Aza-Cope rearrangement

Rearrangements, especially those that can participate in cascade reactions, such as the aza-Cope rearrangements, are of high practical as well as conceptual importance in organic chemistry, due to their ability to quickly build structural complexity out of simple starting materials. The aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a -sigmatropic rearrangement that shifts single and double bonds between two allylic components. In accordance with the Woodward-Hoffman rules, thermal aza-Cope rearrangements proceed suprafacially. Aza-Cope rearrangements are generally classified by the position of the nitrogen in the molecule (see figure): Rearrangements, especially those that can participate in cascade reactions, such as the aza-Cope rearrangements, are of high practical as well as conceptual importance in organic chemistry, due to their ability to quickly build structural complexity out of simple starting materials. The aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a -sigmatropic rearrangement that shifts single and double bonds between two allylic components. In accordance with the Woodward-Hoffman rules, thermal aza-Cope rearrangements proceed suprafacially. Aza-Cope rearrangements are generally classified by the position of the nitrogen in the molecule (see figure): The first example of an aza-Cope rearrangement was the ubiquitous cationic 2-aza-Cope Rearrangement, which takes place at temperatures 100-200 °C lower than the Cope rearrangement due to the facile nature of the rearrangement. The facile nature of this rearrangement is attributed both to the fact that the cationic 2-aza-Cope is inherently thermoneutral, meaning there's no bias for the starting material or product, as well as to the presence of the charged heteroatom in the molecule, which lowers the activation barrier. Less common are the 1-aza-Cope rearrangement and the 3-aza-Cope rearrangement, which are the microscopic reverse of each other. The 1- and 3-aza-Cope rearrangements have high activation barriers and limited synthetic applicability, accounting for their relative obscurity. To maximize its synthetic utility, the cationic 2-aza-Cope rearrangement is normally paired with a thermodynamic bias toward one side of the rearrangement. The most common and synthetically useful strategy couples the cationic 2-aza-Cope rearrangement with a Mannich cyclization, and is the subject of much of this article. This tandem aza-Cope/Mannich reaction is characterized by its mild reaction conditions, diastereoselectivity, and wide synthetic applicability. It provides easy access to acyl-substituted pyrrolidines, a structure commonly found in natural products such as alkaloids, and has been used in the synthesis of a number of them, notably strychnine and crinine.Larry E. Overman and coworkers have done extensive research on this reaction. The cationic 2-aza-Cope rearrangement, most properly called the 2-azonia--sigmatropic rearrangement, has been thoroughly studied by Larry E. Overman and coworkers. It is the most extensively studied of the aza-Cope rearrangements due to the mild conditions required to carry the arrangement out, as well as for its many synthetic applications, notably in alkaloid synthesis. Thermodynamically, the general 2-aza-Cope rearrangement does not have a product bias, as the bonds broken and formed are equivalent in either direction of the reaction, similar to the Cope rearrangement. The presence of the ionic nitrogen heteroatom accounts for the more facile rearrangement of the cationic 2-aza-Cope rearrangement in comparison to the Cope rearrangement. Hence, it is often paired with a thermodynamic sink to bias a rearrangement product. In 1950, Horowitz and Geissman reported the first example of the 2-aza-Cope rearrangement, a surprising result in a failed attempt to synthesize an amino alcohol. This discovery identified the basic mechanism of the rearrangement, as the product was most likely produced through a nitrogen analog of the Cope rearrangement. Treatment of an allylbenzylamine (A) with formic acid and formaldehyde leads to an amino alcohol (B). The amino alcohol converts to an imine under addition of acid (C), which undergoes the cationic 2-aza-Cope rearrangement (D). Water hydrolyses the iminium ion to an amine (E). Treating this starting material with only formaldehyde showed that alkylation of the amine group occurred after the cationic 2-aza-Cope rearrangement, a testament to the quick facility of the rearrangement. Due to the mild heating conditions of the reaction carried out, unlike the more stringent ones for a purely hydrocarbon Cope rearrangement, this heteroatomic Cope rearrangement introduced the hypothesis that having a positive charge on a nitrogen in the cope rearrangement significantly reduces the activation barrier for the rearrangement. The aza-Cope rearrangements are predicted by the Woodward-Hoffman rules to proceed suprafacially. However, while never explicitly studied, Overman and coworkers have hypothesized that, as with the base-catalyzed oxy-Cope rearrangement, the charged atom distorts the sigmatropic rearrangement from a purely concerted reaction mechanism (as expected in the Cope rearrangement), to one with partial diradical/dipolar character, due to delocalization of the positive charge onto the allylic fragment, which weakens the allylic bond. This results in a lowered activation barrier for bond breaking. Thus the cationic-aza-Cope rearrangement proceeds more quickly than more concerted processes such as the Cope rearrangement. The cationic 2-aza-Cope rearrangement is characterized by its high stereospecificity, which arises from its high preference for a chair transition state. In their exploration of this rearrangement's stereospecificity, Overman and coworkers used logic similar to the classic Doering and Roth experiments, which showed that the Cope rearrangement prefers a chair conformation. By using the cationic 2-aza-Cope/Mannich reaction on pyrrolizidine precursors, they showed that pyrrolizidines with cis substituents from E-alkenes and trans substituents from Z-alkenes are heavily favored, results that are indicative of a chair transition state. If a boat transition state was operative, the opposite results would have been obtained (detailed in image below). As is the trend with many reactions, conversion of the Z-enolate affords lower selectivity due to 1,3 diaxial steric interactions between the enolate and the ring, as well as the fact that substituents prefer quasi-equatorial positioning. This helps explain the higher temperatures required for Z-enolate conversion.The boat transition state is even less favored by the cationic-2-aza-Cope rearrangement than it is for the Cope rearrangement: in analogous situations to where the Cope rearrangement takes on a boat transition state, the aza-Cope rearrangement continues in the chair geometry. These results are in accord with computational chemistry results, which further assert that the transition state is under kinetic control. Significantly, these stereochemical experiments imply that the cationic 2-aza-Cope rearrangement (as well as Mannich cyclization) occur faster than enol or iminium tautomerization. If they were not, no meaningful stereochemistry would have been observed, highlighting the facility of this fast reaction.