Glyoxylic Acid Diethyl Dithioacetal

(1; R1 = Et, R2 = H)

[10490-06-9]  · C6H12O2S2  · Glyoxylic Acid Diethyl Dithioacetal  · (MW 180.32) (2; R1 = (CH2)2, R2 = H)

[5616-65-9]  · C4H6O2S2  · Glyoxylic Acid Ethylene Dithioacetal  · (MW 150.24) (3; R1 = (CH2)3, R2 = H)

[20461-89-6]  · C5H8O2S2  · Glyoxylic Acid Trimethylene Dithioacetal  · (MW 164.27) (4; R1 = Et, R2 = Me

[38564-39-5]  · C7H14O2S2  · Methyl Glyoxylate Diethyl Dithioacetal  · (MW 194.35) (5; R1 = Et, R2 = Et)

[20461-95-4]  · C8H16O2S2  · Ethyl Glyoxylate Diethyl Dithioacetal  · (MW 208.38) (6; R1 = (CH2)2, R2 = Et)

[20461-99-8]  · C6H10O2S2  · Ethyl Glyoxylate Ethylene Dithioacetal  · (MW 178.30) (7; R1 = (CH2)3, R2 = Me)

[56579-84-1]  · C6H10O2S2  · Methyl Glyoxylate Trimethylene Dithioacetal  · (MW 178.30) (8; R1 = (CH2)3, R2 = Et)

[20462-00-4]  · C7H12O2S2  · Ethyl Glyoxylate Trimethylene Dithioacetal  · (MW 192.33)

(a-keto equivalent; alkylation of the anions, aldol condensations, and both 1,2- and 1,4-additions to a,b-unsaturated compounds; thioketene and a-oxo dithioester precursor)

Alternate Name: (1) bis(ethylthio)acetic acid; (2) 1,3-dithiolane-2-carboxylic acid; (3) 1,3-dithiane-2-carboxylic acid.

Physical Data: (1) bp 110 °C/0.2 mmHg. (2) mp 90-91 °C. (3) mp 114.5-116 °C. (4) bp 125-127 °C/5 mmHg. (5) bp 70 °C/0.1 mmHg. (6) bp 105 °C/0.6 mmHg. (7) bp 102 °C/2 mmHg. (8) bp 75-77 °C/0.2 mmHg.

Preparative Methods: esters (5), (6), and (8) are available from commercial sources. The thioacetal acids may be prepared by thioacetalization of glyoxylic acid monohydrate3 or by reaction on the appropriate thiol(ate) with 2,2-dichloroacetic acid (or the diethyl acetal) directly4 or under phase transfer5 conditions using Aliquat 336. The esters may be obtained via similar exchange processes or via acid-catalyzed esterification of the corresponding acids.

General.

The most common usage of the above compounds is as a-keto acid equivalents via their corresponding anions (or dianions). There are differences in the reactivity and selectivity of these systems which depend on the nature of the thioacetal as well as the gegenion present in the reaction. Hydrolysis under a variety of conditions to the corresponding ketone1 or reductive desulfurization2 generally proceeds in excellent yields.

Alkylation.

The esters may be deprotonated with Sodium Hydride or comparably strong bases and the resulting anions subsequently alkylated with alkyl halides in good to excellent yields (eq 1).4,6a,b The reaction may also be carried out using phase transfer catalysis.5 Opening of epoxides,6c cyclic sulfonates,6d and displacement of triflates6e also proceeds in good yields. The thioacetal acids may be converted into the corresponding dianion with Potassium Hexamethyldisilazide. The dianions are readily alkylated in high yield by a wide variety of electrophiles (alkyl halides, tosylates, epoxides, N-tosylaziridines).3

1,4- and 1,2-Carbonyl Additions.

The anions of several of the esters undergo Michael addition with a wide variety of a,b-unsaturated compounds (aldehydes, ketones, esters, lactones, lactams, and nitroalkenes)7 in high yields. The role of the gegenion is important in the regioselectivity of this addition (eq 2).8 The reaction can also proceed under phase transfer9a,b (tetrabutylammonium hydrogensulfate) or crown ether (18-Crown-6) conditions.9c Trapping of the enolate resulting from conjugate addition to ketones with Formaldehyde provides a route to substituted lactones (eq 3).10

1,2,4-Benzenetriols may be prepared via a conjugate addition-cyclization-aromatization pathway (eq 4).11

Aldol Condensation.

Condensation of the anions of esters (6), (7), and (8) with aldehydes has been reported.8,12 The reaction can proceed with excellent diastereofacial selectivity (eq 5).12a

Miscellaneous.

