Metathesis fileOlefin Metathesis ROMP: Ring-opening metathesis polymerization •Thermodynamically favored for 3,4, 8, larger ring systems •Bridging groups (bicyclic olefins) make

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

ROMPn

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

NCH3

CH3

PhO

O

F3C

F3C

F3C

F3C CH3

H3C

1-Mo

RuCl

Cl

P(c-Hex)3

P(c-Hex)3

Ph

PhH

2-Ru

RuCl

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:

RuCl

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

metallacyclobutane

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

HCl

E E

+PRu

Cl P(c-Hex)3

H

HCl

E E

P(c-Hex)3E E

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

JACS, 1997, 3887.

JACS, 1975, 3265.EtO2C CO2Et

RuCl

Cl

P(c-Hex)3

P(c-Hex)3

H

H

5 mol%

CD2Cl2, 25°CCO2EtEtO2C

18e complex

NBocNBoc

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, andaldehydes

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

N

PhH2CH+

Cl-

2-Ru

CH2Cl2NaOH

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

CH3E E

E E

H3C

CH3

E E

H3C

NR 93

E EH3C

CH3H3C

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

OR 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

RuCl

Cl

P

P

Ph

H 5-Ru

N(CH3)3+Cl-

N(CH3)3+Cl-

RuCl

Cl

P

P

Ph

H6-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°CCO2EtEtO2C

solvent: CH2Cl2 100%

CH3OH <5%

JOC, 1998, 9904

Substrate Product solvent catalyst yield recovered catalyst%

TBSO HOTBS

CH2Cl2 4-Ru 90 75

TsN NTs CH2Cl2

4-Ru 99 88

TsN

NTsCH2Cl2 4-Ru 72 88

E E

Ph

E E

CH3OH 5-Ru

6-Ru

8095

E E

Ph

E E

CH3OH 6-Ru >95

BocN

Ph

BocN 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

RuLnPh

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 HCl-

5 mol% 3-Ru

CH2Cl2

N

HHCl-

R=H 60%R=Ph 100%

Macrocyclizations and pre-organization

O

OO

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%

PhO

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-Ru6mol%

O O

H H

0.1M90%

OO O O

3-Ru3mol%

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-RuO

OH H

0.12 M 16%0.008M 73%

JACS, 1996, 6634.

O O

H H

LnRu=CHPh

O O

LnRuH H

O O

H

H

RuLnO

RuLn

O

H

LnRu=CH2

OO

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

NCH3

CH3

PhO

O

8-Mo

t-Bu

t-BuCH3

H3C

H3C

H3C

OSiEt3

5mol%

8-Mo

OSiEt3

19%, >99%ee

+

OSiEt3

43%, 93%ee

Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutaneintermediates

Mo

N

Ar

O

O

t-Bu

t-BuCH3

H3C

H3C

H3C

OSiEt3

Favored

H3C

H3C

Mo

N

Ar

O

O

t-Bu

t-BuCH3

H3C

H3C

H3C

OSiEt3

Disfavored

JOC, 1998, 824JACS, 1996, 2499

JACS, 1998, 4041

Mo

N

R R

CH3

CH3

PhO

O

8-Mo R=iPr9-Mo R=Me

t-Bu

t-BuCH3

H3C

H3C

H3C

O 5mol%

8-Mo

+

O

H3C

H3CR R

O

H3CR

R % conversion SM ee (%)

n-C5H11 63 92%

c-C6H11 62 98%

C6H5 56 75%

increasing the size of the alpha-substitutent leads to greaterselectivity; neither 8-Mo nor 9-Mo resolve disubstituted alkenes

Catalytic, Enantioselective Desymmetrization:

R

H3C CH3

R

O

1-2mol% 9-Mo

O

H3C

R

H3CR=H, 85%, 93%ee

R=CH3, 93%, 99%ee

Works for tertiary allylic ethers with 9-Mo:

O5 mol% 9-Mo

O

Ph 91%, 82%ee

JACS, 1998, 4141JACS, 1998, 9720

Dienyne Metathesis

R

n m

LnM

R

n m

R

MLnn

m

R

n m

R

OSiEt3

3-5mol% 2-Ru

R

OSiEt3 R yield

H >98

CH3 95

iPr 78

t-Bu NR

Ph 96

reaction rates decrease as the size ofthe alkyne substituentincreases

JOC, 1996, 1073.

