organo-transition metal chemistry - organische chemie · organo-transition metal chemistry 1. some...

Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 1

Organo-transition Metal Chemistry

1. Some Basics

Chemistry involves intermediates containing transition-metal carbon bonds

M CL2

L4L5

L1

LnM C

LnM C

LnM C

LnM

sp3

sp2

sp LnM

LnM C

LnM CH

ligand sphere

Coordination

LnM H

Metal-ca

L3 LnM C

rbon sigma bond

LnM

LnMC O

Electron Counting:

• Formal neutral ligand (L): PR3, NR3, CO, alkyne, Alkene • Formal anionic ligand (X): R, Ar, H, X, CN, RCO

PdPPh3

PPh3Ph3P

Ph3P

PdPh3P

Ph3P

Ar I

PdI

ArPh3P

Ph3P

ML4 Pd(0) d10 = 10 ePPh3 2 e X 4 = 8 e

18 e

ML2 Pd(0) d10 = 10 ePPh3 2 e X 2 = 4 e

14 e

ML2X2 Pd(II) d8 = 8 eAr, I 2 e, 2 e = 4 ePPh3 2 e X 2 = 4 e

16 e


Ligand Exchange: Ligand Association and Ligand Dissociation

LnM L' + :L'

L-dissociation L-dissociation

PdPPh3

Ph3P

Ph3P

PPh3Pd

PPh3Ph3P

PPh3

MLn

PdPPh3

PPh3

- PPh3

Ligand association

Ligand dissociation

- PPh3

Vacant site

Oxidative Addition/Reductive Elimination

M(n)Ln

I

X

X

+

Oxidative Addition.

Y

IPdPh3P

PPh3Pd0PPh3

PPh3

Pd2

IPPh3

PPh3

M(n+2)LnY

Pd2PPh3

PPh3

R

Pd(PPh3)2

R

usually polar bond

Oxidative Addition.

Reductive Elimination


M(nM(n

I

Y

IPdPdPh3PPh3P

PPh3PPh3Pd0Pd0PPh3PPh3

PPh3PPh3

Pd2Pd2

IPPh3PPh3

PPh3PPh3

M(n+2)LnM(n+2)LnY

Pd2Pd2PPh3PPh3

PPh3PPh3

R

Pd(PPh3)2Pd(PPh3)2

R

usually polar bondusually polar bond

Oxidative Addition.Oxidative Addition.

Reductive EliminationReductive Elimination

Reductive EliminationReductive Elimination

)Ln)Ln X

X

+

Oxidative Addition.Oxidative Addition.

Ligand effect: Electron donating ligands facilitate oxidative addition (e.g. PR3, R, H); electron withdrawing ligands facilitate reductive elimination (e.g., CO, CN, olefins).

Migratory Insertion/De-insertion: Migration of one ligand to a neighboring unsaturated ligand (CO, RNC, alkyne, alkene), generating a vacant site. Usually reversible. Vacant site is cis to the newly formed ligand.

LnM LnMR

O

LnM L MC

CH

R2H

R

n

R

R2

R

Insertion

De-insertion

C O


Carbometallation/β-elimination

LnMLn

vacant site

Carbometallation

β-elimination

M R

R PdH

R

RRR

Φ = 0 O

LnPdH

H Pd Ln

Rβ-Hydride EliminationRRH R

LnPd

H

R

R

R

H R

R

Dehydropalladation

LnPdLnPdH

H PdPd LnLn

Rβ-Hydride Eliminationβ-Hydride EliminationRRH R

LnPdLnPd

H

R

R

R

H R

R

DehydropalladationDehydropalladation

• Carbometallation: Insertion into alkene/alkyne group • Migrating aptitude of β-Eliminaton : H >> Alkyl, Ar > RCO> OR • β-Hydride Elimination : Very common pathway for the decomposition of alkylmetal

complexes

2. Heck Reaction

ICO2Me

CO2Me

10 mol %Pd(OAc)2

PPh3, K2CO3CH3CN100 oC, 90 %

R1 X R2 R2R1 +

cat. PdX

Base, PR3

• R1: Aryl, Vinyl, Benzylic, Allylic, Acyl • X: N2+ > I > Br~OSO2CF3 >> Cl (relative rate of oxidative addition) • PdX: Pd(0) or Pd(II). Active Pd(0) species can be instantaneously made from Pd(II) in

reaction media

• Base : Scavenger of HX • PR3: Prevents Pd(0) from precipitation to make palladium mirror • Solvent: Often coordinating solvents such as NMP, DMA, DMF, acetonitrile but

sometimes toluene can be used • Temperature: room temp. to 140 oC


Catalytic cycle:

