Aza Cope Rearrangements� ( Pericyclic Reactions)�

1. 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.

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• The Aza-Cope rearrangements are examples of hetero atom 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 as a cope rearrangements proceed suprafacially.

1. The first example was the ubiquitous cationic 2-Aza-Cope Rearrangement, which takes place at temperatures 100 to 200*C lower than the Cope rearrangement due to facile nature,which is attributed as cationic 2-Aza-Cope is inherently thermo neutral  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.

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• 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.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 n. research on this reaction.

Thet The cationic 2-aza-Cope rearrangement ionic 2-aza-Cope rearrangement

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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.^.

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Rate acceleration due to positively charged nitrogen

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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.

Synthetic applications of the 2-aza-Cope/Mannich reaction

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The aza-Cope/Mannich reaction is often the most efficient way to synthesize pyrrolidine rings, and thus has a number of applications in natural product total syntheses. Because of its diastereoselectivity this reaction has added to the catalog of asymmetric synthesis tools, as seen in the many examples of asymmetric alkaloids synthesized using the reaction. As we have seen in the first aza-Cope/Mannich reaction and in the elucidation of the reaction's stereochemistry, the aza-Cope/Mannich reaction can be used to form pyrrolidine rings and pyrrolizidine rings. It can be used to create many additional ring structures useful in synthesis, such as indolizidine cycles and indole rings.

The 1- and 3-aza-Cope rearrangements pe rearrangements

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1. The 1- and 3-aza-Cope rearrangements are obscure in comparison to the cationic 2-aza-Cope rearrangement due to their activation energies, which are comparatively much higher than that of the cationic 2-aza-Cope rearrangement.
2. The 1- and 3-aza-Cope have a bias towards imine formation as opposed to enamine formation, as carbon-nitrogen π-bonding is stronger than carbon-nitrogen σ-bonding, meaning the 3-aza-Cope rearrangement is thermodynamically favored, while the 1-aza-Cope rearrangement is not: the imine is nearly 10kcal/mol less in energy. Thus the 3-aza Cope's large activation barriers are kinetically based. Research on both the 1 and 3-aza-Cope rearrangements has focused on finding good driving forces to lowering the activation barriers. Several versions of these rearrangements have been optimized for synthetic utility.
3. The 1-aza-Cope rearrangement is normally paired with thermodynamic driving forces. The 3-aza-Cope rearrangements are generally performed cationically to lower the kinetic barrier to its thermodynamically favorable product.
4. These rearrangements follow much of the mechanistic logic of the cationic 2-Aza-Cope rearrangement. The 1- and 3-aza-Cope rearrangements both occur preferentially via chair transition states , and are sped up with the introduction of a positive charge, as this gives the transition state more diradical/dipolar character. The 3-aza-Cope rearrangement is expected to show even less aromatic character in its transition state in comparison to the Cope rearrangement and cationic-2-aza-Cope rearrangement, contributing to the higher temperatures required to overcome the kinetic activation barriers for these arrangements.

T The 3-aza-Cope reaction

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1. The 3-aza-Cope reaction was discovered soon after the 2-aza-Cope rearrangement was identified, due to its analogous relationship to the Claisen rearrangement. Indeed, in early papers, this version of the aza-Cope rearrangement is often referred to as the amino-Claisen rearrangement, a misrepresentation of the rearrangement, as this would imply that both a nitrogen and oxygen are in the molecule.This rearrangement can be used to form heterocyclic rings involving carbon, most commonly piperidine.

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• One of the first examples of this arrangement was identified by Burpitt, who recognized the rearrangement occurring in ammonium salts, which, due to their charged nature, proceeded exothermically without addition of heat—importantly, without a tetrasubstituted nitrogen, the rearrangement did not proceed. Following this logic, much of the research on the 3-aza-Cope rearrangement has focused on charged zwitterionic versions of this reaction, as the charge distribution helps lower the activation barrier: in certain cases, the rearrangement can occur at temperatures as low as -20 °C.                                       

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e 1-aza-Cope reaction rear

1. The first discovered 1-aza-Cope reaction was a simple analog to the generic Cope reaction and required intense heat to overcome its large thermodynamic activation barrier; most subsequent work on the 1-aza-Cope rearrangement has thus focused on pairing the arrangement with a driving thermodynamic force to avoid these harsh reaction conditions.
2. It has been hypothesized that the 1-aza-Cope rearrangement rate-determining transition state has partial diradical and dipolar transition state character due to the presence of the heteroatom.

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