Substituted fluoroaromatics, process for preparing them and...

Details Substituted fluoroaromatics, process for preparing them and... Substituted fluoroaromatics, process for preparing them and...

2002-11-12

2004-01-13

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

C562S853000, C562S433000, C562S863000, C562S861000, C562S456000, C568S425000, C568S437000

Reexamination Certificate

active

06677479

ABSTRACT:

Benzaldehydes and benzoic acids having trifluoromethyl or trifluoromethoxy substituents, with or without additional fluorine substituents, are described extensively in the chemical literature as starting materials for the synthesis of active ingredients (for example U.S. Pat. No. 3,830,805 for aldehydes, EP-A-612 723 for benzoic acids), electronics materials, (JP-A-06 025 120) or generally as intermediates (EP-B-0 396 987).
However, there is a need for trifluoromethyl- and trifluoromethoxybenzaldehydes and benzoic acids having additional functionalities, since these functionalities ease or even make possible introduction into the target structures. The aim of modifying the activity of agrochemicals or pharmaceuticals through fluorination in the form of the trifluoromethyl or trifluoromethoxy group, with or without additional fluorine substituents on the aromatic ring is achieved by varying the lipophilicity and/or the dipolar moment (Kanie et al., Bull. Chem. Soc. Jpn. 2000, 73, 471). It may also be desirable for electronics materials, in particular liquid crystals, to vary the dipolar moment.
The invention accordingly provides compounds of the formula (I)
where substituents X
1
, X
2
, Y and Z are defined as follows:
X
1
is H or F
X
2
is H or F
Y is CI, Br or I
Z is CHO or COOH or CN
n is 0 or 1
Preference is given to the following compounds in which
a1) X
1
and X
2
: H
Y: Cl or Br
Z: CHO
a2) X
1
and X
2
: H
Y: Cl or Br
Z: COOH
a3) X
1
and X
2
: H
Y: Cl or Br
Z: CN
b1) X
1
: F X
2
: H
Y: Cl or Br
Z: CHO
b2) X
1
: F X
2
: H
Y: Cl or Br
Z: COOH
b3) X
1
: F X
2
: H
Y: Cl or Br
Z: CN
c1) X
1
and X
2
: F
Y: Cl or Br
Z: CHO
c2) X
1
and X
2
: F
Y: Cl or Br
Z: COOH
c3) X
1
and X
2
: F
Y: Cl or Br
Z: CN;
in particular
2-chloro-6-fluoro-5-trifluoromethylbenzaldehyde
2-bromo-6-fluoro-5-trifluoromethylbenzaldehyde
2-chloro-6-fluoro-5-trifluoromethoxybenzaldehyde
2-bromo-6-fluoro-5-trifluoromethoxybenzaldehyde
2-chloro-4,6-difluoro-5-trifluoromethylbenzaldehyde
2-bromo-4,6-difluoro-5-trifluoromethylbenzaldehyde
2-chloro-4,6-difluoro-5-trifluoromethoxybenzaldehyde
2-bromo-4,6-difluoro-5-trifluoromethoxybenzaldehyde
2-chloro-6-fluoro-5-trifluoromethylbenzoic acid
2-bromo-6-fluoro-5-trifluoromethylbenzoic acid
2-chloro-6-fluoro-5-trifluoromethoxybenzoic acid
2-bromo-6-fluoro-5-trifluoromethoxybenzoic acid
2-chloro-4,6-difluoro-5-trifluoromethylbenzoic acid
2-bromo-4,6-difluoro-5-trifluoromethylbenzoic acid
2-chloro-4,6-difluoro-5-trifluoromethoxybenzoic acid
2-bromo-4,6-difluoro-5-trifluoromethoxybenzoic acid
The invention further provides a process for preparing the compounds of the formula (I) where Z=CHO, wherein, a halobenzene of the formula (II) (wherein n, Y, X
1
and X
2
are each as defined in formula (1) in a solvent or solvent mixture at a temperature which does not support aryne formation is reacted with an organolithium compound. The molar ratio of lithium compound to starting product (II) is preferably 1:1 to 1.2:1. The lithium compound obtained, again at a temperature which does not support aryne formation, is reacted with one formyl equivalent of the formula (III) and then subjected to a hydrolysis to (I). The molar ratio (II):(II) is preferably from 1:1 to 1:2.
In (III), R
1
is an alkyl radical having from 1 to 6 carbon atoms, a trimethylsilyl radical or an (optionally substituted) phenyl radical, R
2
is an alkyl radical having from 1 to 6 carbon atoms, a trimethylsilyl radical or an (optionally substituted) phenyl radical and R
3
is —CH(═O) or —CH(OR
4
)
2
; R
1
and R
2
together with the nitrogen atom may also be part of a five- to seven-membered ring. R
4
is an alkyl radical having from 1 to 4 carbon atoms.
