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Org. Synth. 1993, 71, 181
DOI: 10.15227/orgsyn.071.0181
INVERSE ELECTRON-DEMAND DIELS-ALDER CYCLOADDITION OF A KETENE DITHIOACETAL. COPPER HYDRIDE-PROMOTED REDUCTION OF A CONJUGATED ENONE. 9-DITHIOLANOBICYCLO[3.2.2]NON-6-EN-2-ONE FROM TROPONE
Submitted by Karl R. Dahnke and Leo A. Paquette1.
Checked by Antonino Focella, Mittira Amornmarn, and David L. Coffen.
1. Procedure
A. Tropone. A 5-L, three-necked, Morton flask, equipped with a reflux condenser, thermometer, nitrogen inlet, and mechanical stirrer is charged with 81 g (0.59 mol) of potassium dihydrogen phosphate, 200 mL of water, and 2 L of p-dioxane. With vigorous mechanical stirring, 258 g (2.80 mol) of cycloheptatriene (Note 1) is added, followed by 318 g (2.87 mol) of selenium dioxide (Note 2). The mixture is heated to 90°C and maintained with vigorous stirring for 20 hr. After the black suspension is cooled to room temperature, 1 L of water is added and the mixture is filtered over Celite (Note 3). The solution is divided into two halves and each is extracted with dichloromethane (2 × 1.5 L). Each organic extract is washed with saturated sodium bicarbonate solution (500 mL) and the solvent is removed under reduced pressure. The combined, crude, black oil is subjected to bulb-to-bulb distillation (20–110°C at 0.05 mm) with dry ice cooling. The resulting light brown liquid is fractionally redistilled (62–65°C at 0.25 mm) to give 147 g (50%) of tropone as a pale yellow oil (Note 4).
B. 9-Dithiolanobicyclo[3.2.2]nona-3,6-dien-2-one. A 50-mL, three-necked, round-bottomed flask, equipped with a reflux condenser, nitrogen inlet, and magnetic stirring bar is charged with 8.23 g (77.6 mmol) of tropone, 0.75 mL of triethylamine (Note 5), and 11.0 g (93.1 mmol) of 2-methylene-1,3-dithiolane (Note 6). After the system is flushed with nitrogen, the mixture is heated to 110–120°C for 10 hr. The resulting dark oil is cooled to room temperature and purified by column chromatography on silica gel (Note 7). Elution with petroleum ether (1 L) followed by dichloromethane affords 9-dithiolanobicyclo[3.2.2]nona-3,6-dien-2-one as an orange oil that solidifies (10.3 g, 59%), mp 56–58°C (Note 8).
C. 9-Dithiolanobicyclo[3.2.2]non-6-en-2-one. (Caution! Hexamethylphosphoric triamide (HMPA) is toxic and must be handled with gloves.) A 500-mL, three-necked, round-bottomed flask, equipped with an argon inlet, stirring bar, thermometer, and rubber septum is charged with 0.80 g (4.2 mmol) of copper(I) iodide (Note 9) and 150 mL of dry tetrahydrofuran (Note 10). The resulting slurry is cooled to −50°C and treated in turn with 3.2 mL of 1.4 M methyllithium in ether (4.5 mmol), 40 mL of hexamethylphosphoramide (Note 11) and (Note 12), and 50 mL of a 1.0 M solution of diisobutylaluminum hydride in hexanes (Note 13), all via syringe. After 1.5 hr at −50°C, 7.4 g (33 mmol) of 9-dithiolanobicyclo[3.2.2]nona-3,6-dien-2-one (Note 14) in 30 mL of tetrahydrofuran is added over 10 min via syringe. The mixture is allowed to warm gradually to 0°C over a 4-hr period and quenched with 75 mL of 1.6 N hydrochloric acid. The organic layer is separated and the aqueous layer is extracted with ether (3 × 100 mL). The combined organic layers are washed with 1.6 N hydrochloric acid (75 mL), water (3 × 150 mL), and brine (150 mL), prior to drying over magnesium sulfate. Evaporation of the solvent under reduced pressure yields an orange oil which solidifies on standing for a short time (Note 15). The solid 9-dithiolanobicyclo[3.2.2]non-6-en-2-one thus obtained is vacuum dried to give 6.9 g (92%) of material, mp 68–71°C, as one spot on TLC, with no starting material detectable upon NMR analysis (Note 16).
2. Notes
1. Cycloheptatriene was purchased from the Aldrich Chemical Company, Inc., and was washed with 10% sodium hydroxide solution, dried over magnesium sulfate, and distilled prior to use.
2. Selenium dioxide was obtained from Alfa Products, Morton/Thiokol Inc. and used without purification.
3. The solid material containing selenium waste was placed in a container for heavy metal wastes and disposed of by a commercial service according to approved procedures.
4. Spectral characteristics are as follows: IR (CHCl3) cm−1: 3000, 1630, 1580, 1515, 1470, 1210; 1H NMR (300 MHz, CDCl3) δ: 6.88–7.11 (series of m, 6 H).
5. Triethylamine was distilled from calcium hydride prior to use.
6. 2-Methylene-1,3-dithiolane was prepared by the procedure of Dahnke and Paquette, Org. Synth., Coll. Vol. IX 1998, 585.
7. The Rf for this adduct is 0.6 in CH2Cl2. Its presence is clearly visible when anisaldehyde is employed as the staining agent.
8. The adduct exhibits the following spectral properties: IR (CHCl3) cm−1: 2930, 1665, 1603, 1380, 1165; 1H NMR (300 MHz, CDCl3) δ: 2.72 (d, 1 H, J = 15.5), 2.87 (dd, 1 H, J = 6.8, 15.5), 3.21–3.45 (m, 5 H), 3.66 (t, 1 H, J = 7.7), 5.77 (dd, 1 H, J = 2.0, 11.1), 6.13 (t, 1 H, J = 7.9), 6.60 (dt, 1 H, J = 0.8, 7.6), 6.92 (dd, 1 H, J = 8.5, 11.1); 13C NMR (75 MHz, CDCl3) δ: 40.2, 40.6, 42.9, 51.9, 52.1, 70.8, 126.5, 129.4, 139.4, 150.6, 196.3. A sample recrystallized from hexane afforded off-white crystals with mp 62–63°C. As an alternative to chromatography, the Diels-Alder adduct can be purified by pouring the cooled, crude product into 100 mL of ether and rinsing the dark viscous gum with additional ether (2 × 25 mL). The material obtained from evaporation of the combined ethereal extracts is then subjected to bulb-to-bulb distillation. After removal of the volatile impurities, the product distils during the ramping of the temperature from 110–165°C at 0.5 mm. This modification affords a comparable yield of adduct on a 6-fold scale.
9. Copper iodide was purified prior to use by the method of Kauffman.2
10. Tetrahydrofuran was distilled from sodium-benzophenone ketyl before use.
11. Hexamethylphosphoramide (HMPA) was distilled from calcium hydride and stored over molecular sieves before use.
12. Attempts were made to substitute other polar solvents for HMPA in this reduction. Under similar reaction conditions but with substitution of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) no reaction took place, and the starting material was recovered unchanged. The slightly more polar 1,3-dimethyl-2-imidazolidinone (DMI) allowed reduction to take place, but with only 80% conversion to a mixture of 1,2- and 1,4-reduction products after 10 hr. With L-selectride in tetrahydrofuran (THF) at −78°C, 1,4-reduction was achieved in 30–60% yield alongside competitive 1,2-reduction.
13. Diisobutylaluminum hydride was purchased from the Aldrich Chemical Company, Inc. and used as received.
14. Before use, this material should be thoroughly dried by heating to 50°C under high vacuum to constant weight (1–2 hr).
15. The Rf of this product is 0.6 in CH2Cl2. Anisaldehyde was employed as the staining agent.
16. Spectral characteristics are as follows: IR (CHCl3) cm−1: 2930, 2860, 1700, 1425; 1H NMR (300 MHz, CDCl3) δ: 1.82–1.94 (m, 1 H), 2.28–2.38 (m, 1 H), 2.52–2.70 (m, 3 H), 2.83–2.94 (m, 2 H), 3.10 (t, 1 H, J = 7.3), 3.22–3.48 (m, 4 H), 6.14 (t, 1 H, J = 7.9), 6.51 (t, 1 H, J = 8.2); 13C NMR (75 MHz, CDCl3) δ: 27.1, 38.1, 39.4, 39.8, 42.9, 46.8, 49.1, 69.9, 127.3, 137.3, 206.9. An analytical sample recrystallized from ether melts at 74–75°C. Anal. Calcd for C11H14OS2: C, 58.37; H, 6.23; S, 28.33. Found: C, 58.32, H, 6.22; S, 28.63.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Although examples of inverse electron-demand Diels-Alder reactions involving ketene thioacetals and α,β-unsaturated aldehydes, ketones, and esters abound,3 the formation of six-membered carbocyclic products is rarely encountered. Isoquinolinium salts and 4a-azoniaanthracenes are recognized as good 2π acceptors,4 but the use of positively charged reaction partners is not necessary as the condensation with tropone illustrates. An important advantage of such cycloadditions is their ability to distinguish two carbonyl groups from the outset. Furthermore, the example provided illustrates the regiospecificity with which carbon-carbon bond formation occurs.
The methodology employed for the oxidation of cycloheptatriene is based on an original report by Radlick5 as subsequently improved by Rigby and Wilson.6
The second stage of the procedure describes a method for the fully regiocontrolled saturation of conjugated double bonds in the presence of isolated pi bonds. The agent perhaps responsible for this discrimination is a coordinated form of copper hydride. Although "CuH" has been generated in several different ways, the diisobutylaluminum hydride-methyl copper-HMPA complex developed by Tsuda and Saegusa7 is especially attractive because of its quantitative capacity for 1,4-reduction and its ease of generation.8 This chemistry results in regiospecific enolate anion formation and permits ready trapping of these intermediates as illustrated below:9
Consequently, this mild, conjugate reduction may become a powerful tool in synthetic organic chemistry.
This preparation is referenced from:

