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Metal-Catalyzed Heterocyclization of Allenes

Metal-Catalyzed Heterocyclization of Allenes. Chris M. Yates. What Makes an Allene an Interesting Substrate?. Entrance into large number of highly functionalized heterocycles Cyclization products retain an olefin that can be further manipulated

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Metal-Catalyzed Heterocyclization of Allenes

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  1. Metal-Catalyzed Heterocyclization of Allenes Chris M. Yates

  2. What Makes an Allene an Interesting Substrate? • Entrance into large number of highly functionalized heterocycles • Cyclization products retain an olefin that can be further manipulated • Cyclization products can be varied by changing metal and or reaction conditions • Many intramolecular heterocyclizations can be done with high diastereoselectivity • Reactions can be catalyzed by Silver, Palladium, Lanthanides, Cobalt, Ruthenium, Iron, and Gold

  3. Discovery of Metal-Catalyzed Cyclization • First discovered by Alf Claesson and co-workers when attempting to purify allenic amines by GLC at 210 °C • Noticed complete conversion of allenic amine 1 into two new compounds, 2 and 3 • Lead to the discovery of a metal-catalyzed cyclization using Silver (I) Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand.1979, B33, 309-310.

  4. Extension to Oxygen Heterocycle Formation • Synthesis of 2,5-Dihydrofurans • Synthesis of 5,6-Dihydro-2H-pyrans Olsson, L. I.; Claesson, A. Synthesis1979, 743-745.

  5. Diastereoselective Tetrahydropyran Formation • Synthesis of cis-2,6-disubstituted tetrahydropyrans Gallagher, T. J. Chem. Soc., Chem. Comm.1984, 1554-1555.

  6. Diastereoselective Pyrrolidine Formation • Synthesis of cis-2,5-disubstituted pyrrolidines • Synthesis of trans-2,3-disubstituded pyrrolidines δ+ δ+ δ+ δ+ Kinsman, R.; Lathbury, D.; Vernon, P.; Gallagher, T. J. Chem. Soc., Chem. Comm.1987, 243-244. Gallagher, T.; Jones, S. W.; Mahon, M. F.; Molloy, K. C. J. Chem. Soc., Perkin Trans. 11991, 2193-2198.

  7. Formation of Nitrones • Trans-2,6-disubstituted piperidines by trapping nitrone with styrene • Trans-2,5-disubstituted pyrrolidines by trapping nitrone with styrene • 7-Member nitrones can also be formed by this same method Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J. Chem. Soc., Perkin Trans. 11989, 2415-2424.

  8. Cyclization of Allenyl Aldehydes and Ketones to Furans Proposed mechanistic pathways Marshall, J. A.; Wang, X. J. J. Org. Chem.1991, 56, 960-969.

  9. Mechanism for Conversion of Allenones to Furans • Possible pathways are determined by deuterium using labeled allenes and/or deuterated solvents • No incorporation or loss of deuterium upon treatment of 1 or 2 to reaction conditions with no AgNO3 present Marshall, J. A.; Wang, X. J. J. Org. Chem.1991, 56, 960-969.

  10. Pd(II)-Catalyzed Cyclization • All Ag(I) cyclizations are limited to cycloisomerization • Pd(II) allows for further functional group incorporation • Can achieve arylations, vinylations, and allylations of cyclization products • Can achieve CO insertion to obtain ketones and acrylates

  11. Palladium-Catalyzed Intramolecular Hydroamination of Allenes • Cyclization is achieved with catalytic Pd(II) and 1 equivalent of acetic acid • This method can also be applied to six member [(η3-C3H5)PdCl]2 (5 mol %) dppf (10 mol %) acetic acid (1 equiv) dppf = 1,1’-bis(diphenylphosphino)ferrocene [(η3-C3H5)PdCl]2 (5 mol %) dppf (10 mol %) acetic acid (15 mol %) Meguro, M.; Yamamoto, Y. Tetrahedron Lett.1998, 39, 5421-5424.

  12. Proposed Possible Catalytic Cycle Meguro, M.; Yamamoto, Y. Tetrahedron Lett.1998, 39, 5421-5424.

  13. Allylation, Vinylation, Arylation • Aryl, vinyl, and allyl palladium(II) complexes can be formed in situ and trigger cyclization • These reactions seem to be tolerable to various substitution • Cyclization can be completed by a variety of oxygen and nitrogen nucleophiles

  14. Palladium-Catalyzed Allylamination • Stereoselective cyclization of carbamates to form oxazolidinones • All reactions proceeded to give trans-selectivity Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem.1992, 57, 6377-6379.

  15. Mechanism and Stereochemical Model • Reaction is proposed to proceed through either pathway A or B • Stereochemistry can be rationalized according to pathway A Kimura, M.; Tanaka, S.; Tamaru, Y. J. Org. Chem.1995, 60, 3764-3772.

  16. Scope of Aryl and Vinyl Pd(II) Cyclization • Structurally and electronically diverse aryl and vinyl Pd(II) groups can trigger cyclization R-X, Pd(PPh3)4 K2CO3, DMF 70 °C, 1-3 h Davies, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett1993, 85-87.

  17. Formation of Arylated Pyrrolines and Pyrroles • The number of carbons between the nucleophile and allene can affect the cyclization product • Additives and reaction conditions can be used to control product formation Dieter, R. K.; Yu, H. Org. Lett.2001, 3, 3855-3858.

  18. Six-Membered Ring? • Since α-amino allenes give lead to five-member endo-cyclization products, do β-amino allenes give six-member endo-cyclization? No! • Scope of reaction: reaction also works in presence of allylating agents Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett.1997, 38, 6275-6278.