Reactive intermediate species have been derived from several of the thioacetals. Reaction of aldehydes with the lithium anion of (7) in the presence of Trimethylacetyl Chloride with subsequent dealkoxycarbonylation forms ketene thioacetals (eq 6).12c In addition, reactions of the acid chlorides derived from (2) or (3) in the presence of base yield products consistent with the formation of a ketene intermediate (eq 7).13

Retrocyclizations of S-alkylated derivatives of (6) yield a-oxo dithioester intermediates which react with alkenes in a Diels-Alder reaction (eq 8),14 and cycloadditions with styrene derivatives and (1) yield 2-(ethylthio)butyrolactones.15

Ester (6) reacts with various dithiols in the presence of Trimethylaluminum to produce tetrathiafulvalenes in good yield (eq 9).16

A chiral variant of (8) (menthyl ester) has served as an auxiliary (eq 10) in the condensation of aryl alkyl ketones with n-Butyllithium to produce chiral tertiary alcohols (70%, 55% ee).17

Related Reagents.

1,2-Diethoxy-1,2-bis(trimethylsilyloxy)ethylene; 1,3-Dithiane; Ethyl 3,3-Diethoxypropanoate; Ethyl Diethoxyacetate; 2-Lithio-1,3-dithiane; Methyl Glyoxylate; 8-Phenylmenthyl Glyoxylate.


1. Gröbel, B.-T; Seebach, D. S 1977, 357.
2. Nickel boride is a convenient reagent for this purpose. Boar, R. B.; Hawkins, D. W., McGhie, J. F.; Barton, D. H. R. JCS(P1) 1973, 654.
3. Bates, G. S.; Ramaswamy, S. CJC 1980, 58, 716.
4. (a) Eliel, E. L.; Hartmann, A. A. JOC 1972, 37, 505. (b) Lerner, L. M. JOC 1976, 41, 2228.
5. (a) Lissel, M. SC 1981, 11, 343. (b) Lissel, M. LA 1982, 1589.
6. (a) Hoare, J. H.; Yates, P. JOC 1983, 48, 3333. (b) Williams, D. R.; Benbow, J. W.; Allen, E. E. TL 1990, 31, 6769. (c) Paidak, B.; Mikshiev, B.; Yu, M.; Levitan, G. E.; Kornilov, V. I.; Zhdanov, Yu. A. ZOB 1986, 56, 212 (CA 1986, 105, 227 192z). (d) van der Klein, P. A. M.; Filemon, W.; Boons, G. J. P. H.; Veeneman, G. H.; van der Marel, G. A.; van Boom J. H. T 1992, 48, 4649. (e) Imoto, M.; Kusumoto, S.; Shiba, T. TL 1987, 28, 6235.
7. (a) Cregge, R. J.; Herrmann, J. L.; Richman, J. E.; Romanet, R. F.; Schlessinger, R. H. TL 1973, 2595. (b) Herrmann, J. L.; Richman, J. E.; Schlessinger, R. H. TL 1973, 2599. (c) Farina, F.; Maestro, M. C.; Martin, M. R.; Martin, M. V.; Sánchez, F. JCR(S) 1984, 44; JCR(M) 0534. (d) Paulsen, H.; von Deyn, W. LA 1987, 133. (e) Paulsen, H.; Bünsch, H. CB 1978, 111, 3484. (f) Ottow, E.; Recker, H-G; Winterfeldt, E. T 1983, 39, 3669. (g) Seebach, D; Leitz, H. F.; Ehrig, V. CB 1975, 108, 1924.
8. Braun, M.; Esdar, M. CB 1981, 114, 2924.
9. (a) González, J.; Sánchez, F.; Torres, T. S 1983, 911. (b) Farina, F.; Maestro, M. C.; Martin, M. R.; Martín, M. V.; Sánchez, F.; Soria, M. L. T 1986, 42, 3715. (c) Takasu, M.; Wakabayashi, H.; Furuta, K.; Yamamoto, H. TL 1988, 29, 6943.
10. Kato, M.; Saito, H.; Yoshikoshi, A. CL 1984, 213.
11. Ozaki, Y.; Kim, S.-W CL 1987, 1199.
12. (a) Flippin, L. A.; Dombroski, M. A. TL 1985, 26, 2977. (b) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. JOC 1984, 49, 3427. (c) Belletire, J. L.; Walley, D. R.; Fremont, S. L. TL 1984, 25, 5729.
13. Abramski, W.; Belzecki, C.; Chmielewski, M. Bull Pol. Acad. Sci. Chem. 1985, 33, 451 (CA 1987, 106, 84 433m).
14. Vedejs, E.; Arnost, M. J.; Dolphin, J. M.; Eustache, J. JOC 1980, 45, 2601.
15. Plusquellec, D.; Le Floc'h, Y.; Papillon-Jegou, D. BSF(2) 1979, 552.
16. Mori, T.; Inokuchi, H. CL 1992, 1873.
17. Ranu, B. C.; Chakraborty, R.; Sarkar, D. C. SC 1991, 21, 1619.

Gordon S. Bates

University of British Columbia, Vancouver, BC, Canada



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.