Iminium ions reactivity

Argoti, D. et al. (2005) Cyanide trapping of iminium ion reactive intermediates followed by detection and structure... 

Argoti D, Liang L, Conteh A, et al. Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chem Res Toxicol. 2005 18(10) 1537-1544. 

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 tetrasubstituted isomer of the morpholine enamine of 2-methyl-cyclohexanone (20) because cf the diminished electronic overlap should be expected to exhibit lower degree of enamine-type reactivity toward electrophilic agents than the trisubstituted isomer. This was demonstrated to be the case when the treatment of the enamine with dilute acetic acid at room temperature resulted in the completely selective hydrolysis of the trisubstituted isomer within 5 min. The tetrasubstituted isomer was rather slow to react and was 96% hydrolyzed after 22 hr (77). The slowness might also be due to the intermediacy of quaternary iminium ion 23, which suffers from a severe. 4< strain 7,7a) between the equatorial C-2 methyl group and the methylene group adjacent to the nitrogen atom, 23 being formed by the stereoelectronically controlled axial protonation of 20. 

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. 

Iminium ions bearing an electron-withdrawing group bonded to the sp carbon of the iminium function are very reactive dienophiles. Thus, iminium ions 26 generated from phenylglyoxal (Scheme 6.15, R = Ph) or pyruvic aldehyde (R = Me) with methylamine hydrochloride, react with cyclopenta-diene in water at room temperature with good diastereoselectivity [25] (Scheme 6.15). If glyoxylic acid is used, the formation of iminium salt requires the free amine rather than the amine hydrochloride. 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

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. 

Gas phase reactivity toward allyltrimethylsilane was used to compare the reactivity of several cyclic A-acyliminium ions and related iminium ions.203 Compounds with endocyclic acyl groups were found to be more reactive than compounds with exocyclic acyl substituents. Five-membered ring compounds are somewhat more reactive than six-membered ones. The higher reactivity of the endocyclic acyl derivatives is believed to be due to geometric constraints that maximize the polar effect of the carbonyl group. 

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... 

Iminium ions are reactive electrophiles toward both alkenyl and allylic silanes. Useful techniques for closing nitrogen-containing rings are based on in situ generation of iminium ions from amines and formaldehyde.121... 

The reactivity of dipyrrolylmethane 236 has similarly been exploited in its reaction with 4-dimethylamino-l,l,l-trifluoro-3-buten-2-one 239 and trifluoromethanesulfonic anhydride to generate the iminium ion 240 followed by hydrolysis to give the fluorinated product 241 in 56% yield (Scheme 16) <2003CHE776>. 

A very elegant expansion of the synthetic utility of this intramolecular amination was the insertion reactions into ethereal G-H bonds. Du Bois and co-workers have exploited this reactivity to prepare cyclic sulfamates that are then used as iminium ion equivalents. Upon treatment with a suitable Lewis acid, nucleophilic addition reactions... 

Pyrrolidine itself is not sufficiently activated to allow direct C—C bond formation at positions 2 or 3. However, under certain conditions the nitrogen atom may stabilize a reactive carbanion or carbocation (iminium ion). Both approaches have been fruitful. 

Hibberd and Gorrod incubated nicotine-A-l -(5 )-iminium (152) with hepatic homogenates prepared from mouse, rat, hamster, rabbit, guinea pig, and human fetal liver to demonstrate the involvement of such reactive chemical intermediates in the oxidation of nicotine to cotinine (151) 221). The iminium ion (152) was converted to (151) more rapidly than nicotine, thus confirming the intermediacy of the ion between nicotine and cotinine. A series of inconclusive... 

Fig. 8.21 Structures of vesnarinone, and its major metabolite veratrylpiperazinamide. The pathway metabolized by activated neutrophils gives rise to two highly reactive species, an iminium ion and a quinone imine.

CuBr/QUINAP System The CuBr/QUlNAP system was initially used in the enan-tioselective synthesis of proparyl amines via the reaction of alkynes and enamines (Scheme 5.5). It was rationalized that the enamines reacted with protons in terminal alkynes in the presence of copper catalyst to form zwitterionic intermediates in which both the generated iminiums and alkyne anions coordinate to the copper metal center. After an intermolecular transfer of the alkyne moiety to the iminium ion, the desired products were released and the catalyst was regenerated. The combination of CuBr as catalyst and the chiral ligand QUEMAP is crucial for the good reactivities and enantioselectivities seen in the reaction. Another potential... 

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). 

A less developed but substantial opportunity for reaction of iminium ions is the direct 1,2-addition of a nucleophile. Although this can reduce opportunities for developing a catalytic procedure because of mechanistic considerations, appropriate choice of substrates and reaction conditions has provided a number of successful methods that adopt this mode of reactivity. 

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