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  • Cu(I)-Catalyzed 1 3 DipolarCu(I) Catalyzed 1,3 Dipolar Cycloadditions

    Anne-Marie DechertAnne-Marie DechertFeb. 7, 2008

  • Outline

    Introduction to 1 3 Dipolar Cycloadditions Introduction to 1,3 Dipolar Cycloadditions Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and

    Alkynes Cascade Reactions Extension of the Original Methodology

    S th i f L t Synthesis of Lactams Kinugasa Reaction

    1 3 Dipolar Cycloadditions Between Azomethine Ylides and Activated1,3 Dipolar Cycloadditions Between Azomethine Ylides and Activated Alkenes

  • 1, 3 Dipolar Cycloadditions

    AB

    C

    D E

    AB

    C

    D E

    Typical 1,3 Dipoles

    R2C N O R2C N O R2C O O R2C O ONitrones Carbonyl Oxide2 R2

    R

    R2C NR

    CHR2 R2C NR

    CHR2

    R2C O O R2C O ONitrones

    Azomethine Ylide

    Ca bo y O de

    R2C N N R2C N N Diazoalkane

    RC N O RC N O

    RN N N RN N N

    Nitrile Oxide

    Azide

    RC N CHR2 RC N CR2

    RC N NR RC N NR

    Nitrile Ylide

    Nitrile Imine

    Typical Dipolarophiles

    R2C N R Imine

    RC CR

    R2C CR2

    RN O

    Alkyne

    Alkene

    Nitroso

    Padwa, A.; ed., 1,3-Dipolar Cycloaddition Chemistry, John Wiley & Sons, New York, 1984.

    RN NR Azo

  • Stereospecificity

    HHPhH

    PhC N N PhPh

    H

    Ph

    H

    H

    Ph

    Ph

    HN

    N PhPh

    H Ph

    NN PhPh

    H H

    - Stereospecific syn addition with respect to dipolarophile

    Ph H Ph Ph

    H CH3HN

    NPhH N

    NHPh

    N NHCPh

    3

    H3CO2C CO2CH3

    N

    CO2CH3H3CO2CCH3H

    Ph N

    CO2CH3H3CO2CCH3H

    H

    Huisgen, R.; Seidel, G.; Wallibillich, G.; Knupfer, H. Tetrahedron 1962, 17, 3.Huisgen, R.; Eberhard, P. Tetrahedron Lett. 1971, 4743.

  • Regioselectivity

    - Dominated by Frontier Molecular Orbital (FMO) interactions- Sterics can also play a role

    C C

    E

    AB

    C

    E

    AB

    D

    E

    D

    E

    HOMOdipole - LUMOdipolarophile LUMOdipole - HOMOdipolarophiletypical for an electron def icient dipolarophile typical f or an electron rich dipolarophile

    If the energies of the two interactions are similar, both reactions can occur.

    Houk, K.; Sims, J.; Due, B.; Strozier, R.; George, J. J. Am. Chem. Soc. 1973, 95, 7287.

    g ,

  • 1,3 Dipolar Cycloadditions of Azides and Alkynes

  • The Cu(I) Catalyzed 1,3 Dipolar Cycloadditions of Azides and Alkynes

    C CHR1 N N N R2N

    N NR2cat. Cu(I)

    R1

    NOH NNO

    Ph

    NPhN N

    Ph

    NN N

    Ph

    NN N

    HOO

    N NPh

    NEt2

    82% 84%88% 90%

    NN N

    SO

    O

    H2N NN NPh

    HO NNN

    HOOH

    NHNH

    H2NHO HO

    Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.

