Acyliminium ion

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. 

Formation of C — C Bonds by Addition to Imino Groups via yV-Acyliminium Ions... 

The reaction of A-acyliminium ions with nucleophilic carbon atoms (also called cationic x-amidoalkylation) is a highly useful method for the synthesis of both nitrogen heterocycles and open-chain nitrogen compounds. A variety of carbon nucleophiles can be used, such as aromatic compounds, alkcncs, alkyncs, carbcnoids, and carbanions derived from active methylene compounds and organometallics. 

A number of comprehensive reviews1 6on the reaction of A-acyliminium ions, including detailed accounts of their application in alkaloid synthesis7- 8, have appeared. This section does not deal with [4 + 2] cycloaddition reactions of A -acyliminium ions these will be discussed in Section D.1.6.1.1. 

For reactions of A-acyliminium ions with alkenes and alkynes one has to distinguish between A-acyliminium ions locked in an s-trans conformation and those which (can) adopt an s-cis conformation. The former type reacts as a (nitrogen stabilized) carbocation with a C —C multiple bond. Although there are some exceptions, the intramolecular reaction of this type is regarded as an anti addition to the 7t-nucleophile, with (nearly) synchronous bond formation, the conformation of the transition state determining the product configuration. 

V-Acyliminium ions act as dienophiles in [4 + 2] cycloaddition reactions with conjugated dienes13, while A-acylimimum ions that (can) adopt an x-cis conformation are able to act as heterodienes in an inverse electron demand Diels-Alder process with alkenes or alkynes3 (see Section D. 1.6.1.1.). 

A possible side reaction in A-acyliminium chemistry is caused by deprotonation, giving rise to the formation of an enamide. Though this tautomerization is in principle reversible in acid media, this is not always the case. The enamide may react as a nucleophile with the /V-acyliminium ion still present, to produce dimers14. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

Reactivity of A -Acyliminium Ions vs. Iminium and Oxonium Ions... 

Both Friedel-Crafts acetylation and Vilsmeier formylation of the 2,3-dihydrooxazole 5 occur at C-5, indicating that the A-acyliminium ion is more stable than the oxonium ion17. This is corroborated by ab initio calculations, which show that 3-formyl-2,5-dihydro-3-oxazolium 7 is ca. 46 kJ mol 1 more stable than 3-formyl-2,4-dihydro-l-oxazolium 817. 

Generation of A-Acyliminium Ions and Synthesis of Their Precursors... 

For synthetic applications, A-acyliminium ions are nearly always generated in situ in view of their limited stability and high reactivity. Although a large variety of methods leading to A-acyliminium ions are known, only the synthetically more useful procedures, as well as the synthesis of the precursors, will be discussed in this section. 

The A-(l-alkoxyalkyl)amides and -carbamates are stable compounds, thus allowing reactions under neutral or basic conditions to be carried out elsewhere in the molecule before generation of the A-acyliminium ion with an acidic catalyst. 

If the AM 1 -hydroxyalkyl)amide is not stable enough for isolation it is still possible to perform the amidoalkylation in a one-pot reaction. Thus the amide and the carbonyl compound (or the oxoamide) are treated with an acid catalyst in the presence of the carbon nucleophile, so that the equilibrium amount of the (hydroxyalkyl)amide is converted in situ into the /V-acyliminium ion, which is subsequently attacked by the nucleophile. This principle is often applied in the total synthesis of alkaloids -8. 

The synthesis of precursors for the generation of the enantiomerically pure mono- and trans-dioxygenated /V-acyliminium ions of type 335,36 and 643 is achieved by reduction of the corresponding optically active imides. 

Thus, enantiomerically pure (S)35- or (R)36-acetoxysuccinimide derivatives of type 1, easily prepared from (S)- or (R)-malic acid, are diastereoselectively reduced with sodium borohydride in methanol at lower temperature to yield 85 % of an 11 1 mixture of diastereomeric hy-droxylactams of type 2, from which the enantiomerically pure chiral /V-acyliminium ions 3 are generated. 

Bisamides (or biscarbamates), which are easily obtainable from the reaction of an aldehyde with two equivalents of a primary amide (carbamate), are converted into the corresponding A-acyliminium ions on heating, often in the presence of strong (Lewis) acids or acylating compounds1 3. 

A -( 1-Chloro- or bromoalkyl)amides are generally moisture-sensitive, unstable compounds, which are often directly used without further purification. Standard Lewis acids such as boron trifluoride-diethyl ether, aluminum(lll) chloride, zinc(II) chloride, tin(IV) chloride and titani-um(IV) chloride are used to generate the /V-acyliminium ion, although sometimes a catalyst is not necessary. 

Introduction of an electron-withdrawing carboxy function at the x-carbon produces particularly reactive A-acyliminium ions, the so-called glycine cation equivalents, which are of great utility for the synthesis of x-amino acids. 

Formation of A-acyliminium ions via protonation of enamides or enecarbamatcs is occasionally utilized. 

Formation of a vinyl-substituted pyrrolizidine derivative is also observed in case of an allylstan-nane cyclization94. Since the allylstannane moiety is acid sensitive, the iV-acyliminium ion is generated by exposure of the hydroxylactam to methanesulfonyl chloride and triethylamine in dichloromethane. The very rapid cyclization produces the endo-vinyl compound with very high stereoselectivity. 

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