C H Activation

Pd Catalyzed

Functionalization of

Non-Acidic C(sp3)-H Bonds

Lindsey Cullen

Denmark Group Meeting

Oct. 26, 2010

C H

Pd cat.

C X

Carbon-Carbon Bond Formation in Organic

Molecules Traditional:

Functional Group Transformation

Alternative Approach:

C-H Functionalization

Why focus on C-H functionalization?

1. C-H bonds are common / could provide new disconnections

2. Atom economical

3. Cost effective

FG1 R

FG1 R

H R

H R

Challenges to C-H Functionalization

H FG

H FG

3. Regioselectivity

sp2 and sp3 C-H bonds are ubiquitous

1. Intrinsic low reactivity

Large kinetic barrier to cleave C-H bond (104 kcal/mol)

2. Chemoselectivity

Functionalized product may be more reactive

C-H Functionalization: A Definition

2. Inner-sphere mechanism:

Two general mechanisms:

1. Outer-sphere mechanism:

X

[M]

[M] X

[M] XH

C

[M] X CH

[M]

C X H

C H

[M]

C [M]

X

[M]

C X

C-H Functionalization - formation of a C-M bond by cleavage of

a C-H bond

Baudoin, O. et al. Chem. Eur. J. 2010, 16, 2654.

Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.

Reactivity of nonacidic sp3 C-H Bonds C-H functionalization of sp2 C-H bonds has been well studied:

H

R XMLn

R' FG

R X

MH

R'

R'

R X

C-H functionalization of non-acidic sp3 C-H bonds is less explored:

R1 R2

FG

1-2

H

MLn

-H+

R1 R2

FG

1-2

MLn

R' FG R1 R2

FG

1-2

R'

C(sp3)-H bonds lack orbitals to interact with metal center

Pd(II)/Pd(0) Systems for sp3 C-H Activation

PdII (OAc)2

Pd0

C-H

activation

R H

HOAc

PdIIR OAc

reoxidation

R' MR' R

transmetalation/reductive elimination

Pd(II)/Pd(0) Catalysis:

External oxidant is necessary to regenerate Pd(II) catalyst

Pd(II)/Pd(0) sp3 C-H Activation

Yu, J. -Q. et al. J. Am. Chem. Soc. 2008, 130, 7190.

Yu, J. -Q. et al. J. Am. Chem. Soc. 2006, 128, 12634.

NR

H

Pd(OAc)2 (10 mol%)

RB(OH)2

Ag2O, BQ, air

tAmOH, 100 C

R'N

R

R

R' 48-75%

H

NH

O

OMe

R1 R2

Pd(OAc)2 (10 mol%)

RB(OH)2

Ag2O, BQ, K2CO3tBuOH, 70 C

R

NH

O

OMe

R1 R2

41-85%

White, M. C. et al. J. Am. Chem. Soc. 2008, 130, 14090.

Pd(OAc)2 (10 mol%)

O2NCH2R

DMBQ, AcOH

dioxane/DMSO, 45 C

R

HSS PhPh

O O

R

R

NO2

50-70%

Pd(II)/Pd(IV) Systems for sp3 C-H Activation

Pd(IV)/Pd(II) Catalysis:

PdIILn C-H

activation

R H

PdIIR Ln

reductive

elimination

R' X

oxidative addition

PdIVR Ln

R'

X

R R'

Additional oxidative addition step leads to Pd(IV)

intermediates

Pd(II)/Pd(IV) sp3 C-H Activation

Sandford, M. S. et al. J. Am. Chem. Soc. 2005, 127, 7730.

NH

Pd(OAc)2 (5 mol%)

R-I

K2CO3, PivOH

tAmOH, 100-110 C

58-80%

NO H

NH

NO R

Daugulis, O. et al. J. Am. Chem. Soc. 2010, 132, 3965.

72%

N

H

Pd(OAc)2 (5 mol%)

[Ph2I]BF4

AcOH, 100 C N

Ph

Pd(0)/Pd(II) Systems for sp3 C-H Activation

LnPd0

oxidative

addition

R X

reductive

elimination

C-H Activation

R R'

LnPdII X

R

R' HX H

LnPdII R'

R

Pd(0)/Pd(II) Catalysis:

Oxidative addition to coupling partner gives Pd(II) intermediate

Most studied catalytic system for

non-acidic sp3 C-H functionalization

Many Possible Reaction Pathways

Dyker, G. Angew. Chem. Int. Ed. 1992, 31, 1023.

X

R

HPd(0), Base

HX

Pd

R

transmetalation

H

R

FG

Y-FG

Rreductive

elimination

-H

eliminationH

Two major challenges to sp3 C-H activation:

1. Selective sp3 C-H cleavage

2. Favoring one pathway over another

C-H Activation of a Methoxy Group


I

OCH3

Pd(OAc)2 (4 mol %)

K2CO3, nBu4NBr

DMF, 100 C, N23 d

O

H3CO

H3CO

90%

I

OCH3

Pd(OAc)2 (4 mol %)K2CO3, nBu4NBr

DMF, 100 C, N23 d

87%

OCH3

O

OCH3

H3CO

H3CO

Proposed Mechanism


LnPd0

-HII

OCH3

PdLn

OCH3

I

O

LnPd

I

OCH3

+

O

H3CO

PdLnI

-HI

O

H3CO

LnPd

+

I

OCH3

O

H3CO

H3CO

PdLnI

-HI

O

H3CO

H3CO

H3CO

H3CO PdLn

O-Pd0Ln

C-H Activation of a tert-Butyl Group


IPd(OAc)2 (2.5 mol %)

K2CO3

nBu4NBr, DMF, 110 C

N2, 4 d

75%

I Pd(OAc)2 (2.5 mol %)

K2CO3

nBu4NBr, DMF, 110 C

N2, 4 d

59%

+

OMe

Br

OMe

(5 equiv)

Demonstrated cross coupling with electron rich aryl bromides:

C-H activation is not dependent on an adjacent heteroatom

C-H Activation of gem-Dialkyl Groups

Gives -Hydride Elimination

Baudoin, O. et. al. Angew. Chem. Int. Ed. 2003, 42, 5736.

Addition of bulky triaryl phosphine ligands promotes C-H

activation over protodehalogenation

Entry Base 1a (%)

1 Cs2CO3 19

Catalyst

Pd(OAc)2

1b (%) 1c (%)

55 6

1 Cs2CO3 0Pd(OAc)2 58 6

PR3

-

P(tBu)3

3 Pd(OAc)2 dppp Cs2CO3 0 32 10

4 Pd(OAc)2

1d (%)

Steric Differentiation in C-H Activation


C-H activation occurs preferentially at the

less substituted alkyl group

Br

CO2Et

Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol %)

K2CO3DMF, 150 C, 30 min

CO2Et

83%

Br

Pd(OAc)2 (10 mol %)

P(o-Tol)3 (20 mol %)

K2CO3DMF, 150 C, 90 min 60%

CO2Et CO2Et

Br


K2CO3DMF, 150 C, 30 min 95

CO2Et CO2Et CO2Et+

: 571%

Steric Factors Prevail over Conjugation


Steric factors prevail over formation of conjugated olefins

Br

CO2Et



CO2Et

75%

+CO2Et CO2Et+

73 : 19 : 8

Br

Pd(OAc)2 (10 mol %)

P(o-Tol)3 (20 mol %)

K2CO3DMF, 150 C, 90 min 78%

CO2Et

CO2Et

Br



80%

CO2Et +

86 : 14

CO2Et CO2Et

Possible Palladacycle Intermediates


Olefin E could be formed through 5 or 6 membered palladcycle

Deuterium Labeling Studies


Reaction proceeds through a 6-membered palladacycle

OTIPSD2C CD2

H3C CH3

Br

Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol%)

K2CO3, DMF, 150 C78%

OTIPSD2C

H3C

D

D

OTIPS

D3C CD3

Br

Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol%)

K2CO3, DMF, 150 C86%

OTIPS

H

CD3

DD

via

PdLn

OTIPS

H

not

PdLn

OTIPS

H

Favoring Carbon-Carbon Bond Formation

Baudoin, O. et. al. Chem. Eur. J. 2009, 13, 792.

Trisubstituted substrates favor reductive elimination

Br

CN

Pd(OAc)2 (5 mol%)F-TOTP (20 mol %)

K2CO3 (2 equiv)DMF, 100 C

62%

CN

MeH

+CN

4 : 1

PdLn

CN

Me

H

Reductive

Elimination

-H

Elimination

Br

CN

Pd(OAc)2 (5 mol%)F-TOTP (20 mol %)

K2CO3 (2 equiv)DMF, 100 C

62%

NC

H

Intramolecular Arylation of Benzylic Methyl

Groups

Ren, H.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 3462.