Pd(PPh3)4

- HXR 1 X

R 1R 1

R 1R 1

R 1

Ph3)2X R 1

Pd(0 )(PPh 3)2

Pd (II)(PPh3)2XH Pd(II)(PPh3)2X

R 2R 2

H Pd (II)(PPh3)2X Pd (II)(PPh3)2X

R 2R 2

R 2

H Pd(P

H R 2

Pd(PPh3)2X

- 2 PPh3

BaseO xidative A ddition

Syn- Carbopalldation

internal ro ta tion

Syn-β -H-E lim ina tion

R eductiveE lim ination

H H

H H

Intramolecular Heck Cascade

SiMe3

I

SiMe3

SiMe3

SiMe3

SiMe3

SiMe3

SiMe3

Pd(0)

Carbopalladati

Oxidative addition ligand association Carbopalladation

DehydropalladationBeta-H-elimination

ligand association

PdLn

PdLn' I

H PdLn

PdLn

H PdLn

PdLn

on

β-H-elimination

Tandem Heck Reaction

• Intermolecular Heck reaction followed by intramolecular one • Syn-Carbopalladation leads to only one geometric isomer


Stable Organo-Pd intermediate

without syn β-H

Syn-carbopalladation

I

Me MeLnPd MeLnPd

CO2Me

Me

MeO2C

3 mol %Pd(PPh3)4

2.5 eq. Et3N100 oC, 12 h

80 %

Sequential Tandem Heck Reaction

H

OtBu

HMeO

OtBu

Br HPd

POAc

R

OtBu

HMeO

H

H

HMeO

OtBu

H

H

LnPdLnPd Ha

HMeO

OtBu

H

120 oC

(R: o-t10 %Pd(OAc)2,22 % PPh3,

60 oC, 60 h.CH3CN, DMFnBu4N(OAc)

2.0 eq

63 %

Syn- Elimination

LnPd

R

BrBr

HeHa He

ol)

MoreReactive


H

OtBuOtBu

HMeOMeO

OtBuOtBu

BrBr HPdPd

POAcOAc

R

OtBuOtBu

HMeOMeO

H

H

HMeOMeO

OtBuOtBu

H

H

LnPdLnPdLnPdLnPd HaHa

HMeOMeO

OtBuOtBu

H

120 oC120 oC

(R: o-t(R: o-t10 %Pd(OAc)2,22 % PPh3,


10 %Pd(OAc)2,22 % PPh3,


2.0 eq2.0 eq

63 %63 %

Syn- EliminationSyn- Elimination

LnPdLnPd

R

BrBrBrBr

HeHeHaHa HeHe

ol)ol)

MoreReactiveMoreReactive



Stable Organo-Pd Intermediates

• Intermediate organo-palladium species are thermally stable due to the absence of hydrogen β-syn to palladium

R

R

R

R

R1 PdLn

R1 PdLn

R1PdLn

RR

RPdLn

R1

R

R X

R1 PdLn

PdLn

R

R1PdLn

Pd+L2

- X


3. Stille Coupling Reaction

Br

H3C H3C3C

Bu3Sn

10 mol %Pd(PPh3)4

PhCH100 o

R1

• R1, R2 : sp2-hybridized carbon

X R2 SnBu3 R1 R2 X SnBu3+ +cat. Pd

• X: I > OSO2CF3 > Br >> Cl • Ability for transmetalation: alkynyl> alkenyl> benzyl, allyl> alkyl • Exceptional functional group tolerance • High cost and toxicity of organotin reagent

4. Suzuki Coupling Reaction

Br

OHC OHC (HO)2B

10 mol %Pd(OAc)2

PPh3, Na2CO3iPrOH, H2O,reflux. 86 %

B

CNCN

3 mol %PdCl2(dppf)2.0 eq. K2CO3DMF, THF, 50 oC81 %

O

Br

O

• Less expensive, less toxic alternative to Stille coupling • Sp3 carbon can be involved in coupling partner • Relative rates of reductive elimination: aryl-aryl > alkyl -aryl> alkyl-alkyl • Somewhat basic conditions needed


Catalytic Cycle of Stille/Suzuki Coupling

R1R1

R1

X

Pd(II)Ln

X M

R2

Pd(II)Ln

Pd(0)LnOxidative Addition

Transmetallation


X

R2 M

R2

Pd(II)LnX

R2M

R1

R1

• Transmetallation step is supposed to be the slowest in the Stille coupling • Depending on the leaving group, oxidative addition can be a rate determining step in

