Synthesis of vicinal difluoro aromatics and intermediates...

Details Synthesis of vicinal difluoro aromatics and intermediates... Synthesis of vicinal difluoro aromatics and intermediates...

2002-12-30

2004-03-16

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Halogen containing

C570S143000

Reexamination Certificate

active

06706933

ABSTRACT:

BACKGROUND OF THE INVENTION
Aromatic compounds, especially naphthalene derivatives, bearing fluorine atoms on adjacent carbons (i.e., vicinal) have been found to be useful as liquid crystal materials. They are typically made by a multi-step process, starting from the aromatic amine via a fluoro-dediazoniation process (N. Yoneda and T. Fukuhara,
Tetrahedron
, vol. 52, No. 1 (1996), pages 23-36).
No simple methods are known for producing vicinal difluoro aromatic compounds. Methods for defluorinating highly fluorinated compounds are known; but, none of the methods have been shown to produce vicinal difluoro compounds in high yield. For example:
C. Hu, et al.,
Journal of Fluorine Chemistry
, Vol. 48 (1990), pages 29-35, disclosed a method of synthesizing perfluoroaromatics, such as tetradecafluorobicyclo[4.4.0]dec-1(2),6(7)-diene and perfluorotetralin, by defluorination of hexadecafluorobicyclo[4.4.0]dec-1(6)-ene in an aprotic solvent using activated zinc powder as a catalyst. The extent of defluorination depended on the polarity of the aprotic solvent used.
J. Burdon and I. W. Parsons,
Journal of Fluorine Chemistry
, Vol. 13 (1979), pages 159-162, disclose the formation of 2,5-difluorothiophen by pyrolysis of 2,2,5,5-tetrafluoro-3-thiolen over sodium fluoride.
Sergey S. Laev and Vitalii D Shteingarts,
Journal of Fluorine Chemistry
, Vol. 96 (1999) pages 175-185, disclose the reductive dehalogenation of polyfluoroarenes by zinc in aqueous ammonia. In the reaction, hydrogen atoms replace fluorine atoms in the polyfluoroarenes.
JP 2001-10995A (Ogawa, et al.) describes a four-step process for synthesis of vicinal difluoro aromatic compounds involving fluorination of a hydroxy aromatic compound to form a tetrafluoro intermediate in two steps followed by hydrogenation and defluorination under basic conditions. It also discloses reduction of a difluoroketone intermediate with aluminum isopropoxide and then base-catalyzed dehydrohalogenation to form a difluoro aromatic compound. A third method involves reaction of the difluoroketone with lithium aluminum hydride to form a fluoroepoxide, addition of HF, and elimination of water to give a vicinal difluoro aromatic compound. The best overall yield shown is <50%.
There remains a need for an effective and simple method for preparing vicinal difluoro aromatic compounds in high yield.
BRIEF SUMMARY OF THE INVENTION
This invention is directed to a method of preparing vicinal difluoro aromatic compounds in high yield from hydroxy aromatic compounds and to preparing intermediates thereof. The hydroxy aromatic compound can be a mono-, bi- or tricyclic aromatic in which the rings are separate or fused. One or more of the rings can contain heteroatoms, such as oxygen, nitrogen, or sulfur, and can contain substitutions, in addition to the hydroxy substitution. Substitutions on one or more of the rings can include a halogen atom, a C1 to C20 alkyl, a C5-C10 cycloalkyl, a C6 to C12 aryl, an amino, a nitro, a C1 to C10 alkyl ether or thioether, a C1 to C10 alkyl ester, a CF
3
, a R′SO
2
O,
where R′ is CF
3
, a C1 to C20 alkyl, a substituted or unsubstituted C5 to C10 cycloalkyl, or a substituted or unsubstituted C6 to C12 aryl, in which the substitution on the cycloalkyl or aryl can be a C1 to C20 alkyl or a C5 to C8 cycloalkyl; R″ is a C1-C10 saturated or unsaturated alkyl; x is an integer from 0 to 10, and y is an integer from 0 to 10.
The process can be described by the following reaction steps:
where R is a hydrogen atom, a halogen atom (Cl, Br, I, F), R′SO
2
O, CF
3
, a fused aryl, a C1-C20 alkyl, amino, nitro, a C1 to C10 ether or thioether, a C1 to C10 ester, a heteroaryl, wherein the heteroatom can be O, N, S,
or R forms an aryl. R′ is CF
3