Activation of benzylic methyl groups prevents

-hydride elimination

N

Br

R

Pd(OAc)2 (5 mol%)

P(p-Tol)3 (10 mol%)

Cs2CO3

NR

65-83%

Limited to R = EWG

R1

R2

Br

Br

+ MgBr

R3

Pd2(dba)3 (1.5 mol %)

tBu3P (6 mol %)

THF, rt, 20h

R1

R2

R3

78-99%

Dong, C. -G.; Hu, Q.-S. Angew. Chem. Int. Ed. 2006, 45, 2289.

Arylation of sp3 C-H of tert-Butyl Groups

Activation at quaternary carbons can also

Avoid -hydride elimination

Buchwald, S.L. et al. J. Am. Chem. Soc. 2005, 127, 4685.

PCy3

OMeMeO

SPhos

Br

ArB(OH)2 (2 equiv)

Pd2dba3 (1 mol %)

SPhos (4 mol %)

K3PO4 (3 equiv)

Tol

Ar

95-99%

Fagnou, K, et. al. J. Am. Chem. Soc. 2007, 129, 14570.

O

Br

Pd(OAc)2 (3 mol %)

PCy3-HBF4 (6 mol %)

Cs2CO3 (1.1 equiv)

tBuCO2H (30 mol %)Mesitylene, 135 C, 15h

OR R

77-92%

Use of Substrates without Quaternary

Carbons

Reductive elimination pathway can be competitive

with -H elimination

Fujii, N.; Ohno, H. et. al. Org. Lett. 2008, 10, 1759.

Pd(OAc)2 (3 mol %)

PCy3-HBF4 (6 mol %)

Cs2CO3 (1.4 equiv)

tBuCO2H (30 mol%)xylene, 140 C, 6-24 h

Br

N

CO2Me

R2 N

CO2Me

R1R1

R2R3 R3

N

CO2Me

98%

N

CO2Me

80%

H

N

CO2Me

76%

H

H

N

CO2Me

89%

N

CO2Me

38%

Site-Selective sp3 C-H Arylation

sp3 C-H activation is favored over sp2 C-H

and -hydride elimination

Fanou, K. et. al. J. Am. Chem. Soc. 2008, 130, 3266.

Pd(OAc)2 (5 mol %)P(tBu)3-HBF4 (5 mol %)

K2CO3 (1.5 equiv)PhCH3, 110 C

N

O-H

H+

Br

Me

(2.0 equiv)

N

O-

H

Me

89%Pd2(dba)3 (2.5 mol %)

X-Phos (5 mol %)

NaOtBu (3.0 equiv)

PhCH3, 110 C (W)N

O-H

H+

Br

Me

(1.5 equiv)

N

O-

77%

PCy2

iPr iPr

iPr

X-Phos

Amide Directed Intermolecular Arylation

sp3 C-H activation is favored over sp2 C-H activation

and -hydride elimination

Yu, J.-Q. et. al. J. Am. Chem. Soc. 2009, 131, 9886.

Pd(OAc)2 (10 mol %)

Cy-JohnPhos-HBF4 (20 mol %)

CsF (3.0 equiv), 3 M.SPhCH3, 100 C, N2, 24h

NHC6F5

O

R1

R2

H

+

(3.0 equiv)

NHC6F5

O

R1

R2

Ar

Ar I

NHC6F5

O

Me

H

Ph

30% mono

53% di

NHC6F5

OMe

p-Tol

78%

NHC6F5

OH

p-Tol

H

58%

NHC6F5

O

p-Tol

80%

H

sp3 C-H Functionalization Adjacent to

Nitrogen Atoms

NR

X

R'Pd(0) cat.

NR

Pd

R'

R' N R

Desired Product

NR

Pd

R'

H

Undesired

Byproducts

-Hydride elimination can lead to unproductive side

reactions including dehalogenation of the starting material

Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.

Difficulty with Amine Substrates

Lewis basicity of nitrogen has dramatic effect on

the reaction outcome

N

Br H

Pd(OAc)2 (20 mol %)

PCy3-HBF4 (40 mol %)

CsCO3 (1.5 equiv)

PivOH (30 mol %)

Mes, 150 C, 16h

N

Not observed

Starting material recovered in 83% yield

31P NMR shows an unreactive Pd(II) intermediate

Pd

Cy2PBr

N

31P NMR signal

at 47 ppm

Amide substrates lead to desired product

N

Br H

O


Importance of Base and Additives

Bulky pivalate additives greatly increase yield

Entry Base Additive Yield (%)

1 Cs2CO3 none 14

2 CsOPiv none 5

3 Cs2CO3 27AcOH (30 mol%)

4 Cs2CO3 83PivOH (30 mol%)

5 Cs2CO3 88CsOPiv (110 mol%)

N

Br H

Pd(OAc)2 (5 mol %)PCy3-HBF4 (10 mol %)

Base (1.5 equiv)Additive (x mol %)

Mes, 150 C, 16h

N

O O


Counterion Effect

Rb2CO3 was optimal base for preventing

dehalogenation of the starting material

Entry Base Yield (%)

1 Na2CO3 0

2 K2CO3 31

3 Rb2CO3 56

4 Cs3CO3 48

N

Br H

Pd(OAc)2 (5 mol %)


Base (1.5 equiv)

PivOH (30 mol %)

Mes, 150 C, 16h

N

O OMeO MeO


Amide Scope

Selective for methyl C(sp3)-H and deactivated by

electron rich aromatic rings

NR

Br H

Pd(OAc)2 (5 mol %)


Rb2CO3 (1.5 equiv)

PivOH (30 mol %)

Mes, 150 C, 16h

N R

O O

R' R'

N

O

N

O

N

O Ph

83% 68% 37%

N

O

MeO

N

O

MeO

MeO

N

O

F56% 44% 70%


Sulfonamide Scope

Sulfonamides gave similar results


N

S

N

S

N

S

N

S

CH3 N

SMeO

MeO

OTIPS

N

S N

62% 82% 59%

52% 47% 71%

OO

O O O OO

O O O OO O

SN

R

Br H

Pd(OAc)2 (5 mol %)


Cs2CO3 (1.5 equiv)

PivOH (30 mol %)

Mes, 150 C, 16h

NS

RR'

O O OO

Reactivity of sp2 and sp3 C-H Bonds

Complete selectivity for sp2 C-H bond via a seven-membered

palladacycle


N

Br H

Pd(OAc)2 (5 mol %)


Rb2CO3 (1.5 equiv)

PivOH (30 mol %)

Mes, 150 C, 16h

H

N H

O O

88%

SN

Br H


Cs2CO3 (1.5 equiv)PivOH (30 mol %)

Mes, 150 C, 16h

O O

H

NS

O O

H

83%

KIE Effects

The observed KIE shows the the C-H(D) bond is cleaved

in the rate determining step


N


Rb2CO3 (1.5 equiv)PivOH (30 mol %)

Mes, 150 C, 16h

OBr

HDD

N

O

D(H)D

kH/kD = 3.4

N

CH3

O

CH3

Br

vs N

CD3

O

CD3

Br

kH = 3.2 10-6 M/s kD = 4.9 10

-7 M/s

kH/kD = 6.5

Simple Catalytic Cycle

What is a mechanism of C-H cleavage? What is the role

of the base additive?


PdLn

Br

O

N

LnPd

O

N

Br

PdLn

N

O

N

O

Oxidative Addition

C(sp3)-H bond cleavage

mechanism?

ReductiveElimination

Mechanism for sp3 C-H Activation

Concerted metalation-deprotonation (CMD) pathway shown

for sp2 C-H bond activation may be operative


LnPd0

oxidative

addition

R X

reductive

elimination

C-H Activation

R R'

LnPdII X

R

R' HX H

LnPdII R'

R

?

Isolation of Pd(II) Intermediate


N

O

Br

+ Pd(PCy3)2PhCH3, rt, 24h

Pd

CO2NMe2

Br

PCy3

Cy3P

70%

No significant

Interactions between

the amide and the Pd(II) center.

