Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

José S. Madalengoitia


The 1,3-diaza-Claisen rearrangement was discovered and developed in the Madalengoitia group since 2004. The rearrangement is initiated by the desulfurization of the electron deficient thiourea and isothiourea to obtain the highly electrophilic carbodiimide which can be reacted with an allylic tertiary amine to form the zwitterionic intermediate which then undergoes [3,3]-sigmatropic rearrangement. Previous investigation includes multiple examples of successful formation of complex guanidines through intermolecular and intramolecular variants. Providing an easy access to guanidine which is one of the most prevalent functional groups in the biologically relevant system, the rearrangement can be a valuable tool in the organic synthesis.

The ring expanding 1,3-diaza-Claisen rearrangement is facilitated by the thiophilic metal promoted desulfurization of the isothioureas tethered to vinyl pyrrolidine which affords electron deficient carbodiimide. Addition of the tertiary amine to the carbodiimides via intramolecular cyclization forms zwitterionic spirocycles which then undergo 1,3-diaza-Claisen rearrangements to afford nine-membered ring guanidine containing fused bicycles with cis-alkene. The mechanistic study with the various additives and DFT calculations revealed that Lewis acid promoted cationic [3,3]-sigmatropic rearrangement mechanism is at play which results in dramatic rate acceleration. The substrate scope examination with varying tether lengths and electron withdrawing groups has shown the less electron deficient carbodiimides engage in faster rearrangement and works optimal with shorter carbon tethers.

The vinyl piperidine ring expansion reactions exhibited the reaction trend similar to the non-strained system. Desulfurization of both tosyl- and triflate- substituted isothioureas afforded exotic guanidine containing transannular 10-membered ring while le electron withdrawing carbodiimides failed to undergo the rearrangement. Mechanistic investigation with DFT calculations suggested the reaction is zwitterionic [3,3]-rearrangement rather than the cationic [3,3]- rearrangement.



Number of Pages

258 p.