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  • RECENT ADVANCESIN 1,3-DIPOLAR CYCLOADDITIONS

    OF AZOMETHINE YLIDES

    Marina Tanasova

  • 1,3-Dipolar Cycloadditions - the best and most convenient method for construction of five-member heterocycles.

    BA

    C

    R2

    R1

    BA

    C

    R2

    R1

    +R3

    R4

    CB

    AR2 R1

    R4R3

    Five-member heterocycles

    Introduction

    Five-member heterocycles - building blocks for a variety of biologically active molecules.

    Possibility to construct different ring systems.

    Formation of several contiguous stereocenters in one pot.

  • OH

    MeON

    O O

    +TiCl4

    4A MSDCE

    ON

    O O

    H

    O

    O

    NH

    ON

    O

    H

    HO

    Endo Product

    Tamura, O.; Okabe, T.; Yamaguchi, T.; Kotani, J.; Gotanda, K.; Sakamoto, M. Tetrahedron 1995, 51, 119-128.

    Intramolecular 1,3-Dipolar Cycloaddition

    o

    O

  • O

    H

    Me

    N COOMe

    NH

    O

    CO2MeO

    Me

    Me

    Me

    AgOAc, Et3N

    CH3CN, rt+

    Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2090-2013.

    Synthesis of Spiro-Pyrrolidine

    Only endo diastereomer is formed

    Spiro-core with at least one heterocyclic ring,is found in various biologically active molecules.

    Dipole precursor

    O

  • HN

    NN

    O

    OMeO

    MeO O

    HN

    OCO2Me

    N

    MeMeO

    MeSpirotryprostatin B

    Formation of spiro-system by 1,3-dipolar cycloaddition

    Synthesis of Spirotryprostatin B by 1,3-DipolarCycloaddition

    Sebahar, P.R.; Hiroyuki, O.; Usui, T.; Williams, R.M. Tetrahedron 2002, 58, 6311-6322.

    OPh

    Ph

    O

    CO2MeH

    HN

    NN

    O

    OMeO

    MeO O

  • Improved approach to the diastereocontrol of 1,3-dipolarcycloaddition of azomethine ylides with electron deficient mono- and di-substituted olefins.

    Investigation and application of some chiral catalysts in order to increase enantiocontrol of cycloaddition.

    Introduction of chirality through chiral vinyl sulfinyloxides. Recent approach to functionalized 2,5-dihydropyrroles.

    Outline

    Formation of substituted pyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides.

    1,3-dipolar cycloaddition of azomethine ylides with substituted imines, resulting in formation of different imidazo-compounds.

  • R3

    R2 N

    R1

    O

    OR

    R3

    R2 N

    R1

    O

    OR

    R3

    R2 N

    R1

    O

    OR

    R3

    R2 N

    R1

    O

    OR

    H

    M

    MX / Base

    Generation of Azomethine Ylides

    Grigg, R.; Kemp, J. J. Chem. Soc., Chem. Commun. 1978, 101,109-112. Kanemasa, S.; Yamamoto, H. Tetrahedron 1990, 113, 3633-3636. Padwa, A.; Burgess, E.M.; Gingrich, H.L.; Roush, D.M.J. Org. Chem. 1982, 47, 786-791.

    R2 R3

    O

    H2N R1

    O OR

    +

    R3

    R2 N

    R1

    O

    OR

    H

    N

    O

    R1

    R3O

    HON R1

    O

    R3 O

    Ac2O

    R2

    R2

  • N CO2MePh

    N

    MeO2C

    Ph

    +R3

    R4

    NPh CO2Me

    R3R4

    Pyrrolidines

    HN CO2MeAr

    H

    H

    azomethine ylide

    1,3-dipole

    (generation in situ)

    1,3-Dipolar Cycloaddition of Azomethine Ylide

    Simultaneous formation of both C-C bonds Concerted mechanism!

  • NH

    Ph

    X

    HH

    exo endo

    Stereoselectivity

    Regioselectivity

    N

    EDG

    H

    Ph N

    H

    Ph

    EWGhead-to-head head-to-tail

    General Approach to the Selectivityin 1,3-Dipolar Cycloadditions

    N

    H

    Ph

    X

    H

    HNH

    Ph NH

    Ph

    X X

    NH

    Ph

    EDG

    NH

    Ph

    EWG

  • BnO

    R

    NOR1

    N

    ORBnO

    O+

    RO

    O OAr

    NH

    RO2C

    Ar CO2R1

    NOR1

    O

    ArRO2C CO2R N

    H

    RO2C

    Ar CO2R1

    CO2R

    +

    +

    Karlsson, S.; Hofberg, H.E. Tetrahedron: Asymmetry 2001, 123, 1977-1982.Chen, C.; Schreiberg, S.L. J. Am. Chem. Soc. 2003, 125, 10714-10715.Longmire, J.M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401.

