This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg) Nanyang Technological University, Singapore. Molecular transformations using a sodium hydride‑iodide composite Chan, Guo Hao 2018 Chan, G. H. (2018). Molecular transformations using a sodium hydride‑iodide composite. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/103312 https://doi.org/10.32657/10220/47383 Downloaded on 04 Oct 2021 04:31:56 SGT MOLECULAR TRANSFORMATIONS USING A SODIUM HYDRIDE-IODIDE COMPOSITE CHAN GUO HAO SCHOOL OF PHYSICAL AND MATHEMATICAL SCIENCES 2018 MOLECULAR TRANSFORMATIONS USING A SODIUM HYDRIDE-IODIDE COMPOSITE ‘ CHAN GUO HAO SCHOOL OF PHYSICAL AND MATHEMATICAL SCIENCES A thesis submitted to the Nanyang Technological University in fulfillment of the requirement for the degree of Doctor of Philosophy 2018 Acknowledgements First and foremost, I would like to express my deepest gratitude to my supervisor, Professor Chiba Shunsuke, whose patient guidance, insightful discussion, and strict training enabled me to complete my PhD course study. His discipline and perspectives toward chemistry and in life will continue to motivate and inspire me. Completing a Ph.D. is not a simple task for me who began with minimal skills and knowledge. I would also like to thank my company supervisor, Jolyon Perkins who always gave great insights to the chemistry process in the industry and encouragement during tough times. I would also like to thank him for giving me the opportunity to participate in some of the company projects for process improvement. I would like to sincerely thank my mentor, Dr. Too Pei Chui, who took her time to teach me the practical skills and the troubleshooting process in the lab. To my labmates, Dr. Zhu Xu, Dr. Chen Hui, Dr. Xing Gao, Dr. Ya Lin, Dr Yinhua, Kaga, Hiro, Derek, Jia Hao, Dhika, Dr. Wang Bin and Dr. Ciputra for the fruitful discussion and for making a tough working environment a better place to work in. To all the CBC and Pfizer research, laboratory and administrative staffs, thank you for supporting my research over these four years. I would also like to thank EDB and Pfizer Asia Pacific Pte Ltd for providing me the research scholarship for this opportunity. Most importantly, I would like to express my deepest gratitude to my family, Melissa, Matthias, my parents and sisters for supporting me in any given time. With deepest gratitude, Guo Hao i Table of Contents Acknowledgements ................................................................................................................ i Table of Contents ................................................................................................................... ii List of Abbreviations .............................................................................................................. vi Abstract................................................................................................................................. ix Chapter 1 General Introduction ................................................................................... 1 1.1. Strategies for use of Alkali Metal Hydrides ................................................................. 3 1.1.1. Classical Methods ............................................................................................... 3 1.1.2. Modern Methods .................................................................................................. 7 1.2. Strategies for use of Alkaline Earth Metal Hydrides .................................................. 13 1.3. Perspective for the Thesis ........................................................................................ 22 1.3.1. Sodium hydride-iodide composite as a hydride donor ........................................ 22 1.3.2. Sodium hydride-iodide composite as a Lewis acid ............................................. 23 1.4. References ............................................................................................................... 24 Chapter 2 Hydrodecyanation of α-Aryl Tertiary Nitriles by a Sodium Hydride-Iodide Composite ........................................................................................................................ 27 2.1. Introduction .............................................................................................................. 27 2.1.1. Classical Methods for Hydrodecyanation ........................................................... 27 2.1.2. Modern Methods for Hydrodecyanation.............................................................. 30 2.2. Preliminary Discovery and Working Hypothesis on Use of Sodium Hydride (NaH) for Hydrodecyanation ............................................................................................................ 34 2.3. Results and Discussion 2.3.1. Preparation of Various Tertiary Carbonitriles .................................................... 35 2.3.2. Optimization of the Reaction Conditions ........................................................... 38 2.3.3. Scope and Limitation ........................................................................................ 39 2.3.4. Mechanistic Discussion .................................................................................... 41 ii 2.4. Conclusions .............................................................................................................. 44 2.5. References ............................................................................................................... 45 Chapter 3 Reduction of N,N-Dimethylcarboxamides to Aldehydes by a Sodium Hydride/Iodide Composite ............................................................................................... 47 3.1. Introduction ............................................................................................................... 47 3.1.1. Reduction of Amides to Aldehydes Controlled by Amide Substituents ............... 48 3.1.2. Hydride Reagents that Controls Reduction of Amides to Aldehydes .................. 49 3.2. A Perspective of this Chapter ................................................................................... 52 3.3. Result and Discussion .............................................................................................. 53 3.3.1. Preparation of Starting Materials ....................................................................... 53 3.3.2. Optimization of the Reaction Conditions ............................................................ 58 3.3.3. Scope and Limitation ........................................................................................ 59 3.4. Conclusions .............................................................................................................. 69 3.5. References ............................................................................................................... 69 Chapter 4 Amide-Directed C-H Sodiation by a Sodium Hydride/Iodide Composite ........................................................................................................................................... 72 4.1. Introduction ............................................................................................................... 72 4.1.1. Complex-Induced Proximity Effect ..................................................................... 72 4.1.2. Kinetically Enhanced Metalation ........................................................................ 73 4.1.3. Directed C-H Sodiation ...................................................................................... 74 4.2. Result and Discussion .............................................................................................. 80 4.2.1. A Preliminary Finding ........................................................................................ 80 4.2.2. Preparation of Starting Materials ....................................................................... 82 4.2.3. Scope and Limitation ......................................................................................... 86 4.3. Conclusions .............................................................................................................. 94 4.4. References ............................................................................................................... 95 iii Chapter 5 Experimental Section................................................................................ 97 5.1. General .................................................................................................................... 97 5.2. Experimental Data for Chapter 2 .............................................................................. 97 5.2.1. Synthesis of Tertiary Carbonitriles ..................................................................... 97 5.2.2. Hydrodecyanation of Tertiary Carbonitriles ...................................................... 113 5.2.3. A procedure for Scheme 2.22 and characterization of the products ................ 123 5.2.4. A procedure for Scheme 2.23 and characterization of the products ................ 124 5.2.5. A procedure for Scheme 2.24 and characterization of the products ................ 125 5.2.6. A procedure for Scheme 2.25a and characterization of the products .............. 125 5.2.7. A procedure for Scheme 2.25b and characterization of the products .............. 126 5.2.8. Detection of NaCN after the decyanation of 2.8a with NaH-NaI composite ..... 129 5.2.9. References for Section 5.2 .............................................................................