· (MW 232.36)
(lithio derivative is formyl anion equivalent2 but chief uses are in synthesis of phenyl vinyl sulfides3 and a-(phenylthio) ketones4)
Physical Data: mp 38 °C.
Solubility: sol THF, diethyl ether; insol H2O.
Form Supplied in: yellow crystals (white when pure).
Preparative Methods: all methods begin with benzenethiol (Thiophenol, PhSH). An early approach involved reaction of Diiodomethane with PhSNa (generated from PhSH and NaOH in ethanol).2 Dichloromethane (CH2Cl2) has replaced the more expensive CH2I2 in more recent methods either in the presence of triethylamine3 or under phase-transfer conditions with Potassium Carbonate and Benzyltriethylammonium Chloride.5 The hydrogen chloride-catalyzed reaction of benzenethiol with Dimethoxymethane is an effective procedure.6
Purification: recrystallize from petroleum ether.
Handling, Storage, and Precautions: irritating to mucous membranes and upper respiratory tract. Precautions should be followed to avoid inhalation, ingestion, contact with the eyes, or absorption through the skin. Stench. Store in a cool dry place. The toxicological properties appear not to have been thoroughly investigated but exposure can cause nausea, headache, and vomiting.
As reagents for nucleophilic acylation, bis(phenylthio)methane (1) and 1,3-Dithiane were introduced into synthetic methodology at about the same time. Application of (1) to the synthesis of aldehydes involves a sequence of steps (eqs 1-3) analogous to those of 1,3-dithiane. In practice, however, the sequence beginning with 1,3-dithiane is the standard method for nucleophilic acylation while that based on (1) is rarely employed. Nevertheless, there are a number of novel transformations involving derivatives of (1) and it is the applications of these reactions that comprise the major portion of the present account. Before examining these reactions, a brief discussion of the metalation of (1) (eq 1) and the reactions of its lithio derivative (2) is in order.
Metalation of (1) and Nucleophilic Reactivity of (2).
With a pK
a of 30.8 (in DMSO),7 (1) is a somewhat stronger acid than 1,3-dithiane (pK a = ca. 39 in DMSO) and is readily metalated with n-Butyllithium in THF (eq 1).2,3 The resulting clear yellow solution of bis(phenylthio)methyllithium (2) is stable at 0 °C for at least 12 h. Early studies in which sodium amide in liquid ammonia was used in the metalation step gave lower yields of subsequent alkylation products.8 Reaction of (2) with primary alkyl halides gives high yields of phenyl thioacetal derivatives of aldehydes (3) (eq 2).2,9,10 Secondary alkyl halides are less effective alkylating agents but 3-chloro-1-butene, which is a relatively unhindered secondary allylic halide, gives the desired alkylation product in almost quantitative yield and without
allylic rearrangement (eq 4).11
Dialkylation is difficult and requires the presence of metal-complexing agents to enhance the reactivity of the organometallic in the second alkylation step. Thus metalation of 1,1-bis(phenylthio)ethane (4)12 in hexane containing TMEDA, followed by addition of a variety of primary alkyl halides, produced compounds of type (5) in synthetically useful yields (eq 5).13 Similar results were obtained using a procedure in which Sodium Amide was added to a THF-HMPA solution of (4) and a primary alkyl halide.14
Bis(phenylthio)methyllithium (2) reacts with ethylene oxide to give the product of nucleophilic ring opening (eq 6).15 Lithio derivative (2) reacts with epibromohydrin by displacement of halogen, leaving the epoxide ring intact.10
A number of studies directed toward synthetic applications of (1) have described reactions of lithio derivative (2) with aldehydes and ketones as a key step.2-4,16,17 As exemplified in (eq 7), such reactions proceed readily.9a Addition of (2) to a,b-unsaturated aldehydes seems to be exclusively 1,23,18 but a mixture of 1,2- and 1,4-addition products are observed with a,b-unsaturated ketones. The tendency toward 1,4-addition is more pronounced with (2) than with 2-Lithio-1,3-dithiane and is increased in the presence of HMPA (eq 8).19 1,4-Addition predominates in reactions of the cuprate reagent derived from (2).20
Preparation of Phenyl Vinyl Sulfides.
