Influence of microwave irradiation and ionic liquids on ... of microwave irradiation and ionic...

download Influence of microwave irradiation and ionic liquids on ... of microwave irradiation and ionic liquids ... The Povarov reaction ... Microwave-assisted three-component reaction in conventional

of 147

  • date post

    22-Feb-2018
  • Category

    Documents

  • view

    217
  • download

    3

Embed Size (px)

Transcript of Influence of microwave irradiation and ionic liquids on ... of microwave irradiation and ionic...

  • Influence of microwave irradiation and ionic liquids

    on multi component reactions

    Dissertation zur Erlangung des Doktorgrades

    der Naturwissenschaften (Dr. rer. nat.)

    Fakultt Naturwissenschaften

    Universitt Hohenheim

    Institut fr Chemie

    vorgelegt von

    Fadime Mert-Balci

    aus Mersin

    (Trkei)

    2013

  • Dekan: Prof. Dr. Heinz Breer

    1. berichtende Person: Prof. Dr. Uwe Beifuss

    2. berichtende Person: Prof. Dr. Henry Strasdeit

    Eingereicht am: 17.06.2013

    Mndliche Prfung am: 11.07.2013

    Die vorliegende Arbeit wurde am 11.07.2013 von der Fakultt Naturwissenschaften der

    Universitt Hohenheim als Dissertation zur Erlangung des Doktorgrades der

    Naturwissenschaften angenommen.

  • Die experimentellen Arbeiten zu der vorliegenden Doktorarbeit wurden unter Anleitung von

    Herrn Prof. Dr. Uwe Beifuss in der Zeit von Juni 2006 bis Dezember 2008 am Institut fr

    Chemie der Universitt Hohenheim zu Stuttgart durchgefhrt.

  • PRELMINARY REMARKS

    The work presented in this thesis was carried out under the supervision of Prof. Dr. Uwe

    Beifuss at the Institute of Chemistry, University of Hohenheim, from June 2006 to December

    2008. The results have already been published in international peer reviewed journals.

    1. Fadime Mert-Balci, Jrgen Conrad, Kathrin Meindl, Thomas Schulz, Dietmar Stalke,

    and Uwe Beifuss

    Microwave-Assisted Three-Component Reaction for the Synthesis of

    Pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones

    Synthesis 2008, 3649-3656

    2. Fadime Mert-Balci, Jrgen Conrad, and Uwe Beifuss

    Microwave-assisted three-component reaction in conventional solvents and ionic

    liquids for the synthesis of amino-substituted imidazo[1,2-a]pyridines

    ARKIVOC 2012 (iii), 243-256

    3. Fadime Mert-Balci, Hans-Georg Imrich, Jrgen Conrad, and Uwe Beifuss

    Influence of Guanidinium Salts and other Ionic Liquids on the Three Component aza-

    Diels-Alder reaction

    Helv. Chim. Acta 2013, 10.1002/hlca.201200655

  • Concerning the co-authors

    Prof. Dr. Uwe Beifuss was the supervisor of this work. He was always available for scientific

    discussions and made valuable suggestions. He was involved in correcting the manuscripts

    throughout the whole process of publication. He was responsible for all aspects of publication.

    He is also the corresponding author of the publications.

    Dr. Jrgen Conrad was involved in the interpretation of NMR spectroscopic data. Also, he

    measured all NMR samples on the 500 MHz Varian Unity

    Inova.

    Dipl.-Chem. Hans-Georg Imrich has carried out some experiments for the publication

    Influence of Guanidinium Salts and other Ionic Liquids on the Three Component aza-Diels-

    Alder reaction (publication No 3). These experiments are not part of the present thesis.

    Dr. Kathrin Meindl, Dr. Thomas Schulz, and Prof. Dr. Dietmar Stalke (Institut fr

    Anorganische Chemie, Universitt Gttingen) have carried out the X-ray crystal structure

    analysis of compound 109n.

