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    Title Studies on Nickel-Mediated and -Catalyzed Hydrocarboxylation of Ynamides with Carbon Dioxide

    Author(s) Abdullah, Iman

    Citation . () 12887

    Issue Date 2017-09-25

    DOI 10.14943/doctoral.k12887

    Doc URL

    Type theses (doctoral)

    File Information Iman_Abdullah.pdf

    Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP
  • Doctoral Dissertation

    Studies on Nickel-Mediated and -Catalyzed Hydrocarboxylation of Ynamides with Carbon Dioxide



    Iman Abdullah

    Laboratory of Fine Synthetic Chemistry Faculty of Pharmaceutical Sciences

    Graduate School of Life Science, Hokkaido University 2017 9

  • Acknowledgement

    I would like to express my best gratitude to my supervisor, Prof. Yoshihiro Sato for

    his remarkable support, kindness, guidance and help during my PhD time in Hokkaido


    I would like to thank to Professor Nozomi Saito of Meiji Pharmaceutical University

    for his kindness and guidance during my first year in Hokkaido University, as well as

    his kind help in reviewing my PhD dissertation.

    My sincere thanks go to Dr. Ryohei Doi for his kindness, guidance and remarkable

    help on my laboratory experiments as well as on writing the dissertation.

    I would like to thank to Assoc. Prof. Yoshihiro Oonishi for his generosity and

    valuable advices, and Dr. Tsuyoshi Mita for his encouragements, support and

    comments on my works.

    I am also very grateful to Prof. Shigeki Matsunaga of Laboratory of Synthetic and

    Industrial Chemistry for his advices and comments on my PhD dissertation, as well as

    being the chairman of my PhD defense.

    I would like to thank to Dr. Takahisa Taniguchi, previous member of Laboratory of

    Fine Synthetic Chemistry (Sato Laboratory) for his help and guidance on doing

    research in this lab, and to all Sato groups member for their kindness and great help.

    Last but not least, I would like to thank to my family: my beloved parents, wife, and

    daughter for their love and support throughout the time of my PhD.

    Sapporo, August 2017

    Iman Abdullah

  • Abbreviations

    acac acetylacetonate

    aq. aqueous solution

    atm atmosphere

    BArF tetrakis[3,5-bis(trifluoromethyl)phenyl]borate

    Bn benzyl

    bpy 2,2-bipyridine

    C degrees Celsius

    cat. catalytic

    cm-1 wave number(s)

    cod 1,5-cyclooctadiene

    COSY correlation spectroscopy

    Cy cyclohexyl

    DIBAL-H diisobutylaluminium hydride

    DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

    DCM dichloromethane

    DMF N,N-dimethylformamide

    dppb 1,4-bis(diphenylphosphino)butane

    ee enantiomeric excess

    EI electron ionization

    equiv equivalent(s)

    ESI electrospray ionization

    Et ethyl

    EWG electron withdrawing group

    glyme 1,2-dimethoxyethane

    h hour(s)

    HOBt 1-hydroxybenzotriazole

    HPLC high performance liquid chromatography

    HRMS high resolution mass spectroscopy

  • IMes 1,3-bis(2,4,6-trimethylphenyl)-imidazolium

    IPA isoproanol

    iPr isopropyl

    IPr 1,3-bis-(2,6-diisopropylphenyl)imidazolium

    IR infrared absorption spectrometry

    Ln ligand

    LRMS low resolution mass spectroscopy

    Me methyl

    min minute(s)

    MOM methoxymethyl

    Ms methanesulfonyl

    MS molecular sieve

    n normal

    nBu normal butyl

    nbd 2,5-norbornadiene

    NBS N-bromosuccinimide

    ND not detected

    NMR nuclear magnetic resonance

    NOE nuclear Overhauser effect

    PGME phenylglycine methyl ester

    Ph phenyl

    phen 1,10-phenanthroline

    PhMe toluene

    PhOH phenol

    PTLC preparative thin-layer chromatography

    PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

    quant. quantitative yield

    R substituent

    rt room temperature

    sat. saturated

  • t tertiary

    TBAB tetrabutylammonium bromide

    TBAF tetrabutylammonium fluoride

    TBS tert-butyldimethylsilyl

    tBu tertiary butyl

    tBuOH tertiary butanol

    TFE trifluoroethanol

    THF tetrahydrofuran

    TLC thin-layer chromatography

    TMEDA tetramethylethylenediamine

    TMS trimethylsilyl or tetramethylsilane

    Ts p-toluenesulfonyl

  • Table of Contents

    General Introduction 1

    Chapter 1. Nickel-Mediated Hydrocarboxylation of Ynamides and Asymmetric Hydrogenation 7

