Catalyst – solid sorbent – or support therefor: product or process – Catalyst or precursor therefor – Halogen or compound containing same
Reexamination Certificate
2001-05-02
2002-10-29
McKane, Joseph K. (Department: 1626)
Catalyst, solid sorbent, or support therefor: product or process
Catalyst or precursor therefor
Halogen or compound containing same
C558S303000
Reexamination Certificate
active
06472345
ABSTRACT:
The present invention relates to a process for the halogenation of activated methylene or methine groups of organic compounds with electrophilic halogenating reagents, in which said organic compounds are reacted in the presence of catalytic amounts of a titanium tetrahalide or of an alcoholate-containing titanium(IV) trihalide or titanium(IV) dihalide with an electrophilic halogenating reagent; to a process for the enantioselective halogenation of an activated methine group of organic compounds with electrophilic halogenating reagents, in which said organic compounds are reacted in the presence of catalytic amounts of a chiral 1,3-, 1,4- or 1,5-diolate-containing titanium(IV) dihalide with a halogenating reagent.
Fluorine-substituted organic compounds have recently attracted increased interest as active pharmaceutical ingredients and pesticides. The fluorination frequently employs electrophilic fluorination reagents with which it is possible to replace hydrogen atoms in aromatic, olefinically unsaturated or activated aliphatic intermediates or final products. Large numbers of electrophilic fluorination reagents are known. Besides fluorine, those most frequently used are mainly inert gas fluorides, oxyfluorides, N-fluorinated pyridinium salts, tertiary N-fluoroammonium salts and N-fluorinated imides. A review of fluorination reagents is to be found, for example, in Chem. Rev. 1996, 96,1717-1736 by S. Rozen, and in Chem. Rev. 1996, 96, 1737 to 1755 by G. Sanker Lal et al.
The fluorination of carbon acids is generally known and is described, for example, in review articles in Houben-Weyl, 1999, volume E 10a, pages 433 to 499, by S. D. Taylor in Tetrahedron 55,1999, pages 12431 to 12477, and by F. A. Davis in Organic Preparations and Procedures Int., 1999, 31(2), pages 125-143. The fluorination is usually carried out with previous formation of carbanions or enolates by adding alkali metal amides or other strong bases.
Direct fluorinations of keto compounds have also been reported recently. T. Umemoto et al. describe in J. Org. Chem. 1995, 60, pages 6563 to 6570 the fluorination of &bgr;-diketo compounds with N-fluoro-4,6-trifluoromethylpyridinium-3-sulfonic acid, which is referred to as very reactive, at room temperature, the desired compounds being obtained usually in good yields with relatively long reaction times. To reduce the reaction times, bis-(trifluoromethyl)methanol is proposed as solvent, but a mixture of mono- and difluorinated products is formed on use thereof. R. E. Banks et al. propose in J. Chem. Soc., chem. Commun. 1994, pages 343 to 344 the use of 1-chloromethyl-4-fluoro 1,4-diazoniabicyclo[2,2,2]octane bistetrafluoroborate for the fluorination of compounds with a &bgr;-diketo structure, although the long reaction times make industrial use uneconomic. F. A. Davis et al. disclose in J. Org. Chem. 1995, 60, pages 4730 to 4737 the direct fluorination of &bgr;-diketo compounds with N-fluorobenzenedisulfonimide at room temperature, there always being formation of mixtures of mono- and difluorinated products, and it being necessary to add water for predominant formation of monofluoro products. S. Stavber et al. describe in Teterahedron Letters, Vol. 37, No. 20, 1996, pages 3591 to 3594 the use of 1-hydroxy-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bistetrafluoroborate for the fluorination of ketones at 80° C. Finally, T. Umemoto et al. describe, in J. Org. Chem. 1998, 63, pages 3379-3385, the use of N,N′-difluoro-2,2′-bipyridinium bistetrafluorobroate for the fluorination of compounds with a &bgr;-diketo structure in acetonitrile, with relatively long reaction times being necessary despite the reflux temperature.
