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48 Pages·2012·2.42 MB·English

Palladium-Catalyzed C-N Cross-Coupling Reactions Toward the
Synthesis of Drug-Like Molecules
by
Camille Z. McAvoy
SUBMITTED TO THE DEPARTMENTS OF CHEMISTRY AND CHEMICAL
ENGINEERING IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DEGREE OF
BACHELOR OF SCIENCE IN CHEMISTRY AND CHEMICAL ENGINEERING
AT THE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
JUNE 2012
ARCHIVES
C 2012 Massachusetts Institute of Technology. All rights reserved.
MASSACHUSETTS NSTITUTE
The author hereby grants to MIT permission to reproduce ~~X Y
and to distribute publicly paper and electronic
JUN E
copies of this thesis document in whole or in part
in any medium now known or hereafter created.
Lt
62 /4 , 14 Zi
Signature of Author:
Cagpie .McAvoy
Departments of Chemistry and Chemical Engineering
May 11, 2012
Certified by:
i bStephen L. Buchwald
Camille Dreyfus Professor of Chemistry
Thesis Supervisor
Accepted by:
-
K. Dane Wittrup
C. P. Dubbs Professor of Chemical Engineering and Biological Engineering
Chemical Engineering Academic Advisor
Accepted by:
John Essigmann
William R. and Betsy P. Leitch Professor of Chemistry
Associate Department Head

Palladium-Catalyzed C-N Cross-Coupling Reactions Toward the Synthesis of
Drug-Like Molecules
by
Camille Z. McAvoy
Submitted to the Departments of Chemistry and Chemical Engineering on May 11, 2012 in
Partial Fulfillment of the Requirements for the Degree of Bachelor of Science in Chemistry and
Chemical Engineering at the Massachusetts Institute of Technology
Abstract
The development of methodologies for C-N bond formation reactions is an important
scientific challenge because of many academic and industrial applications. This work will focus
particularly on palladium-catalyzed cross-couplings of amine-containing compounds with aryl
halides.
The scope of the BrettPhos precatalyst for the cross-coupling of ortho-substituted aryl
iodides with amides is studied using substrates with a variety of functional groups. Due to
potential metal-chelating issues with some of the substrates used in this study, a proposed ligand
synthesis is discussed in which one of the methoxy groups of BrettPhos is replaced with a
morpholine capable of occupying palladium's open coordination site during its catalytic cycle.
A final C-N bond formation study focuses on the cross-coupling of aryl halides with
amidine salts. For this cross-coupling, a methodology has been developed that can be applied to
various electron-rich, electron-poor, and electron-neutral substrates. Furthermore, the products of
this cross-coupling can be used for a subsequent electrocyclization through a reaction with
aldehyde, demonstrating that a relatively simple two-pot methodology can be used to make
relatively complex substrates with pharmaceutical applications. Both amides and amidines are
common moieties in drug-like molecules because of the various biological activities of these
functional groups (1).
Potential medicinal applications of the developed cross-coupling of amidine salts with
aryl halides methodology are described (2). Thus, methodologies for various palladium-
catalyzed, C-N cross-couplings as well as a potential ligand synthesis to be used for palladium
catalysis are herein discussed.
