[75-08-1]  · C2H6S  · Ethanethiol  · (MW 62.13)

(thioacetal formation; nucleophilic reagent;1-4 cation scavenger and hydrogen donor)

Physical Data: bp 35 °C; d 0.839 g cm-3.

Solubility: sol alcohols, ether, acetone.

Form Supplied in: colorless liquid; widely available.

Purification: dissolve in aqueous 20% NaOH, extract with benzene, steam distill until clear. Cool, acidify with 15% H2SO4, distill ethanethiol. Dry with CaSO4, CaCl2, or 4Å sieves followed by fractional distillation under nitrogen.

Handling, Storage, and Precautions: stench; irritant and flammable liquid. Keep in cool place in a tightly sealed bottle. Refrigerate before opening due to possible pressure build-up. Use only in a well-ventilated fume hood.

Nucleophilic Reagent.

Ethanethiol undergoes reactions typical of a nucleophilic species, including displacement at saturated carbon, addition to electron-deficient alkenes and alkynes, epoxides, and acylations (eqs 1-3).1-4

A useful reaction is the formation of dithioacetals by the acid-catalyzed condensation of carbonyl compounds and ethanethiol (see also 1,2-Ethanedithiol and 1,3-Propanedithiol).5,6 Acid catalysts used include Boron Trifluoride, Zinc Chloride, Lanthanum(III) Chloride, Tetrachlorosilane, Chlorotrimethylsilane, and Tellurium(IV) Chloride (eq 4).7 Acid-catalyzed thioacetalization of lactols produces the corresponding acyclic thioacetal (eq 5).8

Ethylthiosilane is a useful reagent for effecting nucleophilic additions to carbonyl compounds.9 Ethylthiosilane is most readily prepared by heating a mixture of ethanethiol, Hexamethyldisilazane, and a trace of chlorotrimethylsilane.9a Both the thermal and catalyzed carbonyl addition reactions of ethylthiosilane have been investigated.10,11 The combination of alkylthiosilanes and Lewis acids have proven useful in the preparation of thioacetals and hemithioacetals under buffered conditions (eq 6). Small amounts of tetrabutylammonium cyanide, Tetra-n-butylammonium Fluoride, or Potassium Cyanide-18-Crown-6 complex effect anionic-initiated addition of ethylthiosilane to carbonyl compounds. Under these reaction conditions, saturated aldehydes produce hemithioacetals, the product of 1,2-addition (eq 7). Unsaturated ketones and aldehydes yields exclusively silyl enol ethers via the 1,4-addition reaction pathway (eq 8). The 1,4-addition pathway has been used advantageously to generate enol ethers which then undergo stereoselective aldol reaction (eq 9).12

Ethanethiol is weakly acidic (pKa ~10-11) and upon deprotonation generates ethanethiolate.1a,13 The metal salts of ethanethiolate are highly nucleophilic and relatively nonbasic. The combination of these two properties has led to the development of sodium thiolate, and other metal salts of alkanethiolates, as useful reagents in organic synthesis. For example, the cleavage of methyl aryl ethers is accomplished using sodium ethanethiolate in refluxing DMF (eqs 10 and 11).14-16 Sodium ethanethiolate is generated in situ by the deprotonation of ethanethiol with sodium hydroxide under an inert atmosphere.

Alternative nucleophiles for inducing cleavage of aryl methyl ethers include sodium thiophenoxide, sodium benzylselenide, sodium thiocresolate, Sodium Cyanide, Lithium Iodide, and Iodotrimethylsilane. Metal thiolates, such as sodium ethanethiolate, in dipolar aprotic medium have also been used to cleave alkyl esters.17-20 The use of metal thiolates in HMPA is one of the mildest methods devised for effecting cleavage of alkyl esters through an SN2 mechanism (eq 12).19,20 The dealkylation of methyl esters via metal thiolates is particularly useful in cases of hindered ester groups. Ethanethiol also reportedly cleaves aryl methyl ethers and alkyl esters in combination with Lewis acids (eqs 13 and 14).21,22

Cation Scavenger.

