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

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

References and Notes

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23

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

24

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).

25

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).