Suzuki coupling

Termination with Carbonylation

R Pd(II)LnCO

R Pd(II)Ln

stable organo-Pd species

Heck Nu

Suzuki Stille

R

O

R'

R R2

O

R R3

O

R Nu

O

NuR2NHROHArOH

CO

R Pd(II)Ln

O

• Higher affinity and fast insertion of CO ligand to Pd • Relative migratory insertion rate: alkyne > carbon monoxide (ca. 1 atm) > alkene


OtBu

OTIPS

Me3Sn

Ph I

R1 SnBu3

MeN

N

NMe

I

O

R2 X

Ph SnBu3

CO

(PPh3)2PdCl2

R1 R2

O

Ph

O

Ph

OTIPS

OtBu

ON

MeN

MeN

O

X SnBu3+

R2 = Aryl-, Alkyl-, Allylhalogenide und -triflate

+Pd catalyst

+

+11 bar CO

70%

J. K. Stille J. Am. Chem. Soc. 1984, 106, 6417

2.5 mol % Pd2(dba)3+

L. E. Overman J. Am. Chem. Soc. 1993 , 115 , 3966

22% Ph3AsCO (12 bar)LiCl , NMP

70o C80%

OtBuOtBu

OTIPSOTIPS

Me3SnMe3Sn

PhPh I

R1R1 SnBu3SnBu3

MeNMeN

N

NMeNMe

I

O

R2R2 X

PhPh SnBu3SnBu3

COCO

(PPh3)2PdCl2(PPh3)2PdCl2

R1R1 R2R2

O

PhPh

O

PhPh

OTIPSOTIPS

OtBuOtBu

ON

MeNMeN

MeNMeN

O

X SnBu3SnBu3+

R2 = Aryl-, Alkyl-, Allylhalogenide und -triflateR2 = Aryl-, Alkyl-, Allylhalogenide und -triflate

+Pd catalystPd catalyst

+

+11 bar CO11 bar CO

70%70%

J. K. Stille J. Am. Chem. Soc. 1984, 106, 6417J. K. Stille J. Am. Chem. Soc. 1984, 106, 6417

2.5 mol % Pd2(dba)32.5 mol % Pd2(dba)3+

L. E. Overman J. Am. Chem. Soc. 1993 , 115 , 3966L. E. Overman J. Am. Chem. Soc. 1993 , 115 , 3966


70o C80%


70o C80%

Examples of the Stille reaction:

ON

MeO

O

O

OMeMe

OH

OMe

O

Me

Me

OMe O

MeOMe

OH

HOMeO

Me

N

O

O

O

OMeMe

OH

OMe

O

Me

MeI

OMe

O

MeOMe

OH

HOMeBu3Sn SnBu3

20 mol% Pd(MeCN)2Cl2i-Pr2NEt

25 °CDMF/THF48 hours

I

ON

MeMeO

O

O

OMeMeMeMe

OHOH

OMeOMe

O

MeMe

MeMe

OMeOMe O

MeMeOMeOMe

OHOH

HOHOMeMeO

MeMeO

NO

O

OMeMeMeMe

OHOH

OMeOMe

O

MeMe

MeMeI

OMeOMeHOHOMeMe

SnBu3SnBu3Bu3SnBu3Sn

OOMeOMe

MeMe OHOH

20 mol% Pd(MeCN)2Cl220 mol% Pd(MeCN)2Cl2i-Pr2NEt

25 °CDMF/THF48 hours

i-Pr2NEt25 °C

DMF/THF48 hours

I

K. C. Nicolaou, Chem. Eur. J. 1995, 1, 318.

R1 SnBu3 R2 Cl

O

R2 R1O

Cl SnBu3Pd catalyst

R1 = Alkyl, Alkenyl, Aryl, Alkynyl, H

R2 = Alkyl, Alkenyl, Aryl, Alkynyl

++R1R1 SnBu3SnBu3 R2R2 ClCl

O

R2R2 R1R1O

ClCl SnBu3SnBu3Pd catalystPd catalyst

R1 = Alkyl, Alkenyl, Aryl, Alkynyl, HR1 = Alkyl, Alkenyl, Aryl, Alkynyl, H

R2 = Alkyl, Alkenyl, Aryl, AlkynylR2 = Alkyl, Alkenyl, Aryl, Alkynyl

++

The coupling of acid chlorides proceeds without Pd catalyst in many cases.

