Thiophenol

PhSH

[109-98-5]  · C6H6S  · Thiophenol  · (MW 110.19)

(precursor of the thiophenoxy radical, which adds to alkenes and alkynes, initiating cyclizations; cis/trans alkene isomerization; synthesis of vinyl sulfides, alkyllithiums, pyridines; transacetalization; Michael addition)

Physical Data: mp -15 °C; bp 169 °C, 46.4 °C/4 mmHg; n20 1.5893; d20 1.0766 g cm-3.

Solubility: sol alcohol, ether, benzene, methylene chloride.

Form Supplied in: liquid; commercially available.

Handling, Storage, and Precautions: handle under an inert atmosphere as oxygen causes oxidation to the disulfide. This may accelerated in the presence of base. Stench reminiscent of garlic. Very toxic. Handle only in an efficient fume hood.

Radical Reactions.

Thiophenol is best known as a hydrogen atom source or radical initiator in radical reactions. Vinylcyclopropanes can undergo a radical-induced rearrangement (eq 1).1 In this example, addition of the thiophenoxy radical to the alkenic terminus is followed by opening of the cyclopropane ring; this radical may then add to another alkene to give a radical primed to undergo a 5-exo-trig closure onto the remaining alkene. The dienylic cyclopropane can undergo a similar reaction but instead the radical can also undergo cyclization without an added alkene (eq 2).2 As in most radical cyclizations, formation of five-membered carbocyclic rings is generally favored.

Alkynes separated from an alkene by a three-carbon tether are similarly prone to cyclize on treatment with thiophenol.3 This reaction is initiated by addition of the thiyl radical to the alkyne to form a vinyl radical which then closes (eq 3). The cyclization in this case must compete with hydrogen atom abstraction, resulting in low yields. The alkyne addition to form a vinyl sulfide without the cyclization is also known, wherein thiophenol adds across the triple bond of an alkyne in the presence of Triethylborane as radical initiator to form a vinyl sulfide (eq 4) (see below for other routes to vinyl sulfides and for another application of this reaction).4

Another very common usage of thiophenol is to change the cis/trans isomer ratio of alkenes to favor the trans configuration (eq 5).5

Vinyl Sulfides.

A useful application of thiophenol is as an in situ source of Benzenesulfenyl Chloride (generated from thiophenol and N-Chlorosuccinimide or Sulfuryl Chloride).6 This can add electrophilically across alkenes to generate vicinal chloro sulfides (eq 6). Subsequent elimination of HCl using 1,8-Diazabicyclo[5.4.0]undec-7-ene or Sodium Carbonate provides vinyl sulfides which are useful as precursors to sulfones (by oxidation) and to vinyllithiums (see below), or as synthetic equivalents to enols.7 An alternative route towards cyclic vinyl sulfides involves Montmorillonite K10 catalysis (eq 7) and cyclic ketones.

Alkylation; Alkyllithiums.

Thiophenol is also the precursor of choice to make alkyl phenyl sulfides by nucleophilic substitution of an alkyl halide. These have recently become popular precursors to complex alkyllithiums via reductive lithiation of phenyl sulfides (eq 8). These reactions are generally done in THF, utilizing Lithium Naphthalenide,8 Lithium 1-(Dimethylamino)naphthalenide,9 or Lithium 4,4-Di-t-butylbiphenylide.10

Conjugate Additions.

The nucleophilic properties of thiophenoxide are also apparent in Michael reactions. Thiophenoxide is easily formed in the presence of Triethylamine (eq 9) and adds to a,b-unsaturated enones and enoates11 with equal ease and in high yield. It has been used as a key reagent in the synthesis of butenolides from g-hydroxy a,b-unsaturated enoates12 (eq 10).

Michael addition to activated acetylene derivatives, such as propiolate esters, may also be carried out with subsequent trapping by electrophiles such as benzaldehyde (eq 11).13

Pyridine Synthesis.

