Knoevenagel reaction sequential reactions

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

A library of 500 bipyridines was synthesized using a solid state combinatorial approach using five beta-ketoesters, 10 aldehydes, and 10 enamines through sequential Knoevenagel/Hantzsch condensation reactions.56... 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

As an example of selective molecular recognition with the imprinted silica 2, a Knoevenagel C-C bond-forming reaction was performed with a bifunctional reactant (Fig. 9). This type of a sequential reaction system is important in numerous industrial applications such as the dehydrogenation of butylene to butadiene or the partial oxidation of naphthalene or o-xylene to phthalic anhydride [44]. The ability to suppress the B to C reaction avoids production of undesired products in these cases. 

In a review on the intramolecular DA reaction as a key step in tandem or sequential processes, versatile syntheses of tetrahydro-2H-pyrans, chro-mans, heterocycle-fused 2H-benzopyrans and related compounds were considered (14T2857). Although many examples of the synthetic methods of O- and S-6-membered heterocycles are based on the tandem use of the Knoevenagel condensation and a hDA reaction, a review described only domino reactions with Knoevenagel condensation as a step and without the DA step in the synthesis of several types of chromones and coumarins (14T551) and of only coumarins (14SC2756). 

Other reactions that have been applied in the Ugi postmodification strategy are the aza-Wittig reaction [80-84] and copper-catalyzed processes [85, 86], More recently, Domling and coworkers have developed a new approach for the synthesis of polycyclic compounds via Ugi MCR followed by a Pictet-Spengler reaction [87-89]. In 2011, apro-tocol for the rapid access to quinolin-2-(l//)-one scaffold was reported by a sequential 4-component Ugi-Knoevenagel condensation [90]. Hulme et al. have introduced a one-pot, two-step protocol for large-scale production of libraries of novel peptidomimetic-like fcM-pyrrolidinone tetrazoles via the Ugi-3CR-azide reaction of tethered keto ester methyl... 

A Lewis acid-catalyzed one-pot sequential transformation of /3-ketoesters, aromatic aldehydes, and NCS was reported. The reaction proceeds by way of Knoevenagel condensation/Nazarov cyclization/halogenations to give a-chloro-/3-ketoesters in moderate yields with high diastereoselectivities. ... 

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