C H Oxidation

8/10/2019 C H Oxidation

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Recent Advances in Directed and Intramolecular TransitionMetal Catalyzed Oxidative Functionalizations of Carbon-

Hydrogen Bonds

John Heemstra Jr.April 18, 2006

HC

HH

R

XC

HH

R

cat [M]

oxidant

1 step

X= NR2, OR,halogen


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H

CH

HH

(g) + 1/2 O2 (g)

OH

CH

HH

(l)Ho= -30.7 kcal/mol

catalyst?

However, two major problems:

H

C HH

H

OH

C HH

H

Chemoselectivity: product more reactive toward

oxidant than starting alkene

93 kcal/mol104 kcal/mol

if oxidation involves abstractionof H atom, overoxidation to CO2will be observed

Regioselectivity: radical and electrophilic reagents

oxidize 3o>2o>1o

However, the selectivity is often

not high

R

Me

Et

i-Pr

t-Bu

R-H -> R + H

104.9

101.1

98.6

96.5

Stahl, S.S.; Labinger, J.A.; Bercaw, J.E.Angew. Chem. Int. Ed. 1998, 37, 2180

Oxidative Functionalization of Alkanes


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Selectivity: kinetic and thermodynamic preference to form the less

sterically hindered C-M intermediate (1o sp3 > 2o sp3 >>> 3o sp3)

H

CH

HR

MLn

CH

HR

H

MLn

CH

HR

+ H+

or

X

CH

HR

C-H activationfunctionalization

MLn

90-105 kcal/mol

50-80 kcal/mol

X= anything otherthan H

X

oxidative addition

heterolytic cleavage

C-H Functionalization via the Inner-Sphere Mechanism

(alternatively termed organometallic)


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C-H Activation Via Late, Nucleophilic Complexes

*

Typically involves coordinatively and electronically unsaturated Rh(I) and Ir(I)intermediate complexes

Prone to non-productive reductive elimination in the presence of oxidants and

non-productive protonolysis in the presence of protic reagents.

-bonding: C-H -> Md-backbonding: Md -> C-H


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Heterolytic cleavage results in no oxidation state change in metal.

Electrophilic complexes in their highest stable oxidation state are typically

used (eg. PtII and PdII)

Compatible with oxidants (including O2) and provide a route to oxidativefunctionalization.

C-H Activation Via Late, Electrophilic Complexes

-bonding: C-H -> Md-backbonding: Md -> C-H


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The Shilov System


RCH3 + H2O

PtIICl Cl

Cl Cl2-(K+)2

K2Pt(IV)Cl4 (ox.)

120 oC

RCH2OH + RCH2Cl

(cat.)

First reported by Shilov and coworkers In 1972.a paradigm shift

Even though these results were mostly ignored or met with disbelief at first, they are now

seen as the origin of the organometallic class of alkene oxidations.

Robert Crabtree

1o > 2o > 3o

H3C CH3 H3C

CH3HO OHHO

OHH2O+H3C CH3+

OH

3 1

H2O+"Pt"

"Pt"

Although excellent chemioselectivity is observed, only modest regioselectivitieshave been obtained for unfunctionalized alkanes.


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The Shilov System

CH4

PtII

Cl OH2

Cl OH2

PtIICl

Cl OH2

CH3

H

Cl-

PtIICl CH3

Cl OH2

PtIVCl CH3

Cl OH2

Cl

Cl

PtIVCl CH

3

Cl OH2

H

PtIVCl Cl

Cl ClCH3

PtIICl Cl

Cl Cl

OH2

HCl

-K+

-K+

K2195Pt(IV)Cl6

K2195Pt(II)Cl4

or

Cl-

H2O

-K+H2O

2 H2O

2 Cl-

2-(K+)2

CH3OH

PtII

Cl Cl

Cl Cl2-(K+)2

H2O

Pt is late soft metal, allowing

C-H to compete with water

for binding to Pt

No oxidation statechange to metal

Inversion of stereochem

of deuterium labled

substrates



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Chelate-Directed C-H Bond Functionalizations

Basickes, N.; Sen, A. Polyhedron 1995, 14, 202

Substrate Product Yield

Conditions:17 mol% K2Pt(II)Cl4, 50 mol% K2Pt(IV)Cl6,

D2O, 110-120oC, 3 days

For alcohols:

-CH


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O

OH

NH2

O O

NH2dr 2:1

NH

CO2H+ 214 : 1

O

OH

NH2

O O

NH2dr 2:1

NH

CO2H+ 154.5 : 1

NH2

O O + nd2 : 3O O

NH

CO2H no reaction

O

OH

241:3

NH2

OH

NH2

HO+

substrate products /

products

isolated

yield,%

conditions: 0.05 equiv K2PtCl4, 7 equiv CuCl2, H2O, 160oC, 10h

Dangel, B.D.; Johnson, J.A.; Sames, D.S. J. Am. Chem. Soc. 2001, 123, 8149

Chelate-Directed C-H Bond Functionalizations

The chelation effect in amino acids can override the inherent selectivityof the C-H activation step.


