Post on 04-Sep-2018
C-C Bond Formation through Catalytic Functionalization of
sp3 C-H Bonds
Min XieOtc. 17, 2006
Methods of sp3C-H Funtionalization
1. Oxidative insertion of transition metals:
2. Metal catalyzed dehydrogenation by oxidants
3. Lewis acids catalyzed H shift
Why is sp3C-H Activation not Easy?
Bergman, Hoff, Polyhedron 1988,7,1429
sp3 C-M complexes are generally less stable.
Oxidative Addition of Transition Metal into sp3C-H
M = Ti(IV),Zr(IV),Nb(V),Ta(V),W(VI)
Nugent,Organometallics,1983,2,161
Chelation-assited Activation of sp3C-H
Bruce, ACIE, 1977,2,7
sp3C-H Activation by Ru Catalyst
Jun,Chem.Comm.,1998,1405
95%
Jun,Chem.Comm.,1998,1405
sp3C-H Activation by Ru(0) catalyst
Only 1-2% GC yield.
12
13+
15
16
Ru3(CO)12 (20 mol%)
PhMe, 130oC, 1.2h
39% (GC)
70%
12
14+
15
17
26%
60%
reactivity: 15 < 16 < 17
Murai,JACS,2001,123,10935
Ru Catalyzed Coupling Reactions of C-H
Murai,JACS,2001,123,10935
No reaction.
Ru Catalyzed Coupling Reactions of C-H
Ru Activation of sp3C-H in Cyclic Amines
Murai,JACS,2001,123,1093592% (54/46)
Ru Activation of sp3C-H in Acyclic Amines
Murai,JACS,2001,123,10935
CO not employed.Otherwise carbonylation at N-H bond.
Ru Catalyzed Coupling Reactions of Alkenes
CN
n-BuO
R
a Reaction conditions: 1a (1 mmol), alkene (10 mmol), Ru3(CO)12 (0.08 mmol), in 2-propanol (2 mL) at 140 °C in a 10 mL stainless vial.b Isolated yields based on 1a. c The numbers in parentheses are the stereoisomeric ratios.
Fail to react.
Murai,JACS,2001,123,10935
Proposed Mechanism
N
N Ru
N
NRu
N
N Ru HN
N RuRR
- RuN
N
N
N RuN
N Ru H
N
NRu
RR
N
NRuH
Murai,JACS,2001,123,10935
N
N Ru H
H
N
N Ru- H2
OHO
Murai,JACS,2001,123,10935
Cleavage of C-H is not that difficult.
Solvent Effect
Rh Catalyzed Carbonylation at sp3 C-H
Murai,JACS, 2000, 122, 12882
[RhCl(cod)2]2 is superior to [RhCl(CO)2]2 and Rh4(CO)12.
Nalkyl
N N
N
N
N
N
N
HN
N
Ph N
N N
All failed.
Substrate Scope
Murai,JACS, 2000, 122, 12882
Proposed Mechanism
Murai,JACS, 2000, 122, 12882
N
N Rh
N
NRh
N
N Rh HN
N Ru - Rh
N
N
N
N RhN
N Rh H
N
NRhH
CO
N
N RuO
O
Rh Catalyzed Carbonylation of Piperazines
N
MeN
N
N
MeN
N
N
MeN
NO
N
MeN
NO
N
MeN
NO
Path a
Path b
?Murai,Organometallics,1997, 16, 3615
Possible Intermediate
2-Pyridyl is essential for carbonylation, but not for dehydrogenation.
N
MeN
N
Hexene does not effect dehydrogenation.
Murai,Organometallics,1997, 16, 3615
Substituent Effects
NPy
N
O
PyNPy
O
No reaction.
Murai,Organometallics,1997, 16, 3615
Site Selectivity
Murai,Organometallics,1997, 16, 3615
Proposed Mechanism
N
MeN
N
RhN
MeN
NRh H
H2C CH2
N
MeN
NRh Et
- C2H6
- RhN
MeN
N
Rh N
MeN
NRh H
H2C CH2
N
MeN
NRh Et
N
MeN
NRh
COON
MeN
N
- Rh
O
N
MeN
NRh
Not detected by GC.
