Nucleophilic addition to iminium ions

One simple example was the hydrolysis of imines hack to carbonyl compoimds via nucleophilic attack of water. The Mannich reaction is only a special case of nucleophilic addition to iminium ions,... 

It might appear that the simplest possible type of system to which ALPH might apply is a system with one lone pair only, and which does not involve a proton transfer. Reactions of a-substituted amines, or their microscopic reverse, nucleophilic additions to iminium ions, thus suggest themselves as suitable testbeds for ALPH, but the information on such systems is sparse. Stevens (1984) has studied the addition of carbon nucleophiles to tetra-hydropyridinium salts from the standpoint of utility in organic synthesis, and found a preference for axial attack, in accord with ALPH (Scheme 4). 

Triisopropylsilyloxyfurans were effective nucleophiles for the vinylogous Mannich addition to iminium ions that were formed by Rh2(cap)4-catalyzed oxidation of N-alkyl groups by THYDRO <06JA5648>. A stereoselective addition of 2-trimethylsilyloxyfurans to aryl aldehydes-derived aldimines employing a chiral phosphine/Ag complex as catalyst was developed <06AG(I)7230>. The prototypical example is shown below. 

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

Although electron-rich aromatics typically undergo 1,2-carbonyl addition, the iminium ions derived from 4/f-imidazol-4-one 456a are inert to the 1,2-pathway due to steric constraints imposed by the catalyst framework. The heteroaromatic nucleophiles react via the less sterically demanding 1,4-addition pathway (Equation 109). With TEA as the cocatalyst, ee values of 89-97% were obtained with a range of substituted pyrroles (R = Me, Bn, allyl). In addition, ee values of 87-93% were obtained with alkyl, aromatic, or electron-withdrawing substituents on the ot, 3-unsaturated aldehydes (R = Me, Pr , Bn, Ph, MeC02). 

On the other hand, Overman described that additions of iminium ions to alkynes can be achieved when nucleophilic anions are added to the reaction mixture [115,116]. 

The nucleophilic addition of cyanide ions to the electrochemically generated iminium cation is a synthetically very useful reaction and has been studied for a variety of symmetric and unsymmetric ions (Table 10) [266]. 

It was concluded that the amino-substituted allylic halides 6 (X = Cl, Br) are the precursors to the bicyclic compound 7 via Favorskii-type ring closure to iminium ions and subsequent nucleophilic addition of the amine. 

At this point it is only speculation that addition of biologically relevant sulfur-containing nucleophiles constitutes a detoxication reaction for metabolites of nicotine. Finally, because nucleophilic addition to the nicotine iminium ion is reversible, from a practical standpoint, an addition compound will probably only be formed and detected under conditions where the nucleophile is present in large excess. 

Most ir-nucleophiles employed in iminium ion cyclizations have a predetennined postcyclization destiny. For example, aromatic terminators will rearomatize, organosilanes will eliminate silicon through anticipated pathways and acetals and enol ethers will produce carbonyl compounds. However, the cyclizations of simple alkenes have supplied products that are the formal results of eliminations, additions and Wagner-Meerwein rearrangements. Almost exclusively Mannich-type cyclizations of unsaturated amines have been employed to prepare piperidines. 

A-(2-lndol-3-ylethyl)pyridinium ions can be converted to iminium ions that undergo cycloaddition by addition of nucleophiles at C-4 of the pyridine ring. Two chiral nucleophiles have been explored. The anions of h -8-phenylmenthyl malonate or 2-(f-butyl)-6-methyl-l,3-dioxolan-3-one gave moderate yields, the latter with complete diastereoselectivity. The adduct was taken on to the alkaloids (+)-vallesiachotamine and (—)-isovallesiachotamine [349]. 

Experimental evidence has lead to the conclusion that option a does not occur. Kinetic effects, pH dependencies, stoichiometry, and solvent polarity all led to the second option, b, as being the actual mechanistic pathway. Under basic conditions, the key reactive intermediate is the hydroxymethyl amine species 6. The Mannich base 5 is produced through a nucleophilic displacement by the corresponding anion (enolate) of the active hydrogen species 1. As the pH shifts to more acidic conditions, the relative proportions of the reactive intermediates also shift. The hydroxymethyl amine 6 becomes protonated and, with loss of an equivalent of water, generates iminium ion 7. Subsequently, this species can react directly with the active hydrogen species 1 or via the methylene bis-amine 8, formed by the addition of a second equivalent of amine 3 to iminium ion 7 (under conditions of excess amine). 

The Exterior Frontier Orbital Extension (EFOE) model has been applied to predict r-facial selectivity in nucleophilic additions to imines and iminium ions of the cyclohexanone, tropinone, and adamantan-2-one systems." A review of the EFOE model," and other references to its use, are described later under Regio-, Enantio-, and Diastereo-selective Aldol Reactions. 

The nonenzymatic cyclization is an internal imine formation that occurs by nucleophilic addition of the amine to the carbonyl group followed by loss of water. The enzymatic reduction is a nucleophilic addition to the iminium ion a v... 

This reaction can also occur under oxidative conditions. The in situ generation of the iminium ion from the tertiary amine in the presence of DDQ is followed by the (V-methylindole nucleophilic addition to provide the Mannich adduct in 91% yield and >20 1 dr (eq 12). ... 

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