one-pot, benzylic amination reactions of azine n-oxides

134 Pages·2017·6.14 MB·English

ONE-POT, BENZYLIC AMINATION REACTIONS
OF AZINE N-OXIDES

A THESIS SUBMITTED TO
THE GRADUATE SCHOOL OF ENGINEERING AND SCIENCE
OF BILKENT UNIVERSITY
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR
THE DEGREE OF
MASTER OF SCIENCE
IN
CHEMISTRY

By

Menekşe Liman

June, 2017
ONE-POT, BENZYLIC AMINATION REACTIONS OF AZINE N-OXIDES
By Menekşe Liman
June, 2017
We certify that I have read this thesis and that in my opinion it is fully adequate, in
scope and in quality, as a thesis of the degree of Master of Science.

____________________________
Yunus Emre Türkmen (Advisor)

____________________________
Bilge Baytekin

____________________________
Zeynel Seferoğlu

Approved for the Graduate School of Engineering and Science:

____________________________
Ezhan Karaşan
Director of the Graduate School

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ABSTRACT
ONE-POT, BENZYLIC AMINATION REACTIONS OF AZINE N-OXIDES
Menekşe Liman
M.S. in Department of Chemistry
Supervisor: Yunus Emre Türkmen
June, 2017
Nitrogen-containing aromatic heterocycles, found in many biologically active natural
products and pharmaceutical drugs, constitute a highly important class of compounds in
organic chemistry. In this context, areas such as the discoveries of new synthetic
methods for both the synthesis and derivatization of nitrogen-containing heterocyclic
compounds as well as for the introduction of nitrogen to a compound attract significant
attention in the areas of organic and pharmaceutical chemistry. In this study, we have
developed a new one-pot synthetic method for the benzylic amination of azine-N-oxides
containing a methyl group at the 2-position. Following the optimization studies, the
substrate scope of the developed reaction has been investigated in detail. The reaction
tolerates quinoline and isoquinoline N-oxides with electron donating and withdrawing
substituents as the electrophilic reaction partner as well as a broad range of nucleophilic
primary, secondary and aromatic amines.

Keywords: Heterocyclic compounds, Azine N-Oxides, Benzylic amination

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ÖZET
AZİN N-OKSİT BİLEŞİKLERİNİN BENZİLİK AMİNASYONU
Menekşe Liman
Kimya Bölümü, Yüksek Lisans
Tez Danışmanı: Yunus Emre Türkmen
Haziran, 2017
Azot içeren aromatik heteosiklik bileşiklere hem biyolojik açıdan aktif doğal ürünlerin
hem de ilaçların yapısında sıklıkla rastlanmaktadır. Bu kapsamda, azot içeren
heterosiklik bileşiklerin sentezlenmesini, türevlendirilmesini ve bileşiğe yeni azot
eklenmesini sağlayacak yeni sentetik yöntemlerin bulunması organik ve ilaç kimyasında
oldukça önem taşımaktadır. Bu çalışmada, 2 pozisyonunda metil grubu içeren azin N-
oksitlerin benzilik pozisyondan tek basamakta aminasyonunu sağlayacak yeni bir sentez
yöntemi geliştirilmiştir. Optimizasyon çalışmalarının ardından, geliştirilen yöntem ile
substrat kapsamı detaylı bir şekilde incelenmiştir. Belirlenen bu kimyasal tepkime,
yapısında elektron verici ve çekici gruplar içeren kinolin ve isokinolin N-oksit türevleri
ile nükleofilik birincil, ikincil ve aromatik aminler arasında başarılı bir şekilde
uygulanabilmektedir.

Anahtar Kelimeler: Heterosiklik bileşikler, Azin N-oksit, Benzilik aminasyon

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ACKNOWLEDGEMENT
I would like to express my sincere thanks to my supervisor Asst. Prof. Yunus Emre
Türkmen for his valuable knowledge, supervision, support, and guidance during the
course of this research. The door to his office was always open to me whenever I was in
trouble or had a question about my research.
I would like to special thanks to M. Bengisu Başbay for her invaluable friendship and
emotional support. Since the first year of the university life, you have become one of my
best friends. I will always remember our great conversations and wonderful memories.
I am sincerely grateful to my close friends Elif Perşembe, Merve Balcı, Tuluhan Olcayto
Çolak, Muammer Yaman, and Nüveyre Canbolat for their friendship, understanding and
encouragement during my research. I feel lucky to have your friendship.
I would also like to thank members of Türkmen Group, especially Sidra Hassan, Sujit
Pal and Gökçen Aydın for their sincere friendship, support and guidance. It was a nice
experience for me to work with them.
I want to express my gratitude to E. Göksu Sezer for his unconditional love, patient and
for always being there for me.
Last but not the least; I would like to thank my parents and my lovely sister, Hilal, for
their encouragement and understanding throughout all my life. I will be grateful forever
for your love. I cannot imagine a life without you.
TÜBİTAK (The Scientific and Technological Research Council of Turkey) is gratefully
acknowledged (Project No: 115Z865) for providing financial support.
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Dedicated to my beloved mother and father..

