The preparation of thalidomide analogues and new nickel catalysts for organic synthesis

Part I of this thesis describes the synthesis and biological evaluation of analogues of the medicinal drug thalidomide (I). Through a domino hydrogenation-reductive amination one-pot reaction, fifteen new alkyl amino thalidomide analogues (II) were synthesised in generally high yields (up to 98%). All analogues were tested for their ability to inhibit the expression of tumour necrosis factor alpha (TNF) – a generally good indication of the broader biological activity, including anti-carcinogenic activity. While analogues II were less active than those previously prepared by the Stewart group, they gave important insight into the structure-activity relationship of thalidomide analogues. Furthermore, the fluorescent features of analogues II were investigated. In addition, new thalidomide analogues bearing fluorescent probes and/or azide photoaffinity labels (PAL) were prepared to elucidate the molecular mode of action of I. Lastly, a brief study on radiolabelling thalidomide (I) was conducted to give an 18F-thalidomide analogue for potential use in positron emission tomography (PET).

Part II of this thesis deals with the development of new air-stable Ni(0) complexes for use as a catalyst in cross-coupling reactions, for example to prepare analogues of thalidomide (I). Many catalytic cross-coupling processes rely on the use of expensive palladium compounds or air-sensitive nickel(0) complexes. In this work, nickel(0) phosphite complexes were trialled for their ability to catalyse the C–C bond forming Mizoroki-Heck reactions as well as C–N coupling reactions (Buchwald-Hartwig amination). Eventually, this led to the synthesis of five new airstable Ni(0) complexes (III).

Some of these novel complexes (III) proved moderately successful as catalysts in Mizoroki- Heck reactions between aryl triflates and vinyl ethers, and highly efficient in C–N cross-coupling reactions between aryl (pseudo)halides and anilines, primary alkyl amines or imines. In addition, one of the first nickel based catalysts to couple ammonia directly with aryl halides was developed as part of this work. Furthermore, mechanistic details of this nickel catalysed C–N coupling process were elucidated by means of NMR spectroscopy, kinetic experiments and DFT calculations.