[7783-63-3] · TiF4 · (MW 123.9)
Physical Data: mp 284 °C (sublimes).
Solubility: soluble in acetonitrile, DMSO, ethyl acetate.
Form Supplied in: white powder, widely available.
Analysis of Reagent Purity: melting point.
Handling, Storage, and Precautions: corrosive, harmful by inhalation, moisture sensitive, handle under dry nitrogen in a fume hood.
Titanium(IV) fluoride (1) is a useful catalyst for the reaction of trifluoromethylzinc bromide (2) with a carbohydrate containing a free anomeric hydroxyl group to afford a glycosyl fluoride.1 While 2 alone is sufficient to convert a glycosyl bromide to the corresponding fluoride, this reaction fails when applied to glycosidic alcohols. However, addition of less than one molar equivalent of 1 results in the formation of the glycosyl fluoride in good to excellent yields. For example, reaction of the protected glucopyranose 3 with 2 in the presence of 1 afforded a 60:40 mixture of the anomeric glycosyl fluorides 4a and 4b in 83% yield (
Glycosyl fluorides are useful intermediates in the synthesis of glycosides.2a,b Titanium(IV) fluoride (1) is an excellent catalyst for the preparation of 2-deoxyglycosides from the corresponding glycosyl fluorides.2c,d For example, reaction of the secondary alcohol 5 with the 2-deoxyglycosyl fluoride 6 in the presence of a catalytic amount of 1 afforded a mixture of the a and b glycosides 7 and 8 in good yield (
Titanium(IV) fluoride (1) also catalyzes the reaction of 2-bromo-glycosyl fluorides with alcohols, but these less reactive fluorides require the addition of silver perchlorate (AgClO4) for satisfactory results.2d Thus, reaction of alcohol 5 with the 2-bromo-glycosyl fluoride 9 in the presence of 1 and AgClO4 in acetonitrile afforded the a-glycoside (10) exclusively in 54% yield (
In contrast to the exclusive a-glycosylation observed with 9 (axial bromide at C-2), the corresponding reaction with 11 (equatorial bromide at C-2) afforded a solvent-dependent mixture of the a- (12a) and b-glycosides (12b) (1:1 mixture of 12a and 12b in ether; 3:1 mixture in hexane) (
Similarly, trisaccharide 15 was prepared in good yield by glycosylation of protected disaccharide 13 with glycosyl fluoride (14) (benzyl ether substituent at C-2) (
Titanium(IV) fluoride (1), in combination with antimony trifluoride (SbF3), has been reported to react with a terminal epoxide (16) to afford almost exclusively (17:18 ratio = 99:1) the fluorohydrin (17) with the fluorine atom at the more hindered position (
Similarly, a complex generated in situ from 1 and titanium(IV) isopropoxide reacted with epoxide 19 to afford fluorohydrin 20, in which fluoride substitution has also occurred at the carbon atom best able to support a positive charge, in modest yield (
However, reaction of tri-substituted epoxide (21) under similar conditions afforded a mixture of three products: fluorohydrin (22) (38%), ether (23) (42%), and olefin (24) (20%) (
Although it has not been widely used for the preparation of fluorohydrins, it appears that 1, in combination with other Lewis acids, could be a useful reagent for this purpose.
A complex generated by the reaction of titanium(IV) fluoride (1) and (S)-1,1´-bi-2-napthol (S-BINOL) (25) catalyzed the addition of allyltrimethylsilane (26) to a variety of aldehydes in excellent yield and with good enantioselectivity.4a,b For example, reaction of 26 with aldehyde 27 in the presence of 0.1 equiv of the TiF4/BINOL complex afforded, after deprotection of the initially formed trimethylsilyl ether, a 90% yield of adduct 28 with an enantiomeric excess of 94% (
Application of this method to pentyn-4-al (29) afforded the allylic alcohol (30) in 62% yield but only 70% enantiomeric excess (
A similar method for the enantioselective addition of a methyl group to an aldehyde has also been reported.4d Thus, reaction of benzaldehyde (31) with trimethylaluminum (32) in the presence of a complex (33), generated in situ by reaction of excess 32 with the corresponding diol and titanium(IV) fluoride (1), afforded the adduct 34 in 80% yield and 80% enantiomeric excess (
A similar strategy, involving a complex formed by the reaction of titanium(IV) fluoride (1) with triethoxysilane and a chiral bis-oxazoline, has been used for the enantioselective reduction of ketones.4e However, the yields for this transformation were generally low (average 40%) and the enantiomeric excess of the alcohol products was modest (average 60% ee).
Titanium(IV) fluoride (1) catalyzed the addition of a silyl ketene acetal (35) to a chiral imine (36) to afford the adduct 37 in good yield and with good enantioselectivity (70% ee) (
An attempt to effect a similar reaction with an unsaturated imine (derived from cinnamaldehyde) failed under titanium(IV) fluoride catalysis (although it was successful with other titanium halides).5b
Merck Research Laboratories, Rahway, New Jersey, USA