O

O

O

NHBoc

SnMe3HN O

O

O

NHBoc

HN R2

OK2CO3

i-Pr2NEt

R2COCl

Pd2dba3•CHCl3O

O

O

NHBocNHBoc

SnMe3SnMe3HNHN O

O

O

NHBocNHBoc

HNHN R2R2

OK2CO3K2CO3

i-Pr2NEti-Pr2NEt

R2COClR2COCl

Pd2dba3•CHCl3Pd2dba3•CHCl3


Stille reactions with triflates

OMe

R1 R2O

OTfMe

Me3Sn SiMe3

R1 R2OTf

THF, ΔLiCl

Pd(PPh3)4 Me

SiMe3

1. LiNi-Pr2

2. Tf2O

Tf = CF3SO2

W. D. Wulff Tetrahedron Lett. 1988, 29, 4795.

1. LiNi-Pr2(< 1 equivalent)

2. Tf2O

OMeMe

R1R1 R2R2O

OTfOTfMeMe

Me3SnMe3Sn SiMe3SiMe3

R1R1 R2R2OTfOTf

THF, ΔTHF, ΔLiClLiCl

Pd(PPh3)4Pd(PPh3)4 MeMe

SiMe3SiMe3

1. LiNi-Pr21. LiNi-Pr2

2. Tf2O2. Tf2O

Tf = CF3SO2Tf = CF3SO2

W. D. Wulff Tetrahedron Lett. 1988, 29, 4795.W. D. Wulff Tetrahedron Lett. 1988, 29, 4795.

1. LiNi-Pr21. LiNi-Pr2(< 1 equivalent)(< 1 equivalent)

2. Tf2O2. Tf2O

Preparation of stannanes from triflates:

OTfMe Me3Sn SnMe3

SnMe3Me

Pd(PPh3)4

W. D. Wulff J. Org. Chem. 1986, 51, 277.

LiCl, Li2CO3

oder(Me3Sn)2Cu(CN)Li2

OTfOTfMeMe Me3SnMe3Sn SnMe3SnMe3

SnMe3SnMe3MeMe

Pd(PPh3)4Pd(PPh3)4

W. D. Wulff J. Org. Chem. 1986, 51, 277.W. D. Wulff J. Org. Chem. 1986, 51, 277.

LiCl, Li2CO3LiCl, Li2CO3



Heterocycles:

N

N

N

N

N

Br

Br N

OO

Bu3Sn

Pd(PPh3)4

N

N

NBr

N

O

O

+

T. R. Kelly J. Org. Chem. 1997, 62, 2774.

37%

N

N

N

N

N

BrBr

BrBr N

OO

Bu3SnBu3Sn

Pd(PPh3)4Pd(PPh3)4

N

N

NBrBr

N

O

O

+

T. R. Kelly J. Org. Chem. 1997, 62, 2774.T. R. Kelly J. Org. Chem. 1997, 62, 2774.

37%37%


Palladium on charcoal can be used as a source of the catalyst:

H3CO

I

I

OMe

SnBu3

SnBu3

MeO

H3CO

10 mol % CuI20 mol % AsPh312 hrs.

(82 %)

+0.5 mol % Pd (10 mol % Pd/C)

(88%)

0.5 mol % Pd (10 mol % Pd/C)

+

10 mol % CuI20 mol % AsPh316 hrs.95 % trans

100 % trans

Liebeskind , L. ,Tetrahedron Letters , 1995 , 36 , 2191.

H3COH3CO

I

I

OMeOMe

SnBu3SnBu3

SnBu3SnBu3

MeOMeO

H3COH3CO



(82 %)(82 %)

+0.5 mol % Pd (10 mol % Pd/C)0.5 mol % Pd (10 mol % Pd/C)

(88%)(88%)

0.5 mol % Pd (10 mol % Pd/C)0.5 mol % Pd (10 mol % Pd/C)

+


10 mol % CuI20 mol % AsPh316 hrs.95 % trans95 % trans

100 % trans100 % trans

Liebeskind , L. ,Tetrahedron Letters , 1995 , 36 , 2191.Liebeskind , L. ,Tetrahedron Letters , 1995 , 36 , 2191.

Examples of the Suzuki reaction:

OR BrR1

B(OH)2

R1B(OH)2

SR BrOR

OR

R1

R1

+Pd(OAc)2 (2 mol%)

5°C, 2h

45-76%

+Pd(OAc)2 (2 mol%)

5°C, 2h

50-82%

R = H, CHO

NBu4Br

NBu4Br

K2CO3, H2O, 2

K2CO3, H2O, 2

R = H, CHO

The addition of tetrabutylammonium bromide facilitates the reaction.

