Novel Catalytic Transformations of Organophosphorus Compounds

Abstract

The overall aim of this project was to investigate whether it would be possible to develop methods for the successful synthesis of biaryl monophosphonates by using a variety of cross-coupling reactions enhanced via palladium catalysis in which the phosphonate substituent is present on the nucleophilic component to produce potentially advantageous compounds. Three separate, quite distinct approaches to the synthesis of these nucleophilic components have been attempted in this thesis to find the optimal method : firstly, the synthesis of phosphonate-substituted aryl boronate esters by palladium-catalysed borylation of the corresponding aryl bromide; secondly the conversion of bromoaryl phosphonates into the corresponding organozinc pivalates by metal-halogen exchange; and finally, the synthesis of phosphonate-substituted aryl boronates by iridium-catalysed C-H borylation of the aromatic ring. The potential uses of the resulting biaryl monophosphonates are as precursors to phosphorus-containing ligands, in fine chemical synthesis and as leads in the search for new pharmaceuticals that counteract antibiotic resistance or in treatment of heart conditions. A short two-step synthetic route was successfully carried out to make the desired diethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphonate from 1-bromo-2-iodobenzene. In a similar way, the desired naphthyl analogue was synthesised from 1-bromo-2-naphthol following an initial conversion to the corresponding triflate. Diethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphonate was successfully used in a range of Suzuki-Miyaura cross-coupling reactions, utilising the designer monophosphine KITPHOS ligands made by the Knight/Doherty group with low catalyst loadings. The potassium trifluoroborate salt of the ortho-phosphonate phenyl boronate ester was successfully synthesised from diethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphonate using non-glassware etching conditions. However this method did not work when the same conditions were trialled on the corresponding naphthalene derivative. Transmetalation of the ortho-bromo phosphonate (used in the synthesis of the ortho-phosphonate phenyl boronate ester) was accomplished with iPrMgCl and the resulting Grignard reagent was subsequently converted into the corresponding pivalate by treatment with Zn(OPiv)2. Negishi cross-coupling of this species with a range of functionalised aryl bromides gave the biaryl phosphonates in moderate yield. Separation of the products from diethyl phenylphosphonate, produced by competing protonation of one of the organometallic intermediates, proved troublesome in some cases. Regioselective iridium-catalysed C-H borylation of three meta-substituted aryl phosphonates (methyl/methyl ester and trifluoromethyl substituents were used) gave the corresponding pinacol boronate esters in high conversions. Suzuki-Miyaura cross-coupling with a range of aryl bromides gave the corresponding 5-substituted biaryl phosphonates. All the above methods displayed success in synthesising the desired nucleophilic phosphonate coupling partners and in turn, these coupling partners have been successfully incorporated into the relevant cross coupling reactions, producing desired biaryl monophosphonates in good yield. These biaryl motifs can then be further developed in the synthesis of pharmaceuticals or as precursors to phosphine ligands. In the case of the ortho-biaryls made, their potential use as a ligand for asymmetric catalysis in the fine chemicals industry is an attractive proposition.