化 学 系Department of Chemistry

Catellani Reaction

2011.04.09

Introduction

Mechanism

Synthetic Applications

Contents

Conclusions

2

The Nobel Prize in Chemistry 2010

Richard F HeackUniversity of Delaware,Newark,DE,USA

Ei-ichi NegishiPurdu University,West Lafayetle,IN,USA

Akira SuzukiHokkaido University,Sapporo,Japan

For palladium-catalyzed cross-coupling reactions in organic synthesis.

Introduction

3

Marta Catellani

1971,obtained Italian laurea under supervition of Prof. G. Casnati at the University of Parma . 1977,started to work on homogeneous Catalysis with group metals, Ⅷ G.Casnati Group 1978-1979, Postdoc, UC, Prof. J. Halpern 1989-1990, short periods in Sheffied,Tsukuba,Russia and China. 1990-present, full professor at Uiversity of Parma.

Catellani M, Angrew. Chem. Int. Ed. 1997,36,119-122.

Introduction

H

I

H+ I R1

R2+

Pa(0) cat, base

DMA, 20oC, 30hR1 R1

R2

Yield: 31~100%E type: 89~95%

R

R=H, Me, CO2MeR1=n-Bu, BnCH2,n-OctR2=CO2Me, Ph, n-Hex

4

Introduction

Role of Norbornene :1. Essential for this reaction to occur;2. Plays as a catalyst;3. More than stoichiometric norbornene is necessary

norbornene

.

.

.

Catellani Reaction is defined as

Norbornene-mediated

Ortho C-H Functionalization.

5

R1

R2

R

H

X

R

Mechanism

R1= Alkyl, ArylR2=Aryl, Alkenyl, H, CNR = H, or bulky substisuents

R1

PdllX

RPd0

H

PdllX

R

H

R

R2-Y

R1

R2

R

H

X

R

XPdll

Base

Base•HX

R

Pdll

R1-X

R

PdlV

X

R1

R

R1

XPdll

Ternination

Oxidative Addition 1

Carbopalladation with norbornene

Palladacycle

Oxidative Addition 2

Reductive Elimination

Norbornene Extrusion

6

Oxidation Addition 1

Pd0

H

X

R

R1-X

H

PdllX

R

R1-PdllX

R1=alkyl, path 1 predominates.

R1=aryl , it depends on Ligands.

Path 1

Path 2

7

Carbopalladation of Norbornene

Pd0

H

PdllX

R

tranditional cross-copling

carbopalladation of norbornene

R2-Y

H

R2

R

H

R

XPdll

X-Y +

?

1. High reactivity (strain energy 90.4 kJ/mol)

2. Superstoichiomeric quantities

Favored

8

PdllCl

ClPdll

Phenylnorbornylpalladadium(Ⅱ) dimer

PNP dimer

Inoue M, Tedrahendron Lett.,1974(15),8,647-650.

I

+ I n-BuCO2Me

+

K2CO3(2.0 eqv)

DMA, 20oC, 30h

n-Bu n-Bu

CO2Me

Yield:93%

10mol%PNP dimer

1.0 eqv 1.5 eqv2.0 eqv

+

1.0 eqv

Catellani M, Angrew. Chem. Int. Ed. 1997,36,119-122.

9

Carbopalladation of Norbornene

Palladacycle Formation

-Hybride Elimination

H

R

XPdll

?

R

Pdll

H

R

palladacycle formation

1.Inability of bicycle system for beta-Hybride elimination

2.Electrophilic aromatic substisution at ortho aromatic carbon

10

Sicher J. Angrew. Chem. Int. Ed. 1972,11,200-203

Palladacycle Formation

XPdllPdll

L

+L

-X

PdllL

L

H

-H

R R R

EAS:

Parshall G W. Acc Chem Res,1970(3),139-144.Markies BA. J Chem Soc Chem Commun ,1992, 1420-1423.

Wheland-type Intermediate

rate limiting step.

11

ESA: electrophilic aromatic substitution

Pdll

Py

-KCl

Pdll-PhOH

R R

Py

ClPhOK

Pdll

Py

R

Py

PhO PyPy

O PdII

H

D

ClPh3P

PPh3

PhOK

or Ag2CO3

H

PdII

O

Ph3P PPh3

D

PdII

O

Ph3P PPh3

+

1 : 1

Supports ESA for deprotonation is not rate limiting.

Echavarren AM .Chem Eur J. 2001(7), 2341-2345.

