Novel Organoalanes in Organic Synthesis and Mechanistic Insight in Conjugate Addition DARREN WILLCOX, MSci Thesis submitted to the University of Nottingham for the degree of doctor of Philosophy March 2014 Abstract This thesis describes the development of novel aluminium hydrides (HAlCl2•Ln) and organoalanes (Cl2AlCH=CHR and ClMeAlCH=CHR) for organic synthesis, as well as exploring the mechanism by which copper-catalysed conjugate addition proceed with diethylzinc and triethylaluminium. In Chapter 1, the mechanism of copper-catalysed conjugate addition of diethylzinc to cyclohexenone and nickel- catalysed 1,2-addition of trimethylaluminium to benzaldehyde has been studied. The kinetic behaviour of the systems allows insight into which metal to ligand ratio provides the fastest rest state structure of the catalyst to enter the rate determining step. The ligand order in these reactions (derived from these ligand optimisation plots) provides information about the molecularity within the transition state. In Chapter 2, the synthesis of somewhat air-stabilised aluminium hydrides and their subsequent use in palladium- catalysed cross-coupling is described. Stabilised aluminium t i hydrides of the type HAlCl2•Ln, [HAl(O Bu)2] and [HAl(N Bu2)]2 were synthesised. The hydroalumination of terminal alkynes was optimal using bis(pentamethylcyclopentdienyl) zirconocene dichloride, resulting in a highly regio- and stereo- 2 chemical synthesis of alkenylalanes which undergo highly efficient palladium-catalysed cross-coupling with a wide range of sp2-electrophiles. Chapter 3, describes conjugate addition chemistry of ClXAlCH=CHR (X = Cl or Me) under phosphoramidite/ copper(I) conditions (X = Me). Highly enantioselective additions to cyclohexenones (89-98+% ee) were attained. A highly efficient racemic addition of the alkenylalanes (X = Cl) to alkylidene malonates occurs without catalysis. Finally, Chapter 4 includes all the experimental procedures and the analytical data for the compounds prepared in the subsequent chapters. 3 Contents Abstract ................................................................................................................... 2 Acknowledgements ............................................................................................. 8 Abbreviations ...................................................................................................... 10 Mechanistic insight in conjugate addition by ligated cuprates ....... 11 1.0 Introduction ................................................................................................. 12 1.1 General introduction ............................................................................ 12 1.1.1 Conjugate addition of stoichiometric organocopper reagents ............................................................................................................ 12 1.1.2 Catalytic Ligated cuprates ............................................................. 15 1.1.3 Mechanistic investigations of copper-catalysed conjugate addition ............................................................................................................. 25 1.2 Aims of research ........................................................................................ 30 1.3 Results and Discussions ......................................................................... 32 1.3.1 The kinetic protocol .......................................................................... 32 1.3.2 Reproducibility of kinetic runs ...................................................... 37 1.3.3 Ligand effect in conjugate addition ............................................ 39 1.3.4 Effect of the copper source ........................................................... 49 1.3.5 Effect of the terminal organometallic reagent ....................... 51 1.3.6 Ligand rate dependencies .............................................................. 53 The results from Table 4 show that the number of ligands in the fastest rest state of the catalyst which enters into the transition state (ligand optimisation plot) is generally higher than the number of ligands in the transtion state (ligand order). 4 However, this is not the case for trimethylphosphine, where the rest state of the catalyst is akin to the transition state. ............... 55 1.3.7. Non-linear studies ........................................................................... 55 1.3.8. Method of continuous variation analysis ................................ 59 1.3.9. Conjugate addition of Grignard reagents to - unsaturated esters ....................................................................................... 62 1.3.10. Nickel-catalysed 1,2-addition to aromatic aldehydes ..... 64 1.4 Conclusions .................................................................................................. 66 Chapter 2 .............................................................................. 68 Synthesis of air-stabilised alanes and application in hydroalumination chemistry ..................................................... 68 2.1 Introduction ................................................................................................. 69 2.1.1 Aluminium hydrides ............................................................................. 69 2.1.2 Synthesis of alkenylalanes ............................................................ 75 2.1.3 Cross coupling of alkenylalanes .................................................. 83 2.2 Aims of research ........................................................................................ 87 2.3 Results and Discussion ............................................................................ 89 2.3.1 Synthesis of aluminium hydrides ................................................ 89 2.3.2 Hydroalumination of alkynes ........................................................ 96 2.3.2.1 Palladium catalysed Negishi coupling .................................. 100 2.3 Conclusions ................................................................................................ 110 Chapter 3 ............................................................................ 111 Conjugate addition of alkenylaluminum reagents to α,β-unsaturated carbonyl compounds ............................................................. 111 3.1 Introduction ............................................................................................... 112 3.1.1 Conjugate addition to diactivated carbonyls ........................ 112 5 3.1.2 Uncatalysed conjugate addition of alkenylalanes to enones ........................................................................................................................... 116 3.1.3 Copper-catalysed conjugate addition of alkenyl organometallics ............................................................................................ 117 3.2 Aim of research ........................................................................................ 128 3.3 Results and discussions ........................................................................ 129 3.3.1 Conjugate addition to alkylidene malonates ........................ 129 3.3.2 Copper-catalysed conjugate addition of alkenylalanes .... 133 3.3.3. ACA to trisubstituted enones .................................................... 150 3.4. Conclusion ................................................................................................ 154 Chapter 4 ............................................................................ 155 Experimental Section ............................................................ 155 General remarks .............................................................................................. 156 General procedure 1: Kinetic studies using phosphorus ligands ........................................................................................................................... 158 General procedure 2: Kinetic studies Using SIMES ....................... 158 General procedure 3: Kinetic studies of Triethylaluminium with phosphoramidite ligands .......................................................................... 160 General procedure 4: Kinetic studies of the conjugate addition of ethylmagnesium bromide to methyl crotonate ............................... 161 General procedure 5: Kinetic studies of nickel-catalyzed 1,2- addition of trimethylaluminium to benzaldehyde ........................... 162 General procedure 6: Phosphoramidite synthesis ......................... 166 General Procedure 7: Synthesis of Aryl SimplePhos ligands ..... 170 General Procedure 8: synthesis of alkyl SimplePhos ligands .... 176 General procedure 9: Synthesis of dichloroalane adducts51b ..... 182 6 General Procedure 10: Cp*2ZrCl2-catalysed hydroalumination- cross coupling ............................................................................................... 191 General Procedure 11: 2H{1H} and 1H NMR monitoring of hydroalumination ........................................................................................ 192 General procedure 12: Zirconium-catalysed hydroalumination and conjugate addition ............................................................................. 224 General procedure 13: volatile alkyne hydroalumination and conjugate addition ...................................................................................... 230 General procedure 14: Zirconium-catalysed hydroalumination and conjugate addition (neat conditions) .........................................