Iminium intermediate

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

The reductive alkylation reaction under Clarke-Eschweiler conditions has been shown to proceed through an iminium intermediate (142). 

Clemmensen reductions of a-aminoketones that proceed with ring enlargement or ring contraction are presumed to proceed by an iminium intermediate. This reaction has been examined in detail (137-139), and an example is given in the conversion of (94) to an iminium intermediate (95), which is reduced to 96. 

Another iminium intermediate that has been proposed is in the mercuric acetate oxidation of amines (46,9J). This reaction is discussed in the... 

The reaction of enamines with ketene (146) and sulfene (147) are presumed to proceed by a two-step process involving an iminium intermediate such as 99. In fact, reaction with all electrophilic olefins such as acrylonitrile and related reagents could be thought of as going through an iminium intermediate similar to 99. Another example is given by addition to an enamine... 

Some covalent compounds, such as a-aminonitriles D (formation of an iminium ion by solvolysis) or TV-substituted 1,3-oxazolidincs E can be regarded as masked iminium salts because there is evidence that in reactions of these species with organometallic reagents iminium intermediates are involved101214-17. 

These results may be rationalized by assuming an iminium intermediate (see ref 16) as depicted below. 

A catalytic mechanism, which is supported by deuterium-labeling experiments in the corresponding Ru-catalyzed procedure [146], is shown in Scheme 47. Accordingly, the reactive Fe-hydride species is formed in situ by the reaction of the iron precatalyst with hydrosilane. Hydrosilylation of the carboxyl group affords the 0-silyl-A,0-acetal a, which is converted into the iminium intermediate b. Reduction of b by a second Fe-hydride species finally generates the corresponding amine and disiloxane. 

Reductive amination by NaBH3CN can also be carried out in the presence of Ti(0-i-Pr)4. These conditions are especially useful for situations in which it is not practical to use the amine in excess (as is typically done under the acid-catalyzed conditions) or for acid-sensitive compounds. The Ti(0- -Pr)4 may act as a Lewis acid in generation of a tetrahedral adduct, which then may be reduced directly or via a transient iminium intermediate.92... 

Deprotonated trialkylstannanes are potent nucleophiles. Addition to carbonyl groups or iminium intermediates provides routes to a-alkoxy- and a-amino-alkylstannanes. 

Reduction of the iminium intermediate (17) then would produce the N-methyl derivatives (18) (Scheme 4.94). 

It is assumed that the overall process is initiated by a Michael addition of the 1,3-dicarbonyl compound onto the ci,(5-uri saturated carbonyl derivative. There follows the formation of either an aminal and an iminium intermediate which is followed by the formation of two N.O-acetals. 

A type Ilbc approach to pyrroles was employed in the synthesis of pyrrolo[2,l-fc]thiazoles <06S1433>. The key step involved a formylation with the Vilsmeier-Haack reagent followed by a cyclocondensation of the putative iminium intermediate. 

Aldehydes and the corresponding 2-aminopyridine, pyrazine, or pyrimidine are admixed in presence of a catalytic amount of clay (50 mg) to generate iminium intermediate. Isocyanides are subsequently added to the same container and the reactants are further exposed to MW to afford the corresponding imidazo[l,2-a]pyridines, imi-dazo[l,2-a]pyrazines and imidazo[l,2-a]pyrimidines (Scheme 6.48). The process is general for all the three components, e. g. aldehydes (aliphatic, aromatic and vinylic), isocyanides (aliphatic, aromatic and cyclic) and amines (2-aminopyridine, 2-amino-pyrazine and 2-aminopyrimidine). A library of imidazo[l,2-a]pyridines, imidazo[l,2-ajpyrazines and imidazo[l,2-a]pyrimidines can be readily obtained by varying the three components [151]. 

An interesting transformation was discovered by Sakai and Shinma (181) during the chemical investigation of corynanthe alkaloid (V-oxides. Polonovski reaction and sodium cyanoborohydride reduction of hirsuteine A-oxide (331) gave corynantheine (52) and 3-isocorynantheidine (65), the latter likely formed by reduction of the conjugated iminium intermediate 334. 

The precursor to the enamine 58 was identified as iminium intermediate 56 in studies using Streptomyces griseus, copper oxidases (172,173), and peroxidases (78). Although it was impossible to isolate the highly unstable iminium derivative itself, the 16-O-acetyl derivative 57 was stable and isolable. Thus when 16-... 

Scheme 36 Anodic decarboxylation of N-acyl a-amino acids to a N-acycl iminium intermediates.

The anodic lactonization of a 2-pipe-ridinone carboxylic acid (Scheme 28) [39] results from a coupling reaction between the nucleophilic carboxylate and the electrogenerated iminium intermediate. 

When imines are the nucleophiles used, the initially formed iminium intermediates can undergo intramolecular electrophilic alkylation of the other ligands (e.g. Entry 2, Table 2.10 see also [143]). In addition to this, carbyne complexes can also react with azides to give metallatriazoles [185,186] (Entry 6, Table 2.10). 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The formation of bicycles 88 occurred through the iminium intermediate 89, in the similar manner as Ugi-reaction. But in contrast to the four-component classical Ugi-reaction, the protonated Schiff base 89, containing both nucleophilic and electrophilic centers, undergoes [4+1] cycloaddition with isonitrile to the bicyclic adduct 90 followed by rearomatization via 1,3-H shift (Scheme 39). 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

The formation of activated iminium intermediates derived from nitrogen heterocycles has been reported by Comins . The activation of pyridine derivative such as 214 with phenyl chloroformate provides the pyridinium salt 215, which smoothly reacts with the zinc homoenolate 216 leading to the addition product 217 in 66% yield . The reaction... 

SCHEME 63. Reaction of zinc organometalUcs with iminium intermediates... 

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