Process for preparing aryl- and heteroarylacetic acid derivatives
View Patent ↗The invention relates to a process for preparing aryl- and heteroarylacetic acids and derivatives thereof by reaction of aryl or heteroaryl halides with malonic diesters in the presence of a palladium catalyst, of one or more bases and optionally of a phase transfer catalyst. This process enables the preparation of a multitude of functionalized aryl- and heteroarylacetic acids and derivatives thereof, especially also the preparation of arylacetic acids with sterically demanding substituents.
1. A process for preparing a compound of formula (III)
in which
Ar is a
group,
where
R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and are each independently hydrogen, amino, cyano, nitro, halogen, optionally halogen-substituted C 1 -C 6 -alkyl, C 1 -C 6 -thioalkyl, thiophenyl, C 1 -C 6 -alkoxy, C 6 -C 10 -aryloxy, phenyl, —CO—C 6 -C 10 -aryl, —CO—C 1 -C 3 -alkyl, —COO—C 1 -C 6 -alkyl or —COO—C 6 -C 10 -aryl,
the Ar radical may additionally also be a heteroaromatic radical or
the Ar radical may also be 1- or 2-naphthyl,
and
R 6 and R 7 are each independently optionally substituted C 1 -C 8 -alkyl, phenyl, aryl, or NR 8 R 9 ,
where R 8 and R 9 are the same or different and are each independently C 1 -C 4 -alkyl, or phenyl optionally substituted by optionally fluorine- or chlorine-substituted C 1 -C 3 -alkyl, by nitro, cyano or di-C 1 -C 3 -alkylamino, or together with the nitrogen atom to which they are bonded are a saturated or unsaturated, substituted or unsubstituted cycle,
wherein an aryl or heteroaryl halide of formula (I)
Ar-Hal (I)
in which
Hal is chlorine, bromine or iodine and
Ar is as defined above,
is reacted with a malonic ester of formula (II)
in the presence of a palladium catalyst, of a phosphine ligand and
of an inorganic base and of a phase transfer catalyst
optionally using an organic solvent wherein the phase transfer catalyst comprises a quaternary ammonium salt or phosphonium salt of formula (V)
in which
R 13 , R 14 , R 15 and R 16 are the same or different and are each independently C 1 -C 28 -alkyl, optionally branched C 1 -C 28 -alkyl, C 6 -C 10 -aryl, or benzyl,
A is N or P and
X is halogen, hydrogensulphate, sulphate, dihydrogenphosphate, hydrogenphosphate, phosphate or acetate;
or a crown ether of formula (VI)
in which n is a number from 4 to 8
and the R 17 to R 20 radicals are each independently hydrogen, C 1 -C 4 -alkyl or phenyl, where two adjacent R 17 to R 20 radicals may also in each case together form a cyclic radical.
2. The process for preparing a compound of formula (III) according to claim 1 , where
Ar is 1- or 2-naphthyl, 3-thienyl or a
group,
where
R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and are each independently hydrogen, amino, cyano, nitro, fluorine, optionally fluorine-substituted C 1 -C 4 -alkyl, C 1 -C 4 -thioalkyl, thiophenyl, C 1 -C 4 -alkoxy, C 6 -C 10 -aryloxy, phenyl, —CO—C 6 -C 8 -aryl, —CO—C 1 -C 3 -alkyl, —COO—C 1 -C 4 -alkyl or —COO—C 6 -C 8 -aryl,
Hal is chlorine, bromine or iodine,
R 6 and R 7 are the same or different and are each independently C 1 -C 4 -alkyl.
3. The process for preparing a compound of formula (III) according to claim 1 , where
Ar is 1- or 2-naphthyl, 3-thienyl or a
group,
where
R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and are each independently hydrogen, amino, cyano, nitro, fluorine, methyl, methylthio, ethyl, i-propyl, n-propyl, CF 3 , C 2 F 5 , C 3 F 7 , methoxy, ethoxy, phenyl, —CO-phenyl, —CO-methyl, —CO-ethyl, —COO-methyl, —COO-ethyl or —COO-phenyl,
Hal is chlorine, bromine or iodine,
R 6 and R 7 are each independently methyl or ethyl.