Copper(I) Trifluoromethanesulfonate (triflate) is an effective reagent for promoting carbocation formation by cleavage of a phenylthio substituent from bis(phenylthio) acetals (eq 9).21 Deprotonation of the resulting a-phenylthio carbocation yields a phenyl vinyl sulfide. Reaction conditions have been developed for the effective synthesis of phenyl vinyl sulfides by alkylation of (1) followed by copper(I) triflate-induced elimination (eq 10).3
A novel fragmentation occurs when (6) (derived from (2) and 1,2-epoxycyclohexane) as its lithium alkoxide is treated with excess (4 equiv) of copper(I) triflate.22 The product is a phenyl vinyl sulfide (eq 11).
Preparation of a-(Phenylthio) Ketones.
The adducts of (2) with aldehydes and ketones give a-(phenylthio) ketones on treatment with copper(I) triflate in refluxing benzene containing N-ethyl-N,N-diisopropylamine (eq 12).4 The adducts of cyclic ketones yield ring-expanded a-(phenylthio) ketones as illustrated by the example in eq 13. The reaction is believed to proceed by CuI-promoted ionization of one of the phenylthio substituents, followed by epoxide formation, then hydride or alkyl group migration.
A similar transformation occurs when adducts of (2) with aldehydes and ketones are treated with p-Toluenesulfonic Acid in refluxing benzene.9a The adducts of (2) with cyclic ketones undergo an analogous rearrangement via a carbenoid mechanism when converted to their dianions by reaction with two equivalents of Methyllithium or s-Butyllithium in THF at 0 °C.23 The a-(phenylthio) ketones formed by this procedure can serve as precursors to enones (by oxidation and thermal elimination of the resulting sulfoxide)9b and a-(phenylthio) enones (by Pummerer rearrangement).16
Bis(methylthio)methane as an Analogous Reagent.
Deprotonation of bis(methylthio)methane with n-butyllithium affords bis(methylthio)methyllithium, which has been used several times as a formyl anion equivalent. Addition of bis(methylthio)methyllithium to cyclic vinylogous esters24 affords, after aqueous acid hydrolysis, 3-bis(methylthio)methylcyclohexenones (eq 14).25 Thioacetal hydrolysis provides the 3-formylcyclohexenone.
Epoxide opening by bis(methylthio)methyllithium, tosylate formation, deprotonation and intramolecular tosylate displacement affords cyclopropanone thioacetals in good yields via a one-pot procedure (eq 15).26 Reaction of a carbohydrate N-acetylaziridine with bis(methylthio)methane and acetic acid gave in high yield the S-alkylation product (eq 16) via the presumed pathway shown. Clean inversion of configuration at C(7) was observed.27
Electrophilic thionium ion intermediates have been accessed via thioacetals derived from bis(methylthio)methane.28 Successive deprotonation/alkylation steps lead to the cyclization substrates in eqs 17 and 18. In the former, the bracketed thionium ion arises from treatment of the thioacetal with p-Toluenesulfinic Acid in warm acetonitrile. Cyclization and elimination steps yielded the 4-substituted indole.28a Treatment of the thioacetal in eq 18 with Dimethyl(methylthio)sulfonium Tetrafluoroborate provides the spirocyclic enone shown via initial thionium ion trapping by the vinylsilane, followed by allylic sulfide activation and cyclization involving the enol silyl ether.28b These applications highlight the nucleophilic and electrophilic behavior of the thioacetal linkage.
