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Title: Exploring metal-base catalysis in indole C2 selective Mannich and alkylnitrile conjugate addition reactions
Author: Richards, Jonathan Philip
ISNI:       0000 0004 7969 1288
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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The focus of this PhD project dealt with the development of base-catalysed transformations towards novel and pharmaceutically relevant molecules. The first chapter was intended to be an application of our previously reported catalyst, Na-N(SiMe3)2, to a new substrate class, i.e., N-unprotected indoles. Rather than the anticipated C3-selective Mannich-type addition to imines, which would represent the indole's intrinsic Friedel-Crafts-type reactivity, a reaction mixture containing an unexpected C2-functionalised indole was obtained. The optimisation of this serendipitous transformation led to a three-component catalyst system for this unusual C2-H bond activation: copper(I) chloride, sodium tetrafluoroborate, and lithium carbonate. Key features of this transformation are as follows: rare example of a C2-C(sp3) bond formation with N-unprotected indoles; unprecedented C2-selective Mannich-type reaction with N-unprotected indoles; sparse example of the catalytic use of a metal carbonate in organic synthesis. A wide range of both indoles and imines proved to be tolerated under the mild reaction conditions; this transformation was even amenable to a three-component reaction, i.e., the in situ-generation of the imines from aldehydes and ortho-anisidine. Mechanistic and control experiments were carried out in order to elucidate the identity of the catalytically active species and to gain insight into the C2-H bond activation mode. At this stage, it was suggested that a copper(I)/lithium heterobimetallic carbonate was critical for the C2-selectivity, and a traceless directing-group hypothesis was proposed. The second chapter of this thesis was focused on the development of the catalytic use of a so-called carbodiphosphorane (CDP), an unusual carbon(0) species, in C-C bond formation. The intended reaction comprised the conjugate addition of aliphatic nitriles to α,β-unsaturated amides; a decent substrate scope was developed. Other organocatalysts including Schwesinger and Verkade super bases as well as carbenes [carbon(II) species] proved to be substantially less efficient; likewise, various metal-bases were found to be poor in reactivity. Key features of this transformation are as follows: unprecedented catalytic use of a CDP in organic synthesis under metal-free conditions; unprecedented example of a carbone catalysis in C-C bond formation; extremely low catalyst loading in the context of organocatalysis (down to 0.25 mol%). Preliminary mechanistic experiments were carried out to identify a plausible pathway, i.e., Lewis base catalysis vs. Brønsted base catalysis.
Supervisor: Schneider, Uwe ; Lawrence, Andrew Sponsor: Engineering and Physical Sciences Research Council (EPSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: atom-economic transformation ; metal-based catalyst ; Na-N(SiMe3)2 ; C2-functionalised indole ; carbodiphosphorane ; C-C bond formation ; catalysis