Catalyzed fluorination of carbonyl compounds

Details Catalyzed fluorination of carbonyl compounds Catalyzed fluorination of carbonyl compounds

2000-03-27

2001-10-09

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Phosphorus esters

C558S435000, C560S178000, C560S180000, C560S184000, C564S197000, C568S035000

Reexamination Certificate

active

06300511

ABSTRACT:

This invention relates to the fluorination of organic compounds, in particular, to the fluorination of carbonyl compounds especially those having a carbonyl, nitro, nitrile sulphonyl or phosphoryl group in the 3-position to the arbonyl group, notably 1,3-dicarbonyl compounds (also known as &bgr;-dicarbonyl compounds).
Fluorinated carbonyl compounds, for example fluorinated 1,3-dicarbonyl compounds, are very valuable intermediates in the synthesis of other fluorine-containing compounds. International Patent Application No PCT/GB94102547 describes how treating solutions of 1,3-dicarbonyl compounds in various solvents with elemental fluorine gives the corresponding 2-fluoro-1,3-dicarbonyl compounds. Unfortunately, the fluorination of certain 1,3-dicarbonyl compounds proceeds at an undesirably low rate. Surprisingly, we have now found that the fluorination not only of 1,3-dicarbonyl compounds but also of other carbonyl compounds is catalysed by compounds of transition metals.
The present invention provides a method of substituting a carbonyl compound with fluorine at the &agr;-position, comprising reacting the carbonyl compound with a fluorinating agent in the presence of a metal-containing catalyst. The reaction results in replacement of a hydrogen atom by fluorine. The catalyst, which is used in a catalytically effective amount, is preferably a transition metal. In one class of methods the catalyst is a transition metal compound. In another class of methods, the catalyst is an elemental metal, in which case the carbonyl compound has an activating group attached to the carbon atom which is substituted by fluorine.
The invention also provides a method of fluorinating a 1,3-dicarbonyl compound comprising reacting the 1,3-dicarbonyl compound with a fluorinating agent in the presence of a compound of a transition metal. The reaction results in replacement of a hydrogen atom by fluorine.
A further aspect resides in a process for the fluorination of a &bgr;-dicarbonyl compound by means of a fluorinating agent, the process being carried out in the presence of a metal-containing catalyst, the metal preferably being a transition metal.
Methods Catalysed by a Transition Metal Compound
The transition metal compound is preferably a salt. The transition metal is usually a first row transition metal. Exemplary transition metals are those of Groups VIIa, VIII, Ib and IIb. More specific examples of compounds which may be used as catalysts in a method of the present invention are salts and other compounds of copper, iron. cobalt. nickel, manganese or zinc. The identity of the anion of the salt is not critical; suitably it is nitrate, sulphate or acetate of which nitrate is particularly convenient. A mixture of compounds of two or more metals may be used.
Any amount of catalyst may be added to the fluorination reaction but the amount is suitably up to 25 gram atoms of transition metal ion, and preferably 0.2 to 2.5 gram atoms, to 100 moles of substrate. More preferably, the amount of catalyst added is in the range 0.5 to 10 gram atoms of transition metal ion to 100 moles of substrate.
A preferred fluorinating agent is elemental fluorine.
The carbonyl group serves to activate the &agr;-hydrogen which is replaced. The method works well with, inter alia, compounds in which the carbonyl group is ketonic but this feature is far from critical (for example, esteric carbonyl groups are also very suitable). The compounds which are fluorinated preferably have another activating group attached to the carbon atom which is substituted by fluorine, for example another CO group or (R
I
O)
2
PO, SO
2
or CN; R
I
is in principle any organic group compatible with the reaction, e.g. alkyl, cycloalkyl or aryl. 1,3-Dicarbonyl compounds are a very preferred class of carbonyl compounds.
