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  • Recent Advancements In The [2+2+2] Cycloaddition

    Brandon Dutcher January 17, 2007

    Michigan State University

  • Outline Overview of [2+2+2] cycloaddition Mechanism of the [2+2+2] cycloaddition Issues with selectivity

    Regioselectivity Chemoselectivity Enantioselectivity

    Conclusions Acknowledgments

  • Outline Overview of [2+2+2] cycloaddition Mechanism of the [2+2+2] cycloaddition Issues with selectivity

    Regioselectivity Chemoselectivity Enantioselectivity

    Conclusions Acknowledgments

  • General Information

    [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition by Reppe et. al. in 1948. A multitude of metals have been employed on the catalysis of the [2+2+2]

    Ni, Co, Pd, Cr, Rh, Zr, Nb, Ir, Ta, and Ti

    The [2+2+2] cycloaddition has been found to have a wide range in synthesis

  • Important [2+2+2] Cycloadditions

    Used the Nickel complex Ni(PPh3)2(CO)2 Between 25°C and 80°C

    2 CO2R (PPh3)2Ni(CO)2

    benzene

    R=Bu

    CO2R

    HO 3

    (PPh3)2Ni(CO)2

    HO

    OH OH

    OH

    HO

    OHbenzene 65%

    Reppe

    Bertholet First [2+2+2] cycloaddition Thermally induced reaction

    Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767 Reppe, V.W.; Schweckendeik, W.J. Justus Leibigs Ann. Chem. 1948, 560, 104-116

  • General [2+2+2] Cycloaddition

    Tolerant of many functional groups Applicable to many π-bond containing systems Excellent for building aromatic systems – benzene and pyridine moieties Symmetry favored – exothermic (∆H= -594 kJ/mol) High temperature or catalyst required due to entropic factors

    X ∆

    X

    R

    RR

    R R

    R R

    R R

    R R

    R or

    catalyst

    Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

  • Outline Overview of [2+2+2] cycloaddition Mechanism of the [2+2+2] cycloaddition Issues with selectivity

    Regioselectivity Chemoselectivity Enantioselectivity

    Conclusions Acknowledgments

  • π-bond System Approach To The Metal Three possibilities for alignment Two possibilities give the 1,2,4 trisubstituted ring One gives 1,3,5 trisubstituted ring Statistically slightly greater than a 2 to 1 mixture of

    1,2,4- to 1,3,5-trisubstituted rings

    M R

    R M

    R

    R R

    R

    R

    MM

    R

    R

    R

    R R R

    R

    M

    R

    R M R

    R R R

    R

    R

    R R

    Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

  • Metal-Carbon Insertion Mechanism

    M

    R

    R

    M

    R

    R M

    R R

    R

    RR

    R

    RR -M

    M R

    R

    R

    M R

    R

    M R

    R

    M

    R R

    R

    M

    R

    R

    R R

    R R

    R

    R R R

    R

    -M

    -M

    Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

  • Diels-Alder Type Mechanism

    M

    R R

    R R

    R

    R

    M -M

    R

    R M M

    R

    RR R

    R

    R

    R R

    R

    M

    R

    -M

    R

    R

    R

    M M R

    R R

    Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

  • Outline Overview of [2+2+2] cycloaddition Mechanism of the [2+2+2] cycloaddition Issues with selectivity

    Regioselectivity Substrate control Reagent control

    Chemoselectivity Enantioselectivity

    Conclusions Acknowledgments

  • Statistical Regioselectivity of [2+2+2] cycloaddition

    M R

    R M

    R

    R R

    R

    R

    MM

    R

    R

    R

    R R R

    R

    M

    R

    R M R

    R R R

    R

    R

    R R

    Statistically a slightly greater than a 2 to 1 1,2,4- to 1,3,5-trisubstitution ratio

    1,2,4 tri-substituted only

    1,2,4 tri-substituted only

    Mixture of Both

  • “Tethered” Alkynes

    Force regiochemistry of alkyne reaction Speed up reaction – intramolecular reaction Increase yield

    X R1

    R2 X= O, S, C(CO2Me)2 etc.

    X R3R3

    R3

    R3

    R1

    R2

  • Macrocycles by [2+2+2] Cycloaddition

    1:755

    3:449

    1:157

    1:142

    Meta:ParaYield %α,ω-diynes

    O O

    (CH2)6 (CH2)7EtO2C

    EtO2C

    N

    pTol

    N

    pTol

    15 mol% CpCo(CO)2

    o-xylene 140 oC, 100 h

    meta para

    N

    pTol

    O

    O O O

    Maryanoff, B.E.; et. al. J. Am. Chem. Soc. 2006, 128, 3473-3485

  • Macrocycle Regioselectivity

    N

    M O

    O O O

    N

    p-Tol

    Tol-

    O O

    O O

    N

    p-Tol

    O

    O

    O

    O

    M N

    p-Tol O

    O

    O

    O

    N

    p-Tol

    XM O

    O O

    O

  • Outline Overview of [2+2+2] cycloaddition Mechanism of the [2+2+2] cycloaddition Issues with selectivity

