Phenylthiomethyllithium

[13307-75-0]  · C7H7LiS  · Phenylthiomethyllithium  · (MW 130.15)

(nucleophilic organolithium reagent useful for addition to ketones, aldehydes, esters; synthesis of alkenes, epoxides, cyclopentenones, allylic sulfides, g-phenylthioenones, a-phenylthiofurans and butenolides, and (phenylthiomethyl)trimethylsilane)

Preparative Methods: by the treatment of methyl phenyl sulfide with n-Butyllithium in ether (reflux, 15 h),1 or in THF containing 1 equiv of DABCO (eq 1, 0 °C, 45 min).2

Handling, Storage, and Precautions: is generated in situ, under anhydrous conditions, in an inert atmosphere, and used shortly after preparation; as n-BuLi is employed, the precautions for preparation and use would mirror those of n-BuLi and related reactive organometallic reagents.

Alkene Synthesis.

Phenylthiomethyllithium (1) is a versatile reagent for the preparation of alkenes from ketones, and is particularly useful when the carbonyl compound is susceptible to base-catalyzed epimerization.3-5 Addition of (1) to ketones followed by aqueous quench gives rise to b-hydroxy sulfides (which are not generally isolated).2 Conversion to a b-thioester is accomplished by successive treatment with butyllithium and an acylating agent (typically Benzoyl Chloride or Acetic Anhydride).6,7 Alternatively, the lithium alkoxide produced by the addition of (1) to the ketone can be trapped in situ with Benzoic Anhydride to afford the b-benzoyloxy sulfide.6 Lithium Amide or Sodium Naphthalenide reduction affords exocyclic methylene compounds in good to high yields,6,7 even in the case of hindered ketones (eq 2).8

Alternatively, in the case of b-benzoyloxy sulfides derived from ketones, the reduction to methylene compounds may be accomplished by the use of low-valent titanium compounds (prepared by treating pyridine solutions of Titanium(IV) Chloride with Zinc metal)9 or with Titanium metal.10 In a further extension, the reduction of the intermediate b-hydroxy sulfides formed from both ketones and aldehydes may be reduced with titanium tetrachloride-Lithium Aluminum Hydride to provide the methylene compounds in high yields.11

Epoxide Synthesis.

Epoxides are produced when the intermediate b-hydroxy sulfides, from the addition reaction of (1), are alkylated (for example, with Triethyloxonium Tetrafluoroborate or its trimethyl analog) and treated with aqueous base (eq 3).12a The overall yields for the three-step process are high and compare favorably to the one-step methylene transfer accomplished by sulfur ylides, a reaction that is sometimes hindered by steric interference and proton abstraction. Vinyl epoxides can be prepared by the addition of (1) to an a,b-unsaturated aldehyde to give a vinylphenylthiomethylcarbinol, which is alkylated with triethyloxonium tetrafluoroborate, followed by base-catalyzed (Sodium Hydride) epoxide closure (eq 4).12b

Cyclopentenone Synthesis.

The reagent (1) has also found use in the synthesis of cyclopentenones. The addition of (1) to a-chloro-b,g-unsaturated esters has been demonstrated to lead directly to 5-phenylthio-2-cyclopentenones (eq 5).13

Allylic Sulfides, g-Phenylthio-a,b-unsaturated Ketones.

The reagent (1) adds smoothly to cyclic ketones (ring sizes 5-10, 12, 15) and the resultant tertiary alcohols can be readily dehydrated to furnish allylic sulfides (eq 6).14 The addition of (1) to an a,b-unsaturated ketone affords the related tertiary allylic alcohol, which gives a g-phenylthio-a,b-unsaturated ketone on treatment with Pyridinium Chlorochromate on silica gel and ultrasound (eq 7).15

Phenylthiofuran and Butenolide Synthesis.

The reagent (1) has been utilized for phenylthiofuran and butenolide formation in the synthesis of the sesquiterpene (±)-colorata-4(13),8-dienolide (2).16 (1) was added to an a-butylthiomethylene ketone, to afford an a,b-unsaturated aldehyde after hydrolysis (eq 8). The hydrolysis reaction to provide the conjugated aldehyde required 4 weeks at 20 °C, in order to prevent double bond isomerization. Oxidation (Sodium Periodate) and treatment with acetic anhydride and heat led to the desired a-phenylthiofuran in 70% yield.

The conversion of the phenylthiofuran to the target butenolide was again complicated by long exposure times to acid and Mercury(II) Chloride (1 week) to avoid double bond isomerization and give the butenolide (2) in 60% yield (eq 9).

Phenylthiomethyltrimethylsilane.

