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1
NNRR
RR
RR
[Ru]Increased Efficiency in Cross-Metathesis Reactions of Sterically Hindered Olefins
Highly Efficient Ruthenium Catalysts for the Formation of Tetrasubstituted
Olefins via Ring-Closing Metathesis
Pushing the Limits of the Metathesis Reaction:
Design of the NHC ligand
Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Shrodi, Y. Org. Letters 2007, 9, 1589.
Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Letters 2008, 10, 441.
And
Dr. Laurent Ferrié10/18/08
Laurent Ferrie @ Wipf Group Page 1 of 16 10/18/2008
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Metathesis: Principle
Statistical Distribution of the Olefinic Fragments
From the Greek meta= to change and thesis = position
Calderon et al., J. Am. Chem. Soc. 1968, 90, 4133
[M]
Laurent Ferrie @ Wipf Group Page 2 of 16 10/18/2008
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Metathesis: Principle
In the Greek mythology:
The griffin = eagle + lion
The hippocampus = horse + fish
Laurent Ferrie @ Wipf Group Page 3 of 16 10/18/2008
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Metathesis: Catalysts
1931
725 °C
Thermal MetathesisW
CO
CO COCO
COCO
Banks1964
Hetereogenous Catalysis
via W(CO)5=R2
150 °C
CH2
Me
CH2
Me
Me
Me
H2C CH2
Ru
PCy3Ph
Cl
Cl
NN MesMes
Ru
O
Cl
Cl
NN MesMes
Mo
N
i-Pri-Pr
Me
MePhO
O
F3C
F3C
F3C CF3
Ru
PCy3
PCy3Ph
Cl
Cl
Mes =Cy = Cyclohexyl
Shrock CatalystGrubbs Catalyst
2nd generation
Grubbs Catalyst
1st generation
Grubbs-HoveydaCatalyst
1995 1999 20001990
Metathesis Catalysts Used in Organic Chemistry
Laurent Ferrie @ Wipf Group Page 4 of 16 10/18/2008
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Metathesis: Mechanism
Chauvin Y.; Hérisson, J.-L., Makromol. Chem. 1971, 141, 161.
H2C=C H2C=C
M=CR2
C=CH2
M=CR2
M
H2C C
CR2
M
C CH2
CR2
M
CH2
CR2
CR2C=CM=CH2
M
CR2
CH2
C H2C=CR2M=C
++
+
M=CR2
M=CH2
M=C
+
+
H2C=C
H2C=C M=CH2
M=C +
+
H2C=CH2
C=C
2/ Propagation
1/ Initiation
Laurent Ferrie @ Wipf Group Page 5 of 16 10/18/2008
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R1R2+ R2R1
+1) Cross-Metathesis (CM)
2) Ring-Closing Metathesis (RCM) +
3) Polymerizing Metathesisn
+
(ROMP)
(ADMPE)
Metathesis: Application
Laurent Ferrie @ Wipf Group Page 6 of 16 10/18/2008
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Ring-Closing Metathesis: Limitations
E E
E E
E E
E E
E E
E E
5 mol% catalyst
40°C DCM
Substrate Product
Catalyst: Conversion
Ru
PCy3Ph
Cl
Cl
NN MesMes
Ru
PCy3
PCy3Ph
Cl
Cl
100% 100%
82% 100%
0% 40%
Grubbs et al. Tetrahedron Letters 1999, 40, 2247
E= COOEt
-The obtention of tetrasubstituted olefins by RCM is inefficient
- Phosphine free catalysts (Hoveyda or Grela catalysts) do not give better conversion
Grela, K. and al., J. Am. Chem. Soc. 2004, 126, 9318.
Laurent Ferrie @ Wipf Group Page 7 of 16 10/18/2008
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Overcoming the Limitations: Modification of the NHC ligandMeO2C CO2Me MeO2C CO2Me
5 mol% [Ru]
0.1 M, DCM, 40°C
Ru
O
Cl
Cl
NN
Ru
O
Cl
Cl
NN
Ru
PCy3
Cl
Cl
NN
PhRu
PCy3
Cl
Cl
NN
Ph
tBu
tBuBut
But
Ru
O
Cl
Cl
NNRR
Ru
PCy3
Cl
Cl
NN
Ph
RR
5a (R=Me)5b (R=Et)5c (R=i-Pr)
6a (R=Me)6b (R=Et)6c (R=i-Pr)
1
3 4
2
Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Shrodi, Y. Org. Letters 2007, 9, 1589.