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Proposed Catalytic Cycle

Dangel, B.D.; Johnson, J.A.; Sames, D.S. J. Am. Chem. Soc. 2001, 123, 8149

PtIICl O

H

ClH2N

O

CH3

PtII

Cl

ClH2N

H3C

OOH

PtIICl

ClH2N

OOH

+

C-H activation

PtIVCl

ClH2N

CH3

OOHCl

Cl

CuCl2

PtIICl Cl

Cl Cl

O

OHH3C

OH NH2

O O

NH2

H3C

or

O

OHH3C

NH2

HN

K+ -

K+ -

(K

+

)2

2

-

HO2C

reductiveelimination

Alternatively.

O

OHNH2

Cl

HN

HO2C

alkylation

+

-selective pathway = oxygenation

-selective pathway = chlorination


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Has been instrumental in the understanding of mechanistic and selectivityissues related to alkane oxidation by homogeneous transition metal complexes

Moderate to excellent regioselectivity can be achieved in the oxidation of

functionalized alkanes (eg. alcohols and acids) via the chelate effect

However, the platinum mediated chemistry is plagued by low catatyst

turnover numbers.

Pt(IV) is not a practical stoichiometric oxidant (cost) and attempts at replacing

it with other oxidants have afforded decreased chemoselectivity.

Deposition of platinum metal erodes selectivities and the oxidation of Pt(0)

tends to be difficult. Palladium on the other hand..

RCH3 + H2O

PtII

Cl Cl

Cl Cl2-(K+)2

K2Pt(IV)Cl4 (ox.)

120 oC

RCH2OH + RCH2Cl

(cat.)

Summary of Platinum Mediated Alkane Oxidations



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The chelating group believed to both direct and accelerate unactivated sp3 C-H activation

High reactivity for 1o

C-H likely reflects preference for forming 5-memberedpalladacycles and strong steric preference for formation less hindered 1o Pd-alkyls.

N

R1R4

R2 R3

MeO5 mol% Pd(OAc)2

1/1 AcOH/ Ac2O100 oC,

N

R1

MeO

R2R3

Pd

AcO

2PhI(OAc)2 N

R1

R2 R3

MeO

OAc

1.1 equiv

Palladium-Catalyzed Oxygenation of Unactivated sp3 C-H

Bonds

Unlike Pt(II), only 10

-C-H bondsundergo functionalization!

Desai, L.D.; Hull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 9542


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Bonds

1.5 h

5 min

Desai, L.D.; Hull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 9542

These Pd-catalyzed reactions typically proceed under significantly milder conditions, withhigher TON (often 50) and with broader substrate scope than those with Pt catalysts

Single

diastereomer

P ll di C t l d O ti f U ti t d 2 C H


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N

H 1-5 mol% Pd(OAc)2

75-100 oC N

PdAcO

2N

X1-2 equiv oxidant

12 h

Dick, A.R.; Hull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 2300

Yoneyama, T.; Crabtree, R.S. J. Mol. Catal. A 1996, 108, 35


Bonds

X

+ PhI(OAc)2AcOH

100 oC, 21h

+

1 equiv

Pd(OAc)2

1 equivlarge

excess

X

OAc

Substrate yield o:m:p

Benzene 39

Anisole 40 44:5:51

Toluene 39 43:26:31

Low levels of regioselectivity observed


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Dioxidation of substrates: Conditions: 2.3 equiv of PhI(OAc)2, 6-8 mol% Pd(OAc)2,100 oC, 12h, CH3CN

Chelate-Directed Oxidation of sp2 and sp3 C-H Bonds

Monooxidation of substrates: Conditions: 1.1-1.6 equiv of PhI(OAc)2, 1-6 mol% Pd(OAc)2,100 oC, 12-20 h, CH3CN

in MeOH


P ll di C t l d A t l ti f M t S b tit t d


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Conditions:

