Knoevenagel-hDA reaction

A range of pentacyclic thiopyran indole-annulated benzo-6-sultone deriratives are obtained through a domino Knoevenagel-hDA reaction of 2-formylphenyl (B)-2-phenylethenyl sulfonates with indohne-2-thiones in water (Scheme 99) (13TL2685). 

In 2009, Tietze et al. reported the synthesis of d-(+)-forosamine sugars via a racemic Knoevenagel-HDA reaction (Scheme 13.27a) [8]. The resolution of the enantiomers was carried out by chiral HPLC at the end of the synthesis. The authors suggest a stepwise zwitterionic reaction mechanism for this reaction. DFT calculations supported this mechanism two years later, where an improved procedure for the synthesis of sugars of the forosamine and ossamine series was published (Scheme 13.27b) [9]. The zwitterionic intermediates explain the cA-Ztrani -selectivity, as mentioned before. 

A variety of 2-substituted 2//-chromenes can be obtained from the facile reaction of 2-hydroxybenzaldehydes with vinylboronic acids in ionic liquid solvents <04SL2194>. In a one-pot sequence also in an ionic liquid, a Knoevenagel condensation between O-prenylated salicylaldehydes and 4-hydroxycoumarins is followed by an intramolecular hDA reaction to yield ci5-fused chromano[4, 3 4,5]pyrano[3,2-c]coumarins e.g. 20 small amounts of the corresponding chromone are also formed <04S1783>. In like manner, cii-fused furopyranopyran derivatives have been obtained from sugar aldehydes <04TL3493>. 

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). 

An efficient approach to pyrido[2,3-if pyrimidines 171 was reported by Singh et al. in 2011 [72]. The Knoevenagel condensation is catalyzed by L-proUne 170 in refluxing ethanol to give an ori/io-iminemethide intermediate, which forms the desired products by subsequent HDA reaction in moderate to good yields (46-88%) (Scheme 13.41). 

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