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Synthesis of N-Substituted Aryl Amidines by Strong

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Synthesis of N-Substituted Aryl Amidines by Strong SYNTHESIS OF N-SUBSTITUTED ARYL AMIDINES BY STRONG BASE ACTIVATION OF AMINES by MUHAMMAD M. KHALIFA A THESIS Presented to the Department of Chemistry and Biochemistry and the Robert D. Clark Honors College in partial fulfillment of the requirements for the degree of Bachelor of Science September 2014 Acknowledgements This project was supported by Award Number R01AR059833 from the National Institutes of Health (NIH), Award Number 1R25HD070817 from the National Institutes of Health (NIH) through the University of Oregon Summer Program for Undergraduate Research (UO SPUR), and by the University of Oregon Center for Teaching and Learning Undergraduate Research Fellowship (UO CTL URF) program. The author would like to thank Professors Michael M. Haley and J. Andrew Berglund for their tireless support over the past three years, both within the context of this project and beyond. The success of this project would not have been possible without the help and mentorship of Drs. Micah J. Bodner and Leslie A. Coonrod. A deep debt of gratitude is owed also to Gabriel E. Rudebusch, Chris L. Vonnegut, Aaron G. Docter, and Jessica Y. Choi for their support in the laboratory, and to Dr. S. Michael Strain and the CAMCOR staff for support with NMR Spectroscopy for this project. The project described was supported, in part, by Award Number P30ES000210 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). The content is solely the responsibility of the author and does not necessarily represent the official views of NIEHS or NIH. The author acknowledges the Biomolecular Mass Spectrometry Core of the Environmental Health Sciences Core Center at Oregon State University. Many thanks to Professor Peter M. O’Day, Adam E. Unger, and Farleigh M. Winters for their roles in UO SPUR, to Professor Edward J. Kame’enui, Tanya M. Sheehan, and Dr. Kelli Cummings for their roles in the UO CTL URF program, and to iii Professor Louise M. Bishop and Miriam Jordan for their guidance throughout the Robert D. Clark Honors College thesis process over the past four years. The continued support and encouragement of my parents, Faridah Haron, Ed.D. and Amr Khalifa, and of my brother, Ibrahim Khalifa, has made the project both possible and worthwhile. Last, but not least, a sincere thank you to all the friends, family, and acquaintances who talked to me about this project at all stages of its development (both willingly and unwillingly). The opportunities to communicate my work and receive feedback have made this project what it is today. iv Table of Contents List of Figures vi Background 1 Amidines and Amidine Nomenclature 1 Pharmaceutical Relevance of Amidines 4 Amidine Synthesis in the Literature 6 Nitrile Activation via Electron-withdrawing Substituents 7 Nitrile Activation via Acidic Conditions 7 Amidine Synthesis via Transition Elements and Metals 8 A New Approach to Amidine Synthesis 9 Methods and Materials 11 Methods 11 Reaction Conditions 12 Product Purification 15 Product Characterization 16 Yield Calculation 18 Materials 19 Non-substrate Reagents 19 Substrates 19 Purification & Characterization 21 Experimental Results and Discussion 22 Mono-amidine Series 1: Exploring Amine Starting Material Reactivity 22 Mono-amidine Series 2: Exploring Nitrile Starting Material Reactivity 24 Diamine Series: Exploring Synthesis of Large Amidine-containing Motifs 25 Future Directions 28 Further Exploring Starting Material Compatibility 28 Non-aryl Nitriles 28 Secondary amines 28 Chemoselectivity 29 Dinitriles 29 Method Manipulation for Alternate Products 30 Properties of Amidines and Amidine Chemistry 30 Supporting Information 32 Glossary 40 References 44 Additional Reading 46 v List of Figures Figure 1: The amidine functional group 1 Figure 2: Amidine nomenclature 3 Figure 3: Aryl amidine generic structure 4 Figure 4: Benzamidine and its most important derivatives 5 Figure 5: Amidine-containing moieties and pharmaceutically relevant derivatives 6 Figure 6: Amine activation 12 Figure 7: Nitrile addition 13 Figure 8: Acidifying quench 14 Figure 9: Starting materials for Mono-amidines Series 1 20 Figure 10: Starting materials for Mono-amidines Series 2 20 Figure 11: Starting materials for Diamine Series 21 Figure 12: Mono-amidines Series 1 23 Figure 13: Mono-amidine Series 2 24 Figure 14: Diamine Series 26 Figure 15: Bis-amidine byproducts 27 Figure 16: Amidine synthesis from non-aryl nitriles 28 Figure 17: Exploring chemoselectivity of amidine formation 29 Figure 18: Amine nomenclature 40 Figure 19: Nitrile nomenclature 42 Figure 20: Structure of the trimethylsilyl group 43 vi Background This project outlines a new method for the creation of N-substituted amidines