Rhodium Catalyzed Direct C-H Functionalization

陈殿峰2012.10.13

Outline:

1. Introduction

2. Oxidative coupling

3. Nucleophilic Addition

4. Other Reactions

5. Conclusion

2

1. Introduction

3

Rh(I)/ ( III) Direct C-H Funtionalization

R BOH

OH

X BOH

OH

R Rh(I)Aldol-typeMannich-type1,4- addition

Hydrogenation

H2

C-X, C-O CleavageC-N, C-C CleavageIsomerization Yn-En

2. Oxidative Coupling

DG =

See: F. Glorius, J. A. Ellman, Sukbok Chang,T. Satoh, M. Miura Z.-J. Shi, X.-W. Li, T. Rovis, N. Cramer

N

R1

R2

O

R1

O

NR1R2

N

R1

OR2

O

OR1N

X HN R1

O

DG

H

Rh(III) DG

Rh(III)

RDG

R

Rh(III)

H

DG

R

elimination

Rh(I)[OX]

base

HXBase

electrophilicdeprotonation

Oxidizing DG

4

Heck Type

Arylation

Double C-Hactivation

F.Glorious, Angew. Chem. Int. Ed. 2012, 51, 2247

M. Miura, Angew. Chem. Int. Ed. 2012, 51, 5359

2. Oxidative Coupling

DG

H

Rh(III) DG

Rh(III)

DG

Rh(III)

DG

Rh(I)X

X X

[OX]

H

+ Br

[{RhCpCl2}2] (2.5 mol%)AgSbF6 (10 mol%)Cu(OAc)2 (2.2 eq)

as solvent

PivOH(1.1 eq)

CsOPiv (20 mol%)

160oC, 21h

O

N(i-Pr)2

O

N(i-Pr)2R1

R2

H

R1

Br

R2

yield 16%~89%

R2=H or ortho m/p < 3.0/1

single regiosiomer

O

N(i-Pr)2R1

Br

R2

R1 NH2

R2 R2

[{RhcodCl}2] (2 mol%)Cu(OAc)2 H2O (2.0 eq)

O-xylene, 130oC

R1 NH2

R2 R2

yield 73%~98%H H

5

Alkynylation

Y= DG

2. Oxidative Coupling

HR2 R3+

Rh(III) / [OX] Y

R2/R3

R3/R2

Y

Rh(III)

YY

R2/R3R3/R2

Rh(III)

alkyneinsertion

Alkynylation

NN

Ar

Ar

+

[{RhCpCl2}2] (1.0 mol%)Cu(OAc)2 (1.0 eq)

DMF, 80oC

NN

Ar

Ar

Ar

Ar

yield 20%~99%

T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2008, 47, 4019-4022

NN

Ar

Ar

RhX2-HX

NN

RhX

Ar

Ar

Double C-H Cleavage

NH

R1O

SNH

R1O O

NH

N

OH

NH

R1

O

6

N

O

HH

TsR2-NC+

[{RhCpCl2}2] (2 mol%)Cu(OAc)2 (2.0 eq)

DCE, 130oCN

N R2

O

Ts

yield 40%~81%Z/E = 1:7~ >99:1

RhX

N

O

Ts

CNR2

RhX

N

O

Ts

R2

insertion

Alkynylation

2. Oxidative Coupling

NAcS

O O

R1

R2R

Yield 65%~99%r.r = 1.7/1 ~ 8/1N. Cramer, ACIE, 2012, 51, ASAP

N

R1

R2R

O

R'

Yield 22% ~ 98%T.Rovis, JACS, 2010,132, 10565

O

R5

R6

OR1

R2

R3

R4

Yield 81%~97%T. Satoh, M.MiuraOL, 2007, 9, 1407

NAc

R1

R2

Yield 47% ~ 86%K. Fagnou, JACS, 2008,130, 16474

R

Yield 23%~99%T. Satoh, M.MiuraOL, 2010, 12, 2068

NR

R1 R2

N

R1

R2

Ph

Yield 85%~99%T. Satoh, M.MiuraChem. Commun, 2009, 5141-5143

NAc

NC

R

Ph

Yield 70%~72%

R2O2C

R3 R4

H

NHR1

NAc Ph

R5

R4R3

R2O2C

Yield 31%~81%

F. Glorius, JACS, 2010,132, 9585-9587

C. Zhu, Chem. Eur. J. 2011, 17, 12591-12595

Alkynylation

7

F. Glorius, J. Am. Chem. Soc.,2012,134, 8298-8301

2. Oxidative Coupling

O

H

CN+

[{RhCpCl2}2] (5 mol%)Cu(OAc)2 (2.0 eq)