R NO2 H OMe

Minutes for 50% conversation

240 100 10

Catellani M . J Organomet Chem ,1992, 425:151

12

Palladacycle Formation

Oxidative addition 2

R

Pdll

Palladacycle R

PdlV

X

R1R1-X

A side product ofen seen:

Pdll

Palladacycle

reductive elimination

Pd0

+X

1.0 eqv2.0 eqv

Pd(PPh3)4K2CO3

DMF,105oC

X=Br, ndX=I, 62%

Catellani M, Synthesis, 1996,769-772

13

I

NTs

I

Pd(AcO)2(15 mol%)PPh3(33 mol%)norbornene(7 equiv)Cs2CO3(5 equiv)

DME, wave,180oC N

CO2tBu

Ts

CO2tBu+

14

Addition with Alkyl Halides

1,10-phenanthroline

Ligand:

Catellani M, J Organomet Chem, 1993 .458:C12

Lautens M. Angew Chem Int Ed,2007,1485-1488

Oxidative addition 2

80% ee 63%ee

15

Addition with Aryl Halides

Catellani Mechanism:

R

Pdll

Palladacycle R

PdlV

X

ArylAryl-X

Echavarren Mechanism:

R

Pdll

Palladacycle

Aryl X

Pd0

Aryl PdIIX

R

Pdll

Pdll

X

Aryl

Oxidative addition 2

Catellani M, J Organomet Chem, 1991 .407:C30

Echavarren AM .J Am Chem Soc. 2006(128), 5033-5034.

Low energy

16

Reductive Elimination

PdIIN

N

Br

O2N PdIV

O2N

Br

N

N

NO2

PdII Br

NN

NO2

PdII Br

NN

Catellani M. J Organomet Chem,1990.390:251

Not observed

sp2-sp3 bond formation

17

sp2-sp2 bond formation

PdIIL

LPdIV

Aryl

R

Aryl

X

XL

L

R

R=bulkylPdII

X

L

LR

Aryl

R=H

PdII L

L

Aryl

X

The Ortho Effect

Reductive Elimination

Catellani M. J Organomet Chem,1991.407:C30

18

Norbornene Extrusion

PdIICl

2

2F

Br

K2CO3

DMF

PdII

Br

F

F

L1

L1

L1=DMF

+ then

N

CO2MeF F

PdIIL2 L2

Br

L2

Steric factors!

Characterized by NMR

I

O

I

CO2t-Bu

Pd(AcO)2 15mol%PPh3(33mol%)

Cs2CO3(5 equiv)

DME, uwave,180oC

7 equiv

O

CO2t-Bu

47%Lautens M .J Org Chem, 2009(74). 289-293

19

Terminating Events

R1

PdllX

R

Nu HR1

Nu

R

Pd0

PdII

R1

R2

R1/R3

R2PdII

R3

Z

R1/R3

R2Z

R3

20

Synthetic Applications

21

Mizoroki-Heck

R1

R2I

R3 I+EWG+

Pd(AcO)2(20mol%)K2CO3(5.2 equiv)KOAc(5.2 equiv)

DMF, 55oC

2 equiv

R1/R3

R2

R3

EWG

Intermolecular

Catellani M, Angrew. Chem. Int. Ed. 1997,36,119-122.

R3=alkyl

R1 I+EWG+

Pd(AcO)2(10mol%)PPh3(20 mol%)CsCO3(3-5 equiv)

CH3CN or DME, 80oC

6 equiv

X

I

X

EWG

R1

Mark. Lautens. Org Lett .2006,8,3939-3942.

22

I+

Y

X

Y

X

( )n

( )n

R1 R3

R2

Pd(AcO)2(10-20mol%)PPh3(22-44mol%)

norbornene(3-5equiv)Cs2CO3(5 equiv)

DME, 60-180oC

I

R1

Y

Y ( )n

( )n

O

O

NHt-Bu

87%

TsN

O

Ot-Bu

S

S

O

Ot-Bu

O

ON

MeO

54% 52% 57%

O Si

Si

O

Ot-Bu

O

60%

Lautens M. Org Lett, 2003(5). 4827Lautens M. Synlett, 2006. 2629Lautens M. J Org Chem, 2007(72). 775Lautens M. Angew Chem Int Ed, 2007(46). 1485

Mizoroki-Heck

Intermolecular

23

I+ CO2Me +

Br Br

NO2

OHPd(OAc)2(1.25mol%)norbornene(0.8 equiv)K2CO3(3.2 equiv)

DMF, 105oC

1 equiv 3.2 equiv 1 equiv

O

Br

NO2

CO2Me

86%

Catellani M, Org Lett. 2006(8). 3967Catellani M, Synthesis. 2008. 995

Oxyl-Micheal addition

Mizoroki-Heck

Intermolecular

24

R1

R2 +Br

R3

R4

( )n

1 equiv 3-5 equiv

Pd(AcO)2(10 mol%)tri-2-furylphosphine(20 mol%)norbornene(2-6 equiv)Cs2CO3(2-6 equiv)

CH3CN or DME, 85-100oC

R1 R3

R2 R4

( )n

Lautens M (2000) Angew Chem Int Ed 39:1045Lautens M (2001) J Org Chem 66:8127Lautens M (2005) Tetrahedron 61:6283Lautens M (2002) J Org Chem 67:3972

Mizoroki-Heck

Intramolecular

25

I

O

I

CO2t-Bu

Pd(AcO)2 (15 mol%)PPh3 (33 mol%)norbornene (7 equiv)Cs2CO3 (5 equiv)

DME, uwave,180oCO

CO2Me

H

82% ee 78%(80% ee)

Lautens M .Angew Chem Int Ed. 2007(46). 1485Lautens M .J Org Chem. 2009(74). 289

Mizoroki-Heck

Intramolecular

26

I

R1

R2

+ R3 Br ArB(OH)2+

Pd(AcO)2 (1 mol%)norbornene(1 equiv)K2CO3(6 equiv)

DMF, rt.

