Iminium ion intermediates

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

Mechanism of enamine formation by reaction of an aldehyde or ketone with a secondary amine, R2NH. The iminium ion intermediate has no hydrogen attached to N and so must lose H+ from the carbon two atoms away. 

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. 

Different rate-determining steps are observed for the acid-catalyzed hydration of vinyl ethers (alkene protonation, ks kp) and hydration of enamines (addition of solvent to an iminium ion intermediate, ks increasing stabilization of a-CH substituted carbocations by 71-electron donation from an adjacent electronegative atom results in a larger decrease in ks for nucleophile addition of solvent than in kp for deprotonation of the carbocation by solvent. 

In the presence of alcohols, the corresponding ethers are formed and added nucleophiles such as chloride ion40 or azide ion41 lead to the chloro- and azido-amine products, respectively. Rate constants are independent of the concentration of added nucleophile. Labelled 180 from the solvent is incorporated in the product42. All the evidence points to a reaction mechanism where water is lost from the O-protonated reactant to give a nitrenium ion-iminium ion intermediate which is rapidly trapped by a nucleophile (H2O in this case) to give the final product. This is shown in Scheme 7. Protonation at N- is likely to be more extensive, but there is no pathway to products from the N-protonated intermediate. 

A new synthesis of arylmethylene- and arylmethine-pyrroles [25 R = CH2C6H4X and CH(C02H)CH2Y] uses 2,5-dimethoxytetrahydrofuran (26). The reaction is subject to acid-base catalysis, and is typically successful only in solvent mixtures of such character, e.g. acetic acid-pyridine. A mechanistic investigation has identified a number of iminium ion intermediates [e.g. tautomerism (27a) (27b)] to explain by-products in particular cases. 

Hine has demonstrated that simple amino acids, such as glycine and p-alanine, are not capable of intramolecular deprotonation in the reaction with isobutyraldehyde-2-d (Scheme 8) [62], Apparently, the carboxylate moiety in the iminium ion intermediate 29 is a relatively weak base and, as such, external bases, present in the buffer used (e.g. acetate ions), are largely responsible for the formation of the enamine intermediate 30. 

In the initial report by MacMillan, use of the imidazolidinonium salt 12 HC1 to generate iminium ion intermediates identified a new catalytic strategy for the activation of a,P-unsaturated carbonyl compounds towards cycloaddition [3]. Inherent... 

The majority of recent contributions for the conjugate addition of C-H acids to a,p-unsaturated carbonyl compounds catalysed through iminium ion intermediates have come from the laboratories of Jprgensen. The ease with which 1,3-dicarbonyl compounds and nitroalkanes can be deprotonated, together with the soft nature of the nucleophile mean this is a particularly facile reaction which conveniently leads to useful precursors for further synthetic manipulation. 

Although the precise mechanisms for each of these examples have yet to be determined, a pathway involving iminium ion intermediates appears reasonable. Further optimisation of the complex dual catalyst systems may well lead to a general and robust procedure that will prove of considerable use in synthesis. 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

It can be expected that inclusion of 1,2-addition reactions catalysed by iminium ion intermediates will allow for further rapid introduction of architectural diversity into simple building blocks through similar domino type processes addressing one of the critical objectives in contemporary synthetic chemistry. 

Platts and Tomkinson reported a detailed quantitative study of the iminium ion catalysed Diels-Alder reaction between cyclopentadiene and cinnamaldehyde catalysed by trifluoromethyl pyrrolidine salt 182-HPFg [227]. This combination of secondary amine, co-acid and dienophile allowed the isolation and structural elucidation of the reactive iminium ion intermediate. As a result it was possible to... 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

In the presence of the TiCLt catalyst, 6-amino-substituted allylsilanes readily react with isobutyraldehyde to yield piperidine derivatives 88 (equation 60)128. Presumably, an iminium ion intermediate is formed and the Boc group is replaced under the reaction conditions. It is noteworthy that the regioselectivity is different when acid chloride in used as the electrophile (cf Section II.B.5). 

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. 

The synthesis and aqueous chemistry of a-acetoxy-A-nitrosomorpholine (22) has been described.58 It decomposes cleanly, with first-order kinetics, via an A-nitroso-iminium ion intermediate (23), with the pH-rate profile showing acid- and base-catalysed regions, and an extensive pH-independent region between 3 and 9, the latter being ca 100 times slower than its C-analogue, the corresponding piperidine derivative. Implications for the interaction of A-nitrosomorpholine with DNA are discussed. 

Although the anodic generation of a cation in a-position to nigrogen in aliphatic amines is not difficult, this type of reaction is not always useful to the synthesis of alkaloidal compounds, since the cation is not stable and a simple dealkylation is the usual follow-up reaction. N-monomethyl and N,N-dimethylanilines are, however, useful starting materials for the synthesis of the skeleton of tetrahydroquinoline. The anodic methoxylation of N,N-dimethylaniline 20 takes place at the methyl group, and an iminium ion intermediate 22 is easily generated by treatment of the methoxylat-ed product 21 with Lewis add. This intermediate can be trapped in situ with a variety of nucleophiles such as electron-rich olefins yielding tetrahydroquinolines 23 16). 

A mechanistic rational for the ionization of pyrrole-3-triflates 72 was proposed as shown below (Eq. 8). Heterolytic cleavage of the sulfonate ester bond, assisted by donation of the nitrogen lone pair, results in loss of the triflinate ion59 and gives rise to the C-acyl iminium ion intermediate 73. This process is further facilitated by the stabilizing effect of a... 

Evidence that this reduction proceeds mainly via an N-acyl iminium ion intermediate 120 was obtained by carrying out the triethylsilane reduction of 108 in deuterated trifluoroacetic acid (Scheme 49). As before, two C-4 epimeric protected kainoid analogues 121 and 122 were obtained, H NMR showing loss of the C-4 proton in both products accompanied by a simplification in the spin-spin coupling pattern of the C-5 protons.73 A close examination of the 2H NMR spectrum of each diastereoisomer did, however, reveal a trace of deuteration at C-5 indicating that a small percentage of the reduction also occurs via a benzylic carbocation intermediate 123 (Figure 12). 

From a mechanistic point of view, the first step is the formation of the iminium ion intermediate by reaction of the a,/i-unsaturated aldehyde with the chiral... 

Therefore, primary amines get converted to secondary amines and secondary amines are converted to tertiary amine. The reaction is suitable for the synthesis of primary amines if ammonia is used instead of an alkylamine. The reaction goes through an imine intermediate if ammonia or a primary amine is used. When a secondary amine is used, an iminium ion intermediate is involved. 

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