[2689-68-1]  · C6H8O3S  · 4-Methoxycarbonylthiolan-3-one  · (MW 160.21)

(building block for polynuclear heterocyclic compounds;1,9 precursor of substituted thiophenes;10-12 synthetic equivalent of a-acrylate anion13,14)

Alternate Name: methyl 4-oxothiolane-3-carboxylate.

Physical Data: mp 37-38 °C;15-17 bp 128.5 °C/20 mmHg,15 116-117 °C/9 mmHg,18 109 °C/4 mmHg;15 IR (KBr16 or CCl417), 1H NMR,16,17 MS,17 and a study of the keto-enol equilibrium18 have been reported.

Preparative Methods: prepared by Dieckmann reaction of the Michael adduct of methyl thioglycolate and Methyl Acrylate. Careful choice of the reaction conditions (MeONa, toluene, 80-120 °C) and a suitable workup procedure are recommended in order to control the direction of the cyclization which, in principle, can produce both 3-oxo-2-carboxylate and 4-oxo-3-carboxylate isomers.15-17,19 A more sophisticated method to accomplish a direction-controlled Dieckmann cyclization leading to exclusive formation of the target compound as the ethyl ester [78647-31-1] requires the less common ethoxycarbonylethyl thioethoxycarbonylmethyl sulfide as the starting material.20

a-Acrylate Anion Equivalent.

Alkylation of 4-methoxycarbonylthiolan-3-one (1) with a variety of alkyl halides in the presence of Potassium Carbonate provides C-alkylated products in excellent yields. Their treatment with aqueous Sodium Hydroxide affords a-substituted acrylate esters through tandem Dieckmann-Michael retrograde reactions (eq 1).13 This strategy has been successfully applied to the formal synthesis of integerrinecic acid.14

Building Block for Polynuclear Heterocyclic Compounds.

Aniline can chemoselectively react with both the ester and ketone carbonyl groups of (1) affording an enamine or an amide, respectively, depending on the experimental conditions used (eq 2).21

One of the most common synthetic approaches to the construction of heterocyclic compounds involves the reaction of b-keto esters with bifunctional nucleophiles. Thus a variety of reactions of (1) with different bifunctional heteronucleophiles, including hydrazine,1 substituted aminotriazoles,2 2-aminopyridines,3 o-phenylenediamines,5-7 and o-aminothiophenol,8 lead to polynuclear condensed thieno compounds (e.g. 2-8) of potential medicinal interest featuring the pyrazolone, pyrimidinone, benzodiazepine, and benzothiazepine nuclei. Cannabinoid analogs can be prepared through cyclization of the condensation products of (1) with bifunctional oxygenated nucleophiles such as substituted resorcinols.9

Methyl (2R,3S)-2-Methyl-3-hydroxybutanoate.22

This useful chiral building block, which is not easy to obtain with high optical purity by reduction of the corresponding open chain b-keto ester, can be conveniently prepared by diastereo- and enantioselective Baker's Yeast reduction of (1), followed by Raney Nickel promoted desulfurization (eq 3).

Ring Expansion.

The C-alkylated products of (1) with diiodomethane23 and chloromethyl phenyl selenide24 undergo radical-promoted ring expansion on treatment with Tri-n-butylstannane to give the expanded g-keto ester in 64% yield (eq 4).

Related Reagents.

4-Cyanothiolan-3-one; Ethyl Acetoacetate; Ethyl Acrylate; Methyl 3-(Dimethylamino)propionate; Methyl 3-Hydroxypropionate.

1. Robba, M.; Boutamine, N. BSF(2) 1974, 1629.
2. Esses-Reiter, K.; Reiter, J. JHC 1987, 24, 1503.
3. Connor, D. T.; Sorenson, R. J.; Tinney, F. J.; Cetenko, W. A. Kerbleski, J. J. JHC 1982, 19, 1185.
4. Tomé, A. C.; O'Neill, P. M.; Storr, R. C.; Cavaleiro, J. A. S. SL 1993, 397.
5. Press, J. B.; Hofmann, C. M.; Eudy, N. H.; Fanshawe, W. J.; Day, I. P.; Greenblatt, E. N.; Safir, S. R. JMC 1979, 22, 725.
6. Chakrabarti, J. K.; Fairhurst, J.; Gutteridge, N. J. A.; Horsman, L.; Pullar, I. A.; Smith, C. W.; Steggles, D. J.; Tupper, D. E.; Wright, F. C. JMC 1980, 23, 884.
7. (a) Hromatka, O.; Binder, D.; Eichinger, K. M 1974, 105, 1164. (b) Hromatka, O.; Binder, D.; Eichinger, K. M 1975, 106, 375, 555.
8. Press, J. B.; Eudy, N. H.; Safir, S. R. JOC 1980, 45, 497.
9. Razdan, R. K.; Terris, B. Z.; Handrick, G. R.; Dalzell, H. C.; Pars, H. G.; Howes, J. F.; Plotnikoff, N.; Dodge, P.; Dren, A.; Kyncl, J.; Shoer, L.; Thompson, W. R. JMC 1976, 19, 549.
10. Press, J. B.; Hofmann, C. M.; Safir, S. R. JOC 1979, 44, 3292.
11. Banks, M. R.; Barker, J. M.; Huddleston, P. R. JCR(S) 1984, 27.
12. Struharik, M.; Hrnciar, P. CA 1987, 107, 58 771w.
13. Baraldi, P. G.; Barco, A.; Benetti, S.; Moroder, F.; Pollini, G. P.; Simoni, D.; Zanirato, V. CC 1982, 1265.
14. Baraldi, P. G.; Guarneri, M.; Pollini, G. P.; Simoni, D.; Barco, A.; Benetti, S. JCS(P1) 1984, 2501.
15. Woodward, R. B.; Eastman, R. H. JACS 1946, 68, 2229.
16. Rossy, P. A.; Hoffmann, W.; Müller, N. JOC 1980, 45, 617.
17. Liu, H.-J.; Ngooi, T. K. CJC 1982, 60, 437.
18. Duus, F. T 1981, 37, 2633.
19. Hromatka, O.; Binder, D.; Eichinger, K. M 1973, 104, 1348.
20. Yamada, Y.; Ishii, T.; Kimura, M.; Hosaka, K. TL 1981, 22, 1353.
21. Jaunin, R. HCA 1980, 63, 1542.
22. Hoffmann, R. W.; Helbig, W.; Ladner, W. TL 1982, 23, 3479.
23. Dowd, P.; Choi, S.-C. TL 1989, 30, 6129.
24. Dowd, P.; Choi, S.-C. T 1991, 47, 4847.

Achille Barco, Simonetta Benetti & Gian P. Pollini

Università di Ferrara, Italy

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