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Hypervalent Iodine Reagents in Organic Synthesis. Andrew T. Parsons March 23, 2007. Outline. Background Iodine(III) reagents Iodine(V) reagents Conclusions. Hypervalent Iodine: An Introduction.

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outline
Outline
  • Background
  • Iodine(III) reagents
  • Iodine(V) reagents
  • Conclusions
hypervalent iodine an introduction
Hypervalent Iodine: An Introduction
  • Hypervalent iodine: Species that exceed eight electrons in the valence shell, typically IIII and IV
    • Can accommodate up to 12 valence electrons:
    • Species with 10 valence electrons are more common:

Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002,102, 2523-2584.

hypervalent iodine a brief history
Hypervalent Iodine: A Brief History
  • Both Iodine(III) and (V) compounds were first prepared by Willgerodt in 1886 and 1900, respectively
  • Iodine(III) compounds are referred to as λ3-iodanes
  • Iodine(V) compounds are referred to as λ5-iodanes, periodanes, or periodinanes

Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996,96, 1123-1178.

structural characteristics
Structural Characteristics
  • λ3-iodanes:
  • λ5-iodanes:

Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996,96, 1123-1178.

outline6
Outline
  • Background
  • Iodine(III) reagents
  • Iodine(V) reagents
  • Conclusions
preparation of i iii reagents
Preparation of IIII Reagents
  • Most reagents are prepared directly from iodobenzene:

Varvoglis, A. Tetrahedron 1997,53, 1179-1255.

reactions of iodine iii compounds
Reactions of Iodine(III) Compounds
  • Reactivity is driven by the electrophilic nature of IIII
    • Typical reactions proceed through an initial nucleophilic attack of the iodine center:
    • PhIX is an excellent leaving group, on the order of 106 better than –OTf, and therefore substitutions and reductive eliminations are prevalent
reactions of iodine iii compounds oxygenations10
Reactions of Iodine(III) Compounds: Oxygenations
  • Iodosylbenzene, PhIO:
    • Useful for a number of different oxidations
    • Exists as a polymer, which is activated through depolymerization when treated with alcoholic solvents and base
    • Can also be activated in the presence of a Lewis acid or Br - catalyst
    • The active IIII species, PhI(OMe)2, can also be generated from PhI(OAc)2

Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981,22, 1283.

Moriarty, R. M. J. Org. Chem. 2005,70, 2893-2903.

oxidations with iodosylbenzene
Oxidations with Iodosylbenzene
  • Useful in the α-hydroxylation of ketones
  • α-Hydroxylation of ketones can be carried out using CrO3, typically with higher yields
  • PhIO is a non-toxic alternative to CrVI

Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.; White, K. B.

J. Am. Chem. Soc. 1981,103, 686-688.

Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981,22, 1283.

oxidations with iodosylbenzene12
Oxidations with Iodosylbenzene

Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981,22, 1283.

mechanism of hydroxylation
Mechanism of α-Hydroxylation

Moriarty, R. M. J. Org. Chem. 2005,70, 2893-2903.

applications in total synthesis
Applications in Total Synthesis
  • Synthesis of (-)-Xialenon
  • Carrying out this transformation using a Rubottom oxidation provided a dr of 3:1

Hodgson, D. M.; Galano, J.-M.; Christlieb, M. Tetrahedron 2003,59, 9719-9728.

Rubottom, G.M.; Gruber, J.M. J. Org. Chem. 1978, 43, 1599-1602

catalytic acetoxylation of ketones
Catalytic α-Acetoxylation of Ketones

Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K.

J. Am. Chem. Soc. 2005,127, 12244-12245.

catalytic cycle
Catalytic Cycle

Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K.

J. Am. Chem. Soc. 2005,127, 12244-12245.

oxidative rearrangements of aryl alkenes
Oxidative Rearrangements of Aryl Alkenes
  • Koser’s reagent induces an oxidative rearrangement of aryl alkenes to afford α-aryl ketones

Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004,45, 6159-6163.

oxidative rearrangements of aryl alkenes18
Oxidative Rearrangements of Aryl Alkenes

Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004,45, 6159-6163.

oxidative rearrangements of aryl alkenes19
Oxidative Rearrangements of Aryl Alkenes

Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004,45, 6159-6163.

oxidative cleavage of alkenes
Oxidative Cleavage of Alkenes
  • Works well for electron-rich olefins
  • Reaction times typically 0.5-5 h
  • Safer than ozonolysis, cheaper than transition-metal reagents

Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,129, 2772-2773.

oxidative cleavage of alkenes21
Oxidative Cleavage of Alkenes

Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,129, 2772-2773.

oxidative cleavage of alkenes22
Oxidative Cleavage of Alkenes
  • Suggests that an epoxidation precedes cleavage

Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,129, 2772-2773.

Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.; White, K. B.