- 1. (a) Krief, A. T 1980, 36, 2531. (b) Gröbel, B.-T.; Seebach, D. S 1977, 357. (c) Hase, T. A. Umpoled Synthons. A Survey of Sources and Uses in Synthesis; Wiley: New York, 1987.
- 2. Corey, E. J.; Seebach, D. JOC 1966, 31, 4097.
- 3. Cohen, T.; Ruffner, R. J.; Shull, D. W.; Fogel, E. R.; Falck, J. R. OSC 1988, 6, 737.
- 4. Cohen, T.; Kuhn, D.; Falck, J. R. JACS 1975, 97, 4749.
- 5. Lissel, M. LA 1982, 1589.
- 6. Cohen, T.; Ritter, R. H.; Ouellette, D. JACS 1982, 104, 7142.
- 7. Bordwell, F. G.; Drucker, G. E.; Anderson, N. H.; Denniston, A. D. JACS 1986, 108, 7310.
- 8. Fröling, A.; Arens, J. F. RTC 1962, 81, 1009.
- 9. (a) Blatcher, P.; Warren, S. JCS(P1) 1979, 1074. (b) Durman, J.; Elliott, J.; McElroy, A. B.; Warren, S. JCS(P1) 1985, 1237. (c) Blatcher, P.; Warren, S. JCS(P1) 1985, 1055. (d) Gamage, S. A.; Smith, R. A. J. AJC 1990, 43, 815.
- 10. For alkylation in the presence of HMPTA, see: Tsai, Y.; Chang, F.; Huang, J.; Shiu, C. TL 1989, 30, 2121.
- 11. Benedetti, F.; Berti, F.; Fabrissin, S.; Gianferrara, T.; Risaliti, A. JOC 1991, 56, 3530.
- 12. Compounds of the type represented by (4) can be prepared by alkylation of (1) or by reaction of the corresponding aldehyde with benzenethiol.
- 13. Ager, D. J. TL 1980, 21, 4763.
- 14. Schill, G.; Merkel, C. S 1975, 387.
- 15. Ritter, R. H.; Cohen, T. JACS 1986, 108, 3718.
- 16. Durman, J.; Grayson, J. I.; Hunt, P. G.; Warren, S. JCS(P1) 1986, 1939.
- 17. Denis, J. N.; Desauvage, S.; Krief, A. TL 1981, 22, 4009.
- 18. Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. T 1988, 44, 4645.
- 19. Ager, D. J.; East, M. B. JOC 1986, 51, 3983.
- 20. Mukaiyama, T.; Narasaka, K.; Furusato, M. JACS 1972, 94, 8641.
- 21. Cohen, T.; Herman, G.; Falck, J. R.; Mura, A. J., Jr. JOC 1975, 40, 812.
- 22. Semmelhack, M. F.; Tomesch, J. C. JOC 1977, 42, 2657.
- 23. Abraham, W. D.; Bhupathy, M.; Cohen, T. TL 1987, 28, 2203.
- 24. Stork, G.; Danheiser, R. L. JOC 1973, 38, 1776.
- 25. (a) Quesada, M. L.; Schlessinger, R. H. SC 1976, 6, 555. See also: (b) Guingant, A.; Barreto, M. M. TL 1987, 28, 3107. (c) Hackett, S.; Livinghouse, T. JOC 1986, 51, 879. (d) Bergamasco, R.; Horn, D. H. S.; Nearn, R. H.; Wilkie, J. S. AJC 1985, 38, 475.
- 26. Braun, M.; Seebach, D. CB 1976, 109, 669.
- 27. Bannister, B. JCS(P1) 1980, 540.
- 28. (a) Trost, B. M.; Reiffen, M.; Crimmin, M. JACS 1979, 101, 257. (b) Trost, B. M.; Murayama, E. JACS 1981, 103, 6529.
Steven D. Burke
University of Wisconsin-Madison, Madison, WI, USA
Francis A. Carey
University of Virginia, Charlottesville, VA, USA
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