Iminium ions/species

There have been extensive investigations on the reaction mechanism. In most cases the reaction proceeds via initial nucleophilic addition of ammonia 2 to formaldehyde 1 to give adduct 5, which is converted into an iminium ion species 6 (note that a resonance structure—an aminocarbenium ion can be formulated) through protonation and subsequent loss of water. The iminium ion species 6 then reacts with the enol 7 of the CH-acidic substrate by overall loss of a proton ... 

Kobayashi et al. have reported that the TMSOTf-catalyzed ring-opening of benzyl (3-oxytetrahydropyran-2-yl)carbamates with silyl enolates proceeds with high 1,2-syn diastereoselectivity (Scheme 10.71) [200]. It has been proposed that the reaction mechanism involves the transient formation of an acyclic iminium ion species as the reactive intermediate. The stereoselective Mannich-type reaction is applicable to the synthesis of piperidine alkaloids. 

In this process, the presence of p-nitrobenzoic acid (PNBA) as an additive was necessary to improve the yield of the product obtained as a single anh -diastereoisomer in good to excellent enantioselectivity. The presence of PNBA likely helped the formation of the iminium ion species. The final functionalised products have been further elaborated exploiting aldol and reduction reactions. 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

Presumably the species that undergoes reduction here is a carbinolamine an iminium ion derived from it or an enamme... 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

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. 

Imines and iminium ions are nitrogen analogs of carbonyl compounds and they undergo nucleophilic additions like those involved in aldol reactions. The reactivity order is C=NR < C=0 < [C=NR2]+ < [C=OH]+. Because iminium ions are more reactive than imines, the reactions are frequently run under mildly acidic conditions. Under some circumstances, the iminium ion can be the reactive species, even though it is a minor constituent in equilibrium with the amine, carbonyl compound, and unprotonated imine. 

Alkylation reactions by the iminium methide species are well known in the mitomycin and mitosene literature 4,49,51-53 and are largely responsible for the cytotoxicity/antitumor activity of these compounds. As illustrated in Scheme 7.8, the electron-rich hydroquinone intermediate can also be attacked by the iminium ion resulting in either head-to-head or head-to-tail coupling. The head-to-head coupling illustrated in Scheme 7.8 is followed by a loss of formaldehyde to afford the coupled hydroquinone species that oxidizes to the head-to-head dimer upon aerobic workup. Analogous dimerization processes have been documented in the indole literature, 54-56 while the head-to-tail mechanism is unreported. In order to... 

Another method of activation we considered was the use of a secondary amine to generate a more electrophilic iminium species, examples of which have been used in vinylsilane-terminated cyclization reactions, particularly by Overman and co-workers [Eq. (4.8)] [51]. In our case, the unsaturated iminium ion would be activated for... 

Incorporation of CO into an organic substrate usually occurs by insertion of CO into a C-metal bond. The requisite Cl-metal bond is formed by oxidative addition of a Pd(0) species into the Cl-Br bond, the normal first step upon combining a Pd(0) compound and an aryl halide. Coordination and insertion of CO follows. Addition of N to the carbonyl and loss of Pd(0) gives an iminium ion, which is trapped by EtOH to give the product. 

Nicotine is extensively metabolized to a nnmber of metabolites (Fig. 3) by the liver. Six primary metabolites of nicotine have been identified. Qnantitatively, the most important metabolite of nicotine in most mammalian species is the lactam derivative, cotinine. In humans, about 70-80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated primarily by CYP2A6 to produce nicotine-A -iminium ion, which is in equilibrium with 5 -hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminiiim ion has received considerable interest since it is an alkylating agent and, as such, could play a role in the pharmacology of nicotine (Shigenaga etal. 1988). 

Fig. 8.21 Structures of vesnarinone, and its major metabolite veratrylpiperazinamide. The pathway metabolized by activated neutrophils gives rise to two highly reactive species, an iminium ion and a quinone imine.

The majority of transformations reported within the literature using the concept of LUMO energy lowering iminium ion activation have nsed secondary amines as the catalyst. Under the aqueous acidic reaction conditions inherent to this mode of activation it is also possible to nse primary amines as efficient catalysts where the active species is the protonated imine 141 (Fig. 13). Althongh this is a somewhat less explored avenne of research, initial results suggest it will become an equally fruitful area with broad application. 

Rueping has recently reported an interesting alknylation reaction of a-imino esters employing both phosphoric acid Ip and AgOAc as orthogonal cocatalysts [35]. As seen in the catalytic cycle in Scheme 5.21, generation of chiral iminium ion pair I nucleophilic and alkynyl-silver species II proceeds simultaneously. Subsequent nucelophilic addition completes both parallel cycles [36]. 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

The epoxidation of olefins catalyzed by iminium salts and amines (or ammonium salts) is emerging as a new technique for the functionalization of simple aUcenes. These catalysts have relatively simple structures and hence are easily produced at scale they offer potential as green oxidation catalysts. These organic salts are effective oxygen transfer reagents towards electron-rich unfunctionalized olefins. For the iminium salt systems oxone oxidizes an iminium salt to the oxaziridi-nium intermediate, which then transfers oxygen to the olefin and as oxone reacts readily with iminium ions to regenerate the oxaziridinium species catalyti-cally, efficient oxidation is possible. 

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