Process for converting an alcohol to the corresponding fluoride

Details Process for converting an alcohol to the corresponding fluoride Process for converting an alcohol to the corresponding fluoride

1998-11-20

2001-06-19

Keys, Rosalynd (Department: 1621)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C568S607000, C568S615000, C568S616000, C568S618000, C568S623000, C568S663000, C570S136000, C570S142000

Reexamination Certificate

active

06248889

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for converting a primary or secondary alcohol to its corresponding fluoride.
BACKGROUND OF THE INVENTION
Organic compounds selectively substituted with fluorine have utility as drugs, agrichemicals, medical imaging agents, and high polarization additives for ferroelectric liquid crystal compositions, as well as in many other applications. Fluorinated steroids and drugs are often more potent than their unsubstituted analogs due to increased lipophilic behavior, suppression of undesired metabolic reactions, and reduced binding to serum proteins. (See, e.g., J. A. Katzenellenbogen et al., J. Org. Chem. 49, 4900 (1984).) Chiral ferroelectric liquid crystal compounds having a fluorine atom at the chiral center exhibit larger spontaneous polarizations and greater smectic character than their hydrocarbon analogs. (See, e.g., H. Nohira et al., Mol. Cryst. Liq. Cryst. 180B, 379, 385 (1990).)
The preparation of such selectively fluorinated materials poses special difficulties due to a tendency for hydrogen fluoride elimination under the conditions conventionally used to prepare these materials. One commonly used strategy is to replace a hydroxyl group (in a starting compound) with a fluorine atom, but this is not an easy transformation since carbonium ion rearrangements and dehydration to an olefin can occur. (See, e.g., W. J. Middleton, J. Org. Chem. 40, 574 (1975).)
Such side reactions can be minimized by the use of DAST (diethylaminosulfur trifluoride) as the fluorinating reagent. DAST fluorinations can be carried out under mild conditions, making DAST more convenient to use than some other fluorination reagents such as sulfur trifluoride. (See, e.g., M. Hudlicky,
Organic Reactions
, volume 35, page 513, John Wiley and Sons, New York (1988).) However, DAST is not commercially available and is costly to produce (due, e.g., to the need for specialized preparation and handling equipment), and the yields obtained using DAST are often only moderate.
Selectively fluorinated materials have also been prepared from their hydroxyl-functional equivalents (primary and secondary alcohols) using perfluoroalkanesulfonyl fluorides and strong bases in organic solvent (as described by B. Benua-Skalmowski and H. Vorbrueggen in Tetrahedron Letters 36 (15), 2611 (1995), as well as in International Patent Publication No. WO 96/13474 (Vorbrueggen) and U.S. Pat. No. 5,760,255 (Vorbrueggen et al.)). This method has involved the use of 2 to 3 equivalents of base, with addition of the perfluoroalkanesulfonyl fluoride to a premix of alcohol and base.
However, there is a continuing need in the art for a selective fluorination process that is useful on an industrial scale. Such a process should not only be cost effective and capable of being carried out using common multipurpose industrial equipment, but should also be able to consistently provide good to excellent yields under the variable conditions commonly encountered in a factory setting.
SUMMARY OF THE INVENTION
Briefly, this invention provides an improved, industrially useful process for preparing a fluoride from its corresponding alcohol using a fluorinated sulfonyl fluoride as the source of the fluorine. The process comprises the steps of (a) forming a mixture comprising (i) at least one fluorinated, saturated aliphatic or alicyclic sulfonyl fluoride (e.g., perfluorobutanesulfonyl fluoride) and (ii) at least one primary or secondary alcohol (e.g., 6-hydroxyoctene); and (b) adding a molar excess of at least one strong, aprotic, non-nucleophilic, hindered, double bond-containing, organic base (e.g., DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene) to the mixture. (As used herein, the term “strong organic base” means an organic base that is capable of enabling the formation of a sulfonate ester without substantially inducing elimination of, e.g., hydrogen fluoride or sulfonate anion.) Due to the exothermic nature of the reaction, the mixture is preferably precooled, e.g., to a temperature in the range of about −30° C. to about 0° C., prior to addition of the organic base.
