Iminium secondary amines

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. 

The reduction was studied in more detail by Cook and Schulz (52). They demonstrated conclusively that reduction of iminium salts by secondary amines is possible as illustrated in Eqs. (7) and (8). The oxidation... 

Ternary iminium complex salts can be prepared by direct combination of an aldehyde or ketone with a secondary amine complex salt (95). An adaptation of this procedure employing the perchlorate salts of secondary amines provides a simple method for the preparation of the readily crystallized and nonhydroscopic ternary iminium perchlorates (96), Eq. (10). 

The initial investigation of the reaction of aldehydes and ketones with complex secondary amine salts was that of Lamchen et al. (11). A few salts had been observed before by Zincke and Wiirker (24), but the reaction was not examined in detail. Lamchen et al. prepared a number of compounds that were presumed to be iminium salts. The amine salts were halostannates, halobismuthates, haloantimonates, and hexahaloplatinates. Among the reported products were N-ethylidenepiperidinium (13) and N-cinnamili-denetetrahydroisoquinolinium (14) salts. 

A recent adaptation of the procedure employing perchlorate and fluoro-borate salts has been reported by Leonard and Paukstelis (J5). This report includes proof of structure by direct comparison to iminium salts prepared by protonation of enamines. The general reaction reported was that of a ketone or aldehyde with a secondary amine perchlorate to give iminium salts. A large structural variety of carbonyl compounds and several amine... 

It has been shown (140) that enamines react as well, if not better, under the conditions of the Leuckart-Wallach reaction to give amines than do ketones in the presence of ammonia, primary amines, or secondary amines. This implies that in the Leuckart-Wallach reaction the pathway may be through the enamine and, of course, the iminium salt. The Leuckart-Wallach reaction has been reviewed (141). Examples of enamines reduced under the conditions of the Leuckart-Wallach reaction are listed in Table 12. 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

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). 

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. 

This is the most common method for the preparation of enamines and usually takes place when an aldehyde or ketone containing an a hydrogen is treated with a secondary amine. The water is usually removed azeotropically or with a drying agent, but molecular sieves can also be used. Stable primary enamines have also been prepared.Enamino-ketones have been prepared from diketones and secondary amines using microwave irradiation on silica gel. ° Secondary amine perchlorates react with aldehydes and ketones to give iminium salts (2, p. 1178). Tertiary amines can only give salts (12). 

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... 

Addition of Vinyl and Aryl Groups. The reaction of aromatic radicals, generated by decomposition of diazonium salts, with iminium salts in the presence of TiCE in aqueous media produces secondary amines (Eq. 11.53).91 The iminium salts are formed in situ from aromatic amines and aldehydes. 

Cooke and coworkers reported on the synthesis of the amino acid N-benzyl-4-acetylproline (2-889) (Scheme 2.198) [453], as this might represent an interesting synthon for the preparation of bioactive compounds. These authors also used a domino iminium ion formation/aza-Cope/Mannich protocol. Thus, treatment of the secondary amine 2-885 with glyoxylic acid (2-888) primarily provided the corresponding iminium ion, which led to 2-889 in 64% yield as a mixture of diastereom-ers. 

Another method of activation we considered was the use of a secondary amine to generate a more electrophilic iminium species, examples of which have been used in vinylsilane-terminated cyclization reactions, particularly by Overman and co-workers [Eq. (4.8)] [51]. In our case, the unsaturated iminium ion would be activated for... 

Carbinolamines are chemically unstable and, in the case of tertiary amines, dissociate to generate the secondary amine and aldehydes as products or eliminate water to generate the iminium ion. The iminium ion, if formed, can reversibly add water to reform the carbinolamine or add other nucleophiles if present. If the nucleophile happens to be within the same molecule and five or six atoms removed from the electrophilic carbon of the iminium ion, cyclization can occur and form a stable 5- or 6-membered ring system. For example, the 4-imidazolidinone is a major metabolite of lidocaine, which is formed in vivo or can be formed upon isolation of the A -deethyl metabolite of lidocaine if a trace of acetaldehyde happens to be present in the solvent used for extraction (116,118) (Fig. 4.52). 

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. 

The starting material was prepared with the modification on the epibatidine bicychc ring system by repositioning the nitrogen atom to a methylene group. We carried out the Hetero-Diels Alder reaction of cyclopentadiene and iminium ion generated from ammonium chloride and formaldehyde in the aqueous medium and protected resulted unstable secondary amine with benzoyl chloride to provide (3) in good yields [5] (Scheme 38.1). 

Secondary amines react with aldehydes and ketones via addition reactions, but instead of forming imines, produce compounds known as enamines. Initially, there is the same type of nucleophilic attack of the amine onto the carbonyl system, followed by acid-catalysed dehydration but, since the amine is secondary, the product of dehydration is an iminium... 

In Section 7.7.2 we met enamines as products from addition-elimination reactions of secondary amines with aldehydes or ketones. Enamines are formed instead of imines because no protons are available on nitrogen for the final deprotonation step, and the nearest proton that can be lost from the iminium ion is that at the P-position. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

Alternatively, cyclohexanone may initially be transformed into an enamine with a secondary amine, here pyrrolidine. This intermediate enamine can act as a nucleophile and can be alkylated at the P-position using methyl iodide. Finally, 2-methylcyclohexanone may be generated by hydrolysis of the iminium system, effectively a reversal of enamine formation. This gives us two routes to 2-methylcyclohexanone, a short process using the very strong base LDA and... 

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. 

Although the CuBr/QUINAP system is an effective chiral catalyst in alkynylation of imines or iminiums, one drawback is that enantiopure QUINAP is quite expensive. An analog of QUINAP, PINAP (Figure 5.2), was readily synthesized and found as a very effective chiral ligand in the direct addition of alkynes to iminiums generated from aldehydes and secondary amines in situ (Scheme 5.8). ... 

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

Based on the observation that the majority of secondary amines shown to be effective in iminium ion catalysed transformations were cyclic five-membered nitrogen containing heterocycles, it was postulated that a highly nucleophilic nitrogen was central to catalytic activity [44]. This proposal was reinforced by the discovery that secondary amines with a-heteroatoms (a-effect nucleophiles) provided an effective platform for the acceleration of iminium ion catalysed... 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

In each of the tandem iminium ion/enamine cascade processes described above, the enamine is trapped in an intramolecular fashion. The ability to perform the trapping seQuence in an intermolecular manner would allow for the one—pot introduction of three points of diversity. IVIacNlillan has realised this goal and described a series of secondary amine catalysed conjugate addition—enamine trapping sequences with oc P Unsaturated aldehydes using tryptophan derived imidazolidinone 115 to give the products in near perfect enantiomeric excess (Scheme 47) [178]. 

The majority of transformations reported within the literature using the concept of LUMO energy lowering iminium ion activation have nsed secondary amines as the catalyst. Under the aqueous acidic reaction conditions inherent to this mode of activation it is also possible to nse primary amines as efficient catalysts where the active species is the protonated imine 141 (Fig. 13). Althongh this is a somewhat less explored avenne of research, initial results suggest it will become an equally fruitful area with broad application. 

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... 

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