Greener Approaches for Chemical Synthesis – Ball Mill and Microwave Assisted Synthesis of Fluoxetine and Duloxetine and Enantioselective Catalysed Addition of Organometallic Reagents to Aldehydes Ricard Solà Mestres Doctor of Philosophy (PhD) Division of Chemistry & Environmental Science School of Science and the Environment Manchester Metropolitan University 2017 Division of Chemistry & Environmental Science School of Science and the Environment Manchester Metropolitan University Greener approaches for chemical synthesis – ball mill and microwave assisted synthesis of fluoxetine and duloxetine and enantioselective catalysed addition of organometallic reagents to aldehydes Ricard Solà Mestres A thesis submitted in partial fulfilment of the requirements of the Manchester Metropolitan University for the degree of Doctor of Philosophy Manchester, May 2017 ACKNOWLEDGEMENTS I would like to start thanking my Director of Studies, Dr. Beatriz Maciá-Ruiz, for giving me the opportunity to carry out this exciting and challenging project. Not only I have been working on what I love for the last three years, but also I had the opportunity to grow both personally and professionally, get to know this beautiful country and meet a lot of interesting people that have made a great impact to my life. Thank you for the support and the guideance and I wish you all the happiness to you, Gareth and Evan. I also want to thank Dr. Marloes Peeters, for all the help and suggestions on the polymer project. A big thank you to all the technicians from the 6th and 7th floors that have always found some free time to help me and sort out any technical problem with a smile on their faces, especially to Lee, Bill, Allan and Helen. To all the people I have shared the lab with, especially the ones I now consider my friends. Thank you to Jimmy, Jay, Sasha and Neyvero for such an amazing time in the lab. I would like to give a special thank you to all the “Spaniards MMU Fellows”. Thank you for the countless conversations during lunch time, all the good and funny moments, the craziest night outs and for being always there. It would not have been the same without all of you. For a friendship that will last a lifetime, best of luck for the near future! Als meus amics de Calaf, per convertir les meves breus estades en les millors vacances. A la meva família. Al meu germà, l’Adrià per fer-me costat sempre tot i la distància que ens separa. Als meus pares. Gràcies per tot, per donar-me suport, per animar-me a estudiar i per entendre la meva decisió d’anar a viure a l’extranger. Us estimo. And finally to my partner, to the brightest star, Sylwia. With who I have discovered what love is. Thank you for everyday, for sharing with me all the adventures, for all the good moments and for those that are yet to come. For this journey that has only just begun. Kocham cię. TABLE OF CONTENTS LIST OF ABBREBIATIONS ................................................................................... x ABSTRACT ........................................................................................................ xx GENERAL INTRODUCTION .................................................................................. 1 CHAPTER 1 ........................................................................................................ 5 1.1. Introduction ........................................................................................... 5 1.1.1. Non-solvent reactions ....................................................................... 5 1.1.2. Ball Mill ............................................................................................ 7 1.1.2.1. Mechanism at molecular level .................................................... 11 1.1.2.2. Liquid assisted grinding (LAG) ................................................... 12 1.1.3. Non-conventional energy sources .................................................... 13 1.1.3.1 Microwave assisted heating ........................................................ 14 1.1.3.2. Microwave dielectric heating ...................................................... 15 1.1.3.2.1. Dipolar polarisation .......................................................... 15 1.1.3.2.2. Conduction ...................................................................... 17 1.1.3.2.3. Other thermal effects ....................................................... 17 1.1.3.3. Specific microwave effects......................................................... 19 1.1.3.4. Irradiation method .................................................................... 20 1.2. Aim and objectives ............................................................................... 21 1.3. Synthesis of fluoxetine (Prozac) ............................................................. 22 1.3.1. Background .................................................................................... 22 1.3.2. Results and discussion .................................................................... 31 1.3.2.1. Step 1 – Mannich Condensation ................................................. 32 1.3.2.2. Step 2 – Carbonyl Reduction ..................................................... 33 1.3.2.3. Step 3 – O-Arylation ................................................................. 39 1.3.2.3.1. O-Arylation – Scope of the reaction .................................. 52 1.3.2.4. Step 4 – N-Demethylation ......................................................... 55 1.3.3. Conclusions .................................................................................... 57 1.4. Synthesis of duloxetine (Cymbalta) ........................................................ 61 1.4.1. Results and discussion .................................................................... 61 1.4.1.1. Step 1 – Mannich Condensation ................................................. 61 1.4.1.2. Step 2 – Carbonyl Reduction ..................................................... 62 1.4.1.3. Step 3 – O-Arylation ................................................................. 63 1.4.2. Conclusions .................................................................................... 66 1.5. Experimental Part ................................................................................. 68 1.5.1. General instrumentation .................................................................. 68 1.5.2. General methods and considerations ................................................ 69 1.5.3. Experimental procedure and data of compounds .............................. 70 1.5.3.1. Mannich reactions under MW irradiation ..................................... 70 1.5.3.2. Carbonyl reduction in the shaker mill ......................................... 72 1.5.3.3. Carbonyl reduction in solution ................................................... 74 1.5.3.4. Tosylation reaction and substitution in the shaker mill ................. 75 1.5.3.5. Mitsunobu reaction in the shaker mill ......................................... 75 1.5.3.6. MW assisted copper catalysed O-arylation .................................. 76 1.5.3.7. O-Arylation – Scope of the reaction ............................................ 78 1.5.3.8. N-Demethylation....................................................................... 78 1.6. References ........................................................................................... 80 CHAPTER 2 ...................................................................................................... 90 2.1. Introduction ......................................................................................... 90 2.1.1. Background .................................................................................... 90 2.1.2. Catalytic enantioselective addition of Grignard reagents to carbonyl compounds........................................................................ 95 2.1.2.1. Catalytic enantioselective addition of Grignard reagents to aldehydes............................................................................................. 95 2.1.2.2. Catalytic enantioselective addition of Grignard reagents to ketones ...............................................................................................103 2.1.3. Catalytic enantioselective addition of organolithium reagents to carbonyl compounds ................................................................................109 2.1.4. Catalytic enantioselective addition of organoaluminium reagents to carbonyl compounds ............................................................................114 2.1.5. Hydrozirconation reaction for the use of alkenes as nucleophiles .......119 2.2. Aims and objectives .............................................................................127 2.3. Results and discussion .........................................................................129 2.3.1. Catalytic asymmetric addition of organolithium reagents to aldehydes ...............................................................................................129 2.3.2. Catalytic enantioselective addition of methyltriisopropoxititanium to aldehydes............................................................................................137 2.3.3. Catalytic enantioselective 1,2-addition of alkenes to aldehydes .........142 2.3.4. Attempted enantioselective synthesis of fluoxetine ...........................149 2.4. Experimental Part ................................................................................159 2.4.1. General instrumentation .................................................................159