Aza-Cope rearrangement

[2] 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.

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.

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.

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.

[1] 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.

[9] 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.

[11] Significantly, these stereochemical experiments imply that the cationic 2-aza-Cope rearrangement (as well as Mannich cyclization) occur faster than enol or iminium tautomerization.

[1] 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.

[12][13] 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.

[1] 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.

[1][16] 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.

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.

A simple experiment verified that the product was racemic, providing clear evidence of the aza-Cope Mannich reaction as the operative mechanism.

[14] Recent literature from the Shanahan lab supports the rare aza-Prins/pinacol pathway only associated with significantly increased alkene nucleophilicity and iminium electrophilicity.

The stereochemistry of the rearrangement is slightly more complicated when the allyl and amine substituents are installed on a ring, and thus cis or trans to one another.

Strychnine is a naturally occurring highly poisonous alkaloid, found in the tree and climbing shrub genus Strychnos.

The example shown is a facile reaction combining a 1-aza-bicyclo[2.2.1]heptane salt starting material with paraformaldehyde at 80 °C to form the pivotal aza-tricyclic structure of the Stemona alkaloid molecules.

Seven-membered ring cycles are also possible to synthesize, as the enol and iminium ions stay in close enough proximity to undergo Mannich cyclization.

This rearrangement first creates the vinyl oxazolidine from attack on the cyclohexanone by the aminobutenol, which then undergoes the aza-Cope/Mannich reaction using heat and acid (Lewis or protic).

More complex examples attach the oxazolidine to another ring, presenting additional methods for the formation of indolizidine cycles.

The reaction exhibits high diastereoselectivity, and is robust, proceeding even when faced with poor orbital overlap in the transition state.

[9] Ketones and sterically hindered aldehydes are not suitable for the basic aza-Cope/Mannich reaction, as the amine cannot form an iminium ion with them.

Dehydrative oxazoline formation followed by heating in the presence of a full equivalent of acid present a way to get around this issue.

[6][25] Cyanomethyl groups represent an easy way to protect an iminium ion during allylic vinylation of the ketone.

They are typically installed by nucleophilic addition onto an iminium ion, generally produced by amine alkylation with formaldehyde.

The cyanomethyl group protects the nitrogen at the 2-position during formation of the other allylic analog by logic similar to cyanide-type umpolung.

Upon creation of appropriately substituted enamines, intense heating afforded an almost complete rearrangement to the imine product.

This strategy was shown to be relatively robust, allowing for the formation of products even when forced through a boat transition state, when perturbed with substituent effects, or put in competition with alternative rearrangements.

[3] Other methods of overcoming this thermodynamic barrier include pairing it with cyclopropane ring strain release, which allows the reaction to proceed at much lower temperatures.

The 1,2, and 3 aza-Cope rearrangements
The 1,2, and 3 aza-Cope rearrangements
Horowitz and Geissman report the first aza-Cope rearrangement. This also exemplifies one of the many methods for carrying out iminium ion formation by reductive amination .
The rearrangement is shown, as well as the reaction's final products. E-alkenes are pictured in the top half, Z-alkenes in the bottom half. Operative chair transition states are detailed first, boat transition states second. Major products are labeled, and unobserved minor products of boat transition states are depicted. Blue dashed lines indicate a σ bond being broken, red dashed lines indicate a σ bond being formed.
anti starting materials generally lead to cis products. syn starting materials lead to an assortment of products, dependent on the nitrogen substituent's bulk, as shown. Blue denotes σ bond breaking, red denotes σ bond formation.
Bond rotation leading to racemic product. The aza-Cope rearrangement proceeding the bond rotation is omitted for clarity.
The iminium is trapped by the intramolecular nucleophile.
The aza-Cope/Mannich reaction
The aza-Cope/Mannich reaction
This reaction occurred in a single step. The reaction was heated for 5 hours in refluxing benzene. NaOH was added to form the ketone at the final step. Yields typically are around 90%, varying slightly with different substituents.
The oxy-Cope rearrangement
The oxy-Cope rearrangement
A retrosynthetic analysis of strychnine: the Wieland-Gumlich aldehyde is a known precursor of strychnine. A precursor of the Wieland-Gumlich aldehyde is shown, with the aza-Cope/Mannich reaction retron highlighted. Strychnine is synthesized from the Wieland-Gumlich aldehyde in 65% yield.
Molecule "A" has been reconfigured for clarity. The rearrangement substrate proceeds by heating at 80°C in paraformaldehyde , acetonitrile and anhydrous Na 2 -SO 4 . The paraformaldehyde adds the carbon to the nitrogen, resulting in the iminium ion, already pictured. The aza-Cope/Mannich reaction step proceeded in near quantitative yield (98%), 99% ee. [ 20 ]
Some key steps in the preparation of the aza-Cope/Mannich reaction substrate for the Overman synthesis of strychnine
the vinyl substituent was added by vinylithium addition, after which silver nitrate at 50°C afforded the aza-Cope/Mannich product in 80% yield.
Paraformaldehyde alkylated the amine and the reaction proceeded at 80°C in toulene and acetonitrile. This step occurred in 94% yield.
the reaction proceeds with addition of Camphorsulfonic acid (CSA) or silver nitrate at room temperature
the reaction proceeds with addition of Camphorsulfonic acid (CSA) or silver nitrate at room temperature
In the top example, isoprene oxide is first treated with NBS and MeOH, while in the bottom, methanol is not added. The final products of both are afforded in moderate to high yield (~50-90%).
The reaction takes place in refluxing benzene at 80 °C or at room temperature in the presence of Sodium sulfate which activates iminium ion formation. The final product is a 1-azaspiro[4,5]decane.
Vinylation leading to a crinine precursor.
The cyanomethyl group often leaves with the help of silver nitrate. The reaction generally takes place at -78°C.
the 3-aza-Cope rearrangement
the 3-aza-Cope rearrangement
An excerpt of a 3-aza-Cope rearrangement in the total synthesis of deserpidine, by Mariano and coworkers. This step proceeded with 30-60% yield, dependent on allylic substituents (not shown).
Fowler's modification to the 1-aza-Cope rearrangement. Fowler installs a carbonyl group onto the nitrogen, stabilizing the nitrogen lone pair in an amide bond, which helps make the reaction more thermodynamically favorable, although it still requires extreme heating, at around 500 °C.
This example pairs ring strain release with presumed stabilizing resonance with the aldehyde, and proceeds at room temperature.