It has been discovered that the process of the invention, which involves the addition of base to a premix of alcohol and sulfonyl fluoride, surprisingly provides significantly better selectivity and significantly higher yields of the desired fluoride than both the prior art sulfonyl fluoride-based method (which involves the addition of sulfonyl fluoride to a premix of base and alcohol) and the use of DAST. Furthermore, unlike the prior art sulfonyl fluoride-based method (which requires the use of 2 to 3 equivalents of base), the process of the invention consistently provides excellent yields, regardless of the size of the excess of base utilized.
As with the use of DAST, the process of the invention, when carried out using a chiral alcohol, proceeds with complete inversion of configuration at the chiral center. The process can, however, be carried out more safely than processes which utilize DAST as the fluorinating reagent, as, unlike DAST, the reactants do not fume in the open air, decompose violently at temperatures above 50° C., or burn the skin upon contact.
Furthermore, since the process of the invention utilizes fluorinated sulfonyl fluorides, rather than the higher cost diethylaminosulfur trifluoride (DAST), and since it does not require as large an excess of base as the prior art sulfonyl fluoride-based method, it provides better selectivity and higher yields of desired product (than the prior art methods) at lower raw material costs. The process of the invention therefore satisfies the need in the art for a cost effective selective fluorination process that consistently provides excellent yields under variable reaction conditions.
In another aspect, this invention also provides an improved, sulfonyl fluoride-based selective fluorination process that utilizes the conventional premix of base and alcohol but a molar excess of base of less than 2 equivalents per equivalent of alcohol.
DETAILED DESCRIPTION OF THE INVENTION
Sulfonyl fluorides suitable for use in the process of the invention are fluorinated, saturated aliphatic or alicyclic sulfonyl fluorides. A useful class of such sulfonyl fluorides can be represented by the general formula R
f
SO
2
F, where R
f
is selected from the group consisting of perfluorinated alkyl groups having from 1 to about 10 carbon atoms; partially-fluorinated alkyl groups having from 1 to about 10 carbon atoms; unsubstituted or perfluoroalkyl-substituted, perfluorinated cycloalkyl groups having from about 4 to about 8 carbon atoms; and unsubstituted or perfluoroalkyl-substituted, partially-fluorinated cycloalkyl groups having from about 4 to about 8 carbon atoms. Preferably, R
f
is a perfluorinated alkyl group.
Perfluorinated sulfonyl fluorides can be prepared by electrochemical fluorination of the corresponding hydrocarbon sulfonyl fluorides, as described in U.S. Pat. No. 2,732,398 (Brice et al.), the description of which is incorporated herein by reference. (See also P. W. Trott et al, 126
th
National Meeting of the American Chemical Society, abstract at page 42-M, New York, N.Y. (1954).) Perfluorooctanesulfonyl fluoride is also commercially available from 3M Co. under the tradename Fluorad™ fluorochemical sulfonyl fluoride FX-8. Partially-fluorinated sulfonyl fluorides can be prepared from hexafluoropropylene oxide and the ring-opened sulfur trioxide oxetane of tetrafluoroethylene, as described, e.g., in
Kirk
-
Othmer Encyclopedia of Chemical Technology
, Fourth Edition, Volume 11, pages 562-63, John Wiley & Sons, New York (1994).
Representative examples of sulfonyl fluorides suitable for use in the process of the invention include CF
3
SO
2
F, C
2
F
5
SO
2
F, C
4
F
9
SO
2
F, C
6
F
13
SO
2
F, C
8
F
17
SO
2
F, C
10
F
21
SO
2
F, cyclo-(C
6
F
11
)SO
2
F, C
2
F
5
-cyclo-(C
6
F
10
)SO
2
F, H(CF
2
)
4
SO
2
F, H(CF
2
)
8
SO
2
F, and mixtures thereof. Preferably, perfluorobutanesulfonyl fluoride, perfluorohexanesulfonyl fluoride, perfluorooctanesulfonyl fluoride, and mixtures thereof ar

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