Secondary amines addition reactions with enolates

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

Cyclic ketones with exo cyclic methylenes can be prepared in just the same way and used in situ. Morpholine is often used as a convenient secondary amine for the Marmich reaction and the resulting amino-ketones can be methylated and undergo elimination-addition reactions with stabilized enolates such as that derived from ethyl acetoacetate. This starting material was prepared from natural menthone and the mixture of diastereoisomers produced is unimportant because the product is to be used in a Robinson annelation (see below). 

In the case of cationic complexes with unsaturated macrocycles two molecules of nucleophile, such as ammonia, amines and alkoxides, add to carbon atoms of two inline groups. For example, the reaction of [Ni(Bzo[16]octaeneN4)](C104)2 (Table 106) with sodium methoxide or ethoxide yields the compounds (395),2860 while with secondary amines and diamines complexes of type (396) are obtained.28 1 The reaction of (396) with acetone at room temperature yields complex (397) where the enolate anion of acetone, MeC(0)CH2, replaces the diethylamide group (Scheme 58). 2862 The addition of molecules such as bis(2-hydroxyethyl)methylamine and bis(2-hydroxyethyl) sulfide, HOCH2CH2YCH2CH2OH (Y = NMe, S) results in the formation of derivatives which possess one more coordination site just above the plane of the macrocyclic donors (398).2863... 

Imagine a cyclic p-fluoro-enone reacting with a secondary amine in a conjugate substitution reaction. The normal addition to form the enolate followed by return of the negative charge to expel the fluoride ion gives the product. 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

A further extension of these concepts is the alkylation of enolate / secondary amine complexes. Following several early observations [141-143]/ systematic investigations were undertaken by the Koga group [24,25,147-149]. These efforts have resulted in a very selective asymmetric alkylation of cyclohexanone and a-tetralone with activated alkyl halides (Scheme 3.25). As listed in Table 3.10, alkylation of these ketones affords up to 96% enantioselectivity. During the optimization studies, Koga observed an increase in enantioselectivity and chemical yield as the reaction time increased, and ascribed the phenomenon to the formation of a mixed aggregate that includes the lithium bromide formed as the reaction proceeds. Further experiments revealed that addition of one equivalent of lithium... 

Enamines, the products of the acid-catalyzed addition of secondary amines to aldehydes or ketones, can be viewed as weakly nudeophihc enolate anions. Enamines react with a,p-unsaturated carbonyl systems in a Michael-type reaction, introducing new carbon-carbon bonds adjacent to the carbonyl group. Endocyclic enamines, such as pyrroHnes and tetrahydropyridines, are useful for the synthesis of complex heterocycHc compounds, as found in many alkaloids (Scheme 3.19). 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

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