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  • Olefin Metathesis

    ROMP: Ring-opening metathesis polymerization •Thermodynamically favored for 3,4, 8, larger ring systems •Bridging groups (bicyclic olefins) make ΔG polymerization more favorable as a result of strain.

    ROMP n

    ROMP n

    LnRu=

    LnRu=

    RCM:Ring closing Metathesis

    RCM

    LnRu=

    + H2C=CH2

    dilute

    •The reaction can be driven to the right by the loss of ethylene •High dilution conditions favor RCM vs. olefin polymerization. •The development of well-defined metathesis catalysts tolerant of many functional groups yet reactive toward a diverse array of substrates has led to to rapid aceptance of the RCM reaction as a powerful tool for C-C bond formation and macrocyclization. •Where the thermodynamics of ring closure are unfavorable, olefin polymerization takes place.

  • Mo

    N CH3

    CH3

    PhO

    O

    F3C

    F3C

    F3C

    F3C CH3

    H3C

    1-Mo

    Ru Cl

    Cl

    P(c-Hex)3

    P(c-Hex)3

    Ph

    Ph H

    2-Ru

    Ru Cl

    Cl

    P(c-Hex)3

    P(c-Hex)3

    Ph

    H

    3-Ru

    • 1-Mo, 2-Ru, and 3-Ru are the most widely used catalysts for olefin metathesis • Schrock’s 1-Mo is more reactive toward a broad range of substrates, but has poor functional group tolerance, sensitivity to air, moisture, solvent impurities, and thermal instability. • Grubb’s 2- and 3-Ru have high reactivity in ROMP and RCM and show a remarkable tolerance to a wide variety of functional groups

    Easily prepared:

    RuCl2(PPh3)3 + N2= Ph CH2Cl2

    Ru

    Cl

    Cl

    PPh3

    PPh3

    Ph

    H

    P(c-Hex)3

    CH2Cl2

    3-Ru

    • little sensitivity to air or moisture • requires electron-rich ligands (P(c-Hex)3)for increased activity JACS, 1993, 9858

  • A Dissociative Mechanism has been proposed:

    Ru Cl

    Cl

    P(c-Hex)3

    P(c-Hex)3

    H

    H

    R

    RuCl

    P(c-Hex)3

    P(c-Hex)3

    H

    H

    R

    -P

    Ru

    Cl P(c-Hex)3

    H

    H

    R

    [2+2]

    16e complex

    Ru

    Cl P(c-Hex)3

    H

    H

    R

    H

    metallacyclo butane

    Ru

    Cl P(c-Hex)3

    R

    H

    -C2H4

    Ru

    Cl P(c-Hex)3

    E E

    [2+2]

    Ru

    Cl P(c-Hex)3

    H

    H

    Cl

    Cl Cl Cl

    Cl

    E E

    ClRu

    Cl P(c-Hex)3

    H

    H Cl

    E E

    +P Ru

    Cl P(c-Hex)3

    H

    H Cl

    E E

    P(c-Hex)3 E E

    •Evidence for phosphine dissociation: addition of one equivalent of phosphine decreases rate by 20 times

    JACS, 1997, 3887.

    JACS, 1975, 3265. EtO2C CO2Et

    Ru Cl

    Cl

    P(c-Hex)3

    P(c-Hex)3

    H

    H

    5 mol%

    CD2Cl2, 25°C CO2EtEtO2C

    18e complex

  • NBoc NBoc

    substrate product yield

    91

    O

    Ph

    O

    Ph

    84

    O

    Ph

    O

    Ph

    72

    RR

    • 5,6,7-membered oxygen and nitrogen- containing heterocycles and cycloalkanes are formed efficiently

    • catalyst 2-Ru is stable to acids, alcohols, and aldehydes

    •Free amines are not tolerated by ruthenium catalysts; the corresponding hydrochloride salts undergo efficient RCM with 2-Ru

    N

    PhH2C H+

    Cl-

    2-Ru

    CH2Cl2 NaOH

    N

    Ph

    R=CO2H 87

    R=CHO 82

    R=CH2OH 88

    Catalytic RCM of dienes by 2-Ru

    Conditions: substrate + 2-4mol% 2-Ru, C6H6, 20°C

  • For Tri- and Tetrasubstituted Olefins, Catalyst 1-Mo is better

    substrate product yield 3-Ru yield 1-Mo

    RE E R=CH3 93 100

    R=t-Bu NR 96

    R=Ph 25 97R

    CH3 E E

    E E

    H3C

    CH3

    E E

    H3C

    NR 93

    E EH3C

    CH3 H3C

    CH3

    EE

    NR 61

    The standard "Thorpe-Ingold" effect favors cyclizations with gem-disubstituted substrates:

