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Study of Synthesis, Reactions and Enantiomerization of Cα- Chiral Grignard Reagents

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Study of Synthesis, Reactions and Enantiomerization of Cα- Chiral Grignard Reagents Study of Synthesis, Reactions and Enantiomerization of Cα- Chiral Grignard Reagents Neeraj Narendra Patwardhan Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Chemistry Paul R. Carlier, (Chairman) David G. I. Kingston James M. Tanko Webster L. Santos May 2nd 2012 Blacksburg, VA Keywords: enantiomerization, kinetics, chiral Grignard reagents, solvent effects, reaction order, ion-pair separation, entropy of activation, electrostriction, DFT calculations Copyright © Neeraj Patwardhan Study of Synthesis, Reactions and Enantiomerization of Cα- Chiral Grignard Reagents Neeraj Narendra Patwardhan ABSTRACT The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are the chiral organolithium reagents with many reported examples. The primary focus of our research is the development of Cα-chiral Grignard reagents, where the metal bearing α-carbon is the sole source of chirality. Examples of such Grignard reagents are rare owing to the problems associated with their synthesis, and their low configurational stability. We have studied these problems in three different modules of this project. Reactions of 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile with carbon electrophiles are first attempted in order to expand the utility of this configurationally stable Cα-chiral Grignard reagent in asymmetric synthesis. This reagent has been shown to be non-reactive towards carbon electrophiles at low temperatures. Consequently, we attempt to enhance the reactivity of this compound through two different approaches, Lewis-base activation and the “ate-complex” generation. The Magnesium/Halogen (Mg/X) exchange reactions have been shown to be extremely useful in the synthesis of complex Aryl, alkenyl (sp2) and alkynyl (sp) Grignard reagents. Examples of Mg/X exchange reactions of Alkyl (sp3) halides are, however, rare. Even more rare are such examples with secondary and tertiary alkyl halides, justifying the relative paucity of chiral Grignard reagents. In this module of our project, we study the Mg/X exchange reactions on secondary alkyl halides possessing a γ-hydroxyl group, as an internal activator for such Mg/X exchange reactions. Enantiomerization pathways of chiral organolithium compounds have been widely studied. However, few such studies have been performed on chiral Grignard reagents. In this module of the project, we studied the solvent assisted enantiomerization mechanism of the Cα-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile. Rate constant for the enantiomerization of this compound was measured in three different ethereal solvents to study the effect of solvent on the configurational stability. Finally, the order of the enantiomerization process with respect to [Et2O] was studied in order to predict the mechanism of this process in Et2O solvent. Our kinetic studies on the enantiomerization process provided us with a definitive picture for the enantiomerization of the Cα-chiral 1-magnesio-2,2-diphenyl- cyclopropylcarbonitrile, where solvation of the Grignard reagent preceded an ion-pair separation step which eventually lead to enantiomerization of the Grignard species. However, the precise structure of all the involved solvated intermediates could not be determined as kinetics was not able to distinguish between these intermediates. We next performed computational calculations to study the effect of solvation on the analogous 1- magnesio-cyclopropylcarbonitrile in order to address the unanswered questions from our kinetic studies. iii Acknowledgements I would like to begin by expressing my heartfelt gratitude towards my adviser Dr. Paul R. Carlier. I was extremely fortunate to receive his tutelage in the long, often exasperating duration of the graduate program. I am deeply inspired by his zealous attitude towards science along with his disciplined, and at the same time skeptical approach towards tackling any scientific problem. Connecting the dots on this highly scattered picture of my project would not have been possible for me without his guidance. I will always be thankful for the way he patiently helped me overcome the pessimism that arose within me from working on a challenging project. I would also like to thank the members of my advisory committee, Dr. Kingston, Dr. Tanko and Dr. Santos, for all their help and guidance. A special note of thanks is due to Dr. Tanko, for all the helpful discussions on chemical kinetics, which led me to a far better understanding of my project. I would like to thank my colleagues in the Carlier group, Dr. Dawn Wong, Dr. Larry Williams, Dr. Ming