Isolation of Pd(II) Intermediate


N

O

Br

+ Pd(PCy3)2PhCH3, rt, 24h

Pd

CO2NMe2

Br

PCy3

Cy3P

70%

N

Br HRb2CO3 (1.5 equiv)

PivOH (30 mol %)

Mes, 150 C, 16h

N

O O

CO2NMe2

PdBr

PCy3

Cy3P (5 mol %)

67%(76% standard conditions)

Isolated Pd(II) complex is a catalyst precursor for the reaction

Stoichiometric Studies to Probe Role of

Base


Z

Base (10 equiv)Additive (3 equiv)

Mes, 150 C, 4h NZ

PdBr

PCy3

Cy3P

N

Entry Base Additive Yield (%)

1 none none 0

2 Cs2CO3 none 0

3 CsOPiv none 28

4 Cs2CO3 96CsOPivPd

Br

PCy3

Cy3P

N

O

5 none none 0

6 Cs2CO3 none 6

7 CsOPiv none 35

8 Cs2CO3 80CsOPiv

SO2

PdBr

PCy3

Cy3P

N

Potential Pd(II) Intermediates


CONMe2

Pd

O

OMe3P

I

CONMe2

Pd

Br

Me3P

II

PMe3

Coordination of amide does not promote dissociation

of phosphine ligand

Pd

Br

Me3P

IV

NMe2

O

Pd

Br

Me3P

III

O

NMe2

Role of Pivalate and Base Additives


Proposed concerted

metalation-deprotonation (CMD)

transition state:

Pivalate acts as the base

to promote C-H cleavage

Pivalate promotes phosphine

dissociation

Pivalate prevents catalyst

inhibition by excess phosphine

Carbonate is necessary for

irreversible deprotonation of

pivalate ligand after CMD

Proposed Catalytic Cycle


Rate = k[Pd][PivO-]

Fast

Oxidative Addition

Fast

Ligand Exchange

Slow

Metalation-Deprotonation

N

Br

O

Pd

N

Br

O

Cy3P

PCy3

Pd

N

O

Cy3P O

O

N

O

Pd H

O

tBu

OCy3P

Pd

N

O

Cy3P O

tBu

OH

Pd

N

O

Cy3P O

tBu

O

N

O

LnPd(0)

CsOPiv

CsBr + PCy3CO3

2-

HCO3-

H

Irreversible

Deprotonation

Reductive

Elimination

Conclusions & Future Directions

Most substrates to date are designed to prevent -hydride elimination.

Selective intramolecular sp3 C-H functionalization can be achieved by

oxidative addition into an adjacent aryl halide

Further development using intermolecular coupling of aryl or alkyl halides

with an appropriate directing group could great increase the synthetic

utility of this process

X

R

Pd(0), Base

HX

Pd

RRreductive

elimination

H

O H X

I I

X=C, O, N

H Br

CN

H

Br

N

H

The reaction proceeds through a concerted metalation-deprotonation

mechanism with crucial involvement of base and additives.

Different oxidants were explored in this system. Commonorganic oxidants, such as 1,4-quinone and PhI(OAc)2, were notefficient for this transformation (entries 2 and 3, Table 1). Othercopper salts, such as CuCl2, could be employed as an oxidantwith a very low efficiency (entry 5, Table 1). Dioxygen (O2)could not play a role as a direct oxidant; however, it can beused as a co-oxidant in the presence of a catalytic amount ofCu(OAc)2 with a relatively lower conversion (entry 9, Table1). This transformation is not sensitive to Pd(II) species.According to all these studies, relatively cheap PdCl2 wasemployed as a catalyst with 1 equiv of Cu(OAc)2 in the presenceof 16 equiv of AcOH in TEFol for this transformation.Evaluating the Reactivities of Different Alkenes. After

screening the reaction conditions, the different alkenes werefurther explored (Table 2). We found that different acrylic acidesters were suitable substrates, whether methyl, ethyl, n-butyl,or benzyl was the protecting group (entries 1-4, Table 2). Freeacrylamide and N,N-disubstituted amide could also be employedin this transformation to produce the desired ortho-olefinatedproducts in moderate to good yields (entries 5 and 6, Table 2).It is noteworthy that the dynamic !-hydride elimination productwas observed when the methyl group was present at the R-posi-tion of the acrylate (entry 7, Table 2). However, !-substitutedethyl acrylate was not suitable for this transformation (entry 8,Table 2). Furthermore, no desired product was obtained whenstyrene was subjected to these reaction conditions (entry 9, Table2). This may arise from the alkylation of arenes in a Friedel-Crafts manner under the relatively strong acidic conditions.Screening of Different Substituted Benzylamines.Different

benzylamine derivatives were screened under the standardconditions (Table 3). Two methyl groups on nitrogen werenecessary to complete this transformation (entry 1, Table 3).When either one methyl group or both of them were substitutedby a proton, this transformation was completely terminated

(entries 2 and 3, Table 3). When N-methyldibenzylamine wasemployed as a substrate, only one phenyl ring was olefinatedunder this condition in a moderate isolated yield, which mightbe controlled by steric effects (entry 4, Table 3). Moreover, theisolated yield for the cyclic amine derivative was very low (entry5, Table 3). An acetyl substituent on nitrogen instead of one ofthe methyl groups decreased the electron density of nitrogen;

Table 1. ortho Olefination of 1a under Various Conditionsa

a The reactions were carried out in 0.5 mmol scale of 1a in the presenceof 1.0 mmol of 2a and the proper catalyst in 2 mL of different solvents.b NMR yields with the use of CH2Br2 as internal standard. c The reactionswere carried out under balloon pressure of O2. d Isolated yields. e Theproducts were obtained as a mixture accompanied with some esterexchanging products. f This reaction was carried out in the absence ofpalladium catalyst.

Table 2. ortho Functionalization of N,N-Dimethylbenzylamine withDifferent Alkenesa

a All the reactions were carried out in the scale of 0.5 mmol of 1a and1.0 mmol of 2 in 2.5 mL of solvent. b Isolated yields. c The yield wasdetermined by 1H NMR with the use of CH2Br2 as an internal standard.Table 3. ortho Olefination of Different N-SubstitutedBenzylaminesa

a All the reactions were carried out in 0.5 mmol scale under standardconditions. b Isolated yields if without further notes. c NMR yield with theuse of CH2Br2 as an internal standard. d Only one benzyl was olefinated.

A R T I C L E S Cai et al.

7668 J. AM. CHEM. SOC. 9 VOL. 129, NO. 24, 2007

final product 3. The palladium hydride species was transformedto Pd(0) and further oxidized to Pd(II) by Cu(II) to finish thiscatalytic cycle.Application of Developed ortho Olefination-Hydrogena-

tion. 3-o-Tolylpropanoic acid and its derivatives have beenutilized as a key structural unit in bioactive molecules.17According to this developed process, the compound 4rd wassynthesized by this transformation in excellent yield with shortroutes (eq 9).17a This process also offers a new method to quicklyconstruct this type of compound in high efficiency and gooddiversity, which will be beneficial to further unveil new utilitiesof this unique scaffold.

ConclusionsStarting from the easily available N,N-dimethylbenzylamines,

we have developed a novel method to achieve a regioselectivefunctionalization via direct C-H functionalization by tuningthe acidity of the reaction conditions. Although the acid hasbeen applied to the C-H activation by electrophilic attackthrough enhancing the electrophilic ability of metal ions, theacid plays a much more important role to conduct thistransformation. The acidity and quantity of the Bronsted acidremarkably controlled the efficiency of this ortho olefination.Starting from the corresponding functionalized tertiary amines,highly selectively ortho-functionalized toluene and its deriva-tives were synthesized by simple reduction. These two trans-formations could be combined in one vessel to offer a muchmore environmentally benign process. Besides ortho-function-

alized N,N-dimethylbenzylamines,18 3-o-tolylpropanoic acid andits derivatives are also important units of synthetic moleculesand show some biological activity.17 Our development hereadvances a remarkable and useful method to construct both ofthese important scaffolds. Further study to apply these methodsto organic synthesis is underway in our laboratory.Experimental SectionGeneral Methods. All the reactions were carried out in a stoppered

Schlenk flask.19 All the solvents were freshly distilled before use exceptCF3CH2OH. CF3CH2OH, anhydrous Cu(OAc)2, Pd/C (5 wt % Pd), andPd(CH3CN)4(BF4)2 were purchased from Acros. PdCl2 was purchasedfrom Zealand Co. Ltd., and Pd/C (10 wt % Pd) and N,N-dimethylben-zylamine were purchased from Sinopharm Chemical Reagent Co., Ltd.N,N-Dimethylbenzylamine was distilled under reduced pressure andstored under N2 atmosphere. Other commercially available chemicalswere directly used without further purification.Physical Methods. 1H NMR (300 MHz) and 13C NMR (75 MHz)

were registered on Varian 300M spectrometers with CDCl3 as solventand tetramethylsilane (TMS) as an internal standard. Chemical shiftswere reported in units (ppm) by assigning the TMS resonance in the1H spectrum as 0.00 ppm and the CDCl3 resonance in the 13C spectrumas 77.0 ppm. All coupling constants (J values) are reported in hertz(Hz). Column chromatography was performed on silica gel 200-300mesh. IR, GC, and MS were performed by the State-authorizedAnalytical Center in Peking University.General Procedure for Preparation of Functionalized N,N-

