Olefin Metathesis

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
LnRu=
ROMP
n
LnRu=
RCM:Ring closing Metathesis
RCM
+ H2C=CH2
LnRu=
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.
F 3C
F3C
N
Mo
O
H3C
F3C
P(c-Hex)3
CH3
Ph
CH3
O
F3C CH3
Cl
Ru
Cl
P(c-Hex)3
Ph
Cl
Ru
Ph
H
P(c-Hex)3
Cl
H
P(c-Hex)3
2-Ru
1-Mo
Ph
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:
Ph CH2Cl2
RuCl2(PPh3)3
+
N2 =
PPh3
Cl
Ru
Cl
Ph
H
PPh3
• little sensitivity to air or moisture
• requires electron-rich ligands (P(c-Hex)3)for increased activity
P(c-Hex)3
CH2Cl2
3-Ru
JACS, 1993, 9858
P(c-Hex)3
A Dissociative Mechanism has been proposed:
Cl
Cl
JACS, 1997, 3887.
EtO2C
CO2Et
JACS, 1975, 3265.
Cl
P(c-Hex)3
[2+2]
H
Ru
H
-P
R
18e complex
H
P(c-Hex)3
5 mol%
CD2Cl2, 25°C
Cl
Cl P(c-Hex)3
H
Cl
Ru
H
P(c-Hex)3
R
H
Ru
Cl P(c-Hex)3
H
Cl
Ru
H
H
Cl P(c-Hex)3
Cl
H
R
16e complex
EtO2C
Ru
R
metallacyclo
butane
-C2H4
R
Cl
P(c-Hex)3
Cl
H
Ru
Cl
•Evidence for phosphine dissociation:
addition of one equivalent of phosphine
decreases rate by 20 times
H
P(c-Hex)3
P(c-Hex)3
Cl
Ru
E E
[2+2]
E
Cl P(c-Hex)3
H
Cl
Ru
H
E
+P
Cl P(c-Hex)3
H
Cl
Ru
H
P(c-Hex)3
E
E
E
E
Cl P(c-Hex)3
H
Cl
Ru
H
E
E
CO2Et
Catalytic RCM of dienes by 2-Ru
substrate
product
NBoc
yield
NBoc
O
O
Ph
Ph
84
Ph
• 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
O
O
91
• 5,6,7-membered oxygen and nitrogencontaining heterocycles and cycloalkanes
are formed efficiently
72
ClPhH2C + H
Ph
N
R
R
R=CO2H
R=CHO
R=CH2OH
Ph
2-Ru
CH2Cl2
NaOH
87
82
88
Conditions: substrate + 2-4mol% 2-Ru, C6H6, 20°C
N
For Tri- and Tetrasubstituted Olefins, Catalyst 1-Mo is better
substrate
product
E
E E R
H3C E
R
E
E CH
3
93
NR
25
100
96
97
NR
93
NR
61
E
CH3
E
E
yield 1-Mo
E
R=CH3
R=t-Bu
R=Ph
H3C
H3C E
yield 3-Ru
E
H3C
CH3
CH3
JOC, 1997, 7310
conditions, 5mol% catalyst, 0.1M, C6H6
The standard "Thorpe-Ingold" effect favors cyclizations with gem-disubstituted substrates:
O
1mol% 1-Mo
R
R
R RR R
25°C
O R
R
R=H 0%
R=CH3 95%
JACS, 1992, 10978
Recyclable and Water-Soluble Catalysts
CH3
N
Cl
O
Cl
Ru
N(CH3)3+Cl-
P
P(c-Hex)3
Cl
H
Ru
Cl
4-Ru
Cl
Ru
5-Ru
Cl
P
N(CH3)3
CH2
P
Ph
H
Cl-
+Cl-
Ph
P
N
JACS, 1999, 791
6-Ru
H
CH3
CH3
Cl-
JOC, 1998, 9904
• 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
solvent: CH2Cl2
CH3OH
EtO2C
CO2Et
100%
<5%
Substrate
TBSO
solvent
5 mol%
catalyst
yield
CH2Cl2
4-Ru
90
75
NTs
CH2Cl2
4-Ru
99
88
NTs
CH2Cl2
4-Ru
72
88
CH3OH
5-Ru
6-Ru
80
95
CH3OH
6-Ru
>95
CH3OH
5-Ru
6-Ru
30
>95
Product
OTBS
H
Ts
N
Ts
N
E
E
E
E
Ph
E
recovered catalyst%
E
E
E
Ph
Boc
