Simple protonated iminium ions

Synthetic applications of the aqueous aza Diels-Alder reaction involving simple protonated iminium ions... 

Simple imines are generally unreactive toward dienes without activation. In 1985, Grieco and Larson [1] first reported that simple unactivated iminium ions, generated in situ under Mannich-like conditions, react with a variety of dienes in water to effect an exceptionally mild and convenient cyclocondensation reaction. Water as a solvent is particularly suited to using commercially available 37% aqueous formaldehyde in combination with an amine hydrochloride to form the incipient protonated imine heterodienophile. 

A basic group removes a proton from the P-carbon of the iminium and forms the enamine. This enamine then reacts as a nucleophile towards the aldehyde group of glyceraldehyde 3-phosphate in a simple addition reaction, and the proton necessary for neutralizing the charge is obtained from an appropriately placed amino acid residue. Finally, the iminium ion loses a proton and hydrolysis releases the product from the enzyme. 

It was envisioned that the addition of an indole derived from a tryptamine to the activated iminium ion, arising from imidazolidinone catalyst 3 and an a,p-unsaturated aldehyde, would generate a C(3)-quaternary carbon-substituted indo-lium ion. As a central feature this intermediate cannot undergo re-aromatization by means of proton loss, in contrast to the analogous 3-H indole addition pathway. As a result, 5-exo-heterocyclization of the pendant ethylamine would provide the corresponding pyrroloindoline compounds. In terms of molecular complexity, this cascade sequence should allow the rapid and enantioenriched formation of stereochemically defined pyrroloindoline architecture from tryptamines and simple a,/i-unsaturated aldehydes. 

Simple alicyclic enamines are readily hydrolysed by basic or weakly, acidic media, although strong acids merely protonate the nitrogen atom, leading to a stable ammonium ion (6a). Recent studies [222] on enamine hydrolysis show it to be a general-acid-catalysed process involving the unprotonated form (6). This can accept a proton from an acidic species HA at the a -carbon atom to give the iminium ion (7). Nucleophilic attack by solvent or a base then affords the carbinol-amine (8) which breaks down into ketone and amine. 

Notice that enamines are the nitrogen counterpart of enols (p. 448). Now comes an important question Why doesn t the iminium ion formed from primary amines or ammonia (Fig. 16.49) also lose a proton from carbon to give an enamine Why is imine formation preferred when there is a choice (Fig. 16.55) The answer is extraordinarily simple Just as the ketone tautomer is more stable than the enol, the imine is more stable than the enamine and so is preferred when possible. It is only in cases where imine formation is not possible, as when secondary amines are used, that enamines are formed. We hope you have noticed that the imine- and enamine-forming reactions are reversible. The reactions work best under slightly acidic conditions with heat applied to drive off water. If water is added to an imine or enamine, the reverse reaction occurs to yield the carbonyl compound and an amine. 

In several cases, it has been established that the amines do not function as simple bases but instead are involved in prior reaction with the carbonyl compounds as well. Kinetic evidence in support of such a mechanism in the condensation of aromatic aldehydes with nitromethane has been reported. The fact that such condensations are often most effectively catalyzed when a weak acid is present in addition to the amine suggests that amines do not function as simple base catalysts. The reactive electrophile is probably the protonated form of the imine formed by condensation of the carbonyl compound and the amine. This iminium ion will be considerably more electrophilic than a carbonyl group because of the positive charge. 

Treatment of salt 24 with additional TPPP, however, generates a new species in addition to 24. The new species lacks the iminium proton signal at 9.3 ppm in the H NMR spectrum instead, a new signal at 6.35 ppm is visible. This new species is rather unstable and decomposes relatively quickly ( 30 min at 30 °C), but as soon as it is detectable, the addition of the alkene leads to immediate and very rapid epoxide formation. We have previously shown that TPPP does not itself promote epoxidation. Two possible structures for this intermediate may immediately be postulated, both arising from nucleophilic attack of peroxybisulphate at the iminium carbon atom a neutral intermediate 47, the product of simple addition, and the corresponding oxaziridium salt 48, produced by addition and cyclization with expulsion of bisulphate ion (Scheme 5.25). 

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