Palladium Catalyzed C-N Bond Formation

1. Palladium Catalyzed C-N Bond Formation Jenny McCahill 59-636 2003-11-17

2. 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

3. 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

4. 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

5. 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 1 M. Kosugi, M. Kameyama, T. Migita, Chem. Lett.1983, 927-927

6. 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

7. Transmetalation Mechanism Mechanism for aryl halide amination catalyzed by palladium complexes3 3 John F. Hartwig, Angew. Chem. Int. Ed.1998, 37,2046-2067

8. 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

9. 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

10. 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 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

11. 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

12. 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

13. 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

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

15. Formation of Palladium Amide Complex • Amine-ligated aryl halide complexes react with base • Coordinated amine is deprotonated • Three coordinate amido species is generated

16. 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

17. Aryl Bromides Aryl Amines Formed Using Monodentate Ligands 3 J.F. Hartwig, Angew. Chem. Int. Ed.1998, 37, 2046-2067

18. Aryl Amines Formed Using Monodentate Ligands • Aryl Iodides • Intramolecular Amination 3 J.F. Hartwig, Angew. Chem. Int. Ed.1998, 37, 2046-2067

19. 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

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

21. Oxidative Addition of Aryl Halide • Pd complex contains one chelating ligand • No ligand dissociation • Oxidative addition of aryl halide

22. Role of Base • Palladium complex reacts with base to form an intermediate alkoxide

23. Addition of Amine • Addition of amide to form amido intermediate

24. 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

25. Aryl Amines Formed Using Chelating Systems • PDDF Ligand System • BINAP Ligand Systems 3 J.F. Hartwig, Angew. Chem. Int. Ed.1998, 37, 2046-2067

26. 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

27. Aryl Amines from Aryl Halides and Lithium Bis(trimethylsilyl)amide11 • LiN(TMS)2 used as an ammonia equivalent • Formation of aniline 12 S. Lee, M. Jorgensen, J.F. Hartwig, Org. Lett., 2001, 3, 2729-2739

28. 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

29. 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

30. 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

31. 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

32. 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