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 [3,3]-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
The cationic 2-aza-Cope rearrangement, most properly called the 2-azonia-[3,3]-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.
Reaction mechanism Rate acceleration due to positively charged nitrogen
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.
Transition state and stereochemistry 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.
Additional considerations for stereochemistry The aza-Cope/Mannich reaction, when participating in ring-expanding annulations, follows the stereochemistry dictated by the most favorable chair conformation, which generally places bulky substituents quasi-equatorially. The vinyl and amine components can have either syn or anti relationships when installed on a ring. This relationship is typically dictated by the amine substituent: bulky substituents lead to syn aza-Cope precursors. While anti vinyl and amine substituents generally only have one favored transition state, leading to a cis fused ring system, the favored product of syn substituents can change, dictated by steric interactions with solvents or large N-substituents, which may take preference over bulky substituents and change the transition state.
For simple aza-Cope/Mannich reactions that do not participate in ring-expanding annulation, namely condensations of amino alcohols and ethers, bond rotation occurs more quickly than the Mannich cyclization, and racemic products are observed. This can be avoided by using a chiral auxiliary substituent on the amine. Reactions tethered to rings cannot undergo these bond rotations.
Possible thermodynamic sinks for biasing a rearrangement product Horowitz and Geissman's first example demonstrates a possible thermodynamic sink to couple with the cationic 2-aza-Cope rearrangement, where the product is biased by the phenyl substituent through aryl conjugation, then captured by hydrolysis of the iminium. Other methods of biasing a product include using substituents which are more stable on substituted carbons, releasing ring strain (for instance, by pairing the rearrangement with cyclopropane opening), intramolecular trapping (pictured), and pairing the rearrangement with the Mannich cyclization.
The aza-Cope/Mannich reaction
The aza-Cope/Mannich reaction is a synthetically powerful reaction, as it is able to create complex cyclic molecules from simple starting materials. This tandem reaction provides a thermodynamic bias towards one rearrangement product, as the Mannich cyclization is irreversible and its product, an acyl substituted pyrrolidine ring, more stable than that of the rearrangement.
The first aza-Cope/Mannich reaction Overman and coworkers recognized that the cationic 2-aza-Cope rearrangement could potentially be synthetically powerful if an appropriate thermodynamic sink could be introduced. Their logic was to incorporate a nucleophilic substituent into the starting material, namely an alcohol group, which acts only after rearrangement, converted into an enol primed to attack the iminium ion.
This first report of the reaction was a reaction between aldehydes and 2-alkoxy-3-butenamines, which formed an amino alcohol whose aza-Cope/Mannich reaction product was an acyl-substituted pyrrolidine ring. This simple procedure only involved mild heating for several hours. Significantly, the aza-Cope/Mannich reaction occurs in a single step with excellent yield. This procedure is easily applied to condensation of amino ethers (shown below), where the alcohol has been methylated first. After the aza-Cope/Mannich reaction is carried out, the ketone is formed by addition of NaOH. The amine, in this simple case, cannot form the iminium ion from basic ketones; subsequent methods found ways of incorporating ketones into the reaction. The utility of this reaction is evident in the fact that even when a less stable isomer is formed, the reaction proceeds, demonstrating its high thermodynamic favorability.
Reaction mechanism
The general product of the reaction can potentially occur via two separate pathways: the aza-Cope/Mannich reaction, or an aza-Prins cyclization/pinacol rearrangement. These mechanisms have different stereochemical properties, which elucidate the dominance of the aza-Cope/Mannich reaction. The aza-Cope/Mannich reaction forces each atom in the [1,5] diene analog to undergo sp2 hybridization, erasing the starting material's stereochemistry at the labelled R' position, while the aza-Prins/pinacol rearrangement retains stereochemistry at the labelled R' position, pointing to a simple test that reveals the active mechanism. An enantiomerically pure starting material at the "R'" position should lead to a racemic product if the dominant mechanism is the aza-Cope/Mannich reaction, while the stereochemistry should be retained if the dominant mechanism is an aza-Prins cyclization/pinacol rearrangement pathway. A simple experiment verified that the product was racemic, providing clear evidence of the aza-Cope Mannich reaction as the operative mechanism. Further experiments verified this, using the knowledge that the carbenium ion formed in an aza-Prins/pinacol pathway would be effected by its substituent's ability to stabilize its positive charge, thus changing the reactivity of the pathway. However, a variety of substituents were shown to have little effect on the outcome of the reaction, again pointing to the aza-Cope Mannich reaction as the operative mechanism.