    91% 84% 94%

  • Generation of The Cu(I) Catalyst

    C CHR1 N N N R2N

    N NR2

    Cu(I) salt1.0 eq. 2,6-lutidine

    Formation of Byproducts

    RR diacetylenesC CHR N N N R2 N N

    R1

    Cu(I) salt = CuOTf.C6H6, CuBr, CuI

    1.0 eq. 2,6 lutidine

    5- hydroxyltriazolesN

    N NR1

    HO R( ) 6 6

    bistriazoles

    Cu(II) salt (0 25 2 0 mol %)

    NN

    N

    R1

    R

    N N

    N

    R1

    R

    Cu(II) salt (0.25-2.0 mol %)Na ascorbate and/orascorbic acid (5-10 mol %)C CHR1 N N N R2

    NN N

    R1

    R2

    Click Chemistry

    NN NR

    2

    - high yielding- wide in scope- stereospecific- inoffensive byproducts- simple reaction conditions

    C CHR1 N N N R2 copper metalN

    R1

    simple reaction conditions

    Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Kolb, H.; Finn, M.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. J. Am. Chem. Soc. 2005, 127, 210.

  • A Stepwise Mechanism is Proposed

    Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. J. Am Chem. Soc. 2005, 127, 210.

  • The Unexpected Formation of Trisubstituted Triazoles

    OMH

    CuI, rt, 1h, air

    OOH

    N NN

    OMeMeO

    OOH

    N3

    OMeH

    CuI, rt, 1h, airO

    OHN N

    N

    OMe

    OMe

    Unexpected Result

    OMe

    p

    Perhaps Glaser Coupling:

    OOH

    N3CuI, rt, 1h, air

    MeO OH

    OMeMeO

    OH

    OMe

    MeO

    Alternative Pathway:

    O N NN

    OOH

    N NN

    OMe

    H

    CuI, rt, 1h, air

    OH

    OMeMeO

    Gerard, B.; Ryan, J.; Beeler, A.; Porco, J. Tetrahedron 2006, 62, 6405.

    NOMe

    H O N NN

  • Mechanistic Rational for the Formation of Trisubstituted Triazoles

    N3Cu(CH3CN)4PF6(0.2 eq.)

    ligand (0 2 eq )

    MeMe

    MeN

    NH

    Me

    Me

    Me

    Me

    HMe

    ligand (0.2 eq.)DIEA (1 eq.)NMO (0.1 eq.)rt/air

    NN

    N NN

    NN

    NMe

    Me

    MeMe

    Ligands

    Proposed Mechanism:

    Ligands

    Proposed Mechanism:

    R1LnCu R1L CHR1

    HR1DIEA R1L C

    R1

    II

    NNN

    R2N

    NNR2

    RLnCu

    B-H

    HR DIEA

    NNN

    R2

    RLnCuII

    1.[O]2 red elimB H

    BwithoutDIEA

    R1H

    2. red. elim

    R1R1

    Gerard, B.; Ryan, J.; Beeler, A.; Porco, J. Tetrahedron 2006, 62, 6405.

    N NNR2

    R1

    NNN

    R2

    R

  • The Use of N-Sulfonyl Azides as 1,3 Dipoles

    Finzi, P.; Grunanger, P. Tetrahedron Lett. 1963, 4, 1839.Yoo, E.; Ahlquist, M.; Kim, S.; Bae, I.; Fokin, V.; Sharpless, K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46, 1730.Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.

  • Proposed Route to Sulfonamides

    Cu(I), 2 mol %TBTA, 2 mol %Na ascorbate 4 mol %HC C R1

    BnN

    NN NNNa ascorbate 4 mol %

    NaHCO3, 1 eq

    OR1

    HN

    SO2

    R

    N N N SO2R

    N NBn

    BnN NN

    TBTA =

    HC C R1[Cu]

    NN N SO2R

    -N2R1 N

    [Cu]

    SO2R

    R1

    N N N SO2R-H+

    [Cu]R1

    N

    R1NSO2R

    H H2O ONH

    O2SR

    NSO2R

    [Cu]

    NN

    R1

    Cassidy, M.; Raushel, V.; Fokin, V. Angew. Chem. Int. Ed. 2006, 118, 3154.Cho S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16047.

  • A Cu(I) Catalyzed Cascade to Form Azetidinimines

    Ligand t[h] trans-A: cis-A: B

    2,6lutidine 3 80:13:7

    HC C R1NPh

    N N N SO2Tol

    Cu(I), 10 mol %ligand (1 eq.)