Preference is given to reacting (II) with organolithium compounds at a temperature below −60° C., very particular preferably below −70° C., in particular at a temperature in the range from −70° C. to −110° C. The reaction times are in general from 1 to 8 hours. On completion of the reaction (detectable, for example, by TLC or GC), the reaction mixture is gradually heated to −25 to −15° C. and cautiously hydrolyzed using water. The mixture is then acidified using hydrochloric acid to a pH of from 1 to 5 and extracted with a suitable solvent (for example tert-butyl methyl ether, dichloromethane, ethyl acetate, toluene). The extracts of the organic phase are combined and dried, for example, over sodium sulfate). The solvent may be removed under reduced pressure to obtain the desired compound of the formula (I). Any purification required may be effected by chromatography, distillation or crystallization or a combination of the methods mentioned.
The yields are customarily in the range from 50 to 90%, based on (II).
The organolithium compound is preferably the lithium compound of a secondary amine, preferably having sterically demanding substituents. Particular preference is given to lithiumdiisopropylamide, lithium-2,2,6,6-tetramethylpiperidide, lithium dicyclohexylamide, lithium cyclohexylisopropylamide and lithium bis(trimethylsilyl)amide. Very particular preference is given to lithium 2,2,6,6-tetramethylpiperidide and lithium diisopropylamide.
For the compounds of the formula (II) where Y is CI, the organolithium compound is an alkyllithium compound or the lithium compound of a secondary amine; preference is given to n-butyllithium.
Potassium tert-butoxide may also optionally be added for better activation.
In a preferred embodiment, Y in formula (II) is Br.
It may also be advantageous to add materials to the reaction mixture which activate it or influence the selectivity, for example tetramethylethylenediamine or potassium tert-butoxide (preference is given to the latter in the case of compounds of the formula (II) where Y is CI).
The formyl equivalent of the formula (III) is preferably N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide, N,N-diisopropylformamide, N,N-dibutylformamide, N-formylpyrrolidine, N-formylmorpholine, N-formylpiperidine, dimethylformamide dialkyl acetal, N-methylformanilide, N-ethylformanilide or N,N-bis(trimethylsilyl)formamide. The formyl equivalent of the formula (III) is most preferably N,N-dimethylformamide.
For the purposes of the present invention, useful solvents are aprotic solvents, for example ether such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, or hydrocarbons such as hexane, cyclohexane, heptane, pentane or mixtures of aprotic solvents.
The reaction of (II) with the organolithium compound may also be effected in the presence of the compound (III), so that the lithium derivative of (II) formed in situ can react directly with (III). For this purpose, it may be necessary and advantageous to carry out the reaction above −60° C., for example in the range from −20 to +25° C.
The invention further provides a process for preparing compounds of the formula (I) where Z=COOH, wherein a halobenzene of the formula (II) (where E, Y, X
1
and X
2
are each as defined above) in a solvent or solvent mixture at a temperature which does not support aryne formation is reacted with an organolithium compound. The molar ratio of lithium compound: starting product (II) is preferably from 1:1 to 1.2:1. The lithium compound obtained, again at a temperature which does not support aryne formation, is reacted with carbon dioxide (CO
2
) and then subjected to hydrolysis (I).
Preference is given to reacting (II) with the organolithium compound at a temperature below −60° C., very particular preference below −70° C., in particular at a temperature in the range from −70° C. to −110° C. The reaction times are in general from 1 to 8 hours. On completion of the reaction (detectable, for example, by TLC or GC), the reaction mixture is gradually heated to −25 to −15° C. and cautiously hydrolyzed using water. The mixture is then acidified using hydrochloric acid to a pH of from 1 to 5 and extracted with a suitable solvent (for example tert-butyl methyl ether, dichloromethane, ethyl acetate, toluene). The ex

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