Overcoming Kinetic and Thermodynamic Challenges of Classic Cope Rearrangements.

Systematic evaluation of 1,5-dienes bearing 3,3-electron-withdrawing groups and 4-methylation results in the discovery of a Cope rearrangement for Meldrum's acid-containing substrates that have unexpectedly favorable kinetic and thermodynamic profiles. The protocol is quite general due to a concise and convergent synthesis from abundant starting materials. Furthermore, products with an embedded Meldrum's acid moiety are prepared, which, in turn, can yield complex amides under neutral conditions. We have now expanded the scope of the reductive Cope rearrangement, which, via chemoselective reduction, can promote thermodynamically unfavorable [3,3] sigmatropic rearrangements of 3,3-dicyano-1,5-dienes to form reduced Cope rearrangement products. The Cope rearrangement is found to be stereospecific and can yield enantioenriched building blocks when chiral, nonracemic 1,3-disubstituted allylic electrophiles are utilized. We expand further the use of Cope rearrangements for the synthesis of highly valuable building blocks for complex- and drug-like molecular synthesis.

Mechanism of an Organocatalytic Cope Rearrangement Involving Iminium Intermediates: Elucidating the Role of Catalyst Ring Size.

The mechanism of the organocatalytic Cope rearrangement is elucidated through a combined computational and experimental approach. As reported previously, hydrazides catalyze the Cope rearrangement of 1,5-hexadiene-2-carboxaldehydes via iminium ion formation, and seven- and eight-membered ring catalysts are more active than smaller ring sizes. In the present work, quantum mechanical computations and kinetic isotope effect experiments demonstrate that the Cope rearrangement step, rather than iminium formation, is rate-limiting. The computations further explain how the hydrazide catalyst lowers the free-energy barrier of the Cope rearrangement via an associative transition state that is stabilized by enehydrazine character. The computations also explain the catalyst ring size effect, as larger hydrazide rings are able to accommodate optimal transition-state geometries that minimize the unfavorable lone-pair repulsion between neighboring nitrogen atoms and maximize the favorable hyperconjugative donation from each nitrogen atom into neighboring electron-poor sigma bonds, with the seven-membered catalyst achieving a nearly ideal transition-state geometry that is comparable to that of an unconstrained acyclic catalyst. Experimental kinetics studies support the computations, showing that the seven-membered and acyclic hydrazide catalysts react 10 times faster than the six-membered catalyst. Unraveling the mechanism of this reaction is an important step in understanding other reactions catalyzed by hydrazides, and explaining the ring size effect is critical because cyclic catalysts provide a constrained scaffold, enabling the development of asymmetric variants of these reactions.

Controlling, Understanding, and Redirecting the Thermal Rearrangement of 3,3-Dicyano-1,5-enynes.

The thermal [3,3] rearrangement of 3,3-dicyano-1,5-enynes to γ-allenyl alkylidenemalononitriles (the "enyne Cope rearrangement") has largely eluded synthetic value as the desired products, too, are thermally reactive and ultimately yield 6π electrocyclization products. Herein, we describe experimental and computational studies related to the thermal rearrangement of 1,5-enynes, structural features to halt the thermal rearrangement at the allene stage, and a reductive variant for preparing bifunctional allenyl malononitriles. We also describe various ways that the bifunctional building blocks can be manipulated and converted to cyclic and acyclic architectures.