Aqueous Mannich-type reactions

As mentioned in the previous sections, silyl enolates are excellent enolate components in the Mannich-type reactions with imines. Alternatively, it was foimd that vinyl ethers also reacted with imines smoothly in the presence of a catalytic amount of Ln(OTf)3, to afford the corresponding P-aminoketones. In addition, the reactions proceeded smoothly by the combination of aldehydes, amines and vinyl ethers in aqueous media [53]. 

A general scheme for the new Mannich-type reaction is shown below  

The procedure is very simple. In the presence of 10mol% of Yb(OTf)3, an aldehyde, an amine and a vinyl ether were combined in a solution of THF-water (9 1) at room temperature to afford P-aminoketone. 

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On the other hand, Kobayashi has developed a Bronsted acid-combined catalyst for aqueous Mannich-type reactions. Three-component Mannich-type reactions of aldehydes, amines, and ketones (e.g., benzaldehyde, p-anisidinc. and cyclohexanone) were efficiently... 

A possible mechanism for the present reaction is shown in Scheme 9. It should be noted that dehydration accompanied by imine formation and successive addition of a vinyl ether proceed smoothly in aqueous solution and that the first aqueous Mannich-type reaction catalyzed by Ln(OTf)3 has been developed [57]. Use of Ln(OTf)3> a water-tolerant Lewis acid, is key and essential in this reaction. 

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... 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

More recently, Porta and co-workers have reported a free-radical Mannich type reaction based on the selective a-CH aminomethylation of ethers by a Ti(III)/t-BuOOH system under aqueous acidic conditions (Equation 14.27) [34]. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

Reaction of l-(3,4-dimethoxybenzyl)-9-hydroxy-l,2,3,4-tetrahydro-8//-pyrido[l,2-a]pyrazin-8-one with 37% formaldehyde solution gave a tetracyclic tetrahydroprotoberberine analogue in a Mannich-type reaction (78AJC187). Reactions of 2,3,4,4a,5,6-hexahydro-l//-pyrazino[l,2-a]-quinolines with 1 W-pyrrolo[2,3-h]pyridine in the presence of 37% aqueous CH20 and AcONa in AcOH, and with 3-dimethylaminomethyl-l //-pyrrolo[2,3-h]pyridine afforded 3-[(l//-pyrrolo[2,3-h]pyridin-3-yl)methyl] derivatives (94MIP6 96USP5576319). 

Mannich-type reactions of aldehydes, amines, and vinyl ethers proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3 in aqueous media (Eq. 20) [69]. Commercially available aqueous solutions of formaldehyde and chloroacetaldehyde were used directly and the corresponding /3-amino ketones were obtained in good yields. Phenylglyoxal monohydrate, methyl glyoxylate, an aliphatic aldehyde, and an a,/3-unsaturated aldehyde also worked well to give the corresponding /3-amino esters in high yields. 

Cordova, A., Barbas, C. E. Direct organocatalytic asymmetric Mannich-type reactions in aqueous media one-pot Mannich-allylation reactions. Tetrahedron Lett. 2003,44,1923-1926. 

Quite recently, chiral diamine ligands have been used by Kobayashi et al. for highly enantioselective Mannich-type reactions [228, 229]. The chiral complex prepared from chiral diamine 89a and Cu(OTf)2 effects highly enantioselective addition of silyl enolates to a-N-acyhmino esters (Scheme 10.82) [228]. The first example of catalytic asymmetric Mannich-type reaction in aqueous media has been achieved by the combined use of ZnF2, diamine 89b, and TfOH in the reaction of a-hydrazono esters [229]. 

Dong et al. reported the preparation of a novel Brbnsted acid-surfactant-combined halogen-free ionic liquid [DDPA][HSO ] that bears a propane sulfonic acid group in an acyclic dimethyldodecylammonium cation (Fig. 12.69) [42] and its use in the heterogeneous catalysis procedure of one-pot three-component Mannich-type reaction in aqueous media. 

Dong F, Zhenghao F, Zuliang L (2009) Functionalized ionic liquid as the recyclable catalyst for Mannich-type reaction in aqueous media. Catal Commun 10 1267-1270... 

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