Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1996-06-25
1998-06-02
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
552540, 570127, 570261, C07J 100, C07J 900, C07J 1716, C07J 1908
Patent
active
057602557
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel processes for the conversion of hydroxyl groups into the corresponding fluorine compounds, wherein primary and secondary alcohols are reacted in absolute organic solvents with perfluorobutanesulphonyl fluoride or higher homologues, such as perfluorooctanesulphonyl fluoride, in the presence of 2-3 equivalents of strong organic bases.
The process which is at present most frequently used to introduce fluorine atoms into organic molecules involves reacting primary and secondary aliphatic hydroxyl groups with diethylaminosulphur trifluoride (DAST) in a single reaction stage to yield the corresponding fluorine compounds (M. Hudlicky, Organic Reactions 35, 513; J. A. Wilkinson, Chem. Rev. 92, 505-519 (1992)).
The disadvantage of this process is that the DAST used in the reaction is relatively costly. Moreover, the yields of the corresponding fluorine compounds, for example in the reaction of 3-.beta.-hydroxycholestanol with DAST to yield 3-.alpha.-fluorocholestane, are only around 40%.
It has now surprisingly been found that, in sulphonylation reactions with perfluorobutanesulphonyl fluoride, which is produced industrially on a large scale, or the higher homologues thereof, such as perfluorooctanesulphonyl fluoride, primary and secondary alcohols may be reacted smoothly and in sometimes excellent yields to produce the corresponding fluorine compounds in the presence of 2-3 equivalents of pentaalkylguanidines, in absolute organic solvents, such as for example toluene.
The present invention accordingly provides processes for the production of fluorine compounds, which processes are characterised in that hydroxyaliphatics of the general formula 1 are reacted with 1-2 equivalents of perfluorobutanesulphonyl fluoride, 2, or higher homologues, such as perfluorooctanesulphonyl fluoride, in the presence of 2-3 equivalents of a strong organic (org.) base, 3, in an inert organic solvent to yield the corresponding fluorine compounds of the general formula 4, in which araliphatic organic residue aliphatic or araliphatic residues ##STR1##
Aliphatic or araliphatic polycyclic ring systems are, for example, 3-hydroxy- or 17-hydroxysteroids or hydroxyprostane esters.
Strong organic bases which may be considered are, in principle, those having a P.sub.Ka of .gtoreq.12, such as for example all amidine or guanidine bases, such as DBU, DBN, pentamethyl- or pentaisopropylguanidine, which must not contain any reactive NH groups, and novel phosphine/imine bases (Schwesinger bases) such as tert.-butyl-iminotris(dimethylamino)phosphorane and horanylideneamino!-2.lambda..sup.5,4.lambda..sup.5 -catenadi(phosphazene).
The reactants are reacted in an inert anhydrous solvent such as toluene, benzene, xylene, anisole, diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert.-butyl ether, acetonitrile, sulpholane or ethyl acetate, preferably at -10.degree..fwdarw.+24.degree. C., wherein the volatile n-perfluorobutanesulphonyl fluoride, 2, (boiling point 64.degree. C.) is slowly added dropwise with stirring to the solution or suspension of a hydroxy compound, 1, and a strong organic base, 3. The strong dependency of the reaction rate of fluoride formation upon the configuration of the secondary alcohol is surprising. 3-.beta.-Hydroxycholestane with an equatorial hydroxy group reacts very smoothly at an approximately 60% yield to give 3-.alpha.-fluorocholestane, while 3-.alpha.-hydroxyandrostane with an axial hydroxyl group is much more slowly reacted to 3-.beta.-fluoroandrostane.
The compounds which may be produced using the process are of great interest inter alia for the production of pharmaceuticals and agrochemicals (cf. R. E. Banks, D. W. A. Sharp and I. C. Tatlow, eds., Fluorine: The First Hundred Years, Elsevier Seq., 1986) and of fluoropharmaceuticals (I. T. Welck, S. Esra-Kishman, Fluorine in Bioorganic Chemistry, John Wiley, N.Y., 1991).
The following practical examples illustrate the process according to the invention, but without limiting it.
EXAMPLES
1. Production of 3-fluoropropylbenzene
2.7 ml (15
REFERENCES:
patent: 3914265 (1975-10-01), Middleton
Bennua-skalmowski et al., "The reaction of perfluorobutanesulfonyl fluoride with alcohols in the presence of 4-dialkylaminopyridines." Bull. Soc. Chim. Belg. vol. 103, 453-461, 1994.
Knox et al., Steroids. CCXL. The Reaction of Steroidal Alcohols with 2-Chloro-1,1,2-trifluorotriethylamine, J. Am. Chem. Soc., vol. 29, pp. 2187-2194, Aug. 1964.
John A. Wilkinson, Recent Advances in the Selective Formation of the C-F Bond, Chem. Rev., vol. 92, No. 4, pp. 505-519, 1992.
Bennua-Skalmowski et al., A Facile Conversion of Primary or Secondary Alcohols with n-Perfluorobutane-sulfonyl Fluorides, Tetrahedron Letters, vol. 36, No. 15, pp. 2611-2614, 1995.
Bennua-Skalmowski Barbel
Vorbruggen Helmut
Badio Barbara
Bayer AG
Dees Jos,e G.
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