Methylthiomethyl p-Tolyl Sulfone1

[59662-68-9]  · C9H12O2S2  · Methylthiomethyl p-Tolyl Sulfone  · (MW 216.35)

(synthetic reagent for acyclic ketones, cyclic ketones, and conjugated unsaturated ketones)

Alternate Names: MT-sulfone; formaldehyde methyl p-tolyl dithioacetal S,S-dioxide; methyl p-toluenesulfonylmethyl sulfide; methylthio(p-toluenesulfonyl)methane.

Physical Data: mp 82-83 °C; bp 164 °C/3 mmHg.

Solubility: sol DMF (87 g/100 mL), acetone (76 g/mL), CHCl3 (57 g/mL), acetic acid (13 g/mL); slightly sol MeOH (5.8 g/mL), ethanol (3.3 g/mL), ethyl ether (3.0 g/mL), CCl4 (2.2 g/mL); practically insol H2O, hexane.

Form Supplied in: colorless crystals; commercially available. Drying: over P2O5 in a desiccator.

Preparative Method: conveniently synthesized from Dimethyl Sulfoxide in a one-pot reaction, i.e. Pummerer reaction of DMSO with Acetic Anhydride followed by treatment with RS111-.2

Handling, Storage, and Precautions: very stable under alkaline, acidic, and neutral conditions. Handle in a fume hood.

Synthesis of Esters and Aldehydes.

Monoalkylation of methylthiomethyl p-tolyl sulfone (MT-sulfone) with an alkyl halide is achieved by the action of a phase-transfer catalyst (PTC) in toluene-50% aq NaOH.3 Sodium Hydride3 and n-Butyllithium4 also generate a carbanion of MT-sulfone. Arylmethyl derivatives of MT-sulfone are prepared by Sodium Borohydride reduction of the Knoevenagel condensation products with aromatic aldehydes.5 The monoalkylated products are converted into the corresponding methyl esters (eq 1).3,6 This functionalization can be utilized for synthesizing a-alkoxy carboxylic esters (eq 2)3 and a-amino acids (eq 3).7

Irradiation (254 nm) of the monoalkylated product in dioxane-H2O hydrolyzes the dithioacetal S,S-dioxide to produce an aldehyde. This method is suitably applied to the preparation of aldehydes which are susceptible to acidic conditions (eq 4).8

The carbanion of MT-sulfone is stable enough to add to a,b-unsaturated carbonyl compounds in a [1,4] fashion. The (methylthio)(p-tolylsulfonyl)methyl group introduced is easily converted into a (methylthio)carbonyl group or a formyl group.4

Ketone Synthesis.

The monoalkylated MT-sulfone undergoes further alkylation by action of alkyl halide and NaH or n-BuLi to give a dialkylated product. Since the dialkylated product can be hydrolyzed easily, MT-sulfone has proven to be very useful for synthesizing ketones (eq 5).5,8,9 Symmetrical ketones are prepared by direct dialkylation with NaH and alkyl halide in DMF and hydrolysis (eq 6).8 Cyclic ketones are also synthesized from a,o-dihaloalkanes.3,10 An efficient synthesis of a-hydroxy ketones is also achieved by the addition of the monoalkyl derivative to an aldehyde to give an adduct and subsequent hydrolysis (eq 7).11

Acylation of MT-sulfone.

MT-sulfone was acylated by treatment with an ester and excess NaH in THF.3,12,13 The acylated MT-sulfone was oxidized with Hydrogen Peroxide in Acetic Acid, by slowly warming the reaction to give an S-methyl a-keto carbothioate (eq 8).3

An alkoxyacetyl derivative of MT-sulfone exhibits intriguing behavior on treatment with a weak base to form an acetal of 3-methylthio-2-oxopropanal (eq 9).14

Synthesis of a,b-Unsaturated Ketones.

Alkylidene derivatives of MT-sulfone are useful synthetic precursors for a,b-unsaturated ketones (eq 10).15 This method can be extended to provide an efficient synthesis of a,b,g,d-unsaturated aldehydes and ketones (eq 11).16,17

Electrophilic (Methylthio)methylation.

Lewis acids such as Aluminum Chloride or Ethylaluminum Dichloride assist the heterolytic cleavage of the C-SO2 bond of the dithioacetal S,S-dioxide to produce a MeS-stabilized carbocation, which reacts with allylsilanes18 and benzene rings19 (eq 12).

Reactivity of a 1-(Methylthio)-1-(p-tolylsulfonyl)-1-alkene.

1-(Methylthio)-1-(p-tolylsulfonyl)-1-alkenes show extremely high reactivity towards carbon radicals to provide a synthetic route leading to new types of 1-methylthio-1-(p-tolylsulfonyl)alkanes.20,21 They also undergo nucleophilic epoxidation with Lithium t-Butoxide to give an a,b-epoxy-a-methylthio sulfone, a precursor for an a-bromo thiol ester (eq 13).22

Methyl Methylthiomethyl Sulfone.

