Recent Advances in C‐H Activation by Rhodium Based Catalysts by Rhodium Based Catalysts Hui Zhao 10/29/2008 Hui Zhao 10/29/2008
Recent Advances in C‐H Activation by Rhodium Based Catalystsby Rhodium Based Catalysts
Hui Zhao 10/29/2008Hui Zhao 10/29/2008
C‐H ActivationC H Activation
H
R H + [LnMX] R MX+2
Ln
H
Ln
H2O R' NH2R' Br
R'HN R
h fi i i f h C b d i ll diffi l
ROH R' N RR' R
The first step, activation of the C‐H bond is generally very difficult
C‐H bonds are ubiquitous in organic molecules, selectivity is always an issue
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
Shilov ChemistryShilov Chemistry
• Remarkable reaction, converts methane to methanol or methyl chloridemethyl chloride
• Discovered in 1972, a famous example of alkane functionalization under mild conditionsfunctionalization under mild conditions
• After 30 years, the mechanism is still in debate, recent work is from John E. Bercaw
Gol’dshleger, N.F.; Es’kova, V. V.; Shilov, A. E.; Shteinman, A. A. Zhurnal Fizicheskoi Khimii 1972, 46, 1353.Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
Shilov ChemistryShilov Chemistry
Cl OH2 CH C OPtIICl OH2
H2O Cl
+ CH4
- HClPtII
Cl OH2
H2O CH3
PtIVCl62-
CH3OH + HCl
Cl OHCH3
H2O
Stoichiometricloading of PtIV
PtIICl42-PtIVCl OH2
H2O ClCl
g
Gol’dshleger, N.F.; Es’kova, V. V.; Shilov, A. E.; Shteinman, A. A. Zhurnal Fizicheskoi Khimii 1972, 46, 1353.Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
Proposed mechanism for Shilov's platinum catalyzed alkane oxidation
Wilkinson’s CatalystWilkinson s Catalyst
• 1973 Nobel prize• 1973 Nobel prize
• Homogeneous catalytic hydrogenation of olefins
• Rhodium(I) tris (triphenylphosphine) chloride as the catalyst• Rhodium(I) tris‐(triphenylphosphine) chloride as the catalyst
Osbron, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Am. Chem. Soc. 1966, 88, 1711‐1732.
Wilkinson’s CatalystWilkinson s Catalyst
Osbron, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Am. Chem. Soc. 1966, 88, 1711‐1732.
Catalytic C‐H Activation
Outline
• Introduction
Outline
Introduction
• Alkylation of N‐heterocycles
• Arylation of N‐heterocycles
• C‐H Activation by carbene insertionC H Activation by carbene insertion
• C‐H Activation by nitrene insertion
Alkylation of Heterocycles
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013‐1025.
Alkylation of Heterocycles
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013‐1025.
Proposed Mechanism for Alkylation of Heterocycles
Tan, K. L.; Park, S.; Ellman, J. A.; Bergman, R. G. J. Org. Chem. 2004, 69, 7329‐7335.
Alkylation of α, β‐Unsaturated IminesAlkylation of α, β Unsaturated Imines
Two Predictions:
RegioselectivitySt l ti itStereoselectivity
Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 5604‐5605.
Alkylation of α,β,‐Unsaturated Imines
Since the imine was unstable to column chromatography, the crude product was hydrolyzed to the, α,β–unsaturated aldehyde, and then purified.was hydrolyzed to the, α,β unsaturated aldehyde, and then purified.
Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 5604‐5605.
Alkylation of α,β‐Unsaturated Imines
1. 2.5% [RhCl(coe)2]2N
C
Bn
+
[ ( )2]210% FcPCy2 2. Aluminum Chromatography
ColumnO
CR
O
CR
+50°CR H H
Entry Alkene Time(h)
ImineZ:E % Yield (Z:E)
C RH
1 12 >95:<5 91 (10:1)
2 Cl 8 >95:<5 80 (10:1)Cl 8 >95:<5
>95:<5
80 (10:1)
3O
O4 78 (5:1)
4 24 10:1 74 (5:1)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 5604‐5605.
