Exploring metal-base catalysis in Indole C2 Selective Mannich and Alkylnitrile Conjugate Addition reactions
Item statusRestricted Access
Embargo end date01/07/2020
Richards, Jonathan Philip
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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.