Simple protonated iminium ions as heterodienophiles

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. 

Use of alcoholic solvents leads to a decreased reaction rate however, tetrahydrofuran as a cosolvent with water can be employed without any noticeable effect on reaction rate or yield. Substituting the less-reactive cyclo-hexadiene for cyclopentadiene in the above equation requires heating (55 C) and results in a substantially lower yield (35%) of the corresponding fused bicyclic [2.2.2] product. 

Attempts to use other aldehydes in this reaction met with limited success. Substituting acetaldehyde in place of formaldehyde results in a 47% yield of the corresponding exo and endo azanorbomenes 2 and 3 in a 1.5/1 ratio  

The reaction rate is notably slower than the formaldehyde case (16h vs. 3 h) with concomitant formation of more by-products. No Diels-Alder products are detected when simple ketones (e.g. acetone) are employed in the above equation. Substituting benzylamine with methylamine or ammonia in this reaction provides the corresponding Diels-Alder products, albeit in somewhat lower yields. 

The overall cyclocondensation of iminium ions proceeds with the regio-and stereoselectivity expected for a true Diels-Alder process. The formation of a single diastereomer in the reaction of ( , )-2,4-hexadiene with iminium ion 1 is consistent with a concerted [2+4] cycloaddition rather than an ionic, stepwise process  

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