Recent Progress in sp3 C-H Activation Catalyzed by

Palladium

Bo Yao

Concepts related with C-H activationC-H activation

In general definition, C-H activation should refer to any chemical process that increases the reactivity of C-H bond.In organometallic definition, C-H activation refers to the formation of a complex wherein the C-H bond interacts directly with the metal catalyst or reagent. The complexes often afford a C-M intermediate in the absence of free radical or ionic intermediates.

“C–H bond activation” is frequently used as an organometallic term to describe certain metal-mediated processes.

C-H transformation: C-H bonds are transformed into C-C, C-X bondC-H oxidation: The oxidation valence of carbon is increased.C-H functionalization: New functional groups are connected to the carbon.Oxidative functionalization: Oxidant is needed for the functionalization.C-H arylation/halogenation/oxygenation/metallation

H FGM

H

M

A few decades later in 1968, Halpern formulated the need for new approaches to the activation of C–H bonds with a particular focus on saturated hydrocarbons. C–H bond activation, equated with “dissociation of carbon–hydrogen bonds by metal complexes”, was identified as one of the most important challenges in catalysis

Clearly, a new reactivity mode, other than radical or ionic substitution, had been discovered and the term “activation of saturated hydrocarbons” was used.

Challenge in sp3 C-H activation

H

R direct C-C, C-O, C-N and C-X formation

Fujiwara, Sanford, Yu, Shi, Fagnou, Daugulis, Gaunt, etc....

Pd Friedel-Crafts routeElectrophilic attackConcert deprotonation

with Pd(II), Pd(III), or Pd(IV)as reactive intermediate

R3H

direct C-C, C-O, C-N and C-X formation

R2R1

Pd

1. High bond dissociation energy2. Lack of -group to interact with transition metals3. Difficulty in controlling selectivity

Strategies for sp3 C-H activation

1. Oxidation of sp3 C-H bond ajacent nitrogen and oxygen

NPh

HN

+

NPh

NH

5 mol% CuBrTBHP, 50 °C

79%

Cross-Dehydrogenative-Coupling(CDC) catalyzed by Cu and Fe

Chao-Jun Li , J. Am. Chem. Soc. 2005, 127, 6968-6969

NCH3

CH3

NCH2CN

CH35 mol% RuCl3nH2O

NaCN, O2 (1 atm)MeOH/AcOH(3:1)

60 °C

Shun-Ichi Murahuashi, J. Am. Chem. Soc. 2003, 125, 15312-15313

Strategies for sp3 C-H activation

2. sp3 C-H activation triggered by oxidative addition intramolecularly

R3H

R2

X

R3

H

R2

Pd LX

R3

R2

Pd LY

-HXR3

Y

R2

H

R3

R2

I

OCH3

H3CO

H3CO

O

4 mol% Pd(OAc)2K2CO3, nBu4NBr

DMF, N23d, 100 °C

90%

PdI

OCH3

Pd

OH3CO

OH3CO

O

Pd

PdI

H3CO

O

H3CO

PdI

H3CO

O

H3CO Pd

-HI

-+HI

-HI

Pd(0)

Gerald Dyker, Angew. Chem. Int. Ed. Engl. 1992, 31, 1023-1025

Strategies for sp3 C-H activation

3. sp3 C-H activation by directing groups promoted C-H cleavage

R3H

R2

DGR3

Pd

R2

DGR3

Y

R2

DGY

OMe

N

O

OMe

Me

OMe

N

O

OMe

Me

Pd

Cl

PdCl2,NaOAcAcOH75%

B(OH)2

a) Ag2O, DMF 86%

OMe

N

O

OMe

Me

b) MeSO3H, CH2Cl2 83%

a) PdCl2,NaOAcAcOH

b) Then CO (40 atm), MeOHc) SiO2, CHCl3

NH

O

OMe

N

O

OH

Teleocidin B-4 Core

OMe

N

O

OMe

Me

Pd

Cl

65% (6:1)

Dalibor Sames, J. Am. Chem. Soc. 2002, 124, 11856-11857

Recent progress for sp3 C-H activation catalyzed by palladium

Triggered by oxidative addition

I 2.5 mol% Pd(OAc)2K2CO3, nBu4NBr

DMF, N24d, 105-110 °C

75%

Pd(II)-Pd(IV)

Gerald Dyker, J. Org. Chem. 1993, 58, 6426-6428Angew. Chem. Int. Ed. Engl. 1994, 33, 103-105