DMF 100oC

H OR2

R1

R3

R1

R2

CN

R1

R2

Yield 33%~91%

HR3

DG

HR

+ NXS

DG

XR

[{RhCpCl2}2] (1 mol%)AgSbF6 (4 mol%)

PivOH(1.1 eq)

DCE, rt

X=Br, yield 35% ~ 99%X=I, yield 53% ~ 98%

Halogenation(i-Pr)2N O Me2N O n-BuHN O

NH

O

O O

O EtO O NOMe2N

O

Path a : nucleophilic additionPath b : high oxidation-state Rh(V)

Alkynylation

8

B.-Q. Wang, J. Am. Chem. Soc., 2012, 134,16163

Oxidizing DG

DG

HR-H+

Rh(III) / [OX] DGox

HR-H+

Rh(III)DG

R

Oxidizing DG

Yield 27% ~ 95%

N+ EWG

R

OPd(OAc)2 (5 mol%)

NMP, 110 oC

N

R

EWG

HN

R1

R2

R3O

R4+ NsO

HN O

R5

O

Pd(OTs)2(MeCN)2 (10 mol%)

dioxane, 80oC

HN

R1

R2

R3O

R4

NH

R5O O

Yield 45%~90%

Background

X.-L. Cui, Y.-J. Wu, J. Am. Chem. Soc., 2009, 131,13888

2. Oxidative Coupling

W.-Y. Yu, J. Am. Chem. Soc, 2010, 132,12862

R2

N

R3

OAc

R1

Pd(dba)2 (1 mol%)CsCO3 (1.0 eq)

toluene, 150oC

R1

HN

R3

R2

Yield 40%~72%

J. F. Hartwig J. Am. Chem. Soc, 2010, 132, 3676

9

N. Guimond, J. Am. Chem. Soc., 2010, 132, 6908

Oxidizing DG

2. Oxidative Coupling

N. Guimond, J. Am. Chem. Soc, 2011, 133, 6449

NH

O

OMe

R1

R2

R3

+

[{RhCpCl2}2] (1 mol%)CsOAc(30 mol%)

MeOH(0.2 M), 60oC, 16h

NH

O

R1

R2

R3

Yield 48%~90%r.r > 20:1

RhX2

N

R2R3

HOOMe

RhXN

R2R3

OOMe

N

O

R2

R3

ORhX

N

O

R2

R3

XRh

OMe

N-O cleavage

H+NH

O

R2

R3

10

Z.-J. Shi, Angew. Chem. Int. Ed., 2012, 52, 3948

Oxidizing DG

2. Oxidative Coupling

NH

O

O

O

R

NOAc

R1 R2

NH

O

O

R

DG Alkyne/Alkene

HNO

R

N

R1

R2

NH2

O

R

F. Glorius, ACIE, 2012, 51, 7318

F. Glorius, JACS, 2011,133, 2350

S. Chiba, OL, 2010, 12, 5688

Products Reference

O

N

H

O

O R1

R2R

+

[RhCp(MeCN)3(SbF6)2] (5 mol%)

Cu(OAc)2 (20 mol%)

decalin, 120oC

O

R2

R1

R

Yield 12%~90%

C-N Cleavage

RhX2

O

R2R1N

PhPh

carbonylinsertion

Ph

Ph

R2R1N O RhX2

Cu2+ transmetallation

Ph

Ph

R2R1N O CuX

Ph

Ph

O

11

2. Oxidative Coupling

For Rh catalyzed oxidative coupling:

1). Rh(III) is generally efficient catalyst because its high oxidation-state facilitates β-elimination ；

2). Versatile DGs have been well established whereas DG-free coupling reactions are still rare;

3). The fact that more than stoichiometric metal-oxidants (Cu2+, Ag+) are generally needed callsfor eco-friendly pathways (air).

4). Harsh reaction conditions (high temprature, excess oxidant, strong base or acid) lead to poor functional group tolerence.

5). Limited examples involving sp3 C-H activation are reported.

12

DG

H

DG

RhH

[Rh]

Nucleophilic

DG

RhH

X

R2R1

+

DG

XH

R1 R2

Direct Addition

3. Nucleophilic Addition

NBn

H

+ alkyl

Wilkinson's complex

(2 mol%)

toluene, 150oC, 2h

then H+, H2O

O

alkyl

For pioneering work using Ru(0)

R1

O

H

+ R2R1

O

R2

RuH2(CO)(PPh3)3 (4 mol%)

toluene, reflux

Yield 8%~99%

S. Murai, Nature, 366, 529

C.-H. Jun, Angew. Chem. Int. Ed, 2000, 39, 3440

Yield 10%~97%

For Rh(I)

