepared from the compound of the formula 
(I), as is known for other 2-benzylthiophenes (see WO 90/12008 and U.S. 
Pat. No. 5,288,751).

EXAMPLES 
Example 1 
2-(4-Fluorobenzyl)thiophene 
33.8 g of aluminium trichloride were suspended in 217 g of chlorobenzene, 
and a solution of 40.3 g of 4-fluorobenzoyl chloride in 37.4 g of 
chlorobenzene was added dropwise to this at 0.degree. C. over the course 
of 15 minutes. The mixture was then stirred for 1 hour and then, at 
0.degree. C., 21.8 g of thiophene were added dropwise over the course of 
20 minutes. The resulting hydrogen chloride was drawn off and absorbed in 
sodium hydroxide solution. The mixture was subsequently heated to 
80.degree. C. and the remaining hydrogen chloride was removed. The 
resulting solution was added dropwise to a suspension of 7.2 g of sodium 
borohydride in 47.2 g of digylme while stirring at 70.degree. C. over the 
course of 45 minutes. The reaction mixture was then stirred for 90 minutes 
and then cooled to room temperature and discharged into a mixture of 250 g 
of ice, 44.6 g of concentrated aqueous hydrochloric acid and 500 g of 
water. The organic phase which formed thereby was separated off, the 
aqueous phase was extracted by shaking with chlorobenzene, and the 
combined organic phases were distilled. 35.0 g of product with a boiling 
point of 83.degree. C./1.0 mbar and a purity of 99.7% (GC) were obtained. 
This corresponds to 73.9% of theory. The product contained less than 0.1% 
by weight of defluorinated compounds (GC). 
Example 2 
2-Benzylthiophene 
27.2 g of 98.5% pure aluminium trichloride (sublimed) were suspended in 130 
ml of chlorobenzene and cooled to 0.degree. C. 28.7 g of benzoyl chloride 
were added dropwise while stirring and cooling over the course of 30 
minutes, and the mixture was then stirred for 1 hour. Likewise at 
0.degree. C., a solution of 17.3 g of thiophene in 27 ml of chlorobenzene 
was added dropwise over the course of 30 minutes, and the mixture was 
stirred for 1 hour. Remaining hydrogen chloride was driven out by heating 
the mixture and stirring, finally under vacuum. The remaining solution was 
introduced over the course of 40 minutes into a solution of 12.7 g of 
dimethylamineborane in 70 ml of chlorobenzene while stirring at 70.degree. 
C. The mixture was then stirred for 1 hour, cooled and discharged into a 
mixture of 200 g of ice and 50 g of concentrated aqueous hydrochloric acid 
while stirring. The aqueous phase was then separated off and extracted 
with chlorobenzene. The remaining organic phase was extracted by shaking 
with water. The organic phase and the extract from the aqueous phase were 
then combined, the solvent was removed therefrom by distillation, and 38.7 
g of crude 2-benzylthiophene of 79.7% purity were obtained by 
distillation. This corresponds to 88.5% of theory. Redistillation resulted 
in 99.7% pure 2-benzylthiophene with a boiling point of 91.degree. to 
92.degree. C./1.4 mbar. 
EXAMPLE 3 
2-(4-Fluorobenzyl)thiophene 
33.8 g of aluminium chloride were suspended in 200 g of fluorobenzene, and 
a solution of 37.8 g of thiophene-2-carbonyl chloride in 50 ml of 
fluorobenzene was added dropwise to this at 0.degree. C. over the course 
of 30 minutes. The mixture was stirred at 0.degree. C. for 2 hours and 
then slowly warmed, and heated under reflux at 85.degree. C. for 2 hours 
until evolution of hydrogen chloride ceased. The solution was cooled to 
70.degree. C. and then, at this temperature, added dropwise over the 
course of 30 minutes to a stirred suspension of 7.2 g of of sodium 
borohydride in 50 ml of diglyme. The mixture was then stirred at 
70.degree. C. for 90 minutes and, after cooling, discharged into a mixture 
of 250 g of ice, 200 ml of water and 62.5 g of concentrated aqueous 
hydrochloric acid. After addition of 100 ml of fluorobenzene, the organic 
phase was separated off, extracted by shaking with 100 ml of water and 
concentrated. Yield: 58.3 g of product with a content of 61.8% by weight 
of 2-(4-fluorobenzyl)thiophene (GC), corresponding to a yield of 75.1% of 
theory. An organic phase was obtained from the aqueous mother liquor by 
extraction with methylene chloride and concentration and contained a 
further 33.7% by weight of the required product (GC), corresponding to an 
additional yield of 4.6% of theory. Distillation of the organic phase 
resulted in a 99.2% pure 2-(4-fluorobenzyl)thiophene. 
Example 4 
2-(2,4-Dichloro-5-fluorobenzyl)thiophene 
3.8 g of aluminium chloride were suspended in 162.5 ml of chlorobenzene, 
and a solution of 58.9 g of 2,4-dichloro-5-fluorobenzoyl chloride in 33.8 
ml of chlorobenzene was added dropwise to this at 0.degree. C. over the 
course of 30 minutes. The mixture was stirred at 0.degree. C. for 90 
minutes and then, at 0.degree. C., a solution of 21.8 g of thiophene in 
33.8 ml of chlorobenzene was added dropwise over the course of 30 minutes. 
