Benzyl Trifluoromethanesulfonate1

[17674-16-7]  · C8H7F3O3S  · Benzyl Trifluoromethanesulfonate  · (MW 240.18)

(a highly electrophilic alkylating agent used for the formation of benzyl ethers,2-7 and for Friedel-Crafts benzylation13-17)

Alternate Name: benzyl triflate.

Solubility: generated and used in situ in inert solvents such as CH2Cl2.

Preparative Methods: from benzyl alcohol, Trifluoromethanesulfonic Acid, and 2,6-Di-t-butylpyridine in CH2Cl2. When used in Friedel-Crafts alkylation reactions, it has been made from a benzyl halide and silver triflate.15,16

Handling, Storage, and Precautions: generated in situ and used immediately. The compound is extremely readily hydrolyzed. Use in a fume hood.

Introduction of the Benzyl Protecting Group.

Alkyl triflates, such as benzyl triflate, are extremely reactive alkylating agents.1 Benzyl triflate has been used in carbohydrate chemistry2-5 for the protection of hydroxy groups as their benzyl ethers, and is particularly useful for protecting the 2-hydroxy group in pyranosides.2,3 Alkyl triflates have also been used to protect the 1-hydroxy group in sugar acetals without causing anomerization,4 and the reagent is compatible with acetate,2,3 isopropylidene,3 azide,5 and t-butyldimethylsilyl groups.5 The reagent is also a useful alternative to the benzyl halide/base method for making ethers, when strongly basic conditions need to be avoided5 (see also Benzyl 2,2,2-Trichloroacetimidate). Benzyl triflate has been used with compounds other than carbohydrates,6-9 and yields with some base-sensitive compounds can be excellent (eq 1).6 4-Nitrobenzyl ethers have also been made via the triflate,8 as 4-nitrobenzyl bromide is known to be base-sensitive and so not fully compatible with the classical Williamson ether synthesis methodology.

Problems can arise with the use of benzyl triflate when the substrate is a nitrogen-containing heteroaromatic compound, as significant N-alkylation is observed8,9 (hence the use of the expensive, but highly hindered, 2,6-di-t-butylpyridine in the synthesis of the reagent2,3). However, N-benzylation is sometimes required and benzyl triflate has been used for the protection of the hindered, deactivated Nim-3 site in Nim-1-Boc protected histidines (eq 2).10 Other methods for this derivatization need specialized blocking groups to prevent racemization of the substrate under the harsher conditions.

Benzyl triflate mediated benzylation of alcohols in sulfur-containing compounds such as ethylene dithioacetals can cause problems.11 The highly electrophilic agent reacts at sulfur initially and causes ring opening of the protecting group (eq 3).

The thiophilicity of benzyl triflate does mean that thioethers can be conveniently protected as benzylsulfonium triflates (eq 4).12 In this case, protection of the thioether is necessary to prevent concomitant sulfide-sulfone oxidation during oxidation of the primary hydroxy group to a carboxylic acid.

Friedel-Crafts Alkylation.

Benzyl triflate, like other alkyl triflates, is an active agent for Friedel-Crafts alkylation of arenes.13-17 Benzyl triflate can be generated with a benzyl halide and silver triflate,15,16 and then used to alkylate arenes such as alkylbenzenes,15 anisoles,16 and phenols.16 Reaction occurs at rt without catalysis, but other alkyl triflates are generally less active, sometimes only reacting efficiently with a Lewis acid catalyst.15 Recently, benzyl triflate has been reported as a decomposition product of N-nitroso-N-benzyltrifluoromethanesulfonamides, and if this reaction is done in arene solvents such as benzene then Friedel-Crafts alkylation products are obtained.17

1. (a) Howells, R. D.; McCown, J. D. CRV 1977, 77, 69. (b) Stang, P. J.; Hanack, M.; Subramanian, L. R. S 1982, 85. (c) Stang, P. J.; White, M. R. Aldrichim. Acta 1983, 16, 15.
2. Lemieux, R. U.; Kondo, T. Carbohydr. Res. 1974, 35, C4.
3. Berry, J. M.; Hall, L. D. Carbohydr. Res. 1976, 47, 307.
4. Arnarp, J.; Kenne, L.; Lindberg, B.; Lonngren, J. Carbohydr. Res. 1975, 44, C5.
5. (a) Termin, A.; Schmidt, R. R. LA 1989, 789. (b) Termin, A.; Schmidt, R. R. LA 1992, 527.
6. Guivisdalsky, P. N.; Bittman, R. TL 1988, 29, 4393.
7. Beard, C. D.; Baum, K.; Grakauskas, V. JOC 1973, 38, 3673.
8. Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. TL 1990, 31, 389.
9. VanSickle, A. P.; Rapoport, H. JOC 1990, 55, 895.
10. Hodges, J. C. S 1987, 20.
11. Paquette, L. A.; Bulman Page, P. C.; Pansegrau, P. D.; Wiedeman, P. E. JOC 1988, 53, 1450.
12. Roemmele, R. C.; Rapoport, H. JOC 1989, 54, 1866.
13. Gramstad, T.; Haszeldine, R. N. JCS 1957, 4069.
14. Olah, G. A.; Nishimura, J. JACS 1974, 96, 2214.
15. Booth, B. L.; Haszeldine, R. N.; Laali, K. JCS(P1) 1980, 2887.
16. Laali, K. JOC 1985, 50, 3638.
17. White, E. H.; DePinto, J. T.; Polito, A. J.; Bauer, I.; Roswell, D. F. JACS 1988, 110, 3708.

Andrew N. Boa & Paul R. Jenkins

Leicester University, UK

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