1. Norbornene-Mediated Palladium-Catalyzed Synthesis of Fused Aromatic Carbocycles and Heterocycles Dino Alberico Lautens Group University of Toronto Department of Chemistry Charette Group Presentation Université de Montréal January 27, 2006

2. Outline Part 1: Norbornene-Mediated Palladium-Catalyzed Alkylation/Alkenylation Sequence: Synthesis of Fused Aromatic Carbocycles Part 2: Norbornene-Mediated Palladium-Catalyzed Alkylation/Alkenylation Sequence: Synthesis of Tricyclic Heterocycles Part 3: Norbornene-Mediated Palladium-Catalyzed Alkylation/C-H Functionalization Sequence: Synthesis of Annulated Indoles

3. The Catellani Reaction Catellani, M. Top. Organomet. Chem. 2005, 14, 21. Catellani, M. Synlett 2003, 298. Catellani, M.; Cugini, F. Tetrahedron 1999, 55, 6595. Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119.

4. Original Work by Our Group Lautens, M.; Alberico, D.; Bressy, C.; Fang, Y.-Q.; Mariampillai, B.; Wilhelm, T. Pure Appl. Chem. 2006, 78, 351. Lautens, M.; Piguel, S. Angew. Chem. Int. Ed. Engl. 2000, 39, 1045. Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem. 2001, 66, 8127.

5. Mechanism Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336. Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119.

6. Bromoenoate Substitution Patterns Bromoenoates for Six-Membered Ring Carbocycles Bromoenoates for Seven-Membered Ring Carbocycles Alberico, D.; Paquin, J.-F.; Lautens, M. Tetrahedron 2005, 61, 6283.

7. 4’ Substituted Bromoenoates: Six Membered Ring Carbocycles

8. 5’ Substituted Bromoenoates: Six Membered Ring Carbocycles

9. 6’ Substituted Bromoenoates: Six Membered Ring Carbocycles

10. Ortho Insertion of Secondary Alkyl Halides Dr. Nils Rackelman and Alena Rudolph

11. 4’-5’ Substituted Bromoenoates: Six Membered Ring Carbocycles

12. Seven Membered Ring Carbocycles

13. Further Functionalization of Carbocycles

14. Alkylation/Heck Reaction/Diels-Alder

15. Other Bromodienes to Examine

16. Part 2 Norbornene-Mediated Palladium-Catalyzed Alkylation/Alkenylation Sequence: Synthesis of Tricyclic Heterocycles

17. Synthesis of Benzoxepines Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org. Chem. 2002, 67, 3972.

18. Three Component Coupling Pache, S.; Lautens, M. Org. Lett. 2003, 5, 4827.

19. Bis Intramolecular Alkylations Followed by an Intermolecular Heck Reaction

20. Optimization  Concentration (0.05 M, 0.1 M, 0.2 M)  Equivalents of acrylate (3, 5, 8)  Equivalents of norbornene (2, 3, 5, 8)  Equivalents of base (3.5, 5, 8)  Ligands (PAr 3, PR 3, P(OR) 3, AsAr 3 ) Optimization:

21. Microwave Reactions

22. Heck Acceptor Scope

23. Ring Size Scope

24. Mescaline Mescaline - the active hallucinatory agent of peyote cactus - served as the prototype for SAR studies linking molecular structure to hallucinogenic activity - targets serotonin (5-HT 2 ) and dopamine receptors Mescaline Analogues - the dihydrobenzofuran rings serve as conformationally restricted bioisosteres of the aromatic methoxy group in the active conformation of mescaline during serotonin receptor activation Peyote Cactus

25. Tricyclic Mescaline Analogue For previous synthesis, see: 1. Monte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott, D. B.; Nelson, D. L. Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997, 40, 2997. 2. Ahrendt, K. A.; Bergman, R. B.; Ellman, J. A. Org. Lett. 2003, 5, 1301.

26. Tricyclic Mescaline Analogue – Synthesis

29. 1.3% yield over 8 steps Monte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott, D. B.; Nelson, D. L. Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997, 40, 2997. 32% yield over 7 steps Ahrendt, K. A.; Bergman, R. B.; Ellman, J. A. Org. Lett. 2003, 5, 1301.

30. Other Tricyclic Heterocycles Alena Rudolph and Dino Alberico

31. Intermolecular Alkylation Followed by an Intramolecular Heck Reaction Andrew Martins, Neema Kasravi, Udo Marquardt and Dino Alberico

32. Alkylation/Cyanation Sequence Brian Mariampillai, Valerie Bidau and Dino Alberico

33. Alkylation/Cyanation Sequence Brian Mariampillai and Dino Alberico

34. Part 3 Norbornene-Mediated Palladium-Catalyzed Alkylation/C-H Functionalization: Synthesis of Annulated Indoles

35. Aryl-Aryl Coupling via C-H Functionalization (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (d) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625. (e) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55. Coupling using an organometallic compound Coupling via C-H functionalization

36. Annulation via Double C-H Functionalization

37. C-H Functionalization of Indoles

38. Alkylation/Direct Arylation Sequence: Seven-Membered Annulated Indoles Bressy, C.; Alberico, D; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148.

39. Alkylation/Direct Arylation Sequence: Six-Membered Annulated Indoles

40. Alkylation/Direct Arylation Sequence Attempts at Synthesizing Eight-Membered Annulated Indoles C-3 Alkylbromo Indoles

41. Direct Arylation of Pyrroles Dr. Christophe Blaszykowski

42. Alkylation/Direct Arylation Sequence: Annulated Pyrazoles Vangelis Aktoudianakis

43. Direct Arylation of Furans

44. Alkylation/Direct Arylation Sequence: Annulated Thiophenes Andrew Martins and Dino Alberico

45. Conclusions

46. Acknowledgments Professor Mark Lautens Vangelis Aktoudianakis Dr. Christophe Blaszykowski Dr. Cyril Bressy Brian Mariampillai Andrew Martins Dr. Udo Marquardt Prof. Jean-François Paquin Alena Rudolph Neema Kasravi (2002) Olga Lifchits (2004) Valérie Bidau (2005) Members of the Lautens Group Merck Frosst NSERC - IRC University of Toronto University of Toronto – St. George Campus