Formaldehyde Dimethyl Thioacetal Monoxide1

[33577-16-1]  · C3H8OS2  · Formaldehyde Dimethyl Thioacetal Monoxide  · (MW 124.25)

(versatile synthetic reagent used for the production of aldehydes, ketones, a-keto carboxylates, a-amino acid derivatives, and arylacetic acid derivatives)

Alternate Names: methyl (methylthio)methyl sulfoxide (MMSO); formaldehyde dimethyl dithioacetal S-oxide; methyl methylsulfinylmethyl sulfide; (methylsulfinyl)methylthiomethane; bis(methylthio)methane S-oxide.

Physical Data: bp 222-226 °C; d 1.22 g cm-3 (20 °C); viscosity 11.78 cP (20 °C); refractive index (20 °C) 1.5524; specific heat (20 °C) 336 cal g-1 °C-1; surface tension 37.04 dyn cm-1 (20 °C); dielectric constant (15 °C) 3.2; pKa (DMSO) 29.0.2

Solubility: sol acetic acid, alcohol, THF, CS2, CCl4, CHCl3, acetone, benzene, DMSO; slightly sol cyclohexane, hexane.

Form Supplied in: available as a colorless, clear liquid; commercially available.

Preparative Methods: substitution of chloromethyl methyl sulfoxide with sodium methanethiolate3 or oxidation of formaldehyde dimethyl dithioacetal with hydrogen peroxide.4

Purification: distillation under a reduced pressure at a temperature below 100 °C.

Analysis of Reagent Purity: GC.

Handling, Storage, and Precautions: reagent decomposes slightly when heated under acidic conditions. It is stable in alkaline and neutral media. It is desirable to keep the reagent in a tightly sealed container over 4 Å molecular sieves.

Aldehyde and Ketone Synthesis.

The abstraction of a proton from MMSO with Sodium Hydride, Lithium Diisopropylamide, or Potassium Hydride affords a carbanion that readily reacts with a variety of electrophiles. Monoalkylation5 employing alkyl halides or terminal epoxides,6 followed by hydrolysis, yields the corresponding homologated aldehyde (eq 1). Dialkylation of this anion provides a pathway to symmetrical ketones.7 The synthesis of cyclic ketones using this procedure has been effective in the production of both natural products (eq 2)8 and theoretically interesting molecules.9 It should be noted, however, that this method is not suitable for the synthesis of acyclic, unsymmetrical ketones as a protocol involving sequential alkylation with nonequivalent electrophiles failed.10

The addition of a Grignard reagent to MMSO, followed by hydrolysis of the intermediate dithioacetal, affords the corresponding aldehyde in moderate yield (eq 3).11 This procedure is significant when compared to aldehyde formation through the use of 1,3-Dithiane. Since 1,3-dithiane requires an electrophilic coupling partner, the production of aromatic aldehydes is prohibited.

The anion of MMSO also reacts at activated sp2 carbon centers. Michael addition proceeds efficiently when lithio MMSO is added to a,b-unsaturated carbonyl compounds.12 The sodium anion of MMSO adds to 2-bromopyridine, displacing the bromide substituent (eq 4).13 In both cases, hydrolysis of the coupled intermediate affords the corresponding aldehyde. Moreover, the lithium derivative of MMSO condenses efficiently with ketones to provide, after hydrolysis, the corresponding a-hydroxy aldehydes (eq 5).14 The mild nature of the addition/hydrolysis sequence lends itself to the production of sensitive compounds. For instance, the aldehyde generated in eq 5 is difficult to prepare using certain other methods due to its lability toward both acid and heat.

Synthesis of a-Keto Acid and a-Amino Acid Derivatives.

Nitriles react with MMSO in the presence of NaH to give enamino sulfoxides. These versatile intermediates can serve as precursors for both a-keto acids (eq 6)15,16 and a-amino acids (eq 7).15,17 Treatment of the enamino sulfoxide with Copper(II) Chloride in ethanol provides an a-keto ethyl ester. Acetylation of the intermediate enamino sulfoxide, followed by methanolysis and reductive desulfurization, affords protected a-amino esters.

Synthesis of Arylacetic Acid Derivatives.

When a mixture of MMSO and an aromatic aldehyde is heated in the presence of a base, a Knoevenagel-type condensation results (eq 8). Reaction of the condensation products with HCl in an alcohol affords arylacetic esters.18 In the case of electron-rich aromatic aldehydes, hydrolysis of the condensation product often generates the corresponding a-(methylthio)aryl acetate (eq 9). This undesired substrate can, however, be converted to the aryl acetate upon treatment with Raney Nickel.19 For acid-labile arylacetic acids, a two-step hydrolysis involving base can be employed.20

Friedel-Crafts Alkylation.