Laurent Ferrie @ Wipf Group Page 8 of 16 10/18/2008
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Overcoming the Limitations: Reaction Monitoring
Ru
O
Cl
Cl
NN
Ru
O
Cl
Cl
NN
Ru
PCy3
Cl
Cl
NN
PhRu
PCy3
Cl
Cl
NN
Ph
tBu
tBuBut
But
Ru
O
Cl
Cl
NNRR
Ru
PCy3
Cl
Cl
NN
Ph
RR
5a (R=Me)5b (R=Et)5c (R=i-Pr)
6a (R=Me)6b (R=Et)6c (R=i-Pr)
1
3 4
2
Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Shrodi, Y. Org. Letters 2007, 9, 1589.
5a
6a
1
2
4
3
MeO2C CO2Me MeO2C CO2Me5 mol% [Ru]
0.1 M, DCM, 40°C
Laurent Ferrie @ Wipf Group Page 9 of 16 10/18/2008
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Application to Different Substrates
Ru
O
Cl
Cl
NN
3
Ru
O
Cl
Cl
NNMeMe
6a
Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Shrodi, Y. Org. Letters 2007, 9, 1589.
Laurent Ferrie @ Wipf Group Page 10 of 16 10/18/2008
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Cross-Metathesis: General Model and Limitations
Grubbs, R. H. et al. J. Am. Chem. Soc. 2003, 125, 11360
Cross-Metathesis:
Type I + Type I: statistic mixture, good yields
Type I + Type II: good yields
Type I + type III: moderate to low yields
Type II + type III: generally low yields
Laurent Ferrie @ Wipf Group Page 11 of 16 10/18/2008
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Cross-Metathesis: Use of Modified NHC Ligands
Ru
O
Cl
Cl
NN
Ru
PCy3
Cl
Cl
NN
Ph
Ru
O
Cl
Cl
NNMeMe
1 2 3
Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Letters 2008, 10, 441.
Laurent Ferrie @ Wipf Group Page 12 of 16 10/18/2008
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Cross-Metathesis: Formation of Trisubstituted Olefins by CM
Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Letters 2008, 10, 441.
Ru
O
Cl
Cl
NN
Ru
O
Cl
Cl
NNMeMe
2 3
Laurent Ferrie @ Wipf Group Page 13 of 16 10/18/2008
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[Ru]
NN
R'
[Ru]
NN
R'
R
R
+
R
R
+kB
kD
kA
kC
kA~kB
kC<kD
Productive Metathesis
Unproductive Metathesis
Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Letters 2008, 10, 441.
Wagener, K. B. and al. J. Organomet. Chem., 2006, 691, 585.
Productive and Unproductive Metathesis: Mechanistic Aspect
Laurent Ferrie @ Wipf Group Page 14 of 16 10/18/2008
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Ru
O
Cl
Cl
NN
Ru
O
Cl
Cl
NNMeMe
2 3
7
98
7
96
Ru
O
Cl
Cl
NN
PriiPr
PriiPr
7
Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Letters 2008, 10, 441.
Improvement in the Formation of Trisubstituted Olefins by
Using Bulky NHC Ligands
Laurent Ferrie @ Wipf Group Page 15 of 16 10/18/2008
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Conclusion
- The design of the NHC ligands in the Ruthenium metathesis catalysts demonstrated
significant improvements to difficult processes in both RCM and CM reactions
- o-Tolyl NHC ligand, by decreasing steric bulk, allows efficient formation of
tetrasubtituted cyclic olefins by RCM.
- o-Tolyl NHC ligand, by decreasing steric bulk, enhances the CM with substituted
terminal olefins but are not effective for the CM with 1,1 disubstituted olefins.
- Bulky NHC ligands, are the most effective for the CM with 1,1 disubstituted olefins
likely due to a selectivity of productive versus unproductive pathways.
Laurent Ferrie @ Wipf Group Page 16 of 16 10/18/2008