Imine iminium ion

The most important reactions of this type involve addition to the carbonyl group, but reactions involving imines, iminium ions, and nitriles are also synthetically important. 

REDUCTION OF IMINES, IMINIUM IONS, HYDRAZONES AND OXIMES 583... 

A special case of aminals is the one derived from benzotriazole. These Ar-(a-aminoalkyl)triazoles 27 are readily prepared by condensation of an amine, aldehyde, and, in this case, benzotriazole. The derivatives 27 can be regarded as masked imines/iminium ions and can react with the appropriate nucleophiles in a Mannich sense. Thus treating the enolate of cyclohexanone (28) with a diverse array of triazoles (27) was able to give rise to the corresponding Mannich bases 29. 

The protonated imine is the dominant reactive form. Although the protonated aldehyde is more reactive, its concentration is very low because it is much less basic than the imine or the reactant hydroxylamine. On the other hand, even though the aldehyde may be present in a greater concentration than the protonated imine, its reactivity is sufficiently less that the iminium ion is the major reactant. ... 

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. 

Under acidic conditions, imine 12 is protonated to give the iminium ion 13 which undergoes an electrophilic aromatic substitution reaction to form the new carbon-carbon bond. Rapid loss of a proton and concomitant re-aromatization gives the tetrahydroisoquinoline 14. 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

HCN adds to imines, Schiff bases, hydrazones, oximes, and similar compounds. The CN ion can be added to iminium ions ... 

The reductive couphng of imines can follow different pathways, depending on the nature of the one-electron reducing agent (cathode, metal, low-valent metal salt), the presence of a protic or electrophihc reagent, and the experimental conditions (Scheme 2). Starting from the imine 7, the one-electron reduction is facihtated by the preliminary formation of the iminiiim ion 8 by protonation or reaction with an electrophile, e.g., trimethylsilyl (TMS) chloride. Alternatively, the radical anion 9 is first formed by direct reduction of the imine 7, followed by protonation or reaction with the electrophile, so giving the same intermediate a-amino radical 10. The 1,2-diamine 11 can be formed from the radical 10 by dimerization (and subsequent removal of the electrophile) or addition to the iminium ion 8, followed by one-electron reduction of the so formed aminyl radical. In certain cases/conditions the radical 9 can be further reduced to the carbanion 12, which then attacks the... 

Scheme 19 Asymmetric synthesis of 2-(l-aminoalkyl)pyrrolidines and 2,2 -dipyrrolidines from chiral imines and iminium ions...

Scheme 23 Double asymmetric induction in the addition of Grignard reagents to chiral a-amino imines and a-amino iminium ions...

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. 

Addition of enols, enolates, or enolate equivalents to imines or iminium ions provides an important route to (3-amino ketones. 

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

A variety of double bonds give reactions corresponding to the pattern of the ene reaction. Those that have been studied from a mechanistic and synthetic perspective include alkenes, aldehydes and ketones, imines and iminium ions, triazoline-2,5-diones, nitroso compounds, and singlet oxygen, 10=0. After a mechanistic overview of the reaction, we concentrate on the carbon-carbon bond-forming reactions. The important and well-studied reaction with 10=0 is discussed in Section 12.3.2. 

Iminium ions, generated in aqueous solution from secondary amines and formaldehyde, undergo a Barbier-type allylation mediated by tin, aluminum, and zinc. The reaction is catalyzed by copper and produces tertiary homoallylamines in up to 85% yield.67 The imines generated in situ from 2-pyridinecarboxaldehyde/2-quinolinecarboxaldehyde and aryl amines undergo indium-mediated Barbier allylation in aqueous media to provide homoallylic amines.68 Crotyl and cinnamyl bromides... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

It is assumed that the mechanism proceeds via activation of the imine by the ruthenium catalyst (structure 169), followed by reaction with ethyl diazoacetate to generate a metal-bound ylide intermediate. Intramolecular ruthenium- assisted attack of the carbanion 170 onto the iminium ion provides the corresponding aziridine with moderate to high // selectivity. Imines bearing electron-donating groups (R2) showed significant rate enhancement. 

Addition of organocopper reagents to imine derivatives can readily afford functionalized amine derivatives. Three recent examples are shown below (Equations (129) and (130) Scheme 102).498,498a,498b In these cases, iminium ions are employed as an activated imine. 

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