Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-01-14
2001-04-24
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C544S158000, C546S248000, C548S562000, C548S565000, C548S570000, C558S460000, C560S227000, C564S102000, C568S437000, C568S821000, C570S125000, C570S124000, C570S127000, C570S131000, C570S142000, C570S144000
Reexamination Certificate
active
06222064
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
The development of safe, efficient, and simple methods for selective incorporation of fluorine into organic compounds has become a very important area of technology. This is due to the fact that fluorine strategically positioned at sites of synthetic drugs and agrochemical products significantly modifies and enhances their biological activities. The conversion of the C—O to the C—F bond, which is referred to herein a deoxofluorination, represents a viable method to produce selectively fluorinated organic compounds, but the low yields and hazards associated with the current deoxofluorination reagents and processes severely limit the application of this technique.
The introduction of fluorine into medicinal and agrochemical products can profoundly alter their biological properties. Fluorine mimics hydrogen with respect to steric requirements and contributes to an alteration of the electronic properties of the molecule. Increased lipophilicity and oxidative and thermal stabilities have been observed in such fluorine-containing compounds.
In view of the importance of organofluorine compounds, efforts aimed at the development of simple, safe, and efficient methods for their synthesis have escalated in recent years. The conversion of the carbon-oxygen to the carbon-fluorine bond by nucleophilic fluorinating sources (deoxofluorination) represents one such technique which has been widely used for the selective introduction of fluorine into organic compounds. A list of the deoxofluorination methods practiced to date includes: nucleophilic substitution via the fluoride anion; phenylsulfur trifluoride; fluoroalkylamines; sulfur tetrafluoride; SeF
4
; WF
6
; difluorophosphoranes and the dialkylaminosulfur trifluorides (DAST). The most common reagent of this class is diethylaminosulfur trifluoride, Et-DAST or simply DAST.
The DAST compounds have proven to be useful reagents for effecting deoxofluorinations. These reagents are conventionally prepared by reaction of N-silyl derivatives of 2° amines with SF
4
. In contrast to SF
4
, they are liquids which can be used at atmospheric pressure and at near ambient to relatively low temperature (room temperature or below) for most applications. Deoxofluorination of alcohols and ketones are particularly facile and reactions can be carried out in a variety of organic solvents (e.g., CHCl
3
, CFCl
3
, glyme, diglyme, CH
2
Cl
2
, hydrocarbons, etc.). Most fluorinations of alcohols are done at −78° C. to room temperature. Various functional groups are tolerated including CN, CONR
2
, COOR (where R is an alkyl group), and successful fluorinations have been accomplished with primary, secondary and tertiary (1°, 2°, 3°) allylic and benzylic alcohols. The carbonyl to gem-difluoride transformation is usually carried out at room temperature or higher. Numerous structurally diverse aldehydes and ketones have been successfully fluorinated with DAST. These include acyclic, cyclic, and aromatic compounds. Elimination does occur to a certain extent when aldehydes and ketones are fluorinated and olefinic by-products are also observed in these instances.
While the DAST compounds have shown versatility in effecting deoxofluorinations, there are several well recognized limitations associated with their use. The compounds can decompose violently and while adequate for laboratory synthesis, they are not practical for large scale industrial use. In some instances, undesirable by-products are formed during the fluorination process. Olefin elimination by-products have been observed in the fluorination of some alcohols. Often, acid-catalyzed decomposition products are obtained. The reagent's two step method used for their synthesis renders these relatively costly compositions only suitable for small scale syntheses.