- C2H6 1,3 H-shift
Murai,Organometallics,1997, 16, 3615
C-H Activation Directed by N-Acyl Group
Murai, TL, 1997, 38, 7565
C-H Activation Directed by N-Acyl Group
Possible mechanism for the formation of 11?
Murai, TL, 1997, 38, 7565
C-H Activation Directed by N-Acyl Group
Possible mechanism for the formation of 11?
Murai, TL, 1997, 38, 7565
C-H Activation Adjacent to Amides
N
O
1. Oxidative addition into C-H2. Intramolecular olefin insertion into Rh-H
1.β-hydride elimination2. Reductive eliminationRh
Sames, JACS, 2004, 126, 6556
Brookhart ,JACS. 1999, 121, 4385
Sames, JACS, 2004, 126, 6556
Ir Catalyzed Cyclization of Alkene-Amides
Known for catalytic transerdehydrogenation of alkanes.
Active Intermediate
Isolated as solid.
[Ir(COE)2Cl]2 +
O
Ntoluene
50 oC
20 equiv.
IPr (2 equiv.)
Possible Mechanism
IrOCl
IPrN
N
O
IrH IPr
ClC-H activation
C-C formation
N
O
Ir (Cl)IPrHN
O
Ir (Cl)IPrH2
β-hydride elimination
R
R
N
O
N
O
Sames, JACS, 2004, 126, 6556
Sames, JACS, 2004, 126, 6556, SI
Alternative Mechanism: Dehydrogenation Followed by sp2 C-H Activation?
FG Compatibility and Regioselectivity
Sames, JACS, 2004, 126, 6556, SI
Funtionalyzation of C-H through Metal-oxo Species
Murahashi, ACIE, 1995,34,2443
Ru Catalyzed Oxidative Cyanation of 3o AminesWith H2O2
Muraihashi,ACIE, 2005,44,6931
Proposed Mechanism
Muraihashi,ACIE, 2005,44,6931
ρ value = -3.61
Cationic intermediate
KIE for N,N-dimethylaniline: intra 4.1 inter 3.7
Areobic Oxidative Cyanation of 3o Amines
Muraihashi,JACS, 2003,125,15312
Mechanistic Studies
NMeOMe
CD3
NMeMe
CD3
NMe
CD3
NBrMe
CD3
4.2
3.1
2.4
1.1
ρ value = -3.35
kH/kD
Muraihashi,JACS, 2003,125,15312
1 mol of O2 consumed 2 mol aniline.
Cu Catalyzed Oxidative Alkynylation of C-H
Li, JACS, 2004,126,11810
Li, JACS, 2004,126,11810
Substrate Scope
Cu Catalyzed Asymmetric Alkynylation of C-H
Li, OL, 2004,6,4997
Li, JACS, 2005,127,3672
Cu Catalyzed Nitro-Mannich Type Reaction
Cu Catalyzed Coupling of Malonate and Tetrahydroquinoline
Li, PNAS, 2006,103, 8928
Cu Catalyzed Aza–Baylis–Hillman type Reaction
Li, PNAS, 2006,103, 8928
Cu Catalyzed Indolation
Li, JACS, 2005,127, 6968
1.3
Proposed General Mechanism for Cu Catalyzed Cross-dehydrogenative Coupling Reactions
Li, PNAS, 2006,103, 8928
Potential problem: β hydride elinination
Can 1,5-hydride shift take place?
BF3 Et2O (2.0 equiv.)
DCM, reflux, 24h
76%
instead of
1,5 Hydride Shift in Pyrimidinone
Noguchi, JCS, Perkin Trans.1, 1998, 3327
Sames, JACS, 2005, 127, 12180
Lewis Acid Catalyzed 1,5 Hydride Shift/Cyclizaiton
Substrate Scope
Sames, JACS, 2005, 127, 12180
Sames, OL, 2005, 7, 5429
Lewis Acid CatalyzedLewis Acid Catalyzed Cyclizaiton of Aldehydes
Isotop Labeling and Cross-over Experiment
Sames, OL, 2005, 7, 5429
Evidence for 1,5-Hydride Shift
Sames, OL, 2005, 7, 5429