Transition metal catalyzed reactions of pyridinium and iminium ions
Date
2019
Authors
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Publisher
University of Delaware
Abstract
This dissertation focuses primarily on the development of novel methods for the transition metal-catalyzed cross-couplings of alkyl amine derivatives via carbon-nitrogen (C–N) bond activation. Chapters 1–4 focus on the use of Katritzky pyridinium salts, which can easily be obtained in a single step from primary amines. These redox-active amine derivatives can then serve as non-traditional electrophiles in a variety of nickel-catalyzed cross-coupling reactions. This work allows one to consider alkyl amines as substrates in cross-couplings for the first time and may have applications in late-stage derivatization of pharmaceutical targets. Chapter 5 focuses on the development of a copper-catalyzed enantioselective alkynylation of iminium ions to afford α-tetrasubstituted amines, an important motif in a variety of biologically active molecules. ☐ Chapter 1 describes a nickel-catalyzed Suzuki–Miyaura cross-coupling of alkyl pyridinium salts with arylboronic acids. The combination of air- and moisture-stable Ni(OAc)2·4H2O and redox non-innocent bathophenanthroline (BPhen) ligand was found to promote the desired cross-coupling. Both primary and secondary alkyl groups participated smoothly under the optimized reaction conditions with excellent functional group tolerance. Excitingly, we have demonstrated the amenability of this method to pharmaceutical intermediates and amino acid derivatives. Notably, this is the first example of a metal-catalyzed cross-coupling of an amine derivative bearing unactivated alkyl groups. Preliminary mechanistic experiments suggest the intermediacy of alkyl radical species, and the reaction is proposed to proceed via a NiI/III catalytic cycle. ☐ Chapter 2 describes a nickel-catalyzed Suzuki–Miyaura cross-coupling of benzylic pyridinium salts with arylboronic acids. This method enables the synthesis of diarylmethanes, a pharmaceutically relevant motif, from widely abundant benzylic amines. The use of a benzylic pyridinium intermediate allows for the incorporation of heteroaryl substitution, an important facet which is largely overlooked in other cross-couplings to deliver diarylmethanes. Metal-ligand complex PhenNi(OAc)2·4H2O was synthesized to enable facile reaction set-up and a wide solvent tolerance was demonstrated to facilitate the use of this chemistry in synthesis. A one-pot procedure was also developed for the direct conversion of a primary amine into the desired diarylmethane. This work was performed in collaboration with Michelle Garnsey, Brian Boscoe, and Joseph Tucker at Pfizer, Inc. ☐ Chapter 3 describes a nickel-catalyzed Suzuki–Miyaura cross-coupling of benzylic pyridinium salts with vinylboronic acids and esters. This method allows for the rapid construction of 1,3-disubstituted allylic motifs. This chemistry is tolerant of heteroaryl substitution and can employ either the vinylboronic acid or pinacol ester as the coupling partner. Notably, this approach allows for control of the regioselectivity of the alkene. ☐ Chapter 4 describes a nickel-catalyzed reductive cross-electrophile coupling of alkyl pyridinium salts with aryl bromides. This reaction leverages the wide availability of alkyl amines and aryl halides to deliver highly valuable alkylarenes. The optimized reaction conditions employ a catalyst system comprised of NiCl2·DME and 4,4’-diOMeBipy in conjunction with manganese as a stoichiometric reductant. Primary, secondary, and benzylic pyridinium salts are all amenable to this chemistry. Importantly, this method is tolerant of acidic protons and epimerizable stereocenters. We have shown the applicability of this chemistry to amino acid derivatives, pharmaceuticals, and pharmaceutical intermediates. Preliminary mechanistic experiments suggest that a radical-chain bimetallic pathway may be operative. This work was performed in collaboration with Michelle Garnsey, Brian Boscoe, and Joseph Tucker at Pfizer, Inc. ☐ Chapter 5 describes my efforts towards a copper-catalyzed enantioselective alkynylation of iminium ions to form α-diaryl tetrasubstitued amines. The use of cyclic imines containing a removable tether allow for downstream cleavage to reveal enantioenriched acyclic amine products. Preliminary efforts on cyclic N-sulfonyl ketimine substrates have lead to good yields and modest ee’s. Futher optimization of this reaction is ongoing. Additionally, unique conditions have been identified that can achieve kinetic resolution of a related benzisoxazoles.