Elimination Michael adduct, ethyl

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

Addition of phosphonylated Schiff base to ethyl acrylate, under phase-transfer catalytic conditions in the presence of Aliquat 336 and KOH at room temperature, leads to the 1 1 Michael adduct with 60% yield (Scheme 8.57). The tert-butyl and ketimine protecting groups are eliminated under mild conditions (1 M HCl, room temperature) to provide the phosphonic analogue of glutamic acid. 

The 1,2-thiaphospholes (20) react thermally with norbornadiene, norbornene, or diethyl azo-dicarboxylate to produce double Diels Alder cycloadducts (24) and (25). With mixtures of norbornadiene and methyl acrylate or acrylonitrile, crossed double Diels-Alder cycloadducts are obtained. In the presence of AICI3 the 1,2-thiaphospholes (20) react with acrylic esters, acrylonitrile or methyl vinyl ketone to give tandem Diels-Alder/Michael adducts such as (26). The AICI3-promoted reaction of (20) with ethyl propiolate affords with the elimination of a sulfur atom the stable phosphinine (27) (Scheme 4) <94BCJ2785>. 

Indeed, when the pre-formed aminal 12 was treated with ethyl acetoacetate in ethanol, the bis-adduct 7 was isolated in good yield. Knoevenagel s proposal for the mechanism of this reaction therefore was first, condensation of the amine and aldehyde to give the aminal 12, followed by attack of this by the acetoacetate to produce a presumed 3-amino dicarbonyl intermediate 13, which would then eliminate piperidine to give the a,p-unsaturated dicarbonyl compound 14, which in this case underwent a final Michael addition with an additional equivalent of ethyl acetoacetate to provide the bis-adduct 7. 

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