Thiophenol also shows some utility in the synthesis of a wide variety of substituted pyridines from acyclic precursors (eq 12) in overall yields of 45-60%. In this example, treatment of thiophenol with Methyl Vinyl Ketone to obtain the Michael adduct, followed by condensation with a ketone enolate (made with Lithium Diisopropylamide) and dehydration with Thionyl Chloride, provides the 4-(phenylthio) enone. Oxidation to the sulfoxide, Pummerer rearrangement, and treatment with Ammonia provide the pyridine.14

Thioacetals and Glycosides.

It is also possible to take advantage of the nucleophilicity of thiophenol to carry out transacetalizations. These are done in the presence of a Lewis acid. In examples such as MOM ethers this provides a net deprotection, as shown recently in the final step of Corey's synthesis of gingkolide A (eq 13).15 The resulting coproduct is a useful reagent in its own right, shown by Livinghouse to be a formyl anion equivalent.16 Thiophenol's main use in this area, however, is in the synthesis of thioglycosides. Acid-catalyzed transacetalization of either the acetyl glycoside17 or the hemiacetal can provide the required 2-thiopyran ring (eq 14). Lewis acid-catalyzed synthesis must have an oxygen acceptor in the system to work, an example being Zinc Chloride with Phosphorus Oxychloride18 or Trimethylsilyl Trifluoromethanesulfonate.19

Other Applications.

Thiophenol can also be utilized in the transformation of acetylenic alcohols to unsaturated aldehydes with allylic transposition (eq 15).20 The reaction begins with treatment of an acetylenic alcohol with thiophenol to obtain a vinyl sulfide in a radical-induced reaction (see above). Acid-catalyzed hydrolysis then provides a homologated a,b-unsaturated aldehyde.

An interesting photochemical application of thiophenol is in the cleavage of b-phenylthio alcohols (available from reaction of epoxides with thiophenol). Irradiation of these alcohols at 350 nm using benzophenone as sensitizer causes cleavage of the central bond and formation of the ketone in good yield (eq 16).21

Related Reagents.

Thiophenol-Azobisisobutyronitrile.


1. Miura, K.; Fugami, K.; Oshima, K.; Utimoto, K. TL 1988, 29, 1543.
2. Miura, K.; Fugami, K.; Oshima, K.; Utimoto, K. TL 1988, 29, 5135.
3. Broka, C. A.; Reichert, D. E. C. TL 1987, 28, 1503.
4. Ichinose, Y.; Wakamatsu, K.; Nozaki, K.; Birbaum, J.-L.; Oshima, K.; Utimoto, K. CL 1987, 1647.
5. Schwarz, M.; Graminski, G. F.; Waters, R. M. JOC 1986, 51, 260.
6. Hopkins, P. B.; Fuchs, P. L. JOC 1978, 43, 1208.
7. See: Trost, B. M.; Lavoie, A. C. JACS 1983, 105, 5075, and references therein.
8. Screttas, C. G.; Screttas, M. M. JOC 1978, 43, 1064.
9. Cohen, T.; Lin, M.-T. JACS 1984, 106, 1130.
10. The first use of lithium di-t-butylbiphenylide for this purpose was on alkyl halides: Freeman, P. K.; Hutchinson, L. L. TL 1976, 1849.
11. Bakuzis, P.; Bakuzis, M. L. F. JOC 1981, 46, 235.
12. Tanikaga, R.; Yamashita, H.; Kaji, A. S 1986, 416.
13. Bury, A.; Joag, S. D.; Stirling, C. J. M. CC 1986, 124.
14. Konno, K.; Hashimoto, K.; Shirahama, H.; Matsumoto, T. TL 1986, 27, 3865.
15. Corey, E. J.; Ghosh, A. K. TL 1988, 29, 3205.
16. Hackett, S.; Livinghouse, T. JOC 1986, 51, 879.
17. Kozikowski, A. P.; Ghosh, A. K. JOC 1985, 50, 3017.
18. Sinha, B.; Bose, J. L. IJC(B) 1991, 30, 340.
19. Nambiar, S.; Dacuble, J. F.; Doyle, R. J.; Taylor, K. G. TL 1989, 30, 2179.
20. Julia, M.; Lefebvre, C. TL 1984, 25, 189.
21. Gravel, D.; Farmer, L.; Ayotte, F. C. TL 1990, 31, 63.

Onorato Campopiano

DuPont Agricultural Products, Wilmington, DE, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.