5 mol% Pd(OAc)2, 1.1-3.0 equiv PhI(OAc)2,

AcOH, C6H6 or C6H6/Ac2O, 100oC, 0.5-4 h

Unlike directed ortho-lithiation and Ru-catalyzed

C-H activation reactions, OMe, OMOM, and F

Did not exhibit secondary directing effects

Kalyani, D.; Sanford, M.S. Org Lett. 2005, 19, 4149

Palladium-Catalyzed Acetoxylation of Meta-Substituted

Aryl pyridines


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Conditions:

5 mol% Pd(OAc)2, 1.1-2.2 equiv PhI(OAc)2,

AcOH, AcOH/Ac2O, 100oC, 3-12 h

Palladium-Catalyzed Acetoxylation of Aryl Pyrrolidinones

Selectivity forA may be general over many

classes of directing groups in PdII-catalzed

C-H activation/oxidative functionalizations.

Kalyani, D.; Sanford, M.S. Org Lett. 2005, 19, 4149


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Proposed Catalytic Cycle for Palladium Catalyzed


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?

75-100 oC

N

PdII

AcO

2N

OAcequiv PhI(OAc)2

12 h comparibleyield

N

PdII

AcO

2

CH3CN

75-100 oC

12 h

CH3CN

no reaction

N75-100 oC

12 h

CH3CNno reaction+ Pd(OAc)2

benzoquinone

orCu(OAc)2


Proposed Catalytic Cycle for Palladium-Catalyzed

Acetoxylation of Benzo[h]quinone

Mechanistic Investigations of C O Bond Forming Reductive


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Mechanistic Investigations of C-O Bond-Forming Reductive

Elimination of Pd(IV) Complexes

Dick, A.R.; Kampf, J.W.; Sanford, M.S. J. Am. Chem. Soc. 2005, 127, 12790

Expected mechanism A most likely by analogy to C-O bond-forming reactions with PtIV

However.

no observed rate acceleration in more polar solvents and no correlation with solventdielectric constant

S = +4.2 1.4 and -1.4 1.9 eu in d6 DMSO and CDCl3 respectively (ionic reductiveeliminations typically show highly negative values of S).

= -1.36 0.04 (PtVI C-O bond forming reductive elimination = +1.44) Thermolysis in the presence of 5 equiv NBu4OAc resulted less than 5% incorporation

of the acetate in CHCl3 or DMSO

Stable at rt

What experiments would you perform to distinguish between Mech. B and C?



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Elimination of Pd(IV) Complexes

Sanford and co-worker currently favor mechanism C

Selective C H Activation/Halogenation catalyzed by Pd(OAc)


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Selective C-H Activation/Halogenation catalyzed by Pd(OAc)2

Conditions:

1 mol% Pd(OAc)2, 1.1 equiv of N-

Halosuccinamide, MeCN, 100 oC,

24-72 h

Giri, R.; Chen, X.; Yu, J.-Q.Angew. Chem. Int. Ed. 2005, 44, 2112


O

N

Me

Me

Me t-Bu

O

N

Me

Me t-Bu

I

O

N

Et

Me

Me t-Bu

O

N

EtMe t-Bu

I

O

NEt

Me

Et t-Bu

O

NEt

Et t-Bu

I

Substrate Product Yield (%)

92

91 (63:37 dr)

88

Conditions:

10 mol% Pd(OAc)2, I2 (1 equiv)

PhI(OAc)2 (1 equiv), CH2Cl2,24 oC, 48-72 h

Ethanolamine, 2-methyl-2-amino-

propanol, or valinol derived oxazolinesproceed at much slower rate

S l ti C H A ti ti /H l ti t l d b Pd(OA )


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Giri, R.; Chen, X.; Yu, J.-Q.Angew. Chem. Int. Ed. 2005, 44, 2112

O

N

Me

Me

Me t-BuPd(OAc)2

CH2Cl224 oC, 24h

60% yield

C-Hactivation

Oxidative addition/

reductive elimination

PhI(OAc)2(1 equiv)

Pd(OAc)2PdI2

I2(1 equiv)

CH2Cl2, 24 h

Selective C-H Activation/Halogenation catalyzed by Pd(OAc)2

Summary of the Palladium Catalyzed sp3 and sp2 C H bond


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Summary of the Palladium Catalyzed sp3 and sp2 C-H bond

Oxidative Functionalization

Unactivated sp3 and sp2 C-H bonds of oximes, pyridine, pyrazole, imine, and azo-

benzene substrates undergo highly regio- and chemoselective Pd(II) catalyzed

oxygenations with PhI(OAc)2

as a stoichiometric oxidant.