  • Table of Contents

    1. Introduction ..1

    2. Ionic liquids and their role in organic synthesis ...3

    3. Microwaves in organic synthesis ..............8

    3.1. Introduction ............8

    3.2. The use of microwaves in domino- and multicomponent reactions ...........9

    4. Ugi- and Groebke reactions .................................................13

    4.1. The Ugi reaction ........13

    4.2. The Groebke reaction ................................................................15

    5. Diels-Alder- and Povarov reactions ....................................23

    5.1. The Diels-Alder reaction ...23

    5.2. The Povarov reaction ........26

    6. Aim of the study .......................................................................................39

    7. Synthesis of annulated imidazo[1,2-a]pyridines ......41

    8. Beyond the scope of the classical Groebke reaction: Synthesis of

    pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones in one step .........................48

    9. Guanidinium salts as promoters for the one-pot aza-Diels-Alder reaction ......55

    10. References ......62

    11. Summary ....68

    12. Zusammenfassung ......................................................................75

    13. Publications ............................................................................83

    13.1. Microwave-assisted three-component reaction in conventional solvents and ionic liquids

    for the synthesis of amino-substituted imidazo[1,2-a]pyridines .84

    13.2. Microwave-assisted three-component reaction for the synthesis of

    pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones ......................99

    13.3. Influence of guanidinium salts and other ionic liquids on the three component aza-Diels-

    Alder reaction .....111

    14. Abbreviations .......132

    15. Acknowledgments ........................135

    16. Curriculum Vitae ..136

    17. List of publications ...138

    18. Eidesstattliche Versicherung ....139

  • 1

    1. Introduction

    The efficient preparation of heterocycles is an important field of synthetic organic chemistry

    since most heterocycles exhibit biological activities and are therefore of great interest for the

    development of new drugs, diagnostics, and agrochemicals. Domino reactions[1]

    as well as

    multi component reactions[2]

    are among the most valuable tools for the synthesis of

    heterocycles. In multi component reactions, three or more substrate molecules are reacted in

    one pot under identical reaction conditions to yield a product in such a way that most of the

    atoms of the substrates can be found in the product molecule. The advantages of multi

    component reactions include high synthetic convergency, the generation of structural

    complexity in one step, high selectivity, high synthetic efficiency, and high atom economy.

    This is why multi component reactions are particular valuable in combinatorial chemistry and

    diversity-oriented synthesis. They allow for the synthesis of compound libraries which are of

    utmost importance for high-throughput screening in the field of drug discovery.

    Microwave-assisted reactions[3]

    have gained increasing popularity in recent years. In many

    cases, heating of reaction mixtures with microwaves leads to a decrease of reaction times, an

    increase of product yields, helps in avoiding the formation of side products, enhances the

    product purity and improves the reproducibility. It has been demonstrated that not only simple

    chemical transformations but also many domino- and multi component reactions can be

    performed successfully under microwave conditions.

    Ionic liquids are a new class of non-flammable solvents with a high thermal and chemical

    stability.[4]

    They have an ionic structure and consist of an organic cation and an inorganic

    anion. Their melting points are below 100C and their vapor pressure is negligible. Ionic

    liquids are immiscible with many organic solvents. This means that typical organic reaction

    products can be extracted from crude reaction mixtures. It means also that the ionic liquids are

    recyclable. In addition, ionic liquids are considered to be of low-toxicity. Due to these

    advantages ionic liquids have attracted a great deal of attention among organic chemists. So

    far, the main interest lies on imidazolium salts, but for a number of reasons guanidinium salts

    offer a valuable alternative.

    With respect to microwave chemistry the most important features of ionic liquids are their

    high polarity and their stability at high temperatures. Ionic liquids interact very efficiently

    with microwave irradiation through the ionic conduction mechanism and are rapidly heated at

    rates easily exceeding 10 C/s without a significant high pressure build up. This allows the

    rapid and safe heating of reaction mixtures in closed reaction vessels.

  • 2

    The combination of microwave chemistry and ionic liquids offers a number of opportunities

    in organic synthesis.[5]

    This thesis deals with the influence of microwaves and ionic liquids on

    two three component reactions, the Groebke reaction and the Povarov reaction.

  • 3

    2. Ionic liquids and their role in organic synthesis

    Ionic liquids have increasingly gained importance in organic synthesis as solvents and

    catalysts and they have been efficiently used in numerous transformations.[4,6]

    They are liquid

    compounds, which are composed entirely of cations and anions. Their melting points are

    below the boiling point of water.[7]

    Ionic liquids exhibit several crucial properties making

    them very interesting in academia and industry:[7,8]

    1) they are non-volatile, and have a very

    low vapor pressure, 2) they are non-flammable, 3) they can dissolve both organic and

    inorganic compounds, 4) they have a high thermal stability (up to 200C), 5) they have

    densities greater than the density of water, thus they occur as the lower phase in most biphasic

    systems, 6) they are non-corrosive, 7) they can be used as electrolytes in electrochemical

    devices because of their large electrochemical window, i. e. the maximum anodic and

    cathodic potential that can be applied without decom