Diethyl Methylthiomethylphosphonate

[28460-01-7]  · C6H15O3PS  · Diethyl Methylthiomethylphosphonate  · (MW 198.22)

(used for the conversion of aldehydes and ketones to vinyl sulfides, which can be hydrolyzed to yield homologated aldehydes and ketones)

Physical Data: bp 70-72 °C/0.2 mmHg,1 d 1.465 g cm-3.2

Solubility: sol acetone, CH2Cl2, THF.

Form Supplied in: neat liquid.

Preparative Methods: although the reagent has recently become commercially available, a number of methods are available for its preparation.

The Arbuzov reaction between methylthiomethyl chloride and Triethyl Phosphite (no solvent, 110 °C for 6 h) gives good yields of diethyl methylthiomethylphosphonate (eq 1).1,3

Another convenient preparation involves a nucleophilic displacement reaction between dialkyl chloromethylphosphonates and alkanethiolates (eq 2).4

Metalated diethyl methylphosphonate reacts with elemental Sulfur to give isolable a-phosphorylthiols in high yields.2 Alkylation with Iodomethane under phase transfer conditions gives the desired reagent (eq 3).

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

Reactions.

The chief utility of diethyl methylthiomethylphosphonate lies in the synthesis of vinyl sulfides from carbonyl compounds such as aldehydes or ketones via the Horner-Emmons reaction. These vinyl sulfides are stable, easily handled intermediates which upon hydrolysis furnish homologated aldehydes or ketones. Green initially showed that such a procedure was viable for the synthesis of homologous aldehydes.1 Corey's more practical adaptation extended Green's original procedure to the synthesis of homologous ketones.5 Thus diethyl methylthiomethylphosphonate can be metalated and alkylated with MeI to give diethyl (1-methylthio)ethylphosphonate, which can itself be metalated at -70 °C in THF with n-Butyllithium to give a lithio derivative which reacts with aldehydes or ketones. The initially formed adduct eliminates phosphonate to give vinyl sulfides (eq 4). It should be noted that the reaction often fails with readily enolizable ketones. The vinyl sulfides thus produced are easily hydrolyzed using Mercury(II) Chloride in aqueous acetonitrile to give good yields of homologated aldehydes and ketones.

The reaction can be conducted so that water is lost instead of phosphonate, leading to the synthesis of phosphonovinyl sulfides.6 Thus treatment of lithiated diethyl methylthiomethylphosphonate with benzaldehyde furnishes an adduct which can be isolated. Conversion of the hydroxy moiety to chloride followed by b-elimination gives phosphonovinyl sulfides. Phosphonovinyl sulfides can be oxidized to phosphonovinyl sulfoxides or sulfones, which are powerful Michael acceptors (eq 5).

Lithiated diethyl methylthiomethylphosphonate can also react with Carbon Dioxide, which upon acidification provides diethyl a-(methylthio)phosphonoacetic acid.7 This bifunctional reagent can undergo inter- or intramolecular Horner-Emmons reactions, furnishing a-methylthio-a,b-unsaturated carboxylic acids or g- and d-lactones (eq 6).

The reaction of lithiated diethyl methylthiomethylphosphonate with ketones has achieved only limited success. For example, reaction with a b-lactam dione stops at the stage of addition (eq 7) and, unlike lithiated Diethyl Methylsulfonylmethylphosphonate, does not eliminate to give the corresponding vinyl sulfide.8

Mikolajczyk et al. examined the reaction between lithiated diethyl methylthiomethylphosphonate and an a,b-unsaturated ketone and found that the initially formed 1,2-addition product does not eliminate phosphonate, but rearranges to the more stable 1,4-addition product (eq 8).9 The detailed mechanism of this rerrangement has not been investigated.

Lithiated diethyl methylthiomethylphosphonate can react with a wide variety of electrophiles to furnish a variety of a-substituted derivatives which are otherwise difficult to obtain. For example, reaction of lithiated diethyl methylthiomethylphosphonate with dialkyl disulfides to give S,S-acetals proceeds in good yields (eq 9).10 Similarly, reaction with Chlorotrimethylsilane gives diethyl methylthio(trimethylsilyl)methylphosphonate, which after metalation undergoes a highly stereoselective Peterson alkenation with aldehydes to give (E)-vinylphosphonates in good yields (eq 9).11 Zwanenberg and co-workers demonstrated that the isolation of the moisture sensitive diethyl methylthio(trimethylsilyl)methylphosphonate was not necessary in certain cases, and in one pot lithiated and treated with Sulfur Dioxide to produce very reactive sulfines (eq 10).12

The sulfur atom in diethyl methylthiomethylphosphonate can be easily oxidized to either the sulfoxide or the sulfone, depending upon the choice of oxidant.13 Other more unconventional oxidations of diethyl methylthiomethylphosphonate include facile anodic oxidation in NaOMe/MeOH (saturated with CO2) to give the O,S-acetal of diethoxyphosphinylformaldehyde (eq 11).14

a-Chlorination of diethyl methylthiomethylphosphonate has been accomplished by lithiation followed by reaction with N-Chlorosuccinimide (NCS) as shown in eq 12.15 The diethyl chloro(methylthio)methylphosphonate so obtained undergoes a facile Friedel-Crafts reaction with aromatic compounds, giving diethyl 1-arylmethylthiomethylphosphonates in excellent yields.

Kondo et al. have prepared sulfur ylides from diethyl methylthiomethylphosphonate by reaction with MeI/AgClO4 to give a sulfonium salt, which when treated with Sodium Hydride gave an ylide (eq 13).16 The ylide reacts with benzaldehyde to give vinylidene sulfonium salts.


1. Green, M. JCS 1963, 1324.
2. Mikolajczyk, M.; Grzejszczak, S.; Chefczynska, A.; Zatorski, A. JOC 1979, 44, 2967.
3. Mikolajczyk, M.; Zatorski, A. S 1973, 669.
4. Arbuzov, B. A.; Bogonostseva, N. P. ZOK 1957, 27, 2419. (Engl. transl.)
5. Corey, E. J.; Shulman, J. I. JOC 1970, 35, 777 and for the preparation of aryl di- and trisubstituted vinyl sulfides, see, Madesclaire, M.; Roche, D.; Fauve, A.; Veschambre, H. Sulfur Lett. 1990, 11, 67.
6. Venugopalan, B.; Hamlet, A. B.; Durst, T. TL 1981, 22, 191.
7. Mikolajczyk, M.; Midura, W. H. SL 1991, 245.
8. Häbich, D.; Metzger, K. H 1986, 24, 289.
9. Mikolajczyk, M.; Balczewski, P. T 1992, 40, 8697.
10. Mikolajczyk, M.; Balczewski, P.; Grzejszczak, S. S 1980, 127.
11. Mikolajczyk, M.; Balczewski, P. S 1989, 101.
12. Porskamp, P. A. T. W.; Lammerink, B. H. M.; Zwanenberg, B. JOC 1984, 49, 263.
13. Refer to the articles on Diethyl Methylsulfinylmethylphosphonate and Diethyl Methylsulfonylmethylphosphonate for the S-oxidation of diethyl methylthiomethylphosphonate.
14. Costisella, B.; Keitel, I. S 1987, 44.
15. (a). Kim, T. H.; Oh, D. Y. TL 1985, 26, 3479. (b). Kim, T. H.; Oh, D. Y. TL 1986, 27, 1165.
16. Kondo, K.; Liu, Y.; Tunemoto, D. JCS(P1) 1974, 1279.

K. Shankaran & Sherman T. Waddell

Merck Research Laboratories, Rahway, NJ, USA



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