C-H bonds can also be replaced with ether functionality or halides when reaction

are performed in alcohol solvants or in the presence of N-halosuccinamides, or I2.

Pd-catalyzed chelate-directed acetoxylation of meta-substituted arene substratesexhibit high regioselectivity for functionalization at the less substituted ortho-position

These Pd-catalyzed reactions typically proceed under significantly milder conditions,

With higher TON (often50) and with broader substrate scope than those with Pt

catalysts.

The almost exclusive selectivity for 1o C-H bonds is a could be a limitation if one

wanted to develop a stereospecific or enantioselective process.

C-H Functionalization via the Outer-Sphere Mechanism


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Selectivity: involves buildup of radical and/or cationic character at carbonand shows selectivity for weaker C-H bonds:

benzylic, allylic, 3o, or to heteroatoms.

C H Functionalization via the Outer Sphere Mechanism

(alternatively termed coordination)

H

CH

HR

XC

HH

RMLn

LG=X

X MLn

CH

HR

X MLnH

X

CR2: carbene

NR: nitrene

O: oxo

LG

LG

N2

IPh

IPh, ROH

direct insertion

H atom abstraction/rebound

H

H

CH

HR

X MLn

C H Bond Amination via the Outer Sphere Mechanism


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First example of an intermolecular C-H amination

First example of an intramolecular C-H amination

89%

Breslow. R; Gellman, S.H. J. Chem. Soc., Chem. Commun. 1982, 1400

Breslow. R; Gellman, S.H. J. Am. Chem. Soc. 1983, 105, 6728

aryliodinane

Cat.

Rh2(OAc)4

93% yieldAryliodinane intermediateshave poor shelf life

C-H Bond Amination via the Outer-Sphere Mechanism

Tosylamine

First demonstration of the use of the oxidant PhI(OAc)2 and Rh catalyst system

Rhodium-Catalyzed Oxidative C-H Insertion Reaction for


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OHR

O

OHN

R

O

NCOCl3

O

O NH2R

CCl3

O

K2CO3,

MeOH

5 mol%Rh2(OR)4

PhI(OAc)2(1.4 equiv )MgO (2.3 equiv )

CH2Cl2, 40oC

OHN

R

O

A = Rh2(OAc)4B = Rh2(tpa)4

One-pot procedure for formation of aryliodinaneand insertion of metallonitrenoids in C-H bond

Espino, C.G.; Du Bois, J.Angew. Chem. Int. Ed. 2001, 40, 598

Rhodium Catalyzed Oxidative C H Insertion Reaction for

Oxazolidinone Synthesis

Mechanism of Oxazolidinone Formation


28/44

O

OH2N

H

MeMe

O

ON

H

MeMe

PhIPhI(OAc)2

O

ON

H

MeMe

(AcO)4Rh2

Rh2(OAc)2

OHN

MeMe

O

Mechanism of Oxazolidinone Formation

Data suggests a concerted, metal-directed

N-atom insertion process

Espino, C.G.; Du Bois, J.Angew. Chem. Int. Ed. 2001, 40, 598



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OH

R2R1

ClSO2NH2

pyridine,CH2Cl2

O

R2R1

SH2N

OO 2 mol%Rh2(OR)4

PhI(OAc)2(1.1 equiv )MgO (2.3 equiv )

O

R2R1

SHN

OO

90% (A) 75% (B)

single isomer

80% (A)

single isomer

91% (B)

13/1 syn/anti

78% (A) 85% (A)

8/1 cis/trans78% (B)

4/1 cis/anti 60% (A)

Rhodium Catalyzed Oxidative C H Insertion Reaction for

Oxathiazinane Synthesis

A = Rh2(OAc)4B = Rh2(oct)4

sulfamate

Espino, C.G.; Wehn P.M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935



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O

CO2EtPh

SHN

OO S-O and S-N bondlengths of 1.59 A

N-S-O angle of 105o

O

CO2EtPh

SH2N

OOS-O and S-N bond

lengths of 1.58 AN-S-O angle of 103o

sulfamate OS

HN

CO2EtPh

OO

sulfamidate

oxathiazinane

N-S-O angle of 95o

favored

disfavored

Torsional strain induced

in developing product

Wehn P.M.; Lee, J.; Du Bois, J. Org. Lett. 2003, 5, 4823

od u Ca a y ed O da e C se o eac o o

Oxathiazinane Synthesis

Rhodium Catalyzed Amidation of Ethereal C H Bonds


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Fleming, J.J.; Fiori, K.W.. Du Bois, J. J. Am. Chem. Soc. 2003, 125, 2028