Bu BX2I

B MeMe

Me

BX2

B(c-C6H11)2

B(Oi-Pr)2

Bu+

3 mol% Pd(PPh3)4

2 M NaOEt in EtOHC6H6, Δ

E:Z

2

58 94 : 6

49 83 : 17

98 >97 : 3

Yield

BuBu BX2BX2I

B MeMeMeMe

MeMe

BX2BX2

B(c-C6H11)2B(c-C6H11)2

B(Oi-Pr)2B(Oi-Pr)2

BuBu+

3 mol% Pd(PPh3)43 mol% Pd(PPh3)4

2 M NaOEt in EtOH2 M NaOEt in EtOHC6H6, ΔC6H6, Δ

E:ZE:Z

2

5858 94 : 694 : 6

4949 83 : 1783 : 17

9898 >97 : 3>97 : 3

Yield


Yields with alkyl boron compounds are often low because of protodeboronation. Boronates are better reagents. Rate of protodeboronation: 9-BBN > B(c-C6H11)2 > B(OR)2

Coupling of primary alkylboron compounds:

OI

TBSO

BCO2Me

Ph3AsCs2CO3

O

TBSO

CO2Me+PdCl2(dppf)

70-80%

DMF/THF/H2O25 °C

Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.

OI

TBSOTBSO

BCO2MeCO2Me

Ph3AsPh3AsCs2CO3Cs2CO3

O

TBSOTBSO

CO2MeCO2Me+PdCl2(dppf)PdCl2(dppf)

70-80%70-80%

DMF/THF/H2ODMF/THF/H2O25 °C25 °C

Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014..

Diazonium salts can be coupled in Suzuki reactions:

N2

MeO

(HO)2B Pd(OAc)2 Ph

MeO

J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, 1095.

1,4-dioxane22 °C79%

+N2N2

MeOMeO

(HO)2B(HO)2B Pd(OAc)2Pd(OAc)2 PhPh

MeOMeO

J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, 1095.J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, 1095.

1,4-dioxane1,4-dioxane22 °C79%22 °C79%

+

Although not very reactive, chloroarenes can be used in the Suzuki reaction:

Cl

Me O

Ph

Me O

(HO)2B

W. Shen Tetrahedron Lett. 1997, 38, 5575.

+5 mol% PdCl2(PCy3)2

CsF, NMP100 °C

98%

ClCl

MeMe O

PhPh

MeMe O

(HO)2B(HO)2B

W. Shen Tetrahedron Lett. 1997, 38, 5575.W. Shen Tetrahedron Lett. 1997, 38, 5575.

+5 mol% PdCl2(PCy3)25 mol% PdCl2(PCy3)2

CsF, NMP100 °C

98%

CsF, NMP100 °C

98%


5. Pd-catalyzed allylic alkylation (Tsuji–Trost reaction)

CO2Et

CO2Et

10 mol %Pd(PPh3)4, PPh3

NaCH(CO2Et)2THF, reflux

AcO

• General reactivty of substrates: Halide, Carbonate > Acetate > epoxide (?)

• Nucleophile: C-nucleophile- malonate, active methylene nucleophile; heteroatom (N, O, S, P, Si)-based nucleophile; hydride (B-H, Sn-H, Al-H and formates); organo-metallics (Zn-R, Zr-R, Sn-R etc.).

Catalytic cycle:

Pd+

NuNu

Nu Pd(0)

R

RLnPd

PdL X

- XL L

LnPd

Ligand association

Oxidative AdditionSN2'-like (invesrion)

Nu-attackSecond invesrion

Ligand dissociation

X

X

RR

R

R

Pd+Pd+

Pd(0)Pd(0)

R

RLnPdLnPd

PdPdL X

- X- XL L

LnPdLnPd

Ligand associationLigand association

Oxidative AdditionSN2'-like (invesrion)Oxidative AdditionSN2'-like (invesrion)

Nu-attackSecond invesrionNu-attackSecond invesrion

Ligand dissociationLigand dissociation

X

X

RR

R

R

NuNuNuNu

NuNu

Active cationic form of η3- allyl Pd complex intermediate is favoured by the bidentate phosphine ligand. Stereoselectivity: Retention of the carbon atom configuration by double inversion.

