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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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 Allene

  • 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 Allene

  • 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 Allene

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 Allene

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 Allene

  • 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 Allene

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 Allene

  • 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 Allene

  • 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 Allene

  • 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 Allene

  • 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 Allene

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 Organolanthanide-Catalyzed Reaction

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


Stereochemical model for cis piperidines
Stereochemical Model for cis-Piperidines Organolanthanide-Catalyzed Reaction

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 Organolanthanide-Catalyzed Reaction

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


Mechanism of cobalt mediated reaction
Mechanism of Cobalt-Mediated Reaction Organolanthanide-Catalyzed 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 Organolanthanide-Catalyzed Reaction

  • 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 Organolanthanide-Catalyzed Reaction

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 Heterocyclization of Allenes

(±)-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 Heterocyclization of Allenes

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


Synthesis of xenovernine
Synthesis of (+)-Xenovernine Heterocyclization of Allenes

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 Heterocyclization of Allenes

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


Synthesis of kallolide a
Synthesis of Kallolide A Heterocyclization of Allenes

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


Summary
Summary Heterocyclization of Allenes

  • 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 Heterocyclization of Allenes

Dr. Jeff Johnson

Johnson Group

UNC Chapel Hill


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