Electron-withdrawing group Mannich reaction

The classical Mannich aminomethylation is one of the most important ionic carbon-carbon bond forming reactions in organic chemistry [35]. However, only substituents with electron-withdrawing groups are suitable for the ionic addition. Electron-donating groups directly bonded to the carbon-centered radical favor nucleophilic radical addition to methylene-iminium salts. Thus, the radical-type Mannich reaction provides products which are complementary to those obtained with the classical ionic reaction. 

Usually, the reaction involves an electron-rich diene and an imine activated with an electron-withdrawing group. Mechanistically, it is suggested that the aza Diels-Alder reaction is a Mannich-Michael sequence when using electron-rich dienes. Diverse asymmetric versions of this reaction have been developed involving a chiral imine or a catalytic amount of a chiral Lewis acid. ... 

A large number of nitramine-based explosives have been synthesized via Mannich-type condensation reactions (Section 5.13.2). The amines generated from these reactions often have the powerful electron-withdrawing trinitromethyl or fluorodinitromethyl groups positioned on the carbon a to the amino group. This reduces amine basicity to an extent that A-nitration becomes facile. The energetic nitramines (17), (19) and (21) have been synthesized from the condensation of ethylenediamine with 2,2,2-trinitroethanol, 2-fluoro-2,2-dinitroethanol with ethanolamine, and 2-fluoro-2,2-dinitroethylamine with 2,2-dinitro-l,3-propanediol respectively, followed by A-nitration of the resulting amine bases (16), (18) and (20), respectively. 

It was noted above (Section IV,C,3) that the failure of 5-azaindole to undergo the Mannich reaction could be accounted for by its high basic strength. Difficulty might be expected also for 6-azaindole, and less so for 4-azaindole. The only attempt reported was successful with ethyl 5-methoxy-6-azaindole-3-carboxylate, but the predicted pK for 5-methoxy-6-azaindole would be ca. 5.9, which may be lowered further by the electron-withdrawing ester group. It will be of interest to see how the parent azaindoles differ in these reactions. 

Disconnection of TM 2.17a requires new knowledge. This stmcture corresponds to the Mannich base since the terf-amino group is present in the fl-posilion to the strong electron-withdrawing nitro group. The retra-Mannich type disconnection of two bonds leads to simple starting materials, piperidine, formaldehyde and 2-nitropropane. In the same scheme are proposed reaction conditions for the synthesis of TM 2.17. More details on the Mannich reaction are presented in Sects. 4. 4.2 and 6.1. Here it suffices to mention that this three-component reaction affords P-amino carbonyl compounds known as Mannich bases. 

Scheme 27.11). In this reaction, quite high iy -diastereo-selectivity was obtained. The electron-withdrawing imine-protecting Boc-group is important for the reactivity. The Mannich adduct 66 was transformed into a key intermediate alcohol 67 for synthesis of a potent neurokinin substance P antagonist, (-b)-CP-99,994 68. °... 

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