1,3 dipolar cycloadditions

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  • RECENT ADVANCES

    IN 1,3-DIPOLAR CYCLOADDITIONS

    JAYANTA SAHA

    IIT ROPAR

    2015CHS1003

  • INTRODUCTION

    The [3 + 2] 1,3-dipolar cycloaddition is a reaction where two organic

    compounds, a dipolarophile, and a 1,3-dipole (or ylide), combine to

    form a five membered heterocycle

    B

    A

    C

    R2

    R1 R1

    A

    B

    C

    R2

    +R3

    R4

    CB

    AR2 R1

    R4R3

    This reaction is often used as a key step in many natural products and

    pharmaceuticals synthesis

    The asymmetric variants of this reaction using either chiral auxiliaries or chiral

    catalysts are relatively new research fields and have attracted a continually

    growing interest

  • The Dipolarophile

    The dipolarophile in a 1,3-dipolar cycloaddition is a reactive

    alkene moiety containing 2 electrons.

    Thus, depending on which dipole that is present, ,unsaturated

    aldehydes, ketones, and esters, allylic alcohols, allylic halides,

    vinylic ethers and alkynes are examples of dipolarophiles that

    react readily

  • The 1,3-dipole/ylide

    The 1,3-dipole, also known as an ylide, bears a positive and a

    negative charge distributed over three atoms and has 4

    electrons. The most common atoms incorporated in the 1,3-dipole

    are nitrogen, carbon, oxygen or sulfur.

    These are divided into two groups,

    the allyl anion type which has a bent structure and

    the propargyl/allenyl anion type with a linear

    structure

  • Types of 1,3-Dipoles:-

  • Mechamisms for the 1,3-DC reaction

    The 1,3-dipolar cycloaddition reaction of a 1,3-dipole with a dipolarophile

    involves the 4 electrons of the dipole/ylide and the 2 electrons of the

    dipolarophile. The reaction mostly proceeds in a concerted manner, which

    means that all bonds are created simultaneously

    Depending on the nature of the dipole and the dipolarophile, the 1,3-dipolar

    cycloaddition reaction is controlled either by a LUMO(dipolarophile)-

    HOMO(dipole)- or a LUMO(dipole)-HOMO(dipolarophile) interaction but insome

    cases both interactions is involved.

  • Mechamisms for the 1,3-DC reaction

  • The classification of the 1,3-DC reactions onthe basis of the

    FMOs

    NITRONE

    NITRILE

    OXIDE

    Azomethine imine

    Diazoalkene

    Nitosooxide

    Ozone

  • The change in frontier orbitals by coordination

    of a Lewis acid Type II

  • Recent Literature1,3-Dipolar cycloaddition reactions of azomethine ylides with aromatic

    dipolarophiles

    General reaction

    Examples of isoindole-containing natural products, pharmaceuticals and dyes: (+)-staurosporine 4 (indolocarbazole alkaloid),

    mitiglinide 5 (type 2 diabetes),46 lenalidomide 6 (anticancer, multiple myeloma), and Pigment Yellow 139 7 (dye).

  • 1,3-Dipolar cycloaddition reactions of azomethine ylides with aromatic

    dipolarophiles

    Some products formed in this

    manner

    Main reaction

    John H. Ryan,ARKIVOC 2015 (i) 160-183

  • Methods for asymmetric 1,3-DC reactions of Nitrones with Alkenes

    Pellissier, H. Tetrahedron 2007, 63, 3235-3285

  • N

    H

    Ph

    X

    H

    H

    exo endo

    Stereoselectivity

    Regioselectivity

    EDG

    H

    NPh

    H

    NPh

    EWGhead-to-head head-to-tail

    N

    H

    Ph

    H

    H

    XN H

    Ph N H

    Ph

    X X

    N H

    Ph

    EDG

    N H

    Ph

    EWG

    General Approach to the Selectivity in 1,3-Dipolar Cycloadditions

  • Acylaziridines

    Methods for asymmetric 1,3-DC reactions of Nitrones with Alkenes

  • J.Org. Chem. 1995, 60, 4999

    +

    Methods for asymmetric 1,3-DC reactions of Nitrones with Alkenes

  • Application of cycloaddition reaction in natural product synthesis

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