Iminium ions heterocyclic synthesis

The reaction of iminium ions with dihydropyridines is a method, suggested from biosynthetic studies, for the formation of carbon-carbon bonds to these six-membered heterocycles. The 1,4-dihydropyridine (8), a presumed intermediate from the reaction of ammonia with glutaraldehyde, reacts with the cyclic iminium ion (159) to give, after oxidation, nicotine (160) (72CC1091). Another example of this reaction has provided a total synthesis of olivacine (163). The 1,2-dihydropyridine ring system in (161), generated from its chromium tricarbonyl complex, was observed to undergo an intramolecular cyclization... 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

This TiCU-promoted allene cycloaddition has also been extended to the synthesis of five-membered ring heterocycles. In this case, increasing the steric shielding about the silicon atom seems to improve the cyclization process by suppressing the unproductive desilylative alkylation. For example, 1,3-di-methyl(r-butyldimethylsilyl)allene (39) reacts smoothly with cyclohexanecarbaldehyde to give in high yield the dihydtofuran predominantly as one stereoisomer (equation 31). Similar reaction with an N-acyl-iminium ion precursor (40) produces the pyrrolizidine system as a mixture of bicyclic isomers (equation... 

The reported synthesis of the Amarylidaceae alkaloid ( )-epielwesine (50) also employed an iminium ion-vinylsilane in the key cyclization step (Scheme 23). Reaction of the (Z)-vinyltrimethylsilane (48) with TFA generated an intermediate iminium ion, which was trapped by the vinylsilane nucleophile to yield the cis fused heterocycle (49). 

Tandem aza-Cope rearrangement of in situ generated iminium ions-cyclization processes are widely used for the synthesis of heterocycles. For example, dehydroyohimbane (5) is prepared by the reaction sequence shown via the Cope precursor 2962. 

Lastly, Roth has described the reaction of cobalt-complexed propargyl cations with enamines leading to intermediate iminium ion salts which were treated in situ with carbon nucleophiles decomplexation gives precursors for the synthesis of five- and six-membered nitrogen heterocycles [204],... 

In the presence of TMSOTf, BFs.OEtz and dimethyl sulfide, the iminium ions 204 (masked as N,0-acetals) have been employed to couple with a very board range of readily available Michael acceptors, including acrolein and acrylates, in both an inter- and intramolecular MBH-type reaction to give densely functionalized heterocycles 207 (Scheme 1.78). The process has been rendered asymmetric and high enantioselectivity is obtained in reactions of iminium ions 210 (masked as N,0-acetals) and cyclic enones (Scheme 1.79). Finally, the usefulness of the methodology has been exemplified in a short synthesis of ( + )-heliotridine 208 and (-)-retronecine 209 (Scheme 1.78). ... 

Recently, a novel methodology has been developed to prepare densely functionalized heterocycles from the coupling of various Michael acceptors with readily available iminium ions (masked as N,0-acetals) via an intermolecular MBH-type reaction. An intramolecular MBH-type reaction was developed to construct a bicyclic pyrrolizidine ring. As shown Scheme 5.32, the total synthesis of ( + )-heliotridine, as this basic structure unit existed in many plants, was achieved. ... 

BF4] or [bmim][PF6] (Scheme 22.8). Bis-amide 19-catalyzed aldol reactions performed in [bmimllBFJ required a much lower excess of donor ketone 21 (3 equiv. instead of 30 equiv. in proline-catalyzed reactions) and allowed a synthesis of chiral compounds 22 bearing heterocyclic, prenyl, or metallocene units [43], The improved catalytic performance of prolinamide derivatives in ionic liquids might be due to a stabihzation of the iminium intermediate formed from the ketone and the catalyst or because of the enhanced nucleophilicity of the enamine [42]. Notably, IL dilution with water (1 1 by volume) accelerated the enamine/iminium ion hydrolysis and raised reaction rates and product yields, with the enantioselec-tivity being retained or even becoming somewhat higher than under water-free conditions [45], Furthermore, the catalyst/lL/water system could be easily recycled five times without aldol yield, dr, and ee losses. 

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