Synthesis of Incarvillatein
Analgesicagent
Incarvillea SinensisIncarvillea Sinensis
Chi, Y.‐M.; Yan, W.‐M.; Li, J. –S. Phytochemistry 1990, 29, 2376‐2378.Nakamura, M.; Chi, Y.‐M.; Yan, W.‐M.; Nakasugi, Y.; Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nohara, T.; Sakurada, S. J. Nat. Prod. 1999, 62, 1293‐1294.
Ichikawa, M.; Takahashi, M.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2004, 126, 16553‐16558.
Synthesis of Incarvillatein
Tsai, A. S.; Bergman, R. G.; Ellman, J. A. J. Am .Chem. Soc. 2008, 130, 6316‐6317.
Synthesis of IncarvillateinSynthesis of Incarvillatein
Me
TBSO
CO2Et
Me
MeCH2O2Et
Me+ TBSO
NaBH4, MeOH,rt then 60°C
49% overall yieldNe
Ne 49% overall yield
for two steps
Me
TBSO N
OMeH H2 (1000psi)
Pd/C, MeOH, 60°CMe
TBSO N
OMeH
TBSO N
Me
99%TBSO N
MeH
The three stereocenters established from the alkylation reaction help establish the other two stereocenters.
Tsai, A. S.; Bergman, R. G.; Ellman, J. A. J. Am .Chem. Soc. 2008, 130, 6316‐6317.
establish the other two stereocenters.
Synthesis of Incarvillateiny
11 stepsp15.4% overall yield
Ichikawa’s Synthesis:17 steps
3.4% overall yield
Using new C‐H activation methodology, synthesis has been shortened, overall yield is increased.
Tsai, A. S.; Bergman, R. G.; Ellman, J. A. J. Am .Chem. Soc. 2008, 130, 6316‐6317.Ichikawa, M.; Takahashi, M.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2004, 126, 16553‐16558.
Outline
• Introduction
Outline
Introduction
• Alkylation of N‐heterocycles
• Arylation of N‐heterocyclesArylation of N heterocycles
• C‐H Activation by carbene insertion
• C‐H Activation by nitrene insertion
Catalytic C‐H Activation
Catalytic C‐H Activation
Arylation of Heterocycles
X[RhCl(coe)2]2(2.5-5 mol%)
i-Pr2i-BuNTHF X
N NArH ArX+
(5-7.5 mol%)PCy3
[RhCl(coe)2]2Cl
[RhCl(coe)2]2Rh Rh
Cl
PPCy3
Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35‐38.
Proposed Mechanism for Arylation Reaction
Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35‐38.
Side Product from Hydrogenolysis
Side Product: ArH, comes from hydrogenolysis of substrate,f d h h d f h d ld b hfinding the hydrogen source for this side reaction could be thekey issue to optimize the chemistry
Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35‐38.
Side Product from Hydrogenolysis
Side Product: ArH, comes from hydrogenolysis of substrate,f d h h d f h d ld b hfinding the hydrogen source for this side reaction could be thekey step in optimizing the chemistry
Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35‐38.
Proposed Mechanism for Hydrogenolysis
Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman J. A. Org. Lett. 2004, 6, 35‐38.
New Ligand for ArylationNew Ligand for Arylation
HN
I 0.05 equiv [RhCl(coe)2]20 3 equiv PR H
NN
NR
+0.3 equiv PR3
3 equiv basesolvent, heat
N
NR
1 equiv 2 equiv
Entry Base (equiv) PR3 R Yield [%]Entry Base (equiv) PR3 R Yield [%]
1 Et3N (4) PCy3 H 20
2 Et3N (4) 1 H 27
Yi ld i i d ill l
2 Et3N (4)
Et3N (4)
1 H 27
3 2 H 40
PCyCy Yield is increased, still large amounts of benzen, hydrogenolysisof substrates, side reaction still
PCy2
PCy
1
Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem. Int. Ed. 2006, 45, 1589-1591.
exists.
