2,2,2-Trifluoroethyl p-Toluenesulfonate1

[433-06-7]  · C9H9F3O3S  · 2,2,2-Trifluoroethyl p-Toluenesulfonate  · (MW 254.25)

(trifluoroethylation agent for heteroatom nucleophiles; can function as a nucleophile for synthesis of a-keto acids and 2,2-difluorovinyl compounds)

Alternate Name: 2,2,2-trifluoroethyl tosylate

Physical Data: mp 40-41 °C; bp 102-104 °C/0.8 mmHg; n25D 1.4635.

Solubility: sol THF, ether, CH2Cl2, toluene.

Form Supplied in: white crystalline solid, commercially available.

Purification: recrystallize from hexane-ether.

Preparative Methods: easily prepared by treating 2,2,2-trifluoroethanol with p-Toluenesulfonyl Chloride in pyridine1a or in aqueous acetone containing NaOH.1b

Handling, Storage, and Precautions: quite stable; can be handled without any special technique and stored at room temperature; use in a fume hood.

Trifluoroethylation Agent.

Although this reagent is sluggish in substitution reactions compared to its nonfluorinated counterpart,2 heteroatom nucleophiles react with the reagent to permit introduction of the 2,2,2-trifluoroethyl group. Thiols,3,4 thiophenols,3 and phenols3b undergo S- and O-trifluoroethylation via their sodium salts in good yields (eq 1). For the preparation of alkyl trifluoroethyl ethers, there is an alternative route via the alkylation of trifluoroethanol with alkyl halides.3b,5 Trifluoroethylation of alkali selenolates6 and tellurolates7 is also achieved (eq 2), whereas trifluoroethyl iodide is a better choice in the case of tellurium. N-Trifluoroethylation is carried out with amines (eq 3)8a and pyrroles8b under forcing conditions, while the indole nitrogen is not alkylated but undergoes tosylation instead.8c In the trifluoroethylation of less reactive nucleophiles, 2,2,2-trifluoroethyl trifluoromethanesulfonate generally gives better results, especially in case of nitrogen9a and carbon nucleophiles.9b

Synthesis of a-Keto Acids and 2,2-Difluorovinyl Compounds.

The reagent reacts with 2 equiv of Lithium Diisopropylamide10 or n-Butyllithium11a at -78 °C to generate 2,2-difluoro-1-tosyloxyvinyllithium (1). This vinyllithium reagent reacts with carbonyl compounds5,10 to give 3,3-difluoro-2-tosyloxyallyl alcohols (2) which undergo Sulfuric Acid-catalyzed hydration to 2-tosyloxyacrylic acids (3). Base-catalyzed hydrolysis of (3) then affords the two-carbon homologated a-keto acids (eq 4).10

Vinyllithium (1) is also utilized via 2,2-difluorovinylboranes (4) (eq 5) to synthesize a wide variety of gem-difluorovinyl compounds: 1,1-difluoro-1-alkenes,11b-e 1,1-difluoro-1,3-alkadienes,11f 1,1-difluoro-1-alken-3-ynes,11h 1,1-difluoro-2-iodo-1-alkenes,11c b,b-difluoro-a,b-enones,11a and 2,2-difluorovinylphosphines,11g as well as difluoromethyl ketones12 (eqs 6-10). In these reactions, the reagent functions as a building block for a difluorovinylidene unit (CF2=C), to which two different substituents can be successively attached.

In addition, trifluoroethyl ethers, thioethers, and selenoethers prepared as above are available for the introduction of an alkyne moiety, leading to alkynic ethers and thioethers (eq 11)3b and thio-3a and selenoynamines6a (eq 12).

Related Reagents.

Chlorodifluoromethane; Dibromodifluoromethane; 1,2-Diethoxy-1,2-bis(trimethylsilyloxy)ethylene; (Diethoxyphosphoryl)difluoromethyllithium; Diethyl Difluoromethylphosphonate; Difluoromethylenetriphenylphosphorane; Ethyl Diethoxyacetate; Glyoxylic Acid; Glyoxylic Acid Diethyl Dithioacetal; Methyl Bis(2,2,2-trifluoroethoxy)phosphinylacetate; 2,2,2-Trifluoroethyl Trifluoroacetate.

1. (a) Edgell, W. F.; Parts, L. JACS 1955, 77, 4899. (b) Wentworth, S. E.; Sciaraffa, P. L. OPP 1969, 1, 225.
2. Bodor, N.; Huang, M.-J.; Szántay Jr., C.; Szántay, C. T 1992, 48, 5823.
3. (a) Nakai, T.; Tanaka, K.; Setoi, H.; Ishikawa, N. BCJ 1977, 50, 3069. (b) Tanaka, K.; Shiraishi, S.; Nakai, T.; Ishikawa, N. TL 1978, 3103.
4. Bunyagidj, C.; Piotrowska, H.; Aldridge, M. H. JOC 1981, 46, 3335.
5. Metcalf, B. W.; Jarvi, E. T.; Burkhart, J. P. TL 1985, 26, 2861.
6. (a) Piettre, S.; Janousek, Z.; Viehe, H. G. S 1982, 1083. (b) Syper, L.; Mlochowski, J. TH 1988, 44, 6119.
7. Sandhu, A.; Singh, S.; Bhasin, K. K.; Verma, R. D. JFC 1990, 47, 249.
8. (a) Yamanaka, H.; Kuwabara, M.; Komori, M.; Otani, M.; Kase, K.; Fukunishi, K.; Nomura, M. NKK 1983, 112 (CA 1983, 98, 178 838r). (b) Yoshino, K.; Seko, N.; Yokota, K.; Ito, K.; Tsukamoto, G. Eur. Patent 159 677, 1985 (CA 1986, 104, 129 898u). (c) Marzoni, G.; Garbrecht, W. L. S 1987, 651.
9. (a) Sakamoto, S.; Tsuchiya, T.; Tanaka, A.; Umezawa, S.; Hamada, M.; Umezawa, H. J. Antibiot. 1984, 37, 1628. (b) Tsushima, T.; Kawada, K.; Ishihara, S.; Uchida, N.; Shiratori, O.; Higaki, J.; Hirata, M. T 1988, 44, 5375.
10. Tanaka, K.; Nakai, T.; Ishikawa, N. TL 1978, 4809.
11. (a) Ichikawa, J.; Hamada, S.; Sonoda, T.; Kobayashi, H. TL 1992, 33, 337. (b) Ichikawa, J.; Sonoda, T.; Kobayashi, H. TL 1989, 30, 1641. (c) Ichikawa, J.; Sonoda, T.; Kobayashi, H. TL 1989, 30, 6379. (d) Ichikawa, J.; Moriya, T.; Sonoda, T.; Kobayashi, H. CL 1991, 961. (e) Ichikawa, J.; Minami, T.; Sonoda, T.; Kobayashi, H. TL 1992, 33, 3779. (f) Ichikawa, J.; Ikeura, C.; Minami, T. SL 1992, 739. (g) Ichikawa, J.; Yonemaru, S.; Minami, T. SL 1992, 833. (h) Ichikawa, J.; Ikeura, C.; Minami, T. JFC 1993, 63, 281.
12. Ichikawa, J.; Sonoda, T.; Kobayashi, H. TL 1989, 30, 5437.

Junji Ichikawa

Kyushu Institute of Technology, Kitakyushu, Japan

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