Regioselective fluorination of phenyl-substituted triazolinones

Details Regioselective fluorination of phenyl-substituted triazolinones Regioselective fluorination of phenyl-substituted triazolinones

1999-08-27

2001-04-17

Morris, Patricia L. (Department: 1612)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S263400, C548S263800

Reexamination Certificate

active

06218545

ABSTRACT:

The present invention relates generally to processes for preparing 1-(2-fluorophenyl)-substituted triazolinones. In particular, it pertains to the fluorination of the phenyl ring of 4,5-dihydro-1-(4-substituted phenyl)-3,4-disubtituted-1,2,4-triazol-5(1H)-ones.
The 4,5-dihydro-1-(2-fluoro substituted phenyl)-3,4-disubtituted-1,2,4-triazol-5(1H)-ones, for example 4,5-dihydro-1-(4-chloro-2-fluorophenyl)-3-methyl-4-difluoromethyl-1,2,4-triazol-5(1H)-one, are critical intermediates in the manufacture of fine chemicals, such as pesticides. For example, 4,5-dihydro-1-(4-chloro-2-fluorophenyl)-3-methyl-4-difluoromethyl-1,2,4-triazol-5(1H)-one is a known intermediate in the manufacture of the herbicide ethyl &agr;-2dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1yl]-4-fluorobenzenepropanoate.
Fluorination of complex aromatic systems is difficult because of fluorine's high reactivity. As a result, there are only a few practical commercial methods by which fluorine can be introduced regioselectively into complex aromatic systems.
One method of fluorination includes the Balz-Schiemann reaction in which an aromatic ring is fluorinated by the thermal decomposition of diazonium fluoroborates. This method has failed to provide the desired product in appreciable yield.
Another method for the preparation of fluorinated complex aromatic systems, in particular phenyl-substituted triazolinones, includes the use of 2-fluoroaniline or 2-fluorophenylhydrazine as starting materials for the preparation of a corresponding 1-(2-fluorophenyl)-substituted triazolinones thereby avoiding the difficult task of fluorinating a deactivated aromatic ring. These procedures provide low synthetic yields.
Electrophilic NF fluorinating agents have been used to directly fluorinate monosubstituted and disubstituted aromatics to provide mixtures of the ortho- and para-fluoro-phenyl substituted compounds. (
J. Chem. Soc., Chem. Commun.,
1992, pg. 595-596). Substantially isomerically pure para-fluoro-trisubstituted aromatic rings have been prepared with this procedure when at least one of the substituents of the disubstituted aromatic starting material is electron donating. This procedure has not been applied to the preparation of 1-(2-fluoro-4-substituted-phenyl)-3,4-disubstituted triazolinones.
There remains a need for a simple and generally high yielding method for the preparation of the key synthetic intermediates 1-(2-fluoro-4-substituted-phenyl)-3,4-disubstituted triazolinones in substantially isomerically pure or isomerically enriched form using 1-(4-substituted-phenyl)-3,4-disubstituted triazolinones as starting materials.
SUMMARY OF THE INVENTION
The present invention provides a method by which fluorine can be regioselectively introduced into complex aromatic systems. The present invention provides a method for the preparation of 4,5-dihydro-1-(2-fluoro-4-substituted phenyl)-3,4-disubtituted-1,2,4-triazol-5(1H)-one of the Formula I below by the direct fluorination of a corresponding 4,5-dihydro-1-(4-substituted phenyl)-3,4-disubstituted-1,2,4-triazol-5(1H)-one of the Formula II with a fluorinating agent in the presence of an organic solvent.
The present invention provides a high degree of regioselectivity in the fluorination of complex aromatic systems by preferentially fluorinating the pendant phenyl group of the compound of the Formula II at the ortho-position rather than the meta- or para-positions. Treatment of a compound of the Formula II with a fluorinating agent provides a corresponding compound of the Formula I in moderate yields.
It has been unexpectedly found that the fluorination process of the present invention can provide compounds of the Formula I in high regioselective and chemical yield containing less than about 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, and most preferably no detectable amount, of undesired regioisomers.