Thiols, such as ethanethiol, have been used to scavenge liberated cations in organic reactions. For example, protic cleavage of the t-butyl carbamate protecting group used in peptide synthesis liberates t-butyl cations and may alkylate methionine or tryptophan.23,24 Thiophenol is most commonly used to scavenge cations. In a similar fashion, protodesilylation utilizes ethanethiol to scavenge the silyl cation (eq 15).25

Hydrogen Atom Donor.

The sulfur-hydrogen bond of ethanethiol is prone to homolytic cleavage by either the intervention of a radical or photolytic cleavage. Ethanethiol has been utilized as a hydrogen atom donor in radical reactions (eq 16).26 The photoaddition of thiols to a carbon-carbon double bond has also been examined (eq 17).1b

1. The Chemistry of the Thiol Group; Patai, S. Ed.; Wiley: New York, 1974; Parts 1 and 2. (b) Barrett, G. C. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: 1979, Vol. 3, pp 12-19.
2. Belley, M.; Zamboni, R. JOC 1989, 54, 1230.
3. Plancquaert, M. A.; Philippe, F.; Mereny, R.; Viehe, H. G. TL 1991, 32, 7265.
4. Guillot, C.; Maignan, C. TL 1991, 32, 4907
5. Grobel, B-T.; Seebach, D. S 1977, 357.
6. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; p 198. (b) McOmie, J. F. W. Protective Groups in Organic Chemistry; Plenum: London, 1973; p 323.
7. Tani, H.; Masumoto, K.; Inamasu, T. TL 1991, 32, 2039.
8. Kim, K. S.; Cho, I, H.; Hyup, Y.; Yoo, I. Y.; Song, J. H.; Ko, J. H. TL 1992, 33, 4029.
9. (a) Langer, S. H.; Connell, S.; Wender, I. JOC 1958, 23, 50. (b) Abel, W. W. JCS 1960, 4406.
10. Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. JACS 1977, 99, 5009. (b) Evans, D. A.; Grimm, K. G.; Truesdale, L. K. JACS 1975, 97, 3229.
11. (a) Chan, T. H.; Ong, B. S. TL 1976, 17, 319. (b) Ong, B. S.; Chan, T. H. SC 1977, 283.
12. Yura, T.; Iwasawa, N.; Mukaiyama, T. CL 1986, 187.
13. March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; p 221.
14. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; Chapter 3.
15. Kende, A. S.; Rizzi, J. P. TL 1981, 22, 1779.
16. Hannan, R. L.; Barber, R. B.; Rapoport, H. JOC 1979, 44, 2153.
17. McMurry, J. E. OR 1976, 24, 187.
18. Feutrill, G. I.; Merrington, R. N. AJC 1972, 25, 1731
19. Bartlett, P. A.; Johnson, W. S. TL 1970, 11, 4459.
20. Kelly, T. R.; Dali, H. M.; Tsang, W.-G. TL 1977, 18, 3859.
21. Node, M.; Hori, H.; Fujita, E. JCS(P1) 1976, 2237.
22. Node, M.; Nishide, K.; Sai, M.; Fujita, E. TL 1978, 19, 5211.
23. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; Chapter 7.
24. Tam, J. P.; Merrifield, R. B. In The Peptides: Analysis, Synthesis, Biology; S. Undenfriend, S.; Meienhofer, J., Eds.; Academic: San Diego, 1987; Vol. 9, Chapter 5.
25. Roush, R. W.; Warmus, J. S.; Works, A. B. TL 1993, 34, 4427.
26. Baldwin, J. E.; Bottaro, J. C.; Kolhe, J. N.; Adlington, R. M. CC 1984, 22.

Gary A. Sulikowski & Michelle M. Sulikowski

Texas A&M University, College Station, TX, USA

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