Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
José S. Madalengoitia
Abstract
Guanidines are ubiquitous in nature and play pivotal roles in biological, chemical, and industrial applications, occurring in both biomacromolecules and organic materials. Since 2004, the Madalengoitia group has pioneered the development of the 1,3-diaza-Claisen rearrangement, which commences with the desulfurization of electron-deficient thioureas or isothioureas to generate highly electrophilic carbodiimides. These carbodiimides then undergo inter- or intramolecular reactions with tertiary allylic amines to form zwitterionic intermediates, which proceed to guanidines through a [3,3]-sigmatropic rearrangement. However, this protocol exhibits several drawbacks: the mercury or silver salts employed for desulfurization are highly toxic, the method displays limited functional group tolerance, and the inevitably formed triethylammonium triflate byproduct promotes a competing cationic pathway. Additionally, the nucleophilic isothiourea may undergo addition to the carbodiimide, resulting in disproportionation.
The intramolecular variant of this rearrangement is facilitated by a cobalt(II)-mediated cross-coupling of allylamino-tethered isocyanides and sulfonyl azides, yielding the electron-deficient carbodiimide intermediate. Intramolecular cyclization of a tertiary amine subsequently furnishes zwitterionic spirocycles, which undergo the 1,3-diaza-Claisen rearrangement to provide guanidines in favorable yields. Substrate scope investigations of sulfonyl azides have demonstrated that reaction efficiency can be enhanced by increasing the electron-withdrawing capacity of the sulfonyl group. Additionally, the rate of rearrangement can be mitigated by incorporating sterically hindered sulfonyl groups. The substrate scope of the tether length and substitution pattern of amino-tethered isocyanide has shown the methodology works optimally with two carbon tethers and tolerates a variety of functionalities. Although three-carbon tethers generate the corresponding zwitterionic intermediates, these intermediates prove unstable and fail to undergo rearrangement.
Density functional theory (DFT) calculations are employed to estimate rearrangement activation energies by examining potential transition states, with computational results corroborated by experimental data using zwitterionic intermediates bearing two allyl substituents and diverse alkene-stabilizing fragments. Overall, this new method of carbodiimide generation has resulted in a greener and more efficient methodology to generate allylamino-tethered carbodiimides, and expanded the scope of guanidines that can be generated through the zwitterionic 1,3-diaza-Claisen rearrangement.
Language
en
Number of Pages
190 p.
Recommended Citation
Li, Yixiao, "Investigation of the intramolecular Zwitterionic-1,3-Diaza Claisen rearrangement to generate substituted cyclic guanidines via Co(II) catalyzed formation of allylamino-tethered carbodiimide" (2025). Graduate College Dissertations and Theses. 2031.
https://scholarworks.uvm.edu/graddis/2031