  19. Mechanism For Intramolecular Attack of Central Carbon of Allene Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett.1997, 38, 6275-6278.

  20. Palladium-Catalyzed Oxirane Formation • Intramolecular cyclization of 2,3-allenols yields attack at proximal carbon yielding 2,3-disubstituted oxiranes • This is a in contrast to the previously reported cyclization of α-aminoallenes that yield pyrrolines and pyrroles Ma, S.; Zhao, S. J. Am. Chem. Soc.1999, 121, 7943-7944.

  21. Palladium-Catalyzed Aziridination • Switching solvents from DMF to 1,4-dioxane shifts attack on allene Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem.2001, 66, 4904-4914.

  22. Stereochemical model Stereochemistry is controlled by irreversible olefin insertion to the less hindered face Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem.2001, 66, 4904-4914.

  23. Stereochemical model Stereochemistry is controlled by irreversible olefin insertion to the less hindered face Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem.2001, 66, 4904-4914.

  24. Palladium-Catalyzed Formation of Azetidines • Surprisingly the best solvent for this reaction is DMF giving all cis product Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem.2001, 66, 4904-4914.

  25. Stereochemical Model Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem.2001, 66, 4904-4914.

  26. Carbonylation and Alkoxide Coupling • Attempted previous cyclization reactions in the presence of CO and methanol to form acrylate esters Walkup, R. D.; Park, G. Tetrahedron Lett.1987, 28, 1023-1026.

  27. Alternative Method With High Selectivity • Obtain same product, but by addition of Hg(II) first, then palladium catalyzed carbonylation/coupling reaction, high cis selectivity is realized Walkup, R. D.; Park, G. Tetrahedron Lett.1987, 28, 1023-1026.

  28. Source of Selectivity in Hg(II) Cyclization • Selectivity is controlled by the bulky protecting group δ+ δ+ δ+ δ+ δ+ δ+ δ+ δ+ Walkup, R. D.; Park, G. J. Am. Chem. Soc.1990, 112, 5388.

  29. Pd(II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction • When γ-hydroxy allenes are reacted with aryl halides in the presence of Pd(II) and CO one can obtain cyclization-carbonylation-coupling products Walkup, r. D.; Guan, L.; Kim, Y. S.; Kim, S. W. Tetrahedron Lett.1995, 36, 3805-3808.

  30. Expansion to Nitrogen Nucleophiles Kang, S.-K.; Kim, K.-J. Org. Lett.2001, 3, 511-514.

  31. Proposed Catalytic Cycle for Pd (II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction Kang, S.-K.; Kim, K.-J. Org. Lett.2001, 3, 511-514.

  32. Organolanthanide-Catalyzed Intramolecular Hydroamination-Cyclization Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc.1998, 120, 4871-4872. Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.

  33. Kinetic and Mechanistic Studies of Organolanthanide-Catalyzed Reaction Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.

  34. Stereochemical Model for trans-Pyrrolidines Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.

  35. Stereochemical Model for cis-Piperidines Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.

  36. Cobalt-Mediated Acylation-Cyclization of Allenes Bates, R. W.; Devi, T. R. Tetrahedron Lett.1995, 36, 509-512.

  37. Mechanism of Cobalt-Mediated Reaction • When using 1,3-disubstituted allenes, only E olefin products are observed • The reason for the stereochemical outcome has not yet been determined Bates, R. W.; Devi, T. R. Tetrahedron Lett.1995, 36, 509-512.

  38. Ru-Catalyzed Cyclocarbonylation • Good yields are also obtained from β-sulfonamides to obtain δ-unsaturated lactams • Reaction also works to yield seven and eight member rings • Ru-catalyzed cyclocarbonylations also work for hydroxy-allenes Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett.2001, 3, 2851-2853. Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Org. Lett.2000, 2, 441-443. Yoneda, E.; Zhang, S. W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett.2001, 42, 5459-5461.

  39. Ru-Catalyzed Cyclocarbonylation Catalytic Cycle Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett.2001, 3, 2851-2853.

  40. Natural Product Synthesis Using Metal-Catalyzed Heterocyclization of Allenes (±)-Rhopaloic Acid A Clavepictine A: R = Ac (+)-Xenovernine Clavepictine B: R = H (+)-Furanomycin (+)-Kallolide A

  41. Synthesis of (±)-Rhopaloic Acid A (±)-Rhopaloic Acid A Snider, B. B.; He, F. Tetrahedron Lett.1997, 38, 5453-5454.

  42. Synthesis of Clavepictine A and B Ha, J. D.; Cha, J. K. J. Am. Chem. Soc.1999, 121, 10012-10020.

  43. Synthesis of (+)-Xenovernine Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc.1999, 121, 3633-3639.

  44. Synthesis of (+)-Furanomycin VanBrunt, M. P.; Standaert, R. F. Org. Lett.2000, 2, 705-708.

  45. Synthesis of Kallolide A Marshall, J. A.; Liao, J. J. Org. Chem.1998, 63, 5962-5970.

  46. Summary • Hydroxy-allenes and Amino-allenes are versatile substrates that can be utilized to form a variety of heterocycles • Metal-catalyzed heterocyclization of allenes is tolerant to substitution • Many cyclizations of allenes are highly diastereoselective • A variety of metals can be utilized depending on the desired structure • Metal-catalyzed heterocyclization of allenes can be useful for natural product synthesis

  47. Acknowledgements Dr. Jeff Johnson Johnson Group UNC Chapel Hill

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