Oxa-Michael-Mannich reaction

As additional examples, we can first note the use of silylated serine or threonine for the addition of 2-phenylpropanal to vinylsulfone, giving the corresponding adduct in good yields (85-90%) but low ee (44-45%). As a second example, an aza-Michael reaction has been described with the ethyl methyl imidazolium salt of glycine as a catalyst. As a last example, the interest in tert-leucine can be noticed as it could act as a cocatalyst with a pyrrolidine bearing a thiopyridine. The ion-pair catalyst catalysed the domino oxa-Michael-Mannich reaction of salicylic aldehydes with cyclohex-2-enones. ... 

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

Scheme 2.6 Domino oxa-Michael-Mannich reaction catalysed by a combination of a chiral pyrrolidine and n-tert-leucine.

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

We also found that 2-R -chromones 130 react with salicylaldehydes in the presence of piperidine to afford 207 via oxa-Michael addition followed by intramolecular Mannich condensation [27], Treatment of 130 with pyridoxal hydrochloride in the presence of NaOH (2.6 equiv.) gave oxepines 208 in moderate yields. In this case, the reaction proceeded at the alcoholic hydroxyl. Interestingly, using 1.3 equiv. of NaOH, it was possible to obtain 209 [103] (Scheme 67). 

For the same purpose, various chiral pyrroUdine catalysts such as 50-54 have also been introduced [242-250]. The versatile nature of pyrrolidine catalysts has been recognized by other transformations aldol reaction [251], Mannich-type reaction [252, 253], and oxa-Michael reaction [254]. Among these, Maruoka s work on anti-selective Mannich reactions is noteworthy (Scheme 1.19, compare with Scheme 1.8) [253]. In this case, the remote hydrogen-bonding form 57 derived from catalyst 56 can overcome the steric preference so that the opposite sense of stereochemistry should be observed. 

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