The mixture was stirred at 0.degree. C. for a further 2 hours and finally 
heated to reflux for 15 minutes until evolution of hydrogen chloride 
ceased. The resulting solution was added dropwise to a suspension of 7.2 g 
of sodium borohydride in 50 ml of diglyme at 70.degree. C. over the course 
of 30 minutes, and the reaction mixture was subsequently stirred at 
70.degree. C. for 90 minutes and then discharged into a mixture of 250 g 
of ice, 200 ml of water and 62.5 g of concentrated aqueous hydrochloric 
acid. After addition of 100 ml of chlorobenzene and stirring, the phases 
were separated. The organic phase was extracted by shaking with 100 ml of 
water and was subsequently concentrated. Yield: 78.5 g of crude substance 
with a content of 76.7% by weight (GC) of 
2-(2,4-dichloro-5-fluorobenzyl)thiophene, corresponding to 92.3% of 
theory. Distillation resulted in a 97.2% pure (GC) product, boiling point 
140.degree. to 145.degree. C./8 mbar, melting point 60.degree. to 
61.degree. C. 
Example 5 
2-(4-Methylbenzyl)thiophene 
39 g of 4-methylbenzoyl chloride were added dropwise to a suspension of 
33.8 g of aluminium chloride in 162.5 ml of chlorobenzene while stirring 
at 0.degree. C. over the course of 30 minutes. The mixture was stirred at 
0.degree. C. for 90 minutes and subsequently, at 0.degree. C., a solution 
of 21.8 g of thiophene in 33.8 ml of chlorobenzene was added dropwise over 
the course of 30 minutes. The mixture was stirred at 0.degree. C. for 2 
hours and then heated under reflux for 15 minutes until evolution of 
hydrogen chloride ceased. The resulting solution was added dropwise over 
the course of 30 minutes to a suspension of 7.2 g of sodium borohydride in 
50 ml of diglyme heated to 70.degree. C. The mixture was stirred at 
70.degree. C. for 1.5 hours and then discharged into a mixture of 250 g of 
ice, 200 ml of water and 62.5 g of concentrated aqueous hydrochloric acid. 
After addition of 100 ml of chlorobenzene and thorough stirring, the 
organic phase was separated off, washed with 100 ml of water and 
concentrated by distillation. Yield: 57.7 g of crude substance, 71.0% pure 
(GC), corresponding to a yield of 87.2% of theory. Distillation resulted 
in a 99.4% pure 2-(4-methylbenzyl)thiophene with boiling point 98.degree. 
C./4 mbar. 
Example 6 
2-(4-Chlorobenzyl)thiophene 
44.2 g of 4-chlorobenzoyl chloride were introduced over the course of 15 
minutes into a suspension of 33.8 g of aluminium chloride and 162.5 ml of 
chlorobenzene stirred at 0.degree. C., and the mixture was stirred for 90 
minutes. Then, at 0.degree. C., a solution of 21.8 g of thiophene in 33.8 
ml of chlorobenzene was added dropwise while stirring over the course of 
30 minutes. The mixture was stirred at 0.degree. C. for 2 hours and then 
heated to reflux for 15 minutes until evolution of hydrogen chloride 
ceased. 
The resulting solution was subsequently added dropwise over the course of 
30 minutes to a suspension of 7.2 g of sodium borohydride and 50 ml of 
diglyme heated to 70.degree. C. The mixture was stirred at 70.degree. C. 
for 90 minutes and then discharged into a mixture of 250 g of ice, 200 ml 
of water and 62.5 g of concentrated hydrochloric acid. After addition of 
100 ml of chlorobenzene, the organic phase was separated off and 
concentrated. Yield: 66.2 g of crude substance, 73.4% pure (GC). 
Distillation resulted in a 99.4% pure (GC) 2-(4-chlorobenzyl)thiophene, 
boiling point 122.degree. C./3.5 mbar. 
Example 7 
2-(4-Fluorobenzyl)furan 
A solution of 34.4 g of furan-2-carbonyl chloride (95% pure) in 50 g of 
fluorobenzene was added dropwise to a suspension of 33.8 g of aluminium 
chloride in 200 g of fluorobenzene at room temperature while stirring over 
the course of 30 minutes. The mixture was heated to 60.degree. C. and then 
stirred for 1 hour and subsequently at 80.degree. C. for a further 90 
minutes. The mixture obtained in this way was added dropwise to a solution 
of 22.8 g of dimethylamineborane and 60 g of fluorobenzene while stirring 
at 60.degree. C. over the course of 85 minutes. The mixture was stirred at 
70.degree. C. for 80 minutes and subsequently discharged into a mixture of 
250 g of ice, 200 ml of water and 66 g of concentrated hydrochloric acid. 
After vigorous stirring of the mixture, separation and washing of the 
organic phase with water and extraction of the aqueous phase with 
methylene chloride, the combined organic phases were concentrated. Yield: 
50.4 g of 67% pure product (GC), corresponding to 77% of theory. 
Distillation resulted in a 96% pure 2-(4-fluorobenzyl)furan, boiling point 
70.degree. C./3 mbar.