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.

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 

2d Bee C. Leclerc E. Tius MA. Org. Lett.  2003,  5:  4927 

2e Liang G. Gradl SN. Trauner D. Org. Lett.  2003,  5:  4931 

2f Aggarwal VK. Belfield AJ. Org. Lett.  2003,  5:  5075 

2g Janka M. He W. Frontier AJ. Eisenberg R. J. Am. Chem. Soc.  2004,  126:  6864 

2h Liang G. Trauner D. J. Am. Chem. Soc.  2004,  126:  9544 

3 Denmark SE. Wallace MA. Walker CB. J. Org. Chem.  1990,  55:  5543 ; and references therein

4a Harmata M. Lee DR. J. Am. Chem. Soc.  2002,  124:  14328 

4b Harmata M. Schreiner PR. Lee DR. Kirchhoefer PL. J. Am. Chem. Soc.  2004,  126:  10954 

4c Harmata M. Lee DR. Barnes CL. Org. Lett.  2005,  7:  1881 

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 

6b Shindo M. Synthesis  2003,  2275 

6c Shindo M. Synth. Org. Chem. Jpn.  2000,  58:  1155 

6d Shindo M. Chem. Soc. Rev.  1998,  27:  367 

7 Shindo M. Matsumoto K. Shishido K. Org. Synth.  2007,  84:  11 

8 Shindo M. Kita T. Kumagai T. Matsumoto K. Shishido K. J. Am. Chem. Soc.  2006,  128:  1062 

9 Mannekens E. Tourwé D. Lubell WD. Synthesis  2000,  1214 

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.

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 

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.

Interruption of oxyallyl cations:

14a Shoppee CW. Cooke BJA. J. Chem. Soc., Perkin Trans. 1  1972,  2271 

Other examples, see:

14b Magnus P. Quagliato D. J. Org. Chem.  1985,  50:  1621 

14c Asokan CV. Bhattacharji S. Ila H. Junjappa H. Synthesis  1988,  281 

14d Hara S. Okamoto S. Narahara M. Fukuhara T. Yoneda N. Synlett  1999,  411 

14e Wang Y. Arif AM. West FG. J. Am. Chem. Soc.  1999,  121:  876 

14f Dhoro F. Tius MA. J. Am. Chem. Soc.  2005,  127:  12472