    Regioselectivity Substrate control Reagent control

    Chemoselectivity Enantioselectivity

    Conclusions Acknowledgments

  • Ortho/meta Selectivity Of “Tethered” Alkynes

    MeMe

    Me

    R Me Me2 mol%

    [Ir(cod)Cl]2

    4 mole % ligand argon

    Me

    Me

    Me

    MeR

    R O M

    84/1668Benzene reflux 2 hDPPF(CH2)3OH6 86/1483Benzene reflux 1 hDPPFn-Oct5 88/1284Benzene reflux 1 hDPPFn-Bu4 18/8275Benzene r.t 12 hDPPE(CH2)3OH3 19/8180Benzene r.t 1 hDPPEn-Oct2 20/8092Benzene r.t 0.5 hDPPEn-Bu1

    Ratio O/M Yield%ConditionsLigandREntry

    Ph2P PPh2

    DPPE

    Fe

    Ph2P

    PPh2

    DPPF

    Takeuchi, R.; et. al. J. Org. Chem. 2006, 71, 543-552

  • Regioselective Pathways

    Me

    Me Ir

    Me

    P P

    Cl

    R

    Ir

    Me

    Me

    R

    P P Me

    Me

    Me

    R

    Me

    Me Ir

    Me

    PB

    PA

    Cl Me

    Me Ir

    Me

    PBCl PA

    R

    Ir

    Me

    Me

    Me R

    ClPA

    PB

    Me

    Me

    Me R

    Meta Pathway

    Ortho Pathway

    Takeuchi, R.; et. al. J. Org. Chem. 2006, 71, 543-552

  • Substrate Directed Regioselectivity

    C2H2 (1atm) THF

    -40oC to rt, 4 h

    B

    R

    OO

    (Pin)B R B(Pin)R

    CoCp R R

    B(Pin)(Pin)B

    CoCp

    A B

    CpCo

    -tBu1

    4A/4B 1:9 (84)CH2OMe4 5A/5B 1:20 (92)Ph5

    3A/3B 1.5:1 (93)C6H133 2A/2B 1:0 (18)iPr2

    A/B (yield%)REntry

    R B(Pin)

    R(Pin)B CoCp

    R=tBu 59%

    Aubert, C.; Vollhardt, K.P.C.; Malacria, M.; et. al. Angew. Chem. Int. Ed. 2005, 44, 7114-7118

  • 1,2,4 –Trisubstitution Using Titanium- Calixarene Complexes

    R Catalyst

    Na, toluene

    R

    RR R

    R R

    A B

    O

    O

    Ti

    Cl Cl But

    But

    But But

    O

    O

    Si MeMe

    >97

  • 1,3,5 –Trisubstitution Using Titanium- Calixarene Complexes

    S SS O OO

    O

    ButBut

    But But

    S

    Ti

    ClCl

    Ti

    ClCl

    1: 65% yield � ratio A:B 77:23

    O S

    SS S

    O

    Ti

    ClCl But But

    But But

    O

    O

    Ti ClCl

    2: 95% yield � ratio A:B 85:15

    Ph Catalyst

    Na, toluene r.t., 20 h

    Ph

    PhPh Ph

    Ph Ph

    A B

    Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

  • 1,3,5 –Trisubstitution Using Titanium- Calixarene Complexes (continued)

    X X

    X HO OO

    OH

    ButBut But

    But

    SiSi Pri

    Pri Pri

    Pri O

    X

    3: X=S: 93% yield � ratio A:B 83:17 4: X=CH2: 94% yield ratio A:B 1:99

    X OHOH

    ButBut

    5: X=S: 95% yield� ratio A:B 32:68 6: X=CH2: 85% yield � ratio A:B 33:67

    Ph Catalyst

    Na, toluene r.t., 20 h

    Ph

    PhPh Ph

    Ph Ph

    A B

    Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

  • 1,3,5 –Trisubstitution Using Titanium- Calixarene Complexes (continued)

    R 2.5 mol% 2

    Na, toluene

    R

    RR R

    R R

    A B

    100:0141550TMS5 95:5711523Oct4

    75:25731523Pr3 ~100:0303.5234-CF3C6H42

    95:5953.5234-Tol1

    Ratio A:BYield%Time (h)Temp (oC)REntry

    O S

    SS S

    O

    Ti

    ClCl But But

    But But

    O

    O

    Ti ClCl

    2

    Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

  • O S

    SS S

    O

    Ti

    ClCl But But

    But But

    O

    O

    Ti ClCl

    O

    O

    Ti

    Cl Cl But

    But

    But But

    O

    O

    Si MeMe

    Lapido ca

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