1,3-Propanedithiol1

[109-80-8]  · C3H8S2  · 1,3-Propanedithiol  · (MW 108.25)

(1,3-dithiane formation; reduction (carbonyl to methylene, azide to primary amine, peptidic disulfide to dithiol, demercuration); ketene dithioacetal formation)

Physical Data: d20 1.077 g cm-3; bp 170 °C/760 mmHg, 92-98 °C/56 mmHg.

Solubility: slightly sol water; miscible with many organic solvents.

Form Supplied in: liquid; widely available.

Handling, Storage, and Precautions: stench! Use in a fume hood. Can undergo air oxidation to form disulfides. The cyclic disulfide forms a polymeric precipitate in methanol.17a Extraction into aqueous NaOH serves to separate thiols from nonacidic impurities.1f For toxicity data, see 1,2-Ethanedithiol.

1,3-Dithiane Formation.

1,3-Propanedithiol (1) condenses under protic or Lewis acid catalysis with aldehydes and ketones to afford 1,3-dithianes (eqs 1-4).2-5 Useful for carbonyl protection, the 1,3-dithianyl group is compatible with aqueous acid, strong bases, anionic (eq 3)4 and Pd-catalyzed (eq 5)6a C-C bond-forming reactions, catalytic hydrogenation in the presence of the Crabtree catalyst,6b and many other synthetic processes.7 Often, (1) shows useful selectivity in reactions with dicarbonyl compounds (eq 3; structures 2-5).4,8 In contrast to acetalization with diols,9a (1) reacts selectively with a,b-alkenyl ketones in the presence of moderately hindered saturated ketones;1c double bond migration is not observed;1a conjugate addition can compete if sterically favored.9b In a,b-alkynyl ketones (not aldehydes),10a conjugate addition prevails (eq 6).10b

Acetals, enol ethers, and oxazolidines also give dithianes with (1) (eqs 7-12).11a-f,12 This reaction can be useful for opening resistant cyclic structures;13a,c Titanium(IV) Chloride is an especially effective catalyst in such cases.13b Reaction of (1) with dihalomethanes,14a,b or with carboxylic acids in the presence of Tin(II) Chloride,14c also yields 1,3-dithianes.

1,3-Dithianes derived from aldehydes are important synthetic intermediates because they undergo deprotonation to 2-lithio-1,3-dithianes which function as carbonyl anion equivalents (umpolung reagents).1b-e The vinylogous process (eq 4)5 is a subject of current study.15

Regeneration of the carbonyl group can entail a trial-and-error process with the many procedures available.1a-e HgII salts and N-halo amides remain the most frequently employed reagents. Aqueous Iodomethane is a mild alternative.8c Epimerization at an a stereocenter does not normally attend the formation or removal of the dithianyl group (eqs 8, 9, 12, 13).

Reduction.

Raney Nickel treatment of thioacetals is a standard method for carbonyl-to-methylene reduction.1b In the presence of Triethylamine, (1) reduces azides to primary amines (eq 14).16a,b Under the acidic conditions employed for thioacetal formation, this reduction does not occur (eq 8).11b,16c Reduction of peptidic disulfides to dithiols can be conveniently accomplished with (1).17 Treatment with (1) effected demercuration a to an ester diastereoselectively (eq 15).18

Ketene Dithioacetal Formation.

These versatile intermediates1c arise from 1,3-dithiane anions by elimination (eq 8)11b,19 or vinylogous alkylation (eq 4),5 and by condensation of carboxylic acid derivatives with (1) (eq 13).20a Ketene dithioacetals derived from lactones can cyclize to give dithio orthoesters, which can be selectively deprotected (eq 16).20b

Related Reagents.

1,2-Ethanedithiol.