Dimethylbenzylamines 1. Functionalized N,N-dimethylbenzylamineswere prepared by reductive amination according to the reportedprocedure.20 To a solution of NEt3 (4.2 mL, 30 mmol) in absolute EtOH(23 mL) was added dimethylamine hydrochloride (2.48 g, 30 mmol),Ti(i-PrO)4 (9.0 mL, 30 mmol), and the corresponding aldehyde (15mmol). The mixture was stirred at 25 C for 12 h, NaBH4 (0.86 g,22.5 mmol) was added, and the resulting mixture was further stirredfor 10 h at 25 C. The reaction was quenched by pouring the mixtureinto aqueous ammonia (25 mL, 2 N) and filtered through a Celite pad,and the resulting inorganic solid was washed with CH2Cl2 (100 mL).The filtrate was washed with CH2Cl2 (3 50 mL), concentrated toabout 30 mL, and washed with HCl (2 N, 3 10 mL). The solutionwas neutralized to pH ) 9 with 10% aqueous NaOH and extractedwith CH2Cl2 (3 50 mL). Additional NaOH was added to keep theinorganic phase basic. The organic phases were combined and driedover MgSO4 and then evaporated to give the corresponding N,N-dimethylbenzylamine 1 without further purification.General Procedure for the ortho Olefination of Tertiaryamines

with Acrylic Esters. In a typical experiment, PdCl2 (4.4 mg, 0.025mmol), Cu(OAc)2 (90.8 mg, 0.5 mmol), and CF3CH2OH (2 mL) wereadded into a Schlenk tube. Then N,N-dimethylbenzylamine 1 (0.5mmol) was added, followed by 2 (1.0 mmol) and HOAc (0.5 mL, 8.0mmol). The flask was stoppered and heated at 85 C in an oil bath for48 h. The mixture was made slightly alkaline with a saturated Na2CO3solution (3 mL), and a light blue precipitate appeared. The suspensionwas filtered through a Celite pad and extracted with CH2Cl2 three times.The combined organic layers were dried over anhydrous Na2SO4 andevaporated in vacuo. The desired products 3 were obtained in thecorresponding yields after purification by flash chromatography on silicagel with PE, EtOAc, and NEt3.

(17) (a) Bohacek, R.; Boosalis, M. S.; McMartin, C.; Faller, D. V.; Perrine, S.P. Chem. Biol. Drug Des. 2006, 67, 318. (b) Frankish, N.; Farrell, R.;Sheridan, H. J. Pharm. Pharmacol. 2004, 56, 1423. (c) Burlingame, R. P.;Wyman, L.; Chapman, J. P. J. Bacteriol. 1986, 168, 55. (d) Kuhler, T. C.;Swanson, M.; Christenson, B.; Klintenberg, A.-C.; Lamm, B.; Fagerhag,J.; Gatti, R.; Olwegard-Halvarsson, M.; Shcherbuchin,V.; Elebring,T.; Sjostrom, J.-E. J. Med. Chem. 2002, 45, 4282. (e) Conner, S. E.;Knobelsdorf, J. A.; Mantlo, N. B.; Schkeryantz, Jeffrey M.; Shen, Q.;Warshawsky, A. M.; Zhu, G. PCT Int. Appl. WO 2003072100 A1,2003.

(18) (a) Fevig, J. M.; Cacciola, J.; Buriak, J.; Rossi, K. A.; Knabb, R. M.;Luettgen, J. M.; Wong, P. C.; Bai, S. A.; Wexler, R. R.; Lam, P. Y. S.Bioorg. Med. Chem. Lett. 2006, 16, 3755. (b) Kung, H. F.; Newman, S.;Choi, S.-R.; Oya, S.; Hou, C.; Zhuang, Z.-P.; Acton, P. D.; Ploessl, K.;Winkler, J.; Kung, M.-P. J. Med. Chem. 2004, 47, 5258. (c) Hine, J.; Khan,M. N. J. Am. Chem. Soc. 1977, 99, 3847. (d) Nielsen, S. F.; Larsen, M.;Boesen, T.; Schonning, K.; Kromann, H. J. Med. Chem. 2005, 48, 2667.

(19) Safety note: CF3CH2OH is corrosive and H2 is explosive. Thus, greatcaution should be exercised when handling them.

(20) Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928.

Scheme 6. Proposed Mechanism of ortho Olefination ofN,N-Dimethylbenzylamine

A R T I C L E S Cai et al.

7672 J. AM. CHEM. SOC. 9 VOL. 129, NO. 24, 2007

Indirect ortho Functionalization of Substituted Toluenesthrough ortho Olefination of N,N-Dimethylbenzylamines Tuned

by the Acidity of Reaction ConditionsGuixin Cai, Ye Fu, Yizhou Li, Xiaobing Wan, and Zhangjie Shi*

Contribution from Beijing National Laboratory of Molecular Sciences (BNLMS), PKU GreenChemistry Center and Key Laboratory of Bioorganic Chemistry and Molecular Engineering ofMinistry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, Peoples

Republic of China, and Shanghai Key Laboratory of Green Chemistry and Chemical Processes,East China Normal UniVersity, Shanghai 200062, Peoples Republic of China

Received January 26, 2007; E-mail: [email protected]

Abstract: Highly regioselective olefination of substituted N,N-dimethylbenzylamines was developed by tuningthe acidity of reaction conditions based on analysis of their features. The ortho-functionalized N,N-dimethylbenzylamines were further transformed into 3-(2-tolyl)propanoic acid and its derivatives undermild conditions. These two transformations could be combined into one pot, and 3-(2-tolyl)propanoic acidand its derivatives were obtained in moderate to good yields. Mechanistic studies indicated that electrophilicattack on the phenyl ring by the Pd(II) ion assisted by the N,N-dimethylaminomethyl group was a key stepduring this catalytic transformation, which was controlled by the acidity of the reaction conditions.

IntroductionIn the past several decades, many efforts have been made to

direct functionalization of a variety of C-H bonds.1 AromaticC-H activation through different chemical processes has beenstudied.2 Direct functionalization of aromatic C-H bonds byelectrophilic attack of metal ions is one of the most importantpathways.3 Functional groups containing heteroatoms, such as

acetamino, oxazolyl, pyridyl, and imino groups, have beenbroadly utilized to provide either stoichiometric or catalyticortho-metalation of aromatic rings to construct C-C4a-f andC-X (X ) halides, N, etc.) bonds.4g-jPrevious synthetic workon functionalization of N,N-dimethylbenzylamine generallyutilized n-BuLi to ortho lithiate the N,N-dimethylbenzylamine,which limited the tolerance of functional groups in the sub-strates.5 Although the N,N-dimethylaminomethyl group has beenused as a directing group to realize the ortho-metalation bytransition metal complexes to form metallocycles and furtherconstruct C-C bonds in a stoichiometric manner under basicconditions,6 the catalytic version of ortho functionalization ofan aromatic C-H bond directed by an N,N-dimethylaminom-ethyl group has rarely been reported, except one case reportedby Murai and co-workers, in which achieved ortho silylationcatalyzed by Ru(0) was initiated through oxidative addition.7

(1) (a) Murai, S. ActiVation of UnreactiVe Bonds and Organic Synthesis;Springer-Verlag: Berlin, 1999; pp 48-78. (b) Shilov, A. E.; Shulpin, G.B. Chem. ReV. 1997, 97, 2879. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.ReV. 2002, 102, 1731. (d) Arndtsen, B. A.; Bergman, R. G.; Mobley, T.A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (e) Cho, J.-Y.; Tse, M.K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305. (f)Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,2685. (g) Lail, M.; Arrowood, B. N.; Gunnoe, T. B. J. Am. Chem. Soc.2003, 125, 7506. (h) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.; Inoue,Y. J. Am. Chem. Soc. 2003, 125, 12102. (i) Davies, H. M. L.; Hansen, T.;Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (j) Crabtree, R. H. J.Organomet. Chem. 2004, 689, 4083. (k) Sen, A. Acc. Chem. Res. 1998,31, 550. (l) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (m) Stahl,S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37,2180. (n) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (o) Chen, H. Y.;Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995. (p)Brown, S. H.; Crabtree, R. H. J. Am. Chem. Soc. 1989, 111, 2935. (q)Solari, E.; Musso, F.; Ferguson, R.; Floriani, C.; Villa, A. C.; Rizzoli, C.Angew. Chem., Int. Ed. Engl. 1995, 34, 1510. (r) Dick, A. R.; Sanford, M.S. Tetrahedron 2006, 62, 2439.

(2) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,M.; Chatani, N. Nature 1993, 366, 529. (b) Shi, Z.; He, C. J. Am. Chem.Soc. 2004, 126, 13596. (c) Shabashov, D.; Daugulis, O. Org. Lett. 2005,7, 3657. (d) Ishiyama, T.; Sato, K.; Nishio, Y.; Miyaura, N. Angew. Chem.,Int. Ed. 2003, 42, 5346. (e) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem.2003, 3485. (f) Zhao, J.; Campo, M.; Larock, R. C. Angew. Chem., Int.Ed. 2005, 44, 1873. (g) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.;Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78.

