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.
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