Mannich reactions of aldehydes

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

A convenient route to 1-amino-1 //-2,3-benzopyrrolizines (28) was achieved by a Mannich reaction of aldehyde 27. Catalytic hydrogenation of either the base (28a) or trimethylammonium iodide (29) was accompanied by elimination to give compound 30. Treatment of 29 with potassium cyanide gave nitrile 31.28... 

The intramolecular cyclization of /3-carboethoxy-/ -amino acid 379, synthesized from L-proline-catalyzed Mannich reaction of aldehydes with an iminoester and subsequent oxidation, with sodium hydroxide yielded the cyclopentane-spirofused azetidin-2-one 380 (Scheme 56) <20040L2507>. 

The (S)-proline-catalyzed Mannich reactions of aldehyde donors and N-PMP-protected imines of fluorinated aldehyde, such as CF3CHO, C2F5CHO, and PI1CF2CHO, were also used for the expedient synthesis of fluorinated aminoalco-hols [81]. 

Table 2.14 (S)-Proline-catalyzed three-component Mannich reactions of aldehyde donors [71b, 82].

General Procedure for Direct Mannich Reaction of Aldehydes and Preformed Imines [10] (p. 39)... 

Hayashi Y, Tsuboi W, Ashimine I, Urushima T, Shoji M, Sakai K (2003b) The direct and enantioselective, one-pot, three-component, cross-mannich reaction of aldehydes. Angew Chem Int Ed Engl 42 3677-3680... 

Miscellaneous reactions. The starting point of a practical route to P -amino acids is the proline-catalyzed Mannich reaction of aldehydes with a chiral iminium salt derived from A-benzyl-A-(a-phenethyl)amine. Condensation of aldehydes with A-Boc imines furnishes mainly i yn-adducts. "... 

Further reactions have been used for cyclization. Phenylindole and diketene gave the acetoacetyl derivative (89), which on treatment with PPA gave the benzopyrrolizinone (90) <76AP(309)I31, 76AP(309)185>. An efficient synthesis of the aminopyrrolizine (92a) was achieved by Mannich reaction of aldehyde (91). Treatment with sodium cyanide gave nitrile (92b) <71JOC3992>. 

Marques, M.M.B. (2006) Catalytic enantioselective cross-Mannich reaction of aldehydes. Angewandte Chemie — International Edition, 45, 348-352. 

Scheme 5.13 Asymmetric Mannich reaction of aldehydes with preformed Af-Boc-imines.

In analogy with the above-mentioned amine-catalysed aldol reactions, our binaphthyl-based amino sulfonamide catalysts showed unique reactivity and selectivity in the asymmetric Mannich reaction of aldehydes. For instance, the Mannich reaction of propanal with an a-imino ester catalysed by (S)-3 gave the antr-Mannich adduct as a major diastereomer, while the syn-Mannich adduct was obtained in the proline-catalysed reaction first reported by the Barbas group (Scheme 17.8). ... 

Scheme 17.9 Mannich reaction of aldehydes with an IV-Boc-protected imine.

Yao et al. [92] reported one-pot synthesis of flavanone 64 via Mannich type reaction catalyzed by molecular iodine. A simple workup and the high compatibihty of functional groups made this an attractive synthetic approach to access flavanone derivatives (Scheme 10.46). The three-component Mannich reaction of aldehyde, amine, and enolizable ketone to obtain the P-aminocaibottyl compounds has been known, bnt when the Mannich reaction of benzaldehyde, aniline, and 2-hydroxyacetophenone had been explored in the presence of iodine, no trace of p-aminocaiboi l compound is observed and flavanone was formed as the sole product in moderate yield. 

Figure 7.3 Putative coordinated intermediates involved in Petasis borono-Mannich reactions of aldehydes possessing neighboring heteroatoms.

This catalyst was also employed by Melchiorre et al. to promote the first aminocatalysed anti-selective Mannich reaction of aldehydes with A-Cbz-and A-Boc-protected imines generated in situ from stable a-amido sulfones (Scheme 3.11). Besides the high level of efficiency and stereocontrol achieved, this approach introduced important synthetic advantages, by avoiding the requirement to perform the A-carbamoyl imines. 

Scheme 42.2 Three-component Mannich reaction of aldehydes NMP = N-methyi-2-pyrroiidinone.

Scheme 42.27 Sequential three-component Mannich reaction of aldehydes 122, anilines 123, and enecarbamates 124 for the synthesis of 1,3-diamines 126.

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