(3) (a) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.; Kitamura, T.; Fujiwara,Y. Science 2000, 287, 1992. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.Chem. Res. 2001, 34, 633. (c) Hennessy, E.; Buchwald, S. L. J. Am. Chem.Soc. 2003, 125, 12084. (d) Hashmi, A. S. K.; Schwarz, L.; Choi, J. H.;Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (e) Wang, X.; Lane,B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (f) Alexakis, A.;Tomassini, A.; Andrey, O.; Bernardinelli, G. Eur. J. Org. Chem. 2005,1332.

(4) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (b) Boele, M. D.K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries,J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (c)Tremont, S. J.; ur Rahman, H. J. Am. Chem. Soc. 1984, 106, 5759. (d)Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156. (e) Kalyani,D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,127, 7330. (f) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2004, 126, 2300. (g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem.Soc. 2006, 128, 9048. (h) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int.Ed. 2005, 44, 2112. (i) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang,S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416. (j) Tsang, W. C. P.; Zheng,N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.

(5) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Saa, J. M.; Llobera, A.;Garcia-Raso, A.; Costa, A.; Deya, P. M. J. Org. Chem. 1988, 53, 4263.

(6) (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (b) Holton, R. A.; Davis, R. G.J. Am. Chem. Soc. 1977, 99, 4175. (c) Dunina, V. V.; Kuzmina, L. G.;Kazakova, M. Y.; Gorunova, O. N.; Grishin, Y. K.; Kazakova, E. I. Eur.J. Org. Chem. 1999, 1029. (d) Grove, D. M.; van Koten, G.; Ubbels, H. J.C. J. Am. Chem. Soc. 1982, 104, 4285. (e) Holton, R. A. Tetrahedron Lett.1977, 4, 355. (f) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K.J. Chem. Soc., Perkin Trans. 2 1983, 1511.

(7) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani, N.; Murai,S. Chem. Lett. 2002, 396.

Published on Web 05/27/2007

7666 9 J. AM. CHEM. SOC. 2007, 129, 7666-7673 10.1021/ja070588a CCC: $37.00 2007 American Chemical Society

activation[13] and by steric effects in the second C!Hactivation.[14] To further verify our prediction, the moresterically hindered p-xylene was subjected to this trans-formation, and ortho arylation was observed in very low yield,with most of the starting material 1a being recovered.

The scope of N-acetanilides was further investigated(Table 1). N-Alkylated and free anilines were not fit for thistransformation. Different derivatives of N-acetyl-1,2,3,4-tet-rahydroquinoline, regardless of substitution at the aliphatic oraromatic ring, were perfectly suitable substrates for thistransformation (entries 14, Table 1). However, N-methylacetanilide 1e did not serve well as a substrate and quicklydecomposed under cross dehydrogenative arylation (CDA)conditions (entry 5, Table 1). Additional studies indicatedthat acetanilide 1 f was a good substrate, and the N!H bondwas not functionalized (entry 6, Table 1). In this case, only theortho sp2 C!H bond was arylated efficiently.

Furthermore, different common arenes were tested forthis ortho arylation behavior (Table 2). We found: 1) Lesshindered ortho- and meta-dialkyl-substituted electron-richbenzene derivatives could be utilized as the arene source toperform the ortho arylation with excellent selectivities(entries 1 and 3, Table 2). With monoalkyl-substitutedarenes, two isomers (functionalized at the meta and parapositions) were isolated as a mixture (entries 4, 5, 7, and 8,Table 2). Thus, steric hindrance rather than electronic effectsplayed the vital role in controlling the selectivity of the secondC!H activation. 2) Different arenes with fused rings, evenwith heteroatoms, could serve as substrates to complete thistransformation at less hindered positions (entry 6, Table 2).3) Benzene could be employed as the arene source withexcellent efficiency (entry 6, Table 1; entry 2, Table 2). Evenelectron-deficient arenes, such as biphenyl and fluoroben-zene, were also good reagents for this arylation, but a highercatalyst loading was required (entries 7 and 8, Table 2). The

reactivity of these electron-deficient arenes seems to supportthe proton-abstraction pathway to activate the C!H bond of asecond arene to afford intermediate 6 via 5, as described inthe aforementioned catalytic cycle (Scheme 2).[15]

Carbazole and its derivatives further drew our attention,as they are the key structural units in many natural drugs andsynthetic optical materials.[16] On the basis of the newobservations, we aimed to construct the carbazole unitthrough a process free of halogenated and metal-containingreagents (Scheme 3). In our design, the C!N bond ofcarbazole could be constructed by PdII-catalyzed C!Hactivation, as demonstrated by Buchwald and co-workers.[17]

The ortho-arylated acetanilides could be constructed by ournew CDA reaction with commercially available acetanilidesand arenes. Building on the above developments, we envi-sioned that the regioselective ortho palladation of acetani-lides would give a palladacycle analogous to 4. This keyintermediate may undergo further C!H activation of a secondarene to construct biaryl C!C bonds, thereby furnishing theintermolecular cross-coupling product. Thus, the carbazolecore can be constructed through three C!H and one N!Hfunctionalization with a Pd catalyst in a highly chemo- andregioselective manner. Prefunctionalization of arenes with

Scheme 2. Proposed catalytic cycle for highly selective cross dehydro-genative arylation (CDA).

Table 1: Substrate scope of N-acetanilides for Pd-catalyzed crossdehydrogenative arylation.[a]

Entry 1 3 Yield [%][b]

17873[c]

2 71

3 86

4 64

5[d] 16

6[e] 66

[a] All reactions were performed using 1 (0.3 mmol), 2a (1.0 mL), andEtCOOH (1.5 mL) unless noted otherwise (see the SupportingInformation). [b] Yields of isolated product. [c] Yield of isolated producton a scale of 10.0 mmol. [d] Most of starting material 1e decomposedunder these conditions. [e] Benzene (1 mL) was used in place of 2a.

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1116 www.angewandte.org ! 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 1115 1118










17873[c]

2 71

3 86

4 64

5[d] 16

6[e] 66


Communications











17873[c]

2 71

3 86

4 64

5[d] 16

6[e] 66


Communications


halide and boronic acids can thus be avoided in this efficientsynthetic scheme.

We tested the synthesis of the carbazole scaffold withmultiple C!H activation steps, as envisioned. Under thestandard arylation conditions, ortho-phenylated acetanilide

3 fb was produced in a good yield (Scheme 4). This compoundcould be directly transformed into carbazole 8a (isolated in91% yield) under Buchwald conditions. Starting from 1 f, theortho position of the newly installed phenyl ring of 3 fb could

be further phenylated to produce acetanilide 7 through asecond CDA reaction by simply increasing the catalystloading under the same conditions. Carbazole 8b was easilyobtained from 7 through the PdII-catalyzed C!N bondformation in an excellent yield and high selectivity andcould undergo a third cross-coupling to yield derivatives.

With simple processes completely free of halogenated andorganometallic reagents, 4-deoxycarbazomycin B, a degrada-tion product of the natural product carbazomycin B, wassynthesized in few simple steps (Scheme 5).[18] This method-ology allowed the swift development of a diverse library ofcarbazoles with different functionalities from commerciallyavailable acetanilides and common arenes.

In conclusion, our new concept was realized to conducthighly selective cross-coupling of arenes controlled bydirecting groups, and a practical method was developed to

Table 2: Cross dehydrogenative arylation of 1,2,3,4-N-acetyltetrahydro-quinoline 1a with different arenes.[a]

Entry Arene 2 3 Yield [%][b]

17873[c]

2 66

3 46

4[d] 78 (1.1:1)

5[d] 69 (2.5:1)

6[e] 63

7[d,f ] 43 (1:1)

8[g,h] 48 (2.3:1)

[a] All reactions were carried out using 1a (0.3 mmol), 2 (1.0 mL),EtCOOH (1.5 mL), and the appropriate amount of of Cu(OTf)2 (see theSupporting Information for details). [b] Yield of isolated product. Theratios given in parenthesis refer to the relative yield of para- to meta-substituted product. [c] Yield of isolated product on a scale of10.0 mmol. [d] The ratio of the two isomers was determined by GC.[e] Some by-products (less than 10%) were observed, but theirstructures could not be determined. [f ] 5.0 equiv biphenyl was used.[g] 20 mol% Pd(OAc)2 was used. [h] The ratio of the two isomers wasdetermined by 1H NMR spectroscopy.

Scheme 3. A rational design on construction of carbozoles throughmultiple C!H activations by Pd catalysis avoiding organohalides andorganometallic reagents.

Scheme 4. Pathways completely free of halogenated and organometal-lic reagents for the synthesis of polysubstituted carbozoles throughmultiple C!H activations. a) Benzene (1 mL), 1 f (0.3 mmol), Pd(OAc)2(10 mol%), and Cu(OTf)2 (1 equiv) in propionic acid (1.5 mL), 46 h.b) Benzene (1.0 mL), 1 f (0.3 mmol), Pd(OAc)2 (20 mol%), and Cu-(OTf)2 (1 equiv) in propionic acid (1.5 mL), 6 h.

