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nce by pairing the rearrangement with cyclopropane opening intramolecular trapping pictured and pairing the rearrangement with the mannich cyclization 1 15 the iminium is trapped by the intramolecular nucleophile the aza cope mannich reaction edit 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 1 16 the first aza cope mannich reaction edit 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 16 after the aza cope mannich reaction is carried out the ketone is formed by addition of naoh 16 the amine in this simple case cannot form the iminium ion from basic ketones subsequent methods found ways of incorporating ketones into the reaction 16 17 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 12 17 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 reaction mechanism edit 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 sp 2 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 14 recent literature from the shanahan lab supports the rare aza prins pinacol pathway only associated with significantly increased alkene nucleophilicity and iminium electrophilicity 1 6 18 19 the aza cope mannich reaction shows high diastereoselectivity generally in accordance the results of the stereochemical experiments elucidating the transition state of the cationic 2 aza cope rearrangement which follows as this tandem reaction pathway was an integral part of these experiments 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 the aza cope mannich reaction starting material the amino alcohol can also be thought of as related to the oxy cope rearrangement below both for its rate acceleration due to ionic involvement as well as the analogous enol collapsing function of the mannich cyclization and the keto enol tautomerization in the oxy cope rearrangement 7 the oxy cope rearrangement synthetic applications of the 2 aza cope mannich reaction edit 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 1 7 strychnine total synthesis edit main article strychnine total synthesis the classic example demonstrating the utility of this reaction is the overman synthesis of strychnine strychnine is a naturally occurring highly poisonous alkaloid found in the tree and climbing shrub genus strychnos strychnine is commonly used as a small vertebrate pesticide the first strychnine total synthesis by r b woodward 20 represented a major step in natural product synthesis no molecule approaching its complexity had been synthesized before the next total syntheses were not reported until the late 1980s using similar methods namely by using an intermediate available by degradated strychnine all of these syntheses used harsh conditions the overman synthesis sidesteps these problems and is the first asymmetric total synthesis of strychnine taking advantage of the diastereoselectivity and mild reaction conditions of the aza cope mannich reaction the aza cope mannich reaction step proceeded in near quantitative yield the overman synthesis is accordingly several orders of magnitude more efficient than its predecessors 20 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 overman s synthesis of strychnine represents a useful example of the preparation of precursors necessary for the aza cope mannich rearrangement representing effective usage of an epoxide ring opening the key steps of the synthesis of the rearrangement substrate leading to the starting materials necessary for the aza cope mannich reaction included a stille reaction to piece together two precursors an epoxidation of a double bond using tert butyl hydroperoxide a wittig reaction to convert the ketone to an alkene and a cyclization step amine alkylation not shown transforms the molecule to the rearrangement substrate significantly this molecule shows the enantiomeric precision of the aza cope mannich reaction as a simple enantiomeric starting material dictates the final enantiomer the enantiomer of strychnine was produced by using the enantiomer of the starting material 20 21 some key steps in the preparation of the aza cope mannich reaction substrate for the overman synthesis of strychnine the overman synthesis with in depth details of the synthesis of the rearrangement substrate as well as the final steps of the reaction is detailed here overman synthesis of strychnine synthesis of crinine edit crinine is an alkaloid of the family amaryllidaceae and its asymmetric total synthesis was one of the first using the aza cope mannich reaction this synthesis represents a significant step in the development of the aza cope mannich reaction as it takes advantage of several of the most useful synthetic strategies characteristic of the reaction this reaction takes advantage of the cationic 2 aza cope rearrangement s high diastereoselectivity as well as usage of the cyanomethyl group to protect the amine during vinyllithium addition and as a leaving group to promote iminium formation assisted by addition of silver nitrate 22 this synthesis is one example of many of the cyanomethyl group providing a synthetically useful route towards pyrrolidine and indolizidine formation the vinyl