Palladium Catalyzed C-N Bond Formation

Jenny McCahill

59-636

2003-11-17

Outline of Presentation

• Previous methods employed in C-N bond formation

• Focus on aryl amines

– Early palladium catalyzed transmetalation processes

• Limitations of these processes

• Development of tin-free systems

• Palladium catalyzed systems– Mechanism of amination

• Monodentate and chelating ligand systems

Outline of Presentation

– Examples of aryl amines formed• Starting alkyl halides/triflates and amines that can

be used• Limitations of palladium catalyzed systems

• Nickel catalyzed systems– Examples of aryl amines formed

• Starting alkyl halides and amine that can be used

• Summary of Presentation

Methods of C-N Bond Formation

• Synthesis of aryl amines difficult– Reductive amination

• Two-step process• Formation of imine and reduction of imine

– Copper Mediated Substitutions• High temperatures required

– Addition of amines to benzyene intermediates• Regioisomers

– Direct nucleophilic substitution of aryl halides• Excess of reagent• Polar Solvent• Highly activated aryl halides

• Incompatibility of functional groups

Transmetalation with Tin Amides

• 1983 – Kosugi et al.1

– Reaction of tributyltin amides with aryl bromides (catalyzed with Pd)

• Limited to dialkylamides and electron-neutral aryl bromides

NSnR

R'Bu3 + Br

R

L2PdCl2

L = P(o-C6H4Me)3

+ Bu3SnBrNRR'

R

1 M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. 1983, 927-927

Transmetalation with Tin Amides

• Further studies by Paul, Patt and Hartwig2 showed active catalyst was [Pd{P(o-C6H4Me)2}]

• Oxidative addition of aryl halides to form dimeric complexes

• Aryl halide complexes react with tin amides to form aryl amides

2 F. Paul, J. Patt, J.F. Hartwig, J. Am. Chem. Soc. 1994, 116, 5969-5970

Transmetalation Mechanism

Mechanism for aryl halide amination catalyzed by palladium complexes3

3 John F. Hartwig, Angew. Chem. Int. Ed. 1998, 37,2046-2067

Limitations

• Source of amido group toxic, air-sensitive and thermally unstable

• Limited to electron-neutral aryl halides

• Limited to secondary amines

• Low rates and turnover of catalyst

• Stoichiometric amounts of catalyst

• Not compatible with heteroaromatic amines

Palladium Catalyzed Tin-Free Aminations

• Initial palladium systems– Monodentate P(o-C6H4Me)3 ligands

• Addition of alkoxide or silylamide base to reaction of aryl bromides and amines

• Second generation palladium systems– Chelating phosphane ligands

Monodentate Ligand Systems • 1995 – Hartwig4 and Buchwald5

– Reaction of aryl halide with amine in presence of base

– Pd complexes • Ligands used P(o-C6H4Me)3/Pd2(dba)3

– X = Br, I

– Base used NaOtBu or LiN(TMS)2

+X

R

HNRR'Pd catalyst

baseNRR'

R

4 J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609-3612

5 A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem. 1995, 107, 1456-1459; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348-1350

Mechanism

• Steps in the catalytic cycle– Oxidative addition of aryl halide

• Dissociation of one phosphane ligand• Formation of dimeric complexes

– Palladium-amide complex formation• Role of base in catalytic cycle

– Reductive elimination of amine

Oxidative Addition

• Expect oxidative addition directly to the L2Pd fragments

– Subsequent phosphane dissociation and dimerization

• However, ligand dissociation occurs prior to oxidative addition– Inverse first order dependence of the reaction

rate on phosphane concentration

Oxidative Addition

• Two possible mechanisms – One-coordinate 12-electron intermediate adds

aryl halide

– Reversible displacement of phosphane ligand by aryl halide

• Generates an aryl halide complex with C-X bond intact

Pd LL- L

+ LPdL ArX Pd

Ar

L

X

X

PdL

Ar

Pd LL

- L+ ArX

+ L-ArX

PdL Pd

Ar

L

X

X

PdL

Ar

(ArX)

Formation of Palladium Amide Complex

• Paul, Patt and Hartig6

– Dimeric aryl halide complexes react with amines to form amine-ligated aryl halide complex

– Amine complexes• Enhanced acidity of the N-H bond when coordinated

to the metal

L = P(o-C6H4Me)3

Pd

Ar

L

Br

Br

PdL

Ar

2 HNRR'

Pd

Ar

L

NHRR'