    N

    H

    H

    H

    Substitution Pattern on Resulting Pyrrolidines

    3

    4

    4

    2

    3

    5

    23

    4 5

    2

    3 4

    5

    H

    4 3

    4

    2

    3

    5

    Formation through the concerted mechanism

  • NH

    EtO2C

    Ph

    endo: 65%

    NH

    EtO2C

    Ph

    Ph N CO2Et

    Me

    +

    +

    Michael adduct: 10%

    exo: 25%

    Ph N CO2 Pr

    Me

    CO2Et

    LiX / Base

    1,3-Dipolar Cycloaddition of Azomethine Ylidewith Ethyl Acrylate

    Ph N CO2 Pr

    Me

    M

    i i

    CO2 Pri CO2 Pri

    CO2 Pri

    Possible mechanism?

  • Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

    NH

    O

    H

    H

    LiSingle Favorable Conformation

    for Metal Complexed Azomethine Ylide

    Computational and Mechanistic Studiesof Azomethine Ylide Cycloadditions

    NH

    H

    H

    O

    LiX

  • H2C CH2 NH

    O

    NO

    H

    Li

    +

    Orientation Complex Concerted Interaction

    Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

    Concerted Mechanism for the Cycloaddition ofAzomethine Ylide with Ethylene

    LiX / Base

    34

    Pyrrolidine

    2534

    25

  • O2NN

    H

    O

    N

    Li O

    HN

    Li O

    H

    O2NO2N

    endo exo

    + +

    Substitution Effect in 1,3-DipolarCycloaddition Reactions

    Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

    LiX / Base

    A

  • O2NN

    H

    O

    N

    Li O

    HN

    Li O

    H

    O2NO2N

    endo exo

    + +

    2

    3

    4

    Substitution Effect in 1,3-DipolarCycloaddition Reactions

    Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

    5

    LiX / Base

    C2 - C3 bond formationB

    2

    3

    2

    34

    5

    A

  • O2NN

    H

    O

    N

    Li O

    HN

    Li O

    H

    O2NO2N

    endo exo

    + +

    2

    3

    4

    Substitution Effect in 1,3-DipolarCycloaddition Reactions

    Li

    Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

    5

    LiX / Base

    C

    4

    5

    2

    34

    5

    C2 - C3 bond formationB

    2

    3

    A

  • O2NN

    H

    O

    N

    Li O

    HN

    Li O

    H

    O2NO2N

    endo exo

    + +

    2

    3

    4

    Substitution Effect in 1,3-DipolarCycloaddition Reactions

    Li

    Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

    5

    LiX / Base

    C

    4

    5

    2

    34

    5

    C2 - C3 bond formation

    B

    2

    3

    Aendo

  • N

    O

    OR

    EWG

    N

    O

    OR

    EWG

    M

    N

    EWG

    O

    OR

    M

    NH

    EWG

    O

    OR

    R3N

    Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122,6078-6092.

    ORN

    OM

    Stepwise Mechanism in Cycloadditions

    N

    O

    OR

    MXM

    H

    No change in mechanism was detected with N-protonated azomethine ylides.Equimolar endo/exo - 1:1 amounts of products were observed.Presence of metal in 1,3-dipolar cycloaddition reactions causes improvement of endo-exo selectivity and changes the mechanism to stepwise.!

  • N CO2MePh

    NH

    CO2MePh

    MeO2C

    +NH

    CO2MePh

    MeO2C

    +

    endo exo

    CO2Me

    Kanemasa, S.; Uchida, O.; Wada, E. J. Org. Chem. 1990, 55, 4411-4417.Barr, D.A.; Dorrity, M.J; Grigg, R.; Hargreaves, S.; Malone, J.F.; Montgomery, J.; Redpath, J.; Stevenson, P.; Tornton-Pett, M. Tetrahedron 1995, 51, 273-294.

    Search for the Best Metal for Cycloaddition

    + MX / Base

    LiBr / NEt3 - 81% yield for cyclized products; endo: exo - 3:1

    N-protonated ylide - 41% yield, only cyclized products; endo : exo - 1:1

    MgCl2, ZnCl2, MnCl2, NiCl2 and CoCl2 - gave the Michael adduct as the major product

    Michael adduct

  • iN CO2 PrPh

    Me

    NH CO2

    iPrPh

    EtO2C

    +

    NH CO2iPr

    Ph

    EtO2C

    +

    Ph N CO2Et

    CO2iPr

    endo exo Michael adduct

    Solvents

    Bases

    AgOAc

    20-25 oC

    CO2Et

    THF; Toluene; MeCN; CH2Cl2; MeOH

    KOH; NaOH; K2CO3; LiOH; Et3N; DBU

    Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.

    Application of Silver to the Cycloadditions

    +

  • N CO2 PrPh

    Me

    NH CO2

    iPrPh

    EtO2C

    +

    NH CO2

    iPrPh

    EtO2C

    +Ph N CO2Et

    CO2iPr

    endo exo Michael adduct

    CO2Et

    Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.

    Investigation of Better Conditions for Cycloadditions

    +AgOAc -10 mol%KOH - 10 mol%

    Toluene, CH2Cl2, THF - 100% conversion, but 75 - 80h, 88 - 92% yield of endo product

    MeCN - 68% conversion, 90% - endo, 10% -

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