Dehydrogenated Catalyst/Ligand Complex
Further suggests that ligandFurther suggests that ligand dehydrogenation could be the side reaction.
Lewis, J. C.; Berman , A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493‐2500.
Cyclooctene Ligand
• Cyclooctane may be dehydrogenated, becoming the hydrogen source for hydrogenolysis of substrate
• Increase unsaturation, making it less likely to
go through dehydrogenation.
Lewis, J. C.; Berman , A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493‐2500.
Removal of the Bridged System
Cy PCy
new ligand
• Bridged cyclooctene ligandis difficult to synthesizeBridged cyclooctene ligandis difficult to synthesize
• Removing the bridge simplifies the ligand while• Removing the bridge simplifies the ligand while maintaining unsaturation
Lewis, J. C.; Berman , A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493‐2500.
Replace Cyclohexyl with Different R Groups
• The cyclohexane on the phosphine may also undergo dehydrogenation, causing hydrogenolysis of the substrate
• Optimize the ligand by choosing an R group which would be more difficult to dehydrogenate.
Lewis, J. C.; Berman , A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493‐2500.
Results for Screening Different R Groups
t‐Bu
Ph
Cy
Me
yi‐Pr
Me
Plot of conversion versus time for arylation using 5a‐e.
Me < i‐Pr < Cy < Ph < t‐Bu
Lewis, J. C.; Berman , A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493‐2500.
Better Results from New Ligands
Lewis, J. C.; Berman , A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493‐2500.
Conclusion from Parts I and II
A l Rh di N h li b l i
Conclusion from Parts I and II
• A novel Rhodium N‐heterocyclic carbene complex is invovled as an intermediate in the alkylation and arylation of N heterocyclesarylation of N‐heterocycles.
A l i f N h l i PC li d• Arylation of N‐heterocycles using PCy3 ligands are limited by competing C‐H activation of the ligand.D i i li d f C H i i f• Designing new ligands to frustrate C‐H activation of the ligand led to improved arylation of N‐heterocyclesheterocycles.
Metal Carbene or Nitrene C‐H Functionalization ‘ d l’VS ‘Traditional’ C‐H Activation
Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417‐424.
Outline
• Introduction
Outline
Introduction
• Alkylation of N heterocycles• Alkylation of N‐heterocycles
• Arylation of N‐heterocycles
• C‐H Activation by nitrene insertion
C H A ti ti b b i ti• C‐H Activation by carbene insertion
C‐H Activation by Nitrene Insertion
PhI(OAc)2: reacts with sulfamateto form nitreneto form nitrene
MgO: removes AcOH produced from nitrene productionfrom nitrene production
• Present study is confined to intramolecular process
• Regioselectivity: sulfamate has strong bias to form six‐member ring, 3 position is activated
St l ti it C t lli t l ti it i th k i !• Stereoselectivity: Controlling stereoselectivity is the key issue!
Espino, C. G.; When, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935‐6936.
Stereoselectivity
b t t j d t l ti it i ldsubstrate major product selectivity yield
OS
H2N
O O
OS
HN
O O
15:1 91%2CO2Et CO2Et15:1 91%
OS
H N
O O
OS
HN
O O
12
3
OH2N OHN
R R
R=CF3OMe
20:120:1
70%85%
123
OS
H2N
O O
Me
OS
HN
O O
Me 87%20:112
3
When, P. M.; Lee, J.; Du Bois, J. Org. Lett. 2003, 5, 4823.
CO2Me CO2Me
Substrates with Two Syn Groups Fail
• Reaction fails with two substituents in syn position
When, P. M.; Lee, J.; Du Bois, J. Org. Lett. 2003, 5, 4823.
