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

Simonetta Benetti; Stefano Carli; Carmela De Risi; Gian P. Pollini; Augusto C. Veronese; Vinicio Zanirato

doi:10.1055/s-0028-1083378

LETTER

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

Simonetta Benetti^a, Stefano Carli^b, Carmela De Risi*^b, Gian P. Pollini^b, Augusto C. Veronese^b, Vinicio Zanirato^b
^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;

Abstract

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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

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References and Notes

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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%).

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<A NAME="RG21308ST-17">17</A> Brooks DW. Lu LD.-L. Masamune S. Angew. Chem., Int. Ed. Engl. 1979, 18: 72

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.

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.

<A NAME="RG21308ST-20">20</A> Singh V. Batra S. Tetrahedron 2008, 64: 4511 ; and references cited therein

<A NAME="RG21308ST-21">21</A> For an organocatalytic asymmetric tandem Michael and Morita-Baylis-Hillman reaction between α,β-unsaturated aldehydes and Nazarov’s reagents leading to cyclohexane derivatives structurally related to 6, see: Cabrera S. Alemán J. Bolze P. Bertelsen S. Jørgensen KA. Angew. Chem. Int. Ed. 2008, 47: 121

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.

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