Cascade reaction

Br R1 R2

R2R1

R1

R2 = H

R2 = Me

Pd(OAc)2P(o-tol)3 or F-TOTPK2CO3

DMF100-150 °C

R1 = CN, COOR, CH2OTIPS

Pd(OAc)2(tBu3PH)BF4K2CO3

DMF140 °C

Olivier Baudoin, J. Am. Chem. Soc. 2008, 130, 15157-15166; Angew. Chem. Int. Ed. 2009, 48, 179-182Angew. Chem. Int. Ed. 2003, 42, 5736-5740; Chem. Eur. J. 2007, 13, 792-799Adv. Synth. Catal. 2007, 349, 2054-2060

Keith Fagnou, J. Am. Chem. Soc. 2007, 129, 14570-14571Nobutaka Fujii and Hiroaki Ohno, Org. Lett. 2008, 10, 1759-1762

Br

X

Pd(OAc)2 (2.5 mol%)PCy3-HBF4 (6 mol%)

Cs2CO3, tBuCOOHsolvent, heat

R2

CH3

R1X

R2R1

X= O, N-PG

Recent progress for sp3 C-H activation catalyzed by palladium

Triggered by oxidative addition

(HO)2B

+

Br

tBu

tBuPd2(dba)3 (1 mol%)Ligand (4 mol%)K3PO4, toluene

tBu

99% tBu

tBu100 °C, 18h

I

O EWG Pd

O

LL

EWGH

R1

R2

O EWG

H

R1

R2 Helena C. Malinakova,Org. Lett. 2002, 4, 3679-3681Organometallics 2003, 22, 2961-2971

Stephen L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685-4696

More work in this field

I

CH3

CH3

Pd(OAc)2, KOAcDMF, N2, 105°C, 18h

norbornene

H3C

CH2

H3C

H2C

+

Marta Catellani,Chem. Commun. 2000, 2003-2004

X

X'+

BrMg

Pd2(dba)3 (1.5 mol%)tBu3P (6 mol%)THF, rt, 20h

99%

Qiao-Sheng Hu,Angew. Chem. Int. Ed. 2006, 45, 2289-2292Tetrahedron 2008, 64, 2537-2552

N

X N

Pd(OAc)2, P(p-tol)3

Cs2CO3, 110 °C20hEWG

EWG

X = Br, I

Paul Knochel,Angew. Chem. Int. Ed. 2006, 45, 3462-3465Chem. Asian J. 2007, 2, 416-433

Recent progress for sp3 C-H activation catalyzed by palladium

Directing group promoted C-H cleavage

O-methyl oxime

R

NMe

R2 R1

MeO

Me

N

MeMe

MeOPd

AcO

2R

N

R2 R1

MeO

OAc

Pd(OAc)2, PhI(OAc)2AcOH, Ac2O or CH2Cl280-100 °C

tBu

NMeO

OAc

5 min, 86%

N OAcH

H

MeO

81%

N O

OAc

44%

Walter S. McDonald and Bernard L. Shaw, J. Chem. Soc., Dalton Trans. 1980, 1992Melanie S. Sanford, J. Am. Chem. Soc. 2004, 126, 14570-14571

β-C-H activation

Recent progress for sp3 C-H activation catalyzed by palladium

Directing group promoted C-H cleavage

8-aminoquinoline amide

Olafs Daugulis, J. Am. Chem. Soc. 2005, 127, 13154-13155J. Am. Chem. Soc. 2010, 132, 3965-3972Org. Lett. 2005, 7, 3657-3659E. J. Corey, Org. Lett. 2006,8, 3391-3394

β-C-H activation

AuxiliaryNH

O

5 mol% Pd(OAc)2ArI, base, solvent Auxiliary

NH

OAr

SMe

NH

O

N

Me

MeO

O

toluene, CsOAc110 °C 79%

SMe

NH

O

OBn tBu

t-Amyl-OH, K2CO390 °C 65%

SMe

NH

O

Br

t-Amyl-OH/H2O, K2CO390 °C 60%

N

NH

O Me

Me

t-Amyl-OH,Cs3PO490 °C 79%

N

NH

ON

O

O

Me

t-Amyl-OH,Cs3PO490 °C 76%

N

NH

O Me

MeO

neat, AgOAc110 °C 92%

N

Me

AcOH, AgOAc110 °C 51%

10 mol% Pd(OAc)2For R-B(OH)2:Ag2O, BQ, 100 °Ctert-amyl alcohol

N

R2

R1

R

For Methylboroxine:Cu(OAc)2, HOAc, O2100 °C

Jin-Quan Yu, J. Am. Chem. Soc. 2006, 128, 12634-12635

Recent progress for sp3 C-H activation catalyzed by palladium

Directing group promoted C-H cleavageCarboxylate amide and acid

β-C-H activation

Jin-Quan Yu, J. Am. Chem. Soc. 2007, 129, 3510-3511J. Am. Chem. Soc. 2008, 130, 7190-7191J. Am. Chem. Soc. 2009, 131, 9886-9887J. Am. Chem. Soc. 2010, 132, 3680-3681J. Am. Chem. Soc. 2010, 132, 17378-17381