References and Notes
  1. Department of Chemistry, The Ohio State University, Columbus, OH 43210.
  2. Kauffman, G. B.; Teter, L. A. Inorg. Syn. 1963, 7, 9.
  3. Kolb, M. In "The Chemistry of Ketenes, Allenes, and Related Compounds, Part 2"; Patai, S., Ed.; Wiley: New York, 1980; Chapter 16, pp. 669–699.
  4. Fields, D. L.; Regan, T. H.; Dignan, J. C. J. Org. Chem. 1968, 33, 390; Fields, D. L.; Regan, T. J. J. Heterocycl. Chem. 1973, 10, 195; Fields, D. L. J. Org. Chem. 1971, 36, 3002.
  5. Radlick, P. J. Org. Chem. 1964, 29, 960.
  6. Rigby, J. H.; Wilson, J. Z. J. Am. Chem. Soc. 1984, 106, 8217, footnote 14; Wilson, J. Z. Ph.D. Thesis, Wayne State University, Detroit, MI, 1986, p. 95.
  7. Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J. Org. Chem. 1986, 51, 537; Tsuda, T.; Satomi, H.; Hayashi, T.; Saegusa, T. J. Org. Chem. 1987, 52, 439.
  8. Paquette, L. A.; Dahnke, K. R., unpublished work.
  9. Friedrich, D.; Paquette, L. A. J. Org. Chem. 1991, 56, 3831.

