Iminium ions nucleophilic attack

The formation of 88 is postulated to be occurring by the nucleophilic attack of a hydride ion (47), abstracted from the secondary amine, on the a-carbon atom of the iminium salt (89). The resulting carbonium ion (90) then loses a proton to give the imine (91), which could not be separated because of its instability (4H). In the case of 2-methyIhexamethylenimine, however, the corresponding dehydro compound /l -2-methylazacyclo-heptene (92) was isolated. The hydride addition to the iminium ion occurs from the less hindered exo side. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

The diversity of the Ugi-MCR mainly arises from the large number of available acids and amines, which can be used in this transformation. A special case is the reaction of an aldehyde 9-26 and an isocyanide 9-28 with an a-amino acid 9-25 in a nucleophilic solvent HX 9-30 (Scheme 9.5). Again, initially an iminium ion 9-27 is formed, which leads to the a-adduct 9-29. This does not undergo a rearrangement as usual, but the solvent HX 9-30 attacks the lactone moiety. Such a process can be used for the synthesis of aminodicarboxylic acid derivatives such as 9-31 [3, 30],... 

The whole process, formation of the iminium ion by condensation of the aldehyde with an amine (1 min at 900 W in a domestic oven) then nucleophilic attack of the isocyanide (1 min at 450 W and 1 min cooling) takes 3 min to give yields ranging from 56 to 88% of the pure product. 

A hydroxy group can be introduced on this bicyclic system as a nucleophile. The pyrrolo[l,2-c]oxazole system can be hydroxylated at the 7a-position to produce in good yield the corresponding 7a-hydroxypyrrolo[l,2-c]oxazole. The diastereoselectivity of this nucleophilic addition is total, with attack at the iminium ion on the face hindered by the phenyl group at C-3. <2002TL463, 2004JOC7558, 2006TA53>. 

The combination of an amine and an aldehyde under weakly acidic conditions almost always gives an iminium ion very rapidly. Such a reaction forms the N1-C8 bond. Nucleophilic C7 can then attack this iminium ion to give a carbocation. Fragmentation of the C5-Si6 bond gives the product. 

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,... 

Molecular modeling of the reaction predicts attack of the CN" ion on the re face of the iV-allyl benzaldimine carbon to provide an (5)-adduct. The aromatic ring of the imine and the quinuclidine hydrogen bond stabilizes the iminium above the pyridazine, blocking the rear face of the imine bond. Nucleophilic attack by CN is... 

In a series of important papers, MacMillan described the alkylation of electron rich aromatic and heteroaromatic nucleophiles with a,P-unsaturated aldehydes, using catalysts based upon the imidazoUdinone scaffold, further establishing the concept and utility of iminium ion activation. In line with the cycloaddition processes described above, the sense of asymmetric induction of these reactions can be rationalised through selective (F)-iminium ion formation between the catalyst and the a,P-unsaturated aldehyde substrate, with the benzyl arm of the catalyst blocking one diastereoface of the reactive Jt-system towards nucleophilic attack (Fig. 3). 

An example of the 7d-type cyclization is that of iminium salt 38b obtained by decarbonylation of a-(ferf-amino) acid 38a. Attack of the nucleophilic malonate on the newly formed electrophilic carbon of the iminium ion gives dicarboxylate 39a (79JOC4173). 

Hydrogen bonding to substrates such as carbonyl compounds, imines, etc., results in electrophilic activation toward nucleophilic attack (Scheme 3.1). Thus, hydrogen bonding represents a third mode of electrophihc activation, besides substrate coordination to, for example, a metal-based Lewis acid or iminium ion formation (Scheme 3.1). Typical hydrogen bond donors such as (thio)ureas are therefore often referred to as pseudo-Lewis-acids. ... 

Mechanism. The neutral amine nucleophile attacks the carbonyl carbon to form a dipolar tetrahedral intermediate. The intramolecular proton transfer from nitrogen and oxygen yields a neutral carbinolamine tetrahedral intermediate. The hydroxyl group is protonated, and the dehydration of the protonated carbinolamine produces an iminium ion and water. Loss of proton to water yields the imine and regenerates the acid catalyst. 

The nitrogen and sulfur mustards undergo internal ring closure to an iminium ion (Eq. 5-20) which can then open by attack of a nucleophilic atom of the nucleic acid. 

In principle, there are four possible transition states for the attack of a nucleophile on a cyclic iminium ion such as 67. Two of these, 7] and 72, are boat-like transition states and are kinetically disfavored. Of the two possible chair-like transition states, 70 and 73, the latter suffers from an unfavorable 1,3-diaxial interaction between the R group and the incoming nucleophile. Transition state 70 is therefore favored. 

Ring-constrained analogues 37 of the anti-inflammatory drug, diclofenac, have been prepared by acid-catalyzed condensation of aldehydes (or ethylene ketals of ketones) with 36 (Equation 4) <1998MI201>. This reaction presumably proceeds via intramolecular nucleophilic attack by the carboxylic acid group on an iminium ion intermediate from condensation of the secondary amine. Interestingly, the compounds 37 showed comparable activities to diclofenac in the formalin-induced rat paw edema test. 

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). 

The nucleophilic carbon atom attacks an electrophile to give a resonance-stabilized cationic intermediate (an iminium ion). 

Amines react with formaldehyde to give iminium ions, (R2N=CH2)+ which can be attacked by nucleophiles. 

---