C‐H Activation by Nitrene Insertion
• Reaction of hydroxyl group and sulfamoyl chloride installs a sulfamate group, which sets the C‐H amination reaction.
h h l h l k l• Protect the amine group, then nucleophile attack cleave oxathiazinane ring give the aminated compound, with a new substituent in 1 position.
Espino, C. G.; When, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935‐6936.
C‐H Activation of α,β‐Ether Hydrocarbon Bond
Fleming, J. J.; Fiori, K. W.; Du Bois, J.; J. Am. Chem. Soc. 2003, 125, 2028.Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.Stevens, R. V.; Acc. Chem. Res. 1984, 17, 289.
Iminium Ion Equivalent
• Because of the instability of the N O‐acetal structure theBecause of the instability of the N, O‐acetal structure, the reactions are conducted sequentially, without isolation of the intermediate.
• During iminium formation, stereochemistry is lost at carbon 3, hat happens after the formation of imini m ion determineswhat happens after the formation of iminium ion determines
the stereo‐outcome of the product.
Fleming, J. J.; Fiori, K. W.; Du Bois, J.; J. Am. Chem. Soc. 2003, 125, 2028.Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.Stevens, R. V.; Acc. Chem. Res. 1984, 17, 289.
Four Different Situations
Fleming, J. J.; Fiori, K. W.; Du Bois, J.; J. Am. Chem. Soc. 2003, 125, 2028.Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.Stevens, R. V.; Acc. Chem. Res. 1984, 17, 289.
Trans Selectivity
Substitution at position 1 results in amination at position 3 with good trans selectivity .
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
Trans Selectivity
Two factors control stability: 1,3‐diaxial interaction of the iminium structureFelkin –Ahn model with the nucleophile attack
Fleming, J. J.; Fiori, K. W.; Du Bois, J.; J. Am. Chem. Soc. 2003, 125, 2028.
e ode e uc eop e a ac
Trans Selectivity
syn substituents at positions 1 and 2 favorsyn substituents at positions 1 and 2 favor trans amination products at the 3 position.
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
Trans Selectivity
Top transition state does not have 1,3‐diaxial interactions, and also is preferred by the Felkin Anh model
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
and also is preferred by the Felkin‐Anh model
No Selectivity
When two substituents at 1,2 position have a trans relationship, there is no no selectivity in terms of the aminated product at 3 position.
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
No Selectivity
S NH
O
O
O R2
HH SOO
HN H
R2
H
OS
HNO H
R2O
SHN
O O
R3
SO O
HOR3
SO
H
Nuc
SOR3 Nu R2
Nu R3
1,3- diaxiali t tiO
SHN
R2
R3Nuc
O O
interaction
OSO
OO N
HHR2
H
S NH
O
OR2
H
SHN
O
O
ONu
HR2
OS
HN
O O
RNu
R3 R3 R3
R3
H R2
Felkin-Ahndisfavored
Top TS is disfavored by the 1, 3‐diaxial interactionBottom TS is disfavored by the Felkin‐Ahn model
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
Model Fails with One Stereocenter at Position 2
In these cases, the trans product can be explained by the model.
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
Model Fails with One Stereocenter at Position 2
No preference in terms of iminium stability, Felkin-Ahn model predictsthat bottom TS should be favored.
Fiori, K. W.; Fleming, J. J. ; Du Bois, J.; Angew. Chem. Int. Ed. Engl. 2004, 43, 4349.
that bottom TS should be favored.
Some Cases Could not be Explained by the Model
In these cases, the product adopts a trans conformation, which couldIn these cases, the product adopts a trans conformation, which couldnot be explained by the model, Chelation effects between zinc ion and hydroxyl group may direct the nucleophile to syn face
Fleming, J. J.; Fiori, K. W.; Du Bois, J.; J. Am. Chem. Soc. 2003, 125, 2028.
nucleophile to syn‐face.
