Additions to Imines and Iminium Ions

L-threonine. With ligand 27b, the selectivities can even be improved when Zn (OTf)2 is used instead of FeCl2. 

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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. 

R. A. Batey in Boronic acids preparation and applications in organic synthesis and medicine (D. Hall, Ed.). Wiley-VCH Verlag GmhH, Weinheim, Germany, 2005, pp. 279-304. NucleophUic addition reactions of aryl and alkenylboronic acids and their derivatives to imines and iminium ions. 

Nucleophilic Addition Reactions of Aryl and Alkenylboronic Acids and Their Derivatives to Imines and Iminium Ions... 

Figure 7.1 Nucleophilic addition reactions to imines and iminium ions.

Scheme 27 Addition of nitronates, enolates and silyl ketene acetals to chiral a-amino imines and iminium ions...

A few additional scattered examples have been reported of additions of enol derivatives to N-sulfonyl imines and iminium ions. For instance, Kobayashi et al. [40] have found that the condensation shown in Eq. (20) is catalyzed effectively by a lanthanide triflate in excellent yield. 

The direct observation of this reaction is difficult because of the small equilibrium constant for imine formation. This type of reaction is therefore commonly studied by trapping the imine as it is formed with hydroxylamine, which reacts rapidly to form an oxime. Because the equilibrium constant for formation of the imine between methyl amine and acetone is so small, the equilibrium is established very rapidly. (The observed rate constant for a reaction proceeding to an equilibrium position is larger than the first-order rate constant for the forward reaction [7].) Thus the addition of methylamine and acetone to an aqueous solution results in the establishment of an equilibrium concentration of imine (and iminium ion) in several seconds. In several studies described below wherein reactions subsequent to imine formation occur, it is common to find a presumption of rapid imine equilibria prior to the slower o-proton abstraction or decarboxylation events that occur subsequently. 

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... 

An electroreductive Barbier-type allyla-tion of imines (434) with allyl bromide (429) also occurs inaTHF-PbBr2/Bu4NBr-(Al/Pt) system to give homoallyl amine (436) (Scheme 151) [533]. The combination of Pb(II)/Pb(0) redox and a sacrificial metal anode in the electrolysis system plays a role as a mediator for both cathodic and anodic electron-transfer processes. The metals used in the anode must have a less positive anodic dissolution potential than the oxidation potentials of the organic materials in order to be present or to be formed in situ. In addition, the metal ion plays the role of a Lewis acid to form the iminium ion (437) by associating with imine (435) (Scheme 151). 

Ugi multi-component reactions of an amine, aldehyde, carboxylic acid and isocyanide (or the three-component variant with preformed imines) involve a Mumm rearrangement of an imidate in the final step, often considered the stereoselective step. However, experimental and computational evidence for kinetic control has now been reported in Ugi reactions of a o-pentose-derived pyrroline (52). The selective step is the formation of the imidate by the addition of isocyanide to the intermediate iminium ion, with the conformation of the latter determined by its substitution pattern. 

A related approach to porantherine was reported by the Stevens group about 10 years after publication of the Corey synthesis. The Stevens synthesis emphasized the notion that the stereoelectronic requirement for addition of a nucleophile to an imine (or iminium ion) was development of an anti-periplanar relationship between the nucleophile and the developing lone pair on nitrogen. This notion also leads to the disconnection of 2 —> 3 —> 22, and iminium ion 22 was to be prepared by oxidation of piperidine 23. Thus, the major difference between the Stevens and Corey approaches is the choice of a surrogate for the aldehyde required for generation of iminum ion 3. In the forward direction, the lithium reagent derived from 26 was treated with iminoether 27 to provide 28. Hydroysis of 28 gave enamine 29. 

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... 

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... 

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. 

Step b Two acid-catalyzed cyclizations ally silane addition to an iminium ion followed by intramolecular imine alkylation and loss of MeOH. 

If the anodic oxidation of N-alkylanilines is performed in the presence of nucleophiles like enol ethers, nucleophilic substitution in the of-position to nitrogen by the enol ether can be observed in low yields. The electrophilic intermediate is the N-aryl iminium ion or the N-aryl imine after loss of two electrons and one or two protons. These intermediates add to the enol ether to give acetals (up to 26%) as addition products, or the first addition step is followed by an electrophilic aromatic substitution to form tetrahydroqui-nolines (13-39%) [47]. It should be noted at this point that better results for the nucleophilic a-substitution to nitrogen can be obtained with N,N-dialkylanilines (see next subsection). Optimum results, however, are obtained with N-acylated compounds via the intermediate N-acyl iminium ions (see Ref. 8). 

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