Deprotection and Reductive Amination Methodology of N-Boc-3-amino-4-halopyridines

174 Pages·2016·7.99 MB·English

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7-1-2016
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Christopher Alexander Wilhelmsen
Syracuse University
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Wilhelmsen, Christopher Alexander, "Deprotection and Reductive Amination Methodology of N-
Boc-3-amino-4-halopyridines" (2016). Dissertations - ALL. 506.
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Abstract
The following describes a protocol for the one-pot deprotection and reductive amination of
N-Boc-3-amino-4-halopyridines. The intermediate 3-amino-4-chloropyridinium trifluoroacetate
salt combined with trimethylsilyl trifluoromethanesulfonate (TMSOTf) effectively facilitates
condensation with a carbonyl moiety. The corresponding imine is subsequently reduced using
sodium triacetoxyborohydride. The product, N-alkyl-3-amino-4-halopyridines, provides an
effective synthon for our previously reported synthesis of imidazo[4,5-c]pyridines. The current
approach greatly improves upon previously alkylation methods of these aryl amines; providing an
expanded substrate scope with excellent yields.
Deprotection and Reductive Amination Methodology

of N-Boc-3-amino-4-halopyridines
By
Christopher A. Wilhelmsen
B.S. Chemistry, University of North Carolina at Wilmington
Dissertation
Submitted to the Graduate Faculty of
Arts & Sciences in partial fulfillment
Of the requirements for the degree of
Master of Science with Thesis
Syracuse University
July 2016
Copyright © by Christopher Wilhelmsen
2016
All Rights Reserved
Acknowledgements
There are many people that I would like to thank for getting me to where I am today. I
would like to thank my family. My mom and my dad, who took me on eye-opening adventures,
exposed me to the world, and taught me valuable lessons that I will not soon forgot. You both have
supported me so much throughout the years. My siblings, Max, Adam, and Tasha, who have put
up with me and also have taught me lifelong lessons. I would like to also thank my friends, old
and new, for being there and sharing the time in this adventure we call life.
I would like to thank the people that have taught me so many lessons and not only regarding
chemistry. Dan, Dr. Clark, you have given me every opportunity to succeed. I appreciate you
giving your time when I come to your office, unannounced, asking if I can “bother you for a
minute.” I am thankful for my past educators, Dr. Morgan, Dr. Totah, and Dr. Chisholm, who have
helped me become the chemist I am today.
I would like to thank current and former members of the Clark group. Alex Dixon, Dr.
Robert Wilson, and Marty Dolan; you all have taught me a lot and made the past two years a great
experience.

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TABLE OF CONTENTS

Abstract ........................................................................................................................................... i
Deprotection .................................................................................................................................. ii
List of Schemes ............................................................................................................................. vi
List of Tables ............................................................................................................................... vii
List of Figures ............................................................................................................................. viii
List of Abbreviations ................................................................................................................... ix
Introduction ................................................................................................................................... 1
Results and Discussion................................................................................................................ 12
Conclusion ................................................................................................................................... 18
Appendix I: Experimental .......................................................................................................... 19
Appendix II: Bibliography ......................................................................................................... 86
Appendix III: Spectra ................................................................................................................. 89
Christopher A. Wilhelmsen ..................................................................................................... 162

v
List of Schemes

Scheme 1: Classic synthesis of imidazo[4,5-b/c]pyridines ............................................................ 3
Scheme 2: Senanayake’s synthesis of imidazo[4,5-b]pyridines .................................................... 3
Scheme 3: N-alkylation of imidazo[4,5-b]pyridine ....................................................................... 4
Scheme 4: Khanna’s synthesis of imidazo[4,5-b]pyridine ............................................................. 4
Scheme 5: Caron’s synthesis of imidazo[4,5-c]pyridines .............................................................. 5
Scheme 6: Ma’s synthesis of imidazo[4,5-b]pyridines .................................................................. 6
Scheme 7: Buchwald’s synthesis of imidazo[4,5-b/c]pyridines .................................................... 6
Scheme 8: Clark’s synthesis of imidazo[4,5-b]pyridines............................................................... 7
Scheme 9: Clark’s improved synthesis of imidazo[4,5-b]pyridines .............................................. 7
Scheme 10: Clark’s synthesis of imidazo[4,5-c]pyridines ............................................................. 8
Scheme 11: Optimized synthesis of N-Boc-3-amino-4-halopyridines ........................................... 9
Scheme 12: Previously implemented reductive amination methodologies .................................. 10
Scheme 13: General reaction scheme and mechanism of reduction amination ........................... 11
Scheme 14: McLaughlin’s synthesis of indoles and azaindoles .................................................. 11
Scheme 15: Possible mechanism of TMSOTf mediated reductive amination ............................. 14

vi
List of Tables

Table 1: Deprotection and reductive amination acid screen ....................................................... 13
Table 2: Substrate scope for one-pot Boc-removal/reductive amination ..................................... 17

vii
List of Figures

Figure 1: Imidazopyridine nomenclature with selected examples................................................ 1
Figure 2: Biologically active molecules containing imidazopyridine scaffold ............................. 2

viii
List of Abbreviations

Å angstrom(s)
Ac acetyl
Anal. combustion elemental analysis
aq aqueous
Ar aryl
Bn benzyl
Boc tert-butoxycarbonyl
Bu n-Bu normal butyl
tBu tert-butyl
°C degrees Celsius
cm centimeter(s)
δ chemical shift
Cy cyclohexyl
dba dibenzylideneacetone
DCM dichloromethane
DME 1,2-dimethoxyethane
DMF dimethylformamide
DMSO dimethyl sulfoxide
eq/equiv equivalent(s)
Et ethyl
EtOAc ethyl acetate
g gram(s)
Hz hertz
MHz megahertz
IR infrared
J coupling constant
L liter(s)
μ micro
M molar (moles per liter)
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