Scheme 5. Synthesis of 4-deoxycarbazomycin B from substituted acet-anilide and benzene through sequential C!H activation.

AngewandteChemie

1117Angew. Chem. Int. Ed. 2008, 47, 1115 1118 ! 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

Mechanistically, the transformation was initiated fromortho cyclopalladation directed by O-methyl oxime togenerate cyclopalladium species A, which underwent trans-metalation with arylboronic acids to produce diaryl Pdspecies B (Scheme 3).10 Reductive elimination of B producedthe desired ortho arylated product 4. Pd(0) was furtherreoxidized to Pd(II) by Cu(II) species and/or co-oxidant tofulfill the catalytic cycle. In the presence of proper DMOPfor the arylation of aryl aldoximes, the transformation wasterminated at this stage. With the addition of TfOH, thisarylated product was further transformed to product 6.Furthermore, 6 was hydrolyzed to give 9H-fluoren-9-one 7under strongly acidic conditions. Thus, starting from the samereagents, different pathways have been developed to ap-proach different scaffolds by tuning the reaction conditions.

In conclusion, we have developed novel methods toconstruct ortho arylated aryl aldoximes and ketoximes viaPd(II)-catalyzed direct C-H arylation by using arylboronicacids. On the basis of the analysis of ortho arylation of arylaldoximes, cascade transformations toward interesting fluo-renone scaffold were conducted by switching the reactionpathways through changing the reaction parameters. Thesestudies showed various transformations to functionalize arylcarbonyl compounds starting from simple chemicals.

Acknowledgment. Support of this work by the grant fromNSFC (No. 20672006, 20821062, 20925207, and GZ419)and the973programfromMOSTofChina (2009CB825300)is gratefully acknowledged.

Supporting Information Available: Brief experimentaldetail and other spectral data for products. This material isavailable free of charge via the Internet at http://pubs.acs.org.

OL902552V(10) Motoyama, T.; Shimazaki, Y.; Yajima, T.; Nakabayashi, Y.; Naruta,

Y.; Yamauchi, O. J. Am. Chem. Soc. 2004, 126, 7378.

Figure 3. Cascade reaction to produce polysubstituted 9H-fluoren-9-ones 7 via Pd-catalyzed C-H activation. All the reactions werecarried out in 0.2 mmol scale. Isolated yields.

Scheme 3. Proposed Mechanism for Pd(II)-Catalyzed Arylationand Cascade Transformation to Fluorenone

Org. Lett., Vol. 12, No. 1, 2010 187

Pd-Catalyzed C-H Functionalizations ofO-Methyl Oximes with Arylboronic AcidsChang-Liang Sun, Na Liu, Bi-Jie Li, Da-Gang Yu, YangWang, andZhang-Jie Shi*,,

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory ofBioorganic Chemistry and Molecular Engineering of Ministry of Education, College ofChemistry, and State Key Laboratory of Natural and Biomimetic Drugs, PekingUniVersity, Beijing 100871, [email protected]

Received November 9, 2009

ABSTRACT

Useful methods have been developed to construct ortho-arylated aryl aldoximes, aryl ketoximes, and fluorenones via Pd(II)-catalyzed directC-H arylation by using arylboronic acids as arylating reagents based on the analysis of the pathways of direct functionalization of arylaldoximes.

Direct C-H functionalization is the most straightforwardpathway to construct useful and complicated natural andsynthetic molecules. Recently, many efforts have beenmade to pursue this goal.1 Among those methods, func-tional group oriented ortho C-H activation is a commonstrategy to address this problem.2 Actually, the O-methyloximyl group has been successfully applied for orthoacetoxylation and amination.3 Very recently, arylationfollowed by further transformation with aryl iodides tosynthesize fluorenones has also been successfully devel-oped.4

Compared with direct arylation with arylboronic acidsdirected by other anchoring groups, the arylation orientedby CdX (X ) O, N) remains challenging.5 The major issue

College of Chemistry. State Key Laboratory of Natural and Biomimetic Drugs.(1) For recent reviews, see: (a) Godula, K.; Sames, D. Science 2006,

312, 67. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;Lazareva, A. Synlett 2006, 3382. (c) Dick, A. R.; Sanford, M. S. Tetrahedron2006, 62, 2439. (d) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,4, 4041. (e) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.(f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (g) Ritleng, V.;Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (h) Jia, C.; Kitamura,T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (i) Dyker, G. Angew. Chem.,Int. Ed. 1999, 38, 1699. (j) Li, B.-J.; Yang, S.-D.; Shi., Z.-J. Synlett 2008,7, 949.

(2) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.Soc. 2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.2005, 127, 4156. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,M. S. J. Am. Chem. Soc. 2005, 127, 7330. (d) Dick, A. R.; Hull, K. L.;Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (e) Giri, R.; Yu, J.-Q.J. Am. Chem. Soc. 2008, 130, 4082. (f) Tsang, W. C. P.; Zheng, N.;Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (g) Wang, C.; Piel,I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (h) Ackermann, L. Org.Lett. 2005, 7, 3123. (i) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano,S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (j) Campeau, L.-C.; Parisien, M.;Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (k) Shi, B.; Maugel,N.; Zhang, Y.; Yu., J. Angew. Chem., Int. Ed. 2008, 47, 4. (l) Houlden,C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn., K. I. J. Am. Chem. Soc. 2008, 130, 10066.

(3) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2004, 126, 9542. (b) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006,128, 9048.

(4) (a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. Angew.Chem., Int. Ed. 2008, 47, 9462. (b) Shabashov, D.; Maldonado, J. R. M.;Daugulis, O. J. Org. Chem. 2008, 73, 7818.

(5) Gurbuz, N.; ozdemir, I.; Cetinkaya, B. Tetrahedron Lett. 2005, 46,2273.

ORGANICLETTERS

2010Vol. 12, No. 1

184-187

10.1021/ol902552v 2010 American Chemical SocietyPublished onWeb 12/02/2009

Pd-Catalyzed C-H Functionalizations ofO-Methyl Oximes with Arylboronic AcidsChang-Liang Sun, Na Liu, Bi-Jie Li, Da-Gang Yu, YangWang, andZhang-Jie Shi*,,

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory ofBioorganic Chemistry and Molecular Engineering of Ministry of Education, College ofChemistry, and State Key Laboratory of Natural and Biomimetic Drugs, PekingUniVersity, Beijing 100871, [email protected]

Received November 9, 2009

ABSTRACT

Useful methods have been developed to construct ortho-arylated aryl aldoximes, aryl ketoximes, and fluorenones via Pd(II)-catalyzed directC-H arylation by using arylboronic acids as arylating reagents based on the analysis of the pathways of direct functionalization of arylaldoximes.

Direct C-H functionalization is the most straightforwardpathway to construct useful and complicated natural andsynthetic molecules. Recently, many efforts have beenmade to pursue this goal.1 Among those methods, func-tional group oriented ortho C-H activation is a commonstrategy to address this problem.2 Actually, the O-methyloximyl group has been successfully applied for orthoacetoxylation and amination.3 Very recently, arylationfollowed by further transformation with aryl iodides tosynthesize fluorenones has also been successfully devel-oped.4

Compared with direct arylation with arylboronic acidsdirected by other anchoring groups, the arylation orientedby CdX (X ) O, N) remains challenging.5 The major issue

College of Chemistry. State Key Laboratory of Natural and Biomimetic Drugs.(1) For recent reviews, see: (a) Godula, K.; Sames, D. Science 2006,

312, 67. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;Lazareva, A. Synlett 2006, 3382. (c) Dick, A. R.; Sanford, M. S. Tetrahedron2006, 62, 2439. (d) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,4, 4041. (e) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.(f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (g) Ritleng, V.;Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (h) Jia, C.; Kitamura,T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (i) Dyker, G. Angew. Chem.,Int. Ed. 1999, 38, 1699. (j) Li, B.-J.; Yang, S.-D.; Shi., Z.-J. Synlett 2008,7, 949.

(2) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.Soc. 2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.2005, 127, 4156. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,M. S. J. Am. Chem. Soc. 2005, 127, 7330. (d) Dick, A. R.; Hull, K. L.;Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (e) Giri, R.; Yu, J.-Q.J. Am. Chem. Soc. 2008, 130, 4082. (f) Tsang, W. C. P.; Zheng, N.;Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (g) Wang, C.; Piel,I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (h) Ackermann, L. Org.Lett. 2005, 7, 3123. (i) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano,S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (j) Campeau, L.-C.; Parisien, M.;Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (k) Shi, B.; Maugel,N.; Zhang, Y.; Yu., J. Angew. Chem., Int. Ed. 2008, 47, 4. (l) Houlden,C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn., K. I. J. Am. Chem. Soc. 2008, 130, 10066.

(3) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2004, 126, 9542. (b) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006,128, 9048.

(4) (a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. Angew.Chem., Int. Ed. 2008, 47, 9462. (b) Shabashov, D.; Maldonado, J. R. M.;Daugulis, O. J. Org. Chem. 2008, 73, 7818.

