Developments in Nickel-catalyzed Transfer Hydrocyanation Reactions and Novel Skeletal Editing Strategies through Nitrogen Atom Insertion

Nitrogen-based compounds can be found in a variety of essential building blocks, such as nucleic and amino acids, and are pivotal to life. In organic chemistry, the direct insertion of a nitrogen atom (“N”) as well as the addition of a nitrogen-containing functional group, such as a nitrile (“CN”), represent powerful strategies to introduce nitrogen to molecular frameworks. In the first part of this thesis, the introduction of nitrile groups by hydrocyanation reactions that allow the formal addition of H–CN across unsaturated bonds, including alkenes and alkynes, and aryl cyanation strategies are described. While hydrogen cyanide is usually implemented on industrial scales, HCN-free transfer hydrocyanation reactions have recently gained interest as their application on laboratory scale significantly reduces safety concerns associated with the handling of highly hazardous HCN. Herein, a focus on nickel- and Lewis acid-co-catalyzed transfer hydrocyanation using isovaleronitrile or butyronitrile as sacrificial HCN donor reagents is discussed (see Scheme I). Further developments allowed to circumvent the use of air- and temperature-sensitive Ni(0) catalysts by replacement with more robust Ni(II) precatalysts in combination with alkyl-aluminum Lewis acids. In another approach, the design of novel malononitrile-based HCN donor reagents unlocked a nickel-mediated transfer hydrocyanation of styrenes to selectively access the branched nitriles in the absence of co-catalytic Lewis acids. In-depth mechanistic studies, including initial rate kinetics, elucidation of kinetic isotope effects, and DFT analysis, of the transfer hydrocyanation using alkynes allowed us to investigate the challenging C(sp3)–CN bond activation of the sacrificial donor reagents by the nickel catalyst in the absence of Lewis acids. Additionally, the aryl cyanation of aryl chlorides was developed using HCN- and Lewis acid-free reaction conditions. In the second part of this thesis, skeletal editing approaches by the formal insertion of a nitrogen atom into cyclic ring scaffolds are discussed. These novel strategies allowed us to interconvert various (hetero)cycles, including the transformation of indoles into quinazolines or quinoxalines, as well as pyrroles into pyrimidines, indenes into isoquinolines, or cyclopentadienes into pyridines (see Scheme II). The initial reaction design was based on the mechanistic proposal for the previously established Ciamician-Dennstedt rearrangement and the implementation of in-situ generated iodonitrene reagents, generated by mixing commercially available hypervalent iodine(III) reagents and ammonia sources. In an initial reaction development study, the use of TBS-protected indoles enabled the efficient conversion to the corresponding quinazoline or quinoxaline heterocycles depending on the substitution pattern of the indole precursor. Further reaction optimization attempts enabled the insertion of nitrogen atoms into unprotected indoles and pyrroles, thus circumventing the silyl-protection step. In additional studies, commercially available 15NH4Cl salts could be used as the nitrogen source, thus allowing the insertion of 15N atoms into indenes and cyclopentadienes to access the corresponding 15N-labeled isoquinolines and pyridines selectively.

Grantor dc:publisher

ETH Zurich

Year dc:date

2023

Author dc:creator

• Reisenbauer, Julia

Contributors dc:contributor

• Morandi, Bill
• Carreira, Erick M.; id_orcid0000-0003-1472-490X

• nickel catalysis; skeletal editing; transfer hydrocyanation
• info:eu-repo/classification/ddc/540
• Chemistry

Statement dc:rights

• info:eu-repo/semantics/openAccess
• Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International

Licence

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language

en

Identifier

https://doi.org/10.3929/ethz-b-000612836

OAI identifier oai:identifier

oai:www.research-collection.ethz.ch:20.500.11850/612836