Development of [3,3]-Sigmatropic rearrangements of zwitterionic and cationic intermediates formed by intramolecular cyclization of tertiary allylic amines tethered to heterocumulenes

Joseph Pisano, University of Vermont


Guanidines are ubiquitous in nature and serve as useful building blocks in biologically active natural products as well as non-nucleophilic bases and organocatalysts. There is thus a need for methods for the synthesis of guanidine compounds as well as isoelectronic groups such as isothioureas. The 1,3-diaza-Claisen rearrangement represents a powerful reaction by which to synthesize highly substituted guanidines.

The scope of the zwitterionic 1,3-diaza-Claisen rearrangement has been further investigated through the introduction of a two-carbon tether. Electron-deficient carbodiimides can be synthesized through desulfurization of isothioureas, which undergo intramolecular cyclization through a tethered tertiary amine bearing an allylic group to afford zwitterions. Heating zwitterions in benzene affords rearranged cyclic guanidines. DFT calculations confirm the hypothesis that increased stability of the allylic cation and NTs anion lower the activation energy of the rearrangement through elongation of forming/breaking bonds. Deuterium labelling experiments were performed to confirm the favorability of a sigmatropic vs. an ionic process. Scrambling of the NMR signal was observed upon reintroduction of silver to the reaction mixture which is consistent with heterolytic cleavage of the allylic C-N bond and subsequent trapping of the allyl cation at either terminal carbon. Deuterium scrambling was not observed in the absence of silver.

Introduction of chirality to the tether allows for tunable diastereoselectivity, influencing the rearranging allylic group to favor a syn configuration according to DFT calculations. Substitution adjacent to the isothiourea produces a single diastereomer, allowing for a dynamic system in which desired stereochemistry can be obtained.

Preparation of an isothiocyanate through the addition of thiophosgene to the tethered primary amine allows for similar reactivity. This intermediate can undergo a cationic sigmatropic rearrangement due to the presence of HCl generated from reaction with thiophosgene, lowering the activation energy of the 1-thia-3-aza-Claisen rearrangement dramatically. The formation of cyclic isothioureas bearing rearranged allylic groups has been investigated for the 2 and 3 carbon tether substrates.