Piperidinium acetate Knoevenagel reaction

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

As discussed in Section 7.1.4, polymer-bound acetoacetates can be used as precursors for the solid-phase synthesis of enones [33], For these Knoevenagel condensations, the crucial step is to initiate enolization of the CH acidic component. In general, enolization can be initiated with a variety of catalysts (for example, piperidine, piperidinium acetate, ethylenediamine diacetate), but for the microwave-assisted procedure piperidinium acetate was found to be the catalyst of choice, provided that the temperature was kept below 130 °C. At higher reaction temperatures, there is significant cleavage of material from the resin. 

Intramolecular cyclization. Knoevenagel condensation of diphenylacetaldehyde with diethyl malonate (piperidinium acetate catalysis) results in only a trace of the expected product when molecular sieves are present, the a-naphthol 1 is formed in 52% yield.2 A similar reaction is observed with ethyl acetoacetate and ethyl benzoylacetate. 

On the other hand the catalyst is of great importance primary, secondary or tertiary amines or their corresponding ammonium salts are usually used, but many other catalysts such as phase transfer catalysts, Lewis acids or potassium fluoride can also be applied. The most widely employed catalysts are pyridine, with or without added piperidine, and ammonium salts, such as ammonium or piperidinium acetate. Condensations that employ strong bases or preformed metal salts of the methylene component are not covered here since transformations under these conditions are not usually considered to be Knoevenagel reactions. 

Based on a domino Knoevenagel/cne reaction, Tietze and Steinmetz developed a stereoselective solid-phase synthesis of cyclopentane and cyclohexane derivatives of type 326 and 327 using a Merrifield resin modiiled with a propandiol linker 320 as shown in Scheme 4.6.3. Subsequent reaction with monomethyl malonoyl chloride 321 afforded the polymer-bound malonate 322, which, in a two-component domino reaction was treated with unsaturated aldehydes 323 in the presence of a catalytic amount of piperidinium acetate and zinc chloride. Except for a-substituted aldehydes, the initial Knoevenagel condensation occurred without addition of dehydrating agents and the subsequent intramolecular ene reaction gave cyclopentane and cyclohexane derivatives 325 after cleavage firom the resin either by reduction or transesterification. 

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