OutlineOutline
• IntroductionIntroduction
• Alkylation of N heterocycles• Alkylation of N‐heterocycles
• Arylation of N‐heterocycles
• C‐H Activation by nitrene insertion
C H A ti ti b b i ti• C‐H Activation by carbene insertion
Related ReferencesRelated References
Davies, H. M. L.; Jin, Q. Proc. Natl. Acad. Sci. USA 2004, 101, 5472‐5475.
Davies, H. M. L.; Walji, A. M. Angew. Chem. Int. Ed. 2005, 44,1733‐1735.1733 1735.
Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006,128, 2485‐2490.
Davies H M L ; Manning J R Nature 2008 451 417 424Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417‐424.
Surrogate for Aldol Mannich Reaction
Davies, H. M. L.; Beckwith, R. E.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126‐6132.Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. J. Am. Chem. Soc. 2003, 125, 6462‐6468.
Proposed Mechanism for Carbene‐Induced C‐H Insertion
Davies, H. M. L.; Jin, Q. Org. Lett. 2001, 3, 3587.
Combined C‐H Activation/Cope Rearrangement
HR1
R2N2
CO2Me+ Cat. R1R2 CO2Me
R1R2
CO2Me
R3 R R3 R
R
R3 R
Main Product
R1
R2
R
CO2MeR1
R2CO2Me
+
R3
R R3 R
Direct C-H activationproduct
cyclopropanationproduct
Side Products
productproduct
Davies, H. M. L.; Jin, Q. Proc. Natl. Acad. Sci. USA 2004, 101, 5472‐5475.
Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2495‐2490.
Not a Tandem C‐H Activation/Cope Rearrangement
PreliminaryMechanism Study
Davies, H. M. L.; Jin, Q. Proc. Natl. Acad. Sci. USA 2004, 101, 5472‐5475.
Enantio‐differentiation
S‐enantiomerR‐enantiomer
Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2495‐2490.
Catalyst Structure
Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.
Simplified Model of the Catalyst
Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.
Most Stable Conformation of the Catalyst
C1
CC2
, , , , , ,
C4D2
, , ,
Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.
, , ,, , ,
Most Stable Conformation of the Catalyst
Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.
Catalyst Structure
1010
SO2O2S
RhO
O
O
O
O
O
NHSO2
N HO2S
RhO O
O OH
NSO2
HN
O2S
101010
Rh2(S-dosp)4
Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.
Further Simplification
OSO2Ar
When one rhodium atom di t t th b th
RhO
O
O
O
O
ONSO2Ar
H NH coordinates to the carbene, the other rhodium atom is deactivated,
RhO O
O O
NH
ArO2S
NSO2Ar
H only one face of the catalyst is effective.
Only one face of the catalyst is effective
Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.
Enantio‐differentiation
MeTBSOMeTBSO
MeO
Me H
Me
MeO
TBSO
Me H
Me
MeO
TBSO
MeO2C
MeMeO2C
Me
MeHH (S)
TBSOMeO
Me
MeHH (R)
TBSOMeO
CO2MeMe
Rh
TBSO
CO2MeMe
Rh
TBSO
Rh
(R-dosp)catalyst
Rh
(R-dosp)catalyst
Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2495‐2490.
Enantio‐differentiation
Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2495‐2490.
ConclusionsConclusions
• Direct functionalization of nitrogen heterocycles through C‐H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents withregioselectively introducing a variety of substituents with diverse functional groups on to the heterocycle scaffold.
• Alternative approaches by carbene or nitrene insertion for C‐H activation has been developed, which show a great promise p , g pin application of organic synthesis.
Acknowledgements
• Dr. Baker
Acknowledgements
• Dr. Borhan• Dr. Maleczka• Dr. SmithDr. Smith
• Qin Sampa Tom GinaQin, Sampa, Tom, Gina
• Xiaoyong Li Munmun Yong Quanxuan Anil• Xiaoyong, Li, Munmun, Yong, Quanxuan, Anil, Hong,