CH3

OSiEt3

CH3

OSiEt3

83% 0.03M

substrate product yield M

CH3

OSiEt3

CH3

Et3SiO

78% 0.001M

Note: regiochemical control withinunsymmetrical substrates is achieved by substitution of the olefin required to undergo metathesis last.Unsymmetrical substrates containing equally reactive olefins produce mixtures of products:

CH3

OSiEt3

CH3

OSiEt3

+

CH3

Et3SiO

86%, 1:1

Cross Metathesis

BzO7

+ "olefin"5 mol% 3-Ru

BzO7

R

"olefin" R yield E:Z

AcO OAc OAc 89 4.7:1

t-BuO OtBu OtBu 90 7:1

• The use of disubstituted olefins in cross-metathesis minmizes the formation of a methylidene

intermediate (LnRu=CH2) which is a less stable catalyst.

•The disubstituted alkene may be used as solvent to increase the yield of cross metathesis

Procedure: a. homodimerize the more readily available terminal olefin, and b. use two equivalents of this homodimer in cross metathesis with the more valuable terminal olefin

AcO7

0.3 mol% 3-RuAcO

7

OAc

7

O

BnO

BnO

BnO

BnO

+AcO

7

OAc

75 mol% 3-Ru O

BnO

BnO

BnO

BnO

OAc

73%; E:Z 3:1

TL 1998, 7427.

New Ru-Based Catalysts

RuCl

ClP(c-Hex)3

Ph

H

NMesMesN

10-Ru

RuCl

ClP(c-Hex)3

Ph

H

NMesMesN

11-Ru

RuCl

ClP(c-Hex)3

Ph

H

NMesMesN

12-Ru

most reactive Ru-basedcatalysts to date

substrate product 10-Ru 11-Ru 12-Ru

E E tBu

t-Bu

EE

100 100 100

E E CH3H3C

CH3

EE

H3C

40 31 55

E EH3C

CH3CH3

H3C

EE

95 90 87

OL, 1999, 953TL, 1999, 2247

Metathesis of Alkynes and Diynes

MoN

N

Nt-Bu

t-Bu

t-Bu

H3C

CH3 H3C

CH3

CH3

CH3

CH2Cl2 MoN

N

Nt-Bu

t-Bu

t-Bu

H3C

CH3 H3C

CH3

CH3

CH3Cl

14-Mo15-Mo

CH3R

14-Mo (10mol%)R R

R=H 60%R=CN 58%

CH2Cl2, toluene

Substrate Product Yield (%)

O

O O

O O

O O

O 91

N

O

O

O

O

CH3

CH3

N

O

O

O

O 88JACS, 1999, 9453.

Catalyst 15-Mo istolerant of diversefunctional groups:esters, amides, thioethers, and basic nitrogen atoms.

RuCl

ClP(c-Hex)3

H

NMesMesN

13-Ru

CH3

CH3

Cross-Metathesis of Functionalized Olefins

BnO AcO

A B

Functionalized Olefin Alkene Product Yield E:Z

OA

BnO

O

91 4.5:1

O

H

O

H

B

B

AcO

O

H

AcO

O

H

CH3

92 >20:1

62 1.1:1

OB AcO

OH

H55 5:1

Si(OEt)3 B AcOSi(OEt)3

81 11:1

JACS, 2000, 3783.

RCM of Functionalized dienes

Diene Product Yield

O

O

O

O

CH3 86

O O

93

O

O

O

O

97

conditions: 5 mol% 13-Ru JACS, 2000, 3783.

• Substrates containing both allyl and vinyl ethers provide RCM, while no products are observed if vinyl ethers alone are present• !,"-unsaturated lactones and enones of various ring sizes are produced in good to excellent yields

Cross Metathesis of Ethylene and Alkynes

11-Ru outperforms 3-Ru in both rate and overall conversion:

Substrate Product Yield

OROR R=H 73

R=Ac 92R=TBS 91

AcO

OAc

OAc

OAc

69

NTs NTs91

conditions: 5mol% 11-Ru at 60 psi of ethylene pressure

• 11-Ru can tolerate free hydroxyl groups and coordinating functionality at propargylicand homopropargylic positions• Chiral propargylic alcohols afford chiral diene products without loss of optical purity:

Ph

OH

99%ee

11-Ru (5 mol%)

ethylene (60 psi)Ph

OH

99%ee

Enyne Metathesis Reactions Catalyzed by PtCl2

Substrate Product Yield

conditions: 4-10mol% PtCl2, 80°C, toluene

PhO2S SO2Ph PhO2S SO2Ph

96%

O

O OCH3

MeO2C

O

70%

TsN

TsN 80%

JACS, 2000, 6785.

•Remote alkenes are not affected

•commercial PtCl2 used.