(1), produced by the Gilman method,1 readily reacts with Chlorotrimethylsilane to give (Phenylthiomethyl)trimethylsilane (eq 10).17

Related Reactions.

Nucleophilic phenylthiomethyl equivalents have been prepared from phenylthiomethyltrimethylsilane18 and Chloromethyl Phenyl Sulfide.19 Phenylthiomethyltrimethylsilane can be treated with Tetra-n-butylammonium Fluoride (eq 11, path 1)18a or Potassium t-Butoxide (eq 11, path 2)18b to furnish species which will add to ketones. Phenylthiomethyltrimethylsilane has also seen use in the synthesis of aldehydes,17 alcohols,17 ketones,20 and alkenes,21 in conjugate additions to cycloalkenones,21 and in the preparation of chloro(phenylthio)methyltrimethylsilane.22 Phenylthiochloromethane produces a reactive organometallic species when treated with Samarium(II) Iodide and a ketone (eq 12).19 These mild conditions permit the use of readily enolized ketones as substrates for phenylthiomethyl addition.

Methyl phenyl sulfide can be treated with 2.2 equiv of n-butyllithium-TMEDA to generate a dianion which can be efficiently reacted with a range of electrophiles (eq 13).23 Attempts to alkylate the dianion sequentially with two different electrophiles have not been very successful.

1-Phenylthio-1-lithioethane is prepared from 1,1-bisphenylthioethane by reductive cleavage with lithium naphthalenide (eq 14).17 The 1-phenylthio-1-lithioethane thus produced is then captured with chlorotrimethylsilane in 90% yield (eq 14).

Related Reagents.

Bis(phenylthio)methane; Dibromomethane-Zinc-Titanium(IV) Chloride; S,S-Dimethyl-N-(p-toluenesulfonyl)sulfoximine; 2-Lithio-1,3-dithiane; Methylenetriphenylphosphorane; Phenylselenomethyllithium.


1. Gilman, H.; Webb, F. J. JACS 1940, 62, 987.
2. Corey, E. J.; Seebach, D. JOC 1966, 31, 4097.
3. Heathcock, C. H.; Ratcliffe, R. JACS 1971, 93, 1746.
4. McMurray, J. E.; von Beroldingen, L. A. T 1974, 30, 2027.
5. Coates, R. M. AG(E) 1973, 12, 586.
6. Sowerby, R. L.; Coates, R. M. JACS 1972, 94, 4758.
7. Coates, R. M.; Sowerby, R. L. JACS 1972, 94, 5386.
8. Sakurai, K.; Kitahara, T.; Mori, K. T 1988, 44, 6581.
9. Mukaiyama, T.; Watanabe, Y.; Shiono, M. CL 1974, 1523.
10. Welch, S. C.; Loh, J.-P. JOC 1981, 46, 4072.
11. Watanabe, Y.; Shiono, M.; Mukaiyama, T. CL 1975, 871.
12. (a) Shanklin, J. R.; Johnson, C. R.; Ollinger, J.; Coates, R. M. JACS 1973, 95, 3429. (b) Welzel, P.; Böttger, D.; Heinz, U.; Said, A. H.; Fischer, A.; Adams, E. PAC 1987, 59, 385.
13. (a) Mathew, J. JOC 1990, 55, 5294. (b) Mathew, J.; Alink, B. CC 1990, 684.
14. Hannaby, M.; Warren, S. JCS(P1) 1989, 303.
15. Luzzio, F. A.; Moore, W. J. JOC 1993, 58, 2966.
16. de Groot, Ae.; Broekhuysen, M. P.; Doddema, L. L.; Vollering, M. C.; Westerbeek, J. M. M. TL 1982, 23, 4831.
17. Ager, D. J. JCS(P1) 1983, 1131.
18. (a) Kitteringham, J.; Mitchell, M. B. TL 1988, 29, 3319. (b) Hosomi, A.; Ogata, K.; Hoashi, K.; Kohra, S.; Tominaga, Y. CPB 1988, 36, 3736.
19. Yamashita, M.; Kitagawa, K.; Ohhara, T.; Iida, Y.; Masumi, A.; Kawasaki, I.; Ohta, S. CL 1993, 653.
20. Ager, D. J. JCS(P1) 1986, 195.
21. Ager, D. J.; East, M. B. JOC 1986, 51, 3983.
22. Yamamoto, I.; Okuda, K.; Nagai, S.; Motoyoshiya, J.; Gotoh, H.; Matsuzaki, K. JCS(P1) 1984, 435.
23. Cabiddu, S.; Fattuoni, C.; Floris, C.; Gelli, G.; Melis, S.; Sotgiu, F. T 1990, 46, 861.

Mark A. Collins & Steven P. Tanis

The Upjohn Company, Kalamazoo, MI, USA



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