N
Boc
N
Ph
• 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
Example:
N(CH3)3+ClPh
N(CH3)3+Cl-
10 mol% 6-Ru
90%
H2 O
LnRu=
Mechanism:
R
methylidene, R=H
benzylidene, R=Ph
R
LnRu
R
LnRu=
Ph
Ph
RuLn
LnRu
R
R
Ph
•Phenyl substitution within the starting material can also greatly increase the yield of RCM in
organic solvents:
ClH
H
Cl5
mol%
3-Ru
H
H
N
R=H 60%
N
R
R=Ph 100%
CH2Cl2
Macrocyclizations and pre-organization
5 mol% 3-Ru
"template"
O
O
n
O
O
O
CH2Cl2, 45°C
O
O
O
n=1,2
n
template
yield
cis:trans
1
1
2
2
none
LiClO4
none
LiClO4
39
>95
57
89
38:62
100:0
26:74
61:39
n
•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:
12 mol%
1-Mo
H3C
O
88%
Ph
Ph
O
12 mol%
1-Mo
Ph
97%
Ph
O
O
Only catalyst 1-Mo is effective for metathesis of these substrates
Ring-opening, Ring Closing Metathesis
3-Ru
3mol%
O
O
H
O
H
O
0.1M
O
O
O
O
H
H
0.04M
90%
JACS, 1996, 10335
JACS, 1996, 6634.
H
H
3-Ru
6mol%
JOC, 1994, 4029
68%
O
O
H H
6 mol% 3-Ru
H
O
H
O
0.12 M 16%
0.008M 73%
Without sufficient strain in the starting olefin, competing oligomerization can occur
•Higher dilution favors the intramolecular reaction
Mechanism:
LnRu=CHPh
O
O
H
H
LnRu
O
O
H
H
O
O
O
H
H
H
O
O
LnRu=CH2
H
O
H
O
H
H
RuLn
O
RuLn
•Initial Metathesis of the acyclic olefin is supported by the fact that substitution of this
olefin decreases the rate of metathesis
Catalytic, Enantioselective RCM
OSiEt3
OSiEt3
N
t-Bu
O
t-Bu
CH3
H3C
+
8-Mo
Ph
CH3
O
H3C
5mol%
CH3
Mo
OSiEt3
43%, 93%ee
19%, >99%ee
8-Mo
JACS, 1998, 4041
JOC, 1998, 824
JACS, 1996, 2499
H3C
Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutane
intermediates
Ar
Ar
t-Bu
t-Bu
N
H3C
Mo
O
O
H3C
CH3
H3C
H3C
Favored
OSiEt3
H3C
t-Bu
OSiEt3
N
H3C
Mo
O
O
H3C
CH3
H3C
H3C
t-Bu
H3C
Disfavored
R
N
t-Bu
CH3
Mo
O
O
H3C
5mol%
O
R
H3C
O
H3C
R 8-Mo
+
R
H3C
R
O
Ph
CH3
R
% conversion
SM ee (%)
n-C5H11
63
92%
t-Bu 8-Mo R=iPr
c-C6H11
62
98%
9-Mo R=Me
C6H5
56
75%
increasing the size of the alpha-substitutent leads to greater
selectivity; neither 8-Mo nor 9-Mo resolve disubstituted alkenes
CH3
H3C
H3C
Catalytic, Enantioselective Desymmetrization:
O
H3C
CH3
R
H3C
1-2mol% 9-Mo
H3C
O
R
R=H, 85%, 93%ee
R=CH3, 93%, 99%ee
R
Works for tertiary allylic ethers with 9-Mo:
O
5 mol% 9-Mo
91%, 82%ee
Ph
O
JACS, 1998, 4141
JACS, 1998, 9720
Dienyne Metathesis
m
m
n
m
n
n
Ln M
OSiEt3
R
R
R
OSiEt3
R
H
CH3
iPr
t-Bu
Ph
3-5mol% 2-Ru
R
R
substrate
OSiEt3
product
yield
83%
OSiEt3
0.03M
R
yield
>98
95
78
NR
96
reaction rates
decrease as the size of
the alkyne substituent
increases
JOC, 1996, 1073.
