Tris(phenylthio)methyllithium1

(PhS)3CLi

[14572-78-2]  · C19H15LiS3  · Tris(phenylthio)methyllithium  · (MW 346.49)

(nucleophilic carboxylating agent for certain carbonyl compounds2 and alkyl halides;3 homologating agent for trialkylboranes;4 carbene precursor5)

Physical Data: not isolable; decomp above 20 °C to bis(phenylthio)carbene and lithium phenylthiolate.

Solubility: up to 2 M in THF.

Form Supplied in: not commercially available.

Analysis of Reagent Purity: titrate with D2O or MeI.

Preparative Methods: generally prepared from n-Butyllithium and Tris(phenylthio)methane and used immediately; can also be generated from tetra(phenylthio)methane by Li-PhS exchange2c or from diphenyl trithiocarbonate and PhLi.2c

Purification: not generally practical; may contain products derived from ethyl formate used in preparation of tris(phenylthio)methane.

Handling, Storage, and Precautions: although not acutely pyrophoric, the reagent is readily hydrolyzed and should be handled under a dry, inert atmosphere. The reagent is corrosive to biological tissue. Storage, even in the cold, is not recommended because of instability. The reagent, its precursors, and reaction mixtures derived from its use, should be handled in a fume hood because of the smell of thiophenol.

Nucleophilic Carboxylation/Carbene Precursor.

Following early reports6 of the deprotonation of trialkyl trithioorthoformates with alkali amides and their subsequent trapping with reactive electrophiles, the generation and trapping of this reagent were independently reported by Brandsma3 and Seebach.2a More detailed studies of the properties of the reagent were later reported by Seebach.7

The reagent is quantitatively generated at -78 °C in THF by addition of 1 equiv of n-butyllithium to the precursor tris(phenylthio)methane. Upon raising the temperature to near ambient, the establishment of an equilibrium between the reagent and the transiently stable bis(phenylthio)carbene (PhS)2C: was demonstrated by isolation from the reaction of products arising from its formation. These included the dimer tetraphenylthioethylene, as well as sulfur-substituted cyclopropanes obtained when ketene acetals and dithioketene acetals were added. Synthetically useful yields of cyclopropane products were obtained only when dithioketene acetals were used.8

These studies indicate the importance of generating and using the reagent shortly thereafter, if nucleophilic carboxylation is desired. Because the reagent is relatively bulky and has phenylthio groups as substituents, it is less reactive than the corresponding tris(methylthio) reagent (see Tris(methylthio)methane). Its utility as a nucleophilic carboxylating agent is therefore more limited. Primary alkyl bromides and iodides (eq 1), allyl halides, CO2 (eq 2), alkyl and aryl disulfides, silyl chlorides,2a,3 and reactive ketones9 efficiently interact with the reagent to afford the corresponding adducts. Aldehydes, saturated or unsaturated, react with the reagent to give 1,2-adducts (eq 3),2a,5 although some variations in this behavior have been reported.10,11 Ordinary ketones are enolized and recovered. Reactive epoxides and secondary halides give poor yields of alkylation products, apparently because the reagent adds too slowly to these electrophiles and functions as a base. However, unhindered a,b-unsaturated ketones add the reagent in the conjugate sense, affording g-keto trithioorthotriesters in good to excellent yields (eq 4).12 In the case of carbon electrophiles, these adducts are hydrolyzed to carboxylic acids with Mercury(II) Chloride, Mercury(II) Oxide, combinations of the two,13 or Ag(O2CCF3)211 in aqueous acetone, DMF, or dioxane at &egt;25 °C. Yields of carboxylation products are sometimes improved if the adducts are subjected to alcoholysis, affording the ester,12,13a or to partial hydrolysis, affording the thioester.14 Conventional hydrolysis can then be employed if the carboxylic acid is desired (eq 5).15

The reagent reacts with lactones such as d-valerolactone, with various results having been reported (eq 6).16

