Heterocyclic compounds Mannich reaction

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

A second group of substrates displaying chemoselectivity is schematically listed in Table 8 and includes compounds having active sites capable of mutual interaction in the course of the Mannich reaction, as they are constituted by functional moieties, usually unsaturated heterocycles, in which the possibility of equilibrium between different forms of the substrate (tautomers, ete.) may lead to correspondingly different products. 

Kainetani, T., Taguchi, li., Yamaki, K., and Kozuka, A., Syntheses of heterocyclic compounds. DXVII. Syntheses of berberine and related compounds. II Mannich reaction of 1-benzylisoquinolinc under various conditions, Yakugaku Zasshi, 93,529, 197.3 Chem. Ahstr.. 79, 79005, 197.3,... 

Heterocyclic compounds originated by the involvement of the amine moiety of the base (group B) can be prepared from several different classes of Mannich derivatives P-aminoketones in particular, are largely employed. Thus, 4-hydroxypipcridines 322 are obtained from bis-ketones 321 (Fig. 124), prepared by Mannich synthesis with primary alkylaminc. Both the mechanism and the stereochemistry - of the reaction have been investigated it has been demonstrated that cyclization proceeds -stereo.specif-ically, and the resulting product has the configuration depicted in 322. 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

Pyrroles are exceptionally nucleophilic heterocycles and undergo electrophilic substitution reactions with very weak electrophiles. The reactivity of pyrrole may be compared with that of N,(V-dimethyl-aniline or phenol all three compounds couple with the benzenediazonium ion. It is no surprise, therefore, that Mannich reactions of pyrrole and substituted pyrroles have been studied in considerable detail. We will concentrate our attention on recent studies. 

A variant of Mannich polyol synthesis is based on the reaction between phenols and an oxazolidine (OXA), a heterocyclic compound resulting from the reaction of an alkanolamine (primary or secondary, not tertiary) and an aldehyde or a ketone (reaction 15.14). 

The use of hydroxymethylene menthone (170) was mentioned earlier (cf. Vol. 2, p. 28), and part of the work described has been repeated. This compound (170) and the Mannich base derived from menthone (171) have been used to prepare some heterocyclic compounds related to menthone (Scheme 12). Somewhat similar is the reaction of piperitenone (172) with ammonia, leading... 

Highly frmctionalized heterocycles could be assembled using an organocatalytic, asymmetric variation of the Mannich reaction. Cyclic urea 130 could be generated from Mannich base 129. This compound was accessible by the reaction of 127 and 128 catalyzed by the chiral amine 129. 

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