from nitriles and amines. It provides a new tool for synthetic organic chemists interested in producing these types of compounds. Understanding what amidines are, how and why they are used, and the most common methods for preparing them prior to the undertaking of this project is important for a full understanding of this project and its relevance. A glossary clarifying chemistry terms that may be unfamiliar to the layperson has been provided at the end of this work; terms defined in the glossary are underlined at their first appearance in the text. Amidines and Amidine Nomenclature The amidine functional group is a molecular motif featuring a central carbon atom singly bonded to one nitrogen atom and doubly bonded to a second nitrogen atom (Figure 1). Figure 1: The amidine functional group Amidine motif (purple) in a generic molecular context. By convention, carbon atoms are omitted for clarity and “R” groups stand in for any atom. Compounds whose molecular structure contains one or more of such functional groups can be generically termed “amidines”. In Figure 1, the R groups attached to the atoms of the amidine group stand for any atom that may be attached to such an amidine. When these R groups represent anything but hydrogen atoms, they are termed “substituents”. The resulting amidine is appropriately termed a “substituted” amidine, since “substitutions” have been made in place of the hydrogen atoms present in an “unsubstituted” amidine. Note that R4 in Figure 1 is attached to the carbon, and for the purposes of this project represents the remainder of the molecular structure, i.e., the structural context to which the amidine is attached. The focus of this project is on N-substituted amidines, which are amidines with substitutions attached to the nitrogen atom(s). For this reason, further discussion of R groups and substitutions does not apply to R4. For substitutions, the prefixes “mono”, “di”, and “tri” indicate the extent of substitution. Di-substituted amidines may be further classified as “symmetrical” or “unsymmetrical”: a symmetrical di-substituted amidine contains one substituent on each of the nitrogen atoms, though the substituents need not be identical to each other. Accordingly, a di-substituted amidine with both substituents attached to the same nitrogen atom, whether or not the substituents are equivalent, is considered unsymmetrical.1 These relationships are summarized in Figure 2. A molecule containing multiple amidine motifs is denoted by the prefix “bis”, “tris”, etc. This project does not address compounds with more than two amidine motifs, i.e., only mono- and bis-amidines are discussed. 2 Figure 2: Amidine nomenclature Core amidine motif (purple) with substituents (green) determining amidine nomenclature highlighted. This project focuses primarily on mono-substituted and/or bis-amidines. LEGO® building blocks can serve as an appropriate metaphor for organic chemistry: Though simple combinations of a few elemental blocks (one carbon atom and two nitrogen atoms) yield important structural similarities (the amidine functional group), combining such motifs into larger structures leads to myriad possibilities in the features and properties of the resulting creations. Synthesis of new compounds is modular, and this modularity is important to manipulating the properties of all types of compounds, amidines included. We have already defined the central feature of amidines, i.e. what makes an amidine an amidine. We have also briefly discussed sources of diversity within the amidine family, i.e., what differentiates amidines from each other. This project examines synthesis of a specific subset of amidines; using the introduction to amidines previously described, we will now define the subset of amidines in question. Amidines share a number of properties because of their structural commonality, but the effect of substitutions can vary widely depending on the type and extent of substitution(s). The nomenclature of amidines reflects the nature of these substitutions. 3 In this project, we focus specifically on the creation of N-substituted aryl amidines; thus the amidines discussed here are substituted, as previously defined, and specifically so at the nitrogen atoms. The amidines themselves are attached by their central carbon to a distinctive molecular feature, the aryl ring (Figure 3), and therefore fall in the family of “aryl amidines”. Figure 3: Aryl amidine generic structure Aryl amidines are characterized by an amidine motif (purple) appended to an aryl ring (green). This project examines preparation of N-substituted aryl amidines. The importance of this subset of amidines will be discussed in the following sections. Pharmaceutical Relevance of Amidines In addition to a number of applications in material chemistry and organic synthesis, amidines
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