Org. Synth. 1971, 51, 76
DOI: 10.15227/orgsyn.051.0076
Submitted by D. Seebach1 and A. K. Beck.
Checked by Jose F. Pazos and Richard E. Benson.
1. Procedure
A. 5,9-Dithiaspiro[3.5]nonane. A dry, 2-l., one-necked, round-bottomed flask containing a magnetic stirring bar (Note 1) is flushed with dry nitrogen (Note 2), and 1.25 l. of dry tetrahydrofuran (Note 3) and 50 g. (0.42 mole) of 1,3-dithiane (Note 4) are added. The flask is quickly equipped with a three-way stopcock bearing a standard tapered joint, a rubber septum, and a nitrogen inlet, as shown in Figure 1 (Note 5). The solution is stirred with an efficient magnetic stirrer and cooled to an external temperature of −20° with a methanol–dry ice bath. A 3% excess (total of 0.43 mole) of 1.5–2.5 M n-butyllithium in n-hexane (Note 6) is added through the rubber septum with a syringe. The bath temperature is kept between −10° and −20° for 2 hours before the temperature of the bath is reduced to −75° (Note 7) and 65.5 g. (44.5 ml., 0.417 mole) of 1-bromo-3-chloropropane (Note 8) is added with a syringe over 10 minutes. The temperature of the bath is raised to −30° over a 2-hour period by gradually replacing the cold methanol with warm methanol. The bath is removed and stirring is continued until the reaction flask is at room temperature (Note 9). The flask is again cooled to −75° (Note 7) and 0.44 mole of n-butyllithium in n-hexane (Note 6) is added with a syringe over 10 minutes. After the addition is complete, the temperature of the reaction flask is allowed to rise to room temperature overnight (Note 10). The solvent is removed from the product with a rotary evaporator at 50° and aspirator pressure. Water (300 ml.) and diethyl ether (500 ml.) are added to the product in the flask, the ether layer is separated, and the aqueous layer is washed again with 500 ml. of ether. The organic layers are combined, washed with 200 ml. of water, and dried over 10 g. of anhydrous potassium carbonate. The ether is removed by distillation to yield about 75 g. of crude product. Distillation through a packed column gives 44–57 g. (65–84%) of 5,9-dithiaspiro[3.5]nonane, b.p. 65–75° (1 mm.), n20D 1.5700. This product is of sufficient purity for use in Part B (Note 11).
Figure 1.
Figure 1.
B. Cyclobutanone. A 2-l., three-necked flask is fitted with an efficient mechanical stirrer and a water-cooled condenser assembled for downward distillation to which is attached a 250-ml. receiver with a side arm. Two cold traps are attached consecutively to the distillation apparatus as shown in Figure 2 (Note 12). The receiver is immersed in an ice-water bath, and the traps are immersed in dry ice and acetone. To the flask is added 45 g. (0.28 mole) of 5,9-dithiaspiro[3.5]nonane, 900 ml. of triethylene glycol, and 150 ml. of water. Stirring is begun, and 163 g. (0.600 mole) of mercury(II) chloride (Note 13) and 51.5 g. (0.300 mole) of cadmium carbonate (Note 13) are added. A nitrogen-inlet tube reaching to the bottom of the flask is inserted into the third neck of the flask, and nitrogen is introduced at approximately 50 ml. per minute. The reaction flask is heated to 90° in an oil bath, and the temperature is slowly increased to 110° over a 2–3 hour period. Water and cyclobutanone are carried into the receivers. The water in the receiving flask is saturated with sodium chloride, and the resulting solution is transferred to a separatory funnel. The flask is rinsed with 25 ml. of dichloromethane, and this solution is used for an initial washing of the aqueous solution. The aqueous solution is shaken three additional times with 25-ml. portions of 12chloromethane. The dichloromethane solutions are combined and added to the traps to dissolve cyclobutanone. The resulting solution is transferred to a 250-ml. flask, the traps are rinsed with a small amount of dichloromethane, and the rinse is combined with the original solution. The organic solution is dried over 5 g. of anhydrous sodium sulfate, filtered, and the solvent is removed by distillation through a 20-cm., helix-packed, vacuum-insulated column. The product is transferred to a 25-ml. flask, 5 ml. of mesitylene is added, and the product is distilled through a spinning-band column. The fraction boiling at 95–100° is collected, yielding 12–15.8 g. (60–81%) (Note 14) of cyclobutanone.
Figure 2.
Figure 2.
2. Notes
1. Efficient stirring is required throughout the reaction.
2. If available, argon is preferable to nitrogen because of its higher density.
3. The checkers used reagent grade tetrahydrofuran (available from Fisher Scientific Company) from a freshly opened bottle. The submitters used tetrahydrofuran purified by distillation from lithium aluminum hydride. See Org. Synth., Coll. Vol. 5, 976 (1973), for warning regarding purification of tetrahydrofuran.
4. 1,3-Dithiane was prepared as described in Org. Synth., Coll. Vol. 6, 556 (1988), and sublimed prior to use.
5. During the entire reaction sequence a positive pressure of approximately 50 mm. of nitrogen is maintained against the atmosphere with a mercury bubbler.
6. The titer of the solution should be determined prior to use. The checkers used product available from Foote Mineral Company.
7. Only a slight excess of dry ice should be added.
8. Available from Eastman Organic Chemicals. The product was distilled prior to use, b.p. 140–142°.
9. Approximately 2 hours is required.
10. The submitters have found that the ring closure reaction is essentially complete by the time the temperature reaches −20°.
11. GC analysis using a column containing 20% silicone DC 200 on Gas Chrom Z at 160° showed the product to be 96% pure.
12. The traps are attached in a reverse manner. The diameter of the inner tubing is 1.5 cm.
13. Anhydrous practical grade reagents were used.
14. The IR spectrum (neat) shows strong absorption at 1775 cm.−1. The purity of the product is greater than 95% as established by GC on a 4-ft. column containing 20% silicone DC 200 on Gas Chrom Z at 50°. The 1H NMR spectrum (CCI4) shows a pentet at δ 1.83 (J = 8 Hz.) and a triplet at 3.01 (J = 8 Hz.) in a ratio 1:2, respectively.
3. Discussion
The best large-scale preparation of cyclobutanone is the reaction of diazomethane with ketene.2 It requires a ketene generator and necessitates handling large quantities of the potentially hazardous diazo compound. A more frequently used method for the preparation of cyclobutanone starts with pentaerythritol, the final step being the oxidative degradation of methylenecyclobutane,4,3, which can also be prepared from other precursors.5 A general survey of all methods used to obtain cyclobutanone has been published.6,7
The procedure described here is an example of the use of the dithiane method8 for the preparation of ketones. The reactions appear to be general, and the yields are satisfactory. The dithiane method can be successfully applied to the synthesis of rings containing up to seven carbon atoms with a slight modification9,10 of the procedure above. The synthesis of larger rings may require high dilution methods.9
Aldehydes and open-chain ketones are also available from dithiane.9 Carbonyl compounds with high optical activity9 have been synthesized, including those that undergo facile racemization. An extensive review covering all applications of this reaction up to June 1969 has been authored by one of the submitters.9 Methods and limitations for the preparation of silyl ketones11 (R3SiCOR) and germanyl ketones (R3GeCOR) have been described.12

