Efficient catalysts for heterocycle synthesis-a high throughput approach

Abstract

This thesis describes investigations into tandem catalysed synthesis of polycyclic heteroatom containing molecules and the utilisation of high throughput screening (HTS) methodologies to identify active catalysts.

Methodology for the high throughput screening of in situ generated metal complexes as catalysts was developed. UV spectroscopy and Capillary Electrophoresis (CE) were developed as effective methods of screening combinatorial arrays of complexes as catalysts. HTS methodologies were applied to the screening of in situ generated complexes as catalysts for the hydroamination of 2-(2-phenylethynyl)aniline. Two complexes were identified to be highly active hydroamination catalysts in acetone; the in situ combinations of [Rh(CO)2Cl]2/mesBIAN 38/NaBF4 and Ir(COD)Cl]2/NaBF4. Also identified in this work was the formation of the unusual N-(2-methylvinyl)-2-phenylindole catalysed by [IrCp*Cl2]2/NaBF4 from 2-(2-phenylethynyl)aniline via the incorporation of one molecule of acetone.

Complexes of the type [Cp*MCl(N-N)][X] were synthesised (M = Rh(III) / Ir(III)), N-N= bpm 31, bim 32, dmbpm 61, bik 62, mesBIAN 38 and mesim-mim 63, X= Cl-, BF4-, [Cp*MCl3]-). Where N-N was bpm 31 or bim 32 and there was no alternate counterion present, bimetallic complexes formed containing the counterion X= [Cp*MCl3]-. The three dimensional, solid state, structures of the cationic fragments of the bimetallic complexes [Cp*MCl(N-N)][X] (M= Ir, X= [Cp*IrCl3]-, N-N= bpm 31 and bim 32; M= Rh, X= [Cp*RhCl3]-, N-N= bpm 31; M= Ir, X= BF4 -, N-N= bim 32, mesBIAN 38 and mesim-mim 63) are presented. Abstraction of the chloride, in complexes of the type [Cp*IrCl(N -N)]BF4, by AgBF4 created active catalysts in situ with the best catalyst in the series for the hydroamination of 2-(2-phenylethynyl)aniline [Cp*IrCl(mesBIAN)]BF4/AgBF4.

Investigations performed into the synthesis of N-(2-methylvinyl)-2-phenylindole catalysed by [IrCp*Cl2]2/BF4- have shown that the most likely potential mechanism proceeds via the initial catalysed formation of the imine followed by metal promoted cyclisation. The isolation of the complex [IrCl2(2-(2-phenylethynyl)aniline)Cp*] and investigation into its reactivity showed it to be a potential reactive intermediate in the catalytic cycle.

Investigation into catalysed C-C bond formation of N-propargylindole identified the in situ generated complex [Rh(CO)2Cl]2/PPh3 as a catalyst for the generation of pyrroloquinoline as a 1:1 mixture of regioisomers.