synthesis of n-substituted aryl amidines by strong base activation of amines

52 Pages·2014·0.69 MB·English

by  Muhammad Khalifa

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
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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.

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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
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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

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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.

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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.
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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 are of great importance to pharmaceutical chemistry.2-6
Benzamidine (Figure 4), the simplest aryl amidine, is a specific inhibitor of trypsin and
related serine proteases; its derivatives act as antimicrobial and antiparasitic agents and
have been used for the treatment of a variety of diseases, including pneumocystis
pneumonia, antimony-resistant leishmaniasis, and human African trypanosomiasis for
over fifty years.7-9

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