Ar

R1/R3

R2 R3

MeO2C

MeO2C

90% 89%

89% 71%

Catellani M. Chem Commun, 2000. 157

OMe

MeO

MeO2C

MeO2C

88% 82%

89% 71%

I

R1

+ ArB(OH)2

Pd(AcO)2 (1 mol%)norbornene(1 equiv)K2CO3(4 equiv)

DMF, 105oC

R1

R1

Ar

Catellani M. J Mol Catal A: Chem. 2003. 115

Suzuki-Miyaura

27

Cassar-Sonogashira

I+

R1

R2 X +Ph

Pd(AcO)2 norbornene

K2CO3

DMF,rt.

R2

R1 R2

Ph

Yield promoted By KOAc ,Excess alkyl halide

I+

F

R2 X +Ph

Pd(AcO)2(10 mol%) norbornene(1.2 equiv)

KOAc(6 equiv)

DMF,rt.F

Ph

1 equiv 4 equiv 1.2equiv79%

Catellani M. J Organomet Chem. 2004. 689:3741

Copper –free!

~50%

28

I

Pd(AcO)2norbornene

Ligand

n-BuIcranide source

bae

CN

CN

NC

NC

Lautens M. JACS. 2006,128, 14436-14437;

R1

I

H

R2 + Ar Br

Pd(AcO)2(2.5mol%)tri-furylphosphine (6mol%)

K4Fe(CN)(5.5 equiv)norbornene(1.5 equiv)

Cs2CO3(1.5 equiv)

CH3CN,130oC uwave

R1

CN

Ar

R2

CN

O

61%

CN

CF3

CN

OMe

94%

56%

Cl CN

SO2Me

62%

Cyanation

Lautens M . JACS. 2007,129, 15372-15372;

Zn(CN)2K4Fe(CN)6

Direct Arylation

C-H activation of arene is difficultCatellani reaction is a powful strategy for direact arylation.

R

I2 R1C CR2+

Pd(AcO)2

(R2)R1 R1(R2)

R

R

Marta.Catellani. Org Lett. 2001,3611-3614.

Base effect ： K2CO3&Bu4NBr >> Cs2CO3&KOAcSolvents ： DMF>>DMA>>acetontrile

29

60-94%

Direct Arylation

O2N N

CO2Me

86%

Cl

OMe

OMe

NCO2Et

75%

N

O62%

N

N

N

O

O

39%

R1

I

H

R2+

Pd(AcO)2(10mol%)tri-furylphosphine (22mol%)

norbornene(2 equiv)Cs2CO3(2 equiv)

CH3CN, 90oC

R1

R2

YNH

R3

Br( )n

R4

1 equiv 1.5~2 equiv

NY

R3

( )nR4

Mark Lautens. JACS,2005,13148; JOC,2008,1888; OL,2006,3601OL, 2006,2043.

S

Cl

S

AcHNO

S

O2N

O

Cl

77% 70% 66% 53%

Mark Lautens. JOC,2008,8705; OL,2006,4827

30

Buchwald-Hartwig Reaction

Marta Catellani. OL. 2004,4759

R1

I

H

+

Pd(AcO)2( 5mol%)tri-furylphosphine (10mol%)

norbornene(1.5 equiv)K2CO3(2 equiv)

CH3CN, 85oC

R1

1 equiv 1 equiv

Br

HN

R2

Ar

N

R2

O

Ar

N O N O

S

N O

O

N

N

O

Ph

Ph

80% 78%

48% 63%

R1

I

H

+

Pd(AcO)2( 10mol%)tri-furylphosphine (22mol%)

norbornene( 2 equiv)Cs2CO3( 4 equiv)

CH3CN, 135oC

R1

2 equiv 1 equiv

Br

HN

R3

R2

( )nR2

NR3

( )nN

NO2

N N

NO2

NCO2Et

86% 45%

55%66%

Mark Lautens. OL. 2007,5255

31

32

Addition to C=O/C=N and C=C Bonds

R1

IR2 +

R3

X

R4

Y

Pd(AcO)2(10mol%)Ph3P(10-22mol%)

norbornene(0.5~3equiv)Cs2CO3(1-2 equiv)

H2O(0-48 equiv)

R1

R2

R4

R3YH

X= Clor

R1

R2

R4X= BrR=OMe

YDME, 90oC or 150oC

F

OH

F

NHSO

OMe O OH

86% 37%

83% 70%

I+ Br

NHBoc

+

O Ot-Bu

Pd(AcO)2(10mol%)tri-2-furylphosphine(20mol%)

norbornene(2 equiv)Cs2CO3(2 equiv)

DMF, 80oC NBoc

Ot-Bu

O

68%1 equiv2 equiv 2 equiv

Catellani M. Tetrahedron Lett, 2004(45),6903-6907.

Mark Lautens. AICE. 2009,1849

33

Conclusions

Catellani reaction is a useful and mechanistically interesting method for the polyfunctionalization of aromatic

molecules.