    N

    NSO2Tol

    R1 NN N SO2Tol

    pyridine 3 95:5:0

    TBTA

  • Reaction Scope: the Imine Component

    SO2Tol

    HC C PhNR2

    R1N N N SO2Tol

    Cu(I), 10 mol %pyridine, 2 eq.

    MeCN, rt N

    NSO2Tol

    PhPh

    R1

    R1 R2Yield(%) trans:cis

    4-FC6H4 Ph 87 95:5

    4-(MeO)C6H4 Ph 79 95:5

    Ph SO2Ph 5 NR

    CO2Et Ph 53 5:95

    CO Et 4 (MeO)C H 63 5:95CO2Et 4-(MeO)C6H4 63 5:95

    N N N S NO N N N S MO O O O

    Fokin, V.; Whiting, M. Angew. Chem. Int. Ed. 2006, 118, 3157.

    N N N S NO2 N N N S Br N N N S IN N N S MeO O O O

  • Synthesis of N-Sulfonyl-1,2,3-Triazoles

    Yoo, E.; Ahlquist, M.; Kim, S.; Bae, I.; Fokin,V.; Sharpless, K. B.; Sukbo, C. Angew. Chem. Int. Ed. 2007, 46, 1730.

  • Fus Extension to Azomethine Imine Dipoles

    Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.

  • Asymmetric Extension

    NN

    O

    CO2Et

    5% CuI0.5 eq. Cy2NMe

    NN

    O

    CO2Et5.5% ligand A

    PPh2PPh2

    = A

    H Ph 1.2 eq. Ph% g

  • Asymmetric ExtensionO O

    NN

    O

    H PhCO2Et

    1 2

    5% CuI0.5 eq. Cy2NMe

    NN

    O

    CO2Et

    Ph5.5% ligand A = A

    PMeMe

    MeMeO

    NiPrFe

    1.2 eq. Ph

    98%, 90% ee

    MeMe

    O5% CuI

    N

    OP

    MeMeO

    NtBu

    NN

    H PhCO2Et

    1.2 eq.

    0.5 eq. Cy2NMeNN

    CO2Et

    Ph5.5% ligand B

    = BMe

    MeMe

    MeN

    Fe

    100%, 58% ee

    NN

    O

    H PhCO2Et

    5% CuI0.5 eq. Cy2NMe

    NN

    O

    CO2Et

    Ph5.5% ligand C MeMe

    P

    MeMe

    N

    O

    iPrFe= C

    Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.

    H Ph1.2 eq. Ph Me

    MeMe

    100%, 80% ee

  • Reaction Scope: The Azomethine Imine Component

    Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.

  • Reaction Scope: The Alkyne Component

    Me

    NN

    O

    H PhR

    5% CuI0.5 eq. Cy2NMe

    NN

    O

    R

    Ph5.5% ligand

    PMe

    Me

    Me

    MeMeO

    NiPrFe

    H Ph 1.2 eq. Ph MeMe

    Me

    O

    NN

    Ph CO2Et NN

    O

    NMe

    Ph

    77%, 88% ee

    Ph

    100%, 94% ee

    O

    NN

    O

    NN

    O

    Ph

    73%, 88% ee

    Ph

    63%, 74% ee

    Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.- erosion of regioselectivity observed for electron rich alkynes

  • Application to Kinetic ResolutionApplication to Kinetic Resolution

    Downey, W.; Fu, G.; Suarez, A. J. Am. Chem. Soc. 2005, 127, 11245.

  • Limitations to the Kinetic Resolution of Azomethine Imine Dipoles

    Downey, W.; Fu, G.; Suarez, A. J. Am. Chem. Soc. 2005, 127, 11245.

  • Other Cu(I) Catalyzed 1,3 Dipolar Cycloadditions

  • Synthesis of Pyrazoles: A Direct Approach

    i TsNHNH2 NN

    2R1

    O

    HR1

    i. TsNHNH2MeCN, rt, 3h

    ii. 5M NaOH

    N

    R1

    R2

    NNH

    R25

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