Note: regiochemical control within
unsymmetrical 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
Et3SiO
78%
CH3
M
OSiEt3
CH3
m
n
MLn
CH3
Et3SiO
OSiEt3
+
0.001M
CH3
CH3
86%, 1:1
CH3
Cross Metathesis
5 mol% 3-Ru
+ "olefin"
BzO
BzO
7
"olefin"
AcO
t-BuO
R
7
R
yield
E:Z
OAc
OAc
89
4.7:1
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
0.3 mol% 3-Ru
AcO
AcO
7
OAc
7
BnO
BnO
BnO
O
BnO
BnO
TL 1998, 7427.
7
+
AcO
OAc
7
7
5 mol% 3-Ru
73%; E:Z 3:1
BnO
O
BnO
BnO
OAc
New Ru-Based Catalysts
MesN
NMes
Cl
MesN
Cl
Ph
Ru
Ru
H
P(c-Hex)3
Cl
Cl
10-Ru
H3C E
product
E
E tBu
E
H3C E
E
Cl
H
P(c-Hex)3
12-Ru
10-Ru
11-Ru
12-Ru
100
100
100
40
31
55
95
90
87
t-Bu
CH3
E
E
CH3
Ph
Ru
H
P(c-Hex)3
most reactive Ru-based
catalysts to date
E
E CH3
H3C
E
NMes
Cl
Ph
11-Ru
substrate
E
MesN
NMes
H3C
CH3
OL, 1999, 953
TL, 1999, 2247
Metathesis of Alkynes and Diynes
t-Bu
t-Bu
N
Mo
N
N t-Bu
CH3
Cl
CH2Cl2
t-Bu
N
CH3
H3C
CH3 H C
3
14-Mo
CH3
Substrate
O
O
N
O
R=H 60%
R=CN 58%
91
O
O
O
N
CH3
Yield (%)
O
O
O
R
O
O
CH3
O
R
Product
O
CH3
15-Mo
CH2Cl2, toluene
O
O
N
N t-Bu
CH3
14-Mo (10mol%)
R
CH3
H3C
CH3
CH3 H C
3
Mo
t-Bu
O
88
Catalyst 15-Mo is
tolerant of diverse
functional groups:
esters, amides,
thioethers, and basic
nitrogen atoms.
JACS, 1999, 9453.
Cross-Metathesis of Functionalized Olefins
BnO
MesN
NMes
CH3
Cl
AcO
Ru
A
H
P(c-Hex)3
Cl
B
CH3
13-Ru
Functionalized Olefin
Alkene
A
O
H
Product
BnO
91
E:Z
4.5:1
CH3 O
B
AcO
O
H
Yield
H
92
>20:1
62
1.1:1
55
5:1
81
11:1
O
B
AcO
H
O
O
H
O
B
AcO
H
Si(OEt)3
B
O
AcO
Si(OEt)3
JACS, 2000, 3783.
RCM of Functionalized dienes
Diene
Product
O
O
Yield
O
CH3
O
O
86
O
93
O
O
conditions: 5 mol% 13-Ru
O
O
97
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
OR
OR
Yield
R=H
R=Ac
R=TBS
73
92
91
OAc
AcO
69
OAc
OAc
NTs
NTs
91
conditions: 5mol% 11-Ru at 60 psi of ethylene pressure
• 11-Ru can tolerate free hydroxyl groups and coordinating functionality at propargylic
and homopropargylic positions
• Chiral propargylic alcohols afford chiral diene products without loss of optical purity:
OH
Ph
99%ee
OH
11-Ru (5 mol%)
ethylene (60 psi)
Ph
99%ee
Enyne Metathesis Reactions Catalyzed by PtCl2
Substrate
PhO2S
SO2Ph
Product
PhO2S
Yield
SO2Ph
96%
O
O
O
MeO2C
70%
OCH3
Ts
N
TsN
conditions: 4-10mol% PtCl2, 80°C, toluene
•Remote alkenes are not affected
•commercial PtCl2 used.
80%
JACS, 2000, 6785.