Metal catalyzed heterocyclization of allenes
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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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Metal catalyzed heterocyclization of allenes

Metal-Catalyzed Heterocyclization of Allenes

Chris M. Yates


What makes an allene an interesting substrate

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


Discovery of metal catalyzed cyclization

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.


Extension to oxygen heterocycle formation

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.


Diastereoselective tetrahydropyran formation

Diastereoselective Tetrahydropyran Formation

  • Synthesis of cis-2,6-disubstituted tetrahydropyrans

Gallagher, T. J. Chem. Soc., Chem. Comm.1984, 1554-1555.


Diastereoselective pyrrolidine formation

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.


Formation of nitrones

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.


Cyclization of allenyl aldehydes and ketones to furans

Cyclization of Allenyl Aldehydes and Ketones to Furans

Proposed mechanistic pathways

Marshall, J. A.; Wang, X. J. J. Org. Chem.1991, 56, 960-969.


Mechanism for conversion of allenones to furans

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.


Pd ii catalyzed cyclization

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


Palladium catalyzed intramolecular hydroamination of allenes

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.


Proposed possible catalytic cycle

Proposed Possible Catalytic Cycle

Meguro, M.; Yamamoto, Y. Tetrahedron Lett.1998, 39, 5421-5424.


Allylation vinylation arylation

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


Palladium catalyzed allylamination

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.


Mechanism and stereochemical model

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.


Scope of aryl and vinyl pd ii cyclization

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.


Formation of arylated pyrrolines and pyrroles

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.


Six membered ring

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.


Mechanism for intramolecular attack of central carbon of allene

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.


Palladium catalyzed oxirane formation

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.


Palladium catalyzed aziridination

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.


Stereochemical model

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.


Stereochemical model1

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.


Palladium catalyzed formation of azetidines

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.


Stereochemical model2

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.


Carbonylation and alkoxide coupling

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.


Alternative method with high selectivity

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.


Source of selectivity in hg ii cyclization

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.


Pd ii catalyzed cyclization carbonylation coupling reaction

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.


Expansion to nitrogen nucleophiles

Expansion to Nitrogen Nucleophiles

Kang, S.-K.; Kim, K.-J. Org. Lett.2001, 3, 511-514.


Proposed catalytic cycle for pd ii catalyzed cyclization carbonylation coupling reaction

Proposed Catalytic Cycle for Pd (II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction

Kang, S.-K.; Kim, K.-J. Org. Lett.2001, 3, 511-514.


Organolanthanide catalyzed intramolecular hydroamination cyclization

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.


Kinetic and mechanistic studies of organolanthanide catalyzed reaction

Kinetic and Mechanistic Studies of Organolanthanide-Catalyzed Reaction

Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.


Stereochemical model for trans pyrrolidines

Stereochemical Model for trans-Pyrrolidines

Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.


Stereochemical model for cis piperidines

Stereochemical Model for cis-Piperidines

Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics1999, 18, 1949-1960.


Cobalt mediated acylation cyclization of allenes

Cobalt-Mediated Acylation-Cyclization of Allenes

Bates, R. W.; Devi, T. R. Tetrahedron Lett.1995, 36, 509-512.


Mechanism of cobalt mediated reaction

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.


Ru catalyzed cyclocarbonylation

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.


Ru catalyzed cyclocarbonylation catalytic cycle

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.


Natural product synthesis using metal catalyzed heterocyclization of allenes

Natural Product Synthesis Using Metal-Catalyzed Heterocyclization of Allenes

(±)-Rhopaloic Acid A

Clavepictine A: R = Ac (+)-Xenovernine

Clavepictine B: R = H

(+)-Furanomycin (+)-Kallolide A


Synthesis of rhopaloic acid a

Synthesis of (±)-Rhopaloic Acid A

(±)-Rhopaloic Acid A

Snider, B. B.; He, F. Tetrahedron Lett.1997, 38, 5453-5454.


Synthesis of clavepictine a and b

Synthesis of Clavepictine A and B

Ha, J. D.; Cha, J. K. J. Am. Chem. Soc.1999, 121, 10012-10020.


Synthesis of xenovernine

Synthesis of (+)-Xenovernine

Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc.1999, 121, 3633-3639.


Synthesis of furanomycin

Synthesis of (+)-Furanomycin

VanBrunt, M. P.; Standaert, R. F. Org. Lett.2000, 2, 705-708.


Synthesis of kallolide a

Synthesis of Kallolide A

Marshall, J. A.; Liao, J. J. Org. Chem.1998, 63, 5962-5970.


Summary

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


Acknowledgements

Acknowledgements

Dr. Jeff Johnson

Johnson Group

UNC Chapel Hill


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