RX

H

PdLn

R

PdLn

H

NuNu

RH

PdLn


Allylic alkylation with ketone enolates

Enolates can be used as the nucleophile in allylic alkylations, which broadens the scope of the reaction even further. In the example on the left, the enantioselectivity of the reaction (the direction of attack of the nucleophile to the prochiral allyl cation) is controlled by the chiral C2 symmetric ligand (R)-BINAP. The example on the right uses the same chemistry, but a different C2 symmetric chiral ligand to control the enantioselectivity of the reaction. Literatur: Angew. Chem. Int. Ed. 2006, 45, 6952.


6. Palladium-catalyzed Amination

Cl

R1HN

R2

Pd(OAc)2 (1-2 mol%)

R

P(tBu)2

Ligand (2-4 mol%)

Toluol, Raumtemp

Ligand =

NPhMeMe

Me N O MeO N O

RNR1

R1

NHBn

OMe

+NaOtBu (1.4 equiv)

14-20 h

98% 94% 90% 99%

Nucleophilic aromatic substitution. Pd-catalysis allows reaction of non-activated arenes.

Catalytic cycle:


Examples:

Nickel-catalyzed aromatic amination

Copper-catalyzed aromatic amination

Diarylethers are accessible by a similar reaction using phenols as nucleophile.


A variation is the coupling of aryl boronic acids with amines or phenols. The reaction is called the Chan-Lam coupling.

Mechanism:

7. Palladium-catalyzed Alkyne coupling reactions

R1 Cu I R2 R2

R1

A. Castro-Stevens Kupplung

+R1R1 CuCu I R2R2 R2R2

R1R1

A. Castro-Stevens KupplungA. Castro-Stevens Kupplung

+

R1 H X R2 R2

R1

B. The Sonogashira-Hagihara Kupplung

NH

X = I, Br, Cl

PdCl2(PPh3)2 (2 mol%)CuI oder CuOAc(1 mol%)

25 °CAmin = Et2NH, Et3N oder

+R1R1 H X R2R2 R2R2

R1R1

B. The Sonogashira-Hagihara KupplungB. The Sonogashira-Hagihara Kupplung

NHNH

X = I, Br, ClX = I, Br, Cl

PdCl2(PPh3)2 (2 mol%)PdCl2(PPh3)2 (2 mol%)CuI oder CuOAc(1 mol%)CuI oder CuOAc(1 mol%)

25 °C25 °CAmin = Et2NH, Et3N oderAmin = Et2NH, Et3N oder

+


The amine is necessary to deprotonate the alkyne. Best coupling results are obtained in THF.

The mechanism is similar to the Suzuki or Stille coupling, but an organocopper species is transmetallated.

R1 H R1 CuCuI + R1R1 H R1R1 CuCuCuICuI ++

The halide, substituents in both coupling components, the catalyst and the amine influence the rate of the reaction. THF or amines are usually used as solvents.

I

Br

Br

Pd(PPh3)2Cl2 (cat)R2

Cl

R1 R1R2

= > ArI > > ArBr

Et3N, THF

CuI (cat)

I

BrBr

BrBr

Pd(PPh3)2Cl2 (cat)Pd(PPh3)2Cl2 (cat)R2R2

ClCl

R1R1 R1R1R2R2

= > ArI >> ArI > > ArBr> ArBr

Et3N, THFEt3N, THF

CuI (cat)CuI (cat)

4-CHO4-COMe2-CO2Me3-CO2Me4-CO2Me4-COMe4-COMe4-CHO

Me3SiMe3SiMe3SiMe3SiMe3Sin-BuPhPh

R1 R2 [%]

25°C / 1h25°C / 1h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h

9992888788918782

Reaction conditions Yield





R1 R2 [%]

25°C / 1h25°C / 1h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h

9992888788918782

Reaction conditions Yield

ClC5H11

C5H11C5H11

C5H11

[Pd] (5%), CuI (10%), Amin, RTClClC5H11C5H11

C5H11C5H11C5H11C5H11

C5H11C5H11

[Pd] (5%), CuI (10%), Amin, RT[Pd] (5%), CuI (10%), Amin, RT

PdCl2(PhCN)2

PdCl2(PPh3)2

Pd(PPh3)4

Pd(PPh3)4

[Pd] [h] [%]

piperidine

piperidine

piperidine

n-PrNH2

0.5

20

16

60

93

93

11

62

amine time yield

PdCl2(PhCN)2

PdCl2(PPh3)2

Pd(PPh3)4

Pd(PPh3)4

PdCl2(PhCN)2

PdCl2(PPh3)2

Pd(PPh3)4

Pd(PPh3)4

[Pd] [h] [%]

piperidine

piperidine

piperidine

n-PrNH2

piperidine

piperidine

piperidine

n-PrNH2

0.5

20

16

60

0.5

20

16

60

93

93

11

62

93

93

11

62

amine time yield


Mechanisms: Palladium-copper co-catalysis (left); copper-free (right)

