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