Ma, Dr. Nipa Deora, Dr. Josh Harstel, Dr. Chris Monceaux, Dr. Qiao Hong Chen, Dr. Ming Gao, Dr. Derek Craft, Mr. Jimit Mehta, Ms. Stephanie Bryson, Ms. Astha, Mr. Max Hockenbury and Mr. Eugene Camerino, for all the help that they offered to me over all these years. I would like to acknowledge all the help from Dr. Ming Gao who was my partner on a major part of this project. Also, discussions on synthetic chemistry with Dr. Qiao Hong Chen, Dr. Derek Craft, Dr. Chris Monceaux and computational chemistry discussions with Dr. Nipa Deora were extremely helpful. The support I received from my family: my mother Nayana, my lovely wife Shraddha, my younger brother Ninad, his wife Ela, and Shraddha’s parents Prof. V.G. iv Patil and Dr. Mrs. Rekha Patil, was extremely crucial in this phase of my life. I am deeply indebted to my Mother Nayana, for all the success I have managed to achieve in life. The idea of an average person like me writing a doctoral dissertation in life would not have been possible had she not inculcated the constant desire of achieving greater heights in me. I will never be able to thank her enough for the great pains she took in order to provide me with all possible opportunities and amenities in life. Coming to a small town like Blacksburg from a fairly large city in India is a unique experience in itself. My close friends Jimit, Abhijit, Asif, Sujit, Keyur and Nipa made this experience extremely enjoyable. The time we spent together will always be in my memory as the most enjoyable time I ever had in life. Finally and most importantly, I would like to express my gratitude to my beloved wife Shraddha. I would not have been able to maintain my sanity through this exhausting experience if I didn’t have her constant encouragement and support. I am thankful for the patience with which she supported me during all this time. Her ability to support me without expecting anything from me in return is a testimony of her unwavering love, which is the biggest achievement and joy of my life. v Dedication To my mother Nayana and wife Shraddha for their constant love and encouragement vi Table of Contents Chapter 1: Synthesis and Reactions of Cα-Chiral Organomagnesium Reagents. ......1 1.1 Introduction………...…..…………………………...……………...………....1 1.1.1 Metalated nitriles…………..………………………………………………….1 1.1.1.1 Structural properties of metalated nitriles………………………………….....2 1.1.1.2 Synthesis of Metalated nitriles via the metal-halogen exchange reaction………………………………..………………………………………4 1.1.2 Enantiopure metalated cyclopropylnitriles……….…………………………...7 1.1.3 Enhancement of reactivity of Grignard reagents at low temperatures…………………………………………………………………12 1.1.3.1 Ate complexes………………………………………………………….……12 1.1.3.2 Reactivity of ate complexes….……………………………………………...13 1.1.3.3 Magnesate complexes in Mg/X exchange reactions……………………………………………………………………..16 1.1.4 Mg/X exchange routes to secondary sp3 Grignards – potential method for the synthesis of chiral Grignards…………………………………………….….26 1.1.4.1 Magnesium –Halogen (Mg/X) exchange reactions on aryl and alkenyl (sp2) halides………………………………………………….……………………27 1.1.4.2 Magnesium –Halogen (Mg/X) exchange reactions on alkyl (sp3) halides……………………………………………………………………….28 1.1.5 Appropriately placed activators to assist Mg/X exchange reactions………………………………………………………………….….32 1.2 Results and Discussion: Reactions of 1-magnesio-2,2-diphenyl cyclopropylcarbonitrile 1-21 with electrophiles - Reactivity studies………..36 1.2.1 Development of magnesio cyclopropylnitrile reagents bearing smaller substituents and study of their Mg/X exchange reactions….……………….36 1.2.2 In-situ activation of 1-magnesio-2,2-diphenyl cyclopropylnitrile 1- 21…………………………………………………………………………….42 1.2.3 Exploration of anionic magnesates formed from bromonitrile 1- 20…………………………………………………………………...………..45 1.2.4 Conclusions for attempted Lewis base activation of cyclopropyl Grignard reagents……..………………………………………………………………..49 1.3 Results and Discussion: Towards γ-hydroxyl directed Mg/X exchange reactions on secondary alkyl halides –A potential method for synthesizing chiral Grignard reagents……….……………………………………………..50 1.3.1 Synthesis and Mg/X exchange reactions of certain γ-hydroxyl group containing alkyl halides……………………………………………………...51 1.3.2 Conclusions for section 1.3……………………………………...…………...57 1.4 References for Chapter 1…………………………………………………….58 Chapter 2: Solvent assisted enantiomerization of Cα-chiral 1-magnesio-2,2 diphenyl cyclopropylcarbonitrile……………………………...…………………………………62 2.1 Introduction......................................................................................................63 2.1.1: Common methods used to study configurational stability of chiral organolithium compounds……………..…………………………………… 63 vii 2.1.2 Configurational stability of chiral organolithium
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