Synthesis of Multisubstituted Cyclopentadienes from Cyclopentenones Prepared via Catalytic Double Aldol Condensation and Nazarov Reaction Sequence

Abstract

The rhenium-catalyzed synthesis of cyclopentenone derivatives via double aldol condensation and successive Nazarov reaction is described. The cyclopentenones were converted to the corresponding cyclopentadienes using organolithium reagents. Cyclopentadienes with four different substituents could be synthesized by stepwise double aldol condensation using a ketone and two types of aldehydes, followed by treatment with an organolithium reagent.

Key words

rhenium - cyclopentenone - cyclopentadiene - aldol condensation - Nazarov cyclization

References and Notes

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1

Present address: Research Core for Interdisciplinary Sciences, Okayama University, Tsushima, Kita-ku, Okayama 700-8530, Japan.

9

For investigation of several catalysts: Sc(OTf)₃ (5.0 mol%, 150 ˚C, 24 h), 12%; TiCl₄(thf)₂ (10 mol%, 120 ˚C, 16 h), 80%; ZrOCl₂˙8H₂O (10 mol%, 150 ˚C, 12 h), 63%; AuCl₃ (5.0 mol%, 150 ˚C, 24 h), 4%. No reaction (5.0 mol%, 150 ˚C, 24 h): InCl₃, In(OTf)₃, and Cu(OTf)₂. These results were obtained within the scope of this work.

12

Self-aldol condensation of acetaldehyde (2b) also proceeded as a side reaction.

15

When the reaction was quenched with aq HCl, the yield of 5a decreased. See: ref 5.

16

The yield of 5a was low because deprotonation of 3b with 1a occurred predominantly. When the reaction was quenched with D₂O, deuterium was incorporated at the α-position of the carbonyl group of 3b.

18

Chloroform was used as a proton source. When a catalytic amount of p-toluenesulfonic acid was used in the dehydration, the yield of cyclopentadiene 5b decreased.

20

The regioisomers of 5i could not be separated by column chromatography on silica gel or GPC. The ratio between five regioisomers of 5i was determined by ^¹H NMR.

22

General Procedure for the Synthesis of Cyclopentenones 3: A mixture of ketone 1 (0.250 mmol), aldehyde 2 (0.500 mmol), Re₂(CO)₁₀ (8.2 mg, 0.0125 mmol), and toluene (0.1 mL) was stirred at 150 ˚C for 24 h in a sealed tube. Then, the solvent was removed in vacuo and the product was isolated by column chromatography on silica gel (hexane-EtOAc = 20:1) to give cyclopentenone 3.

23

2,5-Dimethyl-3,4-diphenyl-2-cyclopentene-1-one (3a): ^¹H NMR (400 MHz, CDCl₃): δ = 1.25 (d, J = 7.2 Hz, 3 H), 1.93 (d, J = 1.6 Hz, 3 H), 2.31 (qd, J = 7.2, 2.8 Hz, 1 H), 3.89 (s, 1 H), 6.97-7.23 (m, 10 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 10.1, 15.2, 51.2, 56.2, 126.5, 127.4, 128.2, 128.6, 128.8, 135.0, 136.6, 136.8, 141.9, 166.9, 210.8.

24

General Procedure for the Synthesis of Cyclopentadienes 5: To a mixture of cyclopentenone 3 (0.25 mmol) and THF (5.0 mL), an Et₂O solution of organolithium reagent 4 (0.275 mmol, 1.1 equiv) was added dropwise at -78 ˚C. Then the reaction mixture was stirred at -78 ˚C for 3 h. The reaction was quenched with aq NH₄Cl (3.0 mL), and the mixture was extracted with EtOAc. The organic layer was dried with MgSO₄, filtered, and concentrated in vacuo. CH₂Cl₂ (1.0 mL) and TsOH (5.2 mg, 0.0125 mmol, 0.050 equiv) were added to the mixture, and the mixture was stirred at 25 ˚C for 1 h. Then, the solvent was removed in vacuo and the product was isolated by column chromatography on silica gel (hexane-EtOAc = 50:1) to give cyclopentadiene 5.

25

1,2,3,4,5-Pentaphenylcyclopentadiene (5a): ^¹H NMR (400 MHz, CDCl₃): δ = 5.08 (s, 1 H), 6.94-6.98 (m, 4 H), 7.00-7.03 (m, 8 H), 7.08-7.22 (m, 13 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 62.7, 126.3, 126.5, 126.7, 127.7, 127.8, 128.4, 128.5, 129.0, 130.1, 135.8, 136.1, 138.1, 144.0, 146.5.