J. Am. Chem. Soc. 1981,103, 686-688.

oxidative cleavage of alkenes23
Oxidative Cleavage of Alkenes
  • Suggests that an epoxidation precedes cleavage

Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,129, 2772-2773.

reactions of iodine iii compounds oxidation of phenols
Reactions of Iodine(III) Compounds: Oxidation of Phenols
  • Previously:

Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996,96, 1123-1178.

application to spirocyclizations
Application to Spirocyclizations
  • Tether a nucleophile to the phenol:
  • Possible applications in natural product synthesis
spirocyclization of phenols early studies
Spirocyclization of Phenols: Early Studies

Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987,52, 3927-3930.

mechanism
Mechanism

Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987,52, 3927-3930.

current standard catalytic spirocyclizations
Current Standard: Catalytic Spirocyclizations

Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y.

Angew. Chem. Int. Ed. 2005,44, 6192-6196.

catalytic cycle29
Catalytic Cycle

Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y.

Angew. Chem. Int. Ed. 2005,44, 6192-6196.

applications in total synthesis30
Applications in Total Synthesis
  • Synthesis of Aranorosin:

Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993,58, 7195-7203.

phi ococf 3 2 promoted formation of lactols
PhI(OCOCF3)2-Promoted Formation of Lactols

Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H.

Angew. Chem. Int. Ed. 2005,44, 5857-5860.

phi ococf 3 2 promoted formation of lactols32
PhI(OCOCF3)2-Promoted Formation of Lactols

Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H.

Angew. Chem. Int. Ed. 2005,44, 5857-5860.

applications in total synthesis33
Applications in Total Synthesis
  • Synthesis of (+)-Tanikolide

Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H.

Angew. Chem. Int. Ed. 2005,44, 5857-5860.

applications in total synthesis34
Applications in Total Synthesis
  • Synthesis of (+)-Tanikolide

Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H.

Angew. Chem. Int. Ed. 2005,44, 5857-5860.

carbon carbon bond forming reactions cyclizations with phi ocor 2
Carbon-Carbon Bond Forming Reactions: Cyclizations with PhI(OCOR)2
  • PhI(OCOR)2 reagents have been shown to promote attack by carbon nucleophiles:

Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.; Mihara, S.; Fujita, S.; Tohma, H.

J. Org. Chem. 1996,61, 223-227.

c c bond forming cyclizations
C-C Bond Forming Cyclizations

Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.; Mihara, S.; Fujita, S.; Tohma, H.

J. Org. Chem. 1996,61, 223-227.

applications in total synthesis38
Applications in Total Synthesis
  • Synthesis of (±)-Stepharine

Honda, T.; Shigehisa, H. Org. Lett. 2006,8, 657-659.

c c bond forming reactions c h activation
C-C Bond Forming Reactions: C-H Activation

Kalyani, D.; Deprez, N.; Desai, L. V.; Sanford, M.S. J. Am. Chem. Soc. 2005,127, 7330-7331.

Deprez, N.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,128, 4972-4973.

c c bond forming reactions c h activation40
C-C Bond Forming Reactions: C-H Activation

Kalyani, D.; Deprez, N.; Desai, L. V.; Sanford, M.S. J. Am. Chem. Soc. 2005,127, 7330-7331.

Deprez, N.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,128, 4972-4973.

mechanism of c h activation
Mechanism of C-H Activation

Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,126, 2300-2301.

Kalyani, D.; Deprez, N.; Desai, L. V.; Sanford, M.S. J. Am. Chem. Soc. 2005,127, 7330-7331.

outline42
Outline
  • Background
  • Iodine(III) reagents
  • Iodine(V) reagents
  • Conclusions
preparation of i v reagents
Preparation of IV Reagents
  • Caution: There have been reports of violent explosions occurring upon heating of these reagents to >200 °C

Boeckman, Jr., R.K.; Shao, P.; Mullins, J.J. Org. Synth. 2000, 77, 141-152.

Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.

oxidations of alcohols a brief overview
Oxidations of Alcohols: A Brief Overview
  • DMP and IBX have been widely used for the mild oxidation of alcohols to ketones and aldehydes:

Zoller, T.; Breuilles, P.; Uguen, D. Tetrahedron Lett. 1999,40, 6253-6256.

Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Kwon, S. Tetrahedron Lett. 2000,41, 1359-1362.

Smith, A.B., III; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J.D.; Hartz, R.A.; Cho, Y.S.; Moser, W.H.

J. Am. Chem. Soc.2003, 125, 8228-8237.

dehydrogenation of saturated aldehydes and ketones with ibx
Dehydrogenation of Saturated Aldehydes and Ketones with IBX

Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000,122, 7596-7597.

dehydrogenation of saturated aldehydes and ketones with ibx46
Dehydrogenation of Saturated Aldehydes and Ketones with IBX

Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000,122, 7596-7597.

mechanism of dehydrogenation by ibx
Mechanism of Dehydrogenation by IBX
  • Single electron transfer is likely operative:

Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.

J. Am. Chem. Soc. 2002,124, 2245-2258.

applications in total synthesis48
Applications in Total Synthesis
  • Efforts toward the synthesis of Phomoidride B

Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755-767.

tandem conjugate addition dehydrogenation with ibx
Tandem Conjugate Addition/Dehydrogenation with IBX

Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.

