Imines iminium cation

Keywords imine, iminium cations, nitriles, nitroso compounds, azo compounds, azadienes, nitroso alkenes... 

The cyclic metabolite 11.169 was also a substrate in further biotransformations, being (V-demethylated to the corresponding endocyclic imine, and oxidized to phenolic metabolites. Very little if any of the secondary amine metabolite (11.168) appeared to undergo direct (V-demethylation to the primary amine, in contrast to many other tertiary amines, presumably due to very rapid cyclization of the secondary amine facilitated by steric and electronic factors. The possibility for the iminium cation (11.169 H+) to become deprotonated (a reaction impossible for the iminium 11.166 in Fig. 11.20) should also drive the cyclization reaction. 

This approach to the isoquinoline ring, albeit a reduced isoquinoline, is mechanistically similar to the Bischler-Napieralski synthesis, in that it involves electrophilic attack of an iminium cation on to an aromatic ring. In this case, the imine intermediate is formed by reacting a phenylethylamine with an aldehyde. 

We thus have standard imine formation in this case, the secondary amine leads to an iminium cation. This is attacked by the ketone nncleophile. This cannot be an enolate anion because of the mild acidic conditions under which the reaction proceeds, so we formnlate it as involving the enol tantomer. Accordingly, we need to include an acid-catalysed enolization step. 

The mechanism of imine formation is standard, as seen in the other examples. The cyclization reaction is then like the Mannich reaction, attack of an enol on to the iminium cation. This time though, the nucleophile is provided by the resonance effect from the phenol system. 

Under thermal conditions, imines do not react with allyl-tri-n-butylstannane. However, complexation of imines with strong Lewis acids leads to iminium cations, which are reactive electrophiles with allylic... 

The past 35 years have seen both the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines develop into useful methods for the synthesis of chiral amines. Particularly, focused research over the past 15 years has led to highly enantioselective examples of both reaction types and has added aza aromatics, activated imines, and iminium cations to their purview. In addition, the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines have both been apphed to total syntheses. Because they are necessarily isomeri... 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

The [2 -I- 2] cycloaddition of ketenes and imines is an important route to the P-lactam ring (azetidinone), which is a crucial structural feature of the penicillin class of antibiotics. A number of theoretical treatments of this reaction indicate that in solution phase this is a two-step reaction, with the second step being rate determining. The stepwise nature of the reaction is accommodated by the relative stability of both charged moieties, an iminium cation and an enolate anion. 

The product from this first step is an iminium cation that reacts with pyrrole to give a more stable iminium salt. The extra stability comes from the conjugation between the pyrrole nitrogen and the iminium group. The work-up with aqueous Na2C03 hydrolyses the imine salt and removes any acid formed. This method is particularly useful because it works well with Me2NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conventional Friedel-Crafts reaction. 

Crucial to the course of the hydrogenation reaction is the formation of the iminium cation, which competes with the formation of ammonium salts. The hydrogenation of aniline derivatives could be readily accomplished, which copes most probably with the fact that aryl-substituted imines are more basic than aryl-substituted amines. The iminium cations are therefore always accessible in kinetically relevant... 

A mechanism for the reaction is given in the following box. Note the difference between the previously described mechanism for imine formation and this mechanism for enamine formation. In enamine formation, which involves a secondary amine, there is no proton for removal from the nitrogen in the iminium cation intermediate. Hence, a neutral imine cannot be formed. A proton is removed from a carbon adjacent to the former carbonyl group instead, resulting in an enamine. We shall see in Chapter 18 that enamines are very useful for carbon—carbon bond formation (Section 18.9). 

A proton is removed from the carbon adjacent to the iminium group. Proton removal occurs from the carbon because there is no proton to remove from the nitrogen of the iminium cation (as there would have been if a primary amine had been used). This step forms the enamine, neutralizes the formal charge, and regenerates the catalytic acid. (If there had been a proton to remove from the nitrogen of the iminium cation, the final product would have been an imine.)... 

A short review examines nucleophilic trifluoromethylation of C=N bonds imines, hydrazones, and nitrones, together with iminium cations and azomethine imines, mainly focusing on the Ruppert-Prakash reagent, TMS-CF3. ... 