(5) Gurbuz, N.; ozdemir, I.; Cetinkaya, B. Tetrahedron Lett. 2005, 46,2273.

ORGANICLETTERS

2010Vol. 12, No. 1

184-187

10.1021/ol902552v 2010 American Chemical SocietyPublished onWeb 12/02/2009

Org. Lett., Vol. 15, No. 22, 2013 5777

(Scheme 3).Under the optimal reaction conditions, phenyliodide could couple with thiazole but in only 18% yield,whereas the yield can be improved to 47%by elevating thereaction temperature from 100 to 140 !C. In comparison,the p-fluorophenyl iodide and p-methoxyphenyl iodidewere compatible under standard conditions, affording the5-arylated thiazole derivatives in moderate yields (54%and 39%, respectively). However, we failed to improvethe reaction efficiency further at an even higher reactiontemperature (140 !C). Unexpectedly, the sterically hinderedortho-methyl phenyl iodide coupled more efficiently withthiazole specifically at theC-5position inup to60%isolatedyield. Futher studies to promote the efficacy is underway.To further illustrate the regioselective control of our cur-

rent metholodogy, an experiment using 2-phenylthiazole 6as the substrate was carried out (Scheme 4). As expected,the corresponding 5-phenylatedproduct 710was exclusivelyobtained in 44% isolated yield and the otho-phenylatedproduct 8 on the phenyl ring was not observed.

Based on our investigations and previous theoreticalcalculations by Gorelsky,6a,11 the catalytic pathway isconsidered to proceed as shown in Figure 2. After thereduction of the Pd(II) species to aPd(0) species (thismightbe stabilized by the starting thiazole moiety or the corre-sponding product), arylpalladium species 9 is generatedthrough the oxidative addition by aryl iodide (bromide).After the regioselective C!H activation of thioazole toform biaryl Pd(II) species 10, reductive elimination occursto afford the desired biaryl product 3 by releasing the Pd(0)species to complete the catalytic cycle.12

In conclusion, we have developed an efficient, ligand-free, and highly regioselective Pd(II)-catalyzed arylation ofthiazole derivatives. The broad substrate scope and ligand-free conditions made this method synthetically useful.Further investigations to gain insight into the reactionmechanism, to promote the efficacy for other thioazlederivatives, and to apply this methodology to the synthesisof biologically active molecules are underway.

Acknowledgment. Support of this work by the 973Project from the MOST of China (2009CB825300) andNSFC (No. 21072010) is gratefully acknowledged.

Supporting Information Available. Experimental pro-cedures and spectral data for all compounds. This mate-rial is available free of charge via the Internet at http://pubs.acs.org.

Scheme 2. Substrate Scope of Regioselective Arylation of4-Methylthiazole Using Aryl Bromidesa

aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.

Scheme 3. Substrate Scope ofRegioselectiveArylation ofThiazolea


Scheme 4. Evaluation of the Regioselective Arylation versusDirected ortho-C!H Functionalization of 2-Phenylthiazole

Figure 2. Proposed mechanism for regioselective arylation ofthiazole derivatives.

(10) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int.Ed. 2007, 46, 7996.

(11) (a) Gorelsky, S. I.Organometallics 2012, 31, 4631. (b) Gorelsky,S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658.

(12) To investigate whether the reaction was catalyzed homo- orheterogeneously, a further Hg drop test was performed. It was foundthat, in the presence of an additional 400 mgHg, the reaction proceededalso smoothly, affording the desired product in 50% isolated yield. Thisresult umbiguously demonstrated that this catalytic process was homo-geneous. Refer to: Whitesides, G. M.; Hackett, M.; Brainard, R. L.;Lavalleye, J. P. P. M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.;Brown, D. W.; Staudt, E. M. Organometallics 1985, 4, 1819. The authors declare no competing financial interest.

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10.1021/ol4027073 r 2013 American Chemical SocietyPublished on Web 10/31/2013

ORGANICLETTERS

2013Vol. 15, No. 2257745777

Reigoselective Arylation of ThiazoleDerivatives at 5Position via Pd Catalysisunder Ligand-Free Conditions

Xiang-Wei Liu,, Jiang-Ling Shi, Jia-Xuan Yan,, Jiang-Bo Wei,, Kun Peng, )Le Dai, ) Chen-Guang Li, ) Bi-Qin Wang, and Zhang-Jie Shi*,,

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory ofBioorganic Chemistry and Molecular Engineering of Ministry of Education, College ofChemistry, Peking University, Beijing 100871, China, State Key Laboratory ofOrganometallic Chemistry, ChineseAcademy of Sciences, Shanghai 200032,China, Collegeof Chemistry andMaterial Chemistry, Sichuan Normal University, Sichuan 610066, China,andDSMNutritional Products,DSMNutritionCenter,DSM(China) Limited,No. 476LiBing Road, Zhangjiang Hi-tech Park, Pudong new area, Shanghai, 201203, China

[email protected]

Received September 28, 2013

ABSTRACT

An efficient regioselective arylation of thiazole derivatives via Pd-catalyzed C!H activation is reported. The transformation was hypothesized through aPd(0/II) catalytic cycle in the absence of special ligand sets. This method provided an efficient process to direct arylation of thiazoles at the 5-position.

Selectivity is one of the perpetual research topics inorganic synthesis.1Direct functionalization ofC!Hbondsvia transition-metal catalysis has recently emerged as apowerful and practical alternative to the well-applied Pd-catalyzed cross-coupling reactions (e.g., Suzuki!Miyaura,Stille, and Negishi couplings) owing to the ubiquity ofC!H bonds and the avoidance of prefunctionalization of

the starting materials; thus, considerable interest has beeninstigated in the synthetic community.2 To realize theselective functionalization among multiple C!H bondsthat exist in the substrates and products, current solutionsinvolved either a certain directing group2d,j,3 or an inherentdistinguishedC!Hbond exerted by the electronic nature.4Especially, the directing group strategy has exhibited itsadvantages in the past decades. However, the directinggroups are not always desirable in the target molecule, andthe removal of them is usually indispensible, thus obviouslylimiting their synthetic utility.5 Alternatively, the use ofelectronically activated substrates to enable the selectiveC!H bond activation/functionalizaiton was preferable,especially for the derivatization of heterocyclic aromatics.A thiazole-containing structural motif is frequently

found in biologically active molecules, organic materials,and pharmaceuticals (Figure 1).4o In fact, the elaborationof thiazole has been well documented.6 Recently, signifi-cant developments to carry out C!H activations haveenabled direct arylation of heterocyclics and some beautiful

Peking University.Chinese Academy of Sciences. Sichuan Normal University.

)DSM Nutritional Products, DSM Nutrition Center, DSM (China)Limited.

(1) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.(2) (a)Alberico,D.; Scott,M.E.;Lautens,M.Chem.Rev.2007,107, 174.

(b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,1013. (c) Amii, H.; Uneyama, K.Chem. Rev. 2009, 109, 2119. (d) Chen, X.;Engle,K.M.;Wang,D.-H.;Yu, J.-Q.Angew.Chem., Int. Ed.2009,48, 5094.(e) Colby, D. A.; Bergman, R. G.; Ellman, J. A.Chem. Rev. 2009, 110, 624.(f) Daugulis, O.; Do, H.-Q.; Shabashov, D.Acc. Chem. Res. 2009, 42, 1074.(g)Mkhalid, I.A. I.; Barnard, J.H.;Marder,T.B.;Murphy, J.M.;Hartwig,J.F.Chem.Rev.2009,110, 890. (h)Lyons,T.W.; Sanford,M.S.Chem.Rev.2010, 110, 1147. (i) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010, 111,1293. (j) Ackermann, L.Chem. Rev. 2011, 111, 1315. (k) Engle, K.M.;Mei,T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2011, 45, 788. (l) Yeung, C. S.;Dong,V.M.Chem.Rev. 2011, 111, 1215. (m)Arockiam,P.B.; Bruneau,C.;Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (3) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.

