Acid-Catalyzed Nazarov Reaction Controlled by β-Alkoxy Groups

Abstract

Acid-catalyzed Nazarov reaction of β-alkoxy divinyl ­ketones providing 5-oxycyclopent-2-enones has been developed. The effects of the β-alkoxy group on the catalyst efficiency and the regioselectivity are based on the stabilization of the intermediates and the spontaneous elimination of the group followed by trapping. The substrates are easily accessible using the torquoselective olefination of esters with ynolates.

Key words

electrocyclic reactions - catalysis - cyclizations - Lewis acids - ynolates

References and Notes

• For reviews, see:
• 1a Frontier AJ. Collison C. Tetrahedron  2005,  61:  7577 
• 1b Pellissier H. Tetrahedron  2005,  61:  6479 
• 1c Tius MA. Eur. J. Org. Chem.  2005,  2193 
• 1d Habermas KL. Denmark SE. Jones TK. In Organic Reactions   Vol. 45:  Paquette LA. John Wiley and Sons; New York: 1994.  p.1-158  
• 1e Santelli-Rouvier C. Asantelli M. Synthesis  1983,  429 
• For selected catalytic reactions, see:
• 2a Jones TK. Denmark SE. Helv. Chim. Acta  1983,  66:  2377 
• 2b Giese S. West FG. Tetrahedron  2000,  56:  10221 
• 2c He W. Sun X. Frontier AJ. J. Am. Chem. Soc.  2003,  125:  14278 
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• 3 Denmark SE. Wallace MA. Walker CB. J. Org. Chem.  1990,  55:  5543 ; and references therein
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• 5a In contrast, Denmark’s β-silyl alkenes stabilize oxyallyl cations by the β-effect. See: Denmark SE. Jones TK. J. Am. Chem. Soc.  1982,  104:  2642 
• 5b

  In Frontier’s polarized substrate, both of the pentadienyl and oxyallyl cations are stabilized. See ref. 2c.

• For reviews on ynolates, see:
• 6a Shindo M. Tetrahedron  2007,  63:  10 
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• 9 Mannekens E. Tourwé D. Lubell WD. Synthesis  2000,  1214 
• 11 Ohwada reported the O,O-diprotonated dication intermediate in the TfOH-mediated Nazarov reaction: Suzuki T. Ohwada T. Shudo K. J. Am. Chem. Soc.  1997,  119:  6774 
• Interruption of oxyallyl cations:
• 14a Shoppee CW. Cooke BJA. J. Chem. Soc., Perkin Trans. 1  1972,  2271 
• Other examples, see:
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10

General Procedure for the Sc(OTf) ₃ -Catalyzed Nazarov Reaction A solution of the (E)-β-alkoxy divinyl ketone (0.125 mmol) in CH₂Cl₂ (2 mL) was added to a solution of Sc(OTf)₃ (10 mol%) in CH₂Cl₂ (3 mL) in one portion at r.t. and the solution was stirred. After 3 min, a sat. aq NaHCO₃ was added and the mixture was extracted with CH₂Cl₂. The organic extracts were washed with a sat. aq NaHCO₃, and brine, dried over MgSO₄, and concentrated in vacuo. The residual oil was purified through silica gel column chromatography (hexane-EtOAc, 90:10) to give the
α-ethoxy cyclopentenone.
Compound 8: ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (t, J = 7.2 Hz, 3 H), 1.27 (s, 3 H), 1.58 (s, 3 H), 2.38 (d, J = 18.4 Hz, 1 H), 2.67-2.80 (m, 3 H), 2.86 (t, J = 7.2 Hz, 2 H), 3.21-3.33 (m, 2 H), 7.15-7.30 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 7.98, 15.8, 23.2, 32.8, 33.1, 42.4, 59.4, 78.9, 126.4, 128.1, 128.5, 134.9, 140.2, 169.3, 208.3. IR (neat): 1705, 1643, 1088 cm^-1. MS (EI): m/z = 214 [M⁺ - OEt]. Anal. Calcd for C₁₇H₂₂O₂: C, 79.03; H, 8.58. Found: C, 78.81; H, 8.73.

12

General Procedure for the TfOH/Tf ₂ O-Catalyzed Nazarov Reaction Preparation of the TfOH/Tf₂O stock solution: 2.0 µL of a mixture, prepared from TfOH (1.0 mL, 11.3 mmol) and Tf₂O (50 µL), was dissolved in CH₂Cl₂ (50 mL). To the divinylketone (0.210 mmol) was added the stock solution (0.5 mL), containing TfOH (0.2 µmol) and Tf₂O (0.01 µmol), at r.t. under argon and stirred. After 3 min, a sat. aq NaHCO₃ was added and the mixture was extracted with CH₂Cl₂. The organic extracts were washed with a sat. aq NaHCO₃, and brine, dried over MgSO₄, filtered and concentrated in vacuo. The residual oil was purified through silica gel column chromatography (hexane-EtOAc) to give the cyclopentenone.

13

General Procedure for the Tf ₂ O-Catalyzed Nazarov Reaction To a solution of the substrate (0.15 mmol) in anhyd CH₂Cl₂ (0.6 mL), under argon, was added TfOH (0.1 mol%) at r.t. and stirred. After 3 min, a sat. aq NaHCO₃ solution was added and the mixture was extracted with CH₂Cl₂. The organic extracts were washed with a sat. aq NaHCO₃ solution and brine, dried over MgSO₄, filtered and concentrated in vacuo to afford a crude cyclopentenones. The residual oil was purified through silica gel column chromatography (hexane-EtOAc, 90:10) to give the desired α-ethoxy cyclopentenone as colorless oil.