It is also known that optical induction is possible on &agr;-fluorination of ketones when the preformed enolates thereof are reacted with enantiopure N-fluorosultams, see, for example, E. Differding et al., Tetrahedron Letters, Vol. 29, No. 47, 1988, pages 6087 to 6090, Y. Takeuchi et al., J. Org. Chem. 1999, 64, pages 5708 to 5711, and F. A. Davis et al., J. Org. Chem. 1998, 63, pages 2273 to 2280.
T. Umemoto et al. describe, in J. Am. Chem. Soc. 1990, 112, pages 8563 to 8575, the addition of 0.4 equivalent of ZnCl
2
or AlCl
3
in the fluorination of activated methylene compounds with N-fluoro-2,4,6-trimethylpyridinium triflate. The reaction is carried out at elevated temperatures and the reaction times are relatively long despite this. Moreover mixtures of mono- and difluorinated compounds are formed. A. J. Poss et al. use 0.4 equivalent of ZnCl
2
together with 0.4 equivalent of imidazole in the fluorination of ethyl cyclopentanonecarboxylate and 1,3-diphenyl-1,3-propanedione (see Tetrahedron Letters 40 (1999) pages 2673 to 2676). The reaction times are long and, in addition, elevated temperature is used, and difluorination cannot be suppressed.
R. D. Chambers et al. describe in Journal of Fluorine Chemistry 92 (1998), pages 45 to 52, the fluorination of activated methylene compounds with elemental fluorine in the presence of catalytic amounts of selected metal salts such as, for example, Cu, Ni, Cr, Mn, Fe, Co and Zn dinitrate, Cu dichloride, diacetate and sulfate. The yields which can be achieved are unsatisfactory, and a large proportion of difluorinated compounds is observed on fluorination of methylene groups.
Possibilities for the chorination, bromination and iodination of organic compounds, for example ketones, are described in “The Chemistry of Functional Groups”, Supplement D: Chapters 19 and 22, John Wiley & Sons Ltd. (1983), and Chapter 11, John Wiley & Sons Ltd. (1995).
The use of catalytic amounts of Lewis acids in the halogenation of activated methylene and methine compounds with electrophilic halogenation reagents has not yet been described. Nor has enantioselective halogenation of racemic methine compounds using catalytic amounts of optically active Lewis acids been disclosed either.
It has now been found, surprisingly, that catalytic amounts of certain titanium(IV) halides are able to speed up the halogenation of activated methylene and methine compounds with electrophilic halogenation reagents, and halogenation can be achieved with high yields in considerably shorter reaction times. In addition, the selectivity of monohalogenation of activated methylene compounds is considerably improved. It has also been found for the first time, surprisingly, that enantioselective halogenation of activated racemic methine compounds can also be carried out catalytically if titanium(IV) dihalides to which a chiral alkane-1,3-, -1,4- or -1,5-diolate is covalently bonded are used as catalyst. The halogenation can in fact take place under mild reaction conditions such as, for example, room temperature.
One aspect of the invention is a process for the halogenation of activated methylene and methine compounds with at least equimolar amounts of an electrophilic halogenation reagent, which comprises reacting said activated methylene and methine compounds in the presence of catalytic amounts of a titanium compound of the formula I or of a titanium compound of the formula II
R
1
TiX
1
X
2
X
3
(I),
R
2
R
3
TiX
1
X
2
(II),
in which
R
1
is chlorine, bromine or iodine, a substituted or unsubstituted cyclopentadienyl or indenyl, and X
1
, X
2
and X
3
are, independently of one another, chlorine, bromine or iodine, or X
1
, X
2
and X
3
are an organic sulfonate group where R
1
is a substituted or unsubstituted cyclopentadienyl or indenyl;
R
2
and R
3
are a substituted or unsubstituted cyclopentadienyl or indenyl, R
2
and R
3
together are a substituted or unsubstituted and bridged or unbridged biscyclopentadienyl or bisindenyl, or R
2
and R
3
together are a substituted or unsubstituted 1,3-, 1,4- or 1,5-diolate, and X
1
and X
2
are, independently of one another, chlorine, bromine or iodine or an organic sulfonate group.
Activated methylene and methine compounds are to be understood as meaning for the purposes of the invention organic compounds to whose methylene or methine group at least two highly e
Hintermann Lukas
Togni Antonio
McKane Joseph K.
Saeed Kamal
Solvias AG
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