More particularly, the starting compounds are preferably of the formula (A): RCO.CHR
1
.R
2
, where:
R is selected from the group consisting of alkyl, oxyalkyl (i.e. —O-alkyl), cycloalkyl, oxycycloalkyl, aryl and oxyaryl;
R
1
is selected from the group consisting of CO.R
3
, CO.OR
3
, NO
2
, CN, CO.NR
3
2
, SO
2
R
3
and PO.(OR
3
)
2
, wherein R
3
is alkyl or cycloalkyl, and
R
2
is selected from the group consisting of H, F, Cl, NO
2
, CN, alkyl, oxyalkyl, cycloalkyl, oxycycloalkyl, aryl and oxyaryl;
or wherein R and R
1
are joined together to form a cycloalkyl structure, or R
1
and R
2
are joined together to form a cycloalkyl or aryl structure, or R and R
1
as well as R
1
and R
2
are so joined, the two ring structures being fused,
any of the aforesaid alkyl, cycloalkyl and aryl moieties optionally being substituted.
More preferably, the fluorination reaction is the fluorination of compounds having the general formula (B): RCO.CHR′CO.R″ into compounds having the general formula RCO.CFR′CO.R″. In these formulae, the group R may be alkyl, substituted alkyl, cycloalkyl, aryl, or substituted aryl, R′ may be hydrogen, chlorine, nitro, cyano, alkyl, substituted alkyl, cycloalkyl, aryl, or substituted aryl, and R″ may be alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, OR, NR
2
. Further, the groups R and R′ may be joined together to form a cyclic structure. Where in the starting material for the fluorination reaction R′ is H, the product of the reaction may have the formula RCO.CF
2
CO.R″.
For the compounds of formulae A and B suitable substituents include R and R
2
groups or, as the case may be, R and R′ groups; for example, alkyl may be substituted chlorine or fluorine), alkoxy and aryloxy, as well as other groups which are relatively inert to fluorine. Any of the aforegoing substituents may be substituted in turn by one or more other suitable substituents, to form groups such as, for example, haloalkoxy or alkoxyaryl.
The number of atoms in any of the groups R, R
1
and R
2
of formula (A), R, R′ and R″ of formula (B) and R
1
is not critical. since they play no part in the reaction. By way of example. however, the organic moieties may contain up to 10 carbon atoms, e.g. 1 to 4 carbon atoms. Cyclohexyl and cyclopentyl may be mentioned as a suitable cycloalkyl groups, and phenyl and naphthyl as suitable aryl groups, amongst others.
Methods Catalysed by Elemental Metal
In methods of this class. the catalyst is in the form of an elemental metal. A particular example of such a catalyst is metallic copper which may be used in the form of, for instance, a powder.
The carbonyl compound has an activating group in the &bgr;-position to the carbonyl group, like the preferred carbonyl reactants used with the transition metal compound catalysts. Indeed the preferred compounds described with reference to the transition metal compounds are preferred also for the metal catalysts. Most preferably, the compound is a &bgr;-dicarbonyl compound. Preferably, the &bgr;-dicarbonyl compound is a haloacetoacetate more preferably a chloroacetoacetate.
Preferably, the catalyst is used in a small amount. Particularly in the case of metallic copper, a preferred amount is up to 50 mg (8×10
31 4
grams atom) per 100 ml of reactant solution, more preferably 10 to 30 mg (1.6 ×10
−4
to 4.7 ×10
−4
grams atom) 100 ml solution and most preferably about 20 mg (3.15 grams atom) per 100 ml. Typically, the metal is used in an amount of up to 0.04 gram atoms and desirably up to 0.02 gram atoms, per mole of &bgr;-dicarbonyl compound, more preferably 0.004 to 0.012, especially about 0.008 gram atoms per mole of compound.
It is possible that the catalyst operates to speed up the enolisation of the compound carbonyl.
Reaction Conditions
Preferably, the reactions of the invention are conducted in the presence of a solvent. Preferred solvents include formic acid, acetic acid and acetonitrile, the latter being preferably used with a little water to give solubility to the salts.
Where fluorine is used as the fluorinating agent, it is preferably diluted with an inert gas such as nitrogen. Preferably, the fluorine is diluted to 1-50% v/v and, preferably in the rang

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