Iminium ions intramolecular Mannich reactions

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

Euphococcinine and adaline (333) were synthesized from a 2-cyano-6-oxazolopiperidine [699], An anion at C(2) was condensed with 3-bromo-2-methoxy-l-propene, and after elimination of cyanide, the resultant iminium ion was alkylated with either a methyl- or pentyl-Grignard reagent to form the quaternary carbon. The second ring was closed with an intramolecular Mannich reaction. 

Although enol ethers have received moderate notice as nucleophiles to quench intramolecular iminium ions, silyl enol ethers have been given scant attention. The first report of a silyl enol ether participating in an intramolecular Mannich reaction is found in Oppolzer and coworkers synthesis of ( )-vincamine (Scheme 14). 2 Dihydro-3-carboline (25) and silyl enol ether (26) were mixed in DMF, then warmed to 70 C for 64 h in the presence of diisopropylethylamine to provide a 1 1 mixture of cis and trans tetracyclic aldehydes (27) in 74% yield. 

In addition to the oxy-Cope and anionic oxy-Cope rearrangements, an important variant is the aza-Cope rearrangement of A -butenyl-iminium ions (3.175). This rearrangement occurs under mild conditions, but suffers as a synthetic method because of its reversibility. However, with a hydroxy group attached to the butenyl chain (R=OH), the reaction is driven in the forward direction by capture of the rearranged iminium ion in an intramolecular Mannich reaction, to provide an excellent synthesis of substituted pyrrolidines. ... 

The required iminium ion can be obtained readily by the condensation of an aldehyde with a butenylamine. For example, heating the butenylamine 276 with pyridine-3-carboxaldehyde and an acid catalyst (camphorsulfonic acid, CSA), gave the acetyl nicotine derivative 277 (3.176). The initial iminium ion 278 rearranges to the new iminium ion 279, which is irreversibly trapped in an intramolecular Mannich reaction to give the pyrrohdine 277. 

Sol 1. (a) The condensation of pyridine-3-carboxaldehyde (I) with 2-methyl-1-(methylamino)but-3-en-2-ol (II) gives the iminium ion intermediate (III). Ill undergoes [3,3] sigmatropic shift to give another iminium ion intermediate (IV), which is irreversibly trapped in an intramolecular Mannich reaction to give the pyrrolidine derivative V. 

As in the Corey synthesis, an intramolecular Mannich reaction converted 29 to 31. Mercuric acetate oxidation of 31 to the corresponding iminium ion, followed by basification, gave enaminoketone 32. This intermediate does not have the proper stereochemistry for an intramolecular Mannich reaction, but under acidic conditions, epimerization is followed by cyclization to provide 2. The synthesis of porantherine (1) was completed using a Bamford-Stevens reaction to introduce the olefin. ... 

As depicted in Scheme 16.17, treatment of secondary amine 146 with for- O maldehyde afforded the intermediate iminium ion 147. This iminium ion q. participated in an aza-Cope rearrangement to give enol 148, which was followed by an intramolecular Mannich reaction to form 149, containing the d requisite quaternary stereogenic center, in an impressive 98% overall yield. 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

While these various intramolecular cyclization modes make accessible a myriad of azacycles, the practitioner is faced with the delicate art of orchestrating an efficient cyclization. Cyclization conditions must be such that the reactivity of the nucleophile is preserved, while unleashing intramolecularly the electro-philicity of an iminium ion. A listing of the most important routes to iminium ions is found in Scheme It is important to note that many of the methods for iminium ion generation are not conducive to the preservation of certain nucleophiles. The judicious choice of reaction conditions is the key to an effective intramolecular Mannich or Mannich-related reaction. 

In several instances, Mannich-type cyclizations can be carried out expeditiously under photochemical conditions. The photochemistry of iminium ions is dominated by pathways in which the excited state im-inium ion serves as a one-electron acceptor. The photophysical and photochemical ramifications of such single-electron transfer (SET) processes as applied to excited state iminium ions have been expertly reviewed. In short, one-electron transfer to excited state iminium ions occurs rapidly from one of several electron donors electron rich alkenes, aromatic hydrocarbons, alcohols and ethers. Alternatively, an excited state donor, usually aromatic, can transfer an electron to a ground state iminium ion to afford the same reactive intermediates. Scheme 46 adumbrates the two pathways that have found most application in intramolecular cyclizations. Simple alkenes and aromatic hydrocarbons will typically suffer addition processes (pathway A). However, alkenic and aromatic systems with allylic or benzylic groups more electrofugal than hydrogen e.g. silicon, tin) commonly undergo elimination reactions (pathway B) to generate the reactive radical pair. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

In terms of enamine and iminium ion catalysis, an intramolecular cascade conjugate addition/Mannich reaction was shown to be effectively catalyzed by 36 [108]. The reaction involves the construction of a tetracycUc structure from the indoyl methyl enone shown in Scheme 6.53. The highest enantioselectivities were obtained with addition of nitrobenzoic acid and with ethyl acetate as the solvent... 

The use of silyl dienolates in additions to iminium ions is known as the vinylogous Mannich reaction and constitutes an important expansion of this classic. Inter- and intramolecular versions of this transformation have been studied in great detail by Martin in the context of numerous total syntheses [110, 117]. As an example, silyl dienolate 128 intercepted iminium ion 127 to yield adduct 129 in 69% yield (Scheme 11.20) [118]. Subsequently, this adduct could be efficiently converted into 131 by addition to methyl vinyl ketone and intramolecular Michael reaction. Further elaborations of this key intermediate afforded the indole alkaloid (-)-ajmalicine (132). 

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