13

3. Nucleophilic Addition

Direct AdditionDirect AdditionDirect Addition

N

R

R2

O

Yield 34%~95%

N

R1

R2

R3

Yield 14%~98% J. A. Ellman,JACS,

2007, 129, 5332

BnN R1

X

R3

R2

Yield 40%~96%ee 70% ~96%

J. A. Ellman,JOC, 2008,73, 6772

N

N

R1

R2

R3

Yield 71%~92%; ee% 71%~97%

J. A. Ellman,Chem. Commun, 2009, 3910

N

X

R1

R2

Yield 55%~96% J. A. Ellman, OL, 2010, 12, 2978

Y

XR1

R2

CO2tBu

n

yield 10%~95%

N

N

N

NO

O

R3

R4

yield 94%~99%, r.r >99:1

S. Chang, Angew. Chem. Int. Ed., 2012, 51, 3677

R

R1

R2

O

N

Yield 27%~96%H.-M. Huang, Chem. Eur. J. 2012, 18, 9511

14

R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2008, 130, 3645

3. Nucleophilic Addition

Direct Addition

[Rh(coe)2Cl]2 (2.5 mol%)

FcPCy2 (10 mol%)NBn R

R'

+toluene, 100oC

NBn

R

R'

NBn

R

R'

[OX] N

R

R'

Yield 32%~88%

NR1

R2

R3

R4

R5

R6

+Rh(1-2.5 mol%)]

then Na(AcO)3BH

NR5

R4

R6

R1

R2

R3

Yield 52%~95%d.r. 10:1~>99:1

R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2012, 134, 4064

15

3. Nucleophilic Addition

Direct Addition

H

H

R1

O

NH

O

.R4

R3

R2

2 mol% [CpRhCl2]2

30 mol% CsOAc

MeOH/H2O = 20/1

-20oC to rt

H

R1

O

NH

O

R4

R2

R3

.

R6

2 mol% [CpRhCl2]2

30 mol% CsOAcMeOH/H2O = 20/1

rt

R7 R5

R1

O

NH

O

R4

R2

R3

R7

R6R5

yield 53% ~ 90%m/d 12/1~30/1

yield 68%~98%

S.-M. Ma, J. Am. Chem. Soc. 2012, 134, 9597

R4R3

R2

R1

H

O

+H2N-R7

R5 R6

[{RhCpCl2}2]AgBF4

Cu(OAc)2

t-amylOH, 110oC

N

R4

R3

R2

R1 R5

R6

R7

BF4-

yield 58%~91%

C.-H. Cheng, Angew. Chem. Int. Ed., 2012, 51, 197

16

3. Nucleophilic Addition

Direct Addition

R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc, 2011. 133, 1248 J. Am. Chem. Soc, 2012. 134, 1482

R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc, 2011. 133, 11430

Others Acceptors

Imine:

Isocyanates:

NH

R2

HR1

O+ R3 NCO

[CpRh(MeCN)3](SbF6)2 (5 mol%)

THF, 16h

NH

R2

R1

O

NHR3

O

Yield 44%~96%

N

R1TsHN

Yield 33%~ 84%

N

R1HO

Yield 17%~ 90%

Aldehyde:

N

H

NPG

R1

+ Rh(III) N

R1

NHPG

Yield 27% ~ 95%

Z.-J. Shi, Org. Lett, 2012, 14, 4498

Z.-J. Shi, Org. Lett, 2012, 14, 636 Org. Lett, 2012, 14, 4498

17

Notes: 1.DG as acceptors; 2. Strained direct addition

3. Nucleophilic Addition

Delayed Addition

DG

H

R1

R2

+

DG

R2/R1R2/R1

Rh H[Rh]

X

R3 R4

Nucleophilicaddition

DG

R2/R1R2/R1

R4

R3XH

insertion

H

NPh

+

R

R

[CpRhCl2]2 (1 mol%)Cu(OAc)2. H2O (1.0 eq)

DMF, 80oC

Ph

R

R Yield 32%~99%

T. Satoh, M. Miura. Chem. Commun. 2009, 5141

NRhX2

RR

Ph

R

R

NPh

RhX2

delayedaddition

beta-hydrogen

elimination

R

R

NPh

H+

?