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

petroleum ether

brine

9-Dithiolanobicyclo[3.2.2]nona-3,6-dien-2-one

9-Dithiolanobicyclo[3.2.2]non-6-en-2-one

sodium-benzophenone ketyl

diisobutylaluminum hydride-methyl copper-HMPA

hydrochloric acid (7647-01-0)

ether (60-29-7)

sodium hydroxide (1310-73-2)

sodium bicarbonate (144-55-8)

nitrogen (7727-37-9)

selenium dioxide (7446-08-4)

dichloromethane (75-09-2)

copper(I) iodide (7681-65-4)

magnesium sulfate (7487-88-9)

potassium dihydrogen phosphate (7778-77-0)

selenium

Tetrahydrofuran (109-99-9)

copper iodide (7681-65-4)

hexane (110-54-3)

Methyllithium (917-54-4)

triethylamine (121-44-8)

calcium hydride (7789-78-8)

diisobutylaluminum hydride (1191-15-7)

cycloheptatriene (544-25-2)

hexamethylphosphoric triamide,
hexamethylphosphoramide (680-31-9)

p-dioxane (123-91-1)

anisaldehyde (123-11-5)

Tropone (492-37-5)

1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7226-23-5)

KETENE DITHIOACETAL

2-Methylene-1,3-dithiolane (26728-22-3)

1,3-dimethyl-2-imidazolidinone (80-73-9)

copper hydride