substituent was added by vinylithium addition after which silver nitrate at 50 c afforded the aza cope mannich product in 80 yield synthesis of bridged tricyclic alkaloids edit overman and coworkers developed methods to synthesize complicated bridged tricyclic structures using the aza cope mannich reaction these aza tricyclic structures are found in the complex stemona alkaloid family as well as in potential drugs such as some immunosuppressants 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 saliently despite unfavorable orbital overlap due to the sterics of this ring system the reaction proceeds with 94 yield highlighting the power of this reaction even under unfavorable conditions 23 paraformaldehyde alkylated the amine and the reaction proceeded at 80 c in toulene and acetonitrile this step occurred in 94 yield general ring opening and expansion edit the reaction proceeds with addition of camphorsulfonic acid csa or silver nitrate at room temperature the aza cope mannich reaction when coupled with existing ring cycles is often used to create indolizidine cycles a pyrrolidine connected to a cyclohexane ring this typical ring annulation where the cyclopentane moiety is opened with the rearrangement and closed with the mannich cyclization to form a six membered ring attached to a pyrrolidine ring while the most popular aza cope mannich annulation is not the only one seven membered ring cycles are also possible to synthesize as the enol and iminium ions stay in close enough proximity to undergo mannich cyclization 22 macrocycle synthesis has not been reported using this reaction due to the lack of proximity between the enol and iminium 6 vinyl oxazolidines can also be used as rearrangement substrates 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 this example breaks and then forms a five membered ring more complex examples attach the oxazolidine to another ring presenting additional methods for the formation of indolizidine cycles 24 scope of the aza cope mannich reaction edit the aza cope mannich reaction has numerous advantages in comparison to other methods the gentle conditions of the reaction aren t matched light heating normally no higher than 80 c a wide range of solvents and addition of 1 stoichiometric equivalent of acid commonly camphorsulfonic acid csa or a lewis acid other routes toward pyrrolidine synthesis cannot compete with the stereospecificity widescale applications in structures containing pyrrolidine derivatives and large scope of possible starting materials the reaction exhibits high diastereoselectivity and is robust proceeding even when faced with poor orbital overlap in the transition state 1 the advantages of the aza cope mannich reaction have motivated research on the synthesis of the starting materials for the reaction which split into two main categories amine addition and iminium formation red and installation of the vinyl substituent blue a wide variety of n substituents r alkyl and aryl can be used in the reaction some of which affect the stereochemical outcome of the reaction vinyl groups are generally limited to those which are either 1 1 or 1 2 disubstituted vinyl with substituents at r 1 and r 1 r 2 respectively with a wide range of electronic and steric variety tolerated 1 amine addition and iminium formation edit epoxide ring opening edit the ring strain of epoxides provide useful methodology for installation of an amine group two atoms away from an alcohol group the epoxide may be first broken by bromide nucleophilic attack primary amines aromatic amines or lithium anilides can also be used as nucleophiles protective o methylation often follows this step and proceeds easily 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 when sterics allow for attack on only the appropriate carbon the terminal carbon as opposed to the second carbon direct attack by an intramolecular nitrogen is effective as is the case with strychnine synthesis 16 25 iminium ion formation edit the most common way to generate the iminium ion from the installed amine is by adding formaldehyde or paraformaldehyde which undergoes acid catalyzed condensation to form the iminium overman s strychnine synthesis typifies this method 6 25 occasionally intramolecular carbonyls are used 9 other methods for iminium ion formation include using cyanomethyl groups or using oxazolidines as carbonyl precursors amine alkylation edit amine alkylation represents a common method to get to imine precursors amine alkylation by direct s n 2 reaction is only occasionally useful in producing starting materials due to the high propensity of amines to overalkylate 25 reductive amination is a more common and effective alkylating procedure typified in the first aza cope rearrangement 16 26 27 the most useful and standard method of amine alkylation is to have the amine form an amide bond and subsequently reduce it often with lithium aluminium hydride 9 oxazolidine use edit 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 overman has reported the use of oxizolidines to generate the iminium ion requisite for the reaction upon formation overman showed that cyclo...