Angew. Chem. Int. Ed. 2002,41, 996-1000.

tandem conjugate addition dehydrogenation with ibx50
Tandem Conjugate Addition/Dehydrogenation with IBX

Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.

Angew. Chem. Int. Ed. 2002,41, 996-1000.

cyclization of n aryl amides carbamates and ureas using ibx
Cyclization of N-Aryl Amides Carbamates, and Ureas Using IBX

Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A.

J. Am. Chem. Soc. 2002, 124, 2233-2244.

cyclization of n aryl amides and carbamates using ibx
Cyclization of N-Aryl Amides and Carbamates Using IBX

Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A.

J. Am. Chem. Soc. 2002, 124, 2233-2244.

mechanism53
Mechanism

Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A.

J. Am. Chem. Soc. 2002, 124, 2233-2244.

oxidation of carboxamides to nitriles
Oxidation of Carboxamides to Nitriles

Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G.

J. Org. Chem. 2007,72, 662-665.

oxidation of carboxamides to nitriles55
Oxidation of Carboxamides to Nitriles

Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G.

J. Org. Chem. 2007,72, 662-665.

proposed mechanism
Proposed Mechanism

Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G.

J. Org. Chem. 2007,72, 662-665.

conclusions
Conclusions
  • Hypervalent Iodine compounds are versatile reagents that can promote a number of different transformations
  • Alternative to toxic metal reagents
  • Disadvantages:
    • Enantioselective transformations are largely elusive
    • Safety concerns with some reagents
acknowledgements
Acknowledgements

Cory Bauch

Ashley Berman

Mary Robert Nahm

Justin Potnick

Rebecca Duenes

Prof. Jeff Johnson

The Johnson Research Group:

Greg Boyce

Geanna Min

Dan Schmitt

Mike Slade

Austin Smith

Matthew Campbell

Shanina Sanders

Andy Satterfield

Steve Greszler

Chris Tarr

mechanism of tandem conjugate addition dehydrogenation with ibx
Mechanism of Tandem Conjugate Addition/Dehydrogenation with IBX

Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.

Angew. Chem. Int. Ed. 2002,41, 996-1000.

mechanism of thf activation
Mechanism of THF Activation

Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A.

J. Am. Chem. Soc. 2002, 124, 2233-2244.

support of a set mechanism in ibx mediated dehydrogenations
Support of a SET Mechanism in IBX Mediated Dehydrogenations
  • Hammet analysis shows the reaction is only slightly dependent on the electronics of aryl-containing substrates (ρ= -.75, σp+)

Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.

J. Am. Chem. Soc. 2002,124, 2245-2258.

support of a set mechanism in ibx mediated cyclizations
Support of a SET Mechanism in IBX Mediated Cyclizations

Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A.

J. Am. Chem. Soc. 2002, 124, 2233-2244.

support of a set mechanism in ibx mediated cyclizations65
Support of a SET Mechanism in IBX Mediated Cyclizations

Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A.

J. Am. Chem. Soc. 2002, 124, 2233-2244.

nomenclature
Nomenclature
  • Hypervalent compounds are characterized according to the Martin-Arduengo designation, N-X-L, where:
    • Number of valence electrons, N
    • Identity of the hypervalent atom, X
    • Number of ligands, L
  • For example, (diacetoxyiodo)benzene:

Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996,96, 1123-1178.

oxygenation of silyl enol ethers
Oxygenation of Silyl Enol Ethers
  • Typically assisted by a Lewis acid catalyst
  • Similar reactions can be carried out using Tl(lll)
    • Highly toxic
    • Tl(III) is approximately three times more expensive than I(III)

Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.

hydroxylation of silyl enol ethers
Hydroxylation of Silyl Enol Ethers

Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.

mechanism of hydroxylation69
Mechanism of Hydroxylation
  • Similarly to the α-hydroxylation of ketones, the reaction initiates through a nucleophilic attack at I(III)
  • A second nucleophilic attack on the I(III) bearing followed by elimination affords PhI and the product

Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.

progress towards asymmetric hydroxylation of ketones
Progress Towards Asymmetric α-Hydroxylation of Ketones

Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998,120, 708-714.

progress towards asymmetric hydroxylation of ketones71
Progress Towards Asymmetric α-Hydroxylation of Ketones
  • Reaction is hampered by low conversion
  • Only modest enantioselectivity obtained

Adam, W.; Fell, R. T.; Mock-Knoblauch, C.; Saha-Moller, C. R. Tetrahedron Lett. 1996,37, 6531-6534.

Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998,120, 708-714.

oxygenation of silyl enol ethers72
α-Oxygenation of Silyl Enol Ethers
  • In a similar fashion, other oxygen nucleophiles can be employed:

Moriarty, R. M.; Epa, W. R.; Penmasta, R.; Awasthi, A. K. Tetrahedron Lett. 1989,30, 667-669.

slide73
Synthesis of (±)-Cephalotaxine

Yasuda, S.; Yamada, T.; Hanoaka, M. Tetrahedron Lett. 1986,27, 2023-2026.