Org. Lett., Vol. 15, No. 18, 2013 4761

electron-withdrawing or electron-donating groups, werecompatiblewith this arylation.However, the electron-pooraryl groups performed better (3na vs 3ne, 3ni vs 3nm).Notably, the reaction exhibited excellent tolerance offunctional group. For example, fluoro (3na, 3nh, 3nm),chloro (3nb), bromo (3nc, 3nk), iodo (3no), trifluoromethyl(3nd, 3nl), and ester (3nn) groups are tolerated, and thedesired products were obtained in moderate to goodyields.14 The ortho-substituted diarylhyperiodonium tri-flates (3nh) were also suitable with a little decrease ofreactivity, which indicated that the considerable effect ofsteric hindrance. It is important to note that the electron-rich heterocyclic group (3np) could be also transferred in agood yield, which highly expanded the substrate scope.To understand the pathway of this arylation better,

we performed KIE experiments. Both intermolecularKIE (3.8) and intramolecular KIE (3.9) indicated theinvolvement of C!H bond cleavage into the rate deter-mining step (see the Supporting Information, eqs 2 and 3).Most importantly, the H/D exchange was examined bysimply heating the substrate 1b in the presence of thecatalyst in the mixed solvent of AcOD/ClCH2CH2Cl.After 24 h at 120 !C, 46% of deuterium incorporationwas observed at position, thus implying the C!Hcleavage in the absence of diarylhyperiodonium triflates

(see the Supporting Information, eq 1). On the basis ofthese preliminary results, a proposed mechanism is shownin Scheme 3. The coordination of the amide 1b withpalladiumcatalyst formed complex 8, which further under-went the C!H activation to produce 9. Diarylhyperiodo-nium salts oxidized the complex 9 to form Pd(IV) complex10. Following by the reductive elimination, the desiredproduct 3abwas generated, releasing the Pd(II) catalyst tofulfill the catalytic cycle.15

In summary, we reported a successful example of Pd-catalyzed primary and secondary sp3 C!H arylation byfirst using diarylhyperiodonium salts as arylation reagents.Various acid derivatives and different diarylhyperiodo-nium reagents were compatible with this arylation. Thismethod could be applied to direct arylation of naturallyimportant structural units, such as the derivatives of aminoacids and oleic acid. Preliminary mechanistic studies in-dicated the possible Pd(II)/Pd(IV) catalytic cycle of thistransformation. These studies provided a new method foran efficient functionalization of unreactive sp3 C!Hbonds and an alternative way to process direct arylationof primary and secondary sp3 C!H bonds under mildconditions. Further efforts to extend the applications ofthis method are underway.

Acknowledgment. We acknowledge financial supportfrom the National Basic Research Program of China(973 Program, 2009CB825300) and the national NSF ofChina (nos. 20925207 and 21002001).

Supporting Information Available. Experimental pro-cedures and NMR spectra analysis of the products. Thismaterial is available free of charge via the Internet athttp://pubs.acs.org.

Scheme 2. Pd-Catalyzed Direct Arylation of sp3 C!H Bondswith Different Diarylhyperiodonium Saltsa

aThe reactions were conducted with 0.20 mmol of 1a, 0.24 mmol of2a, 0.01mmol of Pd(SIMes)(OAc)2, 0.24mmol ofK2CO3, and 2.0mLofClCH2CH2Cl and stirred for 24 h at 120 !C unless otherwise noted.

Scheme 3. Proposed Mechanism (L = SIMes)

(14) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.(15) For selected reviews about Pd(IV) chemistry, see: (a) Mu!niz, K.

Angew. Chem., Int. Ed. 2009, 48, 9412. (b) Xu, L.-M.; Li, B.-J.; Yang, Z.;Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (c) Hickman, A. J.; Sanford,M. S. Nature 2012, 484, 177. The authors declare no competing financial interest.

4760 Org. Lett., Vol. 15, No. 18, 2013

such arylation conditions, arylation on either the aromaticring or biarylated products was not observed.

Subsequently, we examined the effects of the counter-anion of diarylhyperiodonium salts (Table 2). We foundthat tetrafluoroborates (BF4

!), hexafluorophosphates(PF6

!), p-toluenesulfonates (OTs!), or bromides (Br!)could be applied as counterions, and 3aa was obtainedwith lower efficacy (comparing entry 1 to entries 2!5). Thelow yields can be explained by the solubility of each salt inClCH2CH2Cl. Alternatively, the anion may be participatein the rate-limiting proton-abstraction step. To determinethe reactivity of the corresponding ArI from Ar2IOTf,we also tested PhI as an electrophile. The reaction indeedtook place but the efficiency was much lower. This resultindicated that the reactivity of diarylhyperiodonium tri-flates is much higher than that of ArI under the sameconditions (entry 6).With the optimized conditions in hand, we investigated

the scope of amide derivatives (Scheme 1). We found that(1) various substituents with different electronic featuresat the para- position of phenyl showed good to excellentreactivity (3aa!ae), (2) the steric effectweakly affected thistransformation (3ah), and (3) Other 3-heteroaryl substi-tuted amides, such as thiophenyl and furanyl, could also betolerated and the desired arylation products were obtainedin good to excellent yields (3af and 3ag). Thus, startingfrom different amides and diarylhyperiodonium triflates,there are two alternative routes to approach the sameproducts, which might be the complementary methodsfor each other.Since common sp3 C!H bonds, especially secondary

C!H bonds other than the benzylic position, exhibit poorreactivity, we turned to explore the potential reactivitywith aliphatic carboxylic amides (Scheme 1). We firsttested the cyclic substrates and found that 3-membered,4-membered, and 5-membered ring substrates are arylated

smoothly. However, only the double arylations at bothortho positions were observed (3aj!al). The primary sp3C!H bonds of propionyl derivatives also performed well,while only mono- and diarylated products were isolatedas a mixture at a nearly 1:1 ratio (3am). To extend theapplication of this arylation further, different aliphaticcarboxylic acid derivatives were tested. We found that, ingeneral, the length of the chain did not affect the efficacy(3an!aq), unless a very long chain was involved. Thebenzyl and sterically hindered cyclopentyl and isopropylgroups were compatible, which extended the substratescope (3ai, 3ar, and 3as). We further tested the derivativesof protected amino acids. To our delight, direct arylationtook place, and 3at was isolated in a 69% yield. Thenatural oleic acid derivative was also arylated in goodyield, leaving the double bond and allylic C!H bondsuntouched under these oxidative conditions (3au).13

Considering that different substituents with distinctelectronic and steric features may influence the reactivityof the diarylhyperiodonium salts, we then surveyed differ-ent functional groups of diarylhyperiodonium triflates(Scheme 2). Gratifyingly, a variety of symmetrical or un-symmetrical diarylhyperiodonium triflates successfullycoupled with 1n. Different functional groups on the arylgroup of diarylhyperiodonium triflates, nomatter whether

Table 2. Effects of Counteranions.a

entry X yieldb (%)

1 OTf 86

2 BF4 31

3 PF6 30

4 OTs 12

5 Br 13

6 c 37

aThe reactions were conducted with 0.10 mmol of 1a, 0.12 mmol of2a, 0.005mmol of catalyst, 0.12mmol of base, and 1.0mLof solvent andstirred for 24 h unless otherwise noted. bDetermined by crude 1HNMRspectroscopy. cUsing iodobenzene as arylation reagent.

Scheme 1. Pd-Catalyzed Direct Arylation of sp3 C!H Bondswith Different 8-Aminoquinoline Amidesa

aThe reactions were conducted with 0.20 mmol of 1a, 0.24 mmol of2a, 0.01mmol of Pd(SIMes)(OAc)2, 0.24mmol ofK2CO3, and 2.0mLofClCH2CH2C1 and stirred for 24 h at 120 !C unless otherwise noted.

(13) (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (b) Li, H.; Li, B.-J.; Shi,Z.-J. Catal. Sci. Technol. 2011, 1, 191.

Org. Lett., Vol. 15, No. 18, 2013 4761

electron-withdrawing or electron-donating groups, werecompatiblewith this arylation.However, the electron-pooraryl groups performed better (3na vs 3ne, 3ni vs 3nm).Notably, the reaction exhibited excellent tolerance offunctional group. For example, fluoro (3na, 3nh, 3nm),chloro (3nb), bromo (3nc, 3nk), iodo (3no), trifluoromethyl(3nd, 3nl), and ester (3nn) groups are tolerated, and thedesired products were obtained in moderate to goodyields.14 The ortho-substituted diarylhyperiodonium tri-flates (3nh) were also suitable with a little decrease ofreactivity, which indicated that the considerable effect ofsteric hindrance. It is important to note that the electron-rich heterocyclic group (3np) could be also transferred in agood yield, which highly expanded the substrate scope.To understand the pathway of this arylation better,

we performed KIE experiments. Both intermolecularKIE (3.8) and intramolecular KIE (3.9) indicated theinvolvement of C!H bond cleavage into the rate deter-mining step (see the Supporting Information, eqs 2 and 3).Most importantly, the H/D exchange was examined bysimply heating the substrate 1b in the presence of thecatalyst in the mixed solvent of AcOD/ClCH2CH2Cl.After 24 h at 120 !C, 46% of deuterium incorporationwas observed at position, thus implying the C!Hcleavage in the absence of diarylhyperiodonium triflates

(see the Supporting Information, eq 1). On the basis ofthese preliminary results, a proposed mechanism is shownin Scheme 3. The coordination of the amide 1b withpalladiumcatalyst formed complex 8, which further under-went the C!H activation to produce 9. Diarylhyperiodo-nium salts oxidized the complex 9 to form Pd(IV) complex10. Following by the reductive elimination, the desiredproduct 3abwa

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C H Activation