Thesis Supervisor: Stephen L. Buchwald
Title: Camille Dreyfus Professor of Chemistry
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Table of Contents
Abstract ......................................................... 3
Table of Contents .......................................................................................................................... 5
List of Figures................................................................................................................................ 6
A cknow ledgem ents ....................................................................................................................... 7
Chapter 1. Introduction.............................................................................................................. 8
1.1 Background and Significance ............................................................................................ 8
1.1.1 Synthesis and Applications of Am ines ...................................................................... 8
1.1.2 Im portance of Biaryl Phosphine Ligands and Precatalysts......................................... 9
1.2 Objectives.............................................................................................................................. 9
Chapter 2. Cross-Coupling of Ortho-Substituted Aryl Iodides with Amides ......................... 11
2.1 Introduction......................................................................................................................... 11
2.2 Experim ental Procedure. ................................................................................................ 12
2.3 Results ................................................................................................................................. 12
2.4 Di scussion........................................................................................................................... 15
Chapter 3. Proposed Synthesis of a Novel Ligand for Palladium-Catalyzed Cross-Coupling
Reactions....................................................................................................................................... 17
3.1 Introduction......................................................................................................................... 17
3.2 Experim ental Procedure. ................................................................................................ 19
3.3 Results and Di scussion ................................................................................................... 20
3.4 Characterization. ............................................................................................................ 20
Chapter 4. Cross-Coupling of Aryl Halides with Amidine Salts ........................................... 23
4.1 Introduction......................................................................................................................... 23
4.2 ExperimentalP rocedure. ................................................................................................ 24
4.2.1 Screening: One-pot procedure .................................................................................. 24
4.2.2 Substrate Table: Two-pot procedure......................................................................... 24
4.2.3 Electrocyclization ..................................................................................................... 25
4.2.4 Purification M ethods................................................................................................. 26
4.3 Results ................................................................................................................................. 29
4.3.1 Screening Conditions.............................................................................................. 29
4.3.2 Substrate Table......................................................................................................... 33
4.3.3 Electrocyclization Table ......................................................................................... 34
4.4 Di scussion........................................................................................................................... 36
4.5 Characterization.. ........................................................................................................... 38
4.5.1 M elting Point .......................................................................................................... 38
4.5.2 Spectra.......................................................................................................................... 40
Chapter 5. Conclusions.............................................................................................................. 45
References.................................................................................................................................... 46
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List of Figures
Figure 1. General scheme for C-N cross-coupling via copper or palladium catalysis................. 11
Figure 2. BrettPhos ligand and palladium precatalyst. ............................................................. 11
Figure 3. General conditions for cross-coupling reactions between ortho-substituted aryl iodides
an d am ides. ........................................................................................................................... 12
Figure 4. Cross-coupling of various aryl iodides with benzamide. .......................................... 13
Figure 5. Precatalyst, solvent, and temperature screen for cross-coupling of 2-iodo-1,3-
dimethybenzene to benzamide. The structures of SPhos and XPhos are shown below....... 14
Figure 6. Cross-coupling of assorted aryl iodides with various amides. ................................. 15
Figure 7. Possible metal chelation that would block palladium's amide-bonding site and allow
for side reaction s................................................................................................................... 16
Figure 8. Catalytic cycle of palladium..................................................................................... 18
Figure 9. Potential new ligand for palladium-catalyzed cross-coupling reactions. .................. 18
Figure 10. Proposed ligand synthesis procedure...................................................................... 19
Figure 11. Cross-coupling of p-tolyl triflouromethanesulfonate with benzamidine hydrochloride.
............................................................................................................................................... 2 9
Figure 12. Electrophile, base, ligand, and nucleophile screens. ............................................... 30
Figure 13. Test reaction used to probe change in substrate reactivity with change in base sample.
............................................................................................................................................... 3 1
Figure 14. Scope of aryl halide with amidine salt cross-couplings. ....................................... 34
Figure 15. Electrocyclization synthesis. ................................................................................... 35
Figure 16. Quinazoline substrate table..................................................................................... 36
Figure 17. Drug-like molecules containing amidine-aryl bonds.............................................. 38
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Acknowledgements
Meredeth McGowan,' Brett Fors,' Siraj Ali, ' Abraham Ruiz Jr.,2 Stephen L. Buchwald'
'Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139
2Department of Chemistry, University of Texas, Brownsville, TX 78520
I would like to thank Meredeth McGowan and Brett Fors for their mentorship and
guidance in my research. I would also like to thank the National Institutes of Health for financial
support of this project (Grant GM58160). Additionally I would like to thank Professor Stephen
L. Buchwald for allowing me the opportunity to work as an undergraduate researcher in his lab.
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Chapter 1. Introduction
1.1 Background and Significance
1.1.1 Synthesis andA pplications ofAmines
Carbon-nitrogen bond-forming reactions are among the most important and fundamental
genres of reactions in organic synthetic chemistry. Such reactions allow for the synthesis of a
tremendous variety of molecules with a diverse range of industrial applications. C-N bond-
forming reactions are important to the pharmaceutical industry as such bonds are ubiquitous
amongst biochemical substrates (1, 2). These bonds are also found in various other academic and
industrial applications such as natural product synthesis and agrochemicals. Because of the
various significant roles of the C-N bond, developing novel methodologies for forming this bond
with particularly challenging substrates is an important goal of organic chemistry. One of the
most powerful tools for forming C-N bonds comes in the form of the palladium-catalyzed direct
C-N coupling, which allows for the formation of many varied C-N bonds including bonds
involving aryl and heterocyclic compounds (3, 4).
