Diethyl Methylsulfonylmethylphosphonate

[40137-11-9]  · C6H15O5PS  · Diethyl Methylsulfonylmethylphosphonate  · (MW 230.22)

(used for the preparation of synthetically versatile vinyl sulfones from aldehydes and ketones)

Physical Data: mp 96 °C.1

Solubility: sol acetone, CH2Cl2, DME, THF.

Preparative Methods: conveniently prepared by oxidation of Diethyl Methylthiomethylphosphonate (eq 1). Both inorganic oxidants (e.g. Potassium Permanganate in water1,2 or Hydrogen Peroxide/Selenium(IV) Oxide4) and organic oxidants (e.g. Peracetic Acid in ether3 or m-Chloroperbenzoic Acid in CH2Cl25) have been used to accomplish this transformation.

Handling, Storage, and Precautions: diethyl methylsulfonylmethylphosphonate is reasonably stable for storage. Reactions involving this reagent are best conducted under anhydrous conditions, under nitrogen, in a well ventilated fume hood.

Reactions.

Diethyl methylsulfonylmethylphosphonate has been extensively used for the preparation of synthetically useful vinyl sulfones from aldehydes and ketones via the Horner-Emmons reaction. This generally involves treatment of the phosphonate with a base (a wide variety of bases and solvents have been employed) followed by quenching with a carbonyl compound, resulting in the (often) stereoselective formation of vinyl sulfones.

Sodium Hydride, Sodium Methoxide, or n-Butyllithium are commonly used to generate the phosphonate anion, which can be reacted with aryl and aliphatic aldehydes to give alkylidine sulfones (eq 2).1-3 Enals,6 ketones,7 and heterocyclic aldehydes8 also participate in this reaction, giving the corresponding vinyl sulfones.

Even the sterically hindered C-17b steroidal aldehyde reacts readily with the phosphonate anion to furnish the vinyl sulfone in excellent yield (eq 3).8

Mikolajczyk et al. have shown that the reaction can be carried out under phase transfer conditions, catalyzed by quaternary ammonium salts.9 This reaction was found to be specific for aromatic aldehydes, and fails for enolizable aldehydes and ketones. Among the several quaternary ammonium salts investigated, Benzyltriethylammonium Chloride (TEBA) gave the best yields and was also totally stereoselective in that only (E)-sulfones were produced (eq 4).

Reaction of diethyl methylsulfonylmethylphosphonate anion with enolizable ketones is often problematic and leads to unsatisfactory yields of vinyl sulfones. Fillion and co-workers have shown that the yields are improved when the reaction is conducted under sonication conditions (eq 5).10

Certain ketones readily undergo the reaction, including the sensitive b-lactam dione shown in eq 6.11

The direct synthesis of allenyl sulfones was simply accomplished by the reaction of the sulfonylphosphonate anion with ketenes (eq 7).12 The yields of this reaction are also improved under sonication conditions.13

Minami et al. have shown that diethyl methylsulfonylmethylphosphonate readily undergoes the Knoevenagel reaction, resulting in the formation of 1,1-phosphonosulfonoalkenes.14 A typical example is the condensation of the phosphonate with cinnamaldehyde in the presence of piperidine. The initially formed aldol eliminates water when treated with catalytic p-Toluenesulfonic Acid, furnishing the (E,E)-isomer of 1,3-butadienylsulfonylphosphonate in excellent yield (eq 8).

A similar sequence with formaldehyde constitutes an efficient synthesis of the simplest member of the family (eq 9).15


1. Posner, G. H.; Brunelle, D. J. JOC 1972, 37, 3547.
2. (a). Shahak, I.; Almog, J. S 1969, 170. (b). Shahak, I.; Almog, J. S 1970, 145.
3. Wegener, W.; Courault, K. ZC 1980, 20, 337.
4. Drabowicz, J.; Lyzwa, P.; Mikolajczyk, M. PS 1983, 17, 169.
5. Eberlein, W.; Heider, J.; Machleidt, H. CB 1974, 107, 1275.
6. De Jong B. E.; De Koning, H.; Huisman, H. O. RTC 1981, 100, 410 (CA 1982, 96, 79 616).
7. Durand, A.; Boitard, M.; Carraz, G.; L-Duc, C. Eur. J. Med. Chem. 1980, 15, 67 (CA 1980, 93, 149 847).
8. Fillion, H.; Pera, M.-H.; Rappa, J-L.; L-Duc, C. JHC 1978, 15, 753 (CA 1978, 89, 179 816).
9. Mikolajczyk, M.; Grzejszczak, S.; Midura, W.; Zatorski, A. S 1975, 278.
10. El Fakih, H.; Pautet, F.; Fillion, H. TL 1992, 33, 4909.
11. Häbich, D.; Metzger, K. H 1986, 24, 289.
12. Fillion, H.; Hseine, A.; Pera, M.-H.; Dufaud, V.; Refouvelet, B. S 1987, 708.
13. Fillion, H.; Refouvelet, B.; Péra, M. H.; Dufaud, V.; Luche, J. L. SC 1989, 19, 3343.
14. (a). Minami, T.; Yamanouchi, T.; Tokumasu, S.; Hirao, I. BCJ 1984, 57, 2127. (b) Minami, T.; Yamanouchi, T.; Takenaka, S.; Hirao, I. TL 1983, 24, 767.
15. Mikolajczyk, M.; Grzejszczak, S.; Korbacz, K. TL 1981, 22, 3097.

K. Shankaran & Sherman T. Waddell

Merck Research Laboratories, Rahway, NJ, USA



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