Examples:

Br Br

SiMe3Me3Si

SiiPr3

HH

SiiPr3Pr3iSi

+1) Pd(0) / Cu(I)

2) K2CO3, MeOH

F. Diederich, Angew. Chem. 1993, 105, 437-40

BrBr BrBr

SiMe3SiMe3Me3SiMe3Si

SiiPr3SiiPr3

HH

SiiPr3SiiPr3Pr3iSiPr3iSi

+1) Pd(0) / Cu(I)1) Pd(0) / Cu(I)

2) K2CO3, MeOH2) K2CO3, MeOH

F. Diederich, Angew. Chem. 1993, 105, 437-40F. Diederich, Angew. Chem. 1993, 105, 437-40


BrBr

BrBr

Br

BrSiMe3

H

H

H

H

H

H

+1) Pd(0) / Cu(I)

2) KOH, MeOH

28%

K.P.C. Vollhart, Angew. Chem. 1986, 25, 268-9.

BrBrBrBr

BrBrBrBr

BrBr

BrBrSiMe3SiMe3

H

H

H

H

H

H

+1) Pd(0) / Cu(I)1) Pd(0) / Cu(I)

2) KOH, MeOH2) KOH, MeOH

28%28%

K.P.C. Vollhart, Angew. Chem. 1986, 25, 268-9K.P.C. Vollhart, Angew. Chem. 1986, 25, 268-9..

Indole synthesis:

Ligand (10 mol%)

All in one: Tandem Heck-Stille-Sonogashira Reaction

BrPdLn

SnBu3R'

Br

transmetallation

BrBnO

Br

BnO

OTBS

OTBSBu3Sn

OH

Br

BnOBu3SnBr

BnO

OTBS

OH

Br

BnO

PdLn

TBSO

3 mol %Pd(PPh3)4

2.5 eq. NEt3100 oC, 12 h80 %

Red.Elim.

Pd(PPh3)4, CuI

BrBrPdLnPdLn

SnBu3SnBu3R'R'

BrBr

transmetallationtransmetallation

BrBrBnOBnO

BrBr

BnOBnO

OTBSOTBS

OTBSOTBSBu3SnBu3Sn

OHOH

BrBr

BnOBnOBu3SnBrBu3SnBr

BnOBnO

OTBSOTBS

OHOH

BrBr

BnOBnO

PdLnPdLn

TBSOTBSO

3 mol %Pd(PPh3)4

2.5 eq. NEt3100 oC, 12 h80 %

3 mol %Pd(PPh3)4

2.5 eq. NEt3100 oC, 12 h80 %

Red.Elim.Red.Elim.

Pd(PPh3)4, CuIPd(PPh3)4, CuI


8. Palladium-N-heterocyclic carbene (NHC) ligands for cross coupling reactions

Synthetically useful NHC ligands derived from imidazolium (I) and 4,5 dihydroimidazolium (SI) salts. Aldrichimica Acta, 2006, 39, 97.

General description of NHC generation from various precursors and their complexation with palladium

NHC•HCl Precursors typically used in in situ cross-coupling protocols


Active Pd-precatalysts with NHC ligands

Use of NHC ligands in the Suzuki cross coupling reaction

Ligand 13

Use of NHC ligands in N-aryl coupling reactions


9. Olefin Metathesis

Olefin Metathesis: metal-catalyzed exchange of olefins

R1

R1R1

R1

R2

R2+

M

R2

+

R2

Catalysts: Metal-carbene Complex

LnMR

RLnM

R

XR

Nucleophilic Electrophilic

Schrock-carbene(metal-alkylidene)

Fishcer-carbene(Hetero-atom stabilized)

d0

Pre-catalysts with a defined structure have been developed

N NMes Mes

Ru

PCy3

RCl

ClPCy3

Ru

PCy3

RCl

ClO

OMo

N

Ph

i-Pr i-Pr

F3C CF3

F3C

F3C

WO

Cl O

O Cl

Br

Br

BrBr

Aldehydes

Ketones

Olefins

Olefins

Olefins

Esters, amides

Aldehydes

Ketones

Esters, amides

Aldehydes

Ketones

Esters, amides

Oxophilicreactive

RuPh

PCy3

PCy3

Cl

Cl

PCy3Cl2Ru

PCy3Ph

Cl2Ru

PCy3

N NN N

Mes Mes

Ph Cl2RuPCy3

PhDistorted Square planar


Overview: Modern olefin metathesis catalysts

Reaction mechanism: Sequence of reversible formal [2+2] cycloaddition/ cycloreversion processes.