The a-thioalkylation of aromatic compounds can be carried out by subjecting the aromatic substrate to MMSO and a Lewis acid (eq 10).21 Similar attempts employing chloromethyl methyl sulfide as the electrophile result in poor yields of the desired alkylated aromatics (35% as compared to the 90% in eq 10). Aluminum Chloride is the Lewis acid of choice, providing greater reproducibility than other catalysts that were examined. This method can be extended to heteroaromatic substrates. For example, thiophene and N-methylpyrrole are alkylated in 55% and 50%, respectively, when subjected to thioalkylation.

Heterocycle Addition.

The exposure of quinoxaline to the dianion of MMSO results in the production of an appended third ring (eq 11).22 Dimethyl Sulfoxide, participating in a similar process, affords annulated substrate in a slightly lower yield (51%). This reaction course is in contrast to the addition of a typical organometallic, such as a Grignard reagent, to quinoxaline. For this case, the 2-alkylquinoxaline is usually generated.

Ethyl Analog of MMSO.

Formaldehyde diethyl dithioacetal monoxide can be used in analogous synthetic applications,10,23 although it is not commercially available.

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; Methylthiomethyl p-Tolyl Sulfone; 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.
2. Bordwell, F. G.; Drucker, G. E.; Andersen, N. H.; Deniston, A. D. JACS 1986, 108, 7310.
3. Ogura, K.; Tsuchihashi, G. CC 1970, 1689.
4. Ogura, K.; Tsuchihashi, G. BCJ 1972, 45, 2203.
5. Ogura, K.; Tsuchihashi, G. TL 1971, 3151.
6. Torii, S.; Uneyama, K.; Ishihara, M. JOC 1974, 39, 3645.
7. Schill, G.; Jones, P. R. S 1974, 117.
8. (a) Torisawa, Y.; Okabe, H.; Ikegami, S. CC 1984, 1602. (b) For other syntheses of cycloalkenones see: Ogura, K.; Yamashita, M.; Suzuki, M.; Furukawa, S.; Tsuchihashi, G. BCJ 1984, 57, 1637. Ogura, K.; Yamashita, M.; Tsuchihashi, G. TL 1976, 759. Ogura, K.; Yamashita, M.; Suzuki, M.; Tsuchihashi, G. TL 1974, 3653.
9. Dowd, P.; Schappert, R.; Garner, P.; Go, C. L. JOC 1985, 50, 44.
10. Richman, J. E.; Herrmann, J. L.; Schlessinger, R. H. TL 1973, 3267.
11. Hojo, M.; Masuda, R.; Saeki, T.; Fujimori, K.; Tsutsumi, S. TL 1977, 3883.
12. (a) Ogura, K.; Yamashita, M; Tshuchihashi, G. TL 1978, 1303. (b) Breukelman, S. P.; Meakins, G. D.; Roe, A. M. JCS(P1) 1985, 1627. (c) Tanaka. K.; Kanemasa, S.; Ninomiya, Y.; Tsuge, O. BCJ 1990, 63, 466.
13. Newkome, G. R.; Robinson, J. M.; Sauer, J. D. CC 1974, 410.
14. Ogura, K.; Tsuchihashi, G. TL 1972, 2681.
15. Ogura, K.; Tsuchihashi, G. JACS 1974, 96, 1960.
16. Ogura, K.; Katoh, N.; Yoshimura, I.; Tsuchihashi, G. TL 1978, 375.
17. Ogura, K.; Yoshimura, I.; Katoh, N.; Tsuchihashi, G. CL 1975, 803.
18. (a) Ogura, K.; Tsuchihashi, G. TL 1972, 1383. (b) Ogura, K.; Ito, Y.; Tsuchihashi, G. BCJ 1979, 52, 2013. (c) Artico, M.; Corelli, F.; Massa, S.; Stefancich, G. JHC 1982, 1493. (d) Katagiri, N.; Kato, T.; Nakano, J. CPB 1982, 30, 2440. (e) Schuda, P. F.; Price, W. A. JOC 1987, 52, 1972.
19. (a) Cannon, J. R.; Lolanapiwatna, V.; Raston, C. L.; Sinchai, W.; White, A. H. AJC 1980, 33, 1073. (b) Rizzacasa, M. A.; Sargent, M. V. JCS(P1) 1987, 2017.
20. (c) Ogura, K.; Ito, Y.; Tsuchihashi, G. S 1980, 736.
21. Torisawa, Y.; Atsushi, S.; Ikegami, S. TL 1988, 29, 1729.
22. Vierfond, J.-M.; Legendre, L.; Mahuteau, J.; Miocque, M. H 1989, 29, 141.
23. (a) Herrmann, J. L.; Richman, J. E.; Schlessinger, R. H. TL 1973, 3271. (b) Herrmann, J. L.; Richman, J. E.; Schlessinger, R. H. TL 1973, 3275.

Katsuyuki Ogura

Chiba University, Japan

Jeffrey A. McKinney

Zeneca Pharmaceuticals, Wilmington, DE, USA

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