References and Notes
  1. Institut für Organische Chemie der Universität (TH) Karlsruhe, West Germany. [Present address: Laboratorium für Organische Chemie, ETH-Zentrum, CH-8092 Zurich, Switzerland.]
  2. P. Lipp and R. Köster, Ber. Dtsch. Chem. Ges., 64, 2823 (1931); P. Lipp, J. Buchkremer, and H. Seeles, Justus Liebigs Ann. Chem., 499, 1 (1932); S. Kaarsemaker and J. Coops, Recl. Trav. Chim. Pays-Bas, 70, 1033 (1951); cf. ref. 3.
  3. J.-M. Conia, P. Leriverend, and J.-L. Ripoll, Bull. Soc. Chim. Fr., 1803 (1961).
  4. J. D. Roberts and C. W. Sauer, J. Am. Chem. Soc., 71, 3925 (1949).
  5. J.-M. Conia and J. Gore, Bull. Soc. Chim. Fr., 735 (1963).
  6. J.-M. Conia and J. Gore, Bull. Soc. Chim. Fr., 726 (1963).
  7. D. Seebach, in E. Müller, Ed., "Methoden der Organischen Chemie," (Houben-Weyl), Vol. 4/4, Georg. Thieme Verlag, Stuttgart, 1971.
  8. E. J. Corey and D. Seebach, Angew. Chem., 77, 1134, 1135 (1965) [Angew. Chem. Int. Ed. Engl., 4, 1075, 1077 (1965)].
  9. D. Seebach, Synthesis, 17, (1969), and references cited therein.
  10. D. Seebach, N. R. Jones, and E. J. Corey, J. Org. Chem., 33, 300 (1968).
  11. E. J. Corey, D. Seebach, and R. Freedman, J. Am. Chem. Soc., 89, 434 (1967).
  12. A. G. Brook, Adv. Organomet. Chem., 7, 95 (1968).

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

potassium carbonate (584-08-7)

methanol (67-56-1)

diethyl ether (60-29-7)

sodium chloride (7647-14-5)

sodium sulfate (7757-82-6)

nitrogen (7727-37-9)

acetone (67-64-1)

1-bromo-3-chloropropane (109-70-6)

mercury(II) chloride (7487-94-7)

Mesitylene (108-67-8)

dichloromethane (75-09-2)

Pentaerythritol (115-77-5)

Diazomethane (334-88-3)

n-butyllithium (109-72-8)

Tetrahydrofuran (109-99-9)

lithium aluminum hydride (16853-85-3)

n-hexane (110-54-3)

argon (7440-37-1)

triethylene glycol (112-27-6)

dithiane (505-20-4)

Cyclobutanone (1191-95-3)

1,3-Dithiane (505-23-7)

methylenecyclobutane (1120-56-5)

5,9-dithiaspiro[3.5]nonane (15077-16-4)

cadmium carbonate (513-78-0)