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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

R H + [LnMX] R MX+2

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

- HClPtII

Cl OH2

H2O CH3

PtIVCl62-

CH3OH + HCl

Cl OHCH3

Stoichiometricloading of PtIV

PtIICl42-PtIVCl OH2

H2O ClCl

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.

Alkylation of α,β‐Unsaturated Imines

1. 2.5% [RhCl(coe)2]2N

[ ( )2]210% FcPCy2 2. Aluminum Chromatography

ColumnO

+50°CR H H

Entry Alkene Time(h)

ImineZ:E % Yield (Z:E)

1 12 >95:<5 91 (10:1)

2 Cl 8 >95:<5 80 (10:1)Cl 8 >95:<5

>95:<5

80 (10:1)

O4 78 (5:1)

4 24 10:1 74 (5:1)

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

MeCH2O2Et

Me+ TBSO

NaBH4, MeOH,rt then 60°C

49% overall yieldNe

Ne 49% overall yield

for two steps

TBSO N

OMeH H2 (1000psi)

Pd/C, MeOH, 60°CMe

TBSO N

99%TBSO N

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

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

Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35‐38.

Proposed Mechanism for Arylation Reaction

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

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

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

I 0.05 equiv [RhCl(coe)2]20 3 equiv PR H

+0.3 equiv PR3

3 equiv basesolvent, heat

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

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.

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

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.

Results for Screening Different R Groups

t‐Bu

yi‐Pr

Plot of conversion versus time for arylation using 5a‐e.

Me < i‐Pr < Cy < Ph < t‐Bu

Better Results from New Ligands

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

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

15:1 91%2CO2Et CO2Et15:1 91%

OH2N OHN

R=CF3OMe

20:120:1

70%85%

Me 87%20:112

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.

Four Different Situations

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.

Trans Selectivity

Top transition state does not have 1,3‐diaxial interactions, and also is preferred by the Felkin Anh model

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.

No Selectivity

HH SOO

SOR3 Nu R2

1,3- diaxiali t tiO

interaction

R3 R3 R3

Felkin-Ahndisfavored

Top TS is disfavored by the 1, 3‐diaxial interactionBottom TS is disfavored by the Felkin‐Ahn model

Model Fails with One Stereocenter at Position 2

In these cases, the trans product can be explained by the model.

Model Fails with One Stereocenter at Position 2

No preference in terms of iminium stability, Felkin-Ahn model predictsthat bottom TS should be favored.

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

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

CO2Me+ Cat. R1R2 CO2Me

R3 R R3 R

Main Product

CO2MeR1

R2CO2Me

R R3 R

Direct C-H activationproduct

cyclopropanationproduct

Side Products

productproduct

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

Enantio‐differentiation

S‐enantiomerR‐enantiomer

Catalyst Structure

Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545‐555.

Simplified Model of the Catalyst

Most Stable Conformation of the Catalyst

, , , , , ,

, , ,, , ,

Most Stable Conformation of the Catalyst

Catalyst Structure

SO2O2S

N HO2S

101010

Rh2(S-dosp)4

Further Simplification

OSO2Ar

When one rhodium atom di t t th b th

ONSO2Ar

H NH coordinates to the carbene, the other rhodium atom is deactivated,

NSO2Ar

H only one face of the catalyst is effective.

Only one face of the catalyst is effective

MeTBSOMeTBSO

MeMeO2C

MeHH (S)

TBSOMeO

MeHH (R)

TBSOMeO

CO2MeMe

(R-dosp)catalyst

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,

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