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Synlett 2008(17): 2609-2612  
DOI: 10.1055/s-0028-1083378
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Ethyl 5-[(4-Methylphenyl)sulfonyl]-3-Oxopentanoate: A Bench-Stable Synthon for Ethyl 3-Oxopent-4-enoate (Nazarov’s Reagent)

Simonetta Benettia, Stefano Carlib, Carmela De Risi*b, Gian P. Pollinib, Augusto C. Veroneseb, Vinicio Zaniratob
a Dipartimento di Chimica, Via L. Borsari 46, 44100 Ferrara, Italy
b Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 19, 44100 Ferrara, Italy
Fax: +39(0532)455953; e-Mail: drc@unife.it;
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Publication History

Received 1 July 2008
Publication Date:
01 October 2008 (online)

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Abstract

The easily available adducts of sodium p-toluenesul­finate to both acrylonitrile or acrylic acid were efficiently transformed through a two-step, high-yielding sequence into ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate, a convenient source for the popular Nazarov’s reagent, ethyl 3-oxopent-4-enoate, which could be generated in situ by base-induced β-elimination and used for annulation reactions.

Key words

Nazarov’s reagent - annulations - tandem reactions - ­bicyclic compounds - carbocycles

    References and Notes

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13

Typical Procedures for the Preparation of Compound 2
Method A: A stirred suspension of zinc dust (3.8 g, 58.1 mmol) in THF (28 mL) was treated with MsOH (0.14 mL, 2.2 mmol) and heated at reflux for 10 min. Ethyl bromoacetate (1.0 mL, 9.0 mmol) was added dropwise until it turned green, then 3 (4.0 g, 19.1 mmol) was added. Ethyl bromoacetate (4.0 mL, 36.1 mmol) was successively dropped over a period of 30 min. The reaction mixture was refluxed for 3 h, cooled to 0 ˚C, and treated with 10% HCl (28 mL). The solution was stirred at r.t. for 2 h, then the solvent was concentrated in vacuo. The residue was extracted with EtOAc (3 × 60 mL), the combined organic phases were washed with brine (2 × 100 mL), and dried (Na2SO4). The solvent was evaporated, and the residue was purified by flash chromatography (EtOAc-PE, 1:2) to afford 2 (4.3 g, 75%).
Method B: 1,1′-Carbonyldiimidazole (3.5 g, 21.6 mmol) was added to a solution of the acid 5 (4.0 g, 17.5 mmol) in THF (100 mL). The mixture was stirred at r.t. for 4 h, then the magnesium salt of monoethyl malonate [prepared by stirring monoethyl malonate (4.54 mL, 38.5 mmol) and magnesium ethoxide (2.8 g, 24.5 mmol) in THF (80 mL) for 1 h at r.t.] was added and stirring was continued at r.t. overnight. The solvent was removed at reduced pressure and the residue treated with 1.5 N HCl (80 mL) and extracted with EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2 × 100 mL), the combined extracts were washed with aq sat. NaHCO3 soln and dried (Na2SO4). Evaporation of the solvent and purification of the oily residue by flash chromatography (EtOAc-PE, 1:2) gave 2 (4.2 g, 80%).

18

Selected Analytical Data for Compound 2
White solid, mp 44-45 ˚C (n-hexane). IR: 1740, 1718, 1597 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H), 2.45 (s, 3 H), 3.04 (t, J = 7.2 Hz, 2 H), 3.37 (t, J = 7.2 Hz, 2 H), 3.46 (s, 2 H), 4.17 (q, J = 7.2 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.11, 21.72, 35.66, 49.12, 50.52, 61.76, 128.07, 130.13, 135.87, 145.18, 166.56, 198.68. Anal. Calcd for C14H18O5S: C, 56.36; H, 6.08. Found: C, 56.20; H, 6.23.

19

Typical Procedure for the Preparation of Compound 6 A solution of 2 (0.2 g, 0.67 mmol) and KF (0.16 g, 2.75 mmol) in MeOH (10 mL) was stirred at r.t. for 12 h. The solvent was evaporated under reduced pressure, and the crude residue was purified by flash chromatography (EtOAc-PE, 1:3) yielding 6 as a colorless oil (76 mg, 40%). IR: 3474, 1697, 1655, 1584 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3 H), 1.32 (t, J = 7.2 Hz, 3 H), 1.72-1.84 (m, 1 H), 1.90-2.00 (m, 1 H), 2.18-2.30 (m, 1 H), 2.48-2.52 (m, 1 H), 2.53-2.58 (m, 2 H), 4.13-4.30 (m, 4 H), 4.47 (s, 1 H), 5.73 (s, 1 H), 6.02 (s, 1 H), 12.09 (s, enol OH). ¹³C NMR (100 MHz, CDCl3): δ = 14.13, 14.24, 19.95, 34.02, 42.04, 60.81, 61.06, 71.04, 97.80, 115.83, 143.56, 162.24, 172.52. Anal. Calcd for C14H20O6: C, 59.14; H, 7.09. Found: C, 59.20; H, 7.00.

22

Selected Analytical Data for Compounds 10a and 10b
Compound 10a: colorless oil. IR: 1706, 1650, 1620, 1545 cm-¹. ¹H NMR (400 MHz, CDCl3): δ (less polar isomer) = 0.95 (t, J = 7.2 Hz, 3 H), 2.00-2.12 (m, 1 H), 2.36-2.70 (m, 3 H), 3.96-4.08 (m, 2 H), 4.56-4.63 (m, 1 H), 4.70-4.76 (br, 1 H), 7.17-7.37 (m, 5 H), 12.55 (s, enol OH). ¹³C NMR (100 MHz, CDCl3): δ (less polar isomer) = 13.70, 20.87, 24.83, 42.46, 60.62, 85.99, 96.79, 127.31, 127.60, 128.77, 141.34, 171.41. Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88. Found: C, 61.91; H, 5.80.
Compound 10b: colorless oil. IR: 1710, 1660, 1610, 1550 cm-¹. ¹H NMR (400 MHz, CDCl3): δ (more polar isomer) = 0.96 (t, J = 7.2 Hz, 3 H), 2.00-2.13 (m, 1 H), 2.40-2.76 (m, 3 H), 3.93-4.10 (m, 2 H), 4.50-4.60 (m, 1 H), 4.70-4.80 (br, 1 H), 7.20-7.30 (m, 1 H), 7.46-7.53 (m, 1 H), 8.46-8.56 (br, 2 H), 12.56 (s, enol OH). ¹³C NMR (100 MHz, CDCl3): δ (more polar isomer) = 13.81, 21.24, 25.02, 40.45, 60.94, 85.67, 96.04, 123.66, 135.15, 137.03, 148.89, 149.53, 170.98, 171.98. Anal. Calcd for C14H16N2O5: C, 57.53; H, 5.52. Found C, 57.50; H, 5.60.