R

R

NHPh

or Rh(I)

18

N. Cramer, Angew. Chem. Int. Ed, 2010, 49, 8181

N. Cramer, Angew. Chem. Int. Ed, 2011, 50, 11098.

3. Nucleophilic Addition

NH

RAr+ R1 R2

[Rh(cod)OH]2 (1-5mol %) dppp (1.2 eq/Rh)

toluene, 120oC

R NH2

R1

R2

R'yield 55%~98%r.r for 1 = ~2.0/1r.r for 2 > 30/1

1 2

NH

R1

[Rh(cod)OH]2 (5mol %) Ligand (6 mol %)

toluene, 120oC

R1 NH2

R2yield 55%~98%r.r. 2.3\1 ~ >2.0/1

R+

R2

R

P.-J. Zhao, Chem. Eur. J. 2010, 16, 2619

R1

R2NH

R1

[Rh(coe)OH]2 (2.5mol %) Ligand (6 mol %)

toluene, 100-120oC

yield 43%~90%r.r. 2.0\1 ~ >2.0/1ee 76% ~ 96%

R+

R NH2

R2

R1

R

Delayed Addition

19

C.-H. Cheng, Angew. Chem. Int. Ed, 2011, 50, 4169

F. Glorius, J. A m. Chem. Soc. 2011, 133, 2154

3. Nucleophilic Addition

Delayed Addition

R2

R3O

R1yield 61%~93%

R+

R1 OH

R3

R2

R[{RhCpCl2}2] (1 mol%)AgBF4(5 mol%)

Cu(OAc)2H20(2.0 eq)

t-amylOH, 120oC

Ph

R3

Oyield 40%~70%E/Z = 2/1 ~ 3/1

+ R3

R2

R[{RhCpCl2}2] (2.5 mol%)

AgBF4(10 mol%)

Cu(OAc)2 H20(2.1 eq)

dioxane, 140oC

HR1

HR2

R1

Ph

O +

[{RhCpCl2}2] (2.5 mol%)AgBF4(10 mol%)

Cu(OAc)2 H20(2.1 eq)

dioxane, 140oC

R3

HR2

R1 H

Ph

R R3

R1

yield 51%~80%E/Z = 2/1 ~ 3/1

20

3. Nucleophilic Addition

For nucleophilic C-Rh :

1). Rh(I)/Rh(III) are both efficient catalysts ；

2). More type of acceptors are needed to developed and three components reaction has not been reported;

3). Alkenes or other moities that could insert C-Rh bond may take the place of alkynes

4). Limited assymetric examples have been demonstrated, which indicates, in a way, the limitation of existing chiral ligands.

21

4. Other Reactions

M. Murakami, J. A m. Chem. Soc. 2007, 129, 12086

Nucleophilic addition via C-C Cleavage

N

R3

OHR1

R2

+ R

N

R2

R R1 R3

O

+

Yield 33% ~ 94%

[CpRhCl2]2 (2.5 mol%)Ag2CO3 (1.2 eq)

EtOH, 70oC

M. Murakami, J. A m. Chem. Soc.2012, 134, ASAP.

OHR2

R1 +

R3

R4

[Rh(cod)(OH)]2 (2.5 mol%)

toluene, 100oCR1

R2

OH

R3

R4

Yield 69% ~ 96%

OHPh

1

2

2.5 mol% Rh(I) site product

[Rh(cod)(OH)]2

[Rh(cod)(OH)]212 mol % IPr

2

1 Ph

O

80%

Ph

O 89%

PhO

Rh beta-carbonelimination

Rh

Ph

O

Oxidative Coupling via C-C Cleavage

Z.-J. Shi, J. A m. Chem. Soc.2011, 133, 15244.

22

4. Other Reactions

Carboacylation of Olefins

A

X

O

B

R2

R1 [Rh(cod)Cl]2 (2.5/5 mol%)dppb (6/12 mol%)

toluene, 130oC

A

X

BR2 R1

RhO

BA

O

R2R1 R1= H, 61%~94%

R1=R2=H, 35%R2=H, 10%

X

G.-B. Dong, Angew. Chem. Int. Ed, 2012, 51, 7767

Ring Open of VCP

VCP XR

[Rh(CO)2Cl]2 (2.5 mol%)AgSF6 ( 6mol%)

(R)-8H-BINAP (6.5 mol%)

DCE, 50-70 oCX

R

Yield 40%~90%ee 48%~99%

Z.-X. Yu, J. A m. Chem. Soc.2011, 134, 398.

XY

X

Y

R1

R2

HH [Rh(CO)2Cl]2 (5 mol%)

AgSF6 ( 12 mol%) L (25 mol%)

DME, 60-80oCR1

R2

Yield 46%~91%ee 81% ~ 94%

d.r. > 19:1

O

OP N

Et

Et

L

Z.-X. Yu, Angew. Chem. Int. Ed, 2011, 50, 2144 23

Z.-X. Yu, J. A m. Chem. Soc.2010, 132, 4542.

4. Other Reactions

24

5. Conclusion:

25

1). Rh(I)/Rh(III) are versatile catalysts towards C-H bond activation;

2). Necessary DGs limite the substrates scope;

3). Direct sp3 C-H functionalization remains challenging;

4). Mild reaction conditions are demanded for better functional group tolerence.

5). New chiral ligands or novel asymmetric catalytic circles would highlight Rh catalyzed C-H activation.