    1.1 Introduction 7

    1.2 Hydrocarboxylation of ynamides with CO2 8

    1.3 Asymmetric hydrogenation of enamides 10

    1.4 Determination of the absolute configuration 11

    1.5 Summary of chapter 1 13

    Chapter 2. Nickel-Catalyzed Hydrocarboxylation of Ynamides 14

    2.1 Introduction 14

    2.2 Ni-catalyzed hydrocarboxylation of ynamide 16

    2.3 Investigation of reaction conditions 17

    2.4 Substrate scope 21

    2.5 Mechanistic study 23

    2.6 Attempt for asymmetric hydrogenation 27

    2.7 Attempt for Ni-catalyzed regioselective -carboxylation 28

    2.8 Summary of chapter 2 30

    Conclusions 31

    Experimental section 32

    3.1 Chapter 1 33

    3.2 Chapter 2 40

    References 55

  • 1

    General Introduction

    CO2 is a nontoxic, inexpensive, and abundant renewable carbon source in nature.

    Therefore, utilization of CO2 in organic synthesis such as in carboxylation reaction of

    various types of substrates has attracted great interest for a couple of decades (Figure

    1).1 However, low reactivity of CO2 hampers its broad utilization. In most cases,

    transition metal such as nickel is required in order to activate CO2 and works as a

    catalyst/mediator in carboxylation reaction.


















    Figure 1. Utilization of CO2 as carbon source in the synthesis of fine chemicals.

    It is well known that CO2 coordinates to transition metals such as nickel complex.

    The first isolated and structurally characterized Ni-CO2 complex was reported by

    Aresta in 1975, in which the complex was synthesized by treating Ni(PCy3)3 with

    CO2 in toluene.2 In this complex, CO2 possesses a bent geometry and is coordinated

    to nickel through carbon atom and one of the oxygen atom (Figure 2). Later on, the

    interaction between CO2 and metal complex has been investigated intensively through

    stoichiometric experimental studies.3,4 As shown in Figure 2, there are several

    coordination modes between CO2 and transition metals.5 In complex I, CO2

    coordinates directly via bonding of the metal to carbon atom. Formation of this

    complex is feasible for electron rich metal center via electron transfer from the metal

    to carbon atom of CO2. In complex II, CO2 coordinates via bonding of oxygen to

    the metal center. However, this complex is more difficult to obtain due to the weak

    interaction between lone electron pair of the only one oxygen atom with the metal

  • 2

    center. In complex III, CO2 acts as a bidentate ligand to an electron-deficient metal

    center. Complex IV is a combination of complex I and II, in which electron transfer

    could proceed from metal to carbon and from oxygen to metal to afford a three-

    membered metallacycle. Arestas Ni-CO2 complex belongs to this type of

    coordination. The last possible coordination of CO2 to metal center is via

    coordination of one C=O bond to the metal center as shown in complex V. Among all

    of those possible metal-CO2 coordination modes, type I and IV/V are the most

    common and the most convenient in term of catalysis.1a

    Nickel is a relatively electropositive transition metal.6 Therefore it tends to

    undergo a facile oxidative addition which results in loss of electron density around

    nickel. In addition, nickel also has a number of readily available oxidation states

    which allows different type of reactivity and reaction mechanism. Many

    transformations catalyzed by nickel are based on Ni(0)/Ni(II), Ni(I)/Ni(III), or

    Ni(0)/Ni(I)/Ni(II) cycles.6 Compared to other group 10 metals such as Pd, nickel has

    smaller atomic radius, thus the Ni-ligand bonds are often relatively short. Those

    important properties together with lower cost of nickel in its elemental form, have

    prompted the development of nickel catalyst in various organic reactions including

    carboxylation of unsaturated CC bonds with CO2.

    The first example of fixation of CO2 into unsaturated CC bond of alkyne

    catalyzed by nickel was reported in 1977 by Inoue.7 The reaction was conducted

    using Ni(cod)2 and phosphine bidentate ligand under high pressure of CO2 to afford

    -pyrone as the carboxylated product. Due to a competing [2+2+2] cocyclization

    reaction of alkyne, -pyrone was obtained in low yields (less than 10%). Later in

    1980, the same author reported that the use of disubstituted alkyne improved the yield

    of the carboxylated product up to 60% yield (Scheme 1).8

  • 3

    In 1982, Hoberg reported a ground-breaking discovery of formation of

    nickelalactone complex via oxidative cyclization of alkyne and CO2 into Ni(0)

    center.9 The complex was obtained by coupling reac


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