Synthesis and utilization of Mannich bases

CH3COCH3 + CH2O + (CH3CH2)2NH2Cr - CH3COCH2CH2CH2N(C2H5)2Cr 

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHTI ES WITH CARBONYL GROUPS 

Mannich reactions, or at least some close mechanistic analogs, are important in the biosynthesis of many nitrogen-containing molecules. As a result, the Mannich reaction has played an important role in the total synthesis of such compounds, especially in synthesis patterned after the mode of biosynthesis, i.e., biogenetic-type synthesis. The earliest example of the use of the Mannich reaction in this context was the successful synthesis of tropinone, a derivative of the alkaloid tropine, by Sir Robert Robinson in 1917. 

Acylation of Carbanions. The Claisen, Dieckmann, and Related Condensation Reactions 

The most generally used carbonyl compounds for the acylation of enolate ions are esters. Here, nucleophilic addition of the anion to the carbonyl group is followed by loss of alkoxide from the tetrahedral intermediate. A classic example of this type of reaction is the Claisen condensation—the base-catalyzed self-condensation 

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In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2> and the utilization of A/-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and A(-unsubstituted 3-lactams, available via hydrolysis or reduction of the N—X bond. 

There are undoubtedly many early examples of the phenomenon now known as phase transfer catalysis and a presentation of all of them is neither valuable nor feasible. Some of the early work does merit presentation, however, if only to provide a sense of perspective on the field. Wittig and coworkers demonstrated in 1947 the value of utilizing tetramethylammonium cations paired with trityl and fluorenide ions for alkylation in dry alcohol solution [1 ]. Jarrousse found that cyclohexanol and phenyl-acetonitrile could both be alkylated in a two phase system and the catalytic effect of quaternary ammonium salts was clearly recognized (see Eqs. 1.1 and 1.2) [2] Sarrett, in his classic cortisone synthesis, found that either Triton B or the Mannich base... 

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