Org. Synth. 1974, 54, 39
DOI: 10.15227/orgsyn.054.0039
Submitted by R. B. Woodward1, I. J. Pachter2, and M. L. Scheinbaum3.
Checked by G. S. Bates and S. Masamune.
1. Procedure
Caution! Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving benzene should be carried out in a well-ventilated hood, and glove protection is required.
A. 1-Pyrrolidinocyclohexene.4 A solution of 29.4 g. (0.300 mole) of cyclohexanone and 28.4 g. (0.394 mole) of pyrrolidine in 150 ml. of benzene is placed in a 500-ml., one-necked flask attached to a Dean-Stark trap. The solution is refluxed under a nitrogen atmosphere until the separation of water ceases (Note 1). The excess pyrrolidine and benzene are removed from the reaction mixture on a rotary evaporator. The resulting residue is stored under refrigeration and distilled just before use in the next step, yielding 44.6 g. (98%) of 1-pyrrolidinocyclohexene, b.p. 76–77° (0.5 mm.), 105–106° (13 mm.).
B. 2,2-(Trimethylenedithio)cyclohexanone. A solution of 3.02 g. (0.0200 mole) of freshly distilled 1-pyrrolidinocyclohexene, 8.32 g. (0.0200 mole) of trimethylene dithiotosylate4 (Note 2), and 5 ml. of triethylamine (Note 3) in 40 ml. of anhydrous acetonitrile (Note 4), is refluxed for 12 hours in a 100-ml., round-bottom flask under a nitrogen atmosphere. The solvent is removed with a rotary evaporator, and the residue is treated with 100 ml. of 0.1 N hydrochloric acid for 30 minutes at 50° (Note 5). The mixture is cooled to ambient temperature and extracted with three 50-ml. portions of diethyl ether. The combined ether extracts are washed with 10% aqueous potassium hydrogen carbonate solution (Note 6), until the aqueous layer remains basic to litmus, and with saturated sodium chloride solution. The ethereal solution is dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator. The resulting oily residue is diluted with 1 ml. of benzene then with 3 ml. of cyclohexane. The solution is poured into a chromatographic column (13 × 2.5 cm.), prepared with 50 g. of alumina (Note 7) and 3:1 cyclohexanebenzene. With this solvent system, the desired product moves with the solvent front; the first 250 ml. of eluent contains 95% of the total product. Elution with an additional 175 ml. of solvent removes the remainder. The combined fractions are evaporated, and the pale-yellow, oily residue crystallizes readily on standing. Recrystallization of this material from pentane gives 1.82 g. (45% yield) of white, crystalline 2,2-(trimethylenedithio)cyclohexanone, m.p. 52–55° (Note 8).
2. Notes
1. The time required for this operation generally is 3.5–5 hours.
2. Trimethylene dithiotosylate, m.p. 66–67°,4 as described in Org. Synth., Coll. Vol. 6, 1016 (1988) was employed.
3. Eastman white label triethylamine was distilled from sodium hydroxide.
4. Fisher Reagent acetonitrile was distilled from phosphorus pentoxide.
5. Treatment with the dilute acid effects aqueous extraction of pyrrolidine and hydrolysis of unreacted dithiotosylate and enamine starting materials.
6. Hydrogen carbonate washing ensures removal of the sulfonic and sulfinic acids.
7. The checkers used "Aluminum Oxide" purchased from J. T. Baker Chemical Company.
8. The 1H NMR spectrum of the product (CDCl3) exhibits multiplets in the region δ 1.65–2.45. The IR spectrum (CHCl3) shows peaks at 2980 (m), 2940 (s), 2870 (m), 1690 (s), 1445 (m), 1420 (m), 1120 (m), 1110 (m), and 910 (s) cm−1.
3. Discussion
The preparation of dithianes from enamines by reaction with trimethylene dithiotosylate has been applied with enamines derived from cholestan-3-one, acetoacetic ester, and phenylacetone.5 Reactions of trimethylene dithiotosylate with hydroxymethylene derivatives of ketones also give rise to dithianes; thus, the hydroxymethylene derivative of cholest-4-en-3-one can be converted to 2,2-(trimethylenedithio)cholest-4-en-3-one.6 1,3-Dithiolanes are obtained in a similar manner by reaction of ethylene dithiotosylate7 with the appropriately activated substrate.5,8
This preparation is referenced from:

References and Notes
  1. 1965 Nobel Laureate in Chemistry; deceased July 8, 1979; formerly at the Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138.
  2. Present address: Bristol Laboratories, Division of Bristol-Myers Company, Syracuse, New York 13201.
  3. Present address: Sterling-Winthrop Research Institute, Rensselaer, New York 12144.
  4. L. A. Cohen and B. Witkop, J. Am. Chem. Soc., 77, 6595 (1955); G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, and R. Terrell, J. Am. Chem. Soc., 85, 207 (1963).
  5. R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum, J. Org. Chem., 36, 1137 (1971).
  6. R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. J. Ives, and R. B. Kelley, J. Chem. Soc., 1131 (1957).
  7. R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum, Org. Synth., Coll. Vol. 6, 1016 (1988).
  8. R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum, Org. Synth., Coll. Vol. 6, 590 (1988).

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

acetoacetic ester

hydrochloric acid (7647-01-0)

Benzene (71-43-2)

diethyl ether (60-29-7)

acetonitrile (75-05-8)

sodium hydroxide (1310-73-2)

Cyclohexanone (108-94-1)

sodium chloride (7647-14-5)

sodium sulfate (7757-82-6)

nitrogen (7727-37-9)

cyclohexane (110-82-7)

Pentane (109-66-0)

phenylacetone (103-79-7)

cholestan-3-one (566-88-1)

aluminum oxide (1344-28-1)

pyrrolidine (123-75-1)

triethylamine (121-44-8)

potassium hydrogen carbonate (298-14-6)

ethylene dithiotosylate

trimethylene dithiotosylate (3866-79-3)

1,5-Dithiaspiro[5.5]undecan-7-one (51310-03-3)


1-Pyrrolidinocyclohexene (1125-99-1)


phosphorus pentoxide (1314-56-3)