Ethoxycarbonylmethyl Trifluoromethanesulfonate

[61836-02-0]  · C5H7F3O5S  · Ethoxycarbonylmethyl Trifluoromethanesulfonate  · (MW 236.13)

(alkylation of sulfides,1,3 amines,2 and other nucleophiles;3,4 in situ generation of ester-stabilized ylides via onium salt deprotonation1,2,5-8)

Alternate Name: ethyl (2-trifluoromethylsulfonyloxy)acetate.

Physical Data: mp 22-23 °C.

Solubility: freely miscible with common organic solvents.

Form Supplied in: large colorless needles, refrigerator temperature; colorless liquid, room temperature.

Analysis of Reagent Purity: 1H NMR (CDCl3, d) 1.35 (3 H, t, J = 7.0 Hz) 4.34 (2 H, q, J = 7.0 Hz) 4.98 (2 H, s).

Preparative Methods: from Ethyl Diazoacetate and Trifluoromethanesulfonic Acid, or from ethyl glycolate and Trifluoromethanesulfonic Anhydride/Pyridine.3

Purification: recrystallization from hexane at freezer temperatures.3

Handling, Storage, and Precautions: the reagent is a lachrymator. Like other moderately active alkylating agents, it should be treated as a potentially toxic agent. It can be stored for months under anhydrous conditions in the freezer as the frozen solid.

Onium Salt Formation.

The title reagent is used for the alkylation of sulfur or nitrogen compounds. It has an ca. 100-fold reactivity advantage over ethyl bromoacetate, and is a less potent lachrymator. It also has the advantage of the nonnucleophilic triflate counterion. The resulting ammonium or sulfonium salts are resistant to SN2 dealkylation by the anion, a problem that is often encountered with sulfonium bromides.1 The initially formed onium salts are usually generated in situ and are treated with base to form the corresponding sulfonium or ammonium ylides. Synthetic applications focus on subsequent ylide fragmentation or rearrangement reactions.

Five-Center Ylide Fragmentation to Alkenes.

Alkylation of aminonitriles followed by deprotonation of the ammonium salt with 1,8-Diazabicyclo[5.4.0]undec-7-ene results in the formation of unsaturated nitriles (eq 1).2,5 The intermediate ammonium ylide (1) undergoes concerted a,a-fragmentation. Good yields are obtained with aldehyde-derived aminonitriles (R1 = H), but more highly substituted ylides (R1 = alkyl) undergo competing homolytic C-N cleavage (Stevens rearrangement). Conversion of 2-dimethylaminocyclohexanone into cyclohexenone (68%) can be performed in the same way,2 but fragmentation does not occur cleanly starting with unactivated amines RCH2CH2NMe2. The five-center fragmentation is more facile using sulfides as starting materials (eq 2).1,5 An activating group is not essential, but the five-center fragmentation is faster if an electron-withdrawing group is present at the a-carbon.1

2,3-Sigmatropic Ring Expansion of Ylides.6

Medium ring sulfides or amines can be prepared from cyclic sulfides or amines having a-alkenyl or a-alkynyl substituents (eq 3).6a The intermediate onium salts are deprotonated with DBU, and the resulting ylides rearrange at room temperature or below. A similar ring expansion of a five-membered sulfide has been used in the early stages of a sulfur-based total synthesis of methynolide.7.

Keto Ester Synthesis by Sulfide Contraction.8

Thioamides are alkylated by ethoxycarbonylmethyl trifluoromethanesulfonate to give the salts (2) (eq 4). Treatment with a basic thiophile (3) results in the formation of a conjugated enamine (5) via the episulfide (4). Enamine hydrolysis with methanolic HCl affords the keto ester (6) (85% overall). A similar yield is obtained in this case using ethyl bromoacetate. However, the triflate has an advantage over the bromide if the a-methyl derivative is used.

Miscellaneous Applications.

The title reagent has been used to alkylate imines.4a,d,f The reactivity advantage of the triflate by comparison with the a-bromo ester is increasingly important in more highly branched reagents such as TfOCH(Me)CO2R.4b,c,e The latter can be used successfully in enolate alkylation reactions.

1. Vedejs, E.; Engler, D. A. TL 1976, 3487.
2. Vedejs, E.; Engler, D. A. TL 1977, 1241.
3. Vedejs, E.; Engler, D. A.; Mullins, M. J. JOC 1977, 42, 3109.
4. (a) Ranganathan, N.; Storey, B. T. JHC 1980, 17, 1069. (b) Paulsen, H.; Himpkamp, P.; Peters, T. LA 1986, 664. (c) Kinzy, W.; Schmidt, R. R. LA 1987, 407. (d) Vedejs, E.; Dax, S.; Martinez, G. R.; McClure, C. K. JOC 1987, 52, 3470. (e) Hoffman, R. V.; Kim, H.-O. TL 1993, 34, 2051. (f) Deshong, P.; Cipollina, J. A.; Lowmaster, N. K. JOC 1988, 53, 1356.
5. Yamada, K.; Tan, H.; Hirota, K. TL 1980, 21, 4873.
6. (a) Vedejs, E.; Arco, M. J.; Powell, D. W.; Renga, J. M.; Singer, S. P. JOC 1978, 43, 4831. (b) Vedejs, E.; Hagen, J. P.; Roach, B. L.; Spear, K. L. JOC 1978, 43, 1185. (c) Sashida, H.; Tsuchiya, T. CPB 1986, 34, 3644; Sashida, H.; Tsuchiya, T. CPB 1984, 32, 4600.
7. Vedejs, E.; Buchanan, R. A.; Conrad, P. C.; Meier, G. P.; Mullins, M. J.; Schaffhausen, J. G.; Schwartz, C. E. JACS 1989, 111, 8421. Vedejs, E.; Buchanan, R. A.; Watanabe, Y. JACS 1989, 111, 8430.
8. (a) Shiosaki, K.; Fels, G.; Rapoport, H. JOC 1981, 46, 3230. (b) Shiosaki, K.; Rapoport, H. JOC 1985, 50, 1229.

Edwin Vedejs

University of Wisconsin, Madison, WI, USA

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