Final deprotonation of the iminium cation gives the imine product. 

Recently, Wills and co-workers (344) studied the application of ruthenium catalysts of the Noyori-type catalyst containing W-alkylated TsDPEN derivatives bearing alkyl groups of different size as the chiral ligand for the reduction of cyclic imine I (Fig. 94). The authors suggest that a viable model for the reduction of this imine (Fig. 96) could involve a protonated imine with a transition state allowing the CH-jt interaction between the aryl group of the iminium cation and the arene coordinated to the ruthenium. 

In some cases, less activated iV-aryl imines were transformed into the corresponding trifluoromethylamines by reaction with TMSCF3 in the presence of CsF and TMS-imidazole, or with fluoride initiators such as TBAT or TMAF (eq 14). However, in the latter example higher amounts of fluoride caused the loss of HF and therefore difluoromethylamines were obtained after reduction with NaBH4. When a stoichiometric amount of TMAF was employed, tetramethylammonium amides were formed and further treated with a variety of electrophiles to produce N-substituted trifluoromethylamines. IV-Methyl imines derived from salicyl-aldehydes reacted with TMSCF3 after forming an iminium cation (eq 15). 

Proposed mechanism for the Pd/C-catalyzed oxidative synthesis of 2-substituted benzimidazoles was depicted in Scheme 14.11. The initial step seems to be the insertion of palladium into a C-H adjacent to the nitrogen, leading to a highly active intermediate complex of an iminium ion. The proposed catalytic cycle involves the removal of a hydride from tertiary amine by a metal catalyst to form (putative) oxidized iminium cation species, which undergoes a transamination reaction with o-phenylenediamine to generate intermediate imine, with generation of Imol equivalent of H2. Subsequent formation of... 

A different type of photoreaction in ILs has been studied by Jones and co-workers the photoreduction of benzophenones by primary amines. Prior work by Cohen demonstrated that photolysis of benzophe-none in benzene in the presence of sec-butylamine afforded benzopinacol (and an imine). This reaction proceeds through a radical pair formed by hydrogen-atom abstraction by the triplet excited state ben-zophenone from the amine. In the much more polar environment of an IL, the radical pair may instead undergo single electron transfer to form an iminium cation and a hydroxyl-substituted carbanion. Proton transfer from the cation to the anion will yield benzhydrol and an imine. 

Figure 1.22 The reaction of an imine nitrogen with a proton to form an iminium cation.

Since nitrogen is a better electron donor than oxygen, in cationic derivatives of imines the contribution of the aminomethyl cation structure 385b, compared with that of the iminium ion resonance form 385a, is small.691 695 The same also applies to amidines (386) and guanidines (387). 

The most common fragmentation of amines is a cleavage to give a resonance-stabilized cation an iminium ion. This ion is simply a protonated version of an imine (Section 18-15). 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

Amino-l,2-dithiolium salts are obtained from either / -oxocarbox-amides or ) -oxocarbonitriles by reaction with phosphorus penta-sulfide, followed by addition of perchloric acid (Scheme 6). These cations, which may also be considered as iminium salts, are deprotonated to the corresponding l,2-dithiol-3-imine by ammonia. ... 

On the basis of this rearrangement, an efficient synthetic route to pyrrolidines such as (46) was developed by Overman, starting from oxazolidine (42), via hydroxylated homoallylic imines such as (43 Scheme 22).Mechanistically, the formation of (46) may explained as a tandem-type combination of a cationic aza-Cope rearrangement with a subsequent Maimich cyclization (route a) or, alternatively, as an alkene-iminium ion cyclization/pinacolic rearrangement sequence (route b). 

Compounds able to undeigo solvolysis to sufficiently stable cations are reduced via these carbocations by NaBH4 in alcoholic media sometimes in the presence of acid. Diarylketones (Section 3.2) or the di- or triarylcarbinols are reduced to hydrocarbons (Section 2.4), imines and the iminium salts are reduced to amines (Sections 3.3.1, 3.3.2), and imides to a -hydroxy amides (Section 3.2.8). 

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