Rhodium-Catalyzed Amidation of Ethereal C-H Bonds


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Tandem Rhodium C H Amination Iminium Ion Coupling


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One-pot procedure: rxn mixture filtered to remove MgO and then treated with either

1.5 equiv BF3 OEt2 and 4 equiv allyltrimethyl silane or 0.1 equiv Sc(OTf)3 and 4 equivof silyl enol ether

Fiori, K.W.; Fleming, J.J. Du Bois, J.Angew. Chem. Int. Ed. 2004, 43, 4349

Tandem Rhodium C-H Amination, Iminium Ion Coupling

Reactions

a

a

b

a R = Me b R = CPh3

R = Me

Ketene acetals can also be employed


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A Silver-Catalyzed Oxidative C-H Insertion Reaction for

O lidi d O thi i S th i


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Carbamate C-H insertions sulfamate C-H insertions

Similar yields; however, Rh-catalyzed process proceeds at 40 oC

stereospecific

Both ligand and Ag

Salt commercially

available

Cui, Y.; He, C.Angew. Chem. Int. Ed. 2004, 5, 4210

Oxazolidinone and Oxathiazinane Synthesis

Intramolecular C-N Bond Formations Reactions Catalyzed

B R th i P h i


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*Dirhodium complex afforded 8:1 cis:trans

Highly robust catalyst featuring

up to 59 catalytic turnovers at 1.5 mol%,

and up to 300 at 0.1 mol% catalyst loadings

Single isomer*

1.5 mol% 1

2 equiv PhI(OAc)2

2.5 equiv Al2O3CH

2

Cl2

, 40 oC

Fe and Mn metalloporphyrins afforded

lower yields

By a Ruthenium Porphyrin

Liang, J.-L.; Yuan, S.-X.; Huang, J.S.; Yu, W.Y.; Che, C.-M. J. Org. Chem. 2004, 69, 3610


By Ruthenium Porphyrins


38/44


However, intramolecular C-H amination

is stereospecific!

Data for intermolecular reaction supportsH-atom abstraction mechanism

a) Carboradical is too shortlived to undergo

configuration inversion

b) Nonsynchronous concerted mechanismbearing significant hydrogen abstraction

character

By Ruthenium Porphyrins

Expanding the Scope of C-H Amination Through

Catalyst Design


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Espino, C.G.; Fiori,K.W.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378

Catalyst Design

Chelate effect should disfavor complete

ligand dissociation from metal center and

confer added stability to complex


By a Chiral Ruthenium


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1.5 mol% 2

1.4 equiv PhI(OAc)2

2.5 equiv Al2O3

Liang, J.-L.; Yuan, S.-X.; Huang, J.S.; Yu, W.Y.; Che, C.-M.Angew. Chem. Int. Ed. 2002, 41, 3465

*

[d] in CH2Cl2 at 40oC

[e] in CH2Cl2 at 5oC

[f] in toluene at 0 oC

Chiral porphyrin ligand is both

expensive and difficult to synthesize

By a Chiral Ruthenium


By a Chiral Ruthenium Porphyrin


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Imido phenyl group points toward the smaller methano-bridge

X-ray structure of the major

enantiomer

By a Chiral Ruthenium Porphyrin


By Rhodium and Manganese complexes


42/44

More readily accessible and cheaper

However low selectivity obtained

By Rhodium and Manganese complexes

Fruit, C.; Muller, P. Helv. Chim. Acta 2004, 87, 1607

Zhang, J.; Chan, P.W.H.; Che, C.-M. Tetrahedron Lett. 2005, 46, 5403

Catalyst yield er

A 55% 65:35

B 48% 76:24

A B

L = Cl

JRH1


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Summary of Intramolecular C-H Aminations via the


44/44

Outer-Sphere Mechanism

The intramolecular C-H amination reaction is now a highly dependable and

predictable transformation and has found application in the preparation of a

variety of natural products.

The intramolecular insertion of metallonitrenoids (M = Ag, Rh, Ru) into C-H bond

is a stereospecific process.

The new Rh2(esp)2 catalysts now allows very low catalyst loadings and extremelyhigh catalyst TON (>600)

Enantioselective methods are still in their infancy and a method that provides high

selectivity is still lacking

Documents

C H Oxidation