    JOC, 1997, 7310conditions, 5mol% catalyst, 0.1M, C6H6

    R R

    O

    RR

    1mol% 1-Mo

    25°C

    O R R

    R R R=H 0%

    R=CH3 95%

    JACS, 1992, 10978

  • Recyclable and Water-Soluble Catalysts

    RuO

    H

    P(c-Hex)3

    ClCl

    4-Ru

    Ru Cl

    Cl

    P

    P

    Ph

    H 5-Ru

    N(CH3)3 +Cl-

    N(CH3)3 +Cl-

    Ru Cl

    Cl

    P

    P

    Ph

    H 6-Ru

    N

    N

    CH3

    CH2

    CH3

    CH3

    Cl-

    Cl- JACS, 1999, 791

    • Catalyst Ru-4 offers excellent stability to air and moisture and can be recycled in high yield by silica gel chromatography. • Alkylidenes 5-Ru and 6-Ru are water-soluble Ru-based metathesis catalysts that are stable for days in methanol or water at 45°C. • Although 3-Ru is highly active for RCM of dienes in organic solvents, it has no catalytic activity in protic media:

    EtO2C CO2Et 5 mol% 3-Ru

    25°C CO2EtEtO2C

    solvent: CH2Cl2 100%

    CH3OH

  • Substrate Product solvent catalyst yield recovered catalyst%

    TBSO H OTBS

    CH2Cl2 4-Ru 90 75

    Ts N NTs CH2Cl2

    4-Ru 99 88

    Ts N

    NTs CH2Cl2 4-Ru 72

    88

    E E

    Ph

    E E

    CH3OH 5-Ru

    6-Ru

    80 95

    E E

    Ph

    E E

    CH3OH 6-Ru >95

    Boc N

    Ph

    Boc N CH3OH 5-Ru 30

    6-Ru >95

    5 mol%

    • Alkylidene 6-Ru is a significantly more active catalyst than alkylidene 5-Ru, because of the more electron-rich phosphines in 6-Ru • Substitution of one of the two terminal olefins in the substrate with a phenyl group leads to regeneration of the benzylidene catalyst, which is far more stable than the methylidene catalyst in methanol • cis-olefins are more reactive in RCM than the corresponding trans-olefins

  • Ph

    N(CH3)3 +Cl-

    Example:

    10 mol% 6-Ru

    H2O

    N(CH3)3 +Cl-

    90%

    R

    LnRu= Ph

    R

    RuLn Ph

    Ph

    LnRu

    R

    LnRu

    R

    LnRu= R methylidene, R=H

    benzylidene, R=PhMechanism:

    •Phenyl substitution within the starting material can also greatly increase the yield of RCM in organic solvents:

    N R

    H H Cl-

    5 mol% 3-Ru

    CH2Cl2

    N

    HH Cl-

    R=H 60% R=Ph 100%

  • Macrocyclizations and pre-organization

    O

    O O

    O

    n

    n=1,2

    5 mol% 3-Ru "template"

    CH2Cl2, 45°C O

    O

    O

    O

    n

    n template yield cis:trans

    1 none 39 38:62

    1 LiClO4 >95 100:0

    2 none 57 26:74

    2 LiClO4 89 61:39

    •Preorganization of the linear polyether about a complementary metal ion can enhance RCM • In general, ions that function best as templates also favor formation of the cis isomer.

    ACIEE, 1997, 1101.

    • Although interactions that increase substrate rigidity (i.e. intramolecular hydrogen bonding) and reduce the entropic cost of cyclization can be beneficial in RCM, it is not a strict requirement for macrocyclization by RCM. See: JACS, 1996, 9606.; JACS, 1995, 2108; JACS, 1995, 5855.

  • RCM of enol ethers: H3C

    O Ph

    12 mol% 1-Mo

    O

    Ph

    88%

    Ph O

    12 mol% 1-Mo

    O

    Ph 97%

    JOC, 1994, 4029

    JACS, 1996, 10335

    Ring-opening, Ring Closing Metathesis

    Only catalyst 1-Mo is effective for metathesis of these substrates

    OO

    3-Ru 6mol%

    O O

    H H

    0.1M 90%

    O O O O

    3-Ru 3mol%

    H H

    H H

    68%

    0.04M

    Without sufficient strain in the starting olefin, competing oligomerization can occur •Higher dilution favors the intramolecular reaction

    O O

    H H

    6 mol% 3-Ru O

    O H H

    0.12 M 16% 0.008M 73%

    JACS, 1996, 6634.

  • O O

    H H

    LnRu=CHPh

    O O

    LnRu H H

    O O

    H

    H

    RuLn O

    RuLn

    O

    H

    LnRu=CH2

    O O

    H H

    O O

    H H

    Mechanism:

    •Initial Metathesis of the acyclic olefin is supported by the fact that substitution of this olefin decreases the rate of metathesis

  • Catalytic, Enantioselective RCM

    H3C

    H3C

    Mo

    N CH3

    CH3

    PhO

    O

    8-Mo

    t-Bu

    t-Bu CH3

    H3C

    H3C

    H3C

    OSiEt3