The DAST reagents are recognized as fluorinating reagents in U.S. Pat. Nos. 3,914,265 and 3,976,691. Additionally, Et-DAST and related compounds have been discussed in W. J. Middleton, New Fluorinating Reagents. Dialkylaminosulfur Fluorides, J. Org. Chem., Vol. 40, No. 5, (1975), pp 574-578. However, as reported by Messina, et al., Aminosulfur Trifluorides: Relative Thermal Stability, Journal of Fluorine Chemistry, 43, (1989), pp 137-143, these compounds can be problematic fluorinating reagents due to their tendency to undergo catastrophic decomposition (explosion or detonation) on heating. See also reports on this by J. Cochran, Laboratory Explosions, Chemical and Engineering News, (1979), vol. 57, No. 12, pp. 4 & 74; and W. T. Middleton, Explosive Hazards with DAST, Chemical and Engineering News, (1979), vol. 57, No. 21, p. 43. Difficulties with major amounts of by-products in the fluorination reaction is also noted. See also M. Hudlicky, Fluorination with Diethylaminosulfur Trifluoride and Related Aminofluorosulfuranes, Organic Reaction, Vol. 35, (1988), pp 513-553.
Further, Russian Inventor's Certificate No. 433,136 published Dec. 15, 1974 discloses sulfur dialkyl(alkylaryl)aminotrifluorides.
G. L. Hann, et. al., in Synthesis and Enantioselective Fluorodehydroxylation Reactions of (S)-2-(Methoxymethyl)pyrrolidin-1-ylsulphur Trifluoride, the First Homochiral Aminofluorosulphurane, J. Chem. Soc., Chem. Commun. (1989) pp 1650-1651, disclosed the aminosulfur trifluorides, (S)-2-(methoxymethyl)pyrrolidin-1-ylsulphur trifluoride and N-morpholinosulphur trifluoride as fluorinating reagents for 2-(trimethylsiloxy)octane.
The method and compositions of the present invention overcome the drawbacks of the prior art fluorinating reagents, including DAST, by providing more thermally stable fluorine bearing compounds which have effective fluorinating capability with far less potential of violent decomposition and attendant high gaseous by-product evolvement, with simpler and more efficient fluorinations, as will be set forth in greater detail below.
BRIEF SUMMARY OF THE INVENTION
The present invention is a method for the fluorination of a compound using a fluorinating reagent comprising contacting the compound with the fluorinating reagent under conditions sufficient to fluorinate the compound wherein the fluorinating reagent is an aminosulfur trifluoride composition having a structure with one or more:
wherein m=1-5 and R
1
and R
2
are:
(1) when m=1, individually aryl or meta- or para-substituted aryl radicals in which the meta- or para-substitution is selected from the group consisting of normal and branched C
1-10
, trifluoromethyl, alkoxy, aryl C
6-10
, nitro, sulfonic ester, N,N-dialkylamino and halogens; or
(2) when m=1, individually aryl radicals which are fused or linked to one another; or
(3) when m=1, one of R
1
and R
2
is an aryl radical and the other is an at least 5 member saturated cyclic hydrocarbon radical having zero to three heteroatoms selected from the group consisting of oxygen, nitrogen and mixtures thereof; or
(4) when m=1, one of R
1
and R
2
is an aryl radical and the other is an at least 5 member saturated cyclic hydrocarbon radical having zero to three heteroatoms selected from the group consisting of oxygen, nitrogen and mixtures thereof wherein said cyclic hydrocarbon radical is fused to said aryl radical; or
(5) when m=1, together a cyclic ring having 2 to 10 carbon ring members and 1 heteroatom selected from the group consisting of oxygen, nitrogen and alkylated nitrogen wherein said ring has 1 to 2 alkoxyalkyl functionalities; or
(6) when m=1, together an unsaturated cyclic ring having 2 to 4 carbon ring members and one to three heteroatoms selected from the group consisting of oxygen, nitrogen, protonated nitrogen and alkylated nitrogen wherein said ring has one to three functional groups selected from hydrogen, normal and branched C
1-10
alkyl, haloalkyl, alkoxy, aryl halogen, cyano, nitro and amino; or
(7) when m=1, individually alkoxyalkyl radicals; or
(8) when m=1, one of R
1
and R
2
is alkoxyalkyl and the other is selected from the group co
Lal Gauri Sankar
Pez Guido Peter
Air Products and Chemicals Inc.
Bongiorno Mary E.
Chase Geoffrey L.
O'Sullivan Peter
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