A New Microwave-Assisted Organocatalytic
Solvent-Free Synthesis of Optically Enriched Michael Adducts

Antonio Procopio; Antonio De 
Nino; Monica Nardi; Manuela Oliverio; Rossella Paonessa; Raffaele Pasceri

doi:10.1055/s-0030-1258126

LETTER

A New Microwave-Assisted Organocatalytic Solvent-Free Synthesis of Optically Enriched Michael Adducts

Antonio Procopio*^a, Antonio De Nino^b, Monica Nardi^b, Manuela Oliverio^a, Rossella Paonessa^a, Raffaele Pasceri^a
^a Dipartimento Farmaco-Biologico, Universita` degli Studi della Magna Græcia, Complesso Ninì Barbieri, 88021 Roccelletta di Borgia (CZ), Italy
Fax: +39(0961)36955713; e-Mail: procopio@unicz.it;
^b , Dipartimento di Chimica, Università della Calabria, Ponte Bucci, 87030 Arcavacata di Rende (CS), Italy

Abstract

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Abstract

A high-yielding reaction protocol for the microwave-assisted organocatalytic conjugate addition of diethyl malonate to enones under solvent-free conditions is proposed. The method still permits the use of cheap and commercially available l-proline furnishing very good performance at least in the case of 1-alkyl-3-monosubstituted enones.

Key words - green chemistry - homogeneous catalysis - asymmetric catalysis - enones - Michael reaction

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References and Notes

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Reactions in an oil bath were performed in a 10 mL septum-sealed glass vial.

General Procedure for the Michael Addition
To a solution of the appropriate enone (5.0 mmol), diethyl malonate (6.0 mmol, 910 µL) and piperidine (6.0 mmol, 593 µL), was added a catalytic amount of proline (0.75 mmol, 86 mg). The resultant mixture, after mixing, was put in a Teflon septum-sealed vial and heated with MW at 55 ˚C for 1 h. The reaction was diluted with CH₂Cl₂ and washed with sat. aq solution of NH₄Cl. The organic phase was dried with Na₂SO₄, filtered, and concentrated to furnish a residue which was purified by flash chromatography (hexane-EtOAc, 9:1). The enantioselectivities were determined using an Agilent 1100 Series HPLC (G1311A Quat Pump, DAD G1315B detector and an automatic injector (see the Supporting Information for details).

Data for Selected Products
( R )-(+)-Diethyl 2-(3-Oxocyclohexyl) malonate (1a) Compound 1a was prepared according to the general procedure from 2-cyclohexen-1-one as a colorless oil. Yield 96%; ee 48%. GC-MS: m/z = 256 [M]⁺.^¹H NMR (300 MHz, CD₃Cl): δ = 4.26-4.16 (m, 4 H), 3.30 (d, J = 7.9 Hz, 1 H), 2.61-2.36 (m, 5 H), 2.32-2.20 (m, 2 H), 2.15-1.91 (m, 1 H), 1.80-1.45 (m, 1 H), 1.31-1.25 (m, 6 H).
( R )-(+)-Diethyl 2-(3-Oxo-1-phenylbutyl)malonate (1b)
Compound 1b was prepared according to the general procedure from benzylidenacetone as a colorless oil. Yield 86%; ee 99%. GC-MS: m/z = 306 [M]⁺. ^¹H NMR (300 MHz, CD₃Cl): δ = 7.32-7.15 (m, 5 H), 4.24-4.13 (q, J = 7.2 Hz, 2 H), 4.20-3.88 (m, 3 H), 3.68 (d, J = 10.0 Hz, 1 H), 2.95-2.90 (m, 2 H), 2.03 (s, 3 H), 1.29-1.22 (t, J = 7.3 Hz, 3 H), 1.05-0.95 (t, J = 7.5 Hz, 3 H).
( R )-(+)-Diethyl 2-[1-(2-Furfuryl)-3-oxo-butyl)]-malonate (1c) Compound 1c was prepared according to the general procedure from furfurylideneacetone as a colorless oil. Yield 95%; ee 99%. GC-MS: m/z = 296 [M]⁺. ^¹H NMR (300 MHz, CD₃Cl): δ = 7.29-7.26 (m, 1 H), 6.25-6.23 (m, 1 H), 6.10-6.08 (m, 1 H), 4.21-4.13 (q, J = 7.21 Hz, 2 H), 4.12-4.05 (q, J = 6.58 Hz, 2 H), 3.79-3.75 (d, J = 8.11 Hz, 1 H), 3.05-2.87 (m, 2 H), 2.10 (s, 3 H), 1.27-1.21 (t, J = 7.1 Hz, 3 H), 1.19-1.11 (t, J = 7.1 Hz, 3 H).
( R )-(+)-Diethyl 2-[1-(2-Thienyl)-3-oxo-butyl)]-malonate (1d) Compound 1d was prepared according to the general procedure from furfurylideneacetone as a colorless oil. Yield 82%; ee 56%. GC-MS: m/z = 312 [M]⁺. ^¹H NMR (300 MHz, CD₃Cl): δ = 7.16-7.11 (m, 1 H), 6.91-6.86 (m, 2 H), 4.34-4.25 (m, 1 H), 4.22-4.12 (m, 2 H), 4.09-4.01 (m, J = 7.1 Hz, 1 H), 3.77-3.73 (d, J = 8.7 Hz, 1 H), 3.03-2.97 (m, 2 H), 2.09 (s, 3 H), 1.28-1.21 (t, J = 7.1 Hz, 3 H), 1.16-1.10 (t, J = 7.23 Hz, 3 H).
( R )-(+)-Diethyl 2-[3-Methyl-1-(2-oxopropyl)-2-butenyl]malonate (1e) Compound 1e was prepared according to the general procedure from 6-methyl-3,5-heptadien-2-one as a colorless oil. Yield 55%; ee 56%. GC-MS: m/z = 284 [M]⁺. ^¹H NMR (300 MHz, CD₃Cl): δ = 5.02-4.95 (m, 1 H), 4.24-4.08 (m, 4 H), 3.62-3.51 (m, 1 H), 3.41-3.38 (m, J = 8.3 Hz, 1 H), 2.79-2.62 (dd, J = 4.5, 11.7 Hz, 1 H), 2.54-2.45 (m, 1 H), 2.1 (s, 3 H), 1.28-1.21 (m, 3 H), 1.16-1.10 (m, 3 H).

Supplementary Material

Supporting Information (PDF)