4. The process for preparing a compound of formula (III) according to claim 1 , where
Ar is 1-naphthyl, 2-naphthyl, phenyl, 4-N,N-dimethylaminophenyl, 4-methylthiophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-ethylphenyl, 4-ethoxycarbonylphenyl, 3-thienyl.
5. The process for preparing a compound of formula (III) according to claim 1 , where
Ar is 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 4-cyanophenyl, 4-cyano-2-methylphenyl, 3-cyanophenyl, 4-ethoxycarbonylphenyl, 4-trifluoromethylphenyl, 4-acetylphenyl, 4-nitrophenyl, 4-benzoylphenyl.
6. The process for preparing a compound of formula (III) according to claim 1 , where
R 6 and R 7 are each ethyl.
7. The process for preparing a compound of formula (III) according to claim 1 , wherein the palladium catalyst used is bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or palladium acetate.
8. The process for preparing a compound of formula (III) according to claim 1 , wherein the phosphine ligand used is tri-tert-butylphosphine, tricyclohexylphosphine, tris(1-adamantyl)phosphine, n-butyldi(1-adamantyl)phosphine, benzyldi(1-adamantyl)phosphine, 2-(di-tert-butylphosphino)biphenyl or 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino.
9. The process for preparing a compound of formula (III) according to claim 1 , wherein the phosphine ligand used is tri(tert-butyl)phosphine.
10. The process for preparing a compound of formula (III) according to claim 1 , wherein the base used is potassium phosphate.
11. The process for preparing a compound of formula (III) according to claim 1 , wherein the base used comprises a mixture of potassium carbonate and potassium bicarbonate.
12. The process for preparing a compound of formula (III) according to claim 1 , wherein the phase transfer catalyst used comprises a quaternary ammonium salt or phosphonium salt of formula (V)
in which
R 13 , R 14 , R 15 and R 16 are the same or different and are each independently C 1 -C 28 -alkyl, optionally branched C 1 -C 28 -alkyl, C 6 -C 10 -aryl, or benzyl,
A is N or P and
X is halogen, hydrogensulphate, sulphate, dihydrogenphosphate, hydrogenphosphate, phosphate or acetate.
13. The process for preparing a compound of formula (III) according to claim 1 , wherein the phase transfer catalyst used comprises a crown ether of formula (VI)
in which n is a number from 4 to 8
and the R 17 to R 20 radicals are each independently hydrogen, C 1 -C 4 -alkyl or phenyl, where two adjacent R 17 to R 20 radicals may also in each case together form a cyclic radical.
14. The process for preparing a compound of formula (III) according to claim 1 , wherein the phase transfer catalyst used is 18-crown-6.
15. The process for preparing a compound of formula (III) according to claim 1 , wherein a malonic ester of formula (II) is used as a solvent in excess.
16. The process for preparing a compound of formula (III) according to claim 1 , wherein a temperature of from 100 to 180° C. is employed.
17. The process for preparing a compound of formula (III) according to claim 1 , wherein the phase transfer catalyst used comprises a crown ether of formula (VI)
in which n is a number from 4 to 8
and the R 17 to R 20 radicals are each independently hydrogen, C 1 -C 4 -alkyl or phenyl, where two adjacent R 17 to R 20 radicals may also in each case together form a cyclic radical comprising cyclopentyl, cyclohexyl or 1,2-phenylene.
18. The process for preparing a compound of formula (III) according to claim 1 ,
where Ar is a
group,
where
R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and are each independently hydrogen, amino, cyano, nitro, halogen, optionally halogen-substituted C 1 -C 6 -alkyl, C 1 -C 6 -thioalkyl, thiophenyl, C 1 -C 6 -alkoxy, C 1 -C 10 -aryloxy, phenyl, —CO—C 6 -C 10 -aryl, —CO—C 1 -C 3 -alkyl, —COO—C 1 -C 6 -alkyl or —COO—C 6 -C 10 -aryl.