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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