, a C1 to C20 alkyl, a substituted or unsubstituted C5 to C10 cycloalkyl, or a substituted or unsubstituted C6 to C12 aryl, wherein the substitution on the cycloalkyl or aryl can be a C1 to C20 alkyl or a C5 to C8 cycloalkyl; R″ is a C1-C10 saturated or unsaturated alkyl; x is an integer from 0 to 10, and y is an integer from 0 to 10. The preferred R group is trans-4-propylcyclohexyl.
The yields obtained from reactions (1) and (2) are highly dependent on the solvents employed for these steps. Polar aprotic solvents are desirable for the electrophilic fluorination in step (1) and dimethylformamide (DMF) is particularly preferred because it unexpectedly resulted in yields of greater than 95% difluoro ketone product. Reaction step (2) can be conducted in various solvents including aliphatic and aromatic hydrocarbons, halocarbons, ethers, etc.; however, toluene unexpectedly gives much higher yields of the tetrafluoro product compared to other organic solvents. Step (3) involves reacting the tetrafluoro compound with a reducing agent, such as metallic zinc, copper, magnesium, or a mixture thereof, to form the vicinal difluoro aromatic compound in high yields (e.g., 90% or more). This reaction is preferably carried out in buffered aqueous ammonia in the presence of an organic solvent such as tetrahydrofuran (THF), methyl tert-butyl ether, acetonitrile, ethanol, or DMF. Since the tetrafluoro compound reacts under basic conditions to form a trifluoronaphthalene by-product, the pH of the aqueous ammonia is buffered to <14 by addition of an ammonium salt, particularly NH
4
Cl. Under these conditions, the selectivity to the desired vicinal difluoronaphthalene product is significantly increased.
This method of preparing vicinal difluoro aromatic compounds has the following advantages over known methods:
the difluoro ketone and tetrafluoro intermediates do not need to be purified prior to subsequent reaction,
the product is produced in high selectivity,
the overall yield is 70% or more, and
the product easily can be separated and purified by known methods.
DETAILED DESCRIPTION OF THE INVENTION
In the method of this invention, vicinal difluoro aromatic compounds can be prepared in three steps from hydroxy aromatic compounds by electrophilic fluorination using a fluorination reagent such as Selectfluor® reagent (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis-tetrafluoroborate) to form a difluoroketone intermediate. The difluoro ketone undergoes nucleophilic fluorination by reaction with a deoxofluorinating reagent such as Deoxo-Fluor® reagent (bis(2-methoxyethyl)-aminosulfur trifluoride) to give a tetrafluoro intermediate species. The tetrafluoro intermediate is defluorinated by a metallic reducing agent in the presence of ammonium hydroxide, preferably buffered ammonium hydroxide, to provide the desired vicinal difluoro aromatic compound in high yield. An example of the reaction chemistry is described above in the Brief Summary of the Invention.
In the first step, a hydroxy aromatic compound (e.g., &bgr;-naphthol or substituted naphthol) is reacted with an electrophilic fluorinating agent such as Selectfluor reagent, to generate a difluoroketone intermediate. This reaction can be conducted in various solvents including nitrites such as acetonitrile (CH
3
CN), formamides such as dimethylformamide (DMF), CH
3
NO
2
, carboxylic acids such as acetic acid, water, and an alcohol such as methanol, ethanol, and propanol.
The reaction can be carried out at temperatures ranging from 0° C. to the boiling point of the solvent.
The fluorinating agent can be added to a solution or suspension of the hydroxy aromatic compound in one or more portions, or dropwise as a solution. Alternatively, the hydroxy aromatic compound solution or suspension can be added to a solution or suspension of fluorinating agent.
In the second step, the carbonyl oxygen of the difluoroketone is replaced by two fluorine atoms using a deoxofluorinating agent such as Deoxo-Fluor reagent. The reaction is carried out by reacting the difluoroketone with the deoxofluorinating agent in an organic solvent in an anhydrous atmosphere. Solvents include alkanes such as hexane, heptane, etc.; aromatic hydrocarbons such as toluene, xylenes, etc.; haloalkanes such as methylene chloride, ch

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