Br

6 F. Paul, J. Patt, J.F. Hartwig, Organometallics, 1995, 14, 3030-3039

Formation of Palladium Amide Complex

• Amine-ligated aryl halide complexes react with base– Coordinated amine is deprotonated

• Three coordinate amido species is generated

Pd

Ar

L

NHRR'

Br

basePd

Ar

L

NRR'

Br

- BrPd

Ar

L

NHRR'

Reductive Elimination of Amine

• Favored by increasing the nucleophilicity of the amido group and increasing the electrophilicity of the aryl group3

– Competing β-hydrogen elimination

3 John F. Hartwig, Angew. Chem. Int. Ed. 1998, 37,2046-2067

Aryl Amines Formed Using Monodentate Ligands

• Aryl Bromides

3 J.F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046-2067

Aryl Amines Formed Using Monodentate Ligands

• Aryl Iodides

• Intramolecular Amination

3 J.F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046-2067

Chelating Ligand Systems

• 1996 – Hartwig7 and Buchwald8

– Palladium Complexes of DPPF and BINAP used for amination

– Provides amination for primary alkyl amines, secondary alkyl amines, cyclic amines and anilines

– Electron-rich, electron-poor, hindered or unhindered aryl bromides and iodides

7 M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118, 7217-7218

8 J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 7215-7216

Mechanism

9 J. F. Hartwig, Acc. Chem. Res. 1998, 31, 852-860

Oxidative Addition of Aryl Halide

• Pd complex contains one chelating ligand– No ligand dissociation

• Oxidative addition of aryl halide

PdP

P

+ ArXPd

P

P

Ar

X

Role of Base

• Palladium complex reacts with base to form an intermediate alkoxide

PdP

P

Ar

X

NaOtBu

- NaX

PdP

P

Ar

OtBu

Addition of Amine

• Addition of amide to form amido intermediate

PdP

P

Ar

OtBu

HNRR'

-HOtBu

PdP

P

Ar

NRR'

Reductive Elimination of Amine

• Reductive elimination from the 16-electron, four-coordinate complex

• Not completely understood the importance of chelating ligands

• Chelating blocks phosphane dissociation and accompanying pathways for β-hydrogen elimination and favors reductive elimination to for the aryl amide

Aryl Amines Formed Using Chelating Systems

• PDDF Ligand System

• BINAP Ligand Systems

3 J.F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046-2067

Amination of Aryl Chlorides• Reactivity of C-Cl bond is much lower that

that of C-Br or C-I • 1997 – Beller10 and Tanka11

– Beller used palladacylce and bromide ions as co-catalyst

• Secondary amines

– Tanaka used bulky electron-rich phosphine ligands

• P(Cy)3 and P(iPr)3

• Secondary and cyclic secondary amines

10 M. Beller, T.H. Riermeier, C.P. Reisinger, W.A. Herman, Tetrahedron Letters, 1997, 38, 2073-2074

11N. P. Reddy, M. Tanaka, Tetrahedron Letters, 1997, 38, 4807-4810

Aryl Amines from Aryl Halides and Lithium Bis(trimethylsilyl)amide11

• LiN(TMS)2 used as an ammonia equivalent

• Formation of anilineX

R

+ LiN(SiMe3)2

1.) Pd(dba)2/P(tBu)3

2.) HCl, neutralization

NH2

R

12 S. Lee, M. Jorgensen, J.F. Hartwig, Org. Lett., 2001, 3, 2729-2739

Amination of Aryl Triflates

• Amination of aryl triflates not possible with monodentate ligands but occur when chelating ligand used

3 J.F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046-2067

Aminations of Aryl Bromides with Functional Groups

• Buchwald reported using (rac)-PPF-OMe ligands and Cs2CO3 as base13

• Increased functional group compatibility

13 J.P. Wolfe, S. L. Buchwald, Tetraherdron Letters, 1997, 38, 6359-6359

Nickel Catalyzed Amination

• Ni(COD)/DPPF and NaOtBu systems have also been found to catalyze C-N bond formation14

14 J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 6054-6058

Summary

• Aryl amines are formed via – Oxidative addition of the aryl halide to the Pd

complex – Formation of a amido aryl complex – Reductive elimination of the aryl amine

• Using palladium systems a number of aryl halides/triflates can undergo amination to form aryl amines including anilines, secondary amines and cyclic amines

Reference Material

J.F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046-2067

J. F. Hartwig, Acc. Chem. Res. 1998, 31, 852-860

Other references included in presentation