Methoxy(phenylthio)methane1

(R = H)

[13865-50-4]  · C8H10OS  · Methoxy(phenylthio)methane  · (MW 154.25) (R = Li)

[95540-81-1]  · C8H9LiOS  · Methoxy(phenylthio)methyllithium  · (MW 160.18)

(carbonyl anion equivalent useful for homologation and ring expansion)

Physical Data: bp 113-114 °C/18 mmHg; d 1.047 g cm-3.

Form Supplied in: neat liquid; commercially available.

Preparative Methods: via the base-catalyzed condensation of Thiophenol and Chloromethyl Methyl Ether2 or via the Boron Trifluoride Etherate-catalyzed condensation of thiophenol and Dimethoxymethane.3

Handling, Storage, and Precautions: store under inert gas to avoid air oxidation of the sulfide. Hydrolysis of the reagent releases thiophenol (stench!) which is known to be toxic. Use in a fume hood.

One-Carbon Homologations.

Methoxy(phenylthio)methane is a convenient one-carbon homologation reagent (also see 1,3-Dithiane and Methoxy(phenylthio)trimethylsilylmethane) with distinct differences from similar reagents derived from dithioacetals. Since the reagent possesses two different functional groups (methoxy and phenylthio), chemoselective manipulation of either functional group can be performed, resulting in an extremely versatile reagent. Methoxy(phenylthio)methane undergoes a facile deprotonation at the central carbon upon treatment with Lithium Diisopropylamide or n-Butyllithium at -78 °C in THF. The resultant anion reacts with a variety of electrophiles such as alkyl halides, aldehydes, ketones, and epoxides (eq 1).4 The thioacetal products thus formed can be chemically manipulated to afford a variety of homologated products.

For example, treatment with p-Toluenesulfonic Acid in methanol affords dimethoxyacetals which can be further hydrolyzed to aldehydes (eq 2).4 Aldehydes are also available in one step by oxidation of the sulfide to the sulfoxide with m-Chloroperbenzoic Acid and hydrolytic workup (eq 2).4 Vinyl ethers are produced via a thermal elimination of benzenesulfenic acid (eq 3).4 Alternately, the anion formed from the addition of methoxy(phenylthio)methyllithium to aldehydes can be treated with Carbon Disulfide and Iodomethane to form a xanthate which when treated with Tri-n-butylstannane effects a radical reductive elimination to form (Z)- and (E)-enol ethers (eq 4).5

In addition, carboxylic acids are accessible from the homologated thioacetals via Jones oxidation (eq 5).4 Conjugate addition of methoxy(phenylthio)methyllithium to a vinyl sulfone, followed by Jones oxidation and elimination of benzenesulfenic acid, afforded a dienoic acid (eq 6).6 A novel approach to a-phenylthioaldehydes, which involves a phenylthio migration, results from treating the adducts of methoxy(phenylthio)methyllithium and ketones with Thionyl Chloride in Pyridine (eq 7)7 or by treating the corresponding aldehyde adducts with Methanesulfonyl Chloride and Triethylamine.8 a-Phenylthioaldehydes thus obtained can be homologated further or converted to benzo[b]thiophenes.9

Alkylboronic esters available via the hydroboration of alkenes with dihaloboranes followed by alcoholysis can be homologated by reacting them with methoxy(phenylthio)methyllithium and treating the resulting ate complex with Mercury(II) Chloride followed by Hydrogen Peroxide (eq 8).10 The use of an optically pure boronic ester affords optically pure aldehydes.11

Homologation via Operations on Thioacetals.

Four-carbon 1,3- and 1,4-dicarbonyl homologated compounds are accessible via subsequent manipulation of the adducts resulting from the condensation of methoxy(phenylthio)methyllithium with aldehydes. For example, reaction of the acylated adducts with enol silyl ethers under Lewis acid catalysis results in carbon-carbon bond formation and 1,2-migration of the phenylthio moiety. Such a-methoxy-g-phenylthio ketones were converted into 1,3-dicarbonyl or 1,4-dicarbonyl compounds (Scheme 1).12 Alternately, the a-phenylthioaldehydes can be converted into 1,4-dicarbonyl compounds (Scheme 1).

The use of the thioacetal products as electrophiles in Lewis acid-promoted reactions of allyl- and propargylstannanes allows access to three-carbon homologated methyl ethers or phenyl sulfides (eq 9). Employment of Boron Trifluoride Etherate as the Lewis acid results in the selective cleavage of the phenylthio group to provide ether products. Similarly, the use of Titanium(IV) Chloride results in cleavage of the methoxy group and formation of phenyl thiosulfide products. These reactions partially compensate for the inability of monoalkylated O,S-acetals to undergo dialkylation. Apparently, substitution of one of the alkylthio groups for methoxy sufficiently decreases the stability of an a-carbanion such that it cannot be formed, thus precluding its alkylation (in contrast, dithioacetals can be dialkylated).

Ring Expansions.

Trost first demonstrated the advantages of methoxy(phenylthio)methane over Bis(phenylthio)methane as an acyl anion equivalent in a synthesis of a-methylene-d-lactones via the ring expansion of g-butyrolactones (eq 10).2a Use of the O,S-acetal reagent avoided problems encountered with enolization. Methoxy(phenylthio)methane has also been utilized for the ring expansion of nonenolizable 2-n-butylthiomethylene cyclohexanones to 3-formyl-2-cyclohepten-1-ones (eq 11).13


1. Otera, J. S 1988, 95.
2. (a) Trost, B. M.; Miller, C. H. JACS 1975, 97, 7182. (b) Oae, S.; Masuda, T.; Tsujihara, K.; Furakawa, N. BCJ 1972, 45, 3586.
3. Hackett, S.; Livinghouse, T. JOC 1986, 51, 879.
4. Mandai, T.; Hara, K.; Nakajima, T.; Kawada, M.; Otera, J. TL 1983, 24, 4993.
5. Vatele, J.-M. TL 1984, 25, 5997.
6. Plobeck, N. A.; Bäckvall, J.-E. JOC 1991, 56, 4508.
7. (a) de Groot, A.; Jansen, B. J. M. TL 1981, 22, 887. (b) Jansen, B. J. M.; Peperzak, R. M.; de Groot, A. RTC 1987, 106, 489.
8. Sato, T.; Okazaki, H.; Otera, J.; Nozaki, H. JACS 1988, 110, 5209.
9. de Groot, A.; Jansen, B. J. M. S 1985, 434.
10. Brown, H. C.; Imai, T. JACS 1983, 105, 6285.
11. Brown, H. C.; Imai, T.; Desai, M. C.; Singaram, B. JACS 1985, 107, 4980.
12. Sato, T.; Inoue, M.; Kobara, S.; Otera, J.; Nozaki, H. TL 1989, 30, 91.
13. (a) Guerrero, A.; Parrilla, A.; Camps, F. TL 1990, 31, 1873. (b) Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, A.; Tatsuoka, T.; Meinwald, J. JOC 1986, 51, 773.

Donna L. Romero

The Upjohn Company, Kalamazoo, MI, USA



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