Methyl methylthiomethyl sulfone is the S-methyl analog of MT-sulfone and it is conveniently synthesized by oxidation of methyl methylthiomethyl sulfoxide (FAMSO) with Potassium Permanganate or H2O2-NaOH.23 It is useful for synthetic methods similar to those using MT-sulfone: synthesis of carboxylic esters,24 ketones,25 and a-alkoxy-a-arylacetates.26 In the reaction of this reagent with allylic bromides, a-methylthio-g,d-unsaturated sulfones are obtained by stirring the bromide with Potassium Carbonate and Potassium Iodide in Hexamethylphosphoric Triamide (eq 14), which does not occur with MT-sulfone.24

Related Reagents.

N,N-Diethylaminoacetonitrile; N,N-Dimethyldithiocarbamoylacetonitrile; (4aR)-(4aa,7a,8ab)-Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin; 2-Lithio-1,3-dithiane; Nitromethane; 1,1,3,3-Tetramethylbutyl Isocyanide; p-Tolylsulfonylmethyl Isocyanide; 2-(Trimethylsilyl)thiazole.

1. (a) Ogura, K. PAC 1987, 59, 1033. (b) Ogura, K. In Studies in Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1990; Vol. 6, p 307. (c) Ogura, K. Rev. Heteroatom Chem. 1991, 5, 85.
2. Ogura, K.; Yahata, N.; Watanabe, J.; Takahashi, K.; Iida, H. BCJ 1983, 56, 3543.
3. Ogura, K.; Yahata, N.; Hashizume, K.; Tsuyama, K.; Takahashi, K.; Iida, H. CL 1983, 767.
4. Ogura, K.; Yahata, N.; Minoguchi, M.; Ohtsuki, K.; Takahashi, K.; Iida, H. JOC 1986, 51, 508.
5. Ogura, K.; Ohtsuki, K.; Takahashi, K.; Iida, H. CL 1986, 1597.
6. Krohn, K.; Kohle, H.-J. LA 1987, 1037.
7. Hirama, M.; Hioki, H.; Ito, S. TL 1988, 29, 3125.
8. Ogura, K.; Ohtsuki, K.; Nakamura, M.; Yahata, N.; Takahashi, K.; Iida, H. TL 1985, 26, 2455.
9. Tsuzuki, K.; Yan, F.-S.; Otoguro, K.; Ohmura, S. J. Antibiot. 1991, 44, 774.
10. Carpino, L. A.; Lin, Y. Z. JOC 1990, 55, 247.
11. Ogura, K.; Tsuruda, T.; Takahashi, K.; Iida, H. TL 1986, 27, 3665.
12. Ferdinand, G.; Schank, K. S 1976, 406.
13. Ogura, K.; Yahata, N.; Takahashi, K.; Iida, H. TL 1983, 24, 5761.
14. Ogura, K.; Uchida, T.; Tsuruda, T.; Takahashi, K. TL 1987, 28, 5703.
15. Ogura, K.; Iihama, T.; Kiuchi, S.; Kajiki, T.; Koshikawa, O.; Takahashi, K.; Iida, H. JOC 1986, 51, 700.
16. Ogura, K.; Yahata, N.; Fujimori, T.; Fujita, M. TL 1990, 31, 4621.
17. Yahata, N.; Fujita, M.; Ogura, K. BCJ 1990, 63, 3601.
18. (a) Simpkins, N. S. TL 1988, 29, 6787. (b) Simpkins, N. S. T 1991, 47, 323.
19. Torisawa, Y.; Satoh, A.; Ikegami, S. TL 1988, 29, 1729.
20. Ogura, K.; Yanagisawa, A.; Fujino, T.; Takahashi, K. TL 1988, 29, 5387.
21. Ogura, K.; Sumitani, N.; Kayano, A.; Iguchi, H.; Fujita, M. CL 1992, 1487.
22. Hewkin, C. T.; Jackson, R. F. W.; Clegg, W. JCS(P1) 1991, 3091.
23. Ogura, K.; Suzuki, M.; Tsuchihashi, G. BCJ 1980, 53, 1414.
24. Ogura, K.; Watanabe, J.; Iida, H. TL 1981, 22, 4499.
25. Ogura, K.; Suzuki, M.; Watanabe, J.; Yamashita, M.; Iida, H.; Tsuchihashi, G. CL 1982, 813.
26. Ogura, K.; Watanabe, J.; Takahashi, K.; Iida, H. JOC 1982, 47, 5404.

Katsuyuki Ogura

Chiba University, Japan

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