R1

R2

R1

R2R2

R2

CR2

R1

R1

LnM

R1 R1

R2

LnM

R1

R2

R1

R2

MLn

R1

LnM

R1 R2

R2

pre-catalyst

RR

R

start

MLn

LnM

R R1

R2


Direction of metathesis reactions:

• RCM (Ring-closing metathesis)A B C

• ROM (Ring-opening metathesis) C B A

• CM (Cross metathesis)A B D

• ROMP (Ring-opening metathesis polymerization)

C B E

M

n nn

n n

n a

n

R

A B C

D

E

n( a times)

R

Ways to push the process in one direction:

M

n nn

polymer

• Ethylene gas generally decreases RCM rate • Lower concentration can prevent polymerization and cross metathesis • Higher temperature usually promotes RCM process ( ΔS gain)


Factors influencing the ring closing metathesis:

PCy3Cl2Ru

PCy3Ph

R

Cl2RuPCy

R

31 eq. R'

R1 R1

R1

R1

PhR'

PCy3

3

R1

R1 Ph

N.R.100 8 3k rel

Substrate specific reactivity of catalysts – still difficult to predict!

X

X

X

OH

N NMes Mes

Cl2RuPCy3

Ph

PCy3Cl2Ru

PCy3R

RORO

MoN

Ph

Ar'

1 A 1 B 2A

X

X

X

OH

O O

O

O

O O

O

O

1 A

1 B

2A

> 99 %

> 99 %

> 31 %

> 99 %

> 99 %

20 %

0 %

0 %

> 99 %

> 99 %

93 %

0 %

X = CH(CO2Et)2

35 %

E/Z2:1

39 %

E/Z1.6: 1

15 %

E/Z1.6: 1

Examples of RCM in synthesis:

N

NH

OH

CHOH

HNO

Me

OEM Sugar

OHMeIrcinal A

Dactylol

Fluvirucin


O

O

N

S

O

R2O

O OR1

Yield (E/Z)

86 % (1: 2)65 % (1: 2)

R2

TBSH

epothilone A

R1

TBSHO

O

N

S

O

R2OR2O

O OR1OR1

Yield (E/Z)

86 % (1: 2)65 % (1: 2)

R2

TBSH

epothilone Aepothilone A

R1

TBSH

Fluvirucin B synthesis

Cyclophane synthesis

Large scale pharmaceutical synthesis

Note: Many functional groups are tolerated.


Double RCM reactions:

O

OO

HH

OPMB

PCy3Cl2Ru

PCy3Ph

O

OO

HH

OPMB

PCy3Cl2Ru

PCy3Ph

O

OO

HH

OPMB

O

O

HH

OPMBO

CH2Cl245 oC

25 mol %

88 %

CH2Cl2 45 oC

20 mol %

77 %

Synthesis of macrocycles:

10- 12

OO

R

OO

R

0 %

R: H 52 % -R: CH3 10 % 72 %

Yield of RCM product using

PCy3Cl2Ru

PCy3Ph

O

O

Presence of functional groupthat serves to assemble the reacting sites (not too basic)

Appropriate distance from functional group to olefin (not too close)

Low steric congestion near the olefin

Ring opening and cross metatheses reaction in synthesis:


Examples of cross metathesis reactions:

RCHO

R =AcOCH2(CH2)2

BzO

R

R =AcOCH2(CH2)2

RSi(OEt)3

R =AcOCH2(CH2)2

BzOR

R CHO

R Si(OEt)3

2.0 eq.

2.0 eq.

2.0 eq.

92 % (E/Z >20:1)

81 % (E/Z >4:1)

81 % (E/Z >11:1)

cat. A

cat. A

cat. B

N NMes Mes

Cl2RuPCy3

Ph

N NMes Mes

Cl2RuPCy3

CH3

CH3

cat. A cat. B

Diyne Metathesis

Catalyst (Schrock alkylidyne complex)

(t-BuO)3WMe

MeMe

R2

R1 R3

R4

R1 R3

R4R2

LnM R'

Mechanism:


Examples

R1 = H; 70 %

Alkyne RCM in combination with Lindlar partial hydrogenation is a selective way to generate macrocyclic (Z)-olefins.

LnM R'

R1 R2 R2R1

H2

Lindlar cat.n

n > 4n n

Z


Alkane metathesis

organo-transition metal chemistry - organische chemie · organo-transition metal chemistry 1. some...

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