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 Hartwig 2 showed active catalyst was [Pd{P(o- C 6 H 4 Me) 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 complexes 3 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-C 6 H 4 Me) 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 – Hartwig 4 and Buchwald 5 –Reaction of aryl halide with amine in presence of base –Pd complexes Ligands used P(o-C6H4Me) 3 /Pd 2 (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 L 2 Pd 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 Hartig 6 –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 group 3 –Competing β-hydrogen elimination 3 John F. Hartwig, Angew. Chem. Int. Ed. 1998, 37,2046-2067

17. Aryl Amines Formed Using Monodentate Ligands Aryl Bromides 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 – Hartwig 7 and Buchwald 8 –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 – Beller 10 and Tanka 11 –Beller used palladacylce and bromide ions as co-catalyst Secondary amines –Tanaka used bulky electron-rich phosphine ligands P(Cy) 3 and P( i Pr) 3 Secondary and cyclic secondary amines 10 M. Beller, T.H. Riermeier, C.P. Reisinger, W.A. Herman, Tetrahedron Letters, 1997, 38, 2073-2074 11 N. P. Reddy, M. Tanaka, Tetrahedron Letters, 1997, 38, 4807-4810

27. Aryl Amines from Aryl Halides and Lithium Bis(trimethylsilyl)amide 11 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 Cs 2 CO 3 as base 13 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 formation 14 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