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LIST OF ABBREVIATIONS
EtOAc Ethyl Acetate
FTIR Fourier Transform Infra-Red
HRMS High Resolution Mass Spectrometry
iPr EtN N,N-Diisopropylethylamine (Hünig’s Base)
2
m-CPBA m-Chloroperbenzoic acid
MeCN Acetonitrile
MeOH Methanol
MsCl Methanesulfonyl chloride
Ms O Methanesulfonic anhydride
2
NMR Nuclear Magnetic Resonance
PyBroP Bromotripyrrolidinophosphonium hexafluorophosphate
TLC Thin Layer Chromatography
Tf O Trifluoromethanesulfonic anhydride
2
TsCl p-Toluenesulfonyl chloride
Ts O p-Toluenesulfonic anhydride
2
UV Ultraviolet

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TABLE OF CONTENTS
INTRODUCTION ...................................................................................................... 1
1.1 Heterocyclic Chemistry and Heterocyclic Compounds .................................... 1
1.1.1 General Applications of Heterocyclic Compounds ..................................... 3
1.2 Nitrogen-containing Heterocyclic Compounds in Drug Discovery ................. 3
1.3 Use of Azine N-Oxides in Pharmaceutical Chemistry ..................................... 6
1.4 Methods for Derivatization of Azine Components ........................................... 7
1.5 PyBroP as Activating Agent ........................................................................... 10
1.5.1 Other Activating Agents ............................................................................ 12
1.6 Traditional Methods for Derivatization of 2-methyl Azine Components ...... 14
1.7 Synthesis via Rearrangement Reactions ......................................................... 15
1.7.1 Boekelheide Rearrangement ...................................................................... 15
1.7.2 Ciamician-Dennstedt Rearrangement ........................................................ 18
1.8 Cross-Coupling Reactions for Drug Synthesis ............................................... 19
1.9 One-Pot Synthesis ........................................................................................... 22
1.10 The Aim of This Work ................................................................................. 25
RESULTS & DISCUSSION .................................................................................... 28
2.1 Internal Standard Method ............................................................................... 28
2.2 Optimization of Benzylic Amination Reaction .............................................. 29
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2.2.1 Investigation of Activating Agents ............................................................ 30
2.2.2 Investigation of Base, Solvent and Temperature ....................................... 33
2.3 Substrate Scope ............................................................................................... 35
2.3.1 Preparation of Azine N-Oxide Derivatives ................................................ 36
2.3.2 Screening of Azine N-Oxide Derivatives in the Benzylic Amination
Reaction .................................................................................................................... 40
2.3.3 Screening of Nucleophilic Amines in the Benzylic Amination Reaction . 42
2.4 Scalability of Benzylic Amination Reaction .................................................. 44
EXPERIMENTAL .................................................................................................... 46
3.1 Experimental Details ...................................................................................... 46
3.1.1 Methods and Materials .............................................................................. 46
3.2 Synthesis of Azine N-Oxides .......................................................................... 47
3.2.1 General Procedure I ................................................................................... 47
Compound 1 ................................................................................................. 47
Compound 2 ................................................................................................. 48
Compound 3 ................................................................................................. 49
Compound 4 ................................................................................................. 50
Compound 5 ................................................................................................. 51
Compound 6 ................................................................................................. 51
Compound 7 ................................................................................................. 53
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3.3 Benzylic Amination of Azine N-Oxide Derivatives ....................................... 54
3.3.1 General Procedure II .................................................................................. 54
Compound 8 ................................................................................................. 54
Compound 9 ................................................................................................. 55
Compound 10 ............................................................................................... 56
Compound 11 ............................................................................................... 57
Compound 12 ............................................................................................... 58
Compound 13 ............................................................................................... 59
Compound 14 ............................................................................................... 60
Compound 15 ............................................................................................... 60
Compound 16 ............................................................................................... 61
Compound 17 ............................................................................................... 62
Compound 18 ............................................................................................... 63
Compound 19 ............................................................................................... 64
Compound 20 ............................................................................................... 65
CONCLUSION ......................................................................................................... 67
BIBLIOGRAPHY ..................................................................................................... 68
APPENDIX A ........................................................................................................... 79

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