Amines are commonly found in nature and serve a variety of biological functions.
Examples of naturally occurring amines include histamine, nicotine, and dopamine (1). These
compounds demonstrate how the C-N bond serves a wide array of biochemical functions.
Histamine serves as a vasodilator, while nicotine is a tobacco-derived addictive compound, and
dopamine is a neurotransmitter that has been linked to mood (1). Amines can be synthesized
through a variety of methods, including nucleophilic substitution, reduction of other nitrogen-
containing functional groups, reductive amination of aldehydes and ketones, and metal-catalyzed
C-N bond formation chemistry (1). Metal-catalyzed synthetic routes, often involving either
copper or palladium, have the advantage of being able to take relatively complex precursor
substrates and form otherwise hindered or challenging carbon-nitrogen bonds. In addition, metal-
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catalyzed routes often demonstrate good functional group tolerance and a wider substrate scope,
allowing for a broad range of applications (5).
Amides and amidines are also common biologically active moieties, and thus bond-
forming reactions involving these substrates have an important relevance to the pharmaceutical
industry (2). For instance, the amide group can be found in fentanyl, a narcotic pain reliever, (1)
and the amidine group can be found in Quetiapine, an anti-psychotic drug (6). Probing ways of
making new and improved C-N bond formation reactions will allow for a broader scope of
pharmaceutically important syntheses (1). Palladium-catalyzed C-N bond formation reactions
tend to be attractive relative to copper-catalyzed reactions due to their broader reactivity and
functional group tolerance (3).
1.1.2 Importance of Biaryl PhosphineL igands andP recatalysts
Although palladium-catalyzed direct C-N coupling is commonly used in industry and
academia for various synthetic routes, this reaction is limited by the activity of the palladium
catalyst that is used. Advances in biaryl phosphine ligands for palladium-catalyzed amination
have allowed for a broader scope of reactions using aryl halides and sulfonates. These biaryl
ligands include BrettPhos, XPhos, and RuPhos (7, 8). These bulky ligands prevent the formation
of dimer complexes in the palladium catalytic cycle, allowing for more efficient reactions.
Precatalysts developed using these ligands are air- and moisture-stable and are easily activated in
basic solution (9), making them attractive candidates for catalysis. Many industrially-relevant C-
N cross-coupling methodologies have been developed using these ligands and precatalysts (10).
1.2 Objectives
In order to study potential novel C-N bonding methodologies using palladium-catalyzed
cross-coupling, three separate but related projects were undertaken. The first involved cross-
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coupling ortho-substituted aryl iodides with amides using the BrettPhos precatalyst (11). This
project was aimed at gaining a thorough understanding of the scope of this reaction for these
substrates using this palladium-based catalyst. Drawing from observations in this first project, a
new ligand synthesis project was then undertaken. The proposed synthesis of the novel ligand to
be used for palladium-catalyzed direct C-N coupling was aimed at overcoming the apparent
phenomenon that certain functional groups on the electrophile were able to coordinate to the
open coordination site on palladium during its catalytic cycle, thus inhibiting transmetallation.
The final C-N bond formation project embarked on was focused on cross-coupling
various aryl halides with amidine salts. This last undertaking involved optimizing ligand, base,
electrophile, and nucleophile conditions for this reaction for aryl halides bearing electron-
donating, electron-neutral, and electron-withdrawing functional groups. Moreover, this project
sought to develop conditions for particularly challenging and particularly industrially useful
compounds such as sterically hindered substrates and heterocycles. Another facet of the project
involved a subsequent electrophilic cyclization that was achieved by reacting the products of
cross-coupling reactions with aldehydes in situ. Overall, all three projects sought to develop C-N
bond forming methodologies using the palladium-catalyzed direct C-N coupling. Furthermore,
all three projects have important applications in industry because many drug-like compounds
include C-N bonds, particularly in the form of aryl and heterocyclic moieties (12-16).
Consequently, establishing synthetic methodologies for these types of cross-coupling reactions is
a very important and industrially-relevant undertaking (2, 17, 18).
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