Titanium(IV) fluoride

[7783-63-3]  · TiF4  · (MW 123.9)

(preparation of glycosyl fluorides;1 glycosylation;2c,d preparation of fluorohydrins;3 addition of carbanions to aldehydes4 and imines5)

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.

Purification: sublimation.

Handling, Storage, and Precautions: corrosive, harmful by inhalation, moisture sensitive, handle under dry nitrogen in a fume hood.

Preparation of Glycosyl Fluorides

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 (1).1

Glycosylation using Glycosyl Fluorides

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 (2).2d Interestingly, there was a pronounced solvent effect in this reaction; in ether, 7 and 8 were obtained in a 4:1 ratio in 65% yield while in hexane selectivity was reversed and the ratio of 7:8 was 1:2 (52% yield). This dependence of the a:b ratio on solvent nucleophilicity is nicely accounted for by the author's proposed mechanism for the reaction.2d

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 (3).2d

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) (4).2d

Similarly, trisaccharide 15 was prepared in good yield by glycosylation of protected disaccharide 13 with glycosyl fluoride (14) (benzyl ether substituent at C-2) (5).2e,f The Mukaiyama conditions (SnCl2/AgClO4)2g gave a comparable yield of 15. However, use of triflic anhydride instead of 1 reportedly resulted in an improved yield (92%).2e Thus, 1 is only one of several useful reagents for the conversion of glycosyl fluorides to glycosides.2a,b

Synthesis of Fluorohydrins via Epoxide-opening

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 (6).3a Although only one example was reported, this may be a useful method for the preparation of fluorohydrins. Interestingly, the other halides (Cl, Br, I) reacted under similar conditions to afford almost exclusively the other regioisomer.

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 (7).3b

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%) (8).3b

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.

Addition of Carbanions to Aldehydes

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% (9).4a Similar results were obtained with R-BINOL.

Application of this method to pentyn-4-al (29) afforded the allylic alcohol (30) in 62% yield but only 70% enantiomeric excess (10).4b However, these authors also reported that a superior result was obtained using an alternative procedure4c which involved allyltributyl stannane and a catalyst prepared from R-BINOL and titanium(IV) isopropoxide.4b

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 (11). The enantiomeric excess of the product obtained from variety of aromatic aldehydes under these conditions ranged from 54% to 85% ee.

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).

Addition of Silyl Ketene Acetals to Imines

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) (12).5a Interestingly, substitution of titanium(IV) chloride for 1 in this reaction led to a reversal of the enantioselectivity, resulting in a formation of the R enantiomer of 36 (82% 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

Related Reagents.

Hydrogen fluoride; tin(II) chloride; silver(I) perchlorate.

1. Miethchen, R.; Hager, C.; Hein, M., Synthesis 1997, 159.
2. (a) Shimizu, M.; Togo, H.; Yokoyama, M., Synthesis 1998, 799. (b) Marzabadi, C. H.; Franck, R. W., Tetrahedron 2000, 56, 8385. (c) Kreuzer, M.; Thiem, J., Carb. Res. 1986, 149, 347. (d) Junneman, J.; Lundt, I.; Thiem, J., Liebigs. Ann. Chem. 1991, 759. (e) Wessel, H. P., Tetrahedron Lett. 1990, 31, 6863. (f) Wessel, H. P.; Englert, G.; Stangier, P., Helv. Chim. Acta. 1991, 74, 682. (g) Mukaiyama, T.; Murai, Y.; Shoda, S., Chem. Lett. 1981, 431.
3. (a) Shimizu, M.; Yoshida, A.; Fujisawa, T., Synlett 1992, 204. (b) Raifeld, Y. E.; Nikitenko, A. A.; Arshava, B. M.; Mikerin, I. E.; Zilberg. L. L.; Vid, G. Y.; Lang, S. A.; Lee, V. L., Tetrahedron 1994, 50, 8603.
4. (a) Gauthier, D. R.; Carreira, E. M., Angew. Chem., Int. Ed. Engl. 1996, 35, 2363. (b) Codesido, E. M.; Cid, M. M.; Castedo, L.; Mourino, A.; Granja, J. R., Tetrahedron Lett. 2000, 41, 5861. (c) Keck, G. E.; Tarbet, K. H.; Geraci, L. S., J. Am. Chem. Soc. 1993, 115, 8467. (d) Pagenkopf, B. L.; Carreira, E. M., Tetrahedron Lett. 1998, 39, 9593. (e) Bandini, M.; Cozzi, P. G.; Negro, L.; Umani-Ronchi, A., Chem. Commun. 1999, 39.
5. (a) Shimizu, M.; Kume, K.; Fujisawa, T., Tetrahedron Lett. 1995, 36, 5227. (b) Shimizu, M.; Morita, A.; Kaga, T.,Tetrahedron Lett. 1999, 40, 8401.

T. A. Blizzard

Merck Research Laboratories, Rahway, New Jersey, USA

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