Aldehydes Mannich reactions with

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Fig. 17. Mannich reaction with aldehydes other than formaldehyde.

Enders and co-workers [162] have reported a protocol for the synthesis of aminopentoses and aminohexoses based on the use of 2,2-dimethyl-l,3-dioxan-5-one (25) as the ketone donor in a three-component Mannich reaction with several aldehydes and p-anisidine in the presence of L-proline or (fert-butyl)dimethylsilyloxy-L-proline as organocatalysts. 

The three-component Mannich reactions with various donor aldehydes have been studied also by Hayashi and co-workers [164], giving rise, after reduction, to several aminopolyols with high i yw-diastereo and enantioselectivities. 

The Morita-Baylis-Hillman reaction and its aza-variant - the reaction of an electron-deficient alkene with an aldehyde (MBH) or an imine (aza-MBH) - provide a convenient route to highly functionalized allylic alcohols and amines. This reaction is catalyzed by simple amines or phosphines, which can react as a Michael donor with an electron-deficient alkene, generating an enolate intermediate. This intermediate in turn undergoes the aldol or Mannich reaction with electrophilic C=0 or C=N bonds, respectively, to deliver allylic alcohols and amines. 

The pathway proposed for the reaction of aryl aldehydes and enolizable ketones in DIMCARB involved formation of a putative, transient iminium species that underwent Mannich reaction with the ketone. Subsequent elimination of dimethylamine from the Mannich adduct occurred slowly in situ to afford the 2-arylidene derivative (Scheme 6.1)."... 

As illustrated in Table 10, a wide variety of enolates undergo Mannich reactions with A A -dimethyl-(methylene)iminium salts. They include ester (entries 1), lactone (entries 2-4), a-ethoxycarbonyllactone (entry 5), acyliron (entry 6), aldehyde (entry 7), carboxylic acid (entry 8), and ketone (entries 9-12) enolates. Yields are gener ly comparable to the direct enol silane method except in the case of aldehydes... 

Control of the pH is also of importance for the Mannich-based bispidine synthesis. Formation of an aldol product competes with the Mannich condensation in the basic pH region. It is for this reason that, in some cases, the reaction is sensitive to the order in which the reactants are added to the reaction mixture. It is possible to add the aldehyde and amine components one after another to a solution of the CH-acidic compound, but sometimes the aldol reaction can be disfavored by changing the order. This allows the imminium ion to be formed in advance. The precursors of 45 and 46 have been prepared by this method. In some cases, it has been useful to use a protonated amine component as the acetate salt (e.g., 49 or precursors for 44, 47, and 48), as the chloride salt (e.g., 11) or to carry out the reaction in acetic acid. Aromatic amines (e.g., aniline) give rise to para-substituted aromatic amines if the solution is not approximately neutral. In a very elegant procedure, a condensate of formaldehyde and aniline, which is the trimeric methyleneaniline, was prepared separately, and treated in the Mannich reaction with dimethyl acetonedicarboxylate and formaldehyde to yield the 3,7-diphenylbispidone... 

Various 2-oxo compounds have been subjected to a variety of reactions. Alkylation and acylation result in the formation of 1,3-disubstituted products.Similarly the Mannich reaction with morpholine gives products such as the bis compound 107. Halogenation of the 0x0 compound 108 with bromine in acetic acid," or chlorine in acetic acid, ° or with sulfuryl chloride results in formation of the monohalo derivatives 109. The chlorine atom in 109 (R = Cl) can be removed by hydrogenation over palladium on charcoal. Nitration of the chloro compound 110 with a mixture of nitric and sulfuric acids provides the nitro derivative 111, which may be catalytically reduced to the amino compound 112. If the reduction is carried out in the presence of an aldehyde, the product is a substituted amino derivative (113). Alternatively the amine 112 can be condensed with an aldehyde and the resultant Schiff base reduced to give the product 113. 

Mannich reaction with acetals. The Mannich reaction of formaldehyde with acetals of aliphatic aldehydes with more than three carbon atoms gives aeryl-aldehydes (1) in 50-807o yield (equatioh I). In the case of a chiral acetal, the reaction proceeds with an optical yield of 80%. ... 

Scheme 5.12 Asymmetric Mannich reaction with unmodified aldehydes as nucleophiles.

Also, a large number of indole alkaloids are formed by Mannich reactions involving tryptophan or its decarboxylation product tryptamine with various aldehydes. Both the a- and p-position of the indole nucleus are electronegative, and a Mannich reaction with tryptamine can yield a p-carboline derivative or a 3,3-spiroindolenine [30]. A further example is provided by the tropinone biosynthesis (Figure 1.29) [31 ]. 

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