Mannich-type reaction aqueous media

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

Y(03SCF3)3 to afford a monoaminoalkylation product in good yield in aqueous media.40 Zinc tetrafluoroborate is also highly effective for such couplings in aqueous THF.41 Kobayashi also reported a Mannich-type reaction of imines with silyl enolates catalyzed by neutral salts such as sodium triflate in water as a suspension medium. Unusual kinetic behavior indicates that the presence of the Mannich adduct facilitates the rate of its formation.42... 

The required aldehyde precursor 186 was obtained by a Sn(II)-catalyzed asymmetric aldol reaction [90]. It was then mixed in one pot with o-methoxy aniline 187 and enol ether 188 to afford the key /7-amino ketone 189 in a 2 1 diastereomeric ratio through a Mannich-type three-component reaction. This reaction was performed in an aqueous medium and the use of a surfactant such as dodecyl sulfate (DS) was essential. The diastereomeric mixture 189 was treated with HF and the... 

Plants have taken advantage of this successful synthetic principle for their enzymatic production of isoquinoline (as well as p-carboline ) alkaloids. In the chemical laboratory, this synthetic approach has been exploited for nearly 80 years in numerous biomimetic-type syntheses. This special form of the Mannich reaction requires electron-rich aromatics, if possible with ftee phenolic oxygen functions in ortho or para positions (Scheme 9). As for the carbonyl compound, aldehydes or 1,2-dicarbonyls (and very recently 1,2,3-tricarbonyls - ) are preferred. Due to the mild physiological reaction conditions required with such ideally reactive partners (often pH = 7, room temperature, aqueous medium), this condensation was also found to play a role in human organisms, leading to endogenous mammalian alkaloids... 

The synthetic utility of benzotriazole derivatives as >N—C< >N=C< synthons has been explored by Katritzky and his coworkers. The Mannich reaction of benzotriazole with primary aliphatic amines RNH2 and formaldehyde in an aqueous medium results in the formation of one or more of three types of product BtCH2NHR, (BtCH2)2NR and (BtCH2NR)2CH2 [Bt = benzotriazol-l-yl (93)]. Benzotriazole and aliphatic or aromatic aldehydes yield compounds 94. The parent compound 1-hydroxymethylbenzotriazole reacts with aromatic amines to give secondary amines 95, primary aliphatic amines give the tetiary amines 96 and aqueous ammonium acetate at room temperature yields 97. The 1-benzotriazoles 98 are obtained from benzotriazole, aldehydes and aromatic amines ... 

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