1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991, p 201. (b) Gröbel, B.-T.; Seebach, D. S 1977, 357. (c) Page, P. C. B.; van Niel, M. B.; Prodger, J. C. T 1989, 45, 7643. (d) Kolb, M. S 1990, 171. (e) Ogura, K. COS 1991, 1, Chapter 2.3; Krief, A. COS 1991, 3, Chapter 1.3. (f) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of Laboratory Chemicals, 2nd ed.; Pergamon: Oxford, 1980.
2. Ohmori, K.; Suzuki, T.; Miyazawa, K.; Nishiyama, S.; Yamamura, S. TL 1993, 34, 4981.
3. Jacobi, P. A.; Brownstein, A.; Martinelli, M.; Grozinger, K. JACS 1981, 103, 239.
4. (a) Stahl, I.; Manske, R.; Gosselck, J. CB 1980, 113, 800. (b) Stahl, I.; Gosselck, J. S 1980, 561.
5. Fang, J.-M.; Liao, L.-F.; Hong, B.-C. JOC 1986, 51, 2828.
6. (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Griesser, H.; Lieberknecht, A. S 1992, 1025. (b) Schreiber, S. L.; Sommer, T. J. TL 1983, 24, 4781.
7. (a) Chakraborty, T. K.; Reddy, G. V. JOC 1992, 57, 5462. (b) Jones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond, R.; Volante, R. P.; Shinkai, I. JACS 1989, 111, 1157. (c) Chen, S. H.; Horvath, R. F.; Joglar, J.; Fisher, M. J.; Danishefsky, S. J. JOC 1991, 56, 5834. (d) Rosen, T.; Taschner, M. J.; Thomas, J. A.; Heathcock, C. H. JOC 1985, 50, 1190. (e) Golec, J. M. C.; Hedgecock, C. J. R.; Kennewell, P. D. TL 1992, 33, 547.
8. (a) Xu, X.-X.; Zhu, J.; Huang, D.-Z.; Zhou, W.-S. T 1986, 42, 819. (b) Tani, H.; Masumoto, K.; Inamasu, T.; Suzuki, H. TL 1991, 32, 2039. (c) Myers, A. G.; Condroski, K. R. JACS 1995, 117, 3057. (d) Corey, E. J.; Tius, M. A.; Das, J. JACS 1980, 102, 1742.
9. (a) Reference 1 (a), p. 188. (b) Hoppmann, A.; Weyerstahl, P.; Zummack, W. LA 1977, 1547.
10. (a) Johnson, W. S.; Frei, B.; Gopalan, A. S. JOC 1981, 46, 1512. (b) Ranu, B. C.; Bhar, S.; Chakraborti, R. JOC 1992, 57, 7349.
11. (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. JACS 1977, 99, 2818. (b) Moss, W. O.; Bradbury, R. H.; Hales, N. J.; Gallagher, T. JCS(P1) 1992, 1901. (c) Myles, D. C.; Danishefsky, S. J.; Schulte, G. JOC 1990, 55, 1636. (d) Nakata, T.; Nagao, S.; Oishi, T. TL 1985, 26, 75. (e) Corey, E. J.; Kang, M.-c.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. JACS 1988, 110, 649. (f) Hoppe, I.; Hoppe, D.; Herbst-Irmer, R.; Egert, E. TL 1990, 31, 6859.
12. (a) Sato, T.; Otera, J.; Nozaki, H. JOC 1993, 58, 4971. (b) Sánchez, I. H.; López, F. J.; Soria, J. J.; Larraza, M. I.; Flores, H. J. JACS 1983, 105, 7640. (c) Burford, C.; Cooke, F.; Roy, G.; Magnus, P. T 1983, 39, 867.
13. (a) Alonso, R. A.; Vite, G. D.; McDevitt, R. E.; Fraser-Reid, B. JOC 1992, 57, 573. (b) Page, P. C. B.; Roberts, R. A.; Paquette, L. A. TL 1983, 24, 3555. (c) Corey, E. J.; Reichard, G. A. TL 1993, 34, 6973.
14. (a) Page, P. C. B.; Klair, S. S.; Brown, M. P.; Smith, C. S.; Maginn, S. J.; Mulley, S. T 1992, 48, 5933. (b) Lissel, M. LA 1982, 1589. (c) Kim, S.; Kim, S. S.; Lim, S. T.; Shim, S. C. JOC 1987, 52, 2114.
15. (a) Moss, W. O.; Jones, A. C.; Wisedale, R.; Mahon, M. F.; Molloy, K. C.; Bradbury, R. H.; Hales, N. J.; Gallagher, T. JCS(P1) 1992, 2615. (b) Köksal, Y.; Raddatz, P.; Winterfeldt, E. LA 1984, 450.
16. (a) Goldstein, S. W.; McDermott, R. E.; Makowski, M. R.; Eller, C. TL 1991, 32, 5493. (b) Lim, M.-I.; Marquez, V. E. TL 1983, 24, 5559. (c) Durette, P. L. Carbohydr. Res. 1982, 100, C27.
17. (a) Ranganathan, S.; Jayaraman, N. CC 1991, 934. (b) Lees, W. J.; Whitesides, G. M. JOC 1993, 58, 642.
18. Gouzoules, F. H.; Whitney, R. A. JOC 1986, 51, 2024.
19. (a) Muzard, M.; Portella, C. JOC 1993, 58, 29. (b) Barton, D. H. R.; Gateau-Olesker, A.; Anaya-Mateos, J.; Cleophax, J.; Gero, S. D.; Chiaroni, A.; Riche, C. JCS(P1) 1990, 3211.
20. (a) Corey, E. J.; Pan, B.-C.; Hua, D. H.; Deardorff, D. R. JACS 1982, 104, 6816. (b) Dziadulewicz, E.; Giles, M.; Moss, W. O.; Gallagher, T.; Harman, M.; Hursthouse, M. B. JCS(P1) 1989, 1793.

Raymond E. Conrow

Alcon Laboratories, Fort Worth, TX, USA



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