imines in copper-catalyzed cross-coupling reactions a thesis

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  • Imines in Copper-Catalyzed Cross-Coupling Reactions

    A thesis submitted ta McGill University in partial fulfillment of the requirements for the degree of Doctor of Philosophy


    Daniel Black



    Department of Chemistry

    McGill University

    Montreal, Quebec, Canada

    Daniel Black 2006

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  • Ta my family,

    without whom this thesis would

    never have been possible



    Imines in Copper-Catalyzed Cross-Coupling Reactions

    The purpose of this study was to deve10p new catalytic methods to

    mediate carbon-carbon bond forming reactions with imines under mild

    conditions and in a general manner. We found that copper catalysts were

    compatible in cross-coupling of a range of mi Id organometallic reagents,

    providing simple, efficient routes to a-substituted amides and amines.

    Chapter 2 of this thesis describes a new copper-catalyzed

    multicomponent synthesis of a-substituted amides. This reaction was

    developed based upon previous work in this laboratory, which showed that

    palladium catalysts were competent in Stille-type cross-coupling of imines,

    acid chlorides, and organostannanes. While providing a mild method of

    generating the amide products, a more general procedure able to incorporate a

    wider range of organostannanes was sought. This chapter details the

    development of a copper-catalyzed protocol, which, as well as performing the

    cross-coupling under mild reaction conditions, proceeds with a diverse range

    of aryl-, heteroaryl-, and vinyl-substituted organostannanes and employs an

    inexpensive and readily available catalyst. Through this system, control over

    regioselectivity of addition to a,p-unsaturated imines is also possible.


  • Chapter 3 demonstrates that, in addition to organostannanes, other

    substrates are viable in copper-catalyzed cross-coupling with imines and acid

    chlorides. Herein, the coupling of terminal alkynes with imines and acid

    chlorides is described, leading to an efficient synthesis of tertiary

    propargylamides directly from simple starting materials. This synthesis

    incorporates a wide variety of substituted Immes, acid

    chlorides/chloroformates, and terminal alkynes, providing a rapid synthesis of

    these useful building blocks (reaction completion in only 15 minutes). In

    addition, the process is shown to work with aza-aromatic heterocyc1es, such as

    pyridine, where the alkynylation occurs exc1usively at the 2-position.

    Chapter 4 describes the utility of these rapid multicomponent

    reactions, where the products are directly converted into oxazole heterocycles.

    Copper-catalyzed- and zinc-catalyzed protocols are developed for the

    synthesis of secondary propargylamides from silyl-imines, acid chlorides, and

    terminal alkynes. The secondary propargylamide products are then, in a one

    pot sequence, transformed into trisubstituted oxazoles.

    Chapter 5 describes the development of an atom-economical, non-

    toxic alternative to the organotin coupling described in Chapter 2. This

    involves the use of tri- and tetraorgano-indium reagents, which can transfer aU

    of their organic groups in a copper-catalyzed coupling with imines and acid

    chlorides. This reaction shows good functional group compatibility and


  • further expands the scope of a-substituted amides and N-protected amines that

    can be synthesized through mild copper catalysis.

    Chapter 6 explores the enantioselective alkynylation of nitrogen-

    containing heterocyc1es. As described in Chapter 3, heterocyc1es such as

    pyridine can undergo copper-catalyzed 1,2-addition with terminal alkynes

    upon activation by chloroformates. As this process generates a stereocenter, it

    is possible to introduce enantio-control into the reactions by using a chiral

    copper catalyst. With ligands from the PINAP series, enantioselectivities ofup

    to 84% can be induced in the coupling of nitrogen-containing heterocycles

    (e.g., quinoline), chloroformates, and terminal alkynes. This provides a mild

    and simple synthesis of chiral 2-alkynyl-l,2-dihydroquinolines directly from

    simple starting materials.


  • RSUM

    L'Utilisation d'Imine Comme Substrat en Couplages Croiss Mdis par

    le Cuivre

    Le but de cette recherche tait de dvelopper des nouvelles

    mthodologies pour la formation de liaisons carbone-carbone, dont le

    couplage inclus une imine sous des conditions modres et de faon gnrale.

    On a dcouvert que le cuivre peut faciliter ces ractions de couplage crois

    avec divers ractifs organomtalliques. Ces ractions fournissent des

    mthodes simples et efficaces pour la synthse d'amines et d'amides a-


    Le chapitre 2 dcrit une nouvelle synthse multicomposante d'amides

    a-substitues. Dans notre laboratoire, nous avons dmontr que le palladium

    convient la catalyse combinatoire d'imines, de chlorures d'acides et

    d'organostannanes. Mme si cette raction nous fournit une mthode

    rlativement douce de gnrer ces produits, on a poursuivi une synthse

    encore plus gnrale. Ce chapitre dcrit une nouvelle mthode catalytique,

    dont l'utilisation des sels de cuivre, qui nous offre une synthse plus gnrale

    et en soit tant conomique et facilement disponible.


  • Le troisime chapitre dmontre la diversit des ractifs qui peuvent

    participer dans les ractions de couplage crois avec les imines et les chlorure

    d'acides. En fait, des alcynes terminales peuvent ragir avec des imines et des

    chlorures d'acides, en prsence de cuivre, afin de produire des amides

    propargyliques. Cette raction, qui est termine en une quinzaine de minutes,

    nous offre une synthse rapide et efficace. De plus, la raction n'est pas

    seulement limit aux imines, on peut aussi introduire des htrocycles comme

    une pyridine.

    Le chapitre 4 dcrit l'utilit de ces ractions multicomposantes, avec

    lesquelles on peut convertir les produits directement en oxazoles. Ceci a t

    fournit par de dveloppement de ractions catalyses par le cuivre et le zinc en

    employant les substrats suivants: des silyl-imines , des chlorure d'acides et

    des alcynes. Les amides propargyliques secondaires produites par cette

    raction ont t converties en oxazoles tri-substitues.

    Le chapitre 5 implique une mthode alternative celle dcrite au

    chapitre 2. On dcrit l'utilisation de ractifs organo-indium, qui font le

    transfer quantitatif de leur substituants dans la raction catalyse par le cuivre

    avec les imines et les chlorure d'acides. Cette reaction dmontre qu'une

    grande varit de ractifs y peuvent tre incorpors.


  • Au chapitre 3, on a dcrit la raction entre une pyridine, une chlorure

    d'acide et une alcyne. Ce processus nous donne un carbone chirale, tout de

    mme racmique. En y introduisant un ligand chiral, au chapitre 6,

    spcifiquement de la famille PINAP, nous avons russi des nantioslectivits

    jusqu' 84%. Cette raction nous donne une nouvelle synthse d'amides

    propargyliques cycliques chirales provenant de ractifs simples et



  • r---..


    In accordance with guideline C of the "Guidelines for Thesis Preparation"

    (Faculty of Graduate Studies and Research), the following text is cited:

    "As an alternative to the traditional thesis fonnat, the dissertation can consist

    of a collection of paper


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