In one embodiment, the invention provides a process for the preparation of a compound of the Formula I
wherein:
X is hydrogen, halogen, C
1
-C
6
-alkyl, C
1
-C
6
-haloalkyl, or nitro; and
R and R′ are independently hydrogen, halo, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
3
-C
5
-alkynyl, C
1
-C
6
-haloalkyl, C
2
-C
6
-haloalkenyl, C
2
-C
7
-acyl, C
2
-C
6
-alkoxyalkyl, C
2
-C
6
-cyanoalkyl, C
1
-C
3
-alkylsulfinyl, C
1
-C
3
-alkylsulfonyl, or C
1
-C
3
-alkylthio-C
1
-C
3
-alkyl;
the process comprising the step of treating a compound of the Formula II
with a fluorinating agent at a temperature of about 60° to about 120° C. in the presence of an organic solvent to form a compound of the Formula I; wherein:
X and R are as defined above;
R′ is independently an alkali metal cation, hydrogen, halo, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
3
-C
5
-alkynyl, C
1
-C
6
-haloalkyl, C
2
-C
6
-haloalkenyl, C
2
-C
7
-acyl, C
2
-C
6
-alkoxyalkyl, C
2
-C
6
-cyanoalkyl, C
1
-C
3
-alkylsulfinyl, C
1
-C
3
-alkylsulfonyl, or C
1
-C
3
-alkylthio-C
1
-C
3
-alkyl; and
X, R or R′ can optionally be independently protected with a protecting group which is substantially stable to the fluorinating agent.
In another embodiment, R and R′ are independently hydrogen, halo, C
1
-C
6
-alkyl, C
2
-C
6
-alkyl, C
1
-C
6
-haloalkyl, C
2
-C
6
-haloalkyl or C
2
-C
7
-acyl.
In yet another embodiment, X is H or halogen; R is C
1
-C
6
-alkyl; and R′ is C
1
-C
6
-haloalkyl. In still yet another embodiment, X is chloro; R is methyl; and R′ is difluoromethyl.
DETAILED DESCRIPTION OF THE INVENTION
The yields of the present process depend, among other things, upon the temperature at which the treatment is conducted, the mode, rate or order of addition into a reaction vessel of the fluorinating agent and the compound of the Formula II, the molar ratio of the fluorinating agent to the compound of the Formula II, or the solvent employed or a catalyst employed.
The process of the present invention can be run at temperatures ranging from about 60° C. to a temperature which is at or below the boiling point of the organic solvent(s) used. The optimal temperature for running the fluorination reaction will depend, among other things, upon the organic solvent or combination of organic solvents used to run the reaction. The optimal temperature will generally range from about 60° to about 120° C., preferably from about 80° to about 115° C., more preferably from about 80° to about 85° C.
The modifier “about” is used herein to indicate that certain preferred operating ranges, such as material amounts and temperature, and ranges thereof, are not fixedly determined. The meaning will often be apparent to one of ordinary skill. For example, a recitation of a temperature range of about 60° C. to about 120° C. in reference to, for example, the aforementioned fluorination reaction would be interpreted to include other like temperatures which can be expected to favor a useful rate of reaction, such as, for example, 54° C. or 132° C. Where guidance from the experience of those of ordinary skill is lacking, guidance from the context is lacking, and where a more specific rule is not recited below, the “about” range shall be not more than 10% of the absolute value of an end point or 15% of the range recited, whichever is less.
Fluorinating agents that may be used in accordance with the present invention are electrophilic NF reagents and xenon difluoride. NF reagents are electrophilic fluorinating agents that contain a fluorine atom bound to a nitrogen atom which is part of an organic compound. NF reagents serve as F
+
transfer agents. The NF fluorinating reagents used in the present invention can include those described by Lal et al. (
Chem. Rev.,
1996, 96, 1737-1755), Lal (
J. Org. Chem,
1993, 58, 2791-2796), and Banks et al. (
J. Chem. Soc., Chem. Commun.
1992, 595-596), the relevant disclosures of which are hereby incorporated by reference. Examples of electrophilic NF reagents include but are not limited to fluorine triethylenediamine (F-TEDA), N-fluoro-o-benzenesulfonimide, and N-fluoro-2-pyridone.
The el

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