N-(Methylthiomethyl)piperidine1

[7257-48-9]  · C7H15NS  · N-(Methylthiomethyl)piperidine  · (MW 145.30) (.HCl)

[7960-22-8]  · C7H16ClNS  · N-(Methylthiomethyl)piperidine Hydrochloride  · (MW 181.76)

(methylthiomethylating agent for 1,3-dicarbonyl compounds1 and b-keto phosphonates2)

Physical Data: bp 82 °C/12 mmHg;3 n23D 1.5065;2 .HCl mp 144-149 °C.1

Solubility: insol ether, hexane, benzene; sol CH2Cl2, CHCl3, ethanol, methanol; slightly sol hot THF, hot dioxane.

Preparative Methods: Methanethiol gas (generated by adding conc. Sulfuric Acid (50 mL) to 15% aqueous sodium methanethiolate (150 mL)) is introduced to a soln of Piperidine (16 g) and 37% aqueous Formaldehyde (20 g) at 0 °C. As the reaction progresses an oil separates. The organic layer is extracted with ether, dried, and concentrated. The residual oil (19.5 g) is distilled to give N-(methylthiomethyl)piperidine; yield: 16.6 g (61%). An ethereal soln of this amine is added to ether saturated with hydrogen chloride to afford N-(methylthiomethyl)piperidine hydrochloride; yield 20 g (58% from piperidine). For alternative preparations, see Mikolajczyk and Balaczewski2 and Böhme and Hafner.3

Handling, Storage, and Precautions: the hydrochloride is very hygroscopic and must be stored in the absence of moisture. The reagent is stable for a few years as long as it is kept in a tightly sealed vessel.

Methylthiomethylation.

Active methylene compounds are heated with the reagent hydrochloride in dioxane to give methylthiomethylated products. b-Diketones,1,4 b-keto esters,1 b-keto amides,1 and b-keto phosphonates2 are a-methylthiomethylated in good yields. The closely related reagent N-(phenylthiomethyl)piperidine hydrochloride5 may be used similarly to prepare a-phenylthiomethyl b-diketones (eqs 1 and 2).4

The a-methylthiomethyl b-diketones are useful intermediates for preparing unstable a-methylene b-diketones1,4 via oxidation to the sulfoxide and thermal elimination,6 as illustrated in eq 3.1 The elimination reactions are conducted in refluxing toluene containing catalytic amounts of Calcium Carbonate1,4a,4b or Acetic Acid.4c These procedures were instrumental in the synthesis of a-methylene derivatives of acetal-protected aryl 1,3,5-triketones as intermediates in biogentic-type cyclizations producing fulvic acid and the 4H,5H-pyrano[3,2-c][1]benzopyran-4-one nucleus of citromycetin.4a,4b


1. Yamauchi, M.; Katayama, S.; Watanabe, T. S 1982, 935.
2. Mikolajczyk, M.; Balaczewski, P. S 1984, 691.
3. Böhme, H.; Hafner, H. AP 1967, 300, 647.
4. (a) Watanabe, T.; Katayama, S.; Nakashita, Y.; Yamauchi, M. CC 1981, 761. (b) Yamauchi, M.; Katayama, S.; Nakashita, Y.; Watanabe, T. JCS(P1) 1984, 503. (c) Yamauchi, M.; Katayama, S.; Todoroki, T.; Watanabe, T. CC 1984, 1565; (d) Yamauchi, M.; Katayama, S.; Todoroki, T.; Watanabe, T. JCS(P1) 1987, 389.
5. Gillot, G. F.; Felton, H. R.; Garrett, B. R.; Greenberg, H.; Green, R.; Clemmenti, R.; Moskowitz, M. JACS 1954, 76, 3969.
6. (a) Trost, B. M.; Salzmann, JACS 1973, 95, 6840. (b) Reich, H. J.; Renga, J. M. CC 1974, 135. (c) Grieco, P. A.; Peap, J. J. TL 1974, 1097. (d) Paterson, I.; Fleming, I. TL 1979, 993, 995.

Masashige Yamauchi

Josai University, Saitama, Japan



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