Methyl Phenyl Sulfone

[3112-85-4]  · C7H8O2S  · Methyl Phenyl Sulfone  · (MW 156.22)

(generally used as the lithiated form, which reacts with a variety of electrophiles1)

Physical Data: mp 86-88 °C.

Solubility: sol ethanol, benzene.

Form Supplied in: white solid; widely available. [13C]Methyl phenyl sulfone is also available.

Preparative Methods: by the reaction of Sodium Benzenesulfinate with Dimethyl Sulfate; by oxidation of methyl phenyl sulfide with 30% Hydrogen Peroxide in acetic acid; or by the reaction of polymer-supported benzenesulfinate anion with Iodomethane in refluxing benzene.2

Purification: recrystallized from carbon tetrachloride and 1:3 ethanol-water. On a small scale, water is convenient for recrystallization.3

General Discussion.

The lithium salt of methyl phenyl sulfone reacts with electrophiles by alkylation to give homologs which possess acidic methylene protons for further synthetic transformations. Alkylation of [(phenylsulfonyl)methyl]lithium (PhSO2CH2Li) with primary iodides proceeds smoothly in THF in the presence of HMPA to furnish homologs (eq 1).4 The factors that control mono- vs. dialkylation of methyl phenyl sulfone have been studied. Alkylation of methyl phenyl sulfone using a lithium base can lead to significant polyalkylation. Use of a potassium base such as Potassium Hydride enhances formation of monosubstituted product, presumably by decreasing ion pairing.5

Double coupling reactions of sulfonylmethyl anions with epoxides and then with aldehydes have been developed for the synthesis of homoallyl alcohols (eq 2).6 The difficulties experienced in the coupling reaction with hindered epoxides may often be overcome by the use of solvent additives (especially Hexamethylphosphoric Triamide) and/or Lewis acids such as Boron Trifluoride Etherate. Indeed, reaction of [(phenylsulfonyl)methyl]lithium (2 equiv PhSO2CH2Li; HMPA/THF/-78 °C) with the hindered epoxide shown proceeds smoothly in the presence of BF3.OEt2 (2 equiv) (eq 3).7

Treatment of methyl phenyl sulfone with 2 equiv of n-Butyllithium in THF at 0 °C produces [(phenylsulfonyl)methylene]dilithium (PhSO2CHLi2), which has been used as a powerful nucleophile. Geminal dialkylation of this a,a-dianion with 2 equiv of epoxides has been applied to a synthesis of trans-2,6-disubstituted piperidines (eq 4).8

Alkylation followed by intramolecular alkylation with PhSO2CHLi2 serves as a method for the construction of carbocyclic frameworks. PhSO2CHLi2 reacts with dihalo alkanes (eq 5), as well as with halo epoxides to furnish cyclic products. In the case of halo epoxides, initial attack occurs on the epoxide terminus to give the larger of the two possible cyclic products (eqs 6 and 7).9

In acylation reactions, the use of excess base or sulfonyl carbanions is necessary, because the acidic b-keto sulfone product consumes up to half of the starting sulfonyl carbanion by proton transfer. This problem is often overcome by employing PhSO2CHLi2, which provides directly the anion of the b-keto sulfone product. Condensation of either acid chlorides10 or esters with PhSO2CHLi2 gives keto sulfones (eq 8).11

The reaction of PhSO2CHLi2 with ethyl 4-bromobutyrate gives the enolate of the b-keto sulfone, which is further converted to vinyl ethers as a mixture of (E)- and (Z)-isomers (34:44) through intramolecular O-alkylation. The cyclopropyl ketone is also observed as a minor product, which presumably arises by equilibration of the enolates (eq 9).12

The counter cations of phenylsulfonylmethide influence the outcome of stereochemistry when added to the chiral aldehyde pentodialdo-1,4-furanose. When the counter cation is magnesium, the anti-product is highly favored over the syn-product. When PhSO2CH2Li is treated with Zinc Chloride and HMPA, the selectivity reverses to mainly the syn-product (eq 10).13

The homologation of a-diketones using PhSO2CHLi2 is considered to involve attack on both electrophilic sites followed by ring opening of the cyclopropanediolate involving the expulsion of sulfinate anion. Electron transfer competes in this reaction, judging from the fact that benzoin is isolated in as much as 30% yield (eq 11). In the case of 2-chlorocyclohexanone, the ring-expansion product results (eq 12).9

(E)-Vinyl sulfones are stereoselectively prepared in one pot through phosphorylation of PhSO2CHLi2 followed by Horner-Emmons reaction of the resulting phosphonate with aldehydes (eq 13).14

1. (a) Magnus, P. D. T 1977, 33, 2019. (b) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon: Oxford, 1993.
2. (a) Baldwin, W. A.; Robinson, R. JCS 1932, 1445. (b) Cram, D. J.; Scott, D. A.; Nielsen, W. D. JACS 1961, 83, 3696. (c) Manescalchi, F.; Orena, M.; Savoia, D. S 1979, 445.
3. Field, L.; Clark, R. D. JOC 1957, 22, 1129.
4. Barrett, A. G. M.; Raynham, T. M. TL 1987, 28, 5615.
5. Pine, S. H.; Shen, G.; Bautista, J.; Sutton, C., Jr.; Yamada, W.; Apodaca, L. JOC 1990, 55, 2234.
6. Craig, D.; Smith, A. M. TL 1990, 31, 2631.
7. Nakata, T.; Saito, K.; Oishi, T. TL 1986, 27, 6345.
8. Najdi, S.; Kurth, M. J. TL 1990, 31, 3279.
9. Eisch, J. J.; Dua, S. K.; Behrooz, M. JOC 1985, 50, 3674.
10. Thomsen, M. W.; Handwerker, B. M.; Katz, S. A.; Belser, R. B. JOC 1988, 53, 906.
11. White, J. D.; Avery, M. A.; Choudhry, S. C.; Dhingra, O. P.; Kang, M.; Whittle, A. J. JACS 1983, 105, 6517.
12. (a) Mussatto, M. C.; Savoia, D.; Trombini, C.; Umani-Ronchi, A. JOC 1980, 45, 4002. (b) Mussatto, M. C.; Savoia, D.; Trombini, C.; Umani-Ronchi, A. JCS(P1) 1980, 260.
13. Kim, K. S.; Ahn, Y. H.; Park, S. B.; Cho, I. H.; Joo, Y. H.; Youn, B. H. J. Carbohydr. Chem. 1991, 10, 911.
14. Lee, J. W.; Oh, D. Y. SC 1989, 19, 2209.

Yoshiyasu Ichikawa & Minoru Isobe

Nagoya University, Japan

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