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DOI: 10.1055/s-0028-1083378
Ethyl 5-[(4-Methylphenyl)sulfonyl]-3-Oxopentanoate: A Bench-Stable Synthon for Ethyl 3-Oxopent-4-enoate (Nazarov’s Reagent)
Publication History
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
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References and Notes
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%).
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.
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.