Recently, a nucleophilic carboxylation using this reagent to prepare the glyoxylate synthon tris(phenylthio)acetaldehyde, was reported (eq 7).11

Conjugate addition of the reagent to cyclic unsaturated ketones has the feature of generating regiochemically homogenous enolates which can be trapped in situ with appropriate electrophiles (eq 8).17

A useful property of the adducts of the reagent is their continued ability to undergo further lithiation or generate carbenes. These reactive intermediates can, if generated in the appropriate location, induce further transformations typical of carbanions or carbenes such as ring expansions,9 hydrogen shifts,5 and conjugate additions (eqs 9-11).18 Although the reagent is of very limited utility in cyclopropane synthesis when used intermolecularly, intramolecular trapping of the carbenoid center by a nucleophilic alkene is an excellent route to sulfur-substituted cyclopropane-containing bicyclic ketones (eq 12).19

Homologation of Trialkylboranes.

When treated with relatively unhindered trialkylboranes, the reagent serves as a homologating agent, affording either ketones or tertiary alcohols. The best substrates for the reaction are boranes containing primary alkyl or cycloalkyl groups. The products are obtained after standard oxidation with basic Hydrogen Peroxide, and their nature depends on the presence or absence of mercury(II) chloride. In the absence of Hg2+, ketones are obtained, whereas in its presence, tertiary alcohols are the products. Primary alkyl groups migrate preferentially. The stoichiometry of the reaction is illustrated in eq 13.4


1. Gröbel, B.-T.; Seebach, D. S 1977, 357.
2. (a) Seebach, D. AG(E) 1967, 6, 442. (b) Seebach, D. AG 1967, 79, 468. (c) Seebach, D. CB 1972, 105, 487 (CA 1972, 76, 99 736).
3. Wildschut, G. A.; Bos, H. J. T.; Brandsma, L.; Arens, J. F. M 1967, 98, 1043 (CA 1967, 67, 81 912).
4. (a) Pelter, A.; Rao, J. M. CC 1981, 1149. (b) Pelter, A.; Rao, J. M. JOM 1985, 285, 65.
5. Cohen, T.; Yu, L.-C. JOC 1984, 49, 605.
6. Fröling, A.; Arens, J. F. RTC 1962, 81, 1009.
7. (a) Seebach, D.; Beck, A. K. JACS 1969, 91, 1540. (b) Nitsche, M.; Seebach, D.; Beck, A. K. CB 1978, 111, 3644 (CA 1979, 90, 86 467).
8. Seebach, D. AG(E) 1967, 6, 443.
9. (a) Knapp, S.; Trope, A. F.; Ornaf, R. M. TL 1980, 21, 4301. (b) Ferrier, R. J.; Tyler, P. C.; Gainsford, G. J. JCS(P1) 1985, 295.
10. Solladié, G.; Berl, V. TL 1991, 32, 6329.
11. Trost, B. M.; Grese, T. A. JACS 1991, 113, 7363.
12. Manas, A.-R. B.; Smith, R. A. J. CC 1975, 216.
13. (a) Ellison, R. A.; Woessner, W. D.; Williams, C. C. JOC 1974, 39, 1430. (b) Woessner, W. D. CL 1976, 43.
14. Smith, R. A. J.; Keng, G. S. TL 1978, 675.
15. Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, G. S. JACS 1977, 99, 6756.
16. (a) Hengeveld, J. E.; Greif, V.; Tadanier, J.; Lee, C.-M.; Riley, D.; Lartey, P. A. TL 1984, 25, 4075. (b) Yates, P.; Krepinsky, J. J.; Seif-el-nasr, A. CC 1989, 177.
17. Hayashi, M.; Mukaiyama, T. CL 1987, 1283.
18. Ramig, K.; Cohen, T.; Kuzemko, M. A.; McNamara, K. JOC 1992, 57, 1968.
19. Ramig, K.; Cohen, T.; Bhupathy, M. JOC 1989, 54, 4404.

Conrad Santini

Merck Research Laboratories, Rahway, NJ, USA



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