10 mol% Pd(OAc)2BQ, Ag2O, K2CO3tBuOH/DMF, 70 °C, 18h

NNH-OMe

O

PhB(OH)2

10 mol% Pd(OAc)2BQ, Ag2O, K2CO3

2,2,5,5-tetramethylTHF70 °C, 18hiBu-B(OH)2

10 mol% Pd(OAc)2BQ, K2CO3, air and N280 °C, 48 h

10 mol% Pd(OAc)2BQ, Ag2CO3, K2HPO4tBuOH, 100 °C, 3h

Me

Me

COOH

Ph

BO

OPh

10 mol% Pd(OAc)2 Ag2CO3, K2HPO4

tBuOH, NaOAc130 °C, 3h

PhI

COOH

Me

Ph

38%

20%

Me COOH

PhPh

70%, 5:2

Me

Me

COOH

Ph

O

O

Ph

NH-OMe

O

iBu

60%

iBu-B(OH)2

58%75%

10 mol% Pd(OAc)220 mol% Cy-JohnPhosCsF, ArI, 3A MS, toluene

R2

R1 Me

NHX

OX = C6F5

R2

R1

NHAr

O

Ar

N

OR1

R2 Ar

BnO2C CO2Bn

X = C6F5, p-CF3-C6H4

10 mol% Pd(OAc)2LiCl, Cu(OAc)2, AgOAcDMF, N2, 120 °C

X = p-CF3-C6H4

10 mol% Pd(OAc)2AgOAc, KH2PO4, TEMPOn-Hexane130 °C

N

OR1

R2 Ar

O

Recent progress for sp3 C-H activation catalyzed by palladium

Directing group promoted C-H cleavage

Jin-Quan Yu, Angew. Chem. Int. Ed. 2005, 44, 2112-2115Angew. Chem. Int. Ed. 2005, 44, 7420-7424Org. Lett. 2006, 8, 5685-5688

Diaselective oxidation trinuclear alkyl-Pd complex

OxaR1

R2

OAc10 mol%Pd(OAc)2Dodecanoyl peroxideAc2O, O2, 50 °C

Oxa =O

NtBu

OxaR1

R2

Me

OxaR1

R2

I

10 mol%Pd(OAc)2I2, PhI(OAc)2CH2Cl2, 24 °C

OxaR1

Me

OAc

OxaR1

Me

I

diaselectively

OxaR1I

I

R1

Oxa

10 mol%Pd(OAc)2IOAcEtOAc, 100 °C

(PhCOO)2

Benzene115 °C

β-C-H activation

N

ON

O

Ar

2.5 mol% Pd2(dba)35 mol% X-Phos1 eq. ArI3 eq. NaOt-Bu in toluene110 °C(mw), 45 min

(1.5 eq.)

N

NBz

5 mol% Pd(OAc)212 mol% Dave-Phos1 eq. ArI3 eq. Cs2CO3 in DMF70 °C, 16h

(1.1 eq.)

N

NBz

Ar

André B. Charrette,Org. Lett. 2008, 10, 1641-1643

Keith Fagnou, J. Am. Chem. Soc. 2008, 130, 3266-3267

RN

Boc

H

cat. Pd(OAc)2IOAc, DCE, 60 °C

RN

Boc

OAc

Melanie S. Sanford, J. Am. Chem. Soc. 2005, 127, 7330-7331

N

R

5 mol% Pd(OAc)2[Ph2I]BF4, 100 °C

N

RPh

R = H, 72%R = Ph, 60%

NO

NH

5 mol% Pd(OAc)2AgOAc, ArI, no solvent70 - 130 °C

R

NO

NH

RAr

α-C-H activation

Olafs Daugulis, J. Am. Chem. Soc. 2005, 127, 13154-13155

Jin-Quan Yu, Org. Lett. 2006, 8, 3387-3390

γ-C-H activation

Recent progress for sp3 C-H activation catalyzed by palladium

Other metalsFe, Ni, Cu, Ru, Rh, Pt,

Ir…

1. Find directing groups which are easy to attach to and deattach from substrates.

2. Develop the methods with milder condition and broader scope.

3. Site-selective C-H activation.

4. Mechanism is far from clear.

Challenges